WHO Classification of Tumours of hematopoietic and lymphoid tissues 4th edition

World Health Orga nization Classifica tion of Tumours Hamilton SR. Aartonen LA (Eds.) : World Health Organization

Classification of Tumours , Patholog y and Genetics of Tumours

of the Digestive System (3rd edition) . IARC Press: lyon 2000 ISBN 92 832 241 0 8

Eble J .N., Sauter G .• Epstein J E., Sesterreon l.A . (Eds.) World Health Organization Classification of Tumours. Pathology and Genetics of

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4th Edition

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Edited by

Steven H. Swe rdlow Elias Campo Nancy Lee Harris Elaine S. Jaffe Stefano A. Pileri Harald Stein JOrgen Thiele James W. Vardiman

Intern ational Agency for Resea rch on Cancer Lyon , 2008

World Health Organization Classification of Tumours Series Editors

Fred T. Bosman, M.D. Elaine S. Jaffe. M.D. Sunil R. Lakhani. M.D. Hiroko Onqaki, Ph.D.

WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues Editors

Sleven H. Swerdlow, M.D. Elias Campo. M.D. Nancy Lee Harris, M.D. Elaine S. Jaffe , M D. Stefano A. Pileri. M.D. Harald Stein, M.D. JOrg en Thiele, M.D. James W. Vardi man, M.D.

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University of Chicago Cancer Research Center

The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues presented in this book reflects the views of a Working Group that convened for an Editorial and Consensus Conference at the International Agency for Research on Cancer (fARC), Lyon October 25-27. 2007. Members of the Working Grou p are indicated in the List of Contributors on pages 369-374.

Published by the International Agenc y for Research 00 Cancer (IARC), 150 cou rs Albert Thomas, 69372 Lyon ceoex 08, France

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Format for bibliographic citations: Swerdlow S.H., Campo E., Harris N,L., Jaffe E.S" Pileri S.A., Stein H" Thiele J , Vardiman J.w. (Eds.): WHO Classification of Tumours of Haematopoietic and Lympho id Tissues, IARC: Lyon 2008

IARC Ubrary Cataloguing in Publication Data WHO Classific ation of Tumou rs of Haematopo ietic and Lymp hoid Tissues Edited by Swerdlow S.H.. Campo E., Harris NL , Jaffe E.S.• Piled SA, Stein H., Thiele J .. Vardiman JW.

1. Haematopoie hc System Neop lasms - genetics

2. Haematopoielic System Neop lasms - pathology I. Swerdlow. Steven H. ISBN 978-92-832-243 1-0

Contents WHO Classifjcatioo Summary table Introduction to the classification of tumours of haematopoietic and lymphoid tissues Introduction and overview of the classification of the myeloid neoplasms

2 Myeloproliferative neoplasms

9

10 14 17

31

Chronic myelogenous leukaemia. BCR-ABL 1 positive 32 Chronic neutrophilic leukaemia PoIycythaemia vera Primary myelofibrOsis Essenliallhrombocythaemia

Chronic eosinophilic leukaemia. NOS Mastocytosis Cutaneous mastocytosis Systemic mastocytosis Masl cell leukaemia

Mast cell sarcoma Extracutaneous mastocytoma Myeloproliferative neoplasm, unc lassi fiable

38 40 44

48 51 54

57 58

61 61 61 64

3 Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA.

PDGFRB Of FGFRl

67

4 MyelodysplasticJmyeloproliferative neoplasms 75 Chronic mveiomonocync leukaemia 76 Atypical ctYonic myeloid leukaEmia. BCR-ABL 1 negative 80 Juvenile myelomonocytic leuk aemia MyelodysplastiC/myeloproliferali ve neoplasm , urclasaifiable

5 Myelodysplastic syndromes Myelodysplastic synd romes/n eo plasms , overview Refractory cytope nia with unilineage dysplasia Refractory anaemia with ring side rob lasts Refractory cytopenia with multilineage dysplasia Refractory anaemia with exc ess b lasts Myelodysp lastic synd rome with isolated de l(5q) Myelodysp lastic synd rome, uncrasslttabte Childhood mye lodysp lastic synd rome Refractory c ytopenia of c hild hood

82 85 87 88 94 96 98 100 102 103 104 104

6 Acute myeloid leukaemia (AML) and related precursor neoplasms AML with recurrent genet ic abn or malities AML with t(8:21 )(q22:q22); RUNX1 -RUNX1T1 AML with inv( 16)( p 13.1q22) or 1(16:t6)(p 13.1;q22): CBFB-MYH 11 Acute orornveiocvnc leukaem ia with t(15:17)(q22 :q 12): PML- RARA AML with us.11)(p 22:q 23): MLLT3-MLL AML with t(6:9)(p23 :q34); DEK-NU P2 14 AML with inv(3)( q2 1q26 .2) or t(3;3)( q2 1;q26.2); RPNt ·EVI1 AML (megakaryoblastic) with t( 1;22)(p13;q 13): RBM15-MKL 1

109 11 0 11 0 11 1 11 2 114 115 116 117

AML with mutated NPM 1 AMLwith mutated CEBPA AML with myelo dysplas ia-related changes Therapy -relate d myeloid neoplasms Acu te myeloid leukaemia, NOS AML with minimal diff erentiation AML withOut matu ration AML with maturabon Acute myelomonocytic leukae mia Acute monoblastic and monocytic leukaem ia Acute erythroid leukaemia Acu te megakaryoblastic leukaemia Acute basophilic leukaemia Acu te paomveosrs with myelofibros is Myeloid sarcoma Myeloid proli ferations related 10 Down synd rome Transient abnOrmal myelopoiesis Myeloid leukaemia associated with Dc:rwn syndrome Blastic plasmacytoid dendritic cell neoplasm

7 Acute leukaemiasof ambiguous lineage Acute undlHerentiated leukaemia Mixed phenotype acute leukaemia wilh t(9;22)(q34;q 11.2): BCR-ABL 1 Mixed phenotype acute leukaemia with t(v:11q 23): MLL rear ranged Mixed phenotype acute leukaemia , B/myeloid, NOS Mixed phenotype ac ute leukaemia , T/myeloid , NOS Mixed phenoty pe acu te leukaemia, NOS· rare types Other ambiguous lineage reukaerraes Natura! killer (NK)-celilympho blastic leukaemi a/lymphoma

120 122 124 127 130 130 131 131 132 133 134 136 137 138 140 142 142 143 145 149 151 15 1 152 152 153 154 t 55 155

8 Introduction and overview 01 the c lassification of the lymphoid neoplasms

9 Precu rsor lymphoid neoplasms B lymp hob lastic leukaemia/lymphoma, NOS B lymphob lastic leukaemia/ lymphoma with recu rrent gene tic abn orma lities B lymphob lastic leukaem iallymphoma with t(9 :22)(q 34;q 11.2): BCR-ABL 1 B lymp hoblastic leukaemia/ly mpho ma with l(v:11q 23): ML L rearranged B lympho blastic leukaemiall ymphom a with t(12:2 1)(p1 3;q22 ): TEL-AMLl (ETV6--RUNX 1) B lymphoblastic leukaemia/lymphoma with hyperdi ploi dy B lymphoblastic leukaemiallymphom a with hypodiplOi dy (Hypodiploi d ALL) B lymphoblastic leukaemiallymphoma with t(5; 14)(q31;q32); IL3-IGH B lymphoblastic leukaemiallymphoma with t( 1;19) (q23:P13.3): E2A-PBX1( TCF3-PBXI) T lymphoblastic leukaemiallymphoma

157 167 168 171

171 171 172 173 174 174 175 176

10 Mature B-ceUneoplasms Chronic lymphocytic leukaemia Ismail Iympt'locytic lymphoma :f s-een prolyrT¢lhocytic leukaemia Splenic B-cell marginal zone lymphoma Hairy cell leukaemia Splenic B-cell Iymphomalleukaemia, unclassiliable Splenic diffuse red pulp small B-ceil lymphoma Hairy cenleckaeme-....anent lymphoplasmacytic lymphoma Heavy chain diseases Gamma heavy chain disease Mu heavy chain disease Alpha heavy chain disease Plasma cell neoplasms Monoc lonal gammop athy 01 undetermined significance (MGUS) Plasma ce ll myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Monoclonal immunoglobulin deposition diseases Extranodat marginal zone lymphoma of mucosaassocia ted lymphoid tissue (MALT lymphoma) Nodal marg inal zone lymphoma Follicular lymphoma Primary cutaneous follicle centre lymphoma Mantle cell lymphoma Diffuse large B-celllymphoma (DLBCl), NOS T celilhi stiocyte-rich large B-ce ll lymphoma Primary DlBCL of the CNS Primary cutaneous DlBCl . leg type EBV positive DLBCl of the elderly DLBCL assoc iated with chronic inflammation Lymphomatoid granulomatosis Primary med iastinal (thymic) large B-celilymphoma Intrav escurer large B-celi lymphoma ALK positive large Been lymphoma Plasmablastic lymphoma large a-ceu lymphoma arising in HHV8-associated multicent ric Castleman disease Primary effusion lymphoma Burkitllymp homa B-cel1lymphoma, unclassiliab le, with features intermediate between DLBCL and Burkitllymphoma B-ceillymphoma, unctessmebie. with features intermediate between OLBCl and clas sica l Hodgkin lymphoma 11 Mature T- and NK-cell neoplasms r-cea prolymphocytic leukaemia t- een large granular lymphocytic leukaemia Chronic Iymphoproliferative disorder of NK cells Aggressive NK cell leukaemia Epstein-Barr virus (EBV) positive t-een Iymphoprol ilerative diseases of ch ildhood Systemic EBV+ t-een Iymphoproliferalive disease of childhood Hydroa vacclnrtorrne-uk e lymphoma Adull T-ceil leukaemia/lymphoma Extranodal NK/T-cell lymphoma. nasal type

,

•

179

180 183 185 188 191 191 192 194 196 196 197 198 200 200 202

Enteropathy -associated t-een lymphoma Hepatosplenlc t -een lymphoma Subcutaneous panniculitis-like t-een lymphoma Mycosis fungoi des Sezary syndrome Primary cutaneous CD30 posi tive t-een Iymphoprolilerative disorders Primary cutaneous per ipheral t-een lymphoma s, rare subtypes Primary cutaneous garnna-della T-cen lymphoma Primary cutaneous COB positive agg ressive ep idermotrop ic cytotoxic T-celt lymphoma Primary cutaneou s CD4 positive small/medium T-cell lymphoma Peripheral t-een lymphoma. NOS Ang ioimmunoblastic t -een lymphoma Anaplastic large cell lymphoma. AlK positive Anapla stic large cell lymphoma . ALK negat ive

289 292 294 296 299

300 302 302

303 304 306 309 312 317

208 208 209

214 218 220 227 229 233 238 240 242 243 245 247 250 252 254 256 258 260 262

265

267 269 270 272 274 276 278 278 280 281 285

12 Hod gkin lymphoma Introduction Nodular lymphocyte predominant Hodgkin Iymptuna Classical Hodgk in lymp homa. introduction Nodular sclerosis classical Hodgkin lymphoma Mixed ce llularity classical Hodgkin lymphoma Lymphoc yte-rich classical Hodgkin lymphoma lymphocyte-depleted classical Hodgkin lymphoma

32 1 322 323 326

330 331 332 334

13 1rnmunode ficiency-assoc iated Iymphoproliferative disorde rs 335 Lymp hoproliferative diseases associated with primary immune disorders 336 Lymphomas associa ted with HIV infection 340 Post-nansotanttsmpnooronterauve disorders (PTlD) 343 Plasmacytic hyperp lasia and infectiousrroooo ocieose-uke PTlD 345 Polymorphic PTlO 346 Monomorph ic PTlO 347 Classical Hodgkin lymphoma type PTLO 349 Other iatrogenic immunodeficiency-assoc iated Iymphoproliferative disorders 350 14 Histiocytic and dendritic cell neoplasms Introd uction Histiocyt ic sarcoma Tumours der ived from langerhans cells Langerhans cell histiocytosis Langerhans ce ll sarcoma Interdigitating dendrit ic cell sarcoma Follicular de ndritic ce ll sarcoma Other rare dendritic cell tumours Disseminated juvenile xanthogranuloma

Contributors Clinical advi sory oorrrnittee Source of Charts and photographs References Subject index NOS, no! otherwise specifi ed

353 354 3S6

358

3S8 360 36 1

363 365

366 369 374 376

300 429

WHO Classification 4th Edition

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WHO Classification of tumours of haematopoietic and lymphoid tissues MYELOPROLIFERATIVE NEOPLASMS

MYELODYSPLASTIC SYNDROMES

Chronic myelogenous leukaemia , BCR-ABL 1 positive

987513

Chronic neutrophilic leukaemia

996 3/3

Polycythaemia vera

995 0/3

Primary myelofibrosis

996 1/3

Essential thrombocythaemia

996213

Chronic eosinophilic leukaemia, NOS

9964 /3

Mastocytosis

Cutaneous mastocytosis

9 74011

Systemic mastocytosis

9 74 1/3

Mast cell leukaemia

974 213

Mast cell sarcoma

974 0/3

Extracutaneous mastocytoma

974 0/1

Myeloproliferative neoplasm , unctassitlable

Refractory anaemia

9980/3

Refractory neutropenia

999 1/3

Refractory thrombocytopenia

9992/3

Refractory anaemia with ring sideroblasts

9962/3

Refractory cytopenia with multitineage dysplasia

9965/3

Refractory anaemia with excess blasts

9983/3

MyelodysplasUc syndrome associated with isolated del(Sq)

Myelodysplasticsyndrome, uncJassifiable

9966/3 9969/3

Childhood myelodyspla suc syndrome Refractory cytopenia of childhood

996513

9975/3

MYELOID AND LYMPHOID NEOPLASMS WITH EOSINOPHILIA AND ABNORMALITIES OF PDGFRA, PDGFRB OR FGFRI

ACUTE MYELOID LEUKAEMIA (AML) AND RELATED PRECURSOR NEOPLASMS AML with recurr ent genetic abnormalities

AML with t(6 ;21)(q22;q2 2); RUNXI-RUNX1Tl

9696/3

AML with inv(16)(pI 3.1q22 ) or t(16;16)(pI3.1;q2 2); CBFB-MYHl1

9671/3

Acute promyelccytlc leukaemia with t(15 ;17)(q22 ;qI2); PML-RARA

9666/3

AML with t(9 ;11)(p22 ;q23); MLLT3-MLL

9697/3

AML with 1(6;9)(p2 3;q34 ); DEK-NUP214

986513

MYELODYSPLASTIC/MYELOPROLIFERAnVE NEOPLASMS

AML with inv( 3)(q2 1q26.2) ort(3; 3)(q21;q 26.2); RPNI -EV/1

9869/3

Chronic myetcmonocytic leukaemia

9945/3

Atypical chronic myeloid leukaemia. BCR-ABL 1 negative

AML (megakaryoblastic) with t(I ;22)(p I 3;q I 3); RBMI5-MKLI

9911/3

967613

AML with mutated NPM1

986 1/3

Juvenile myelomonocytic leukaemia

9946/3

AML wrlh mutated CEBPA

9661/3

Myeloid and lymphoid neoplasms with PD GFRA rearrangement Myeloid neoplasms with PDGFRB rearrangement Myeloid and lymphoid neoplasms with FGFR1 abnormalities

9965/3 9966/3 9967/3

Myelodysplasticlmyeloproliferative neoplasm. unclassifiable 9975/3 Refractory anaemia with ring sideroblasts associated WIth marked thrombocytosis

10

Refractory cytopenia with unilineage dysplasia

WHO ctassrtceton

AML with myelodysplasia-related changes 969513 Therapy-re lated myeloid neoplasm s

99 6213

99 2013

Acute myeloid leukaemla",NOS

9861/3

AML with minimal differentiation

987213

AML without maturation

9873/3

AML with maturation

9874 /3

Acute myelomonocytic leukaemia

9867 /3

Acute monob lastic and monocytic leukaemia 9891 /3 Acute erythroid leukaemia

984013

Acute megakaryoblastic leukaemia

99 10/3

Acute basoph ilic leukaemia

987013

Acute panmyelosis with myelofibrosis

9931 13

Myeloid sarcoma

993013

Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis

989811

Myeloid leukaemia associated with Down syndrome

9898/3

Blastic plasmacytoid dendritic cell neoplasm

9727/3

B lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities

B lymphoblastic leukaemiaflymphoma with 1(9;22)(q 34;q l 1.2); BCR-ABU

9812/3

B lymphoblastic leukaemiall ymphoma with t(v;11q23); MLL rearranged

981Y3

B lymphoblastic leukaemiall ymphoma with 1( 12;21)(p13;q22); TEL-AMU (ETV6-RUNX1)

9814/3

B lymphoblastic leukaemiallymphoma w ith hyperdiploidy

981513

B lymphoblastic leukaemiallymphoma with hypod iploidy (hypod iploid ALL)

981613

B lymphoblastic leukaemiallymphoma with t(5;14 Xq31 ;q32 ); IL3-IGH

9817/3

B lymphoblastic leukaemia/lymphoma with t(1;19 )(q23 ;p13 .3); E2A-PBXl

(TCF3-PBX1)

9818/3

T lymphoblastic leukaemia/lymphoma

9837/3

MATURE B-CELL NEOPLASMS

ACUTE LEUKAEMIAS OF AMBIGUOUS LINEAGE Acute undifferentiated leukaemia

980 1/3

Mixed phenotype ac ute leukaemia with t(9;22)(q3 4;q 11.2); BCR-ABL1

980613 9807/3

Mixed phenotype ac ute leukaemia, B/myeloid, NO S

9808/3

B-cell prolymphocytic leukaemia

983313

Splenic Bccell marginal zone lymphoma

968913

Hairy cell leukaemia

9940/3

Splenic diffuse red pulp small B-cell lymphoma

9591/3

Hairy eel/leukaemia-variant

959 1/3 9671/3

Lymphoplasmacytic lymphoma

9809/3

Natural killer (NK) cell lymphoblastic !euKaemiallymphoma

waldenstrom macroglobulinemia Heavy chain diseases

PRECURSOR LYMPHOID NEOPLASMS B lymphoblastic leukaemiaflymphoma B lymphoblastic leukaemiall ymphoma, NO S

982313

Splenic B-cell fymphomalleukaemia, unclassifiable 959 1/3

Mixed phenotype ac ute leuka em ia with t{v;11q23); MLL rea rranged

Mixed phenotype ac ute leukaemia, Tfmyeloid, NOS

Chronic lym phocytic leukaemia! small lymphocytic lymphoma

98 11/3

9761/3 9762/3

Alpha heavy chain disease

9762/3

Gamma heavy chain disease

9762/3

Mu heavy cha in disease

9762/3

Plasma cell myeloma

9732/3

Solitary plasmacytoma of bone

9731/3

Extraosseous plasmacytoma

9734/3

WHO classification

11

I

~l..

Systemic EBV positive T-celllymphoproliferative disease of childhood 9724/3

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

9699/3

Hydroa vaccin iforme-like lymp homa

972513

Nodal marginal zone lymphom a

9699/3

Adult T-cell ieukaemia/lymphoma

9827/3

9699/3

Extranodal NKIT cell lym phoma, nasal type

9719 /3

9690/3

Enteropamy-associated T-cell lymphoma

9717/3

9690/3

Hepatosplenic T-cell lymp homa

971613

Primary cutaneous follicle centre lym phoma

959713

Mantle cell lymphoma

967313

Subcutaneous panniculitis-like T-cell lymphoma

970813

Mycosis fungoides

970013

Sezary syndrome

970113

Paediatric nodal marginal zone lymphoma

Follicular lymphoma Paediatric folliculaf lymphoma

Diffuse large B-eelllymphoma (OlBCl), NOS 968013 T-ceillhistiocyte rich large B-eelilymphorna

9688/3

Primary DLBCl of the CNS

968013

Primary cutaneous DlBCl. leg type

9680/3

EBV positive OLBCL of the elderly

9680/3

Ol BCl associated with chro nic inflammation 968013 l ymphomatoid granulomatosis

9766 /1 9679/3

Intravascular large B-cell lymphoma

971213

AlK positive large B-cell lym phoma

9737/3

Plasmablastic lymphoma

973 5/3

l arge Bccell lymp homa arising in HHV8associated multicentric Castleman disease 9738/3 Primary effusio n lymphoma

9678/3

Burkitt lymph oma

968 7/3

B-ceillym phom a, uncl assifiable, with feature s intermediate between diffuse large g-ceu 968 0/3 lymph oma and Burkitt lymph oma B-ceil lymph oma , unclassifiable, with feat ures intermediate betwee n diffuse large 8-cell lymphoma and classica l Hodgkin lymphoma 9596/3

MATURE T-CELL AND NK·CELL NEOPLASMS

j-cen prolymphocytic leukaemia

9834/3

'f-celllarqe granular lym phocytic leukaemi a

983 1/3

Chronic Iymphoproliferative disorder of NK..cells

983113

Aggressive NK cell leukaemia

9948/3

WHO

ciassitcenon

lymphomatoid papulosis

9718/1

Primary cutaneous anaplastic large cell lymphoma

9718/3

Primary cutaneous qamma-delta

r -ceuivmpncma

Primary med iastinal (thym ic) large B-celllym phoma

12

Primary cutaneous CD30 positive F-eel! Iymphoproliferative disorders

9726/3

Primary cutaneous COB positive aggressive epidermotropic cytotoxic T-cefl lymphoma

9709/3

Primary cutaneous CD4 positive smalVmedium T-cell lymphoma

9709/3

Peripheral Tccelllympboma, NOS

970213

Angioimmunoblastic 'l-cetl Iyrnphoma

970513

Anaplastic large cell lymp homa, ALK positive 97 14/3 Anaplastic large cell lymphoma, ALK negative

970213

HODGKIN LYMPHOMA Nodular lymphocyte predomi nant Hodgkin lymp homa

9659/3

Classical Hodgkin lymp homa

9650/3

Nodular sclerosis classical Hodgkin lymphoma

9663/3

l ymphocyte-rich classica l Hodgkin lymphoma

965113

Mixed cellularity classica l Hodgkin lymphoma

965213

l ymphocyte-depleted classical Hodgkin lymphoma

965313

_

HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS

Histiocytic sarcoma

9755 /3

l angerhans cell histiocytosis

975 1/3

langerhans cell sarcoma

9756/3

Interdigitating dendritic cell sarcoma

9757/3

Follicular dendritic cell sarcoma

975813

Fibroblastic reticu lar cell tumour

9759/3

Indeterminate dendritic cell tumour

9757/3

Disseminated juvenile xanthogranuloma

POST·TRANS PLANT LYMPHOPROUFERATIVE DISORDERS (PTLO) Early lesi ons

P1asmacytic hyperplasia

9971/1

Infectious mononucleosis-like PTLD

9971 /1

Polymorphic PTLO

9971/3

Monomorphic PTlO (B- and TINK-cell types)' Classical Hodgkin lym phoma type PTLO'"

NOS, not otherwise speci fied . The italicized numbers are provi siona l cod es for the 4th edition of lCD -D . While they are expected to be incorporated in the next ICD -O editi on , they currentty remain

subjectto changes. The italicized histologi c type s are provisional enti ties , for which the WHO Working Group fe ll the re was insufficient evidence to recognize as distinct diseases at this time. "These lesions are classi fied according to the leukaemia

or

lymphoma to which they correspond, and are assigned the respective tCO-G code.

WHO classification

13

.. .

Introduction to the WHO classification of tumours of-haernatopoletlc and lymphoid tissues

NL Harris E. Campo E.S. Jaffe SA Pileri

Why classify? Classification is the lan-

The WHO cl assification of tumours of the

classification , involvement of clinicians is essential to ensure its usefulness and acceptance in daily practice 18971. At the lime of publication of the WHO classi fication (3rd edition), prop onents of other cla ssifications of haematologic neoplasms agreed to use the new cl assification, thus ending decad es of cont roversy over the classification of these tumo urs 147. 478 . t 89. 1B9A, 190, 673,7750 , 1344A. 18198 1,

haematopoietic an d lymphoid system is based on the principles initially d efined in the "Revised Europe an-Amer ican Classifica tion of Lymp hoid Neoplasms" (REAL). from the Interna tiona l Lymphoma Stud y Group (ILSG) 18981. In the WHO classification, these p rinciples have also been appl ied to the class ification of myeloid and his tiocy tic neoplasms, The gu id ing prin cip le of the REAL and WHO cl assific ations is the attempt to define "real" d iseases that c an be recognized by pa tholo gi sts with availabl e techniques. and that appear be distinct clinical entities . There are 3 important com ponents to this p rocess First. recognizing tha t the underlying c auses of these neo plasms are often unknown and may vary, this approa ch to cl assifica tion uses all available information - morpholog y, immunop henotype, genetic features, and cl inical features- to define diseases. The relative impo rtance of eac h of these features varies among diseases, d epend ing upon the state of current knowledge, and there is therefore no one "g old standard ," by which all di seases are defined . Second. rec ognizing that the com plexity 01 the field makes it impossib le for a single expert Of small g roup to be comptet ely authoritative, and that broad agreement is necessary if a classificati on is to be ac cep ted, this cta ssrncanon relies on bu ild ing a consensus among as many experts as possible on the def inition and nomenclatu re of the diseases, We recognize that com promise is essential in orde r to arrive at a consensus, but bel ieve that the only thing worse than an imperfect classification is multiple competing classifi cati ons . Finally. wh ile patholog ists must take pr imary respon sib ility for developing a

As indicated above , there is no one -gold stand ard ," by which all diseases are def ined in the WHO cl assific ation. Morpholog y is alway s important, and many diseases have ch aracteristic or even diagnosti c morphologic featu res, Immunephe notype and genetic features are an important part of the definition of tumours of the naematopolettc and lymphoid tissues , and the av ailability of this information makes arriving at conse nsus definitions easier now than it was when only subjec tive morphologic criteria were available . lrrmunophenotyping studies are used in routine diagnosis in the vast majority of haematolog ic mali gn ancies, both to d etermine lineage in malig nant processes and to dis tinguish be nig n lrom ma lignant processes . Many disea ses have a chara ct eristic immunophenotype. such that one would hesitate to make the diagnosis in the abse nce of the immunep henot yp e, while in others the immunoonenotvpe is only part of the diagnosis, In some lymphoi d and in many myeloid ne0p lasms a speci fic genetic abnorma lity is the key defining criterion, while etters lack specific known genet ic ebnomantes. Some g enetic abnormalities, while characteri stic of one dis ea se, are not specific (such as MYC. CCND 1or BCl2 rearrangements or mutations in JAK2). and others are prognostic factors in several diseases (such as TP53 mutations or FLT3-ITO) , The inc lusion of jr munoohenotvoc leatures and genetic abnormalities to define entities not only provides ob jective criteria for disease recogni tion but has identified antigens, genes or pathways that can be targeted for therapy; the success of rituxima b , an anti-CD20 molecule, in the

guage of medic ine: diseases must be described , defin ed and named before the y

can be diagnosed , treated and stud ied . A consensus on definition s and termin olog y is essent ial for both clinic al practice and investigation . A cl assification should contain diseases thai are clearly defin ed . c linically d istinc tive . norKlVerlappi ng (mutually excllsive) and that together comprise all known entities (collectively e xha ustive).

II should serve as a ba sis lor future investigation . and should be able to incorporate new information as it becomes ava ilab le. Classification has two aspects: clas s discovery - the proces s of identifying categories of diseases, and class pre diction - the process of determining which cere-

gory an individual case belongs to. Pamerogi sts are critical to both processes . The World Hea lth Org anizati on (WHO) Classi fication of Tumours of the Haematopoietic and Lymp hOid Tissues (4th Edition ) was a coll aborative project of the European Association for Haematopathology and the Society lor Hematopatholog y. It is a revision and update of the 3rd Edition 11039 }. which was the first true worldwide consensus c lassific ation of baematoiocic malignancies. The update, which began in 2006, had an a-me mbe r steering committee composed of membe rs of both societies, The Steering Comminee, in a series of meetings and discussions, agreed on a proposed list of diseases and chapters and selec ted authors. with input from both soc ieties. As with the WHO 3fd ed ition 189 71. the advice of clin ical haematologists and oncologists was obtained . in order to ensure that the classifica tion will be clinica lly useful. Two Clinic al Adv isory Committee s (CAG). one for myeloid neoplasm s and other acut e leukaemias and one for lym phoid neoplasms. were convened, The mee tings were org anized aroun d a ser ies of questions, inc luding disease definitions, nomenclature, grading. and clinical relevance. The committ ees were able to reach consensus on mos t of the questions po sed . and muc h of the inp ut of the 14

Introduction to the classification

committees was incorporated into the class ification. Over 130 pa thologists and haem ato logis ts from around the world were involved in writing the chap ters. A consensus meeting was held at the head quarters of the IARC in Lyon, France. to make final d eci sions on the classi ficatio n and the con tent of the book.

H. Stein S.H. Swerdlow J Thiele J w. Vardiman

treatment of. B-cel! neoplasms, and 01 imatinib in the treatment of leukaemias associated with ABL 1 and oth re!lrrangements inv olving tryoene kinase genes are testament to this approach. Finally. some diseases require know ledge of clinical features - age, nodal versus extranodal presentanon. specific anatomic site . and history 01 cytotoxic and other therapies - to make the diagnosis. Most 01 the diseases described in the WHO classification are considered to be distinct enti ties ; howev er. some are not as clearly defined, and these are listed as prov isional entities, In addition . borderline categories ha....e been created in this edition for cases that do not c learly fit into one category, so that well-de fined categories ca n be kept homogeneous, and the borderline cases can be stud ied further. The WHO classification stratifiesneoplasms primarily ac cording to lineag e: myeloid, lymphoid, and histiocyticfdendritic c ell. A normal c ounterpart is postulaled lor each neoplasm. While the goal is to define the lineag e of each neoplasm, lineage pla sticity may occur in precursor or imma ture neoplasms, and has recently been identified in some mature haematotymphoid neoplasms , In addition, genetic atooerreuues suc h as FGFR1, PDGFA and PDGFB rearrangements may give rise to neoplasms 01 either myel oid or lymphoid lineage associated with eosinophilia ; these disorders are now recognized as a separate group. Precursor neoplasms (acute myeloid reukaemes. lymphoblastic Iymphomasfleukaemias, acute reukaerraas 01 amb iguo us lineag e, and blast ic p lasmacytoid de nd ritic ce ll neop lasm ) are considered separately from mo re mature neoplasms [myeloproliferative neoplasms (MPN). myelodysplastic/myeloproliterative neoplasms, myelodysplastic syndromes , mature (peripheral) B-cell and T/NK -cell neoplasms, Hodgkin lymphoma. and hisIiocyteldeodritic-c ell neoplasms] . The mature myeloid neoplasms are stratified according to the ir bi ologica l features (myeIopl'oIiferative, with effective baereiopoiesis. ....ersus myelodysplastic , with ineffective neematcootesfs . as welt a s by genetiC feature s). Within the mature lymphoid neop lasms , the diseases are listed broadly ac cord ing to clinical presentation (disseminated often leukaemi c, extran coat. indolent. aggressiv e). and to some extent according to stage of differentiation when this can be postulated: howe....er the

ord er of listing is in part arb itrary, and is not an integral part of the cl assification. The 4th ed ition of the WHO classification inc orpo rates new information that has emerged from basic and clinic al in....estrgat ions in the interva l since pu b lication of the 3rd edition . It inc ludes new defining criter ia for some disease s, as well as a number of new entities. some def ined by genetic criteria - particul arly among the myeloid neoplasm s- and others by a combination of morpholog y. immunoph eootype . and clinic al features. The frequent application of immunophenotyping and genetic stud ies to peripheral blood, bone ma rrow, and lym ph node samp les has also led to the de tection of small clonal populations in asy mptomatic pe rsons . These include small clones of cells with the BCR-ABL 1 translocation seen in chronic myelogenous leukaemia. small cl ones of ce lls with BCL2-IGH rearrangement. and small populat ions of c ells that have the imm uoopheootype of chronic lymp hocytic leukaemia (e l l ) or folli cu lar lymphoma (mo noc lonal B lymphocytosis, follicular lymphoma-in Situ , paediatric follicul ar hyperplas ia WIth monoclonal B c ells). In man y case s. it is not clear whether these represent earty involvement by a neoplasm, a precursor iesoo. or an inconsequential find ing. These situations have some ana logies to the identification of small monoclonal immunoglobulin components in serum (monoclonal gammopathy of unknown significance), The ch apters on these neoplasms include recommendations for dea ling with these situations. The rec omm end ations of international con sens us group s have bee n co nsidered. with regard to criteria for the d iagnosis of e ll, plasma cell myeloma, Waldenstr6m macroglobulinemia, and new subtypes of cutaneous lymphomas, as well as in the development of new algorithms for the diagnosis of MPN .

the WHO classification has produced a new and exciting degree of cooperation and conmunic ation among patholog ists and oncologists from around the world . which stould facilitate con tinued progress in the understand ing and treatment of haema totog ic manqnaocies . The mulliparameter approach to c lassification, with an emphasis on defining real disease entites. tha t has be en ad opted by the WHO classification, has been shown in inte rnational studi es 10 be reproducible: the disea ses d efined are c linically disttnct iv e. and the uniform definitions and terminology facilitate the interpretation of clinical and translational stud ies 15 1, 791 . In addition, accurate and precise classifi c ation of d isease entities has facilitated the discovery of the genetic bas is of my eloid and lymphoid neoplasms in the ba sic science laboratory

A critic al feature of any class ification of diseases is that it be periodically reviewed and updated to incorpor ate new information. TheSocietyfor Haematopathology and the European Association for Haematopathology now have a more than to-year record of couebceaton and coo pe ration in this effort. The societies are comm itted to updating and revising the classification as needed . with input lrom clinicians and with the collaboration of the WHO . The experience of developing and updating Introdu ction to the cl assification

15

• )

CHAPTER 1 Introduction and Overview of the Classification of the Myeloid Neoplasms

•

-, "

..

Introduction and overview of the classification of the myeloid neoplasms

J.w. Vardiman A.D. Brunning D.A . Arter M.M.Le Beau

The WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissue s (3rd edition) published in 200 1 reflected a pa radigm shift in the approach to c lassification of myeloid neoplasms { 1039). For the first time. genetic information was incor porated into diagnostic algorithms provided lor the vario us en tities. The publicat ion was prefac ed with a comment pred icti ng future revisions nec essitated by rapidly eme rg ing gen el ic information. The cu rrent revision is a commentary on the significant ne w molecular insights mat have bec ome avail abl e since the publication of the last ctass'ncauon . The first entity described in this monograph . chronic myelogenous leukaemia (CML) rema ins the prototype for the identification and c lassific atio n of myeloid neoplasms This leukaemia is recognized

genetic features is used in an anerrctt c define d isease entities , such as CML, that are biolog ically homogeneous and clinically relevant - the same approach used in the 3rd ed ition of the classification. Altho ugh the previous scheme began to open the door to including genetic abnormalities as c riteria to classi fy myeloid neoplasms, this rev ision firmly acknow ledges that as in CML, recu rring ge netic abno rmali ties provi de not onl y objec tive c rite ria for recognition of speci fic entities but also identification of abnormal gene product s or pathways that are potent ial targets for therapy. One example in this revised sc heme is the addition of a new subgroup of mye loid neoplasm s (Tabte 1.01) assoc iated with eos inoph ilia and chromo somal ab normalities that involve the oiateiet-oenved growth factor rece ptor

by its c linic al and morphologic features, and its natural progression is charac terized by an inc rease in blasts of myeloid , lymphoid or m ixed myeloid/lymphoid immunop henotype. It is always associated with the BCR·ABL 1 fusion gen e that results in the production 01 an abnormal protein tyros ine kinase (PTK) with enhance d enzyma tic ac tivity. This p rotein is sut tcrentto ca use the leukaem ia and also provides a targ et for prote in tyrosi ne kinase inhibi tor (PTKI) the ra py tha t has prolonge d the lives of thousands of pa tients with this often tatal illness {6 151. This successful integ ratio n of cl inical , morphologi c and genetic information embodies the goal of the WHO classific ation scheme. In th is revis ion . a combination of c linica l, morpholog ic . imm uno phe noty pic and

.-"""'"

Table 1.01 Themyeloid neoplasms' major sul:9'OUJlS and d\al;U::i tstic features at ~

0.....

MPN

MyeIoidIIymphoid neoplasmswith eosinophilia and abriof· malilies of PDGFRA.

8M ctllularity

'10 MIrf'OW bluts

Usually increased. often normalin ET

tbmaJ or sIighlIy increased: <10% in dI'onic phase

Increased

Normal or $IigM~ increased: <20% irl cnronc phase

Present

Nom1al or increased:

Preserlt

..........,

--

HatrnatopOitsit

G••,,,''''''',

En-.

Relatively normal

Elfectrve

relabYe/y normal,

"""""""", """""'"

A. Porwit A . retten C.D. Bloomfield J. Thiele

.... """"

VanabIe; 008 or

"""..-

IifIeage usually irullallyincreased Eosinophilia

-

Co<m>oo

Com~

j~t 5x10ir1.)

PDGFRB Of FGFRI MOS

"''''as."

=-

~aror

M''''''PN

"""""' """'..." """" .......

""'.

~lasia

inoreor

-,,- --_"" incl'eased;<20'10

"""'"

Usually oneormae

......

rrft'!lal cIyspIaSIa

_>2ll%.

eQPl in some cases 'l'Illh specific cybJeneIlc abnorrnaIilies or in

some cases of erylhroIeukaemia

Inel!&Cti'Ie

Cytopenia(s)

U_

......

..--

\IariabIe. WBC

Co<m>oo

more myeloid lineage

......,

-......

"",",

May Of may J'IOl be

-...

""""""'"

dyspIaslai'loneor

Moy""Y ......

-

WllC_ ........ ........

or e"ect1ve

.........

"""'-

Mf)N, myeloproliferative neoplasms: MDS, myelod)'spla:slic syndromes; MDSlMf)N, myeIodysplasbcJmyeloprolifefalive neoplasms: AMl, ICIJIe myeloid leukaemia; ET, esseflIlaj Ihfombocylhaemia, JMML. ju¥&nile myelomonocytic leukaemia, wec. wniIe bloocI e&II$.

18

'

Introduction and overview of the c lassif ication of the mye loid neoplasms

]

alpha (PDG FflA) Of platelet de rived growth factor recep tor beta (PDGFRB) genes -a subgroup defined larg er9 by genetic events that lead to consti tutive act ivat ion of the receptor tyrosine kinase, PDGFA, and that respond to PTKI therapy {13 1, 466. 8121 . Similar examples are found througho ut the classification in each major subgroup, and inclu de not only neoplasms assoc iated with rmcroscoprcally rec og niza ble chromosomal abnormalities but also with gene mutations without a cytogenetic correlate as weu. On the other hand . the importance 01 careful clinical, morphological and immunophenotypic characterization of each

myeloid neoplasm and coeretanoo with the genetic findings cannot be over-

emphasized. The discovery of activating JAK2 mutations has revolutionized the approach to the diagnosis of the myeloproliferative neoplasms (MPN) 1163, 1044 , 1186,12681. Yet JAK2mutatiQns are not specific for any single clinical or morphologic MPN phenotype, and are also reported in some cases 01 myelodysplastic syndromes (MDS), myeiooysplasnc/ myeloproliferative neoplasms (MDSlMPN) and ac ute mye loid leu kaemia (AMl). Thus, an integ rate d, multidisciplinary approach is necessary for the classification of myeloid neoplasms. With so muc h yet 10 learn, there may be some 'missteps" as trad itional approaches to categorization are fused with more rrcecuarfy-orentec clessifcaton schemes , Nevertheless, thi s revi sion of th e WHO classification is an attempt by the authors, editors and the c linic ians who served as members of the Clinica l Advisory Committee (CAC ) to p rovide an "evidencebased" c lass ifica tion that ca n be used in daily p ractic e for therap euti c deci sions and yet pr ovide a flexib le framework for integration of new data ,

Prerequisites for classification ofmyeloid neoplasms by WHO criteria The WHO c lassification of myeloid neoplasms relies on the morphologic, cytochemical and immunophenotypic features of the neop lastic cells to esta bl ish thei r lineage and deg ree 01 ma turation and to decide whether cellular p rolife ration is q101ogica lly normal or dysplastic or esecuve or ineffec tive . The classification

is based on cr iteria applied 10 initial specimen s obtained prior to any definitive therapy, includ ing growth lactor therapy, for the myeloid neoplasm. The blast percentage in the per ip her al b lood , bone ma rrow an d other involved tissues remains of p ractica l impo rtance to categorize myeloid neoplas ms and to judge their progression . Cytogenetic and molecular genetic studies are requ ired at the time of d iag nosis not only for recoq r nton 01 specific genetically d efined entities, but for establiShing a baseline against which futu re studies can be judged to assess disease progression. Beca use of the multidisciplinary approach req uired to diagnose and classify myeloid neoplasms it is recomnended thaI the various diagnostic studies be correlated with the clinical findings and reported in a single, integ rated report. If a definitive classification cannot be reached the report should indicate the reasons why and provide guidelines for additional studies that may clarify the diagnosis. To obtain consistency, the following guidelines are recommended for the evaluation of specimens when a myeloid neoplasm is suspected to be present. It is assu me d tha t this evalua tion will be pe rformed with full knowled ge of the clinical history and pertinent laboratory data. Morphology Periphera l blood: A perip heral b lood (PB) smea r sho uld be exa mined and co rrelate d with result s of a co mple te b loo d c ount. Freshly mad e smea rs shou ld be sta ined with May-Gnmwald -Giernsa or Wright-G iemsa and examined for wh ite bloo d ce ll (WBC) , red b lood ce ll (AB C) and plate let abnormal ities It is impo rtant to ascerta in that the smears are we llstained, Evaluation of neutrophil g ranularity is imp ortant when a myelo id d isor der is suspected; de signat ion of neut rophils as abnormal b ased o n hypog ranular cytoplasm alo ne shoul d not be conside red unless the stain is well-controlled . Manual 2OO-cell leukocyte di fferentials of PB smea rs are recommended in patients with a myeloid neoplasm when the WBC count permits. Bone manowaspirate: Bone marrow (BM) as pi rate smears should also be stained with May-G rQnwald-G iemsa or WrightGie msa for optimal visua lization of cytoplas mic g ranules and nuclear chromatin. Because the WHO Classification relies on percentages of blasts and other specific Introduction and overview of the

11111111 111I 1111 1111 111111

456 F'S!. 1.01 Bone marrow tIeI:Me biopsy, Bone marfOW b'ephinebiopsies should be alleast 1.5 em in length and ollt<w1ed at right angles10 the cortical bone. cells to categorize some eoutes. it is recommended that 500 nucleated BM cells be counted on cellular aspirate smears in an area as close to the particle and as undiluted with blood as possible. Countll"lQ from multiple smears may reduce sampling error due to irregular distribution of cells. The cells to be counted include blasts and promonocytes (see definition below) . pronveocvtes. myelocytes, metamyelocytes, band neutrophils, segmented neutrophils, eosiropnns. basophils, fTlQIlOcytes , lymphocytes. plasma cells , erythrOid precursors and mas t cells. Megakaryocvtes. including dysplastic forms. are not inc lude d. If a concomitant non-mye loid neoplasm is present, such as p lasma ceu myeloma, it is reasonable to exclude tho se neo plastic cells from the coun t used to evaluate the myeloid neop lasm. If an aspirate ca nnot be obta ined du e to fibrosis Of ce llular packing, touch preparatio ns of the b iop sy may yield valuable c yto log ic informa tion, but d ifferential co unts from touc h preparations may not be repr esentative . The d ifferential co unts obta ined from marrow aspi rate s should be compared to an estimate of the p ropo rtions of cells o bserved in avai lab le biop sy sections, Bone marrow trephine biopsy: The contribut ion of adequate 8M bio psy sections in the diagnosis of myeloi d neoplasms cannot be overstated. The tre phine biopsy provides information rega rdin g overall cellularity and the to pog raphy, propo rtion and maturation of baematopolenc cells , and allows evalu ation of 8M stroma. The biopsy also provid es material for immunohistochemical studies th at may have diagnostic and prognostic importance. A biopsy is essential whenever there is myelofibrosis, and the classification of sore entities , partiCularly MPN, relies heavily on trephine sections, The specimen must be

ctassncauoo at the myeloid neoplasms

19

adeq uate, Iake n at rig ht angle from the cortica l bone and at least 1.5 cm in length to enable the evaluation of at least 10 partially preserved inter-trabecular areas. It should be well-fixed, thinly sectioned at 3-4 micra, and stained with haematoxylin and eosin and/o r a stain such as Giemsa that allows lor detailed morphologic evaluation . A silver impreg nation method for reticulin fibres is recommended and marrow fibrosis graded according to the European consensus scoring system 122141, A periodic acid-Schitt (PAS) stain may aid in detection 01 megakaryocytes. Immunohistoc hemical (IHe) study of the biopsy is often indispensable in the eva luation of myeloid neoplasms and is discussed belOw, Blas ts: The percentage of myeloid blasts is important for dl8gnosis and ctasstcaton of myeloid neoplasms , In the PB the blast percentage should be derived from a 200-cell leukocyte differential and in the 8M from a 500-cell count of cellular 8 M aspirate smears as described above . The blast percentage derived 'rom the 8 M aspirate should correlate With an estimate of the blast percentage in the trephine biop sy. although large foca l clusters or sheets 01 blasts in the biopsy should be regarded as possible disease progression. Immunohistochemical staining of the BM biopsy for CD34+ blasts often aids in the correlation of aspirate and trephine biopsy findings, although in some myeloid neoplasms the blasts do not express CD34 , Flow cytometry determination of blast percentage should not be used as a substitute for visual inspection. The spec imen for flow c ytometry is otten haemoouute. and may be affected by a number of preanalytic variabl es. and as noted for the

biopsy. not all blasts express CD34 . Myeloblas ts. monoblasts and megakary<> blasts are included in the blast count. Myeloblasts vary from slightly larger than mature lymphocytes to the size of monocvtes or larger. with moderate to abundant dark blue to blue-grey cytoplasm. The nuclei are round to oval with finely granul ar chromatin and usually several nucleoli. but in some nuclear irregularities may be prominent. The cytoplasm may contain a few azurophil granules (Fig 1,03), Monob lasts are large cells with abundant c ytoplasm that can be light grey to deeply blue and may show pseudopod formation (Fig 1.04 A. S). Their nuc lei are usually round with deli cate , lacy chromatin and one or more large prominent nucleoli.

They are usually strongly positive for n0nspecific esterase(NSE) but have no or only weak myeloperoxidase (MPO) activity, Promonocytes are considered as ' rroooblast equivalents " when the requisite percentage 01 blasts is tallied for the diagnosis of acute monoblastic . acute monoc ytic and acute myerorronocync leukaemia. Promonoc vtes have a delicately convoluted. folded or grooved nucleus with finely dispersed chromatin, a small , indistinct or absent nucleolus, and finely granulated cytoplasm (Fig 1.04 C, 0), Most promonocytes express NSE and are likely to have MPO activ ity. The distinct ion between mono brasts and prornonocvte s is often difficu lt. but because the two cell types are summated

... .,

20

Introduction and overview of the classification of the myeloid neoplasms

•

as rr onootasf s in making the diagnosis of AML, the distinction between a monoblast and promonocyte is not aly,.ogys critical. On the other hand , distinguishin g promonocvtes from mo re matu re b ut abnormal leukaemic monocytes can also be dilficult, but is critical, because the designation 01 a case as acu te monocytic or acute myelomonocytic leukaemia versus chronic myelomonocytic leukaemia olten hinges on this distinclion . Abnormal rrooocv tes have more clumped chromatin than a p romonocyte, variably indented. folded nucl ei and grey cytoplasm with rrore abundant lilac -colored granules . Nucleoli are usually absent or indi stinct (Ftg 1.04 E.F). Abnormal monocytes are rot consider ed as monoblast eouvaeots. Megakaryoblasts are usually 01rreoen to large size with a round , indented or irregular nucleu s with finefy reticular chromatin and one to three nucleoli. The cytOplasm is basophiliC, usually agranular, and may show cytoplasmic blebs (See Chapter 6 on acute myeloid leukaemia, NOS). Small dysplastic megakaryocytes and micrornegal<.aryocyt es are not blasts. Inacute promyelocytic leukaemia, the blast equivalent is the abnormal promyelocyte . Erythroid precursors (erythroblasts) are rot included in the blast count except in the rare instance of "pure" acute erythroid leukaemia, in which case they are cons idered as blast equiva lents (See Chap ter 6 on acute myeloi d leukaemia, NOS). Cytochemistry and other special steins: Cytochemical stud ies are used to determine the lineage 01 blasts, althou gh in some laboratories they have bee n supplanted by immun ologi c studies usin g flow cytometry an d/or immunohistochem istry. They are usu ally perform ed on PB and 8M aspirate smears but some can be performed on sections 01 treph ine b iop sies or other tissues . Detec tion 01 MPO indicates myeloid d ifferentia tion b ut its absence does not exclude a myeloid lineage because early myelobl asts as well asmonoblasts may lack MPO. The MPO activity in rrweiobtasrs is usually granular and etten concentrated in the Golgi region whereas monobtasts. although usually negative,may show line, scattered MPO+ granules, a pattern tha t becomes mo re pronounced in prcmonocvtes . Erythroid blasts, megakaryoblasts and Iymphoblasts are MPO negat ive . Sudan Black B (SSBl staining parallels M PO but is less speetc. Occ asional cases of lymphoblastic leult.aemia exhibit SSB POSitiVIty, in which

A

B

,

-~ ~ . • •

c

o

E

F

Fig. 1.04 Monoblasts, promonocytes and abnormal mcnccytea from a case of acute monocytic laukaemia. A, B Monoblastsarelarge with abundant cylOlJlasm that ma y contain a few vacuoles Of fine granules and have roullCl nuclei withlacy chroma~n and one Of more variably prominent nucleoli. C, D Prornor.ocytes have more irregular ancl delicately folded n~ withfine chroma~n, small indistinct nucleoli and finely granulated cytoplasm. E, F Abnormal monocytes appear immature, yet have more condensed nuclear chroma tin, con'o'Q/uled Of fdded nuclai, and more cylopIasmiC granulaboo (Courtesy of Or. J. Goasguen).

case light grey granules are seen rather than the deeply black granules that characterize mverobrasts. The non-specific este rases . u nap hthyl butyrate (ANB) and (,( naphthyl acetate (ANA). show diffuse cytoplasmic activity in monoblasts and monocytes. Lymphoblasts may have foca l punctate activity with NSE but neutrophils are usually negative. Megakaryoblasts and erythroid b lasts may have some multitocal. punctate ANA positivity, b ut it is partia lly resistant to natrium ffuorid e (NaF) inhibition whereas monocyte NSE is totally

inhibi ted by NaF, The combination of NSE and the specific esterase , naph thol-ASDchloroaceta te esterase (CAE), which stains primarily cells 01 the neutroph il lineage and mast cells, permits ident ification of monccvtes and immature and mature neutroph ils simultaneously. Some cells , particularty in myeIornonocytic leukaemias, may exhib it NSE and CAE simultaneously. While norma l eosinoph ils lack CAE, it may be expressed by neop lastic eosooohne. CAE can be performed on tissue sections as well as PB ()( marrow asp irate smears.

Introduction and overview 01 the ctass.tcanoo 01 the myeloid neoplasms

21

In acute erythroid leukaemia. a PAS stain may be helpful in that the cytoplasm of the leukaemic oroervmrobreate may show large globules of PAS positivity. Wellcontrolled iron stains should always be per formed on the 8M aspirate to detect iroo stores. normal side roblasts and ring side robrasts. the latter of which are defined as erythroid precursors with 5 or more granules of iron encircling one-third or more of the nuc leus. Immunop henotype Immunophenotypic analysis using either multiparameter flow cytometry or IHe is

an essential tool in the cha racterization of myeloid neoplasms. Differootiation antigens that appear at various stages of haematooo'euc develo pment and in corresponding myeloid neoplasms are illustrated in Fig . 1.05. and a thorough descriplion of lineage assignment criteria is provided in the chapters on mixed phenotype acute leukaemia, The techn iques employed and the antigens anafyzed may vary according to the myeloid neoplasm suspected and the information required 10 best characterize it as well as by the tissue available. Although often important in the diagnosis ol any haematoiogicaJ neoplasm.

immunophenotyping in myeloid neoplasms is most com monly required in AML and in determining the phe notype of blasts at the lime of transfo rmation of MOS. MOS!MPN and MPN, Mulliparameter flow cytometry is the prefer red method of immuno phenotypic analysis in AML due to the ability to analyze high numbers of cells in a relatively short period of time with simultaneous recording of information about severer antigens for each individual cell. Usually. rather extensive panels of monoclonal antibodies directed against leukocyte differentiation antigens are applied because

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ing commitme nt of leukaemic c ells into the different haemat op oieti c tlneages is limited Evaluation of exp ress ion patterns of several antige ns, bo th membrane and cytoplasmic, is necessary for lineage assignment. to d etect mixed phenotype acute leu kaemia, and 10 detect aberran t

phenotypes allowing lor follow-up of minimal re sidua l d ise ase .

Irrmunopheootypic analysis has a ce ntral role in disting uishing be tween minimally dllferentiated acut e myeloid leu kaemia and acute lymphoblastic leukaemia, and in CML between myeloid blast pha se and lymphoid blas t phase. Among AM L WIth recurrent genetic abnormalities , sev eral have characteristic phenotypes. These

patterns. described in the respective sections, can help to plan molecular genetIC {lluorescence in situ hybrid ization (FISHlI and molecular inv estigation s in individual patie nts, lm munophe notyp ic features or the other AMl categor ies are extremely heterog eneo us. probably due to high genetic d iver sity. Although it has been sugges ted that express ion of c ertam antiqens, such as CD?, COO, C Ol lb, C014. CD56 and CD34 cou ld be associated with an adver se prognosis in AMl, their independe nt prognostic value is still controversial. Aberrant or unusual omorophenotypes have been found in at least 75% of ca ses of AMl. These c an be described as c ross-lineage antigen expression, matura tional as ync hronous expression of antigens , antigen overexpression, and the red uction or abse nce of antigen expressio n, Sim ilar aberra ncies have also been reported in MDS as we ll. and their presence ca n be used to sup port the diagnosis in ear ly o r morpholog ica lly ambiguous cases of MDS (See Chapter 5). lm11unophenotyping by IHC on 8 M b iopsy sections can be applied if ma rrow cell suspensions are nol available for flow cytcmetry analysis. Antibodies reactive with paraffin-embedded BM biopsy tissue are available for many lineage-associated markers (e,g. MPO.lysozyme, CD3, PAX:s, C033, etc.). As noted previously, CD34 staining of the biop sy can fac ilitate the detection of blasts and their distribution , provided the blasts expres s CD341 1650/. For cases rich in megalob lastoid erythroblasts. immunohistolog y for glycophorin or haemoglobin may be helpful in dist inguishing those cells from myeicotasts (eg. in cases of RAEB or acute erythro1eI.Memia), and COOl or CD42 oflen aid

cvto-

in the id entification of abnormal megaka rvoc ytes. Genetic studi es The WHO classi fication includes a numbe r of entities defined in part by scecmc genetic abnormalities. including gene rearrangemen ts due 10 chromosomal nansrccarrons and to specific gene mutations. so de term ination of genet ic features of the neoplastic cells must be performed if possible. A complete cytogenetic ana lysis of 8M shou ld be perlormed at the time of init ial eva luat ion to establish the cytogenetic profile, and at regu lar intervals thereafter to detect evidence of genetic evolution . Additional d iag nosti c genetic studies should be guided by the diagnosis suspected on clinica l, morpholog ic a nd imTulophenotypi studies. In some cases, reverse transc rip tase-pol ymerase c hain reaction (AT-PCR) and/or FISH may detect gene rearrangements thai are present in low frequency and not observed in the initial chromosomal ana lysis, in c ases with var iants of typical cytogenetic abnormalities, and in cases in which the abnormality is cryptic , such as the PDGFRA-FIP1L 1 fusion in myeloid neoplasms associated with eos inophilia, Depending on the abnormality, qu ant itative PCR performe d at the time of diagnosis may also p rovide a baseline against whic h the response to therapy c an be monitored . A num ber of gene mutations d etect ed by gene sequencing, allelespe cific Pe A and othe r techniq ues have em erge d as importa nt diagnostic and prognostic ma rkers in all ca tegories of mye loid neoplasm s, Mutat ion s of JAK2, MPL , NRAS, NFl , PTPN 11, and KI T in MPN and MDS/MPN, and NPM1, CEBPA, FLT3, RUNX1 and KIT, among others. in AMl are impo rta nt for d iagnosis and p rognosis. and some. particularly JAK2, FLT3, NPM 1 an d CE8PA figure importantly in this revised classification . Furthermore , the role of gene over- and unde r-expression as well as loss of hete rozygosity and copy number variants detected by array-based approaches are on ly now being recognized as impo rtant abnormalities that may well influence d iagnostic and prognostic models in the near future 11531AI . Nevertheless, m icroarray prof iling studies. alt hough import ant in the research setting , have not yet been tested in cl inic al practice .

Revised WHO classification of myeloid neoplasms Table 1,0 1 lists the major subgroup s of myelold neop lasms and their characteristic features at diagnosis. The nomenclature for the myeloprolife rative entities has been c hanged from "c hronic mye lopro liferat ive diseases" to ·myeIoproIiferative neoplasms" and the subgroup formerly designated as "myelod ys pl as ticfm y e lo p ro li fe rati v e dis eases" has been ch ang ed to "myelod ysplasticJmyelo proliferative ne0prasms" to und erscore the ir neoplast ic nature . Beside s the addition of the new subgroup. "Myeloi d and lymp hoid ne0plasms with eosinophil ia and abnormalities of PDGFRA, PDGFR8 and FGFRt ,· new entities have been added and/or diagnost ic criteria updated with in each subgroup. Myeloproliferative neoplasms (MPN) The MPN (Table 1.02) are c lonal haeretcporenc stem cell d isorders Characterized by pr oliferation of one or more of the myel oid lineages (l.e. granulocytic , ery thro id . megakaryocytic and mast cell). They are primarily neoplasms of ad ults that peak in frequency in the 5th to 7th decade, but some subtypes. parti cu larly CM l and essential thrombocythaemia (ET), are reported in children as well. The inc id enc e of all sub types combined is 6-10/ 100,000 population annually {1053, 1059. 1060 f, Initially. MPN is cha racterized by hypercellularity of the BM with effective naematoporetc maturation and increased numbers of gra nulocytes, red blood ce lls and/o r plate lets in the PB. Splenomegaly and hep atomeg aly a re co mmon and caused by sequestration of excess b lood cells or proliferation of abnormal raematopoietic cells, Despite an insidious onset each MPN has the potential to undergo a Table 1.02 ~live neoplasms (MPN).

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introouctco and overview of the ctassrncanon of the myek>id neoplasms

23

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stepwise pr ogr ession that term inate s in marrow failur e d ue to myelofib rosis , ineffective haemat opoi esis or Iransformalion 10 an acu te blast phase. Evid ence of ge netic evo lution usually heralds disease

progression as may increasing organamegaly, increasing or decreasing blood counts , myelofi brosis and onset 01myelodysplasia. The finding of 10-19% b lasts in the P8 Of 8M generally signi fies accelerated disease and 20% or more is suHicient for a di ag nosis 01bla st pha se .

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Rationale for tho diagnosis and classification of MPN In previous cl assification schemes the detect ion of the Philadel phi a chromosome and/or BCR-ABL 1 fusion g ene was used to coolirm the diagnosis of C Ml wher eas the remaining MPN sub types were diagnosed by their cli nical and labo ratory features with relatively minor contributions to the diagnosis from morph ologi c findings. A number of criteria were required not only to distinguish 24

subtypes of MPN from each other but from reacti ve granulocyt ic . erythroid andl or megakaryocyt ic hyperplasia . Revisions in the criteria for cla ssification of MPN in the cu rrent scheme have been influen ced by two fac tors - the recen t discovery of gen etic abnorm alities involved in the pathogenesis of BCR-ABL 1 negative MPN and the wide r appreciation that histologic features (megakaryocytic morp hology and topograph y, marrow stromal changes, id entific ation 01specific cell lineages involved in the proliferation) cor relate with clin ical features and c an be used as criteria to identi fy MPN subtypes {2 177. 22 16, 22221. Mo st if not all MPN are assoc iated with clona l abnormalities involving g enes that encode c ytoplasmic or receptor PTKs. The abnormalities described to da te include transicc anons Of point mutations of genes that result in abnormal, co nstitutively abnormal PTKs that activate signal transdu cti on pathw ays leading to the abnormal proliferation . In some c ases,

Introdu::tion and overview of the classi fication of the myeloid neoplasms

these genetic abnormalities. such as the

BCR-ABL1 fusion gene in CMl . are essocia ted with consistent clinical, laboratcry and morp hologic find ing s that allow them to be utilized as major criteria for classfication, whereas others provide proof that the myeloid prolifera tion is neoplastic rather than reactive. Ac quired somat ic mutations of JAK2. at chromosome 9p24. have been shown);) playa p ivotal role in the pathogenesis d many cases of BCR-ABL 1 negative MPH 11 04 4, 1163, 1186, 1287A , 12881. The most comm on mutation , JAK2 V6 17F, results in a constitutively active cytoplasmic JAK2 that activates signal transducer and ac tivator of transcription (STAT), mitogen activated p rotein kinase (MAPK) and phospholidyllnositol a-kmase (P13K) sigo naling pathways to prorote transforma1Ol and proliferation of baemaroooenc pro. g enitors (Fig. 1.07). The JAK2V617Fmutation is found In almost all patients wit~ polycythaemia vera (PV) and in n ear~ one-half of those with primary myelofil:Jrosis

(PfvlF) and wit~ esseotelmoroocvmaeraa (ET), In the few PV patients wno lack the JAK2 V6 17F, an acti vat ing JAK2exon 12 mutation may be fou nd , and in a small proportion of cas es of PMF and ET, an activating mutation 0 1 MPL W5 15l or W5 15K is seen. It is important 10 no te that JAK2 V617F is not specific for any MPN nor does its absence exd ude MPN . Furthermore, it has been reported in some cases of MDS/MPN, in rare cases of AMl, and incombination w ith other well-defined genetic abnormalities such as the BCR-A8L 7 110641. Thus, diagnostic algorittvns for PIl, ET and PMF have been altered to take the mutationalstatus of JAK2 into account as weN as 10outline the additional laboratory and histo6ogic "ndi~JS required to reach an accurate classification 01 c ases, regardless 01 whe ther the mu tation is or is not present. In addition to the changes in the cr iteria lor N , ET and PMF, information reg ardi ng abnormal PTK toncnon due to rearrangementsof the POGFRA, PDGFRBor FGFR1 genes in patients with myeloid neoplasms associated with eosinop hilia led to reappraisaland new diag '1ostiC algorithms for those syndromes as well (see below). The appreciation 01 the role altered PTKs pla y in the pathogenesis of C Ml, PV, ET and PMF also argues lor the inclusion of similar chronic myelo id pronteranons related 10 PTK abnormalities under the MPN umbrella. Thus, systemic ma stocytosis, wh ich has many features in common with other MPN entities and is alm ost always associated with D816V mutation in the KIT geneencoding the recep tor PTK, KIT, has been added to this categ ory 121761 St ill, tI"1e molecular pathogenesis of nearly half of all cases of ET and PMF, of all cases of chronic neutrophilic leukaemia and a mm ber of myeloid neo plasms ass oc iated with eosinophilia remai n unkn ow n . For these reliance on cli nical, laboratory and morphologic features is essenti al for diagnosis and classification,

Stmnary 01major c hanges in the classilication of MPN I . The nomenclature , 'mveiopronte ranve disease" has bee n changed to "myeloproliferative neoplasm " 2, Mastocytosishas been includ ed in the MPN category 3 Some cases previously meeting th e Cfllena for chronic eosinophilic leuka emia (CEll may now be categorized as myeloid (J ~ d neop lasms with eosinophilia

and ab normalities 01 PDGFRA. PDGFRB or FGFR1 , If none of the se rearrangements are d etec ted, and there is no BCR-ABL 7 fusio n gene , they should be ca tego rized as GEL, not otherwise specified 4. The d iagnostic al go rithms for PV, ET and PMF ha ve been substantially c hanged to incl ude infor mation rega rd ing JAK2 and similar ac tivat ing mutations as well as pertinent histolog ic featu res 01 the 8M biopsy as d iag nostic Criteri a. 5. The threshold of the p latelet count for the di ag nos is of ET has been lowered to ~4 5Ox 1 Q91l. 6. Crit er ia for CMl in accelerated phase have been suggested w ith the caveat that they have not been fully evaluated in the era of PTKI therapy: studies 10 determine

their relevan ce are in progress and revisions may be necessary. Myeloid and lymphoid neoplasms with eosinophilia and abnormalitie s of

PDGFRA, PDGFRB or FGFR1 De termi ning the ca use of marked , persistent eosinophilia (~ 1 .5x1()9/l) in the blood can be challengi ng and is sometimes cli nically urg ent beca use 01 the potential damage to the heart, lungs , central nervous and other organ systems caused by the eosinophilic infiltration and release of cvtocnes. enzymes and other proteins. The eoeoooous may be derived from the neoplastic clone of a myeloid neoplasm, such as GEL, GMl or AMl, or lhey may be reactive due to abnormal

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Introduction and overview of the classification 01 the myeloid neoplasms

25

cytoki ne relea se from reactive or neoplastic r -ceus. In a numbe r of ca ses. no underlying cause can be fOund and the clonahty of the eos inophils ca nnot be proven: these cases are app ropriately termed "idiopathic hypereosinophilic ssndrome" (See Chapters 2 and 3). Rationale for diagnosis and classification of myeloid and lymphoid disorders with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR, Since the last edition of the WHO c lassification it has been recog nized that many cases of eosinophilia, incl udin g a substantial number conside red as "idiopathic" are clonal myeloid neoplasms caused by abnormalities in genes that encode the alpha or beta chains 01 the receptor PTKs, platelet derived growth factor receptor (PDGFR) or fibrobl ast gro wth fac tor reo ce ptor 1 (FGFR1), Rearrangements 01 PDGFRB at chromo some band 5q33 that lead to constitutive activation of the beta moiety of PDGFA were first recogni zed in cases variably reported as CEL or chronic myelomonocy tic leukaemia (CMML) with eosinophilia 11 31 , 8 12. 20851. More recen tly the gen e that encodes the alpha moiety of the PDGFR, PDG FRA, at chromosome b and 4q12. was found to be involved in cryptic translocat ions in CEl and in nearty one-half of cases reported as idiopathic hypereosinophilic syndrome 14661· In addition , rearrangements of the FGFR 1 tyrosine kinase gene have also bee n implic ated in myeio oronteratrons with prom inent eosinophilia 13, 13541. However, the c linica l and morphologi c presen tations associat ed with FGFR 1 rearrangement are variable, and include not only presentation as a myeloproliferative neop lasm with eosinophilia, bul also as AML and they may even present as, or evolve to. precursor T or B lymphoblastic leukaemia/lymphoma with prominent eosinophits Cases associated with PDGFRA rearrangements can likewise present as AMl or precursor t -een neoplasms 114691.

Tlb.. 1.03 Myeloid and lymphoid neoplasms W11t1 eosmphi lia ard abnormal~m ol POOFRA, POOFRB, or FGFR1 . Myeloid and lymphoid neoplasms with PDGFRA real1"angement

Myeloid nooplasms with PDGFRB

rearrangemeot Myeloid aoo IylTVIOid neoplasms wiltl FGFRf abnormallbes

Although it might seem most efficient to categorize these cases as CEl within MPN, this would ignOfe cases WIth PDGFRB abnormalities that present as CMML as well as cases of FGFR1 and PDGFRA rearrange ments that may even have a lymphoid conoooenr. To accommod ate Ihese transiccatons. a new subgroup defined largely by the genetic abno rma lities of PDGFRA, PDGFRB or FGFR1 has been added (Table 1.03). Detect ion of one of these abnormalities places the case in this category, regardless at the morpholog ic classification. Cases of myeloid neoplasms with eosinophilia that lack all of these abnormalities and that meet the criteria for CEL. NOS, in the MPN catecov should be placed in that group. Myelodysplastic/myeloproliferative neoplasms (MDSlMPN) The MDS/M PN (Table 1.04) include clonal myeloid neop lasms that at the time of initial presentation have some clinical, laborato ry or morphologic findi ng s that support a diagnosis of MDS, and other findings more consistent with MPN They are usually cha racterized by bvpercenularity of the BM due to proliferation in one or more of the myeloi d lineages . Frequently, the proliferation is effective in some lineages with increased numbers of circulating cells that may be morphologically and/or func tionally dysp lastic . Simultaneously, one or more 01 the other lineages may exhi bit ineffective proliferation so that cytopenlate) may be present as well. The blast percentage in the BM and blood is always <20%, Although hepatosplenom egaly is common, the clinical and labo ratory find ings vary and lie along a continuum between those usually associ ated with MDS or those usually associated with MPN Patients with a welldefined MPN who develop dysplasia and ineffective haematopoiesis as part of the natu ral history of their disease or after chemotherapy should not be placed in this category. Rarely, some patients may present in a transformed stage of an MPN entity in which the chronic phase was not reco gnized, and may have findin gs that suggest that they belong to the MDS/MPN gro up. In such cases, if c linical and laborato ry stud ies fail to reveal the nature of the und erlying proce ss, the designation of MDS/MPN, unc lassifiable may be ap· orcorare. Paneots wro have the BCR·ABL 1 fusion gene or rearrangements of PfX3FRA

nurooocuoo and overview 01 the classification of the myeloid neoplasms

TableU4

~neopIasms

(MDSlMPN).

cmnc myelomonocyllc leukaenU (CMMl) Atypocal chrooiC myeloid leukae~ , BCR-ABLI negative (aCMl) JIMIrIiIe myelomooocytic leukaemia (""' Ml)

MyekldysplastcIMyeloproliferative neoplasm, undassdiable (MDSlMPN ,U) Provisional entity: Refractory anaemia wittl Mrlg sideroblasts and ltJramt>ocytasis (RARS-n should not be categorized as MDS/MPN. and in contras t to the criteria used in the 3rd edition of the WHO classification, cases of CMML with PDGFRB rearrangements are also excluded Rationale for diagnosis and classification of MDSlMPN This diagnostic ca tegory was introduced in the 3rd edition amidst controversy as to wl1ether some entities, particularly CMML, would be better categorized as either MDS or MPN depend ing on the extent of mye loprol iferation as evidenced by the WBC cou nt. Some cases of CMML have low neutroph il co unts and only modestly elevated monocyte co unts and resemble MDS clinically and morphologically whereas others have markedly elevated WBC counts and org anomegaly more in keep ing with MPN. yet criteria that clearly distinguish biologiCally relevant subtypes of CMML remain to be defined . To date, a lew cases of CMML and atypical chronic myeloid leukaemia, BCR-ABL1 neg ative (aCML) have been reported to demonstrate JAK2mutations that characterize BCR-ABL 1 negative MPN, but the prol iferative aspec ts of most cases of MPD/MPN are related to aberrancies in the AAS/MAPK signaling p athways. In juvenile myelQmonocytic leukaemia (JMML) nearly 80% of patients demonstrate mutually exclusive mutations 01 PTNPN1', NRAS or KRAS, or NFl 11329. 2096, 21621. all of wl1ich encode signaling proteins in AAS dependent pathways, and approximately 30- 40% of cases of CMML and aCML exhibit NRAS mutations {1686, 231 1, 24171. In view of the lack of any spec ific genetic abno rmality 10 suggest that these entities should be relocat ed 10 another myeloid subgroup, they remainin this "mixed" category which acknowledges the overlap that may occ ur between MDS and MPN. Casesof CMML with eosinophilia associated with PfX3FRB rearrangements are excluded , but rare cases of CMML

with eosinophilia that do not ex hib it such rearrangements sho uld be cJassified in this categOry The most controverstat issue in the su bgroup at MDSIMPN is the provisional entity. refractory anaemia with ring siderob lasts and thrombocytosis (RAR5-T). The ma jority (SO- 60%) 01 cases of RARS-T studied lor JAK2V6 17F carry this mut ation 1234. 354.762 , 1835. 1839. 1969,2081,2139. 23581. This has prompted the notion that RARS-T should be moved to the MPN group of myeloid neoplasms. whereas othershave argued thaI RARS-T is not an entity at all but merely one of the better recogniZed MPN entities, such as PMF or ET. i'l which genetic evolution has led to a dysplastic teanse. ring sideroblasls 11966. 2139. 23581. In a few cases reported. hl:1Never. the cells of patients with RARS-T. when studied by in vitro cul ture techniques, have growth characteristic more in keeping with MOS than MPN 1234, 18351. An additional question is hOw to clearly distinguish RAR5- T from RARS, in which moderately elevated pla telet counts are etten repo rted . This question is morepressing in view of the revised c riteria for RARS-T that lowers the p latele t threshold from ~x lrJl/L to ~450x 1rPlL, in parallel with the revised threshold lor Ef It is important to note that the d iagnostic criteria for RARS-T include not only the Iinding of an elevated platelet coun t in conjunction with anaem ia and ring elderoblasts in the 8 M, but al so mo rp hologicallyabnormal megakaryoc ytes similar to those of ET or PMF. Only a few pat ient s with RARS and plate let counts in the 450,500x W 9/L rang e have be en studi ed for JAK2 mutat ions and in mo st with platelet counts in the lower rang es no mutations have been found . Neverth ele ss, more stud ies are need ed , and we rec ommend to test for JAK2 mutation s in patents who have RARS and pl atelet counts above the normal range . The sum of current information reg arding RAR5-T argu es for its continued placemen t in the MDS/MPN category. but in view of the debate regar ding its precise definition and nature, it is best reg arded as a 'provisional entity" until more data are available, lastly. classification of myeloid neoplasms that carry an isolated isochromosome t 7q and that have less than 20% bl asts in the P8 or BM may prove difficult. Some authOrs suggesl this cytogenetic defect defines a unique disorder characterized

by mixed MOS and MPN features associated with pro minent pseuoo-Percer-Hoet anomaly of me neutroot urs. low 8M blast count, and a rap id ly p rog ressive clinical course. Most c ases rep or ted have a prominent monoc ytic component and meet the c riteria lor CMML, b ut in some, the PB monocyte coun t may not reach the low er threshold fo r that dia gnosis 1708, 14371· In cases that do not fu" ill the c riteria lor CMML or another well de fined myeloid category. desig nation as MOSIMPN. unclassifiable. with isolated isochromosome 17q abnormality, is most ap propriate.

$urTmary of major changes in MDSIMPN 1. Some cases of CMML with eosinophilia are relocated to the category, "Myeloid neoplasms with PDGFRB rearrangement" 2 . The c ategory, "Atypical CML" has been renamed as •Atypical C ML . BCR-ABL 1 negative" to emphasize this disease is not merely a va riant of BCR-ABL 1 positive CM L. 3 . RAR$-T remains as a provisional enlity, classified as MDS/MPN . uncrassiuabre . until furthe r data clarifies its approp riate designation. The crite ria for its recognition have been modified. The platelet threshold has been lowered to ~ 45Ox 1rPll, and meg akaryoc yte s w ith morp hology simil ar to those seen in ETor PMF must be present Myeladysplastic synd romes (MOS) These disorders , usually characterized by the simultaneous prolifer ation and apo ptests of baematopoienc cells that lead to a normal or nvoerceuurar BM bi op sy and PB c ytopenia(s), remain among the most c halleng ing of the myeloid neop lasms for p rope r d iagn osis and class ification , The general fea tures of MOS, as well as specific gu ide lines fo r diagnosis and c lassific ation are outlined in Chapter 5. An impo rtant add ition to the MOS ca tego ry (Table 1.05) is the provision al entity, refractory c ytopenia of c hild hood (RCG), This categ ory is reserved for c hildre n with MOS who have <2% b lasts in their PB and <5% in their 8M and pe rsistent cvtopenia(s) with d ysp lasia , In contrast to MDS with ref rac tor y cvtc oentee in eo utts. the majority of cases of ACC have hypoc ellular 8M bio psy specimens, and the d istinction from acqui red apl astic anaemia and inherited BM fai lure syn dromes is often c hallengin g 117841, An issue appro priate 10 menton at this point is the cntene used for ctassmcatco of myeloid neoplasms in which more lhan

50% of the BM ce lls are erythroid precutan d for which ac ute eryt hroid leukaemia is co nsidered a po ssible dia gnosis. In such cas es. if blasts acc ount for fewer than 20% of WBC in the PB and 01 all nucleated 8 M cells, and for less than 20% of the non-erythroid c ells in the BM (lym phocytes, plasma c ells, etc. are also excluded in this latter calculation), the case is considered as MOS. In this scenario. there is lac k of consens us among mem ber s of the WHO committee as to whether the MOS should then be classified according to !he b last perceotace of all nucleated 8 M cells or according 10the blast percentage of all non-erythroid BM cells. but the majority recommend s that the MOS be classified using the blast percentage of all marrow nucleated cells. Many cases of refractory anaemia with ring sioerobrests as well as refrac tory anaemia have marked eryth roid proliferation and using the b last percentage of the non-erythroid cells lo r classification of such cases might c ause these to be placed in an unnecessarily high-risk category. On the other hand , if there is severe multiline age dysplasia, very bizarre erythroid morphology. and/o r minimal or no maturation to segmented neut roobus. and the btast percentage of total 8 M cells is not sufficienl to place the c ase into a hig h-g rade MOS c ategory, the case shoul d be flag ged tor clin ical co rrelation an d discussion, with ca refu l follow- up (Tab le 1.06 ). More stud ies are needed however to cla rify this controversial issue.

sors.

Acute myeloid leukaemia (AML) AML is a d isease resul ting from the c lonal expansion of my eloid blasts in the PB, 8M , or othe r tissue, It is a heterogeneou s di sease c linically, mo rphologicall y and ge neti cally and may involve only one or Tabl. 1.05 Myelodysplastcsyndromes, Reffacto!y ~nia wlltlll1 iWleage dysfllas48 (RCUD) Reffa<:byanaemia (RA) Refracloty neutropenia (RN) Refradcry ltuQmbocytopenia (RT) Re!fadclry allaemia with ri1gSiderObIasts (RARS) Relractory cytlpenia with ITIJlblineage dysplasia (RCMD) Refractory all8e/l'M8 wiII1 excess bIasls (ME B) MyelodyspIa$llc syncWmewilI1 iSOIatecI dfll(Sq) Myelodysplllsbc syndrcIme. undas.sJliable (J.I>S.U)

C*hood ~ syrw:lrome Pn:MsicnaI nty Refra:t:ry ~ ~ d*hlod (ROC)

Introduction and overview of me classification 01 the myelOId neoplasms

27

... . -

Table 1.06 PMSib1e d~ when erythroid precursors ~50'10 of bone marrow nucleatedcells.

- -_."""""-

% Erythroid ~

Blocdhnarrow findirlgl.

0ltIer f1odlng&

DIagnosis

~ blasts in blood or

Case meets alteria lor AMLwith my8lOdysplasia·

AML With fl'lyelodyspIaSia related changes

of all nucleatedmarrow

~

inmatln IJyIIwid

Few • lit'{ myeIclt:Qsts

""""" ..., """'" matlJflllJon

>5011

' 50'

blasts <m d II

"""""

<20% blasts in blood, blasts <20% of all

"""'"' """""-

related changes

_01" """""'

Miwnall <Wly

fIm.>MiKi1I ~celsll

.."

"""""

... """""

Blasts <20% 01 all in

~roid' cells

PIn 8I)tWIlid IeWemia

-,-....... MDS: classifyMDS

acx:oroing 10 number of blasts in blood and blasts as pen:entIge d II

"""""" """""-

• Erythroid precursors , lymphoid cells andplasmacens aresubtracledfrom a" nlJdeatedmarrowcells to calDJlate the"noo-erythroid eels" in thebone marrow.

all myeloid lineages. Worldw ide the incidence is app roximately 2.5-3 cases per 100,000 popu lation per year, and is reportedly highest in Australia. Western Europe and the United States. The median age at diagnosis is 65 years, with a slight male predominance in most c ountries. In Children less than 15 years of age, AML com prises 15- 20% of all c ases of acute leukaemia, with a peak incidence in the first 3-4 years of lite 1559A, 2463AI. The requisite blast perce ntage for a diag· rosrs of AML is 20% or more mveiobtasts and/or monoblastslpromonocytes and/or meg akaryo blasts in the P8 or BM. The di agnosis of myeloid sarcoma is synonymous with AML rega rdless of the numb er of blasts in the PB or BM, unless the patient has a prior history of MPN or MDS/MPN, in wh ich c ase myeloid sarcoma is evidence of acute transformation . The d iagnosis of AML can also be mad e when the blast percentage in the PB and/or BM is less than 20% if there is an associated t(8;21XQ22;Q22), inv(16)(p 13.1Q22), t(16:16XP13.1;Q22) or t(15;17)(Q22:q 12) chromoso mal abnormality, and in some c ases of acute erythroid IeuI
IntroductIOn and

matur ation, the d iagnosis doe s not necessar ily translate into a mandate to treat the pa tient for AML; c linical factors. including the pace of prog ression of the dise ase, most atways be taken into consloerenon when deciding therapy. Rationa le for the WHO diagnosis and classification of AML The 3rd edition 01 the WHO ctassrncatoo ushered in the era of formal incorporati on of gene tic abnormalities in the diagnostic algor ithms for the diagnosis of AML. The abnormalities included were mainly ch romosomal transiocenoee involVing transcription fac tors and associated with charac teristic cl inical , morpholog ic and immunophenotypic features Ihat formed a ·clinico-pathologic-genelic· entity. As know ledge regarding leukaemogenes is has increased, so has the acceptance that the genetic abnormal ities leading to leukaemia are not only heterogeneous, but complex, and multiple aber rations often coo perate in a multistep proce ss to initiate the co mple te leukaemia phenotyp e. Expe rimental evide nce suggests mat in many ca ses, although rearrangement of genes such as RUNX1, CBFB or RARA that enc ode transcncuon factors impair myeloid differentiation, a sec ond genetic abnormality is necessa ry to promote proliferation or survival of the neoplastic clone (Fig . 1.08) 11135A I. Often. the additional abnormalities are mutations 01genes such as FLT30 r KITthat encode proteins that act ivate signal transduct ion

overvIew of the ctassuceuoo of the myeloid neoplasms

pathways to promote proliferation/survival A similar multistep process is also evident in AMl that evolves from MDS or that has myelodyspl asia-related features, often characterized by loss of genetic material and haploinsufliciency of gene s. Within the last few years, genetic mutations have also been identilied in cytog enetically normal AML 115321. Sane of the rrutations, such as those of CEBPA and perhaps NPM1 invdve transcriplion faclors. whereas erne-e. including those of FlT.J and NRASIKRAS. affect signal transduction. Not only have these mutations led to an unde rstand ing of leukaemoc enests in c ytogenetic ally normal AML, bul they have proved to be powe rful prog nostic factors 115321. In summary, genetic abnormalit ies in AML eluci date the pathogenesis of the neoplasm, provide the most reliable prognoslic information, and will likely lead 10 dev elopment of more successful targeled therapy. One of the challenges in this revision has been how to incorporate important and/or recently acquired genetic information into a classific ation scheme of AMl and yel adhere to tile WHO principle of defining horoogeneOuS, biologically relevant entities based not only on gene tic studies or their prognostic value, but also on clinic al, morpho logic and/or immu nophenotypic studies . This was particular ly prob lematic for the most frequent and progn ostically impo rtant mutat ions in c ytogenetically normal AML, mut ated FLT3 , NPM 1 and CEBPA. They have few or variably consistent mor phologic, irrwnunophenotypic and clinical features reported to dale , and the mutation s are not mutuall y exc lusive. For the most par t, the framework coostructec in the 3rd edition proved flexible enough to incor porate the new entities propo sed by membe rs of the WHO c0mrmttee and the CAC (Table 107). The entities initially described in the subgroup · AML with recurring genetic ab normalnee' remain with only minor mod ifications (Table 1.07) and three more entities, characterized by chromosomal transtocatioos associated with fairly unilorm morphologica l and cl inic al features have been added . Cases with muta ted NPMl and CEBPA are added to the same subg roup as ' provisional entities' ind icating that more study is needed 10 lully characterize and estab lish them as unique entities Although mutated FLT3 is not includ ed as a separa te entity because it is found to be associated with a number of other entities,

Class I mutations

Class II mutations

FLT3-ITD FLT3-TKO KIT RAS PTPN11 JAK2

PML-RARA RUNX1-RUNX1Tl CBFB-MYH11 MLL fusions CEBPA NPM11

Proliferation and/or survival advantage; not affecting differentiation

its siqrsbcance should not be uoderestmated, and it is essential that it be tested for in all cytog enetically normal patients, including those who demonstrate NPM 1 and CEBPA mutations. Modifications have been made in the subgroup previously ter med "AM L wi th multilineage ovsprasta." Initially, it was envisioned that this g rou p would encompass biologically unique AML charac terized by MD$ -like fea tures, in cl ud ing unfavourable cytogenetics, a higher lnc toence of ove rex pressfon 01 multidrug resistance gfycoprotein (AS CS 1 or M DR-1) and an unfavou rable respo nse to therapy. Dysplasia in ~50 % of ce lls in tw o or m or e heematop oienc lineag es w as used as a universally-ap plic ab le surrogate m arker for the myelodysp las ia- re late d featu res . Although the c linical sig nificance of th is grOl.lp has been verified in so me stud ies , it has been d isputed in othe rs in w hic h multivariate anal ysis showed tha t m ultilin eage dyspla sia had no independent significance in predi c ting clinical outcome wen cytogenetic findings were mc orporated in tne analysis 169, 869, 2356, 24651. Accordingly, in this revision, this group has been renamed as "A ML with myelodyspl asia- related changes," Patientsmay be assigned 10this ca tegory if they evolve Irom previously documented MOS. have specific myelodysplasiarelated cytogenetic abnormalities. or lastly, if they exhibit mo rphologic mu ltilineage dysplasia as def ined above. Pat ients in Ianer group with a normal karyotype

to their g enetic a bno rm alities, but until more data are available, we recommend thai such c ases be classi fied as AM L with m yelodysplasia-related c hanges (multilineage dysplasia) with the muta tional status of the gene appended, Therapy-related myeloid neoplasms (t-AMLJ

t·MDS and t-AMlIt-MDSlMPN) remain in the revised classificatio n as a distinct subgroup. How ever, most patients who develop therapy-related neoplasms have

Impaired haematopoietic differentiation and HqUent .poptos~

.ub-

should be evalu ated for FLT3, NPM I and CEBPA rnutanons. Cu rrently, however, the clinical significance of a mutalion of one or more of these genes in the setting of mo rpholog ic multilineage dysplasia is not clear. Future studies may well prove that such cases are better classifie d according

received therapy with both alkylating agents as well as with topo isomerase II inhibitors, so that a division according to the type of the rapy is usually not pr actical and not recommended in this revision. It has been argued that 90% or more 01 cases with I-AMLIt-MDS or t-AMl/t-MDSI MPN have c ytog enetic abnormalities similar to those seen in A ML with recurrent genetic abnormalities or AML with myelodyspiasia-relaled features and could be assigned to those categories. However, except for patients w ith t-AML who have inv(16Xp 13.1q22), t(16;16XP13.1;q22)or t(15 :17Xq22;q 12), in most reported series those w ith therapy-rel ated myeloid neop lasm s have a significantly wor se c lin ical outcome Ihan the ir de novo counte rp arts with the same genetic abnormalities 136,

Table 1.07 Acutemyeloid leukaemia andrelatedmyeloidneoplasms, Atutt myeloidIeukaemi,with recurrent gtllllIlIt Ibnormalitles AMLwith ~8;2 1 )(Q22:Q22): RUNXt-RUNXm AML with inv{16)(p13.1q22} c. \(16:16Kpl3.1:q22); CBFB-MYHIt APl with \(15;17)(q22:Q12); PML-RARA AMLwitht(9:11){p22:q23}: MLLT3-MLL AMl with t(6:9)(p23;Q34): OEK-NUP214 AMl with inv(3KQ21Q26.2) ort(3:3J(Q21;q26,2); RPN1·EVl l AML (megakeryoblastic)with 1(1;22)(p13; q13): RBMI5-MKL 1 Provisional entity:AMl with mutated NPM1 Provisional entity: AML with mutated CEBPA Acutemyeloid leukaemia with mye!ody,plilil-related changes Therapy-related myeloid neoplil5m, Acutemyeloid leukaemia, no! otherwl$l spec;lrted AMLwith minimal diffe!lll1tialiorl AML without maturation AMLwith mallJ"aUon Acute m~ leukaemia Acute roonoblasticJmooocytic Ieukaemla Acute ~ IeukaelBas PIse erythroid leukaemia EIythroleukaemia, 8I')1hroidfmyeloid Acute megakaryoblas.lic Ieukaetnia Acute basophl1ic Ieukaen'Ha Acute panmyeIosis with myebfibrosis Myeloid sarcoma Myeloid proliferations related to Down syndrome Transaent abnormal myelopoiesis Myeloid leukaemia ISSOCiaIed with Down syndrome Blastic plil5maC}'loid dendritic u1llll1oplalms

Introduction and overview of lhe classification 01 the myeloid neoplasms

29

227 , 1886~ 2034 , 204 1}, suggesting some biological differences between the two groups. Fur thermore, the stu dy of therapy-related neoplasms may provide valuable insig ht into the pat hogenesis of de novo d isea se by p rov id ing c lues as to wh y a few pat ients de ve lop leukae mia wher eas most p atients treated with the same therapy do not. Therefore, patients with therapy- related neoplasms should be de sig nated as suc h, but the specific c ytogenetic abnorma lity shou ld also be listed, for example, "therapy-related AML with «s,11}(p22;q23)". Acute myeloid leukaem ia , not otherwise specified, encompasses those cases that do not fu lfil the spec ific criteria of any of the othe r entities. This g roup accounts for only 25-30% of a ll AM L that are not assigned to one of the mo re specific ca tegories. As more genetic subgroups are iden tified , the num ber of pa tients that fall into the AMl , NOS c ateg ories w ill cantmoe to diminish . Of note is that infor mation used to characterize the subgroups within this c atego ry, suc h as epidemic-logic or clinical out come , is oft en ba sed on older stud ies tha t inc lud ed patients now assigned to d ifferent diagnostic ca teg or ies. and may not be reliable. Althou g h the p roposal to collapse th is category into fewer subgroups has bee n made. the notion that some of these may yet be found to be associated with spec ific genetic or b iologic abnormalities argued to maintain this category. Myeloid sarcoma, an extramedullary tumour mass consisting of myeloid blasts, is inc lud ed in the classifica tion as a d istinc t pa tholog ic entity. How ever, wh en mye loid sa rco ma occu rs de novo, the d iagnosis is eq uiva lent to a d iagnosis of AML . and fu rthe r evaluation , including genetic analysis, is necessary to determine the approp riate cl assific atio n of the leukaemia 117421. When the PB and BM is concurrently involved by AMl. mese tissues may be used for ana lysis and furthe r

30

classification . However, when the myeloid sarco ma precedes ev idence of PB or BM invotvement. the irrvnunophenotype should be ascertained by flow cytometry and/or irrvnunohi stoc hemistry, and the genotype determined by cytogenetic analysis, or in the absence of fresh nssue. by FISH o r molecular ana lysis for recurrent g enetic abnormalities. Myeloid sarcoma may also be the initial ind ic atio n 01 relap se in a pat ient previously d iagnosed With AM L or may indicate disease progression to a blast phase in pat ients with a pr ior d iagnosis of MDS, MDS/MPN o r MPN. Lastly, the unique featu res of Down synd rome- related myeloid neoplasms has been rec og nized in a separate listing that incl udes transient abnormal myelopo iesis and mye lo id leukaemias (MDS/A ML ) assoc iate d with Down synd rome.

Summary of major changes In AML 1. AML with recurrent genetic abnorma lities, a ) AML w ith t(8;2 1)(q22;q22), AMl w ith inv( 16}(p 13 .1q 22 ) or I( 16; 16}(p 13. 1;q 22), and APL with t(15;17}(q22 ;q 12) are considered as AM L regard less of bla st count; for all othe rs, b lasts 2:20% of P8 or of all nucleated BM ce lls are req uired . b) In API... with1( 15;17)(Q22;q12); FM..-R.AR4, varia nt RARA uenslocaucos with other partner ge nes are recognized separately ; not all hav e typica l APl featu res a nd some have ATRA resistance . c ) The termer cat egory, AM L with 11q23 (MLL) abnormalities has been re-defined as -AML with 1(9;11)(p22;q23); MLLT3-MLL". Balanced transtocanons other than that involving MLLT3 should be specified in the di agn osis. Ot her abn or malities of MLL , such as partial tande m du p licatio n of MLL should not be placed in this categ ory. d) Three new cytogenetically delined entities are ad ded : AML with t(6;9)(p23;q23); DEK-NUP214, AML with inv(3)(q21q26.2) or t(3;3)(q21 ;q26 .2); RPN1-EV/1; and AMl (megakaryoblaslic) with t(1 ;22)(p 13;q 13) ; RBM15-MKL t.

Introduction and ove rview of the classification of the myeloid neo plasms

e) Two p rovi siona l ent ities are added: AML with mutated NPM1 and AMl with mutated CEBPA. Although not included as a distinc t entity, examination lor mutations of FLT3 is slron gly rec orrwnended in all cytogenetically normal AM L. 2 . AM L with mye lodysplasia-related changes . a) Name changed from · AML with rru llilineage dysp lasia". b ) Cases of AML are assig ned to this categ ory if 1) they have a previous history of MDS and have evol ved to AML , 2) they have a myelodysp las ia-related cytogenetic abnormality, or 3) if ;<:50% 01cells in two or more myeloid lineages are dysplastic , 3. Therapy -related myeloid neoplasms. Cases are no longer subcategorized as "alkyl ating agent related " o r ' tccoisomerase tl-intubttor related " or "other", 4. AM L, NOS. a) Some c ases previously assigne d to the subcategory of AMl. NOS as acute erythroid leukaemia may be re-classihed as AML with myelodysplasia-related changeS. b ) Cases previously ca tegorized as AML NOS. acute megakaryoblastic leukaemia should be placed in the appro priate ge netic category il they are associa ted With inv(3)( q2 1q26 .2) or t(3:3)(q21 ;q26.2); RPN1-EVlf, or AM L (megakaryoblastic) with t(1;22)(p 13;q 13); RBM15-MKL 1.1JcM'n synd rome related cases are excluded from this ca tego ry as well . 5 . Myeloid proli ferations related to Down syndrome. New ca tegory to inc or porate trans ient abno rmal mye lopoies is as we ll as myeloid leukaemia that is Down synd rome related MDS related to Down syndrome is conside red biolog ically identical to AML related to Down syndrome.

,

.

,

/~ •

Chronic myelogenous leukaemia, BCR-ABL 1 pos it ive

Definition

Chronic myelogenous leukaemia (CMl) is a myeloproliferative neoplasm thai originates in an abnormal plur ipotent bone marrow (8 M) stem cell and is consistently associated with the BCR-ABL1 fusion gene located in the Philadelphia (Ph) chromosome {154. 1455 . 1607, 18841. Although the in.tial major finding is neu trophilic leW
ICD-O code

9875/3

(WBC) count performed at the time of a routine med ic al exa mination is found to be abnormal 1486 . 755, 1942/. Common findi ngs at p resentation inc lude fatigue. wei ght loss, nig ht sweats, splenomegaly and anaemia 1486. 19421. Atypical presentations include marked thrombocytosis unaccompanied by a significantly elevated WBC count as well as initial presentation in BP without a previously detectable C P 134 ,486. 17301. In the absence of curative treatment most patients progress from CP to BP either suddenly or through a transitcoat AP. although some die in AP without progression. The transformed phases are generally accompanied by worsened performance status and by symptoms related to severe anaemia, throm bocytope nia or marked sp lenic enla rgement 17551.

J W _Vard iman J ,V. Melo M . Bacc arani J . Thiele

for less than 5% of the marrow cells in CP and 10% or more indicates disease progression 14821- Erythro id precu rsors vary but erythroid islan ds are usually reduced in number and size {222 11 . The megakaryocytes of CML are smaller than normal and have hypolobated nuclei ("dwarf megakaryocytes"). Althou gh they may be normal or slightly decreased in number. 40-50% of patients exhib it moderate 10 extensive megakaryocytic proliferation 1296.775,22 15.222 1). The initial biopsy

Synonyms Ch ronic gr anulocytic leukaemia ; ch ronic myeloid leukaemia

Epid emiology CM L has a wo rldwi de annual inci dence of 1- 2 cases per 100 ,000 po pul ation. The

disease can occur at any age, but the median age at diagnosis is in the 5th and 6th de cades of life There is a slight male oreoorno ance 1755, 1053 , 1826 1. Etiology Factors p red isposing to CML are unknown. Rad iation exp osure has been implica ted in some c ases 1226, 4791. There do es not appear to be an inherited di sp osition. Sites of Involvement In CP, the leukaemic are minimally invasive and the proliferat ion is la rg ely confined to naerocoieuc tissues, primarily b lood . BM an d sple en although the liver may be infiltrated as well . In BP, extramedullary tissues, including lymph nodes, skin and soft tissues may show infiltration by blasts 1486,1029,15341.

cens

Clinical featu res Most patients are diagnosed in CP which usually has an insidious onset. Nearly 20-40% of patients are asymptomatic and are diagnosed when a white blood cell

· 32

Myelop",lile"tive neoplasms

Morphology Chronic phase (CP) In CP the peri pheral blood (PB) shows leukocytosis (12-1 000x 1()lI1L. median - 1OQx1CPIL) d ue to neutrop hils in different stages of maturation wit h peaks in the pe rcent of mye locyt es and seg mented neutrophils 1486, 755, 1164, 1942, 20671 . There is no significant dysplasia 11 89 , 2458 }. Blasts usua lly account tor less than 2% of the wac 1189, 206 7l. Ab solute basoph ilia is invariab ly pr esent and eosinop hilia is common (2067l. Ab solut e monocytosis may be p resent but the frac tion of rnonocvtes is usua lly <3% (189 1. except in rare c ases assoc iated with the p 190 BCA -A8 L 1 tsoto rm. in whi ch case monoc ytosis is nearly always present and con fusion with c hronic myelom onocytic leukaemia is possib le 114581 The platelet co unt usually rang es tram normal to gre ater than 1000 x1()91L and thrombocytopeni a is uncommon 119421. The 8 M cellular ity is incr eased due to g ranulocytic proliferation with a maturation pattern similar to that in the blood 1486, 1534 1. In biopsy sections the paratrabecutar Cuff of imma ture neutrophile is often 5- 10 cells thick in contrast to the normal 2-3 cell layer and 1he mallie neutroph~s are situated in the intert rabecutar areas. Eosinophils may be prominent. Blasts usually account

F""i-2.o1 CML. ctvoricphase. A ~ blood SlTlllit" showing Ieukocy1osis and neu1rophiIic eels at varyI1g stages d malnIKn 8asqJIiIia is ~ ttl dyspIasiI iii ~ B Bone marrow biopsy $I'lOw$marked hypeIc:eIIuIanty due to granulocytic prolderabon. C The megaka/yOC)1es in CMl are c:harac:leilsbcaly ~ ItIan ~ megakaryocyIes.

stoNs moderate to marked reticulin fibrosis in approximately 30% 0 1 cases wh ich often correlates with inc reased numbers 01 megakaryocytes, larger spleen size and reportedly. a worse p rognosis 1293 , 540, 1217.2215. 222 11. Pseudo-Gaucher cells and sea-blue histiocytes are commooly observed secondary to inc rease d cell turnover and are de rived 'rom the neoplastic clone 135. 22271. More than 80% of patients have sign ifican tly redu ced or no iron-laden macrop hag es 120451. In CP the spleen is enl arge d du e to inliltration of the red pulp co rds by g ranulocytes in differe nt mat uration sta ges , A similar infiltrate may be seen in the hepatic sinusoids and port al areas. Disease progressionltra nsformed phases in CMt The recognition of di sea se prog ression from CP to the transfo rmed stages of AP and BP is impo rtant for prog nosis and treatment, but the c linica l and mor phologic boundaries between the se stag es olten overlap and the parameters used to identify them have va ried among di fferent investigators [118, 293, 481 , 482, 829 , 1100.194 11 . Furthermore, there are only scant data relevant to d isease pr ogre ssion in the era 01 protein kinase inhibitor (PTKI) therapy. Bone ma rrow c hanges following short and long term PTKI trea tment have been extensively stu died showing a reduction 01 g ranulocytic eelkJlaflly. normalization of megakaryopoiesis, regression of fibrosis and inc rease in eccctosis associated with decrease in proIilerative act ivity 122191.

Acce lerated phase (AP) In the 3ld ed ition of the WHO Classifica tion 110391, it was suggested that the d iagnosis of AP could be made if any of the follOwing paramete rs were present: 1) persistent or inc reasing WBC (> 10x1()9!L) and /or pers istent or increasing splenomegaly unres ponsive to the rapy, 2) persistent mrontocvrose [> 1000xlcYlL) uncontrolled by therapy, 3) pe rsistent thrombocytopen ia

« 100xl()9!L ) unrelated to therapy, 4) clonal cytogenetic evolution oc curring afte r the initial diagnostic karyotype. 5) 20% or more basophils in the per ipheral biooo . and 6) 10-19% myeloblasts in the blood or 8M. Criteria 1- 4 are more likely 10 be ass oc iated with transition from CP to AP, whereas c riteria 5 and 6 more frequently indicate a transition between AP and SP. Although modifications to

Fig. 2.04 CUL dVonicphase, "Pseudo-GaiI:: eels in CML.. A Pseucb-Gauchef cells In COITIllOl'Ily obsenoed i'l the marTOW aspIate$ aI pabents WIth CML. B They Ina)' also be ~ as loamy or strialed eels in ITIlI"I'OW biopsy sedions. TheseI'listo:)"es are seaJndary " increased celllm::Ner. <We del'ived from the neopIaslic dln and easily ~ from the &mal rnagakaryoc:yte tt-" rn8f9I").

Chronic myelogenous leukaemia. BCR-ABL I positive

33

,

A

Fi9. 2.05 Splenomegaly 11 CML A The gross appearara of Itle spleen is solid and uniIonnIy deep red, although areas of inlartt IlI8)' appear as IlghIer aIloured regions, 8 TIll red pljp disbibubon of!tie infiltrate usually (XIll1lfesse5 alldobhlefates lhe while pulp. C The leukaemiC cells are present in!he SInuses as wei asin!he spleniccools of lhe red pulp.

these criteria have been suggested and different criteria proposed by others [4821. it is recommended tha t the paramete rs liste d abo ve sti ll be conside red as evide nce of d isease pr ogression. Whether they or other parameters, such as drug resistance, necessarily ind ica te shortened survival times or imminent blast nanetorma hon is not c lear in view of the efficacy of current trea tment strategies, and more studies are needed to accurately identify criteria for AP in the face of PTKI therapy. Often in AP the BM is hypercellular and myelodysplasia is seen 11534, 24581. The increase in myeloid lineage blasts may be readily appreciated with stains for CD34 performed on the biopsy 116501. large clusters or sheets of small , abnormal megakaryocytes associated with marked reticu lin or COllagen fibrosis are commonly

34

Myeloproliferative neoplasms

observed and may be considered as pres umptive evidence of AP. although these find ing s are almost always associated with one or more of the othe r c riteria listed ab ove 1289, 293,15341. The find ing of lymphoblasts in the blood or ma rrow is unusual in AP and should raise concern for lymphoblastic BP 15571.

cases the blasts are Iymphoblasts 1557. 1138. 1558, 1706. 1913,24541. In BP the blas t lineage may be ob vious morpho logic ally bu t often the b lasts are p rimitive or

heterogeneous and cytochemical and immunophenotypic analysis is recommended. If accumulations of bl asts occupy focal

but significant areas of the 8M , e.q. an Blast phase (BP) The BP may be d iagnosed when 1) blasts equal or are greater than 20% of the PB WBC or of the nucleated cells 01 the BM, or 2) when there is an extramedullary blast proliferation. In approximately 70% of cases. the blast lineage is myeloid and may inc lude neutrophilic . eosinophilic. besophilic . monocytic, megakaryocytic or erythroid blasts or any combination thefeof. whereas in approxi ma tely 20-30% of

entire intenrabecular region, a presump-

tive dtaqrosrs of BP is warranted , even if the remainder of the 8M biopsy shows CP 12891. Immunohistochemical studies lor CD34 andlOf terminal deoxynucleotidyl transferase (TdT) may help in distinguishing such foci of blasts in BP from the loci

01 promyelocytes and myelocytes thal often are prominent in paratrabecutar and perivascular regions during CPo Extramedullary blast proliferations most

v- --

0 0

II

c:orrvnonly present in the sk in. lym ph node, spleen. bone or central nervous system, but can occur anywhere, and may be 01 myeloid or lymphoid lineage 110291.

Irrm.oopheootyp

The oeutrophils in CP have markedly decreased neutroph~ alkaline phosphatase {16401. In myeloid BP the blas ts may have strong. weak or 00 myetoperoxidase activity but express antigens associated withgranulocytic, monocytic , megakaryoblastic and/or erythroid differentiation. In the majority of c ases the myeloid b lasts will express one or more lymp ho id an tigens as well {557. 1138 , 1558 , 19 13 1. Mos1 cases of lymphoblastic BP are precursor B in origin but cases of T lym phoblastic origi n also oc cur p 138 , 1558 , 19131. In lymphoblastic BP, one or more myeloid antigens are co-expressed on the ¥nphoblasts in the majority of c ases, Ap proximately 25% of BP cases fulfill c riteria for mixed phenotype acute leukaemia (MPAL) 1557. 1138. 1558, 19 131, but these are considered as exa mp les 01 BP and are different from de novo MPAL, Genetics At diagnosis. 90-95% of cases of CM L have lt1e characteristic t(9 ;22)(q 34 :q 11,2) reciprocal translocation tha t resu lts in the Ph chromosome [der (22q)] 11607. 18841. This translocation fuses sequences of the BCR gene on ch romosome 22 with regions of the ABL 1 gene from c hrom osome 9 11541. The remaining cases either have variant trens'ocauons that involve a third or even a fourth chromosome in addition to ch romo somes 9 and 22 . or neve a cryptic translocation of 9q34 and 22<;11.2that canno t be identified by reotile cytogenetic ana lys is. In suc h cases, 'tie BCR-ABL 1 fusion gene is present and C¥l be detect ed by FISH analysis . AT-PCR Of Southern blot tec hniques 114541. The

site of the breakpoint in the BGR gene may influence the phenotype of the e nsease 11454) . In CML, the breakpoint in BGR is a lmost always in the major breakpoint cluster region M ~8C R . spanning exons 12-16, (previously known as b1-b5) and an abnormallusion protein, p2 10. is formed wh ich has increased tyrosine kinase activity {1454 1. Rarely, the breakpoint in the eGR gene occurs in the 1J-8CA reg ion , spanning exons 17-20 (p reviou sly known as C1-C4 ) and a larger fusion prote in, p230, is encoded . Patien ts with this fusion may demonstrate prominent neutrophilic maturation and/orconspicUClUS throm bocytosis {1454 , 1685 1. Although breaks in the minor breakpoint region, m-BCR (BCR exons 1-2) lead s 10 a shorter fus ion p rotein (pl90) an d is most freq ue ntly associ ated with Ph positive

ALL , small amounts of the p190 transcript can be detected in >90% of patients with classical p210 CML as well, due to alternative splicing of the OCR gene 11907, 23061 . However, this breakpoint may also be seen in rare cases of CML that are d istinctive for having increased numbers of monocytes and thuscan resemble chronic myelomonocytic leukaemia 114581. The enhanced tyrosine kinase activity of BCR·ABL 1 is responsible for coosntunve activation of several signal transduc tion pathways 15391. This resu lts in the leukaemic phenotype of CM L ce lls which encompasses deregulated proliferation , red uced adherence to the 8M stroma and defective apoptotic response to mutagenic st imuli . The understand ing of the abnorma l signaling in CML cells led to the design and synthesis of small

F"tg. 2.08 0r.I... myeloid bla ~ ptlase. A ~ l:tlodofl pllientWllh myeIoidbllst phase . Tht ma;onty oftle "'* l:tlod oats
Chronic myelogenous leukaemia, BCR-ABL 1positive

35

A Penphetal blood smear. 8 Bone malTOW biopsy C Mam:lw aspirate smear.

Fig. 2.10 0Al.. myeloid bIasI phase , in 8Ile~ site . A,8 l~ node biopsy obtained from iI pabent with a tIiStor'y 01 CML lor 3 ~_ The lymph node ¥d1iteclln is Iatgely eIIaoad by a proIrfefatlon 01 medir.Jmkllarge Sized cells. C l~ im~ confirms the myeloid lineage ollhe blasts,

molecules that target the tyrosine kina se ac tivity of BCR -AB L 1, of which imatinib was Ihe first to be successfully used to treat CML 1616, 6 171. lmatinib competes wi th ATP lor b ind ing to me BCR-ABL 1 kinase domain thus preventing phosphorylation of tyrosine resid ues on its substrates, Interruption of the oncogenic sig nal in this way is very effective for control of the d isease , particularly when used early in CPo However, the eme rg ence of sub-c lones of leukaemic prog enitor c ells

with point rrutations that prevent the bnding 0 1 the inhibilOf to the kinase domain of BCR-ABL 1 can lead to d rug resistance, p articularly in AP and BP 11103. 23731. The second generation compounds nilotmib and d asatinib can circumvent this form of d rug failure in the case of most but not all kinase domain mutations assoc iated with imatinib resistance 11103, 2373} . The mol ecu lar ba sis of d isease tran sformation is still large ly unknown . Progression is usua lly associated w ith clo nal evolu tion

1657, 1487, 14881, and at the time of

transformation 10AP or BP, 80% of patients demonstrate cytogenetic changes in additlOO to the Ph ch romosome, such as an extra Ph, . 8, . 19 , or i(17q). Genes shown to be altered in the transformed staqes include TP53, RB1, MYC, p1 f7'"""" {CDKN2Aj, RAS, AML 1 and EVil , but their role in lhe transformati on , if any, is currently unknown 1821 , 1455 , 14871- The recent introduction of gen ome -wide expression profiling by mrc roarray tech nolog y has started to reo vea l othe r cand idate genes assoc iated with the ad vanc ed stages , and has also revealed similar gene expression patterns betwee n AP and BP, suggesting that the genetic even ts lead ing to transformation in AP and BP occur in late CP or early AP 11608, 1624 , 18031. Postu lated celt

of origin

It is curren tly accepted that CML-CP originates from a plu ripotent 8M stem eel. However. disease progression may originate in more corrvn itted precursors lhan previously supposed, as myeloid BP has Fig. 2.11 Fluorescence il SItu hybAckzalion (FISH) with dual color and dual fusion probe on a normal metaphase eel (A) 8Ild metaphase preparaOOn (8) from a patient witht(9-,Z2)(q34;q11 .2~ AWal alia' anddual fusion InInsloc:aIion probe is used (VysisR corporatlon). The ABL I and BCR probes are labeled with SpectrumOrange and SpectrumGreen respecIJYeIy. In J'lOfmllI eels (A) two orange Signals represenbng the ABL 1 gene al 9q3.4 and two green SIgnals representing the BCR at 22(111.2are &hown. In the pall&nl's CMl cells (8) one orange (J'lOfmllI 9q34), onegreen (normal 22q11.2) andtwo orangeJgteen(yelOw) signals, repl"esenOOg derivative 9q3.4 and 22q11 ,2, respedively, are detected.

36

Mye loproliferative neoplasms

been repor ted to involve the g ranulOcytemac rop hage prog enitor pool rather than the naerroooletc stem cell pool 114741. Whether the same applies to lymphoid BP is not know n,

l

L-

AlP-bind ing com etitors

\m t?9;22)(q34 ;q11.2) ---.J

BCR.ABL1

813a2 .1402 p210 A

B

rig. 2.1 2 ... SC1lemabc representabDn of !he U:9:22) chromosomallranslocabon, me fusion mRNA ~ encoded by !he BCR..-&.1 tl)trid gene geoeqted in !he 22q. or

F'IlIacletiIlia (PIli chi OliiO«Jmll , and hi nnslated BCR-ABL1 kl5ion protOO, ...nose oncogenic ptqlllrties I'e/y pl'lIl'IiIdy' on ts conslllUOVely actrvaled tyrosne U1ase en:xlded bytie s..:~ I ISH1)domain i'llicatedby ltle red Orde. Some of It1e oltlef ~ UlcWlaI don'IaI'S CQ'1tnlluted by tie BCR andABLl pcnons oIlhe Oi iCClPi oceifl n sI'lowfl. These n 1Ile dMnensaliOn domain (00): Vl n wtlich is !tie allloptlosphoryllion s<1e crucial lor binding to 008-2; the ptIospho-Ser and -Thr SH-binding dorr'I<Wl; a region turdogaIs tI Rho guarlIdne ru:Ieoticle exet.ange laclots (Rho-GE.F): ee ABll regoJa1o"y SH3 and SH2 domains; Y412 as !he map Slt8 r:I ~ wiltlillhe StU IrNse dcrnarI; ru::i8ar kx:att:alitw, J9IaIs (tt.S) and lhe DNA- and adn-I:imng danains.. B Mectllnsm 01 adIion 01 acR-A8I..l \yrtliW1e kNse ~ 'M1ereas h physdogicaI tning rJATP III its poDelllbn BCR-ABLllO phosphorylate seIeded tyrosWle residues onrts SI.tIslrales (left
t,..

~ and predictive factors

Based on historical data prior to any effective therapy, median survival times in CML ranged bet ween 2-3 years {7671_ With conventional c hem othe rapy (bus ulfan, Hydroxycarbami de) me dian survival

was about 4 years, but progression to AP and BP was only slightly delayed w ith 10year overall survival (OS) less than 10% 1767, 1948, 2022). Interfe ron-u -based regimes delayed prog res sion signilicarttly, with median survival of approximately 6 years and to-yea r OS of - 25% 1115l. With allogenic stem ceutransotant. 1O-year OS ranges between 10 and 70%, depending on d isease phase, patien t age

and donor ty pe 1116 , 828, 20221. Thre e pr ognosl ic models ba sed on baseline pr ognostic variables including age , spleen size, p late let count , the percentage of mveiobrasts in PB as well as the percentage of basophils and eosinopnns in the PB allowed the c alc ulation of rela tive risk, hence of the life expectancy, of patients treated with conventional chemotherap y an d inte rferon 1905, 1101 , 2044 1 and w ith im atinib { 116, 6 15), b ut not those treated wi th all ogene ic stem ce ll tra nsp lant. Som e stud ies have show n that the p redictive va lues of these models can be fur ther improved by the inclusion of morphologic parameters, particularl y the

pres ence or abse nce of m ye lofib rosis 1292 , 293, 12 17, 12 181. Pretra nsplant myelof ibrosis ha s been reported to be associat ed wit h a delayed or failure of naematoooenc reconstitution 1293, 22071. How ever, in the current era of PTKI therapy, the most important prognosti c ind icator is the response to treatment at the haematologic , cytogenet ic and molecular level 1116/· Cu rrently the comple te cytogenetic response rate to ima tin ib is 70-90%, with a 5-year progression free survival and OS between 80 -95% 1116,

6151

Chrooc myelogenous leu kaemia, BCR-A BL 1 po sitive

37

Chronic neutrophilic leukaemia

B.J . Bain

RD. Bru nning JW. Vardiman J . Thiele

Definition Chronic neutrophilic leuk aemia (CNL) is a

rare myeloproliferative disease . cha racterized by susta ined peripheral bloOd (PB) neut rop hilia. bone marrow (8M) hypercellulanty d ue to neutrophilic granu locyte proliferation. and hepatosplenomegaly. There

is no Philadelphia (Ph) chromosome or BCR·ABL 11usion gene, The diagnosis reo quires exc lusion of reac tive neutrophil ia

and other myeloproliferative neoplasms, ICD.Q cod e

996313

Epidem iolog y The true incidence 01 CNL is unknown ,

but only about 150 cases have been reported. In one study 01 660 cases of chronic leu kaemias of myeloid origin. not

a singlecase 01 CNL was observed 120031. CNL gene rally affects olde r adults. but has also been reported in adolescents 1909, 2474, 2504}. The sex distflbulion is nearly equal 1231 . 640, 2474, 25041.

Etiology The cause of CNL is not known. In up to 20% of reported c ases, the neutrophilia wa s associated with an und er ly ing neoplasm , most usua lly multiple my e loma 1355, 58 4, 20761. To dale, no cases of CNL as sociated with myeloma have been rep orted in wh ich a clonal c hromosomal abnormal ity o r evid enc e of cronauty by molecular tec hniques has been co nvinc ingly d emons trated in the neutroonns 120771. II is thus likely that most cases of CNL associated w ith mye lom a are not autonomous prolif erations of the neuuophi ls , but are secondary to abnorma l cvtokme release from the neoplastic plasma cells or othe r cells regulated by the plasma cell population . The same may be true of C NL associated with other neoplasms. However, it should be noted that evolution to acute myeloid leukaemia (A ML) occurred in one pat ien t with CNL associated with multip le my eloma {5841 . Sites of involvement The PB and BM are always involved, and the splee n and liver usually show leukaemic 38

Myeloprol iferat ive neoplasms

..

. :t

I

Fig. 2.13 Ovtnc newophIc ~ _ A The neutrophiia dIatac:IeristIc oIltie ~ t*:xx1 il CNL B The. . granUatiolllXlr!JTllldy obset'o'ed. Reproduced from Anastasi and ~ (3SAJ. C The bone rnatfOW asprDt SI!W der!lcmIrates neutrophil proWerabOn from myebcytes to ~ forms 'Mlh toO: granu/abOn, 1M no olIW" s9'ificant abnormaibes. D The bone marrow biopsy specimen is hyperceWar, showing a markedly eIevMld myeIoicI:erylM:lid ratio WI!h increased IIJrmers of nNrophk, partK:tarly maturesegmented bms.

infil trates 12257. 2474 . 2504 1. How ever, any tissue may be infiltrated by the rectrophils 12257 , 2474, 25041. Clinical features The most constant c linical feature reported is sp lenome ga ly. whi c h may be symptomatic . Hep atomeg aly is usu ally present as we lt 12474 , 2504 1 A history of b leed ing from mu cocutaneous surfaces or from the gastrointestinal tract is reported in 25-30% of patients 1909, 25041. Gout and pruri tus are other possi ble symptoms 12504 1.

--

The PB smear shows neu trophilia w ith a wh ite b lood celt count ~25x l ()9/L.. The neutrop hils are usuatty segmented, b ut there may be a substantial increase in band for ms as we lt. In almost alt cases, neutrophil precursors (pn::rnyeIocytes, myeiocytes. metemyetocytes) account for fewe r than 5% of Ihe white cells, but oc casionally, they may account f()( ~p to 10% 1231 ,640 , 909 , 2474. 25041. Myeloblasts

are almost never observed in the blood The neutrophils often ap pear toxic . with abnorma l, coa rse granules, but they may also a ppear normal. Neutrop hil dysplasia is not present. Red blood ce ll and platelet morphology is usually normal. The 8M b iop sy shows hypercel lular ity w ith neutrophilic p roliferat ion. The myeloid:e rythroid rat io may reac h 20 : 1 or greate r Myelo blasts and p rom yeiocytes are not inc reased in percentag e at the time 01 diagnosis, but the percent of mvelocvtee and mature neutrophils is inc reased. Erythroid and megakaryocytic prol ifera tion may also occur 1231, 24741. Sig nific ant dysplasia is not present in any 01 the cell lineages and, if found , another diag nosis. such as atypical chronic myel oid leukaemia . should be considered (See Chapter 4). Retic ulin fibros is is uncommon 1231, 640 , 2474, 25041. In view of the reported frequency of CNL in association with multip le myeloma, the BM should be examined for evi dence of a pl asma ceu neoplasm 1355, 584, 2076, 20771. If plasma

cell abnormalities are p resent, clona lity 01 the neutrophil lineage should be supported by c ytog enetic or molecular tec hniques be fore making a diagnosis of CNL. Splenomegaly and hepatomegaly result from tissue inliltration by the neutrop hils. In the spleen , the infiltrate is mainly confined 10 the red pulp; in !he liver. the sinusoids, portal areas or both, may be infutrated 12474, 25041.

Cy\ll(:hen>stry The neutrophil alkaline phosphatase score IS usually norma l or inc reased. but no OCher cvtocoencarabl"l()(mahty has been fepor1ed

"""""'"

Table 2.01 Diagnostc criteria lor chronic neu troph~ iC Ieu ~aemia. Peripheral blood leukocytosis, wac <:25xW/L 5e9meflted neutrophils andband folms Bftl >80% of wtlite bloodceas ImmatlKEl granu~es (promyelocytes, myebcytes, metamyelocytes) <10%ofwtllte bloodcells Myeiotllasts<1 %of I't11ite blood cells

2.

HyperceftlJar bone matTllW biopsy Neutrophilicvanuloc)1es increased II'l pen;enlage andnumber Myeloblasts <5% 01 rWeated IT\CIl'ltI'IIf' cetIs NeutmplVliC maluration paneronormal Megaka ~ normal or left shifted

3.

Hepatosplenomegaly

4

No ideflt!f.able caJ5e lorptrysioIogic neutrophika or. if presanl, denw:lnslration 01 donaIiIy ofmyeloid eels by cytogenelic or molllo.I* studies Noinfecbous or J1lIarnmaIory JlItlC8SS

5

NoPtlitadelphia cMlmo5ome or BCR-ABL 1 Mlon gene

6.

No ~ d PDGFRIo , PDGFRB or FGFR1

7.

No ~ of polyc'y1tlaenia vera. pti'Tlaty A'I)'elofibmsis or essential ~

8.

Noevidence 01 a myebcIysplaSllC ~ or a myeIodyspIasIicImyeloproleraliw neop(asms No gtafUcqtc dysplasia No myelodysplaslic changes II'l olher myeloid hages MonocyIes
1909. 2504 1.

CytogenetIC studies are ooemat in nearly 00% 01 patients. In the remaining patients, clonal karyotypic abnormalities may include +8, +9 . +2 1, del(2Oq ), del (1 1q) andde~12pl l 566. 640 , 736, 1415, 24661. Clonal cytogenetic abnormalilies may appear during the cou rse of the disease . There is noPh chromosome Of BCR-ABL 1 fusion gene. A vana nt of chronic myelogenous leukaemia, BCR·ABL 1 positive (CML) has been repo rted that demonstratesperipheral blOOd neutrophil ia stmilar to that seen in CNL 1168 51. In such cases, a variant BCR-ABL1 fusion protein , p230, is found. Cases with this molec ular variant of the BCR·ABL 1 fusion gene should be considered as CMl , not CNL. Occasional patients with a JAK2 rnutation have been reported [1083, 14351and this bassometimes been homozygous 110831. Ccrnplete cytogenetic remission with imatnib was reported in a patient with CNl

No_.. . .

and 1(15; 19)(q13:P13.3), suggesling the possibility of an unident ified fusion gene in some cases 1433 J. Postulated cell of origi n Cell of origin is unknown. It is most likely a BM stem cell with limited lineage ooten tiaI 1736, 2466 1. Prognosis and predictive fac tors Although generally regarded as a slowly prog ressiv e disord er, the survival of pa tients wi th CNl is variable , ran gin g

from 6 months 10 more than 20 years. Usually the neutrophilia is p rog ressive. and anaemia and thrombocytopenia may ensue. The development of myelodysplastic features may signal a translor mation of the disease to AML, which has been reported in some patients 1909, 2504 1. It is not clear whether the transformation was relate d to previous cytotoxic therapy in the cases rep orted.

Chronic neutrophrlic leukaemia

39

Polycythaemia vera

Definition Poiycvtbaemra vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by increased red blood cell production independent of the mechanisms that normally regu late erythropoiesis. Virtually all pat ients carry the somatic ga in-ol-lunction mutation 01 lhe Janus 2 kinase gene, JAK2 V617F or anothe r functionally similar JAK2 mutation thai results in proliferation not only 01 the erythroid lineage but of the granulocytes and megakaryocytes as well , t.e "panmyelosi s". Three phase s 01 PV may be recognized : (1) a prOdromal, prepo lycythaemic phase c harac terized by borderline to only mild erythrocytosis; (2) an overt poIycythaemic phase. associated with a significantly increased red cell mass ; and (3 ) a "spent" or post-oo'vcvtnaemic myelofibrosis phase (post-Pv MF) in which cvtooeruas. including anaemia . are

associated with ineffective haematobone marrow (8M) fibrosis. extramedullary haematoooesrs (EMH) . and hypersplenism, The natural progression of PV also includes a low incidence of evolution to a myelodysplastic/preleukaemic phase and/or to acute leukaemia (AML). All causes of secondary eryth rocytosis, inheritab le po lycythaemia and othe r MPN mus t be excluded. The d iagnosis requires integration of c linica l, laboratory and 8M histolog ica l features as outlined in Tab le 2,02 .

J. Thiele H ,M , Kvasnicka A,Orazi A TeHeri G , 8irgegard

Evolution _

...10"Jl,,;15'Mi ....21 Idl!!!9-U-

Manifestation

- - - - - - -•• Transformation Post -polycythaemc myeIokl metaplasia (post-PV MF)

1 t

. - -_ _ 20 %

1

~.Iy

L.._ < 10 %

definite increase In red cell mass I

Post-PV MF WIth biasbc transformation 11

II

Tennin.J1 sage

Fig. 2.14 SdJematic presentabOn of ee 8YOIuliOn of 1hedisease process ., ~ vera.

poese.

ICD-Ocode

9950/3

Synonym Polycythaemia rubr a vera,

Epidem iology The reported annual incidence of PV increases with advanced age and varies from 0.710 2.6 per 100 000 inhabitants in Europe and North America. but is much Iavver in Japan 110591. Most reports indicate a slig ht male predominance, with the M :F ratio rang ing from 1- 2:1 ISO. 1389 1. The median age at d iag nosis is 60 years . and p atients you ng er than 20 years old are only rarely reported 117001.

40

Myeloproliferative neoplasms

Etiolog y The underlying cause is unknown in most cases. A genetic predisposition has been reported in some famil ies 11778 , 20321. Ionizing rad iation and occupational expo sure to toxins have been suggested as po ssib le causes in occasional pa tients 1312}.

Sites of involv eme nt The blood and 8M are the major sites 01 involvement, but the spleen and fiver are also affected and are the major sites of EMH in the later stages, However, any organ can be damaged as a result of the vascular co nsequences of the increased red cel l mass .

Table 2,02 Diagnosticcriteria lor poI~emia vera (PV). Diagnosis requires the presence 01 bottl major criteria and onemM criteriOn or \he presence of the firstmajor cri tel'\orl togeth&r with two minor criteria. Majorcriteria

t. Haemoglobin >18.5gJdL., men, 16,5g!
in 'Io'OfT'l8l1 orother evidence of eceeseo red cell voll,lTlEl'

2. Preserce of JAK2 V617F or otnerfunctionaly slnVlar mutiltion sudl as JAKZe_on 12 rl'lI.ltalion

Minor criteria

t . Bone marrow biopsy shoWing hypercellularily lor ageWIth lJirIeage growttl (panmyelosis) wiltl prrITWIefll erytIvoid, granulocytic aodmegakaryocytJc proMerabon

2. serum erylhl'ClPClie'n levelbelowthe reIerenc:e range lor normal 3. EI'IOOgenous eryttvoid colony Iormabon II'l VItto • Haemoglobin Of haematoall >99th pertentile of rneIIlod-speofJ reference range lor age. sex, albtude of resideool a hael,qJobiI. >11 gill. 10 men. 15 Wdl in women • assoaaled WIth a doI:menled iIfld sustaned Mease of alleasl 2 gldL from an indMdual's baseline value Il\al tarl nol be attnbuted 10 correctlOn 01 irOn defDency, or lll&vated red c:eI f'lIa$$ >25% llbove mun normal predicIer:l value

I

Clinical features The major symptoms of PV are related to hypertension or vascular abnormalities causedby the increased red cell mass, In nearly 20% of patients an episode of venous or arterial thrombosis, such as deep vein thrombosis, myocardial ischaemia or stroke, is documented in the medical history lSOI and may be the first manifestation of Pl/lSO, 197, 1389.20711. Mesenteric, portal or splenic vein thrombosis and the Budd-Chiari syndrome should always lead to coosideration of PI/ asanIJlderlying cause and may precede the onset 01 an overt polycythaemic phase ISO, 2701. Headache, dizziness. visual disturbances and paraesmeses are major complaints, and pruntus. erythromelalgia and gout ere also common. In the full-blown polycythaemic stage physical findings usually include plethora and palpable splenomegaly in 70% and hepatomegaly in 40% 01 patients 11445,

20711. Clinical laboratory studies that aid in confirmation 01 the diagnosis of PV include subnormal erythropoietin (EPO) levels [223. 15271. endogenous erythroid c:oklny (EEC) formation 15951. and oetectoo at the JAK2 V617F or functionally similar mutations, e.q. JAK2exon 12 mutations

Fig. 2.15 F'dycylhaemiaveta, ~stage. A I.WcIy hyperc:eWa' bone If\ilIJOIIWsI'oIro'rIga ~01 large megakaryocytes in ee bone mafI'OW secUon. B Many large ¥ld gianttlyperIobuIated ( ET~ ke) megak¥yotytes in a pa\leIIl dilic:ally mrrickJng ET, because 01 a platelettxUlt in excess 0I 10D0xlO'1t- Note ee my dIy inaeased ~ lnf ef)'tt"ropoiesi (panmyelosis), beUerdlImDl ostraIed by ~ esterase f9ClCtiOrL

the morphological findings are of sufficienl specificity to allow distinction of PV from secondary poIycythaemla as well as other subtypes of MPN 122031,

Pre-polycythaem ic phase and overt poIycythaemia Generally, in the pre-polycythaemic and polycythaemic phases of PV the major features in the peripheral blood (Pal and 8 M are attributable to effective proliferalion in the erythroid , granulocytic and megakaryocytic lineages, Le. there is pannweosrs. The PB shows a mild to overt excess of

normochrcmie, normocytic red blood cells. If iron deficiency due to bleeding is present. the red cells may be hypOchromic and microcytic. Neutroptufia and rarely basophilia may be present. Occasional irrmature granulocytes may be detectable in the overt polycyttlaemic phase, but circulating blas ts are generally not observed , Because of prominent thrombocytosis, up to 15% of cases of early phase PV may clinically mimic essential thronbocvthaerma (Ell 122101 but such cases eventually evolve into an overtly polycvmaemc stage 11047, 2007, 22101.

11 981,2168. 21771. Occasionally. patients may present with clinical symptoms suggestive of PV b ut WIth a haemoglobin level and/or red cell volume not sufficiently e levated to substantiate the d iagnosis. Such patients may be in the pre-oo'vcvtbaemrc phase, wtlich was previously refe rred to by some authors as "latent PV' or as ' p ure id iopathic erythrocytosis" 1197,1559, 1715, 1697,2224), The detection of a sub normal EPO level, a JAK2V617F or funct ionally similar mutation andlor abnormal EEC lcmaton. in combination with the typ ical morphologic features described below, will allow the diagnosis of this phase of PV; these features are not found in secondary or spurious polycythaemia. The ore-ooivcvtnaemc phase may be expected to become overtly poIycythaemic at a later time.

Maphology The morphological lind lngs in BM biopsy specimens at patients with PV must always be correlated with other clinical and taboratory fmd ings in order to firmly establish the diagnosis 121771. However, eYen n the earty pre-po/ycyttlaemi stage PoIycythaemia vera

.

41

FIg. 2.11 AcuteIeukaen'ilWl poIycyth8emia WlflI . Blood a pabenl M1h. ~ Ilist:Iy of PII. The patient had been treated with a/kyIabng agents !bing !he poIycyIhaemic stage. The blasts C013. C033. C0117 alld C03-f. and had a compleJ karyotype. COf1SISlenl wrIh Il'lerapy-related aalte myeloid ~ from

eeeseee

.......

Bone marrow cellular ity has been reported to range from 35-100%, with a median cellularity of about 80% [641 1, but c haracteristically the BM biopsy is hyperceuular for the pa tient's age. A finding that is especially noteworthy is increased ce llularity in the subcortical marrow space, an area which is nor mally nyooceuurar (775 , 2203] Panmyelosis accounts for the inc reased ce llularity b ut an increase in the numbe rs of e ryth roid pr ecursors and of meg akary oc ytes is often most promin ent {641, 775, 22031. Erythropoiesis is normobl astic, and granulopoiesis is mor p holog ica lly no rmal. The pe rcentage of myeloblas ts is not increased. Mega karyocvtes are increased in number. particularly in cases with an excess of platelets, and display characteristic morphological abnormalities, such as hyperlobated nuclei, even in the early phase of the disease , The presence 01 the panmyelosis, which although less prominent in the pre-poivcvtnaenc than in the overt polycythaemic phase, is nevertheless detectable and helps to distinguish early PV from ET, whi ch it may otherwise resemble clinically 1221 01· As in the pre-pdycythaefr phase, megakaryocytes seen in the poIycythaemic stag e 01 PV are clearly di st inguishable from those seen in ET. 42

MyeloproliferatIve neoplasms

They typically tend to lo rm loose c lusters or to lie close to the bone trabeculae, and often show a significant degree 01 pleomorphism with a mixture of different sizes . The major ity of the megakaryocytes exhibit normally folded or deeply lobulated nuclei, and usually lack significant cytologica l abnormalit ies, alt hough a minori ty show bul bous nucle i and othe r nuclear ab norma lities, pa rticularly when assoc iate d with a minor incr ease in ret icu lin {22 111. When taking the c ha racte ristic histological pattern of PV into account, d iscr imination of PV from ET and PMF as

well as the distinction from reactive erythrocytosis and thrombocytosis is feasible {2211 , 22221. Reticulin stains will show a normal reticulin libre network in about 80% 01 patients . but the remainder display inc reased reticulin and even borderline 10 mild collagen fib rosis {297 , 641 , 775, 1189,221 1] de pen d ing on the stage 01 disease at first dia gnosis, Reactive nodular lymp hoid agg regates are found in up to 20% of cases {22031. Sta ina ble iron is lack ing in the 8M as p irate and biopsy specimens in mo re than 95% of the cases

1641, 22221 .

Tabl.2.03 Diagooslicaileria fOf postiJOlycythaemic myelofibrosis (posl-PV MF )

Required criteria 1. Documentation ofa previous diagnosis of'MiQ.defined PV 2,

Bone mallOlll1ibl"os4s grade 2-3 (000-3 $C8Ie) orgr-ade 3-4 (000- 4 scale)

Additional criteria (2 art rtquiredj 1. Anaemia' Of sustained km of ei1hef pl1Iebotomy r~ the abseoce of ~ therapy)orcytoreduc:M lrealmenl requilKnent b~s

2,

Leukoel)1hroblaslic penpheral blood picbQ

3.

Incteasll1g spIenornegllIy defIOlld as .rther aninaeasein palpable SPleoomegaIy of >S an from baseIint ldistanee from the left costal marg.n) Of Iht 1pp&afaflC8 of newly palpable spleoomegaly

4

Development of >1 of 3 consblulional symploms: >1 0%weighlloss i'l61'1'lC11'1\tts, iWJhI sweats. 6 unexplained Ie'o'eI' (>31.S C)

"Spent phase"and post·polycythaemic myelofibrosis (oost-Pv MF) During the later phases of PV, e rythropoiesis progressively decreases. As a consequence, the red blood cell mass normalizes and then decreases, and the spleen further enlarges. Usually these Changes are accompanied by corresponding 8M aneranons 1641 . 20711. The most common pattern of disease progression is posf-Pv MF accompanied by myeloid metaplasia which is characterized by a Ieukoerythroblastic PB smear, poikilocy' ioss wil h teard rop-shaped red blood cells. and splenomegaly due to EMH , as defined in Table 203 {143A). The morphological hallmark of th is slage of the disease is overt reticulin aOO collagen fbrosisofthe BM 1641 . 775 , 2203, 22221, The CelkJarity varies in this terminal stage. tu: h'y1:loceIIular specimens are coreroo. CUsters of megakaryocytes, olten with hyperchromatic and very dysmorphic nuclei, are prominent Eryth ropoiesis and granulopoiesis are decreased in amount. and are sometimes foun d . along with megakaryocytes, lying within dila ted marrcw srcsocs 12203 1. Osteosclerosis may also occur 164 1, 775 1, The splenic enlargement is a consequence of EMH , ....nich is characterized by the presence of erythroid. granu locylic and megakaryccvnc elements in the splenic sinuses and cords of Billrot h. An increase in the number of immature cells may be observed in these stages, butme finding of ) 10% blasts in the PB or 8 M or the pre sence of signific ant my e lodysp lasia is unusual, and mosl likely sig nals tran sformation to an acce lerated phase and/or a myelodysplastic synd rome (MD S), Cases inwhich 20% or more blasts are found are AML 11701, 2071, 2203, 2222).

cnsoerec

""""phenotype No abnormal phenotype has been reo

"",eo Go'o'" The mosf frequent genetic ab normality in PV is the somatic qam-ot-tuncnon mut atoo JAK2 V617F. Altho ug h il occurs in >95%of patients with PV, it is not specific and is found in other MPN as well. but in

splerJedoi"r

Fig. 2.19 ~ Ylll'a, ~ rnyelofbosis (pos&-PV MF) and"¥lbd metaplasia , specinen. The splenic enlarvement in the ~ ptIase isdue IlIMlIy b eJb"ameOJlary Ilaema!DpoIesis !hat Cll:X:ln II1 It1e splenic sftlses , as wei 11$Iibrosis.-.d lll1trapmenl d platelets and tIaernalopoieli eels II1lhe splenic

coos iower freq uencvltea. 1044 ,1 186 , 12881. The mutation occurs in a haematopoielic stem cell , and is found in all of the myeloid lineages. Hence cells that utilize JAK2 kinase in the intr acellular signaling path way may be hyp ersen sitive to g rowth fa ct ors a nd other cvtokmes. inc lud ing EPO . A fun ct ionally similar mutat io n in exon 12 of JAK2 has also been reported 11981/. so that virtually all patient s with PV have a JAK2 aber ration , St ill, no ge ne tic defect enti rely specif ic to PV has been ide ntified . At diagnosis, c yto ge ne tic ab normal ities are detectab le in ab out 20% of pa t ients. The mo st c ommon rec urring abnormalities inc lude +8, +9, del(20Q), de l( 13q) and de l{9p) : sometimes +8 and +9 are found tog ether 142, 2394/. There is no Philade lphi a c hromosome or BCR-ABL 1 fusi on g ene . The se c hromosomal ab normalities are seen with increasi ng frequency with d isea se progression and in near ly 80-90% of those w ith post-PV MF 1421, Almost 100 % o f those wh o develop MDS or AMl have cyt ogenetic abnormalities. inclu ding those commonly o bserved in the rapy-related MD S and AMl (See Chapter 6 ).

Postulated cell of ori gi n Heemetopoteuc stem cel l. Prog nosi s and pred ictive fact ors With currently available treatment, median survival li mes > 10 ye ars are commonly repor ted {SO, 1215 , 1548,2071/ . although controversy persists about the risk factors other than olde r age {1215, 1389, 17021 . Most p atients d ie from thrombosis or haemorrhage , but up to 20% succumb to myelodysplasia or acute mye loid leukaemia ISO, 1389, 207 11, The factors tha t p red ict the risk of thrombo sis or haemorrhage are not well d efined 11389, 1700,20711, The incid ence of MDS and ac ute leukaemic transformation is only 2-3% in patients who hav e not been treated with cy totoxic agents , but increases to 10% or more follow ing ce rtai n types of c hemot hera py {704 , 1389 , 1548 , 170 1, 1702 1_

PoIycythaemlCl vera

43

Primary myelofibrosis

J . Thiele H M . Kvasnicka A. Tefferi G. Barosi A. Orazi JW. Vardi man

ICD-O code

Definition Primary myelofibrosis (PMF) 11464 1 is a clonal myeloproliferative neoplasm (MPN) characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow (8M) that in fully developed d isease is associated with reactive deposition of fibrous connec tive tissue and with extramedul lary haematopoiesis (EM H) . There is a step wise evolution from an initial prefibrotic phase 121771 cha rac terized b y a hypercell ular BM wit h absent or minimal reticulin fibrosis to a fibrotic phase with marked reticulin

9961 /3

Synonyms Chronic idiopathic myelofibros is (CIMF); Agnogenic myeloid metaplasia (A MM); Myelofib rosiS/scl erosis with myeloid metaplasia (MMM) ; Id iopathic myelofibrosis .

or collagen ubrosrs in lhe 8M and often

Epidemiology The overt fibrotic pha se is estimated to oc cur at 0.5- 1,5 per 100 000 persons per year {1060,21671. It occur s most C()fTV'TK)ll1y in the sixth 10 seventh decade of life, and both sexes are nearty equally affected 121671. Children are rarely affected 136n

osteosclerosis. This fibrot ic stage of PMF is characterized by ieukoervtbrobiastosis in the booo witll teardrop-shaped red cel ls. and by hepatome galy and sp lenomegaly (Tabl e 2,0 4 ).

Etiology Exposure to benzene or ionizing radi ation has been documented in some cases {5881 Rare familial c ases of 8 M fibrosis

Table 2.114 Diagnos1ic crilefialor primary myelofibrosis:
MaiOI' eritltria t . Presence d

n

~ ........... 1

atypiI", usuaIylaXllTlpalied byllitlerreIla*l inlier a:tagen ~

'"

nile absenat d sig1Icat /W)Jin Iibrosi:s, tle ~ chat'gesIl'LISI be llCClJI'llliDed by a'l 1lcJeaged bone ITI8fTOWcelIularrty characlenzlld by granuIol:yIic pn:jferabDn and often deaea:Sed erythn;lpooesis ~ e. p!VftlroIic ceItEr-pllase disease ).

2. Not meeting WHO Criteria lor poIy<:ythaemia~. BCR·ABLt+ chronic myeIogeoous leukaemia'. myelodysplaslic syndrome'.fJ( other myejoid neoplasms

in yo ung chil d ren have been reported How often this represents an MPN is ~ known. but at least some cases appear 10 represent an autoscmal recessive imented families with a oondilioo 118731· In somewhat later age of onset . the leal1.Xes havebeen consistent withan MPN, suggesting a familial predisposition to PMF 13691.

oee-

Sites of involveme nt Blood and BM are always invo lved. In the later stages of the d isease , EMH (also kno wn as myeloid metaplasia) becomes prominent, in particular in the spleen 117731. In the initial stages. randomly distnbcted C034+ prOlJenitors are slightly increased in the 8 M. but not in the pe ripheral b lood {PBl· Only in the tate stag es they ap pear in large numbers periphe rally (1592, 22091 This increase of CD3 4 + ce lls in the PB is a ph enomenon large ly restric ted to overt PMF and is not seen in non-fib rotic po lycythaemia vera (PV) or essential thrombocythaemia (ETl 141 ,1 45,17031 . It has been postulated that EMH is a consequence ot me peculiar ability of the spleen to sequestrate the numerous ci rculating CD34+ cells 122081. Liver. lymph nodes. kidney ad renal gland. dura mater, gastrointestinal tract, lung and ple ura. b reast skin and sott tissues are other possible sites of EMH 1216n

3. Demonstration of JAK2 V6t7F or other donal marker (e,g. MPL W515K!L),

'"

in the absence 01 a clonal marker. 00 evidence lhatlhe bone marrow fibrosis et otherc:Nlnges aresecondary kl mecoon.autorr1rrone dison:ler r:K0lIlerchronic I1ftarnnatory t'a'llIIJon hairyC8lI ~ et OCher IyrnJ:tMjd neoplasm, metasta1ic mal9'ancy. et klxiC (etvonic) myeIopaltlies"

Minor aiteril 1 .l~ '

2. Increase on serum lactate deIlydrogerIase level' 3, Ar\aemIa.

, I

b

S""""""",, Small to largemegakaryocyteswith an aberrant nuclearlcytoplasmic ratiO and hyperchromatic, bulbous, or irregularly loIded nuclei and dense clustering Requires !he lailure 01 ironrnpiacemenllherap)'to increasehaemoglobin level 10 tile potycythaem~ vera range in the presence 01 decfeased serum fembn. ExckJsion of poIycylhaemia vera is based on haemoglobin and haematocrit levels.n red eel massmeasurement is not required,

< Requns the absence oIBCR.ABL.1 , " Req!.ns atlMnce01 dyW)'ltliopoiesi$ and:~. • Patients WIth an:libons associaled wilhreactve Ill)'IlIofitlro llfe not be COIlSide1 lld n std1 cases ~ olhercntena are mel I Degree of abnorrnalIIy could be borderline or martell .

44

Myeloprolifera tive neoplasms

mn.one kl PMf. ;rod . . ~ stxUd

Clinical featu res Up to 30% of patients are asymptomatic at the time of diagnosis and are d iscovered by octcctco of splenomegaly during a routine physical examination or when a routine blood count discloses anaemia . leukocytosis and/or thrombocytosis. Less commonly. the dia gnosis results from d isc over y of une xplained teukoervmrobtastosis or an increased lactate dehydrog enase (LDH) {366 . 2 16 7, 2 1771. In the initial p refib rol ic phase of PMF. the only find ing may be marked th rombocytosis mimicking ET 12177, 220 11. Therefore. a sustained thrombocytosis cannot. by itself, discriminate between prenbrotc PMF and ET 12201, 2202. 22041. Constitutional symptoms may include fatig ue. dyspnoea. weigh l loss, night sweats. Iow-grade fever

and bleeding episodes, Gouty arthritis and renal stones due to hyperuricaemia may alsooccur. Splenomegaly of varying degee is detectedin up to 90% of patients and may be massive: nearly 50% have t'epa!l:megaty 1143, 366. 367, 1635, 2 1671. The JAK2 V617F mutation may be found n ~50% at patients in the fibrotic pha se: its incidence in the prefibrotic stage has no! been well studied. Althoug h helpful in disllnguishing PMF from react ive condiboos thaI may result in 8M fibrosis, the mutation is not speci fic for PMF but is tound in PV and ET as well 121721.

-

The classical pic ture of advanced PMF includes a PB smear that shows leukoerythroblastosis and anrsopo'knocvtosrs (particularly with teardrop-shap ed red cells) associated with a hvp oceuura r BM with marked reticul in andlor c ollagen fibrosis and organomegaly caused b y EMH, However, the morp holog ical and clinical findings vary c onsiderably at diagnosis depending on whether the patient is first encountered during the prefibrolic or the fibrotic stage of the disease (2177, 22041. Bec ause the pr ogressive accumulation of fibrous tissue parallels diseaseprogre ssion, it is impo rtant to reproducibly and sequentially grade the amount of BM fibrosis semi~ntitatively by using a sCOfing system 122141(Table 2.05). PreffJroticandearly stage PMF:No registrybased prevalence ligures are available b" the incidence otme prehbrotic pha se ol PMF, but series der ived from various 'llfereoce centres reveal that 30-40% of patlerlIs arefirsl detected in a prodromal, preltbmllC phase without a significant increase in reticulin and/or collage n fibres

1297.775.2202,22041 _In these cases the BM biopsy is nvperceuotar with an increase in the number of neutrophifs and atypical meqaaarvocv tes . There may be a mild "left shin- in granulopoiesis, bu t usually metamyeloc ytes. bands and seqmented forms predominate. Myelob lasts are not increased in percentage. and conspicuous clusters of blasts or of CD3 4+ progenito rs are not obse rved {2202 , 22041_ In most cases, erythropoiesis is red uc ed in qua ntity. but early erythroid precur sors are promi nent in some patients 122281_ The megakar yocytes are markedly ab normal, and their ntstotocography and morphology is the key to the recognit ion of the prefibrot ic stage of PMF, The megakaryocytes often form den se

Evolution _

clusters of variable size that are frequently edrecent tc 8M vascular sinuses and the bone trabeculae 1297.775,2204 .22161 . Most megakaryocytes are enlarged, but small megakaryocytes may also be seen, and theif detection is greatly facilitated by the use of immunohistochemistry with antibodies react ive with meg akaryocytic antigens 12201, 22041 . Deviations from the normal oucrear.cvtoptasmc ratio (an expression of defective maturation). annormal pa tterns of chromatin clumping with bulbous, "cloud -like" or "balloon-shaped" nuclei , and the frequent occurrence of bare megakaryocytic nuclei are all typical findi ngs, Overall in PMF the megakaryocvtes are more atypic al than in any other typ e of MPN. Vascular oronteeanon is

Manifestation - - - - -•• Transformation

initiat Biage

GJ ~

CD e;,.",d

~_I

MF-O

MFo I

11

Mf.2

Mf.]

I

Prefibrotic:-early PMF AdYilnced PMF (MMHJ

Fig. 2.21 ~ oI lhe disease process 11'1 (rr'IllCWI values) arid associaIed fibre ~

PfWnarY lIlJ8lDIiblosis (PMF) withassocialed ~ (lata Primary myekllibrosis

45

usual in the 8M 11 214 1, and lymphoid nod ules are found in about 20% to 30% 1220 1, 22041 . Careful 8M morphological examination is particularly crucial in distinguishing pretiorotrc PMF with accompanying thromb ocytosis from ET 1712. 796,2 177.220 1.22161. Reticulin fibrosis is minimal or even absent (corres pon din g to grades 0 and 1)during this stage 122141; if present. It is usually foca l and tend s to be concentrated around vessels . The rnajority of cases with pretrbrotic and early (reticu lin) fibrot ic stages of PMF even tually transform into overt ubronczscrerotrc myelofi brosis associated with EMH 1295. 775. 1189 , 2204. 22 181. Fibrotic stage: Most pat ients with PMF are initially diagnos ed in the overt fib rotic stage 1143, 366. 1635, 2 1671. tn this stage the 8M b iopsy demonstrates clear-cut reticulin or collagen fibrosis (fibrosis grades 2 and 3) . The 8M may stilt be focally nvpercenurer, b ut more often is normocellular or hypocellular. with patches of active naerretopoeers alterna ting with hypocel1ular regions of loose connective tissue andlor fat. Foci of immature cells may be more prominent. although myelob lasts account for < 10% of the 8M cells {297, 775. 22041. Atypical megakaryocytes are often the mo st conspicuous find ing ; these oc cur in large c lusters or sheets, often within dilated vasc ular sinuses 1295, 2204). Sometimes lhe 8M is almost devoid of haematopoi etic c ells, showing ma inly d ense reticulin or collagen fib rosis, with small islands of haematopo ietic precursors situated mostly within the vascu lar sinuses. Associated with the de velopmen t of myelofibrosis is a sign ifica nt proliferation of vessels showing marked tortuosity and luminal dis tension, often assoc iated with conspic uous intras inusoidal haemato(1214, 1347, 1463). Osteoid seams or eooossionarnew bone formatioo in budlike endop hytic plaqu es may be ob served {775, 22041. In this osteoscl erotic phase. the bone may form broad , irregular trabeculae that can occupy >50% of the 8 M space. With exception of allogenei c stern cell transplan tation 11592. 22131, develop-ment of myelofibrosis in PMF is not significan tly influence d by treatment modalities. an d is obviously related to disease p rogression 1295. 22 17, 22181 · In patients with a previously established diagnosis of PMF, the finding of 10-19% bl asts in the P8 and/or 8M and the oerectco by immunohistochemistry of an increased number of CD34+ cells With cluste r formation and/or

Tlble 2.05 SemiQuanlitati~ grading of bone marrow fibrosis (MF). GflIding

08$criptlon'

MF • 0

Scatlemd ftar reticulin WlItl ro IOte~ (CIOS$-OWlI'S), CO!reSpCJnding to normal booemarrow

MF- 1

loose networt of reliaJlin wl\tl many i'ltersections, especiallyin perivasa.dar ereas

MF- 2

Diffuse arr:l dense increase In rebaJlin wrtll eJ:tenSlYe intersedtons. occasionally 'frilh local burr:lles 01 coIagen and/or local OSleosderosis

MF- 3

0l1fuse and dense II"lCl'eaSe IIIreticulin 'M!tl extensive II'IIer$edIons ilIICl coarse bundles of collagen, often associated 'frilh ~

coese

46

Myeloproliferative neoplasms

~~~) ..

Fig. 2.23 Primary myelofibrosis, fibrotic stage, WlIIl ellrameduallary haemalopoiesis in Iivet. A In the Mr, tie sirtUSOids are prominenUy involved by bilineage prolilerallOll. B Megakaryotyles are the hallrnart. 01 abnonnll irltrasinusoidal haematopoiesis.

an a normal endosteal loc ation in the 8M 12204. 22091. ind ica te an accelerated p hase of the disease, whereas ~% b lasts is consid ered as acute uanstometeo. Patients with PMF may also present initially in an accelerated phase Of an

acute phase . In cases with 20% Of more blasts in the PB and/Of 8 M at presentation in which other find ing s may suggest PMF, the diagnosis 0 1 acute leukaemia shOOd be made with only mentiOnof the possible derivation from PMF.

I

I

Extramedullary baenatoooleeta The most common site of EMH is the spleen , followed by the liver 117731. The spleen shows an expansion of the red pulp by erythroid, granulocytic an d megakaryocytic cells. Their identification can be aided by immunohistochemistry [ 16 13, 2 1991. which also allows an appreciation of an increase in neoanqioqenesis / 144\ . Megakaryocytes are often the most conspicuous component of the EMH. Occasionally large aggregates of rreqakeryocytes. growing COhesively. can ooocce macroscopically evident tt.mOUral lesions. In the presence of nodular lesions and , in general. in any advanced stage disease with large amounts of EMH, the PQS&bility 01 a myebd sarcoma should be c:onsidefed and carefully excluded by perlaming irrmunohistological studies with CD34 117731. The red pu lp cords may exhibit fibrosis as well as pooling 01 platelets. Hepatic sinuses also show pr0minent EMH. and cirrhosis of the liver may occur /21671. Immunophenotype No abnor mal phenotypic fea tures have been reported .

Fig.2.24 PrWncwy myeIoIilrosis. 6brollc stage . A ThIs penrtIerBl bloodsme
Genetics No ge netic d efec t specific for PMF has been ide ntified 11832AJ. Ap proximately 50% of pat ients with PMF exhibit the JAK2 V617Fmutation. Althou gh the presence of the mutation confi rms the croneltty of the proliferation, it is a lso found in PV and ET and thus does not dis tingu ish PMF from these MPN {163 , 1044 , 1064, 1186, 1288J. A funct iona lly similar ga in-o f-f unc tio n mutation of MPL (MPL W5 15K/l ) has been repo rted in up to 5% at PMF cases. but in occasional cases of ET as /16891. Cytoge netic abno rmalities occur in up to 30% of patients (630, 1832, 21 741. There is no Philadelp hia chromosome or BCR·ABL 1 fusion gene. The presence of either del( 13)(q 12-22 ) or der(6) t( 1;6) (q21-23 ;p2 1.3 ) is strongly suggestive b ut not diagnoslic of PMF [5861. The most common rec urring abnormalilies inc lude del (2Oq), and partial trisomy 1q , allhough +9 and/or +8 are also reported {63O. 1832A, 21741. Deletions aNeeting the long arms of ch romosomes 7 and 5 occur as 'Nell. but may be associated with prior cytotoxic therapy used to treat the myeloproliferative p rocess.

wen

Postulated cell of orig in Haematopoi etic stem cell Prog nos is and p red ict ive fac tors The time of survival in patients with PMF ra ng es from month s to d ecades. The overall p rog nosis de pends on the stage in wh ic h PMF is firstly di agnosed 11215. 22041. The median survival time is approximately 3 to 7 years in patients diagnosed in the fibrotic stage {142 , 366 . 367 . 630, 2 167/. which contrasts with a 10and ts-vear relative survival rate of 72% and 59% respectively, in patients diagnosed in the early prefibrotic phase 11215. 12191. Factors at presentation that

adversely affect pro gnosis include age >70 years . Hb <10 g/d l , platelet count <1 00x l ()6/l , and an ab normal karyotype 11 42 , 143.366,630, 12 15 , 12 19, 1832A, 2105 ,2174,22041 . The major causes of morb idi ty and mortality are 8M fa ilure (in. tecnon . haemorrhage). thromboembolic events , portal hypertension, cardiac failure and acute leukaemia (AMl) {21671. The repo rted frequency of AMl ranges from 5 to 30% 1366, 630 , 21671. Although some cases of AMl are related to prior cytotoxic the rapy. many have been reported in patients who have never been treated, confirming that AMl is pa rt of the natural history 01 PMF Primary myelofibrosis

I

47

Essential thrombocythaemia

Defin ition Essen tial thrombocythaern ia (Ell is a

chronic myeloproliferative neoplasm (MPN) that involves primarily the megakaryocytic lineage. It is characterized by sustained thrombocytosis
eral blood (PS), increased numbers of large. mature megakaryocytes in the bone marrow (8 M), and c linica lly by ep isod es of

thrombosis and/OI' haemorrhage, Because there is no known genetic or biological marker specific lor ET. other causes for thrombocytosis must be excluded , including other MPN, inflammatory and infectious disorders, haemorrh age and

other typ es of haematopoietic and nonhaemat opo ielic neop lasms. The presence of a BCR- ABL 1 fusion gene exc ludes the diagnosis of El

IC[).() code

9962/3

bocytose, haemorrhagic thrcrnbocythaemia.

Sites of inv olvement Bone marrow and blood are the principal sites of involvement. The spleen does not show signilicant extramedullary haematopoesrs (EMH), but is a sequestration site for platelets 1705. 902. 21751. EtiOlogy The etiolog y of ET is unknown.

1. SllSIairled' platelet count ~45Ox 10"1t 2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased nlll'11bers of9l1larged. matul'tl megakaryocytes. No signllical1t increase Of Iefl-sMtofOOlItrophiI glanoopoiesis orer,1IWOpoiests

3. Not meetlng WHO atSerialor poIycyIIlaema vera,· P'JI'Nf'Y myelofIbrosI$.< BCR-ABL f posiWe ct.ror.: myeIogenouIlMaetnia' ormyeIodysplaslic syndrtml" Of oIher myeklid ~ 4. Demonstration 01 JAK2V617F orolher donal maricer. or in !tie absenteofJAK2V617F, no e-.1dence lor reeceve thrombocy1osls'

• Sustatned ooring the W(ri.-up process. • Requires Itle fcMure of iron repIaoement ItIefapy toincrease IIaemoglcOf1 level10I!'oe polyc)1IIaemia "'llfa fange Illhe presence of deaeased serum lerTilin. Ex
48

Myelopro liferative neop lasms

H M. Kvasnicka A.Orazi A. Tefleri H. Gisslinger

Epidemiology The true inc idenc e of ET is unk now n, bu t when di ag no sed according to the g uidelines of the Polycythaemia Vera Stu dy Group (PVSG)115491. it is estimated 10 be 06-2.5 per 100 000 persons per year {1055. 10591. Most cases occur in patients 50-60 yea rs 01 age , with no major sex predil ect ion. How ever, a second peak in frequ ency, pa rtic ularly in women , oc c urs at about 30 years 01age 1705. 902 . 10551. ET can also be seen in ch ild ren , albeit infrequently 118151, but must be distinguished from rare cases 01 hereditary thrombocytosis 1585. 24011.

Synonyms Primary thrombocytosis: id iopathic mrom -

J . Thiele

Cli nical features More than one half of patients are asvrrptomauc when a markedly elevated platele! count is discovered lortUitously at the tJml! of a routine PB count 1705, 802 , 9022 1751. The remaining patients preset with some manifestation of vascular occ lusion or haemorrhage 1210, 4581 Microvasc ular occlusion may lead to trarlstern iscnaemc attacks, digital ischaemia with paraestheeias. and gangrene 1210. 458 . 1473. 18291. Thrombosis of map arteries and veins also occur. and ET may be a cause 01 splenic or hepatic veil thrombosis as in the Budd-Chiari syndrome . Bleedi ng occurs mos t comrrow from mucosal surfaces. suc h as the gastrointestinal trac t or upper airway passages 1379. 802, 1549. 19551. If h criteria established by lhe PVSG 101 E1 are used. mild splenomegaly is present approximately 50% of pa tients at diagnosrs and hepa tome ga ly in 15-20% 1705, 802. 902, 1549 , 2 175 1 How ever, when !he WHO classification is applied and patients with thrombocytosis associated the p relibrotic stage 01 primary myeIcj. brosis (PMF) are excluded. spIencrneg
In ee past, the platelet threshold for the diagnosis of E'r was :!:600x109/l115 49J, but some patients have haemorrhag ic or ltuombolic episodes at lower platelet cents 11272, 1829, 19031. In order not to C01lprcmise the diagnosis in such cases, a number of investigators convincingly argued tOl" a lower platelet thresho ld for ee diagnosis of ET. and the WHO has adopted the recommenda tion of a platelet COltlt ~450 x 1 l)l'IL, a value that exceeds !he 95th percentile for normal platelet counts adjusted for gen der and rac e (1272. 1897, 1903.21771. Although this llYeshoid will encompass more pat ients 1Io'!lh ET, it will also include more pat ients 'I4lCCflditions that mimic ET. It is therefore essential that all Criteria listed in Table 200 for the diagnos is of ET be met to exewe olher recotastc and non-neoplast ic causes 01 thrombocytosis 12 1771. The 8M bi:psy is particularly helpful in exc luding ere myeloid neoplasms associated with excessive platelet counts. such as myelodysplastic syndrome (MDS) associated wltrl isolated del (5q). the prov isional 'l'r)'eIodysplasticlmyeloprohferative entity refractory anaemia with ring sioerobras ts and thrombocytosis (AAAS-T), and the cetoronc phase of PMF. Althou gh the JAK2 V617F mutation is fou nd in only 40-50% ot cases of ET and is not specific b' ET, when present it does exclu de reectve mrorroocv tosrs 121771. Similarly, in eeo enocqeroue erythroid and/or meg akaryocytic colony formation, althoug h not specrlic tor ET, also exc ludes reactive ltYombocytosis 15941.

a normocel lular or moderately hypercellular 8 M {775, 22161. The most striking abnormality is a marked proliferation of megakaryocytes with a predominance of large to giant forms displaying abundant, mature cytoplasm. and deeply lobulated and hyperlobu lated (stag- horn like) nuclei. The rnegakaryocytes are usually dispersed throughout the BM but may occur in loose clusters. Bizarre, high ly atypical megakaryocytes, such as those observed in PMF, are not found in ET and if present. the diagnos is of ET should be ques tioned 1712, 796 , 2200 , 22051. Proliferation of erythroid precursors may be found in a few cases, p articularly if the pat ient has exper ienced haemorrhages. but granuloc ytic proliferation is highly unusual; If

present. the increase in granulopoiesis is usually only of mild degree. There is no increase in rnvetobtasts nor is myelodysplasia observed, The network of reticulin fibres is normal or only minimally increased in ET. and the find ing of signif icant retic ulin fibrosis or any collagen fib rosis excludes the diagnosis of ET 1712, 775, 796, 2177, 2205, 22161. Bone marrow aspirate smea rs also reveal the markedly increased numbers of megakaryocytes of large size with hyper lobutared nuclei and . in the background. large sheets of platelets. Emper ipoles is of BM elements is frequentl y observed in ET. but is not a spec ific find ing. Stainable iron is present in the aspira ted BM specimens of 40-70% of patients at diagnosis 116491.

f ig. 2.27 Essential ttwombocylhaerma, bone marrow aspl'ate smear. AAll increase in the nurrtler and size of the megailaryocyles. B NoIe the deeply Iobutaledmegaka'yocytic ~, as well astarge pools01 pla te~_ Note that the aspirate smears fail to reveal the overall marrow archilecture anddistribution of the rnegar.aryocytes thatcan be (Illy seen in the biopsy,

Mo'phology The major abnormality seen in the PB is marked thrombocytosis, The plate lets often display anisocytosis, rang ing from tiny torms to atyp ica l large, g iant platelets. Bizarre shapes, pseudopods and agranular platelets may be seen, but are rot common. The white bloo d ce ll (WEq count and Ieueocyte differential ~e usually normal, although a borderline eevaton in the WBC count may occur (705,802.902, 21751. Basophilia is usuaMy absent or minimal 115491 _ The red blOOd cells are usually normocytic and rcerccnrcnc unless recurrent haerrormage has caused iron deficiency, in W"Mch case they may be hypochromic and microcytic. Leckoervtnrobleetosts ¥d teardrop-shaped red blood cells are IQ seen I'l ET 121751. ~ rrosl cases, the BM core biopsy shows Essential thrombocythaemia

49

react ive thrombocytosis , An abnormal karyotype is found in onl y 5-10% of patients with ET when d iagnosed according to lhe previou s PVSG criteria {15491. There ; is no consistent abnormality. but those reported include +8, abnormalities of 9q, and del(2Oq) {939, 1682 1. Ahhoogh isoIatoo del(Sq) has also bee n reported in ET. cerelui rrorphologic examination is required 10 distinguish such cases from MOS associated with this abnormality 116821. Postulated ce ll of ori gin Haematopoetc stem cell. Prognosis and predictive factors ET is an indolent disorder characterized

The lTIOfphological findings in the 8M biopsy are essential to distinguish ET from other MPN. myeloidosooes and reactive

may initially present wittl thrombOCytosis without leukocytosis and can mimic ET cl~

conditions tha t p resen t with sustained ttlrcmbOCytosis , The finding of even a mild degree of combined granulocytic and erymroo proli feration should raise consideration of prodromal stage poIycythaemia vera (PV) 122101. and the finding of granulocytic proliferation associated with biza rre. hig hly atypical megakaryocytes should p rom pt concern lor the prefibrotic slage of PMF 12201,22231 . Significant dyserythropoiesis or dysgranulopoiesis sug gest a d iagno sis of MOS rather than ET. The large me gakaryocytes with hy per lobulated nucle i of ET contrast with the medium-sized monoioba ted megakaryocytes associated with de l (Sq ) as an isolated ch romosom al abnormality in MDS and with the small. dysplastic megakaryocytes associated with the inv(3)(q21q26 2) or t(3;3)(q 21;q26.2) chro mosomal abnormality. Lastly, some patients with c hronic mye logenous leukaemia (CML)

ET can be easily distinguished from the sma ll -dwarf" megakaryocytes of CML. cytogenetic and! or genetic analysis to exclude a BCR-ABL 1 fusion gene is recommended for all patients in whom a diag nosis of ET is considered 11841 1.

;cany. AJ1hough !he ""90 rnegaJ
rroecuer

Immunophenoty pe

No aberrant pherotype has boon described Genetics No mol ecular genetic or cytogenetic abnormality specific for ET is known. Approxim ately 40-50% of cases ca rry the JAK2 V617F or a functi ona lly sim ilar mu tation 1163. 1044,1064.1186.1 2881, Thesemutatoos are not specific for ET and are found in P\I and PMF as well, A gain -of-Iuncti on mutation of MPL. MPL W515K/L , has been reported in 1% of cases of ET {16891. None of these mutations are found in cases of

Table 2.07 WHO diagnosbc cnleria lor posl~ssenlial thrombocythaemia myelofibrosis (post·ET MF),

R.quired criteria 1. Documenlatiol'l of a prevklus diagnosis of WHQ-defined essential ttlrombocythaemia

2. Bonfl marrow fibrosis grade 2-3 (011 0-3 scale) or grade 3-4 (oo 0-4 scale )

Additional crittril (2 are ~j..-cl) 1. Anaemia'« 22{1dl decrease from baseline haemoglol*1leve1 2. A leukoefythrobla pe~ bloodpiclufe

3. Incr&aSingsplenomegaly defiMd as &$ler an Increase in palpable splenomegaly of>5 emfrom baseIne (lislance Ircm ltIeleft C05laI margin) orIle appearance 01 newly p.alpable splenomegaly 4. Increased LDH (atloYe reference level) 5, Development 01 >1 of3 CXlIlSlrtlllional s~ : >10% weight bss in 6 month$. right sweats, I,Il8lplBined illver{>37.5-C1

50

MyeloproliferatIVe neoplasms

by long symptom-free intervals, inter, ruptec by occasional ute-mreaten thromboembolic or haemorrhagic episodes 1705, 802, 902, 12 15, 154 9, 2175 Although after many years a few pat with ET may develop 8M fibrosis associ-ated w ith mye loid metaplasia (EMH such progression is uncCll'TYTlOl1 1297, 775. 1189.22201. Precise diagnostic guidelines lor diagnosing post-Ef MF are given in Table 2 .07 . Strict adherence to and other WHO c riteria 1143A . 21771 necessary to prevent diagnostic comus associated with early PMF accompa by thrombocytosis 1365}. Transformation~ ET to ac ute myeloi d leu ka emia or MOO occurs in <5% of patients, and when does occur is likely related to previous cytotoxic therapy 1705 , 802, 90 2, 1800 M ed ian survivals of 10-1 5 yea rs are common ly rep orted . Beca use ET usu al~ occurs late in midd le age. the [,Ia ex pecta ncy is near normal for m an~ patients {1215. 1702 , 2200 . 2430}. Fi nal~ it is noteworthy that the maj ori ty of c lini stud ies are based on prev iou s d iag l10stic gu id eline s 11 549 } that fail to d ifferentiate clearly between the early prefibrot stages of PMF wit h accompan ying thr bocvtosrs an d ET ac cordi ng 10 the classification 11215, 2200, 2205} . A su stannat d ifferenc e in ove rall prognosis been reported w hen these two di ffer ctessmcanon sys tems are ap plied to same pa tien t population 112151.

Chronic eosinophilic leukaemia, not otherwise specified

-

Ctwooic eosinophilic leukaemia (CEL) is a

myeloproliferative neoplasm (MPN) in

which anautonomous. clonal proliferation

01 eosinophil precursors results In perSistently increased numbers of eosiroptliIs in the peripheral blood (PS), bone

(BM) and penooerarnssoes. with being the dominant baemak*lgical abnormality. Organ damage ccClSS asa result oueceaemc infilt ration or ee releaseof cytokines, enzymes Of other proteins by the eosinoctas. Chronic

matrON

eoSKlOPh~ia

eosinophilic leukaemia . not otherwise

specified, (GEl. NOS) excludes patients WIth a Philadelphia (Ph) chromosome, BCR-ABL llusion gene or rearrangement 01 PDGFRA, PDGFRB or FGFR1. In eEL, NOS the eosinophil count is n5xl ~1L in the blood. There are fewe r than20% blasts in the PB or 8M . To make adiagnosis 01CEl. there should be evidence/or clonality of the eosiropbus or an ecreese in myeloblasts in the PB or 8 M. In many cases however, it is impossible to proyeclonalrty 01 the eosoo ptuls. in w hich case, if there is no inc rease in blast cells, the diagnosis of "id iopathic hypereosinophilic syndrome" is made . The idiopathic hypereosinophilic synd rome (idiopathic HES) is de fined as eosi nophilia (~1.5~ 1CfJ/L) persisting for at least 6 months, for which no und erlying ca use

can be fou nd , and w hich is associated with sig ns of organ involveme nt and dysfunction 1443, 23821; there is no evidence for eosinophil clonality. It is a diagnosis 01 exclusio n. and may inc lude some cases of true eosinophilic leukaemia that cannot currently be reccqnrzeo. as we ll as cases 01 cytokin e-d riven eo sino philia that are due to the ab normal release of eosinophil gr owth fa ctors, e.q . interleukin (IL) 2. 3 and 5, fOf unknown reason s (128 , 443 , 1971. 2072 , 238 21.

ico-oeeee

9964/3

Synonym Hypereosinophilic synd rome (not recommend ed) . Ep idemiology Due 10 the p revious dilfic ulty in d istingu ishing CEL f rom idiopat hic HES. the true inc id enc e of these di seases is unknown, althou g h th ey are rare . Many patients wh o wou ld until rec ently have bee n c lassified as hav ing idiopathic HES ca n now be show n to have C El assoc iated w ith a FJPtL 1-PDGFRA fusion gene {466 1. Since this co ndition oc cur s mainl y in ad ult me n, the male dominanc e and the peak inc ide nce in the four th decad e prev iously descr ibed in "HES" {443 , 1971 , 2072, 2382 ) are now exp lained , at least in

BJ. Bain D.G. Gi lliland J W , Vardiman H .-P. Horny

pa rt. The epidemiological features of cases of HES that rema in idio pathic have not vet been c learly d efined.

Sites of involvement

eEl

is a multisystem disorder. The PB and BM are alwa ys involved . TIssue infiland release of tration by the cytokines and humoral factors from the eosinophil g ranules lead to tissue damage in a number of organs, but the heart. lungs , central nervous system, skin and gastrointestinal tract are commonly invoiveo. Evidenc e of sp lenic and hepatic invo lvement is p rese nt in 30-50% of patients 1443. t97 1. 2072 , 23821 .

eos.roonns.

Clinical features Sometimes eosinophilia is detected inc identally in patients who are otherwise asymptoma tic . In othe r pa tients, co nstitutiona l symp toms , such as fever, fatigue , cough, ang ioed ema . musc le pa ins, pr uritus and d iarr hoea are found . The mo st serious clinical findings relate to endomyoc ardi al fibrosis . with ensu ing restrictive ca rdiomeg aly. Scarring 01the mitralltricu spid valves leads to valvula r regurgitation and formation of intrac ard iac thro mbi, w hich may embouze to the brain or elsew here, Perip heral ne urop athy, cen tra l nervou s syste m dy sfu nction, pulmonary symptoms due to lung infiltration, and

Chronic eosinophilic leukaemia. not otherwise specdied

51

rheoma toroptcar findings are other frequ ent ma nifestations (443, 1971 , 2072 ,

-

2382 1

In CEL, NOS the most striking feature in the PB is eosinophilia, there being mainly ma ture eosinophils with only small numbers of eosi no p hi lic myelocytes or promyelocytes {443. 710, 12OJ. 1971, 2072, 23821. There may be a range of eosinophil abnormalities, including sparse granulation with clear areas of cytoplasm, cytoplasmic vacuolation, nuclear hype rseg men tation or hyposeg me ntati on, and enlarg ed size, These c hanges ma y be seen in cases of reec uve as well as of neoplastic eosinophilia, however, and are thus not very he lpful in deciding whether a case is likely to be CEl {1281. Neutrophilia often accom pani es the eosinophili a , an d some c ases have monocytosis, M ild basoph ilia has been reported 17101, Blast cells may be present but are less than 20%. The BM is nvoercenotar due in part to eosinophilic proliferation 1289, 443. 710, 1200, 2382 1 In most cases, eosinophil maturation is orderly, w ithout a d isp ro portio na te inc rease in m ye loblasts. Ch arcotl eyden crystals are often present. EryttTopoiesiS and megakaryOCytopoiesis are usually normal. The finding of inc reased num bers of m yelob lasts (5-19%) supports a di agn osis of CEl, as does the ob servation of dysp lastic features in other cell linea g es. M ar row fibrosis IS seen in some cases 1289, 7101. Any tissue may show eosinophilic infiltration and Charcotleyden crystals are often present. Fibrosis is a common find ing . an d is caused by the d egr anu lati on of the eo sin op hile wit h the release of eosinophil basic protein and eosinophil cationic proteins {443, 1931 ,2382} .

,

Fig. 2.31 Ch ron ic~oop/l i l ic ~uk.aem ia . Peripheral blood smear from a patient With ahistory ofpersjstent eosi1c?* Immatureaswell as mature eosinophilsarepresent CyloQenebc arlalysis showed trisomy of chromosome 10,

disease 1128. 19311. In addition, a number of neoplastic disorders such as lym phoma, Hodgkin lymphoma, sys tem ic ma stocytosi s, acute lym p hob last ic leuk· aemia and other MPN may be associated with abnormal release of Il2, 1l3, ILS or GM-CSF and a secondary eosinophilia tha t mimics CEll 128 , 1168, 1172, 1450, 1616. 1924, 1931,246 11: in systemic mas tocytosis there can also b e eosinop hils be looging to the neo pl astic clone. The BM should be carefully inspected for any process which might explain the eosinophilia as a secondary reaction, such as vasculitis, lymphoma, acute lymphoblastic leukaemia , sys tem ic m as toc ytosis o r gran ulomatou s d isorders. Some cases of persistent eosinophilia are due to the abnormal release of cvtocnes by t-eens that

t-een

are immunophenotypical1y aberranl an:! tha t mayor may not be clonal 1286, 1156. 202 41. When such an aberran t T-c ell pop. ulati on is presen t, the case is not CEl00 is it idiopathic HES. If the monocyte con is > 1x1r:P1L a diagnosis of chronic mye;o. monocytic leukaemia with eosinoptlU may be more appropriate, but if there are dysplastic features and> 10% neutrophl precu rsor s in the PB and no rnonccytoss. a d iag nosis of atypical chronic myebd leukaemia with eosinophilia should Sifn. larly be considered. The distinction between GEl. NOS. arc idiopattuc HES is important. Idiopattlc HES can be diag nosed onl y in fUlly investigated pa tients and on ly when (i) there, an eosinophil count of
Differential diagnosis D iag nosis re qu ires posi tiv e evidence of the leukaemic nat ure of the co ncnton and exclusion of cases of MPN with rearrangement 01 PDGFRA. POGFRB or FGFR1. The diagnostic process often starts wi th exclusion of reactive eosinophil ia. A d eta iled histor y, physical exam ina tion, b loo d count an d blood film ar e essential. Conditions to be excluded include parasitic otectoo. allergies, pulmonary d iseases such as Loetner's syndrome. cyclical eosinophilia. skin diseases such as anqictymphoid hy perplasia, colla gen vascular d isorders and Kimu ra 's 52

Myeloproliferative neoplasms

1. There iseosinophilia(eosinophil count
3. There is nott.5;12)(q31-35.p13)« ohIr ream1l9B"*~of PDGFRB -4

There is no FlP1l1-PDGFRA fusion gene crotherrearrangement 01 PDGFRA

5, There is noI'88rrangemerlt of FGFR1 5. Theblast cell count in the peripheral blood and bone marrow is less than 20"10 and there is 110

'l\'(15)(p13Q22) IX 1(16;16)(p13;q22) IX oIher lealureGagrlosbc ofAML 7. There is a cbIaI cytol}eneIiC or rnolecaar genetic abnormaIrty, IX bIasleels aremore lhan ~ in !he ~ bk:Jod« men than 5% in !he bone marn:ow ·If apatient haseoiil"lOPhilia bul lhese mlenaare not met !he dial;Joos4S may be reactive eosinopt1ilia,idiOpa1tMc

hypereosinophilia or idiopathic hypereosinophilicsyndrome,

,. e

tiC

1m

Nc

m,

G. No

"'"

;d

a, • Fa lu

ca wit

GEl

con

maO as

•

eosinophilia is excl ude d by appropriate h:lrcxJgh investigatoo ; (iii) AML. MPN, MOS. MPN/MDS and systemic ma stocytosis are excluded; (iv) a cytokine-prod ucmq. ~icalty-aberrant. t-een pop ulation is excluded; (v) and there is tissue damage as a result of hyper eosinophilia . Hcnteria i-iv are met but there is no tissue damage. the app rop riate d iagnosis is ocoamc hyperoosinop hilia . Patl8rlts in whom a diagnosis of idiopathic Itypefeosinophilia or id iopalhic HES is made should be kepi und e r reg ular review since evidence may su bsequently Emel'g8 that the con dition is leukaemic in !'laue, Treatment may also be necessary

e,tlchemstry Cytochemical stains c an be used to identify eosinophils bu t they a re no t essential for diagnosis , Partial degranulaeco can lead to eosinop hils ha ving reduced peroxidase con tent.

-

No specific immuno p henotypic ab nermalily has been reported In CEL.

Geretics No single or spec ific cytogenetic or molecular genetic ab normality has been identified in CEl. NOS . Cases with rearrangement of PDGFRA, PDGFRB or FGFRI are spec ific ally excluded , The detectOO d a Ph cbrcroscre or BCR-ABL 1 fusion gene ind icates one of the rare cases of chronic myelogenous leukaemia wnh dominant eos inoph ilia . rather than eEL. Ellen when eosinophilia occurs in conjunction with a ch romosomal abnormality that is usually mye loid neoplasmassociated, it may be difficult to decide

_.-

F"l9- 2.32 kiopaltiC HES. Ablood smeard a pabertWlth ca-dIaclai.n,1eukot'yt:lsi$ and~ .

whether the eosinop hils are pa rt of the clonal process. since react ive eosi nophilia can occur in patients with myeloid neo-pla sms 17111. However, the linding of a recurring ka ryotypic abnormality that is usually ob served in my elo id d isord er s. suc h as +8 or i( 17q), does suppo rt the d iagnosis of CEl 1128, 1692 ). Occasiona l pat ients have a JAK2 mutat ion 1106 41. x-unkeo polymorphism ana lysis of the PGK or HUMARA genes c an oc ca sionally be used in fema le patients to dem onstrate cionautv 1392, 13501.

Prognosis and predictive factors Survival is quite varia ble. In some series in which pat ient s with idiopathic HES as well as those with probable eosinophilic leukaemia were incl uded. 5-year survival rates ap proached 80% 1443. 19 71,2072, 23821. Marked splen ome g aly. as well as the find ing of b lasts in the b lood or inc reased b lasts in the 8M , cvtcqeneuc abn ormalities and dysplastic features in othe r my eloid lineages have been reported to be unfavourable prognostic find ings [443, 1971. 2072 ,2382].

Postul ated cell of or ig in The ce ll of orig in is a haemopoietic stem cel l, b ut the lineag e potential of the affec ted cell may be var iab le.

Chronic eosocobtc leukaemia. not otherwise specified

.

53

.

Mastocytosis

H ,-P' Horn y'

n.o. Metc alfe J.M . Bennett B,J . Bain

Definition Mastocytosis is due to a c lonal, neoplastic prolife ration of mast cells thai accumulate

in one or more organ systems. It is characterized by the presence of mult ilocal

compact clustersor cohesive aggregates! infiltrates of abnormal mast cells. The d isorder is heterogeneous. ranging from skin lesions that may spontaneously regress to highly aggre ssive neoplasms associated w ith muttiorgan failure and short survival (Table 2.09). Subtypes of mastocytOSis are recog nized mainly by the distribution of the disease and cli nical manifestations . In cutaneous mastocyt osis (eM), the mast cell infiltration remains confined to the

Solitary mastoc ytoma of skin Indolent systemic mastocytosis Systemic mastocytosis withAHNMO" Aggressive systemic mastocytosis Mast cell leukaemia Mast cell sarcoma Extracutaneous mastocytoma

skin, whereas systemic mastocytosis

Synonym Mast cell d isease .

IC[)..() codes Cutaneo us mastocytosis (urtica ria pigmentosa) Diffuse c utaneous mastocytosis

9740/1 9740/ 1

Table 2.09 Classification of mastocytosis. , Cutaneous mastocytosis (CM)

2, Indol&nt s)'5t&mic mastocytoSis (ISM)

3. Sy5temic mastocytosis wittl associatedclonal haematological non-mast-celliineage disease (SM·A.HNMDj

4 AggressiwSy5temic masklc)'toSis (ASM) 5, Mast cellleul<.eemia (MCl)

6. Mast c:eII sarcomlI (MCS) 7. Ertacutaneous meslocytoma

For the partlClpl!lms 01 the Vear 2lXXl Wortung Group ceeeeece on Mes\OCytOllS .....no ~ flo.ooIved in the def,r1llJOIl 01 crwarU. I( Sollar. ~ $perl. P V8Ienl. .IN 'laid.. man. K WOlIf

54

MyeloproliferatIVe neoplasms

9740/1 974 1/ 1 97 41/3 97 41/3 97 4213 974013

974011

"AHNMO, ass oc iated naematoioqrce! c lonal non-mast cell d isorder

(SM) is characterized by involvement of at least one extracutaneous organ with or without evidence 01 skin lesions . Mastocytosis shoul d be strictly separated from mast cel l hyperplasia or mast cell activation slates without morphological an dJor m0tecuer ab normalit ies that characterize the neoplastic proliferatio n.

C. Akfl L Escribaro P. Valert

Fig. 113 Cutaoeoos maslOCytosiS. Darier"s '91- TIl skit lesions 01 III bms 01 0Jtane0us II'\a:Stlc)t::s ~ wI'len stroked A. palpable wileaI ~. IN moments afterhlltJysical sllrIUatIon, lkJe" hi,.. 0I1t1slamnt from !he mastcells,

Epidemiology Mastoc ytosis may occur at any age Cutaneous mastocytosis is most common in c hil dren and may be present at birth. About 50% of afflic ted chil dren develop typical skin lesions before 6 months of age . In adults. CM is less frequently diagnosed than in ch ildre n 12055 . 2436 1. A slight male predominance has been rep orted in C M. SM is generally di ag nosed after the second decade of life ; the ma le to female ratio has been report ed to va ry from 1:1 to 1:31 181, 1465, 1694). Sites of involvement Approximately 80% of patients with mas toc ytosis have evid ence of skin involvement {16871 . In SM the bone marrow (BM) is almost alwa ys involved, so morp hological and molecula r anal ysis of a BM b iop sy specimen is stron gly rec ommend ed 10 con firm or exclude the diagnosis [287. 290, 971, 12751. Rare ly. the pe riphe ral blood (PB) shows leukaemia due 10 significant numbe rs of circulating mast ce lls {972. 14841. Other organs that may be involved in SM inclu de the sp leen. lymph nodes, liver and gastro intest inal tract mucosa, b ut any t issue may be affected

1287,966.968.973, 1275, 1334. 1466. 1694 1. Skin le sions occur in more than

50% of SM pat ients, and are more often observed in those with an indol ent course.

Fig. 2.34 Cutaneous mastocytosis, Numeroos typi:;i

eac nar and maCtllop.apular pigmented eseu ct urticaria ~gmentosa in a young child "

Fig. 2.35 Ditluse artaneous mastocytosrs. T'I'OenC. reddlSh'peau ~' 1esic:In$ d'Ia'acteI'isbc oIlilta

cutaneous mastocytosis This variant ocan exdusiYely in d*\'eIl

am:..

In contrast. aggress ive va riants of SM often present without skin lesion s [97 11 . However, some SM patients withou t skin escos may on occasion present wit h an indolent form of SM, most often isolated 8M mastocytosis.

I

CIricaI features Cutaneous mastocyt osis includes several cetrct cmco- nistocettoicqcar en tities. l esions of all form s 01 CM may urticate when stroked ("Darier's sign 4 ) and most snow intraepidermal accumulation of melanin pigment. The term 'wtcana 4 ptgmentosa mac roscop ically describes two clinical features. Blister ing ("b.bJs mastocytosis") does n:lI represent a separate subtype but rather an exaqgeralion 01 urticaria. Blistering is usually seen IrIpatients less than 3 years of age. m may be assoc iated with all forms of CM 11 68 7, 2055, 24361. Symptoms in SM at presentation have beefl grouped into 4 c ategor ies: 1) conSbtUtIOO8! symptoms (fat igue, weight loss, Mr, diaphoresis). 2) skin manifestations (prurituS, urticaria, dermatographism). 31mediator-related systemic events (abdcminal pain. gastrointestinal d istress , Dushing. syncope, headache. nvpoienson. tachycardia. respira tory symptoms) and 4) musculoskeletal complaints (bone pain. oeteoceora'osteoporoers. frac tu res, <JltIralgias, myalgias) {181, 22901 . These symptoms range from m ild in many pabents to severe, life-threatening med iatorrelated events in othe rs, Sym ptoms ma y also be related to orga n impa irme nt (du e 10 mast cell infiltrates), pa rticularly In patients with high-grade ag g ress ive or eukaernic disease variants, Physical findings in SM at d iagn osis m ay InClude splenomegal y (o ften minimal). \lltile~dooopalhy and hepatome galy are foond at signif ica ntly lower trequencies !966,968, 973. 1275, 1466 1. Organornegaly is often absent in the m ost rormon variant. indolent systemic mastocytOSis(ISM). but is usuall y p resen t, alo ng w impaired organ function, in aqq resSNesystemic mastocytosis (AS M) an d in leukaemic variants. Severe systemic ~s may occ ur in patients w ith ISM bbwIg eceosve release and generatIOn rJ bcctemcar mediators including tustaI'!'f'e. eicosanoids. poteases and heparin. For example, gastrointestinal symptoms S\.d1 aspeptic ulcer disease Of diarrhoea n more corrmonly attributed to release rJ biologiCally active mediators than to

Fig. 2.36 Indolent syslelTllt mastocytosis. Dense infiltrate conSisting mainly 01 spind~ sti\tJ1Iy ~nUar

mast eels.

sese

ceeoanc

Fig. 2.38 Indolent systel'lic mastoeylOSis. A loo5eIy scattered spmd\Hhaped tlypograrlular mast cells WJlhooI tendency III awegate. Diagnosis is lacihlatedI'fhen addibonal imrrI.rnostaHWI and moIeaJIar analysis n performed. B IrrITlIA'lOSlain withCD25 shows an atypical ~ 01 mast eels with rnentlralle assooated reactivity.

Fig. 2.39 Systemic mastocytosis, Skeletal lesions ate common in systemic masloc,1OSiS. This X-ray shows paldty osteosclerosis, osteoporosls WId multiple IyIiclesions mille lemur, infiltration of the g astrointestinal trac t by excessive numbers of abnormal m ast cells P8 1. 1334 , 2288 1. Ha ema tologica l abnormalities in 8 M include an aemia , leukocytosis, blood eosinophilia (a frequent f inding). neutropenia . and thrombocytopenia 1130, 287.7 13.971 , 1162 , 16871. Bone ma rrow

failure is encountered only in patients with aggressive or leukaem ic disease varian ts. Significant numbers of circulating m ast celts are rarely observed and are suggestive of mast cell leu kaemia 122901. In up to 3)% of cases with SM. an associated ,

clonal haematological. roo-mast cellileage d isease (AHNMD) is d iag nos ed before. MasfOCytosis

55

T~ble

2.10.Criteria lor cutaneous end systemic maslocytosis

Cutaneous mastocytosis (CM)" SIOO lesions demonslrebng!he typical dinicallindlng5 ofUPIMPCM. diffuse cutaneous mastocytosis or soIttary mastocytoma, and lypiCBltlistoIogical i1filtrates 01 masl cells in a lTlJltJlocal or dlfIuse ceeem in anadequate skill biopsy. Inaddition. a tiagnosbc prerequiSIte b thediagnosis of CM is theabsence 01 features/aliena sufficiant toestablish the ~s 01 SM °l/p(laled and &I9llly modified cnteliab skin i1YO/YemerJt in mastoey!OSiS have recetlUy been suggested {
S)'Itemic mastocytosis (SMI

The diagnosis 01 SM CBl be made when the IIIaJOI' critenon and one IIIir'Ia criterion or at least Ihnle mnor crrteIia are prMel'll

lIIajor crilerion; t.UlrfocaI, dense rliIlrates rJ mast eels (::!:15 mast celI$ n ~) deleded i1 sections of bone I'IllIITOW and/or OCher eltraaAaneous organ(s) Minor criIW:

1. In biopsy sedJons rJ bone nwrow orOlIlItel1raCUlaneOuS organs, :>25%ollhe mast eels r11he infihle are ~ orhaveatypocaIlll(llllI1CJIog or, d aI mas! eels n bone m.arrtM'asprate smeaR, :>25% aremnalln oratypical.

.........

2. Deleclion of an ICtiYaII'lg poI"It rnuta\lI:Wl at c:odor1816 of KIT~ bone manow. blocdor anolher eJ:lraCula.

3. MastOBIs itI bone marrow. blocdor oItler eJhcutaneous organs express CO2 and'orC025 in adl;1itlOII ~ nonnat mast 011 maR-eB.
simultaneously with. or after the diagnosis of SM. In princi ple, any defined myeloid or lymp hatic malig nancy may occur as the AHNMD. but myeloid neoplasms predominate, and chronic myelomonocy tic leukaemia (CMML) is most common 197 1, 9 75. 2056, 2066, 2095, 22901. In patient s with SM-AHNMO, clinical sympt oms and disease course relate both to the associated baematoioqrcat disorder and to SM 11977, 2290). Serum tryptase levels are used in the evaluation and monitoring of patients with mastocytos is, The finding of a pers istently elevated serum total trypta se > 20 ng/mL is suggestive of SM and is used as a "minor" criterion for diagnosis, unless there

Fig. 2.40 Typical skin lesion of a d\Ild WIlh ur1icatia pigm&nIosa. Aggregales of mast cells Iil Ihe papIIafy demIII a'ld edllnd as 5he8ls into Ile f'8tJCWr clemis.

56

Myeloprol!ferative neoplasms

is an assoc iated clonal myeloid non-mast cell disorder, in which case this parameter is not valid. Serum trypta se levels are normal to slightly elevated in mos t pat ients with CM and have also been found to be independent of the patient's tryptase hap lotype 11977, 2290). Morphology The diagnosis of mastocyt osis requ ires demonstration of rnultifocal clust ers or co hesive aggregates/infiltrates of mast cells in an adequate 8M biopsy specimen (Table 2, 10), The histolog ical pattern of the mast cell infiltrate may vary according to the tissue sampled 1130, 290 , 7 13, 966, 968 ,973, 1162, 1466 1. A d iffuse interstitial

infiltration patt ern is def ined as loosely scatte red mast cells in the absence of compact aggregates. It must be noted. however, that this pattern is also observed in reac tive mast cell hyperplasia and in cases of mveromastccvnc leukaemia. a term used for cases with advanced myeloid neoplasms in whom elevated numbers of immature atyp ical mast cess are found , but criteria for SM are not met 120651. In patients with the diffuse infiltration pattern it is therefore impossible to establish the diagnosis of mastocytosis Without ad ditional studies including the demonstration of an abe rrant illYT'lUfl(} phenotype and/or detection of an acliva!· iog point mutation in KIT1977, 978 , 1196 2056,20571 , In contrast, the presenced rruttifocal compact mast cell infiltrates ora diffuse-compact mast cell infiltration pattern is highly compatible with the diagnosis d mastocytosis during first inspection. H0wever, additional immunohistochemical a'Id molecular studies are strongly reccnmended even in these cases. In tissue sections stained with H&E, ~ reactive mast cells usually are loosely sca ttered througho ut the sample, and display round to oval nuclei with clumped ch romatin, a low nuclear/cytoplasmic ratio. and nucleoli that are absent CI indistinct. The mast cell cytopl asm is abundant and usually filled with small faintly visible granules. Dense aggregates of mast ce lls are only very exceptionalfy detected in reactive states or in patere treated with stem cell factor (SCF) 11 275 1694. 22901. In smear preparations, mast ce lls are read ily visible in Romanowsky stains as med ium-sized round or oval cells with plentiful cytoplasm , con ta in i~ densely packed metachromatic granules and round or oval nuclei. In norrnarreao tive states, mast cells are easily dislil'\o guished from the smaller metactvonac

TIIbIt 2.11 SubdaSSlf?tiOn 01cutaneous mastocy1osis,

1. ~ pioJnenIosa (UP V~

ewneous mastoeylosis (MPCM)

1.

2 DIuse l:lJWoeou$ mastocylO$ls 3,

Sl*arI mamcytomaof skin

basophils which have segmented nuclei, and larger and fewer granules. With enzyme cytochemistry. mast cells reac t strongly wrth naphthol·ASD-chlofoacetate esterase (CAE) but do not express rnye!operoxidase In mastocytosis. the cylOIogy of mast cells vanes, but aboor'!'tal cyIo1ogic features are almost always oetected. nckJdlllQ marked spindling and hypOgrarJJlarrty 122901. Cytanorpnoiogical atypia is pronounced 1'1 higtl-gfade lesions 01 mastocytosis. ee occurrence of metachromatic ees cells being a usual feature 01 mast celleukaemia 122901. The finding of treQUeft mast cells with bi- Of multi lobated I\dei rpromastocytes") usually indicates if! aggressive mast cell proliferation. aIItOJgh these cells may be seen at low IreQuency in other subtypes of the disease 122901. Mitotic figures in mast cells Ii) occur, but are infrequent even in the aggressive or leukaemic variants of SM. Kl assess mastcell numbers with cowenlO"aISlalning procedures, Giemsa or toiuidine blue are employed 10 detec t the metachromatic mast cell g ranules and CAE IS alsohelpful 122901. However, the roost specitc methods lor ide ntific atio n of nmature or atypical mast ce lls in tissue sectons utilize immunohi stoch emic al staimng fortryptase/chymase and CD 117 and, for neoplastic mast ce lls. C0 2 and CD25, The morpholog ic features of th e common subtypes of mas toc ytos is are tescnoeobelow.

~dk19nosis of

eM requires the d emon-

strahon of typical clinical find ing s an d 'VSlOIogical proof of abno rma l mast ce ll atoo ol the dermis (Table 2.10). In cases a isolated eM. there is no evide nce ~ systemiC involvement using such oa1I'l"ell!fS as elevated levels of total ser um ryptaSe or organomegaly. Recently, consnus craeria for the diagnosis of CM Il8've been further relined. and three • vanants of CM are now recogniZed

1atIIe 2111122861.

IndolentsystemicmlStoeytosis(ISM) Meets arteria b" SM. No"C" findings (see below). No evldence of afl associated non.roastc:elli'leage cJonaj I1aematOOgicaI mali\1laflc.yldlsonlel" (AHNMOI· In !hisvanant. !he mast cellMOefllS low and skin lesions areaWnosI i'lVaria ~ present

1.' BDnemarrow mastocytosis As above (ISMI wiIIl bone marrow involvement. but noskin lesions. 1.2 Smouldering systemicmastocytosis As above (ISM), but wI\tl 2 oc ITIOl'e "8' fn:l1l'lgS but no "C" ffldings.

2. Sptemie mastocytosis with n soeiBted clonal hMmaI~ norHnUt c:.Illl. . . . disease (SMAHNMO)

Meets CriIeria torSU and cntenalor an assoaaled. donIlIl'IIemaloklgicI flOIloITIaII eel lineage disorder. AHNMO !MOS, MPN .AJ.IL,~ . oc ott. ~ neopasm tIal meets !he aliena b" a disbnd~ " tie WHO cIasslticaIm). 3.

AggrlSSivt systemic: mastocylosis (ASM)

......

Meets c:nena b SM.
*

Cutaneous mastocytosis (eM)

I

Table 2.12 Criteria lor variants 01 systemic mastocytosis

3.1 l~hic mastocylOiIs with t
.t. Mast c:elileukaerrlia (MCl) Meets cnteria lor SM. Bone marrow biopsy shows a ~ lrlfiIIrabOn. usualy oompacl. by aIypicaI, immaturemast cells. Bone IT1arnl\lr aspirate smears snow 2O"It or more mast eels In typitaI Mel . mast cells aa::ountfor 10%oc more of~ blood wtIIte eels. Rarevanllfll: aleukaenK mast c:el leukaernla - as above. but <1 0% ofwlile bloodcells aremast cells. Usualy wiIhouI sbl lesions 5

6.

Mas. c:ell 5MComa (MeS) . lJfIifocaI mast celllurr'OJr. No evidence 01 SM. Oesll'uClive grow\tl pattern. HiQh1lrade cytology,

-

Extl'illcutaneous mastocytoma UnilocaJ mast cell ltl'TlOU', Noevidence 01 SM. Noskin lesions. NoOOestruetiYe !1owth pattern, Low-grade

-8" findings 1.

Bone marrow biopsy showing >30% infinratkin bymast cells (focal, ceose aggregates) andlor serumlolal lryptase level >20 nglmL.

2. Signs of dysplasia or myeloproliferation. in ten-mast ceil lineage(s). but insufficient criteria for definitive diagnosis of a haematopoietic neoplasm(AHNMD), with nonnal or only slightly abnormal bloodcooors

3. Hepatomega ly withoutimpairment 01 ~v&r function , andlO!" palpatlle splenomegaly without hypersplenism, and/or lymphadenopathyon palpalfon or imaging "C" findings 1_ Bone marrow- dyslunction mal1lfasted by ooe Of more cy\OI)a!1ia (ANe <1.Ox10'1l.. Hb <10 gJdl, lX platelets <1 Clli10"Jt). but noobvious noo-mas! ceU haematopoielic malignancy 2, Palpahla !lepatDmagalywiltl impairment oI ~ver 1uncIlon. ascites and/or portal hyperterlSior1. 3. Skeletal i1'o'Oi'o'eman1 withlarge osteolytic lesions d Ol' palhologtcallractures. .t. Palpablesplenomegaly With hypetSJlielVsrn.

S. Malabsorption WlIh we9Jl loss due 10 GI mast cell infiftrates,

Urticaria pigmentosa (UP)lmaculopapufar cutaneous mastocytosis (MPCM) This is the most lre q uent form of CM. In child ren,1he lesions of UP tend to be larger and papular. Histopathology typically reveals agg regates of spindle-shaped mast cells filling th e papilla ry dermis and extending as sheets and ag gregates into

the retic ular dermis, et ten in per ivasc ular and pena dnexar pos itions 124361. A subvariant. usually occurring in young children. presents as non-pigmented. pl aqu e-forming lesions. In adul ts . the lesions are d isseminated, and tend 10 be red ex brown-red and macular or maculopapul ar. Histopathology of adult UP tends to reveal Mas tocytosiS

57

Rg. 2.43 A Booe marrow smear of a patJenI WIth indolent systemiC masUytosi$. The eel is atypical. witIlan indenled nucleus in an eccentric Iocabon, and cytoplasm ... .... an ~ emson WIt1 ~ dIslr1buIim of ~ 8 Sysl8rlIc rnastlc)tlsIs. The eels may haw bland ru:lel WIIIl moderate ~ of 1* tyqllasm , spinIed _ _ .. I'MeITtlle fibroblasts. or IctllAated nuclei WIth ab.nln dear C)'kIpIasrn The Ialler eels mayresermle rnonoc:ytes or his/ioq'Ies. and ant more oommooly seenin aggnssift

"' .....

fewer mast cells than observed in children. The numb er of lesoner mast cells may sometimes ove rlap with the up per range of mast cell number s found in normal or inflamed skin. In some cases, examination of multiple biopsi es and immunohistochemical analysis may be necessary to establi sh the diagnosis of e M 12286, 2436).

Diffuse cuta neous mastocytosis This clin ically remarkable subvanent of CM is much less frequent than UP and presents almost exclusively in childhood . Here the skin is diffusely thickened and may have a peau chag rine or peau d'aange (orange peel) appearance. There are no individual lesions. In patients with cl inica lly less obvious infiltration 01 the skin, the biopsy usually shows a band-like infiltrate 01mast celts in the papillary and

•

upper reticu lar dermis. In massively treted skin , the histological picture !Tll'f be the same as that seen in solitary mas» cytorna 12055, 24361.

•

c

Mastocyt oma of skin This oc cu rs as a single lesion, almost exc lusively in infants. without predi lecl~ of site. The histolog ic picture is one ~ sheets of mature-appearing highly metachromatic mast cells with abundant C'/'I> plasm that densely infiltrate the oa and reticular dermis . These mast eel trates may extend into the suocoteoece tissues (11541 . Cytological atypia is na detected . This allc:M's separation 01 mas» cytoma from an extremely rare mast eel sarcoma 01 the skin 119581.

•

c

n s

Cl

a

w

Systemicmastocytosis (SM)

sa

The prerequisites for the diagnosis of So\! are outlined in Table 2.10. In most cases. ag greg ates 01 atypical mast cells a1 readily found in tissue sections. The crtt9'll lor variants 01SM are given in Table 2.12.

di,

He

Fig. 2.45 SystemiC mastocytosis, booe marrow bklpsy. A The local lesions01 mast cellschenconsist of a central core ol lymp/lOCyles, surrourldlld by polygonal mast cells with pa~ . faintly lJ"iJrlUlarcyIOplasm. WIth reactive eosinophils at the outer margirl ol lhe lesion. 8 The lesiOns are often well-circumscribed. and may OCCIJ" irl parauabecular or perivascular Iocabons, but may be I'lV'ldorTWy dislnbuted in the interll'abeclAar regionsas wei.

58

Myeloprol!terative neoplasms

Bone marrow In most cases of SM, multifocal . sllar~ demarcated compact infiltrates 01 rna; cells are the most common and easily ce tect able feature in the BM bio psy. The infiltrates are found pred ominantly If paratrabecutar and/o r perivascular locations 1290, 965, 971, 977, 978. 11981. The focal lesions are co mprised 01 varyiOj numbers of mast ce lls. intermingled w varying numbers of lymphocytes , eoere phils , tusnocytes. and fibrob lasts. These diagnostic "mixed" infiltr ates are o/tell

ex era fr

of

s my pl. my 00<

d isl 0' qUE

148

'he

seen in ISM and generally show eithe r a central core of lymphoc ytes surrounded bymastcells, or a central compact mast eel aggregate with a broad rim of lymphocytes 19651· In other cases , the lesions are mot e rronorooptec and are many composed of spindle-shaped mas! cells that abut Of stream along the bony trabeculae 1977 . 9781 . Significant relJCulin fibrosis and thickening of the adlacent bone are frequently Observed . ScrnetIITles. the 8 M space is d iffuse ly replaced by compac t mast cell infiltrates , which may resemble sheets of fibroblasts 19711. Marked reticulin or even collagen fibrosi s is frequentl y observed in such cases 1971 , 977, 9781. Usu ally, there is a mixture of both spind le-shaped and round mast cells. Rarely, co mpac t infiltrates may exclusively consist of round hype rgr anu'af mas! cells, which meets the criteria for so-called trvptase-c ostnve round cell l'lfiltratioo 01 8 M (TRDCI-8 M) 19761. In cmrest to spind le-shaped tryptaseexpresSing cells that are alw ays mast cells, the round nvptase-posmve cells in TROCI are either mast ce lls (coexpres9IOl'l li C0111 and c hymase), neoplastic !laSl:ViIS (primary or secondary basoIt1k leoIo:aemial or myeloblasts in the

should be classified according to established WHD criteria . II is important to note whether the re is inc reased cellularity of the marrow or d isturbed maturation of haematopoietic cell s, because. even if c riteria lor a coexisting myeloid neoplasm are not completely fulfilled , hypercetlutarity Of abnormal myeloid maturation patterns cou ld be associated w ith an unfavourable out come (progression to ASM or SMAHNMD) or with a smouldenng variant of SM in which the out come is uncertain 122901. Inter pretation of findi ngs must include consideration that reac tive , nonclonal mast cell hyperplasia may accompany a var iety of haematolog ical

disorders, including myeloid and especially lymphoid neoplasms, such as lym phoplasmacytic lymphoma or hairy c ell leukaemia 122901. In such reactive states , the predom inantly round mast cells lac k major" cytological atypia. and are almost always loosely sc attered throughout the tiss ues. a find ing that c learly contra sts with the compact aggregates 01 reooiastc spindle-shaped mast cellsfound in mastocyt os is 122901. The d ocumentation of 8M involvemen t accompanying SM is usually established by examination 01 a 8M trephine biopsy specimen. However. the analysis of marrow aspirate smears does provi de useful

Fig. 2.46 Systen'ic masb;ylosls, spleen, A Sl)Ieen tom a pa\letIt 'lII'i01 systen'ic maslIXylosls. B Aggregates rJmast

eels may be seen II \tie red orwliIe pulp, orbolh. ~ his case, mast eels ate seen II a penloIi::IJNlocation.

sett.ng of a trvotase-oosmve acute

'l'IyflIOId eokaene. CaretlJ inspec tion of the 8M no t at!ected by mastoc ytosis is of crucial ecctarce. Often, the una ffected 8M is II1remarkable with a normal distribution of tal cells and haematopoenc p rec ursors . Such cases usually eithe r belong to ISM o\'lthinvOvemen! of skin and 8M , or re preSMt isolated mastoc ytosis of the 8M , However, in othe r c ases th e 8M not drectly infiltrated by mast cel ls may be extremely hypercellular due to the prolifescoof cells of non-mast cell lineages, tduding neutrophils, rnonocytes. or less frequently, eosoopbns or b last cells. DePQ"Ong on the type of proliferating cells, lindlngs may be reactive (myeloid ~ ), or may indica te the presence d acoexisting naematoooeuc neoplasm ll.d! as acute myeloid leukaemia , a ~ollferatiYe neoplasm, a myelodyssyndrome or myelodysplasliC/ ~ferati ve neoplasm, Of chronic ...""llc ~. Lymphoproliferahve diseases, such as plasma cell myeloma ~ malignant lymphoma. are less Ire(JJllfl\Iyseen 1110, 969 , 971, 975.1 147 , 1484 2056,2066, 20951. In all such cases, ~ associated naematoroorc d isea se

eese

I t

e

• e 9 ~

m

Fig. 2.43 SM-AHNUD (acutemyeloid Iel.Jkaemia). A The streaming, spindled eels of a largemast eel aggregate can be seen on one side rJ lhe booy lrabecUkJm (arrow), weeeas a rTlCIllOIonoUs J)Opljabon of blast cellsis seen onlhlI opposite side . B The spiodledcells of mastcell disease abut on a large aggregale of blasts.

Mas tocy tosis

59

A

granulomatoid lesions in the caranececular and paratoucurar areas. or within the lymphatic follicles, or as diffuse infiltrates within the red pulp. As in other tissue sites, eosinophilia and fibrosis are frequently observed in areas of mast eel infiltration. In some cases. an associated haematolog ical disorder may be present, but this is often difficu lt to diagnoseusirg splenic tissues alone 1973, 14661.

...C

Liver Liver involvement in SM usually presen With disseminated small granulomat foci of mast cells within the periportal tracts and as loosely scattered mast eels within the sousoos . Severe liver i~ rrent is only rarely seen in SM. WiderWg and fibrosis 0 1 periportal areas is cctmonly found . but fully developed cirrhosis is rare 1966, 14661.

f~ 2,49 SystemicmastlcyloliswiltI associ8led hl*yt:ell Waerria. A Bone marrow aspi'a'B smear Wllh hairycels and al)1liCal mast eels B The spirded mast cells M pteSel11 adjacentto the hairy eel i'lfiItJate il lhe intersbbaI regions oI1he IT\il'I'OW Although hairycelleubemia may occasioRaIy assume a spindledlTW)IJlIlology, in Ihis case lhe mast eel tryplase lustrated in (e ) dearly demonslrales !he masl eel origin 01 ltle spindled tens. alll! an imuIostaIn for C020 idenlifles ltle IIaify eels in (D).

additional information and is c rueial lor the diagnosis of mast ce ll leukaemia and 01 some suovanante of $ M-A HNMD 122901. In ISM, most mast ce lls are found within

the thicker regions of the aspirated crushed fragments. Mast cells in ISM, which should always be assessed in the thin region s and at a fair di stance from 8 M part ic les , usually com p rise < 1% of all nucleated marrow ce lls. This is in contrast to mast ce ll leukaemia, where mast cell numbe rs b y defini tion equal or excee d

20% of all nucleated cells in aspirate smears 1290, 977, 978, 2290}, Lymph node Lymph nodes appear to be rarely involved in 8M in that significant lymphadenopathy is unusual. The mast cell infiltrates within lymph node s may involve any of the anatomical compartments but particularly involve the paraooncat areas. Mast cell infiltrates can be either foca l or diffuse, but rarely totally efface preexisting archi tecture. Hyperplasia of germina l ce ntres, evide nce of angi oneogenesis, tissue eosinophilia, plasmacytosis and reticulin/coll agen fibrosis usually accompany the mast cell infiltrates 1968. 14661. In a few patients, lymphadenopathy is marked , with a progressive clinical co urse mimick ing malignant lymphoma . II Sig nificant blood eosinophilia is present. such cases

60

Myeloproliferative neoplasms

have been reported 10 belong to a defined subset of ASM, namely "Iymphadenopathc SM with eosinophilia" 11484, 22901. In such cases, studies for rearrangement of PDGFRA are recorrmeoded, and if present, the cas e should be reassigned to the category of myeloid neopla sm with eosinophilia and rearrangement of PDGFRA. Spleen The white and red pulp of the spleen may be involved in SM, with rare case s showing preferential infiltration of the lymphoid follicles of the wh ite pulp (9731 . Here. mast ce ll infiltrates often present as focal

Gastrointestinal (GI) tract mucosa Involvement 0 1 the GI tract mucosa bf mastocytosis is frequently suspected ctnically but may only rarely be assessed morpholog ically. As in omer tissues, • least one compact mast cell infiltrate isrequireo to support the diagnosis of SM. IfI typical cases. these mast cells shOw an abnormal immunophenotype with expression of CD25, and an activating poirt mutation of KIT is present. Due to the Irequency of CD25- positive lymphocytes. careful examination of the tissue is recessary to avoid false positive results. To eva luate a GI biopsy for mastocytosis, both antt-trvotase and anti-C0117 anti' bod ies should be applied in order to avoid false positive results due to strong bac kg round staining when only ant~ tryp tase ant ibodies are used. A lew

exceptlOl'l3l cases exhibit a diffuse compact infiltration of the lamina p ropf"ia mu cosae by atypical mast cells , and this 'f'B1 reseroe inlIanTnatory bowel disease r:1 malignanl lymphomaat first glance . AIklgelher, lour patterns of involveme nt of theGI tractmucosa by mastocytosis can be dlscnminaled 1171 1: 1) Loosely scattered mast cellswithout dense ag gregates W wrth an atypical immunophenotype and an activating point mutation of KIT, usual~ in the settinq 01 SM of some duraioo and involving the 8M, 2) Slight increase in loosely-scattered mast c ells withoccasional dense aggreg ates and an atypical rrmoopterotvce with expression ct CD25. usually associated with an actr~ating point mutation of KIT, 3) Diffuse Cl:lmpaCI infill ralion 01 the mucosa by atypiCal mast cells, resembling the ag~ive variant of SM in other tissu es 171 1and 4) Localized mast cell sarcoma (based on one published case with in'OteTlerC oIlhe ascending colon) 111761.

_ 1esK>ns

Of osteoporosis is another frequent find-

ing in patients with mastocytosis, and may occur in any variant.

Mast eel/leukaemia (MCL) In mast cell leukaemia , mast cells equal or exceed 20% of all nuc leated cells in aspi rate smears 1290 , 977, 9 78, 22901. In this rare and hig hly ag gressive lorm of SM , the BM reveals a diffu se, compac t infiltrate with marked redu ction of fat ce lls and normal haematopoietic precu rsor s. The mast ce lls often show sign s of marked atypia with hypogranu lar c ytop lasm, irregularly shape d monoc ytoid or b ilobated nuclei (p romas tocy tes), and may even pr esent as me tach romatic b lasts 122901. In some cases, the nucleoli may be prominent. In typ ical cases , mast cells ac c oun t for 10% or mo re of the c irculating nucleated cells . If mast cells comp rise less than 10% the circulating cens. the diagnosis of an "a'eukaem.c" variant of MCL is appropriate 122891.

The lfequency of bone changes varies

ee subtype of disease. \-\'hile pu re tduse ceteoscerosis is unusual in ISM Iil(:U 6%0), it is observed in about one

Mast eell sarcoma (MCS)

dWl:lol patients with ASM. The most comradlOlOglcallinding associated with ISM crests of concurrent osteosclerotic andOSleolytic lesions (45%). Osteopenia

Ma st cell sarcom a is extremely rare and cha racterized by a localized and destruc tive growth of highly atyp ical mast cells, which c an be id entif ied only after

llO'I

application 01 appropriate immunohistochemical markers, particularly anti-tryptase and anti -CD l17 . AlthOugh initially localized , distant spread followed by a terminal phase resembling MCl is seen alter a short interva l. Mast cell sarcomas have been report ed to occur in the larynx, large bowel, meninges , bone and skin 1265, 970, 11761 .

Extracutaneous mastocytoma This localized tumour consists of an ac cumulation of mature-appearing granulated strongly metachromati c mast cells , in contrast to the hig hly atyp ica l mast cell s observe d in a mast c ell sarcom a. Extra cutaneous mastocytoma is exception ally ra re, and the reported cases involved the lung {3981. Irrm.mopheooIype Mast cells co-express COO, CD33, CD45 , CD68 and CD 117 but lack severa l rnyelomonOCytic ant9S"S, including CD14, CD15 and CD16, as well as most T- and B-eell related antigens 1974, 977 , 978 , 1073, 1292, 1687, 22901, Virtually an mast cells , irrespective of stage of maturation or neoptasnc state , react with antibodies against trvp tase . a cell not expressing tryp tase ca nnot be id entified as a mast cell immunohistoc hemically. Chymase is Mastocvtose

61

expressed in a subpopulation 01 mast cells. Chymase is highly specific but much less sensitive for the identification of atypical and immature mast cells than C0117, whereas COl17 expression is a highly sensitive but rather nonspecific marker of mast cells. Neoplastic mast cells show a similar antigen profile to that of normal mas t cells, but in con trast to normal mast cells. they also coexpress C02 or C02 and C025, These latte r observanons are of considerable value in the diagnosis and in the differential diagnosis of mastocytosis and related tumours, and can be applied in immunohistochemical as well as in flow cytometry studies j650, 1655. The application of antiC025 enuoooree has been found particularly useful in the histopathological evaluation lor suspected SM. Howeve r. C02~posilive T-cells are usually present in tissues and must be taken into account before an atypical C02-positive mast cell population can be properly iden tified . p.J. together, it can be assumed in the routine diagnostic evaluation 01 mastocytosis that cells expressing uvptaserctrsmase and C0117 are mast cells, and cells coaxpressing tryp tase/chymase, COl17 and C02/C025 are neoplastic mast cells 120571. C025 expression may be inconstant or even unde tectable on mast cells in some rare subvartants of the disease, such as welt-dilt erentiated SM or in a subgroup 01patients with mast cell leukaemia

.. •." . ~

~

~

. e

205n

1141. Genetics Mastocytosis is frequently associated with somatic activating point mutations within K IT 121761. In most cases, co don 816 mutations in the tyrosine kinase domain are detectab le. Rare familial cases with qecmune mutations of KIT have bee n repo rted [ 14,15, 1331,1332, 1333, 1557, 21761. In patients with SM-AHNMO additional genetic de fects are det ec ted, depending on the type of AHNMO, Somatic point mutations of the KIT protQoncogene that encodes the tyrosine kinase recept or for SCF are de tected as recurring abnormalities in mastocytosis 11 4,15, 1331, 1332, 1333, 1557, 1656, 21761 _ The most commonly observed mutation shows substitution 01 Val for Asp at codon B16 (D816V). This mutation results in ligand-independent activation 01 KIT tyrosine kinase and provides relative resistance to the prototypical tyrosine kinase inhibitor imatinib 1995, 15571. 62

Myeloproliferative neoplasms

Fig. 2.53 Mast celleull.aem&a A ~ blood smear. Note lhe biIobed ru:tel and relatively ~ cytoplasmoften seen in Itll5 awessive form of rnastIcykIIas. B Theborle marrow biopsy is li1IuseIy inIiIlr.*ldby ~slJC mastcells, C derronslriIles !he 'dear aIr appearance !hat is due ~ !he poorgratlJIalion of the ltIatis typical of inmature mast eels ofmast eelleukaernia. 0 All irmI.JnohisD::h slainbr masteel ~

""""' .......

The DB16V mutation is identified in the mast cells of 95% or more of adults with SM when sensitive methods are used, inclu din g nested PNA-PCR or PCR on poo led micro-dissected single mast cells, Other activating point mutations of axon 17. such as DB16Y, D816H and 08 16F are rarely seen {756. 1332, 1333, 20561 . The DB16V mutation is seen in only about one third 01CM in paediatric patients 114, 1331, 1332) and the frequ ency of point mutations other than 08 16V is significantly higher in CM than in SM, In patients with SM-AHNMO, add itional ge netic defects may be detected, depending on the type of AHNMO. For example, in SM associated with AML, the RUNX1-RUNX1T fusion gene may be found , whereas in cases of

SM associated with myeropronteratse neoplasms. JAK2 V617F may be found The de tection of the FIPIL 1-PDGFRA fusion gene has been reported in patients with mast cell proliferation and eosinophilia 122861. Although patients presenting wlt'I elevated serum trvptase levels. clonal8M eosinophilia with a F/P1L1·PDGFRA fusion ge ne and a few scattered atypical mast ce lls have been described as having an unusual variant 01SM {130, 713, 11621 most of these patients do not fulfili 8M criteria, particularly as compact mast cel infiltrates are missing , and they are best classified as a mye loid neoplasm With eosinoph ilia and rearrangement 01 PDGFRA (See Chapter 3) 122871.

Postulated C~ II of oriQin Haematopoietic stem cells. Prognosis and predictive factors In children, CM usually has a favourable outcome and may regress spontaneously before or during puberty. In adul ts, cu taneous lesions generally do not regress and are. in contrast to a previous belief, oI1en associated with SM, usually the ocoient variant. One study identified predictors of a poorer prognosis as rate onset of symptoms , absence of CM. ttrembocytopenia. elevated lactate dehyciogenase (lOH). anaemia. 8 M hypercelk81ty. qualitative PB smear aboorrehtes.

elevated alkaline phosphatase and hepatosplenomegaly. The perce ntage and morphology of mast cells in 8M smears have been ide ntified as additional important and independent pred ictors of survival in mastocytosis 122901Currently, there is no cure lor SM. and the prognosisdepends on eediseasecategory 1228 7, 22881. Patients with high-grade (agg ressive) disease inclUding mast cell leukaemia may survive only a few months, whereas those with indolent SM usually have a normal life expectancy 12287. 22881. SM patien ts with cutaneous invotvement usually also follow an indolent course, whereas patients With aggr essive

disease often have no skin lesions 122901 However. isolated 8M mastocytosis as a sobvanant of ISM with excellent prognosis also presents without cutaneous lesions. If there is an associated baematoroqrcet malignancy, the clinic al course and prognosis are usually domina ted by this related haematological malignancy 19751_ Patients with aggressive SM generally show a rapid cl inical course with a survival of only a few years. MCS shows a prog ressive course with death within months . Patients with ASM, Me l and MCS are thus candidates lor cvtoreduc tive therap ies.

MastocytosiS

63

Myeloproliferative neoplasm, unclassifiable

Definition The designation. myeloproliferative ne0plasm. unctassmaore (MPN . U) should be applied only 10 cases that have definite cl inical, labora tory and mor pholo gical fea tures of an MPN but that fai l 10 meel the criteria for any of the specific MPN entities, or that present with featu res that overlap two or more of the MPN ca tegories. Most cases 01 MPN. U, will tall into one of three groups: 1) Early stages of poIycythaemia vera (PV), primary myelofibrosis (PMF) or essootial thrcmbocythaemia (El) in which the c harac teris tic featur es are not vet fully d eveloped: 2) Advanced stage MPN, in wh ic h p ronounc ed myelofib rosis. osteosclerosis. or transformation to a more aggressive stage (r.e . increased blasts and/or dysplasia) obscures the underlying disorder 1775, 1216, 2206, 22 16,22221 : or, 3) Patients with convincing evi de nce of an MPN in whom a coexisting neoplastic o r inflammator y d isord er obscures some of th e diagnostic c linic a l and/or morp hological featur es , The presence of a Philadelphia (Ph) ch romosome, BCR-ABL 1fusion gene or rearrang eme nt of POGFRA, POGFRB or FGFR 1 genes excludes the diagnosis of MPN ,U. The diagnosis MPN,U shou ld not be used

64

Myeloproliferative neoplasms

wren clinical data necessary for proper c lassification are insufficient or not available, when the bone marrow (BM) specimen is of inade q uate q uality or size for acc urate evaluation (1216, 22 16 , 22221, or w hen there has bee n rece nt cy totoxic or growth factor therapy - p rob lems that account for the ma jority of the unclassifiable cases encountered in routine practice . In such cases it is often preferable to describe the morphological findings, and to sug gest additional cl inical and laboratory p rocedures tha t are nee ded to further classify the p rocess, inClud ing ad eq uate pe riphe ral blood (PB) and BM biopsy and aspi rate specimens. When a d iag nosis of MPN, U is made, the repo rt should summarize the reason for the difficulty in reaching a more specific diagnosis, and. if possible, specify which of the MPN can be excluded from consideration . If a c ase does not have the features of one of the we ll-d efined entities, the possibility that it is not an MPN must be strongly consi de red, A reac tive 8 M response to infection and inflammation, loxins, chemotherapy, and administration 0 1 growth tactors. cvtokmes and irrmunosuppressive agents may closely mimic MPN and must be exc luded, Furthermore,

H.M. Kvasnicka B.J . Bain J , Thiele A. Orazi H.·P. Horny JW , vardiman

a number 01 other naenatopoeuc and rco-neenatcooenc neoplasms, suchas lymphoma or metastatic ca rcinoma , may infiltra te the marrow and cause reactive changes, inc lud ing dense fibrosis and osteosclerosis that ca n be misconstrued as an MPN 122061. Dete ct ion of a clonal cytogenetic abnormality, a JAK2V617F a othe r functionally similar JAK2 mutatIOn, or an MPL IMP/.. W515K1L) rrutation distinguish an MPN from such reaclrve conditions, although not all cases of MPN U express a currently recognized aeretc marke r 12171, 21771. In add ition, thedefining c harac teristics of each MPN must be considered with the realization that, as with any other biological process, variations 00 occur, and they may progress thrt:llJ!1l different stages so that the c linical 31"(1 morphological manifestations of the disease will change with time 12177, 22161 ICD..Q code

997 513

Epidem iolog y The exact incidence of MPN, U is ur*~ but some reports indicate that the pelcentage of unclassifiable cases ecccn for as many as 1~ 15% of all cases Ii MPN 1775, 2222 1, The frequency varies

I

•

,

,

e

e

significantly aCGord ing to the exper ienc e l1lhe diagnostician and the specific erassfication system and criteria utilized to dassifyMPN 11216, 22161.

ElOOgy The cause is unknown.

Sites 01 W1voIvement 5mlar to the other MPN

cncaJ leatures

r-e dI1icaI features 01 MPN. U are similar Iltoseseen in the other MPN, In pat ients , . early, tn:: lasgjfjable disease, organo-regaly may be minima l or absent. but sclen:lmegaIy and hepatomegaly may be 'T'8SSNe i1 those with advanced d isease " "IIto'n 8M scecerees are characterized 0, ~ myek)flbrosis and/or increased rurtlers of blasts 122161. The baemato~ valles are also variable , and range \rem mild leukocytosis and moderate to 'I'.arlo:ed thrombocytosis, with or without ~nying anaemia, to severe cvtoPfJ'8S ae 10 8M failure. Some patients wilt1 1IlN. Upresent WIth otherwise unexplained p:fIai or splanchnic vein thrombosis.

Iil
(post-Pv MF) or rarely ET (post-ET MF) 1143A1 and lhe overt fibrotic-osteosclefotic stage of PrlAF may be impossible if there is no previous history or histology for review 12203, 22CX'i, 2216, 22221· Although Chrc:K1ic myelogenoos leukaem ia (CMl) may also be accompanied by marked myelofibrosis, the sma ll size of the megakaryocyt es will alert the morphologist to the correct diagnosis, and cytogenetic and mole cular qenetc demonstration of the Ph chromosome or the BCR-ABL 1 fus ion gene will con firm the di agnosis of CMll775, 2216. 22221. More than 10% b lasts in the PB or 8M and/or the findin g of significant myelodysp lasia gen erally indica tes a transition of the disease to a more agg ressive, often terminal b last phase. If the initia l diag nostic speci men has features of a myeloproliferative proces s that cannot be spec ifically ca tegorized , but shows 10-19% b lasts in the PB or BM, the diag· nosis of an accelerated stage of an MPN, U, is appropriate, Irrmu notlistochemical staining of the 8M biopsy sec tions for CD34 ma y be of diagno stic value in these cas es by demonst rating increased number s an d/or clusters of blasts 12216, 22221. If bl asts account for 20% or more of the perip heral white blood cells or nucleated 8 M cells in the initial specimen , then the diagnosis is acute leukaemia , and the suggestion that the case may be a bl ast transformation of a previous but uncl assifiable MPN is appropriate, Myelodysplastic features may appear dur ing the natur al p rogression 01 an MPN even without prior cytoreoucuve therapy. How ever. if the initial pretreatment specimen demonstrates myelodysplasia , the diagnosis of a myelodysplastic syndrome or of

a myelod ysplaslictmyeloproliferative reoplasm, incl uding the provisional entity, refractory anaemia with ring sidercblasts and thrombocytosis, should be considered 11 27,1 29,865.1 245,1406.2082,2169/. Inwrunophenotype No abnormal phenotype has been ported for this group of patien ts.

re-

Genetics There is no cvtcqenetc or molecular genetic finding specific for this group. There is no Philadelphia chromosome, BCR·ABL 1fusion gene , or rearrangement of PDGFRA. PDGFRB or FGFR1. Some cases with a mutation of JAK2 as a sole genetic abnormal ity do not meet the criteria for a specific MPN or any other speci fic disease ca tegory, and are thus best ca tego rized as MPN, U. Postulated ce ll of origin Haematop oietic stem ce ll. Prognosis and predi ctiv e factors In patients with the initial stages of an MPN that is urctassmabie. follow-up studies performed at intervals of 4-6 mon ths wilt etten provide sufficient information for a more precise classification {2216, 2222/. Such patients in the early stages of disease will have a prognosis similar to those of the group into which their disease eventually evolves. Patients with advanced disease in whom the initial proc ess is no k>nger recognizable due to 8M fibrosis or bla stic infiltration wou ld be expected to have a poor prognosis.

Myeloproliferative neoplasm, unciasSlfiable

65

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of

PDGFRA,PDGFRBorFGFR1 Myeloproliferative and lymphoid neoplasms associated with rearrangernenl of PDGFRA.

PDGFRB and FGFA1 constitute three rare

B,J . Bain D,G Gilli land

H.-P. Horny JW. Vardiman

,

specific disease groups, which have sore sha red features and some that differ. All result from lormalion of a fusion gene encoding an aberrant tyrosine ki-

nase. Eosinophilia is characteristic but not invariable. II has been established that, in the case 01 POGFRA and FGFR t-related neoplasms. the cell of origin is a mutated plu ripotent (lymphoid-myeloid) stem cell.

It is possible that this is also true for PDGFR~relaled

neoplasms, but this has yet to be established.

All three disorders can present as a chronic myeloproliferatIVeneoplasm (MPN) , but the frequency 01 manifestation as a lymphoid neoplasm varies . The clinical

.. 4,, .'•. .. . '.'

and neen ercoocer features are also influenc ed by the partn er g ene involved . In the c ase of PDG FRA-related disord ers, prese ntation is usua lly as c hronic eo sinop hilic le ukae mia (CEl) with promi nent involve ment of the mast cell linea ge and sometimes of the neutr oph il lineage. l ess often , pr esent ation is as ac ute my eloid leuka emia (AMl ) or precur sor-T lymp hoblastic lymphoma (T-LBL), in both instances with ac companying eos ino philia , In the c ase of PDGFRB-related disea se, the features of the MPN are more va riab le but are often those of c hronic myelomonocytic leukaemia (CMML) with eosinophil ia, Proliferation of aberrant mast c ells can again be a feature. Acute tran sformations that have been d escribed to date have been myeloid . In the case of FGFR r-reteteo disease, a lymphoma tous presentation is COOlmon, pa rticularly T-18L with accompanying T~" 3.01

""

,

.

~

f ig. 3.01 FIP1L 1-PDGFRA-ffllaled etvonic ~leu kaerlia. A PenpheraI blood IilmstIOlWIg Ihree rrlllder*f degranulated eosinopl'lils. Romanowsky stain. B Trephine biopsy section. Abundanl eosinophils and eosI'q)lli precursors, Giemsa stain. C Trephine biopsy S&ClIOO. Abundalll mast cells. many of wI\it:tI are spindle-shaped, Iormingsmalloose dosleB, Masteel tryp\lIS8 staining, 0 Trephinebiopsy section. CD25expression in tilemast CIk

eosinophilia, Other patients have had CEL, precursor-B lym phoblastic leuka emia / lymp homa or AML. The importance of recog nizing these di so rde rs is that the aberrant tyro sine kinase activity can make the d isea se responsive to tyrosine kinase inhibitors, This hope ha s already been reali zed for MPN with rearrangemen t of PDGFRA o r PDGFRB, whic h are resp onsive to imatin ib and some related ty rosine kinase inhibitors . Similar specific therapy has not yet been de ve loped for FGFR 1-relale d disease. Rele va nt c ytogenetic analysis,

Diagnosticctitena of an MPN' wilt1 eoslnophilia associated witt1 FIP1U -PDGFRA.

AmyeloproIlferatMl neoplasm .",111 promnenl eosmoph~ia

molecular genetic analysis or both should be car ried out in all patients in whom MPN w ith eosinop hilia is suspected and also in pat ients presen ting with an acute leukaemia or lymphoblastic lymphoma with eosinophilia. Recognition of PDGFRA related disease usually requires molecular genetic ana lysis, sinc e the majority of cases resu lt from a cryptic deletion, whe reas c ytogenetic anal ysis will reveal the ca usative abnormal ity in the case of PDGFRB- and FGFR1-related d isease.

Myeloid and lymphoid neoplasms with PDGFRA reanangement

AND Presence of a FIPILl-PDGFRA fusion gene'

Definition

• Patients preserUlg witt1 aculemyekidledaema or tyr1lJhDbIastic ~ with8CJSinOPt*l and a FIP1L1.f'OGFRA lusion geneare also aSSlgfllld tobs categoIy. ! II appropnate OI)IeaJar.-.alysis is not 1IYIilable.lhisliagnosis slJ:ll*S be suspected ilU1ere is. Pt\-negalrve MPN lIiIlIh Ihe ~ teahns of chronic eosirq:lhIc leukaemia assooateeI WIfI ~, • marked ~ of 58I0OI YltaJfWI812. eIeYaliort of serum tryplase and incteasecI bone Il'llWI'lM mast llllI!.

The most common MPN assoc iated wll1l PDGFRA rea rrangement is that asSOCIated with F1PIL l-PDGFRA formed as a result of a cryptic de letiorl at 4q 121466l (Table 3.0 1). Presentation is generally as eEL but can be as AM L, T·LBL or bon

68

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities 01 PDGFRA . PDGFRB Of FGFRI

smcuaneously (14691. Acu te transformation can follow presentation as GEL.Organ damage occurs as a result of leukaemic infiltration or the release of cvtokines. en zymes or omer proteins by the eoeropnns and possibly also by mast cells. The peripheral blood (PB) eosinop hil count is markedly elevated (in cases reported to dale it has almost always been ~ 1.5x1rPlL) atthough it should be noted that. in some series of patients . investigation was confined to patients with eosinophilia. There is no Ph chromosome or BCR-ABL 1 fusion gene. Except when there is transformation kl acute leukaemia, there are <20% blasts fl the PB and bone marrow (8M),

roo _ a The provisional code proposed for the fourth edition of IGOoO is 996513

---

~".

~opi . .. . ,

1',...... eEL_

_c:,........., nptIine

---, --I

I~"!.-­

@

-=Iya&.

b60CIaY Met

1n,"tiglClonb

Synonyms

~~ I

Chronic eosinophiliC leukaem ia: chron ic eosinophilic leukaemia wilh FIPIL1PDGFRA; myeloproliferat ive var iant of the hypereosinophilic syndrome.

Epidemiology The FIP1Ll ·PDGFRA syndrome is rare. It is considerably more common in men than women; the M:F ratio is - 17:1. Its peak incidence is bet ween 25 and 55 years (median age of onset in late 40s) with reported cases ranging in age from 7 10 77 years 1131). Etiology The cause is unknown, althoug h several cases have been reported following c ytotoxic chemotherapy 11 625, 2157) and a case of chronic myeloid leukaemia with a BCR·PDGFRA fusion gene also followed combination chemotherapy 119061 . Sites of involvement GEL associated with FIP1L1-PDGFRA is a multisystem disorder, The PB and 8 M are always involved , Tissue infiltration by eosinophils. and release ot c v tokmes and humoral factors from the eosinophil granuleslead to tissue damage in a number of organs, but the heart, lungs , central and peripheral nervoussystem. skin and gastrointestinal tract are commonly involved . The spleen is enlarged in the majority of patients. Cinical features Patients usually present With fatigue or pruritus, or with resp iratory. cardiac or

eel

~~~

.,

t,G --_.......... @ e --,

r.::==:=:::'::-l ~

(lncludiog

f _ I ...u..tI.1(11 nut

....

Hoi ~\I.

....

idiopathic HES

Fig. 3.02 Flow diagram showing the diagnostic process in hypereosinophilia, e EL, chronic eosinophilic leukaem ia The definitivediagnosis is shown within blue circles/ovals,

gastrointestinal symptoms 1466 , 139 1, 2309 1. The majortty of p atients have splenomegaly, and a minority have hepatomegaly. The most serious cl inical findings relate to endomyocardial fibrosis, with ensuing restrictive cardiomyopathy. Scarring of the mitral/tricu spid valves leads to valvular regurgitation and formation of in· tracardtac thrombi, which mav emtonze. Venous thromboembolism and arteria l thromboses are also observed . PulrTl()l1ary disease is restrictive and related to fibrosis; symptoms inc lude dyspnoea and cough; there may also be an obstructive element. Serum tryptase is increased (> 12 ng/mJ). usually to a lesser extent than in mast cell disease but with some overlap. levels of serum vitamin B12 are

markedly elevated (2309). FIP1L 1-PDGFRAassociated GEL is very responsive to imatinib , the gene prod uct being 100-fold more sensitive than BCR-ABl 1 1466J. MorphOlogy The most striking feature in the PB is eosinophilia. the eosinophils being mainly mature with only small numbers of eosinophil mveiocvtes or promyelocytes . There may be a range 01 eosinophil abnormalities, inclUding sparse granulation with clear areas " cytoplasm, cytop4asmc vacuolation, smalle r than norm al granules , immature granules that are purplish on a Romanowsky stain . nuclear hypersegmentat ion or hyposegmentation and increased eos inophil size 1466, 23091.

Myeloid and lymphoid neoplasms associated with POOFRA rearrangement

69

These chanQes may, however, be seen in cases of reactive as well as 01 neoplastic eosinophilia 11281 and, in some cases, of FIPIL I-PDGFRA·associated CEL, the eosinophil morphology is c lose to normal. Only a minority of patients have any increase in peripheral blast cells 123091. Neutrophils may be increased. while basophil and monocyte counts are usually normal 118541. Anaemia and thrombocytopenia are sometimes present. Any tssue may show eosinophilic infiltration. and Charcot-leyden crystals may be present. The 8M is hypercellular with ma rkedly inc reased eosooprars and precursors. In most cases . eosinophil maturation is orderly, without a d isproportionate inc rease in blasts. but in a minority the percentage of blast cell s is increased. There may be necrosis and Charoot-leyden crystals. particularly in those cases where the disease is becoming more acute 14661. Bone marrem mast cells are often but not always increased on trephine biopsy 11163. 1688} and mas t cell proliferation should be rec ognized as a feature of FIP1L 1-PDGFRAassociated MPN. The mast cells may be sca ttered Of in loose noo-cot1esive clusters orin cohesive clus ters {1163. 16881. Many cases have a marked increase in C025+ spindle-shaped atypical mas t cells , and in occasional c ases morpho logical features are indistinguishable from those of systemic mastocytosis. Aeticulin is increased 111631. Patients presenting with AMl or T-l Bl have had coexisting eosinophilia (PB counts 1 4- 172x 109/l ) and in the majority of cases ore-extsunq eosino p hilia was also documented (1469 1. Cyt ochemi stry Cytochemical stains are not essen tial for diag nosis. The reduced g ranule conten t of eosinophils can lead to reduced pe roxidase con ten t and inaccurate automa ted eosino phi l counts. Immunoph enotype Eosmcptuls may show immunophenotypic evidence of ac tivation such as expression of C023, C025 and C069 11163}. The ma st cells in this syndrome are usually C02-negative 11162} but some times are C02-negative C025· negative 114691 and occasionally C02· positive C025-poSitive 11469J. In conpanson , the mast cells 01 systemic mastocytosis are almost always C025-positive and are C02-positive in about two thirds of cases.

cozs-coense

70

Fig. ] .03 Myeloid neoplasm with eosinophilia associated WIlt! PDGFRB rearrangement Penpheral blood lWn d a palienl 'MIh 1(5;12) showing numerous abnoImaleosiIlOphis; eosmphis were 40% cIleukoc)1eS. Genetics Usually cytogenetic ana lysis is normal, with the FIPIL I-PDGFRA fusion gene resu lting from a cryptic del(4)(q12). Occasionally there is a chromosomal rearrangement with a 4q12 breakpoint such as t(1:4Xq44:q12) 14661 or 1(4;10) (q12;p1 1) /21631. In other patients there is an unrelated cytogenetic abnormality. e.g. trisomy 8, which is likely to represent disease evolution. The fusion gene can be detected by AT-PCA, nested AT·PeR often being required 14661 The causative deletion can also be detected by fluorescence in situ hybridization (FISH) analysis, often using a probe lor the CHIC2 gene. which is uniformly deleted , or using a b reak -apa rt probe that encompasses FlP tL 1 and PDGFRA. Since the maiontv of patients do not have an increase of blast cells or any abnor mality on conventional cytogenetic analysis, it is usually the detection of the F/P 1LI -PDGFRA fusion gene that per mits the definitive d iag nosis of a myeloid neop lasm . Cytoge netic ab no rma lities ap pear to be more com mon when evolut ion to AML has occurred (1469 1 Postulated cell of origin The c ell of origi n appe ars to be a p luripotent haemopoietic stem cell able to give rise to eosmophtts and in some pa tients neutrophils. rronocytes, mast cells. T cells and B cells {18541 . The detection 01 the fusion gene in a lineage does not necessarily correla te with morphological evidence 01 involvement 0 1 that lineage . lymphocytosis. for example . is not usual, even in those with apparent involvement of the B or the T lineage 118541. In chronic phase disease, involvement is predominantly of eosinophils and to a lesser extent mast cells and neutrophils. Acute phase disease may be myelOid or T lymphoblastic 11469}.

Prognosis and pred ictive teeters Since FIPtL 1-PDGFRA-assoc iated GEL and its imatinib responsiveness were recognized lor the first lime only in 2003 14661. the Iong-Ierm prognosis is not yet known . However. prognosis appears favourable if cardiac damage has not already occurred and imatinib treanre« is available. lmatinib resistance can develop, e.g . as a result of a T6741 mutation (which is equivalent to the T3 151mutation that can occur in the BCR-ABL 1 gene) 1466. 844} . Alternative tyrosine kinase inhibitors such as PKG412 and sorafenib may be effective in these patients 1468. 1297. 2 103}. Patients presenting as AMl or T lymphoblastic lymphoma can achieve sustained complete molecular remission with imatinib 114691. Variants A number of possible mo lecula r variants of F/P1L 1-PDGFRA-associated GEL have been recognized in wh ich there are other fusion genes inco rpo rating part of PDGFRA. A ma le patient with imatinibresp onsive CEL was found to have a K /F5B-PDGFRA fus ion gene assoc iated with a com p lex ch romosomal abno rmality invol ving chromosomes 3. 4 and 10 119 79 1. and a female patient had a CDK5RAP2-PDGFRA fusion gene associated with ins(9:4)( q33:q 12Q25) 123541. A male patient with t(2;4)(p24:q 12) and a STRN-PDGFRA fusion gene 14971 and ano ther with t(4; 12)(q2?3;p1?2) and an ETV6-PDGFRA fusion gene, both with the haematological features of CEL responded 10 low-dose imatinib 14971. Patients with t(4 :22)(q12;q1 1) and a BCR-PDGFRA fusion gene, four cases which have been described, have deease characteristic s intermediate betweer. those of FIPIL 7-PDGFRA-associaled eosinophilic leukaemia and those BCR-ABL t-poseve chrcnic myeIogenec:l.lS

Myeloid and Iymphotd neoplasms With eosinophilia and etoomannes of PDGFRA. PDGFRB 0' FGFR 7

a

a

, (

E T n

a

"

rr

/:

leukaemia; eosinophilia mayor may not be prominen t 1162 , 765, 1906, 22661. Accelerated phase 11621 and T 11 621 and B lymphoblastic transformation 122661 have been report ed . The condi tion is imatinibsensitive 11906, 2266/ .

Myeloid neoplasms with PDGFRB roanangement

Table 3 02 Diagnostc criteria of MPNaSsoclated witll ETV5-POGFRB tusioo gene oroItIer rearrangement of PDGFRB fn:I ecreeres witt1 ~ orflUlX)'tlsis AND f'ntsence of 1(5:12)(q31""Q33;pt2)or a variant translocatiOn' or,demonstrabor1 of an ETV6-PDGFRB fusion gene or of reBlfBngememof PDGFRB A~~ , often -MIl ~eosilqlhIa

, Because t(5;ll)(q3t""Q33;p12) does IIOl always INd 10 an ETV6-PDGFRB fusion gene, rnoIei::uIM conlirmation is ~ (lesjrable If I'lJClIe(Uar ana/ySiS is not avaiable. Ihis dtagnosJs sho\j:j be suspected if there IS a f'Il. negative MPN asscrialed wi1tI eosirqIhiIiIlnd witha ~sIocaborl Wllh I 5q31-33 brealqloint.

Table 3 03 f.Aljecu1ar variants of MPN associated WIth ETVU'DGFRB Modified from It31) FUIlon V&I1t

Definition A distinctive type of myeloid neoplasm occurs in association with rearrangement ~ PCXiFRBat 5q31-33 (Table 3 .02) . UsuaIy there is t(5 ; 12XQ31 - 33 ;p 12) with formalion of an ETV6-PDGFRB fusion gene 1812. 11341. In l/OCOITITlOfl variants. other "ansIocations with a 5q31-33 breakpoint lead to the formation of other fusion genes, incorporating part of PrX;FRB (Table 3.03). In cases with t(5 ;12) . and in the variant rransiocatcne. there is synthesis ~ an aber rant, consti tutively activated ty!OSine kinase. The haematological features are most often those of CM ML (usually With eosinophilia) but some patients have been charac terized as atypical ch ronic myeloid leukaemias (aC ML) (usually with eosinophilia), CEL and MPN w ith eosinophilia 1131. 20851; Single cases have been reported of AML. probably superimposed on ch ronic idiopathic my elofibrosis 12245). and of juve nile my elomon oc ytic eukaemia 115 13J, the latter associated /jith a variant fusion gene . Eosino philia is usual but not inva riab le 12085 1 Acute sensiorrnaton ca n occur, ofte n in a relatively short period of tim e . MPN with PDGFRB rearra ng eme nt is sensi tive to tyrosine kinase inhibitors such as imatinib

sse

t(1;3:5)(p36J)21;q33)

WDR48-POGFRB

ca

d8r(1lll1 ;5)(p34:q33). dert5)1(1:5)(p34:ql5). der(11 )ils(11;5Xp12:ql5q33)

GPfAP1-PDGRFB

ca

1(1:5)(q21;q33)

TPMJ.POGFRS

ca

1(1:5)(q23:q33)

POE4DII'POGFRS

l(4;5;5)(q23:q31;q33)

PRKG2-PDGFRB

l(3;5)(pll·25;q3t-35)

GOtGA4-POGFRB

l(5:7)(q33;q1t .2)

HIP1.pf)GFRB

CMML WIth eosirloptlia

l(5:10l(q33:q21)

CClJC6.PDGFRB

aCMLWllh eosinoph6a, MPD with eosinophN

t(5;ll)(q31.J3;q24)

GIT1.p()GFRB

eEl

l(5;14)(q33:q24)

NIN.PDGFRB

Pl'H'lega1ive CML (13% eoV1ophils)

t(5;t4)(q33;q32)

KlAA1S09-POGFRB

CMML wrlh eosinophilia

1(5;15){q33:q22)

TP53BP1-PDGFRB

Ph-negabveCML with prominent eosinoptlIa

t(5:16)(q33:p1J)

NDE1-PDGFRB

CMML

t(5:17)(q33:pt 3)

RABEP1 -PDGFRB

CMML

t(5;17}(q33: pl1.2)

SPECC1 -PDGFRB

JMML

aCML. alypical chronicmyeloidl6ukaemia; CEl , chrooic eosinophilk:leukaemia: CML, chronic myeloid leukaemia: CMML, chronic myelornonotybc leukaemia: JMML, juvenile myelomonocytiC leukaemia: MPOIMOS, myeloproliferativeJmyeioctysplastic syndrome: MPN, myeloproliferative lleOpIasm.

;64). ICD-O code The provisional code pro posed for the foorth editio n of ICO- O is 996613.

Syronym Chronic mvetomonocvnc leukaemia with !IOSinophilia associated with t(5 ;12) .

-"'ogy

T!'IIS neoplasm is considerab ly more com~

in men (M :F.,2:1) an d has a wide

age range (8-72 yea rs) with the p eak

rcoerce being in mi ddle-aged ad ults; reoen age of onset is in the late 405

00lS1.

•

rl

_

Fig. 3.04 Myeloid neoplasm wI\tI ~ associa1ed wilh PDGFRB ~ Trephine biopsy sedion In:lm a pa\llll'It WIth 1(5;12) showing a mar1o.ed increase in eosWlclphiII. Myeloid and lymphoid neoplasms associated

W Ith

PDGFRB rearrangement

71

Sites of involvem ent MPN associated with t(5; 12Xq31-33;p12) is a mul tisys tem disorder, The PB and BM are always involved, The spleen is enlarged in the majo rity of pa tients. Tissue infiltration by eosmoctats and release of cvtounes. humoral factors or granule contents by eosinophils can contribute to tissue damage in a number of organs. Clinical features Patients often have splenomegaly, with hepatomegaly being present in a minority. Some patients ha ....e skin infiltration and some have cardiac damage lead ing to cardiac failure . Serum tryptase may be mildly or moderately elevated The great ma;ority 01 patients who have been treated with erenmo have been found to be responsive.

M
Geneti c s Cytog enetic analysis usually shows t(5;12) (q 31-33 ;p 12 ) with the translocation result ing in formatio n of an ETV6-PDGFRB fusion gen e {8 12/ (p re viously known as TEL-PDG FRB), In one patient ETV6· PDG FRB resulted from a four-way translocation, t( 1; 12;5 ; 12 )(p 36 ;p 13;q33;q24) {489J, and in anomer occurred in association with ins(2 ; 12)(p21;q?13q?22) 15121. The 5q breakpoint is sometimes assigned to 5q3 1 and sometimes to 5q33, although the gene map loc us of PDGFRBgene is 5q31·32. Not all translocations characterized as t(5 ;12)(q31 ;p13) lead to ETV6-PDGFRB fusion . Cases without a fusion gene are not assigned to this category of MPN and. importantly. are not likely to respond to imatinib; in such cases an alternative Ieukaemogenic mechan ism is upregulation of mterleukin 3 (IL3) 146 71. AT-PeA. using primers suitable for all known breakpoints, is therefo re rec om me nd ed to confirm ETV6·PDGFRB {498 / but if molecular analysis is not available a Irial of imatinib is justi fied in patients with an MPN assoc iated with 1(5; 12).

Variants A number of molecular variants of MPN with ETV6-PDGFRB fusion have been reported 1131, 20851. In addition, a patie!t who acquired eosinophilia at relapse (j AML was found to have acquired 1(5:14 (q33;q22) with a TRIPl1-PDGFRBf gene. A number of other patients ha", rearrangement of PDGFRB but With second gene involved being unl<.novo1l. Complex rearrangements appear to be common (e .g. a small inversion as~. translocation) 120851. Because of the apeutic impl ication s, FISH (break·~ FISH with a PDGFRB probe) is indicaled in all patients with a presunptive of MPN who have a 5q31-33 break particularly. but not only. if there , eosinophilia. However, FISH analysis not always demonstrate rearrangemercd PDGFRB, even when it is detectable Southern Blot analysis 120851. MoIect.iJ analysis is not indicated if there is 5q31-33 breakpoint on classical genetic analysis since all cases re to date have had a cytogenetically delectable abnormality.

Postulated cel l of origin The cell of origin appea rs to be a multipo tent baemocorenc stem cell , which is able to give rise to neutrophils, monocytes. eosinophils and probably mast cells,

Myeloid and lymphoid neoplasms with FGFRI abnonnalities

Progn osis and predi c tive factors Pre- imatinib, the med ian survival was less than 2 yea rs, Ther e are not yet re liab le data on surviva l of imatini b-treated pat ients, but in a small series (10 patients) the med ian surviva l was 65 mont hs 15121 . Med ian survival is likely to im prove as patients are recog nized and sta rted on approp riate treatment at d iag nosis rather than when c ardi ac d ama ge or transformati on has alread y occurred

Table 3.04 Diagnosbc 0'Itetia of MPNor actIIe leuk.aerria associated withFGFRf rearrangement A myeIoproIlleralive neoplasm lMlh promIfIent eosmpI1E and sometines withneutrophilia or rTW:IAClC)'Iosi

OR

Acute myebd leukaemia or preanor T<eIIor preanor EkeII tymphoblasliC ~ {~ associated with periphetaI blood or bone JTIilITlI'W eosonophIia)

AND Preseoce r:A .8;13)(P11;q12) or. v;nnl\Jallsb..aboil!eadlng kl FGFRf~ delrorkStJaIed in ITI)'8Ioid eels, ~sts or boItl

72

Definition Haematoroqrce! neo plasms with FGFRJ rea rrangemen t are hetero geneous.They are de rived from a pluripote nt baemaio poietic stem ce ll, altho ug h in differet'l patients or at d ifferent stages of the disease the neop lastic ce lls may be precursa cells or mature ce lls. Presentation call be as an MPN or, in tra nsfor mation, as AML T or 8 lineage lymphoblastic lympt'loo'lQl leukaemia or mi xed p heno type acute leukaemia (MPAL) (Tabl e 3.04). ICD-O code The provisional code proposed fOf tl"E fourth enuon of ICO-o is 996713.

Synonyms 8p 11 myeloproliferative syndrome, 8p11 stem cell syndrome, 8p1 1 stem eel leukaemiallymphoma syndrome.

EpklemKllogy This neoplasm occurs across a wide age range (3-84 years) but most patients are young . with a median age of onset iJi

Myeloid and lymphoid neoplasms With eosooobne and abnormalities 01 PDGFRA. PDGFRB Of FGFRI

aroun d 32 yea rs {1354 1. In contrast 10 MPN with rearrangemen t of POGFRA and PDGFRB, there is only a moderate male predominance ( 1.5:1)

Sites of involvement Tissues primarily involved are 8M , PB, lymph nodes, liver and spl een. lymphadenopathy is the result of infiltration byeither Iymphoblasts or myeloid c ells. Clinical features Some patients present as lymphoma with mainly lymph node involvement . while others present with myeloproliferative leatures. such as splenomegaly and hypermetabolism. and yet others wilh features of AML or myeloid sarcoma 13. 1006. 13541. Systemic symptoms such as fever. weight loss and night sweats are otten present 11311.

~ Presen tation may be as CEL, AML, T-LBL or. least often. precursor B lymphoblastic leukaemiallymphoma . Cases 01 acute leukaemia/lymphoblastic lymphoma may be of mixed phenotype . In patients who present with CEL. there may be subsequent transformation to AML (including myeloid sarcoma), T or B lineage lymphoblastic leukaemiall ymphoma or MPAL. Lymphoblastic lymphoma ap pea rs to be rrore common in patients with t(8;13) than in those with variant transiocatons 113541. Patients who present in chronic phase usually have eosinophil ia and neutrophilia and, occasionally. mono cyto sis. Those who present in tran sformation are often also found to have eosinop hilia, Ove rall, about 90% of pat ients have PB Or BM eosinophilia (1354). The eosinophils belong to the neop lastic clone, as do the

Iymphoblasts and myeloblasts in cases in transformation. Basoph ilia is not usual but patients with BCR-FGFR1 fusion may have basophilia {18791. An association with polycythaemia vera has been observed in three patients with t(6;8)1FGFRIOP I-FGFRI fusion 11770, 23401 . T precursor lymphoblastrc lymphoma charact eristically shows eosinophilic infiltration within the lymphoma. Cases should be classified as leukaemia! lymphoma assoc iated with FGFR1 rearrangement, followed by further details of the specific p esenatco. e.g. "~ lymphoma assoc iated with FGFRI rearrangement/chronic eosilophilic IelJ
Cytochemistry Neutrop hil alkaline phosphatase score is often low, but cytochemistry is not important in the diag nosis. Immunophenotype Immuno phenolypic analysis is not useful in chronic phase disease, but is importa nt to demonstrate the T or B lineage 01 precursor Been or pr ec ursor leukaemiallym phoma.

r-ceu

Genetics A var iety of transloca tions with an 8p 1 t breakpoint ca n underli e this syndrome, Secondary cytogene tic abn ormalities occu r, among wh ich trisomy 2 1 is most often obser ved. Dependi ng on the partner chromoso me, a variety of fusion gene s inco rpo rating part of FGFR1 are formed . All fusion genes encode an abe rrant tyrosine kinase (Tab le 3,05)

Table 3.05 Chromosomal rearrangements and fusion genes reported in MPN associated wiltl FGFRt rearrangemenl·. Modrtied from (1311.

Cytogeoetica

M~laf

geoetic:s

1(8; 13)(pl l;q12)

ZNFI98-FGFR'

t(8:9Kp11 ;q33)

CEPf1O-FGFR1

t(6:8l(q27:pl1-12)

FGFRIOP1.FGFR1

1(822l(pl1;ql1)

BCR-FGFR1

(l' .8l(q34:pl1 )

TRJN2.f.FGFRJ

1(8.11)(pl1:Q23)

lrlY018A-FGFR1

1(8:19)(pl2;q13.3)

HERVK-fGFR1

n(12:8)(p11;pl1p22)

FGFR10P1-FGFRf

N'

"•

• 5

• tI adclillon, FGFRJ fl!IilfTiIl'iQt!ilelt has been ku1d II iISSfJciaIio'. will ~: 12l(p11;q151aocl.8:17XP1l;q25) but h suspected IwoIYement d FGFRt 1I1(8:tl ) (p11,pt5) wasnot confrmed. I rvrtln ~ tern MaI::OoniIId iIl"Il Cross (1354).

Postulated cell of orig in The cell of origin is a pluripotent tymphoidmyeloid naema topoietlc stem cell. Prognosis and pred ictive factors The prognosis is currently poor. There is no estab lished tyrosin e kinase inhibitor therapy for MPN with FGFRI rearrangement. althou gh PKC 142 was effect ive in one case 14001. Interferon has induce d a cytogene tic response in several pa tients 11354. 14021. Until specific therapy is develop ed. haematopoietic stem cell tran splantation should be considered . even in those who present in chron ic phase.

Myeloid and lymphoid neoplasms associated WIth FGFRI abnormalities

73

CHAPTER 4

Myelodysplastic/Myeloproliferative Neoplasms Chronic mye lomonocytic leukaemia Atypical chronic myeloid leukaemia. BCR-ABL 1 negative Jwenile myelomonocytic leukaemia Myelodysplasticlmyeloproliferative neoplasm. unclassifiable

Chronic myelomonocytic leukaemia

A. Orazi J. M. Bennett U. Germi ng A.D. Brunning B.J. Bam J . Thiele

Definition CIvLric~ IeU1x 1()9/L in the peripheral blood (PBl; 2) absence of a Philadelphia (Ph) ch romosome and BCR-ABL 1 fusion gene; 3) no rearrangement of POGFRA or PDGFRB (should be specifically exclude d in cases with eosinophilia); 4) lewer than 20% blasts

(promonocyles are considered as blast equivalents) in the PB and bone marrow (8M) ; and 5) dysplasia involvi ng one or more myel oid lineages. Howe ver, II c onvinc ing myelodysplasia is not pre sent, the diagnosis of CMML can still be mad e if the other requ irements are mel, and an acqu ired. clonal cytog ene tic or molecular genetiC abnormality is present in the 8M cells . or if the monocytosis has per sisted for at least 3 mon ths and all other c auses of monocytosis. such as the presenc e of malignancy, infection or inflammation, have been excluded, CMML is further subdivided into two subsets. CMML· 1 and CMML·2 , depending on the number of blasts plus promonocytes in the PB and BM. The clinical, haematological and morphological features of CMML are heterog eneou s, and vary along a spec trum from predom inantly myelodys plastic to ma inly myeloproliferative in nature. In contrast with the BCR·ABL 1negative myeloproliferative

76

2.

No ~ cf1romosomeor BCR-A8L11usion gene

3,

No rearrangement of POOFRA or POGFRB (sllouldbe spealicaRy e~duded 11 cases Wlth eosinophial

4

Fewer than 20% blasts" in the blood al'(j in ee bone marrow

5.

Dysplasia In oneor more myeloid lineages. If myelodys~asia is absent or minimal. the diagnosis of CMM,. may stil l be made iflhe other requirements aremet. and' • anacquired, ctooa l cylogenelic or moleculargenetic abnoonality is present in thehaemopoietic cells. r:r • the monocytosis hasp&rSisted forat east 3 months and • aijother causes 0( monocytosis have been e~duded

• Blasts irl<:IWe myeloblasts. monobIasts and prornotlOC)'le5. Promonocytes owe monocytic precursors WI1Il ab\.IIdallt light grey or sIif1Iliy besophilic cytoplasmwitha lew scattered. h liIac-<::oIoIJ-ed p1UIes. finelydislrtluled. sWied nudear etwomabn. variably prominent nudeoIi. WId delicale nud8arloIding oroeasilg. rd in tIIisdassilicaliorl are equivalenl lO~. AbnormaIITIClI'IOCy1eS wnen can be present baCh ti the ~ blood and bone marrow are excluded from lhe blastCCUIIl

neoplasms. JAK2 V617F mutation is uoccmmon in CMML 11058. 20821·

ICD-Ocode

9945/3

Epidemiology There are no reliab le inc id enc e data for CMML. because in some epidemiolog ica l surveys CMML is grouped with chronic myeloid rewaemras and in others is rega rded as a myeioovsptasnc syndrome (M OS) \108] In one stud y in which CMML accounted for 31% of the cases of MOS. the incidence of MOS was estimated to be approximately 12,8 cases per 100 ()(X) pe rsons per year (2414). The median age

Myelodysplastic/myeloproliferative neoplasms

at dia gnosis is 65--75 years. with a male predominance of 1.5-3:1 148. 683. 777 2047.21021· Etiology The etiology of CMML is unknown. 0CCupenona t and environmental carcinogens and ionizi ng irradi ation are possible causes in some cases 1108. 20261 . Sites of involvement The PB and BM are always involved. The spleen. liver. skin and lymp h nodes arethe most common sites of extramedu llary leukaemic infiltration 148. 683, 777).

Clinical features Inthe majority of patients, the white blood cell (WBC) count is increased at the time of diagnosis. and the disease appears as an atypical myeloproliferative neoplasm. Inother patients, however, the WBC is normal or slightly decreased with variable neutropenia and the di sease resembles MOS. The incidence of the most common presenting comp laints of fatigu e, weight css. fever and night sweats is similar in re two groups 01pa tients. as is the rate of otectooand of b leed ing due to thrombocytopenia 148, 683 , 777, 2047 , 2 1021. AI· ilough splenomegaly and hepatomegaly rn'irf be present in either gr oup, they are more frequent (up to 50%) in patients with leukocytosis 177n

Morp/loklgy and cytochemistry Peripheral blood monocytosis is the hall mark of CMML. By definitIOn, monocytes are always >lxl Q91l and usually range

from 2 to 5 x10~/L, b ut may excee d 8Ox 1()91l [48. 683, 1396, 14711. Monoc ytes are almost always > 10% of leukoc ytes \ 189.20031 . The monocytes generally are mature. with unremarka ble mo rphology. bu t can exhibit abnormal granulation, or unusual nuclear lobation or chrom atin pattern 111851. The tatter cells are best termed abnormal monocvtes -a designation used to describe rronocvtes that are immature, bu t. in com parison to promonocytes (and monoblasts). have denser chromatin, nuclear c onvolu tions and folds, and a more gre yish cytoplasm , Blasts and promonocytes may also be seen , bu t if the sum of blast s plus the promonocytes is 20% or more , the d iagnosis is AML rather than CMML. Other changes in the PB are variable . The may be normal or slightly decreased . with neutropenia, but in nearly one half of patients it is inc reased due not only to monocytosis bu t also to neu troph ilia

wac

(777, 1396. 164 51 . Neutrophil precu rsors (promyelocytes, myelocytes) usually account for < 10% of the leukocytes 1189, 2003 1. Dysgranulopoiesis. including neutrophils with hypolobated or abnormally lobated nuclei or abnormal cytoplasmic granulation . is present in mos t cases , but may be less prominent in patients with leukocytosis than those with a normal or low wac 1'185, 13961. It may be difficult in some c ases to distingu ish between hypogranular neutroph ils and dysp lastic moooc vtes. Mild basophilia is sometimes present. Eosinophils are usually normal or slightly inc reased in number, but in some cases eosinophilia may be striking. CMML with eosinophilia may be diagnosed when the criteria lor CMML are present. but in addition the eosinophil count in the PB is 2: 1.5xlQ1JIl. Patients in this category ma y hav e complication s related to the degranu lation 01 the eosinophils. These "hypereosinophilic " cases of CMML may

f1. U 2 Chn:nc myeIomonocytic IeukaenU-l. The degree of ~s, neutrr.optMia and dysploIsia is YiWiabIe .. CUt.4L. A The ..... bIoocI eel Cl:Ullis eIINaIed wiIh rnirImaI ~

in !he ~ series. B A noonaI wtJIe bIoocI eel axn WIth absokJte monocytOSis. ~ and dysgrarUopoiesls. C A bone marrow biopsy splDnen Inlm a CJM..·1. Oftsn, " grarUoqIlc WI.-u"" ~ is mosl obYil::lIJs lin se biopsy ~, iW'llI monocyI8S may nol be rNliIy appreoaIed. D The tllded ru:IeIlnl dek:aIe .... c:t'ttInRn em..... iiIic fA monocyI8S CM be appreciated IIIIO'IQ 1he~. ..,.. .

Chrorllc myelornooocylic Ieuka8ffila

!

77

closely resemble cases of myeloid neoplasms with eo sinophilia associated with specific cytogenetiC/mol ec ular genetic abnormalities involving POGFRA or PDGFRB genes. for which suc h c ases should always be exam ined . These d isorder s are con sidered sep arately from CMML. Mi ld anaemia . etten nor mocytic but som etimes mac rocytic. is c ommo n. Platelet counts vary, but moderate thrombi> c yto pen ia is often pre sent. Atypical , large platelets may be ob served 148. 13961· The BM is hyperc e llular in ove r 75% of cases. bu t rorrrcc enorer and even hypoc ellula r sp ecimen s also occur (1471, 21021. Granu loc ytic prol iferation is often the mos t striking find ing in the BM biop sy but an increa se in erythroid pr ecursor s may be seen as well (189. 14711. M0nocyt ic proliferation is invariably present. but can be d ifficu lt to appreciate in the biopsy or on 8M aspirate smears. Cytochem ica l and immunohistOChemicalstudies that aid in the identificatiOn of mcoocvtes and their less mature term s a re strong ly recommended when the d iagn os is of CMML is suspected 121701· Dysqranulcpoiests. similar 10 that found in the blood. is present in the 8M of most panent s with CMML. and ovsevmroooesrs (e.g. megaloblastic changes, abnormal nuclear contours. ring srderoblasts) is observed in over one ha lf of patients 177 7, 1396 , 147 11 . Micromegakaryocytes and/or meqekervccytes with abnormally lobated nuclei are found in up to 80% of patients [1396. 1471 1.

A mild to moderate increase in the amount of reticulin fibres is seen in the 8M of nearly 30% of patients with CMM L 114061. Nodules c omposed of mature p lasma cytoid de ndritic c e lls (plas mac yto id monocytes) in the BM b iopsy have been reported in 20% of cases 116491. These cells have round nuc lei. finely d ispers ed chromatin, inconspicuous nuc leoli and a rim of eos inop hilic cytop lasm. The cytop lasm ic membrane is usua lly d istinc t. with we ll-defined cyto plas mic borders. This imparts a c ohe sive ap pearanc e to the infilt ratin g c ells. Apoptonc bodies. often within star ry sky testrocvtes. are frequently pre sent. The rela tionship of the plasmacytoid dendritic cell proliferation 10 the leuka emic ce lls has been consider ed uncertain 1120, 655 , 895 , 9671. A recent study. however. has show n that they are c lon al. neo pl astic in nat ure , and closely related to the associated myeloid neoplasm 123351. The splenic enlargement in CMML is usua lly due 10 infiltration of the red pu lp by leukaemic cells. Lym phadeno pa thy is uncommon, bu t when it occurs. it may signal transfor mation to a more acut e phase. and the lym ph node may show d iffuse infiltration b y mye loid blasts. Sometimes, there is lymph node and (les s commonly) sp len ic involveme nt by a diffuse infiltration of plasmacytoid dendriti c cells. In some patients generalized lymphadenopathy due to tumou ral prol iferations of plasmacytoid dendritic ce lls may be

the presenting manifesta tion of CMML Blast cells plus oromonocvtes usually account for fewer than 5% of the periphera; b lood leukocytes and fewer than 10% ci the nucleated BM cells at the time of d iagn os is. A higher number of blasts (p lus promonocytes) than this may ident4y pat ients who have a poor prog nosis or a greater risk of rap id tran sformation to acut e leukaemia {48. 682, 683. 833. 2102. 2 170. 24431. Thus. it is recommelldecl that CMML be furt her d ivided into two subcategories. dependil"lQ on the runt:lEJ of blasts (plus promonocytes) found i'l PS and 8M . as follows :

CMML- 1 Blasts (including promonocytes) <5% r: ee PS , <10% in the BM ; CMML·2 Blasts (incl uding promonocytes) 5-1 9\ in the PB or 10- 19% in the 8M . ex I'tte1 Auer rod s are present irrespective of the b last p lus p romonocyte cou nt. The value of this approach has been recently con firmed 17801. Cytoc hemic al or immunop henotypic studies are strongly recommended whenever the d iagnosis of CMML is c onsidered When performed on P8 and 8M aspirate smears. alpha naphthyl acetate esterase or alpha naphthyl butyrate esterase, used alone or in combination with naphtt'dASD-chloroacetate esterase (cbioroacetae

I A;. 4.03 Chronic myelomonocytlc teokaemia-2. A Blood smear from a newly ~ patient. 0C:casi0naI bl9:sls W8f1l noled.,!he perVleIaI blood smear. B Bilpsy~ ..

same palJefW. The Im\aIJ.ny of !he ba1e fllamlW BIemenIs c:ar1 be rea:iIy appreciated. C BIasts.-.d pI'Ofl'IOf'IOC) ICCOU'IC lor 12".110 of !he I'fllIm)fr eels (~ ~ 78

Myelodysplasticlmyeloproliferative neoplasms

esterase, CAE) is extremely useful to assess the monocytic component. Inmunophenotype The PB and BM cells usually exp ress the expected myelomo noc ytic antigens, suc h asCD33 and C013, with variable exp ression of C01 4, C068 and C064 1243, 1377, 24421. The PB and BM monocytes often express aberrant phenotypes with :...oar more aberrant features by flow cvtometric analysis. Some, such as decreased expression of C0 14 , may reflect relative rronocyte immaturlty_ Other aberrant characteristic s include overexp resscn of C056, aberrant expression of C02 or cecreesec expression of HLA-OA, C0 13, C015. CD64 or C036. There may be aberrn phenotypic features on maturing granulocytic cells and neutroonas may also stlCM' aberrant scatter properties . An percentage of CD34 + cells or emerging blast population with aberran t .rrrnunophenotype has been associated tilth early transfor mation to acute eukaerma (AML) 1626. 2442 , 24591. Irrmunohistoc hem istry on tissue sec tions b the identi fication of monocytic cells is -etanvelv insensitive as compared with cytochemistry or flow cytometry. The most reliable marke rs are CD68R and CD l63 11649J. Lysozyme used in conjunction with cytoc hemistry for CA E can also faci l~ate the id entifica tion of monocytic cells, ...nich are lysozyme- positive but negative lor CAE, in contrast with the c renulocytrc precursor ce lls, wh ich are pos itiv e for bolh, An increa sed perc entag e of C0 34 + cells detected by immunohistochemistry has also been ass oc iated with tran sfo rmation 116491 . The plasmacytoid d endritic cells associated \II'ithCMML have a c haracteristic immunopeeootype. They are positive for C 0 123, CD14, C0 43, C068, C 068R, C 0 4SAA, C033 (weakly) and CD4. Granzy me B is also regularly exp resse d. but TIA 1 an d perforin are not. Variable C056 expression is seen in a minor ity of the cases, whi le tceu-assoctateo an tig ens suc h as C02 !'Id CDS can also be present.

rceaseo

F"tg.4.04 Onncmyelomooocylic leukaemia, Some dl9'8801fibrosrsmay beseen in upb3O"1i 01 cases. A,8 These pl1oklmicrographs 1ustra1e retiaJIin fibnls$ in a mafTllW blopsy specimen 01 a pabefIl WIIt1 CMML.

an

1

,8 Fig, U 5 CI.-onic myelornonocytIc leukaemia ANodI.*s COfl'IPOMd 01 pIastr1ac:ybd tter'01tiC eels in the bone R'IiIrrow 01 a patient WIIt1 CMML. B com is posilMIin pIasmaqtid dendriIic eels

mutations of RAS genes at diagnosis or dunnq the d isease course {1686, 2 118, 24171- The approp riate categorization of baematoroqrcat neo plasms associated w ith isolated isochromosome 17q is uncertain at this tim e. Although a p roportio n 01c ases meet the crite ria for CMML, others may be more ap propriately ca tegorize d as MDS/MPN , uncrassmabre {708 . 14371Abnormal ities of 11q 23 are unc ommon in CMML, and instead suggest the diagnosis 01 AML. Cases of MDS/MPN with eos ino phi lia associated with t(S;12)(q31 -33;p1 2) and an ETV6-PDGFRB fusion gene, whic h were formerly incl uded in the CMML c atego ry, a re no w co nside red a d isti nct en tity, Cases resembling C MML may express the p1 90 BCR-ABL 1 Isotorm and should be c lassified as ch ronic myelog enous leukaemia (CM L). Thus, if a t(9 ;22)(q 34 ;q 11) is not detec ted by cytog enetic analysis it is insufficient 10 use only PeA analysis for the presence of p 210 to exclude CML.

is 20-40 months {48. 682 , 683. 777 , 779. 833,2047,2102,2170.2443 1_Progression to A ML occurs in approximately 15-30% of cases. A num ber of clinical and haematological pa rameters, includi ng splenomegaly, seve rity of ana emia and degree of leukocytosis, have been reported to be important factors in predicting the cou rse 01the di sease . However, in virtually all studies, the percentage of PB and BM blas ts is the mos t important factor in de term ining survival j48 , 480 , 682, 683 , 777 , 780, 833, 2047, 2102 , 2170 , 2443 ).

Genetics Cb'lal cytogenetic abnormalities are found in 20-40% of pat ie nts w ith CMML, but rme is specific 148, 683 , 684 , 777 ,867, 2102, 2170, 2260 1_ The most frequent re:urng abnormalities include +8. -7/deI(7q) ind structural abnormalities of 12p. As many as 40% of patients exhibit point

Postu lated cell of origin Heerropoeuc stem cell.

Prognosis and predictive factors Survival of patients with CMML is reported to vary from one to more than 100 months, but the median survival time in most series Chronic myeklmonocytic IeukaerTlla

79

Atypical chronic myeloid leukaemia, BCR-ABL 1 negative

Def inition Atypical chronic myeloid leukaemia. BCR-ABL 1negative (aCMl) is a leukaemic disorder with myelodysplastic as well as myeloproliferative features at the lime of initial diagnosis. It is characterized by principal involvement of the neutrophil lineage with leukocytosis resulting from an increase 01 tnOfphologically dysplastic neutrophils and their precursors. However, mullilineage dysplasia is common and reflects the stem cell origin 01 aCML. The neoplastic cells do not have a BCR·ABL 1 fusion gene. ICD-
Synonym

987613

.

Atypical chronic myeloid leukaemia.

Epid emiology The exact incidence of aCMl is not krlOWn, but is reported to be only 1- 2 cases for every 100 cases of BCR·ABL 1 positive C ML 1200 31. Patients with aCMl tend to be elderly. In the few series repo rted to dat e, the med ian age at di agnosis is the seve nth or eighth d ec ad e of life bu t th e d isea se has been reported in teen ag ers as we t11266 , 928, 1208, 1396,20031 , The report ed maie.temare ra tio var ies , b ut based on the larger series reported , is approximately 1:1 1266 ,928 , 1208,1 3961. Sites of involvem ent The pe riph eral blood (PB) and bone ma rrow (BM) are alwa ys invol ved: sp lenic and hep atic invo lvement are also common.

Table • •02 Dl3QOOSoc critenalor at)1Ial dlronic myeloid leuUemIa, BCR-ItBL nega!lYe (acML). ~ t*;lod

Ieukocylosi$ (WBC 2: 13alO'1l) cl.Ie 10IllCtlliIsed runbers 01 neutn;lp/'iIs arKI their

prewrsor5 WIth prominent ~

NoPh dlromosome or BCR-ABI..1 fIlSIOIl gene NorearrMgBI'IlllI 01 PDGFRA or POGFRB Neulrophi prectJS(n {pfomyelocyles, myeIocyles,~) ~1 0% 01 leukocytes hh'naIlIbsokIIe ~ : b9soptlis USUIIy 4"4 0I1IIukocyles

Ncor II'III'IirrIClI absoUe~ ; lMl'lOC)1eS <10'1t oI~

pi" . '

~arbone mafTtM'wiII~ and ~~. W!ltl or wrtloul dysplasia n h etyflroict and megakaryocyIc Irl9Iges

less than m bIiIsts n fie blood and n h bone rr8lUW

counts in excess 01 3OOx1091l 1266, 928, 1208, 1396 ,20031. Blasts are usually less than 5% and always less than 20% 0I1eu~ cvtes. Neutrophil precursors (promyelocvtes. rnveiccvtes and metamyelocytes) usually comprise 10 - 20% or more of the leu kocyte d ifferent ia l. Although the absolute monocyte count may be increased, the perc entage of rnonoc yte s ra rely exceeds 10. Baso p hilia may be observed but is no t prominent 1189 . 266. 928. 1396 . 20031. The ma jor feature that characterizes aC ML is ovsqranctoooese. which is often pronounc ed , Ac qu ired Pelger-Huat or othe r nuc lear abn or malities, suc h as abnorm ally clumped nu c lear c hroma t in or bi zarrely seg me nted nuclei, and abnormal cytop lasmic granu lar ity m ay be obse rved in the neutrop hils. Mod erate anaemi a is frequ ent and the red blood cells may show c hang es indi ca tive of dysery th ropoiesis, inc ludi ng macrcovaiocvtosrs. The platelet cou nt is variab le, b ut thrombocytop enia is

Cl inic al features There are only a lew reports of the clinical featu res of pa tien ts with aC ML. Most patients have symptoms related 10 anaemia or some times 10 thrombocytopenia. whereas in others the chief complaint is rela ted to

spleromega" 1266. 928 .1206. 1396.20031. Mor phology and cytochemistry The white blood cell (WBC) count is always ~ 13x 1r1fL 11891 but median values ra ng ing from 24-96x1Ql'1L have been reported and some patients have WBC 80

JW, Vardiman J.M. Bennett B,J, Bain R D , Brunning J , Thiele

MyekldysplasticJrnyeloproliferative neoplasms

common 1189 , 928,1396,20031 . The BM biopsy is hypercellular due to an increase 01 neutroph ils and their pecesos Blasts may be modestly inc reased 111 number, but are always less than 20'%: large sheets or clusters of blasts are rICK present. Dysgranulopoiesis is a constant find.ng and the changes in the neutroptil lineage observed in the 8M are similar to those described for the blood, Megakaryocvtes may be decreased. no rmal or increased in nu mber, but in most cases some oysmeqakarvopoiesrs is present including sm all me gaka ryocytes and mic rorreqakarvocytes and/or megakaryo. cvtes with hy po lobu laled or non-lobulated nuclei 1266, 9281. Usually the M:E ratio is g reater than 10:1, but in some cases ery· th roid p rec ursors ac count for ove r 30% 01 the 8 M ce lls, Dy serythropo iesis is present in at leas t 50% of c ases 11 89, 266, 9281_ Inc rea sed reticu lin fibres are seen in some c ases at the time of d iagno sis , or may

». -, . - ..... ~

Fog. ' .07 Atypical chrOIlIt myeloid leukaemia. A Bone IT\lIITOIfI'biopsy shows 1Iypetc:eIIWnty. 0Je to~ proMerabon B NcJ(e anncrease "' Ihe l1JITtler of rnegak.afyocytes, ... smal abnonnallorms From the biopsy alone. !he fT'OlIhology wWd be dlfliQjt to tjft'erentlale from BCR-ABl. po5IbYe chronic myelogenous leukaen'ia C Bone marrow . . smear. Oysplasia in !he ~ and the megakaryo:;ybC lineages is eWlenI.

appear later in the course of the disease. Most cases reported as the 'syndrome of a~mal chromatin clumping " can be considerec:l as a ....ariant of aCML 1276. 680, 10071. These are characterized in the P8 .nt 8 M by a high percentage 01 reuno:tits and precursors that exhibit exagger· eeock.mping of the nuclear chromatin .

'«> specific cytochemical abnormality has been reported 10 date, although stains to detect a significant rnoncx:ytic component can be use ful to exclude chronic myelomonocytic leukaemia (C MML) . A nonSPecific este rase react ion performed on a BM asp irate may identify sign ific antly more monocytes than are ap prec ia ted by routine stains. l e ukoc yte alka line phosphatase scores may be low, normal o r

elevated. and thus are not useful for diagnosis 11208. 13961 . Immunophenotype No speci fic imm unop henotypic c haracteristics have be en reported to date, A s with cytoc hemistry, immunohistochemical studies for CD 14 o r CD68R on biopsy sections may he lp to id entify monocytes: fnding a significant 8M monocytosis sllould call the di agn osis of aCML into

coesnon.

Genetics Karyotypic abnormalities are reported in up to 80% 01 patients with aCML. The most CCfTITlOlI abnormalities are +8and del(2Oq) , but abnor malities of chromosomes 13, 14, 17,19 and 12 are corrvnonly repor ted as 'Nell 1266, 928.13961. Rarely, patients whose neoplastic c ells have an iso lated isochromosome 17q may have features of aC ML although most will fulfill the cr iter ia for CMML 11437f. There is no BCR·ABL 1 fusion gene. Cases with rearran gement of PDGFRA or PQGFRB gen es are also specifica lly excl ude d. The ac tiva ting JAK2 V617F mutation has been reported in some c ases of aCML {1064, 12871. Approx imately 30% of cases are ass ociated with acquired mutat ions of NRASor KRAS1 2311 1, Some c ases of t(8; 9)(p22;p 24 ) with the PCM1..JAK2 fusio n gene have bee n reported as "aCML" 1259, 18331 but d ata cu rrently ava ilable suggest they hav e eosinophilia and lack mye lody sp lasia and may be better regarded as chronic eosinoph ilic leukaemia. Meticulous description of the morpholog y of atypical mye loid proutera tions associated with var ious geneti c defects will be necessary to assign them to appropriate ca teg orie s,

Postulated cell of origin Bone ma rrow haematopoietic stem cell.

Prognosis and predi ctive factors Patients with aCML fare poorly, The series reported to the present time include only small numbers of patients, but median survival times range from 14 -29 months 1266, 928, 1208 , 20031. Age >65 years , female sex. W8C >50x 1Q91l thrombocytopenia, and Hb <10g1dL have been repo rted to be adverse prognostic findings {266. 9281. Howeve r, pa tients who rec eive 8M nansptantanon may have an improved outcome 111781. In approximately 15- 40% of patients, aCM L evolves to acute mye loid leukaemi a. wherea s the remain de r die of marrow fail ure {266. 12081,

AtypIcal crvooc myeloid leukaemia. BCR-ABL 1 reqanve

81

Juvenile myelomonocytic leukaemia

Definition Juvenilemyel:m:>nocyt<; ""-'
blood (PB) and bone marrow (8 M). Erythroid and megakaryocytic abnomaunes are frequently present 132. 303, 14771. BCR·A8L , is absent, whereas rrctato-s involving genes althe RASIMAPK pathway are cha rac teristic .

ICD-Ocode

994613

Epidemiology The inci dence of JMMl is estimated to be approximately 1.3 per millio n ch ildren 0- 14 years of age per year. It accounts for less than 2-3 % of altleukaemias in chi ldren, but for 20-30% of all cases 01 mye lody splasl ic and mye loproliferative disease in patients < 14 years of age 1907.

17041. The age at diagnosis ranges from one month to early ado lescence, but 75% of cases occur in child ren <3 years of age 1345, 1346 , 1595 1, Boys are affec ted nearly twic e as freq ue ntly as g irls , Ap proximat ely 10 % of cases occur in c hild ren with the c linica l diagnosis of neurofibromatosis type 1 (NF l) 1345 , 1595,2 10 11.

Etiology The c ause of J MML is not known . Rare c ases have b een repo rted in identical twins \17051. The association between NF 1 and JMML has long been established 1345. 1595 , 2 1011. In contrast to adults who hav e NFl . children with NFl are reported to have a 2OQ. to 5(X).fold increased risk of developing myeloid malignancy, mainly J MML 115951.Occasionally young infants with Noonan syndrome develop a JMML-like disorder, which resolves without treatment in some cases and behaves more aggressively in others 11211 , These children carry germhne motanons in PTPN11,lt1e gene encocting the protein tyrosine phosphatase SHP2121621 or in KRAS 119741 . Sites of involvement The PB and BM always show evidence of myerononccvnc p roliferation. Leukaemic in filtra tion of the liver and spleen is found in virtually all cases, Although any tissue may be infilt rated, lymph node, skin an d t he resp iratory t rac t are other co mmon sites of invo lvem ent 1345, 134 6 , 15951.

Clinical features Most patients p resent w ith constitutio na l sym ptoms o r ev idence of inf ect ion \34 5 , 1346, 1595l . There is generally ma rked hepatosplenomegaly, Oc casionally sp leen size is no rm a l at di agn osis but rap id ly inc reases thereafter, About half the patient s

Table 4.03 Diagoosticarteria of juveoile myelomonocytic leukaemia"

1. F'eflpheralblood ~ >b lO'IL 2. Blasts (ird.Jdlng ~)" In <:!(l%of lie leUor.ocyles II eeblood 1Rl of !hermeated beneITI8ITtlW eels

3 No Ph d\lomosome or BCR-ABL1 fusion gene .4

Plus two ex more dille loIowing: - HaemogIoI:lln F irocrea&ed lor age - Irm'Iature granulocyles in the peripheral blood - WBC counl >10J;10"/l • Clonal d1I01TC1SOm111 abrlormIldy (may be monosomy 7) • GM.csF hyper'5enIIbviI of myeIold progerIIIor5 on I'itro

"McOfled from 11596}. ."In IIliScialslkalJon. protI'I(lllCICy In equivaIer( 10 bIa5ts.

82

Myelodysplastic/myeloproliferative neoplasms

I Ba umann J ,M. Benn ett C.M. Niem ey er J , Thiele K , Shannon

•• <)

-

.

•

•

•

•

•

.~

•

1

•

FIg.4.111

..hJyrie myek:m:lnocytlc IUaeITia I.MU PenpheraI blood smeal" shoWn;l abnornIaI ~ wotrl C)t:IpIasmic vacuolesand two oormoblasl5.

have lymphadenopathy. In addition , Waemic infiltrates may give rise to markedy enlarged tonsils . Signs of bleeding are frequent and about a quarter of the caress have skin rashes. Cafe au tait spots are noted in patients with NFl . A remarkable feature of many JMML cases is a ma rke dly increased synthesis 01 haemoglobin F, specifically in cases WIth a normal ka ryotype 1345. 1595 1. AddrtiClrl! fea tures include polyclonal hyp ergammaglobulinaemia and the p resenc e of autoantibodies 1345, 159 5 1. The cl inical and laboratory featu res of JMML sometimes clos ely mimic infectious diseases, including those du e to Epstein-Ba rr virus , cytomegaloviru s, human herpesviru s 6 and others 11 376, 1596, 17511, Ap p ropriate laboraicv testing inc luding mo lecu lar stud ies and if1 vitro c ultures may be requ ired to exclude infec tions as a c ause for the clinical arc haematoroqc find ing s In vitro, there is ma rked hy persensitivityol myeloid progeni tor cells to GM -CSF 16441; this has become the hallmark of the d isease and represents an important diagnostic lo:t Morphology and cytochemistry The PB is the most important specimen III proving the d iagnosis. It gener ally stoes leukocytosis, throm bocytopenia and anaemia 1345.1346. 15951. The median reported .....tIile blood count ('NBC) varies lrcm 25-30x1Ql1Il, but rarely is >l00xll1i\. The leukocytosis is comprise d mainly aI neutroohns. with some immature ceus such as promyelocytes and mveocytes.

oae-

as well as of roonoc ytes . Blasts (includ ing promonocytes) usuall y account for fewer than 5% of the white cells, and always less than 20%. Eosinophilia and basophilia are ooseved in a minority of cases, Nucleated red blood cells are often seen . Red blood cell changes include macrocytosis, partieularty in patients with monosomy 7, but normcx:ytic red cells are more common, and recrocv tosrs due to iron deficiency or acQOired thalassaemia phenotype 1961} may be seen as well Although platelet counts are variable , thrombocytopenia is usual and may be severe 1345, 1346, 1595, 17051. Bone mar row f indings are not by themselves diagnost ic . The 8M aspi rate and biopsy are hyperce Uular with gral'lUloCytic proliferation , although in some patients erythfoid p recursors may p redominate \1595, 17051. Monoc:ytes in the BM are often less impressive than in the PB . generally accounting lor 5-10% 01 the BM cells. Blasts (including prorooocytesj account tor <20% 01 the 8 M cells. and Auer rod s are neve r seen . Mos t often dysplasia is minimal. However, dysgranuccorese. including pseudO Pelqer-Heet neutrophils or hyp:>granularlty may be noIed n some c ases and eryt hroid precursors may be enlarged, Meg akaryoc ytes are cnen reduced in number, but marked rregakaryoc ytic dysplasia is unusual 1345, 1595, 17051 . Reticulin fibrosis has been noted in some patients 13451. Leukaemic infiltrates are common in the skin where myelomonocyt ic ce lts infiltrate the superfic ial and d eep der mis , In the IUl"Ig, leukaemic cells spread from the capillaries of the alveo lar septa into alveola e . ¥ld il"l the spleen they infiltrate the red pulp , and have a predilect ion for trab ecular and central arteries , In the liver, the sinu soids the portal tract s are infiltrated , ~ specific cvtocterracai abnormalities have been repor te d in JMML. In 8M as pirate smears. c ytoc hem ical sta ins for alpha naphthyl acet ate esterase Of butyrate esterase, alone o r in combin ation wi th naphthol-ASD-chloroacetate esterase, may be helpf ul in detection of the monocytic compone nt . A lthou g h leu kocyte all.aline phos p hatase scores are reported to be elevated in about 50% 01 patients, this test is not helpful in establishing the diagnosis 113461.

Fig. •U t Juvenile myeIomooocytlc leukaemia, A The bone marrow- aspole &IM3f usuaty refIecls thed\afIge$ noted in the blood. buI !he monocyle ~ lllIlI is dmft10 appreciate, 8 ACOlTiw'oed alpha naplhyI acela1e eslefase and naptl~ esterase ' eaclion idenblies the vanulocytlt (blue reaction product) and the ITIOflOCYlIC component (brown feacbon product). A lew eels contain bolh pnxIuct$

•

Fig. 4.10 Juvenile ~ lOCytJc leukaemia, A The b<:Jre marrow is ~ wrlh g~pn:lilefabon. B The megakalyocytes are reduced in IlUfTlbef, but appear rTlOIphologlcally IlOffIIII in Ihe biopsy Blasts are not substantially ineteased in rvnber.

foC~

eoo

- type

"' speo!ic ~abroonaJ'" rave been reported in JMML. In extra~ 1JSSUeS, the monocytic COflXIl8llI

*

Fig. 4.11 JU'.'OOile rnyeIofnoncq1ic leukaemia. The leukae ~ infiltrate in the Iivef isin the portalregiOns (AI as wei as in !he hepalic sinusoids (8) , C The leukaemicI1filtrale in !he red pulp of !he spleen encroadles ~ !he gemiIIaI ten. Int. 0 The infiltJale is compfised mainly of immalufltand maluflt neutrophils and fTIOflOCY\es.

is best detected by irTVTlunohistochemica l techni ques that detect lysozyme and CD68 R. However, individual cases may show almost excluswetv infiltration by myeloperox idase-positive granulopoietic precursor ce lls .

Gene tics Karyotyping studies show monosomy 7 in about 25% of patients, other abnormalities in 10%. and a normal karyotype in 65% 115951. Philadephia chromosorneand the BCR-ABL I fusion gene are absent. JlIVenile myebnonocytic leukaemia

83

There is evidence that JMML is, at least in part. due to aberrant signal transduction resulting from mutations of components of the AAS/MAPK signaling path way, Somatic mutations in PTPN 11 occur in 35% of patients 11329, 21621. and oncogenic mutation of the RA$ genes, NRAS and KRAS2, and of NFl are each seen in appro ximately 20% 121621. Mutations in PTPN1' , the RAS genes and NFl are largely mutually exclusive, suggesting that pathOlogical activation of AAS dependent pathways plays a central role in the pathophysiology of the disease. In JMML cells of children with NF 1, unrparenteral dlsomy results in dUplication of the mutant NFJ allele 1714, 20961 . Since the NFt gene product, neurouoromo. is a negative rroourato- 01 AAS function, the loss of the normal NFt allele is associated with AAS hyperactivity 119971, Postulated cell of orig in Haematopoietic stem cell. Prognosi s and pred ictive factors Although JMMl rarely trans forms into acute leukaemia. it is a rapidly fatal diso rder for most children If lelt untreated . The median survival time Without allogeneic stem cell transplantation (HSCT) is about one year. Low platelet co unt, age above 2 years at diagnosis and high haemoglobin F at diag nosis are the main pred ic tors of short survival 1345. 1595. 17051. In the absence of effective treatment, most children

GM~SF

I

SO~

She

G, b2 Ga b2!

SHP-2 - -

~

R a s -GDP

~ --.......r-, Neurofibforrin

.-I

"..,""'"""~

GM~SFR

PTPNU Mutation (-35%)

I EttK tor Path ways Fig.4.12 Molecular lesions ~ Ras sir¥'*'!l prOWlS in JMM.. GM-CSf normaIy binds kI its rec:epD". in1al I'IeterIXlin1er ¥d asserrbIes 8 ~. d S9'*9 mclIo.JIes a'ld adaplets flat i'le1.I::les She: and GttI. ThesI proieln$. " un. ftICI"Uit Gab2. SHP-2 and 505. 1IltliCh eataIyzeI ~ IWJd80lIde ~ lllI Ras and iwnases

oee

a

irr.IoeI.D"leYeIs d Ras-GTP. aetvaaed, Ras-GTP ~ ..... rurtJerd ~ elfectIrs, The Gw. lIdMI\log proB1s pt2OGN' and net.6OIibn:mn brld kIRas-GTP and aoc:eIerate lXlfI'o'eIWn d Ras-GTP kI Ras-W' ~ kI GM-CSf is a ceIlW haImart. d JtAt. ltIal resulls from a rurtJer d lisln::l genetic ~ t.lJtaIioI1s in PTPNfl increaseSHP·2 phosphatase acIYlty a'lderNIce Ras SigrlafrIg. SiTI1arIy. cancer-associaled . . . acid Slbsl.iluIiCI'I in NRAS or KRAS2 red in /TJJlarIl: Ras prol8in:s IIaIlICO.Il1Jiate " ee acINe. GTP-b:u1d c:onbmalion. FnaIy. inacIivaIiorI ofllle NF l ~ ~gene ~ Rassigoahng ItlrtXJgh loss ofneurofib'orm

die from organ failure. such as respiratory failure. due to leukaemic infiltration . Haernatc poietic stem cell transplant (HSCT) from a related or unrelated HLA com patible donor c an cu re about half the patients 113261. Relapse is the major ca use of treatment failure, There is clea r evid ence that graft versus leukaemia

effect plays an impo rtant role, since a substantial proportion of children can be cured alter a failed HSCT by donor 1ymphocvte infusion and immunomodulatory therapy 117871. The role of anti-leukaemic eeaov prior to HSCT is currentlyu-ceten

•s (

1

s ti

C

T o

• 2

84

MyelOdysplasticJmyeloprolilerative neoplasms

Myelodysplastic/myeloproliferative neoplasm, unclassifiable

JW. Vardiman J.M . Bennett B.J, Bam I. Baumann J , Thiele A. Orazt

Definition Myelodysplastic/myeloprohferative neopIasm. lI'lClassifiabie. (MDWPN. U) meets !he criteria lor the MDSIMPN category in lhat, at the time of irntial presentation , eee are clinical, laboralOf'y and rrceprobgicaI features that overlap both MOO and

MPN. Cases classified as MDS/MPN, U 00 not meet the criteria lor chronic myelomooocytic leukaemia . juvenile myelomonocytic leukaemia or atyp ical d'rlnc myeloid leukaemia The finding 01 a oc:R-ABL , fusion gene or of rearrangement 11 PDGFRA, POGFRB or FGFR' excludes tie diagnosis of MDSlMPN , U .

It is important that the designation UDSnvtPN, U not be used for patients with aprevious, well-defined MPN who develop Oysplastic featu res in ass oc iat ion with eans'ormeton 10 a more aggressive rrase. HoNever, MD5'MPN, U may inc lude sere patients in whom the c hronic phase 01 an MPN was not previously detected. :rld who initially present in Iransformalion

MIh myelodysplasticfeatures. If the under~ MPN c annot be identified . the desigration of MDS/MPN , U is appropriate. If there has bee n any rece nt cytotoxic or arowth fact or therapy, follow-up clinical and laboratory observations are esse ntia l kl demonstrate that the peripheral b lood (PS) and bone marrow (BM) c hanges are 'lOt due to the treatm ent.

ICD-O code

9975/3

Synonyms \lIXed myeloc routerawe/myelocysptastc syndrome , unctasstnebre : "overlap" synacme, unclassilia ble .

&las of involvement The BM and PB are always involved: spleen, liver and other extramedullary ':ISSUeS may be involved.

The case has dirucaI, laboratory and ~ IN!ufes rJ onerJ !he ca1egories rJ MDS (reifacklry ~ WIItl unineage: dysplaSIa, relraalryaJla&mia WI\IlI'IIgSiCIerObIasIs. reIracIory tyqlenia 'MIhIlUbIileage ~. relradory anaemia -.ilh elC8SS 01 blasts) and <20"4 blasts in the blood and bone marrow

"" no ""

Has proITWlenI mye!oploilelalMlleatLres, e.g. pIMeleIaut a 45OJ;10'lt associaIed -.ilh megakaryotytlc proIileration, or WBC COld~ 1 h1 l1'lt , MIh or WI1hOul P'tJn*Ienl spIeIlllfTIllgaIy tia$ preceding tGlfy rJ In ~ W'N or rJ KlS , no hlst:lryrJ n!CeflI L)'k*JXlC or ~ Iador \hel'apy ~ ccokl e.'(j)lain !he ~ or 1ll)eIopi00000llti.. feaUes , IIfId no F'hiadelphia chCfl'CSOlII8« BCR-ABL1 k.tsion 98"8, no realral'9lll,.ltrJ PDGFRA. PDGFRB or FGFRf,1IfId no isolated del(5q},l(3:3)(Q2I;(l26) or1fI'l'(3)(Q21q26)

The palienlhas de rICM) disease WI\tl nned myeIoprolilnlrt'8 and myelodyspIastIc features IIfId eatnlt be assigned to i1It'/ olhercategory rJMOS, MPN«rJMDSIMPN.

Morphology and cytochemistry These disorders are charac terized by proliferation of one or more myeloid lineages that is ineffec tive, dysp lastic or both and simultaneously, by effective pro liferation . with or without dysplas ia, in one or more of the other mye loid lineages, l aboratory features usually include anaemia of variable severity, w ith or without mac rocytosis and ofte n d imor ph ic red blood c ells o n the per ip heral smea r. In addition, there is evidence of effec tive proliferation in one or more lineages, e ither as thrombocytosis (platelet count ~ 45Ox1Q91l) or leukocytos is (w hite b lood c ell c ount ~ 1 3 x 1 09/l ) , Neutroph ils may show dysplastic features and the re may be g iant or hypog ran ular pl ate lets, Blasts ac count for <20% of the leukocytes in the PB and of the nucleated cells of the BM , and a find ing of > 10% bl asts in the PB or BM likely indicates tranetoenetoo to a more agg ressive staqe. The 8M bio psy specimen is hypercellular and may show proliferation in any or all of the myeloid lineages. However, dysplastic featu res are simultaneously present in et least one ce ll line . Cytochem ica l find ing s may be similar to lhose seen in MDS or in MPN,

~icaI featu res

The c linical features of MDSlMPN , U

IrrmJnophenotype

OYerlap those found in d iseases of the l.tOS and MPN categories 1129. 1588. 23111.

May be similar to findings in MDS and/or MPN .

Genetics

There is nocvtooeoetc or rooIecular genetic finding specific tor this group. A Philadelphia c hromo some and BCR-ABL 1fusion gene should atways be excluded prior to making the diagnosis of MDSlM PN, U. Cases with rearrangeme nts of POGFRA, PDGFRB or FGFRI or w ith iso lated de l(5q) or 1(3 :3) (q2 1:q26) or inv(3Xq21q26) are excluded from th is category as well. In diff icult cases . the p resence of a JAK2 V617F mu tation may help to confirm a haematopoietic neoplasm. thoug h the significance of such mutations in this entity is unce rtain. Occasional cases w ith isolated del(5q) and JAK2 V6 17F mutation have been repo rted to have features that overlap MDS and MPN 110051. Postu lated cell of origin Haematccoretrc stem cell.

Refractory anaemia with ring sideroblasts (RARS) associated with marked throm bocytosis

Definition

In the third editionof the INHO Ciasetcaton RAR$- T, previously also referred 10 as essentia l thrombocythaemia (ET) with ring sioerobiasts . was proposed as a provisiona l entity to encompass pat ients who have the cuncat and morphological features of the myelodysplastic syndrome,

MyelodysplasticJmyeloproliferative neoplasm, uoclassifiable

85

AARS, bu l who also have marked thrombocytosis assoc iated with abnormal megakaryocytes similar to those observed in the BCR-ABL 1 nega tive MPN, such as ET or eartv-staqe primary myelofibrosis (PMF) 1865,1077,21091. However, some investigators have suggested that MAS- T is not a unique entity but instead rep resents cases of other subtypes of MDS or well-defined MPN that have acquired ring sidercbtasts as a secondary form of dysplasia 119661. It is not clear whether AAAS-T is a distinct entity, one end of the spectrum of AAAS . a progression of AAAS due to an addrtiooat acquired genetic abnormality. or less likely. Ihe occurrence of two rare diseases in the same patient. Therefore . until these questions are more ctearly answered . AAAS-T remains a provisional entity In support of a myeloproliferative component to this neoplasm, the majority of cases reooeted as RAAS- T have shown the JAK2 V617F mutation, or much less commonly. the MPL W515KIL mutation 1234. 354 , 762, 1835. 1839. 1969. 2081 , 2 139. 2358 1_ On the other hand. the few reported cases with this mutation that have been studied for endogenous colony form ation in vitro have demonstrated a pattern mo re akin to that of MDS 1234. 18351 . Thus it may be that the provisional design ation of an MDS/MPN accurately reflects the underlying biology in a substantia l pr oportion of the p atients 1762J; more stud y is neede d to further ctarify this diso rder. Cases with isolated del(SQ),t(3;3)(q21;q26) or inv(3)q 2 1q26) are exc lude d from this ca teg ory, as are cases with a BCR·ABL 1 fusion gene, In ad dition, if there has been a prior d iagno sis of an MPN without ring sioerc otasts. or there is evide nce that the ring stoerotsasts might be a consequence of therapy or represent disease prog ression in a patient wi th features tha t meet the crite ria of another well-de fined MPN, this designation should not be used.

IC().() code

9982/3

Morphology These cases have features of AAAS (anaemia With no blasts in the PB and dysplastic , ineffective erythroid prolif8fation often with megaloblastoid features, ring sideroorasts :2:- 15 % 01 the erythroid precursors. and <5% blasts in the BM) and thrombocytosis With a platelet count :2:- 450x1CJ1Il associated with proliferation 86

..

Fig.' .13 Refractory eneema WIth ring SideI'Ob~s andlhfombocylosis This sequence of rnitrophotogriljtls AtsIr3lt blood and bone marrow 01 a 62-year-old man who presenled with severe anaemia anda plateletcount oI85lb:10"l A Abnormal red cells and Ihrontlocylosis. B El)'lhroid proliferation and abnormal megakaryocylll$ reserrtIing megNyccytes seen in ET. C Mild dyserythropote$is. 0 The majority01 erythroid pIlICllfSOrS were ring sicleroblasts.

of targe atyp ical mega karyocytes similar to those observed in BCR-ABL 1negative MPN (See Chapt er 2). The minimum plat elet co unt requ ired for inclusi on has been lowered to 450xl CY'/L from 600x 109/L for consis tenc y with the d efining criterion for ET, and because severa l studies have demonstrated that pa tients with platelet coun ts lower than 6OOxlCY'/L may have biological features, includ ing JAK2V6 17F mutations, similar to those with coun ts ~x1Cf1A..1354I . It is importan t to note that the criteria for AAAS-T includes morphologically abnormal meqakarvocytes similar to those observed in ET and in PMF. This criterion should aid in distinguishing AAAS-T from those cases of RAAS commonly reported to have a modest increase in their platelet count. Nevertheless, we recommend testing for JAK2 V6 17F when the platelet count is elevated in patients with AARS until the borderline between AAAS and AAAS-T is more clearly defined

MyelodyspiastiC/myelop rollferallVe neoplasms

Genetics The recent discovery that up 10 60% of pa tients with AARS-T harb our the JAK2 V617F mutation (an inc idence similar to that found in ET and PMF) or less cornmon ly, the M PL W515KjL mutation, not only elucidates the reason for the proliferative aspect of AARS-T but also woold seem to move it closer to the MPN catego) 1234, 354. 762. 1835, 1839, 1969,2081, 2139, 23581. Thus. studies for JAK2V617F, and. if ind icated, for the MPL W515M mutation should always be performed in such cases .

CHAPTER 5

Myelodysplastic Syndromes

Myelodysplastic syndromes/neoplasms. overview

Refractory cytopenia with unilineage dysptasia Refractory anaemia with ring siderobtasts Refractory cytopenia with multilineage dysplasia Refractory anaemia with excess blasts Myeladysplastic syndrome with lsoleted del(Sq)

Myelodysplastic syndrome, unclassifiable Childhood myelodysplastic syndrome

Myelodysplastic syndromes/neoplasms, overview

-

Definition The mve'oovsptasnc syndromes CMOS) are a group of clonal haematopoienc

A.D. Brunning A.Orazi U. Germing M .M . Le Beau

APOfWit I. Baumam J .W. Vardiman E. Hellstrom-Lindberg

I

stem cell diseases characterized by cvtopeorats). dysplasia in one or more of the major myeloid cell lines. ineffective baematopoesis. and increased risk of development 01 acute myeloid leukaemia (A ML) 1190. 353, 23101. There is an enhanced degree of eoootosrs which contributes to the cytopenias 12601. The thresholds for cytopenias as recommended in the International Prognostic

SCoring System (IPSS)

lor risk stratification

in the MDS are haemoglobin < lOgJdL. abso lute reurroptut count (ANC) < 18x l(Jl/l and platelets
Myelodysplastic syndromes

:.

.It

Fig. 5.01 Bone mamJIIIII smear from a pa\lel1t 'Mlh ~s B19 irltedlon showing mal1<.ed eryttvoid hypoplasia wiltI occasional pi eryttYoblasts 'Mlh dispetsed dwomalin and line cyIqllasmic YlICUllIM.

•

Fig.5 .02 Bone marrow smear from a . 1.year-d:l 'Mlh pancytoperia being cIYooic:aIy poiscWled lneIic. There is ma'ked ~

Fig. 5.03 Bone marrow smear from a 57-yeaf-okl woman ¥r1'Io received several dl&molh&rapetJtlC ageots lor breast carcinoma ir.clooing loIic acidantagonists.

Ep ide miology Myetodysplastic syndromes occur princ ipally in olde r adu lts with a median age of 70 years . with a non-age corrected annual incidenc e of 3-5/100 000 p ersons bu t rising to >20/ 100 000 amo ng tho se ove r the age of 70 years {109, 7831. App roximately 10 300 inciden t cases of MOS were d iagnosed in 2003 in the USA {1351 1. There is a male predominance . Thera py-related mveioovsptasuc syndromes are discussed in Chapter 6. Cli nic al featu res The major ity of patients present with symptoms related to cvtooentats): most of the patients are anaemic and transfusiondependent. less frequent are neutropenia and/or thrombocytopenia. Organomegaly is infrequ ently observed.

Etiology Prima ry or de novo MOS oc cu rs without a know n history of c hemotherapy or race expos ure. Possible etiolog ies for pre ma ry MOS Include benzene exposure at levels well abo ve the m inima allowed by most government age nc ies. cigarette smoking, exposure to agricultural cherricats or solvents an d family history ci heematoootenc neoplasms 121131. Some inherited haematolog ic al d isorders. SUCll as Fanconi anaemia. dyskeratosis Cl)f\o geni ta. Shwachmann-Diamond evnocre and Diamond-Brackten syndrome are also associated with an increased risk MOS.

non

a

M"",hoIogy The morphological classitication 01 MOO is principally based 00 the percent blasts in the 8M and PB. the type an:!

a

degree of d ysplasia and the pr esence of ring sideroblasts {1 90 I. The cy topen ias generally co rrespond to the d ysp lastic lineage. but discordance may be present (Table 5.0 1) 123271. To determi ne the blast perc entage in the BM, a 500-ceU differential of all nucleated cells in a smear ortrephine imprint is recommended and in the PB, a 2QO.leukocyte cnnerentrat In severely cvtooenrc patients, butfy coat smears of PB may tacuuare performing the Odferential. The charac teristic s of the d ysplasia are relevant when diSlinguishing between the various types 01 MOS and may be important in predictmg biology. In addition , some cytogenetic abnormalities are associated with characteristic d ysplastic features, e.g isolated del(Sq) and hypolobated and non-lobated megakaryocyte

nuc lei and det( 17p ) with hypo lobe ted neutrophil nuclei / 12371 Assessment 01 the deg ree of dysp lasia may be pr ob lematic depending on the quality of the smear preparations and the stain. Poor quali ty smears may result in misinterp retation of the presence or absence 01 dysplasia particularly in assessing neutrophil granula tion . Because of the critical importance 01 recognition of dys pl asia to the diagnosis of an MOS, the necessity 01 high quality slide preparations cannot be overemphasized. Slides for the assessme nt of dysplasia should be made from freshly obtained specimens ; specimens exposed to anticoa gulants for more than two hours are unsatisfactory As a general precaution, no patient should be diagnosed as having MOS without knowledge 01 the clin ical and

"'ReIrDIlyq10perIIas 'III\I1lriineage dysplasia (RCOO) Refraclory anaemia (RA); Relracloryneutropenia (RN);

_ _ IRT)

Retacklry anaemiI WIth nngsidetobltsts (RARS)

drug history and no case of MOS should be reclassified while the patient is on growt h teeter therapy, inclu ding erythropoietin. In add ition, cytopenia(s) in the absence of dys pl asia shoul d not be interpreted as an MOS. A presumptive diagnosis of MOS may be made in the absence of dysplasia il certa in cytogenetic abnormalities are present (See Genetics). Persistent cytopenia without dysplasia and without one of the specific cytogenetic abnormalities c onsidered as presumptive evidence of MOS should be viewed as the recent ly described "idiopathic cytopenia of undetermined siqrufcance" ( leUS), and the patent's haematologic and cytogenetic status should be cerefuny monitared 124221 . In an attempt to more accurately pred ict chnical behaviour, cases of MOS without

8100dMdinp ~ or bicytopenia'

-

t«I or rareblasts « 1%)1

No "''''

Cylopenia(s) No or fare blasts « 1'10)2 NoAlIeI'rods <'~10"11. monocytes

IJn*Ieage dysplaSIa. 2:10% dille cells Ifl onemyebd i1eage

<5%_

<15'10 01 eryIhrOId precursors are nngSlderobIasts

2:15% 01 eryIhroid precursors on rilg SlderobIasts Erylhmid dysplasia only <5%blasts

Dysplasia i'I 2:10% 0I1I'le cells in 2: two myeloid Iil'le
Refradory anaemia With e~C8SS b1asts--1 (RAEB-1)

Cytopenia{s) <5%blasts' NoAutlr rod s < 1 ~1O"fl mooocytes

Unilineage or ml,lttl l~age dysplasia 5-9% blasts l NoAuerrods

Refractory ana&mia with excess blasts-2 (RAEB·2)

Cytope nia(s) 5-19% blasts Auerrods t 1

Unilineage ormullilineage dysplasia 10-1 9"1o blasls Auer rods 1;1

<1~10'J1. mooocytes

M)'elodj'Splastic syndrome - undaSSifJed (MDS-U)

Cytopeflias 5:1% blasts '

"""""

UsuaRy J'M)n1I3I or we.ased pIaIeIet COUI1l Noor rareblasts «,%)

Uoequivocal d~sia in less \Il
tJwoIobated fIUdei

<5% blasts Isolated _ del{5q) cytogenetic al:inl:lrmlliTy No_

8q'qlenIa may 0CCiI5i0naIy be obseMld cases Wl1l'I pancytopenia should be classified as t.I05--U. myeloblast perc:entBge is <5% bul1tlEWe ere 2--4% myeIoblasls nee blood, ee liagnosticdass1Iic:aticrl is RAEB 1. Cases 01 RCUO and RCMDIIo'ilh I %Il)'IlIoblasts IIIlhll blood shoUlIbe dassifled as MOS, U

I . . . JIlafl'DW

Cases W1111wfII rods nI <5% myetlbIasls III 'lie blood arw3 0(10% inee I'!llll1tIW sInJId be d8s$lIied ... RAEB 2.

-

,--

--""

-.

Fig. 5.05 A Blood smear from a pa\J8I"It on grarUocyte COOny sbmulating!acttJr. A neutrophil W'IIh a bIlobed nucleus and naeased azuror:I* grClruabon. B The same SI)Itinen as (A) showing a myeloblast.

-

•

an increase in blasts are recognized as manifesting ei ther unilineage or multilin-

eage dysplasia In RA and RAAS. the dysplasia is generally confined 10the erythroid lineage. Unilineag e dysplasia may also occur in the neutrop hns. refrac tory neutrop enia (AN), an d megakaryocytes. refrac tory thrombocytopenia (AT), but these processes are much less frequ ent than unilineage dysplas ia invo lving the

erythroi d cells. In refractory cytopenia with mul lilineage dysplasia (RCMD) with or without ring sioe robleete. significant dysplastic features are rec og nized in two or more of the major myeloid cell lineages. The reco mmended req uisite percentage of cells manifesting dys plasia to qualify as sig nific ant is ~ 10% 11864J in the erythroi d p rec ursors and granulocytes, Significant megakary ocyte dysplas ia is defin ed as

Tab le 5.02 Summary of cytopenias anddysplasia characteristics in MOS without an illCfease of marrow blasts. Cytopenia(s)

Oysplasla

Categories

Unicytopenia Bicytopenia

Unilineage

Refractory cytopel1ia with unilineage dysplasia (RCUD) Refractory anaemia (RA) Relfactory I'le(Jtropenia (RN ) Relfactory tnrombocylcpenia (RT)

p- -"---... Biq10penia

UflIinelIge and

""","",

(2:2 myeloid eels Ines)

"'"'-

90

Relr
2:15"" ringSideroblasts

Myelodysplastic Syndromes

MyelodysplaslJc syndrome. uocIasS/fled (MD5-U) Retractory cyIOpenia Wllh mullilneage d:y$plaSiII

(RCMO)

~ 1 0% dysplastic megaka ryocytes basec on evaluation of at least 30 megakaryo. cvtes in smears or sections, Future snoes may result in modification or this reccomendation 114201. Mcromeqakaryocves and mullinucleate megakaryocytes are the most reliable dysplastic findings inttl megakaryocyte series 11420. 23271. Although the majority of patients w MDS and unlineage dysplasia pre with a single cytopenia. this revised etcatoo allows lor bicytopenia in refracb'y cytopenia with lXlilineage dysplasia (00,.q and RARS (Table 5.02). The majority ~ patients with RCMD have 2 cytopeMS

118641. Ch.aracteristics of dysplasia Dyserythropoiesis is manilest prine by alterations in the nucleus ine budding, internuclear bridging , karyCIrhexis , mu/tinucl€arity and megalobla changes; cytoplasmic features . ring siderobIasls. vacooIisalion and penxk acrd-Sctnf positivity. either diffuse (I granular (Table 5.03). Dysgranu!opoiesl is characterized primarily by nudelJ hypolobation (pseudo Pelqer-Hoetj a~ hypersegmentation. cytoplasmic hypogranularity. pseudo Chediak-HigaS'J granules and small size. MegakaryocytP dysplasia is characterized by micromegakaryocytes with hypolobated nuclEi, non-lobated nuclei in megakaryocytes Ii all sizes, and multiple, wrderv-seoaraiea nuclei, Megakaryocytic dysplasia maytlt more readily app recia ted in 8M secncs than smears and both types 01 specimers should be eva luated The cha racteristics of the dysplasia maj be relevan t in pred icti ng biology of a mveicoysorastc d isorder and the relatcoship to specific cy toge netic abnormalities, ego Sq-syndrome {2327}, Unilineagedysptaaia is o bserved in RCUD and RARS Multilineage dysplasia involving two c. three of the myeloid ce ll lines is rTlOfe frequently observed in the high-graClt MDS an d is used to distinguish ReM!) from ACUD 118641. Similarly, the presence 01 multilineage dysplasia is used separate RARS from RCMD with n sroerobtasts. the latte r of which has a similar clinical course to RCMD_ increased number of ring sioerotnasa occasionally> 15% of the erythroid precursors. may be observed in refract anaemia with excess blasts (RAEB). TIt defining criteria of RAEB- l or RAEB-2 dictate the classification in such cases

,

of AAEB-2 o r CM ML-2 in the con tex t of MOS or MOS/MPN rega rdless of the blast perc entag e. This concept is reta ine d in the p resent classification. Cases of MOS with <5% blasts in the 8M and < 1% in the P8 may rarely have Auer rods. These cases have be en reported to be associated with an adverse prognosis 124151.

Fig. s.ar A AtmrmaI bcaizaIon 01 inmaIu'e~. Bone marrow sectJon lI'om I ease 01 RAE&-l allIlain$ I locus 01 immature myeloid preo.nor$. SAlocus 0I1nmnJrec:eIIs in. bone rnatTOW biopsy from aesse 01 RAE&-2 reacted wl1t1 I nbbody kI C034. A lI'Iap:II'Ity oIlhe mmature eels are posilMl.

The relationship betw een cvtopenras. type of dysplasia. and classification is summarized in Table 5.02 . The significance of the Auer rod in myeloid disorders has histo rically been sonewttat uncertain. For severa l d ecades Its detection was viewe d as virtually di agnestle of AML. There was no specificity applied to it with the introduction 01 the concept of MDS by the FA8 gr oup. In the revised FAB c lassi fica tio n of 1982 it was veweo as evid ence of a high -gr ade MOS. refrac tory anaem ia with excess of b lasts in transformat ion , (RAEB t ), irresp ectiv e of the blast perce ntage in the PB or 8 M 11901. In the pri or WHO Class ification of the MDS it was considered as evidence

Differential diagnostk: considerations A majo r problem in the diagnosis 01 MOS is the determination whether the presence 01 myelodysplasia is due to a clonal disorder or is the result of some other factor. The presence 01 dysplasia is not in itsell definitive evidence of a clonal disorder. There are seve ral nutnnoner. toxic and other factors which may cause myelodysplastic changes, including but not limited to vitamin 8 12 and folic acid deficiency, essential element deficiencies and exposure to heavy metals, parncutarts arsenic and several commonly used drugs and biologic agents 12601. The antibiotic cotreroxezoie may cause marked neutrophil nuclear hypolobation indistinguishable from the changes observed in MOS. In some patients on multiple d rugs it may be d iffic ult to id entify the causative agent of the neut rophil changes 11136. 2 1411. Congenital r eematoioqcat disorders such as conge nital dyseryth ropoietic anae mia must also be considered as a cause of dysp lasia when it is con fined to the erythroid cells. Parvovi rus B 19 infection may be assoc iated with ervtn robreetopente wil h gi ant megaloblasl oid eryl hrob lasls: the imm unosu p p ress ion age nt mycophe nolate mofetil may also be associated with erythrob lastopenia. Chemotherapeutic age nts may resu lt in mar ked dysp lasia of al l mye loid ce ll lineag es. Granuloc yte colony- stimu lating fact o r res ult in mo rp holog ic alteratio ns in the neo trophns. incl udin g m arked hypergranularity and

•• :-

.

~

-- •

f.. 5.01 M~a stJc dysery1hropoIeSil. Bone MlIo ~ Inm., ao:Ul JT8B -Mlh fefracUy ~ .. rrUl*leage dysplasia (RCMD) and complex ~ 8t:n:lnnIIlItle N:tdng del(17p) and del(Sq).

• A.

...

Fig. 5.09 Dysplasbc megakaryocy\eS. Bone n'llWl'OW as-

pirate smear from a 37-year«l male WIIh ~ stIotMg megaka-yocyleswithdysplaslic features.

Fig. 5.10 Neutn:lphi WIlll a r'lOI'Hlbaledru::Ieus (pseuclo PeIger-HuiIJ in. bbXI smear from a paIienl on ~ mol3ZOle. ApproXllTlalely 50 percent 01 the neuIrtlpt* had a simiar appearance.

FIg. 5.11 BtnucIeate mega~ in a bone marrow smear from a pabeflt with• ~ history 01 refrackIry 1hrontlocytopen There is a central !13f1JIOt'nere and a peripheral hyalomere.

striking nuclear hypolobation 11968): blasts may be observed in the PB and may reach levels of 9- to% and rarely higher in p atients with no evidence of AML or MOS. The 8 M b last perc entag e is generally normal, but may be inc reased as well. Paroxysmal noct urna l hae moglo binuria may also present with features similar 10 MOS. As a result 01all these possibilities. it is extremely impor tant to be aware of the c linical history including expos ure 10 d rug s or c hemica ls and cons ider nonclo nal d isorde rs as possible etiologies when evalua ting cases with myelod ysplasia, particularly those c ases with no increase in b lasts. Repeat ed 8 M biopsies. including cytogenetic studies, over a period of severa l months may be necessary in d ifficu lt cases. Histopatho logy The value of the BM biopsy in MOS is well established 116471. It may aid in confirming a suspected diagnosis by excluding reactive conditions in which ovsnaematopoietic changes may also be observed: it can also increase the diagnostic accuracy and helps in refining the IPSS score 123281. Assessment of 8M cellularity and strcmal reactions, e.g. fibrosis. B!eadditi:Jrl<W Overvrew-

91

cases of MDS with inadequate aspirates, the blast determination requires a aM biopsy and immunohistochemical studies for C034 may prove invaluable.

Fig. $.12 A Bone marrow bI:lpsy from a case of MDS (RAfB) WIth /I'I)'eIOfb'osi 5everaI ~ iIIe presenl B Retio.anstain ona marrow bclpsy from a case of MDS wilh myelofibrosis. There is a marked inaease II retia.Wl MIres.

important diagnostic features of the biopsy. The 8M in MDS is usually hypercellular ex oormocenutar: the cvtopenras result from the ineffective reenatcooese. Histologically, aggressive MDS may be characterized by the presence of aggregates (3-5 cells) ex clusters (>5 cells) of blasts in 8M biopsies usually localized in the central portion of the 8 M away from the vascular structures and endosteal surfaces 01 the bone trabeculae. These are frequently present in RAEB. The blasts can also be identified by immunohistochemistry with an libody to CD34, an antigen expressed in p rog enito r cells and

Table 5.lJ3 Morphologic marule$tabons 01 ~ Oyserylhropolesll N....er

Noclear budding Int&rTll.lClear bridging Karyorrtlexis Mll ~inuclearity

Nuclear hyperlobation Megaloblastic changes Cytoplasmic Ring sideroblasts ~izaliOn

PeriodiC acid-SChiff positvily ~granulopoie. l.

SmaI or oousually largesize Nuclear hypoiobaliOn (pseudo Peiger-Huet: peIgeroid) IrT9{PJIar hypetSl:lgmentation Decreased granules : agrarWrity PseucIo QledIak-HtgastH ~arws

.... """

--

~l)'ocytopoiIs ls

NudNt hypoklbllJon ~ (normaI .,..katytq1es in I.lI'W'IJl:illI wilh kltdaled nudeI)

92

Myekxtysplaslic syndromes

early p rec ursor 8M cells in lhe majorIty of cases. Antj-C034 can be used to demonstrate pathologic accumulations of blasts both singly and in clusters in aggressive subtypes of myeloid neoplasms 120501. With some fixatives, CD34 will also immunoreact with megakaryocytes in MOS , IrTYTlunohistologicanalysis with anti-C034 may be especially useful in cases 01 MDS with fibrosis or hvpoceuuiar marrows as well as therapy-rela ted cases to assess b last percentage. In these instances the p resence 01 fibrosis ()( fany changes in the 8M may make accurate cbaractenzanon of the process very di fficult.

Hypoplas tic MDS In a minority of the cases of MDS, approximately 10%, the 8M is hypocellular. These c ases have been referred to as hypoplastic MOS. This group , which has independent prognost ic signific ance per S8, may lea d to d iffic ult ies in the d if/eren lial d iag nos is w ith aplas tic a naelT)i~ 1 834. 1648 1. In add ition, anti-thymocyte g lobulin and other therapies used for aplastic anaemia have been used with some deg ree of success in this sub group 1260, 1302, 2477, 24781. It is also impo rtant when consid ering the diagnosis of hypoplastic MDS 10 excl ude toxic myelopathy and au toimm une di sorders .

no

MDS with myelofibrosis Sig nilicant degrees of myelofibrosis are o bserved in ap proximately 10% o f the cases of MO S. These cases have been referred to as MDS w ith fibrosis (12461. Most of the cases with fibrosis have excess of blasts and an aggressive clinical course. Such cases may erroneously be consid ered low-grade MOS if only the blast count determined from the 8M aspirate, which is usually diluted With P8 , is evaluated. In the fib rotic group, as in other

1l1VTlUnophenotyping Published studies on immunophenotyprg by flow cytometry in MOS have focused CI'l several stra tegies, including determrwg the size and immunophenotype of ee blast population and assessing the maturation pattern 0I1he myeloid cell popUatol More specifically. these studies included immunophenotyp ing of CD34+ cells, ap. plication of SCOfing systems, and pattern recognition strategies uSing muttiCOO analysis and comparison with norrn;iI reactive PB and 8M. There is generally good correlation between the percentage of blasts as ceremined by morphologic examination iJ fOJtine smearor irr'pV'ltor ~ preparations and percentage of CD34. cells determined by flow cytometry ( FC~ However. in some cases there may be significant discordance due to signilicart myelofibrosis and haemodilute samples As a result, Fe percentages 01 CD34+ eels cannot replace differential counts 00 smears, However, Fe may be informal1Ye~ abnormal phenotypes of C034+ cells are detected: this could be additional evidence dysplasia. In addition, an emerging athological population of CD34 IJ 01 17 cells in low-grade MDS could Sl.I9" gest evolution of the d isease 116221. Ma tu rat io n pa tte rns of erythropoie tic g ranuloc ytic, and monocytic difterentiatcn in the normal/reac tive 8 M, as well as the immuno phenoty pe of the mature cells in PB have been thorough ly desc ribed using fou r-co lor FC. Erythroid abnorm alities as de termined by the pattern of exoressce of H-ferritin , CD7 1 and C010S in gly· cophorin A (GPA) posi tive nucleated cells reportedly ca n pred ic t morphological erythroid dysplasia with 98% sensitivity [5501, A be rran t maturation patterns in granulopoiesis could pred ict morphological dysplasia and abnormal cytogenetics in ap proximately 90% of cases 112121. ThJs flow cytorretrv results co rreiate well with morphology and cytogenetics in MDS However, in cases with borderline dys. plasia by morphology and no cytogenetic abnormalities. FC results are highly suggestive for MOS only if there are three IJ more aberrant features in erymropoietc. g ranulocytic or monocytic maturation; single aberrant features by FC are na

f:

signific ant. .Cases with inconclu sive morphologic an d cytogene tic find ing s and three or mo re aberrant fea tures by flow cytometry should be reeva luated over seve ral mon ths for definitive rrorprologic or cytogenetic evidence of MOS,

Genetics Cytogenetic and molecular studies have a major role in the evaluation of patients with MOS in regard to prognosis, determnaton of clonality {833, 16411, and the 'ecognltion of cytogenetic , morphologic , m clinical cor relates . Clonal cytogenetic abnormalities are observed in - 50% of I,()S cases. Myekxtysptastic syndromes associated with an isol ated del(5q) occur orinarity in women, are c ha racterized by megakaryocy1es with roo-ocetec Of hypoklbated nuclei, refractory macrocytic anaemia, normal or increased platelet Cl:lOO t, and a favourable clinic al c ou rse, and are recccneec as a scecinc type of MDS in this c lassification , The oc c urrence (j 17p loss is assoc iated wi th MOS or AML with pseudo Pelger-Hu6t anomaly. small vacuol ated neutroohlrs. TP53 mutation and unfavourable c linical course: it is rest common in therapy-related MOS (12371· Complex karyotypes (2:3 abnormalities) typically include chromosomes 5 andfOf 7 [-S/del(5q), -7/del(7q )), and are generally assoc iated with an unfavourable clinical course . Several olher cytogenetic lindings ap pear to be assoc iated with characteristic morp hologic abnormalities such as isolated del(20q) w ith involve ment of eryt hroid ce lls and meg akaryocvies. and abnormalities of c hromosome 3 (irw (3)(q2 1q 26 ,2) or t( 3 ~ 3)( q 21 :q26,2 )]. which are associated with MOS and AML withincreased abno rma l meg akaryoc ytes 1289, 866, 1207j. Some clonal cytogene tic abnor mal ities occuring in MOS are not definitive evidence for this disorde r in the absence of morpholog ic al crtterte. e.q . -Y, +8 or ool(2Oq) as the sale abnormali ty, The other abnormalities listed in Tab le 504 in presence of a refractory c ytope nia , but no morphologic evidence of dysplasia, are considered presumptive ev idence for MOS. It is recommended tha i tnese pallefllS be followed caretcuv lor emerging roorphologi c al evidence of MOS. FISH tJOVides increased senSitivity in monitoring Sl.Ch pateots.once a recurring abnormality res been identified ,

ee

Tabl. 5.04 ReCl.lning cluumosomal abnormalities and their frequency in re myelod~aslic syndromes at diagoosis.

Postulated cell of origin Haematoooetic stem cell. Prognosis and predictive factors The morphological subtypes of MDS can be generally categorized into three risk groups based on duration of survival and incidence of evolution to AM L. The Iow-risk groups are RCUD and RARS. The intermediate-risk groups are RC MD with or without ring srderobrasts and RAEB-1 , Patients with RAE&-2 constitute the high-risk group. It shou ld be noted that patient s with bcvtopema in RCUO and RARS have been reported to have a shorter surviva l tha n patients with one cyt openia 123271. Pat ients with one cyt openia in the con text of RCMD had a longer survival than patients with two cvtocenra s 123271· The importance of c ytog enetic studies as a prognostic indic ator in MDS has been recogniZed and c od ified by the International My ekxtysplaslic Synd rome Work ing Group 18331· Three major risk categ ories of cytogene tic findi ng s have been d efined : i) good risk -normal karyotype, isolated del(5q), isolated del (2Oq) and -Y; ii) poor risk ---com plex abnorma lities, l.e., 2:3 a bnormalities, or abnormalities of ch romosome 7; and iii) intermediate risk - all other abnormalities. A scoring system for predicting survival and evolution to A ML based on percent 8 M blasts. type of cy togenetic abnormalities , and degree and number of cytcoentas has been pro posed by this g roup (Table 5.05) 1833, 833A I, Four risk g roups based on this sc oring system are recog nized : low, O' INT (inte rme diate) - 1, 0 ,5- 1.0; INT-2, 1,5- 2.0; and high , 2:2 ,5. In general, the higher-risk groups are related to higher 8 M bl ast percent ag e, mo re unfavou rab le c ytogenetic find ings and mo re

A_"

MO'

""""""""

' 0% ' 0% ' 0%

' S'

·1 or del(7Q) -5 or del(Sq)

. ..

- ,' .r

S% . S%

~ 17Q)

or l(17p) .13 or del(13Q) del(11Q) del(12p)Of 1(12p)

-,

-

,-110,

""' ""'

'"'" '"

' .2% ' .2%

dc(X)(Q13)

... .

1( 11;16)(q23,p13.3) 1(32 1)(q262;q22.1) 1(1;3)(p36.3:~1.2)

1(2;1l)(p21:Q231 ~3)(q21 q26.2)

1(6:9)(p23;q34)

'"

2%

, The ceseece of these at:JnormaIIies as the sc*l ~ abrmnaiIy 11 !he absence of rrupho-

logic aTlenais no! considered deMiIive evidence lor 1.40S, In !he seltlng of persistent eytapenias ol ~ origin. lhe oll'ler abnormahties shoWn are IXIO~ ~ve evidence 01 MDS in the absenc:e 01 defu'itive ITlCfPlIOIC9C features.

severe degree of cytopenia. Constderatoo of age improves predict abilityof survival ; patients young er than 60 years of age have impro ved survival in the ind ividual risk ca tegories compa red with patients older than 60 years. The cytoge netic subg rouping of the IPSS system also has an independ ent value in pred ict ing the outco me of allog eneic stem cell transplantation in pati ents w ith MOS

15321.

Table 5.05 International Prognostic SC:or1'1g System(IPSSllor MDS (833,833Af. See Prognosis and pt'edidive faclQrs

lor interpretation,

•

,,~

Prognostic variables " bone marrow blasts Karyotype" C~s -

•••

<5.

5-1 0%

.-,

Intermediate

Good

,

,.s

2

11 - 19"110

20-30%'

Poot

2-3

"This ~ is ~ as AML in the wtK) classificabon. - Karyotype: Good" normal, -Y,del(5Q). del(2Oq). Poor " ~l ~ lIbnormaIiIies) or ....~~mlTlOSOl""'m.. 18 7...::ma1ies: Intermecliate " otherIIbnormaIrt.oes - Cylopenias:

Hgb<1llgk1. NeutropIiIs <1.8xlll'11.

i

PIaWets <1 00x 1 ~ Overview

93

Refractory cytopenia with unilineage dysplasia

Definition Refractory cytopenia with unilineage dysplasia (RCUD) is intended to encompass those myelodysplastic syndromes (MDS) which present with a refractory cytopenia with unilineage dysplasia and includes refractory anaemia (RA) , refractory neutropenia (RN) and refractory thrombocytopenia (AT) . Although refractory anaemia with ring sioercoiasts is also characterized by unilineage dysplasia. it is considered as a distinct entity of its own . Refractory bicytopenia may be inCluded in the AGUD category il accompanied by unilineage dysplasia. It is recomnet ICIed that refractory pancytopenia with unilineagEl dysplasia be placed in the category 01 rnyelodysplastic synd rome. unctassrnaore (MDS·U). The recommended level lor dysplasia is ~ 1 0% in the cell lineag e affected. The recommen ded levels for defining cytopenias are haemoglobin <10g/dL. absolute neutrophil count (ANG) < 1.8x1Ql1IL and platelet count <100x1(19/l1833, 833AJ. However, values above these levels do not exclude MDS if definitive morphologic and/or cytoge netic ev idence of MOS is p resent. The typ e of c ytopenia in the majo rity of cases w ill cor respon d to the type of unilineage dy spl asia , e.q. anaemia and eryth roid

dys plasia, although discordance between type of cytopenia and cell lineage dysplasia may be observed 123271. Some of the cases previously classified as M05-U may be included in this category. e.q. RN, RT All non-clonal causes tor the dysplasia must be explored and excluded before the diagnosis of MOS is established These inc lude, but are not limited to, drug and toxin exposure, growth factor therapy. viral infections, immunologic crsorcers. congenital disorders, vitam in deficiencies and possible essential element deficiencies, such as copper deficiency 18371_ Excessive zinc supplementation has also been reported to be associated with severe cytopenia and dysplastic changes 110 10 1. It a clonal cytogenetic abnormality is not present, there should be a period of observation of six months from initial examination before a diagnosis of MOS is established unless more definitive morprologic or genetic evidence eme rges during the observation per iod . The presence of pe ripheral blood (PB) blasts esse ntially excludes a diagnosis of RCUD although in an occasional case a rare blast may be id entifie d: pa tients w ith the find ings of RCUO and 1% blasts in the PB and <5% in the bone ma rrow (BM) on

A.D. Brunning

A.P. Hasserjian A . Porwit J.M. Bennett

A. Orazr J. Thiele E. Heustrorn -Ltndberq

two successive evaluations should be placed in the category of MOS-U because of the uncertain biology of this constellation of findings. Patients with 2-4% blasts 11"1 the PB and <5% blasts in the 8M should be classified as refractory anaemia With excess btasts-t (RAEB-1) if other cntere lor MOS are present. The number d cases with these findings is very low ana these patients stoJd be careftAly coseoec for increasing 8M blast percentage 111651, Refractory cytopenia with unilineage dysplasia should not be equaled wiVl "Id iopa thic cytopenia of undetermined signiftcance" (ICUS) which lac ks the minimal morphologic or genetic criteria requisi te tor a diagnosis 01 MOS and should not be considered as such [24221.

Synonym Refractory anaemia. Epidemiology Refractory cytopenia with unilineage dysplasia comprises 10-20% of all cases of MOS 1782, 1371/. It is primarily a dsease of older adults; the median age is around 65-70 yea rs There is no signifi· cant sex pred ilection , The vast majorityo! RCUD c ases are RA. Refractor y neutropen ia and refr actory thrombocyt openia are rare an d extreme c aution should be used in making either of these d iagnoses. Sites of involvement The P8 and 8 M are the p rinci pal sites 01 involvement, Clinical feature s In RCUO. the presenting symptoms are related to the type of cytopenia, The cytoper nas are refracto ry to haernauruc therapy, but may be respo nsive 10 growth factors 19831. Mo
Refractory anaemia code 998013) In the PB in RA, the red blood cells are usually normochrcmic, normocytic or normoctYomic, macrocytic. Unusually, there is anisochromasia or dimorphism with a

oco-o

Fig. 5.13 Refradory WIlIeIT'Iia, This bone IIWTt7W smear speomen shows dyspIasbc Jeatures criy in !he8f)1tVOld preo.nors; octaSiOnaI erythrobIasl$ sI'lClW vacu:lIat8d c:ytopIasm Mel ~ megakXVst*! 1'oldBi.

94

Myelodysplastic syndromes

_

AS

Fif!. 5.14 A Refraclory neuuopel'lIa Bklod smear m a 56-year-old male;!tiel'lIllAJq)hI in lhe bwer IeflIS normal aweamg with weI-grarIJIated cytJpIa$ITI and a namaIy M!1I'*'*I 1IJdIus. The A8IA"ophI inltle l4lP8l' is dysplastic wiIh ~ ~ cyq:.Ia$mWld oc:casionaI 0CHe bode&. The I1.JdM; shows retarded MglIl8lI!alJOll. ApprounaleIy IlIIf01 fie nMropI'Iis 'III'8l1l dyspIaslic. Cytogenetic S!I..des showed .. extra toP'I d cnomosome 8 lWld perlOlft'lc rNer1ion d ctvornosare 12. B A tIyspIastic megakaI)uyte in a ~ ItTl8al' from a ll-year-okl male WIlIl a two year hISlory oIrelradory II1rtlmbocyk:Jp Theie is ~ Ikdearcylopiastllc dewelopll.,1 '/IIllh a ~ ~ and 8 norHobated mnaltn nucleus. CytIgeoelic slldIes ' I this !line stoNed a missing Y chromosome. There was SlbsequenC evokIIIon at which lime ~ -.oes shcMoed a rrWsSlI'lg Y, addltIonaI9 and deletion 13.

rv-

population of hypochromic red blood cells. Anisoc ytosis an d po ikilocytosis va ry from none 10 marked. Bla sts are rarely seen and, if present, acc ount for <1% of the while blood cells. The nectrocnns and p latele ts are usually normal in number and rrorpno-

Neutropenia secondary to drug therapy, toxic exposu re, infectious processes , immune mechani sms, or other causative factors must be exclud ed , The other myeloid cell lines do not show signific ant dysplasia

«10%).

logy. How ever, some degree 01 either neutropenia or thrombocytopenia may be

present The erythroid precursors in the 8M in RA vary from decreased to rnatkedty increased ;
principally by alterations in the nucleus includ in g budding, internuclea r br id ging ,

karyorrhexis. multinuclearity and mecatoblastoid ch anges: cytoplasmic features in. coos vacuolization and periodic acid-Schiff positivity, either diftuse or granular. Aing sideroblasts may be present but are <15% iJ erythroid precursors. Myelob lasts acooun1 for <5% of the nucl eated BM cel ls, The neutrophils and megakaryocytes are 'l:lm'IaI or may show rnnimaJ dysplasia, but ~ways < 10% in either cell line , The BM biopsy is generally hypercellular due 10 rcreased erythroid precursors. but may be rorrccenoiar or even hypocellular.

Refractory neutropenia (lCD-O code 999 1/3) Refractor y neutropeni a is ch aracterized by~ 1 0% dysplastic neutrophils in the PB or 3M; the dysplasia is principally manifesl as ru:::1ear hypoIobation and hypogranulation.

e

--

s

a

Refractory thrombocytopenia (ICD-O code 9992iJ) Refra ct ory thrombocytope nia is characterized by 2': 10% d ysplastic megakaryocv tee of at lea st 30 megakaryocytes eva luated : hypolcbate megakaryocytes, b inucleate and multinucleate megakaryecytes and mrcromeqakarvocvtes are the most reliab le and reproduci ble featu res of mega karyocyte dysp lasia , Dyspl astic megaka ryocyles may be more eviden t in sections than smea rs and usually well exceed the 10 % threshold . The megakarvocvtes may be increased or decreased . The other myeloid ce ll lines do not show sign ificant dysplasia (<10%). Distinction frem chronic autoinvnune thrombocytopenia is cntc at and may be extremely difficult clinica lly and morphologi ca lly. Cytogenetic studies may be of consi derable aid in this distinclion 18661. Immunophenotype In refractory anae mia abe rrant immuneph enotyp ic features of erythropo ietic precursors can be found by flow cytometry ana lysis 15501. There are no d ata on RN and RT.

Genetic s Cytogenetic abnormalities may be observed in up to 50% of ca ses of refractory anaemia 1782J Several difterent acquired clonal chromosomal abnormalities may be observed. and although useful for establishing a diagnosis of RA, they are not specific. The abnormalities generally associated with RA include del(2OQ), .8 and abnormalities of 5 aod/Of 7. The number 01 reported case s of AN and is 100 low to allow for generalizations, although del(2Oq ) has been reported in AT 1866. 19381.

m

Postulated cell of origin Haematopoietic stem cell. Prognosis and predictive factors The clinical course is protracted ; the median survival of patients wilh RA in one series was approximately 66 month s and the rate of progression to AML at 5 years was approximately 2% 17821 . In another study, the median survival tor pat ients over 70 years 01 age with AA, RARS and MOS with del(Sq) was not sigml icantly different frem the non-affected population 11371 1. Approximately 90-95% 01patients with RA have low or intermediate International Prognostic Scoring System (IPSS) scores 1833, 833AI. Approximately 80-85% have good to intermed iate cytogenetic profiles 1782, 13711, Most patients with AT have tow IPSS scores and 90% of the patients live more than two years 119381.

Refractory cytopenia with unilineage dysplasia

.

95

Refractory anaemia with ring sideroblasts

R.P. Hasserjian N. Gatterman n J.M. Bennett A.D. Brunning J . Thiele

Detinitioo Refractory anaemia with nng stderoorasts (RARS) is a myelodysp lastic syndrome (MDS) cha racterized by anaemia. morpho-

may be symptoms related to p rog ressive iron overload .

logic dysplasia in the eryth roid lineage and ring eoercoteste comprising ~ 1 5% of the bone mar row (B M) erythroid precursors , There is no signif icant dysplasia in non-erythroid lineages. Myeiobiasis comprise <5% allhe nucleated 8 M cells and are not present in the peripheral blood (Pe) , Secondary causes of ring sroeroblasts must be excluded.

ICD-O cod e

998213

Epidemiology RARS accounts for 3-11% of MDS cases. It occurs p rimarily in older indivi dua ls with

a median age of 60-73 years and has a simi lar freq uenc y in males and females

1267.782. 13711. EIOOgy Ring sideroblasls represent erythroid pre-

cursors with abnormal accumulation of iron within mitochondr ia. includi ng some deposited as mitoch ondria l ferritin 1352, 82 7f. Primary def ect s of haem synthes is (such as the a-amlnolevonruc acid synthetase defect in hered itary X-link ed srderoblastc anaemia) ca n largely be exclud ed be cause p rotoporphyrin IX, the end prod uct of po rphyr in synthes is, is not decreased in RARS 11 2091. Furthermore , acqu ired mutations in g enes of the haem synthetic pathway have not been demonstrated in AAAS {20841 Therefore. a pr imary defect

•

A

of mitochondrial iron metabolism is suspect ed . This de fect ma y be caused by soma tic mutations or deletion s in nuclear or mitochondrial DNA. Potentially analogous congenital d isorde rs inc lude the Pearson mar row-pancreas synd rome , whic h features s.oerooiastc anaemia and is caused by congenital large oeetcos of mitochondrial DNA 1478/ . Somatic point mutations 01 mitochondrial DNA have been ident ified in the BM 01 some patients with AA AS t7631 bu t it rema ins 10 be established whether they cause the soeob lastic p henotype 11 4221. Clona lity 01 CD34-positive progenitor cells and erythroid and granulocytic elemen ts has been demon strated in RARS patients by x-cbrorosome inactivation analysis {549. 2 1261. Stem cells from AARS patients d isp lay poor eryt hro id colony formation in vitro and manifest abnormal iron deposition at a very ea rly stage 01 erythroid deve lopment {444, 2 1781 . This evide nce suggests tha t RARS re prese nts a clonal stem cell d efect that manifests as abnormal iron metabolism in the erythroid lineage and results in ineffec tive eryt hropo iesis . Sites of involvement The PB and BM are the prin cipal sites of involvement. The liver and splee n may show evidence of iron over load. Clinical features The presenting symptoms are related to anaemia. which is usually of mode rate degree; some pati ent s may additiona lly be thrombocytopenic or neutrop eni c . There

""""hology Patients typically p resent with norrTll'> ch rom ic macrocytic or normochromic normocytic anaemia. The red blood eels in the PB smear may manifest a d imorphic pattern with a major population 01 normochromic red bkxxt cells and a minor population 01 hypochromic cells Blasts are not present in the PB. The 8M aspirate smear shows an inc rease in erythroid precursors with erythroid lineage dysplasia. inc ludi ng nuclear lobation and megaloblastoid fea tures . G ranulocytes and megakaryocytes show no significant dysplasia «10% dyspl astic forms). Haemo sid erin-Iaden macrophages are often abundant. Myelob lasts are less mao 5% of the nucleated 8 M cells. On an ironstained aspirate smea r, 15% or more of the red cell prec ursors are ring srceroblasts, as defined by 5 or more iron g ranules enci rcli ng one thi rd or more of the nuc leus. The 8 M biopsy is norrnocellularto markedly hyperceIlular. usually witha marked erythroid proliferation. Meqakaryocytes are normal in number and morphology. Ring sid eroblast s are frequen tly observed in other types 01MDS 1776, 10781. For examp le , c ases with ring sideroblasts that hav e exc ess blas ts in the PB or 8M are cl assifi ed as refractory anaemi a with excess of blasts (RAEB). When ring stoero bl asts a re 15% o r more of the eryth roid precur sors but there are 10% or more dyspl astic cells in any non-erythroid lineage.

_

Fig. 5.15 RefratQy..aema WItl'l rtog siderobIasts. A Blood smear wilh dmorphic red bklod eels and macrocyIeS (WrJItII-Giemsa). B 8lnI 1l\WfOlf aspt'aIe smear stlowIWlg I marked 8l)'ttlroid proIiferallon with a d)'5!JIBstlc Mderate bm (WrVrt-Giecnsa). C Ironslain d bone Il\WfOlf iISpQI8 sIll:JrMng I'U"I'letOUS ring sdetoblasts.

96

Myelodysplas!iC svnorores

and bla sts are < 1% in the PB and <5% in the 8M with no Auer rods or mo noc yto sis, the case is cl assi fied as refractor y cytopenia with mullilineag e dy sp lasia (RCMD ), Such patients have infe rior surviva l to patients with AARS. tbHleoplastic causes 01ring sideroblasts . includ ing alcohol. toxins (lead and benzene). dr ug s (isoniazid), zinc aorrurustraton. copper defic ienc y and congenital sderootastc anaemia, must be excluded

1201. Irrrnunopheootyp In refractory anaemia with ring stderooests . aberrant immunophenotypic tealures of erythropoietic precursors can be lound by flow cytometry analysis 15501.

100

eo 0;

.~ 60

,

---1....-

0

"•~

RCMD with 2:15% RS

~RARS

40

Q.

20

0 0

100

200

300

Months

Genetics Clonal chromosomal abnormalities are seen in 5-20% of c ases of AARS and, when presen t. typic ally involve a single

chromosome 1267. 776. 7781 .

FIg. 5.16 Stn;vaI Ctro'eS aller long-lenn ~oI' 161 patients WIth RARS and 318 RCMO patients WIltJ 2'15%mg siderotlIasts (RSI. showing i'ltenor survival lor lIIe pallents WIth mg sideroblasts and nUtiIineage dysplasia (p:O.ClCIOOS)(Datafrom ltIe Dusseldorf UDS regislry),

Postulated cell 01 orig in Haematopo ielic stem cell. Prognosis and p red ictive fac tor s Approximately 1- 2% of cases of AAA S evolve to ac ute mye lo id leukae mia. The reported ove rall median survival is 69- loa months 1549, 7781.

Aefractory anaemIa with ring

soercoiests

97

Refractory cytopenia with multilineage dysplasia

Definition Refractory cytopenia with multilineage d ysp lasia (ACMD) is a type 01 myelodysplastic syndrome (MOS) with one or more cytopenias and dysplastic changes in t'NO or rrore of the myeloid lineages: erythroid . 9mnulocytic. n-egaka
cytes in the P8 are less than l xHJ'I\.. The recommended levels for defining cytopenias are haemoglobin < lOgfdL absolute neutrophil cocnt <1.8xl()9/l and platelet count <100xl()11I\.I633. 833A1 . However, values in excess 01 these thresholds are not exclusionary of a diagnosis of MDS if definitive morphologic and/or cytogenetic findings are consistent with a diagnosis. e.q. complex cytogenetic abnormalities . The thresholds lor dysplasia are ~10% in each of the affected cell lines. In assessing dysp lasia it is recommended that 200 neutrophils and precursors and 200 erythroid pre cursors be evaluate d in smear and /or treph ine imprint preparations. The neutr oph il dysplasia may be evaluated in PB or BM smears. At least 30 meg akarycc ytes should be evaluated for dysplasia in BM smears or sec tions, In some ca ses, dysplastic meg akaryocyt es may be mor e readily identif ied in sec tions than smears, In particul ar the presenc e of micromegakaryocyte s should be noted . Cases with multilineage dyspl asia and 2-4%

98

Myek:!dYSplastlC syndromes

R D. Brunning J ,M . Bennett

E. Matures A. Orazi J.w. Vardiman J. Thiele

b lasts in the PB, <5% in the BM, and no Auer rod s should be classified as refrac tory ana em ia with excess of blasts (RAEB)- l ; cases with 1% blasts or fewer in the PB and <5% blasts in the BM, and Auer rods should be classified as RAEB-2 ; cases with 1% blasts in the PB and <5% in the 8M and no Auer rods should be classified as MDS-U. Some cases of RCMD have 2:15% ring sideroblasts (782 . 137 11 . ICD-Ocode

998513

Epid emiology Refractory cytopenia With multilineage dysplasia occurs in older ind ividuals: the median age is approximately 70 years. There is a sligh t predominance of males. The peak incidence for males is 70-74 years, for fema les 75-79 years (7821. It accounts for -30% of cases of MDS 1782. 137 11 . Sites of involv ement Blood and bone ma rrow Clinical features Most patients present with evidence 01 BM failure with cy topenia 01two or more myeloid cell lines. Morphology The BM is usually hypercellular. Neu trophil dy splasia is cha racte rized b y

....... Fig. 5.1' Refractooy ~ withrn.J~~ Bone marrow smear shows eviOenCe 01 dyspasia...bl:tl ee erythroidprecursors andthe neutropnils. The maI\tt neutrophils aresmall andMvallypolobulated rn.cIeI.

hypo granulation and/or nuclear hyposeq. ment ation with ma rked clump ing of the nuclear ch romatin (p seudo Pelqer-l-iuet nuclei), The nuc lear hyposegm entation may occur as two clumped nuclear lobes con nec ted by a thin chromatin strand (ptoce-nez type) Of marked ly clumped non-lobated nuclei , Myeloblasts account for <5% of the 8 M ceus. In some cases there is a marked inc rease in erythroid precu rsors . Erythroid p recursors may show cytoplasmic vacuo les and marked nuclear irregularity, inclu ding internuclear chromatin bridging, multilobation, nuclear bu dd ing, multmucleation and megalobrastord nuclei. The vacuoles are usually poorly defined and dissimilar to the sharply demarcated vacuoles observed in toxic alterations such as alcoholism The vacuoles may be pe riodic acid-Schlll (PAS) positive; there may also be diffuse cytoplasmic PAS positivity. In RCMD,

variable numbers of ring stoercorasts may be identified Megakaryocyt e abnorma lities which may be obse rved inclu de nonlobated nuclei, nvpotonered nuclei, binucleate or multinucleate megak aryocvtes and micromegakaryocytes; the micromegakaryocyte is defined as a megakaryocyte approximately the size of a promyelocyte or smaller with a nonlobated or bitobed nucleus and is the most reliab le and reproducible dysplastic feature in the megakaryocyte series {1 4201_

Immunophenotype See Chapter on mye lod ysplastic synoromesrneo otasms. overview. Genetics Clonal cytog enetic abnormalities including trisomy 8, monosomy 7, del(7q). monosomy 5, del(5q ), and del(2Oq), as well as com plex karyotyp es, may be found in up to 50% of patients with RCMD {782, 8331. Postulated cell of origin Haematopoietic stem cell .

Prognosi s and pred ictive factors The clinical course varies. The majority of patients wilh RCMD has International Prog nostic Scoring System (IPSS) scores in the intermediate category 1833, 833AI. Prognosli c factors relate to the degree ot cytopenia and dys plasia . The frequency of acute leukaem ia evolution at two years is - 10% in RMCD 17821. The overall median survival is approximately 30 rron ms. Patients with complex karvorvpes have survivals similar to patients with refractory anaemia with excess of blasts (AAEB) 17821.

Refractory cvtooeoa With multJ!ineage dysplaSia

99

Refractory anaemia with excess blasts

A.Orazi

R D. Brunning

R P. Hasserjian U. Germing J. Thiele

Definition Refractory anaemia with excess blasts (RAEB) is a myelodysplastic syndrome (MDS) with 5-19% myeloblasts in the bone marrow (BM) or 2-19% blasts in the peripheral blood (PB) Because of differences in survival and inc idence of evolution to acute myeloid leukaemia (AML). two categories of RAEB are recognized: AAEB-l, defined by 5-9% blasts in the BMor 2 -4% blasts in the PB, and RAEB-2 , defined by 10-19% blasts in the 8M or 5-19% blasts in the PB 18331. The pres-

ence of Auer rods in blasts qualifies a case as RAEB-2 irrespective of the blast percentage 17811. ICD-O code

998313

Ep;demkllogy This disease affec ts primarily individuals over 50 years 01 age . It accounts lor approximately 40% of all patients with MOS. Etiology The etiology is unknown. Exposure to environmenta l toxins, including pesticides, pet roleum derivatives and some heavy metals inc reases risk, as d oe s cigarette smok ing 12113AI. Sites of Involve me nt Blood and bone marrow , Clinical features Most p atients initially present w ith symptoms rela ted to BM fail ure , includ ing anaemia, thrombocytopenia and neutrope nia.

"'"""",Iogy The PB sme ar freq uently shows abnormali ties in all th ree myeloid cell lines. including red cell anisopoikilocytosis. large, giant or hypogranular platelets and abnormal cytoplasmic granUlarity and nuclear segmentation of the neutrophils. Blasts are commonly present. The BM is usually hyperceHular. The degree of dysplasia may vary. Erythropoiesis may be increased with macrocyticlmegaloblastoid changes . The erythroid precursors may 100

FIg. 5.19 Relractoryanaemia Wl1tJ excess b1asts-1(RAEB-1J. Bone rnatrOWsmear. The malJ.l'e ~ I'Ihsc. show nuclear hypolobulabon (pseudo Pelger-Hll8I nuclei) and cytoplasmic hypograrnunty.

show d yserythropoiesis including the presence of ab no rmally lobulated nuclei and internucl ear bridging, Granulopoiesis is frequently incr eased and shows var iable deg rees of dys p lasia. This is cha racterized primarily by sma ll size neutrophils with nuclear hypo lo bation (pseudo Pelq er-Hoe t nucl ei) or nucl ear hype rsegme ntation , c ytop lasm ic hypogranularity and/or pseudo Chediak-Higashi g ranules. Megakaryopoiesis is va riable in quantity b ut is frequentl y no rma! to increased. The megakaryocyt es often show a tend enc y to c luster. Oysmegakaryopoiesis is a lmost inva riably present and is usually cha racterized by the p rese nce of a bnormal forms predomin antly of small size, incl ud ing micromegakaryocytes 122261. Howeve r, megakaryocytes of all sizes as well as for ms wi th multip le widely-separated nuclei can also occur. The BM biopsy shows alte ration of the normal tnstctopography. Both erythropoiesis and megakaryopoiesis appear frequently dis located towards the paratrabecular areas that are normally predominantly occupied by granulopoietic cells. In a minority of cases the BM appears

normocellular or hvpocenuar. RAEBcases with hypocellular 8M represent only a small proportion of ca ses of hypoplasbC MOS, since most of these cases do rd show an increased numbe r of blasts ana belong to the g roup of refractory cvtooere with unilineage dys plas ia (RCUD) or less common ly to refractory c yto penia witn mu ltilineage dy sp lasia (RCMDl , The 8M bio psy ca n be very useful in documenting the presence of an exc ess of blasts perticula rly in cases w ith subo ptimal aspirate smears such as those assoc iated wim a hypocellular and/or fib rotic BM. Blastsi1 AAEB of ten tend to form cell clusters II aggregates that are usually located a~ 'rom bone trabeculae and vascular snc teres. a histologic find ing formerly referred to as abnormal localization of immature precursors (AlIP). Immunohistochemical staining for C034 may be particularty helpful in their identification. RAEB wilh fibrosis (RAEB-F): In about 15% of patients with MOS, ee BM stews a sign ificant d eg ree of re\lCl.irl fibrosis . Such cases have been termed MDS WIth fibrosis (MDS-F) (1246. 1400/.

MyelOdysplastiC syndromes

\

Since myelQfibrosis can be seen also in cases otmerapv -rerateo MOS, myelop roliferative neoplasms, and, rarely, in reactive dyshaematopoietic con ditions (e·9 HIV·related myelopathy) these conditions need to be excluded. Because of the lack of consensus on the degree of fibr osis necessary to characterize a case as MDS-F, it is stilt unclear whether fibrosis represents an indepe ndent prognostic parame ter 12083 1. The cur rent wo rking definiloo of MOS-F requires diffuse coarse reticulin fibrosis with or without coocomilant collagenizalion , associated with dysplasia in at least two cell lineage s 12083, 23121. Most of the cases def ined as MOS· F belong to the RAEB category (RAEB-F), The presence of an excess of blasts in these cases ca n usually be demonstrated using immunohistoch emistry. particularly for CD34. The BM smears are usually inadequate. A cha ract eristic finding in RAEB-F is an increased number 01meg akeryccv tes with a spectrum of cell size (including micromeg akaryocytes) and a high degree of dysplasia 112461. Cases of RAEB·F may morpholog ically over lap acute paomveiosts with myelofibrosis (APMF) previously referred to as acute (malignant) myelofibrosis. APMF is d isne t from RAEB-F by its abrupt onset with 'ever and bone pa in 11651 , 22251.

Irrmunoph enotype Flow cytometry in RAEB often shows increased numbers 01 cells pos itive for precursor ce ll assoc iated antigens CD34 and/or C0 117. These cell s are usually positive for C038. HLA-DR and myeloidassoc iated antigens CD13 and/or CD33 . Asynchronous expression of granulocytic maturation antigens CD1S, C011b and/or COOS can be seen in the blast population. Aberrant expression 01C07 on blast cells is seen in 20% 01 cases and C056 is present in 10% of cases . while exp ression of other lymphoid markers is rare {1210. 1623J, In tiss ue sec tions, C034 immunoh istochemistry may be used to co nfirm the presence of an increased number of blasts; it allows the apprec iation of their arrangement into clusters or agg regates, a cha rac teristic finding seen in most of the cases of RAEB 120501. Antibodies such as C061 or C042b can aid in the identification of micromegakaryocytes and other small dysplastic forms. wh ich are particu larly numerous in cases of RAEB-F 11246, 22261_

Postulated cell of origin Haematopoietic stem ce ll. Prognosi s and pl'edictive factors Refractory anaemia with excess blasts is usually char acterized by prog ressive BM failure with increasing cytopenias. Approximately 25% of cases 01 RAEB-l and 33% of pat ients with RAEB-2 progress to AML; the remainder succu mb to the sequelae 01 BM failure. The median survival is approximalely 16 months for RAEB-1 and 9 months for RAEB-2 17811. CD7 exp ression has been assocrateo with poo r prognosis {16231. RAEB-2 patients with 5- 19% blasts in the PB have a median survival of 3 months similar to that of myelodysplasia-related AML 121 t 41 , In contrast, cases defined as AAEB-2 based only on the presence of Auer rods . have a prognosis which is similar to that seen in cases of RAEB-2 with 2-4% periphe ral blasts (median survival. 12 months) 121141.

Genetics A variable percentage of cases of RAEB (30- 50%) have clonal c ytogenetic abnormal ities, including +8 , -5, de l(5q ). -7. del(7q) and del(2Oq). Complex karyotypes may also be observed 17821.

Refractory anaemia with excess blasts

tOl

Myelodysplastic syndrome with isolated del(5q)

RP. Hasse rjian MM LeBeau AF. li st J.M . Bennett J . Thiele

.

,. • ,

Definition Mveiccvsoiasnc syndrome with isolated del(Sq) is a myelodysplastic syndrome (MDS) cnaractertzeo by anaemia with or without other cvtopenrasand/or thrombocytos is and in which the sole cytogenetic abnormality is del(Sq), Myeloblasts conprise <5% of nucleated bone marrow (8M) cells and < 1% 01 pe ripheral blood (PSI leukocytes and Auer rods are absent.

Synonym MyeIodyspIastic syndrome with 5Q deletion (Sq- syndrome) . EpidemK>logy MDS with isolated del(Sq) occurs more oflen In women, with a median age 0167

years. Etiology Pres umed loss of a tumou r suppressor ge ne in the d eleted regioo . Possible ca ndi dates include the early g rowth respo nse 1 (EGR 1) and c -ceterm (CTNNA I) genes and as-vet-untcennted genets) in 5q32 1256, 1075, 1324). The RPS14 gene that encodes a ribosomal protein has been propo sed as a can didate in the Sq- syndrome, raising the possib ility that a defect in ribosomal p rotein func tion ca uses that di sorder 1256. 635 , 1075. 1324 1. Sites of involvement Blood and bone ma rrow, Clinicalleatures The most common symptoms are usually related to anaemia. whic h is often severe and usually macrocytic. Thromboc ytosis is present in one third 10 one half of patients. while rnromcoocytopenle is uncommon {794, 14171.

non-lobated and hypolobated nuclei. In contrast, dysplasia in the erythroid and myeloid lineages is uncommon 1257. 794}. The term "Sq- synd rome - has been used to desi gnate a subset 01 cases with macrocytic anaemia. normal or eleva ted platelet count and BM erythroid hypoplasia 1257,23621. The number of blasts in the BM is <5% and in the PB is < 1%. Genetics The sole cytogene tic abnormality involves an interstitial deletion 01 chromosome 5; the size of the del etion and the breakpoints are variabl e, but ba nd s q 31 · q33 are invariab ly deleted . If any ad ditional c ytoge netic ab nor mality is p resent (With the exception of a loss of the Y chromosome), the case should not be p laced in this cateqoey 11 has bee n recen tly reported that a small subset of patients with isolated del(Sq) m ay show a concomitant JAK2 V617F mutation. Until more data are collected for such cases and their clinical behaviour and respon se to therapy such as lenalidomide are clarified. it is prud ent to classify lhem as MDS with isolated de~5q) (rather than in the MDS/MPN category) and to note the presence of the JAK2V617F in the diagnosis

110051. Mo
MyelodysplastJc Syndromes

Postulated cel l of origin Haernatoootetrc stern cell . FISH analysis has confi rme d p resence of the del{Sq) abnormality in differentiating erythroid. myeloid. and megakaryocytic cells, but

generally not in mature lymphoid cells

139.2191. Prognosis and predictive fact ors

This disease is associated with a rrecen survival of 145 months, with transformatioo to acute myeloid leukaemia occurring II <10% of patients 17941. Patients with del(Sq) associated with other chrorTlOSlmll abnormalities or with excess blasts have an inferior survival and are excluded frOOI this diagnosis 17941. Recently. the thali a; mide analogue lena fidomide has been shown to benefit MDS patients with isolated del(Sq) as well as d el(5q) with additional cytogenetic ab normalities. Transfusion inde pendence was achieved in two thirds of p atients and was c losely linked to suppression of the abno rmal clone (795,

13201

Myelodysplastic syndrome, unclassifiable

Definition Myelodysplastic syndrome. unclassifiable (MDS-U ) is a subtype 01 MDS which init~1y lacks findings appropriate for classi-

fication into any other MDS category Three possible situations which qualify patents tor inclusion in this category are listed under -morp hology·.

9989/3

A.Orazi AD Brunning I. Baumann

R.P. Hasserpan

--

Genetics

There are no specific morphological lindiogs. The diagnosis of myerocvsplasnc syndrome, unctasslnabie. can be made in the followi ng instances:

1. Patients with the findings 01 refractory cytopenia with unilineage dysplasia (RCUO) or refractory cytopenia with rn.Jltilineage dysplasia (RCMD) but with 1% blasts in the P8 qualify for MDS-U 111651.

Sjrooym Uyelodysplastic syndrome, NOS.

EpOdemk>logy The incidence of mvetodvscrasuc 5YO-

2. Cases of MOO with tXlihneage dySplasia which are associated with pancytopenia. In contrast. the RCUD category only allows for a single cytopenia or bi-cytoperna .

cone. uoctassmame. is unknown. Sites of irwotvement The peripheral blood (PB) and bone mal1'C1W (8M) are the principal sites of involvement.

Clinical featu res Patients present with symptoms similar 10

n ose seen in the other myetcovsprasnc

syndromes.

3 . Patients with persistent cvtooemats) with 1% or fewer blasts in the blood and fewer than 5% in the BM , unequivocal dysplasia (Table 5.03) in less than 10% of the cells in one or more myeloid lineages. and who have cytogenetic abnormalities considered as presumptive evidence 01 MOO (Table 5.04) are p laced in this category MDS-U p atients should be carefully fo llowed for evid enc e of evolution to a more specific MDS type.

See Table 5 .04. Postu lated cell of origin Haematopoietic stem ce ll.

Prognosis and predic tive factors If characteristics of a specific subtype of MDS develop later in the course 01 the disease , the case should be reclassified accordingly. In cases diagnosed as MOS. U. it is unknown both the percentage 01 patients which translorm to acute myeloid leukaemia as we ll as the disease survival . Cases with features otherwise consistent WIth a diagnosis 01 RCUD Of ACMO. but in which 1% blasts are detected in the peripheral blood, have been shown to have a prognosis which is intermediate between ACUO (or ACMO) and that of refractory anaemia with excess blasts (AAEB)

11 1651.

Myelodysptasttc syndrome. unclaSSiflable

t03

Chi ldhood myelodysplastic syndrome

Myelodysplastic syndrome CMOS) is very

UflCOrTlfl"lOf1 in children, accounting lor less than 5% of all haematcooenc neoplasms in patients less than 14 years of age (Table 5 .06) 1908. 910 , 1595A, 2079AI . The de novo or primary form of MDS in children should be distinguished from cases of "secondary MOS· that follow congenital or acquired bone marrow (8M) failure syndromes and from therapy· related MDS that tollows cytotoxic therapy tora previous neoplastic or rco-reootastc condi tion. Furthermore. although MOS associated with Down syndrome has been reported to account lor 20-25% 01

cases of childhood MDS in the past {2079AI, this disorder is now considered as a unique biologic entity synonymous with Down syndrome-related myeloid leu kaemia and cnstmct from other cases of chil dhood MDS (See Chapter 6). Many of the morphologic. immonophenotypic and genetic features observed in MDS in adults are also seen in ch ildhood forms of the d isea se b ut the re are some signific ant d ifferen c es reported , part ic ularly in pat ients who do not have increased blasts in the ir pe ripheral blood (PB) or Table 5.06 Ir.cKIence of haematoklgical malignancies in children 0 - 14 years, Combined data from Dtlnmark. 1980-1991 and British Columbia 1982-1996(907, 908}. N

% Incidence' 79 38.5

AU AMl1

915 115

11

5.4

"lOS'

38

4

Myebd leuk.aemia of OS

19

2

1.8 0.9

JMMl

25

2

1,2 0,6

13

1

'VIET

3

Unclassified

3

o o

0.1 0.1

1031

100

48.1

CMl

T","

ALl. acute IyrnpIlobIaSbC leukaemia; AML. acute myeloid leukaemia; MOS, ~SbC s)'l'klrome; JMML,;.wetiIe m~ leukaemia: CUl . etworic myelogenous leukaemia. PII. poIytytllaeITia vera; El essenbal ttvorrtlocyII'I , Exdudng Down 5)'I»'ome (OS) I per n-.on poptAalJon peryear

104

Myelodysplastic syndromes

BM. For example, the subtypes 01 refractory anaemia with ring stoeroblaets and MDS associated with isolated del (Sq) chromosomal abnormality are exceedingly rare in chil dren 11595A1. Isolated anaemia, which is the major presenting rnamtestatton of refractory anaemia (RA) in adults, is unCOlTIllOO in chil d ren, wto are more likely to present with neutropenia and thrombocytopenia 1908, 11091. In addition, hypocellularity of the BM is more commonly observed in childhood MDS than in older patients. Therefore, some chi ldren have findings that do not readily fit into the "low grade" MDS categories. To address these differences, a provisional entity, refractory cytopenia of childhood (RCC) is introduced and defined below. For ch ildren with MOS in whom there are 2-19% blasts in the PB or 5-19% blasts in the BM . the same criteria utilized for adults with refrac tory anaem ia with excess blasts (RA EB) should be ap pl ied . Cu rrently, in contrast to adult MOS, the re are no availab le stu di es that have investigated the prognos1ic sig nific ance of distinguishing RAEB-1 and RAEB-2 in chil dren, bu t it is rec ommended th at this distinc tion be made for future investiga tion. Children with RAEB generally have relativ ely stable PB co unts for weeks or months , Some cases d iagnosed in children as ac ute myeloid leukaem ia (AML) with 20-29% blasts in the PB and/or BM that have myelodysp lasiarelated c hang es. includ ing cases w ith myelodysp lasia-related c ytogenetic abnormalities (See Cha pte r 6 ) may also have slowly progressive d isease. These c ases, co ns idered as refract ory anaemia with exce ss blasts in transformation in the French-Amer ican -British cooperative classification. may lack the cli nical features of acute leukaemia and be have more like MOS than A ML 19081. thus follow-up PB an d BM studies are often necessary to measure the pace of the d isease in such c ases. Children who present with a PB and/or BM disorder associated with t(8;21)(q22;q22), inv( 16)(p13.1q22) or t( 16; 16XP13. 1;q22) or t( 15;17Xq22;q 12) should be considered to have A ML regardless of the blast count

I. Bau mann C,M. Niemeyer J .M , Bennett K. Shannon

• ~IQ .

5J l

Relractory~dd'ikhxld(RCC~_

marrow smear showing abnormal nuclear IctUabcwl d

an twyttYopoietIc precursor eel alld a smaI megaQ"rocyle WItIl a IJi.lobed 1IUdeus,

Refractory cytopenia of childhood (RCC) Definition Refractory cytopenia of childhoocl (RCC}1S a mveioovsotastc syndrome (MDSl char· by persistent cytopenia with <5% blasts in the BM and <2% bla sts in the PB {908) . Although the pre sence of dysplasia is required for the d iagnosis, the cytological evaluation of dysplasia by itself const itutes only one aspect of the morpho logical diagnosis of RCC , The evaluation of an adeq uate BM trep hine biop sy specimen is indi spensable for the d iagnosis 01 RCe in c hildren, About 75% of ch ildren with RCe show co nsi de rable hypocellularity 01 the BM 117841. Conseq uently, it may be very cha llengin g to d ifferentia te hypocellular RCC from other BM failure disorders, especially from acquired aplas tic anaere and inherited BM failure disorders. Down syndrome-related myeloid neoplasms are excluded from this diagnosis. The WHO Working Group assigned RCC to a groop of provisional entities.

actenzeo

ICD-{) code

998513

Synonym Refractory anaemia of childhood.

Epidemkllogy

RCC is the most corrmon subtype 01 MDS in childhood accounting for about 50%ct

< f

• •

,

..

., ./

••

. I ....~

'~

~

~

..

1-'

ire cases 11704, 1784 /. II is diagnosed in

all age groups and affects boys and gi rls with equal frequency 111091.

Stes of involvement Blood and 8 M are alw ays affected. Gen efally. spleen. liver and lymph nod es are rot sites of initial ma nifestation .

Clinical features The most common symptoms are malaise, bleeding , fever and infection /1109). lym-

Morphology The classica l p ictu re of RCC is a PB sme ar that shows red blood cell antsopolknocytosts and macrocytosis. Anisochromia may be present. Platelets often di splay anisocytosis and occasionally g iant p late lets can be de tected. Neutrope nia wit h pseudc -Pelg er-t-luet nuclei and/or hypogranularity of neutrophil

Table 5.07 Minimal diagnostic criteria for reffactory cytopenia of childhood.

phadenopathy secondary to local or systemic infec tion may be present, but hepatosple nomegaly is ge nerally not a feature of RCe , In up to 20% of p atients, eocjrucal signs Of symptoms are reported

11 109/. Congenital abnormalities of different organ systems may be present. Three Quarters of patients have a platelet count be low 150 x10 9/L. whi le anaemia with a haemoglobin concentration 01less than 10 g/d L is noted in aboul half of the affected children 111091. Mac roc ytosis of fed cells evaluated accord ing to the patient's age is seen in mos t The wh ite blood count is generally decreased with severe neutropenia not ed in about 25 %

11 1091. Etiology The etiology is unknown in most cases.

c ytop lasm may be note d . Blasts are absent or account for less than 2% of the white blood cells . On 8M aspirate smears dysplastic changes should be present in two ditlerent myeloid cell lineages, or exceed 10% in one sing le cell line (Table 5.07). Erythroid abnormalities inc lude nuc lear budding , mcmnucreanty karyorrhexis , internuclear bridg ing. cytoplasmic granules and macr0cvnc Changes . Cells of granulocytic lineage ma y extubtt hyposegmentation with p seud o-Pelqer-Huet nuclei . hypo-fagranularity of the cyt oplasm , mac rocytic (giant) bands and cyt oplasmic-nuclear maturation asynchrony. Myeloblasts account lex" fewer than 5% of the 8M cells. Megakaryocytes are usua lly absent or very low in nt.rn ber. The detection of micromegakaryocytes is a strong ind icator 0 1 RCC . Ring sioerobla sts are not fou nd . In RCC with norma- Of hypercetlular 8M specimens there is slight to moderate inc rease of erythropoiesis with accumulation o f immature precursor cells. mainly proerymrootaste. Increased numbers of mitose s indicate ineffective erythropo ies is. Granu lopoies is appea rs slightly 10 moderately decrease d and ce lls of granulocytic lineag e are loo sely scattered. Blasts ac count for less than 5% of the 8 M cells , and C034 staining on the biopsy is useful for verification of the blast percentage. Megaka ryoc ytes may be nor· ma l, decreased Of incre ase d in number and display dys plasia with non-lob ulated nuclei. abnorma lly sep arated nucl ear

Bone marrow aspirate

Bone marrow biopsy

Erythropoiesis

Granulopoiesis

Megakaryopoiesis

Dyspl astic changes' andlor megaloblastoid changes in at least 10% of ery\tlroid PfeoJ~

Dysplasbc changes" in at 18ast 10%of granulocytic

precursors and neutrophils: <5%blasts

Unequivocal micromegakaryocytes, othefdysplasticchangesl in variable numbers

A lew dusttl'Sof at least20 erythroid precursors.

No minimal diagnostic cmeria

UnequiYocal

micromegakaryocytes:

Stoll in maturatiOn with

irnrl'lJnohistoctlemistry is obIigab')' (COOl , CD41 ). oltlerdysplasti: cIIange5t ill variable I1lSI1bers

increased numbers of

1''''0''''''''''' lncmased I1UIT'tlers of mitoses. Peripheral blood

Dysplastic changes' nat I8ast10%of neutrophis;

""

....

• AbnormaII'IIdear lobulation, mutIirKIdear oeh. I'lUdear bfidge$. r Pseu:Io-PeIger-HlJiit eels. tlypo-or agrardanly, IJ'if'l b8rlds (In cases of severe neutropenia lI'»s crilena may nol be fuIIiIed ). f Megakaryocytes of vanabIe see WIttl $&p8r31ed nuclei orround emude refraclofy C)'IOPel'Iia of chitJlood.

IlI,dei.Theabsence of megak¥yIX:yIes

"not

Childhood myeocvsotasuc svocrore

105

bbl, 5.08 Comparison Of rnlIIphologicaI cnlefiaaI hypoplastic refracby cytopeoiaof childhood and aplasticanaemia inchildhood R,1ractofy cytopenil of childhood

--- -_d_

lbIe m.tm::lW. . C)'tc*lgy

Pattry dcstrtluIion lell shift

.......,..."

~-­

Agranuiabon ofcytoplasm

Ni.dear
Marked dea8ase Dysplastic manges Miaomegakaryocytes

M~

Lymphocytes

May be increased focally or dispersed

May be increased

C034+ cells

Noincrease

MulI ~e

separated nuclei

Small round nuclei

Aplastic lNemia in childhood BoN tIJafJDW' ISpI(BIe ~

--

l.Icting or single smaI bcus WlIh Ie5slhat110cels W11tl

lICkflg or Y8IY lew eels, WIthool. dysplasia or megalobIastlid change

I.JIc:UIg or ~ decrease, Y8IY lewsmalloci 'NIth maturation

-

l.adUng orY8IY few, no dysplastlc

-""

May be increased bcally Of

C034+ cells

No increase

lobes and charact eristic micromegaKaryocytes. There is no incr ease in reticulin fibres. The majority of patients with RCC show a marked decrease of 8 M cellularity, down 10 5-10% o f the normal age matched veroe. The morphologic findings are similar to those observed in the normally cellular Of hypercetlular cases. Immature erythroid precursors form one or several islands consisting 01 at least 10 cells . This patchy pattern of evtreoooests is usually accompanied by sparsely distributed granulopoiesis. MegaKaryocytes are sig. nilicantly decreased or absent. Although micromeqakaryocvtes may be rare or not always found, they should be searched lor carefully as they are impo rtan t in 106

May be increased

Myelodysplastic syndromes

establis hing the diagnosis, Multiple sections prepared from the biopsy may be helpful in roermtcanoo of abnormal rneqakarvocytes and immunohistochemistry to identify mictomegakaryocytes is obligatory. Fatty tissue between the areas of haematopoiesis can mimic aplastic anaemia (Table 5.08). Thereforeat least two biopsies at least two weeks apart are recommended to facil itate the detection of representative 8M spaces containing foci of erythropoiesis.

Differential di agnosi s In children, a variety 01 non-haematological d isord ers such as viral mtecuons. nutritional deficiencies and metabolic diseases can give rise to secondary myelodysplasia,

thereby mimicking RCC (Table 5.09). In the absence of a cytogenetic marker the clinical course of cases suspected lX RCC has to be carefully evaluated before a clear-cut diagnosis can be made. rte haematological differential diagnosis .... ciuoes acquired aplastic anaemia. riter· ited 8M failure diseases and paroxysrral nocturnal haemoglobinuria (PNH). In ceotrast to RCe. acquired aplastic aneere presents with adipocytosis of the 8M spaces with few scattered myeloid cells there are no erythroid islands wllh increased numbers of immature erythroblas ts, no granulocytic dysplasia and no micromegakaryocytes (Table 5.08). CO'\< trary to wnat is sometimes reported in adUls with aplastic anaemia, at presentation acquired aplastic an aemia of childhood does not have mega loblastic features; IQl. lowing immunosuppressive therapy, the histological pattern of acquired apiasic anaemia can no longer be separated fnm tha t observed in RCC. The inherited au failure oeoroers such as Fanconi ereera ovskeratosrs conqemta . ShwachmarDiamond syndrome, amegakaryocytC thrombocytopenia or pancytopenia radioulnar synostosis show overlap morphological features with ACC, They have to be excluded by medical hisl~ phySical exemoanoo and the appropraale laboratory and molecular studies belen a definite diagnosis of RCC can be made The clinical picture of PNH is rare in C/"Ml(j. hood. although PNH clones in the absence of naemoivsts or thrombosis may be observed in children with RCe 122921 The relation between RCe with two (It" mo re dysplastic lineag es and retractor cy topen ia with mu llilineag e dysplasia (RCMD) has not vet been evaluated, Currently il is recommended that children who otherwise fit the criteria for RCMD be considered as RCC until such studies cla rify whether the number 01 lineages involved is an important prococsc discriminator in childhood MOS. Immunophenolype Mlcromegakaryocytes can be missec easily in H&E stained 8M trephine biopsy sectcos but can be more readily aweciated by the expression 01 platelet g/y(» proteins like C061 (glycoprotein lila), C04I (glycoprotein lib/lila) or von Willebrancl factor. Myeloblasts do not account ta more than 5% of the 8 M cells , and oetectton of 5% or more CD34, mvetooeroe dase, lysozyme and CD 117 positive biaS!

cells may lnc ncate progression to high grade MOS. Clusters of myeloblas ts are -ot seen in ACC.

Genetics The genetic changes predisposing to !.lOS in childhood remain largely obscure. The presumed underlying mechanism may also give rise 10 subtle phenotypic abnormalihes noted in many children with MOS. Monosomy 7 is the most common cytogenetic abnormality /1 109, 1704, 17841 . Other cytogenetic abnormalities IlChJding complex karyotypes may also be observed. Most cases of ACC show a rnmal karyotype irrespective 01 8M eelltarrty. There is no difference in morpholOgy between cases with Of without -oonosomy 7. PtlstuIated cell of origin saematopoenc stem celt with multihneage potential , Prognosis and pred ictiv e factors (aryotype is the most important factor 'or progression 10 advanced MOS. Patents with monosomy 7 have a sign ificantly higher probability of progression f an patients with other chromosomal abrcmannes or normal karyotype 111091.

Table 5.09 Dfsofders which maypresent witll morp hoj ogic.a lleal~ res indisbnguishable from refractory cytopenia ofct1ildhood,

Infectioos (e.g, c:ytomeo;lalovirus, herpes Wuses. parvovirus 819, YiscerailelsnmaniasiS) Vrtamin detiOeocy (e,g.deficiency of vitamin B12,Iolale, Yilamln E)

Metabolic: disorders (e.g, mevalonatemase delk:iency) Rhel.maliC disease A.utoirmuIe I)mphoproIIferative dISOrders (e,g, FAS deftciency) Mllochondrial deleloos (Pear9on S)YIdrome) ~ bone marrow laikJre disorders(e,g Fanconi anaema. dyskeratosis congeniIa, 5hwactmam-Oiarnond

syndrome , amegakaryocyIit~,1hrorTtlocytope WI1h absent radii, radioulnar syMSlO$lS.

Sedtel syndrome) P~nochrnaI ~ (PM-I) ~ apIasbc anaemia

dlmg haemalologicall'llCOYllfy

Spontaneous disappearance of monosomy 7 and cytopenia has been reported in infants, but remains a rare event I t3801. In contrast to mooosomy 7, patients with trisomy 8 Of norma l karyotype may experiencea long stablecourseof their disease, Currently, haematopoietic stem ce ll transplantation (HSCT) is the only cu rative therapy and is the treatment of choice for patients with monosomy 7 or complex karyotypes early in the course of their disease . In view of a low transplant-related mortality HSCT can also be recorsrenoed for pa tients with other karyotypes if a SUIt· able donor is available /1784 . 21041.

An expectant approach with careful observation may be reasonab le for patients in the absence of transfusion requirements. severe cytopenia Of infections. Because early 8M failure can at least in part be mediated by t-een immunosuppression of baenatoooese. irrmunosuppressive therapy can be a successful therapy strategy for improving outlook in some children with ACC 12033, 24711 .

Childhood myelodysplastlc syndrome

107

CHAPTER 6 Acute Myeloid Leukaemia and Related Precursor Neoplasms

Acute myefoid leukaemia with recurrent genetic abnormalities Acute myeloid leukaemia with myelodysplasia-related changes

lllerapy-related myeloid neoplasms Acute myeloid leukaemia, not otherwise specified Myeloid sarcoma Myeloid proliferations related to Down syndrome Blastic plasmacytoid dendritic cell neoplasm

Acute myeloid leukaemia with recurrent genetic abnormal ities

AML with balanced translocations/inversions This group is characterized by recurrent genetic abnormalities of prognostIC significance. The most commonty identified are balanced abnormalities: 1(8;21)(q22:q22), inv( 16)(p 13. l q22) or I(16:16)(p 13 .' ;q 22), 1(15;17}(q22;q12) and 1(9.11 )(p22;q23) 1306. 72 1, 848 , 20361 . Each 01 these structural ch romosome rearrangements

creates a fusion gene encoding a chimaeric protein that is required. but usually

not sufficient. for leukaemogenesis 120631. Many of these d isease groups have charac teristic morphological and immunop henotyp ic features 1651. The categories of acu te mye loid leukaemia (AML) with 1(8 :2 1)(q22:q22), iov( 16 )(p 13. 1q22) or 1(16:16)(p 13 .1;q 22 ) or l(lS;17)(q22:q 12)

are considered as acute reukaermas without rega rd to blast cell cou nt. It is not yet c lear if all c ases with t(9; 11Xp22;q23) , t(6 ;9)(p 23 ;q34 ). inv(3 )(q2 1q26,2), t(3;3) (q 21;q26 2) or t( 1;22)(p 13;q 13 ) shoul d be c ate go rize d as AMl when the blast cell count is <20%. Many of the trans loca tions are dete cted by AT-PCA whic h has a higher sensitivity (1x 10"5) than c ytogenetic analysis (1x 10-2 ) . Cases of therapy- related AMUmyel odyspla st ic syndrom e (MD S) may also have the balanced transloc ations and invers ions that are d escribed in this section, but the se should be diagnosed as therapy-re lated AMUMDS with th e associated g enetic abnormality noted.

Acute myeloid leukaemia with t(8;21)(q22;q22); RUNX1· RUNX1T1 Def inition Acu te myeloid leukaemia. with t(8 ;2 1) (q22;q22); RUNX 1-RUNX7 T1 is an AMl gene rally showing maturation in the neutrophil lineage.

ICD-Ocode

110

9896/3

D .A, Arber R D , Brunning M .M. le Beau B , Falini

J.w.

Vard ima~

A. POrNIt J. Thiele CD. Bloomfield

Epidemiology The t(8 ;2 1)(q 22;q 22 ) is found in -5% of cases of AMl and in 10% 01 the prior acute myeloblast ic le ukaemia with matu ration (M2) c ategory of the French -AmericanBritish cl assification. It occurs predominantly in younger pat ients . Cli nical featu res Tumour manifestations , such as myeloid sarconas. may be present at presentation . In such cases the initial bone marrow (BM) aspiration may show a mis leading low number of b last cells. but should be diagnosed as AMl despite a b last percentage in the BM of <20, Morphology and cytochemistry The co mmon morphological features inc lude th e presenc e of large blasts with abundant basophilic cytoplasm, often containing nume rous azuroph ilic granules and perinuclear clearing or bots . A few b lasts in many cases show ve ry large gra nules (pseu do-Chedrak-Hiqashi gran ules), sug gestin g abnormal fusion . Auer rods are freq uently found and appear as a sing le long and sharp rod with tap ered e nds; they may be de tect ed in mature neutrophns. In addition to the large bla st c ells , some smalle r bla sts, pred om inantly in the peripheral blood (PBj, may be found. Promyeroc vtes, myeiocytes and mature neutroph ils with var iab le dy sp lasia are present in the BM. These ce lls may show abnormal nuc lea r seg mentation (e.q. pse uoo-Pelqer-Hoet nuc lei) and/or cy toplas mic staining ab nor malities, including homogeneous pink colo ured c ytoplas m in neutrophil s. Dyspl asia of othe r Cell lines, however, is uncommon. Eosinoph il precutsees are frequently increased. but they do not exhibit the cytological or cytoc hemical ab normalities charac teristic of AMl associated with ab nor ma lities of c hromosome 16: basop hils and/or mast cells are sometimes present in exce ss. A monocytiC component is usually minimal or absent. Erythrob lasts and meg akaryocytes are morphologically normal. Rare c ases with a BM blast percentage <20 occur, These should be cl assifi ed as AMl and not as MOS.

Acute rnyelord leukaemia and related p recursor neo plasms

FIg. lOl /IoI/IIl myeloid IeUlaen'ia Wlltl .8 11XQ22:Q22'

Bone marrow tllasts s/'lowirlg abl.n:lant pUr qtIpIasm WIlh ~deari'1g em Wge~

.........

Fig. 6.02 Myeloid sarcoma Biopsy of an orbitaIl'I'IaSl from a child w;th AML with a ~ a;21)(q22;q22). There in precursors scattered in !he preOominat1l lNs1 poplI lation.

eosinoph~

Immunop henotype Most cases of AMl with the (8;21 )(q22;q22) transloc ation d isp lay a characteristc imm uno phenotype with a subpopulatioo of blas t cells show ing hig h intensity expression of CD 34, together with HLA-DR, myercoeroxidase (MPO) and CD13. bJ relatively weak expression of CD33j114Q, 17751. There are usually sig ns of granulocyt ic differen tiation with subpopuianonsd cells showing granulocytic rnaiuranco demonstrated b y CD15 and/or COO expression . Sometimes po pulations cI blasts showing matu ration asynchrony are present (e .g . co-expressing COOt and CD15 ). These leukaemias frequen express the lymphoid marke rs CD19 and PAX5, and may express cvtoptasrre CD79a 1996, 1155. 2236} . Some cases are terminal deoxynucleotidyf transferase (TdT) posi tive ; however, TdT exoresscoe

generally weak. C056 is expresse d in a fraction of cases and may have adverse prognostic significance {1231· Genetics

The genes for both reteroosreoc components of core bindll)Q lactor (CBF), RUNX I (atso known as AML 1or CBFA) aOO CBFB ere involved in rearrangements associated WIth acute reukaemes {20631. The t(8 ;21) (Q22;q 22 ) involves the RUNXI gene, which encodes core- bi ndin g factor subunit alpha and the RUNX 1T1(ETO) gene {608, 1294, 17331. The RUNX1 -RUNX1T1 fusion transcri p t is consistently detected in patients with 1(8;21)(q 22;q 22) AML. The CBF transcripti on factor is essential for baematopolests. and tr ansformation by RUNX 1-RUNX 1T1 likely results from transcriptional repression of normal RUNX1 target genes via abe rrant recr uitm ent of nuclear transcription al co- repressor complexes. Over 70% 01pati ents show aooiIIQll3I chromosome abnormalities: e.q. loss rJa sex chromosome or d el(9q ) with loss rJ 9Q22. Secondary cooperating mutations rJ KRAS or NRAS are common (30%) in caedtamc CBF·associated leukaemias ~l. Mutations of KIT occur in 20-25% 01 cases (16961. Postulated nor mal cout erpart Myeloid stem cell wilh predominant reunophil differentiation. Prognosis and predictive factors Acu te myelo id leukaemia with t(8;21) (q22;q22) is usually associated with a

16

Acute myeloid leukaemia with

inv(16)(pI3.1q22) or t(16;16)(pI3.1;q22); CBFB· MYH11 Definition Ac ute myeloid leu kaemia with inv(16) (p1 3.1q22) or t(16: 16)(p13,1:q22); CBFBMYH11 is an AML that usually shows monocytic and gra nuloc ytic differentiation and characteristically abnormal eosinophil component in the BM {1258. 1393, 20631. ICD-O code

9871/3

Synonym Acute myeloid leukaemia with abnormal marrow-eosoconns .

Epidemiology Either inv(1 6)(p 13.1q22) or t(16 ;16) (p13. 1;q22) is found in 5-8% of all cases of AM L. They can occur in all age grou ps but are found predom inantl y in younger patients.

Fig. 6.04 Acu1e myeloid leukaemia with associated inv(16Kp13.1q22). AbnonnaI eosi~ . one VIlth Large basophiliccoloured granules. aAl present

Clinical features Myeloid sarco mas may be p resent at initial diagnosis or at relapse and may c onstitute the only evidence of relapse in some patient s. Morpholog y and cytochemistry In these cases. in addition to the usual morphological featu res of acute myelomonocytic leukaemia, the 8M shows a variable number of eosinophils (usually increased. but soretrres <5%) at all stages 01 rretoratco without significant maturation arrest. The mos t striking aboomantee involve the immature eosinophilic granules. mainly evident at the promyelocyte and myelocyte stages . The abnormalities are usually not p resent at later stages of eosi nophil maturation . The eosinophilic granules are often larger than mose normally pr esent in immature eosmocnus. p urp le-violet in colo ur, and in some cells are so dense that they obscure the cell

inv(16)

• --<>

• .

A

goo d response to ch emotherapy and a high com pl ete remission rate with longterm d isease-free surv ival when treated with high dose cytaratnne in the consolidation phase 1228. 8481. Some factors appear to adversely affect prognosis including C056 expression aOO the presence of KfTmutations 1123. 16961.

• --<>

XI• 16

I

inv (16)

:~:>:

Fig. 1.03 Acute myeloid leukaemia with inv(16)(pt 3.1q22). A The inversion 16 results from breakage and rejoining of bands 16p13.1 and 1&;22. G-banded normal (nI) linrTIosome 16 and irW(16) are shown. B Dual rolor ftUOfllSC6OC6 in situhybridizalion: !he 5' regll)llof CBFB is labeled in red; !he3' regionin pen Anonnal ettromosome 16 has ~ 5'and 3' regions ~ 10 e
Acu te myeloid leukaemia with recurrent genet ic abnormalities

11 1

•

morpho~y. The mature eosinophils may occasionally show nuc lear hyposegmenlal ion . The naphthol-ASD-chloroacelale esterase reaction. which is normally negative in eosinophils, is charactenstically faintly pos.tive in these abnormal eosmophils. Such a reaction is 001 seen in eoerophils 01 AML with the 1(8;21)(q22;q22). Auer rod s may be observed in myeloblas ts. At least 3% of the blasts show mveioperoxioase (MPO) reac tivity. The monob lasts and promonocvtes usually show non-s peci fic esterase reactivity, although it may be weak er than expected or even abs ent in some c ases. In ad dition 10the predominant monocytic and eosinoph il compo nents, the neutroph ils in the 8M are usua lly sparse, with a de cr eased number of matu re neutrc phils . The PB is not different from other cases of ac ute mveromonccvnc leu kaemi a; eosinoobus are not usua lly increased. but an occasional case has been rep orted with abnormal and increased eosi nophils in the PB. While the major ity of cases 0' inv( l6)(p13.1Q22) have been identified as having abnormal eosinophils, in some cases they are rare and d iffic ult to lind . Occasooar cases with this genetic abnormality lack the eosinophilia or show cxty myeloid mansatcn wilhoul a I"ro"lOCytic CCJITlX)IlE!lll or only rro-ocvtc d ifferentiation. Not infrequently, the blast percentage is only at the threshold level 0120%or oc:casionally lower. Cases with inv( l6)(p13.1 q22) or t(16; 16):( p l3. l ;q22) and less than 20% 8 M blasts should be di ag nosed as AML. The BM treph ine biop sy is usually hyperce llular, but may occasionally be normoce llular.

Immunophenotype Most of these leukaemias are c haracte rized by a complex immunop henotype with the presenc e of multiple b last populations: immature b lasts with high CD34 and CD l 17 expression and pop ulations d ifferentiating toward s gran ulocytic (CD13, CD33. CD l5. CD65. MPO positive) and monocytic (CD 14. CD4. CDl 1b. CD64. CD36 and lysozyme positive) lineages Mat urat ion async hron y is often seen. Co-expression 01CD2 with myeloid mark ers has been frequently documented but It is not specmc for this di agnosis.

cone.

Genetics The inv( 16)( p 13, 1q22) foun d in the vas t major ity of this subtype and the less common t(16; 16)(p13, 1:q22) both resu lt in the 112

fusio n of the CBFB gene at 16q22 to the MYH 11 ge ne at 16p 13.1 120061. MYH11 codes for a smooth muscle myosin heavy chain 15061. The CBFB gene codes for the core binding factor (CBF) beta subunit, a heterodimeric transcription tactoe known to bind the enhancers of t-een rece ptor (TCR). Cylokine genes, and other genes. The CBFB subunit heterodimerises with CBFA, the gene product of RUNXl, one of the genes involved in AMl with t(8;21 )(q22;q22). Occasionally cytological features of AM l with abnormal eosropnns may be pr esent without karyotypic ev id ence of a c hromosome 16 abno rmality, the CBFB-MYH 11 being neverthe less demonstrated by molecular genetic studies (1533 , 1882) By co nventional cytogenetic ana lys is, the inv(1 6)(p1 3,lq22l/t(16:16) (p1 3 ,1;q22) is a sub tle rearra ng ement that may be over looked when metaphase pr epa rations are suboptimal. Thu s, at dia gnosis, the use 01 FISH an d RT-PeR methods may be necessary to document the genetic alte ration . Secondary cytogenetic abnormalities occur in approximately 40% of cases, with +22, +8 (10 -15% each), and del(7q) or +21(-5%) most commonly observed 113901. Trisomy 22 is fairty specific for inv( l6XPl3.lq22) patients. being very rarely detected with other primary aberrations in AM l. whe reas +8 is commonly seen in patients with other prtmary aberrations. Rare cases of A ML and chronic myelogenous leukaem ia with both inv(16 )(p 13 ,1q22) and t(9:22)(q34:q1 l.2) have be en reported, an d this findi ng in ch ronic myelog enous leukaemia is usually assoc iated with accelerated or blast phase of the disease 12454 J Mutations of KIT occ ur in approximately 30% of cases 116961.

Acute promyelocytic leukBemia with t(15;17)(q22;qI2); PML-RARA Definition Acute promyelocytic leukaemia (API. or AML with t(15 ;17)(q22;q12)J is an AMLII which abnormal promyelocytes predcmnate. 8cttl hypergrarUar'or "l'ypil:3" APLcnl microgranular (hypogranular) types emt ICD-O code

986613

Synonym AM l with 1( 15;17)(q22;qt2). Epidemiology Ac ute promyeloc yte leukaemia comprises 5-8% of AMl {20 78 1. The disease can occur at any age b ut pati ents are predom inantly adul ts in mid-life. Clin ical featur es Typical and rricrograrlAar API.. are lrequerty associated with disseminated inlravasoJa' coagulation (DIG) . In microgranular API.. unlike typical API.., the leukocyte COlJ'lt IS very high, with a rapid doubling time

Postulated normal counterpart

Haemetcooienc stem cell w ith potential to differentiate into g ranuloc ytic and monocytic lineages .

Prognosis and predictive factors Clinical studies have shown that pa tients with AMl with inv(16)(p13 .1q22) or 1(16;16) (p13.1;q22) achieve longer complete remissions when treated with high dose cytarabine in the consolidation phase 1848, 15301. j-owever. older patients have d ec rea sed survival and tho se with KIT mutat ion s have a higher risk of relapse and worse survival 1546. 16961. Patients with +22 as a secondary abnormality have bee n reported to have improved ou tcom e 11390. 196 21.

Acute mye loid leukaemia and related precu rsor neoplasms

~ B Fig. '.05 Acute promyeIocybc leukaema. A ~ ~ type n bone marrow smear. Theft we IM'i abnormal prornyelocyles wilhITIense amq:hIc,..... lam. Sewr1lI ollhe promyeIocyles oontaillUl-.all Auef rods(Iaggot oeIs). B M~ vWrt. 1'1 Ptripheral bloocI smear. There are several abnclmll promyelocy!es 'Mthlobl,Jlaled. almostc:eretlnbm ru:Il The cytoplasm coolains numerous small alI.tllPl* granules: other ~Is appear sparsely ganlMr.

nl

15

d .~15 )

15

17

II A

1(15 ;17XQ22;Q12)

~ U16 AcuIe prorll)'8locybc Ieuilaen'U WIIh 1(15;11Mq22;q12), A The D'lslocabon 15;11 t'&SUts from br9akage a'ld r-.nion of bands 15q22 a'ld 11q12. G-bMded normallnl) 15 111 17 dY\::Jnc:lsanes (Ieft.l a'ldthe derivatNe ldetl 151n:l11 reslAng from ee IransIocation are sIlOWl'I on hi fil1C. BOuaIlDorl'unscence" sill hybtidiZ.alion M1h probes Pf.C. l'~ iIl'lll RARA(17ql2) derroostrate the presence of a Pl.UWtA.lusion ~ from the 15;11 transIoca1o'l. Eactlof hi fw'ee IlBphase eels has one sep;nte red (PK) J9W. (W'II sepataIe ween (RARA) sigIaI, In:l one \'dOw or~ ~greet1 si!r.aI ronsislenl..,1Il1tle pttl5etIC8 of a PMJRARA gene Iusioo.

IbphoIogy and cytochemistry

The nuclear size and shape in the aboorrrel promyelocytes of hypergranular APL ere irregular and greatly variable; they are ::tten kidney-shaped or bilobed . The cytoplasm is marked by densely-packed or even coalescent large granules, staining :Yight pink, red or purple in Romanowsky stains. The cytoplasmic granules may be solarge andior numerous that they totally rescore the nuclear cytoplasmic margin . In some cells. the cytoplasm is filled with Ire dust-like granules. Characteristic cells containing bundles of Auer rods ("faggot cells") randomly dis tributed in the cytoplasm are present in most cases, Myeloblasts with sing le Auer rod s may also be Observed, A uer rod s in hyper gr anu lar APL are usually large r than in other types rJ. AML and they may have a c haracteristic rrorpholog y at the ultras truct ural leve l '.vith a hexagonal arrangement of tubular structures with a specific period ici ty of aeoroxrnaterv 250 mm in contrast to the 6-20 lamina r periodicity of Auer rods in erertypes of AML. The MPO reaction is always strongly positive in all the exaernc oromyeiocvtes . with the reaction product covering the entire cytoplasm l"Id often the nucleus . The non -specific esterase reaction is weakly positive in ao;>rQximately 25% of cases. Only occaSJOnaI obvious leukaemic prooweiocvtes may be observed in the PB. Cases of rracrcqranurar (hypogranular) A.PI. arecharacterized by distinct morphoQJicaI features such as apparent paucity CJ absence of granules. and predomiI'lafltly bilobed nuclear shape 18111.

The apparent hypogranular cytoplasm relates to the submicroscopic size of the azurophilic granules. This may cause c0nfusion with acute monocytic leukaemia on Romanowsky stained smears; however, a small number of the abnormal promyelocvtes showing clearly visible granules and/or bundles of A uer rods (faggot cells) can be identified in many cases. The leukoc yte count is frequently markedly elevated in the microgranular variant of APL with numerous abnormal mcroqranular promy elocytes in con trast to typical APL. The MPO reaction is strongly pos itive contrasting w ith the wea k or negative reaction in monocytes. Abnormal promveocytes w ith deep ly baso ph ilic cy toplasm have been de sc ribe d ma inly in the rela pse phase in patients who have be en p reviou sly treated w it h al l-tran s rettnoic acid (ATRA), The 8M biop sy is usual ly hypercel lular, The abnormal promyelocyt es have relatively abu ndant c ytoplasm with nume rous g ranul es: occasionally Aue r rods may be identified in well-prepared specimens. The nuclei are freq uently convoluted Immunophenotype Acute p rom vetoc vtrc leukaemia with the t( 15 ;17)(q22;q 12) (hypergranular or "typical" variant) is characterized by low expression or absence of HLA·DR. CD34. leukocyte integrins CD11a, CD 11band CD18. a homogeneous, bright expression of CD33, and heterogeneous expression of CD13_ Many cases show expression of CD117, although sometimes weak . The granulocytic differentiation markers C015 and COO5 are negative Of only

weakly expressed 11654. 1678} and CD64 expression is common. In cases with microgranular morphology or cera Iran. scr ipt of the PML-RARA fusion gene there is frequent expression of CD34 and C02, at least on a fraction of cells 16531. Ap proximately 20% of APl cases express C056. which has been associated with a worse outcome 16901· Using enrourocvtoChemis try, antibodies against the PML gene product show a characteristic nuclear multigranular pattern with nucleolar exclusion, in contrast to the speckled relatively large nuclear bodies seen in normal oromverocvtes or blas ts from other types of AML (6621. Genetic s In ad d ition to its thera pe utic imp act, the sensi tivity of APL cells to ATRA has led to the d iscovery that the retinoic acid receptor alpha (RARA) gene on 17q12 fuses with a nuclear regulatory fac tor gene on 15q22

Fig. 1.07 Aone promyeIocytic Ieukaema. Bone IIIiWTtIW biopsy. Abnormal prorrt)'eIotyIe wilIl abl.ndal'll hyper. gran,Aated cytlpIasm. Thenudei are genefaIylWId tI oval. SewlraI of !tie nudei llfll lfregU;w and I!YagrIaled

Acute myeloid leukaemia With reconenr genetic ebroerrautes

113

the p rognosti c signific ance of FLT3-JTO mutations in this di sease remains unc lear /690 , 1199 1.

Fig.6.08 PM!. anI1bod'y n aaM promyeIocybc Ieukaen'Ia showing a etlaractetistic Ill.Ideaf mufbgrnular paltem \MIll ru:leoIar exclusion.

(o ronvelocvnc leukaemia Of PML gene) giving rise to a PML-RARA fusion gene produCII506, 529 . 14521. Rare cases 01 APt. lacking the classic t(15:17)(q22;q 12) on routine cytoqenenc studies have been described with complex variant transiocations involving both chromosomes 15 and 17 with an additional chromosome Of with submicroscopic insertion of RARA into PML leading to the expression of the PML -RAR4 transcript ; these latter cases are considered as cryptic Of masked t(15 ;17) (Q22;q12) /6471. Mor pho log ic al analysis shows no major d ifferences be tween the t( 15;17)(q 22 ;q 12) positive group and the PML -RA RA positive p atients wi thout t( 15; 17)(q22;Q12) , Secondary cytogenetic abnormalities are noted in - 40% of c ases . with +8 being the mos t frequen t (10- 15%). Mutatio ns involving FLT3, including internal tand em duplic ation (ITO) and tyrosine kinase doma in mutations (TKO) oc cur in 34-45% of A PL. FLT3-l TO mutation s are mo st co mmon and a re associated with a high er white b lood ce ll co unt. mlcrocranurar b last ce ll mo rph olog y and involvement of the bcr3 b reakp oint at PML 1318, 747 ,1 199). Postulated normal counterpart Myeloid stem ce ll with potential to d ifferent iate to granulocytic lineage. Prog nosis and pred ictive fac tors Ac ute promyetocyttc leukaemi a ha s a p artic ular sensi tivi ty to treat ment w ith ATRA. which acts as a dilferentiating ag ent 1342. 2 152/. The prognosis in APt.. treat ed optimally With ATRA and an anlhrac ycl ine is more favou rab le than lor any other AML cytogenetic subtype. and cases of relapsed or refractory APt. show a generally good respo nse with arsenic tr ioxide th era py 1607.6851. Expression of CD56 is associ ated with a less faVlJU(able prognosis while 114

Variant RARA transl ocations in acut e leukaem ia A sub set of c ases. often with mor phological fealures resembling acute ~ cvtc leukaemia. show variant nensocetcos involv ing RARA . These variant fusion partners inc lud e ZB TB 16 (previously known as pr omv eiocvtrc leukaemia zinc finger gene or PLZF) at l 1q23; the nuclear matrix assoc iated g ene (NUMA 1) at l 1q 13; the nuc leophosmin gene (NPM1)at5q35 and STATSB at 17q l 1.2 124881. Some c ases with vari ant transiocanons we re initially reported as having APL morphology 119141. However. the t(l l ;l7) (q23;Q12); ZBTB16-RARA subgroup shc1ws some morphological d ifferenc es with a predominance of cells with reg ular nuclei, many granules . usual absence ot Auer rod s. an increased number of Pelg eroid neutroph ils and strong MPO activity {19141 . The initial cases of APL associated With t(5 ;17)(q35 ;q1 2) had a p redom inant population of hypergran ular promyeiocvtes and a minor population of hypogranular promyelocytes; Auer rods were not oennteo by ligh t m ic rosc op y 147 6 1. Some acute promyelocytic leukaemia variants. incl ud ing t( 11; 17)(q 23;q1 2) w ith ZBTB16-RARA and cases wit h S TAT5B· RA RA fusion s are res istant to ATAA 114521, A PL with the t(5 :17)(q35;q 12 ) appears to resp on d to ATRA {1452]. Cases with these va riant transroc atlons should be d iagn osed as AML w ith a va riant RARA transloc ation.

Acute myeloid leukaemIa with t(9;II)(p22;q23); MLLT3·MLL Definition Ac ute myeloid leuk aemia with t(9; 11) (p22;q23): MLLT3-MLL is usually associated w ith monocytic featu res .

ICD-O code

present in 9-12% of paed iatric and 2%rJ adult AML 1306 . 721 1.

Cunicalteatures Patients may pr esent with d isseminaled intravascular coagulation. They mayhave extramedullary myeloid (monocytic) serco mas and/or tissue infiltration (gingiva, skn~ Morphology and cylochem;Sby There is a strong association between acute monocytic and myelomooocytlc leukaemias and t(9; 11)(p22;q23). altho.ql occasionally the t(9 ;11) is detected i'l At.( with Of without maturation. MonobIaSlS and promonocytes typically predominale Monoblasts are large cells . with abt.r1ci
osecco

Immu nophenotype Cases 01 AML with the t(9: 11)(p22;q23) ir1 c hild ren are associated with strong exp ression 0 1 CD33, CD65 , CD4 and HLA-DA, while exp ression at CD 13, CD34 and CD 14 is usually low /491 1. Most AML c ases w ith 11q23 abnormalities express the NG2 homologue (encoded by CSPG4j, a c hond roitin sulfate molecule reacting with the Mab 7.1124561. MostacU: AM l case s w ith 11q 23 ab normalities exp ress some marke rs 01 monocac differentiation including CD14, CD4, COlle CO l lc. CD64. CD36 and lysozyme, v.tIire variable expression of imma ture markers suc h as CD34 and CD1 17 and of CD56 has been reported {154 11.

9897/3

Genetics Synonym Ac ute myeloid leukaem ia . 11q23 abnorma lities.

Ep;demk>logy The t(9;11)(p22;q23) may occur at any age. but is morecomnor I in child ren. being

Acute myeloid leukaemia and related precursor neoplasms

Molec ular studies have iden tified a t1t.rna'I homologue of the Drosophila trithorax gene design ated MLL (HRX), that results in a fusion gene in translocations invo/Vllg 11q231 1141. The MLL p rotein is a histl)1!! mettwnransterase that assembles in pro. tein complexes tha t reg ulate g ene Iran.

scription via ctuomato remodel ing. The ~9:11)(p22:Q23) involving MLLT3 (AF9 ) is toe most common MLL translocation in AML and appears to represent a distinct enhty. Secondary cytogenetic abnormalities are common with t(9:11) (p22:Q23). with +8 most commonly observed, but do not appear to influence survival [306, 15311. Postulated normal cou nterpart aaenaiopoeuc stem cell with multiJineage

ootennar. Prognosis and pred ictive factors Acute myeloid leukaemia with the . 9:11XP22;Q23) has an intermediate sur.....aI and one that is supefior to AML with e:tner l1Q23 translocations 11531. 18911. Cases with the t(9: 11) and <20% blasts II'IJSt be monitored closely fOf development of more definite evidence of AML. 'fi1riant MLL translocations in acute leukaemia C>ief 80 different translocalions involving MLL are now described in adult and paediatric acute leukaemia, with over 50 eensiccato n partner genes now cnaraclenzed 11 470. 20081. rrensiccetcoe involving MLLT2(AF4). resuitmq predominantly n acute lymphoblastic leukaemia (ALL). end MLLT3(AF9). resuhing predominan tly n AML, are the most common. Other MLL eensccauons that commonly result in AML rcuoe the MLLT1(ENL). MLLTIO (AF1O), MLLT4 (AF6) and ELL as partner genes, Other than the ML L-ELL fusion resulting Irom the t(1 1:19)(q23:p13,1), which is res often associated with only AML, these fusions occ ur pr edom inantly in AML, but may be seen in ALL as well. Up 10 one third of MLL transiocauons in AML ee not detectable on co nventional karyotype analysis , and FISH or other molecular stud ies may be necessary to dentify these variant translocations 120081. AML with these fusions usually have myelomonocytic or monoblastic rro rpnobgic and immunophenotypic features While in the p ast all of these translocali:lns were encompassed by the category rj AML with 11q23 abnormalities. the diagnosis should now specify the specific abnormality and should be limited to cases with 11q23 balanced translocations fI'o'OIving MLL. For example. a case of AMl with an MLL-ENL fusion would be dl8gnosed as acute myeloid leukaemia dh ~11 ,19)(q23;p13.3): MLL-ENL. 40Jte myeloid leukaemia with cytogenetic

B Fig. 6.09 AML (monoblaslic) WIth t(9;1'Xp22;q23). Bone marrow smears A 5evefall'l'lOl'lllblasts. some WIth very allur'l
'"

..

Fig. 6.'0 Mt. (1TIOI'I:ltyIic) \Mlh 1(9;11)(p22;q23}. Bone tJWI(M ~ A ThenlarelilMlt8llfOIObIasts and ~ with very pale cytor*lsm containing numerous fine anrophiic ~_ The promonocyles have delicate rudear lolds. B Noo-speci1ic esterase S\aII"I_ The pn::monocytes are intensely reactive.

abnormalities associated with prior therapy or myelodysplasia. such as t(2; 11) (p2 1;q23) or t( 11:16)(Q23:p 13.3), should be diagnosed as therapy- related AML or AMl with myelodysplasia- related changes (See Cha pter on therapy-related myeloid neoplasms),

Clinical features Acute myeloid leukaemia with t(6:9) (p23 ;Q34) usually presents with anaemia and thrombocytopenia, and often with pancytopenia, In adults, the presen ting white blood cell count is gener ally lower than other AML types with a median white blood cell count of 12x1()9/L 120351,

Acute myeloid leukaemia with t(6;9)(p23;q34); DEK-NUP214

Morphology and cytoche mistry The BM blasts of AML with t(6:9XP23:q34) may have morphologic and cytochemical features of any FAB subtype of AML other than acu te promyelocytic leukaemia and ac ute megakaryoblas tic leukaemia. with AML with maturation and acute mveromonocytic leukaemia the most common 128, 1676,20351_ Auer rods are present in approximate ly one third of cases, Blasts are myeloperoxidase positive and may be positive or nega tive for non-specific esterase . Therefore , there are no features specific to the blast cell population in this entity Marrow and PB basophilia. defined as >2% , is generally uncommon in AML but is seen in 44-62% of cases of AML with t(6;9)(p23:q34). In addition. most cases ""'" evidence oIgarL
Definition Acu te myeloid leukaemia with the 1(6 :9) (p23:q34); DEK-NUP214 is an AML with or without monocytic features that is often associated with basophilia and multilineage dysplasia {17 14, 20351 . ICD-Ocode The provisional code proposed for the fourth edition of IGO-D is 986513. Epidemiology The t(6:9Xp23;q34) is detected in 0.7-1 .8% of AML, and occurs in both children and adul ts with a median age 01 13 years in childhood and 35 years in adults 1306. 2035,20361.

Acute myeloid leukaemia wIth recurrent genetic eoocereetes

115

• a re presen t in a subset of cases, The per-

centage of 8M blasts is variable. and some cases may present wi th less than 20% bl asts. Immunophenotype The blasts have a non-specific myeloid immunophenolype with consistent expression of myeloperoxidase. CD13,CD33. C038 and HLA-DA 128, 1676,20351 . Most

cases also express CDl17. CD34 and C0 15 while a subset 01 cases express the monocyte-associated marker CD64 and approximately hall are terminal oeoxvoodeotidy1 transferase (TefT) positive . Other Iymp/loid antigen expression is Ul'lCOlTITlOl1 . Gene tics The 1(6:9)(p23:q34) results in a fusion 01 DEK on chromosome 6 with NUP214 (CAN) on chromosome 9. The resulting nocieoporin fusion protein ac ts as an aberrant transcription factor as well as altering nuclear transport by binding to soluble transport factors 119491. The 1(6:9) is the sole

clonal karyotypic abnormality in the vast majori ty of cases, but some patients will have the t(6:9)(p23:q34) in association with a complex karyotype 120351. FLT3-lTO mutations are very common in AMl with t(6;9)(p23;q34) occurring in 69% of paediatric cases and 78% of adult cases 11676. 20351. Fl.T3-TKO mutations appear to be uncommon in this entity.

Postulated normal count erpart Haematopoietic stem cell with mullilineage potential. Prognos is and predictive factors Acute myeloid leukaemia with t(6:9) (p23;q34) in both ad ults and children has a generally poor prognosis. similar to other AMl with unfavourable cytogenetic abnorm alities . Elevated white blood cell counts are most predictive of shorter overall survival and increased 8M blasts are assoc iated with shorter disease-free survival. Based on limited data. allogeneic stem cell transp lantation may be associated with better overall survival compared to patients with no stem cen vansptantatoo 12035I·Cases with t(6;9XP23:Q34) and <20% blasts must be monitored closely for development of more definite evidence of AML.

Acute myeloid leukaemia with inv(3)(q21q26.2) or /(3;3)(q2/;q26.2); RPN/·EVIt Definition Acute myeloid leukaemia with inv(3) (021026.2) '" 1(3;3Xo21;q26.2); (RPrvI-EVII) is an AML that may present de novo or arise from a prior MOS. It is often associated with normal or elevate d PB platelet coun ts and has increased atyp ical BM meoakarvcc vtes with mono- or bi-lobated nuclei and assoc iated multil ineage dysplasia (225, 1983,2 131). ICO-O code The provisional code propo sed for the fourth edition of ICD-O is 986913. Epidemiology Acute myeloid leukaemia with inv(3) (q21q26.2) or t(3:3)(q21;q26.2) represents 1- 2% of all AML 1306 . 20361. It occurs most commonly in adults with no sex predilect ion.

Fig.S." AML. with t(6:9)(p23:Q3-t). The blasts are adn...ed with dyspIastlc erythroid precursors and

Clinical features Patients most co mmonly present with anaemia and a normal preteret count . although marked thrombocythaemia occurs in 7-22% of patients 1845.19831. Patients may present de novo or have a prior MOS. A subset of patients present with hepalosptencmegaty. but "",,",,deropathy is UllCOI' llllOlI11983. 2C04, 21891.

scallered ~ (centre. '9ll).

116

Acute myelOid leukaemia and related orecursoe neoplasms

Morphology and cytochemistry Periphe ral bloo d chan ges may include hypog ranular neutrophils with a pseudoPetcer-Hcet anomaly, with or without assoc iated peripheral blasts. Red eel abnormalities are usually mild withOOt teardrop cells. Giant and hypogranulat platelets are common and bare megakaryocyte nuclei may be present 12251. The 8M blasts of AML with inv(3)(q2 1q26.2l cr t(3 :3) (q2 1:q26.2) may have morphologic and cytochemical features of any FAa SUbtype of AML other than acute promyeIlr cytic leukaemia with acute myebd Ieukaertia without maturation. acute myeIomonocytic leukaemia and acute mega. karyobIastic leukaemia morphologies rn:lSl cornrnon 1715. 19831. A subset of cases has less than 20% blast cens at the tiTle of diagnosis. including cases with fsallles of chronic myelornonocytic leukaemia Multihneage dysplasia of non-blast eel BM elements is a frequent finding WII/1 atypical megakaryocytes most cQlTllTlCll 1715. 1054. 19831. Megakaryocytes may be normal or increased in number WI many small IJm) monoIobed a bilobed forms. but other dysplastic mega. karsocvtc forms may also occur. Dysplasia of maturing erythroid cells and neutroptws is also corrrnon . Marrow eosooonss. teso phils and/or mast cells may be increased The BM biopsy shows increased sma hyr:x>lobated megakaryocytes. Bone marnJo\! cellularity is variable with some cases presenting as hypoc ellular AML Marrow fibrosis is variable.

«30

Immunophenotype Immunophenotypic studies of AML with inv(3)(q21q26.2) or t(3:3}(q21:q26.2) are limited. The blast cells generally express C0 13. C033. HLA-OR. CD34 and C03S Blast cells of some cases also abe rranf express C07 and a subset may express meg akaryocytic markers such as CQ4t and C06 1. Abe rrant expr ession of lym. photo markers other than C07 appears uncommon [20041. Genetics A variety of abnoemauties of the long arm of chromosome 3 occur in myeloid rnalo(t nances. with inv(3)(q21q26.2) and t(3:31 (q21 ;q26.2) being the most common. The abnormalities involve the oncogene EVIl at 3q26.2 . or its longer form MOS1-EV! and RPN7 at 3Q21 APN1 may act as <WI enhancer of EVIl expression resulting increased cell proliferation , and impaireo

cell differentia.lion: it induces naen etoooreticcell transformati on ( 1236, 1609, 21251 . Other cytog enetic aberrations involving 3q26.2, such as t(3:2 1)(q26.2:q 22) res~tting in an EVI1-RUNX 1 fusion and usually seen in therapy-related disease, are not included in this disease ca tegory. Secondary karyoty pic a bnormalities are common with inv(3)(q21 q26.2) and t(3;3) (Q21;q26.2) with monosomy 7 most common, occu rring in approximately half of cases, followed by 5q deletions and com"'" ...",.",..1 1963/. These abroonalrties may precede the development of the 3q262 abnormality 116091. Patents with AMl with inv(3)(q21q26.2) ««3:3Xq2 1;q26.2) show overexpression d EV/1 and GATA2, bulthese fIndings do ro appear to be specific for the genetic aonormality 11236,16091 . Patients with chronic myelogenous leu-.aemia may acquire inv(3)(q21q26.2) or (3:3kq21;q26.2), and such a finding usually portends accelera ted or blast pha se of !heir disease , Cases with both t(9 :22) (Q34;q11.2) and inv(3 )(q 21q 26.2) or t(3;3 ) (q21;q26.2) are best considered as ag g-essive phases 0 1 ch ronic myelogenous leukaemia. rather than AMl with inv(3) (q2tq26.2) or t(3;3)( q2 1;q26.2). PosllJlated normal counterpart tiaematopoietic stem cell with multilineage POtential. Prognosis and predictive factors AML with inv{3)(q 2 1q26 .2) or t(3;3) (q21:q26.2) is an aggressive di sease with sort survival 171 5 , 1834, 1983 1. Two patients with AMl with inv(3)(q2 1q 26.2) were reported to show a response to a rsen ic trioxide with thalidomid e, w ith one act uevi'19 complete rem ission 11 824 j , Cas es lI,ttl inv(3)(q2 1q2 6 ,2) or t(3:3)(q 21;q2 6 .2) and <20% bla sts must be mo nitore d ClOSely for development of more d efinite evidence of AMl.

Acute myeloid leukaemia (megakaryoblast/c) with ~ 1;22)(p I 3;q I 3); RBMI5-MKL 1

ICD-O code The p rovisional cod e prop o sed fo r the fourth edition of ICD-D is 991 1/3, Epidemiology The t(1; 22)( p13:q 13) is an uncommon abnormality in A Ml, repr esenting < 1% of all c ases. It most commonty occurs in infants without Down syn d rome, with a female pred ominance . Clinical features Acute mye lo id leukaemia with t( 1;22 ) (p13;q13) is a de novo AMl restricted to inf ants and young chi ldren (3 yea rs or less) with most cases occurring in the first 6 months of life (median, 4 months). The 'last rnajonty of cases present with marked organomegaly, especially hepatosplenomegaly. Patients alsohaveanaemia, and usually have throm bocytope nia and a moderat ely eleva ted white blood cell count. Morphology and cytochemistry The PB and BM blasts 01AML with t( 1;22 ) (p13;q 13) are similar to those of acute megakaryoblastic leukaemia of AM l, NOS. Small and large megakaryo blasts may be p resent and they may be admixed with more mor ph olo gically und iffe rent iated b last ce lls with a high nuclear-cytoplasmic ratio resembling ivmorobrasts. The megakarvobtasts are usually of medium 10 large size ( 12- 18 urn) with a round, sligh tly irrequrar Of indented nucleus with fine reticular ch romatin and one to three nucl eoli. The cytopl asm is ba sophilic , often ag ranular, and may show d istinct ble b s o r pseudopod formati on. Mic romeg akaryocvtes are common , but d yspl astic features of gra nu locytic and eryth roid c ells are not usually p resent The 8 M biopsy is usually normocellular to hyperce llular with retic ulin and co llage nou s fib rosis usually presen t. Cases may show a stromal pattern o f BM infiltration mimicking a metastatic tumour 120 5, 341 1. Cy toc hemical stains for Sudan black B (SBB) and MPO are cons istently negative in the megakaryob lasts. A subset of cases will have less then 20% BM bla sts. but a low blast cell count due to difficu lties aspira ting BM secon dary to fibrosis sho uld be excluded .

-

Fig. 6.12 AML WIth irlV(J)(Q21 q26.2). Bone marrowaspAte wrlhincreased blasts and atypica, rncnJIobaIed

marker CD42 (g lycoprotein Ib) is less frequently present. The myeloid~associated markers CD 13 and CD33 may be positive. CD34 , the pan-leukocyte marker C045, and HLA-DA are often negative; CD36 is Characteristically pos itive . Blasts are negative With MPO antibodies. lymphoid markers and terminal deoxynucleotidyl trans ferase (TdT) are not expressed, Cytop lasmic exp ression of CD4 1 or COBt is more specific and sensitive than surface staining ; the higher specificity is due to possible adherence of p late lets to b last cells in othe r types of AML, which may be misin terpreted as positive staining by flow

cvtometrv Genetics Patients sho uld have karyotypic evidence of t(1 ;22)(p1 3 ;q13) or molecul ar genetic evidence of a RBMI5-MKL 1fusion, In most cases, t( 1:22)(p 13;q 13) occurs as the sole karyotyp ic ab normality, This trans locat ion resu lts in a fusion of RNA-b inding motif protem-rs (RBM1S) (also known as OTT) and megakaryoc yte Ieukaemia- t (MKL 1) (also known as MAL) (1352 ). RBMIS enco des RNA recognition motifs and aspen par alog and ortholog C-terminal (SPOC) domain , whi le MKL 1 encodes a DNAbin d ing motif involved in chromatin organization. The fusion gene may modul ate chromatin orga nization . HD X-ind uced differenti ation and extrace llular sig naling pathways 11461}. Postu lated normal counterpart Myeloid stem cell with predominant megakaryocytic d ifferentiation .

Defi1ition ,' cute myeloid leukaemia with t( 1;22) (p13;q 13); RBM15-MKL 1 is an AMl genEJaJy showing maturation in the megakaryocyte lineage.

IrrmJnophenotype

The megakaryoblasts express one or more of the platelet g lycoproteins: CD41 (glycoprotein lIb/l lla ), and/or COO1 (glycoprotein ilia). The more matu re platelet-associated

Prognosis and predictive factors Although early report s suggested a poor prognosis for AM l with t( 1;22)(p13; q 13) 1205.34 11. more recent studies have found the patients to respond well to intensive

Acute myelotd leukaemia WIth recurrent genetic abnormalities

117

AML chemothe rapy with long disease-free survival 16201. Cases wi th the t(1;22) (p13;Q 13) an d <20% blasts on aspirate smears should be correlated withthe biopsy to excjooe 8M fibrosis as a cause of a falsely low b last cell count. 11 this is exc luded, these pat ients must be monitor ed closely for d evelopment of more definite evide nce of AML, such as the pres enc e of extramec ouary di sea se or myeloid sarco ma,

AML with gene mutations In add ition to translocations and inversions, specific gene mutations also occur in AML. They include frequent mu tations of fmsrelated tyros ine kinase 3 (FLT3), nucleophosmin (NPM 1) and . less corrmonly, mutations of the CEBPA gene (encoding the CCAAT/enhancer bi nding protein -c). KIT, MLL. WT1 , NRAS and KRAS. Alone or in com bination, mutations of FLT3, NPMI and CEBPA have been reported in patients with AML with a normal karyotype where they have prognostic significance in the co nte xt of most cu rrent therapies . althoug h they may be seen in pat ients with ab normal karyotypes as well 115321, FLT3, loc ated at 13Q1 2, encodes a tyrosine kinase rec ep tor that is involved in haematopoietic stem cell differentiation and proliferation. FLT3 is expressed on these progenitor cells as w ell as on the b last cells in most cases of AML. FLT3 mutations may occur with any AML type (20-40% of all cases) and in MOS, but a re mo st com mon in AML with 1(6 ;9) (p23;q34 ), acute promy elocytic leukaemi a and AML with a norm al karyotype 11184, 2035 1, The two primary typ es of FLT3 mutations a re intern al tandem duplications (FLT3-ITO) within the lu xtamemb rane doma in (75 - 80%) and mutations affecting codons 835 or 836 01 the second tyrosine 118

kinase domain (TKO) (20-35%). 'vVhile FLT3 mutations may occur in association with recurrent cytogenetic abnormalities, such as t(6;9XP23 ;Q34) and t( 15;17){Q22;Q12), they may also occur with other so-called cooperating mutations. FLT3-HOmul ations are associated with an adve rse outcome, b ut the sig nificance of the less common FLT3- TKO mutations remains c ontroversial 1117, 1447,2396 1. Detection of FLT3-lTO is important be cause th e prognosis of most cytogeneti cally normal AML subtypes correlates with the presence or ab sence of this muta tio n KIT, loca ted at 4Q11-12, is a mem be r of the type III tyrosine kinase family and encodes a 145-kO transmembrane glycoprotein. Gain-of-function mutations of KIT occur in a variety of d iseases, including g astrointestinal stromal tumours. germ cel l tumours , mastocytosis and AML Mutations of KI Thave been shown to have prog nostic signifICance among AML with t(8;2 1)(Q22 ;Q22) and inv( 16Xp13.1 Q22)1 t(16;16)( p 13.1;Q22), in which mey are associ ated with a poo r prognosis 11696 1. These KITmutations most common ly occur within exoo 8 and 17. To date, WT1 rrotat cos have been shown to co nfer a poor prog nosis in AML patients with a rormat karyotype 11 696A I, but there is less compelling evi de nce of p rognostic significance for the less freq uent mutations of MLL, NRAS and KRAS . Molecular studies have shown tMtthe MLL gene is rea rrang ed more freQuently than is revea led by conventional cytogenetic studies. A partial tand em dup lic ation of MLL has been reported in 5- 10% of ad ults Wi th a norma l kary otype [313,6031 and in patients with isolated trisom y 11[3141. Its adv erse prog nostic significance in patients with a normal karyotype is reported to be e liminated in pati ent s rec eiv ing an auto logous stem ce ll tran sp lant in first rem ission 123951. NPM1 mutations occur in about one third 01 adul t AML an d CEBPA mutations in

Acute myeloid leukaerTlla and related precursor neoplasms

6-15% of all AML. NPM 1 mu tations are typically heterozygous and the leukaema cells retain a wild-type allele [6671. They usually oc cur at axon 12 01 the NPMr gene 16661 but rarely involve exon 9 a t1 11 About 40 mutation variants ha...e been described 16671. the most COf1Yl"O'l being mutation A, a TCTG tenanucreotoa dupl ica tio n at posi tions 956 to 959, which accounts lor 70-80% of ad ult AML wltn NPMI mut ation , Ind ep end ent of type, NPM 1 mutat ions g enerate common ejeatrons at the C-terminus of NPM t leukaemic mutants, i.e. re plac ement o! tryp tophan (s) at position 288 and 290Mld cre ation of a nuclear export signal (NESl motif, which mediates aberrant localization of NPM to the cytoplasm 16671. CEBPA (CCAAT/enhancer-bind ing pro. teo-c) mutations occur only in AMl <W'C are usually baneic mutations . The normal ge ne encodes a transcription factor Illvolved in control 01 proli feration and dd· ferent iatio n of myeloi d p roge nitors. Whi'e mutations may occ ur throughout the whole gene sequen ce , tw o general c ategories of mutat ion occur: out-of-frame insertions and deletions in the N·term inal regioo art in-f rame insertio ns and de let ions in t'le C-terminal reg ion. Mutations of NPM I ere CEBPA are freq uently observed in At.l with a normal karyotype an d , in the absence of FLT3-lTO, are associated wma favourable prognosis 1216, 602 , 19711 2198 ,23311. In view of the freque ncy :; Ihese mutations. the ir prognostic sigMcance. and their association with certan morpho logic and clinical features , it has bee n sug gested that they may ident~' uniqu e subse ts of AML. Therefore, tIW new provision al entities, AML with mutated NPM 1 and AML with mutated CEBPA are proposed. These have been giv en provisio nal status bec ause they have beer on ly rec ently described and more sfudt is requi red to confirm these categories as

n

"

E re p

Tillie &.01

Moleculaf geneticalteratioos allectlrtg dir1ical outcome of AML patients in specific qtogeoeUc groups.

Geoetics

Cytogenatiu

KiT mutabon$

t(8:21)(q22;q22)

Prognosticslgnillcance

Signlfocann~'~"""' ~~-:"'''',,~uenls

wiId-~

OFS andRFS Wlth KITmutatons (especially ecse ill 8loo17) lXIIf4)8red 'Mtt1 KlTpalients {233A., 2Q09A, CIRandRI Slgoificantly higher fof peteots wilh KITmutaloons compared Wlth patients with wild.fype KIT{310A, 1696} EfS signlf!canny shorter forpabents with KITmutatons (especialy eese n e.oo 17) ~red IIIilh pall8/1ts with w~ KIT(233A.

1969Aj

OS si!1liflCalltly shortef I'tlr patents WIth KITmuta!lorls (espec:iaIyIhOs8 ill elOfl 17)compared wrltJ pabents wr01 wiId-4ype KlT{233A.. 31QA. 1969A. 2009A} No Slgf1fflcanl dllJerence 111 0$ bereeen patients IIIilh -"' wilhOul KITmutatl(lllS {1696}


FiJ>
ilw(16)(p131q22)1 RR'IIIOfSe lor patients wrltJ KlTmutatioos 111 el M 8 COIf4lilred WIlt1 patients \\'III'l wid-type KrTf33Ml t(16.16)(p13,1;q22) CIR hIglMlI' and OS '/II'OIWfor pabents WIth KIT rrotations 11 elOfll1 c:unpared wr01 PI1ients with wid-typeKIT{1696} No Sigr*ant dillereooe in EfS , RI, RFS and OS between pabentS withand 'Mlhoul KJTrnuIatols (2~ 31 0A)

Normar

......... .

CRa and DFS ~ shor1erfor pabenl$ WIth Fl.T3-lTD comparedwith palienls 'IIIClOlIl A.TJ.lTD {193A., 216. 736A 2394A) EfS SiglWanty sI'o18r lor patents WIth fLT3-fTO comperedwotll palienl$ 'IlIltI'loIA A.TJ.lTD (2338) OS~, sIlcrterlor patlents wotll A.T3-ITO c:unpared withpalients wrlholA FLTJ.lTD {193A. 216. 736Ai No SIgI'ificart dIIetence in OS b8t'ween palietn WI!! a'ld witlCUfLT3-lTD(2338, ~ OfS .-.:I OS sqv6c:¥llIy shorter b patients Wlth FlT3-lTO and no 8~ rJno-l)1:Ie FlTJaIele ~ 'MiD'! ~ W!IhOut FlTJ.lTD (m4A)

RJJ.m)MII t'1)

t,peRTJaWe

""00 w.-P1D

e_

::lflAli mutabCW'lS

.."".

OFS sagnficantty shorter for patienls wit! FLT3-TKD «ll'I'IPB!t:Id Mlh petlenls WIth wild-type FlTJ*'es (23961

"""'" """'"

CRD (but not OS) SignlfIcal1Uy srorter for patletlts WIlt1 AILL-PTD compnd with peli8nlsWIVlout ULL-PTD (313. 603) Noli&renoe in OFS cnl between patlenIswiIhand ntW AoIl-PTD recero'rlg I'IS8nSr¥e treamenllIW*1g a**lgous SCT {2395l

N,,,,,,,

kaizalion 01

NPM

os

CRD and OS ~ longer £or patients WIll1 CEBPA mulabalsa:mpared wrlh patients with~ CEBFl4. genes {216, 731} NoSigMIcant diIIereoce in OSbetweeI'l patienls 'lWilh and withOut CEBFl4. mulalions f233B} EFSsignlflcanUy shorter forpatJeflts with CEBPA rnutaliolls compared Willi patients 'IIIIh wid-type CEBPA genes f2338} CRrate of pabellts WIth cytopIaSlTic Iocaizaboll of NPM not 19'1ifical'lUy I)/Ieren! from CRrateof pabenls WJ\ll nudearIocaJiZatiOn of NPM in l,I'Iivariable analysis. Cyloplasri; IocaIzabon 01 NPM wasan intIepen(lenllaYOUr3ble prognosbc Iador for CR achievement in mulbvBl1a!e Iogislic-regres&Oll model inckIding WBC. age, NPM localizatIOn and FLTJ mutations {666}

N'''''''

CRrate Sigoificantly betterlor patents wrtI1 NPM1 mulatiOns lhal'llor palienls W1lh wi:l-type NPMl geoes {1970} ~ Sigl'lilical'll dillerel1C8 il'lCRrates between patiarllswith arid witt10ut NPMI mutations {139A. 233B} DFSaodRFS sigl1lfical'l~y lorIQeffor peeems willi NPM1 mlllabor1$ compared wtlhpatients W1lh wild.fype NPMl genes {602, 219l1} ~ sigMicaol diflerel1C8 fnRFS between pabenls withandWithout NPM1 mutatiorls {139A. 2338. 1970} EFSsigniflCilnlty ooget' 101' patients with NPM1 mlltatforls compared withpatients with wild-twa NPMl genes {1970} ~ Significam dillerel'lC8 in EFSbetween patents withandwitr.out NPMl mutatiOflS {139A, 233B} Nosignificant dillerence in OSteween patients withandwithout NPM l rl'llItations {139A, 233B. 602, 1970, 2198}

Normal

CRrales, EfS, RFS, DfS andOSsignificantly better lot patients with NPMf mutations wholackFLT3-ITD compared withpatients wittl NPMl mu tations andFLTJ-iTD or thosewith wild·type NPMI gelleS withor without FLTJ-ITD NPMl mutations do notseem to significantly alleet poorprognosis of patients with FLTJ-ITO {B02, 1970, 2198) Nosignificant dillereoces in EFSand 05 between patents with NPMl mutations andnoFLTJ-ITD compared with patients with NPMf mutations andFLTJ-ITD arid those with wild-type NPMl genes with or without FLTJ-ITD {139A/

IfTlmulations

Normal

Failureto achieve a CRwith standard induction chemotherapy lor patients With WTl mutations andFLTJ-ITD {2120Ai, OFS andOSsignificantly shorter forpati$nts with WTl mutallons compared With pabents Wltt'l wiId·type WTI alleles {1696A}

BAAle

i'bmaI

CRrateandrate01 primary resistant disease significantly WOfSelor patients withhigh e~pression oflhe BAALC gene in blood compared willi patients withlow eJqlreSSiOn of the BAALC gene{1358} No significant diflereooe in CRratesbe\Weel'I patieols withhigh aodpaLenls With lowe.pressiOn 01 the BAALCgeoe {l 35A, 216} DFS, EFS. RR and OSsignificat1Uy WOfSeaooCIR significantly htgher for patients With high elpression of lhe BAALCgeoe 11 blood compared 'Mth pabents withIoYt eqJre'SSlon oIth8 BAALCgeoe {1J5A.. 1356, 216}

Normal

CRrates, EFS, CIA, andOS SIgnificantly worse lor PlltJents widllligtl e~ioo oIlhe ERG gene in blood compared withpalieols wrlt1 lowe~oflt18 ERG gene{1J9OA, 139OB}

Normal

OS and RFS significantly shorter and RR higher for pallenl$ WIth high e~ of the MN f genecompared WIth pabents withIoYt elp(8SSion altha ",NI gene (9J7A)

'ftIl mutations

""e...,

lblIiIcI by[) Mn\z8k from MrOzek and Bloomtiekl {1531A).-.d MrOzek et Ill, {1532} WIth pemlI$SiDn. EFS ...... SUl\'lYII: RFS, ralapse-frM Sl.fVival: OS, ova-aI surYi'IaI; CIA, eurnulative inl:icIence of relapse, RI. relapse inQdence: OFS, d1seas&4ree SUI'YMl; RR.fisk of . . .. FL1J.ITO .,.,. tandem duplalllOll of the FLngene, FLT.HKD,1IkJtlOOns 11 the tyrOSII18 kinase domiIIo offhll FLDgene, CRO. compIeIe remission dIntioo ; AIU.n ,pnal llwldemduplicabon of118 AIU gene: SCT. stem cellrWlsplanta1ior CR. ~ I'eITissIon; ". NMnal kar)'otype,

Acute myeloid leukaemia with reclKrent genetIC abnQIrnaliltes

11 9

•

disease. entities rather than prognostic teeters . A small number of AML will show both NPMl and CEBPA mu tations. which would no t fit well into the proposed classification structure. In addition, the prognostic signi ficance 01 the chromosome aberrations reported to occur in 5-15% of AML with NPM 1 or CEBPA mutations is

not yet clear. There fore. the presence of any of the recu rrent nanstoc ations or inversions should be identified in any AML d iagnosis . In ad d ition , because of the adverse prognos tic impact of FLT3mutations in AML with NPMI mutations. mutation analysis 01 FLT3 should always be performed with NPM1 and CEBPA

These mutations are not de tectable by cytogene tic an alysis and are usually detected by PeR. Detec tion of cytoplasrri: NPM by immunohistochemistry coretaes well wi th the molecular m ethod [6641. btl similar immunohistochemical surrogate tests are not currently available lor aI known mutations.

Acute myeloid leukaemia with mutated NPM, Definition Acute myeloid leukaemia with rnnaied NPM 7 carries mutations that usually f'\o valve exon 12 of the NPMf gene AbetraW cytoplasmic expression of nucleophosrTrl (NPM) is a surrogate marker of this gefIe mutation 16661. This AML type IreqJef1l, has myeIomonocytic or rrooocstc feall.Jes and typically presents de novo in ~ adults with a normal karyotype. The WHO Working Group ass igned !his lesion 10 a group of provisional ennnee

ICD·Geode

9861/3

Synonym Fig. 6.101 Acute myeloid leukaemia with NPAlt mutations and myelomonocytic features. A Bone marrow biopsy showing complete teplacemel'l1 by large blaSCs With abuooanl cytoplasm and IoIded nuclei. B l elillaemic cells are CD34-negalive. C l eukaeJTllC eels show aberrant cyloplasrric expression of rkJdeopilosrr'Wfl (NPM). D EXpt"ession of C231nodeolin is restricted to Itle nucleus. CEB~ +5 _ ~

CEBPA+lo\C.L-PTD+ 1.2%

FLJ'3.TKD+/KL· PTD+ 0 .8% FlJ'3.TKD+ 2."% R.T3-lTD+/CEBPA+1.6%

Fl T3-lTO+IMLl·P"TO+ 2."% FlT3-lTO+ 8 .1% NPM'+lFLJ'3.TKD+/ } O " CEBPA +/KL-PTD+ "

NPM'+tf:;Un;::;: }o.,,% NPMl+IFLT.J-TKD+/ } , _ CEBAI'+

-" ,.

NPAI, +,Fl n.rTO+l } , ' " CEllA" NPtrI1+,f=LT.J-m)+/ } , ' "

FLJ'3.TKD+

-

NPM1+.<:ESPJIl,+ 3. ~

Fig. 6.15 Pie dlaf\ based on 2"6 pabent$ analyZed tor Itle Ilf99l!I'lC8 01 mutations in Itle NPUI and CEBPA genes. FLT3-ITD. FLT3-TKD and AIU.-PTD. E.actI seclof nIc3les the peI'C8flIllge 01 pabenIs harbotmg one Of ITOOl 0I1he ab'emenliOlllld muIabons. WT rocates pabef\tS WlIh only ~ alleles01 genes tes1ed. FromIkozek (If 11I.(1532) lnlltdapled!ram 00IVlllf (If Ill. (602}.

120

Acute myelOid leukaemia and related precursor neoplasms

Acute myeloid leukaemia wilh cytooasrc nucreopnosrsn (NPMc+ AML) .

Epidemiology

NPM1 mutation is one of the most COOlTOl recur ring genetic lesions in AML [283, 602.666.667.2198.2331 1. Prevalence increases wit h age, occurring in 2-8%ci c hil dhood AM L an d 27% -35% of adLJII AML. NPMI mutat ions occur in 45- 64%ci adult AML w ith a nor mal kar yotype 1283 351, 439, 666.2 198, 2331). This disease appears 10 show a fem ale pr ed ominance

Clinical featu res Acute myeloid leukaemia with NPMl mutation usually pre sents without a history of a MDS or MPN {6661. Patients otten exhibit anaemia and thrombocytopenia. b ut onen have high er whi te blood cell and platelet coun ts tha n other AML types 16021. Patients may show extramedullary involvement. the most frequently affected sites be ing gingiva, lymph nodes and Skm. Morphology and cytochemistry There is a strong association betweee acute myelomonocytic and acute rrceocytic leukaemia and NPMI mutation {666 6671: notably. 80-90% of acute rTIOf()o cvtc leokaerntas show NPMl mctetce,

,,

,

However, N.PM1 mutations are also detected in AML with and without ma turation and in acute erythroid leukaemia. A subset 01 cases shows multilineage dysplasia. These cases usually have a norm al ~aryotype and the blast cells are CD34 negative. The 8 M biopsy is usually markedly nvcerceuutar. Bone ma rrow blast percentages are generally higher in AML with muta ted NPM1 than in other acute myeloid reukaermes with a normal karjOlype

16021.

The diagnosis relies on the identific ation ~ the genet ic lesion by molecular tech!1IQUE!S and/or imm unohistoc he mic al

detection in paraffin sectoos of aberrant cytoplasmic expression of NPM 16671. mronostaining with anti·NPM antibodies reveals involvement of two or IT'K)(e 8M lineages (myeloid . monocytic . erythroid. megakaryoc ytic ) in the vast majority of ML Wlltl NPMl mutation 116981. The vanab~ lty of 8M cell types showing NPM 1 rrutations accounts for the wide rrorprological spec trum of this leukaemia. Immunopheno type In addition to myel oid an tigen s (CD13,

« Fig. 6.16 W*eage IMIlvement in AAlt. WItl'l NPM1 mutabons. A Bone m<mlW biopsy. Massive replac:eITetlt by myeloid blasts wittl maturalJon; !here are also megakaryocyles and occasional irTIrn
CD33. MPO), the blasts in AML with

NPM I mutalion frequently express markers 01 monocytic differen tiation , incl uding C0 14, CD 11b and the macrophagerestricted CD68. The roost striking inYnunophenotypic featu re 01 AML wi th NPM 1 mutation, which is independent of the degree of maturation of leukaemic cetls, is the lack of expression of CD3 4 (666). By immunohistoch emistry on p araffin sections, antibod ies aga inst NPM show f e characteristic abe rrant exp ression of the protein in the c yto plas m of leuk aem ic cells(6661. In co ntrast, positivity for C23/ nucleolin (another major nucleolar protein) isrestricted to the nucleus of leukaemic cells. Immunohistoc hemical detection of caoorasrnic NPM is predictive of NPM I euatoos 16641. since the mutations c ause critical changes in the structu re of NPM native protein (c haracteristically located '" the nucleolus), leading to its inc rease d export tram the nucleus and aberrant accumulation in the cytoplasm.

-c , 2

NPM1 gMfe ~ •

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Genelies Acute myeloid leukaemia with NPMl ITkrtation is usually associated with a normal karyotype . however. 5- 15% of AML W!ttl NPMt mutation show chromosomal aberrations 1666, 667J, inc lud ing +8 and de/(9q) 121961. NPMt m..rtabons are usually

Fig. 6.17 AclJte myebd leukaerria with NPM1 "'-IlaIions. Mutations usualy 0lXIS at exon 12 of tlle NPAlI gene. The irs! i:lenlified NPU1rIlIlabons (A" F)Ill! shown (666}. MiDtIon A1$fie most hqI.Jenl acaulbng lcr 70-80'10 01 cases. AI rn.Jtabllns feSUIt in a:mnon changes at fie e.tllmwu (COOH) 01 fie WlJd.type NPM protein. These dlanges (asl!lnst in the NPM nwtated proIeIn) c:onsisl of replacement of ~s) aI posibon 288 and 290 and aeation d I ~ export sqJaI (NES) motil. whiCtllre boIh responsible lor the inc:reased nuclear eJPl and abemIrlt t')'lcIpliIsrrC aca.oTUabon of !he NPM 1TlJIlwits.

Acute myelOId leukaemia With recurrent genetic abnormalities

121

-

• ~-

POCO 000 1

l-

.._..

1-

NPMt-IFl r:J.fI'D-I

I:

~_.

-

.-.

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-

P-O.71

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CESPA-

No-Donor

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• , • • r_• _• • • • • •

Acute myeloid leukaemia with mutated CEBPA

NPM r-tFl rJ.,lTO"'"

.-.

•

C NPM""'/FL T34TD-o

.\-

P
l_

CE8I'A -

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favou rab le prog nosis to AML with a chromosomal aberration or with multilineage d ysp lasia.

B

A

• , • • • •T_ • •_, 0 _

-

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ICD-Ocode

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CEBPA rrc tanons occur in 6-15% 01 de

Postula ted normal counterpart

Haenatopoenc stern cell 113941·

122

9861 /3

Epidemiology

•• •

-

Donor

,

.

No-Oonor

• • • • • • • , • • • T_ _

Fig. 6.18 Prcq10sis ofAML paltents. A,B ThegenotypesNPM' -JFL1J-lTlY'" and CEBA
mutuallyexclusive of the recurrent genetic abnormalities tha t define the AML entities desc ribed in the p rec eding sec tion 16651 and with par tial tandem duplicat ions of MLL and CEBPA muta tions, although concurrence of these abnormalities with mutated NPMI have been reported 1602, 2198 1. Ab out 40% of AML with NPM1 mut ations a lso ca rry FLT3-ITD (6661. NPMl mutations ap pear to precede FLT3ITO and these Ieukaermas are mo re genet ically stetne during disease evolution 1439, 21981. AML wilhcytoplasmic mutated NPM1 shows a di sti nct ge ne expression p rofile characterized by up- reg ula tion of HOX genes 119. 233 11 that di ffers from th at of other AML typ es. inc lud ing AML with MLL rearrangement 11539).

Definition Acute myeloid leuk aemi a with rnctaiec CEBPA usually meets criteria for AML maturat ion or AML without maturation, bul some cases may sho w myel ornonocyliC or monobtastic features. This leekaema usually presents de novo. The WHO Working Group ass igned ~ lesion 10 a group of provisional entities

Prognosis and predictive factors Acute mye loid leukaemia with mutated NPM1 typ ically shows a good response to induction the rapy 1666 ) Acute myelo id leukaemia with mutated NPMI and a normal karyotype, in the abse nce of a FLT3-ITD mutation. has a characteristica lly favourable p rognosis {283 , 60 2, 1970 , 2198 , 2331 1. The coexistenc e of FLT3·ITD mutations is associated with a poorer prog nosis. b ut Ihese patients still appear to have an improved prognosis c ompa red to AML that is NPM1 negative and FLT3-ITD positive 17461. Younger ind ivid uals with AML and a norma l karyotype exhi biting the genotype NPM 1 mutated!FLT3-lTD negat ive show a prog nosis that is comparable to that of AML with t(8 ;21)(q22;q22) or inv(16) (p 13.1q22) and may possibly be exemp ted from allog ene ic stem cell transplantation in first complete remission 16021. It is not known whether a NPM1 mutated;flT3-lTD nega tive genotype also confers a

Acute myelotd leukaemIa and related precursor neoplasms

novo AML and in 15-18% of AML W1:tl norma l karyotypes 1216, 737, 12801. rtee are no apparent age or sex d ifferences between CEBPA mutated and l"IOI"HTUIale:! AML [20401 Clinical features Acute myelo id leukaemia with metered CEBPA tends to have higher haemogkbn levels . lower p latelet counts. lower lactae dehydrogenase leve ls and higher PB bl ast cell co unts when c ompared to CEBPA non-mutated AML. This leukaemia type also has a lower frequency of 1ymphadenopathy and myeloid sarcoma 1216,

7371. Morphology and cyt ochemistry There are no distinctive morpholog ic leatures ot AML with normal karyotype an~ CEBPA mutations. but the vast majority d cases have features of either AML withoJ Of with maturation Less commonl y. cases have monocytic o r mveromonocvtc leatures. Three percent or more of the blasts are myelope roxid ase or Sud an black B positive, and most cases are non-specific este rase neg ative.

Immu nophenotype Leukaemic blasts usually express one (J more of the myeloid-associated antigens. CD13. CD33, CD65, C01 1b , and COIS There is usually ex pression of HLA·[)A and CD34 on the majority of blasts Monoc ytic markers such as C014 anc C064 are usu ally absent. C07 is preset in 50-73% of cases, while expression It

CD56 or otner lymphoid antigens is uncommon 1216. 13081.

Postu lated normal co unterpa rt Haematopoietic stem cell.

Genetics Seventy percent of A ML with CEBPA mutation have a normal karyotype . Fl.T3-lTD mutations occur in 22-33% of

Prognosis Acu te myeloid leukaem ia with a normal karyotype and CEBPA mutation is associated with a favourab le prognosis. similar to that of A ML with inv(16)(p13.1q22)

cases.

or t(8:2 1)(q22;q22). The significance of FLT3-lTO on the prognosis of this group (s currently unclear. with small studies suggesting either no impact or a negative impact on prognosis 1737, 17801. Although uncommon , the prognostic significance of A ML with CEBPA mutations and other chromosomal aberrations remains unclear.

Acute myeloid leukaemia With recurrent genetic abncemanoes

123

Acute myeloid leukaemia with myelodysplasia-related changes

DA ArOOr R D . Brunning A .Orazi

Definition Acute myeloid leukaemia (AML) with myelo dysplasia-rela ted changes is an acute leukaemia with 20% or more periphe ral blood (PB) or bone marrow (8M) blasts with morphological features of myelodysplasia or a prior history 01 a myelodysplastic synd rome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDSlMPN), or MOS-related cvtogenetic abnormalities, and absence of the specific genetic abnormalities of AMl with recurrent genetic abnormalities. Patients should not have a history of prior cytotoxic or radiation ther apy tor an unrelated d isease . Therefore , there are three possible reasons for assig ning cases to this subtype: AML arising from previous MDS or MO S/M PN ; A ML w ith an MOSrelated cytogenetic abnormality; and AMl with multilineage dysplasia. A given case may be assig ned to this subtype for one, two or alt three reasons (Table 6.02).

morphology, dysplasia must be present in at least 50% 01 the ce lls in at least two 8M ce ll lines. Dysq raoulo poresis is characterized by neutrophils with hypograOlJa' cytoplasm, hyposegmented nuclei (pseLti> Petqer-Huet anomaly) or bizarrely segmented nuclei . In some cases, these features may be more readily identiliedoo PB tha n BM smears. ()yseryItlropoiesls IS characterized by megaloblastosis, karprhexis and nuclear irregularity, lragTllll1ahan or multinucleation. Ring sideroblasts, cytoplasmic vacuoles and periodic acidSchiff (PAS) positivity are addlt~ features of cvsevtnroooesrs. Dysmegakaryo poiesis is characterized by microme gaka ryocytes and normal sized r:J larg e megakaryocytes with non-lobulated or multiple nuclei. Dy sp lastic megakaryo. cvtes may be more readily appreciated n sections than smears 169, 7421. cases wiU not have sufficient cell 8 M elements 10 adequately assessb multilineage dysplasia or have sufficietw; non-blast cells but do not meel the crilera described above for a morphologic nosis of AML with multilineage dysplasia These cases are diagnosed as AML mveiodvsptasta-retated changes by ee detection of MD&-related cytogenetic aDnormalities anellor by a prior history ofMDS.

ICD-O code

989513

Synonym Acute myeloid leukaemia with multilineage dysplasia.

-

Epi d emiology This ca tegory of AML with mveiccysptasiarelated cha nges occurs mainly in elderly pat ients an d is rare in chi ld ren 1913, 12691. Although the d efinition 01 rnultitineage dysplasia is variable in the literature , this category appears to represent 24-35% 01 all cases of AML 169, 869 , 1493 , 2465). Clinical leatures Patients with AML with myeiooysprasiarelated changes often present with severe pancytopenia. Some cases with 20-29% blasts, especially those arising from MDS or in ch ildhood , may be slowly progressive. These cases, w ith relative ly sta b le PB co unts for weeks or months, co nsidered refrac to ry anaemia with exc ess b lasts in transformation in the Frenc h-A mer icanBritish Cooperative Group ctassmcauon. may behave clinically in a manner more similar 10 MDS than 10 A Ml.

_

and cyt """,,",stry

Most, but not all cases in this category of AML have morphological evidence 01 muniuneaoe dysplasia which must be assessed on well -stained smears 01 PB and BM. To classify an AM L as having mve covsoasta-retateo changes based on

BJ. Barn

sore

A.P<xw< JW VardllTal MoM. LeBeau P.L Greertlefg

rcoees

•

Fig. 6.19 Acute myeloid le~~ with myelodysptasia-felated changes (murtilillllage dysplasia). The marrow aspirate shows numefOlJS I9"8nulaf blasts as wei as actIuII: hypogrardar neutrophiIs with dul1lled nucleardWomatin and erytt'ftid preanors \MttI irreQlAar nuclear am..n. AA small. l'lypoIobated rnegakaryotyIe is IQS80I al lhe txb. BAIigher magOOicaIion 01 anoltl8fcase showing rl'ICIre irregIJar nuclearfeatures 01 eryIhroi:I l)"eanors and ~ wiIhcbnped IIUd&ar etwomatn

.

124

Acute myelOtd leukaemia and related precursor neoplasms

Immunophenotype Immunophenotyping results are variable dueto the heterogenei ty of the underlying genetic changes, In cases with aberralions 01 chromosomes5 and 7. a high incidence oICD34, terminal deoxynucleotidyl trans!erase (Td T), and CD7 expression has been reported 123241. In cases with anieceoent MOS. CD34+ cells frequently const itute only a suboopuraton of blasts m may have a stem-cell related immunopheootype with low expression of CD38 M"dkx HLA-DA. Blasts often exp ress pan myeloid markers (CD13. CD33). The re is 'Tequently aberrant expression 01 CD56 and CD7 116231. The maturing myeloid cells may show patterns of antigen excesson differing from thOSe seen in nQ{mal myeloid development, and there may ee alterations in the light scatter properDeS of maturing cells, particularly neutrotfWs, There is an increased incidence of 'TUlKinJg resistanceglycoprOlein (MOO-1) expressiOn in the blast cells 11206, 1268,

t(2;1 1)(p 21;q23 ), if not associated with prior cytoto xic therapy, should be classified in this group rath er than as a variant translocation of 11q23 , Cases of AML with multilineag e dysplasia may carry NPMI and/or FLT3 muta tions [23561. Most NPMI mutated cases would be expected 10 have a normal karyotype, CD34-negative blasts and no history of prior MDS 120151. However, the presence of an MDS-associated karyotypic abrormality should take diagnostic precedence over the detection of an NPMI or CEBPA mutation for classification purposes until the significance of such rare genet ic c0mbinations is clarified . In patients wIth AML with multilineage dysplasia and a nQ{mal karyotype. information regarding the mu· tational status of NPMI, CEBPA and FLT3 may provide important prognostic informauon. and the presence of these mutations should be noted along with the diagnosis of AML with myelodysplasiarelated changes (multilineage dysplasia)

12691.

123561.

Genetics Chromosome abnormalities are similar to

Differential d iag nosis The principal differential d iagnoses are refractory anaemia with excess blasts , acute erythroid leukaemia, acute megakaryo blaslic leukae mia and the other categories of AML. not otherwise specified (NOS). Caref ul b last cell counts. adnerence to the diag nostic criteria for morphological dys pl asia and evaluation for MDS· re lated c ytogenetic abnormal ities shou ld resolve most cases, with this ca tego ry having priority over the purety morpholog ic ca teg ories of AML , NOS, For exam ple, a ca se with >20% 8 M myeio blasts, multilinea ge dy spla sia, ove r 50% BM erythroid precursors and monosomy 7 should be c onsidered as AML with myelod ysplasi a-reiated c hanges rathe r than acu te e rythroid leukaemia, Simila rly, a case with over 20% 8 M megakaryoblasts and multilineage d ysplasia would be considered AML with myelod ysp lasiarelated changes (megakaryoblastic type),

bose found in MDS and often involve gain or loss of major segments 01certain chromosomes with complex karyotypes and -7/del(7q) and -5/del(5q) being most ccmmon 11 269 , 1530 , 1641J, Additional abnormalities that are considered sufficient for inclusion in this ca tegory are given in Table 6.03, While trisomy 8 and del(20Q) are also common in MOS, these ffJdingsare not co nside red to be d iseasespecific and are not, by themselves, sufficient to co nside r a case as AM L with myelodysplasia-related c hanges, Similarly, bss of the Y ch romosome is a nonspecific find ing in o lder men and should oo! be consi dered sufficient for c yto[Ie!1etic evidence of this d isease ca tegory Balarced translocations are less common in tnis disorde r, but when they occur are of:en franslocations involving 5q32-33, Tile t(3;5)(q25 ;q 34 ) is associated with rrOtilineage dysplasia and a younger age al presentation than most other cases in tis disease group 1661. In addition, AML W1h inv(3)(q2 1q26.2), t(3;3)(q21 ;q26 .2) or W#l t(6;9)(p23:q34) may show evidence of rru/tilineage dysplasia, but these are now :ecognized as distinct entities in the AML 'MIll recurrent genetic abnormalities goup and should be classified as such . '*'wever, cases with the specific 11q23 wrangements. t(11 ;16)(q23;p13,3) and

Postulated normal counterpart Multipotent haematcooreuc stem cell. Prog nosis and pred ictive fact ors Acute mye loid leukaemia with myelodysplastic features generally has a poor prognosis with a lowe r rate of ach ieving complete remission than other AML types 169. 742 , 1269 , 1493 , 24651. While the re are no overall prognostic differences

Table 6.02 Criteria lor the diagnosis of AML with myelodysplasia-relatedfealu!'&S. ~ 20%

blood Of mam;lW blasts

AND Anyof !tie Ioi:lwing PreW:lus hislDry of myeIodysplaslic syndrome MyeIodysj::QsbC syndrome--relaled L)'IogenetIc abnormalrty (seeTable6.03) Mullilineaga dysplasia

AND

......."bdh

?nor cytlItWc therapy lor an I.MlIaIed disease RlICllfTing ~ abIllllT1lahl)' as descnbed in AMl-Mlh reamlOI genetic abroomIakbes.

CytlgenetJc abnorr!\alIbes suIIicienI m
Table 6.03

('.oorpe. ~ '

UnbtIIItdd aMoonaiilies

·llde(7ql

.-5qJ

~ l1q)'l l1p)

·131de1(13q) del(t1q) del(12pj/l(l2p)

"'l9q1 idic(X)(q13)

&tI1l11Ud abnoonaiities t1:11 ;t 6)(q23;p13,3)" t1:311 )(q26.2;q22.1)"' t1:1:3)(p36.3:q2t ,1) t{2:11)(p21:q23)"o 1(5;t2)(q33:p12) t(5;1)(q33:qtl .2) t(5;11)(q33;p13) t(5;10){q33;q21) t(3;5){q25:q34)

' >3 unrelated abnomlalities, none of which are includedin theAML withrecurrent genetic abnormalities subgroup: such casesshould be dassjfied in the aPPfClPriate cytoger.etic group. 0' These abl'lormalities most commonly occur in tnerapy-ffllated diseaseand lherapy-relatedAML

should be excluded before u~ng these abnormalilin asevidence lor a diagnosjs of AML with myeiodysplaSlB-related features.

between cases with and without prior MDS 1691. recognition of cases with prior MDS and relatively low blast counts may identify cases with less clinically aggres sive disease. Some cases with prior MDS and 20-29% 8M blasts, considered refractory anaemia with excess blasts in transformation in the French-AmericanBritish Cooperative Group ctess'ucatcn.

Acute myeloid leukaemia WIth myelodysplaSIa-related changes

125

may behave in a manner rrore similar to MOO than ome AML. These cases . as well as cases with myelodysplasia and just under 20% blasts, require regular monitoring of PB counts and 8M morpholOgy lor changes suggesting disease progression to overt AML. Although AMl with mu ltilineage dysplasia is generally associated with a poor prog· nests. several studies have not found morphology to be a significant parameter when using multi-variant analysis thaI also incorporates the results of cytogenetic analysis, high risk cytogenetic abnormalities being more significantly associated with prognosis {869, 2356, 24651. Therefore, mUltilineage dy splasia should b e conside red as a po ssible indicator of high risk cy togenetic abnormalities, bu t in the abse nce of such abnorma lities. may not be important. In such c ases, fluorescence in situ hybrid ization (FISH) stu dies for MO$-related abnormalities may be useful. It is cu rren tly unclear whe ther a NPM1 posl livefFLT3-negative genotype in AMl with multilineage dysplasia confers the same good prognosis as in other AMl with NPM, mutations. Cases of AML with multilineage dysplasia and NPM1 metanone usually do not have adverse cytogenetic findings or a history of prior MOS 120151. However. the clinical impact of mutation status versus the presence of multumeaqe dysplasia requi res more investiga tion. Therefore, it is not yet clear how cases of AML with multilineag e dysp lasia without prior MOS or MOS·related cytogenetic abno rmalities and with an NPM1 mu tation or a CEBPA m utation should be c lassified . How ever, as noted

126

••

I

,!

--t_

•

4...

, v.... ,,""' .......

Fig. 6.20 Survival curve lor cases of acu te myeloidleukae mia with adverse cytogenetic find ings in the "tRC-AMl IO trial Reproduced from Grimwade Det al. {MB}.

above, at this time cases of AMl with MOS-related cytogenetic findings and one of these mutations should be diaqnosed as AMl wi th myelodysplasiarelated changes as well as noting the mutation detected. Diagnostic term inology Because there are different pathways to a diagnosis of AML with myelodysplasiarelated changes, which upon further study may have clinical differences, it is recommended that the reason(s) for dia gnosing a case as such be included in the di agnosis. For example , a c ase di agnosed solel y on mo rphology would be considered "AMl with myelodyspla siarelated changes (rnultitineage dysplasia)": a case arising from p reviou sly diag nosed

Acu te myeloid leukaemia and related p recursor neoplasms

MOS without assoc iated dysplasia idl!f$the lime 01 AMl diagnosis woUd be considered ~ AMl with myelodysplasaarelated changes (following prevos MOSt; and a case with prior MOS. dysplastic features and monosomy 7 WCllil be considered "AMl with rnyeIoctyspIase related Changes (fotleJ'oNing previous Ml.li MDS-associated cytogenetic a~ and muttilineage dysplasia). Cases NPM1, CEPBA and/or FLT3 mutatll)'lS should also indicate the mutation hndrYJ (r.e. "AMl with mverocvsotasta-reraiec changes (multilineage dysplasia) aM NPM1 mutation"). Finally, because ollhe possible cli nical heterogeneity of cases with low blast cell cou nts (20-29%), tt:E b last count should be cl early stated in t~ repo rt.

ueo at

I"" Therapy -related myeloid neoplasms

Definition Inis category include s therapy -rela ted acute mye loid le ukaemia (I·AML). rnyelodysplastic synd rome (I -M DS ) and m yelodysplastic/myelop ro life rative neoplasm s (t-MDS/MPN) occurring as late compliea'ons 01 cytotoxic chemotherapy an d/or -adtatlOn therapy adminis tered lor a pr ior '«lPIastic or non-neoplastic disorder. AIh:lu'Jh some patients may be d iagnosed nnpt'dogicatty as 1-"'-105, t-MDS/MPN ()( ~AML according to the number 01b lasts present. all of these therap y-related neoplasms are bes t considered together as a IIlJque clinical syn d rome . Exc luded fro m mig categor y is tran sfor mati on of MPN srce it is etten no t possible to determine if !his is disease evolution or therap yrelated.

992013

&,nlnym Therapy-related acute myeloid

ielJ:.aemia. NOS.

-k>Iogy Therapy-related t-AMl.../t-MDS and t-AMLJ l.MDS!MPN ac count fo r 10 - 20% of a ll cases of AML, MDS and MDS/M PN 11278, 1433, 1536 1. The incidence among paieras treated w ith c ytotoxic agents varie s ElC cording to the underlying di sease and fe treatment strategy. Any ag e group rray be affected b ut the risk associated lIllh alkylating agent or rad iation therapy jjerlefally increases with age whereas the rsillor those treated with topoisornerase II II'hbIlors is similar ac ross all ages 1651,

12781,

E"*'lJy Therapy-related neoplasms are thou ght to bethe conseq uence of mutational eve nts mceo by cytotoxic ther apy, Som e indiOOualsmay have a heritable predis position due topolymorphism s in genes that affect drug metabolism or DNA -repair rnecha ~sms. but for most cases the und erlying 08thOgenesis rema ins uncertain 11899 1. Cy1oIoxic agents commonly imp licated ire istec in the Table 6.04 . Although other

JW. Vardiman DA Arber RD. Bruming RA Larson

E. Malutes I. Baumann J Thiele

the rap ies such as hydroxycarbamid e (hyd roxyu rea), rad ioisotop es, L-aeo araqinase and naematcootetrc growth teeters have been sugg ested to be reukae mogenic, their pr imary role in thera py-related haema tologic neoplasms. if any. is not clear. Characteristic clinical, morphologic and genetic features often relate to the previous ther apy received .

Sites of involvement Peripheral b lood (PB) and bone ma rrow (BM) are the princip le sites of involvement . Clinical features Near ly an equal number of patient s give a history of treatment fo r a p revious baematologi cal ma lignancy as for a non -haematolog ical solid tumo ur. How ever. 5 - 20 % of patients are reported to have rece ived cytotoxic therapy lor a rco-oecoasrc disease. A smlar num ber develop a therapy-related myeloid neoplasm afte r high dose chemotherapy and autologous haematoporenc stem cell transplant for a prev i. ously treated malignancy 11 433. 20411 . Two subsets of t-AMlIt-MDS and t-A MU t-MDS/MPN are generally recognized , The most common occurs 5- 10 years afte r exposure to alkylating agents an d/or ioniz ing rad iation. Patien ts often pr esent with t-MDS and ev idence of 8 M failure with one or mul tiple cyto penias, although a minority will present with t·MDS/MPN or with overt t-AML This c ate go ry is com mon ly associated with unbalanced loss of genetic material . often in volv ing chromosomes 5 and/or 7 . The second category of t-A ML/t-MDS and t-A ML/t-MDSIMPN encompasses 20-30% of patients. has a latency period of about 1- 5 years, and follows neannent with agents thai inte ract With DNA tcoosorerase II (topoisornerase II inhibitors). Most patient s in this subset do not have a mveioovsotasnc p hase bu t pre sen t initia lly with ove rt acute leukaem ia tha t is ofte n assoc iated with a bal anced cororoscrat translocation 1651, 1716, 20411, A lthough it may b e useful to c onsid er t-A MlIt- MDS and t-A MU t-MDSIMPN as being alkylating agent and/or rad iationrelated or as top:lisctnerase II irtlibitor-related.

Fig. 6.21 Therapy.retaled AML with t(9;11)(p22;q23). This pabenl deYeloped 1-AMl. 1essltlanone yearfoIow. ing instilulion oIlherapy lor osteosartoma. The therapy included both alkylabl'lQ agentS and ~ II inhibilorn.

in practice many p atients have rec eived polychemotherapy that includes both classes of drug s an d the boundary between the two categories is not always sharp 120411.

t.1o p hils include abnormal nuclear lobation, particularly hypolobatoo, and cytoplasmic hypogranulation . Baso philia is freq uently present 11 4721. The 8M may be hyper. ce llul ar, no rmcceuurar or twpoc euuiar. and slight to mark ed 8M fibrosis occurs in approximately 15% of c ases. Dysgranulcpoiesis and dy serythropo iesis are pre sent in mos t patients , Ring siderobla sts are rep orted in up to 60% of cases and in some c ases exceed 15% of the erythroid precu rsors. Meg akaryoc ytes ....ary in nurnTherapy-related myeloid neoplasms

127

°

00 000 00 O· __ 000 0 0°0°° 00.p~ . • _ o 0000°000 &0 , _

000 00 0

10.Q 0 0 000 ~ 00 0 00 00

°

0

00 .

00 0

0 00 0

00 0 1 A O OO. O O O_O..~O!?C .

,

•

Fig.6.22 Thefapy-relaled MDSlAML This 42-year-old man was lrealed withABVD therapy lor dassical Hodglin IymJ:tloma but retapsed 161T1OflthS laterandwas!Jven 9vage chemolt1erapy and radiolt1erapy, Two years later he presented W11t1 pancytopenia in l!le PB(A), a BM asprate (8) and BM tMopsy (C) st'lowtld ilCteased bass and mullili1eaile dysplaSia. A complex karyotype Jnduded lossof d1romosomes 5 and7.

ber but dysp lastic fo rms of variable size with rnooo- or hypolobated or widely separated nuclei are seen in the ma;orlty of ca ses 11472, 164 71- The percenteae 01 b lasts also varies but in patients presenting with a rnyelodysplastic pha se a lmost 50% will have less than 5 % 8 M b lasts 11472, 2026J About 5% of pat ients have features of MDS/M PN, suc h as c hronic mveromooocvnc leukaemia 120261. Althou gh patient s presentmq With rnyeiodyspl asia and cvtoperaas may be desi gnated as l-Moo or t-AMl depending on their mo rphology an d b la st counts. suc h subclassification may lack clinical sig nifica nce 120261. In 20-30% of c ases, the first man ifestation of therapy-re late d mye loi d neoplasm is ov ert acut e leu kaemia without a preceding myelodysplastic phase , Often , but not invariably , these cases follow toposomerase II inhibitor tnerapy. The majority of the cases are associated with balanc ed rec urren t c hromosomal transtocanons that frequently involve 11q 23 (MLL) or 21q 22 (RUNX1) , and hav e morphology that resembles de novo ac ute leukaemi a

associated wi th these chromosomal abnormalities 136. 1886 . 2034 1although a lew cases may pr esen t as MDS or have dysplastic teatures as well . Many cases fall in the categories of acute monoblaslic leukaemi a or mverononocvtc leukaemia. but ca ses with granuloc ytic d ifferentiation al so occur Case s mo rph ologi ca lly (and cytogenet ica lly) identical to those observed in all of the subtypes of AMl With rec urring cytogenetic abnormalities have been descri be d , inc luding acute pronverocvnc leuk aem ia , Such cases should be designated as t-AMl with the ap propriate cytogenetic abnormality indi c ated. e.q. t-AML with t(9; 11)(p2 1;q23 ). Cases of lymphoblastic leukaemia (All ) also occur in this group , usually associ ated with a t(4 ; t 1)(q2 1;q 23) c hromosomal abnormality 11022,19841. Immuoophenotype There are no specific immunophenotypic findings in t·AMUMDS ()( in t-AMljt-MDS/ MPN. lmmunophenotypi ng stud ies reflect the heter og eneity of the und erly ing morph olog y and often show c hanges similar

....kylating agents Melphalan. cydophosphamide , nitrogen mustard, cI*lrafnbldl. MuIIM, carboplalin. eisplabn ,

dacarbazirle, procarbazine.carmustine. mitomycin C .lh~epa,lomus ~ne. etc. Ionizingradiationtherapy

large fields IfIcIuding active bone marrow Topoi_

aMIl inhibiton

EIOpOSide. 1eoipO!iiOe. dolOf\ban, d8ulorIbcin.lIWJ.dnlrorle, arnsacrnt. acIIrom';an "TCJP(lI5OlTIeIaS IIirlhbIr:Jts may abo be associated WIltIIherapy-related ~ leukaemia

""""

Anilmetaboilles: thiopurines, ITl)'tOI)Ilenolate, fludarabine An titublJlin agents(usuallyin comblnenco withother agents):vincristine, vinblastine, virdesine, paditaxet,

docetaxel

128

Acute myeloid leukaerrua and rela ted precursor neoplasms

to their de novo counterpa rts 1681. Blasts are generally CD34+ and express panmye loid markers (CD 13, CD33), There 1$ freq uent aberrant expression of CD56 and lor the lym phoi d- associated marker CD7 . The ma turing myeloid cells may show patterns of antigen expr ession that diff er from that see n in norm al myeloid development. and there may be alterations in the light sc alier properties of maturing cells. particularly reutropnus . Genetics The leukaemic cells of ove r 90% eX patients with t-AMUt-MDS show an abn ormal kary ot yp e , The cy tog enetic abn or ma lities often co rre late with the laten t pe riod be tween the initial l herapy and the onset 01 the leukaemic disorder and With the pre vious cytotoxic therapy 11254.1433,1716, 1886,20411. Approximately 70% of patients harbour ureaanced chromosomal aberrations. mainly whole o r oaruat loss of ch romosomes 5 and /or 7, that are often assoc iated wit!l one o r more ad d itional ch romosomal abnormalities [e .g . d el(13q ), del(2OQl, d el( 11q ), del(3p), -17, -18 , -2 1, +8} in a complex karyotype. These changes are usually associated with a long latent period . a preceding myelodysplashc phase or t-A Ml with dysplastic features, and alkylating agen t and/or rad iation therapy The remaining 20 -30% of patients have balanc ed c hromosomal transloc aticns that invo lve rearrang ements of 11Q23 [including us,11)(p22:q23l and t( 11 :19) t(8;2t) (q23 ;p13l] . 2 1q22 [inc lud ing (q22;q22) and 1(3;21)(q26.2:q22.1)] and other abnormalities such as 1(15;17) (q22;q12) and inv (16)( p 13q22) , The balanc ed transtocano ns are generally associ ated with a short latenc y period, most often present as ove rt AMl without a pr ec ed ing mverocvsptasnc phase. and

are associated with prior toootsomerase II inhibitor therapy. Postulated normal counterpart Haematopoietic stem c ell. Prognosis and predictive factors The prognosis 01t-AML./l-MOS and t-AMU \-MDS/MPN is generally poor. although it is strongly influenced by the associated karyotypic abnormality as well as the comorbidity of the underlying malignancy or disease for which cytotoxic therapy wasl'itialyrequired. CNeratl, 5-year SlJVivaI

of less than 10% is commonly reported . Cases assoc iated with abno rmalities of chromo some 5 and/or 7 and a com ple x karyotype ha ve a particularly poo r outcome. with a median survival time ot less than one year regard less 0 1 whether they pre sent as overt acute leukaemia or as t-MOS 11472, 20261. In contrast to de novo MOS, some report s have suggested that neither the blast percentage nor subclassification have a significant impact on clinical outcome, and the designation of t-AMUt-MOS or t-AMUt-MDS/MPN may be more appropriate 11472. 20261. Patients

with balanced translocations genera lly have a be tter prognosis, but. except for those with t(15;17)(q22;q 12) and inv(16) (p 13.1q22) or t( 16;16)(p 13.1;q22). median survival times are shorter than for their de novo count erparts 136. 227 , 1886.

2034 .20411 . It shou ld be noted that occ asional patients assigned to the category of therapyrelated myeloid neoplasms represent coincidental disease and would be expected to behave like other de novo disease.

Therapy-related myeloid neoplasms

129

Acute myeloid leukaemia, not otherwise specified

The c ategory of ac ute myeloid leukaemia, not otherwise spec ified (AML. NOS) enco mpasses those cas es that do not fulfil criteria lor inclusion in one of the p revi ously desc ribed groups with rec urrent genetic abnormalities, myelodysplasia-relate d c hanges or tha i are therapy-related . These tumours are fell 10 be derived from haematopoietic stem cells . The clinical relevanc e of some subgroups 01 AML. NOS is of q uestionable significance 169. 21531 bu t they are reta ined in the cl assi fication because they define criteria for the d iagnosis 01 A ML ac ross a diverse morpholog ic spectrum and include the unique d iagnostic criteria for ervmroreukaemra. Mutation ana lysis and cytoge netic studies are rec ommend ed for c ases in this ca tegory and may offer more prognostic sig nificanc e than the morphologic subtypes. The pr imar y basis for subclassification within this category is the morphological and cylochemical/immunophenotypic features of the leukaemic cells that indicale !he major lineages involved and the degree of maturation. The de fining cntenon for AML is 20% or mo re mveioorasts in the peripheral b lood (PBl or bo ne marrow (BM): the promonocytes in AML wiltl monocytic di fferentiation are consi dered blast equiva lents, The cl assification of acute eryt hroid leukaem ia is uniqu e and is based on the percent ag e of abnorma l eryth roblasts for pu re ery throid leukaemia and the percen tage of myeloblasts among non-erythroid cells for the eryt hroid/myeloid type. It is rec ommended that the blast percentage in the BM be determined from a 500 cell differentia! count using an acceptable Roma nowsky stain . In the PB, tne differential shoul d include 200 leukoc ytes: If Ihere is a marked leukopeni a, b ufty coa t smears can be used , Should an aspi rate smear not be obtainable due to BM fibrosis and if the b lasts exp ress CD34, immun ohistochemical detection of CD34 on b iopsy sec tions may p rovide valuab le information and may allow the diagn osis of AML if the 20% b last threshold is me l. The major crite ria required for this c ategory are based on examination of BM aspirates,

130

D.A. Arber

R D. Brunning A.Orazi

L. Peterson J. Thiele M.M. Le Beau

A. Porwil

PB smears , and 8 M trep hine b iopsies, The recommendation s for cl as sif ic ation are applicable only to specimens obtained prior to chemoth erapy. It should be noted tha t most of the epidemiolo gic data cited for each AMl, NOS entity has been lar gely g athered from studies using the p rior FAB classi fication scheme, and may not directly apply to series of patients classi fied by the WHO sys tem, in which most patients will be classified into other, more specific entities , and fOf which sufficient epid emiologic d ata is not yet available.

Acute myeloId leukaemia with minimal differentiation Definition Ac ute myeloid leukaemia with minimal differentiatioo is an AML with no evidence 0 1 myeloi d differentiation by morphology and light mic roscopy cytochemistry. The myeloid nature 0 1 the bl asts is demonstrated by immunological markers and/Of ult ras tructural studies including ultrastructural cytochemistry. Imm unop henotypi ng studies are essential in all cases to distingui sh this disease from acute lym phoblastic leukaemia (ALL) , ICD -O code

9872/3

Epidemiology These cases comprise <5% of cases of AML. The disease may occur at any age, bu t most patients are ei ther intants or older adul ts. Clinical features Patients wiltl AML, minimally differentiated usually present with evidence of BM failure With anaemia, ltl rombocytopenia and neutropenia. There may be leukoc ytosis with a mark edly inc reased number of b lasts, Morphology and cytoc hemistry The blasts are usually of medium size with dispersed nucl ear chromatin, round or slightly ind ented nuc lei with one or two nucl eoli . The cytoplasm is agranular with

Acute myelold leukaemia and related precursor neoplasms

~

..

f ig. 6.23 AcuIe myeloblastiC leukaemia. minirnaI"· enlJated. A&nI 1I8TOW sme¥. The blasts wary II Silt. ilITICV1t d ~ and prorrWlen(;e d ru:id. ThM ate no QfferenlIabng lealU'8$. B Bone man'OW sedioIl TIis lxlne marrow is COl,lpIetely replaced by tusts..,. Olf 11l1lerenbalJng I8alures.

a varying degree of basophilia Less frequently, the blasts are small with more cond ensed chroma tin, inconspicuous nucleoli and sca nty cytoplasm resemb ling lymp hoblasts. The c ytochemical reactions for myeloperoxid ase (MPO), Sudan Black B (SBB) and naphthol-ASDctnoroacetete esterase (CAE) are neqetive «3% positive blasts): a naphthyl acetate and butyrate es terases are negative or may sbow a noo-specmc weak C1 local reaction distinct from that 01 rT"IOOl> cvtrc cells 1186, 1084, 1880 1. In some unusual cases of AML with minimal ditter· ennanon there may be a residual norma population of maturing neutroo nue. These c ases ma y resemb le AML with maturenon. but are distingui shed by the absence of MPO or SBB positivity in the b lasts and the abse nce of Auer rods, The BM sections are usually markedly hvoerceuuie with poorly differentiated blasts. With sensitive ultrastructural studies, MPO, CAE ac tivity may be demonstrated in sma

•

granules. endoplasmic reticulum, Goigi area and/or nuclear membranes.

1",,,,,,,OP" 011Otype Most cases express earty, heernetoooetcassociated antigens (such as CD34, CD38 and HLA-DR) and lack antigens associated with myeloid and monocyti c maturation. such as CD 11b. C01S , CD14, CD64 and CD65 Biasi ce lls usually express CD13 and/or CO l 17 while expression of CD33 is found in approximately 60% of cases, Blasts are negative tor Band T-assoc iated cytoplasmic lymphoid markers cCD3, cCD79a and cCD22 . MPO is neg ative by cytochemistry. but may be positive in a fraction 01 blasts by flow cytometry Of immunohistochemistry. Nuclear terminal oeoxvnocieonoyttransterase (Td T) is positive in approximately

50% of cases. Expression of CO? has been reported in approximately 40% of cases, while expression of o ther membfane,lympood-associated markers is rare. Genetic s No unique chromosomal abnormality has been identi fied in AM L with minimal differentiation. The most co mmon abnormalities previously reported are complex karyotypes and unbalanced abnormalities, such as -5/del(Sq), -7/del(7q), +8 and del( 11ql , but the presence of some 01 these abnormalities would now pl ace the case in the category of AML with myelodysplasia-related changes. Mutations of RUNX 7 (AML 7) occur in 27% of cases and 16-22% of cases have FLT3 mutations. Differential diagnosis The differential diagnosis incl udes ALL, acute megakaryoblas!ic leukaemia, mixed phenotype acute leukaemi a and more rarely. the leukaemic phase of large cell lymphoma. Immunophenotyping studi es are essential to dis tinguish these condi-

oons Acute myeloid leukaemia without maturation Definition Acute myeloid leukaem ia without maturation is characterized by a high percentage o! 8M b la.''-.ts »l~I,~\1 $~":li~ic.5\'71· evidence of maturation to more matur e neutrophils. Blasts constitute ~% of the roo-erythroi d cells. The myeloid nature of

Fill.6.2" Acute myeloid leukaem ia without maturation. Bone marrow smear. AThecellsarepredominanlty myelobIasts: OCC3S;onal myeloblasts contain azllrophilic grarlules or Aller rods. There is rIO e'o'i Oenc41 01 maturation beyornllhe myeloblast stage. B Myeloperoxidase reaction showing OOmertlUSmyeIoblasls with strong peroxidase reactivity. There areseYeraI peroxidase negative tfYlhroid precursors ifl the centre.

the blasts is demonstrated by MPO or S8B (3% or more of blasts) posi tivity and/or Auer rod s. ICD-O oode

9873/3

Epidem iology Acu te myeloid leukaemia without maturation comprises 5- 10% of cases of AML. It may occu r at any age but the majority of patients are ad ults; the median age is approximately 46 years. Clinical features The patients usually present with evidence of 8M failure with anaemia, thrombocytopenia and neutropenia, There may be a leukocytosis with marke dly increased blasts. Morphology and cytochemistry Some cases of AML without maturation are characterized by obv cos mveicorasts. some of which have azurophilic granulation and/or unequivocal Auer rods. In other cases, the blasts resemble Iymphob lasts and lack azurophilic granules: MPO and SBB positi vity are present in a varia ble number of bl asts , but always in at least 3% . The 8M biopsy sections are usually markedly nvperceuutar although rormocellular or nvooceuuiar cases may occur. Immunophenotype Acute myeloid leukaemia without maturation usually presents with a popu lation of blasts expressing MPO and one Of more of myel oid -associated antigens suc h as C0 13, C033 and C0 117. C0 34 and HLAOR are positive in approximately 70% of

cases.

r,~q'6' , ~ ~%'l '~\~' ,';\7 ex~<%'S\iJ'l'i'

of markers assoc iated with granu locytic matu ration such as C0 15 and C065 or rrcnocync mark ers such as C0 14 and

C064. C0 11b is expressed in a fraction of cases. Blasts are negative for B- and Tassociated cytoplasmic lymphoid markers: cC03. cC079a and cCD22 . CD7 is foond in -30% of cases , while expression of other membrane , lymphoid-associated markers such as C02, C0 4, CD 19 and C056 has been described in 10- 20% of cases Genetics There is no demonstrated association between AML without maturation and specific recurrent chromosomal abnormalities. The immunoglObulin heavy chain gene and T-eel! receptor chain genes. in most cases , are in a germline configuration. Differential diagnosis The differential diagnosis includes ALL in cases with blast cells lack ing granules or having a low percentage at MPO-positive blasts, and AML with maturation in cases with a higher percentag e of MPD-positive blasts.

Acute myeloid leukaemia with maturation Defin ition

Acu te myeloid leukaemia with maturation is cha racterized by the presence of ~ blasts in the BM or PB and evidence of maturation (~10% matUringcells of neutrophil lineage); cells of monocyte lineage com prise <20% of BM cells. ICO-D cod e

9874/3

~~iilblbm'

Acute myeloid leukaemia with maturation com prises approximately 10% of cases 01 AML (691. It occurs in all age groups;

Acute myeloid leukaemia. not otherwise specified

131

expression of HLA-OR, CD34 and/or CDl 17, which may be present only in a fract ion of blasts. Monoc ytic ma rkers such as CD 14 and CD64 are usually ab sent. CD7 is present in 20-30% of cases. while exp ression of CD56, C02, CD19 and CD4 is uncommon (- 10% of cases) .

N»ts l'I'Iylllod leulo:BMilI Wllh mlll.ralD'" Booe marrow &ITlNf. kl ~ tJ !he myeIobIa$l$. lhere 8111 sewraI more malure nevtrophIs; one neutrophI has a psetJdo Pelger-HIJill Ikldeus. F" 1g.6.25

20% of patients are <25 years of age and 40% are ~ years of age 120781.

O inical features Patients often present with symp toms r elated to anaemia, thrombocytopenia and neutropeni a. The white blood cell coun t is variable as is the number of blasts. _ o g y and cytochemisOy Blasts with and without azurophilic granu· larion are present. Auer rods are frequently present. Promyelocytes , mveiocvtes and mature neutroph ils com prise at least 10% of the BM cells; variable degre es of d ysplasia are frequently present. Eosinophil precur sors are frequ ently increased but do not exhibit the c ytolo gical or cytochemic al abnormalities ch aracteristic of the eosinophils in acute myelomonocyti c leukaemia. associated with inv(16)(p13,l q22). Basophils and/or mast ce lls are some times increased . The BM biopsy is usually hyoe rceuular.

Immunophenotyp e l eukaemic blasts in AML with maturation usually express one or more of the myeloid-associated antigens, C0 13,C033, C065, C0 11b and C01 S. There is often

132

Genetics There is no demonstrated association between AM L with maturation and specific recurrent chromosomal abnormalities. Differential diagnosis The differential diagnosis includes retractOf'y anaemia with excess blasts in cases with a low bl ast percentage, AML withOut maturation when the percentage of blasts is high, and acute myelomonocytiC leukaemia in cases with increased monocvtes.

Acute myelomonocytic leukaemia Definition Acute myelomonocytic leukaemia is an acu te leukaemia characterized by the proliferation of both neutrophil and monocyte precu rsors, The PB or BM has ~20% blasts (including prorronocvtes): neutrophils and their precu rsors and monocytes and their precur sors eac h comprise at least 20% of BM cells, This arbitrary minimal limit of 20% monocyt es and their precu rsors disting uishes acute myelomonoc ytic leukaemia from cases of AML with or without maturation in which some monocyte s may be present. A high number (usually ~5x 1 09/L) of monocytic cells may be present in the PB, ICD-O code

Acute myeloid IeukaEtnlla and related precursor neoplasms

9867/3

Ep id em iology Acute myelomonocytic leukaemia c0mprises 5- 10% of cases of AML. uoccca n all age groups but is more corrrnoo in ddEJ individuals; the median age is 50 years, There is a maleJemaIe ratio of 1.4:1 120781. Clinical features Patients typically present with anaerre and thrombocytopenia, fever and fatigue The white blood cell coun t may be high with numerous blasts and promonocytes

Morphology and cytoct>erT;sOy The monoblasts are large cells, wm abundant cytoplasm which can be m0derately to intensely basophilic and may show pseudopod formation. Scaneeo fine ezurconmc granules and vacuoles may be present. The monoblasts usuaJy have round nuclei with delicate lacy ceemann and one or more large prominert nucleoli. Promonocytes have a more irregular and delicately convoluted nucIe
--~7" f'll. 6..27 Acute myeIomonocytIe 1eI*aen'ia. A BIoocI smear. myeloblast monoblast al'ld prormnocytes. B Bone marrow smeaf. MyelobIas1s.1ld smnIlOOre mallJ'e mooocyte5 rdudir9 prornonocytes, C Nm-specific esterase reactionon• bone marrow smear. 5eYetaI NSE positi'Ie eels819 presert. The l'ICIl'Hll8dII1 eels 8111 ~ myeIcitlIasls m~ preaJ ~.

!rrmunophenotype These ieusaemras generally show several populations of blasts variably expressing myeloid antigens C013. CD33, COO5 and CD15, One of the b last populatio ns is usually also positive for some markers

find ing s and perc ent of mo nocyt ic cells. The differential d iagn osis with c hron ic myelo monoc ytic leukaemia is c ritical and rel ies on the p ro per id entific ation of p romo noc ytes.

characteristic of monocytic d iffer entiation

such as CD 14, CD4, C0 11b, COl le,

CD54.CD36, macrophage-restricted CD68 (PGM1), CD l63 and lysozyme. In pa rticular. co-exp ressio n of CD15 and strong C064 is characteristic of monocytiC di lferentiatoo. There is often also a popctam ol irrmature blasts tha i express CD34
Genetics Myeloid-assoc iated , non-s oecrnc cytogenetic abnormalities, e.g. +8, are present in the majority of the cases. Differential diagn osis The major d iffe renti al d iagnoses inc lude AML with matu ration , acut e mo noc ytic leukaemia and c hronic mvelomonocync leukaemia. The distinction from the other Mi L types is based on the cytochemical

n;. 6.21

Acute monoblastic and monocytic leukaemia Def inition Acute monoblastic leukaemia and acute monocytic leukaemia are myeloid leukaemias in which 80% or rrcre of the leukaemic cells are of monocytic linea ge incl udi ng monoblasts, prorooocvtes and monocytes : a minor neutrophil component, <20%, may be present. Acute monobIastic leukaem ia an d ac ute mo nocyti c leukaemia are d istingu ished by the relative proportion s of mono blasts and p romo noc ytes. In ac ute monobreettc leukaem ia, the major ity of the monocytic c ells are monob lasts (typ ica lly ~80 % ) , In acu te monocytic leukaem ia, the majority of the mo nocyti c c ells are crornonocvtes. ICD-O cod e

9891/3

A Acute monoblaslic leukaemia, Bone marrow biopsy showing complete replacement by a ~lation of

llrge blasts wilh abundant cytoplasm. The nuclei aregeneraly rOI.Ild to oval: occasional nuclei are di&lol1ed <TIO'lOCytiC leukaemia Bone marrow sedion . The nudea!'IoIds in the promonocyles arepfOmineol.

8 Acute

Ep idem io log y Acut e monob lastic leukaemia com prises <5% of cases of AML. 11 may oc cur at any age bu t is most co mmon in young individuals, Extramed uliary lesions may occur. Acute mo noc ytic leu kaemi a comprises <5% of cases 01 AML : the mare.ternare ratio is 1.8:1. It is more common in ad ults (median. 49 years) 120781. Clinical features Bleed ing d isorders are common presenting featu res . Extramedullary masses . cutaneous and gingival inlit1ration. and c entral nervous system (eNS) involvement are common. Morphology and cytochemistry Monoblasts are large cells , with abundant cytop lasm which c an be moderately 10 intensely baso philic an d may show pseudop od formation. Scattered fine az urop hilic g ranules and va cuo les may be present. The monob lasts usually have round nuc lei with delicate lacy c hromatin, and one o r more large prom inent nucl eoli , Promonocytes have a more irregular and delicately con voluted nuc lear con fig uration; the cytoplas m is usually less ba sophilic and sometimes more obv iously g ranulated , with occasional large azurep hilic g ranules an d vacuoles. Auer rod s are rare in acute mono blastic leukaemia and. when present, are usu ally in ce lls ident ifiable as myeloblasts. Haemophagocytosis (eryttrophagocytosis) may be 0bserved and suggests an associated t(8;16)(p11 .2:P13.3) chromosomal abnormali ty 120 791. Haemoph agocytosis wilh an associated t(8 :16)(pll.2:p 13.3) may also be observed in AML with maturation . The monobtasts and p rornonoc ytes usually show intense non-sp eci fic este rase activity in mos t cas es, In up to 10-20% of ca ses of acute monooasnc leukaemia, the

Acute myeloid leukaemia, not otherwise spec ified

133

can be dis tinguished with well-stained smears . The differential diagnosis with chronic myetomonccytc leukaemia is critical and relies on the proper identification of promonocytes and their inclusion as blast equivalents. The abnormal promyebcvtes in APL are intensely MPO and CAE pos itive whereas the monocy tes are weakly reactive or negative. Fig. 6.29 Acute monocytic leukaemia, testcclar infiltralion Al ow magnification of a biopsy ot a testis from a patienl with acute monocytic leukaemia. There is extensive expansion and infiltrationof tile space between the seminiferous tubu les. 8 ThemonocyIic cells nave relati ~e ly abundant cytoplasm and ~ery dispersed chroma tin.

non-specific esterase reaction is negative or very weakly positive. In some of these , immunophenotyping may be necessary to estab lish monocytic diffe rentiation , Monoblasts are typically MPO negative; promonocvtes may show some scattered MPO positivity. The BM biopsy in acute monobtastrc leukaemia is usually hypercellular with a predominant population of large, poorly d ifferentiated blasts with abundant cytop lasm, Nucleoli may be prominent. The prornonccytes in acute monocytic leukaemia show nuclea r lobulation. The extramedul lary lesion may be predominantly of monoblasts or prornonocvtes or an admixture of two cell types. Immunop henotype By flow cytomet ry these leukaemias variably express myeloid antigens C013, C033 (often very bright), C015 and C065. There is gene rally exp ression of at least two markers characteristic of monocytic differentiation such as C014 , C04, C011 b, C011c , C064, C068, C036 and lysozyme, C034 is pos itive only in 30% of cases, while C0117 is more often expressed, Almost all cases are positive for HLA-OR. MPO may be exp ressed in acute monocytic leukaemia and less often in monoblastic leukaemia. Abe rrant expression 01 C07 and/or C056 is found in 25-40% of cases. By immunohistochemistry in paraffin-embedded 8 M biopsy specimens and in extramed ullary myeloid (monobtast'c) sarcomas , MPO, CAE are typica lly negative but may be weakly positive. Lysozyme is often positive, but is relatively non-specific. Macrophage-specific CD68 and C0163are oftenpositiveand appear to be morespecific for monocyticdifferentiation.

134

Genetics Myeloid-assoc iated, non-specif ic cytoge netic abno rmalities are present in the majority of the cases. The t(8;16)(p 11.2;p13.3) may be associated with acute monocyt ic leukaemia or acute myelomonocytic leukaemia and , in the majority of cases, is associated with haemophagocytosis by leukaemic cells, particularly erythrophagocytos is and coagulopathy 12079). Differential diagnosis The major differential diagnosis of acute moncorastrc leukaemia incl udes AML without maturation , AML minimally differentiated and acute megakaryoblastic leukaemia. Extramedullary myeloid (monablastic) sarcomas may be confused with malignant lymphoma or soft tissue sarcomas. Occasi onal cases resemble prolvmphocytic leukaemia; they are readi ly distinguished by immunophenotypic analysis and cytoch emistry. The major differential diagnosis of acute monocytic leukaemia inc ludes ch ronic mvelomonocytic leukaemia, acu te myelomonocytic leukaemia and microgranu lar acute promyelocyt ic leukaemia (APL). These

Acute erythroid leukaemia Definition Acute erythroid leukaemias are acute leukaemias that are charac terized by a predominant erythro id popu lation. Twa subtypes are recognized based on the presence or absence of a significant myeloid (granu locytic) component: Erytnroleukaernia (eryth roid/myeloid) is def ined by the presen ce in the 8M of ~ 50% erythroid precursors in the entire nucleated cel l popula tion and <::20% myeloblasts in the non-erythroid cell population, i.e. the myeloblasts are calculated as a percen t of the non-erythroid cells. Pure erythroid leukaemia represents a neoplastic proliferation of immature cells (undifferentiated or proerythroblastic in appearance) committed exclusivelytothe erythroid lineage (2:80% of BM cells) with no evidence 01 a significant myeloblastic componen t 1753). ICD-O code

9840/3

Epidemiology Erytnroleukaernia (erythroid/mye loid) is predominantly a disease of adults (20781. It compr ises <5% of cases of AML. Pure erythroid leukaemia is extremely rare and can occ ur at any age, including childhood

.'•

•

Fig. 6.30 Acute erythrcleukaemia. erythroid/myeloid. BOlle marrow smear. A Myeloblasls and erythroid precursors with dyserythropoietic changes are present. B Bone marrow smear Perocc acid-Schiff reaction. There are se~eraI erythroid precu rsors atvaryingstagesof maturation wilh PAS-positi~ cytoplasm. The more immature precursors Mile a coarsely granu laril10bular reaction; thelater stage precursors havea diffuse cytoplasmic positi~Fty.

Acute myeloid leukaemia and related precursor neoplasms

"

,... .

Fig. 6.31 Acute erythroid leukaemia, erythroid/myeloid. Bone marrow biopsy, There is a population of erythrokl precursors and myeloblasts refi ecting the duallineage proliferation. A binucleate megakaryocyte is present.

Clinical features The clinica l features of the eryth roid leukaemias are not unique but profound anaemia and circulating erythrob lasts are common, Erythroreukaernia (erythroid! myeloid) may present de novo or evolve from MDS or, less common ly, from chronic myeloproliferative neop lasms (MPN), Morphology and c ytoc hemistry Erythroleukaemia (erythroid/myeloid) All maturation stages of the erythroid precursors may be present, frequently with a shift to immatu rity. The erythroid precursors are dy splastic with meparobras torc nuclei and/or bi- or multinucleated forms ; the cytoplasm in the more immature ce lls frequently contains poo rly dema rcated vacuoles, which may coa lesce , Large multinucleated erythroid cells may be present. The rnveioorasta are of med ium size, often con taining a few cytoplasmic granules and occasionally Auer rods and aresimilar to the mveiobrasts in AML with and without maturation. Dysplastic changes of maturing neutrophils and megakaryocytes are common, The iron stain may show ring siderob lasts and the perio dic acid-8ch iff (PAS) stain may be positive in re erythroid precursors either in a globular or diffuse p attern. The MPO, CAE and SBS stains may be positive in the myeloblasts. The 8 M biop sy in erythroid! myeloid leukaemia is usually hypercelluar. There may be prominent mega karyocytic dysplasia. Pure erythroid leukaemia The undifferentiated form of pure erythroid leukaemia is usually ch aracterized by the presence 01 medium to large size erythroblasts usua lly with round nucl ei, fine chromatin and one or more nuc leoli

-

Fig.6.32 Pure erythroid leukaemia. Bone marrow smear with numeroos very immafure erythroid precursors; these cells have cytoplasmic vacuoles which occa sionally

Immunoph enotype Erythrole ukaemia (erythroid/myeloid) The erythroblas ts in ervtbroieokaemia generally lack myeloid-assoc iated markers and are negativ e with anti-MPO; they react with antibodies to haemog lobin A and glycophorin, but the more immature ce lls may be negative. An aberrantly low expression of CD71 may be present. The immunophenotype of the myeloid population usually co rresponds to that 01 AML without differentiation or AML with minimal differentiation.

coalesce,

(proerythroblast): the cytoplasm is deeply basoph ilic, often agranular and frequently con tains poor ly demarcated vac uoles which are often PAS-posi tive, Occasionally the blasts are smaller and resemb le the Iymphob lasts of ALL. The ce lls are nega tive for MPO and SBB; they show reacti vity with a -naphthyl acetate esterase, ac id phosphatase and PAS, the latter usually in a block-like staining pattern, In the BM biops ies of pure acute erythroid leukaemia the ce lls appea r undifferentiated.

Pure erythroid leukaemia The more differentiated forms can be detected by the expressio n of glycophorin and haemoglobin A and absence of MPQ and other myeloid markers; the blasts are often negat ive for HLA-DR and CD34, but may be pos itive for CD117. The more immature forms are usually negative for glycophor in or this is only weakly expressed in a minority of blasts. Other markers such as ca rbon ic anhydrase 1, Gero antibody against the Gerbich blood group or CD36 are usually pos itive as they detect erythroid progeni tors at earlier stages of differentiation. However, CD36 is not specific for ervtbrobrasts and may be

Fig.6.33 Pure erythroid leukaemia,Bone marrow section, A Apredominant population of veryimmature erythroid precursors , some of which aremuRilobated (arrow). B The immature erythroid precursors and mrtotic figures showpositivity fof glycophorin A.

Fig.6.34 Pure erythroid leukaemia. A Bone marrow smear shows fourabnormal ptcerythrcblasts. The erythroblasts are large withfinely dispersed chromatin. prominent nucleoliand cytoplasmic vacuoles, some ofwhfch are coalescent. B The cytoplasm of the proerythroblasts shows intenseglobular PAS staining.

Acute myeloid leukaemia, not otherwise specified

135

expressed ..by mo-ocvtes and mega karyocvtes. Antigens associated with me gakaryocytes (CD41 and CD6 1) are typically negative, b ut may be partially expresse d in some cases . Immunohistoc hemistry to haemoglobin A or glycophorin may be helpf ul in establishing cell origin in biopsy specimens.

Genetics There is no specific chromosome abnormality described in this type of AML. Complex karyotypes with multiple structural abnormalities are com mo n, with -5/del(Sq), -7/del(7q) and +8 the most corrvnon 112821. However, cases with -5/del(Sq), -7/del(7q) and/()( complex chromosomal aonomaunes should be classified as AML with myelodysplasiarelated changes if the other requirements f()( that category are satisfied.

Differential d iag nosi s ~(~)shouId

be distinguished from refractory anaemia with excess blasts (RAEB) , AML with mye lodysplasia-related changes, AML wi th ma turation with increased erythroid precu rsors and reactive eryth roid hyperplasia follow ing therapy sx administration of eryt hropoietin. A BM differential coun t of all nuc lea ted cells should be pe rforme d. If the ove rall percentage of b last cells is ~20% and muJlilineage dysplasia is prese nt in ~50 % of the cells of two or mo re lineages, a di agnosis of AMl with myelodysplas ia- relate d c hanges should be made . When there are <20% total blasts an d the erythroid p rec ursors are ~ 50% of all cells, the di fferential co unt of non-erythroid ce lls shou ld be ca lcu lated . If blasts are ~20% of non-eryth roid ce lls , the di agn osis is erythro leukaemia (erythroid/myeloid ); if <20%, the d iagnosis is usually MOS. The d ifferential diagnosis of pure erythroid leukaemia inc lud es megaloblas tic anaemia due to vitamin B 12 or folate de ficienc y. In eq uivoc al cases, a trial of 81 2 o r folate thera py should be considered. Pure erythroid leukaemia without mo rphologic evidence of erythroid maturation may be diffic ult to distinguish from othe r type s of AML . particularly megakaryob lastic leukaemia, and also from ALL or lymphoma lack of expression of lymphoid antigens will exclude the latter diagnoses. Distinction from megakaryoblastic leukaemia is the most difficult: If the immunophenotype is characteristic of 136

er ythroid pr ec ursors, a diagnosis can be e stab lished , howeve r some cases are am big uous and there may be cases with concurrent erythroid-megakaryocytic involvemen t. Prognosis and predictive factors Erythroi d/myeloid leukaemia is generally associated with an aggressive clinical course. The morphologic find ing s may evolve to a mo re predominant myeloblast picture. Pure erythroid leukaemia is usually associated with a rap id clinical course.

Acute megakaryoblastic leukaemia Definition Acute megakaryoblastic leukaemia is an acute leukaemia with 20% ()( more blasts of which at least 50% are of megakaryocyte line age; however, this category excludes cases of AML with myelodysplasia-related changes, AML with t(1;22)(p13;q 13), inv(3)(q21q26.2), t(3;3) (q21 ;q26.2) and Down syndrome-related cases. ICD-O code

99 10/3

Ep idemiology Ac ute meg akaryo bl astic leukaemia occ urs in bo th adults an d children. This is an unc ommon d isease compris ing <5% of ca ses of AML . Clinica l features Patients present with cyto pe nias. often thromb ocytop enia, although some may have thrombocytosis. Dysplastic features in th e neutroph ils, er ythroid precu rsors, p late lets and me ga karyocytes may be pres en t. Hep atosplenomeg aly is intre-

Acute myeloid leukaemi a and related precursor neoplasms

quent. An association between acute

meqekarvonrasnc leukaemia and mediastinal germ cell tumours has been ocserved in young adul t males 115941.

Morphology end cytochemistry The megakaryobl asts are usually of medium to large size (12-18 jJm) with a round , slightly irregular or indented l'MJcieus with fine reticular chromatin andce to three nucleoli . The cytoplasm is baseprune. often agranular, and may showdistinct blebs or pseudopod formation. In some cases the blasts are predominaf1ty small with a high nuclear-cytoplasmic rato resembling Iymphoblasts; large and small blasts may be present in the sere patient. Occasionally, the blasts occur I'l small clusters. Circulating micromegakaryocytes. megakaryoblastic fragments, dysplastic large platelets and hypogralurar neutrophils may be present. Micromegakaryocytes are small cells with 1rx 2 round nuclei with condensed chromalfl and matu re cytoplasm: these should rwx be counted as blasts. In some patients, because of extensive 8 M fib rosis restJ!.ing in a "dry tap ", the percent of 8M blasts is estimated from the 8 M biopsy. Imprints of the biopsy may also be uselul. Although acu te megakaryoblastic leukaemia may be associate d with extensive fibrosis, this is not an inva riant finding. The histopathology of the b io psy vanes from cases with a uniform population of poor ly d ifferentiated blasts to a mixtureof poorly differentiated blasts and maturing dysplastic megakaryoc ytes; varying deg rees of reticulin fibrosis may be present. Cytoc hemical stains for SBB, CAE and MPQ are co nsistently negative in the megaka ryob lasts ; the blasts may show reac tivity with PAS and for ac id phosphatase and punctate or foc al nonspecific esterase reactivity.

r

•

_ B

:.til

fig.6.36 ACVle mega~ 1eI.*aenia. A Bone marrow smear. The two megaka-yoblasts are large ceHs with GytlpIasmic pseudopod lonnatiOn: portIOnS of the cytqllasm are "zoned" with granular basoplliliC areas and dear ~_ Nucleoli cwelAl$lJ3ly ptCIII1nerL B Bone marrow smear reac:t8d wrth alllilOOy to CD61 (pIal9lel: gIycopro.., II). The eyklpIasm of the ITlI!9lkalyoblasls is in&enSeIy reactJYe

0rm.n0phen0Iype The meqakarvobtests express one or '!'(Jfa of the platelet glycoproteins: CD41 19yooprotein 1Ib/llla). and/Of COOl (glycoprotein ilia). The more mature plateletassociated marker CD42 (glycoprotein Ib) s less frequently present The myeloidassociated markers, CD13 and CD33. 'fay be positive. C034. lhe pan-Ieukocyte

marker CD45. and HLA-OR are often negalIVe. especially in children; CD36 is characteristically positive. Blasts are negative with !he anti- MPO antibody and with other markers 01 g ranulocytic differentia tion.

Lymphoid markers and TdT are not expressed. but there may be aberrant eqxesson of CD? Cytoplasmic expression of CD4 1 or C06 1 is more specific and sensitive than surface staining, due tl possible adherence of pl atelets to bl ast ,:ells, whic h ma y be m isi nte rp re ted as positive sta ining by f low c ytometry In cases with fibrosis, immuno phe no ty ping 011 BM trephine biopsies is particularly mportant for di agn osis. M eg akary ocytes and in some cas es rr eq ak arvo brast s can te recognized by a positive reac tion w ith antibod ies to von wmeorand's factor, the platelet glycopro teins (CD6 1, CD 42b) irld LAT (linker of activation of r -cenej the eetecton of platelet glycop roteins is the rest lineage specific but detection is Ilighly dependent on procedures used for ixation and decalcification.

Genetics There is no unique chromosomal aonorTe'rty associated with acute meqakarvoblastic leukaemia in adults . Complex r.aryofypes typical of MD S, inv(3) !:321(126.2) and t(3;3Xq21q26.2) can all be associated with megakaryoblasticl n!gak.aryOcytic differentiation 1507, 16371

but these cases are all assigned to other categories of AML (See AML with recurrent genetic abnormalities) , In young males with mediastinal germ cell tumours and acute meqakarvobtasuc leukaemia. several cytogenetic acoomauties have been observed of which i( 12p) is characteristic. Differential diagnosis The differential diagnosis inc ludes minimally d ifferenti ated AML, AML with myelodyspl asia-rela ted changes, acute panmyelosis with myelofibrosis, ALL , pure erythroid leukae mia and blastic transforma tion of chronic myelogenous leukaem ia or rneqakarvobrasnc crisis of any MPN. In the latter tw o conditions, there is usu all y a history of a chronic phase an d splenom eg aly is an alm o st consta nt find ing. Some metastatic tumours in the 8M, particularly in c hild ren , e.q alveo lar rhabdomy osarcoma , m ay resem ble acute m eqak aryobla stic leukaemi a. In g en eral. acute meqakarvoblastic leukaemia repr ese nts a p rol ifer at ion pr ed omi nan tly of rne q ak arycbta sts. whe reas acut e p anm yelosis is c har acterized b y a trilineage proliferation, i.e. granulocytes, megakaryocvtes and erythro id precursors. The distinction between acute megaka ryoblastic leukaemia, ac ute pan myelosis with fibrosis and AML with m yelodyspla sia-re lated Changes is not always clear. Prognosis and predictive fact ors The prognosis 01 this category 01 acute mecakarvobtasnc leukaemia is usually poor when compared to other AML types as well as in comparison to AML with t( 1;22XP13;q 13) 1620 , 16371 and acute megakaryoblastic leukaemia in Down syn d rome,

Fill, 6,37 Acu1e megakaryoblastic 1e\Jkaen'ia. Bone Il'\¥I'OW biopsy shows vi1uaRy ~ repIacemenl by

a popuIaIion 0/ blasts CI'ld weW1IerenhaIed megakaryo. cya There is a n'WlOl" popJabon 0/8I)'IIVOid preanors,

Acute basophilic leukaemia Defin ition Acute basophilic leukaemia is an AML in which the primary differentiation is to ba-

sopnns. ICD-O cod e

987013

Epidem iology This is a very rare disease with a relatively small number of reported c ases, comprising < 1% 01 all cases of AML. Clinical fea tures As in other acute reokaemras. patients present with featu res related to 8 M failure and mayor may not have c irculating bl asts, In addition, cutaneous involvement, organomegaly, lytic les ions and symptoms related to hy perhistam inemia ma y be present. Morphology and cytochemistry The circulating PB and 8 M bla sts are of medi um size with a high nuclear-eytoplasmic ra tio, an oval, round or b ilobed nucleus c harac terize d by disperse d chromatin an d one to three p rom inent nucleo li. The cytoplasm is moderately basophilic and contains a varia ble numbe r of coarse basophilic granules wh ic h ar e positive in me tachromatic stains; vacuolation of the cytoplasm may be present. M ature basephi ls are usually sparse. Dysplastic tealures in the erythroid precursors may be present. Electron microscopy shows that the granules contain structures characteristic of basophil precursors; they contain an electron-dense particulate substance, are internally-bisected, e .g. have a theta character, or contain crystalline ma terial arranged in a pattern of scrolls or lamellae , the latter finding is more typical of

Acute myeloid !eukaerma, not orrerwse specified 1

137

ma st cells. ,Coe xistenc e of basop hil and mast ce ll granules may be iden tified in the same immature cells {17321. The mo st charac teristic c ytochemi cal react ion is metac hroma tic positivity with toluidi ne blue. In addition. the blasts usually show a diffuse pa ttern of staining wit h acid p hosp hatase and . in some cases. PAS· posi tivity in b locks or lakes; the blasts are often neg ative by light mic roscopy for SBB, MPO. CAE and non-specmc esterase. The BM trephine biopsy shows diffuse replac ement by blast ce lls. ' rrm.Jnophenolype Leukaemic blasts expre ss myeloid markers such as C0 13 arldJor C033, and are usually positive for CD 123. C0 203c and CD 11b. but negative for other monocytic markers. Blasts may express CD34 and in contras t to normal basophils may be positive lor HLA-DR but are negative for CD 117. Immunopheno typic detec tion of abnormal mast cells expressing CD1 17. mast cell tryptase and C0 25 will distinguish mast cell leukaemia tram acute basophilic leukaemi a. Usually blasts show exp res sion of COO. Some cases may be positive for memb rane CD22 and /or Td T. Other mem brane and cytop lasmic. Iymp hoidassoc iated markers are usually negative 11295.207 41.

F"Ii- 6.38 Acute ~ 1eINema . Bone marrow smear. A Blasts and irrmature basophiIs. The bascJpIj pUIs vary from large roarsegraUes III smaI8rpUBs. B Bone marrow trepl1n8 biopsy. The bIa:sls /we pco1y~

Clinica l features Patients pre sent acutel y with severe constitutional sympt oms including weakne ss and fatigue ; fever and bone pain are also frequently ob served. Pancytopenia is alwa ys p resent. There is no or minimal sp lenomeg aly. The clinical evolution is usually rapidly progressive 122251.

Occasional neutrophil precusors inc::kJl:ilv bla sts may be id entified . Dvsotastc Changes in myeloid cells are frequent Abnormal platelets may be noted . aoe marrow aspiration is frequently uosocce ssful: either no 8M is obtained or ee specimen is suboptimal. Bone marroe biopsy supplemented with immunohis:o. logy is required for diagnosis /2124. 2225 1. The 8 M b iopsy is hypercelljjw and shows , within a diffusely fibrotIC stroma . an increased p ronteratco of erythroid precu rsors. granulocyte precursors and megakaryocytes (panmyelosis). wt'ich is variable in terms of the relative prooction of each given component. Characteristic findings include foci of immature baematcpolettc cells including blasts associated with cons picuously dvsplastc megak aryocyt es p redominately of smat size with eosinophilic cytoplasm showing variable d egrees of cytological atypia il'leluding the presence of hypolobulated cr non-lobulated nuclei with dispersed crso matin. Mic romegakaryoc ytes may be present but should not be cou nted as bla sts. The visib ility of the small meqakaryoc ytes may be ac centuated with the PAS stain and immunohistochemistry l 22251. The overall frequency of blasts ir APMF marrows is uncertain. Based onBIll biopsy, a median value of 22.5% was found in a recent study /165 11. Mosl cases have a range of 20-25%. The degreed myelofib rosis is variable. In most patients there is a marked increase in reticulir fibres with coarse fibres; frank collageroo; fibrosis is. however, uncommon.

_logy and cylochem;stty The PB shows panc ytopenia whic h IS usually marked . The red blood cells show no or minimal aniso poiknoc v tosrs and variab le macrocytosis; rare erythroblasts c an be seen b ut teardrop-shaped c ells (d acryocytes) are not observed.

Immunophenotype If sufficient 8 M specimen is obtained!o' immunologic markers or circulating bIas:s are p resent in the P8 . the c ells sh:)w phenot yp ic heterogen eity, with va~ d egrees of expression of myeloid-aSSOCIated antigens . The blasts usually express

Prognosis and p redictive factors Since this is a rare type of acute leu kaemia. there is little information on survival. The cases observed have genera lly been associated with a poor prognosi s.

Acute panmyelosis with myelofibrosis Definition Acute panmyelosis with myelofibrosis (APMF) is an acute panmyeloid proliferation with inc reased bla sts and accompanying fibrosis of the 8 M {168, 2 1201 that does not meet criteria for AML with myelodysp lasia-related changes. ICD-O code

Genetic s There is no consistent chromosomal abnormality identified in these cases. AML with t(6:9)(p23;q 34) is speci fic ally excluded as are cases associ ated with a BCR-ABL 1 fusion gene. Differential diagnosis The d ifferential d iagnosis inc lud es bl ast ph ase of MPN, other AML subtypes with ba sophilia suc h as AML with t(6;9) (p23:q 34), mast c ell leukaemia and , more rare ly, a subtype of ALL with prominent coarse granules. The clinical features and cytogenetic pattern will distinguish cases p resenting de novo from those resulting 'rom transformation of chronic my elogenous leukaemia and from other AML subtypes With basophilia. Immunologica l markers will distinguish between granulated AlL and acute basophilic leukaemia and light microsc op ic c ytochemist ry lo r myelope roxidase and elect ron mlcroscopy will distinguish acute basophilic leukaem ia from other leukaemias.

138

993 1/3

Synonyms Acute (malignant) myelofibros is, acute (malignant) myelosclerosis. Epidem iology Acute panmyelosrs with myelofib rosis is a very rare form of AML APMF oc curs de novo. It is primar ily a disease of adu lts but has also been reported in children.

Acute myeloid leukaemia and related precursor neoplasms

the progenilotlearly precur sor-associated market CD34 and one or more myeloid associated antigens: C013, C033 and CD117 11651, 2 124, 2225 1. Myeloperoxidase is usually negative in the bla sts. In some cases a proportion of immature cells express erythroid antigens. Immunohistochemistry can facilitate the identi fication of the relative proport ions of the various myeloid components on the biopsy specimen and is g enerally used to confirm the multiline age nature of the proeteranon. This is usually d one by employing a panel of antibodies which inclodes myeloperoxid ase, lysozyme , antimegakaryocytic markers (C06 1. C0 42b , C041 or anti-von Wil1ebrand 's fac tor) and erytIYOid markers such as g tycophofin and haemoglobin A. These confi rm the preseoce 01 parvnyelosis and allow exclusion ci specific ·unilineage" -predominant proilerations.such as acute rnegakaryObtastic ~emia .

GeneIics If sufficient specimen for cytogenetic analysis is obt ained , me results are usually abnormal. The d etec tion of a com plex karyotype, frequ ently Involving ch romosomes 5 and/or 7 [-51del(5q), -7/d el{7q)] 122251, means that the case is assigned to AML with my elodysp lasia-related changes, not to ac ute panmyelosis. Differential diagnosis The major di fferential diagnosis of APMF includes other type s of AML with associated BM fibrosis including acute megakaryoblastic leukaem ia 116511. Usual ly ess problematic is the di stinction from primary myelofib rosis (PMF), po st-p olycythaemia vera myelofibrosis, post-essen~ a l lh rom boc yt h ae m i a myelofibrosis, and eon other neopla sms that c an be encountered in a myelofib rotic BM such as metastatic malig nancies with a de srnoplastlc stromal reaction . The distinction between AML. particularly c ases of AML with myekxiysplasia-related changes with multi~neage dysplasia and myelofibrosis and acute megakaryoblastic leukaemia with myelofibrosis, and APMF may be difficu lt,

particularly if no specimen suitable for cytogeneti c analysis can be obtained. If the proliferative process is predominantly one cell type. i.e. myeloblasts, and there is assoc iated myelofibrosis, the case should be classified as AML with a specific subtype, e.g. AML-myelodysplasia-related . and then desig nated with the qua lifying phrase ·w ith mveronbrosrs". Acute megakaryoblastic leukaemia is assoc iated with the presence of 2': 20% b lasts, of which at least 50% are mega karyobla sts. In contrast, the b lasts of APMF are more heterogenous, poorly differentiated and express CD34. The majority of blasts do not display megakaryocytic reactivity, and the proliferative proces s involves all of the major BM c ell lines. Particul arly difficu lt is the di stinction between APMF and cases of MOS associated with both an excess of blas ts and myelofibrosis (AAEB-F), since the latter cases c an share roost of the morphological finding s seen in APMF. Clin ica lly, APMF can be separated from MOS by its more abrupt onset with fever and bone pain. In APMF.

histology of the BM shows more numerous megakaryocytes and , on average, a higher numb er of blas ts than what are found in AAEB. Cases of AAEB-2-F. except for their usually less acute clinical presentation , may be indisti nguishable from APMF 116511. APMF is distinguished from PMF by the more numerous blas t ce lls in the former and the distinct cytological characteristics of the megakaryocy tes in the latter (See Chapter 2). The presence of a metastatic malignancy or, rarely a lymph oid disorder c an be excluded by studies with appropriate antibodies. Postulated normal cou nterpart Haematcpoie tlc stem cell. The fibroblastic proli feration is secondary. Prognosis and predictive fac tors The disease is usually associated with poor response to chemotherapy and usually only a few months survival 1165 1, 21241 .

Acute myeloid leukaemia,

Il(){

otherwise spec ified

139

Myeloid sarcoma

SA Pileri A. Orazi B. Falini

Definition A myeloid sarcoma is a tumour mass consisting of myeloid blasts with or without maturation occurring at an anatomical site other than the bone marrow (BM) . Infiltrates of any site of the body by myeloid blasts in leukaem ic patient s are rot cl as-

sified as myeloid sarcoma unless they

Sites of involvement Almost every site of the body c an be involved , the skin, lymph node, ga strointestinal tract, bone, soft tissue and testis be ing more frequently attectec 1663. 1742 1. In less than 10% of ca ses . myeloid sarcoma presents at multiple anatomical sites 1663, 17421.

proportion of c ases, it d isp lays rnyelomonocytic or pure monoblastic morphology 1663. 17421. Tumours with trilineage haematopoies is Of predom inantly erythroid precursors or megakaryoblasts are rare and may occu r in c onj unction W1tt1 transformation of MPN 117421.

Clinical featu res Myeloid sarcoma ma y occur de novo: its detection should be conside red as the equivalent of a d iag nosi s of AM L. It may precede or coinci de w ith AML or represent acute b lastic tran sfor ma tion of myelodysplasti c syndromes (MDS), MPN or MDS/MPN 1663, 17421. Finally, myeloid sarcoma may also be the initial manifes tation of relapse in a pa tient with prev iously diagnosed AML, regard less of blood or 8M findi ngs 1t7421.

On imp rints, cytochemical stains for myelo pe roxid ase (MPO), naphthol-AS(). c hloroacetate esterase (CAE) and l'"Il;no specific estera se (NSE) ma y assist in d ifferentiating granukx::ytic lineage (Mfl()+, CAE+) from rroooblasnc forms (NSf+~ In addition , CAE reaction can be applied to rout ine sec tions , although the results may depend o n fixation and d eca lcifying agents.

present with tumour ma sses in which the

tissue arch itecture is effaced

ICD-Ocode Synonyms Extramedullary myeloid tumour; granulo-

cytic sarcoma : cmorona Epidemiology There is a predilect ion for ma les and last de cades ctute. The mare.t emaie ratio is 12 :1. The median ag e is 56 years (rang e. 1 month-89 yea rs) 1663 . 17421.

Etiology The same as for acute myeloid leukaemia (AMl) and myelop roliferative neop lasm s (MPN).

140

Cytochemistry

Morphology A myeloid sarcoma most c ommonly consists of myelobl asts with or w ithout features of promyeloc ytic or neut rophilic maturation that pa rtially o r totally efface the tissue arch itecture. In a sig nific ant

Acute myelotd leukaemia and related precursor neoplasms

Immunophenotype On immunohistoc hemistry in paraffin sections, C D68 /KP1 is the most c ommonly expressed marker, followed in decreasing frequency by MPO , CD t 17, CD99 . CD6&' PG-M t , lysozyme , CD34 , termin al deoxvnucreoncvt trans ferase (TdT ), CD56, CD6t/lAT/von Willeb rand antigen, CD30,

glycophorin, .and C D4 117421 . Foc i of plasmacytoid dendritic c ell differentiation (C0 123 +) are occasionally observed in cases carrying inv(16) 117421 . The combination at the above mentioned markers allows the recognition of tumo urs with a more immature mye loid pheno type, as well as of c ases with mveromonccvtrc. monoblastic, erythro id or megakaryocytic differentiation. Exceptionally, aberran t antigenic expres sions are obs erved (cytokeratins. B- or T-cell marker s). Ca ses that meet cntena for mixed phenotype AML are not c lassified as my eloid sarcoma (See Chapter 7). Flow cvtorenlc ana lysis on cell suspensions revea ls posmvmes for C0 13. C033. C0 117 and MPO in tumour s with myeloid d ifferentiation. and for CD 14. COl 63 and COll e in the monob las tic

ones.

Geneti cs By FISH andlor c ytog enetics, c hromosomal aberrations are detec ted in ab out 55% of cases. They incl ud e rnonosomy 7, trisomy 8, MLL-rear rangement. inv( 16). trisomy 4, monosomy 16, 16q-, 2Oqand trisomy 11 {17421. About 16% of cases carry evidence of NPM 1 mutations as shown by aberrant cytopl asmic NPM expre ssion 1663. 666/. The t(8;2 1Xq22;q22) observed in paed iatric series seem s to be less frequent in adu lthood 1' 742 , 19 781.

sc-.

Differential d iag nosi s The major d ifferential d iag nosis is with mali gn ant lymphoma , The d iag nosis of my elo id sar coma is valid ated by the results of c ytochemical and /or immu nophenotypic analyses. These allow the d istinction of myeloid sarcoma. from: 1ymphoblastic lymphoma, Burkitt lymphoma . diffuse large B-cell lymphoma. small round

c ell tumours, part icu larly in child ren, and blastic pl asmacyt oid dendritic cell neopla sm 11742/. These tumours must be di stinguished from non-effa ci ng tissue infiltrates by AML or MPN Postu lated normal counterpart Haernatopoietic stem c ell. Prog nosis and predictive factors The cli nic al be haviou r and respon se to therapy seem not to be influenc ed by any of the following factors: age , sex, anatomical site(s) involved . de novo presentation, clinical history related to AMl. MDS or MPN , histological fea tures. immunophenotype and cytogenetic find ing s 117421. Pat ients 'Nho undergo allogeneic or aUIOOgous BM transp lantation seem to have a hig her pr ob ab ility of prolonged surviv al or cu re 1268. 17421.

MyelOId sarcoma

141

Myeloid proliferations related to Down syndrome

Individuals with Down syndrome (OS) have an inc reased risk of leukaemia compar ed to non-OS individ uals 1716. 23651. The inc reased risk is variously estimated at 10 to 100 Iold . The inc reased risk ex-

tend s into the adult years. In addition to the increased Incidence, the ratio of acute lymphoblastic leukaemia (A LL) to acute myeloid leukaemia (AMl) in OS chil dren less than 4 years of age is ap proximately equal, 1.0 :1.2, compared 10 non·DS children in the same age group in which the ratio is 4 :1 . There is an approximately 150 fold increase in AML in OS children less than 5 years of age; 70% of the cases of AM l in OS children less than 4 years of age areacute megakaryoblaslic leukaemia in con trast 10 the 3-6% incidence otttns to m of leu kaemia in r"lOfl-DS child ren . The acut e megakaryob lasl ic leukaemia whic h occurs in OS children has somewhat uniqu e morpho logic, imm unophenotypic, mol ec ular and clinical characteristics wh ich d ist ing uish it from other forms of ac ute megakaryob lasli c leukaemia, inelud ing GATA 1 mutations 1635. 1362 J These va riou s featu res serve as the rationale for the recog nition of this form of leukaemia as a d istinct type in the WHO c lassification, In add ition to the uniq ue characteristics of the pred ominan t form of AM L in OS ch ild ren less than 4 yea rs of age , ap p roximately 10% of OS neonates manifest a haema tolog ic di sorder refe rred to as transient abnormal my elop o iesis or trans ient myelop roliferative otsoroer wh ic h may be morphologi ca lly ind isting uishab le from the predominant form of AML in OS child ren 127 1, 1409 1, This disorder resolves sponta neously over a peri od of seve ral weeks to 3 mo nths , In 20-30% of the affected cases. non-remi tting ac ute megakaryoblastic leu kaemi a su bs eq uently develop s in t to 3 yea rs. It is important to rec og nize that altho ugh the atore mennooeo d isorders have rec eived the most attention in OS p atient s , they occur in a specific age g rou p and other fo rms of ac ute leukaemia, bo th ALL and AML. affec t OS individuals. The ove rall inc reased risk for OS individuals includes all types. The same approach lor characterizing the 142

I. Baum ann C M, Niemeyer AD. Brunning O.A. Arber A, Porwit

specific type of teukaemia in OS patients m ust incl ude the same ca reful morpholoqic, lmmunoonenotvoic. cytogenetic and mol ecular eval uation as in non-OS individu als to ensure that appropriate the rapy is administered 124891.

Transient abnormal myelopoiesis Definition Transient abnormal myelopoiesis (TAM) is a unique d isord er of Down syndrome (OS) newborns that presents with clinical and mo rphologic find ing s indistinguishable from AML. The blasts have morphologic and irrrnunologic features of megakaryocytic lineage. ICD-Ocode The provisiona l code proposed for the fourth edition ofICO-O is 9898/1. Synonym Transient mye lopro liferative d isord er. Epide miolog y Trans ient abnormal myelopoi es is occurs in approximately 10% of OS newborn s: it uncommonly occ urs in phenotyp ica lly normal neonates with trisomy 21 mosaic ism, Clinical fe atures At presen tation , thrombocytopenia is most commo n; other c ytopeni as are less freq uently encoun tered, There may be a ma rked leukoc ytosis and the pe rcentag e of blasts in the per ipher al blood (PB ) may exceed the blast pe rce ntage in the bon e ma rrow (BM ). Hepatospl enomeg aly may be present. Rarely, cl inical complications incl ude ca rd iopulmonary failure. hyper. viscosity. spl enic necrosis and p rogressive hepa tic fibrosis 15921. The proc ess in the major ity of patients undergoes spontaneous remission Within the first three months of life; a few chil dren experience life th reaten ing or even fatal clinical complications.

Acute myeloid leukaenlla and related precursor neoplasms

.-

Fig. 6.41 Blood 5me¥ from a ore day-old Ilfanl ... 00rM'l synOrome and lransieot abnofmal ~ The PB contailed 55% f*Ists. C)1Jgenek studystx.:l horny 21 as hi soleabnormality. The process ~ ~1MIl" a period ofbJ" weeks.

Morphology and immunophenotype The morphologic and immunophenotyplC features of TAM are simila r to those of the blasts in most cases of OS AML. Peripheral blood an d 8 M blasts ouen have basophilic c yto plasm w ith coa rse besop hilic gra nules and cytoplasmic blebbing suggestive of meqakervobiasts. Some patients have PB bas op hilia; eryth roid and meg akaryoc ytic dysplasia is often present in the BM 127 11. Blasts in TAM d isp lay a cha rac teristic immunoph enotype 11 25 11 . In most cases the bl asts are positive fo r C034, CD56. C0 117, CO t3, C D33, CD7 , CD4 dim, C041, C0 42, TPO-R, lL-3R, C036, COOt, C071, and a re negative for myeio pe rc» case. C0 15, C0 14 and g lyc oph orin A The bl asts in approximately 30% of cases are posi tive for HLA-DR. Antibod ies to C04 1 and CD61 may be p artic ularly useful in id entifying cells of megakaryocytic lineage in immunohistologic prepa rations . Genetics In ad dition to trisomy 2 1, ac quired GATAI mutations are present in blast cells of TAM 1635,942,2347/. While gene eneysnoes have suggested differences in expression between AM L of OS an d TAM. these findings have not yet been cootsrreo 1258, 1298, 1439/.

A

·..:....."!;;.4 . ....," -'

FIg. 6.42 UyeIoid 1eukaerr'U associaled wilh Down syrdome in a two year-dd d*l. A Bone marrow smear. ThePB and8M smearsc:ontarled ITIJIbpIe blasts as ~_ loWry ollie bIasls contained runetOUS coarse basoIlI*CI:lIcAnd gJarUes . wtidl were myeloperoxidase ~_ Cy!OgenetJC sludy et 1M bme showed trisomy 8 in ali:lIbDn kllrJsomy 21. B Bone marrow trephrle biopsy !rom !he same pabenl There aft! I'II.I'flef'OI. blasts and occasional megakaryocyles induding one with a IIOIHobated IllJl::llM. C An irTmJnl> IJst*9C readJon WIth CD-61 antibody. There are r...metOUS readJng eels indtdng otMous megakatyocyles and sevetaI smaIer eels .

Prognostic and predictive factors

individuals beyond the neonatal period .

Although the d Isorder is characterized by a high rate of spontaneous remission, rco-nansent AML develops 1 103 years

There are no biok>gical differences in OS individuals between myelodysplaSbC ~

later in 20-30% ot mese children 125031. Indic ations lor chemotherapy in TAM are

not firmly established ,

Myeloid leukaemia associated with Downsyndrome Definition Individuals with OS have a 50 fold increase in incidence of acute leukaemia during the first 5 years of life compared to

non-OS individuals. Acute myeloid leukaemia in OS is usually an acu te megakaryoblaslic leukaemia, accounting for 50% of cases of acute leukaemia in OS

drome (MOS) and overt AMl; therefore, a comparable diagnost ic differentiation algorithm is not relevant and would have no prognostic or therapeutic consequences. Since this type of disease is unique to ch ildren with OS the term myeloid leukaemia of OS encompasses bOthMOS and AML. ICD-Ocode The provisional code proposed for the fourth edition of ICo-O is 9898/3. Epidemiology The great majority of children with OS with myeloid leukaemia are under 5 years of life. Abou t 1- 2% of ch ildren with OS will develop AML dur ing the first 5 years of

Fig. 1.'3 SedicI'I d iWI atldl:ri'III ~ node In:lm • eNd wrltl Ck:Jr,yrJ syncmne lnl ac:uIe megakar'yobl9sbc Ieo..*aerTia The I'lXIe is ~ ~ by b8sls wifl occasicI'laI ~. sane d.n::n ae dyscllasIc.

Iile. Children with OS account lor - 20% of all paediatric pat ients with AMUMOS 1271 .592.9081 _Myeloid leukaemia of OS occ urs in 20-30% 01 children with a pr ior history of TAM and the leukaemia usually occ urs 1-3 years after TAM.

Sites of involvement Blood and BM are the princip le sites of involvement . Extramedul lary involvement, mainly of sp leen and liver, is almost always present. Clinical features The disorder manifests predominantly in the first 3 years of life, The clinic al course in children with tess than 20% blast cells in the 8M appears to be relatively indolent and presents initially with a period of thrombocytopenia. A preteokaemc phase comparable to refractory cytopenia of ch ildhood (RCG)generally preceeds MOS with excess blasts or overt leukaemia. Morphology In the pre-leukaemic phase. which can last for several months, the disease has the features of RCC (See Chapter 5) lacking a significant increase of blasts. Erythroid cells are macrocytic. Dysplastic features may be more pronounced than in primary refractory cytopen ia. In cases of AML, blasts and occasionally erythroid precursors are usually present in the PB. Erythrocytes often show con siderable anrscooikllocytoele. sometimes dacryocytes. The platelet count is usually decreased and giant platelets may be observed, In the 8M aspirate, the morphology of the leukaemic blasts shows particu lar features with round to slightly irregular nuclei and a moderate amount of basophilic

MyefOid proliferatIOnsrelated to Down syndrome

143

c ytoplasm; cy topl asmic b lebs may be present. The cytoplasm of a variable number of blasts co ntains coarse granules resembling b asoph ilic gra nules. The granules are generally myeloperoxid ase negalive. Erythroid p recursors often show megaloblastic changes as well as dysp lastic forms, including bi- Of trinuc leated cells and nuclear fragments. Dysgranuloporesrs may be present . The 8M core may show a dense network of reticulin fib res, making adequate 8M aspi ration difficult or impossib le. Erythropoiesis may be increased in cases with a low blast percentage and decreases with disease progression. Maturing cells of neutrophil lineage are usually decreased. In cases WIth a dense blast cell infiltration rare dysplastic megakaryocytes may be seen. In other cases of acute megakaryootasnc leukaemia. megakaryocytes may be markedly increased with clusters of dysplastic small forms , micromegakaryocvtes and occasionally an increase in promegakaryocytes.

144

Immunophenotype Leukaemic blasts in acute megakaryocytic leukaemia of OS display a similar immunoph enotype to blasts in TAM /125 11. In mos t cases, the blasts are posi tive for CD 11?, CD 13, CD33 , CD? , CD4 , CD42 . TPO-R, IL-3R. CD36, CD4 1, CD61, CD7 1. and are negative for myeloperoxidase, C0 15. CD1 4 and glycophorin A. However, in con trast 10 TAM, CD34 is neg ative in 50% of cases and approximately 30% of cases are negative for CD56 and CD4 1. Leukaemic blasts in other types of AML in OS display phenotypes corresponding to the particular AML category Antibodies to C041 and C061 may be particularly useful in identIfying c ells of megakaryocytic lineage in irrvnunohistologic preparations.

Genetics In addition to trisomy 21, senate rmtatcos 01 the ge ne encoding the transc npnon factor GATA1 are considered pathognomonic of transient ab normal mveicooeeis

Acute myeloid leukaemia and related precursor neoplasms

of Down syndrome (TAM) or Mo S/AMl oi OS 1835 . 942, 13621. Children above the age of 5 with myeloid leukaemia may not have GATA 1 mutations and such cases should be consi de red as 'conventional" MDS or AML. Trisomy 8 is a comrTlO'l cytogenetic abnormality in myeloid leukaemia of OS occurring in 13-44% at patients 1908, 9181. Monosomy 7 is very rare in Ds-associateo myeloid leukaemia Postulated nonnal cou nterpart Haematopoietic stem cell.

Prognostic and predictive factors Clinical outcome for young children WlI!l OS and myeloid leukaemia with GATAI mutations is unique and is associated with a better response to chemotherapy and very favourable prognosis to non-OS children with AML 112501. rte children should be treated on DS-specrllc protocols. Myeloid leukaemia in older OS children with GATA' mutation has a poorer prognosis comparable to AMl i'l patients without OS {75 11.

corceec

Blastic ·plas macyto id dendritic cell neoplasm

Definition Blastic plasmacytoid dend ritic cell (BPDC) recoesm is a clinically agg ressive tumour defived from the precursors of otasrnacvklid dendritic cells (also known as pro tesSlOnaI type 1 interferon producing cells or plasmacytoid morocvtes). with a high trecuencv of cut aneous and bo ne marrow (8M) involvement and leukaemic d issemination.

ro
9727/3

Sjoonyms Blasbc NK-celilymphoma 11039/. aqraniJaf CD4. natural kille r cell leukaemia 12771. blastic natural killer leukaemia/lympt'(ma \576 J, aaranurar CD4 +CD56+

reematooerrmc neoplasm 117361ltumour

19201 Epidemiology This is a rare form of haem atologic neoplasm. without any known racial or ethnic predilection. It has a male/fema le rano of 33:1; most patients are elderly, w ith a «eererecnan age at diagnosis of 61-67 years. but it can occ ur at any age , inCkldlngchildhood 1702. 920 ,1031 1.

Ebology There are c urrently no cl ues to the etrobgy 01 BPDC , bu t its association w ith myelodysplasia in some cases may suqgeS! a related pathogenesis. There is no association with Epstein-Ba rr virus (EBV) .

F. Pacchem D.M. Jone s T. Petrella

Sites of involvement The d isease tends to involve mul tiple sites . w ith a p redi lection for skin (almost 100% of cases). followed by 8 M and peripheral blood (PB) (60-90%). and lymph nodes (40 -50%) 1920, 17351 . Clinica l features The pat ients usua lly present with asymptomatic solitary or multip le skin les ions that c an be nod ules, pl aque s. o r b ruiselike areas, Reg ional lympha denopathy at presentation is c ommon (20%); PB and BM involvement can be minimal at pre sentation . but invaria bly develops w ith progression of d isease . Cytopenias (especia lly thrombocytopenia) can occur at d iag nosis, and in a minority of cases can be seve re, indic ating BM failure 1702, 920 1. Follo wing initial respo nse to chemotherapy , re lapses invariab ly oc c ur, involv ing skin alone. or skin associated with othe r sites . includ ing soft tiss ues and the centrat nervous system. In most cases a fulminant leukaemic phase ult imately develop s 1702 1. About 10-20% of cases of BPOC are associated with or develop into a mveromonocytic leukaemia or acu te myeloid leukaemia 1702, 920, 924 , 1142 . 1735 , 18301 . Thes e second teukaermas can evo lve from underl ying mye lodysplasia, or appea r sud de nly upon prog ression or relapse 1702, 924 ,1 1421· BPDC must be d istinguished from the occasional association of a myeloid neoplasia (especially chronic myeIornonOCylic

leukaemia) with massive nod al or extranodal localization of plasmacytoid dendritic cells, in which the plasmacytoid cells are rrnphoIogica/ly mature and C056 negative 123351.

oeoouc

Morpho
,

r.. •.-" 8IastJC pIasmacyIoid llendnOC eel neoplasm.

"' '\;I''~CIoJii.

A Ski'I tI.I'I'lWfand plaques. B The inIiIlrate diftu$ety imoIYes !he demis andedends tl subc:Wnews fat. but spares lIle 1Pde!fM, CThe neoplasbc eels are mediI.m-sized. wiIh lineetwomatin and scanly cytoplasm. reminiscentof undlf!erentiated blasts,

Blastic p lasmacytoid den d rrtic ce ll neop lasm

145

Immunophenotype Tumour cells express CD4, CD43, CD45RA and CD56, as we ll as the plas mac ytoid dendritic cell-assoc iated antigens CD123 (interleukin-3 a-chain receptor), BDCA-2/ CD303, TCU , CLA (cutaneous lymphocyte-associated antigen) and the interferon-a dependent molecu le MxA (92, 920,924 , 1735-1737, 1739, 1747, 1830, 22791. Rarely, the C056 antigen can be negat ive, which does not rule out the diagnos is if CD4, CD123 and TCl 1 are present. Tumours that share some but not all immunophenotypic features of BPDC may be better class ified as "acute leukaemia of ambig uous lineage". C068 (an antigen typical ly found on normal plasmacytoid dend ritic ce lls) is expressed in 50% of cases , in the form of small cytoplasmic dots (1735 , 1739J. Among lymphoid and myeloid-associa ted antigens, CD7 and C033 are relatively common ; and some cases have shown expression of C02, CD36 and CD38 , while CD3 , CDS, CD13, CD16, CD19 , CD20, CD79a, LAT (linker for act ivation of T cells) , lysozyme and myeloperoxioase are regularly negative , Granzyme B, which is reg ularly found in norma l plasmacytoid de ndritic cells , has bee n demonstrated on flow immunophenotyping and mRNA analysis in BPDC [395 , 820\. but it is most ly negative on tissue sec tions, similarly to other cytoto xic molecules such as oertonn and TIA 1, Terminal deoxynucleotidyl transferase (TdT) is expressed in about one third of cases , with pos itivity rang ing between 10% and 80% of cells; CD34 and CD117 are negative. EBV antigens or EBV-encoded small nuclea r RNA (EBER) are not found. Except for CD56 and TdT, the immunophenotype of BPOC largely overlaps with that of plasmac yto id dendritic cells occu rring in reactive lymph nodes and tonsils [654}. Because other heematotoqic neop lasms (such as acute myeloid leukaemia, extranodal NK/T-eeil lymphoma, nasal type and mature T-cell lymphomas), with or without skin involvement, may express CD56 with or without CD4, an extensive immunohistochemical and/or genetic analysis is manda tory before a definitive diagnosis of BPDC is made (92, 173,386,920, 1386).

gamma rearrangement 1920, 1735}. Two thirds of patients with BPDC have an abnormal karyotype: specific chromosoma l aberrations are lacking, but complex karyotypes are co mmon; six major recurrent ch romosomal abno rma lities have been recognized, including 5q21 or 5q34 (72%), 12p 13 (64%), 13q 13-21 (64%), sqza-qter (50%), 15q (43%)and lossofchrornosome9 (28%) 11279, 1737, 18301. Gene expression

profiling and array-based comparativegenomic hybridization have shown recurrent de letions of regions on chromosome 4 (4q3 4), 9 (9p 13-p11 and 9q12-q34) and 13 (13q 12-q31) that conta in several tumour suppressor genes with diminished exp ression (RB 1, LATS2), while elevated exp ression of the products of the OrtCGgenes HES6, RUNX2 and FLT3 is notassociated with genomic amplification (5781.

Genetics

J-ceu and a-cen receptor ge nes are usually ge rmline {92, 1735, 1830}, except for a few cases that showed T-cell receptor 146

Acute myeloid leukaemia and related precursor neoplasms

L

Postulated normal counterpart The normal co unterpart is the p recursor of the plasmacytoid den dritic cells . Data on anligen 139 5. 396 . 820 , 920. 924. 1031 , 1051,1736, 1739.2279landchen"ll> kine rec ep tor expression {18Sf, in vitro functional assays {18S, 3961. gene e xpression profiling 15781. as well as on the tumour-derived cell line CAL-l 11361 1all point toward a derivation from the precursors of a special subset of dendritic cells, !he plasma cytoid dendrit ic cells 1356, 857,20591 . These c ells are distinguished by their p rod uction of high amounts of u Interferon in humans 1357l; in the pas t. !hey have been defined with many different terms. such as lymphoblast, t-essocrated plasma cell , plasmacyt oid T-ce U and plasmacytoid monocyte {6541 . The i'nmunophenotypic heterogeneity with regards 10 TdT and the assoc iation with myeloid disorders suqqests a multihneage po tential lor some cases 01 BPOC.

Prognosis and pred ictive factors The c linical co urse is aggressive . with a median survi val of 12-1 4 months . irrespective of the initial pa ttern of disease . Most cases (80 - 90%) show an initial response 10 mulliagent chemotherapy, but relapses with subsequent resistanc e to drugs are regularly observed . Long-lasting remissions have been documented in spor adic c ases, usua lly occurring In young p atients who have been treated with acute leukaemia-type induction therapy, followed by allogeneic stem cell transplantation in first complete remission

192.920, 17351·

Blastic plasmacytoid cencntc cell neoplasm

147

CHAPTER 7 Acute Leukaemias of Ambiguous Lineage

Acute leukaemias of ambiguous lineage

Ac ute leukaemias of ambigUOlls line age encompass those leukaemias that show no clear evidenc e of differentiation a long a singl e lineage. They include Ieukaemias with no lineage-specific antigens (acute und ifferentiated leukaemia. AUL) and those w ith b lasts that express antigens of more tha n one line age to such a degree that it is not possi ble to assign the \eukaefT'Wa to any o-e lineage with certainty (mi xed phenotype acute ieukaermas . MPAL). The latter can eithe r contain d isIinc t b last populations. each of a different line ag e. or one population with multi ple an tigen s 01di fferen t line ages on the same cell s. or a com bin ation. Historically, there has been confusion both in the term ino log y and d efinitio n of MPAL. The term ac ute b ilinea l (o r b ilineag e) leukaem ia ha s been ap plied to leukaemias con taining separate po p cta.nons of b lasts of mo re than one lineage, and the ter m b iphenotyp ic leukaemi a to thos e co nta ining a sing le populat io n of b lasts c oexpressing antigens of mo re thanone lineage I885, l267, 1427 , 21 19}, although some times the ratter term also encom passed blnneaueu kaemta. Here the term mixed p henot yp e acute leukaem ia applies to this g roup of lesions in general, and , as d efined b elow, the mo re spec ific terms B/my e lo id (B/MY) and T/mye lo id (T/MY) leukaemia to refer to reu keemra s c onta ining the two linea ges specified, irres pec tive of whether one or mo re than one po pulation of bl asts is seen . Some well-d ef ined mye lo id leukaem ic en tities may have irnrnunoonenorvplc features that might suggest that they be classified as Bimye loid (BlMY ) Of Tlmyeloid (T/MY) leukaemras. However, MPAL, as de fined here, exc ludes c ases that c an be cl assified in another category, eithe r b y genetic or clinical features. These speci fic ally inc lud e c ases with the rec urrent acu te myeloi d leukaemia (AML)·associetec uansiocenons 1(8;2 1), t( 15;17 ) or inv( 16); the first of these especiall y freq uently exp resses muniple Bceu markers /22361. In addition, cas es of leu kaemi a with FGFR I mutations are not con side red TIMY leuk aemias Cas es of c hronic

150

mye logenous leukaemi a (C ML) in b last c risis, MDS-re lated AMl and therapyrelated AMl shou ld be cl assified pnma rily as suc h , even if they have a mixed phe notype, with a secon dary notation that they have a mixed phenoty pe . The d iag nos is of amb ig uou s lineage leukaem ias rests on irnmunophenotyping . Flow cytometry is the preferr ed method for establishing the d iagnosis, especially when a d iagnosis of MPAl is de pen dent upon demonstrating coexo ressoo of 1ymphoid and myeloid d ifferentiation antigens on the same cell. Cases in which the d iag nosis rests on demonstration of two distinct leukaemic populations with a d ifferent p henotype may also be established by immunohistochemistry in tissue sections, or with cytochemic al stains for myeloperoxid ase on smears c oupled with flow cvtomet ry to detec t a leukaemic B or T lymphoid population. The myel oid component of an MPAL c an be rec ogn ized in one of three ways: 1) When ther e are two or more d istinct pop ulations of leukaemic c ells, one of whic h wo uld meet immu no pheno typic c riteria for ac ute mye loid leukaem ia {with the exception that this po p ulation need not c omprise 20% of all nuc leated cel ls} 2} When there is a sing le population of b lasts that by itself wou ld meet c riteria for B acute lymphoblastic leukaemia (B-ALL) or T acute lymphob lastic leukaemia (T-ALl) and the blasts also expressmyeloperoxidase,

M ,J Borowitz M ,-e , Bene Nt.. Harris A. Porwit E. Mat ures

most freq uently show n by flow cvtomeuc positivi ty, on b last c ells coexp ressing 1ymp hoid mar kers. The myeloid lineage anngens CD 13, CD33 and CD l 17 are no! specific enough to allow identification cA a mixed phenotype leukaemia. 3) When there is a single population ot cells that by itself would meet criteria forB Of T-All in which the blasts also show tXIequivocal evidence of monoblastic differen tiation: either d iffuse positivity !t;) non-specific esterase or expression cA more than one monocytic marker such as CD 11c, CD 14, CD36, CD64 Of lysozyme The first of these three ins tances wooId previously have be en consid ered -bilineage leukaemia" while alternatives 2 and 3 represent wha t wou ld have been termed "bi phenotypic leukaemia". The t-een component of an MPAl is recognized by strong express ion of cvtop lasmic CD3, either on the ent ire blast population, or on a sepa rate suo oc ouanon of leukaemic c ells. Surface CD3, thOugh rare, also ind icat es T-cell lineage, Expres sio n of cC D3 is bes t determined by flow c ytometry using relatively brighl fluo roph ores such as phyc oerythrin or er lophyc oc yanin , and should be as bright o r nea rly as br ight as that of norma l residual T ce lls p resent in the samp le. T-cell linea ge can also be demonstrated by CD3 expression on b lasts by immunohistoc hem istry on bone marrow biop sies, thou gh it should be noted that polyvalent

Table 7.01 RllQuiremefils for assigrlingmore than onelineage toa Single ~asl populaton.

Myeloid lineage ~xidas.e (fbw cylomeIfy,

immunohislOChemistry or cytoChemistry)

"

Mi:Inocy1icdifterentiaticl'l (al least2 of lhe kllIowrng: NSE. CDlle , C014, CD64 ,~) Tlineage

Cytoplasmic COO (!kM' cytomeIry wi1l'l antibodies 10COO epsilon etIatn: irnn~nolliStoehemistry USIIIg polydonaI <W1b-C03 <W1tbody maydeled CD3zeta chain, wt\id'I is not T<:eII spec::ific)

"

SOOace COO (rare W1 mixed pIlenoIype lClJIe leUkaen'liasj 8 lineage (multiple antigens requnct )

Strong C019 wiltl a1ieas11 oftnefclowing strr.Tf/'I e~ . CD79a. C)1OpIasrrMc C022. COlO

"

Weak CD19withill least 2 oIlhe IoIowilg 5IfOn!lIY exp!&S:Sed: C079a, cyqMsmic C022.CD10

Acute ieckaenes of ambiguous lineage

T-cell antibodies used in immunohistochemistry also reac t with the zeta (~) Chain of the receptor present in the cytoplasm of NK-c ells , an d are thus not absolutely specific . In contrast to w hat is d esc rib ed above with mye loid and t -een lineages, no single marker is sufficie ntly specific to indicate B-cell differentiation with ce rtainty, so that a constellation of find ing s is needed. Been diffe rentiation can be recognized v.tIen there is a distinct subpopulation of cells that by itself meets criteria for B-ALL When only one population of cells is present. then B-lineage assignment requi res either 1) strong Co 19 exp ression coupled with strong exp ression of at least one of the follow ing antige ns : C01O, Co79a or cCD22; or 2) weak CO 19 exp ression co upled with strong ex pression of at least two of the following : C01O, Co79a and cCD22. Rarely, a case may be ass igned as B lineage even If C0 19 is negative, though care must be taken when doing this because of the relative lack of speci!iclty of C010 and Co79a. Cases of MPAL based on one cri terion at diagnosis (e.g. 'biph enotypi c leukaemia ") may c hange ove r tim e or at relap se to the other (" bilineage leuk aem ia"), o r vic e versa. Also, following therapy, per sistent disease or relap se may occur as eithe r pure ALL o r AML. Some cases of wh at 'as been termed "lineage switch" 11684, 18251may reflect this phenomenon Ambiguou s lineage leukaemias are rare and account for less than 4% of atl cases ol acute leukaemia. Many cases of w hat have been rep o rted as undiffe rentiated 'eukaemia ca n b e d emon str ated to be eokaemtas of un usua l lineag es, and 'TIany ca ses of what have been reported as biphenotypic acu te leukaemias may in tact represent acute lymphoid or myeloid letJkaemias With cross-lineage ant igen expression , so that the actual frequency may even be lower, The se leukaerruas occur both in children and adults but -rore frequent ly in the latter, although some su btypes of MPAL may be more common in c hild ren 11145, 16711 . Avariety of genetic lesions hav e been reported in am bigu ous lineage leukaemi as, especially MPAL. Two of these , the t(9 :22 ) (Q34;q 1l ) BCR-ABL 7 translocation, and sansrocanons associated with the MLL gene occur frequently enough and are associated with distinctive features that lhey are considered as sep arate entities.

t-een

t-een

Acute undifferentiated leukaemia

Genetics There are too few case s des cnbed to know whether any consistent ge netic lesions occur.

Definition Ac ute undifferentiated leukaemia expresses no markers co nsidered specific for e ithe r lym pho id or myeloid line ag e . Before categorizing a leukaemia as undif ferentiated, it is necessary to perform irnmunophenotyp ing w ith a comprehensive panel of monoclonal antibodies in order to exclude leukaemias of unusual lineage s, such as those derived from myeloi d Of p lasmac ytoid dendritic cell p rec ursors, NK-c ell precursors, basophils or even non-baernatocoietrc tumo urs

Prognosis and predictive factors While anecdotal experience generally considers these leukaemias to be of poor prognosis , information is too scanty to make any defin itive statements.

ICD-O c od e

(q34;q11.2); BCR-ABL1

980 1/3

Synonyms Acute leukaemia, NOS; stem c ell acute leu kaemia. Epidemiology These leukaemfas are very rare , and nothing subs tantial is known about the ir frequency. Sites of involvement Bon e ma rrow and b loo d . There a re too few cases to know wh ether the re is a predilect ion for othe r sites. Clinical featu res There are no features that distinguish this from other ac ute ieukaemias. Morphology The b lasts have no morp holog ic feature s of myeloid d ifferentiation . Cytochemistry The blasts are negative for nweicoe ro xlcase and esterase. Immunophenotype These reukaemas typ ically express no more than one membrane ma rker of any given lineage. By definition , they lack the T or my eloid lineag e specif ic ma rkers cC 03 and MPO and do not expr ess Bce ll specific ma rkers such as cCD22, cC079a or strong C0 19. They also lac k specific features 01other lineages such as megakaryocytes or p lasmacytoid denontrc ce lls. Blasts otten express HLA-oR. CD34 , and/or C038 and may be posi tive for terminal d eoxynuc leoti dyltransferase .

Postulated normal cou nterpart Haematopo ietic stem cell.

Mixed phenotype acute leukaemia with t(9;22) Definition This is a leukaemia meeting the criteria for MPAL in which the blasts also have the t(9 :22) tra nslocation or BCR-ABL 1 rearrangement. Some pat ients with chronic myeloid leukaemia may develop or even presen t with a mixed blast phase that would meet criteria for MPAL, however this d iagn osis should not be made in patients know n to have had CML. ICD-O code The provisional code proposed for the fourth edition of ICo-o is 980613.

Epidem iology Althoug h this is the most common recurrent genetic abnormality seen in mixed p henotyp e ac ute leukae mia. it is a rare leukaemia , prob ably accountin g for less than 1% of ac ute leukaemias. It occurs in bot h children an d ad ults , b ut is more common in ad ults 1338 ,11 451. Clinica l featu res Patients present with features similar to those of other patients with ac ute leukaemia. Though there are not enough da ta to be ce rtain , it is likely that they present with high white b lood cell counts , similar to patients with Ph-s ALL. Mof'phology Many cases show a dimorphi c blast population , one resembling Iymphoblasts and the OIher nwecotasrs. although some cases have no d ist inguishing features Cases generally do not show significant myeloid maturation ; care shoold be taken abou t making this diagnosis in a case of

Acute leokaernias of ambiguous lineage

151

• Mixed phenotype acute leukaemia with t(V;11q23); MLL rearranged

Immunop henotype In the majority of cases it is possib le 10 rec og nize a lymp hoblast popula tion With a CD 19-positive , CDlO-negative B prec ursor (p ro-B) irnmuncphenotype , frequently positive for CD15. Expression 01 other B markers such as CD22 and CD79a is often we ak. In addition to this, cases also fulfi l criteria lor myel oid lineage as defined above, most comrnonly via demonstration of a separate papUa. tion of myeloid. and usually monobIaSIJC leukaemic ce lls 1167 1. 237 11. Coexpessian of myeloperoxi d ase on Iymphold blasts is rare. MLL translocations can also produce T.ALL, so that it is thOOfeticaly possible that T/myeloid Ieukaemias oc cur, although these have not been reported .

Definition

Genetics

•

Fig.1 .01 ElJrnyeIoid I8ulalInN with 1(9.22Nq34;q11 2). Theblasts vary from smaI ~ iIppeWVlg bIasIs kl ~ blasts WIlh dispersed c:lVl:lmaIin, prorninefJl nudeoIi and a Il'llXlefllte ann.n of pale ~.

myeloid leukaemia with maturation that also expresses lymphoid markers, because such a pattern may be seen in patients with blast phase 01CML. Irrvnunopheootyp The grea t majority 01 cases have bl asts meeting c riteria tor 8 and myeloid line age, as descr ibed above , though some cases have T and myeloid b lasts . Triphenotypic leukaemi a has also rarely been reported .

Genetic s All cases have either the 1(9;22) detect ed by classical karyotyp ing . or the BCR-ABL1 transloc ation d etect ed by FISH or PCR. Many c ases have addit ional c ytogenetic abno rmalities, and of ten have comp lex kary olypes.

Postulated normal counterpart Murnootent haematopoietic stern cell. Ther e is no evidenc e thai this leukaem ia derives from a di fferent cell from other cas es of Ph+ acute leukaemia . Progn osis and pred ict ive factors This type of leukaemia has a poor orogno sis ; it a ppe ars to be worse than that of other patients with MPAL {1 145 1, It is not c lear whether the p rog nosis is wo rse than that of patient s with Ph+ ALL, or if d iffere nt therapy can improve ou tcome. There a re no known fact ors among pa tients with this leukaemia that c an p red ict who w ill do better or worse. It wou ld be expected that imatinib and related tyrosine kinase inhibitor s mig ht be useful in the treat ment of this type 01 leukaemia; how eve r. there are no data availa ble to state this with ce rtainty.

152

Acute

This is a leukaemia meeting req uiremen ts for mixed phenotype acute leukaemia in which the b lasts also have a translocation invo lv ing the MLL gene . Many cases of A LL wi th MLL transiocauons express myeloid-associated an tigens , bu t these should not be considered MPA L unless they meet the specilic c riteria noted above. ICD-O code The prov isiona l code p ropo sed for the fourth ed ition of ICo-O is 980713. Epidemiology This is a rare leu kaemia that is more common in child ren th an in adults . As with AL L or A ML with MLL rearran gem ent s, th is leukaemia is relatively more co mmon in infancy 11 145 , 16711. Clinical featu res Patients present similarly to other patients with acu te leukaemia. As with other ac ute ieukaemras w ith MLL transtcceuons. hig h wh ite blood cell counts are common .

ewa

All c ases have rearrangements of se MLL gene, with the most corrmon partner gene being AF4 an chromosome 4 bafld q2 1 1338. 16 71 1. r ranstocanons t(9:111 and t(1 1;19 ) have also been reported The rearrang ement may be detected either by standard karyotyping or by FISH with an MLL breakapan probe or, less com monly, by Pe R. Cases w ith deletions 01 ch romosome 11Q23 detected by karyo typing shoul d not be considered in this ca tego ry. The MLL tra nsloc ation may be the only lesion present or there may be other seconda ry cytog enetic or rrolecular ab nomaunes althoug h no additiooal g enetic lesions common to multiple cases have been d escr ibed Progn osis and p redi ct ive factors This is a poor prognosis leukaemia 111 45, 237 11. Patients with B/myelo id leukaemia with MLL translocations are often treated di ffere ntly from patients d iagnosed witn ALL with MLL transtocatlons . but there is no evidence that this is nec essary or helpful.

Morphology Most commonl y these leukaemias display a d imorph ic blast population , with one population clearly resembling monoblasts and the ot her resembling Iymphob lasts . However. in other cases they may have no d istinguishing features and appear only as undiffe rentiated b last cells. Cases in whi ch the e ntire blast po pulation is monobtasnc are more likely to be A ML with an MLL translocation.

'eokaenes of ambiguous lineage

Mixed phenotype acute leukaemia, B/myeloid, NOS Definition This leukaemia mee ts c riteria for assign. ment to both B an d myeloi d lineage as described above. but in which the btass lack the above-mentioned g enetic abrc-

mantes.

ICD-O cod e _ The provisiona l code propo sed for the ftxmh edition of ICD-O is 9808/3 Epidemiology This is a rare leukae mia , p rob abl y ac counting for ab out 1% 01 leukaemi as overall. It can be seen bo th in ch ildre n and adul ts bu t it is mo re common in adults.

Clinical features

Immu noph enotype Blas ts meet the criteria for both Bclymproto and myeloid lineage assignment listed ab ove. Mveiooeroxioase-po sluve rnyeloblasts or mon ob lasts commo nly also express other mye loid -assoc iated marker s includ ing CD 13, CD33 or CD 117. Exp ression of more mature markers of Bcell lineage such as CD20 is rare but may occur, particu larly when a sepa rate population of B-cell lineag e is id entified {23 71 I,

There are no uniq ue c linical features,

""""""'" Most

cases have blasts with no d istin-

(p.ishing features, morph060gicaJIy resembk'lg ALL, Of hav e dImorphic ocoutetcns with one rese mbling Iymphobl asts and

ee other resembli ng myeloblasts.

--.f""""C"

5: .~"( -.. ,

Genetics Most cases of B!myeloi d leukaemia have c lonal c ytogenetic abnormalities. Ma ny d ifferent lesions have been demonstrated. thou g h none is of such frequency to sug g est specifici ty for this g roup of leukaemias. lesions that have been seen in more than a single case include de l(6p) ,

Postulated normal counterpart Multipotentia l naematopoeuc stem cel l. There is g rowing evidence of a poss ib le relation ship be tween a-.cell and mye loid d evelop ment suggesting either involvement 01a corrrnon precursor, or of a precu rsor of one lineage that has reactivated a d.tte renueton program of the other 11 127, 12401 · Prognosis and predictive factors B/myeloid leukaemia is generally cons ide red a poor prog nosis leukaemia. Many pat ients mee ting c riteria lor B/myeloid leukaemia have the unfavourable ge netic lesio ns and it has bee n sugg ested that this ac cou nts for the ir poor prog nosis 11145 1. Whether ad verse cytog enet ic features entirely exp lains the poor outcome is not definitively established 11267, 23711.

-- _ .

~

Sf" .·'-,j"-"" ;: ..~ -. '

12p 11.2 abnormalities, del (5q) , structural ab normaliti es of 7, and numerical abnorma lities inc ludi ng near tetraploidy [338, 16711, Com ple x karyotyp es may be seen There are insufficien t da ta in the literature to sugg est that B/mye loid and T/myeloid leukaemias have differ ent freque nc ies of oeterent genetic lesions, once the t(9:22) and MLL rearra ngements have been accounted for.

..::<:-'...

;. ' • ' I' :"'.: .

..

. ,

Mixedphenotype acute leukaemia, T/myeloid, NOS

,

A

Def inition This leukaemia meets c riteria for assign ment to both T and mye loid lineage as desc ribed above , but in which the blasts lack the above men tioned genetic abnormalitie s.

COlO m e

ICD-O code The provi siona l code proposed for the fourth ed ition of ICD-O is 9809/3.

,, ;.

. ...' I"

8

.:,~.; . :.~.. : C

of.,'" ''':-1 '' , Ii., eN . ~ )

I

FITe

Fig. 1.D2 FkIw L)'IOmetty in EIJmyeIoid 1euUemia. A C045 'IS Side scatter display ShoWlIlQa ma,a popuIaIlon of din COt5+ !:*lsts. B ~ 1111 bloe. residual normal B cells red and rnyeIoperoxidas posIbYe c:eIls (ndudong boIh tesls and I1ISiduaI nonnaI ceh)~ . aeTheIk:et ~ CD19 and C022 areslrOI9Y expressed on !he B Iym~ blasts. II"" CXlll1lIlable b!hal seen WIII'I residual nonnaI Ek:eIs (in red). 0 t.b;t of !he B-ceI blasts IaciMPO ..., many hJu!1l nol aI of !he ~ blasts are MPO posiIi'Ie. There is a smaIpopUabonof blasts eoexpmsing 1I1l9 rei MPO.

Epidemiolog y This is a rare leukaem ia, probab ly ac co unting for less than 1% of leukaemias overall. It can be seen both in c hildren and ad ults . It may be relatively more Irequent in c hildren than is 8/myeloid acute leuka emia . C linical features There are no unique clinica l features.

Acute leukaemias of ambiguous lineage

153

the t(9:22) and MLL rearrangements teve been accounted lor. Pos tulated normal counterpart

Mctnpot entrar haematopoietic stem cell. There is growing evidence 01 a possible relatio nship between T-c ell and myeloiO development suggesting either irM:llverne1: 01 a common precursor, or of a Iymphoicl precursor that has reactivated a myeloid differentiation program 11 127, 12401. PrognosiS and predic tive factors Tfm ye loi d leukaemia is generally CQl'lSI' dered a poor prognosis IeU
Mixed phenotype acute leukaemia, NOS· rare types

""""""Most cases have blasts with no cnstmguishing features. morphologically resembling ALL, or have dimorphic populations. with one resembling lympboblasts and the other resembling myeio-

addition to cCD3, the

t-een com ponent t-een

fre quently expresses othe r ma rkers including C07,CD5, and C02. Expression of surface G03 may occur when a separate population of line age is ioenu-

t-een

fied 123711.

b lasts.

lmmunophenotype Blasts meet the criteria for both T-lymphoid and myeloid lineage assig nment listed above. My eloper oxid ase-p ositiv e mvero-

blasts or monoblasl s com monly also ex· pr ess othe r m yeloid-associated ma rkers

including CD 13. CD33 or CD 117. In

Genetics Most cases have clonal chromosomal abnor ma lities , although no ne is of such frequency to sug gest specific ity fo r this g roup ofleukaemias. There are insufficient data in the literature to sug gest tha t B/MY and T/ MY le uka emi as hav e d ifferent freque nc ies of d ifferent ge netic lesions, once

-

,

Fig. 7.001 ThnyeIoid 1euIlaenU. ThIn ill . dimlrphicpop.MtionaI blasts wilh many smaI~ ; larger blasts alsoMoe high ~sm 1'lIlio. h manatin arid inalnspicuous rndeoL 154

Acute leukaemlas 01 ambigUOUS lineage

Some cases of leukaemia have been seen in which leukaemic blasts show clear-cut evidence of both T and B lineage commitment as defined above. This is a very fare phenomenon, with a frequency that is likely lower than what has been reported in the literature. As strictly applied, the most recent EGIL c rite ria for biphenotypic leukaemia (scores hig he r tha n 2 in more than one lineage), whic h assigned 2 points to CD79a expression 153, 187) would likely overest imate the inc idence of BIT leukaemia bec au se CD79a can be detected in T-ALL 11 750). In assig ning B lineage to a case of T-cell leukaemia, CD79a and CD 10 should not be considered as evidence of B-celt d ifferentiation. There have also been a few c ases with e~i­ dence of trilineage (8, T and myeloid lineage) assignment. Overall ther e are too few cases of either of the se to make any specific statements about cl inical features, genetic lesions or prognosis. To date, there have been no reports of B or T/meg akary ocyt ic or B or Tferythro1eukaerJias. Because it has been suggested that erythroid and megakaryocytic lineages are the earliest to branch off from the plur ipotent haematopoietic stem cell , lea...· ing progenitor cells w ith T, 8 and myeloid potential 1111 , neoplasms of these corenations of lineages may not occur. If It'ey

do occur, it is possible that the definitions used here might not detect all cases, as these leukaem ias would not be expected to express MPO .

_.-

, '.

-.. .•. -

."

Other ambiguous lineage feukaemias Under some circumstances leukaemias may express combinations of markers that do not allow classification as either AUL or MPAL as defined above. yet de Iinitive c lassific ation along a singl e lineage may be difficult. Examples of suc h cases mig ht includ e cas es that express J-ceu-assoctated but nol markers suc h as C D7 and C OS without cytoplasmic C03. along with myeloid-associated antigens such as C0 33 and CD13 without mvetoperoeoase. Such cases are best considered ac ute uncle ssiliable teukaemes. With more extended panels containing newer, less commonly used markers, such leukaemi as might be able to be c lassified.

B -'j'-'<':;;;,;,......: . .~.. _, , ...., . .. ,. , CVTOPlo\SMlC f1"O

coe """"

rrrc

r-cen-soecmc

Natural killer cel l tymphobIastic leukaemia!

.,',',- C

.;:

i

., ,...., . . ..,., "Ii, ,..,., SS L..

~phom.

This neoplasm has been very difficu lt to define, and there is con siderable con fusion inthe literature, Con tributing to the confusion is that many cases rep orted as NK leukaemia because of the expression of N-CAM (COS6) are now recognized to represent cases of plasmacytoid dendritic cell leukaemia 11735, 1736J. Similarly, the entity at mye loid/NK-cell acu te leukaemia 11980, 2129J, whic h has been suggested to be of prec ursor NK origin 11660) has a primitive immunophenotype that cannot be d istinguished from acu te myeloid leukaemia w ith minimal different iation, and until further evidence emerges these should be considered as cases of AML. Early in development, Nrc-celt progenitors express no spe cifi c markers 17331 or ex pressmarkers that overlap with those seen inT-cell All.., including C07. C02 and even CDS and cytoplasmic C03 120701. so that distinguishing between T·ALl..and NK -ce ll tumours may be d ill icult. More mature but rrore specific markers suc h as C016 are rarely expressed in any acute leukaemia. while some markers that m ight be c on sidered relatively more scecmc . but st ill expressed on NK progenitor s. suc h as CD94 or C0161 17331 are not commonly tested. Some we ll c ha rac terized cases of NK precursor tumours WIthlymphomatous

..

:

'

cf'FOFlTC

...

.' ,

.

.. .' ~.

. ,.~

. ..' .-

~

,.

F

presentations that expressed NK -specilic CD94 lA transcripts have been de scr ibed 113061. It is hoped that wider availability of more specific NK markers includ ing panels 01 antiboclies against killer inrnunog lObuhnlike receptors (KIRs) will he lp c lanfy this d isease. but until then th is is best coosrcereo a provisional ent ity. The diagnosis of precursor NK lymphoblastic leukaemia}

lymp homa may be considered in a case thai expresses C056 along with immature T-associated markers such as COl and C0 2 and eve n incl udi ng cCD3, provided that it lacks B-eell and mye loid markers, and IG receptor genes are in the germline configuration\1128, 1174, t6601 and blast ic plasmacytoid oenonuc c ell leukaemia has been excluded

t-een

Acute leukaemias 01 ambiguous lineage

155

CHAPTER 8

Introduction and Overview of the Classification of the Lymphoid Neoplasms

Introduction and overview of the classification of the lymphoid neoplasms Defini tio n B c ell and liNK c ell neopl asm s are clonal tum our s of matu re and immature B cel ls , T ce lls o r natural Killer (NK) c ells at various stages of differentiation , Because NK ce lls are closely related . and share some

immunopheno typic and functional properties with T cells , these two classes of neoplasms are considered together. B-cell and T-cell neopla sms in many re-

spects appear to recapitulate stages 01 normal B-cell or t -een differentiation, so tha t they c an be to some extent c lass ified accord ing to the correspon d ing no rma l

staqe . However, some common B-cell neo pl asms. e.q . hai ry celt leukaemi a, do not c lea rly correspond to a no rmal B-cell

differentiation stage. Some neoplasms may exhibit lineage heterogeneity. or

j lnnate immune system

E.S. Jaffe N.L. Ha rris H. Stein

E. Campo SA Piler i S.H. Swerdlow

even more rarely. lineage plasticity 11037 , 13571, Thus, the normal co unterpa rt of the neop lastic ce ll c anno t at this time be the sal e basis for the c las sification. Pathob iology of lymphoid neoplasms

and the normal immune system The re are two major arms of the immune system tha t d iffer, both in the nature of the target and the type of the immune response, known as the innate and adaptive immune responses , Ce lls of the innate immune system represent a first line of defense, a primitive response. Cells of the inna te immune system inc lud e NK cells, CD3+ CD5 6 + t-eens or NK -like t-eens. and y6 T ce lls. These ce lls playa ro le in b arrier defenses inv o lv ing mu cosal and c utaneous immu nity. They d o no t need to

IAdaptive immune system I

•• ••

yl T - . _ _

T_._--.

Toll like receptors Not MHC Class II restriCted Cytokines Chemokines Complement

Agopeafic

-'''''

on B + T cells

First line of defense with a maJor role in banief immunity

Ag presentation to T cells in context of MHC

Immunological defense cha racterized by specificity and memory

Fill, 1.01 There are I\lIO mainarms of tile immur.e system. the innate immur.e system, and the adaptive immuroe system, Diagram shows respective roles 01 lymphocyte sutlpopulations in the innate and adaptive immuneresponses NKcells, N K~ike Tcells, and yfo Tcellsfunction with othercell types including granulocytesand macropha ges asa first Hna of defense. These cells havecytotoxicgran ules (shown in red) oontainingperIorin andgranzymes The inna teimmuoe system lacks specilidty and memory. In the adaptive invnuoe system, B 00115 andToeIIs r&COgnize anligeos (Ag) lhrough specific rec:e~ , immunoglobulin (Ig) and !he T-eeII recepD" rompIex (TCR) respediwly, Antigen presenta, tion to T eels must take pIac:e via anligen-presenling cells (APe) in lhe conlell of Ihe appropnale majorhlstoa::lmpatibihly c:omplex (MHC) ClassIIantigens. FiglIe R'I()Ijfied from {1035}.

158

Introduction and overview 01 the cassmcatoo 01 the lymphoid neoplasms

encounter an tigen in the context of the major histoc ompatib ility co mplex (MHC), and thus do no t require antig en presenting ce lls to ini tiate an immune response, The adaptive immune sys tem is a more sophisticated type of imm une response. It is specific for a particular pathogen; two key feature s of the adaptive immune response are specifici ty and memory This con trasts with innate immune responses whi ch are non- specific lor the target. and do not req uire o r lead to immunological memory.

B-eeli lymphomas: lymphocyte differenti· ation and function Bccell neo plasms tend to mimic stages 01 normal B-cell d iffe rent iation , and the reo semblance to normal c ell stages is a ma jor basis for their classification and nomenclature. Normal B-eeU d ifferentiation begins WIth precursor B c ell s known as progenitor B c eli sIB Iymphoblasts (b last ce lls thaI are the precursors of the ent ire B-eell line) , wh ich undergo irTYnunoglobuhn IDI gene rearrangement and differentiate into man se surface immunoglobulin (slg) pesitive (lgM+ IgO+) naive B cel ls via pre-8 cells with cytoplasmic ~ heavy chains and imma tu re IgM+ B cells Naive B cells . that are often CD5 + , are sma ll rest ing lymphocytes that c irculate in the peripheral blood (PB) and also occupy pr ima ry lymphoid foll icl es and follicle mantle zones (socalled recircula ting B cells) 11004A, 1152AI. Most cases 01 man tle c elilymphoma are thought to correspond to CDS positive naive B cells 1994A I. On encountering antigen that fits their 51.1' face Ig rec eptors, naive B cells undergo transformation, prolifera te, and ultimately ma ture into an tibody-secreling plasma cells and memory B cells. Translormed cells formed from nerve B c ells that have encountered antig en may ma ture d irectly into plasma ce lls mat produce the early IgM antibody respon se to antigen. T-cell ind epend en t ma turation can take place ou tside of the germinal centre 14241, It is debated whether somatic hypermutatiOl"l of the IGH@ genes occurs du ring this

Central lymphoid tissue Precursor s-cene Bone marrow

Peripheral lymphoid tissue Peripheral (mature) B-cells Interfollicular area

Na...

Follicular area

Perifollicular

area

•

B<e<1. Progenitor

.... AG

B<e<1

.......

Memory B-cells Marginal zone

ExtrafotJiCular

Pre-Ekell

(@f~ 4

Immature B-<ell

«c: --

I

I / / /

-------

8-<011

Precursor B-cell neoplasms B lymphoblastic Ieukaemlallymphoma

/

Pre-GC neoplasm Mantle cell lymphoma

GC neoplasms Follicular lymphoma Burkill lymphoma OLBGC. (some) Hodgkin lymphoma

Post-GC neoplasms

Marginal zone & MAlT lymphomas lymphoplasmacytic lymphoma DlBCl(some) Plasma cell myeloma Fig, auz Diagrammatic represenlatiooof ~II diflerentiatioo and relationship to major ~II neooasms. ~II neocasme correspond to stages of B-cell maturation, even ItIoogh the precise cell counterparts are not known in all Instances. Precursor s-ceu nat mature in the bone marrow may undergo apcotose or develop intomature naive B-cells that, fol.. '(lw'ng e~sure to antigen and blast transformation, may deveiop into shOl1·lived plasma cells or ent8l'thegerminal centre (GC) where somatichyp&mlulatiOn and heavy chain class switchingoccur. Centroblasts, the transf()(ll16(j cells of the GC, either undergo apcotcsis or develop into centrocytes. Post-GC cells include both klng-lived plasm a cells and mem-

cursu:

ory/marginal zone B-cells. Most B-cells areactivatedwithin the GC, butT-cell independent activation can take place ootsideof thegerminal centreandalsoprobably leads to memory type B-cells. Monocytoid B-cells, many of which lack somatic hyperm utatioo, are not illustrated. Dl.BCl, diffuse large Bcell 'Ymphoma; CLUSll, chronic lymphocytic leukaemia/sma ll 'Ymphocytic lymphoma; MAlT, meccsa-essccated lymphoid tissue; AG. antigen; FDC, fojlic· u1W Oeooriticceli. Red bar. irmnurKlglobulinheavy cha in gene (IGH@) rearrangement;bluebar,immunoglobulinlightchaingene(IGl)rearrarJgem&nt; b1ad1 insertions in thered and blue tersindK:ite !WI'Iatic hypermutation.

extratollicular maturation . Other antigenexposed B cells rniqrate into the ce ntre of a primary follicle, proliferate, and fiJi the follicular d endr itic cell (FOG) mesh work, forming a germinal cenlre (l 325A, 1355AI. Germinal centre centrobtasts express low levels of slg. and also switch oH exp ression of BGL2 p rotein; thus . they and their progeny are susceptible to death through acootose ( 1828A1. Centrobtasrs express COlO and BGlS protein. a nuclear tran scription factor that is expre ssed by bo th centroblasts and centrocytes. BCL6 is not expressed in naive B cells and is switched

off in memory B cells and plasma cells 11346 . 1760 1. In the germinal centre, somatic hypermutation occu rs in the imm unoglobulin heavy and ligh t chain variable (IGV) region genes; these mutations may result in a non-funct ional gene. or a gene tha t produces antibody with lower or higher affinity for antigen than the native IG gene. Also in the germinal cen tre some cells switch from IgM to rgG or Ig A production. Through these mechanisms, the germinal centre reac tion gives rise to the higher aHinity IgG or 19A antibodies 01the

late primary or secondary immune response 11 356 A I. The BCL6 gene also undergoes somatic mutation in the g erminal cen tre, however, at a lower freq uency than is seen in the IG genes l 1698A 1. Ongoing IGVregion gene mutation with intraclona l diversity is a hallmark of germinal cent re cells. and bo th IGV reg ion gene mutation and BCL6 mutation serve as markers of cells that have been through the germinal c entre. Most dilfuse large B-cell neoplasms (DLBCL) are composed 01cells that at least in part resemble cantrobtasts and that have mutated IGV

Introduction and overview 01the classification of the lymphoid neoplasms

159

Table 8.01 Immuoophenotypic featuresof CO!M'!OIl mature B-<::el reooasme.

Neoplasm

slg;

C05

C0 10

C023

CQ.t3

C0103

BCL6

c~

CWSL l

IRF.....

CyeUn

MUMI

D1

ANXA1

(+PCI

LPl

+/.,+

HCl

.

."

;.

.,.

•

',' MALT lymphoma

Iym_. f ollicubr

• .• t,

.,

. ;.

MCl

•

•

' ,'

~

IIrge 8-cIll lymphoma

. /.;. /.

811ttitl

. ;-

--

."

01·-

....

NA

•

,.

NA

.,

NA

.'~

. /-"

•, >90% 01 cases -: . /., >50% 01 cases -: 01., <50% 01 cases e:-,
Iabng Iacb' 4:ANXA1 , AnneXll"lAl; PC, praIileratIon celllreS: " plasma eel c:ornponent po$IllYe;', some grades

p1asmacylic lymphoma; MIL, ITIlIrgmI zone I)mphoma; MeL nlall1le eeI~ .

P~B

Pre-8

Immature

Mature

Gemlinal

B

naive 8

eeoee B

Antigen Independent

Memory B (Marginal zooe)

Plasma cell

Antigen Dependent I,-,--~==~=

I CD79A

[PAX5

=

[ CD20

n nnours. Centrobrasts ma ture to centrocstes. and these cene are seen predomina ntly in the light zone of the ge rminal cen tre. Centrocvtes express slg that has an altered antibody combini ng site as compared WIth that 01 their oroqenrtors. based both on somatic mutations and hea vy chain class Swit ching Cen trocytes with mutations thai result in increased affini ty are rescued from eocotose and they re-express Bel2 protein 11355A1. Throug h inleraction"";tn surface molecules on FDC 's and t-cees. such as CD23 and CD40 ligancL centrocytes swilch off BCL6 p rotein expression 1346, 17601. and oitterennate into either memory B-eetts Of p lasma 1t 355AJ. BCL6 and IAF4/M UM 1 are rec iprocally exp ress ed , w ith IAF4/MU M l being positive in late cer nrocytes and plasma cells 166 1. t 9t4AI. IRF4/MUM 1 plays a critical role in down-regulating BCL6 expresser 11914AI, Follicu lar lymphomas are 1lJTlCU'S of g er minal c entre B-c etts (centrocytes and centrobiasts) in wh ich the germinal c entre celts fail 10 undergo apcorosts. in most cases du e to a chromosomal rearran gement. t{14 :18), that prevent s the normal switc hing off 01 BCL2 proten expression, Centrccvtes usua lly preooninate ove r cen t roblas ts , and these neoplasms tend to be ind olent. Post-germinal ce ntre memory Bccells cir· cu lat e in the PB and comprise at least in the follic ular marginal some of the zone s of lymph nodes, spleen and mucos a-assoc iated lymphoid tissue (MALT). Marginal zone e-cens of this co-roanmen t typ ica lly express pan-B antigens, surfac e Ig M w ith only low level IgO and lac k both COS and COlO 12064 A. 2293Bl. produced in the ge rminal Plasma c entre enter the PB and home 10 the bone marrow (BM). They conran predom inantlY IgG or IgA ; they lac k slg and CD20, bI.C exp ress IRF4/ MUM 1, C D79a , C03B and CD 138. Both memory B-eetl s and long. lived p lasma cens have mutated IGV reg ion genes , bu t d o not continue 10 undergo mutation . Posl-germinal centre Beene reta in the ab ility to home to tissues in wh ic h they have undergone antigen

cens

cens

ceus

1

fig.I.O] SChematic diagram showing pherlotype 0/8 ~ at ~ stages of mah.ra1ion. TOT is II feature of earty Iyn1)hOid preanors, irdIclIng boIh Band T IyrrfJhobIasts. as wei as!he blasts in some cases of acu1ll myeloid leukaemia. C079A and PAX5 appNI' allhe bme of heavy etlan ger-.e rearral'lQelTlelll. COlO is I'IOt e~ IA'ltIIIhe stage of inIrrI.JllOgIobuIirlliljll chain gene (/GLJ I'8aITllflQE!I' TOT, Iermml ~ IransJerase; SHM, soma1lc~ ; Red t .,/GH@ ~ll blue bar./GL rearrarJgelTleflt; Pre-8CR. pre-8<eI receplor ~ sisIi1g 01 a IG heavy thaI'l and !he IIWfOgale io,tJl chail (YItIch is ~ d two lri;ed smaI pepIides VpreB llf'Id 45, represenled in ~J; BCR. B celIl'llOfII*;Irol rnetln 8 eels : Redbar and blue bar wiItl bladti'lser1DJs, fNIfIIIglId IGH@ and IGl. QeIleS WIth somabc h~. 160

ge nes , consis tent with a derivation from c ells that have been exposed to the qe minal centre. Burkitt lymphoma cells are BCL6+ and have mu tated IGH genes, and are Ihus also though l to correspond to a g erminal cen tre b last celt. Both Burk itt and DLBCL co rrespon d 10 prolferating c ells. and are cli nically aggressr.oe

Introduction and overv-ew 01 the ctess.tcauoo of the lymphoid neoplasms

stimulation, probably through su rface integrin exp ression, so that B-cells that arise in MA LT tend to return the re, while those that arise in lymph nodes will home to nodal sues and BM p03AI . Marg inal zone lymphomas of MALT. splenic . and nodal types correspond to post germinal centre, merTIOfY B cells of marginal zone type thaI derive from and proliferate specifically in extranoctal, splen ic or nodal

nssoes. Plasma cell myekma corespooos to a 8M homi ng p lasma cell. T-cell lymphomas : lymphocyte differen tia·

tion and function Tlymphoc ytes arise from a 8M prec ursor that undergoes maturation and acqui sition of function in the thymus g land . Antig en specific T cells mature in the thymic co rtex, Tcells recognizing selt-peptides are eliminated via eccotosrs. in a process med iated

Peripheral lymphoid tissue

Central lymphoid tissue Precursor T-cene

Bone

ryi.i;;~:"

.. ... ..... ,

,

t-een

receptor. The 0.1\ and structu re of the "}'IS chains are each composed 01a variable (V) and const ant (C) po rtion. They both are associated with the CD3 complex. which con tains 't- 0 and t chains. NK-cells dO not have a complete 'r-cen receptor com plex, ac tivated NK cells exp ress the t and l; c hains of COO in the cytoplasm. They express C02. COl , and sometimes C DS. but not surfa ce COO. They also typi cally express CD16 , CD56, and variably COSl and contain cytoplasmic cytotoxic granule p roteins . NK-cells kill th eir targets. through antibody depend ent cytotoxicity (ADCC) or a second mechanism involving killer activating rec ept ors and killer inhibi tory recept ors , (KIRs). As NK-cells do not rearrange the T-cell rec eptor genes, analysis of clonali ty in NK -c ell prol ifera tions c an utilise antibod ies to the various KIR receptors ,

b y cortical e pithelial cells an d thymic nurse cells. Co rtical thymocytes have an imma lu re j-ceu phenotype . and express termina l deoxynucleolidyl transferase (TOTl. CO la . COO. CDS, and COl. CD3 is lirst expressed in !he cytoplasm, prior 10 complete t-een receptor gene rearrangement and export to the ce ll membrane. Cor tical thymoc ytes are initially dou ble-negative lor bo th CD4 and CDS. These ant igens are co-expressed in rnaluring mvmocytes. and later more mature T-c ells express only CD 4 or CDS. These varying sta ges 01 j-ceu matur ation are ref lected in T lymphoblastic leu kaemia! lymp homa (T-ALULBL). Med ullary thymo cyt es have a ph enotype similar to that of mature t-eens of the periph era l lymphoid o rga ns, There are two classes of t-eens: o.~ t-eens and ~ T-c ells 12841. This d istin ct ion is b ase d on the

Peri heral mature T- and NK-cells

. Skin

""W T

T-binI , . . "

c;ell

~ ~f ~, -,------+-------?~ffl' AG

®L~ ZT~' Thymus T tvmphoblastic Iymphomaneukaemia

FDC

Follicle Peripheral (mature) T-cell and NK-cell tymphomaslleukaemlas

Fig. ' .0<& Diagrammatic representation d T-cel drflerenbabal. T-<.:eI neopIastnscorrespond lCI dJflerent stages 01 mabntion. Lymphoid progenilClfs enteree thymus wherePfflCU'sorT-cees deYeIop intovaried typeS 01 naive T-ceis. The~ rnauationaI palhd natural kiIer cells andy6 T<.efls is not filly ~tood. Thea~ T<:eIsleave1he1l'Iyrrus where \.p)n expl)Sl.Q 10 anligen they mayUI'ld9rgo b1asllranslormabon and developfurther intoC04+andCD8+ elledor andmemory T<ets, T regulalory eels en 1hemajortype 01 COol· eIIector T<ells. AnoIhllf speciIic type 01 eIJedor T<eIls is the IoIliculaf helperT-eel that is found in gernjnal centres. Upon anligetjc stimulabal, T-cel teSj)(Ilses may OCW" irJd&. pendenl ollhe gemWoal ceoue. or in 1hecontext 01 a germinal centre reaction. FDC. Follicular dendritic cells: AG. antiQen.

Introduction and overview of the classifica tion of the lymp hoid neoplasms

161

Toll-like receptors playa role in ce ll-cel l interac t ions and sig nal ing. They p laya critical role in the rec og nition of infectious agents, init iating signaling through NFKB. While they func tion most prominently in innate immune respo nses, t hey also have a role in the adaptive immune system [ 1282AI· The lym phomas of the innate immune sys tem are pr ed ominant ly extra nocal in p rese ntation, mi rroring the d istrib ut ion of the fun ction al componen ts of this system. It is interesti ng that ma ny t-een and NK-ce il lymp homas o bse rved commonly in the paed iatr ic and youn g ad ult age group are de rived from cells of the innate immun e system {10351. These inc lude aggressive NK -c ell leu kaemia, systemic EBV-positive t-een lymphoproliferat ive disease (LPD) of ch ild hood. most heo atosp lenic t-een lymp homas, and y8 Teen lymphomas affectin g cutaneous and mucosal sites. Anaplastic larg e cel l lymphom a (ALC L) is the most comm on paedi atri c T-cell lymphom a , and also is of cytotoxic origi n. However its normal cellular co unte rpa rt, if o ne exists, is unkno wn. y8 t-eens exp ress nei ther CD 4 nor COB, and also usually lack CDS. A subpop ulation expresses COB. They comprise less than

r-ceus.

5% of all nor mal and show a restricte d d istrib ution, being found mai nly in the sp lenic red p ulp , intestinal ep ithelium, and other epi the lial sites. It is notable that these sites are mo re com monly affected by yo T-cell lymphomas, w hich otherwise are relatively rare 147, 241, 1303j. yO T-cells hav e a restricte d range of antigen recognition, and repr esent a first line of de fense against bacterial oeotroes, such as heat shock proteins l2841. They are often involved in respo nses to mycobac terial infec tions, and in mucosal immunity More rece ntly, the pattern of c ytolytic molecules has been investigated and co rrelated with both c ellular origin and funct ion . For exa mp le, to da te five g ranzymes have been demon strated in human cel ls j 1984Aj. These enzymes are simi lar in struct ure, but differ in their substrate speci fic ity and chromosomallocanons. G ranzyme M, a nove l me mber of this family, has unus ual e nzyme specificity, preferring clea vage after meth ionine, leuci ne or no rleuc ine. It has been sugg ested that this enzyme may p laya role in the effector phase of innate immune responses . Its expre ssio n is rest ric ted to NK-cells, CD3+ CD56 + t-eens. and yo J-ceus, bu t it is absent in other cytotoxic Ml:tdullary

(3

88~~e~"

a-cens.

CD1a CD2ICDS

C0 3

Cytoplasmic

Surface

CD4 + CD4/CD8

Double +

CD8+

I I~T~-ce=':Iym=P:h:"':":':bc=lou:k:.:om=_ ===m:':(:T-Al =:lIl:B:l~)IIPeripheral T-eell lymphomas

I I

I

TOT

Fig.8.05 Schematic diagram of T-<:ell maturation illustrating changes inantigenic expression. Tccell receptor (TCR) genes (TRA@, TRB@, TRG@,TRD@) are shown schematicallywith solid red bars indicating absence ofrearrangement, and rearrangement ofrelevant TCR genes as additional black segments.The TRG@generearranges first, followed by TRB@ and TRD@ . up T cells delete the TRD@ gene during TRA@ gene rearrangement, as TRD@is contained within the TRA@ locuson14q11.2. HOIVevef, yO Tcells may haverearranged TRB@genes,withoutassembly ofa complete up TCR Productive rearrangement gives rise to two mainT-<:ell populations. ul3and yO. wiltlexpression ofltle relevantTCR complex on the cell membrane (shown as double red bars). 162

t-een subsets , Granzvme M is expressed in bepatosorenrc T-cell lymp homas, cutaneous .,8 t-een lymphomas, and most intestinal t-een lymphomas tested, linking these neoplasms to the innate immune system 11 1911. T-cells of the adaptive immune system are heterogeneous and functionally comp lex, and inc lud e naive. effector (regulatory and cy toto xic) , and memory t-eens. Interesting ly, t-een lymphomas of the adapt ive immune system p resent pr imarily in adu lts, and are mainly nodal in origin, contrasting w ith the extranodal r -cenfym. phomas of the innate immune system /10351. CD4-positive T-cells are primarily regulatory, acting via cytokine production CD4-positive ce lls a re divided into two maj or types, based on their cytokine sec retion profiles, known as Th1, and Th2. Th1 cells secrete inter leuk in {IL)-2 and interferon t , bu t not IL·4 . 5, or 6. In contraer , Th2 ce lls secrete IL·4, 5, 6 , and 10 12841, Th 1 cel ls provide help mainly to other t -eens and macropbaoes. whereas Th2 ce lls provide help ma inly to Bcens. in the prod uction of antibodies /2851. CD4-positive T-cells can act to both help and suppress immune responses, and cons ist of mu ltiple sub po pu lations only rece ntly recog nized . Recen tly much has been learned about a unique CD 4+ t-een subset found in the normal germinal centre. These cells, termed fo llicular T-helper ce lls (TFH), provide help to B-cells in the co ntext of the ge rm inal centre reaction j63 1, 852. 1656A l . They have a unique p henotype. exp ressing the germinal centre-associated ma rkers BCL6 and COlO, norma lly found on TFH exp ress CD 4, CDS? PD· 1, and p roduce the chernckine CXCL13 and its rece ptor CXCR5, CXCL 13 causes ind uction and prolife ration of FOe; CXCL 13 also facili tates the migr ation of 8 and T cel ls exp ressing CXCR5 into the germina l cen tre. Recen t stud ies have identified inc reased expression of CXCL13 in angioimmuno blastic T-cell lymphoma {A ITL}, a finding that he lps to link tog ether many of its c linica l and pathological teatures 163 1, 852. 1656A l . Notably AITL is associ ated with polyclonal hype rpamma. glo b ulinaem ia and expansion and prolif· eration of bot h B-ce lls and CD2 1+ FDC's within the lymph node. A CD 4+ T ce ll with very d ifferent properties is the regulatory T cel l (Trag), w hich fuoctrons to shut off and sup press immune responses 12043Aj . This cell is thoug ht to

Introduction and overview of the c lassification of the lymphoid neoplasms

Table a.o2

Imm~typic

Neoplasm.

features 01 common manse T-cell arid NKoCeII reooasrns.

CD)

CD4

CDS

CD7

COS

C02

TlA1

GrB

CDJO

CD2S

C056

C016

COS7

•

•

BCl6

COlO

EaV

EMA

PM

teu T.lGl Ani.

Ao'l" ENKIT, Maul typt

EATL

• • •

., .,

•

"ISS

•

Pmry cutMllOU• .,6 T"", _

AITl

AlCl,ALK+ AlCl,AlK·

•

.,•

.

•

•

•

•

•

• • •

.,.,.,-

• •

•

•

.,-

••

•

•

•

•

•

•

•

• • •

• •

•

•

•

•

•

-.

•

<•

"

•

•

•

•

HSTL

•

•

•

•

SPTCl

.,-

• • •

.,-

•

•

• •

• • <.,

• •

•

,'- .,- • , .,- .,- .,- .,-

•

•

.,-

-,.

.. ..

.. ..

.,-

.,

-'

-' •

-'

--

.. •

c, cytopla~ C03(01)'. restricled to C03&: " T<eII receptor 'l'6: 'IIi, a rJIfIOriIy of cases expresses the o;fI T-ceHreceptor. " cose is exprMSed in Iha moIlO1'lOI"phic t)1Itt of EAR 0( Type II: " , EBVis Ibsenl in neoplastic cess. but is nearly always present in a subpopuIabon of backgrourld 8-ceIs; . , PTCl. OOS is 001 a Slrg\e disease, buI a hettrOgenttOUS group, andItlefelore, a vanety of imml.flOPhenotypic proftles canbe seen. A, a subset of PTC,l. NOS Ire 0&riVed !rom loIicuIar helper T-eels FH), and often express CDS7, COlO and BCl6: T·PLl , T~ proIymphocytic leukaemia; T-LGl, T<eIIlarge gra1u!af lymphocyllC leukaemla; ATLl, adiJft T-<;8" leukaemia/lymphoma: AggNK, aggressive NK-cel leukaemia, ENKIT-nasaltype. Mranodal NKfr-telllymphoma, nasa~lype; EATL, enteropathy-associated T-eelIlymphoma; HSTl. hepatosplenic T-ceH lyrr¢loma: SPTCL, subcutanlC!JS panl'licu~tis-li ke T-een Iymptloma; MFISS, mycosis tungoides and sezary syndrome: primary cutaneous COJO+ lPD, primary cutaneous CD30+ T-<;elI lymphoproll!erative disease, including primary cutaneousanaplasticT-cell lymphoma: AlLY. ang'oimmunoblestic T-ce~ lymphoma: PTLC, NOS, periphlfa! T-cell lymphomas, nototherwise specified: ALCL, anaplastic large cel lymphoma. 00, granzyme B; Per, perforin,

rr

play an imp ortant role in preven ting autoimmunity. Tregs exp ress high den sity CD25, and the tran scription fact or FOXP3, in com binatio n w ith C04, Adul t T-cell leukaem ia/lymphoma (ATLL), ha s been linked to Treg ce lls b ased on expression of both C025 and FoxP3 , and this finding helps to explain the marked m munosuppression associated with ATLL

11862A1· Recent studi es have tried to relate the pathological or c linical manifestati ons of t -een lym phom as to c vtokme or onemokine expre ssion by the neoplastic cells, or accompanying ac cessory cells w ithin the lymph nod e . For exa mple. the hypercalcemia assoc iated with ATLL has be en linked to sec retion of fact ors with osteoClast-activating ac tivity 1664, 13581. The haemophagocytic synd rome seen in scme T-cell and NK-celt ma ligna nc ies has bee n

associated wit h sec retion of both cy tokines and c herno kmes . in the selt ing d efect ive cytolytic function (737 , 12761. Geneti cs Seve ral ma ture B-cell neopla sms have characteristic genetic abn ormalities tha t are impo rtant in determining their biologi c features and can be useful in d ifferential d iagnos is . These includ e the t( 11:14) in mantle c etl lymphoma, t(14 :18) in follicu lar lymphoma, 1(8 :14) and var iant s in Burkttt Iymphana, and 1(11:18) in MALT lymphoma 1515 ,1 104, 12851. The 1(11;14) is seen in both mantle c ell lymphoma and a fraction of c ases of pla sma cell myeloma, but mino r differences in the tra nslocation exist , invol ving d ifferent portions of the irnrronoglobu lin heavy chain gene (IGHO) (1991. The most common paradig m tor trans locations involving the IGHtlon 14q ,

is tha t a c ellula r proto-oncogene come s under the influence of the IGH @p romo ter For example, in follic ular lymphoma. the overexpreeeton of BCL2 blocks apoptosrs in germinal c entre Bccells. The t(11;1 8), c ommon in MALT lymphoma, results in a fusion ge ne , AP/2/MALTI 1574, 1837, 2 109AI. The expression of API2 inhibits the act ivity of several caspases. The partner g ene , MALTI, act ivate s the NF",B pathway, as do other nensrocatons found in MALT lymp homa, suc h as t(1; 14) and t(14 :18). Only a few T-cell neoplasms have thus far been associated With speci fic genetic abnormali ties . Anap lastic larg e cell lymphoma, AU< +, is def ined by trensocercos involving the ALK (anaplastic lymphoma kinase) gene on ch romosome 5, (t(2;5) and variants 1582 .12291). Hepat osoieoc lym phoma is assoc iated with

r-cea

Introduction and overview of the classification of the lymphoid neoplasms

163

• Diffuse large B-cell 37% • Follicular 29% WII... T l)rnp homa 9% ManUe celll)rnphoma 7%

.CLLlSLL 12% • Primarymed large B-cell 3"A: • High Grade B. NOS 2.5% • Burkitt 0.8%

• Splenic marginal zone 0.9% • Nodal marg inal zone 2% l)rnphoplasmacylic 1.4% Fig. 8.06 Relative frequencies of B-celilymphoma subtypes in adults. Significant differences exist in different geographicregions. However, dilluse large B-eelilymphoma(OlBCl) and~ I icular lymphoma are the most common subtypes irrespective of geographicor ethnic group. Note that these figures unoerasmate theincidence of CLUSLl, as only patients presenting clinically with lymphoma were included, MCl , mantle 0011 lymphoma; ClUSlL, chronic lymphocytic Ieukaemialsmali lymphocytic lymphoma; PMLBCl , primary mediaslinal large B-celi lymphoma; SMZl, splenic marginal zone lymphoma; NMZL, nodal marginal zooe lymphoma. Oala based on {51}.

isochromosome 7q . However, the molecular pathogenesis of most other T-cell and NK-cell neoplasms remains to be defined, Multiple othe r genetic tools have been broug ht to bea r on the study of mature lymphoid neoplasms, These include com parative genomic hybrid isation (CGH) , and the newer and more sens itive tech nique of array CG H, both of which can identify areas of deletion or amp lification within the genome \165-167}. Gene exp ression microarrays can interro gate the exp ression of thousands of genes at the RNA level, helping to elucid ate pathways of activation and transformation 1509, 510,513,701, 1507, 1867, 1944}. Most recently, studies have begun to explo re changes at the epigenetic level that control the expression of multiple genes {13141. Principles of classification The class ification of lymp hoid neoplasms is based on utilisation of all available information to define disease entities 1898l. Morphology and immunophenotype are sufficient for the diagnosis of most lymphoid neopl asms. However, no one antigenic marker is specific for any neoplasm, and a combination of morpholog ic features and a pane l of antigen ic markers are necessary for co rrect d iagnosis, Most B-cell lymphomas have c haracteristic 164

immu nophenotypic profiles that are very helpful in dia gnosis. However, immu ne profiling is somewhat less helpful in the subclassification of T-cell lymphomas. In add ition, wh ile certain antigens are commonly associated with specific disease entities, these assoc iations are not entirely disease-specific. For example, CD30 is a universal feature of ALCL, but can be expressed in other T-cell and B-cell lymphomas and classical Hodgkin lymphoma (CHL), Similarly, while CD56 is a ch aracteristic feature of nasal NKff-cell lymphom a, it can be seen in other T-cell lymphomas, and in plasma cell neoplasms 1208,701,13251. Within a given disease entity, variation in immunoph enotypic features can be seen For example, most hepatosplenic 'teen lymphomas are of yi5 't-een phenotype, but some cases are of aj3 derivat ion. Likewise, some follicular lymphomas are CD1Q-negative. Additionally, the presence of an aberrant immunophenotype may suggest or help to confirm a diagnosis of malignancy (10341 , While lineage is a defining feature of most lymp hoid malignancies , in recent years there has been a greater appreciation of lineage plasticity within the haematopoietic system, Lineage switch, or demonstration of mUltiple lineages is most often encountered in immature haematolymphoid neop lasms,

lntroduction and overview of the class ification of the lymphoid neoplasms

but also can be seen rarely in mature lymphomas l451A, 675A, 88DAI. Genetic features are playing an increasing ly impo rtant role in the classification of lymphoid malignancies, and for manyofth:l small 8-celllymphomas and leukaemias, recurren t genetic alterations have been identi fied. However, the molecular pathogenes is of most T-cell and NK-ceillymphomas remains unknown,Genetic studies, in pa rticu lar PCR stud ies of IGH@and Teen recep tor (TCR) gene rearrangements and fluorescence insituhybridization (FISH), are valuable diagnostic tools,both for determinat ion of clonantv in 8-ce ll and T-cell proliferations (aiding in the ditteren. tial diagnosis with reactive hype rplasia), and in identifying translocations associated with some disease entities, The WHO class ification emphas izes the impor tance of knowledge of clinical leateres, both for accu rate diagnosis, as well as for the definition of some diseases, such as margina l zone lymphoma of MALT type versus noda l or splenic marginal zone lymp homa, mediastinal large B-celilymphoma versus DLBCL, and roost mature T-cell and NK-ce ll neoplasms. Diagnosis of lymphoid neoplasms should not take place in a vacuum , but in the context of a complete cl inical btstorv Lymphoid malignancies range in their cl inical behaviour from low grade to high grade, Howeve r, within anyone entity a range in clin ical behaviour can be seen Moreover, histological or clin ical proqressian is often encountered during a patient's clin ical co urse. For these reasons, the WHO class ification does not attempt to stratify lymphoid malignancies in terms of grade . Both morphology and immunephenotype often change over time, asthe lymphoid neoplasm unde rgoes clonal evolution with the ecqutstion of additional genetic changes , In addition, evolution over time does not necessar ily lead tothe develop ment of a more aggress ive lymphoma, For example, patients with DLBCL can relapse with a more indo lent clonaity related follicular lymphoma, Some of these clonal evolutions can be unexpected and not obv iously connected, such as the development of a plasmacytoma in a patient with CHl [1042B). Traditionally,classical Hodgkin lymphomas (CHL) have been considered separately from so-called "non-Hodgkin lymphomas' However, with the recognition that CHL is of B-cell lineage, grea ter overlap has been app reciated between CHL and

many form s Qf Been ma lignancy. The 4th edition of the WHO classifica tion reco gnizes these gr ey zones, and provides fo r the recog nitio n of c ases tha t bridg e the gap between the se various forms of lymphoma 12265). Epidemiology Precursor lymp hoid neopl asms incl ud ing B lymphob lastic leukaemia/ lympho ma (B-ALL.JLBL) and T fyrnphoblastic leukaemia! lymphoma (T·A LLJLBL) are p rimarily d iseases of c hild ren. 75% of cas es occur in children unde r six years of age Ap oroxrmately 85% of cases presenting as ALL areof precur sor B-ce ll type. whereas lymphoblastic ma lig na nci es of precursor T-cell type more often present as lymphoma, with med iastinal ma sses. A mal e predominance is seen in lym ph ob lastic malignanc ies of bot h B-c e ll and T-cel l lineages. Mature s-een neoplasms comprise over 90% of lymph oid neoplasms worldwide 151, 791. They repr esent approximately 4% of new cancers each year. They are more common in d evelop ed coun tries , particularly th e United States. Australia, New Zealand and Weste rn Europe. The most recent surve y from the Survei llance, Epidemio log y and End Resu lts (SEER) program in the United States indic ated an incidence rate per 100 000 per sons per yearof 33.65 for al l lymp ho id neop lasms, 26.13 for a-ce.r neoprasms. 1.79 for all Tcell neoplas ms, a nd 2.67 for Hodgkin lymphoma 11525A). The most co mmon types are foll ic ular lymp homa and DLBCL, which tog ether mak e up more than 60% 01 al l lymphomas excl usive of Hodgkin lymp homa and plasma c ell myeloma 137, 511. The inc idenc e of lymphomas. in pa rtic ular Been lymph omas, is increasing worldwid e, with mo re than 280000 cases occurring ann ually each year 121 12A) . The ind ivid ual a-cen neoplasms vary in their relative freq uenc y in different parts of the world . Follic ular lymphoma is more common in th e United Slates (35% of non-Hodgkin lymp homas) and Western Europe, and is uncommon in South America, Eastern Europe , Africa and Asia. Burkitt lymp homa is ende mic in equatorial Africa, where it is the most common c hildhood mal ig nanc y. b ut it comprises on ly 1-2% of lymphomas in the United States and Wes tern Europe. The med ian age for all types of mat ure Bcell neoplas ms is in the 6th and 7th decades, b ut med ias tina l large B-c ell

c AduI T..::eI leukemlatlylT1jlhomll 9 no

. Al'IalUs lic I8fge cell lymphoma. Al K. e n. . Anaplas tic '-lie cel

lym~ AlK .

55",

C P fim ary Cu!arlIIOUll Ala. 1.7%

c l.lnctall s
fig. 8.07 Relative frequenciesofmature T<elllymphoma subtypesinanadultpatient population. Significant differences exist indifferent geographic regions. However. peripheralT<elllymphorna. not otherwise specified (NOS)and AITL are two ofthemost common subtypes intemationally.' Notethatlhe category of enteropathy-type T<elilymhpoma (Erel )' used inthisstudy was not eqllivalent toenteropathy-associatoo T<eII ~ (EATL)as deflood in this monograph. ErCL was utilized largely asageneric category lor most T<ell lymphomas ifl'/Ol'ving theintestine. inclusive of EATL and )'0T-<:elI lymphomas. Data courtesyofJ. Vase and The International PeripheralT-CellLymphoma Project (57A).

lym p homa has a med ian age of -35 year s. Of the mature B-cel l lymphomas , only Bu rkitll ymphoma an d DLBCL occur with any sig nifica nt frequen cy in chi ldren . Mo st type s have a mal e p redo minance (52 -55%), but ma ntle cel l lymp homa has a str iking ma le p redo minance (74%) , wh ile fema les pre dom inate in follic ular lymp homa (58 %) and most partic ularly in pr imar y me diastinal large B-ce ll lymphoma (66 %). Primary med iastinal large B-c e ll lymphoma a nd cl assical Hodgkin lymphoma of the nodular sclerosis subtype have simi lar cl inica l p rofiles at presen tation , most commonly affecti ng ado lescent an d young ad ult females. These common clinical featu res first prompte d co nsrce ratton that these lymphomas might be related 11870, 1944, 2265) O ne majo r known risk factor for mature B-ce ll neop lasia appea rs to be an abnormal ity of the imm une sys tem, e ithe r immunod efic iency or autoimm une d isease. Although evide nc e of immune system ab no rma lities a re lac king in most patients with mature B-c ell neop lasms, immunodeficie nt p atients have a ma rkedl y inc rease d inc idence of a-cen neoplasia , partic ularly DLBCL and Burkitt lymphoma (193,33 1. 1569 }. Major forms of immunod efic iency c urrently incl ud e infec tion with the human immunode ficiency virus (HIV), iatrog enic immunosuppression to preven t

allog raft rejection or graft versus host d isease (GVHD) and primary immun e defic ienc ies. Some autoimmune diseases are also assoc iated with an inc reased risk of lymphoma, pa rticu larly B-ce illymp homas in patients with lympboepithelial sraraoentis or Hashimoto thyroiditis 11114, 11161. Mutations in genes con trolling lymphoc yte epo ptosfs have been linked to a risk for both autoimmu ne d isease and lymphoma (ma inly B-cell types). Patients with the autoimmu ne Iymp hop roliferative syndrome. wh ich usua lly is ca used by ge rmline muta tions in FAS, have an inc reased risk for a-cer lymp homas and Hod gk in lymp homas 12108). Somatica lly acquired FAS gene mutations also have bee n reported in some spo rad ic B-cell lymp homas, most co mmo nly marg inal zone lymphomas 1855). Recen t stud ies employing mo lecula r epidemiology have identified pol ymorp hisms in a number of immun ore g ulator y genes that appear to impa ct both risk of lymphoma and prognosis within a patient cohort l359A. 1248A , 2358C) . Molec ular ep idemiology is a relatively rec ent area of investigation and more data will be accumulated in the com ing yea rs. For example , a recent stu dy foun d incre ased risk associated with polymorph isms in certain drug metabol izing enzymes 116A}. Mature T-c ell and NK-c eil neoplasms are

Introd uction and overv iew of the c lassificat ion of the lymp hoid neoplasms

165

relatively uccorrmon. In a large international study that evaluated lymphoma cases from the United States, Europe, Asia and South Africa, T-cell and NK-cell neoplasms acco unted for only 12% of all non-Hodg kin lymphomas [51}, The most com mon subtypes of mature t -een lymphomas are peripheral r-eef lymphoma, not otherwise specified (NOS) (25.9%) and angioimmunoblastic T-cell lymphoma (AITL) (18.5%), respectively (57A}. T-cell and NK-cell lymphomas show significant variations in incidenc e in different geog raphical regions and racial populations In gene ral, "l-cell lymphomas are more common in Asia [6161 . These differences result from both a true increased incidence , as well as a relative decrease in the frequency of many B-cell lymphomas, such as follicular lymphoma. One of the main risk factors for T-ce ll lymphoma in Japan is the virus, HTLV-1. In endem ic regions of southwestern Japan, the seroprevalence of HTLV-1 is 8-10%. The cumulative life-time risk for the development of adult r-cenieokaemlaavrrctoma (ATLL) is 69%"for a seropos itive male and 2.9% fora seropositive female [6831. Other regions with a relatively high seropreveience for HTLV-1 include the Caribbean basin. where Blacks are primarily affected over other racial groups {760f. Differences in viral strain also may affect the incidence of the disease [523,13451. Another major factor influencing the inc idence of r-cea and NK-ceil lymphomas is racial predisposi tion. EBV-associated NK and T-cell neoplasms. including extranodal NKfT-cell lymphoma, nasal type, aggressive NK leukaem ia, and paediatric EBV+ T-cell and NK-cell lymphomas are much more common in Asians than they are in other races {2n In Hong Kong, nasal NKfT-cell lymphoma is one of the more common subtypes, accou nting for 8% of cases By contrast, in Europe and North America , it acco unts for less than 1% of all lymphomas. Other popu lations at increased risk for this disease are individuals of Native American descent in Central and South America , and Mexico {40,3411. who are geneticall y related to Asians [8921. Finally, enteropathy-associated J-ce!l lymphoma is most co mmon in individuals of Welsh and Irish descent, who share HLA haptotvpee that confer an increased risk of gliadin allergy and suscep tibility to gluten-sensitive enteropathy 154S}. 10 PTCL occu r with increased frequency 166

in the setting of immune supp ression, especially following organ transp lantation, a finding that is not well understood {758A, 1582Al The comb ination of two factors, both immunosuppression and ch ronic antigenic stimulation. appear to increase risk. Hepatosptenic T-cell lymphomas are most com mon, but primary cuta neous and mucosa-assoc iated T-cell lymp homas have been rep orted as well {3311. Recent data from the SEER prog ram indicate a modest inc rease in the inci dence of t-ceu neop lasms in the United States to 2.6 cases per 100000 persons pe r year, with the greatest increase occu ring in the category of cutaneous T-eeillym phoma (492A, 1525A). Etiology Infectious agents have been shown to contribute to the development of several types of mature B-cell, T-cell and NK-cell lymphomas. Epstein-Barr virus (EBV) is present in nearly 100% of endemic Burkitt lymphoma and in 15- 35% of sporad ic and Hrv-assocrateo cases {877, 1780Al. and it is involved in the pathogenesis of many B-eelilymphomas arising in immunosuppressed or elde rly patients, including many post-transp lant Iymphoproliferative disorders, plasmablastic lymphoma and EBV+ large B-ceillymphoma of the elderly. EBV is also associated with extranodal NKfT-cell lympho ma and two paediatric t -een lymphomas. systemic EBV+ t-een LPD of childhood and hydroavaccin iforme-like t-een lymp homa. The exac t ca use of these EBV+ T-cell lymphomas of childhoo d is not clear. Risk factors may be either high viral load at presentation, or a defective immune response to the infect ion {179n Chronic active EBV infect ion may precede the deve lopment of some EBV+ t-een lymphomas {1094, 1797f.In cases associated with chronic EBV infection, a polyclonal process may be seen early in the course, with progression to monoclonal EBV+ T-cell lymphoma 11 094}. Human herpesvirus-8 (HHV8) is found in primary effusion lymphoma and the lymphomas associated with multicentric Castleman d isease, mainly seen in HIVinfected patients {372). It is of interest that the same virus ca uses a number of B-cell Iymphoproliferative disorders whic h differ in their cl inical manifestations {617A) . Human T-ceil lymphoma/leukaemia virus type 1 (HTLV1) is the causative agent of adult T-cell lymphoma/leukaemia, and is

Introduction and overview of the classification of the lymphoid neop lasms

clona lly integrated into the genome of transformed T-cells !2148). In this condition as in HHV8-associated disorders, a spec trum of clinical behaviours are seen, although most cases of ATLLare aggressive. Hepatitis C virus has been implicated in some cases of Iymphoplasmacytic lymphoma associated with type II cryoglobulinaemia. splenic marginal zone lymphoma, noda l margina l zone lymphoma and DLBCL 112A, 88A, 527A, 534A, 1073A, 1434, 1775A, 2506), The role of the virus in tumour initiation is not clear. However, it does not directly infect neoplastic and appears to influence lymphoma development through activa tion of a B-cell immune response. Bacteria, or at least immune responses to bacter ial antigens, have also been implicated in the pathogenesis of MALT lymphoma. These include H. pylori in gastric MALT lymphoma (998, 1587,2444,2445), B. Burgdorferi in cutaneous MALT lymphoma in Europe {192), Chlamydia psittaci. C. pneumoniae and C. trachomatis in ocula r adne xal MALT lymphomas in some geogra phic areas {394, 18981and Campy lobac ter jejuni in intestinal MALT lymphoma associated with alpha heavy chain disease {1781, 1812f Environmental exposures also have been linked to a risk of developing B-ceil lymphoma. Epidemiolog ical studies have implicated herbicide and pesticide usein the development of follicular lymphoma and DLBCL !460A, 903A) . Exposure to hair dyes had been ident ified as a risk factor in some olde r studies, but newer dye formations have removed potential carc inogens {2496AI.

a-cens.

Conclusion The multipa rameter app roach to classification adopted by the WHO classification has been validated in international studies as being high ly reproducible, and enhancing the interpretation of clinical and translational studies. In addition, accurate and precise class ification of diseaseentities facilitates the discovery of the molecular basis of lymphoid neoplasms in the basic science laboratory151, 1034, 1525A1.

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B lymphoblastic leukaemia/lymphoma, not otherwise specified

Definiti on B lymphoblastic leukaemia/lymphoblastic lymphoma is a neoplasm of precursor cells (lymphoblasts) corrmined to the Bcea lineage. typically composed of small to medium-sized blast cells with scant cytoplasm. moderately condensed to dispersed chromatin and inconspicuous nucleoli, involVing bone marrow (BM) and blood (8 acute lymphoblastic leukaemia/ALL) and occasionally presenting with primary involvement 01 nodal or extranodal sites

(B lymphoblastIC IymphomallBl), By cooventon. the term tymphcma is used when the process is confined 10 a mass lesion with no or minimal ev idence of peripheral blood (PB) and 8M invo lveme nt. With extensive 8M and PB involvement, lym phoblastic leukaemia is the appropriate term . If the patient presents with a mass lesion and Iymp hob lasts in the 8 M. the d istinc tion between leukaemia and lymphoma is arbitrary 11 550 1. For many treatment protocols, a fig ure of 25% BM blasts is used as the thresho ld for defi ning leukaemia . In contrast to mye loid Ieokaemtas. there is no ag reed-upon lower limi t for the perc entag e of b lasts required to establish a d iagn osis of lymphoblastic leukaemtas In g eneral, the d iagn osis sho uld be avo ide d when the re are few er than 20% blasts, Presentations with low blast co unts c an occur b ut are unc omm on; c urrently there is no co m pe lling evidenc e that failure to treat a pat ient whe n there are fewer than 20% 8M Iymph ob lasts has an ad verse effect on ou tcome, The term B-ALL shoul d not be used to indicate Burk itlleukaemia/lymphoma, in spi te of its historica l assoc iation with tha t lesion, Cases of B·ALU LBL with recu rrent genetic abnormalities are considered separately below ICD-O code The p rovisional code proposed for the four th edition of ICO-O is 981 113 Epidemiolog y Acute lymphoblastic leukaemia (AL L) is primarily a d isease of children; 75% of cases occur in c hild ren under six years of 168

Precursor lymphoid neoplasms

M .J, Borowi tz J ,K ,C. Chan

age . The worldwi de incidence is estimated at 1- 4.75/ 100 000 pe rsons pe r year {18271. The estimated number of new cases in the United States in 2000 is approx imate ly 3200, with approximately 80-85% bein g of precursor B-cell phenotype {1845 , 20391. B-lBL constitutes -10% 01 lymphoblastic lymphomas. and the rema inder are of "T lineage 12421· Ap proximately 64% 0198 cases reported in a literature review were less than 18 years of age 113671. One report indi cated a ma le predominance {13101. Etiology Some transiccenons associated with B-ALL have been detected in neonatal specimens long befo re the onset of leukaemia. and monozygotic twins with concordant leukaemia frequently share genetic abnormalities {832, 15t41 , suggesting a genetic cornponen tto at least some c ases. Many of these trans locations appear to be p rimary initiating events.

Sites of involvement By definition, BM is involved in all cases c lassi fied as B-AL L, and PB is usually invol ved. Extramed ullary invo lvement is frequent. with parti c ular pred ilect ion for the c entral nervous system , lymph nod es, spleen. liver and testis in males. The most frequent sites of involvement in B·L BL are th e skin, soft tissue, bo ne and lymph nodes 1202, 1310, 13671- Med iastinal mass es are infreq uent {202, 1367, 19281. Clinical features Most patie nts with B-ALL presen t with evidence and consequences of BM failure: throm bocytopenia and/or anaemia and/or neutropenia, The leukocyte count may be decr eased , norma l or markedly elevated, Lymphadenopathy, hepatcmegaly and splenomegaly a re frequent. Bone pain and arIt1ralgias may be prominent. Patients with B-LB L without leukaemia are usually asymptomatic , and most have limited stage disease. Head and neck presentations are particularly common, especially in children. Marrow and PB involvement may be present . but the

Fig. 9.01 B lymphoblastic leukaemia, Bone rnarJOll smear. A 5everal ~asls with a highIIlIdearIc't lopiasmic ratiO and variably conoensed nudear dWl). mallO, B B Iymphoblasls containing numerous eo
percentage ollymphoblasts in the 8M is <25% 11310,13671 . Mor phology The Iymphoblasts in B-ALlA.BL in smear and imp rint preparations vary from sma" blasts with scant cytoplasm, condensed nuclear ch romatin and indistinct nucleoli to larger cells with moderate amounts of light blue to blue-grey cytoplasm

occasionally v ac uolated . d ispersed nuclear chromatin and mult ip le variab ly oronrent nucleoli. The nucl ei are round , tregUar or corwoIuted. Coarse azurophilic granules are prese nt in some fvmoroblasts in approximately 10% of cases. In some cases. the Iymphoblasts have a cytoPlasmic pseudopod (hand mirror cells) In most cases the morphology of the Iympeootasts differs from that of no rmal Be en precu rsors (haematog on es) with which they may be confused . The latter typically have even highe r oucieu s/cytoplasm (N/C) ratio s, mo re homogeneou s chromatin and no discernible nucleoli, In BM biopsies. the Iymp hoblasts in B-ALL are relatively uniform in app earanc e with round to oval, indented or co nvoluted nuclei. Nuc leoli range from inco nsp icuous to prominent. The c hromatin is fine ly dispersed The number of mitotic figures varies Lymphob lastic lym phoma is generally charac terized by a di ffuse , o r less comrT'lOflly, paracomca r pattern 01 involvement of lymph node or other 1JSSUe. A single-file pattern of infiltration of sot! tissues is common. Mitotic figure s are usually numerous and in some cases \hefe may be a foca l "starry sky " pattern. The morphologiC features of Band T lymphoblastIC proliferations a re inoisnngliShable. Cytochem~try

Cy10chemistry seldom con trib utes to the diagnosis of ALL lymphoblasts are negative 'or nweiope roxio ase. Gran ule s, Ifpresent, may stain light g rey with Sudan Black-B staining bu t are less intense than myeloblasts. lymphob lasts may show PAS

A

positivity, usua lly in the form of coarse granules . Lymphob lasts may reac t with non -specific esterase with a mutntocat punctate or Galg i zone pattern that shows variable inhibition with sodium fluoride . Immunopheoo
cytoplasmic C022 and nuc lear Td l ln the inte rmedi ate stag e. so called common ALL. the b lasts expre ss C01O. In the most matur e precursor B d ifferentiation stag e, so c alled pre-B-ALL. the blast s exp ress c ytoplasmic ~ c hai ns (c -u ). Surface immunoglobulin is c harac teristica lly ab sent alt hough its pre senc e does not exc lude the pos sibil ity of B-AlLllBL (15841. provided that other immuno p henotypic teatures, morphology and c ytog enetics are co nsistent With B-AlL. Although CO l O. positivrty is seen both in B-ALl and in normal haematogones. the immunophenotype of prec urso r B-AL l differs in alm ost all cases from that seen in no rmal Been precu rsors, The tatter sho w a continuum of expression of ma rkers of 8-cell maturation. includ ing surface Ig light c hain. and d isp lay a reprod uc ible pattern of acqui sition and loss of normal antigens {14421.ln con trast. c ases of B-A LL show patterns that d iffer from normal with either overexpres sion o r uno erexpres sion of many markers incl udi ng CO l O, CD45, CD38, C058 or Td T, among others 1326. 401. 134 2. 23721. These crttererces c an be very use ful in evalua tion of followup BM specimens for minimal resid ual d isease,

Genetics Antigen recep tor genes Near ly all cases of B-ALL have clonal OJ rearrang eme nts of the IGH@gene. In ad d itio n, t-een recepto r gene rearr angeme nts may be see n in a sig nifican t proportion of c ases (up to 70%) 122941so that these rear rangements are not helpful for lineag e assignmen t.

•

Ft;. 9.03 B~sbc lymphoma, A Skin, The ~Iic cells diffusely infiltrate the dermis -Mlh sparing of theepidermis. B Samecase aI h p magnification shows ~ SI.mU'ldW'9 a blood vessel.

8 lyrnp hobtastic leukaemiaJlymph orna. not otherwise speci fied

169

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Fig. 9.04 IrIcnIased haemalcJlp'le$ A Bone marrow sedJon . B Bone marrow smear In::m an et;;rt year.Qd male. showing tympnoid eels with I high nucIeaIlcyqJlasmicratio and hcm:lgeneou$ nudear dlromaW1; nucleoli . . not observed or areindl$1lllCl These cells resemble!he ~ in All 01 dtilood.

Cytogenetic abnormalities and onrogenes Cytogenetic abnormalities are seen in the majority 01 cases of B-AlLABl; in many cases they define specific entities with unique phenotypic and prognostic features. These cases are considered separately Additional genetic lesions that are not associated with these entities include del(6Q), del(9p). del( 12p). though mese do not have an impact on prognosis. Some genetic lesions that may be assoc iated with poo r prognosis include the very rare 1(17;19); E2A·HLF ALL and the lonachromosonat amplification 01the AML 1gene on chromosome 21 (iAMP21), whic h ac cou nts for about 5% of cases of All 11510]. The latter is being recognized with increasing frequency with the increased

170

Precursor lymphoid neoplasms

use 01 FISH studies to detect TEL ·AML 1 translocations, because it can be detected with the same AML 1 probe. Postulated normal counterpart Depending upon the specific leukaemia , B-ALL arises in e ither a naematopoienc stem cell or a B-ceU progenitor. Prognosis and p red ictive factors B·ALL has a good prognosis in ch ildren, but it is less favourable in adults . In c hild ren, the ove rall complete remission rate is >95% and in adults 60-85%. Approximately 80% of children with B·ALL appear to be cured, while this fig ure is less than 50% for adults Mo re intensive therapy makes a d ifference in c ure rates , and

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9.05 B IympIw)I:lIask leukaerria. L~ rnje. The

neoplastiC eels infiIlrate cMlusely sparW1g IUmallaides

there is some evidence tor youngeradlAls at least , that therapy with more intensive "paediatric-type" regimens is associated with better outcome 1233, 8721. Inlancy. increasing age (> 10 years), higher white blood cell count, slow response to initial therapy as assessed by morphologic ex· emmanon 01P8 and/or 8M , and the presence 01 minimal residual disease after the rapy are all associated with adverse prognosis 1488, 679, 19 76 , 2023 , 2093. 22951. The presence of eNS disease at diagnosis is associated with adverse out· come, and requi res specific therapy 14461. The prognosis of B-LBL is also considered relatively favourable. and as with BALL appears better in ch ildren than accns

113671.

B lymphoblastic leukaemiallymphoma with recurrent genetic abnormalities

This group of d iseases is c harac terized by recurrent genetic ab normalities, in-

clud ing balanced translocations and abnormalities involving ch romosomes, Many ch romosomal abnormalities that are non-rand omly associated w ith B acu te tymphoblastic leukaemia (B·ALL) are not inCluded as separate ent ities in this sectal. While inclusion or exclusion 01 a genetic -entity- is somewhat arbitrary, those lesions that are specifically mentioned are chosen because they are associated with distinctive clin ical or phenotypic p ropertes. have important proqnosnc implie arcos.demonstrate omerevidence that they ale biologicall y di stinct an d are generally mutually exc lusive w ith other ent ities.

BLymphoblastic leukaemiallymphoma with ~9;22)(q34;q 11 2); BCR·ABLt

Oefrlition Aneoplasm of Iyrnphoblasts corrmitted to lhe e -cen lineage in whic h the blasts harbour a trans location be tween the BCR gene on ch romosome 22 and the ABL 1 oncogene on ch romosome 9

ICD-O code The provis ional co de prop osed for the fourth ed ition of ICO-O is 98 12/3. Epidemiology and cl inical features Presenting features are generally similar to those of other pat ient s w ith B-All. BCR-ABL 1 associated ("Ph . -) All is relatively more common in adults than Children, accounting for about 25% of adult All but only 2-4% of childhood All. Most chil dren with Ph. B-All woul d be consid ered "hig h risk " b y sta nd ard age and white b lood ce ll (WBC) feat ures, but there are otherwise no cha racteristic docalf indings Though patients with t(9;22) B·Al l may have organ invo lvement. lymphomatous presentations are rare

_

and cytochemistry

There are no un ique mor phologic or

MoJ. Borowitz J.K.C. Chan

cytochemic al feat ures that d istingui sh this from other type s of ALl. Immunophenotype B-Al l wit h t(9;22 ) is typicall y C 01O . C0 19. and TdT • . There is more frequ ent expression of myeloid -assoc iated anngens C0 13 and C033 19851: COl17 is typically not expressed . C025 is highly associated with t(9.22) B-All, at least in adu lts 116791. Rare ca ses of t(9 :22) All have a T precursor phenotype. Genetic s The t(9 :22) results from fusion of BCR at 22q l 1.2 and the cy to plas mic tyrosine kinase gene ABL 1 at 9q3 4. w ith produ c tion ot a BCR-AB lfusion protein, In most chi ld hood cases of Al l w ith the t(9 ;22), a p1 90 kd BCR-ABU fusion p rotein is produced. In ad ults, ab out o ne half of cases of ALL w ith the t(9 .22) prod uc e the p2 10 kd fus ion protein that is present in chronic myelogenous leukaemia (C ML) . and the rema inder prcouce the p190. No de finite cl inical differences have been attribu ted to these two different gene produc ts. The t(9 ;22) may be associated with other ge netic abnorm alities, inc lud ing rare cas es that mig ht othe rwise c ause a cas e to be plac ed in one 01 the other categories below, It is ge nerally conside red that cl inica l features in suc h c ases are governed by the p resenc e of the t(9:22) .

Fig. 9.06 Ttis bone marrow from ., iICkJIl WIth 119"22) posIbve &-ALl is ~leIy replaced by tyrnp1ctlIasb. Mitolic figl.l'eS areI'lUI'IlefOUS.

ad d ition to hig h-dose c hemotherapy has been reported to imp rove early event-free survival {19751.

B Lymphoblastic

leukaemiallymphoma with t(v;11q23); MLL reafT8t1ged Definition A neoplasm ol lymphoblasts ccmm ined to the B lineage that harbours a transl oca tion between the MLL g ene at band t 1q23 and anyone 01 a large number of differe nt fus ion pa rtne rs. Patien ts with leukaemias that have dele tions of 11q23 w ithout MLL rear rangemen ts are not incl ud ed in trns group ,

Postulated normal counterpart There is some suggestion that the c elt 01 origin of t(9 :22) ALL is more immature than that of othe r B-All cases 14521.

ICD-O code The p rovis iona l code proposed for the fourt h ed ition is 981313

Prognosis and pred ictive factors In both c hild ren and adults , t(9 ;22 ) All has the worst prognosis among pat ients with All. Its hig her frequency in adu lt All expl ains in pa rt but not completely the relativ ely poorer outcome of ad ults w ith All. In ch ild ren . the prese nce of favourab le c linical features inc lud ing age. white count and response to thera py, is associated with somewhat better outcome 1771. althoug h prognosis is still cons idered relatively poor . Treatment with imatinib in

Etiology Wh ile the specific et iology of leukaemia with MLL transJocations is unknown . this translocation may occur in utero. with a sho rt latency between the transloca tion and dev elopment of d isease , Evidence for this inc lud es the fact that these leu kaemias are frequ ent in very young infants, as well as the fact that this translocation has been identified in neonatal b lood spots of patients who subsequently develop leukaemia {7451.

oucn-o

B lymphoblastic leukaemia/lymphoma With recu rrent genetic abnormalities

171

proteo-qryca n neural-glial antigen 2 (NG2) is also characteristically expressed and is relatively, thoug h not absolutely, spec ific.

Genetics

Fig, 9.07 B tymphoblasbc le ukaemia~ym phom a with MLL reerrarqement FISHstudy usingan MLL breekapa rt probe. The normal MU gene"MLL(11q23)"appears as ajuxtaposed red and green, Of sometirnas yellow signal, The trensJocatioo is demonstrated by separation of theredandgreen probes r MLLsp") (Cocrtesy of Or AJ carroll)

The MLL gene on chromosome 11Q23 has many fusion partners. The most cammon partner gene is AF4 on cnrorosore 4q 21. Othe r commo n partner genes incl ude ENL on chromosome 19p13and AF9 on chromosome 9p22. MLL·ENL fusions are also co mmon in T·ALL and fusions between MLL and AF9 are more typ ica lly associated with myel()d leukaemia. Leukaemias with MLL nanslocations are frequently associated with overexpresston of FLT-3 l 801. Cases with deletions of 11q23 are not included in this group of leukaemias as they appear not to share the same clinical, phenotypic or prognostic features.

Prognosis and predictive factors Leokaerreas with the MLL·AF4 translocation have a poor prognosis. There is some cont roversy as to whether reukeenee with translocations other than the MLL-AF4 rearrangement have as poor a prcqross as trcse that do , Infants with ML1. translocations, particularly those <6 monfhs ~ age, have a particularly poor prognosis

B Lymphoblastic laukaemlaJlymphoma with

1(12;21)(p13;q22);TEL-AML 1 (ETV6-RUNX1) Flg.9 .08 B tymphoblastic leukaemialtymphoma with1(12;21) (p13:q22); TEUAML 1 (ETV&-RUNX1) FISH study using a red probe against RUNX1 and a green probe against ETV6. The normal genes appear as isolated red or green signals, wMe evcerce of the fusion gene (arrows) appears asa yelklwsignal, (Coortesy of Or. AJ carroll).

Epidemiology and clinical features ALL with MLL rearrangements is the most common leukaemia in infants < 1 year of age . It is less common in older child ren and inc reases with age into adulthood . Typica lly pa tients with this leukaemia present with very high white blood cell counts, frequently> 100 OClO/J-J-L. There is also a high freq uency of eNS involvement at diagnosis. While organ involvement may be seen , pure lymphomatous presentations are not typical. Morphology and cytochemistry There are no uniq ue morpholo gic or 172

Precursor lymphoid neoplasms

cytochemical features that distinguish this from other types of ALL. In some cases of leukaemtas with MLL rearrangements it may be poss ible to recog nize distinc t lymphoblastic and monoblastic popul ations , which can be confirmed by immunoph enotyping; such cases should be consid ered Blmyeloid leukaemias . Irrrnu nophenotype ALL with ML L transiocanons. and most especially t(4;1 1) ALL typically have a CD 19+, Cu tn-neqenve. CD24-neg ative pro-B immunophenotype, also positive for CD15l985, 169 11. The Chondroitin sulfate

Definition A neoplasm of Iymphoblasts committed to the B lineage with a translocation between the TEL (ETV6) gene on chromosome 12 with the A ML 1 (RUNX 1)gene on ctecrcsome 12. ICD-O code The provisional code proposed for the fourth edition ol lCD-O is 98 14/3. Epidemiology and clinical features This leukaemia is common in chiklren accounting lor abou t 25% of cases ~ B-ALL It is not seen in infants and decreases in frequency in older children to the point that it is rare in adulthood. Presenting features are generally similar to those of other patients with ALL

Morphology-and cytochemi stry

•

There are no unique morphologic or cytochemica l features that diSlinguish this from ot her types of ALL.

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Imrru1ophenoIyp Basts have a C019+ , C010+ phenotype and are most often CD34+; other phenotypic features. includ ing near or complete absence of COO, C020 and CD66c 1245, 533,9851. are relatively but not absolutely specific. Myeloid-associated an tigens. especially CD13, are frequently expressed, but this does not indicate mixed phenotype acute leukaemia 11551. Genetics The t(12;21)(p13;q22): ETV6-RUNX1 translocation results in the p rodu c tio n of a fusion prote in that likely ac ts in a dominant negative fashion to interfere with normal func tion of the transcri ption factor RUNX1. This leukaemia appears to possess a unique gene expression signature 12469 1. The E1Y6-RUNX1 translOCahon is co nsid ered to be an ea rly lesion in leukaemog enesis, as evidenced by studies of neonatal blood spots that have shown the presence of the translocation Il'l child ren who develop leukaemia many years later 124001. There is evioeoce that the translocation is necessary but not suHicient for the development of leukaemia 12400 1. Postulated normal counterpart This leukaemia appears to d erive from a Been progeni tor rather than from a naematoooetrc stem cell 13441 Prognosis and predictive factors B-Al l with the TEL·AML 1 transloc ation hasa V8fY favourab le prog nosis with c ures seen in >90% of c hildren, espec ially if they have other favo ura ble risk factors. Relapses often occur muc h late r than those at other types of ALL. Beca use this translocation appears to occur as an early event, it has been sug gested that some laterelapses in fact de rive from pe rsistent "preleukaemic· clones that ha rbour the lI'ansIocalion and unde rgo ad ditional genetic events afte r the first leukaemic cICIIe has been eliminated 17191 Ch ildren "MIh this leukaem ia who also harbour adverse prognostic factors . such as ag e ewer 10 years or high white count d o not have as good a prognosis, b ut may still lare better as a g roup than other patients with these same adverse fac tors .

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Fig. U9 Hyperdiploid ALL. G banded karyotwe stlowlng 55d'll'omosomes. indudlng trisomies of 4. 10 and 17and kltrasomy 2t. Thefe are nostruc:llnl abnor'malitJes. (Courtesy of Dr. AJ carrol).

B Lymphoblastic leukaemia! lymphoma with hyperdiploidy Defi nition A neoplasm of Iymphoblasts comm itted to the B lineage whose b last s c ontain >50 and usually <66 c hromosomes, typically withou t uansiocanons or other struc tural a lterations . There is controversy as to whet her specific c hromos omal ad ditions. rather than the specific numbe r of c hromosom es. should be part of the def inition 1894. 1806,21231. ICO-D code The p rovisional co de pr op osed for the fourth edit ion ofICD·D is 981513. Synonyms Hype rdi ploi d ALL; high hyp erd iploid ALL : ALL with favo urable trisom ies.

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This le ukaemia is common in children , accounting for about 25% of c ases of B-ALL It is not seen in infa nts, and decreases in freq uenc y in older c hild ren to the point that it is rare in adulthood. Cli nical featur es Presenting features are generally similar to those of other pa tients with ALL.

cvtocremcet teatores that distinguish this from other types of ALL.

Irrm.mophenotype Blasts are C0 19 +, C01O+ . and expre ss other markers typi cal of B-ALL Most c ases are C 0 34 + and C045 is often ab sent 19851. Patients with T-ALL with hyperdiploidy should not be considered part of this group, though most such patients have near tetrap loid karyotypes. Genet ics Hyperd iploid B-Al L contains a numerical increase in chromosomes. usually without struc tural abnormal ities . Extra co p ies of c hromosomes a re non random. with ch romosomes 21, X, 14 and 4 being the most co mmo n and ch romosomes 1. 2 and 3 being the least of ten seen 19151. Hyperd iploid B-AlL may be detec ted by standard karyotyp ing , FISH or flow cvtomet ric DNA ind ex 11 40 11. Some ca ses that appear as hyperdiploid ALL by standard karyotyping may in fact represent hypodiploid ALL that has undergone enooreouoncetco. doubling the number of chromosomes. Specific chromosomes that appear as trisomies may be more impo rtant to prognosis than the actual number of chromosomes, with simultaneous trisomies 014. 10 and 17 carrying the best prognosis 121231.

Morphology and c ytochemistry There are no un iq ue morph o log ic or B lym phob lastic leukaemia/lymphoma with recu rrent genetic abnorma lities

173

Prognosis and predictive factors Hyperdiploid B-ALl has a very favourable prognosis with cu res seen in >90% of children. especially if their risk p rofi le is favourab le Presence of adverse tee te rs. such as ad vanced age or high white count may ad versely affect the prognosis, but patients may not fare as badly as otbers without this favourable abnormality.

B Lymphoblastic leukaemiallymphoma with hypodiploidy (HypodiploidALL) Definition A neop lasm of Iymp hob lasts committed to the B lineag e whose blasts co ntain <46 chromosomes. A stricter definition of <45 chromosomes , and possib ly even <44 chromosomes , more accurately reflects the clinic al pa thologic entity 115541. ICD-O code The provisional code p roposed for the fourth edi tion ofICD-O is 981613. Epidemiolog y and clinic al features Hyp odiplo id ALL accounts for about 5% of ALL overall, but if the d efinition is restric ted to those with <45 chromosom es the figure is close r to 1%. It is seen in both chil dren and ad ults. although near haploid ALL (23-29 chromosomes) appe ars limited to ch ildhood . Presenting teamre s are gene rally similar to those of other pa tents with ALL

stand ard karyotyping because the hypodip loid clone may undergo endoredo oucanon . doubl ing the number of ch romosomes. reSUlting in a near dip loid or hyperdiploid karyotype. Flow cytomeny c an gene rally detect a clone with a ONA index <10 , though this may be a minor popul ation . FISH may also de tect c ells hyp odi ploid for certain ch romosomes, and this diag nosis should be suspected when there is a discrepanc y between karyo type and FISH results with respec t to the number of ch romosomes present. Prognosis and predictive features. Hypodiploid B-ALL has a poor prog nosis. The prognosis depends on the number of chromosomes: those with 44- 45 chromosomes have the b est p rognosis! 1554). and tho se with near hap loid B-AL L fare worst in some b ut not all studies [900, 15541. There is some evid enc e that. in con trast to other type s of B-ALl. patien ts may fare poorly even if they do not have minimal residual disease follc::Nving therapy.

B Lymphoblastic leukaemiallymphoma with t(5;14)(q31;q32); 1l.3-IGH Definition A neoplasm of IymphOblasts comnitted 10 the B line age in which the blasts harbour

a translocation between the IL3gene and the JG H@ gene. resulting in a variable eosinophilia. This diagnosis may be made ba sed on immuno phenotypic and qenetc finding s even if the bone marrow (8M) blast count is low. ICD-O code The p rovision al co de proposed for the fourth edition of ICO-O is 981 713. Epidemiology and clinical features This is a rare d isease. accounting for < 1% of cases of ALL. It has been reported 1'1 bo th children and ad ults. Presenting clin ic al ch aractensncs may be similar 10 other pa tients with ALL , Of patients may present with an asymptomatic eosinophilia, and blasts may not even be presen n the PB 10 raise the suspicion of Ieu~.

MorpOOlogy and cytochemistry Blasts in this neop lasm have Ihe typical morphology of Iymphoblasts. but the striking finding is the presence ot an incr ease in circulating eosmcotes. This 1$ a reactive population and not part of the leukaemic clone. Immunophenotype Blasts have a CD 19+C0 10+ phenotype Finding even small numbers of blasts with this p henotype In a patient with eosirop hiha should strongly suggest this diagnosis .

Morp holog y and cytochemist ry There are no unique morphologi c or cytochemic al features that distinguish this from other types of ALL Immunophenotype Blasts have a Bcprecursor phenotype, typically C01 9+. C01O+ b ut there are no other d istinc tive ph enotypic features. Geneti cs All patients b y d efinition show loss of one or more chromosomes, having from 45 chromosome s to near haploid . Structural ab normalities may be seen in the remaining chromosomes though there are no spec ific abnormali ties that are characteristically associated Structural abnorma lities are uncommon in near-haploid B-ALL The diag nosis of near haploid or low hypodip loid B-ALL may be missed by 174

Precursor lymphoid neoplasms

Fig. I .10 B IymphoblastJc ~ with l(5;14MQ31:Q32j. Bone manow smear sl'kMng a jXlIl\AbCrId typicaIlymphobIasls along Wlth I'U'l'l9fOO$ mature eosinophil$. Thegrar.J1e Iislnbubon in some 01 the ~ illJIusual, bullhisis not a consisIenl lactor.

Genetics The unique characte ristics of this neoplasm de rive from a functional rearrangement between the fL3 gene on chromosome 5 and the IGH@ gene on chromosome 14, resulting in constitu tive overexoresson of the IL3 gene 18461. Functional consequences of this rearrangement other than eosinophilia . if any. are not well understood. The abnormality is typically detected by standard karyotypi ng ; it can also be detected by FISH. though app ropriate probes are not widelyavailable. Prognosis and predictive features The prognosis is no! considered to be ditlerent from other cases of ALL. though there are too few cases 10 be ce rtain . Blast percentage at diagnosis is not known to be a pred ictive tacror.

B Lymphoblastic leukaemia! lymphoma with 1(1;19) (q23;p I3.3); E2A·PBXl (feF3-PBX1) Definition This is a neoplasm of lympho blasts committed to the B lineage with a t( 1;19) uaosrocatron between the E2A(TCF3) gene on chr omosome 19 and the PBX 1 gene on chromo some 1.

ICD.Q code The provisiona l co de proposed for the fourth edition of ICD-O is 981813. Epidemiology and clinica l features This leukaemia is relatively common in chil dren, accounting for abo ut 6% of cases of B-ALL. It is also seen in adults . but not at as high a frequency. Presenting features are genera lly similar to those of other patients with ALL.

_

logy

and cylochem;stry There are no unique morphologic or cytochemical features that d isting uish this from other types of ALL. Immunophenotype Blasts typically have a CD19 +.CD10+ cytoplasmic u (ctJ) heavy chain-positive ore- e-ceu phenotype. although not all cas es of pre·B-ALl have the t( 1:19). This leukaemia can be suspected even when cu is not determined as these teukaemias typ ically show strong exp ression of COO and lack CD34 , or show very limited CD34 expression on only a minor subset of leukaemic cells 12441 .

Genetics The E2A-PBX1 translocation results in the production of a fusion protein that has an onco ge nic role as a transcri ptional activator, and also likely interferes with the normal function of the transcription factors

coded by E2A and PBX t 112621. The functional fusion gen e resides on chromosome 19, and there may be loss of the derivative chromosome 1 in some but not all cases , resulting in an unbalanced translocation. Gene expression profiling studies have shown a unique signature to this lesion 124691 . An alternative E2A translocation t(17:19) occurs in rare cases of ALL involving the HLF gene on chromosome 17 and is assoc iated with a dismal prognosis. Thus demonstration 01an E2A rearrangement by itself is not a diagnostic criterion for this leukaemia. A subset 01 B-AlL, usually hyperd iploid B-ALL has a karyotypicaIIy idenlicall( 1;19) translocation that involves neither E2A nor PBX1 and sholAdnot be confused with this entity. Cases of B-All with t(1;19) that lack the expected phenotype probably do not represent E2A-PBXl B-Al L.

PrognosiS and predictive features In early studies , E2A-PBX1 was associated with a poor prognosis, but fhis is now read ily overcome with modern intensive therapy. Many treatment protocols no longer require identification of this genetic lesion, but the findings of unique immunephenotypic and genetic features supports its inclusio n as a distinct entity.

B lymphoblastic leukaemla/lymphoma WIth recurrent genetic eboomautes

175

T lymphoblastic leukaemia/lymphoma

•

Definition T lymphoblastic leukaemia/ lym pho b lastic lymphoma is a neoplasm of Iymphoblasts committed 10 the t-een lineage . typ ically composed of sma ll 10medium-sized blast cells with scant c ytopl asm . moderately con de nse d to d isper sed c hrom atin an d inco nspicuous nucleoli, involving bone marrow (8M) and b lood (T-acu te lymp hob lastic leukaemia, T-AL L) or p resenting w ith primary involvement of thym us, nod al or exlranodal sites (T-ac ute lympho blastic lymphoma, T-LBL). By co nvention. the term lymphoma is used when the process is confined to a mass lesion with no or minimal evidence of peripheral blood (PBl and 8 M invo lvement. With extens ive 8M and PB invo lvement, lym phobl asti c leu kaemi a is the appropriate term . It the patient p resen ts w ith a mass lesion and Iymphoblasts in the 8M. the d istinction between leuk aemia an d lym phoma is arbitrary. Fo r many treatment p rotocols . a figu re 01 >25% 8 M blasts is used as lhe threshold lor defining leukaem ia, In contrast to myeloid leukaemi as. mere is no agr eed -upon lowe r limit lo r the pe rcentag e 01 blasts req uired to estab lish a d iag nosis 01 ALL In genera l, the d iag nosis should be avoided wh en there a re <20% bla sts, ICD -D cod e The p rovisional co d e p ropo sed l or the fourth ed ition of ICD -Q is 983713. Epidemiology T-ALl comprises abou t 15% 01 c hild hood ALL; it is mo re common in adolescents than in younger c hild ren and mo re common in ma les than in females . T-ALl comprises ap prox imat ely 25% of cases of ad ult ALL T-l Bl comp rises approximat ely 85-90% of all lymphoblastic lymphOmas; similar to its leukaemic counterpart , it is mos t freq uent in ad olesc ent males but may be seen in any ag e group.

Etiolog y One study repo rted T-ALL in monozygotic twins that share the same rece ptor ge ne rearra ngement 17201. sug gesting

t-een

176

Precursor lymphoid neoplasms

on

M .J. Borcwttz J.K.C. Chan

_~",1

Fig. 9.11 T-lymphoblasticleukaemia, A Blood smear. The Iymphobla sts varyinsize from large cells tosmall cells with a very highnuclear/cytoplasmic ratio, B Bone marrow section.

an in utero origin at the earliest ge netic lesions . Sites of involv eme nt The 8 M is involved in all cases 01 T-All, and in contrast 10 B-All, aIet.Jkaenjc presentations in the face of 8M replacement are UI'"ICO'MlOfl . T-L8l frequently shows mediastinal (thymic ) invotvement, though it may involve any lymp h nod e or extr anod al site. Skin, ton sil, liver, splee n, central nervous system and testis in males may be involved, although presentation at these sites withou t nodal or mediastinal involvemen t is uncom mon. Cli nical features T-ALL typ ica lly presents with a high leukoc yte c ount, and often a larg e med iastinal mass or other tissue ma ss. l ymp hadenopathy and hepatosplenomeg aly are cammon. For a given leukoc yte c ount and tumour b urden, T·Al L pa tients often show relative sparing of no rmal 8 M hae rnetopoie sis c ompared with 8 -ALL T-lBL frequently p resents with a mass in the ant erior medi aslinum , often exh ib iting rap id gr owt h , and some time s p resen tin g as a respiratory eme rgency. Pleural effusions are corrmon.

Mar_

The Iymphoblasts in T-AlL..A..8 L are morp hologi cally ind isting uishab le from those of 8 -AlLJL8 L. In sme ars, the c ells are of med ium size with a high nuclearl cytopl asmic ratio; there may be a co nsid erable size range from small !ymphoblasts

with very conde nsed nuc lear chromat in and no evident nuc leol i 10 large r blasts with finely d ispersed c hromatin and relatively prominent nucleoli . Nuc lei range !rom round to irreglJar to con'lOluted , Cytl>' plasmic vacuoles may be present. sionally blasts of T-Al l may resemble more ma ture lymphocytes ; in such cases immuno phenotypi c stud ies may be requ ired to d istingu ish this d isease Irom a mature (peri pheral) t-een leukaemia. In 8M secti ons the Iymphoblasts have a high nuclear/cytoplasmic ratio, thin nuclear memb rane. finely-s tipple d c hromatin and inconspicuous nucleoli. The numbe r of mitotic fig ures is report ed to be hig her in T-ALL than B-ALl. In T-LBL, the lymph node ge nerally shows com ple te ettaceme nt of arch itec ture and invo lvemen t of the ca psule . Partial involvement in a paraco rnea! loc ation with sparing of germinal ce ntres may occur- Sometimes, a mu ltinod ular pattern is p roduced du e to stretching 01 the fib rous framework, mimic king follic ular lym phoma. A starry-s ky effect may be present, thus sometimes resembling Burkln lymp homa , althoug h typically the nucleoli arld cytoplasm are less prom inent. The blasts can have round or convolu ted nuc lei, Mitol ic figures are often numerou s. In the thymus, there is ext ensive replacement 01 the Ihymic pa rench yma and pe rmeative infiltration . Cases with histological finding s 01 T-LBL with a sig nific ant infiltrate of eosinophils among the lymphoma cells may be assoc iated with eosino philia and mye loid hyperplasia and a Bp 11.2 cytogenetic

occa-

abnormality inyolving the FGFR1 gene 13, 10061 (See Chapter 3). Cytochemistry TIymphoblasts frequently show focal acid phosphatase activity in smear and imprint preparations. though this is not spec ific . Irrmunophenotype The Iymphoblastsin T-ALlABL are usually TdT positive and variably express COla, C02, COO, C04 , CDS, C07 and COB. Of these, C07 and cytop lasmic C03 (cC 03) are most often positive , but 01 these only C03 is considered lineage specific. C04 and COB are frequently co-expressed on the blasts, and C010 may be posit ive. These latter phenotypes are not speci fic for T-AU as C04 and COB double positivity may be seen in T-PLl and C010 in peripheral t-een lymphomas, most commonly angioimmunobiastic r-ceu lymphoma. In addihon to TdT, the most specuc markers to indicate the precursor nature of T Iymphoblasts are CD99, CD34 and COla: the first of these is most useful 118521. In 29-48% of cases. there is nuclear staining for TAl· l , but this does not necessarily correlate with presence 01 TAL-1 gene alteration 1407. 543J , CD79a positivity has been obse rved in approximately 10% of cases 117501. One or both of the myeloid associa ted antigens C0 13 and CD33 are expressed in 19- 32% 01cases 11 139, 22771 . COl17 (c-kil) is occasionally positive; such cases havebeen associated with activating mutations of FLT31 1677 1. The presence of myeloid markers does not exclude the diagnosis of T-ALLjLBL, nor does it indicate

mixed phenotype T/myeloid leukaemia. Many markers characteristic of immature t-eens such as C07 and C02, and even CD5 and cCD3 may also be seen in natural killer cell precursors [20701. Thus it may be very difficult to distinguish the rare true NK precur sor All from T- AlL that expresses only immature markers. C056 expression. while characteristic of NK-cells, does not excl ude t-een leukaemia. T-ALUlBL can be stratified into different stages of intrathymic differentiation according to the antigens expressed: pro-T (cC03 +, C07 +. C02-. COl ao. C034+/-); pre-T (cC03+ , C07+. C02+. COlao. C034+f-) ; co-nee! T (cC03 e-, C07+. C02+ , cora-. C034-) and medullary T (cC03+. C07 +. C02+, COla-, CD34-. surface COO+). The pro-T and pre-I stages are double-neg ative toC04 and C08. and the co-neat T stage shows a double-positive (C04+ COB+) phenoty pe. The medullary T stage expresses only either C0 4 or C08 1187, 8791. Some studies have shown a correlation between the stages of T-cell differentiation and survival 15001· T-ALltends to show a more immature immunophenotype compa red with T·lBL but the groups overlap 123761· Genetics Antigen receptor genes T-AlULBL almost always shows clonal rearrangements of the T-cell rece ptor genes ( TCR), but there is simultaneous presence of IGH@gen e rearrangements in approximately 20% of cases 11749, 2138).

Fli- ' .13 T IyrnphobIasllc 1eIJkaerRa. 1I'I this example. the IyrnphobIasts Iaci nudear convoIution$ The dVomatil is lilely $~. Cytogenetic abnormalities and oncogenes An abnormal karyotype is found in 50-70% of cases 01 T-AlUlBl /830. 8791. The most common recurrent cytogenetic abnormality involves the alpha and delta TCR loci at 14Q11.2. the beta locus at 7Q35, and the gamma locus at 7p14- 15. with a variety 01 partner genes {830. 8791. In most cases. these translocations lead to a dysregulation of transcrip tion 01 the partner gene by juxtaposition With the regulatory region of one of the TCR loci. The most commonly involved genes include the transcription factors HOX 11 ( TLX1) ( lOq24) occurring in 7% of childhood and 30% of adult T-Al L, and HOX1 IL2 (TLX3) (5q35), occurring in 20% of childhood cases and 10-15% of adu lt 18301. Other transcr iption factors that may be involved in translocat ions incl ude MYC (8Q24.1), TAU (l p32), RBTN1 (LM 01) (11p 15), RBTN2 (LM02) (11p13) and LYL 1(19p1 3) 1519, 830) The cytoplasmic tyrosine kinase LCK (1p34.3-35) can also be

FlO- ' .12 T/ynllI'lObIaStic 1'fnllhOma. A low ~tion 01 a tyn'4lh rode ~ ~ repIac:ement by ~ 1ympI'loma. Nwerous IrIgibIe 00dy rnacropnages ll(ll scauered fYoul1IOul the rode. B H9'I rnagM:atlorl ol lhe specimen lin (A) s/'JcJwWlg ~ WIltI I'llUI"d tooval to ~-s/'Iaped nudei withdisperse(l etvorna!Jn a"d lisra bul nollllUSUaly PfOIl'W*'Il ru:W. 5eYeraI nvloIic ligIns en preset'(

T lymphoblastic leukaelTllaJlymphoma

177

Gene expression profiling studies have identified several gene expression signatures. some of which correspond to specific stages of normal thymocyte development: LYl1+ sig nature corresponds to pro-T stage. HOX 11+ to early cortical stage, and TAL1+ to late co rtical thymocyte stage /6891. The HQX11+ group appears to have a relatively favourable prognosis. Postulated normal counterpart t-een progenitor (T-ALL) or thymic lymphOCyte (T-LBL).

Fig. 9.14 T ~!ynllhoma.

lowmagriflcabon

stowi"lg a ~a~pattem ltlalcan

sometimes ITWlIC IoIil::l8" lymphoma.

•

involved in a translocation. In many cases transiocanons are not detected by karyotyping but only by molecular genetic studies. For example, the TAL 1locus is altered by translocation in about 20-30% of cases of T-ALL. In only about 3% of cases c an a t(1, 14)(p32;q1 1) transloca tion be detected , but much more often it is fused to the SIL gene as a result of a cry ptic interstiti al deletion at ch romosome 1p32 1281,914 , 1046 1, Aberrant TAL1 expression interferes with differentiation and proliferation by inhibiting the transcri ptional act ivity of E47jH EB {16151. Other important transloc ations in T-ALL include PICALM-MLLT10 [CALM-AF 10, t( 10:11) (p13:Q14)), occ urring in 10% of c ases, and transloc ations involvin g MLL (8%), most often with the partner ENL at 19p 13 {B301. Neither of these is T-ALL sp ecific, as the first occurs in AML and the seco nd in B-ALL. Abe rrant expr ession of TAL1, LYL1, HQX11 and HOX11L2 appea r to be mutually excl usive from eac h other and also from PICALM and MLL transioc ations, sugges ting non-overlapping, patho-

178

Precursor lymphoid neoplasms

gen etically distinct subgroups (5191. Deletions also occur in T-ALL. The most important is del(9p), resul ting in loss of the tumour suppressor gene CDKN2A (an inhibi tor of the cvcun -oepenoent kinase CDK4). which occurs at a frequency of about 30% by cytogenetics, and a highe r percentage by molecular testing. This leads to loss of G1 control of cell cycle. About 50% of cases show ac tivating mutations involvi ng the extracellular heterodim ertzation domain and/or C terminal PEST domain of the NOTCH 1 gene , which encodes a protein critical for early t-een dev elopm ent {2385}, The d irect downst ream target of NOTCH1 appears to be C-M YC, which contributes to the grow th of the neop lastic ce lls [23861. Acc ord ing to one study , NOTCH1 mutation is asso ciated with shorter survival in adult but not paed iatric pa tients {24gB}. In abou t 30% of cases, there are mutations in hCDC4 gene. a negative regulator of NOTCH " These missense mutations result in increased half-lite ot the Notch1 protein {13751. 4

Prognosis and predictive factors T·ALL in childhood is generalty considered a higher risk disease than B-AlL though this is in part due to the frequent presence of high-risk clinical features (older age, higher while blood cell count). HO'Nevet", T-ALL patients without high-risk features dO not fare as well as B-ALL standard risk patients unless intensive therapy is given. Compared to B-ALL patients, T-All patients have increased risk for induction failure, early relapse and isolated eNS relapse 18091 _In cont rast to B-ALL. while count does not appear to be a prognostic factor. The presence of minimal residual disease following therapy is a strong adverse prognostic factor 124061. In adult protocols, T-ALL is treated similarly to other types of ALL. The prog nosis of T-ALL may be better than B-ALL in adults. though this may reflect the lower incidence of adverse cytogenetic abnormalities. The prognosis of T-LBL. as with other lymphomas, dep end s on the age of the patient, stage and LDH levels /15121. Rare c ases of indolent T lympho b lastic proliferation involving the upper aerodigestive tract, charact erized by multiple loca l recurrences but no systemic dissemination, have been desc ribed 12106. 23231. These cases are morphologically and immunophenotypica lly indistinguishable from T-l BL. bu t lack clon al rearrange ments of the TCR genes.

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~.

C HAPTER 10 Mature B·cell Neoplasms

Chronic lymphocytic leukaemia Ismail lymphocytic lymphoma B-cell prolymphocytic leukaemia Splenic marginal zone lymphoma Hairy cell leukaemia Splenic tyrnphomaIIeukaemia, unclassifiable Lymphoplasmacytic lymphoma Heavy chain diseases Plasma cell neoplasms ExtranodaI marginal zone lymphoma 01 mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma FoUicular lymphoma

Primary cutaneous follicle centre lymphoma Mantle cell lymphoma Diffuse lerge B-ceillymphoma (DLBCL), NOS T-ceUhli stiocyte-rich large s-.celllymphoma

Primary DLBCL 01 the CNS Primary cutaneous DlBCL, leg type EBV positive DLBCL of the elderly DLBCL associated with chronic Inflammation Lymphomatoid granulomatosis

Primary mediastinal (thymic) large B-eelllymphoma Intravascular large 8-celilymphoma

," .....

ALK positive large B-ceillymphoma Plasmablastic lymphoma Large B-ceillymphoma arising in HHV8-associated multicentric castleman disease Primary effusion lymphoma

Bur1
••

•

•

•

4

Chronic lymphocytic leukaemia/small lymphocytic lymphoma

H.K. Muller-Hermelink E. Montserrat D. Catovsky

E.Campo NL Harr is H. Stein

,

Defi nition Chronic lym phocytic leukaemia/s mall lymphocytic lymphoma (C Ll/SLL) is a neop lasm com posed of monomorphic small, round to slightly irregular B lym phocytes in (he peripheral blood (PS) , bone marrow (8 M), spleen and lymph nodes. admixed with pro lymphocytes and parammunoblasts forming proliferation centres in tissue infiltrates.The CLUSlL ceus usually coexpress COS and CD23. In lhe absence of extramedullary tissue involvement. there must be ~5x l ()91l monoclonal lymphocytes with a ell phenotype in the PB. The intemanoret Workshop on Chronic Lymphocytic Leukemia (IWell) report requ ires that the lymphocytosis be p resent for at least 3 months and also allows for the d iagnosis of eLL to be made with lower lymphoc yte counts in patien ts with cytopenias or disease-related symptoms 1873AI. Whethe r patients who would have fulfilled the Criteria In the past for Cll but who luHili the criteria only for monoclonal B lymphocytosis (MBl) are better considered 10 have low stage Cll or MBl remains to be determined. Some may prefe r to sun consider many of these cases more like Cll. The term Sll is used for non- leukaemic cases with the tissue mor phology and immunophenotype of Cll. The IWCl l definition of Sll requi res lym phad enopathy, no cytopen ias due to BM infiltration by Cll./Sll and <5x 1CP/l PB e-ceus [873AI . ICD-O code

9823/3

Epklemiology Cll is the most common leukaemia of adults in Western countries . The incidence rate is abon 2-6 cases per 100,OCO person per year, increasing with age reaching 12.81 100,000 at age 65 , the mean age at diagnosis 11888]. It is now diagnosed more often in younger ind ividuals 15251. e l l has a male:fema le ratio of 1,5- 2: 1. CLUSll accounts for 6.7% of non-Hodg kin lymphomas in biopsies (5 11. It is very rare in far Eastern countries. This low incidence is maintained in migrant populations speaking in favou r of a genetic predisposition. 180

Mature 8 '< e1l neoplasms

Etiology B-ce ll recep tor s (BCR) of Cll ce lls demonstrate high ly selected immun og lobulin heavy c hain variab le (lGH V) gene usag e or even very simila r entire antigenb ind ing sites, coded by both heavy and lig ht chain genes, and thus d iffer from the much b roa d er diversity found in normal B lymphocytes. These findings argue in favour of a limited set of (auto-)antigens promoting div ision of precursor cells and clonal evolution 1423, 1153,22431 . Sites of involvement Peripheral blood and BM are usually involved, lymph nodes, liver and spleen are also typ ically infiltrated, and other exiranoda l sites may occasionally be involved. Rarely, patients with ClllSLl present with aleu kaemic tissue involvement, but usually develop BM and PB involvement during the evolution 01 the disease.

Clinical feature s Clinical features are very variable including presentation, co urse and outcome. Most p atients a re asym ptoma tic, bu t some presen t with fatigue, autoimmune haemolytic anaemia , infections, sple nomegaly, hepatomegaly, lymphadenopathy or extranodal infilt rates 1221 , 18051. A small M-eomponent may be found in some patients .

Monoclonal B-cell lymphocytosis Healthy indiv iduals may show monoclonal or oligoclonal Been expansions with the characteristic phenotype of e l l in about 3.5% of tested subjects >40 years old ]1395, 1823). Monoc lonal B·ceil lymphocvtosis with a non-cu. phenotype (CD5-) may correspond to similar phenomena in other B-cell neoplasms [301. Whether MBl is a predisposing condition or even a precursor of overt CLL has to be elucidated.

~. """'" . ". C'

'\30''''''

~......

s ·l

..

~.'" Fig. 10.01 AALymph node in'o'Olved bydllooic ~ leukaemja, showing regularty·spacedproliferation centres in a dar1l background (Giemsa stain). B High mllQflilicatiorl ilIustrabng a mixture of small lymphocytes with sen C'r'JPIasrn ed dYomattn. SOOlasIig1Iy larger ~ wiIIllTO'e disper$ed cMmabn and small ~ and single paralnwnunoblasts (arrows), lIIrtlidl are larger cells WIth I'OIJnd to oval nudei, dispersed chromalJn and a

""""-

-logy

Lymph nodes and spleen

Enlarged lymph nodes in patien ts with CLLlSl L show effacement of the architecture , with a pseuootomcurar pattern of regularly-distributed pale areas corresponding to proliferation centres contain-

ing larger cells in a d ark bac kground of small cells 11 84, 12731 . Involvement may be limited 10 inle rfo llic ular areas. The p redominant ce ll is a small lymphoc yte, which may be slig htly larger than a normal lymphocyte, w ith c lumped c hroma tin,

usually a round nucleus, and occas ionally a small nucleol us. Mitotic ac tivity is usually very low. Prol iferation centres conta in

a continuum of small, med ium and large cells. ProIymphocytesare smallto mediumsized cells with rela tively c lumped chromatin and smallnucleoli; parairrmunoblasts are larger cells with round to oval nuc lei, dispersed chroma tin, cen tral eosinophilic nucleoli and slightly basophilic cytoplasm. The size of pro liferation centres and number of pa raimmunoblasts vary from case to case, but there is no correlation between tymph node histology and clinic al course 11841. In the spleen , white pulp illV'Cllvement is usually prominent. but the red pulp is also involved; proliferation centres may be seen bu t are less con spicuous than in lymph nodes. In some

cases, the small lym phoi d cells show moderate nuc lear irregularity, which c an lead to a differential diagnosis of man tle cell lymp homa {2351· Some case s show plasmacytoid differentiation. Bone marrow and blood On BM and PB smears, CLL cells are small lymphocytes with clum ped ch romatin and scanty cy top lasm 11 9 11. Smudge or ba sket ce lls are typi cally seen in PB smears, The p rop ortion of prolym ph oc ytes (larg er cells with p rominent nuc leoli) in PB films is usua lly <2%. Increasing number s co rrelate with a more aggressive d iseas e co urse. More tha n 55% prolympho c yles, however, would favour the diagnosis of B-cell prolymphocytic leukaem ia ( B-PLL ). Atypical CLL shows less condensed nuclear chromatin an d nuc lear irregularities in PB lymp hocytes. These findings are more frequent in cases with trisomy 12 and other chromosomal abnormalities {19 11. Bone marrow involvement as seen in treph ine b iop sies may be interstitial, nodular and /or diffuse {1509, 18881: proliferation centres are less common in the 8M than in lym ph nodes; pa ratrabecurar aggregates are not typical. The definition 01 m inimal 8 M involvement required to diagnose CLlISLL in the absence of other

de fining features is not established , although the IWCLl describes >30% lymphoid cells as "charac tenstcanv" present

18l 3AI lmmunophenotype Using flow cytometry, the tumou r cells exp ress dim surface IgM/ lgD, C020, C022, COS, C019, C079a, C023, C043 and Co 11c (wea k). COlO is negative and FMC7 and CD79b are usually neg ative or weakly expresse d in typical CLL. The immunop henolype of PB lymphoc ytes has been integ rated into a scoring system that helps in the differential diagnosis between CLL and other B-c ell leukaemias 1t 430, 151 11 , In tissue sections. cy toplasmic Ig may be detectable, and cvcun 01 is negative 12508 1; howeve r cvcnn 0 1 has been detected in cells of the proliferation centres 116141. Some cases may have an atyp ical immunep henotype (e.g COS- or C023-, FMC7+ or C01 1c+, strong slg , or C079b+) 1492 ,14291 . Genetic susceptibility CLL has the highest genet ic pred isposition of all haernatologic recotases. A family predisposition can be documented in 5- 10% of patents with CLL based on finding 2 or more cases in the same family. The overall risk is 2-7 times increased in

Chronic lymPhocytIC leukaemialsmalllymphocytic lymphoma

181

firsl degree tetanves of Cll patients 18 10, 19901. Family members of patients with Cll show an increased incidence of ellphenotyp e monoclonal Been lymphocytosis at all ages, but espec ially in thase <40 years old 15301.

Genetics Antigen receptor g enes IG genes are rearranged with 40- 50% of

cases unmutated (> 98% homOlogy with ge rmline) and 50-60% showing somatic hypermutation 1505, 8761. These two subtypes differ in many other biologica l and clinical parameters. IGHV gene usage in Cl l is highly selective, and etten associated with autoantibody reactivity 11658) , BCR signaling is most important in unmutated ell 1403, 538, 1252). Gene expression profiling

,

Mutated and unmutated Cl l show a single distinctive signature, although there is a group of genes that distinguishes these two genetic subtypes 11160. 18671· The tyrosine kinase ZAP-70 is among the genes whose expression is associated with an IG H V unmutated Cll genotype 124021. Ftow cytometry assays for ZAP-70 have been developed as a surrogate for Cl l mutational status; however, in up to 20% of the cases the mutationa l status and ZAP-70 expression are d iscordant 1490, 1653, 18221· Cytogenetic abnormalities and oncogenes About 80% of the cases have cytoge netic abnormalities de tected by FISH 160 11. About 50% of Cll show del 13q14.3, about 20% trisomy 12 and, less commonly. deletions of 11q22-23, 17p 13 and 6q21 1601 ,1196. 1197,1 4291 . Thed istri· button of these abno rmalities varies based on mutational status. The possible Tab1l 10.01 Retation of VHmutaliOn slalusand genorNc abefrationl ll CLl(1197) Mutated VH 11"'132 (44%)

Unmutated VH

80'10 65"4

84'4

50"4

26'Il.

iTriSOmy 12 11qdeleIIon'

15"4 4%

19"4 271i.

17p~'

3% 7"4

10"4 35'4

Abemtion

cmaI aberTMon& ~ 3q ~. Isolaled 13qdeleIO'l'

17por 11qdelebon'

n:168 (56'1l.)

(8'Il.

• Signi~cant dll!$!tlfICe belWeen cases 'Mlh and WIth· out VH mutations.

182

Mature B-c ell neoplasms

Fig. 10.05 Aow t)'1omeIJy detection of ZANO in ClL. The left pIol shows \tie selecbon of the ~ subpopWbons ac:etlIding to the ~ (T-<:eIs in dar1l blue. NK<eIII iI'llight blue. CI..L cells iI'lllf'llllge and resdJaI normal B-cells n grey). The CLl cellsate C05+ (see n left plot) arw:l CD19+ (seen II otherpIols). The plotin !he centrll shows a CLl wilh noIN'·70 expression (2".4 positive CI..L cells) and the plot on the right a CI..L with t9 ZAP·70 e.pression (65% positive CLlcelli). CLl cases with mote than 20% ZAp·70 e~ are usuallyconsidered as positi ve.

targets in the 13q14.3 region are two micro-RNA genes, miR-16- 1 and miR-15a, ATM in the l1q22-23 region and TP53 in the 17p13 region 1475, 601, 19571. A specific micro-RNA expression signature that includ es miR- 16-1 and miR-15a has been reported to distinguish between mutated and unmutated Cll and ZAP-70 negative versus positive Cll13151. Postulated normal counterpart Antigen expe rienced B-<:eIl14241 . Prognosis and predictive factors The Rai and Binet clinical staging systems are used to define disease extent and prog nosis 1221, 18051. New biolog ical prognostic factors have become increasingly impor tant especially in early stage CLL 1222, 1129, 1986J. Patients withmutated Cl l have a bette r progno sis than those with unmutated Cll, at least for those with a low stage (median survival 293 months versus 95 months for patients with Binet stage A) 18761. Expression of ZAP-70 and CD38 are both associa ted with an adverse prognosis 17901 . Dell1 q22· 23, del17p and del6q are associated with a worse outcome and isolated del 13q14.3 is associated with a more favourab le clinica l course 1475, 6011 . Usage of VH3-2 1 independen t of VH mutation status is an adverse prognostic marker 122441. Additional adverse pred ictive factors inctude a rapi d lymphocyte doubhog time in the PB «12 months) and serum markers of rap id celt turnove r. includin g elevated thymidine kinase, sCD23 and ~ · 2 microglob ulin 12221.

Progression and transformation of Cl l to hig h grade lymphoma Over time, Cl l may show an increase in cell size and proliferative activity as well as confluence 01 proliferation centres in lymph nodes and BM. Often, this may correlate With an increase in prolymphOcvtes in the PB. Progression of ell to B-PLl is extremely rare. 2-8% of pat ients with Cll develop dif· fuse large B-<:elllymphoma (OlBClj and < 1% develop classical Hodgkin Iyr1'lpt"ona (Hl) 12691. The median survival for patients with DlBCl (Richter's syndrome) is less than one year. The majority Of the DlBCl have been reported to be clonally related 10 the previous Cl l and are unmutated. whereas the cioneuv unrelated cases 01 DlBCl usually occurred in rnutated Cll 11385, 22401. The vast majority of Hl cases occ ur in mutated ClL. Epstein-Barr virus (EBV)-associated Hodgkin Of Reed-Sternberg (RS) cel ls frequently are unrelated to the Cll clone 11 3851. Some Cll cases show scattered EBV· positive or sometimes negat ive ReedSternberg cells in the backg round of Ctt. These cases should not be diag nosed as Hod gkin lymphoma. The diagnosis of Hodgk in lymphoma in the setting 01 CU requires classical RS cells in an aoorconate background . EBV-associated Iymphoproliferative disorders includ ing Hodgkin lymphomas may occur after fluda rabine therapy 14. 22341 .

• B-cell prolymphocytic leukaemia

Definition B-cell prolymphocytic leukaemia (B-PLl) is a neoplasm of B prolymphocytes affecting the pe ripheral b lood (PS ), bone marrow (8 M) and spleen, Prolymphocytes must exceed 55% of lymphoid cells in the PB, Cases 01 tran sformed ch ron ic lymphocytic leukaemia (ell). ell with in· creased p rolymphocytes and lymphoid prQifefationS with rela~ smlar m0rphology bu t carrying the t( 11;14)(q13:Q32) translocation are ex cluded. IC().() code

983313

Epidemiology B-PLl is an extremely rare disease, com prising approximately 1% 01 lym p hocytic leukaemias. Mos t pa tients are over 60year-old . with a median age of 65-69 and similar male.temale distribution 11456 1.

Sites of involvement The leukaemic cells are found in the PB, 8M and sple en .

Clinical features Most pat ients present with B symptoms, massive sp lenomeg aly wi th abs ent or minimal per ipher al lymp had eno pathy, and a rapid ly rising lymphoc yte count,

usually over 1(X)x1()llA... Anaemia and thrombocytopenia are seen in 50%

{11941. Mo55% and usually >90%) of the circulating cells are prolymphocytes -medium-sized cells (twice the size of a lymphocyte) with a round nucleus, moderately condensed nuclear chromatin. a prominent central nucleolus and a rela tively small amount of faintly basophilic cytoplasm 1750 . 1456 1. Although the nucleus is typically round . there may be some ind entation in some cases. The 8 M shows an interstitial or nodu lar infiltrate of nocieotateo cells with an intertrabe c ula r d istribution. Tissues other than bone marrow The morpho logy of B-Pl l in tissues is not we ll know n since pr evious histolog ic al studies have inc lude d cases with the t(11; 14) transloc ation that co rrespon d to leu kaemic variants of mantle cell lymphoma (MC l ) 11892.1963). The sp leen shows expanded white pulp nodul es and red pu lp infiltrat ion by intermediate to large ce lls with abu ndan t c ytoplasm and irregu lar or round nuclei with the presence

•. •

E. Campo 0 , Catovsky E. Montserrat H ,K , Muller-Hermelink N.L. Harris H . Stein

of a central eosino phil ic nuc leolus 118921. l ym ph nodes show d iffuse or vaguely nodular infiltrates of similar cells . Proliferation centres (pseudofollicles) are not seen. Oistinctioo from bl astoid variants of MCl . splenic ma rginal zone lymphoma . and Cll with an inc reased number 01 prolymphocytes may be diff icult 00 morphological grounds. The differential diag nosis req uires immunophenotypic and genetic studies. in part to rule out the presence 01 the t{1 1. 14) translocation or c yctm 01 overexpresson. Immunophenotype

The cells of B-PLL strongly express surface IgM +/ - IgO as well as B-c ell antigens (C019, C02O . C022. C079a and b. FMC7) : COS and C023 are ooly positive in 20 -30% an d 10-20% of cases, respectively 1542. 1194. 18921. ZAP-70 and C038 are expressed in 57% and 46% 01 the cases but they are not related to the mutational status 01 the immunoglob ulin genes

15421· Ge netic s Antigen receptor genes Immuno g lo bulin genes are c lonally rearranged with an unm utated heavy chain ge ne in ab out half of the c ases. All B--PLL

--

'

.~

B-cell prolymphocytic leukaemia

183

have been reoorteo to use mem bers 01 the VH3 (68%) and VH4 (32%) gene families 15421.

the progressive course and relative treatment resistance of B-PLL. FISH analysis detects deletions at 13q14 in 27% of the cases 15421. Trisomy 12 is unconvnon

Cytogenetic abnormalities and oncogenes Initial studies had demonstrated the t(11 ;14)(q13;q32) translocation in up to 20% 01 B-PLL 12741 Howe ver, these cases are now c onsidered leukaemic variants of MCL {1892, 1963, 2439J Cornplex karytotypes are c ommon 11963J Del(17p) is dete cted in 50% 01 the cas es 15421 and is associated with TP53 gene mutations 11 2771. This probab ly underlies

15421.

•

164

Mature B-cell neoplasms

Postulated normal cou nterpa rt Unknown mature B-cell. Prognosis and pred ictive factors B·PLL respond s poor ly to therapies for eL L and median survival is 30- 50 months 1542. 18921 Neither ZAP-70 expression. CD38 positivity. 17p dele tions nor the

mutational status 01 the immunoglobu lin genes seem to correlate with survival 15421. Splenectomy may improve the patient's symptoms. Responses have been recorded with the ccnomatco CHOP (cytcxan. adriamycin. vincr istine and prednisone), and the nucleoside analogs fludarabine and cladribine. A co mbination of chemotherapy and ntuximab may b e a reasonable approach to treat these patients 11194J

Splenic B-cell marginal zone lymphoma

Definition Splenic marginal zone lymphOma (SMZl) is a Been neoplasm composed of small lymphocytes which surrCM.Jnd and replace the splenic white pulp germinal cen tres , efface the follicle mantle and merge with a peripheral (marginal) zone of larger ceus includ ing scattered transformed blasts: both small and larger celts infiltrate the red pulp . Splenic tater lymph nodes and bone marrow (8M) are often invotved : lymp homa cells may be found in the peripheral blood (PSI as villous lymphocytes

ICD-Ocode

9689/3

Synonym Splenic lymphoma with circulating villous lymphoCyte s (SLVL).

Epidemiology SMll is a rare disor der, comprising less than2% of lymphoid neoplasms 179}. but it may accoun ttor most cases of otherwise unclassifiable ch ronic lympho id

ieckaemies that are CD5-, Most patients are over 50 and there is an equa l se x incidence 11951.

J'-

P. G. Isaacson M .A Piris F. Berger S,H. Swerdlow

C, Thieblemont S, Pillaluga NL Harris

Sites of involvem ent The tumo ur involves the spleen and splenic hilar lymph nodes, BM and often the PB. The liver may be involved. Peripheral lymph nodes are not typ ically involved 1195, 14971. Clinical features Patients present with splenomegaly, sometimes accompanied by autoimmune thrombocytopenia or anaemia and a variable presence of PB villous lymphocytes. The BM is regularly invol ved, but pe ripher al lymphadenopathy and extrarooar infiltration are extremely uncommon. About one third of the patients may have a small monoclonal serum protein, bu t marked hyperviscosity and hypergammaglobulinaemia are uncorrrnon 1195, 1497 1. An association with hepa titis C virus has been described in southern Europe 172, 9261 Morphology In the splenic white p ulp, a central zone of small round lymphocytes surroun ds . or more commonly replac es reactive germinal centres with effacem ent of the norma l follicl e man tle 11 0 14, 149n This zone merges with a peripheral zone of small to med ium-sized c ells with more di sp ersed

Fig. 10.08 Splenic rnatgIl'IaI zone ~. Gtoss ~ 01 spleen shoIfIling m;rled e~ dh wtWI pUp. as.el as Plllralion dille red pUp,

chroma tin and abundant pale cytoplasm. which resemb le marginal zone cells and interspe rsed trans formed blasts. The ted pulp is always infiltrated. with both small nodules at the large r cells and sheets of the small lym phocytes, which often invade sinuses. Epithelioid histiocytes may be present in the lymphoid aggregates, Some c ases may have a markedly pred ominant population of the larger marginal zone-li ke cells 18781. Plasmacytic differentiation may occur and in rare c ases, clus ters of p lasma cells may be present in the ce ntres of the white p ulp nodules, In sp lenic hila r lymp h nodes the sinuses are dil ated an d lymphoma

........._

~~~_

Splenic B-eell marginal zone lymphoma

185

in the PB, they are usually, but not always , characterized by the presence of short polar villi. Some may appear p lasmacytoid 114571. The differential diagnosis includes other small Bccell lymphomasJ leukaemias. including ch ronic lymphocytic leukaemia. hairy cell leukaemia, mantle cell lymphoma. follicular lymphoma and Iymphoplasmacytic lymphoma. The nodular pattern on BM biop sy exclu des hairy cell leukaemia. bu t the morphologic featu res o n BM examination may not be sufficient to disting uish between the other subtypes. This requires integration with the morphology and immunophenotype of the cells in the PB and BM.

Irrrounophenotyp

Fig. 10.09 SpIel'IiClTI<WgI'Ial zone lymphoma. Peripheral blood containing tumour cells with ~ar villi (villous IymptlocylesJ.

,

surrounds and replac es ge rminal centres, but the two cell types (small lymphoc ytes and marginal zone cells) are etten more intimately admixed without the forma tion 01 a distinct "marg inal" zone. This has given rise to doubts about suggestions that the tumour arises from sp lenic marginal zone cells. In Ihe BM there is a nodular interstitial infi ltrate cytologically similar 10that in the lymph nodes. Occasionally, neopl astic ce lls surround reactive follic les. Intrasinusoid allymphom a cells, better revealed after C020 immunostaining , are a helpful feature although they are sometimes observed in othe r lymphom as [7271. When lymphoma cells are p resent

Tumour cells express surface IgM and usually, but not always, Ig O, are C020+ , C 0 79a +, C05-, C01O-, C023-, C043and ann exin A1 - P014, 14281. C0 103 is usually. but not always, negative and cyclin 0 1 is absent 119451. Staining for Ki67 shows a d istinctive targeto id patte rn based on the presenc e of an inc reased g rowth fraction in both the germinal centre (if p resent) and the marginal zone. The absence 01 cycnn 0 1 and the infrequent exp ression of C05 are usefu l in excluding mantle cell lymphOma and chronic lymphocytic leukaemia respectively. Absence of ars-exm A1 excjuoes hairy ceueckaeraa. and absence 01 COlO and BCl6 helps to exclude follicular lymphoma 119451. Ge netics Antigen receptor genes Immunogl ob ulin heavy and lig ht chain genes are rearr anged and approximately ha lf 01 th e c ases hav e somatic hypermutation . Bias in VH1-2 usage has been

found in both mutated and unmutated

cases suggesting that this tumour derives from a highly selected Been populat ion

1231. Other

biased VH gene usage has also been reported 11251. In addition , intraclonal variation has been rarely detected. suggesting ongoing mutations 1624. 249n

Cytogenetic abnormalities Allelic loss 01 ch romoso me 7q31·32 has been de sc ribed in up to 40 % of SMZL 11 416 1. Oysregulalion of the CDK6 gene located at 7q21 has been report ed in several cases of SlVL wilh translocations involving this region 14741. Trisomy 3q and a number 01 other cytogenetic abnorma lities have been described 1319, 766, 859, 929 , 1669llNhile BCl2rearrangement and t(14 ;18) are absent. CCNDl rearrangement , t(11 ;14) and cyclin 01 express ion have been reported in a small propoton 01 the cases; however, the possibility that these cases represent examples of mantle cell lymphoma has not been excluded, since c ycnn 0 1 exp ression is absent Irom weu-cbaractere ec cases of SMZl119451 . Transloc ation t(1 1; 18), common in extranodal marg inal zone lymphoma of mucosaassociated lymphoid tissue (MALT) type. is not a leature of SMZL 1575, 18371. Splenic marginal zone lymphoma has a specific transcnptooat profile compared with other B-eell , especially small B-eell lymphomas. This specific molecular signature includes genes involved in the signaling cascade of the AKT1 pathway and B-eell receptor signaling {374. 21971. Postulated norma l counterp art B-ce ll of unknown di fferentiation stage, The prese nce 01 IG gene somatic hypermutations in 50% of ca ses suggests

B Infillnlbon 01 red pulp sinuses. 186

Mature 8-eell neoplasms

I

fig. 10.11 Splenic margI'IaI ZOfIll~ . .. SpIeric!*lr Iymj:tII"IJde s/'loIWIg a nodlNr infillra1e C High ~ shows a rrU1ured smaI ~ and larger cells.

exposure to antigen in the germinal centre microenvironment.

Prognosis and pred ictive factors The clinical course is indolent , even with 8M involvement 172. 195, 1538, 2196, 219n Response to chemotherapy of the type that is typically effective in other chronic lymphoid leukaemias is often

I

poor, but patients typically have naematoloqrc responses to splenectomy. with long-term survival. Transformationto large B-cell lympho ma may occur , as in other indolent Bccetl neoplasms 115381. HeVpositive cases have been reported to respond to antiviral treatment using interferon r with or without ribovarine 1926. 21951. Adverse clinical prognostic factors

include a large tumour mass or poor general health status 13741. A clinical scoring system has been proposed 1721 and cases with mutated TP53 may show an aggressive course 18581. The presence of 7q dele tion and unmutated IGHV genes may be associated with an unfavourable outcome 123, 22631.

,

I

( Splenic B-eefl marginal zone lymphoma

187

Hairy cell leukaemia

Definition Hairy ce ll leukaemia (HCL) is an indolent neoplasm of small mature B lymphoid ce lls with oval nuclei and abundant c ytoplasm with "hairy" projections invo lving per ipheral blood (PBl and diffu sely infiltrating the bone marrow (8 M) and splenic red pulp.

ICD-O code

994013

EpidemOOgy Hairy ce ll leukaemia is a rare disease. comprising 2% of lymphoid leukaemias . Patients are predominantly midd le-aged to elderly adults with a median age of 50 years ; HCl has been di agn osed rarely in patients in their 20's, but is exceptionally unc ommo n in children , The male.ternare rali o is 5:11642/ .

Etiology

•

Although the natu re of the underlyin g oncogenic events in HC L is not known, severersiudies provide an explanation for many of the unique features of this entity 1157. 348 ,22351 (Table 10.02 ).

Sitesof involvement Tumour c ells are found predom inantly in the 8M and spleen . Typically a small number of c irc ulating c ells are noted. Tumour infiltrate s may occu r in the liver and lymph nodes, and oc c asionally also in the skin . Rare pat ients demonstrate prom inent abdom inal lymphadenopathy, whi ch is associ ated w ith large ha iry cells; this may rep resent a form of transformation 119991.

.-smears.

Fill. 10.13 Hairy cel leukaemia.

K. Foucar 8 . Falini D. Calovsky H. Stein

Cli nical featur es The most common pr esenting symptoms include weakness and fatigue, left upper quadrant pa in, fever and bleeding . Most patients present with sple nom egaly and pa ncytopenia with few circulating neoplastic cells. Monocyto penia is ch arac teristic. Other common distinctive manifestafions include he patomegaly and recurrent ooportunistic infections. while less corrroon unique findings includevasculitis , bleeding d isorders. neurologic disorders , skeletal involvement and othe r immune dysfunc tion /95 1}.

Fig. 10.14 Hairy oeI leukaemia. The spleenis ~ enlarged wittI ddIuse eqllllSion of the red pulp ....,. pulp is nol. discema ble. Numerous blood ceII lBkes of vaf}'ing size are visible.

Mor phology Peripheral blood and bone marrow Ha iry ce lls a re sma ll to med ium-sized lympho id cells w ith an oval or indent ed (b ean -shaped ) nucl eus w ith hom og eneou s, spon gy. g rou nd- gl ass c hromatin that is slig htly less c lumpe d than that of a normallyrnphoCyte . Nuc leol i are typicall y absent or inconspicuous. The c ytoplasm is abundant and pa le blue , with circumferent ia l "h airy" p rojections on smears 1212, 19991. Occasionally the cytoplasm contains d iscrete vacuoles or rod-s haped inclusions that rep resent the ribosom e lamellar complexes that have be en identified by electron micr oscopy 11999J. The d iagnosis is be st made on 8M biopsy. The exte nt of 8 M effacement in HCl is variab le . The pr imary pattern is interstitialor pa tc hy with some preservation of fat and naematoporetrc elements . The infiltrate is c haract erized by wideIy...gpaced lymphoid ce lls with oval or indented nuclei.

in contrast to the c lose ly packed nuclei of most other ind olent lymphoid neoplasms invo lv ing the 8 M. The abundant cytopla sm and pr om inent cell borders may p rod uc e a "frie d-egg " ap pearance 1212, 19991. Mitotic figures are virtually absent. When inf iltration is minimal, the subtle c lusters of hairy cells can be overlooked. In patients with advanced d isease. a dr!fuse solid infiltrate may be evident. The obvious d iscr ete aggregates that typ ify 8 M infiltrates 01 many other chronic JyrTVioprol iferative d isord ers are not a feature of HCL. An inc rease in reticu lin fibres is associ ated with all hairy c ell infiltrates in 8 M and othe r sites, and often results in a "drytap ". In a proport ion of patients, the 8M is hypocellular with a loss of haematopo ietic eleme nts , espec ially the gra nulocyt ic noeage, which can lead to an erroneous diagnosis01 aplastic enaeraa. In such cases, invnunostain ing lor a B-eell antigen such

• A,B Note 1helyf:icaI ~ fealuresoiciroJlatWlg hairycels ~ the range in nuclear morphology. C There isstrong~

tesistanl acid p/'lOSpI'IaIaSe posiMy c:IIar'aderisbc oIl1aily oeI lNaemia

188

Mature B-eeU neoplasms

•

as C020 is esse ntial tor the identification of an abnormal B-ce ll infiltra te , prompting the cedomance of more specific immunohistochemical stains lor HCl. The pr oduction of cytokines by the hairy c ells is presumed to be the cause of mrs haematopoietic sup pression 13481. Other leukaemiaS/1ymphomas suc h as splenic marginal zone lymphomas and some urclassihable splenic Iymphoma sl leukaemias show mor phologic and immunopheootypic ove rlap with hairy cell

Table 10.02 Palhogenesjs ofhairy ~Ilel;ka&mia Property

Proposed pathogeneticmechanism(s)

Derived fmm I'Nlture memory B-cell. Leukaemic llairy eels diller from fIOITIIal memory B.oeIls because of altenldeJqll"ession of c:hemolOO8 and adhesiOn I"8ClIJlkn Inlluenced byo'<'enlllpreSSiDn and consbtuIive ~ of members of Rho lamit)' of smaI GTPases and ~ oflhe ~ eresspetlfJcmolecule Gas7.

Hairy cell morpI1oIogy

May relate toconstlbJtrve 8ClMIbDn of adhesiDMootiIit rec;eplor$, tIItryoeIsI11Brad sponIaneously WIllextraeeIIAar maW; c:ornponera; MIry cells lIlJIere and bI'llI frMy onto ftbronecbn in bone nwrow miODeI'wrcnment

W
HCl eels synIheslzeand bI'llI to fibrooedin in bone ma-mw ~

eovworwnent. Proc1Jctictl me oflbonedin I5INer 00fltrtlI cJawR baSIC rtJroblast ~ IKU (bfGF) seoeled by hlwycels. Translon'ring ~ tactJr lit (TGF131) also ~ a IOIe in reliwiInfbtlsis

Spleen and other tissues In the spleen . HCL infiltrates are found in the red pulp. The wh ite pul p is typically atrophic. The cells characteristicall y fill the red pulp cor ds. Red blood cell lakes, collections 01 pooled erythrocytes su rrCllMlded by elongated hairy cells, are the presored consequence of d isruption of normal blood flow in the red p ulp 1212. 19991. The liver may show infiltrates of hairy cells , predominantly in the sinusoid s lymph node infiltration may occur especially with ad vanced d isease , and is variably mtertouicurarzparacoruc ar, with sparing of follic les and intact sinuses.

~tobMemamlW . ~~

liair'fcels home to ~ Q)Ii"',enls ¥ia ~

~

actovaIed integrin ~ and over expres:siDn cJ matIJ-mecaIDpr'oIeinasfI mitIikn.. Down ~ 01 dWll,()Q18 rec:epkn Sl..Id1 as CCR7 iIl'ldCXCR5e~ absence 01 ~ node ~

ill'lCl hepatic sftIsDidS

"",.""""

Pseudosinus bmalion

CMl!expressiM 01 Amen'l1 and adI'I pos:stlIe rnediakn. f1 spleen

Related toconstitutrve eel aetiYllflDn. Cons1itubve prOl:b:bon ollJ.mi:U necrosis Iador (TNF), intetIeum ~ (IL-6) and 0YeI'e~ d apopt06is irhbib. BCL2_ lnhibiIion 01 noonaI haemalopoiesis

Cytochem;SUy The only cytoc hemical stain utilize d in the diagnosis is tartrate-resistant ac id phosphatase(TRAP), and this techn ica lly chal lenging cytoc hemic al stain has be en largely supplanted by immunophenotypic/ immunohistoc hemica l tech niques. If appropriate air-dried unf ixed slide p reparations are ava ilable , vi rtually all cases of HCL will contain at least some ce lls w ith strong , granu lar cytoplasm ic TRAP positivity, while wea k staining is not of d iagnostic utility (212, 1999 1.

InleraetIa1 d hairycelI5l11'iltJ 8fIdoltlIUI cells rMl.Cing in repIacemenl of MdDlheIiaI c:elIl by Ieiukaemic hairycells.

(hypocelllW Hell References {157, 348,2235}.

ConstiMive PI'(lllJcliDn 01 tr.InslomW1g growth fada~

""'-

(TGF~ )

by

Immunophenotype

The assessmen t of an anti gen profi le that takes into account inte nsity of antig en expression and assessment 01 multi ple antigens is very useful in the d iag nosis of HCl. The classic immunophenotypic profile of HCL consis ts of bri ght monoty pic surface immunoglobulin, bri ght coexpression 01 C020, CD22 and CO lle, and expression of C0 103, C025. C0123, t-eet. Annexin A l (A NXA1), OBA.44, FMC-7 and cycun 0 1 (usually weak) 1348. 541 ,670, 1062, 1423 , 1999 . 23921 . Most cases 01 HCllack both COlO and CDS. although irrmunopheootyp variants are welt known 1404, 1050 1· Anne xin A 1 is

Hairy cea leukaemia

189

the most specific marke r since it is not exp ressed in any B-cell lymphoma other than HCL 16 701 Expression of Annexin A 1 can be used to distinguish HCL Irom splen ic marginal zone lymphoma and HCL variant which are bo th Annexin A 1 neg ative 16701. Immunostaining for Annexin A 1 must always be com pa red wi th that lor a B-cell antigen (e.g . C020), since Annexin A 1 is also expressed by myeloid cells and a p roportion of t-ceus 16701. For this rea son, Annexin A 1 is not a suitable marker for mon itoring minimal residual disease . More suitable approaches for assessment lor residual d isease after therapy include either mutticolor llow cytometry targ eting the d istinctive HCl profile or ITml..nohistochemical techniques including C020, TRAP, DBA 44 and 'l-bet. However, low numbers of TRAP positive Of OBA.44 posi tive cells may be seen in normal BM 114231. Similarly, some t-eens may be I-bet posmve. and weak staining for T-be t may be seen in other B-ce ll neoplasms 110621, The clinical value 01monitoring for residual disease is not yet estab lished .

•

• ~"

F-'g, 10.16 Huy cellel.taenN. A.S Bone marrow biopsy. Hypoc:eljar ha-y cel leuk.aerlia lIIilhsublIe netsbtIaI .... lillrcIles(A). lrmuIoperoxidas lor C020 ~ sublIe Ieukaenic: in6Itrates in hypocelUar HCl (B). C Spleen.Red pulp i1iIlraticI'I lIIilhrunerous red bkxxlcel lal<es, 0 LiwM". Bo8l portal iI1d SinJ5CidaI irI6Ilr.3lion by ~ eelsis presert

Gene tics Antigen recep tor genes Although exceptions have been reported . the majority (>85%) of cases of HCl demonstrate VHgenes with somatic hypermutation indic ative of a post germinal centre stage of maturation 183. 348, 22351. A unique feature of HCl is the comm on c oexpression of multiple cronauv related 19isotypes. sug gesting arrest at some point during lsotype switching (22351. Cytogenetic abnormalities No c ytogenetic abnormal ity is specific for HCl: numerical abnormalities of chromosomes 5 and 7 hav e been de scribed, but transl ocations are distinctly uncommon

13481

Fig.10.17 Hairy cel leukae!l"ia, iml'T'l.J~ features. A,B,C Bone malfOWbiopsy. AD8A44 positivityothai'y

Postulated normal cou nterpart late, activat ed memo ry B-cell .

eels accef1luat nghairy projedlons. B com ~tYity ot hairy cells C Hairy cees express Annexin 11'ttli1e eryttwoid prew-scn arenegaUve. 0 Uver. Sinusoidal inFiltration byAn!lexinA1-pClSjbve leukaemichairycells.

Prognosis and predictive factors HCl is uniquely sensitive to either a -interferon or nucreosices (purine analog s) such as pentostatin and ctaonbme. Patients receiving pu rine an alogs often achieve com plete and durabl e remissions {2235 1. Prolonged remission may also result Irom splenectomy, but this is uncommon 17981. The overall t n-year surviv al rate exceeds 90% {642, 7981. Rituximab

offers therapeu tic effica cy in combination with pu rine analogs in patients with renact orwreiaosed HCL: experimental therapeutic ag ent s incl ude anli-C022 ant ibody therapy or anti-C0 25 immunotoxin therapy 118501. l ong term HCL survivors have an inc rease d risk of second cancers com pared to the general population with a cumulative probab ility of 30% for secon d neoplasms by 25 years after

190

Mature B-cell neoplasms

HCl diagnosis 1940 1- Hodgkin and nonHod gkin lymphomas as well as thyroid cancer pr edominate in these long term survivors 19401.

Splenic B-cell lymphoma/leukaemia, unclassifiable

M . Piris K. Fouca r M . Mollejo E. Campo B . Falini

There are a number 01 variably well-

Synonyms Splenic ma rginal zone lymphoma (SMZL)diffuse variant {1496 1, lym phocytiC lymphoma simulatin g hairy cell leukaemia 116811, splenic B-c eil lymphoma with villous lymphocytes (also used for SMZl and HCl-vatiant), splenic red pulp lymphoma With numerous basophilic villous lymphocytes 122621-

defined entities that represent small Be en Clonal lymphoprolil erations involving the

spleen, but which do not fall into any of the other type s of B-cell lymphoid neoplasms recognized in the WHO classifteaton. This chapter reviews the two best oeteeo of these relatively rare provisional entities. splenic diffuse red pulp small B-cel lymphama and hairy cell leukaemia variant. The relationship of splenic diffuse red pulp small Been lymphoma to hairy cell leukaemia variant and omer p rimary splenic B-celllymphomas remains uncertain, the ir precise diagnostic criteria are not fully established and the most appropnale terrTWdogy is wserned. Other splenic small B-cell lymp homas not fUlfilli ng Ihe criteria lor either otmese provisional enti ties or for other tetter established B-eall lymphomas should be diagnosed as splenic Been Iymp homall eu kaemia. uoclassifiable until more is known . Splenic diffuse red pulp small B-<elllymphoma Definition Splenic diffuse red p ulp sma ll B-c eillymphoma is an uncommon lymphoma w ith a diftuse pattern of invo lve ment ot the splenic red pu lp by small monomorphous B lymphocytes. The neopl asm also involves bone marrow (8 M) sinu solo s and peripheral blood (P8 ), co mmonly w ith a villous cytology, This is a provisional entity that needs add itional molecu lar studies tor defining its main features and

d iag nostic markers. This diagnosis should be restricted to ch arac teristic cases, fulfillin g the majo r fea tures d escr ibe d here and not applied to any lymphoma grow· ing diffusely in the spleen. Chronic 1ymphocytic leukaemia (CU). hairy cell leukaemia (HeL), _ " " " " Y l C IynVooma (Lf'L) and prolympI-ocybC ieLl
_

fCD-OCOde

959113

Epide miology Splenic d iffuse red pulp small B-cell lymphoma is a rare disorder, accounting lor < 1% of non -Hodgkin lymphomas. It rep resents about 10% of the B-c eil lymphomas diagnosed in splenectomy spec imens. Most patients are over 40 and there is no gender bias . Sites of involvement All c ases are diagnosed at clinical stage IV, with spleen, 8M and PB involvement. Periphe ral lymph node involvemen t is only rarely repo rted. Clinical features Sp lenic diff use red p ulp smal l B-ce Ulymphoma is a leukaemic neoplasm , usually w ith a relativ e ly low lymphoc ytos is. Almos t all patients have, frequently massive, sp lenomeg aly. Altho ugh not consistent among all stud ies, thromboc ytopenia and leukop enia a re frequently pres ent. while anaemia has been reported more rarely, B symptoms are infreq uent. A sma ll group of these patients show cutaneous infiltration

~

.". . _ .. ao

flll.10,18 Sj:IIehc do1luse red pulp smaI fk:elI~. A Peripheral blood cyloIogy wrItl YiIous eel. B Reticulin stairIIog oullinn!he mixed lllfillTation 01 bolh red Pl4I CllI\'Wl8I'IlS: cordsarwj SinIsOidS. C BentITWTtIW innsilusoidal ldillratlon hiQt6lt4edby C020 Ulrlg

SplenIC B-celllymphomalleukaen"Na. uoctassmatae

191

translocation t(9;14)(p13:q32) inIJo!ving

PAX5 and IGH@genes have been fOlind in thes e cases 11411 bUI they lack del 7Q and t( 11:14). Frequent TP53 alterations have been des cr ibed , with inc reased p53 expressio n 114961. Othe rs have reported a frequent absence 01 any cytogenetic abnormalities and occasio nal cases of det 7q /2262 1. Postulated normal counterpart Unknown pe ripheral b lood Be en. Prognos is and predictive factors This is an indol ent but incurable disease. with good responses after sp lenectomy.

Hairy cell leukaemia-variant (HCl.v)

in the form 01 erythema tous and pruritic papules at the lime of the initial d iag nosis. Presence 01 a pa raprotein has not been reported. Morphology Peripheral b lood: Villous lymp hoc ytes similar to those reported in SMlL are p resent. Bone marrow: lntreslnusolc at infiltration is the rule, occasionally as a sale find ing This can be accompanied by inte rstitia l and nodular infiltration, l ymphoid follicles, as in SMZl. have not been repo rted, Sp leen. A diffuse pattern of involvement of the red pulp, with both co rd and sinu soid infiltration is present. Characteristic intrasinusoidal aggregates with occasional p seud osinuses lined by tumoural cells may be seen. In contrast 10 SMlL, the tumou r shows an ab sence of follicular rep lacement, bipnasc cytology or marginal zone infiltration. The neoplastic infiltrate is corcceec 01 a monomorphous population of small to me di um-sized lymphocytes. with round and regu lar nuclei. vesicular c hroma tin and occasional d istinc t small

192

Merure B-ceu neoplasms

nucleoli, with scattered nucreorateo blas t ce lls. Tumoural cells have a pale or lightly eosinophilic cytoplasm. with plasmacytoid features but lac king other featu res of plasmacytoid differentiation, such c ytoplasmic Ig o r CD38 exp ression.

Definition The de sig nat ion HCL· v encompasses c ases 01 B c hronic lym phop roliferallYe d isord ers that resemble cl assic HCl but exhibit variant "cvroneematotoqc" features (i.e. leukocytosis. pre sence 01 morocytes. cells with prominent nucl~, c elts with bla stic or convoluted nuclei andJor absence of ci rcumlerential shaggy co ntou rs). var iant immunophenotype (i.e. ab sence of C025, anne xin-A 1, or TRAP) and resistance 10 conventional HCl ther· apy (r.e . lac k of dramatic respo nse to claonbme). These cases are no longer considered to be biologically related 10 HCL

ICD-Q code

959 1/3

Cytochemistry Tartrate-resistant acid prosoatase (TRAP) staining is not p resent.

Synony m Prolymphoc ytic variant of HCL.

Immunophenotyp e The ch arac teris tic profile is CD20+, DBA44+, IgG+, Ig D-, Annexin A1-, C025- , COS-, C0103-, CD123-, C0 11c-, C01O- , C023- P 429 A, 1496, 19221. Ig O+ c ases can be seen with similar featu res. Others have rep o rted c ases with IgM+ lgG±, CD103+ an d COt t c- with infreq uent CDS and C0123 exp ression 122621.

Ep idemiology Cases of HCL-v account for about 10% of HCL with an inc idence of approxrrnately 0.03 per l 00 ,CXXl persons per year 118501. Middle-aged to elderly patients are attecteo and there is a slight male predominance 11431 1. Cases of HCL-v have been des cr ibed in Asian patients where HCl -v may be more comroon than HCL 114311.

Genetics Most c ases seem to harbour a relatively low load of somatic hypermutation in the JGHV genes. No bias lor VH1.2 gene has been seen , as in SMZl. Overrep resentstton of VH3-23 and VH4-34 . as in HCl, has been reported 122621. Complex cytogenetic alterations, including

Sites of involvement Sp lee n. 8M and PB are involved but hepatomegaly and lym phadenopathyare relatively uncommon / 143 11. Involvemert 01other solid tissues is rare. Clinical features Patient s with HCL-v typically mamfesl

I

..

• A

signs and symptoms related to either splenomegaly or cytopenias. Leukocytosis

is a consistent feature with an average white blood cell count of about 35xl()9/L. while thrombocytopenia is present in about half of the patients and anaemia in one quarter 114311. The absolute mono-

cyte coun t is typically within normal range.

""-y

Circulaling HCL-v cells are read ily appar-

ent on the PB smear ; commonly these cells exhibit the hybrid features of prolymphoc ytic leukaem ia and classic HCl . although several o ther morp hologic sub-

may be subtle and very inc on spicuous, otten requ iring irrmunohistochemical stains to high ligh t the pattern and extent of infiltration 13731. Recent publicati on s note a distinct p redilec tion lor nearly exclusive sinusoidal infiUration 1373, 1431, 24601 Similar to HCL and splenic diHuse red pul p small Been lymphoma. the red pulp of the spleen is dittuselv involved and expan de d in HCL-v, resulting in atretic or abs ent white pulp follicl es. The leukaemic c ells fill dilated slnusoios and red b lood cell lakes ma y be noted 1143 1] Liver involvemen t is characterized by both portal tract and sinuso idal infiltrates.

types (blastic, convolu ted) have also been described 11 850 1, Nucl ear fe atu res

range from condensed c hromatin with prominent ce ntral nucl eol i o f a prolym pho-

cync cell to dispersed chroma tin with highly irregular nuclear co ntours. Cytoplasmic features are similarly variabl e, although some degree of hairy project ion s is typically noted 13731 Transformation to large cells with co nvoluted nucl ei has been describe d an d c ases of so-called convoluted HCL may be explained by this phenomenon 114311. Unlike Classic HCL , the 8M is aspirab le without significant reliculin fibrosis 13731_The infiltrates of HCL-v

Cytochemistry Unlike classic HCL, cytoc hemica l staining for tartrate-resistant acid pnospetase (TRAP) is weak to negat ive in HCl -v (541. 1431, 18501. Immunophenotype Cas es of HCl·v sha re man y immunop henot yp ic and immunohistochemical (IHe) features with HCl , although HCl·v cells characteristica lly lac k several key HCl antigens usually includ ing C025. Anne xin A 1, TRAP-IHC. C0123 and HC2 1670, 1431, 18501. Positive "markers" in

HCL·v includ e DBA .44. pan-B-cell antigens. COlle. br ight monotypic surface imm unoglob ulin (more frequently Ig G ), CD 103 and FMC711423. 14311.

Genetics There are no known specific genetic changes. Some cases demonstrate complex cytogenetic abnormalities involving t 4q32 or 8Q24 and TP53 deletions 114311. Postulated norma l counterpart Activated Been at late stage of maturation. Prognosis and predictive factors These patients have an indolent cou rse with a long survival l ime, even though patien ts with HCl -v do not typ ic ally respond to either IFN-a or pu rine nucleoside analogs (oeoxvcotormvcln and cladrib ine ) !l 850 ). Recent p reliminary studies sug gest that monoclonal antibody therapy (rituximab and anti-C022 immunoto xin ) is highly ellective 11850 1 In add ition. good clinical responses have been achieved with resolution of cytopenias after sple nec tomy 118501.

Splenic B-ceillymphoma/leukaemia, unclasslhable

193

Lymphoplasmacytic lymphoma

SH. Swerdlow F. Berger

SA Pilen N.L Harr is E.S. Jaffe H. Stein

..

Definition lymphopl asmac yt ic lymp homa (LPL) is a neoplasm of small 8 lymphocytes, plasmacy toid lymp hocytes, and plasma cells. usually involving bone marrow (8 M) and sometimes lymph nodes and spleen , which does not fulfill the c riter ia for any of the other small Bccell lymphoid neoplasms that may also have ptasmacytlc differentiatiOn. Because the distinction be-

tween lPL and one of mese other lymphomas. especially some marginal zone lymphomas (MZL), is not always clear-cut. some cases may need 10 be diagnosed

as a small Bceujvmoboma with plasmacvtrc di fferentia tion and a d ifferential diagnosisprovided. Although often associated with a paraprotein usually of IgM type, it is not required for the diagnosis, Waldenstr6m macroglobulinemia (WM) is found in a significant subset of patients with LPL and is defined as LPL with 8M involvement and an IgM monoclonal gammopalhy 01 any concentration (16731.

,

ICD-{) code

967113

Epldem k>logy LPL occurs in adults with a median age in the 60s and a slight male predominance 1581,23371. Etiology A familial predispo sition may exist in up to 20% of pa tients with WM {29, 2267f. These pa tients are diagnosed at a younger age and with greater 8M involvement .

194

Mature B-cell neoplasms

_..

-.

fl9- 10.22 lym~ ~ A Bone marrow biopsy shows a ~ infiltrate """ a PASpo5Itrve Ouk::her body (8fTOW). B The ~smaq1ic I1fi1lrale is alsoseen in ee asptalesme¥. Hepatitis C virus (HCY) is associated with type II c ryoglobulinemia and with LPL in some but not all series, perhaps related to geog rap hic d ifferenc es 1534 . 1271, 1450A, 1597 , 1680 , 1791 . 1932,21661 . Some of the HCV-associated Iymphoplasmacytic proliferations even if monotypic, are non-progressive and others may be more like chronic lymphocytic leukaemia (Cll) 11506. 23261. Treatment 01 these patients with anti -viral agents may lead to regression 01 the Iymphoplasmacync proliferations {1434 . 2 1661. Apart from the role 01 HCY, mast cells may help drive the proliferation in LPL 122591. Sites of invol vemen t Most c ases involv e the BM and so me, lymph nod es and other extranodal sites. About 15- 30% of patien ts with WM also have splenomegaly, hepa tomegaly and/or adenopathy {5811· Per ipheral blood (PB) may also be involved.

Cli nica l features Most patients present with weakness and fatig ue , usua lly related to anaemia. The majority of pa tients have an IgM serum parap rotein although othe rs may have a different paraprotein or no paraprotein at all. A minority have both 19M and IgG or other paraororens. Hyperviscosity occurs in up to 30% 0 1 patients, The paraprote in may also have autoantibody or cryog lobulin activity, resu lting in autoimmune phenomena or cryoglobulinemia (seen 10 up to -20% 01 patients with WM). Neuropathies occur in a minority 01 patients and may result from reactivity of the IgM parap rotein with myelin sheath antigens, cryoglo b ulinemia or pa raprotein deposition, Depos its of Ig M may occur in the skin or the ga strointestinal trac t, where they may cause diarrhoea Coagulopathies may be caused by Ig M binding to clotting factors. platelets and fibrin . Ig M paraproteins are not diagnostic 01 either LPL or WM as they can occur in patients with other lymphoid

neoplasms or without an oven neoplasm. A minority of pa tients inJ\ially present with an IgM -related disorder such as cryo-

globulinemiaor IgM-monoclona1gamrT"l()o pathy of undetermined significance and only later develop an overt lPl 1370. 1230. 15241.

-

Bone manowand peripheral blood Bone marrow involveme nt is c ha rac terized by a nodular. dlftuse and/or interstitial infiltrate usually composed predominantly of small lymphocytes admixed with variable rwroes of plasma cells and plasmacytoid tymphocytes 11672.16731 · Paratrabecular aggregates may also be p resent. Increased mast cells are often present. Similar cells may be present in the PB . but the white blood count is typ ica lly low er than in ClL.

Lymph nodesand other tissues In the most class ic cases that are usually associated with WM , lymph nod es show retention of normal architec tural fea tures with dilated sinuses with PAS+ material and sometimes small port ion s of residual germinal centres. There is a relatively mo nolonoos proliferation of sma ll lymphocytes. plasma cells an d plasmacyto id lymp hocytes with relatively few transformed cells. Dutcher bod ies (PAS+ intranuclear pseudoinclusions), increased mast cells and haemosiderin are othe r typical features . Other cases show greater arch itectural destruction, may have a vaguely follicular grcmlh pattern . more prom inent residual germinal centres, epithelioid histiocyte clusters and sometimes a much g reater proportIOn of plasma cells or a more poIynn-phic appearance with more numerous transformed cell slimmu no b lasts 11934AI. Protilerahon centres. as seen in CWsmal1 ~ic lymphoma (Sl l ) must be abo seN: and the presence of paler-appearing

margina l zone type cntterennatoo shou td suggest the diagnosis of one of the MZL There may be associated amyloid. other immunoglobulin deposition or crystal storing histiocytes. Spleens demonstrate a IymphopIasmacytc infiltrate tha t may form small nodules in the red pulp or grcrw more d iffusely.

invotving the CCND1, MALTt , BeL 10 or BCL2genes with the possible rare exception of the tarter. WM is reported to have a homogeneous gene expression profile. independent of 6q deletion, that is more sendar to CLl and normal Bcens than to myeloma 14291. This study also suggested the importance of upregulated Il6 and its downstream MAPK signaling pathway

",.",unophenoIype Most cells express surface Ig and the ptasmacvnc cells express cytoplasmic Ig . usually IgM. sometimes IgG and rarely IgA . They are typ ically IgD- , express a-conassociated an tigens (CD 19. CD2O, C022 , CD79a) and are COS-. CD1o-. CD 1Q3-and CD23- with frequent but not invariable CD25 and CD38 expression. Some studies report more varia tion especially in CD22 and CD23 expression . The p lasm a cells are CD 138 positive . lack of CD5 in most bu t not all cases an d the presenc e of strong cytop lasm ic Ig are useful in the d istinct ion from ClU SLl. Genetics Antigen receptor genes IG genes are rear ranged usually with V regions that show somatic hyp ermutation but lac k ongoing mutations (2349). The re ma y be biased VHusag e 11026 , 1193 ).

Cytogenetic abnormalities and oncogenes No speci fic c hromosomal or oncogene abnormalities are recognized in lPl. The previou sly reported IGH@!PAX5t(9;14)is rarely. if ever, found in lPlI463, 774, 13791. Deletion 6q is reported in up to somewhat over haN of BM-based cases but it is not a specific finding and appears at best to be infrequent in tissue based LPlI464 . 1379, 16 17, 19721. Trisom y 3 and 18 are infrequent . Trisany 4 has been reported in about 20% of WM 121831. lPl do not demonstrate any of the other B-eell Iymphomaassociated transocetoos such as those

Postulated normal COlSlIe rpart Probable post-follicular B-eel1lhat d ifterentiates to plasma cells.

Prognosis and predictive factors The clinical course is typically indolent , WIth median survivals 015- 10 years 1581. 23371Advanced age. PB cvtcoemas especially anaemia. oertomance status and high f}-2 microglobulin levels have been repor ted to be associated with a worse prognosis 158 1. 2337f. Cases w ith incr eased transformed ce lls/imm uno blasts may als o be associated with an adverse prognosis; however, a va lida ted g rad ing system doe s not exist 143, 1941. Cases with del(6q) have been associated with feature s 01 adver se prognosis 116171 . Transformation to d iffuse targe B-eeillymphoma occurs in a small propo rtion of the cases an d is assoc iated with poor survival 113111. Patients who have developed Hodgkin lym phoma are also reported 118631. Variant: gamma heavy chain disease Gamma hea vy chain dis ease results trom secretion of a trunca ted gamma chain, whic h lac ks uqnt-cnam bin ding sites. It is usually associated with a lymphoma that fulfills the cri teria lor LPl involving lymph nodes. 8M. liver. spleen and PB but some cases resemble plasma cell myeloma. The clinical course is vari able , but probably more aggressive than that of typical IgMproducing lPl.

l ymphOplasmacytic lymphoma

195

Heavy chain diseases

Definition The hea vy chain d isea ses (HCD) comprise

3 rare Be en neoplasms that produce monoclonal heavy chains and typically no light chai ns. The monoclonal immunoglobulin component is composed of either IgG (gamma HeD ). Ig A (alpha HCD) or 19M (mu HCD ), The heavy chain is usual ly inc om plete and thu s incap able of lull assembly. Variab ly sized p rotein s are produced , thai may not pr odu c e a c ha rac teristic se rum prot ein elec trophore-

sis peak. and require immunoelectrophoresis or immunofixation to detect.

Nt.. Harris P G . Isaacson 1 M. Grogan E.S. Jaffe

tight chain binding sites and does not bind to light chains to form a complete immunoglob ulin molecule. Synonym Franklin d isease .

Epidemiology Thi s is a rare d isea se of adults wi th a med ian age of 60 ; approximately 130 cases hav e been described 1687 , 23521. There

is no partic ular geo graphic d istribution , and a slight male predominance in most but not all series 123521.

Alpha HCD is conside red to be a varian t

of extranccar marginal zone lymphoma of rrccose-essoceteo tyrrVOO tissue(MAln. Ga'mla HeO is characterized by a ~ plasmacytiC population resembling Iymprcctasmacync lymphoma and Mu HeO typically resem bles eLL: however bolh are sufficiently distinctive to be considered separate enti ties .

ICD-O code

976213

, Gamma heavy chain disease Definition

Gamma heavy chain disease (gamma HCDj is a neoplasm of lymphocytes, plasmacytoid lymphocytes and plasma ce lls that p rod uce s a trun ca ted gamma immunog lobulin heavy ch ain, whi ch lacks

Sites of involvement The tumour may involve the lymph nodes, Waldeyer ring . gastrointestinal tract and other extranodal sites, bone marrow (8M), liver, spleen and peripheral blood (PB).

Clinical features Most patients have systemic symptoms such as anorexia. wea kness. lever. weight loss or recurrent bacterial infec tio ns. Au toimm une manifes tations are found in about 25% 01 the cases. mostlreq uently rheumatoid arthritis, but also autoimmune haemolytic anae mia or thrombocytopenia or both, va sc ul itis, SjOgren synd rome, systemic or cu taneous lupu s erythem atosus, myasthenia g ravis or thyroidit is 168 7, 997 . 235 2 ) Autoimmu ne d isease ma y pre ce d e t he di agn osis of lymphoma by seve ral yea rs Most pat ients have

~ .

~

..J!.

...,

Fig. 10.24 Gamma heavy lilain disease. A. This polymorptIous tymphoplasmacytic proIifefabon is coovised 01 admixed plasma cells, plasmacytoid ~es and IympIloid cells. B Immunollistochemistry shows monotypic staining lor gammaheavy chain,

196

Mature B-eell neoplasms

generalized disease, including lymphadenopathy, sp lenomegaly and hepatomegaly; involvement of Waldeyer ring, skin and subcutaneous tissues . thy. raid . salivary glands or gaslrointestinal trac t may occur, and PB eos inophilia may be present 16871. Circulating p lasma cells or lym phocytes may occasionally be p resent. The pa tients generally do not have lytic bone lesions or amy loid deposit ion, The 8M is invo lved in 30-60% of the cases 168 7, 997, 23521, Cl inica l and laboratory dis tinction from an infection or inflammatory process may be difficult in view of this co nstellation of symptoms and the some times broad band or near-nome serum protein electrophoresis. The diagnosis is made by demonstration 01 IgG without light chains by immunofixation in the PB, urine Of both.

-

L ymph nodes typically show a poIymor. phous proliferation with admixed lymphocytes. plasmacytoid lymphocytes, plasma cells. Wrm.JnobIasts. histiocytes and phi ls I 1540AI· The presence 01 eosinephils , beuocvtee and immunoblasts may ca use a resemblance to ang ioimmunoblastic T-eeill ymphoma (A ITl) Of Hodgkin lym phoma (HL); it is not cl ea r whether rare repo rted cases of gamma HCD assoc iated with AITl or HL rep resent a true association or a resem b lance of the infil· trate 01 ga mma HCD to HL 1565, 992J, In some cases plasma ce lls p redominate and may resemble plasmacytoma The PB may show lymphocytosis with or Wlthout plasmacytoid lymphocytes. reserrtJling chronic lymphocytic leukaemia (CLL) a Iymphoplasmacytic lymphoma. Transfor· mation to diffuse large B-eell lymphoma (DLBCl) is rare 16871 The 8M may stlOt¥ Iyrnphoplasmacytic aggregates or only a subtle increase in plasma cells with monotypic garrrna heavy chains WltholA light chains.

eosoc-

," ""'-

The cells contain monoclonal cytootasnc ga mma chain w itho ut lig ht chains, exp ress CD79a, CD20 on the lymp hocytic

Fig. 10.25 Gamma heavychain oseese. Bone marruw biopsy. ASmall ~les cx:mposed of plasma cells Md tympnoid eels arepreserK. C(ll'I'Ipl'iSing awroxma!ety 5%oflhe overaI marrow cellularity Some plasma cells appear malin. wtIile others are atypical WJ\h open etwomatin (B). C Immunohislochemital stain shows cytoplasmic IgG Images COU'leSy of Dr. AJiyah Rallemtula h {1~l

component, CDl38 on the plasma cell component. and are CDS and CD to negative (1S40Al. Genetics Immunoglob ulin genes are cronauv rearrang ed and conta in high levels of somatic hypermutation 16861. Deletions in the gamma heavy chain gene are present that result in expression of a defective heavychain protein that cannot b ind light cnem to form a complete irrvnunog lobulin molecule 121 . 658. 686 , 728 , 732. 1989, 235 11. These deletions involv e the VHregion and variab le amounts of the CHI region. and there may be insertions 01 large amounts of DNA of unknown origin 16861. Abnormal karyotypes have been present in about half of the reported cases. but no specific or recurring genetic abnormality hasbeen reported 123521. Postulated normal counterpart Post-germinal cen tre 8 cell with the ability to diHerentiate to a p lasma ce ll, with a defective gamma heavy cha in gene. Prognosis and predictive factors The clinical outcome is variable, ranging trom indolent to rapidly progressive; the

median survival has been reported to be 12 months (6861; but a recent study of 23 cas es rep orted a med ian of 7.4 yea rs, with over hall the deaths not related to the Iympnoprotiferative disorder 123521 Most patients with low-grade appearing Iymphoprasmacvtc infiltrates appear to respond to non-anthracycline-containing che motherapy, and respo nses 10 rituximab have been reported 123521.

Mu heavy chain disease Definition Mu heavy chain disease (mu HCD ) is a EkeII neoplasm resembling chronic I'ympt1ocvnc leukaemia (Cll). in which a defeclive mu heavy chain lacking a variable region is produced . The 8M contains an infiltra te of characteristic vacuolated plasma cells, admixed with small, round lymphocytes Epidemiology This is an ex treme ly ra re disease of adu lts. with between 30 and 40 c ases reported; a med ian age of 60 and an approximately equal frequency in males and females {6861. Sites of involvement Spleen. liver, 8M and PB are involved; peripheral lymphadenopathy is usually not present

Fig. 10.2! Mu heavy chain disease. Bone marrow asprIIe shows predomlnanlly plasma cells with prominenl C)t:ifJIasmic vacuolation.

Clinical features Most patients present with a slowly progressive disease resemb ling chronic 1ymonccvtlc leukaemia Mu HCD differs from most c ases of Cl l in the high frequency of hepatosplenomegaly and the absence of peripheral lymp had enop athy. Routine serum protein electrophoresis is frequently

normal. Immunoelectrophoresis reveals reactivity to ann-rno in polymers of diverse sizes. Although mu cha in is not found in the urine, Bence Jones light chains are commonly found (50%) in the urine, particularly kappa chains . The tatter. while stilt produced in mu HCD, are not assembled into a complete immunoglobulin protein because of heavy chain gene aberrancies leading to truncated forms 1136, 23501. Mo
Immunophenotype The cells contain monoclonal cytoplasmic mu heavy chain , with or without monotypic light chain , express a-cen antigens , and are CD5 and COlO negative. Geneti cs Immun oglobul in genes are clonally rearrang ed and contain high levels of somatic hype rmutation (6861. Deletions in the mu heavy chain gene are presen t that result in expression of a defective heavy chain protein that cannot b ind light Chain to form a complete immunoglobulin molecule 1686, 7291 . These oeienons involve the VH region and variable amounts of the CH 1 region , and there may be insertions of large amounts of DNA of unknown origin {686) Postulated normaJ coun terpart Post-germinal centre B cell which is able to differentiate to a plasma cell , With an abnormal mu heavy chain gene . Prognosis The clinical course is slowly progressive in most cases (136. 686, 729. 23501. Heavy chain diseases

197

Alpha heavy chain disease

•

-. A ....

...

...

,

•

•

• • •

.

~

,

•

Fig. 10.27 Serum protem aleclrophoreSlI (SPE) and unne protein eleclrophoreSlS (UPE) in gamma heavy chain

eeeese. It dis1Inc:! bInd .... 1dent1fJed by SPE in Ih8irTIrluIogIotUn region1IIlOdal1o!he panof ongIl (A. IIITOW) The 1ok:oi.4IOi iIMllyped as IgG(t\llnoIed by the bind seen in lhelgG lane). but WIlhout a IXlrT9$pOI'ldin igIt d'\8Wl (0t'Iy lain: pctyck:Jnal pa1lemS . . . seen in !he kappa and Iam/xIa tales) (A). UPE periormed rewaIedsirrU results , WIth a broad ITIOIlOdonaI band correspondlllg 10 IgG withoul a rorrespooding lighl chain (B). Repmted from 11540A). (1ma!;Ies allRlsy of Or. M. .......)

Variab le size deletio n in HCO

Ant igenbinding site

light-ehainbinding site:

deleted in HCD

• Complement-

(H ,

}

(Hl

binding site

Fe-receptorbind ing sit e

eOOH

eOOH Fig. 10.28Structure ol1heimmunoglobtJIIn rnoilIaMin heavychain disease. Animmunoglobl*1 mollIaM is ~ of two heavy chains (H) and two I9rt chains ll}. which are JOined by d,sulflcle bonds (5-S). The nmnallleavy ellalll constant region has 3 ronstanl domaill5: CHI is responsible for binding 10 !he li!;.f11chain. CH2 10r binding to ~ and CH3 b' bindI'Ig 10 Fe recepttn. kllhe absence of an associaled (gill d1ain. lhe CH1 domain biIds to heat-shock J:fCI\8in 78 and U"ldergo&$ ~ degadation; 1l1us. normaI lreeheavychains ae not secreted. In I1eavy chain dtseases (HCD). ~ deIebons in lhe CHl domail preventboIh bi1dJng a11he heavychain 10 the light diann de\1'adation IIIh proteasane, and free heavy chalns are secreIed VanablHized delebons also OCXU' inIhe heavy dIain lliversiIy I8giOn (OH). !he heavychain joining region(JH) and the I1eavy chainv.wiabIe rtlgiOn (VH), COR denoIes COi ' .'ilh'llarily-.deteillil_tg region. a. light dIain const.Tlregion. COOH cartloxyt \emWIal.l igIt chainjoiWIg region. NIi2 llITW'O lerrrN M:I VLIg1l chainv<wiclbIe region. ReprI1Md WIltI pemis:sicrllrom {154MJ. (FJP8 QlU1esy cI OrN, M!nhi)

198

Mature B-eell neoplasms

Definition The ter m a lpha heavy chain d isease (alp ha HCD) has been extensively used in the liter ature , sinc e many case s are initially recognized by the p resence of an abn ormal alpha chain in the serum. However, the term nnmunoorouteranve small intestinal d isease (IPSID) was adopted by the WHO in 1978 and will be used here. IPSID is a variant of extranodal marginal zone lym phoma of mucosa assoc iated lym phoi d tissue (MALT), in whic h defective alpha heavy c hains are secr eted ; It is also d iscussed in the ch a pter on MALT lymphoma. It occurs in young adu lts and involves the g astrointestinal tract , resulting in malabsorption and d iarrhoea. tPSID beg ins as a process somet imes reversible by antibio tics but may progress to diffuse large B-ce tl lymp homa (DLBCL ). EpKlemKllogy This is the mos t common of the heavy chain d isea ses. Unlike the ot her HCD, IPSID involves a young age group with a peak inc id ence in the second and third decades: it is rare in young ch ildre n and older adults, and there is an equa l incidence in ma les and females. It is most common in areas bordering the Mediterranean inc lud ing Israel, Egypt. Saudi Arabia and North Africa . It is assoc iated with low socioeconomic status including poor hygiene, malnutrition and frequent intestinal infec tions {178 1, 18 12, 1988).

Etiology Chronic intestinal infec tio n, with Campylobacter jejuni in some ca ses, is believed to result in c hronic inflammation, a setting in which neoplastic transformation of a clone of abnormal 8 cells develops (12641. Sites of involvement This disorder involves the gastrointestinal tract, mainly the small intestine and mesenteric lymph nodes; gastric and co lonic mucosa may be involved 1686J. The 8 M and othe r organs are usually not invo lved . although rare respiratory tract involvement is described I1988 J. Clinical featu res at presentation Patients typica lly present with ma labsorption, d iarrhoea , hypocalcem ia, abdominal pain . wasting . fever and steatorrhoea . Because of defective heavy cha in assembly and con seq uent d iversaty oIlgA molecular

forms, the serum protem elect rophoresis (SPE) is usually normal or shows hypogalTVTlaglobulinemia. Typically. specific anti·lgA antibody is requ ired to de tect aberrant lgA by immunofixalion 119881.

Mo
Immunop henotype The plasma cells and marg inal zone cells exp ress monoc lonal cytopl asmic alpha c hain without light chain. Marg inal zone cells express CD20 and are CDS and COlO negative; plasma cells are typica lly CD20 negative and CD138 positive 110 121.

DNA of unknown origin 16861. Cytoge netic abnormalities have been reported in rare sing~ cases. The t(1' ,18) associated with gastric and pulmonary MALT lymphomas has not been de scribed 117211. One reported case had t(9 ;14)(p11;q32) 11 7211.

Genetics Immunog lobulin heavy and light cha in genes are cioreuv rearranged and contain high levels of somatic hyp ermutation 16861. Deletions in the alph a heavy chain gene are present that result in expression of a defective heavy c hain prote in that cannot bind lig ht chain to form a complete lmmurcqiobuun mole cu le. These deletions involve the VH region and CH I reg ion, and there may be insertions of

Prognosis and pred ictive factors In the early phase, IPSID may completely remit with antibiotic therapy. Many patients, however, expe rience transformation to diffuse large B-ceil lymphoma, and a latal outcome is frequent 1182,1 9881. Treatment With anthrac vcnne-contammq regimens has been repor ted to result in remission and long-te rm survival in some pat ients 1161.

Heavy chain diseases

199

Plasma cell neoplasms

The p lasma cell neo plas ms resul t trom me expa nsion of a c lone of immu nog lob ulin (Ig )-sec reting , heavy-chain c lass-switc hed , terminally d ifferenti ated B ce lls thaI typ i-

A.w McKenna RAKyle WM Kuehl T.M. Grogan N.L. Harris RW. Coupland

Monoclonal gammopathy of undetermined significance (MGUS)

cally secrete a single homogeneous (monoclonal) immunoglobulin ca lled a pa raprotein or M-protein; the presence of such a protein is known as monoclonal gammopathy. The true plasma cell neoplasms, discussed in this chapter. include

plasma cen myeloma. plasmactyomaand

,

the syndromes ueuneo by the consequence of tissue immunoglobulin deposilion, p rimary amyloidosis (Al) and light and heavy chain deposition diseases. The presence in the pe ripheral b lood (PB) ot a tow leve l of pa raprotein that is be low the us ual thr eshold for th e diagnosis of plasma ce ll myeloma may prece de the development of overt myeloma for a varying time: this phenomenon , kno wn as monoclonal gammopathy of undetermined significance (MGUS), is also included in this chapter as a precursor lesion. Other immunoglobulin-secreting neoplasms that comprise both lymphocytes and plasma cells, including lymphOpiasmacytic lym phoma. Walden strom macroglobulinemia and the heavy chain diseases. are d isc ussed in other chapters, ---

Defin ition MGUS is defined as the p resenc e in the serum of an M-protein <30 gJ1..., bone marrow (BM) clonal plasma celts <10%, no end organ damage (CRAB: hypercalcemia, renal insuffic ienc y. anaemia. bone lesions) and no evidence of B-eell lym phoma or other disease known to produce an M-protein. Although it reflects the presence or an ex panded clone of immunoglobulin-secreting cells. this process is not co nside red neop lastic since it does not alw ays progress to overt malig nancy. The presence 01 a sma ll IgM paraprotein (lg M MG US) is associated with a clone of Iymphoplasmacytic cells that may progress to a Iymphop lasmacytic lymphoma. and/ or Walden strom macroglobulinemia (WM). Non- lg M MGUS (lgG, IgA l is associated with tbe presence of clonal plasma cells, and may progress to a malignant plasma cell neoplasm . Although the two forms of MG US may be id entica l in their clinical presentation. they have a different genetic b asis and different outcomes in terms of malig nant prog ression , ICo-O code

9765/1

Tabl, 10.03 Plasma cellneoplasms

-""-

~g~y~uooe~

SI\1IIficanc.e (MGUS)

"""'""'" " '"

_1"-""' Plasma celleukaema

Soktary plasmacyloma of bone E.w-llOSSeCWJS (ell.tramedulary) p1aSlllaC)1Oma

Immunoglobulin depositiondiseases Primaryamyloidosis Systemic light andheavy cha in deposrtoo diseases

Osteosclerotic rnyeIoma (POEMS $yrUome)

200

Mature a-cen neoplasms

Synonyms Mo noc lonal g ammopathy, unattnbuted/ unassoctateo : Benign monoclonal gammopathy; Idiopathic paraproteinemia; Noo-myelomatous gammopathy.

Ep;c'emioiogy When sensitive techniques of deteclion are use d, MG US is found in approximately 3% of persons ove r age 50 and in mo re than 5% of individuals past 70 11232 1. MGUS is mo re common in men than women (- 1.5:1) and more than twic e as frequent in Afric an American s as in Ca ucas ians 11 229 , 12491.

Etiology No specific cause of MGUS has been

F"1g.10.29 Rodtyapliof(Aj Wja'ld{B) IernoraI hM:I detnonslrcIle nulIlpIeIy1ic tOle lesions.

identified, It may be associated with connective tissue disorders, peripheral neurop athies. dermatological, endocrine and liver d isea ses [ 12291. Transie nt oligoc lonal and mo noc lonal ga mmopa thies have been described in patient s following solid organ and 8 M/stem ce ll transplantation /1229. 149 1}. Sites of involvement The clonal plasma cells producing nonIgM MGUS are in the 8M ; Iymphoplasmacytic cells that produce IgM MGUS may be in BM and other sites . such as spleen and lymph nodes. Clinical features Patient s exhibit no symptoms or physical findings related to MGUS. The typical taborator y and rad iog raph ic abno rmalities associated with plasma ce ll myeloma are lacking, The M-p rotein is usually discovered unexpectedly 00 serum protein electrophoresis . Approximately 70% are IgG.

I

Table 1D.G.(

Oi ll9';lOS ~C

criteria forMGUS

Booe f1'\llflOW donalplasma cells <10'4andlow lel'8l ofplasma eel flNtrabon in a trephinebiopsy

No ~ organ 01' bfo$Ul rmpauTI'l8fl\ (CRAB: 1lypercalcemIa. renal nsufticiency. a'\allIIlI3 , blwle 1e$IOn$)

Lblirled m 156}.

15% 19M. 12% IgA and 3% are biclonal

112291. UP to 20% 01 MGUS may consist only of an 19 light chain that may be detected only with me serum free light chain assay 11124 . 13741 . Reduction 01 un in'o'O'Jed ~ns is h.rld in 3)-4O'Jb 01 patients with MGU S and monoclonal light chain in urine in nearly a th ird 112331.

-

Marrow aspirates contain a median o f 3% plasmacells and trephine biopsies sho w

no or a minimal inc rease in plasma cells that are inte rstitia l and evenly sc attered

throughout the 8 M, or occ asionally in small clusters 1561- They are usually ma-

both nume rica l and struc tural abnormalitie s in most patients { 113, 430 , 717, 7 18J. The abnormalitie s in non-lg M MGU S are the same as those fou nd in myeloma although the p reva lence may d iffer. Iransocations involving the IGH@gene ( 14q 32) are fou nd in nearly hall of the c ases with differen t studies showi ng tha t t( 11; 14) (q23:q 32) is present in 15-25%, t(4 ; 14) (p 16.3:q32) in 2-9% and t( 14.16XQ32:q23) in 1- 5% 1113, 7 171. De letion s of 13q are pres ent in 40 - 50 % of cases of MGU S compared to 50% of those with myeloma {717 , 7 18. 11801. It is not clear if 13q deletions sometimes are associated with progression of MG US (1125, 12291 Hyperdiploidy is o bserved in about 40% 01 MGUS with chromosomal trisomies similar to those in myeloma 14301. No obvious cl inical correlations are associated wi th chromosome abnormalities in MGUS bu t this may refl ec t lack 01 sufficient data 17171. Ac tivating K- and NRA$mutations are much less frequent in MGU S (-5%) compared to myeloma (30-40%) 11 821 1. Although genetic alterations and gene expression patterns prob ably can distingu ish adv anced myeloma Irom MGU S there are no uneq uivocal intri nsic differences that d istingui sh MGUS from myeloma .

Postulated normal counterpart IgG and Ig A MGUS are p roduce d by post-ger minal centre plasma c ells wit h immunoglobulin genes that have somatic hypermutation of the varia ble regions and are class-switched . IgM MGUS is p roduced by B lym phocytes with somatic hyperm utalion of the IG V genes but without class swi tch 112341. Prog nosis and predictive tectore The clinical course in most persons with MGUS is stable WIth Il M-protein or other evidence of progression. However, there can be evolution to an overt plasma cell myeloma . amyloidosis (in non-lgM MGUS), WM or other Iymphoproliferative oisoeoer (in IgM MGUS) 156. 1229}. The risk of progression is aoout1% per year and indefinite, persisting even after 30 years 112331. Thus, MGUS should be considered a p re-neo plastic condllion 116971. Size and type of M- protein and serum free light chain ratio are significant clinical risk factors 156, 1233. 16971. Risk of prog ression lor patients with an M.prOlein of 25 gil is >4 lime s mat of one with <5 gil. Patients wi th an IgM or IgA MGUS are at g reater risk of progression (- 1.5% per year) to a mali gn ant disord er than

noocrease

lUre appearing but mil d changes. inc luding cytop lasmic inclusions an d nucleoli, areoccasionally observe d.

Irrmunophenotype Staining tor CD 138 fa cil itat es enumeratio n of plasma ce lls on 8M trephine b iopsies.

Detection of the p lasma c ells that express monotypc cyto plas mic Ig of the same isotype as the M-protein is often d iffic ult, because the c lone may be small and in a background of normal p lasma c ells: moootypic light c ha in sta ining is not always detec tab le by im munohistochemistry [17311. Immuno phenotyp ing by trow cytometry freq uen tly shows two po putatone of plasma cel ls , one wit h a no rm al i'rmJnophenotype (CD38 brig ht+ , CD19 +, CD56-) that is polyclon ar an d a mon oclonal population w ith an aberrant phenotype, most etten either CD 19-/CD56+ orCD19-ICD56- 11726 I. The monoclonal population may exhi bit wea ker expression at CD38 and other aberrant antigen expressioo 11618, 1643. 17261.

Geretics Abnormal karyotypes are rarely seen in UGUS FISH studies have damonstrated

.

A

1_.'

.

. •, :-:

< .~ •

• J ;

.~.

' .... ~

Fig.10.30 Plasma cell myeloma. A Gross photograph af thevertebral column. showingmultiple IyticIeSiOOs. filledwith grey, fleshy tumour. B V&rtebral c:oh;mn after maceration, showingr'r'll; ltiple lytic lesions.

Fig. 10.31 Plasma eel myeloma. low (A) and high lB) rnagMJealions of a bone marrow biopsy. There is exler\SMl marrow repIacernenI WItllneoplastic plasma eels. The palIem of in'O("Ii l8l ~ is mixed. fIIerstitJal nl loc3. The plasma eels embil mature Iea!lns WlIh abI.ntaA: ~. eeeenn: Ikldei MltI marse dJromBtrl; II'OSlladc visible ru:leoI.

Plasma cea neoplasms

201

trose with IgG 11229. 1234 1. In addition, the fraction of 8M plasma cells with an abnormal irnmunophenotype. the detection of DNA aneuploidy and scorormar levels of poIyclonal 19 also appear to be significant clinical risk factors {17261_

Plasma cell myeloma Definition Plasma cell myeloma is a 8M-based , rntJltifoc al plasma ce ll neoplasm associa ted with an M-protein in serum andlor urine. In most cases there is disseminated 8M involvement. The disease spans a clinical spectrum from asymptomatic to aggressive forms and disorders due to deposilion of abnormal immunoglobulin cha ins in tissues 113741. The diagnosis is based 00 a combination of pathOlogical, radiological and clinical features. ICD-O code

9732/3

Synonyms Multiple myeloma: Myelomatosis:medullary plasmacytoma; Kahler's disease.

,

•

Epidemiology Plasma cell myeloma comprises about 1% of malignant tumours. 10- 15% of haema topoietic neoplasms and causes 20% 01 deaths from haematologic mauqnancies {1052, 16441. An estimated 2O,(XX) cases were diag nosed and more than 10,000 patients died of myeloma in the United States in 2007 110521. Plasma cell myeloma is more common in men than women (1.4: 1) and occurs twice as frequently in African America ns as in Caucasians 11844) Myeloma is not found in children and only rarely in adults less than 30 years of age; the incidence increases progressively with age thereafter, with approximately 90% of cases occurring over age 50 and a median age at diagnosis of about 70 years . The risk of plasma ceu myeloma is 3.7 fold higher for individuals with a first degree relative with the disease {2821. \

Etiology Chronic antigenic stimulation from infection or other chronic disease and exposure to specific toxic substances or radiation has been associated with an increased incidence of plasma cell myeloma {1289, 131 51 . An antigenic stimulus giving rise to mulliple ben ign clones 202

Mature B-eelt neoplasms

SymptOlTllltic plAma e.ll myelorTll

Bone marrow clonal

plasma eels orpIasmacylomI"

Related organ orlissue impalrment . (CRAB Irypertalcerma. renal nsutfioerq, AfIa6Wia,bone lesions) Asymptomatic tsmoldeliogj myeloma M-protein in S6f\J mat myeloma ~vels (>3OgIL)

AND/OR

10% or more donal plasma ~I s in bone mai'TOW Norelated organ or bssoe impairment [end organ damage or bone IesionI(CRAB: hypercalcerria, nlIIaI inSufticjency, anaema. bone lesions))orrnyeIom&-it!lat s~ • No IeYeI 0( serum orume M-proIeIl is I1dlJl:led M-prolein in most cases II >3(91. 0( IgG or >25g.t 0( IDA or >19''24 Iv 0( unne Igtt d\ain I:d some pab8nts WIll! S)'frPIomabc III)"!lDma I'aYe ItveIs lower than htse.

• UonodcI'IaI plasma eels usuaIy exceed 10'% 01 nucleated eels i'llhe marT\1IfI' I:d no!1Onal1eWtl is designaled because abl:M: 5% 01 pabenls WIth s~tic; myeloma Ilave < 1O"fe manow plasma ceh. • The mo5l impcItantcrilerlalor symptomaoc myeloma aremaru1estalions 0( eod organ damage I1cIudIng 8naen'ia, hypercak::erma.1ytJC bone lesions, renal insu!lioeoty. hypefVlSCOSlfy. amy\Oidosts orl ecurrent i'llections. Modified from ,56).

could be followed by a mutagenic event initiating malignant transformation 18731. Most patients have no identifiable toxic exposure or known chronic ant igen ic sterwlation 113151. Sites of involvement Genera lized 8M involvement is typ ically present. lytic bone lesions and focal tumour al masses of plasma cells also occur . The most common sites are in 8M areas of most acti ve haemetopolesls . Extramedullary involvement is generally a manifestation of advanced disease. Clinica lleatures Symptoma tic plasma cell myeloma is defined by the presence 01 end-organ damage (CRAB: hypercalcemia. renal insuffic iency, anaemia , bone lesions) in a patient with an M component and clonal 8M plasma ce lls. In most patients there is a constellation of clini cal , laboratory, radiological and pathOlogical findings 113741. Radiog raphic sludies reveal lytic lesions. osteoporosis or fractures in 70% of cases of myeloma at d iagn osis, often assoc iated with bone pain and hypercalcemia 156, 1224, 18401 Renal failure is due to tubular da mage resulting from monodonal light chain proteinuria; recurrent intecuone may be partly a consequence of depressed normal immunoglobulin

produ ct ion; and anaemi a (67%) results from 8M replacement and renal damage with resultant loss of erythropoietin. An M-protein is found in the serum or urine in abou t 97% of patients 112261 (lgG 50%. IgA 20% , light chain 20% 1561, IgD. IgE. IgM and bicl onal < 10% ); - 3% of cases are non-secretory. The serum M-protelf"l is usually >3Og/l of IgG and >2Og/l of IgA. In 90% of patients there is a decrease in polyclonallg «50% of normal). Otherlaborat ory findings include hypercalcemia (20% ), elevated creatinine (20-30%) 112261. hyperuricemia (>50%) and hypoalbuminemia (- 15%) 1842, 12261. Clinical variants Asymptoma tic (smoldering) plasma cell myeloma In asymptomatic plasma cell myeloma. the diagnostic criteria lor myeloma are met but no related organ or tissue impairment (end-organ damage) is present 156, 12271. AsymptomatIC plasma cell myeIOrna is similar to MGUS in its lack of clinical manifestations. but is much more likely 10 progress to symptomatic myeloma 1582. 123 1, 12331, Patients with o ore -sanoo stage I disease are included in this category and in some series so are asymptomatic patient s with an apparent solitary plasmacytoma but with add itional bone abnormalities detected only by MRI 156,

582). About S% of patient s with myeloma areinitially asymptomatic 1123 11. The mao Jority have between 10 and 20% 8 M plasma cells and the med ian level of serum M-protein is nearly 3OgIL. Normal poIyclonal immunoglobulins are reduced in >90% of patients and -70% have mono-Clonal light chains in urine 11 226 1. Patients may have stable disease lor long periOds bulth e cumulative probability of progression to symptomatic myeloma or amyloidosis is 10% per year lor the first 5 years. 3% per year for the next 5 years and approximately 1% for the subsequent 10 years (1231}. Non-secretory myeloma

In approximately3% 01 plasma c elt mye1omas !hefe is absence of an M-protein on rTmXIOIixalion electrophoresis 156, 12261. Cytoplasmic M-protein is present in the reopiasnc plasma c elts in about 85% 01 these when eva luated b y immunohistochemistry. consi stent with impaired secretion ollg 1561 . In about 15% 01 these patients. no cytopl asmic Ig synthesis is detected (non-prOduc er myeloma). Acquired mutations of the Ig light chain variable genes or alteration in the light cha in constant region have been implicated in the pathogenesis of the non-secretory state 1477. 6221. In up to two-thirds of cases. however, elevated serum free light chains and/or an ab normal free light chain ratio are detectable , suggesting that manyare atreast minimally secretory 16101. The clinical features of non-secretory myeloma are similar to other plasma ce ll myelomasexcept tor a lower incide nce of renal insufficie ncy and hyperc alc emia and less depression of normal Ig (56,

20371

Ftg.10.32 Plasma cel myeloma. A PernnaIirMi¥emenl (e~ pIasmacyDna ). ~ assay pefWenal pIasmacyloma B Section of kidney shoMlg renallIbAr lanMI ~ sitionWIth casts refteclt,g renallI.Witr Sera JMes ~ reabsorpIloo (1rmu1opero ~. ~ ighI chain). ~1s lambda IighI~

characteristic s of the leuka emic pla sma cells span much of the morphologfc spectrum found in other myelomas but often. many of the plasma c ells are small with relative ly unte cytop lasm and may resemble plasmacytoid lymphocytes 1288 1. Typic ally, the immunophenotype of PCl differs from that of most other myeloma s by the lack of aberrant CD56 expression {17191. An abn orma l karyotype is more frequently found and there is a higher inc idence of unfavourable c ytoge netics

Macroscopy In plasma cell myeloma. the bone defects on gross examination are filled With a soft gelatinous. fish-flesh. haernorrhagic nssce.

Urilr~

SeN M

~- I

I

I .

•e

~

~ •

••

1 ~

Plasma cell leukaemia (peL) In PeL. the number of clonal plasma cells in the PB exceeds 2x1Q9A..or is 20% of the leukocyte differential count {56}. In addi100 to PBand 8 M, the neop lastic plasma cells may be found in extramedulla ry tissues. such as spleen and liver and in pleural effusions, ascites and ce rebrospinal fluid. pel may be present at the tsre of diagnosiS(primary PCl) or evolve as a lale feature in the course 01 plasma cell myeloma (secondary PCl) 17571. Primary Pel is found in 2-5% of cases of myeloma 1112. 583. 7571 . Compared to IgG Of IgA myeloma. a higher proportion of ~g ht chain only. IgD . or IgE myeloma present as PCl 1757. 916 1. The c ytologic

11121. Most clin ical signs of myeloma are observed in PCl. aJthough osteo ivtc lesions and bone pain are less frequent and lymphadenopathy. organomegaty and renallailure are more often present!75n PCl is an aggressive disease with short survival 1112. 583, 7571 .

.\-...!'"<'C. " •

.1> •

w

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-.EL

.. ... .... • ~

1

~ . 10.33 Serum and urW1e prolein el8dropholesis and mrudtxalion from a 65-year-old llfl)III(Ifl wrth plasma ~ who presented wrth bact. reo,arv:l peMc PlWl arv:l ge. .... iilized weakness.There was .., t1ypeicaloei'la, laUe oranaemia; howeYer. a skeletal Sl6'o'9y' I'8'o'eIIed Il'UIipIeIytJc tesions i'I tle sJuA. nbs . peIYis. etaYides, sc:apda em spI'le_ A bMe marrow biopsy slowed 13%plasma Pro!er'I eledJophole$iS {ElP) f£'YeIled a 31 !J'1- ~ IgGk M-proIein and a 341.4il'9'24 h.1oI'ine M-proIeln. The M-proIeil was il:lenbMd byirmulofiuIial ...... UlNes4 (IFE) as IgG kappa (C
..-..

"'"

'*_

Plasma cell neoplasms

203

Fig. 10.34 Plasma eel myeloma Ifl a bone marrow biopsy, A discrete plasma eel mass dIsplaces normal rnafTOW fat cellslWId haemalopoietJc eIemef1ls, I'4ear the myeloma mass nole prtIfl1ineotosteodaslic activity in the trabecular bone

Morphology Bone marrow biopsy In co ntrast to normal plasma cells, which are typi ca lly found in small clusters around 8M arterioles, myeloma plas ma cells usually occur in interstitial clusters, focal nodules or diffuse sheets 1152, 2881. There is often conside rable 8 M spa ring and preservation of normal naernaropoesis. with interstitial and focal patterns of involvement With diffuse involvement, expansive areas of the BM are replaced and haematopoiesis may be markedly suppressed. There is typically progres o sion from interstitial and focal disease in early myeloma to d iffuse involvement in

advanced stagesof disease 1152) , Generalfy, when 30% of the 8M volume is comprised of plasma cells, a diagnosis of myeloma is likely, although rare cases of react ive plasmacytosis may reach that level. A tumoural mass of plasma cells disp lacing normal 8 M elements strongly favours a diagnosis of plasma cell myeloma, even it the overall percen tage of plasma cells is <30. Occasionally prominent osteoclastic act ivity is observed in biopsy sec tions. resulting in the bone lesions on radiographs . Immunohistochemistry is useful in Quantifying plasma cells on biopsies, in confi rming a monoclonal plasma cell

proliferation and in disting uishing myeloma from other neop lasms. A CD138 stain is useful for quantifying plasma cells. and ctonentv can usually be established with stains for kap pa and lambda light chains

156. 17311· Bone marrow aspiration The number of plasma cells seen on aspirate smears varies from barely increased to upwa rds of 90% 112261. Myeloma plasma cells vary from mature forms indistinguishable from normal 10ifn. mature , ptasmabiasuc. and pleomofphic 1152.288, 8401 . Mature plasma cells are usually oval. with a round eccentrc

•

---

Fig. 10.36 Plasma cel myeloma. cykIlogic features If1 marrow aspirations showing 'o'ariatJon from mature l A-B) kl immature (e ,0) plasma cells. The more mallJ'e ceRs haveckJnped I1UCIe
204

Mature B-cell neoplasm s

, Fig. 10.37 Plasma cell myeloma. rncwphoIogic vnrG on ~~_ A So-called Mott c:el MIl abundant "grape-like" c-,1OPIasmic indo.JSi)ns d irnml.Jnoglobulin, B Numerous Russel tooes based

nucleus and "spoke wheel " Or "cloc kface" chromatin without nucleoli . There is generally abundant basop hilic cytoplasm and a perinuclear ror. In con trast, immature forms have more dispersed nuclear chromatin, a higher nuclear/cytoplasmic ratio. and often, prominent nucleoli. In almost 10% of case s there is plasmablastic morphology 18401, Muhinueleated, poIylobated. pleomorphic plasma cells are prCml nent in some case s 11 52 , 2881. BeC8lJSe nuclear immalu rity and pleomorphism rarely occ ur in react ive plasma cells. they are reliable indicators of neoplastc plasma cells. The cytoplasm of myeloma cells has abundant endoplasmic reticulum (ER), which may c on tain , condensed or crystallized c ytop lasmic Ig producing a variety of morphologically osnrcnve hOdi ngs, includIng : multiple pale bluish-white, grape-like accumulallOl'l (Molt cells, Morula cells), cherry-red refracnve round bootes (Russell bodies), ~ stalr'Ii"Ig gtycogen-rich rgA (flame cells). overstuffed fIbrils (Gaucher-like ceas. thesaurocyt es) and crystalline rods 12881. Other than the presence of crystalline rods, these changes are not palhognomonic of mye loma since they may be found in reactive p lasma cells . In about 5% of cases of symptomatic myeloma there are < 10% p lasma cells in ee 8M aspirate smears 1561, This may be due 10 a sub-optimal BM aspirate or the frequent focal d istribution of myeloma in the 8M In such instances, larg er numbers of plasma cells and foca l clusters are sometimes obse rved in the trephine biopsy sections, Biop sies d irect ed at radiographic lesions may be nec essary to establish the d iagno sis in some pa tients.

Peripheral blood Rouleaux formation is usually the most striking feature on PB smea rs and is related to the quantity and type of M-protein. Aeckoevmrobtasnc reac tion is obse rved in some cases. Plasma cells are found on PB smearsin approximately 15% of cases, usually in small numbers . Marked plasma cytosis eccoroenee plasma cellleul<.aerm. KK1ney

Bence Jones protein accumulates as aggregates of eosinophilic material in the k.mna of the renal tubules. Renal tubular reabsorption of Bence Jones p rotein is largely responsible for rena l damage in plasma cell myeloma .

!

~

I

.. . COlO

CD20

,

-

FIg.1D.38 FlowcyDneIry tMstogams cia bcrle marlOWfrom, pabent WI01 plasma eel ~_ The l'lElq)Iaslic plasma eels !We painB:! red: normal B~ _ bloe. The myeloma OllIs IlIPf8SS brlljlt C038and arenegatiY8 krano, C019and COlO. They express CD56 and P<Wtial C045. arenegalI\'e lor surface igt4chains and eqJreSS cytIplasmic

-

IrmlUnophenotype Plasma cell myelomas typically have monotypic cytoplasmic Ig and lack surface Ig. They usua lly express CD79a, VS38c, CDl38 and strong CD38, simila rly to normal p lasma cells but in con trast 10 nor ma l p las ma c ells, they are nearl y always CD19 negative ; CD56 is aberranll y expressed in 67- 79% of c ases 113 12. 1719, 19081. In add ition to CD56, my eloma plasma ce lls may aberranuy express CDl17. CD20 , CD52 and CO lO, in decreas ing o rder of frequency , and occasiona lly, myeloid and monocytic ant igens are found (26, 850 ,131 21 Unlike most myelomas. about 80 % of pl asma ce illeukaemias are CDS6 neg ative 1757. 1719 , 19081. Some c ases are cy clin 0 1 po sitive , This fin d ing correla tes with the p resenc e of 1( 11;14)( q13;q32) involvi ng Ihe CCNDI g ene and has bee n associated with a Iymphopl asmacytic rrorpnologic appearance. Genetics Antigen recep tor genes Immunog lobulin heavy and ligh t c hain genes are rearranged. There is a high load of IGHV gene somatic hypermutation consistent with de rivation from a post-cerrnmar centre, ant igen-driven B~II 11341. Immu nog lobu lin gene deletion is sometimes found ; in patients WIth

cloreuv

light chain only disease or Bence Jone s proteinuria, JH seg ments and/or parts or all of chromosome 14 may be lost 11401. Genetic abnormalities and oncogenes Abnormalities are detect ed by conventional cytogenetics in abo ut one third of myelom as 156 1, 19471- Fluorescence in situ hybr idizatio n (FISH ) inc reases the proportion with c hromosomal abnormalities to >90% 111 1, 430, 718 , 1181 , 19471Both nume rica l an d structural abnormalities are found and includ e trisomi es, whole or par tia l c hromosome d eletions and transccatons: complex cytogenetic abn orm aliti es a re co mmon 15611. The mos t frequ ent c hromosome translo c ationa involve the heavy chain locu s (lG H@)on chromosome 14q 32 and are present in 55-70% of tumours 1113. 7181. Five major recurrent onc oge nes are involved in 14q32 translocations: cvcun 0 1 (1 1q 13) ( 15 - 18%); C-MAF( 16q23) (5%); FGFR3/MMSET( 4p16.3) (15%); eye/In D3 (6 p21 ) (3%) ; and MAFB (2Oq1 1) (2%) 1111, 199,200,12011 . Tog ether theseS trensocanons are foun d in about 40% of cases of myeloma , most of which are nonhyperdiploid and/or >75 chromosomes). The rema ining tumou rs, which only infrequently have one of the five recurrent [email protected] hyperdiploid. usually with gains in the odd numbered ch romosomes. 3, 5 , 7. 9. 11,

«48

Plasma cell neoplasms

205

Table10.06 Group

Tra n~tion

and Cyclin 0 groops in plasma oeI myelomas.

Primal)'

"""

O-Cytlin

Ploidy

F~qu&IlCy

Progno.i.

transJoc.tion

"'1

6021

CCNDJ

03

HH

3%

eeee

l1q1J

11Q1J

CCNOI

01

O.NH

16%

Go«

01

"'"

H

3"

Go«

"'" "'"

"'" "'" "'" ....

01 0 1+02

H

....

H,NH

11%

? "" ?

HH

'"

01+02

D2

D2

"'"

"'" "p16

FGFR3IIIMSET

02

NH>H

"'"

16q23

""'"

02

NH

D2

NH

4016

21lq11

",,/8

..

,.

15\

'"

1>, diploid: H.~: NH. ~. UocifIed from (2OOJ

? Go«

""

"" ""

,

ce.

Fig. 10.39 IlI1eIpIIase FISH 31'1illyses of reoJrrent abnormalities in plasma myeloma A FU$IOI1 signals for U:".1")(p16:Q32)./gHprobes-geen; MMSETIFGFRJ probes-fed. Two fusion sigIaIsinlicated by ye/kM' ~ mosl likely idefrtIlyderl"j and derl1") but txlUIlI represert two ccees oIllerj"). B Em copiesollhreedlromosomes 11 3 tly_ penjipIoId \l.fTllu. TIvee copies 01 chtol nOSOn. 5 (lSI D5S231D5S721"9f1!e11) alll cmmosome9 (CEP ~ [drded] and bs copies 01 cMlmosome 15 (CEP 15-ted). CTwo copies 01 etrom:lsome 17 and doIefi:)n 01 one copy 01 TP5J. TP53--fed, CEP 1111ll8fl. 0 Loss 01 one mpyolctrorrosome13/13Q. LSI13(CXI'lIiIining RB1}green. Dl3S319-fed. In all flu p;wleIs. 11'18 C)'tIplasm is tu ck.Ie m irmuloslair'Wlg 0I 1gobppa Of ~ ex.pressed by lhe U'noI.rplasma eels, and tie ptObe$ we mn Vysis. C»1asy 01 Or SColt \laJ'I We and Or Ra1aeI Fonseca

206

Mature B-cell neoplasms

15, 19 and 2 1 1430,431, 718,20991. Both IGH@ uanstocations and hyperdip loidy, appear to be early events in the genesis of plasma cell neoplasms, unified by associated upregulation of one of the eye/in 0 genes (0 1, 02, 03) 1199, 201, 405 , 20991. Gene expression profiling can determine the expression levels of eye/in D " 02 and 03 and identify myeloma that overexpress oncogenes dysregulated by the five recurrent IGH@ translocations. Using patterns of nensocations (T) and cycnn (C) D expression (TC groups) plasma cell myelomas can be classified into 8 groups that are based mostly on initialing ()( early pathogenic events 12001· Some or all of these groups may represent distinct disease enunes that require different therapeutic approaches I2CXlI. Anothe r molecular classification is based on unsupervised clustering of tumours by gene expression profiles 124951. This identifies seven rrolecurar groups that are similar although not identical to the TC groups, Withone at the seven molecular groups being defined by progression events that lead to increased proliferation . Monosomy or partial deletion of ctrcrosome 13 ( 13q14), which is found in nearty half of tumours by FISH, is another early event in pathogenesis, although the precise timing of these various early events is poorly understood 111t , 7181. Activating mutations of K-or NRAS are presentin about 30-40% of tumours. and are thoug ht to represent an early event in prog ression, perhap s mediating the MGUS to myeloma transition in some patients (718, 182 11. Some other recurrent genetic chan ges associat ed with di sease progression in bo th non-hype rd ip loid and hyperd iploid tumour s inc iude the following : secon dary IGH@ or IGL translocanons. deletion and/or mutation of TP53 (17p13), traosrocenons involving MYCor less often N·MYC, gains of chromosome 1Q and loss of t p , mutations of genes that result in activation of the NF-kappa B pathway, mutations of FGFR3 in tumours with 1(4:14), and inactivation of p lIr"""or RB 1145, 111, 200, 571, 880 , 1131, 1201, 2017,20991 . Epigenetic cha nges manifested by DNA memyianon also are associated with tumour proqression. Although genetic events appear to play the key role in initiation and progreso son of plasma cell myeloma. the 8M microenvironment is also important in pathogenesis and progressioo 114891.

Extracellular. matrix proteins, secrete d cytokines and growth fac tors, and/or the functional consequences of di rect interaction of the 8M stromal cells with neoplastic plasma cells are major constituents that influence the pathophysiology of myeloma 11 489/. Postulated normaJ cou nterpart Post-germinal centre long-lived plasma cells in which the immunog lobulin genes have undergone class switch and somatic hypermutatiOn.

Prognosis and pred ictive factors Plasma cell myeloma is usually incurable, with a median survival of 3-4 years. but the range varies from <6 months to >10 years 18421, The Durie and Salmon (OS) staging system applies commonly avaaable clinical parameters to predict myeloma cell turTlOUr burden - low, intermedia te and high tumour cell burden 1160, 6331 (Table 10.07). There is a significant dlHerence in survival between each of three tumour mass stages; normal renal function versus renal insufficiency further defines lower versus higher risk patients in each stage 1633, 842. 18081. Additional indicators of higher risk patients include elevated serum 11-2· microglobulin (R2M), low serum albumin , elevated lactate dehydrogenase, high O reacnve protein, increased plasma cell proliferative activity , high degree of 8M replacement, plasmabl astic morphology and genetics PS9 , 160,84 1. 18081. An international stagi ng system (ISS) for plasma cell myeloma provides highly significant prognostic correlations, using acornbination of serum r..2M and albumin level to define 3 stages (8421 (Tabl e 10.08), Patients with abno rmal ities by conventional (metaphase) cytogenetics have a significantly shorter median survival than those without 1111, 4 16, 428, 787, 842, 880, 912, 1132, 1181, 2000, 20991. The most important independent negative prognostic indicato rs include: high risk ~4; 1 4) and the MAFtransJocations t( 14;16) and t(14;2O), deletion of 17p/TP53 se· qcences and increased serum B2M. A high-riSk molecular signature based on the expression 01either 70 or 17 genes provides perhaps the most robust , independent prognoslic indic ator 12001/.

F.g.10.40 5pectrakaryotypic(SKY)a'WysIsd~n1~l*smaoelrnyebna . ....C ~ spreads "lispIaycolcn. B,OQassdicalion dchOlllOlOl 'oes;A, B Hypenipklid Lm:u'Mlh 53 c:hOl 'iUSOIfIeS, n::t.d-

ing bs rearrnnged chDmDSQllleS IlYoIWlg two or fI'IOl'edtrerenl chOlllOSOllleS , trisOlnIesdchOlllOSOltleS 3, 9, u . 19 and letr'ascrT1es d c:MJmornes 15and 21. From f ISH MlaIyses (not$hDwrl), \here 1$no lGHor JGL ba lSkX:abol., tu ltYC is i'lSerIed 0l'I d'nomosome 6p23. C,O ~ bnlU WlfJ 46dlOllllSOl1eS,1lckDrlqalleast hee ~ ctrcrnosomes invoMng two orfI'ICII'e dillerenl d1n:Jrros<:mes. antrtemally deleted dVomosome l.t, andbss d one CWI ofchromosome 13. FISH anatyses (notshown)a:m.rm ltle presence d a l(2;1.tKp23:q32) iM:lIving N-M'fCanda karyoIypicaIly silent l(-4;1.tKp16;q32). Courtesy afDrAnna Rosdi;e and DrAna Gabrea Table 10 07 Myeloma sIq1g syslem Mod.f1ed from DIn! and Salmon {633} Stage I: - lCM M-protein ~s : IgG <~ .1gA <3OgIt; Urine BJ ~4hr - Absent or soitary bone lesions, - ~ haerrogk:lbin, serum calCiwn, 1g Jevels (non-M protein),

Stage II: O'IeraU vanes between I and III Stage III: Arry one ormore ollhe following : - High M-protein: IgG :>70g1l, IgA :> 5Og/L: Urine lightchain :>12g124hr - Acvanceo, multiple lytic bone lesions - Haemoglobin <8,SgldL, serum calcium :>12mg1dL. Subclassification: Based on renallunclion A" serum creatinine <2mgldL B " serum creabnine zz mgldL

Table 10.GB International staging system fof pasroa cellmyeloma.

,

s....

Criteria

Serum ~ <3 5 mg.1.. Serum albumin :>3.5 gldL

" "'

Median 5urvival

"moo"

Notstage I orIll"

Serum ~ :>5 5 mg1l

"There are two calegorie$ Jar stage II: serun ~ <3.5 mgIl.. but seIVIl aItlumi'l <3.5 gll1.: or sen.m ~ 3.510 <5.5 mgIl.. rmpecbwe 01 the sen.rn all\rlWlleYeI. ModIfIed from (842).

Plasma cell neoplasms

207

Table10.09 Cytogeneticprogoostic groups in plasma cell myeloma. Unfivotll'lble risk:

Delellon 13IS ~ by meta(:tIa$& analysis 114,14) or11 14:16)or1(14;20) by FISH Deleboo17p13 byFISH Hypodiploidy F~" risk :

Absence ollWlfavcuable risk geoetIC$ and presenceafhyperdiploilty.1( 11;14) or116,14) by FISH Modified from {2099},

Solitary plasmacytoma of bone Definition Solitary plasmacytoma 01 bone (osseous plasmacytoma) is a localized bone tumour consisting 01 monoclonal plasma cells, Co mplete skeletal rad iogr ap hs show no other lesions. There are no clinical feat ures 01 plasma cell myeloma an d no evidence 01 8 M plasmacytosis except for the solitary lesion 156, 20611. ICD-O code

•

9731/3

Epidemiology Solitary plasmacytoma of bone comprises 3-5% of plasma cell neo p lasms 1561. It is more c ommo n in men (65% ); media n age at d iag nosis is 55 yea rs 156, 5821. Sites of involvement The most common sites are bones with active 8 M naema topole sle: in orde r of freq uency , the vert ebrae . rib s. skull, pelvis, femu r, clavicle and sca pul a 15821. Thoracic vertebrae are mo re commonly involved than cervical or lumbar, and long bone invo lvement below the elbow or knee is rare 156. 5451.

ad d itiona l lesions and is c onside red a prerequi site for di ag nosi s by some investigators 11296, 206 11 ·

Mor phol ogy, irrmunophenotype and genetics Plasmac ytom as are usually ea sily recogniz ab le in tissue sec tions unless the p lasma cells are very poorly d ifferentiated , e.g. pla sma bla stic or anaplastic . Confirmation of a clon al p lasma ce ll lesion can be ac complished by immunohisto chemistry Even when the d iagnosis is ap parent. oererrrsnauon of light c hain type is suggested. The irrmunophenotype and genetics are simi lar to those of plasma c ell myeloma Progn osis and pred ictive factors Local con trol is achieved by radiotherapy in most cases, but up 10 two third s of patients even tually evolve to ge neralized myeloma or additional solitary or multiple p lasmac ytomas 156, 545, 9551 Approximately one -third of patients remain disease free lor >10 years; median overall survival is - 10 years 1561. Older patients and those with a sol itary plasmacytoma la rge r th an 5 cm or per sistenc e of an M-protein following local rad iotherap y repOrled ly have a higher incidence of prog ression 156. 582 , 1296, 2272, 24031, However. these unfavourable features have not been consistent betwee n series 1206 11, Osteopenia and low leve ls of uninvolved immunoglobu lins . both 01 which suggest occult plasma cell myeloma. are also reported as adverse prognostic lactor s 1582, 10301. Measurement 01the free lig ht chain ratio is usefu l l or predi cting progression (5871.

Extraosseous plasmacytoma Definition

Clinical leatures Patients most frequently present with bone pain at the site of the lesion or with a pathological fract ure . Verte bral lesions may be associated wi th symptoma tic cord com p ression 15451 . Sofl tiss ue extension may p roduce a pa lpa ble mass 1561. An M-protein is toone in se rum or urine in 24-72% of patients 156, 582 , 206 1,24031, In most cases ooivcionar immunoglobulins are at normal levels 1582, 206 11. There is no anaemia, hyperca lcemia or rena l failu re relate d to the plasmacytoma 156 1. MAl is useful to exclude 208

Mature B..cell neoplasms

Exuaosseou s (ext ramedul lary ) pl asmacytomas are loc a lized plasma cell neoplasms that arise in tissues o ther than bone. Lymphomas with prominent plasmac ytic d ifferentiatio n, partic ular ly extranod al ma rg inal zone (MALT) lymp ho ma, must be excluded, ICD-O code

973413

Synonym Plasmacy toma. extramedullary.

Epidemiology Extraosseous (ex trame d ullary) plasmacytomas constitute 3-5% of aU plasma cell neoplasms 1221. Two thirds of patients are ma le; the median age at diagnosis is about 55 years. Sites of invo lvement Approximately 80 % of extraosseoos plasmacytomas occur in the upper respirato ry tract , incfuding the oropharynx, naso pha rynx, sinuses and larynx, but they may occur in numerous other sites, including the gastrointestinal tract (Gil, lymph nodes. bladder, CNS. breast. thyroid . testis . parotid and skin 1221. Plasmacytomas of the up pe r respiratory track sp read to cer vic al lymph nodes in - 15% of cases 114601. Clinical features Symptoms are generally related to the tumour mass and include rhino rrhoea, ep istaxis and nasal obs truc tion , Radiographic and morphologic assessments show no evidence of BM involvement. Approximately 20 % 01 pat ients have a small M-p rotein, most commonly IgA 156. 20611· There are no c linical features of plasma cell myelo ma.

-

The mo rph Ologic features are similar to those of solitary plasmacytoma of bone, However, in extraosseous sites, distinction be tween lymphomas that exhibi t extreme plasma cell differentiat ion and p lasmacytoma may be diff icult 15801. Ma rg inal zone lymphoma 01 MALT type, Iymphop lasmac yt ic lymp homa and occ asionall y, immu noblas tic or plasmablaslic large cell lym phomas may be misdiagnosed as plasmacytoma 1580, 9991 . Disnocton from a marginal zone lymphoma with marke d plasma cell differentiation is espec ially problematic , particu larly in skin and G I, and may not be possi ble in some instances. Areas With features of marginal zone lymphoma may be identified in tissue sections in some cases and in others a clonally related lymp hoc yte population may be identified by flow cyto mefry Irrmunophenotype and genetic features The immuoopheootype and genetic teatures are not extensively studied. but appear to be similar to thos e 01 plasma cell myeloma, Immunohistoch emistry or In situ hybridization for Ig light chains can be useful in d istinguishing neoplastic from

reactiveoiasma cell infiltrates. Expression of CD20 by lymphocytes within the lesion or by the plasmacytoid cells or expression of IJ rather than y heavy chain favours a diagnosis of lymphoma over pla sma cytoma Prognosisand predictive factors In most cases the lesions are eradicated with local radiation therapy. Reg ional recurrences develop in up to 25% of patients and occasionally there is met astasis 10 distant extraosseoue sites. Progression to plasma c ell myelom a is infrequent, occurring in -1 5% of cases 1221, About 70% of patients remain disease free at 10 yea rs 15791 , This indolent course may sug gest that many cases are more c losely related to MALT lym phoma than to myeloma.

Monoclonal immunoglobulin deposition diseases

I

The rrooodonal irrm..x'loglobulin oeooston diseases (MIDO) are closely-related disorDers that are charac terized by visceral and soft nssue d eposition 01 immunoglobulin, resulting in com promised organ fLr1ction 1100, 304 , 934.1085, 1225, 1779, 1814. 1994.24331. The und erlying disorderis typically a plasma cell neoplasm, or

~

~

,

~

Fig. ' 0.• t Plasmacytoma showlng absence dCOlO (A) iIfkl expressiorl dCD38IBI_

rarely a Iym phoplasmac ytic neoplasm 1785, 7861; however, the immunoglobulin molec ule accumulates in tissue before the development of a large tumour b urde n. Thus. these patien ts typ ica lly do not have overt myelom a. or rvmpncorasmacvuc lymphom a at the time of the diagnosis. The MIOO appear to be chemically di fferen t mani festations of similar pathological p rocesses, resulting in clinically similar but not identical countcoe. There are two major c ateqones of MIDD: primary amyloidosis and lig hl chain deposition d isease (LCDD); rarely ligh t and heavy chain deposition disease (LHC DD) and heavy chain oeoositoo disease (HeDD) may be seen

Primary amyloidosis Definition Primary amyloidosis is c aused by a plasma c ell. or rarely. a Ivmoboorasmacvnc neoplasm that sec retes intact or frag ment s of abnormal immunog lobulin light chains, or rarely, heavy ch ains, wtuch depo sit in various tissues and form a Bp leated sheet structu re (AL amyloid) that b ind s Congo red dye with cha racteristic bi refringence 1785, 786, 813, 1157,1225. 19941.

lCQ.O oode

9769/1

Epidemiology The median age at dia gnosis of p rimary <myloidosis is 64 years and >95% c:I pa1lE!fltS are over 40; 65- 70%are male 11 225, 12281.

,...1&...~;:.La ili.& fig. 10,. 2 Plasmacy1oma. Composrte figufe illuslrates immllooglobulin expression, A Typical plasma cell morphology B CyIoj)Iasmic kappa light chain posdlYity CAbsenc8 01 lambda \ighl chaindiseaseexpl"llSSion. 0 Expression of cy10plasmicgammahea'IY chain, E.FAbsence 01 mil aridalpha hea'IY chains,

Plasma cell neoplasms

209

",

Fig. 10.43 PlasmaC811 grarUoma. A The "masselJed'oIp1asma cels SOlllates a neoplasm. ~ stamsl'lCM' poIytypiccy1qllasnic~Wilh someplasma eels 8xpre$$1l'1Q (81 ~ 19l1 cham and somee~ (e) Ianbda i(;Tl d1aons

Approximately 20% of patients have plasma cell myeloma but most have criteria for MGUS with production of a M-protein that results in pathologiCal deposition 0119 light chains in various tissues . Among patients with myeloma, up 1010% have or will develop amyloidosis 156. 1225, 1226,1 9941, Sites of involvement AL amyloid ac cumulates in many tissues and organs inCluding subcutaneous tat , kidney, heart, liver, Gr, pe ripheral nerves and 8M. The diagnostic biopsy site generally is the abdominal subcutaneous tatpad. 8 M or the rect um 11225.1 994 1.

•

Clinical features Clinical findi ngs are usually related to deposition 01 amyloid in organs, resulting

in organomegaly Purpura (15%) (particularly periorbital or facia l). bone pain (5%) , peripheral neuropathy (17%) and carpallunnel syndrome (21%) are early signs of disease. Haemorrhagic manifestation s are found in approximately one fifth of cases. Bleeding may occur due 10 inc reased frag ility of blood vessels from am yloid deposits. binding of coagulation factor X and/or vascular structures to amyloid proteins. Symptoms referab le to con g estive heart failure (17%), nephrotic syndrome (28%) or ma labsorption (5%) are all relatively common 112251. Hepatomeg aly is foun d in 25-30% of pa tients and ma crogl ossia in about 10% {12251. Ed ema is otten present in p atients with congestive heart failure or neph rotic syndrome / 1225). An Mprot ein is found in the serum and /or urine by immunofix ation

in >90% of patients with primary amyloidosis and with a combination of immunofixation and serum free light cha in ratio analysis in 99% 157. 1123 . 12251. Thelighl chain is lambda in 70% of patients 112251. Palhophyskllogy AL amyloid is composed of intact immunoglobulin light cha ins or rarely, heavy cha ins that are secreted by m0nocl onal plasma celts and then ingested. processed and discharged by macrophages into the extracellular matrix . The accumulated amyloid includes both intact light chain and fragments of the variable (V) NH2-terminus region . All tight chain V region fragmen ts are potentially amylodoqenic. and all plasma cell neoplasms that produce VAVI have AL 11225 . 1994), Macrosc opy On gross inspec tion amyloi d has a dense "porce lain-like" or waxy appearance,

•-

.

~ pIasmacybma 0( Ih8 skr1 wrlhabundard. Russel body tormabon (A B) wtidll3l prockIce ~ stanng by irmlullOhiSb:tletfislry. MonodonaIity is dem:nstraled by IlllIHadioacDve i'I situ hybridaabon ~ absence of kappa (e) and presence of Ian'bda mRNA ~ (O).

f ig. 10."

210

Mature B-cell neoplasms

Morph ology Biopsy section s of 8M vary from no pathologi c findings to extens ive replacement with amyloid, overt myel oma, or rarely. lymp hopl asmac ytic lymph oma. The most com mon findi ng is a mild inc rease in pla sma c ells that may appear norm al or exhibi l any of the changes foun d in pl asma cell myeloma 11 2251, Amyloid is p resent in many other tissues and organs. In H&E stained sectio ns, it is a p ink. amorphous. waxy-appearing substance , With a ch aracteristic cracking artifac t. Typically, it is found foc ally In thic kened blood vess el wans. on basement membranes , and in the mtersmnm 01 tissues such as tat or BM 124331. Macrop hages and foreign-body giant celts may be found around deposits Organ parenchyma may be massively replaced by amyloid (amyloidoma). Plasma

.

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f,,,

'(;,,<,.

,J ,t-' I '"

"L

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•

;it,,~~..'..a>:L:l...,i'

A

FIg. 10.45 APrrnaty amyIaIdosIs in a pabetIl withplasma eel myeloma. Grossp/K*)graph of a section of heal1shows !he Iiffuse rilrgement charactefiStlC 01 amyloid deposition, es;e::.ally III !he left 'tllfllncle. Bone marrow biopsy of pnmary amyloidosis sha.Wng etIaraclerisbc pale. waxy arnotpl'lous deposits (BI and associated hlSbocyte$, otIen 1TUlrIucIea1ed. andneoplasbc plasma eels (C).

cellsmay be increased in the adjacent tissues. Congo red stains amyloid pi nk to red by standard light microscopy and under polarized lig ht p roduc es a c baractereuc "apple-green" birefring ence . Elec-

Iron microscopic studies will differentiate

Al amyloid from t c o n . Irrvnunophenotype The immunophenotypic features of the plasma cells are simila r 10 lhose of myeloma , Immunoh istochemical sta ining of 8M seclions for kappa and lambd a IigN chains shows a monoclonal plasma cell staining pattern unless the clone is IAlsually small and masked by rormat poIyclonal plasma cells 1675, 2433, 24521 . Staining lor amyloid P componen t is posmve. Immunohistochemical techniques using anti-amyloid fib ril antibodies to At kappa and lambda are use lul in distinguishing prima ry and secondary amyloidosis (AA) in some c ases but are definitive less than half the time {6751. AA amyloid , however, can be rec og nized by immunohistochemistry in essentially all cases (571.

Genetics The genetic abno rmalities reported ih pr imary amyloidosis are simil ar to those in rm-lgM MGUS and plasma cell myeloma. One exception is the unexplained observabon that lhet( 11;14) is p resent in >40% 01 individuals with amyloidosis but on ly 15-20% of those with a d iag nosis of nonIgM MGUS or myeloma 1718. 9121.

Parame ters that ha ve been associated wit h poor pr ognosis include elev ated serum c reatinine , hep atomegaly, major we ig ht loss, excretio n of lambda lig ht c ha ins in the urine (vs kappa light chains or no M-protein), elevated 112 mic rog lobulin levels an d a large whole bod y am yloi d load {57. 784 , 1228/. The single most frequent c ause of death is amyloid rela ted cardiac disease ( -40%) {122BI .

_ l i ght and heavy chain deposition dis8ases Definition Monoclonal light and heavy c hain deposition diseases are plasma cell or rare ly Iym phoplasmacytic neoplasms that sec rete an abnormal light or, less otten. heavy c hain or both, which deposit in tissues causing orga n dysfunc tion but do not form amy loid B-p leated sheets, b ind Congo red or con tain amyloid P-component [ 106,304, 580,934 , 1085, 1779 , 18 141. These d isorders include lig ht chain deposit ion di sease (lC DD) (304.1 776, 1779, 18 141. heavy c ha in d eposition disease (HC DD ) {106 . 934 ,1 08 51 and ligh t and heavy c hain deposition disease (LH CDD)

1304.5801

Synonym Randall d isease {18141. Epid emiolog y These are rare d iseases of adults (med ian age 56 years. range 33 -79) which occur in association with either myeloma (65% 01 cases) or MG US 1304, 1085 , 1776, 1779 1. There is no evidence of an ethnicity effect and the rnale.ternale incidence is nearly equal{304. 1085. 1779/.

Sites of lnvotvement lCDD and HCDD may involve many organs . IT'OSl <Xm'T'IOl'lIy the kiOOeys 117761. The liver. heart. nerves. blood vessels and occasionally JOints may be involved 1106, :»4,934, 1005,1779,181 4,2433I .Thereis prom inent deposition of the aberrant 19 on basement membranes, elastic and cotIagen fibres . Pulmooary involvement, eitherdiffuse or nodular. has been reported {214. 18751 Clinical feat ures Patient s present w ith symptoms 01 organ dysfun c tion as a result of di ffuse, systemi c imm unoglobul in deposits, usually manifested by nephrotic syndrome and/or ren al failure 1564 . 1776 1, Symptomatic extrarenal d eposition in lCDD is unco mmon and involves the heart (21%). liver (19%)

Progoosi. The median survival for patients with primary amyloidosis is approximately 2 years trom diagnosis 112281. Patients with amyloidosis and plasma cell mye lom a have a shorter survi va l than tho se wit h amyloidosis or myeloma alone 11225 1. Plasma ce ll neoplasms

211

~

. ...•

• o• • .•"

•• •

and peripheral nervous system (8%) 1304, 1462. 1776 1. HCDO of IgG3 ex IgGl .sotypes result in nypocomoiemen terea since the IgG3 and IgG 1 subclasses most read ily fix complement 19341, There is an M-prot ein in 85% of cases.

Pathophysiology

•

The M-p rotein in non-amyloid MIDD has unde rgone structural change due to deletion a! and mutational events 1304 , 580 , 1085, 17791. In LCDD the primary d efect involves mul tiple mutationS 01the Ig ligh t ch ain va ria ble reg ion wi th ka ppa lig ht c hain of V"IV typ e nota bly over represented 1304. 580, 17791. In HCDD the cntlear eve nt is de letion of the CH 1 constant doma in which ca uses failure to associate with heavy c hain b indi ng protein, resulting in p remature sec retion 1106. 934. 1085 , 17791. In HC DD the variable regi ons also contain amino ac id subs titutions that ca use an inc reased propensity for tissue dep osit ion and for bind ing blood element s 1106, 304,10851, Morphology There are prom inent tissue d epo sits of a non -amyloid , nonnbrtnarv amorphous eosinophil ic ma teria l, which d o not stain with Co ngo red. They are often see n as

refrac tile eos inophilic material in the glomerular and tubular basement membranes . bu t may also be seen in BM and other tissues. LCOD is usually diagnosed by renal biopsy using fluorescent antilight chain antibodies and electron microscopy 11 776 1. Kappa chains a re observed by immunoflourescence in the renal glomerular and tubular baseme nt mem brane. The hallmark 01the disease is the p rom inent, smoo th, ribbon-like linear per itubular deposits of monotypic irrrnunoglobulin alon g the oute r ed ge 01the tubular ba sement memb rane. These depo sits by electron mic rosco py are typically discr ete. den se pu nct ate , granular, nonfib rillary deposits, with an absence of the a-oreateo sheet structure by X-ray di ffrac tion. Althoug h in some ca ses plasma ce lls are found in the vic inity of deposits, it is more c ommon to find 19 deposition in visceral organs with few, jf any, plasma ce lls, Bone marrow p lasmacyt osis is prese nt in most cases; rarely, a Iymphoplasmacyt ic or marg inal zone lymphoma has b een repo rted 1214, 305, 23911. Immunophenotype In contrast with pr imary amyl oid o sis, which has a predominance of lam b da lig ht chain with overreoreser uaton of the

.-

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~

••

•

•

• •

c:• •

•

V1IV1 variable reg ion , LCDD has a prevalence 01 kappa light chains (80%) with overepreseotatco of the VICIV variable region 13041· Irrmunohistochemistry on 8M sections may reveal an abe rrant kappa! lambda ratio 124331.

Prognosis The med ian ove rall survival lor patients with LCDD is approximately 4 years. Prognosis is correla ted with age. the presence of plasma cell myeloma and emarenat lig ht chain depos ition 11462 , 17761.

Osteosclerotic myeloma (POEMS syndrome) Definition Osteosc lerotic myeloma is a p lasma cell neoplasm c ha racterized by fib rosis and osteosclerotic chan ges in bon e trabeculae, and often with lymph node changes resem bl ing the plasma ce ll va riant of Castleman disease, This disorder is often a co mponent of a rare synd rome that inc ludes polyneu ropathy, organomega ly, endoc rinopathy, monoc lonal gammopathy. and skin c hang es (POEMS) 11483). The relations hip of thi s d isease to typical pla sma cell myeloma is not known .

Synonym Crow- Fukase synd rome. Epidemiology This is a rare disease. occurring predominantly in adu lts, and estimated to c0mprise 1- 2% of plasm a celt dvscrasas 114831. Many cases have been reported from Ja pan. Men are affec ted slightly more often than women (M.F ratio 1.41) and the median age is about 50 years F~ 10,48 lighI chain depoSlbon disease in kOIeyshowring (A) pale anorphous palttIes IIo'Iltlin gIorroenAi (nodulaf gIomenJosdetosi) and (81 ~ stain stlowing renalllMar andel1rabbJlar c\epOSlbOn ~ Il.ippa IicJ1l chain in a smooIh inearpallem.

2 12

Mature B-eeU neoplasms

15901.

Etiology An imbalance of p ro-inflammator y c ytokines is common in POEMS syndrome. Vascular endothelial growth factor (VEGF) produced by the tumour cells may be responsible for some of the symp toms of the disease 1634. 23631 . Some cases of POEMS syndrome . especially those associated with Cas tleman disease, have been reported to be associated with hl¥l'laflherpesvirus 8 (HHV8) 1175. 14831· Q inica! teensee Most patents do not present With all of the manifestations of POEMS syndrome and not all are requi red for diagnosis. The map clinical feature is a chronic pr ogressive polyneuropathy 15901. O rganamegaly is present in at least 50% of patients and enoocnocoamv and skin changes each in two-thirds 15901. In 75-85% of patients ther e is a serum M-protein that is either IgG lambda or IgA

lambda; the quantity is typic ally low (median 1.1 g/d l ) 15901. An M-p rotein is found in urine in <50% of patients. Relatively c ommon clinic al findi ng s include edema an d serou s c avi ty effusions, pap illedema, thrombocytosis. weight loss, fatigue, clu bbinq. bon e pain and arthralgias. Hypercalc emia, renal insufficiency. and pathological fractures are rare. nacographic bone abnor malities are found in nearly all cases. These vary from single sclerotic lesions in about ha" to more than three lesions in one-th ird of cases 15901_ Morphology

The charac teristic lesion is an osteosclerotic plasmacytoma. which ma y be single Of multiple. The lesion is comprised of focally thickened trabecular bone Wi th closely associated perat-etecctar fibrosis with entrapped plasma cells . The p lasma cells may appear elongated due to distortion b y small bands of connective

tissue. The 8 M away from the osteosclerotic lesion usually con tains <5% plasma cells, which are typically normal appearing. In a minorit y of p atients with more generalized osteosclerotic myelona. > 10% p lasma cells may be found in random 8M b iopsies 120581. Two-third s of patients with lymphadenop athy have ch anges conserera with the plasma cell variant of Cesneman's disease 15901. Immunophenotype The plasma cells con tain monoclonal cytoplasmic Ig which may be IgG QII IgA. The ligh t chain is lambda in almost all p atients.

Prognosis The median overall survival is 14.7 years 1590, 14831. The most corrmon causes of death are cardiorespiratory failu re and infection.

Plasma cet! neoplasms

213

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

P.G Isaac son A.ChoU S. Nakam ura H.K. MOlier-Herme link N.L. Harr is S,H. Swerdlow

Definition Extranodal ma rginal zone lymphoma of

rrocosa-asscctaiec lymphoid tissue (MALT lymphoma) is an extranodat lymphoma composed 01 morphologically heterogeneous small Bcens including marginal zone (centrocvte-nke) cells . cells resembling monocytoid cells. smaJllymphocytes. and scattered immunoblasts and centroblast-like cells. There is plasma cell differentiation in a proportiOn of the cases. The infiltrate is in the marginal zone 01 reac tive B-cell follicles and extends into the inlerfoIrictJlar region. In epithelial tesces. the neoplastic cells typically inliltrate the epithe-

lilm laming tymphoeprtheliallesions 110 131. ICD-{) code

9699/3

Synonym Extranodal ma rg inal zone B-ceillymphorna

of mucosa-associated lymphoid tissue.

•

Epidemiology MALT lymp homa compr ises 7- 8% of all B-eeillym phomas 151). and up 1050% of pr imary ga stric lym p homa [600. 1801 1,

Most cases occur in adults with a median age of 61 and a slig ht female prep onderanc e (male: female ratio 1' 1,2) 151 1, There appears to be a highe r incidenc e of ga stric MALT lymphomas in north-east Italy 16001 and a special sub typ e pr eviously know n as alpha heavy c hain di seas e and now c alled immun oproliferative small intestinal di sease ( IPSID) occurs in th e Middle Ea st 117511, the Ca pe reg ion 0 1 South Africa 117811and a varie ty of othe r trop ical and sub tropical loc ations, Etiology Hussell and colleagues 19981have shown that contmuec prolif erat ion 01 gastric MALT lymp homa cells lrom pat ients infected with Helicobacter (H.) pylori de pends on the presence 01 t-eens specifically activated by H . pylori antigens. The enoortance of this stimula hon in vivo has been clearly demonstrated by the induction 01 remissions in gastric MALT lym phomas with antibiotic therapy to eradicate H . pylori 124441. A role for antigenic stmJIation 2 14

Mature s-een neoplasms

Fig. 10.0 ExtranociaI m
by Chlamydia osittacr. Campylobacter jejuni and Borrelia burgdorferi has been proposed for some cases of ocular adnexal MALT lymp homa. IPSID and cu taneous MALT lymphoma respectively 1364. 695, 12641. Isaacson has suggested that "acqoreo MALT" secondary to autoirrrnune disease or infec tio n in these sites may form the subst rate for lymphoma oeveto pment 11011}. Precursor lesiorls In man y cases of MA LT lymphoma, the re is a history of a ch ronic inflammatory d isorder that results in acc umulation of extranocrat lymphoid tissue , The c hronic inflammation may be the result of infec tion , autoimmunity o r othe r unknown stimulus. Examples of infec tious organism s that may cause ac cumu lation of MALT that preced es MALT lym phoma include H. pylori (g astric MA LT lymphoma) (2445l. Chlamyd ia osrnacr (ocular ad nexal MALT

lymphoma) 1394. 6951. Campvobacte jejuni(IPSID) 11264. 1781, 18121 and Borrelia burgdoferi (cutaneous MALT 1ymphoma) 13641. At least in ocular and cutaneous MALT lymphomas , there is great varia tion in the strength of these associations that might relate in part to geographic dive rsity 1394. 1290, t898I.ln the lirst study in which the association 01 gastric MALT lymphoma with H. pylori inlection was examined. the organism was presen t in over 90% of c ases 124451, Subse q uent stud ies have shown a lower incidence 115661 but also that the density and detectability of H. pylori decrea ses as lymphoma evolves from c hronic gastritis (1562) The orga nism may be undetectab le using histopathological techniques in patient s who are seropositive 16361 . Auto immune based c hronic inflammatio n in the form of SjOgren syndrome and Has himo to thyro id itis is known respect ively to pre cede salivary gland

Fig. 10.5(1 Gaslnc MALT Iynll/1oma AThe\lmol.r oek SIIl'OUI'Id readNe IoIides al'lCl infjtraJe fie 1TIJCOSa. Thebkles have a twicaI staTy-sky appearanal. B The rna-gm zcne eels Itfillfaleltle IanwIa propria n a cIiIIMpaIIIm a'ld haYe ooIaizedfie gemIIIiII oanIres d f8Idw B-alI",TheaJIonizecI kllIic:Jes donoI show a slaITy-sky ....

) and thyroid . MALT lymp homa, Patie nts with SjOgren synd rome (85) o r Iymphoepithelial saieoeruus (LESA) have a 44-fold increased risk 01 d evelop ing overt lymphoma. com prisi ng a bout 4-7% of pa tients 111 14, 21501. Approximalely 85% 01 lymphomas in pa tients with SS/LESA are MAlTlymphomas. Patients with Hashimoto thyroiditis have a 3-lold excess risk of developing lymphoma and a lO- fold increased risk of thyroi d lymphoma, for an overall lymphoma risk of 0.5-1 .5% 160. 958.11161_94%01 thyroid Iymphcmas have evidence 01 lymphocytic thyroiditis 15581.

distribution and sprea d ou t to form larger confl uent areas which eve ntually overrun some or most of the follicl es 11018. 10 191. The charac teristic marginal zone have small to medium -sized , sli gh tly irreg ular nuclei with moderately d isper sed

a-cens

ch romatin and incons picuous nucleoli, resem bling those 01 cerurocvtes: they have relatively abundant, pale c ytoplasm. The accu mulation of more pale-staining cytop lasm may lead to a monocytoi d appearance. Alterna tively. the ma rginal zone

Sites 01 irrvolvement

)

The gastrointestinal(GI) tract is the most common site of MALT lym phOma , compriSing 50% of all cases, and within the GI tract. the stomachis the most common 10calion (85%) {18011 . The small intestine is typically involved in patients with I?SID . Other common srtes inc lude saliv ary gland. lung ( 14%) . head and neck (1 4%),

ocular adnexa (12%), skin (1 1%), thyroid (4%) and breast (4%) 121931.

)

OinicaJ features The majorityof patients present with stage I or II disease . A min or ity of patien ts (2- 20%) have bone marr ow (8 M) involvement 179. 1802. 2 1941. The trecuencv 01 8 M invo lvem ent is low er in gastric cases and high er in MALT lymphomas arising in the lung and ocular adnexa 12193. 2 194). Multip le extranooa! sitesmay be involved in up to 25% of gastric cases and 46% of extragastric c ases at the time of presenta tion 118021. Multifocal nodal invo lveme nt is rare (7.5% of thecases) 121931 . App lication of stag ing systems for nodal lymphomas can be misleading in MALT lymphomas. since involvement of mult ip le extranod al sites , particularly of pai red org ans (e .g . salivar y glands) or org an systems (e.q . ga strointestinal tract. skin) may not reflec t trul y disseminated d isea se. Prasmecvnc differenneuoe is a feature of many of the cases and a serum paraprotein (M-compo nenl) can be detec ted in a third of patient s with MALT lymphoma 124291. The majo r ex ception is IPSID. in wh ic h an a berran t a.lpha heavy chai n ca n usua lly be found inlhe peripheral b lood 1178 11.

-

The lymphOma cells infilt rate around reactive B-cell follicles. exte rn al to a preserved follicle ma ntle . in a ma rginal zone Extranodal marginal zone lymphoma of mucosa-associated lymphoid nssoe

215

cells may more closel y resemble small lymphocytes. Prasmecync diff erentia tion is present in approxima tely one third of gastric MALT lymphoma s. is frequently found in cuta neous MALT lym p homas and is a c onstant and often striking feature in thyroid MA LT lym phomas. The histological feat ures 01 JPSID are simi lar to those 01 other cases 01MALT lym phoma. bu t typi cally show striki ng p lasma cytic d iffere ntiat ion 11 82, 101 2 , 1781 1. l arg e cells resemb ling centrobtasts or irnmunoblasts are usually present, but are in the minority. In glandular tissues. epithelium is often invaded and destroyed by discrete aggreg ates 01 lymphoma cells resutting in the so-called Iymphoepithelial lesions. Lymphoepilheliallesions are ag gregates of three or more marginal zone cells with d istort ion or destruction of the ep ithelium , etten together with eosroophilic degeneration of epi thelial celts The lymphoma cells some times specifically colonize the ge rminal centres of the reactive follic les and in extreme examples, this ca n lead to a close resemblanc e to follicular lymphoma . In lym p h nodes, MALT lymphoma invades the marginal zone with subs eq uent intertonicula r expa nsion. D iSc rete aggregates 01 monoc yto id may be presen t in a paratomcurar and oensmusoioat d istribution . Cytological heterogeneity is still pr esent and both plasma c ell diff erentiat ion and fo llic ular colonization may be seen. MALT lym phoma as def ined is a lymphoma composed predominantly of small celt s, Transfo rmed centrobtast- or immunobrast-uke cells may be pre sent in var iab le numbers in MALT lymphoma but, when solid or sheet -lik e proliferations of

a-ceus

•

transformed ce lls a re present, the tumour should be d iagnosed as d iffuse large B-ce Ulymp homa and the prese nce of ac com panying MALT lymp homa noted. The ter m "hig h-g rade MALT lymphom a" shou ld not be used , and the term · MAl T lymp hom a" shou ld not be applied to a larg e Bccell lymphoma even if it has arisen in a MALT site or is assoc iated w ith

tymoroeonreuauesons. Differential diagnosis The d iffer ential diagnosis of MALT lymphoma incl udes the react ive inflammatory processes that typically precede the 1ymphoma including Hencobacter pylori gastritis, Iymphoeplthelial Hashimoto th yroiditis and other small B-c elf lymphomas (follicular lymphoma, mantle cel l lymphoma, small lymphocytic lymphoma). Distinction from reactive proc esses is based mainly on the presence of destructive infiltrates of extrafollicular Bceus. typically with the morphology of marginal zone cells 12444 1. In borderline cases, rrmcropbenotypi ng 0..- molecular genetic analysis to ass ess s-een cronantv is nec essa ry to he lp establis h or exclude a d iag nosis of MALT lym ph oma, although molecular studies may also de monstra te clonal Bcells in some non-neoplastic MALT proliferat ions or per sistent cl onal population s in gastric MA LT lymphomas even afte r histo log ic co m plete remi ssio ns 11502, 1792,2457 1. Distinction from other sman Bccell lymphomas is based on a co mbination of th e c harac terist ic morpholog ic and immuno phenotypic features .

sraraoenes.

Table 10.10 AnatomiC Site distribution and freq~ (%) ofd1romosoma1lrans.localioos and trisomies 3 and 18 in MALT ~s' t(11 ;1B) (q21;q21)

t{14;18) (q32;q21)

t{3;14) (pl• •t ;q31)

t{l;14l (p22;q32J

'3

."

' -16

t-s

0

0

11

s

-.,"'"

12-56

0

0

0-13

75

25

0-10

0-25

0-20

0

38

13

0-5

0-16

0

0-,

55

19

31-53

6-10

0

2-7

20

o-a

0-"

0-10

0

20

,

""""

0-17

0

0-50

0

17

0

Silo

-......... St.,...

....

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-Data ~ ~ kI StreItleI Sf II. (2109A) rid Remstein at II {18J6}.

216

Mature B-cell neoplasms

7

Immu noph enoty pe Tumour c ells typi cally exp ress 19M, and less ofte n IgA or Ig G. and show light c ha in restric tion. In IPSID, both the pla sma ce lls and marginal zone celts express alph a heavy c hain without any light c hain 11 01 21. The tumour c ells of MAlT lym phoma are C D20+, CD79a+, CD5-, CO lD-, CD23-, CD43+f-, C D11c+I-(weak). Infreq uent cases are CD5 +. The lymphom a c ells exp ress the marginal zone ce ll-associated antigens C02 1 and CD35, Staining to..- C02 1 and COOS also typically reveals expande d mesh works of follicular d endritic cells corres pon ding to COil> nized follicles. There is no spectc marlier for MALT lymphoma at present The demonstrat ion of imm unoglobulin ligtt chain restriction is important in the differential diagnosis with benign lymphoid

infiltrates. In the differential diag nosis with othersmall B-ceillymphomas. absence of the characteristic markers tor those neoplasmsis important: lack of C0 5 is useful in distinction from most mantle ce ll and small lymphocytic lymphomas , cychn 0 1 in distinction from mantle cell lymphomas andCOl Oin the differential diagnosis with many lollicular lymphomas.

Genetics Antigen receptor genes Immunoglobulin heavy and light chain genesare rearranged and srow somatic hypermutalion of variable regions, consistent with derivation from a post-germinal centre. memory B-ceIl1618. 1789 1.

Cytogenetic abnormalfties and ona>genes Chromosomal translocations assoc iated with MALT lymphomas include t(11;18) 1021;021). ~ 1. 1 4Xp22;Q32I. X'4;18XQ32;q211 and t(3;14)(p 14. 1;q32). resulting in the production of a ch imeric protein (API2MAl Tl) Q( in transcriptional deregulation (Bel lO.MAlTl , FOXP1)respectively 1574. 1285. 1667.2110.2111 .2416,24461 . Trisomy 3, 18 or less commonly of other chromosomes is a non-specific but also not infrequent finding in MALT lymphomas. The frequencies at which the nanslocations or trisomies occur vary markedly with the primary site of disease. The t(11 ;18)(q21;q21) is mainly detected in pulmonary and gastric tumours, the t(14;18)(q32:q2 1) in ocu lar ad nexae/orbit and salivary glan d lesions and the t(3:14)(p 14.1 ;q32) in MALT lymph omas arising in the thyroid, ocular aonexae/orbrt and skin. Similarly, geogr aph ic variability inincidence and anatomic site specific ity

of the translocations has been noted, suggesting different environmental influences such as infectious Q( other etiologic fac tors 11636. 2 1101. Postulated normal counterpart Post germinal centre, marginal zone B-ceIL Prognosis and predictive teeters MALT lymphomas have an indolent natural cou rse and are slow to disseminate. Recur rences. that can occur after many years, may involve other extrancda t sites and occur more often in patients with extragastric MALT lymphomas than in patients with primary gastric disease 11 8021 . The tumours are sensitive to radia tion therapy, and local treatment may be followed by prolonged disease-free intervals.

Involvement of multiple extranodal sites and even 8M involvement do not appear to coo ter a worse prognos is 121941. Protrac ted remissions may be induced in H. pyIoi-associated gastricMAlT ~ by antibiotic therapy lor H. pylori 11587. 24441. Cases with the t(11;18)(q2 1;q2 1) appear to be resistant to H. pylori eraorcnon therapy 113211. In IPSIO. remissions have followed therapy with broad-spec trum antibiotics 11 82, 12641 . Antibiotics have also been used to succ essiunv treat selected other MALT lymphomas. Transformation to diffuse large B-ce ll lymphoma may occ ur.

ExtranodaJ marginal zone lymphoma 01 mocose-essocateo Iymphofd tissue

217

Nodal marginal zone lymphoma

E. Campo SA Pileri E.S. J affe HK MOller·Hermelink B.N, Nalhwani

Definition Nodal marginal zone lymphoma (NMZl) is a primary nodal B-ceH neoplasm that morphologically resembles lymph nodes involved by MZL of exnarooet or splenic types, but without evidence of extranodal or splenic disease.

ICD-{) code

9699/3

Synonyms Monocytoid Been lymphoma; peratonicutar s-een lymphoma: Nodal marginal zone B-cefllymphoma.

Epidemology Nodal MlL comprises only 1.5-1 .8% of aillyrnphoid neoplasms 1195. 15781. Most cases occur in adults with a median age around 60 years and a similar proportion in males and females 1731 _ This lymphoma may occur in children {21401. Hepa titis C virus has been de tected in

20-24% of the patients in some studies 173, 25061, but has not been observed in other series {2264 1. Sites of involvement Peripheral lymph nodes. occasionally bone marrow and peripheral blood 1195. 1578/.

Clinical features Most patients present with asymptomatIC. localized or generalized peripherallymphadenopathy 173. 1951. Presence at a primary extrarocar marginal zone 1ymphoma should be ruled out since approximately one third of the cases pesentrqes nodal MZL represent nodal disseminalial

•

F'IQ. 10.59 SpIIlIlIc type nodal marg.naI zone IympI'loma AAlIow magnrfJcation. note the loIIic:aar!1OWlh pallemwdh pa/IlI C8II1haI1ocaIy SInOIRl porbonsofIeacllYe genrnI ceees B The ll.m:u lli ~ d a proIiIerabon aIsmall eels exp;vvjng between a reactiYe g&mWIiJI oentrean:!an IItIenua1ed mantle cell wf, C IgD ~ sI'OlIIS .. _ positivity aI tile b'nol.r t8Is IhaIIlmUld !he negaIrW lIllfII'*laI oenIre..tlefeas the residIJaI manIIe CJ!JIs are ~ posiIi'ooe. DCOlO staI'ing. The ILfro.J" eelsare oegaIMt _ _ toe resOaI gemWIaI centre iI jIOSltrYe EBCl2 stainrlg, The hm:ltI' eels are posANe wtlefeastie reacM gerrrWlaI centre is I"lllgaM 218

Mat ure B-cell neoplasms £

Mg. 10.60 NOOaI margnallOI18 ~. paediatnc typeCXIIllITIOIiy ex1Iibtts progressive ~sJormabon d gemW'IaI 0ilI'hS (A). The atypical eels are b..nd pnmarjyin !he irrtelloIiaAr areas andmay disrupt !he IoIices. B ~ SlaMWlg

hlfi\tIIIlhe lhr\4lI8d and elP'lnded manlle cvff: the lunJ::U eels are \gO negabve. 01 a MALT lymphoma. particularly in patents with Hashimoto thyroiditis or S;Ogren syndrome 1328.16011.

~

The tumour cells surround reac tive follicles and expand into the mtertomcutar areas. Follicular colonization may be present. In cases with a diffuse pattern. follicl e remnants may be detected with stains forfollicular denonnc cells and germinal centre markers . The tumour cells are composed of variable numbers of marginal zone (centrocvte-uke and monocytoid) Beene . plasma cells and scattered transformed B-c ells 1321, 1578. 1601 , 2264J . Cases with a predominant rrcoocvtoio Been populatio n are uocommonoPlasma cell differentiation may be prominent and the different ial diagnosis with Iymphoplasmac ytic lymphoma or even nodal plasmacytoma may be diff icult. Some of these cases may have prominent eosinophilia. The presenc e of remnants of follicul ar dendritic mesh works suggestive of co lonized follicles would favour the diagnosis of noda l MZL. Somecases have more numerous large transformed cel ls (som etimes >20%). However. these ce lls are usual ly mixed with small cells and may be more common in the colonize d germinal centres

11578.22641· Some cases mimic splenic MZl with the tumour cells composed of small to medium size lymphocytes with pale cytoplasm and occasional transformed cells gfO'Ning inside an attenuated mantle zone and often around a residual germinal centre 1328). Conccene nodal MZl and Hl have been reported 124931. Immunophenotype Most nodal MZl express pan-Been markers with C043 coexpression in 50% of the cases. C05, C023, COlO . BCl 6 and cyclin 0 1 are negative and BCl2 is positive in most cases. IgO is positive in a minority of the c ases . Tumours mimicking splenic MZl have a similar phenotype but are usually IgO positive 13281 . Genet ics The imm unoglobulin genes are clonauy rearranged with a predominanc e of mutated VH3and VH4fam ilies 1321, 2263), Trisomies 3, 18 and 7 have been observed. The translooations associa ted with extranodel MZl are not detec ted 1575, 22641. Postulated normal counterpart Post-germinal centre marginal zo-e s -een.

Prognosis and pred ictive factors 60 - 80% of the pa tients survive longer than 5 years 1731 The prog nosis ot mese patients may be predicted using the follicular lymphoma international prognostic index (FlIPI) 173 J. The number of isolated large cells does not seem to be of prognostic significance 122641. Transformation to a large B-ceillymphoma may occu r. Diagnosis of transformation requires the identification of sheets of large cells .

Paediatric nodal marginal zona lymphomas Nodal MZl in the paediatric age have distinctive clinical and morphological characteristics 121401. They present predominantly in mates (ratio 20:1) with asymptomatic and localized (90% stage I) disease , mainly in the head and neck lymph nodes . Histologically the tumour is similar to that seen in adults except that there are often progressively transformed germinal centres in which the outer border of the follicles is disrupted and infiltrated by neoplastic cells. The immunophenotype is similar to adult NMZl 121401 . The diffe rential diagnosis with atypical marginal zone hyperplasia with monotypic Ig expression may be difficult because the large cells in this con dition also express C0 43 11 00 1. Althoug h this latter process has been reported in extra noda l sites, some ca ution is advised as a similar process might also occ ur in the lymph nodes. Particularly for these reasons. studies for clonal rearrange ments of the IGH@chain are necessa ry to help distinguis h paed iatric NMZl from reactive conditions (21401. The prognosis of paediatric nodal MZl is excell ent with a very low relap se rate and tong survival after conservative treatment.

Nodal marginal zone lymphOma

219

Follicular lymphoma

NL Harris S.H Swerdlow E.S. Jaffe

G.Olt

Definition Follicular lymphoma (Fl ) is a neoplasm

compo sed of follic le ce ntre (ger minal centre) e-ceas (typica lly both ceotrocy tes

and c entroblasts/large trans formed c ells). wh ich usuall y has at least a partially follicu lar pattern. If diffuse areas of any size comprised predominanlly or entirely of blastic cells are present in any case of follicul ar lymp hom a. a di agnosis 01 diffuse large B-cell lymphoma is also made. Lym-

phomas composed of centrocytes and cemootasrs WIth an entirely diffuse pattern in the sampled tissue may be included in this category. Primarycutaneous lympho-

mas 01 germinal centre cells are separately classified .

ICD-O codes Foll icul ar lymp hom a Grade 1 Grade 2 Grade 3A Grade 38

BN Nathwani D. de Jong T. Yoshino D. Spagnolo

969013 969513 9691/3 9698/3 9698/3

Epi demiology FL accounts for about 20% of all lymphomas with the highest incidence in the USA and Western Europe. In Eastern Europe , Asia and in developing countries the incidence is much lower 1371. It affects predominantly adults, with a median age in the 6th decade and a maJe:female ratio of 1.1.7 {511. FL rarety occurs in individuals under the age of 20 years ; paeeenc patients are predominantly ma les 1707, 133 7, 1754, 2 132 1.

FIg.10.61 Ft6:Uar Iymphcma. The ~lcAdes aredosely padled.locaIy snow M aIm:lst back~ pattern. and lad manIIe zone!

T.bl, 10.11 Follicular tympnoma grading. Grlding Definition Grade 1-2 (low gl1lde) 0-15 centroblasts per hpl o-s cenlroblasts perhpf 6-15 cenwotllasls per hpf 2

,

•

>15teIlIrobIIsls per ~

""'" 3

]A

JB Reportingof pft1em

Follicular Follicular and diffuse Focally f~ l ieu lar

."'"

.......

~ Sold _ _ da~~"'''_b_

Proportion folliCul. >75% 25-75% • <25%·

"'..

Diffuse.fNI contIiining>15c:entrobla5t5 per hpf are ~ n diffuse a.rgt lkell tym. ~ with foIIitu~ 1ymphomI1~ 1-2, Gritde 3.A Ot Grade 381'.

rmr

"". hi!J1-power field 01 0.159 (-4Olc objective, 18 mm field 01_ oct&; counll 0 hpl and dMde by 10), If using 820 mm fiekl of view ocular, count 811pf and divide by 10 0((::0"'11\ 10 hpfand divideby 12 10 get the numba\' of centrobiastslO.159 mml hpf If using a 22mm field of viewowlar, counl7 hP and lM:Ie by 10 or CW'Il 1D hpfand drVIde by 15 mQ8I: Itle nuntIer 01 ~.1591ff1'i 11Jf. ·GiYe~"oleachi'l~

- If !he biopsy ~ is smaI. a rdlI shoIAd be iIlkled thallhe absence d bides ma.,. refted S
220

Matur e 8-cell neop lasms

Sites of inv olvement FL pred om inantly involves lymp h nod es, bu t also spleen, bone mar row (BM ), peripheral blood (PB) and Waldeyer ring. InIJOIvement ol non-haematopoietic extranodal sites , such as the gastrointest inal tract (GI) Of soft tissue may occur in a setting of widespread nodal disease. Fl ma y occasionally be primary in extranodal sites, inc luding ski n , GI tract , pa rtic ula rly the duodenum, ocular adnexa , b reas t an d testis. Clinical features Most patients have widespread d isease at diagnosis , incl Ud ing peripheral and central (abdominal and thoracic) lymphadenopathy and splenomegaly The BM is involved in 40-70%. On ly one third 01 patients are in Stage I or II at the lime 01 the di ag nosis 1511. Despite widesprea d d isease , patients are usually othe rwi se asymptomatic . Morphology Pattern Most cases of FL have a p red om inant ly fol licul ar pattern w ith closely-packed fol licles that efface the oocat architecture . Neoplastic follicles are often poorty defined and usu ally have attenuated or absent mantle zon es . In contrast to reac tive

germinal centres where cen troblasts BOO cenrrocytes occupy d ifferent zone s (pcranzanon). in FL the two types of cells are rand omly distributed . Similarly, tingible body ma cr ophages, c harac teristic of reac tive germin al ce ntres, are usually absent in FL. In some cases, follicles may be large, irreg ular, and serp iginous, resembling diffuse areas . Staining for follicular dendritic cel ls (FOC) (CD21K::D23) may be necessary to d istinguish between large foll ic les and d iffu se areas. Interlollieular spread by neoplastic cells is cormm and this does not constitute a diffuse pattern.

r.. IU3 FoIaAr IymJ:k.ma gradIlg. A Grade1·2 of], There is a monotonous pop,Aalion of smalleels 1IIidI irrelJJIar ru:Iei (oenb'OCyle$) WIth ody rare largeeels (cenlroblasts) "'1lJ" II'O'W ~ oudeoI allda moderilIe amoum d tylopIasrn (amrov). Most of the largeru:Iei presentin this field are !hosed kAcular de!mlic cells (FOC) (amM16ad): . . . DIlls IllrIe more dek:ate ru::lear merrtJranes and YIOIet-lXlloured 1'lJdri. alldare oIIen binucleate. B Grade 1-2d 3. The majority d the eels are centrocyles. but ~ fU1lfJIQII ter*obIasts all! present (arrows): several FOC WIth double nudeiall! present(arrowt1eatj). C Grade 31.. There all! more than 15 C8fIlrobIasls per high power field. bul cnot)1eS in SIiI present. 0 GracIe 36. The majority01 tile cellsall! cerrtroblasls.

The interfollicular neoplastic cells are often ceruccvtesthat are smaller than those in the germinal centres, with a less irreg ular nuclear contour, and they may show immunophenotypic differences from the cells in thegerminal centres 15991. Dffuse areas may be presen t, often with

sclerosis. par ticularly in mese nteric and retroper itoneal infiltrates, A diffuse area is defined as an area of the tissue completely lacking follicles defined by CD2 1+/C023+ FDC. Distinction between an extensive interfollicular component and a diff use c omponent may sometimes be arbitrary,

Diffuse areas comprised predominantly of

ce ntrocytes are not thought to be clinica lly sign ificant. Howeve r. the presence of diffuse areas com prised entirely or predomi nantly of large blastic/transformed cells (that would fulfill criteria for Grade 3 follicu lar lymphoma) in a FL of any grade

•• • .....

'.~.~~'I:':'

Fig.IUI FoIcuIar lymphoma. Grade 1-2. with marginal zone dlfferentialion. A AI theperiphery d !he 1oI1ic:llls. ItIere is a pale rim lXlrT8SjXlIlding kl marginal zone tifferenlialion. 8 The centres oIlhe IoRides cootain tile typical mixture 01 cenlrocytes and cerllroblasl$, C The cells a1!he periphery 01 the IoIlides alll medill'l'l-SiZed cells wi1h slightly iflllQlAar Q nI abI.nlao1ligh~y eosinophilic topale stainillQ C)1OllIasm, consistentwith marginal zone or monocytoKl fkells ,

Follicular lymphoma

221

.

is equivalent to diffuse larg e B-c ell lymphoma, and a separate dtagnosis of diffuse large Be en lymphoma should be made 18971 (See grading of follicular lymphoma qelowl · Despite the unclear clinical significa nce of diffuse areas comprised predomina ntly of centrocvtes with ooly rare centroblasts (Grade 1-2), It is recommended that the relative pro por tions of follicu lar and diffuse areas be noted in the pathology repo rt as follicu lar (> 75% follic ular), follicular and diffuse (25 - 75% follicular ), or foc ally follicular/pred ominantly d iffuse «25% follicular) 18971. Diffuse follicular lymphoma Rare lymphomas with the morphology al'ld immunophenotype of FL have an entirely dIffuse growth pattern. This p henomenon is usually seen on small biopsy specimens. and likely represents a di ffuse area in a Fl that is not adequately sampled. In these cases, the p athologist sho uld sug gest that more tissue be obtained if possible. A diagnos is of di ffuse FL may be mad e when the lymphoma is c omposed of cells resembling cen trocytes. with a m inor compo nent of centrobl asts and an entirely diffuse pattern ; both the small and large cells must hav e the immunophenotype of germinal centre cells or presence of a classical t(14:18) translocation should be demonstrated. Thus. a diagnosis of diffuse FL cannot be made without these ancillary studies. Partial nodal involve men t and "in situ· follicular lymphoma Non-neoplastic follicles may be pre sent in lymph nodes involved by otherwise typic al Fl, and their presenc e has been repor ted to predict for lower stage at diag nosis 181. Non-neop lastic follicles may also be partially colo nized by FL ce lls, both in lymph nodes with area s of obv ious Fl, in lymph nodes adjacent 10 those involved by Fl or occasionanv in isolate d lymp h nodes in patients with or without H, elsewhere. The latter pattern has been called • in situ" follicular lymphoma (see be low) 14621.

Cytology Fl is typically composed of the two types of Bceus roemanv found in g erminal centres . Small to medium-sized cells with angulated. elongated , twisted Of cleaved nuclei, inconspicuous nucleoli and scant pa le c ytopl asm are c alled centrocvtes. Large ce lls with usually round or oval, but occasionally ind ented or mu ltilob ated nuclei , vesicular chromatin , 1 to 3 peripheral nucleol i and a narrow rim of cytoplasm are c alled ce ntrobtasts. Typi cally, they are at least 3 times the size 01 lymp hoc ytes, b ut they may be sm aller in some c ases . Oentrocvtes p red ominate in most cases; centroorasts are always pres ent. but are usually in the minority, so that most cases have a monomorphic eppeeraoce . in contrast to reactive follicles . The number of centroblasts varies from c ase to case and is the basis 01grading . In some c ases, neopl astic centrobleste may have irregular or lobulated nuc lei resembling large centrocytes, and infrequent c ases sho w nucl ei with very di sp ersed c hromatin and a lymphob last -like appearance, In about 10% of FL there may be disc rete foci of marginal zone or monocytoid-appearing Be ene. typically at the pe riphery

of the neoplastic follicles 1816, 1577, 22521. These cells are part of the neeplastic clone 118531. Ptasmacvnc differentiation may be ma rked and signet ring cells may also occur. Grading of follicula r lymp homa Fl has been graded in many classifications (Rap papo rt 118201. Working formulation 147}. R EA L. (898}. WHO 3rd edition 110391) ac cording to the proportion of larg e cells (ce ntrob lasts), and a number of studies suggest that this histological grading predict s clinic al ou tcome , with ca ses with mo re larg e cells behaving more aggressively an d having a higher likelihood of progression to a diffuse large celilymphonla than those with fewer large cells 138, 47. 153. 748. 806 , 807 . 1070. 1102, 1335 , 1400 , 18201. However, the optimal method and clinical significance of grad ing have been deb ated , and no met hod has shown high reproducibility 151, 1468, 15791 . The 3rd edi tion of this series used the method of counting large transformed cells (centroblasts) described by Mann and Berard 11039. 1378, 15791, to define 3 grad es. It has been suggested that the number of grades could be reduced, since there are no important clinical

Fig. 10.65 Follicular lymphoma assooated WJltJ DLBCL A ~ JoIdes arepresent on the rY1Itc. ...... . dlse on the Iefl The ddluse Nea is a:JIIllI1sed precbninamlyof large eels linse'll. so• separale diagrUrs ~ Cx.BCt. is 1T1
Nea

Bone marrow and blood In BM, Fl ch aracteristic ally localizes to Ihe par anabecurar region and may sp read into the interstitial areas, A follicular growth pattern with a meshwork of follic ular dendritic cells is rare but can be seen, The morpholog y of the tumour cells most commonly resembl es that of the neoplastic intertomcutar cells in lym ph nod es. The same cells may be seen in the PB. 222

Mat ure

a-cen neoplasms

Fig. 10.66 Bone rnarroIlt il'oUvement by loliaJlar~ . AAl kIwITIiIJ'Ilbbon .lhere lRpa'atr'abeo.*JlynllhcIl BThe ~ are small cenln::JtyIe$

~.

for follic ular dendritic ce lls (FOC) may be esse ntial. The vast major ity of fo llic ular lymphomas are grade 1-2 (80-90% in most unselected series). Paed iatric ca ses are more likely to be g rade 3 1707, 133 7, 1754 , 21321. On ly a few stud ies have compa red the fre quency of gra de 3A vs 3B cases, In published studies 1883, 1 t 19, 16681, 3r'f'O'lQ pt.6ety follicular casesof grade 3 FL.. the poportion of grade 3B cases is 20-25%. Areas 01 diffuse large B-cetllymphoma are present in 60-80% of grade 3B cases and less frequently in grade 3A 1883. 1119 1.

rig. IU7 IrmulophenoIype of loIlicIAr~. AThe loIicIes and i1terlo1ioAar rtlgIORS contain CD20+ B-celIs. BThe /oIIides are ISIilormIy BCl2+. C BCL6 is expressed by lhe follicles, but to a lesser degree by i1lerlollicular neopIasbcceHs 0 COlOexpresslOfl is SII'l'Iilar 10 Ihat 01 BCL6.

oneercee between grades 1 and 2. Dishnchon of grade 3 cases from low-grade (grades 1 and 2) cases is cl inically relevant Although it is still con troversial, there is evidence that there may be im portant clinical and biolog ica l di fferenc es between grade 3A and grade 3B c ases (248,249, 1119, 16681 . The re is insuff icient evidence at this time to recommend an alternative method or to recomm en d eliminating grad ing a ltog ethe r. FolliCularlymphoma is g raded by co unting orestimating the absol ute numbe r of c en«obasts (large or small) in ten neop lastic foll icles, expressed pe r 40x high-power microscopic field (hpf) 11039, 13 78 , 15791. At least 10 high power fields within dilterent follicles are eva luated; these should be rep resen tat ive follicles, not selected for those with the mos t numerous large cells. Grade 1 and g rade 2 cases have a marked predomin anc e of cen trocy1es and only few cen uo brasts (g rade 1 '" ()"5 centroblastS/hpf; g rade 2 '" 6 -15 cenuoblastS/hpf) . Since grad es 1 and 2 represent a continuum and are both clinically indolent, distinction between them e not eocouraged, and a g rade of · 1-2 of 3- can be reported. Grade 3 cases have

> 15 centrobtas tsmpt . Gra de 3 is further subdivi d ed accordi ng to the propor tion of

centrocytes. In gr ade 3A, centroc vtes are still present, wh ile g rade 3B follicl es are co m po sed entirely of large blastic ce lls (centroblasts or immunobl asts), If dist inct areas of g rad e 3 FL are present in a b iopsy of an ot herw ise g rad e 1-2 Fl, a separate d iagn osis of g rade 3 FL should also be made, and the approx imate am oun t of each g rade rep orted Since bot h pa ttern and c ytology vary among foll ic les, lymp h nod es mu st be adeq uately samp led . Any area of d iffuse large B-ceillymphoma (Ol BCl) in a FL shou ld be repo rted as the primary d iag nosis , with an estimate of the proportion of OlBCl and Fl, p resent. Thus , in grade 3 follicu lar lymphoma, the presence of a diffuse c omponent warrants a separate d iag nosis of d iffuse large Bcell lym phoma. In other words , it is never correct to make a di agnosis of "follic ular lymphoma, g rad e 3 (A or B) with d iffuse areas": the di agnosis is: "1. Diffuse large B-c eil lymphoma C%) 2. Fo llic ular lymphcma, g rade 3 (A 01 B) L %). To d istinguish large , co nfl uent fo llicl es or inte rfollicular invotvement from areas of DLBCL staining

Immunopheootype The tumour cells are usually Slg+ (lgM+/IgD, IgG Of rarely IgA). express B-cell associated antigens (C019, C020, C022, C079a) and are BCL2+ . BCL6+, CDlO+ , CDS- and CD43-. Some cases, especially grade 3B , may lack CO lO, but retain BCL6 expression 1248, 346, 1111. 1239, 1668, 17601. COlO ex pression is often stronger in the follicles than in interfollicutar neoplastic cells . and may be absent in the mtertoucotar component, as well as in areas of marginal zone d ifferentiation, PB and BM 1599. 8991. BCl6 is frequently downregulated in the jntertonlcutar areas . IRF4/M UM 1 is typically abse nt in FL. Rare c ases of predominantly Grade 3B, C01~ FL have been described that express IRF4/M UM 1 and lac ked BCL2 rearrange· men t; 59% were associated with OLBCL 111111, Meshwork s of FOC are present in fo llic ular areas 12508 ); thes e may be spa rser than in normal foll icl es, and may variab ly express C 0 21 and C023. so that ant ibo dies to both ant igens may be needed to de tect FOC meshwork s. BCL2 p rotein is expressed by a variable pro por tion of the neo plastic ce lls in 85-90% of cas es of g rade 1 and g rade 2 FL , but only 50% of gra de 3 FL using standard antibodies 112381. In a proportion of the cases, abse nce of BCL2 p rotein is d ue to mutations in the BCL2 ge ne that eliminate the epi tope s rec og nized by the most commonly used antibody, and BCL2 ca n be de tect ed using antibodies to other BCL2 epitopes 119731. BCL2 protein can be useful in diSlinguishi ng neoplastic from reac tive follicles, although ab sence of BCL2 protein does not exclu de the diagnosis. It is essential for the d iagnosis of "in sltil' Fl; in these cases and in partially involv ed follicles, the expression of BCl2 is etten much stronger than in more typical neoplastic follic les. BCL2 protein is FollICular lymphOma

223

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w w

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Fig.10.61 Survival Q.fVM lor pabents .... loIic:ljar ~. gr.Ided according to !he WHO cnteria {237.cj. A 0veraISIIViYaI d pabents lreatedWJlh regimens nollX:l'llaiWlg am. (pdiative Ihefapy):!here is no cllfterenc:e in ~ lor patients with!J'ilOe 1 'IS grade 2 toIicuIar lymphoma (o- SO and 51·150 centl'ObIastsl10 hpf). those Mlh!Jade 3 (>150cenIrtJblas3I1 0 ~ hada sigMicamIy worse oYefaI survival. B 0ieraI $UI"o'FvaI of patientstrealed WIlh adriamycin-alnI regmeos (ar.tIMl intoot): Ihe 3 StniYaI a.nes areidentical. irdcaIlrlg lhallhent is 110 Slnival benelk lor pabents WI1Il grade 1 and !1acIe 2 FLIrealed .... ~ 1M Ihat!he adYefse PfO!1lOSis of pde 3 Fl is elirTwWd by 8WessiYe therapy. C Faln-lree Sln'ivaI of pabenls trealed with adriaJTl)Ul: lhere isa suggestion d. plaleau in Ihe cuvelor pde 3 Fl (>150 ~10~. SUlpSlng Ih8 ~ 01 an lor some d It'lese pabeflls; in lXlIlIrasl, palierlls WIth !7ade 1 rod grade 2 Fl conlInue toexperience re6apse$.

""'*

8ITl)'QIl

not useful in d istingu ishing fol licular from other types of k:lw-grade B-cell lymphoma, mos t of which also express BCL2 protein. The interpretation of BCL2 immunostainiog in germinal centre c elts req uires caution as r-ceus. primary follicles and mantle zones normally expres s this protein, Occasional cases of grade 3 follicular lymphoma are C D43 +. In ad dition 10 FOC, neop lastic follicles contain numerous other non-neoplastic cells normally found in germinal centres. incl ud ing follicular t-eens (CD3+ , CD4+ . CD57+ . PD 1+ , CXC L13+ ) and varying numbers of t asnocvtes. The pro life ration ind ex in FL generally co rrelates with histologic grade; most g rade 1-2 c ases have a proliferation frac tion <20%. while most g rade 3 cases have a pro liferation fraction >20%, altho ug h there is co nsi de rab le variation among stud ies, prob ably du e to tec hnical di fferenc es in immun ostaining 11 183, 1400 , 1668, 2358 BI. A subg roup of morp holog ica lly low -gr ad e FL with a hig h T~ bIe

10.12 Genetic aboofmalities in fdliaJlar 1ympOoma.

Cytoge netic abnormalities ~1 4:18)(Q32;q21) 80%

.,

20%

. 16

20% 15% 15% 15%

3Q27-26 6Q23-26' I7p'

~ abnonnalitln

BCL2 reafT8rged

IlO%

BCl6~

15% 40%

BCL6 S' muIabons

"Associated with a 'IlIOI'Se prognosis{2239}.

224

Mature B-ceU neoplasms

proliferative index ha s been described 11183. 23588 1. which behaved more aggressively than those with a low proliferative index. and similarly to grade 3 Fl 123588 1. Thus , Ki67 staining should be considered as an adjunct to histologiC grading and its use is c linic ally jrsnned. although not formally requ ired at this time. Genetics

Antigen receptor genes Immunog lo b ulin heavy and light c hains are rea rrang ed ; variable reg ion genes show extensive and ongoing somatic hypermutation {448, 16701. As a result of these mutations in the CD R-regio ns, PCR prime r annealing may be hampered and de pend ing on the primers used. immunoglobulin-PCR may not yield monoclonal pro d ucts in a pr opo rt ion of FL cases (10 - 40%) . Mu ltip lex PCR reactions using B IOMED-2 expa nded pr imer sets d etect cl ose r to 90 % of IGH(V-D-J) g ene rearrang ements, and clonantv det ection approximates 100% when p rimers detectin g IGH(D-J) and light c hain g ene rearrang ements are inclu ded [652 1.

Cytogenetic abnormalities and oncogenes FL is genetically characterized by the translocation t( 14:18)(q32 :q2 1) and BCL2 gene rearrangements. Alternative BCL2 translocations to imm unogl o bulin ligh t chain ge nes have been re po rted . The t(1 4; 18) is pr esent in up to 90% of the gr ad e 1-2 FL 19 79, 18851but the proportion depends on the technique used 118. 93 . 1508 . 22801_ FISH see ms 10 be tre most sensitive and specific method 122801 . BCL2 rearrangements are much less freq uent in grade 3B Fl 116681 Geographic variation in the detection of

BCL2 tran slocatioos in FL between Western and Asian populations has been reported 121 51. The BCL2/IGHO rearrangemen t is found in the P8 of 25-75% 01 hea lthy donors . and also in reac tive rooes. particutarty if using sensitive nested or RT-PeR assays 11876. 1967, 21211. A rece nt study suggests tha t rather than be ing naive B-cells, these BCL2-rearranged ce lls are memory Beene 118771. Abnorma lities of 3q27 and /or BCL6 rearrangement are found in 5-15% of FL. most co mmon ly in gr ade 38 cases 11119, 16681. FL grade 3B associated with DLBCl have been reported 10have a frequency of BCL6 rearrangemen ts similar to that seen in DlBCL 1248, 249 , 1119, 16681. In addi tion to the t(14 :18) , other genetic a ltera tions are found in 90% of FL and most co mmon ly inc lude loss of to. 6q, tcq an d 17p and ga ins of chromosomes 1, 6p , 7, 8, 12q , X and 18q/dup [954, 1621, 22 39 ), The numbe r of ad dit iona l alterations inc reases with histo logi cal grade and transformation 11930}. Rare cases of FL ca rry the t(8:14) or variants tog ether with the t(14;18) [ 102, 23431. Gene expression prof ile stud ies have show n the im po rtanc e of the mic roenvironment in the pat hogenesis. evolution and prog nosis of FL 1510. 8041 . Transformation to DLBCL may totlOlN oneeragenetic pathways including inactivaticn of TP53. p 1~, and activation of MYC 1513,637, 1338,1756. 19301. Postulated oormaJ counterpart Germinal c entre B-cei L Prognos is and p redictive factors Prognosis is c losely related to the extera 01 tbe d isease at diagnosis. The International

Prognostic Index (IPI) and especially the International Prognostic Index for FL (FlIPI) are strong predictors of outcome 149. 5 1,

20481 Histologicalgrade correlates with prognosis in follicular lymphoma, with grade 1-2 cases being indolen t and not usually CU"able, except for the infrequent localized cases /40, 806. 1070 , 1335 1. The majority of published studies show a signi fic antly more aggressive clinical course for ular lymphomas cl assified as large ce ll or Grade3/40. 153. 1400. 14431; but the use of regimens containing ad riamyc in and/or rrtuximab may obviate these d ifferenc es and requires further stud y 138, 153 ,752 , 807,863 , 1102, 1860 , 2374, 23841. Many stud ies have ind ic ated /47 , 1273 , 1820, 23601 that the p resence of even very large diffuse areas in fo llicul ar lymphoma classi fied as grade 1-2 ("small cleaved" or "mixed sma ll and larg e ce ll") doesnot significantly alter the p rognosis . In most repoted studi es. cases 01g rade 3 Fl with diffuse areas >25% (no w rec ognized as areas of DLBCL) have a worse prognosis than purely follicular cases 138, 153,752.807,883. 1860.2346.23841. The presence 01 more !han 6 ctromosomal breaks and a compl ex ka ryoty pe ha s been shown to be assoc iated with a poor outcome: in addition, de l 6q~26 , de l 17p and mutations in TP53 as we ll as - 1p. + 12. +18p. - xp cooter a wor se prognosis and a shorter lime to tran sformation /1284. 22391. Rare c ases w ith both «14;18) and t(8;14) have a poor prognosis [102.23431. Recent gene expression data have suggested a role of the microenvironment, includi ng T-cells and accesso ry cells including FOG and macrophages in determining the clin ical behaviour of FL 1510. 804, 893J Currently, no spec ific markers are available other than histo logicgrade and proliferation traction that can be used in cli nica l prac tic e to predi ct

tome-

outcome or direct therapy. In 25 -35% of pa tients w ith FL, tra nsformat io n or ' p rog ression' to a hig h grade lymphoma oc c urs , usually DLBCL. bu t occasio nally resembling Burkin lymp homa Of with features intermediate between DL BCL an d Burkitt lymphoma 128A. 748. 964A. l803A 1· This occurrence is usually associated with a rapidly progressive cl inical cou rse and death from tumour thai is refract ory to treatment {88 B, 748 1. Rare pa tient s develo p acute B-ee ll lym p hobl astic leukaemia. whi c h in most cases appears to repr esent blast transformation of the orig inal B c ell tumour [5 18A. 764A. 1197A ). Transformation typically involves additional genetic abnorma lities , partic ularly MYC tranetccatrons: the combination of a BCL2 and a M YC rearrangement is associated with a partic ularly aggressive course {702A. 1266A. 2468 AI· Rec ently. the occurrence of histioc ytic/d endr itic cell sa rcomas has been described in patients with FL, in which the sarcomas shared both IGHtI and BCL2 rearrang ements With the FL. This ph enomenon may represent de-differentiation of a B cell due to loss 01PAX5 activity /675A I.

Variants Paediatric follicular lymphoma This va riant often involves cervic al lymph nodes. other periphera l lymph nodes or Waldeyer ring ; however. other extrarooat involveme nt also oc cur s, with FL of the testis well des cribed 1707 . 1337. 1754, 2132 1. Ch ild ren with FL typ ically have early-staqe d isease 1707, 1337, 1754 , 21321 Paed iatric follicular lymp homas have many features ind istinguis hab le from those seen in adults, but demonstrate an inc reased proportion that are loc a lized. lac k BCl2 protein expressio n and 1(14:18) and are grade 3 11337.21321. They also

tend to have larg e expansite follic les . Rare cases of florid tomcutar hyperplasia. particu larly in you ng ma les . may have clonal populations of CD1O+ Beene detected by flow cytometry and molecular analysis. A d iagnosis of lymphoma should not be made in the absence of morphologic features of malignancy 11 21 11- The prog nosis of paediatric patients ap pears to be good, with the majority of reported cases d isease free at the l ime 01 last follow -up 1707. 133 7, 17541. Expression of BCl2 protein in paediatric FL was associated in one report w ith hig her stage at diagnosis and a worse out com e than BCL 2 negative cases I 1337f. Prim ary intestinal follicular lymphoma The majority of cases of primary follicular lymphoma in the Gt trac t occur in the small intestine , and involvement of the d uodenum is a freque nt feature 11486. 1939. 2005 , 24721. Duodenal follic ular lymphoma is p red ominantly found in the second portion of the duodenum, p resen ting as multiple small polyps. often as an incidental findin g on endoscopy pe rformed for other reasons. The morpholOgy, immunophenotype and ge net ic feat ures are similar to those of nodal follicular 1ymphomas . Most pa tients have localized disease (Slage IE or liE). and survival appe ars to be excellent even without treatment. Other extranodal fol licu lar lymphomas Follicu lar lymphoma s c an occur in almost any extrenodel site (6971 . In many of these site s. the morphology. immunophenotype and genetic features appear to be similar to those 01 nodal FL, although da ta are spa rse. Despite this, patients usually have localized ex tra nodal d isease, and systemic relap ses are uncommon . Testicula r follicu lar lymphomas are reported with inc rease d freq uency in ch ildren but also are reported in ad ults 11191.

F"'II. lD.69 PalKMtric follicular lymphoma. A Follicles of varying size and shape. many WJlh preserved mantle zones. extending beyond 1tle ~ rooe capsuie. ~ of centroblasts (Grade 3). C The folliCleS are negative Jar Bell.

Follicular lymphoma

225

.. '."'"~'

l

A large nodules 01 lymphoid eels are present in lhe rru::tl5a The lolIides are I.IiformIy posItIveb BCL.2 (8) a'ldposiIiye lor C010 (e).

Intrafollicular neoplasiann

situ- follicular

lymphoma Cases occur in whiCh architecturally normal-appearing lymph nodes and other ~ tissues haveone or more follicles that demonstrate BCL2-overexpressing centrocytes and cennootasts. with or without a monomorphic cytologic ap-

pearance suggestive of follicular 1ymphoma 14621. Some of these patients are found to have follicular lymphoma elsewhere, either before or simultaneously,

some develop overt Fl later, and others have remained without evidence of Fl. In patients with overt Fl elsewhere , this phenanenon likely represents colonization at pre-existing follicles by neoplastic follicle centre cells. In patients without known Fl, the significance of this phenomenon is difficult to ascertain. It may represent the tissue counterpart of circulating clonal Bcells with BCL2 rearrangement -lhal is. a clone of cells that have the translocation but not the other genetic abnormalities to

resu lt in overt progressive malignancy, Of in some cases it may represent the earliest evidence of a true follicular lymphoma that will progress 10 overt Iymphc:ma . This phenomenon cannot be recogniZed withoul BCl2 staining , The pathology report shou ld indicate that the significance of the finding is unknown, and that c linical evaluation for evidence of overt H elsewhere is suggested .

'.

•

226

Mafure

Been neoplasms

Primary cutaneous follicle centre lymphoma

DefiMion Prinary cutaneous follicle centre lymphoma (PCFCL) is a tl.rnour of neoplastic follicle centre cells, including centrocvtes and variable numbers of cemrootasts. w ith a follicular, follicular and d iffuse or d iffuse gro.vth pattern, thai generally pr esen ts on the headOf trunk 124071. Lymphoma s with a diffuse growth pattern and a monotonous proliferation of centrobasts and immunoblasts are. irrespective of site , cl assified

as primary cutaneousdiffuse large B-cell Ijmphoma (PCLBCL). leg type 124071

ro.ocode The provisional COde proposed lor the fourth edhon oi ICD-Q is 959713. Synonym Peucuotnsnocvtoma or me dorsum Ic rostrs disease) 12061.

_ohlgy Prinary cutaneous follicle centre lymphoma is the most common type of pri mary c uta-

neous B-cell lymphoma, acc ounting for approximately60% 01 all cases, It mainly atJects adultswith a median age of onset of 51 years and a male:fema le ratio of approximately 1,5:111993, 2502).

Siles of involvement Primary cutaneous follicle cent re lymphoma characteristically presen t with solitary or localized skin lesion s o n th e sc alp , the forehead or on the trunk. Approximately 5% present with skin lesions on the teg s. and 15% with muttltocat skin lesions (1170. 1993. 25021 Clinical features The clinical presentation consists of firm erythematous to violaceous plaq ues, nodlAesa nmocrsof variable size. Particu larly on thetrunk. tumours may be surrounded by erythematous papules and slightly infiltrated . sometimes figu rate plaq ues. which may precede the de velo pment of 1I.m:lurous lesions by mon ths o r yea rs 1200, 1933. 2409/. In the past PCFCL with such a typical p resenta tion 00 the ba ck 'Nel"e referred to as "reticulohistiOCytoma

R, Willemze SH . Swerdlo w N.L. Harris B. Vergier

of the dorSlfll" or "Crosus tymphcrna" 1200/. The skin surface is smoot h and ulceration is rarely ob served . Presentation with multifoca l skin lesions is observed in a small minority of patients, but is not associated with a more unfavourab le prognosis 1824. 1993/· II left untreated, the skin lesions graduaUy incr ease in size over years, but d issem ination to extrecutereoue sites is lXiCOIlil 0 I (-10% of patients) 11993, 25021. Recur rences tend to be proximate to the initial site of cutaneous presentation

Fig. 10.72 PrYnary eutaneolIs lctide t'efWe~. Characlerisbc clinical presentabon with bcailed $lli1 lesionson !he scalp.

Mo
show perivascu lar and oenacrexar to d iffuse infiltrate s with almos t cons tant sparing of the epi d ermis. The infiltrates show a spectrum of growth patt ern s with a morphologic continuum from follic ular to follicul ar and d iffuse to diff use 11 933 , 2407, 24091. The lesions are composed predominan tly of med ium-si ze d and la rge centrocy tes and variable proportions of centrobtasts. In sma ll andlor early lesions a cl ear-cu t fo llic ular gr owt h pattern or more often remnants of a folli cular growth pattern may be observed, In contrast to c utaneous follic ula r hype rplas ias, the follic les in these PCFCL are ill-defi ned , show a mo notonous p roliferation of BCL6+ follicle ce ntre ce lls enmeshed in a network of CD21 + o r CD35 + follicula r dendritic ce lls, lack ting ible body mac rophage s and gen erally have an attencat ec or absent mantle zone (360, 818) Reactiv e Tc ells may be numerous and a prominent strom al component is usually present. Advanced tumours usually show a monoton ous population of large centrocvtes and multilob ated cells and in rare cases sp ind le-shaped c ells, with a variable ad m ixtu re of centro btasts 1206 . 36 2, 824, 1933,2409). React ive t-eens are less pronounced and follicular struct ures. if present before, are no longer visible exce pt for occasional scattered CD2 1+ or CD35+ follicular de ndr itic cells. Imm unophenoty pe The neoplastic cel ls express C02Q and C0 79a, but a re usua lly Ig negative ,

Fig. 10.73 Primary urtaneces follicle centre lymphoma Characteristic clinical presentation with localized skin

lesions 00 th echest

Primary cutaneous follicle centre lymphoma consistently express BCL6, while CD10 is often posi tive in cases with a follicular grow th pat tern and gene rally nega tive in cases with a di ffuse growth pattern 1522, 819.949,1146,1170,1 485, 19931 Most cases do not express BCL2 or show faint BCL2 staining (weaker than ad mixed t-eens) in a minority of neoplastic Be ene [360,363. 419, 768. 949, 1170. 19931. However, several studies report BCL2 expression in a signi ficant proportion of PCFCL with at least a partially follicular growth pattern 113, 819, 1146, 14851. Notw ithstandin g, strong expression of both BCL2 and CD 10 by the neoplastic B-eells should always raise suspicioo of a nodal follicular lymphoma involving the skin secondarily Starning for IRF4/MUM 1 and Fox-P t is negative in most case s 11170. 1993/. Simi1arty for CDS and CD43 is negative in the tumour cells.

Pnmarv cutaneous follicle centre lymphoma

227

Fig. 10.74 Pmlatyeutaneous bide c:enn Iyn..,tonaWIth a cjtfuse growth pattern. A DrIfuse ~ inNIrate. BThe lI.rncU' ceIIlexpress CD2O. CAl tigher magIlIftcabon, aAllar iflfiltrllle containS many fTIIAt*:lbated

eees.

•

Genetics

Antigen receptor genes Clonalty rearranged irrmunoglobulin genes, with somati c hype rmutation are p resent, but may be not detec tabl e by PeR.

dele tions of a small region on c hromosome 9p 21.3 co nta ining the COKN2A and COKN2B gen e loc i are either absent or only rarely foun d in PCFCL 15771.

Postulated IlOfmal counterpart Cytogenetic analyis and oncogenes In many studies , PCFCL, inc lud ing cases with a follicu lar g rowt h pattern , do not show BCt.2 rearrangements 1363, 4 19 , 768,8 18.819. 2329}. However, other stud-

ies report BCt.2 rearrangements in about 10-40% of PCFCL with a follicular growth pattern using PCR and/or FISH 113,1 146, 14851. Primary cutaneous tolticle centre lymphoma show the gene expression profile of germinal centre-like large B-cel1lymphomas, and often show amp lil ica tion 01 the C.f1EL gene 11, 577, 948} . Deletion ol c hromosome 14q32.33 has been reported 1577}. In contrast to PCLBCL, leg typ e , 228

Matu re

s-een neop lasms

Mature ge rmin al lymphocyte.

centre

d er ived

8

Prognosis and predictive factors Irrespective at the growth pattern (follictJlar or di ffuse) , the number of blast cells, the presence at t{14;18) and/Or BCl2 expressian or the presence 01either loca lized or multitocal skin d isease, PCFCL hav e an excellent prognosis with a 5-year·survival over 95% 1818. 824. 1485 . 1933 . 1993, 2502}. Primary c utaneous follicle cen tre lymp homa p resentin g on the leg are reported to have a more unfavourab le prognosis {1170. 19931. Cuta neo us relapses,

o bse rved in - 30% of pa tients, do not indi cat e prog ressive dis ease . Systemic th erap y is only required in pa tients with very ex tensive c utaneous d isease , extreme ly thick skin tumours or with ext racutaneous d isease 16 11, 19931 .

Mantle cell lymphoma

Definition Mantle cell lymphoma (Mel) is a B-eell

neoplasm generally composed of monorropnc small to medium-sized lym pho id cells with irregular nuclear contours and a GeNO' translocati on 1139. 329. 1253. 1276,1693.2134.2246/. Neoplastic transfOfmed cells (centroblasts), parairrmunoblastsand proliferation centres are absent.

C linical features Most pat ients present with stage III or IV d isea se w ith lym ph adenopat hy. hepatosplenomegaly and 8M involvement 1247. 329, 1605 , 2136 1. Per ip hera l b lood involv eme nt is common and present in almost all pat ients by flow cytometry 16911. Some pati ents have a marked lymphocytosis mimicking p ro/ymphocytiC leukaemia (74, 247 . 1605 1

9673/3

SH Swerdlow E. Campo M. Seto H .K. Mu ller-Herme link

A

t.1o
Mel comprises approximately 3- 10% of non-Hodgkin lymphomas 151/. 11 occurs in middle-aged to older individuals with a median age of abou t 60 and a va riably marked male predominance (about 2 :1 Of greater) 174, 247, 329. 1253 .2134,21361. Familial aggregation of Me L or Me l with

other s-een neoplasms has been re-

eoneo 122551. Sites of involvement Lymph nodes are the most commonly involved site; the splee n and bone marrow (BM), with or without per iph era l blood (PBj involvement. are oth e r impor tant sfes 01 disease 174. 24 7, 160 5 , 2 134 1. Other extranodal sites are frequently involved, including the gastrointestina l tract and Waldeyer ring 1772 , 1916) , Mo st cases of multiple lymphomatous po lyposis represent mant le ce ll lymphoma 11203,161 1,19OO}.

Cl assical MC l is a monomorphic lymphoid p ro/iferat ion with a vaguely nodular. diffuse. mantle zone or rarely follic ular g rowth pattern 1139, 1253 . 1276, 2134. 22 46}. Infrequent cases may show involvement almost exclusively restricted to the inner mantle zones or 10 narrow mantles pn situ· MC l ) 11602 . 184 21 . Most c ases are com pos ed of small 10 med iumsized lym phoi d c ells with slig htly to marked ly irregu lar nuc lear co ntours. mosl c losely resem blin g cenncc vtes. The nuclei have at least somewhat d ispersed c hromati n but inconspic uo us nuc leol i, Neop lastic transfor med cells resemb ling cenncotaets. immunoblasts or paraimmunoblasts and p roliferation centres are absent. Hvaunrzeo sma ll vessels are co mmonly seen. Many cas es have sc atte red sing le epit helioid bistiocytes which in occasional cases ca n c reate a "starry sky" ap pearance. Plasma ce lls may b e p resent but are almos t always non -neoplasti c (2475},

TIbIt 10.13 Morphologic variants of mantle cell lymphoma. ~.Iv.

vMlllnts

cells resemblelymphoblast's with dispefSed chromatin anda highmitoticrate (usually at !east 2!r3l}'10hpt),

• fllasIoij:

· PIeo:Jraphic: calls art pleomorphic: butmany are IafgeWllh CMlI to irregularnudear coolours, geoeraIty pale ~ and often prominent nudeoli 11 at leastsome of the ceHs.

--

- SrnII eel: SrTllll IOJnd ~ WIth IIIOlll dumped chromalin, either admiJled or predlmnant, ITWIDJng • SlfIII tymphocytic tymplloma. · I,l;rgnI zone.Ike: prominenI loci r:A eels withabu'ltIanl pale ~ reserrtIIrlg marginal zone or ~ 8-alIsIlWIIIdling a ma'gIIl8I zone ~; sometines these paIef locimay aisO reserrtJle ~ C8'lIres r:A dnlnic ~ IIlukaerriaIsma ~~ .

B Fig. 10.17 Mand. cell ~ invotving the alIon (~ ~ pcIyJxlsis). !Jt'S5 ~. A

Overview showing one large and muftiple smanpolypoid mucosal lesions. B Closeup showing tiny polypoid mucosal lesions.

Histolog ic al transformation to typical large ce ll lymphoma doe s not occur; however, loss of a mantle zone growth pattern , increase in nuclear size, pleomorph ism and c hromatin d ispersal , and increase in mitotic activity may be seen in some case s at relap se 174 , 1253 , 1605 , 2 134 1. Some of the latter cases w ill fu lfil the cr iteria for a bl astoid or p leomorphic man tle ceil lymphoma . A spectrum of morphologic variants is recog nized . The b lastoid and pl eomorphi c va riants are con side red to be of important clinical sign ificance (Table 10 .13 ). Although MCl is not g rade d. eva luation of the prol iferation fract ion either by counting mitotic figur es or estimating the proportion 01 Ki67 positive nuclei is important because 01 its p rog nostic impact. Immunophenotype The cells express relatively intense surface IgM/lgD. more treq uenny with lambda than kap pa restriction 1329.2 134, 22461. They are usually positive for CD5, Mantle celllymphoola

229

fig. 10.7' Mantle c:eI~ . ~ nodes. A There is dllfuse afChitedInI e!lacement and typical pale IIyaftzed vesseb . B in addl1JCl'l ~ ItfIuse areas. nofe!he prorrn!IC vague neoplasbenodules. C A mantle zone QJOWlI1 pattem is seen II1ltis ~ node WIth an intacl artMBclure

•

230

Mature B-eell neoplasms

FMC·7 and G043. but negative for COlO and BCl6. C023 is negative or weakly positive. Aberrant phenotypes have been described . sometimes in assoc iation with blastoid/pleomorph ic variants, including absence of C05 and expression of COlO and BCl 6 {323. 1518, 2470l , IrTVTIUnohistological stains demonstrate loose me shworks of follicular dendrilic c ells. All ca ses are BCl2 protein positive and almost all expresscyclin 0 1, incl uding the m inority at cases that are C 0 5 negative {4 12. 2135.2 137. 2250.2467.25091 . Cyclin 01 stainingmay be required to recognize the casesof "in silli' MCL

[

BMI1

~

.1. -

INK4

Restriction Po int Control

~

G1

t

p16 1NK .... p15 , p11. p1i

COK 4/6 Cyciin 01

~

------

pR B I!) + E2F

•

r· ~ Cyclin E COK 2

pRB/E2F /

CiplKlp

Genetics Antigen receptor genes IrtYnunogtObu lin gene s are rea rranged. Variable region g enes are unmutated in the ma;ority 01 the cases. but in 15-40% d the cases. /G g enes show somatic hypermutation although the load of mutations is usually lower than in mutated C l l {322. 1143. 1652. 21921. A biased use of !he VH genes is reported in MCl. suqgesting that these tumour s may originate trom speci fic sub set s of a-ceus 1322 . 11 43. 1652. 2 1921. In cont rast to cu., VH3-21 gene usage in MCl occurs mainly in cases that are uomuteted. have fewer genomic imbalances and a better prognosis 121921 · Also in contrast to Ct.t . the VH gene muta tional status in MCl does not correlate with survival or ZAP-70 expression 1322. 340. 11431. Cytogenetic abnormalities and oncogenes

The t(11;14){q13;q32) between IGH@an d cyclin 0' (GGN01 ) genes is present in almost all cases and considered the primary genetic eve nt (1291, 1866. 2281. 2308, 2410.24111. Variant GGN0 1 translocations with the immunog lobulin ligh t enema have also been reported [11791. The translocation results in deregulated cverexpression of GCND 1 mANA and protein [246. 515, 19951. Some MCl express aberrant transcripts resulting in an increased half-life of cyc lin 01 . Tumours w,ththese truncated transc ript s have very high levels of cy clin 0 1 expression {246, 515. 19951. high proliferation and mo re aggressive clinic al behaviour {18 711. Deregulated expression of c yclin 01 is assured to overcome the cell cycle suppressive effect of AB1 and p27k ipl , lead1'910 the development 01 MeL{1048. 17931. W::l carries a high number of ron-rancon secondary chromosomal aberrat ions

J INK4

Cell death

H MOM2 11-

p 14 ARF

ATM

Fig. 10.10 CeI cyde and DNA damage repw palhways altetedin matllle cel lymphoma. The cydin Ol lcydin dependent kinase (CDK) 4/6 CQrr4lIeJ promoteS phospIuyIation d!he relinoblastoma prolein (pRB). This leads10 release of ee ElF lransmption racIors Yoftctlltlen lead 10 prt9'eSSiOn of ee eel cyde inlo!he S phase . Thecydin D11COt< 416 compleJ isinhibiled by p16-. 8MIl is a ~ repressor of !heINK4afARFIocus.AbnonnaIiIies in MeLltJat lead kl progresslOO of cells from GI to S phase incUIe increased cydin 01 in amost aI cases and b&s of pl6"""". RB deletions. increased CDK4 alld increased 8MII in a minority of casesespecially lhose lhal are more aggressive_ Dere\r.Jlated E2F also induces p14'" 1rw11Crip1lon. p14'" leads lDsIabiliz.ation of p5J by iMibIbng 1Ile activiIy of MOM2 whietlleadsIII 1hedegradationof p5J. The Iurnl:u'suppressor p53leads 10 ifIcrea:sed expteSSlOll of p21 in addition 10 leading 10 eel cycle arrest or apoptosis. The AT'" gene is required lor activation 0/ p5J after DNA. damage. Many Mel ha~ ATMabnormalilies and some pabents have gernine mutabons ollhis gene. SCme Mel have loss or tran~1 repression oIlt1e INK4afARFlocus lacking p16-,p14.... 1oss or mutation 01 TPSJor high Ieves otMDM2. Finally. cycIin ElCDK2 coepexesalso lead 10 cellcycle progression andare inhiMed by p21Ip27kipl . ln Mel. increased levels of cydil'l 01 lead 10 seqtleSlraliOn eteese ce~ cycleinhibitors and. in addition, they may increase p27degradalion.

inclu ding ga ins of 3q26 (31 -50%), 7p 21 ( 16-34%) and 8q24 (16-36%: MYG) , and losses of 1p13-p3 1 (29-52% ), 6q23-q27 (23 - 38% ). 9p 21 (18-3 1%), 11q 22-q 23 (21 -59%). 13q11-q 13 (22 - 55%). 13q 14. q3 4 (43-51 "!o) and 17p 13-pter (2 1-45%) {165, 1890 . 19951. Trisomy 12 has been repo rted in 25% of cases {496 1. In addition to chromosomal imbalances, MCl may demonstra te tetraploid clone s that are more common in pleomorphic (80 %) and blastcid variants (36%) than in c ases with typical mo rphology (8%) {16661. The presence of a t(8:14)(q2 4;q32 ) with MYG translocat ion occurs rarely and is associ ated with an agg ressive cl inica l course {22831. BGL6/3q27 transrccanons also oc cur uncorrrnonly and are reportedly associated with BCl6 protein expression 13231. Some cyt og enetic abnormalities may also have associat ions With variou s clinical parameters incl uding a leukaemic presentation 169 1, 16931.

Oncogenic alterations have been found in several genes targeting the DNA damage respo nse pathway and c ell cycle regulatory eleme nts l 688) inact ivating mutations of the ATM g ene at 1tq22-23 have been detected in 40- 75% of Mel [320. 19561. ATMmutations have been also detected in the germline of some patients with MCl [3201. Highly proliferative variants 01MCl have frequent TP53mutations, homozygous deletions of JNK4alARF, the CDK inhibitor p l81NK4c, amplifications and overexoresson of the BMll poIycanb and COK4 genes and occasional microdeletions of the RBl gene {165, 166,329, 839 .930. 1341, 1755, 1757.2412,24131. CycJin 01 negative Me L Aare Mel are negat ive for cyelin 01 and the t(11. 14) but have an expression profile and other features indistinguishable from con ventiona l MCl 1738, 1871, 19181. These cases have a high expression of

Mantle cell lymphoma

231

Naive B lymphocyte GermHne

ATM

Classical MCl

Early MCl

Blastoid MCl

. --

CHK2 t(11;14) Cyclin 01

~ ~

p16/CDK4/Rb

ARF/MdM2IQ53

~

Rb

Increased Genomic Inst.bUIt)'

High Proliferation

Fig.1U1 Proposed model of IIlCIlecWr patl10genEtSlS in Ihe deYeqmenl and progression of MCL The presence of ,A,1M or CHK2 ifIadivaIing nI.IlatiORS ifllhe gemWne 01 some paller'll$ suggests Ihat they ITI3)' IacilrIale lhe ~ ofltle MrloIJ". The 1(11;14) transb:atiOn occurs in an immatJ.n 8-<:eII aI'lCIleads to Itl8 oonstitulive dereglJabon 01 cydln 01 _..,.,. •• ~ r:A IlnGur ~ on............. of lymphoid ~ Acquqd inectrvaIion 01 DN " ~ ~ paIIlways may tac:iIRale!he dirteIoprt'«Il aI addJbmaI geneticalIeralions and expansion of MCt eels witha dassicallT'IOIphokIgy. Increased genomiC instal*y maytiWgel genesin the cJ3I C)'de and senesoence ~ pahways 1tIat \IlIOUd lead ~ JTOlI aggressi\'e Ya"IafIls of MCl. ModrIied WIth perrrissicrllrom J¥es P. 8f aI. (1048A)

cyclin 02 ()( eye lin 03. Some 01 these cases carry a t(2; 12)(p12;p13) translocation fusing cychn 02 to the kappa light chain gene locus 17891. This diagnosis must be made only with great caution due 10 the many lymphomas that may mimic

MeL. Postulated normal count erpart Peripheral Bccell of inner mantle zone, mostly of naive pre-germinal centre type. Prognosis and predictive factors Mantle cell lymphoma has a median survival at 3-5 years, but the vast majority of patients cannot be cured 1329 , 21361. The impact of some of the newer therapeutic approaches remains to be established 11917. 2487AI. The most consistently reported adverse nrstopatnoioqicat prognostic parameter is a high mitotic rate

232

Mature s-een neop lasms

(>10-37.5115 hpf. >5OImm") 174, 247 , 2134. 22371. A high proportion of Ki67 positive cells, ego >40% or >60% . is also an adverse prognos tic ind ica tor 11120, 22371. The most significant prognostic indicator identified in a major gene expression profiling study was the proliferation signature score 118711. Although not necessarily all independent of the proliferation fraction, the following have been rep orted in at least some studies to be adverse progn ostic features: blastoidl pleomo rph ic morpholog y. trisomy 12, karyotyp ic com plexity. TP53 mutation/ overexpressionnoss and a variety of clinic al parameters including overt PB involvement (at least in patients with adenopathy) {165 . 247 , 329 . 496. 839, 1341,1761 ,1918.21341. Gains of chromosome 3q and deletions 01 9q are associated with a poor prognosis independent

of the proliferation fraction 119181. The small cell variant appears to have a more indolent course with the impact 01 a mantle zone or nodular pattern less settled 1247. 1253. 1368. 1605, 1871, 2134. 2237l. Patients presenting with PB. 8M and some times splenic involvement but without adenopathy have been reported to have a better prognosis (median survival. 79 months) 116521. Although not a progn ostic ind icator, mutated IG genes were associated with the long-term survivors in the latter study, Patients with in situ MeL also may have a better prognosis with long term survival even without therapy. although caution is advised as this morphologic pattern may be associated with more overt disease and a rapid course 11602. 18421.

Diffuse large B-cell lymphoma, not otherwise specified

Definition [Muse large EkelllymphOma (DLBCL) is

aneoplasm of large B lymphoid cells with nuclear size equal to or exceecnq nomal

macrophage nuclei or more than twice the size of a flOfma l lym p hoc yte . thai has a diffuse growth pattern .

Morphological, biological and clinical studies have subdivided diffuse large

B-<:eI tymphomas into morphological variants , molecular and irTvnunophenc>(ypical

subgroups and distinct disease entities (Table 10 .14) . However. a large number of cases remain that may be biologically heterogeneous, but for which the re are no clear and accepted c riteria for subdivision. These are classified as DLBCL, rot otherWise specified (NOS). OLBCL NOS

cotonses all OLBCL cases that do not belong 10 specific subtypes or d isease entities mentioned in Table 10 .14

ICD-OCOde

9680/3

Epidemiology DLBCl . NOSco nstit utes 25-30% of ad ult

non-Hodgkin lymphomasin western couneesand a higherpercentage in developing countries. It is more common in the elde rly The median age is in the 7th deca de but it may also occur in c hild ren and youn g adults, It is slightly mor e common in ma les than in females 15 1, 79 1.

Etiology The etiolog y of DLB CL , NOS rem ains uOO1own.1t usually arises de novo {relerred

Fig. lU2 Spleen IIvoIYed by drfIuse large B-eeI

WOlllIIXlttaIlS largelumol.r nodlJes.

H. Stein

RA Warnke W.C . Chan E.S. Jaffe

to as prim ary) bu t c an represent progression or transformat ion (relerred to as second ary) of a less ag gressive lymphoma, e.g. chronic lymphocytic IeukaemiaI small lymphocytic lym phoma (CLLlSLL) . follicula r lymphoma, ma rginal zone lymphoma Of nodular lymphocyte predominant Hodgkin lymphoma (NLPH L). Undertying iTn'I..nxiefici is a sig1fficant risk tectoDLBCL, NOS occurring in the setting of irTYrunodeficiency are more often EpsteinBarr virus (EBV)-positive than scoreorc DLBCL, NOS. In DLBCL cases without an overt irTVTlUnodefic iency. the EBV infect ion rate is app roxima tely 10% 1993. 1690 1. Sites of involvement Patientsmay present Vv'iIh rKldaIlJ extranodal disease wiItJ up to 40% being at least initially confi ned to extranod al sites 18981· The most common extran odar site is the gastrointestinal trac t (stomach and ileocoecal region ) but virtua lly any extranodal loca hon may be a prima ry she. Other common sites of extranodal presentation incl ude bone, tes t is. spl een, Wald eyer ring . sal iva ry g land , thyroi d, liver, kid ney and adren al g land . Cutaneous lympho mas co mposed 01larg e B lym phocytes are dea lt w ith separately in this volu me , Bone m arrow (BM) invo lve m ent is reported in 11- 27% of c ases 1327, 442 ) The de tec t ion ra te of minimal invo lvement ma y be inc reased if an ci llar y studies like immunohistochemistryor p e R are added to the mo rpnoioqical evaluation of the BM specimen (2 15 11. Bone m arrow in volve ment may be with

J K C . Chan K.C, Gatter E. Campo

DLB CL (corcoroann but more commonly discord ant 14421. wit h the p resenc e of a low-grade B-c ell lym phoma in the BM. The frequency of discordant BM involvement varies in d ifferent reports from rare to 70% of the positive cases 167, 945 , 11901, Mo rphologic examination of peripheral blood (PB) smea rs revealed that approximately one third 01 DlBCL patients with BM invotvement also ha d malignant cells in the PS1671 .

Clinical features Pat ients usuatty present with a rapid ly entargu'IQIl.mOUr mass at single Of multiple nodal or extranodal SIIes_Almost ha lf 01 the patients have stage I or II d isease. Most patients are asym ptoma tic but when symptoms are p rese nt they are highly dependent on the site of involvement 151, 791 . Morpho logy Lym ph nodes demo nstrat e a d iffuse p rolife ration of large lym phoid ce lls that have tota lly (more common pattern) or par tially effaced th e arc hitecture . Partial nod al invo lvement ma y be mtert oulcuter and/or less commonly sinusoid al. The perinodal tissue is often infiltrated , Broad or fine bands at sclerosis may be observed. Cytomorphologi cally, DLBCL, NOS is d iverse and c an be d ivided into co mm on an d rare mo rph olog ic va ria nts. Cases pr ed om inated by medium-sized c ells may require spe c ial stud ies to ex clude ex tramed ulla ry teckaemta s. Bu rkitt lymphoma variants and bl astoid m antle cell lym phomas,

-

Fig. 10.83 DdIuse large B--c:eI~. cenlrotllastic vlll"ia'1l A T)'PIClII appearance. B In llise~, h II.m:u eels have a potymorpnic and ~ed appearance. Diffuse large B-celf lymphoma . not otherwise specilied

233

..

Corrmon mo rpho logiC variants Three common and additional minor morphological variants have been recognized. All variants may be admixed with a high number of t-e ens and/or btstrccytes. These cases should not be ca tegorized as T-cell/histiocyte-rich large B-cell lymphoma (TCABCL) as long they do not fulfil all the criteri a of this DlBCL subtype . Centroblastic varian t: This is the most carmon variant. Centroblasts are mediumsized to large lymphoid cells with oval to round, vesicular nuclei containing li ne chroma tin. There are two to four nucl ear membrane-bou nd nucleoli. The cytoplasm is usually scanty and amphophilic to basop hilic . In some cases, the tumour is monomorp hic, i.e. it is composed entirely (>90%) of centroble sts. In most ca ses. however, the tumour is polymorph ic with an admixtu re of cen troblasts and invnunoblasts «90%) 1645, 12741. The tumou r cells may have multilobated nuclei which predominate in rare instances , especi ally in manifestations of the bone and other extranodal sites. Immunoblastic variant: Greater than 90% of the cells in this variant are immuno blasts with a single ce ntrally located nucl eolus and an app reciab le amount of basophilic cytoplasm. Imrnunoblasts with plasmacytoid different iation may also be pre sent, Clinical and/or imm unophenoly p ic find ings may be e ssential in differenti ating this variant from extramedullary involvement by a p lasmab lastic lymphoma or an immatu re plasma cell myeloma. The distinction of the immunoblastic variant from the common cen trobl astic variant has generally met With poor intraobserver and mreronserver reproducibility {8981.

Anaplastic variant: This variant is characterized by large to very large round . oval or polygonal cells With bizarre pleomorp hic nuclei tha t may resemble, at least in pa rt, Hod gkin and/o r Reed-Sternberg c ells, and may res em ble tumour cells of

Table 10.1" DiI Me largeB-ceI tymphoma: variants, subgroups ancl SI.tJtype$Ienhlie$. Dlffuselarlle B-eeillymphoma., not otherwise s peelf~ (NOS)

Common morphologic vari¥lts

""""""'"

~astiC

ArlapiasliC

Rare rTlOI'phologicvereots MoIeaJlar subgroops GemWIaI~~e {GC8 1

Activated 8<:eI-ike (ABC)

ImmurdlisllXtiemicalsubgroops CD5-posiliveDLBCL Germinal oontre EkelI-like (GCB) Noo-ge!minaI OlIfltrelk:eHke (non-GCa) DifluHlargeEken Iymphom. subtypes

T<.ellfhlsllocyte-rich large B-OOllymphoma Pnmary DL8Cld!he CNS Pm1ary cutaneous Ct.BCl.1eg ttPe E8VposiM OlBCl d eeeldeIty Otherlymphomas of lerge B t elll

PrImary mediastinal (1hynIe) Iatge!k::eI ~

wmva:sa.w large !k::eI ~ OLBCL associated Wllh dIronic inftarrrnation Lymphomatoidgranulomatosis AlK-poslbve LBCl PIasmabiaslie lymphoma large 8-aII1y!r9'lcma arISIflg II HHV8-assooated rWIicenIrie C3slIeman disease

PrYnary el'lusioo ~

-

Borcl.rllneeases

!k::eIIymphoma, undassItiable• ...,;ttlfeatures intermediate between dllMe 1arge!k::ellympOOma and

.....

B-<:eI~,

undassiflable. WJtllleatL.res IIIermediate between dJse largeB-eeI Jyrnphoma and

classical HoOgklfl Iympnoma

234

Mat ure B-c elJ neoplasms

anaplastic large cell lymp homa. The cells may show a sinusoi dal and/or a cohesive growth pattern and may mimic uncitterennated ca rci noma /8911 . They are biolog icall y and cli nica lly unrel ated 10 anaplastic larg e c ell lymp homa which is

of Cytotoxic t-een derivation and unrelated to ALK·positive lBCL Raremorpholog ic variants: Rare cases of DlBCl. NOS have a myxoid stroma ()( a libriIary matrix. A few cases show pseudoroselle formation . Occasionally the neoraaetc cees are spindle-shaped ()( display features of signet ring cells. Cytoplasmic granules. mic rovillous crojectone and intercellular junctions can also be seen .

"""""""henotype

The neoplastic cells express pan s-een markers such as C01 9 . C02O. C022 and CD79a, but may lack one or more of these. Surface and/or cytoplasmic immunoglobulin (lgM>lgG> lgA ) ca n be demonstrated in 50-75% of th e cases (1328) . The presence of cytop lasm ic immunoglobulin does no t correlate with the expression of plasma cell ma rkers such as C0 38 and C0138. Both markers are rarely co-expressed in CD20 posmve cells. CD30 may be expressed especially III the anaplastic variant I 17581. The neoplasticcells express C05 in 10% of the cases 121421· These CDS positive DlBCl cases usually represent de novo DlBCl Mdonly rarely arising from ClUSLL. COS poseve DLBCL can be distinguished from the otastoio variant of manne cell lymphoma by the absence of cvcun 01 expression 11418.24631. The reported incidence of CO to . BCl6 and IRF4/MUM1 expression va ries . Expression of CO 10 is found in 30-60%. BCl6 in 60-90% and IRF4/MU M1 in 35-65% of the cases (3 1. 196 . 460 . 521 . 994, 1547). Unlike normal germinal ce ntre in whic h the ex press ion of IRF4/MUM1 and BCl6 is m utua lly exclusive. co-expression of both markers was found in 50% of DlBCl in one study 16611. A uniform high expression of FOXPI has been reporte d in OlBCl cases that lack the germinal centre onerotype and express IRF4/MUM1 and BCL6 n the absence of t(14 ;18) 11461. ExpressiOn of BCl6 varies in different reports. ranging from 47-84% 1460. 759.

Bceus.

925.9941. The prollferatloo fraction as detected by ~7 stall'ling is high (usually much more than 40%) and may be greater than 90% n SOOle cases 114781. p53 is expressed n2O- 60% of cases 1420.1171 . 1281 . 24761.

Subgrouping VL BeL, NOS by immunoph enotyping An immunophenotypical subdivision of DlBCl, NOS into germinal centre-like (GCB) and non-germinal centre-like (reoGCB) subgroups has been proposed by dillerent groups using a combination of antibodies toCD10, BCl6and JRF4!MUM1 /460 .8821. Cases with CD10 expression by >30% of cells are regarded as GC type as well as cases that are CDlO-. BCl6+ , IRF4!M UM1· . All other cases are regarded as of ron-Go type 18821. H0wever. this irTllTlunophenotypic subdivision does not correlate exactly with gene exp ression-based sUbgrouping of OlBCl 1994. 1869 1. The add ition of other markers such as BCL2 and Cyclin 02 may lead to an imp rovement in the imm unop henotypic subg rouping of DlBCl13 11. This immunophenotypic subgrouping does not currently determine therapy. Gene tic s Antigen receptor genes Cionally rearranged irrmunoglobulin heavy and light chain genes are detectable. They show somatic hypermutations in the variable reg ions .

between diffuse larg e B-cell lymphoma and Burkilllymphoma".

Gene expression profiling AJizadeh et al1241 identified I'M> subgroups of OlBCl. One subgroup (termed GCBlike) has the gene expression profile of germinal centre B-cells (45-50% of cases ) and the other (termed ABC-like) has the profile of act ivated peripheral Bceus. This was confirmed by a subsequent study 118691 _1000ially. a third subgroup (termed type 3) was defined. This proved to be a collection of cases that cannot be class ified as the GCB- and the ABC-SUbgroup and does not represen t a d istinct subgroup (994, 24491. The two established subgroups are associated with d ifferent chromosomal aberrat ions. The ABC-Dl BCl subg roup has frequent gains of ac, 18q 2 1·q22 and losses of 6q2 1·q22, whereas the GCBDlBCL subgroup displays frequent gains at 12q1 2 /167, 2 1421. A number of the eca-ue cases carry a BCL2 rearrangement {526. 9881. The immunoblastic variant and the centroblasti c va riant cases with a polymorphic centrobrast-uke cells and/Of a higher Galtenl of irTrTulobCastsare more corrmon

i1 the ~ blJ:werealsool::lservecl

Abenant somatic hype rmutations Aberrant somatic hypermutalions targeting multiple genetic loci, including the genes PIMI. MYC . RhoHITTF (ARHH) and PAX5 are encountered in more than 50% of OlBCl cases. These genetic alterations may contribute to the oncogenesis of this lymphoma group 116991.

Chromosomal translocations Up to 30 % of cases show abnor malities of the 3q27 region involving the BC L6 gene, which is the commonest fransocaton in OlBClI 158. 1620, 16261. Transloc ation of the BCL2gene. Le. 1(14:18), a hallmark of follicular lymphoma, occurs in 20-30% of cases 1994. 13 16 . 2379}. A MYC rearrangement was observed in up to 10% of an unselected series 01 cases 124811 and is usually associated With a complex pattern of genetic alterations 19941. The MYC break certoer is an IG gene in 60% and a ~IG gene in 40% of cases 19941. Approximately 20% of cases with a MYC break have a concurrent fGH-BCL2 translocation and/or BCL6 break or both 1994. 22781. These cases usually have a high proliferation (>90% Ki67+) and may be better categorized as "B-ceillymplunas. uncl assified with features inter mediate

in the GCB-subgroup. This indicates that the eca-me and ABC-like subgroups cannot reliably be recognized by morphology. The correlation between the gene expression subtypes of OlBCl and those defined as GC and non-GC DlBCl by immunohistochemistry is variable 1882 . 994 1. Table 10.15 Intemational Prognostic Index fex aggressi\ltllymphomas

Unfavourable variables Age >60 yaars Poor petfonnance status (ECOO:a) Advanced Ann Arbor stage (1II-N)

Extranodal invOlvement zz sites tigh sen.rn lDH (>normal) Risk group

Unfavourablt v"riables AI patJeIlt$ Pati9nU SfU

0« 1 2 3

0 1 2

4«5

3

' In patlel'Its s60year-okl fie age-.adjusted nternatiOnal prognosbc index (aaiPiI is caIcUated VIOIh tnree unlavourable variables ltJal lOdude poor per. formance slalus.aovancedAnnAibor stage and

higl serum l DH

Diffuse larg e B-ce il lymphoma. not otherwise specified

235

Postu lated normal cou nterpart Peripheral B-cells of eith er ge rm ina l c entre or post ge rminal c entre (ac tivated B-cell ) origi n. Prognos is and predict ive factors In me pre-ritu ximab era the long- term remissi on rate was betwee n 50-60% . Although Indi vidual prog nosis varies widely. the Internatio nal Prognostic Ind ex (IPI) based on clinical parameters has proved to be hig hly valuable 1791 . However, the IPI seems to lose some of JlS predictive value in patients treated wilh rituximab 11985 1 whi ch has im p rOVed prognosis signIficantly 14551. Concordant BM involvement is associated with a very PQOf p rognosis (5-year overall survival . 10%) while oiscoecanr involvemen t does not influence the clinical outcome significanlly (5-year overall survival, 62%). The PQOf survival associated wi th concordan l invotvement was independent 01 the IPI score {327, 442.1 65 11. MoqJholcgy There are many conflicting repo rts on the prognostIC impact of ffinJnobIastiC leatures {79. 275, 645 , 1453 . 19 15{. Some studies lound an adverse orocrosnc impact of inrnunoblastlCmorphology whereas others d id not

•

Immunophenotype A larg e num be r 01immuno histoc hemical markers have been report ed to be assoc iated with prog nostic effects: the expression 01 BC l 2, X-li nked inh ib itor of apo ptosts (XIAP), IRF4/MU M1, c vcnn 0 2, cyclin 03, p53, C05, FOXP1, PKC-/I, ICAM1, HLA-OR, c- FU P have been associated with an adverse p rogn osis and the exp ression of acts, COlO , l M02 with a favo urable outcome {10, 146, 196, 460, 526. 759 , 88 1, 925, 1009, 1479 , 1546 , 23 18. 2463 ) However, the results o btained in thes e different stud ies are often co nllic ting and the ir interp retation is thus con troversi al. Finally. the addit ion 01the anti-G020 antibody rituximab has improved the surviv al of patients with OLBCl considerably {4551 and was repo rted to have elimina led the nega tive impact of the expression of BCl2 and the positive impact of BCl6 on cli nical outcome {455, 1528, 1529, 2423/. Patients with EBV-infected OlBCl , as revea led by EBER in Situ hybridization, have be en found in one study to have a worse c linical outcome tha n patients with an EBVnegative OLBCL 11690/. 236

Mature B-celf neoplasms

Proa re ssia n -free s u rvtvat . ~

•• •

r.

,-

1 •· •

-.--

----

r.. ~ :-t"- I "

..

~-,

• •

Low-risk

-

•

•

•

--

~-

•

overall survival

.

r.. 1."

•

-.--

. 1\ •

High-risk

-

. r..

•

--

1.." ~-

•

low-fisk

-

• •

•

"' ~l)

•

H igh -ri sk

-

Fig.10.85 OvefaB al'ld progreSSiOn-free surrival in diffuse large B-cellymphoma according 10 the age.adJusted Intemabonal Prognostic Index in patients trealed W11h CHOP WIU1 and IIII'I1houI ntuximab ao::udI'lg to the study em dl.ded byIheGElA (courtesy of Dr8. Corffier).

Immunohistochemical panels Hans et al. I882} reported that a combination of CO lO, Be l 6 an d IAF4!M UM 1 expression, the so-ca lled "Hans cla ssifier". cou ld subdiv ide OlBC l patients into long- and short-term surv ivors; this result has been co nfirmed by some studies b ut not by others 131, 460 ,1 339 , 1526, 16 10, 230 1). Whether the ad di tion of rituximab to

CHOP will eliminate its p rognostic value needs to be further invest iga ted {l 6101 . The study of other immunohistoc hemical pa nels inc lud ing markers such as cyclin 0 2, BCl2 and LM02 may improve the prognost ic pr ed iction {3 1, 15801, However, the use of immunohistoc hemica l panels to ass ig n prognostic groups does not c urrently have a role in rout ine c linical

practice. One of the major limitations is the well-documented problems with re producibility in the per formance and interpretation ot some immunohistochemical stains (518, 2505 1.

Proliferation A high proliferation fraction , as assessed by the Ki67 index, has been associated withworse survival in scme series 11478 1_ This is supported by one gene exp ression study in which the proliferation signature proved to be a strong predictor of an adverse ootcome I1869J . However other studies have failed to confirm a prognostic value for the Ki67 index 1460, 1904.2423. 24961

Genebcs In some studies, BCL6 translocation has been reported 10 be associated with a better prognos is, but not in others 1158. 1056.1188. t543 . 1596, 1620, t728.2339I. In contrast. the presence of a MYC break is ~nk ed with a very untavouratne outcome 19941. TP53 mutations have been

associated with poo r su rvival in some series of OLBCL incl udin g one study in wh ich mutations in the DN A binding domain proved to be the most important predictcrj420, l OCXJ. 1171, 128 1. 2421, 24761_ p53 p rotein expression does not seem to be of prog nostic value in DLBCL patients 11 187.1353,20431. Patients with a molecularly defined GCB-subtype of DLBCL have been shown to have a significantly better c linical outcome than those with the ABC subtype 124. 994. 18691 Whether this difference persists in patients treated with rituximab remains to be seen . Other subgroups, i.e. · oxidative phosphorylation". - BC A/proliferation" and ' best response" identified by gene arrays, did not predict survival , but may suggest targets lor therapy 115071. Microenvironment

The ilTYllUne response appears to have a strong impac t on the clinical outcome after cnerrotherapy The MHC cl ass II gene expression signature correlates with a favoorable outcome 11 479. 1869.23181 _

The loss 01 MHC class II gene and protein ex pression in pa tien ts with OLBCL was tound to correlate with red uced numbers and a ol lumour-infill rating C08+ poor outcome 11846 1. The lymph node signa lure as identified by gene expression proliling is associated with a good cl inical outcome 118691- This signature is characterized by genes that encode components of extracellular matrix and coooecnee tissue growth factor.

t-eens

The"'PY DLBCL are aggressive but potentially cu rable with multi-agent chemotherapy. The CHOP regimen has been the mainstay of therapy for several decades. Whereas attempts 10 improve ou tcome with more intensive chemotherapy failed to show additional benefit. The addition of the antiC020 monoclonal antibody rituximab to CHOP (R-CHOP) has led 10 a marked improvement in survival 14551.

Diffuse large B-celllymphoma , not otherwise specified

237

T ceillhistiocyte-rich large B-cell lymphoma

C . De Wolf-Peel ers J. Delabie E Campo ES. Jaffe

G, Delsol

Definition

t-cemusnocvte-nchlarge B-eelltymphoma

(THALBCL) is c haracterized by a limited number of scattered, large, atypical B cells em bedded in a backg round of ab und ant T ce lls and frequently tusnocyres.

ICD-Q code

968813

Synonyms t -een-non B-celt lymphoma 118131. large 8 -eefl lymphoma ric h in t-eens and simulat ing Hodgkin d isease {4261. histiocyte rictVT-eell-nch large B-eeillymphoma 15441. Epidemiology THRLBCL attects main ly m idd le-aged man . It accounts for < 10% of all diffu se large B-eeillymphomas (DlBCL) Sites of involvement THRLBCL mainly affects the lymph nodes b ut bone ma rrow (8M), liver and spleen involvement a re frequently found at d iag-

nose . Clinical featu res

Patients present w ith fever, malaise . splenomegaly and/or hep atomeg aly. A l-

most half of them are at advanced Ann Arbor stage with an intermed iate to high risk Inter nat ional Prognostic Index (IP I) score. The d iseas e is often refractory to chemotherapy pre sently in use.

..... .,. ....

b blt 10.17

T~

StageIII-/V

largeIk:eIIympIw)ma

12-61 )'Un

75% 64%

l iv&r inYOIvemeni

13-70%

Spleen in'lOlv&ment

33--67%

Bone marrowinvolvement

17-60%

Data based on277 cases of patients withT<.efLI hi6tlOCyte-nCh large B-oaI !yn"VIoma illhe M_ lure {13A, 251, 252. 125, 1329A, 1361A, 1841A.

223M. 2273A.. 2358A}_

238

Mature B-cell neoplasms

Morphology THRLBCL has a diffuse or less comm only vaguely nodular gro wth pattern replacing most of the no rma l lymp h node parenchyma . It is comprise d of scattered. sing le, large B cells embed ded in a ba ckground of small lymphocytes thai represent T cells , and var iable numbers of tustocvtes. The tumour ce lls are always d ispersed and do not form aggregates or sheets. These cells may mimic the neoplastic lymphocyte pred omina nt (LP) c ells of nodular lymphocyte-predominant Hodg kin lymphoma (NLPHL), but usually show a more pronounced variation in size and in some c ases may resembl e centroblast s or more pleomorphic ce lls mimick ing Reed -Sternberg or Hodgkin cells 1598, 12991 They are typ ica lly found with in clusters of bland-looking non -ep ithelioid taetiocvtes thai may not be obvious on conventional examinatio n. These histiocytes represent a main and d istinct ive component of THRLBCL and are useful for the diag nosis 161. The background lymphocytes a re nearly all of r-cennoeaee. Eosmopnns or p lasma cells are not founo. The histolog y resem bles cases of NLPHL with a d iffuse co mponent, in which the LP cells have infiltrate the exnatoulcutar compartment but these THALB CL-l ike areas in NLPHL do not represent a transition towards THRLBCL and do not c arry a bad prognostic signific anc e {252 1. Nevertheless. the re are some ca ses of histologi cal progression in NLPHL , in wh ic h the process is en tirely diff use and lhe histolog ical ap pea rance is virt ually ind isting uisha ble from de novo THRLBCL. The relationship between secondary THAL BCL and pr imary cases rema ins controversial . They may represent distinct, but morphologically and immu~ ph enotypically similar entities. In the spleen. a multifoc al or mcroncouiar involvement of the w hite pulp is found and in the liver th e lymphomatous foci are local ized in the portal tracts 1598) In these extranooet loc ations as wel l as in the BM . the lym p hom a is characteri zed by the same co mposition as in the lymp h nod e . On rec urrence. the num ber of atyp ic al

cells may incr ease, resulting in a pic ture of DLBCL , The tatter heralds a bad outcome within a short time 17lSeveral studi es have recogni zed ca ses with similar morpholog y but without histiocvtes. wneme r these cases represent the same entity as typic al THRLBCL is not still c lear. Studies incl udi ng cases rich in T cells With and Without histocvtes have defined a more heterogeneous group of large Be en lymphomas. which p robably include more than one entity 12, 836, 1195 . 1299 . 1813 . 186 11. Further studies should clarify the relationship between these lymphomas. At present. while cases lacking sig nific ant numbers of histiocytes may be incl ud ed in THRLBC L. the absence of histiocytes should be noted , Lympho mas co nta ining B ce lls with a spec trum of cell siz e, mo rphology and d istrib ution (clusters or sheets of medium to large B cells), should not be included within the category of THRLBCL. and may be considered a subtype of DLBCL. NOS,

Immunophenotype The large atypical cells ex press pan B-cell ma rkers and BCL6 ; a variable numbe r stain for BCL2 and EMA and no expressio n of C0 15. C030 and C0 138 is found The bac kg round is co mpos ed of var iab le number of C068-po sitive histocvtes and C0 3, COS, positive T cells. T-cell rosett es around the tumour cell s and ramnants of B foll ic les or clusters of small B lym phoCytes are ab sent. Lack of residual IgO positive mantle cells and follicular d ntic cell meshwork are of turtner diagnostic hel p differentiating THRLBCL from NLPHL 16. 7251. There are aggressive B-ceillymphomas, ric h in reactive in wh ic h the neoplastic cells are sparse, and are EBV-po sitive . In such c ases. the neoplastic cells may exhibit a Hodgk in-hke morp hology , Suc h cases should not be class ified as THRLBC L, and should be co nsidered w ithin the spectrum of EBV· pos itive OLBCL 11 2991.

oeo-

r-cees

Genetics The tumou r B cells have the same clonal rearranged IG genes carrying high rurber

of somatic mutations and intraclonal diversity 12631as germ inal centres ce lls. l imited karyotypic studies have not shown recurrent abnormalities. Comparative genomic hybri dization on rrucrodesectec tumour cells demonstrated more imbalances in NLPHL than in THRlBC L wiltl common anomalies involving 4q and 19p (7311. Gene expression profiling has

identified a subgrou p of DLBCL characterized by a host immune response and a very bad prognosis {15071 and includes most of the cases diagnosed as THRLBCl, Postulated norm al c ounterpart Germi nal centre B ce ll 12631.

Prognosis and predictive factors THRLBCL is cons idered an agg ressive lymp homa although clinical heterogeneity is described Cases with t usto cytes are reported to represent a more homogeneous group of pa tients with a very aggres sive lymphoma. frequent failure of current therapies and with the IPI score being the only parameter of prognost ic significance 17, 2511.

J

T-celllhlstiocyte-rich farge B-eelllymphoma

239

Primary diffuse large B-cell lymphoma of the eNS

P.M. Kluin M , Dec kert J.A. Ferr y

Definition Diffuse large B-cell lymphoma 01 the central nervous system (eNS DLBCL) represents all primary intracereb ral or intraocular lym phomas. Excluded are Iym. phones of the dura . intravascula r large B-eell lymphoma. lymphomas with evidence of systemic disease or secondary lymphomas. as well as all inYTlUnodeficercv-eesoclatec lymphomas. ICD-Ocode

Synonyms These cases arealso diagnosed as prinary e NS lymphoma (PCNSL) or prima ry intraocular lymphoma (PIOL) .

Ep;dem;,1ogy e NS DLBCL represents < 1% 01 all nonHodgkin lymphomas (NHLl and ap prox imately 2-3% 01 all brain tumours. The med ian age is approx imately 60 yea rs. and there is a slight preponderance of male patients, Some studies suggest an increase in the incidence of e NS DlBCl 1485 1. bu t it is unk nown whether this is due to improve d diagnostic tools or reflect s a real increase. Etiolog y Epstein-Barr virus is generally ab sent from CNS DLBCL in immunocompetent patients, Exp ress ion or abse nce of c hemo kines and c bemo une rec ept o rs or c yto kines may co ntribute to the spec ific localization (2038 1. Tumour ce lls and endothelial cells may interac t via ac tivation of Il 4 to crea te

Fig. 10.81 Nuclear ~bc resorIafIC8 imaging (MRI) of CNSOlBCL 11 aller gadoIinit,I'n infection IA);n:I tid attenuated iflvefSion re<XIYf!f)' (FLAIR) sequenceslBI, There are I'l1O eManclflg mass lesions ifl lhe basal gar9a (Courtesy of Or. F Glaus).

a favourable mic roenvironment for tumo ur grCM'ttJ {18891. CNS DLBCl show a restricted homi ng to the main immune sanctuaries (b rain , eyes and testis). Many DlBC L of the CNS and testis show decreased or absent expression of HLA c lass I and II protein s allow ing the tumo ur ce lls to further esc ape from immu ne attac k 1240 , 1843 ). Sites of invo lvement Appro ximately 60% of all CNS OlBCl are loca ted supratentorially. In 20- 40%, multip le lesion s are p resent. Us ing NMR I, CNS DlBCl may show a homog eneo us lesion but also sig ns of centr al necrosis. The leptome ning es are affec ted in 5% .

Approximately 20% of the patients develq:l intraocular lesions. and 80-90% of patients with intraocular DlBCl develop conlralateraltumo urs and parenchymal eNS lesions, Dissemination to extraneural sues including the bone marrow is very rare, Cli nical feat ures Foca l neurologi cal defi c its are observed in 50-80% of the patients, Neurc osvcbarc symptoms (20 -30%) and symptoms due to inc reased intracr anial p ressure are also seen, leptomeningeal involvement presents with headache and asymmetric cranial neuropathies. Intraocular disease presents with a blu rred vision and floaters.

Fig. 10.88 Prmary cWIuse Iarge~ ~ oflhe CNS. A Aa:urIUalionof1u'nou" cells wtil ee perlVaso.b' space B More sold patIem. WIll stI scme ~ . Ihe petivascUar space, C Strong IRF4IMUM1 stalnrog ifl JTDre than 7O'lIo of ee tumlu eels 1'1 CNS OLBCL

240

Mature B-cell neoplasms

Deletion

'I

6p21.3

Gain

I i

_..

6p21.3 (HLA r.... lon)

Testis hemizygous

...,11

• I

Testis homozygoI.a ""'21 17

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,

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Fig. l0J9 Alrwy CGtl analysis 0# 9 ~CNS Dl8Cl. 17primaryleslicular OLBO. and 18 primary nodal(stage U11) tlBa.. s/'IoIWIg (somelimes vwy small
~

Most intraparenc hymal lym phomas show adiffuse growth pattern; cha rac teristically, Il,r nCM cells are present in the perivascular space, which is best appreci ated at the periphery of the tumour or areas where the tumour cells d issoc iate . The tumour cells mostly resem ble c entrootas ts. b ut slYinkage artefacts may hinder assessment 01 the exact nuclear size Tumour cel ls may be intermingled wit h react ive sma ll bmotoc vtes. mac rop hages, activated microglial ce lls and rea ctiv e astro cytes. large areas of nec ros is o r foamy cvtes may be present , pa rticularly in patients treated w ith high dose co rtic osteroids, This may result in so-called ' vanlShingtumours' ,

nrst.o-

Immu nophenotype All tumou rs are positive for B-eell markers C020, C022 or C079a, CO lO expression is pre sent in approximately 10-20%, BC L6 in 60 - 80% and strong IRF4/MUM 1 in appr ox imately 90 % 126 1, 324, 1305 1: BCL2 express ion, not related to the t( 14: t 8)(q3 2 :q21) , is freq uent 14531.

Cytogene tic abnormalities and oncogenes Approximately 30-40% of CNS DLBCL have BCL6 transiocattons bu t 1( 14;18 ) (q32:q21) and t(8: 14)(q24:q32) are ex trem ely rare 1453 1. There are common de letions at 6q and gains at 12q , 22q and 18q 21 w ith co py number inc rea se or amplification 0 1 BCL2 and MALT1 123681. Homozygous or hemizygous d eletions at 9p21 freq uently affect CDKN2Alp1B"-'~ 14531, Small deletions. not visi ble by convennonar comparativ e genom ic hybridization (CGH), affecl6p2 1.3 (HLA reg ion ) and contribute to loss of HLA class II and I expression 1240 ,18431.

Postulated normal counterpart Ac tivated (late ger minal centre) B-eell. Prognosis and predictive factors The for merly poor prog nosis has been rema rkab ly ameliorated by novel chemotherapeutic protocols that inc lude methotrexate . Most relapses affect the e NS. The spo rad ic systemic relapses may involve any organ but relatively frequently the testis and b reast 110431. Ind ivid ual biological prog nostic fact ors have been desc nbed . but so far they have not bee n va lidated in ind epende nt stu dies 1261. 324. 1767/,

Genetics Antigen receptor genes CNS DLBCL contalna very high load of (ongoing) soma tic hypermuta tions (up to 27%) and a striki ng ma intenance 01 the open readi ng frame 115031. A biased use of VH ge nes , in pa rticu lar VH4/34 , suggests an antigen dependent prolifera tion. Mutations also affect BCL6, PIM1 , MYC, RhoH/TTFn and PAXS 115051 .

Primary diffuse large B-eelllymphoma of the eNS

241

Primary cutaneous DLBCL, leg type

Definition A pr imary cutaneous diffuse large B-cel1 lymphoma composed exclusively 01large transformed Beene. most corrmonly arising in the leg.

ICD-Ocode

968013

Epidemk>logy Primary cutaneous diffuse large Bccell lymphoma (PClBCL. leg type) constitute 4% of all primary cutaneous lymphomaS and 20% of all primary cutaneous B-cell lymphomas 124071 and typically occur in elderly panents. in pa rticular in women, with a M:F ratio of 1:3 - 4. The median age is in the 7th decade 123341.

Sites of involvement These lym phomas preferentially affect the lower legs . bu t 10 - 15% arise at other

sites 11170. 1993,25021. Clinica l features

PCLBCL, leg type presents with fed or b luish-red tumo urs on one or both of the lower legs 1824 . 1170, 2334, 25021. These

C,J. L.M , Meijer B, Verg ier L.M. Duncan R. Willemze

lymphomas frequently disseminate to extracutaneous sites , Histopatho logy These lymphomas are comprised of a monotonous, d iffuse, non-epidermotropic infiltrate of confluent sheets of ceotrootasts and immunoblasts, many with a striking round cell morphology 1824, 23341 . Mitotic fig ure s are frequently observed. Small B-ce Us are lacking and reactive are relatively few and often conlined to perivascular areas

f ig. 1o.t1 Pnn1ar)' a.1aoeous DLBa., leg type, Typical ~bon WlIh Uro.n on a leg

t-eens

drical

1".,..mOllheootype

Genetics

The neo plastic Be ene express monotypic Ig, C020 and CD79a, In contrast to primary cutaneous follicle centre lymphomas (PCFCL), PCL BCL, leg-type nearly always strongly express BCl2, IRF4/MUM 1, and FOX -P 11768 , 8 19, 826, 948, 950, t1701 , However, approximately 10% of cases do not express either BCL2 o r IRF4/MUM l 11 170 . 19931. BCL6 is expressed by most cases, wher eas CO l O staining is usually neg ative 19501.

PCLBCL, leg-type show many genetic similarities with diffuse large B-cell 1ymphomas (DLBCL) arisin g at othe r sites bU: marked differences with PCFCL Interphase FISH analysis 1874 1 frequently shows na nstoceno ns involving c- MYC. BCL6 and IgH genes in PCLBCL. leg-type Using array-based CG H and FISH analyses, high-level DN A amplifications of 18q 2 1.3 1-q 2 1.33 , including the BCL2 and MA LT1 genes, were d etec ted in 67% of the cases 15771. Amplificat ion of the BCL2 ge ne may well explain the strong BCL2 expression in thes e cases, particularly bec ause the t( 14;18 ) is not found in these lymphomas 1577 , 875 1. Deletion of a small region o n c hromosome 9p21.3 co ntaining the COKN2A and CDKN28 gene loc i has been reported in 67% of PCLBCL , leg -typ e, PCLBCL, leg-type has the gene expressco profile of activated B-eell-like DlBCll948l, Postulated normal counterpart Peripheral B-cells of post-germinal centre origin. Prog nosis and predict ive factors These lym phomas have a 5-year survival ot ap p roximately 50% {82 4 . 23341. The p resence of multiple skin lesions at diagnosis is a significant adv erse risk faclor {8241. BCl2-negative cases have the same prognosis. Inact ivation of CDKN2A, either by deletion or promoter hypermethylatiOn. has been found to be an IS\' favourable p rognostic tacto- 15771.

242

Mat ure B-c ell neoplasms

EBV positive diffuse large B-cell lymphoma of the elderly

S. Nakamu ra E.S. Jaffe SH Swerdlow

Definition

Sites of involvement 70% of patients present with extr anodal disease (most commonly skin. lung. tons il and stomach) with or without sirrultaneous lymph node involvement; 30% of pat ients have lymph node disease alone /12 13. 16751,

EBV-POSlbve diffuse large B-cell lymphoma (OlBCL) of the elde rly is an EBV. c lonal B-cell lymphoid prolife ration that occurs fl patients >50 years and without any knOwn immunodeficiency or p rior lym-

11674, 1675.20111. Rare cases of asiTlilar lymphoma may occur in younger

phoma

individuals; however, the possibility of an t.r'ldiagnosed underlying immunodeficiency must be very strongly considered

e eese circumstances. Cases of lymphomatoid granulomatosis, infec tiou s mononucleosis or other well-defined discoes (such as plasmablaslic lymphoma, pnmary effusion lymphoma and DLBCl associated with chronic inflammation) that may be EBV + are excluded from this c atego
ICl>{) code

9680/3

Syronyms Senile EBV-associated B-c elf Iympho-

proliferative disorder; age-related EBV.

Iymp hoprolifera tive disorder; EBV-associated B-cell lymp hoproliferative disorde r of the elderly.

Epidemiology

In Asian countr ies. EBV. DlBCL of the el derly accou nts for 8-10% 01 DlBCl among p atients wi thou t a documented p redisposing immunodeficiency 11675 . 16901. with little data for Western countries . Among DlBCl. the proportion of EBY + cases inc reases with inc reasing patient ag e with the highest proportion seen in those >90 years of ag e (20-25%) 116751 _ The median age is 71 years (range: 45-92 yea rs), with a male:female ratio of 1.4: 1. Etiology EBY-positive DlBCL 01the elderly is an EBY-d riven Been lymphom a be lieved to be rela ted to immunolog ic al de terioration or senescenc e in immun ity that is a part of the ag ing proce ss /1674, 1675, 20111.

Clinical features The clinical features at presentation are variable . More than half of the patients have high or high-intermediate International Prognostic Index (IPI) scores 11213, 1675, 1690.24731. Morphology The arch itecture of the involved tissues is effa ced in contrast to infec tious rrooonucleosis. Although no longer considered to be of clinical importance 116751. cases were initially divided morphologically into polymorphous and large-eell lymphoma subtypes. both of which inclu de many large transformed cellslimmunobl asts and Hodgkin and Reed-Sternberg (HRSl-like

EBY posmve diffuse large B-eeillymphoma 01 the elderly

243

gian t cells. J he polymorphous subtype shows a broad range of B-cell ma turation and a variable component of reactive elements such as small lymp hoc ytes, plasma cells, t usuocvtes and epithelioid cells . In the targe-ceillymphoma sub type . most of the cells appear to be transformed . Both subtypes may demonstrate large areas of geographical necrosis and the histology is often variable from area to area. indica.ting a con tinuous spectrum between the two subtypes.

lrrmunophenotype The neoplastic cell s are usually positive f()( C020 and /or C079a. and light chain restriction may be difficult to demonstrate. COlO and BCl6 are usually negative.

244

Mature B-eeU neoplasms

while IRF4/MUM 1 is commonly posi tive. Cases with immunoblas l ic or plasmabla stic features may lack CD20 expression and have delectable cytoplasmic immunoglobulin . The large atypical cells are l MP1 and EBNA-2 positive in 94% and 28% of cases . respe ctively 11674.16751 . The cells are variably CD30-positive . but are CD 15-neg ative. Genetics

Cnonanrv of the immunog lobulin genes and EBV can usually be detected by molecular techniques. These studies are helpful for distinguishing the polymorphous cases from infectious mononucleosis of the elderly.

Postulated rormet cou1erpart Mature B lymphocyte. transformed by EBV Prognosis and pred ictive factors The clinical course is ag gressive. with a median survival of about two years 11675. 16901. Neither IPI score nor histopatholog ic subtype affects prognosis. The presence of B symptoms and age >70 years appear to be reliab le p rognostic factors. Patients with O. 1 or 2 of these factors have median overall survival limes 01 56 . 25 and 9 months. respectively

116751.

DLBCL associated with chronic inflammation

J.K.C . Chan K. Aozasa P. Gaulard

-

Difluse large s -een lym phoma (DLBCl) associated with chronic inflammation is a lymphoid neoplasm occurring in the contextollong-standing chronic inllarTma tion. and showing association with EpsteinBarr (EBV). Most cases involve body cavities or narrow spa ces . Pyothoraxassociated IyrrV'lcnla (PAL) is a prototypic bm. and develops in the pleural cavity of patients with long -standing pyothorax.

.,

wus

960013 Ep;demiology The interval between the onset of c hronic trfIarrwnatiOf1 and malign ant lymphoma is usually over 10 years 1408, 1024, 10251. PAL develops in pat ient s with a 20-64 (median 37) year history of p yothorax resuning from arti ficial pneumothorax lor treatment of pu lmonary or p leural tuber-

culosis 163. 1024 , 1568 . 173 4 1. Age at dlagnosis ranges Irom 5th to 8th decad e. W11t1 a median age around 65- 70 year s l1568j. The mal e 10 female ra tio is 12 .3

11024) versus near unity for c hronic ~8.)(, suggesting thaI males are mor e

susceptible to this type of lymphoma than females, Although most ca ses of PAL beve been reported in Japan, this tymphona has also been desc ribed in the West 188,1398, 17341,

Fig. 10.94 Pyoltuax-associaled~, MasM U!Iw' p ...... aw, SUffOlA'ldng !he'IIItoaie kJng

via Il-6 and u . -s receptor 11095. 10981. For OlBCl occurring in other sellings of long standing chronic suppuralion/inl lammation, such as chronic osteomyelitis, metallic implant or chronic skin ulcer, the tested cases have been EBV-pos,tive {408, 4711. Sites of involvement The com monest sites of involvement are the pleural cavity (PAL), bone (esp ecially l emur), joint and pe riarticular so ft tissue 14081. In PAL, the tumour mass is larg er than 10 ern in more than half of the cases 1631. There is direct invasion of adja cent structu res, but tumour is often confined to the thoracic cavity at the time 01 diagnosis, with about 70% of patients presenting with clinical stag e 111I d isease 115681.

PAL thus differs from primary effusion lym phoma. which is charac terized by lymphoma tous serous effusions in the absence of tumour mass lormation. Patients with rheumatoi d arthritis may develop large Be en lymphoma around chronically inflamed joints, but these cases are EBV-negative. and probably best not classified into this c ategory {8171. Clinical features Patients with PAL present with chest pain, back pain , l ever, tumourous swelling in the c hest wall , or respiratory symptoms such as productive cough. haemoptysis or dyspnea. Radiolog ic exami nation reveals a tumo ur mass in the pleura (80%), pleura and lung (10%), and lung near the pleura (7%), The serum lactate

EOOIogy ArMicial pneumothorax, used in the past

asa loon ofsurgical therapy for pulmonary tuberculosis, is the only significant risk factor for development of PAL amon g ehronic pyothorax patient s (62. 960 1. PAL is strongly associated with EBV, with expression of EBNA·2 and /or l MP1 klgethef with EBNA·' 1739 , 1629, 1936, 2t471_The EBV latency pattern is type III I'Irrore than 60% of cases 11734. 2 1461_ 1hefe is probably a role for chronic I'Iftanrnation at the local site in the pronterabOO of EBV-translormed B cells by enabling them to escape from the host rrm..ne surveillance through prod uct ion d l·1O,animmunosuppressive cytokine, ;ro~ autoeme to oeec-re growth

_l~

Tuberculous pleuritis

..

Ctvonic pyOthOrax (latent)

DevelOpment otlymphoma

> 20 years

OlBCl associated with chronic inflarrrnation

_

245

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Flg.l0.96 Pyoltloralc-assoaated!yrT1lhoma. AMuse proliferatIOn al larye Iyrr1Ihoid cells WIth invrNJnoblastJc ~~. BTlIITll:U eels express COlO. C POSItive !q'lI15 It EBV 11 the nudeus of IurTna' eels by i'I situ hybrdzation WIth EBER probe.

dehydrogenase level is commonly elevated 11 568. 17341 . Patients whO develop lymphoma in the bone, joint, periar tic ular soft tissue Of skin

many years after lhe onset of chronic os teomyelitis, insertion of metallic im plant

in a joint or bone, or chronic venous ulcer usually pre sent With pain or mass lesion. The invol ved bo ne typi cally shows lytic lesions on radiologic e xa mination .

m!!I!lIHlmlll

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Flg.l0.t1 Patterns of gene e~ 11 PAL and I'kldal dilluse larva lken lymphoma (OlBCl) are Signlficaly dillel'lln\. ModrfJed Irom Nistiu et 1M. (15991_

246

Mature B-cell neoplasms

-

The morphologic features are not different from DlBCL NOS. Most cases ShOw cen troblastic{lfTVTlunoblastic morphology. with round nuclei and large single or multiple nucleoli. Massive nec rosis and ang locentric g rO'Nlh may be prese nt.

lmmunophenotype

Most cases express CD20 and C07 9a However, a proportion of cases may shOw plasmacytic differentiation, with loss 01 CD20 and/or C079a, and expression 01 IRF4/M UM 1 and CD1 38. CD30 can be

stimulation of jnterterco-c . in keeping Wllh the role of chronic inflammat ion in this

cond ition. Down-regulalion 01HLA classI expression. which is essential lor efficient induction of host cytotoxic T lymphocytes (ClL), and mutations of CTl e p tcoes in EBNA-3B, an immunodomi nant antigen for CTl responses, might also contl'lbutetl escape of PAL cells from host CTlI1096, 1097 1. Postulated normal cou nterpart EBV-transformed late ge rminal ce ntrel po st-germinal ce ntre

a-cen

expressed. Occasional casesmay express in addition one or more t- een markers (C0 2, CD3 , CD4 and /or COl), causing problems in lineage assignment 11516, 1568, 1734, 22471.

In most cases, ISH for EBV discloses EBER expression, and a type III LMP1+! EBNA-2+ latency profile 117341 . Geneti cs Immunog lob ulin g enes are clo nally rea rran ged an d hy pe rmutated 114921. TP53 mutation s are fou nd in about 70% of cas es, usu ally involving dipyrimid ine sites, which a re kno wn to be susceptible to mutagenesis induced by ionizing radia tion {960 I. Cytogenetic studies show complex karyotypes with numerous numerical and struc tural abnormali ties 12 1471 The ge ne expression profile of PAL is d istinct from nodal OLBCl {15991. One of the most d illerentially expressed genes is interferon-inducible 27 (/F/21). wh ich is known to be ind uced in B lymphocytes by

Prognosis and predictive factors OlBCl ass oc iated with chronic inflammati on is an aggressive lymphoma For PAL. the 5-year overall su rviva l ranges 'r om 20-35% 11 568 , 15721. For those achieving complete remission with c hemotherapy and/or rad iotherapy, the s-year survival is 50% 115681. Complete tumour resection (pleuropne umonec tomy wi th o r w ithout resec tion of adjacent involved tissues) has also been reported to give good results 115601. Poor performance status, high se rum levels of lac tate dehydrogenase. glu tamyl pyruvic transaminase or urea , and advanced clin ical stage are unfavourable prognostic fact ors 16 1, 15721.

Lymphomatoid granulomatosis

-

l ymphomatoid granulomatosis (LYG) is

an enqccentnc and anctocestrucnve tyr1ltlOprOIderative disease involving extranodal sites. composed of Epstein-Bar r

virus (EBV}-posilive 8 cells admixed with rea;tJve Tcells . which usually preconoate. The lesion has a spectrum of hislological g"ade and clinica l aggressiveness, which IS/elated to the proportion of large B celts.

-

with underlying immunodeficiency are at inc reased risk {86 1. 8881. Pred isposing conditions include allogeneic organ transplantation, wiskon-Aioncn syndrome, human jrrmcrcoeucencv virus (HrV) infection and x-unkeo Iymphoproliferative syndrome. Moreover. pat ients presenting without evidence 01 underlying immunodeficiency usually manifest red uc ed immune function upon carelul clinical or leooratov analysis 12053. 24201.

976611

Lymphomatoid granulomatosis is a fare It usually presents in adult life. blt may be seen in c hild ren with immuno-

conclr{lOI'l .

0Ektency disorders. It affects males more often thanfemales (M:F ratio ~: 1 ) 11 1211. • appears to be morecommon in western countries than in Asia.

EbOogy L~toid granulomatosis is an EBVdnYen Iymphoproliferalive disorder. Patients

A

F'II_11.91 ll'ftlPhomalold granuIomalosis

A LlII19

MwIld bfWUr\iklid ~_ Large I'I:ll1JIe5 ... tn'il cMallon. B Large nec:tOtIl: noduIe$ are ..,brd"lle k4'ley.

Sites of invotvement Pulmonary involvement occurs in over 90% 0 1 patients and is usually present at initial diagnosis . Other common sites of invo lvement include brain (26%), kidney (32%), liver (29%) and skin (25-50%). Upper respiratory tract and the gastrointesunartract may be affected, but are relatively uncanmon 14931. Lymph nodes and spleen are very rarely involved 11 04 2. 1121,1182, 14461. Clinical featu res Patients frequ ently present with signs and symptoms related to the respiratory tra ct. suc h as co ugh (58%) , dy spnoe a (29%) and c hest pai n (13%). Other co nstitutional symptoms are common , including fever, malaise , weig ht loss, neu rologi cal sympto ms , arthralgi as , mya lg ias and ga strointest inal sy mptoms . Patients w ith cent ral nervous system disease may be asymptomatic or have var ied pr esent ation s depe nd ing o n the site of invo lvement suc h as hearing loss, d ip lopi a, dy sarthria , ataxia and/or altered mental status 1170 71 Few pa tients present with asym ptomatic disease «5%) 110421 Macroscopy Lymphomatoid granulomatosis most commonly presents as pulmonary nodules that vary in size. The lesions are most often b ilateral in distribution, involving the mid and lower lung fields . Larger nodules freq uent ly exhibit central necrosis, and may cavitate. Nodular lesion s are found in the kidney and brain. usually associated with central necrosis . Skin les ions are extremely d iverse in appearance.

S. Pittaluga W.H. Wilson E.S. Jaffe

Nodular lesions are found in the subcutaneous tissue. De rmal involvement may also be seen . sometimes with necrosis and ulceration . Cutaneous plaques or a rrecuooaouiar rash are less COlTVTlOI1 cutaneousmanifestationsl170. 1042. 1121. 14461.

-

L ymphomatoid granulomatosis is characterized by an angiocentric and anqooestructive polymorphous lymphoid infiltra te 11 121. 11821. Lymphocytes predominate, and are admixed with plasma cells, immunoblasts and tustocvtes. Neutrophils and eosinophils are usually inconspicuous. The baCkground small lymphocytes may show some atypia or irregul arity. but do not appea r overtly neoplastic. Lymphomatoid granulomatosis is composed of a variable, but usually small, number of EBY·positive B cells admixed with a promi nent inflammatory bac kg round 1861, 11221. The EBY-pos itive c ells usually sho w some atypia. They may resemble immunoblasts or, less commonly, have a rroreoeonopnc appearance reminiscent of Hod gkin ce lls. Mu ltinucleated forms may be seen. Classical Reed -Sternberg

F*IQ. 1U9 l ympllomaDd granUomakJsis. Chestra» graph ldentifles rrdbpIe nodules, mainly aIIed;ng !he tower U1gflekls.

Lymphomatoid granulomatosis

247

• cells are gen erally not pr esent. and if seen. should raise the possibi lity of Hodgkin lymphoma. Well-formed granulomas are typ ic ally absen t in lung and most other extrarocat sites 11 3171. However, skin lesions often exhibit a prominent gran ulomatous reac tion in subcutaneous tissue 11701. Vascular changes are prominent in lymphomatoid granulomatosis. Lymphocytic vasculitis, with infiltration of the vascu lar wall is seen in most cases. The vascular infiltrahon may compromise the vascular integrity, leading to infarct-like tissue necrosis. More direc t vascular damage in the form of fibrinoid necrosis is also cornmon, and is mediated by chemokines induced by EBV 121651. Lymphomatoid granulomatosis must be dist inguished from extranodal NK/T-cell lymphoma. nasal type, which often has an aoqiodestrucnve growth pattern, and is also associated with EBV 11037). Grading The grading of lymphomatoid qranuiomatosts relates to the proportion of EBVpositive B cells relative to the reactive lymphocyte background 1862, 13 171. It is most impo rtant to dis tinguish gr ade 3 from grade 1 or 2. A uniform population of large atyp ical EBV-posilive B cells without a polymorphous background should be classified as diff use targe B-cell lymphoma. and is beyond the spec trum of lymphomatoid granulomat osis as currently defined ,

Fig. 10.100 CutroeoA manilestabon aI ~ shorIwlg sutx:uIaroIlM inlihbon, WlIh lal necrosis ¥1d a ~ response. ~.

248

Mature B-cell neoplasms

Fig. 10,101 lymphomatoid granulomatosis. ... Grade I lesion of ltle king shows a potymorpnous infiltrate n lhe vasculard . 8 A Qade mlesion oIlhe brlIlIl(X)rQlns runerous largelraIlSbll iid Iymp/loid eels, C These eels IN positive lor Epstoo-Barr virusby in $Au Il)tInlZalJOO .... 1tle EBER prnbe. 0 ~ pleoo1aphic eels may be seen. mostcommonly n Grade 111 lesions. rarety in Grade II.

Grade 1 lesions contain a polymorphous lymphoid infiltrate without cytologic atypia. Large transformed lympho id cells are absent or rare. and are bett er appreciated by immu nohistoc hemist ry. Necrosis is usually focal, when prese nt. By in situ hybridization with EBER probe only infrequent EBV-positive c ells are identified « 5 per high po wer field) 124201 In some cases, EBV-positive ce lls may be absent, but in this setting the diagnosis should be made with caution , with studies to rule out other inflammato ry or neoplastic c ond itions. Grade 2 lesions cont ain occ asional large lymphoid cells or immunobla sts in a polymorphous background . Small clusters c an be seen espe cia lly by C020 stain, Necrosis is more commonly seen, In situ hybridization for EBV readily iden tifies EBV-positive cells, which usually number 5-20lhigh powe r field . A variation in the number and distribution o f EBV-posi tive cells ca n b e seen within a nodule or among nodules. and occasionally up to 50 EBV-positive cells/high power field can be obs erved. Grad e 3 lesions still show an inflarrmatory backgroond , but cont ain large atypical B cells which are readily identified by COlO eoo can form larger aggregates. Markedly pleomorphic and Hod gkin-like cells are often present, and necrosis is usually

extensive. By in situ hybri dization, EBVposit ive cells are extremely numerous (>50lhigh power field) , and focally may form small con fluent sheets. It is important to take into co nsideration that in situ hybridization for EBV c an be unreliable when large areas of necrosis are present due to poor RNA preservation; additional molecular studies for EBV may be help ful Immunophenotype The EBV-positive B ce lls usually express C0 20 1862, 2159 , 24201. The c ells are variably positive lor C030, but negative for C0 15. LMP1 may be positive in the larger atypi ca l and more pleomorphic ce lls. Stains for cy toplasmi c immunoglobulin are frequ ently non-informative, although in rare cases monoc lonal cytoplasmic immunog lobulin expression may be seen, part icu larly in cells showing plasmacytoid differentiation 1242O}, The backgroond lymphocytes are C03-positive T cells. with C04+ cells more frequent than COB+ cells. Genetics In most cases of Grade 2 or Grade 3 disease . clonality of the immunoglobulln genes can be demonstra ted by molecular genetic techniques {861. 14461. In some cases different clonal popul ations may be identified in different anatom ic sites

11490. 24201, .Southern blot analysis also may show clona lity of EBV {1448 1. Demonstration of c lona lily in Grade 1 cases is more inconsistent, an observation which may be related 10 the relative rarity of the EBV-positive cells in these ca ses . Alte rnatively, some cases of lymphomatoid granulomatosis may be poivctonar. t -een receptor gene analysis srows no evidence ofrnonoc looalily 11446 , 14481. Altera tions at oncogenes have no t been identified.

Postulated normal counterpart Mature B lymphocyte. uenstorreo by EBV

Prognosis and predict ive factors Some patients follow a waxing and waning clinical course wit h rare spontaneous remission s wi tho ut the rapy However, in most patients the disease is more agg ress ive , with a median survival of und er two years based on historical series 11121 1. More recent series have shown responses to aggress ive chemotherapy w ith rttuximab for g rade 3 lesions. Grade 1 and 2 lesions usually achieve durable responses to mterteroo -c 2b 124201. l ym phomatoid g ranulomatosis ma y progress to an EBV+ d iffuse large B-ceil lymphoma (DlBCl).

Althoogh some patients with grade 3 lympho mato id granulomatosis may show spontaneous reg re ssio n with immunotherapy or modification of the immune state. for clinical purposes these patients should be approached as diffuse large B-ceil lymphoma 124201.

lymphomalOld granulomatOSIS

249

Primary mediastinal (thymic) large B-cell lymphoma

Definition A diffuse large Bcemvmprorre aris ing in the mediastint.rn from putative thymic Been origin with distinctive clinical, immunophenotypic and genotypic features. ICD-{) code

9679/3

Synonym Mediaslinallarge B·c eli lymphoma .

Ep;demlology Primarymediastinal large B<el11ymphoma (PMBl) accounts tor 2-4% of non-Hodgkin lym phomas (NHllI 150. 3501 and occurs pre dominantly in young adults (median age. -35 years) with a female predominanc e (M:F ratio, about 1:2) 1350. 1257,

1943, 25001. Sites of invo lvement PMBL most likely arises within the thymus. Patient s p resent with a loca lized antero-

superior mediastinal mass. The mass is often "bu lky· and frequently invades adjacent struc tures such as lungs. p leura or pe ric ardium. Sprea d 10 sup racl avicular and cervi cal lymph nodes can occur (150, 350, 1257}. Ab sence of other lymph node or bo ne marrow (BM) involvement is a pre requisite 10 excl ude a systemic DlBCl with secondary med iastinal involvement. Clinical features Symptoms are related to the medi astinal mass, frequently with supe rior ven a ca va syndrome, B symptoms may be present.

P. Gaulard N.l. Harris SA Piled J.L. Kutok

At progression, dissemination to distant extranodal sues incl uding kidney, adrenal. liver or cen tral nervous system is relatively common but BM involvement is usually absen t.

-

PMBl shows a wide morphologicaVcytological spectrum from case to case 117121. II is commonly associated with compartmentalizing atveotar fibrosis 1150. are 350. 1499.1712,17441. Tumour medium-size d to large cells with abundant pale cytoplasm and more or less regular round or ovoid nuclei. In some cases, lymphoma cells have pleomorphic and/or multilob ated nuclei which may resemble Reed -Sternberg cells and raise suspicion of Hod gkin lymp hom a (Hl) 11712, 22651. Rarely, there are "grey zone" borderline cases combining teatures of PMBl and classical Hod gkin lymph oma (CHl) or c ases 01 composite PMBl and CHlI22651.

F"'ll.10.103 PnmatymeliastJnat1arge8<:el ~

cens

Irrmunophenotype PMBL expresses B-cell antigens such as CD 19, CD 20. CD22 and CD79a, but, as a rule, lacks immunoglobulin (Ig) 1150, 1092, 1328, 17441. CD30 is p resent in mo re than 80% of the cas es, however, usually weak and heterog eneous, co mpared to Hodgkin lymph oma 1938, 1744 1, CD 15 is occasionally present 115001. Tumour cells are freq uently posi tive for IRF4/MUM1 (75%) and CD23 (70%), have variab le expression of BCl2 (55 - 80%) and BClS (45- 100%) and CO lO is less common

CIA weee str::Mlg Aeshy ILmw' \ffllh necrosis.

(8-32%) 1311. 520, 17441. Tumour cells are also positive for MAL antigen, CD54 and CD95. coexpress ffiAF1 and nuclear REL 1470, 472, 185 7l. Variable defects in the expression 01 HLA class I and/or class II molecules have been found in most 01 the cases 11498. 1500 1. Genetics Antigen receptor genes Imm unog lob ulin genes are clonally rearranged with a high load of somanc hypermutations without ongoing mutational activity 11 270 ).

Cytogenetic and oncogene abnormalities Compa rative genomic hybr idization (CGH) demonstrated gains in chromosome 9p24 (up to 75%) and 2p15 ( - 50%), but also in chr omosomes XP11.4-2 1 (33%) and XQ 24-26 {33%l [192, 1072,23931. Candi d ate genes include REL and BCL 11A (at 2p ), which are amp lified in a pro po rtion of PMBL [2387,

Fig, 10,11)2 Pnmaty meciII5tlrl8I large 8<:eI ~, A Nuclei are lW'ld (centroI:llasl-Q) or someIines rTJ.IIlIlobated. by ooIlIgenous Iilrosil. C Medium-silecI eels with large pale cyklplasm.

$epllIil1ed

250

Mature B-cell neoplasms

H. Stein A.M Kovrigina E S, Jaffe P. MOiler

J

2389). and J/iK2 , POL 1and PDL2 (at 9p) 11072,1459,18701. Nuclear acc umulation of REl protein is common 11 857 , 23871 with an impe rfect correlation with REL amplification and AEL transcr ipt ab undance 1701, 23871. PMBL has a unique transcriptional signature, but shares featu res with CHL 11870, 19441. PMBL has consti tutive ly ac tiv ated NFt;B 17011 and JAK-STAT signaling pamways 1864. 1459 1, frequently related to Inactivating muta tions 01 SOCS111459,

23881. Rearrangements 01 BCl2. BCL6 and M YC genes are absent or rare 11944 . 1953 . 22711 whereasoecnvatco 01 P and TPS3genes have been reoortec {19531. The discordant expression of components of the B-cell receptor (BC A) (CD79a +. slg-) is characteristic 01 PMBL 11092 .

'fI'«-

1328. 17441. It cannot be ascribed to a

lack of functional/G gene rearrang ements

nor to a defect

in the transcription lactors

BOB.t , OCT·2 and PU. 1{ 1328, 17441 but, rather, to a downregulation of the intronic heavy chain enhancer 118481 or posteenecrouonnar blockage / 13281. Postulated normal cou nterpart ~ medullary, asteroid , (AID-positive) , 8-<:eIl 1953. 1016, 1494 J. Prognosis and pred ictive factors Variations in mic roscopic appe aranc e do not predict d ifferences in survival 11712/, Response to inten sive c hemo therapy , with or without rad iothera py, is usually poco. Extension into ad jacent thorac ic vscera, pleural or perlca roial effus ion and poorperlormance status (350, 1257,1943) Mas been associat ed with a poo r prognosis, According to recent stud ies, outc ome ofPMBL patients is at least equ ivalent to or superior to that 01other DLBCL pa tients (350. 1943, 25001with a pla teau seen in the sorvivat c urves bey ond 2 year s /1943), In addi tion, the PMBL mo lec ular signature was associat ed wi th a more favourable survival (compa red to Gce ar.cl ABC DLBCL) 118701. su p po rting a esect naiurat history for PMBL.

Fig. 10.107 Primary mediaslinal Iafge Ek::eIIlympl'loma A Most tumour cells express express MAl. with a L)'loplasmlc re.nloroemenl in lhe Golgi area

_

con

8 Tumour cells also

Primary mediastinal (thyrmc) large B-celllymphoma

251

Intravascular large B-cell lymphoma

S, Nakamura M. Ponzon i

E. Campo

Definition

ratio of 1.1:1. The frequency and clinical p resentation differ accord ing to the geographical origin of the pa tients between the West and the Far East {621. 694 , 15451.

h.mina of vessels , particularty capillaries, with exception of larger arteries and veins.

Sites of involvement

Intravascular large a-cen lymphoma (lVLBCL) is a rare type of extranodallarge B-ceil lymphoma characteri zed by the selective growth of lymphoma cel ls within the

ICG
97 1213

This lymphoma is usually widely d isseminated in exnarooat sites including bone ma rrow (8 M) and may present virtually in

any organ. However, lymph nodes are Synonym

usually spared ,

Angiotropic large cell lymphoma.

Clinical features Epkl~

This tumour occurs in adul ts (median. 67 years; range, 13 - 85 years) and with a M :F

•

•

Two major patterns of clinical presentation have been rec og nized , a Western form c harac terized by symp toms related to the

eels .

main organ involved . predominantly neur0logical or cutaneous, and an Asian variant in wh ich the patients present with mumorgan failure, hepatosplenomegaly. pancvtcoeoa and _ _ syrd"""". These presentations are seen more treQuently, although not exclusively. in Western and Far East countries. respectively 162 1, 69 4. 1544, 1545 , 17681. B symptoms are very common (55-76% of patients) in both types 01 presentation. An isolated cutaneous variant has been identified invaria bly in Western females; it is characterized by limitation of the turncu to the skin and is associated with a better p rognosis 16931. Conventional staging

F'15I·10.1081nr.tYasoAar large B-oaIIyrlVana. A The largeWona !he ¥llin lrir/II~) n capIaty (I8ft~. B The Iarglluncu eels are presenl,, !he SQISe5 fA hl booe marrow. hMlg abl.nQInt t)'tIpIasm ~ a Il'O'e 01 less JTecPar rudeus. C The large~ celliNIh ID.Jses 11 tle adrenal gland. 0 The IiIrge Uro:r eels Ir8 P'esenl ll !he Unen fA smaI ~ 11 !hecernI rlllI"IWS syslem

252

Mature

a-ces neoplasms

'...->.

procedures are generally associated with a high proportion of false neg atives b ecause of the lack of detectab le tumour masses.

~ The neoplastic lymphoi d cells are mainly lodged in the lumina of small or intermediate vessels in many organs. Fibrin ttrombi , haemorrage and necrosis may be observed in some cases. The tumour cells are large with prominent nucleoli and trequenl mitotic figures. Rare cases have cells WIth anapl astic featu res or smaller size 117691. Minimal extravascular joceIial 01 neoplastic cess may be seen. SirosoidaI involvemen t occurs in the liver, 8M 117691. Malignant cells are occasionally detected in peripheral blood

\

sceenard

""'-'>op/lero Tumour cells express B-cell-associated antigens. Co5 and CotO coespresson is seen in 38% and 13% 01 the cases, respectively. Almos t all 01 Co1~neg ative

Fig. l0.l 09 Skin involved by intravascula r ....,..,.

large B-cell

cases are IRF4/MUM 1 positive. Anecdotal cases of intravascular T-cefl or NK-eell ~ phoma have b een report ed 12145 1. bu t they shou ld be considered a different entity. The intravascular growth pattern has been hypothesized to be secondary to a defect in homing receptors on the neooiasnc cells 1698}. such as the lack of C029 (lJ1 integrin) and C054 (ICAM-1) adhesion P-moIaculesj 1766}.

Genetics Immunoglobulin ge nes are clonally rearranged. Karyotypi c abnorma lities have been described but too few cases have been stud ied 114951 .

Postulated normal counterpart Transformed peripheral B-cell . Prognosis and predictive factors This is an aggressive lymphoma which responds poorly to chemotherapy 1692}. The poor prog nosis reflects in part frequent del ays in diagnosis due to the protean pr esentation. Neither clinical types 01 prese ntation nor clinical parameters predicts patient survival, with the exception 01 the b etter prognosis for the c ases with disease limited to the skin 1693, 17681 .

Intravascular large 8-celllymphoma

253

ALK-positive large B-cell lymphoma

G_ Delsol E. Campo AD. Gascoyne

Definition ALK positive large B-ce ll lymphoma (ALK-positive LBCL) is a neopl asm of AlK-posi tive mooomorphic larg e immunoblast-like B cells, sometimes with erasma blaslic di fferentiation.

ICD-O code

9737/3

Synonyms Large B-eell lymphoma expressing the ALK kinase and lacking the 1(2;5) transl ocation; AL K-positive piasmatnesnc B-eell lymphoma.

Epidemiology This lymphoma is very rare « 1% of DLBC L) . w ith less than 40 c ases so fa r been repo rted 1183 11. It seem s to occur more frequ ently in ma le adu lts (M :F ratio, 3:1) and sp ans all age group s (9-70 years ) (med ian, 36 years) 118311.

Sites of involvement The tumour mainly invotves lymph nodes {9, 553, 761 , 1023, 1831,20751 or present s as a medi astina l mass {527. 7881. Involvement of extranodal sites have been also reported includin g na sop har ynx 11 644 1. to ngue 1527f, stomac h {1444j. bone 1164-t) and soft tiss ues 14 171, Cl inical featu res Most pat ie nts prese nt with advanc ed stage Ill/IV.

na.

10.112 ALK-posibve large B-eeil lympnoma, morpnologic features A T~re is massive invasion of lymphatic sinuses B Neoplastic cells show immunoolastic and pla smablastic features

MO'Phoklgy This lymphoma shows a sinusoid al growth pattern and is composed of rrooororptuc larg e imm unobtast- like cells with round pa le nuclei co ntaining la rge central nu c leoli and abundant cytop lasm. Some cases show plasmablastic differentiation {553 . 761 1_Atypical multinucleated neop lastic g iant cells may be seen . Immunophenotype Lymphoma ce lls are strong ly positive for ALK prot ein wi th a restricted g ranul ar c yto pl asmic stainin g pa ttern highly ind icative of the exp ression of CLTC·AL K

p rote in. Few c ases may show cytoplasmic, nucl ear and nucleolar ALK staining associated with the NPM-Al K protein. In adcIition,lhey also characteristically sl1rXr:jy express EMA and plasma cell markers such as CQ138 and VS38, being negative for lineage-associated leukocyte antigens (COO, C020, C079a) 1283, 553, 1962, 1963. 2075} . C0 45 is wea k or negative 1553. 761}. C030 is negative 1553}, although focal and weak staining has been reported in few cas es (2075] Most tumours express cy top lasmic Ig (usually IgA, mo re rarely IgG) with ligh t ch ain restrict ion 1553). As de scri be d in some p lasma c ell tumours,

FIi- 10.111 IrrmJnoptlenoIype ofALK-posilive Iaf9lI ~ 1)mI:tloma. The turroor eels arepositive forEMA (A)WIth a CjIOpIasmiCmembranous pattem.IgA(BI. and ALI( (C} ..... a ntStricled CjIOpIasmiC~ pattem tir;;IIy iJclic3Iived \he e~ of \he CLTC-ALK fusion protein.

254

Mature B-cell neoplasms

occasion al c ases are positive for c ytokeratin which, in addilioo to EMA posi tivity and weak/negative staining for CD45, may lead to the mista ken diagnosis of carcinoma 120751 The tumours may be also positive for CD4, CD57, IRF4/MUM1 120751. focally for CD43 120751and perIorin120751. These tumours shoul d be distinguished from CD30-po sitive AlK-positive T/null eneoiastc large cell lym p homa and other large B-ceil lymphomas with a sinusoidal growth panern . and AlK-negative imrronoblasticlplasma blastic lym p homa s, such as those involving the oral ca vity in Hrv+ patients 14591.

Genetics The immunog lobulin genes are clonally rea rrang ed 1417, 761}. This tumo ur may ex press full-leng th ALK 1553} b ut the key oncogenic facto r is the AlK fusion p rotein due to genetic alteration of the ALK locus on chromosome 2. The most freq uent abnormali ty is the t(2;17Xp23;q23) respo nsible for Clathrin-ALK (CLTC-ALK) fusion protein 1417 , 527 , 761 , 788 , 1023, 1444, 1831}. Few cases are assoc iated with the t(2;5 Xp23 ;35) as de scr ibed in AlK-posjrive TlNull anaplastic large cell lymphoma (AlCl ) 19, 16441. A c ryptic insertio n of 3'ALK gene sequences into chromosome 4q22-24 has a lso been repor ted 120751,

Postulated normal cou nterpart Post-germinal centre B cell with plasma cell differentiation . Prognosi s and pred ictive factors The overall median survival of high stage III/IV patients was 11 months 118311. Long survival (> 156 months) has been reported in children 1553, 16441. These tumour s are usua lly negative for CD20 antigen and are thus insensitiv e to ntuximab.

AlK-positrve large B-eeillymphoma

255

Plasmablastic lymphoma

H. Siein

N.l. Harris E. Campo

Definition P1asrnablastic lymphoma (PBL) is a diffuse proliferation of large neoplastic cells most of 'Nhich resemble B immunoblasts, but in which all tumour cells have the immunephenotype of plasma cells. It was origina lly described in the oral cavity but may occur in other, predOminantly extrarooat sites .

ICD-O code

973513

Epidemiology PSL is uncommon. It has its highest incidence in j-uv-ocenve individuals. predominantly males It may also be associated with other immunodeficiency sla tes, including advanced age. The median age at presen tation is around 50 years , with a broad distribution, but mainly anecnnq adults. Rare cases are seen in chi ldren with immunodeficiency 1459. 5471.

Etiology Immu nodefic iency. caused in the majority

of cases by HIV, predisposes to the development of PBL Other causes 01 immunodeficiency such as iatrogenic immunosup press ion for autoimmune drsease or prevention of po st-transp lant trie rapy a llog raft rej ec tio n may also be impl icated, There are also cases w ithout any history of immunodeficienc y, but those pa tie nts tend to be elde rly. The t umo ur

cells are EBV-infected in the majority of patients 124 1, 459 . 547 , 6041 .

Sites of involvement

PBl presents most frequentty as a mass in the oral c avity, but it is also encountered in other extrarocat sues -particularly mucosal sites- including the sinonasal cavity. orbit . skin. bone. soft tissues and gastrointestinal tract. Nodal involveme nt is seen but it is not corrvnon 1459 . 547 , 6041. Ptesmabrestc lymphomas not associ ated with HIV-inlection present more commonly in lymph nodes. Clin ical features Most pati ents are at an advanced stage (ItI or IV) at presentation 1459, 547 , 6041 . The inte rnational oroqrosnc index (IPI) is 01 inte rmediate or high risk score. Computed tomography an d positron emission tomogr aphy may show d isseminated bone involvement 121841 . Tumours with features of PBL may occur in patients with p rior plasma celt neoplasms, including p lasma c ell mye loma . Such cases should be co nsidered p lasmab lastic transform ation of my elo ma and d isting uished from primary presmabrastc lym phoma. Morp holog y PBL show a morp holog ic al spec trum vary ing from a ditluse and c ohes ive

prolife ration of cells resembling immunoblasts to cells with more obvious plasmacync differentiation, which may resemble cases of prasmabtasnc p lasma ceM myeloma. Mitotic ligures are frequent Apoptouc cells and tingible body macrophages may be present. but are generaly less prominent than in diffuse large B-eel lymphoma. Cases with monomorphic p1asmablastic cytology are most cx::mnc:ny seen in the setting of H IV-infec lion and i'l the oral. nasal and paranasar area (oral mucosal type). Conversely, cases 'Mth plasmacytic differentiation tend to OCClJ" more corrmonly in othe r extranodaJ sues as well as lymph nodes 1459 . 5471. The differential diagnosis in the cases with crasmacvnc differentiation may incluce anaplastic or plasmablastic p lasma eel myeloma, The presence of a high prolif· eranon fractioo, extranodallocalization, a history of immune de fic iency. and the presence of EBV by in situ hybridizahO"l for EBER are useful in esta blishing the d iag nosis of orasmabtasnc lymphoma Immu nophenotype The neoplast ic cell s ex press a plasmace ll ph enotyp e includ ing positivity for CD t38 , CD 38, Vs38c and IRF4/MUM1 and are negative or only weakly positive for CD45, C0 20 and PAX5. CD79a is pas. itive in appoximately 50- 85% of the cases

F"tg. 10.tt3 It Plasmablaslic Iyr'I1Ihorna of the orallTUCOSilllrilh a ITlOlllJlmlll/liC prokIefalion of large.1mulobIastIc eels MIl promrlflflI oocleoIi. B PIasmabIasbc lymphoma" plasmacytic dlllerenlialiOn. The Iur'ncU cells are large with rtu'Id nudei and showing coarse d'lnlfIIIbn and smaller or unapparenl nudeoIi. Smaller eels wrlh ~
256

Mature B-ceU neoplasms

Cytoplasmic immunoglobulins are expressed in 50 -70% of the cases, most Ireqoefltty IgG and either kappa or lambda ig ht chain. C056 is usually negative in ee oral mucosal type of PBl , bu t may be seen in cases with plasmacytic differentiation. The expression of C056 should rai se suspicion for underlying plasma cell myeklma. EMA and CD30 are frequently expressed. K167 index is usually very high (>90%). EBV EBER in situ hybridization is in 60-75% of the cases but LMPl

ccseve

is rarely expressed. The rate 01 EBV-positivity is nearty 1(}()% in the oral mucosa! type 01 PBL, in association with HIV-infeclion. H HV8 is consistently absent 1459 .

Postu lated normal counterpart Plasmablast. r.e. a blastic proliferating B-celt thaI has switched its phenotype to the plasma cell gene expression program.

547,604,23191_

Genetics Clonal IgH chain gene rearranqement is demonstrable , even when irrmunoglobulin expression is not detectab le , and the IgH genes may show evidence of somatic hypermutation or be in an unmutated con figu ration 1744 1.

Prognosis and predictive factors The c linical course is very aggressive Vvith most of the pat ienls dying in lhe first year atter diagnosis 1459, 547, 6041, although the outcome may have imp roved more recenuv possibly due to a better management of HIV infect ion 121841.

Ptasmablastic lymphoma

257

..

Large B-cell lymphoma arising in HHV8·associated multicentric Castleman disease De finition Large B-cell lymphOma arising in human herpes virus 8 (HHV8)-associated multicentric Castleman disease (HHV8 MCD) is composed of a monoclonal proliferation 01 HHV8-infected lymphoid cells resembling plasmablasts expressing 19 M and arising in the selting of multicentric Castleman disease (MCD) . It is usually associated WIth nenan immunodeficiency virus (HIV) infec tion . The term plasmablas tic is used for this lymphoma because the cells mor-

phologically resemble plasma cells and have abundant cytoplasmic immunoglobulin : however II corresponds to a naive, 19M-p roduc ing plasma cell without fG somat ic hypermulation . This lymphoma must be distinguished from p lasmablastic lymphomas presenting in the oral c avity or other extrenooat sites that frequently sho w class-switched and hypermutated JGgenes

ICD-Ocode The p rovisional code proposed for the fou rth edition of ICD-O is 9738/3.

PG , Isaac son E. Campo N .L. Harris

in 'Nhic h rarely It mani lests as a leukaemia 1627, 16381. Clinical featu res On a ba c kg round of the cnorcatteamres of HHV8 CD , patients 'Nho are developing HHV8 PL present with p rofound immunod efic ie ncy, enlarging lymph nodes and massive splenomegaly otten eccoroanec by manifestations of Kaposi sarcoma 1627, 1638}. MOfIlhology HH V8-positive mufticentric Castleman disease The B-eell follicles of lymph nodes and spleen show varied degrees of involution and hyalinization of their ger minal cen tres with a pr ominent mantle zo ne that may int rude into the ger minal cen tres and complete ly efface the m . Amo ng these mantle zone cells, there are variable numbe rs of larger plasmab lastic c ells with dense amphophilic cytoplasm and vesicular, oflen eccentrfcenv p lac ed , nuclei

Fig. to.m HHV&-pos4lYe pIasmabIastlC Iyn'VlI:ma Wrighl.Qemsa stained UnOlJ' eels in pefllIleraI blood.

con taining one or two prominent nucleoli. Similar cells may be scattered in the interfomcurar area which, in addition, is heavily infiltrated by mature plasma cells As the disease progresses, the ptasmablasts coalesce to form confluent mic roscopic clusters (so-called microlymphomas) and sheets both within and outside the germinal centres 16271.

Synonyms HHV8-p ositive p lasmab lastic lym phoma (HHV8 PL), Kap osi sarcoma herpes virus (KSHV)-po silive p lasmabl astic lymphoma , Epidemio log y HHV8 PL occurs worldwi de in HIV-po sil ive patients who have develop ed HHV8 Mc a , It less commonly occurs in HIV-neg ative pat ients who have d evelop ed HHV8 MCD usually in reg ions whe re HHV8 is end em ic (Af ric a and Med iterranea n coun tries)

12501. Etiolog y The neoplastic cells are positive for HHV8 in all cases. HHV8 encodes more than ten homologues to cellular genes that provide proliferative and anu-aooptouc signals 159,84 ,9 1, 10491. Sites of involvement The lymphoma characteristically involves lymph nodes and sp leen but can crsseminate to other viscera via the blood stream

258

Mature B-c elt neoplasms

f$;~:li"":':"''::-'",,~;j~il-lioi:lIll' """"...",,0iiI'. .• '. . ..

Fig. 10.116 HHV6-positive n1J1bc:errtrJc cas1l9man lisease. A The Ik:8I tilde WIth a IIOITlIiII genIWIII cenR ISU· I"OI.I'lded by a broad mantlezone. B ManIIe zone corUInsscattered plasmablasts. C This B<:eI lolIide shows pai1II hyalftzalion 01 the germnaI centre WIth Bn atleoual8d manlle zone, D Gem.1aI centre contaiIWlg l'UTleI'OUl

...

~""",-

HHV8-positiv,e plasmablastic lymphoma The emergence of frank lymp homa is heralded by expansion of the small confluent sheets of HHV8 latent nuclear an tigen 1 (LANA- 1)-pos ihve plasmablasts to completely efface the lymph node and splenic architecture. with massive splenomegaly. Infiltrates may also be present in the liver. lung. qastromtesunat tract and in some cases there is leukaemic involvement of the peripheral blood 1627, 16381·

""""'phenotype

The p1asmablasts described above {16381

..1' . " I

.-. .

",.

show stippled nuclear staining for LANA- 1, VIla! Ainterleukin-6 and strongly express c1gM Wllh Alight cha in restriction , They are

C02O+ or -, C079a-, COl38-. C038-/+. C027· and Epstein-Barr encoded RNA (ESER~tive. The interlotlicular plasma cells are typically clgM negative. c lg A

cosmve.

express polytypic light c hai ns

and do not shc:rN rocear expression of ~- 1

anIlQ8O.

•

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.noW....

.

.,...,

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!u

.:~

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Fig. 10.117 HHVS posltMll'flllllcenlric CaslIeman disease Wmulostained u HHV8 (A1. 1gM (8). (~d'Iafl (C)and A light chain (D). The plasmablasts e.press ntranudear HHVS lANA. c1gM and show AIiI;;lt chain teSlrictIon. InIeffoIK:uIar plasma cells e~ poIytypic IgIgtrl d'Ians.

Genetics AntJgen receptor genes Despse constant expression of monotypic IgM by the plasmablasts in HHV8 MCO. careful molecular studies have shown that trey constitute a poivcionar population 161 91. The mic rolymphomas thai develop asthedisease progresses may be monoor polyclonal and the frank HHV8 PL are moooc ionai. In both disorders. the IG genesare unrnutated.

Genetic abnormalities and oncogenes Activation of the IL·6 rec eptor sig naling pathway has been prop osed to p lay a role ntte development of HHV8-infected naive Blymphoproliferative lesions (619 ). There is no information abo ut c ytogenetic ab normalities in the tumours Postulated normal co unterpart Naive Bcell. Prognosis and pred ic tive factors Botti HHV8 MCO and PL are highly aggressive disorders with a median survival 01a few months. Associated con d itions Kaposi sarcoma is freq uently present in eerents With HHV8 PL and MCD . Primary etfusion lymp homa (PEL) and its extracavitary cou nterpart may complica te HHV8 MCD b ut unlike HHV8 PL. the neoplastic cells do not express Ig and are

Fig. 10.118 HHVBilositive p1asmablasticlymphoma. A Sheetsof p1a$ffi3bjasls efface normal lymph node archilectlJl1l B High magnificaton of p1asmahlasts in (A),TUITlOIJ" cells immunostained !of ( 1g lightchain (C) and Achain(0) stow Alightchain restriction ,

usually co-infec ted with EBV. In the g erminotropic Iymphoproliferative disord er. ano ther monotypic HHV8-posinve lymphop ronterauve lesion that occurs in HIV neg ative individuals. HHV8-posItive prasmabrasts infiltrate ge rm inal centres {6 18AI. The plasmablasts show either l( or A lig ht chain restr iction but . like HHVB MCD , these cells are polyClonal. Co-infection with EBV is also characteristic.

Large B-eeU lymphoma ansmq in HHV8-assoclated multicentric Castl eman disease

259

• Primary effusion lymphoma

J. Said E. Cesarman

Definition Primary effusion lymphoma (PEL) is a large B-cell neoplasm usually presenting as serous effusions without detectable tumour masses. It is universally associated with human herpesvirus B (HHVB). also named Kaposi sarcoma herpesvirus (KSHV). It most often occurs in the setting of immunodeficiency. Some patients with PEL secondarily develop solid tumours in adjacent structures such as the pleura. Rare HHV8-positive lymphomas indistinguishable from PEL present as solid lumour masses, and have been termed extracavitarv PEL.

~

ICD-O code

in elderly patients (both men and women) , mostly from areas with high p revalence lor HHV8 infection such as the Mediterranean 121881. In these tetter patients the lymphoma cells con tain HHV8 and may lack EBV 1454. 191 11. Etiology The neoplastic cells are positive for HHV8 in all cases. Most cases are co-infected with EBV 158, 85. 963 . 19121, but EBV has restricted gene expression and may be not required for the pathogenesis. HHV8 encodes more than ten homoIogues to cellular genes that provide proliferative and anti-apoptotic signals 159. 84, 91.10491.

Synonym

Epidem iology The majority of cases arise in young or middle-aged homosexualor bisexual males with hum an immunodeficiency virus (HIV) infection and severe immunodeficiency 11 555. 19 12). There is co-infection with monoclonal Epstei n-Ba rr virus (EBV) 1372, 1555, 19121 . PEL has been repor ted in recip ients of solid org an transp lant s 1606, 1066, 13491. The disease also occurs in the absen ce of immunod eficienc y, usually

_ ....

Fig. 10.120 Prirnafy e!Iusion ~ (PEl). PBnI b::I CfDotJ1.There is rra1led.......' 01109••• ptri'e1: Iu::teoIi and a pIasirac:ybd appear;n::e in lie cytlpIaslIl

W'9'JIstarl. patients have pre-existent or develop Ka-

967813

Body cavity based lymphoma.

.A

Sites of involvement The mo st common sites are the pleural. pe ric ardtal and peri toneal cav ities. Typ ically only one body cav ity is involved {169.556, 16651. Extracavitarv tumours with morphologic and phenotypic cha rac teristics simila r to PEL occur in extranod al sites inclu ding the gastrointestinal tract. skin. lung and CNS. or may involve lymph nodes 1377, 487. 556}, Clinic al features Patients typi cally present with effusions in the abse nc e of lymphad enopathy or organomega ly. App roximately half of the

pest sarcoma 1581. Occasional cases are associated with multicentric Castleman disease 121881. PEL cases should be distinguished from rare cases of HHV8negative effusion based lymphoma morphologically similar to PEL that have been described in ascites from patients with liver disease 11Q01, 1604. 18621: and the EBV associated HHV8-negative large B-cell lymp homas also occurring with ch ronic sup purative inflammation , such as pyo thorax associa ted lymphoma 163, 47 11.

Fig. '0.'" PmIafy eIlusion ~ (PEl.). A SokIlissue mass tomI'Ie ITIllliasIn.rn of an HIV+ patIenl WI\h PEl presenIing WI\h pINal elIusicln$. The 03Is<We Iar9t n WI\h eosiIlOphIcIIIICfOflUdeoI and abundanl. cytoplasm. Mq ha\oe an anapIaslie or pIasmacybd appeatlI"It8. B ~ PEL asa INl$$ in lht Ilwgtbowel of 8fI HIV+ palJlri. The ru:Iei _ sml'jy positiYe lor IaIenlI*f\l8 Iltl1d1cn 'IIIilh nbocty m0RF13l..NA-1 f1.ANA).

'*"*.0.. ...

260

Mature B-cell neoplasms

presenIilg""""

Morphology . In cytocentrifuge preparations, the ce lls exhibit a range of ap pea rances, from large immunoblastic or plasmab lastic cells to cells with more anaplastic morphology. Nuclei are large, rou nd to more irrequtar in shape, with promi nen t nu c leol i. The cytoplasm can be abundant and is deeply basophilic with vacuoles in occasional cells. A pe rinuclear hoI consistent with plasmacytoid differentiation may be

seen. Some cells resemble Reed-Sternberg cells. The cells often appear more uniform in histolog ical sec tions tha n in cvtoeoln

preparations 158. 556.15551.

inmJnopheootype lymphoma cells usually express CD 45 . but lack pan-Been markers such as CD 19, CD2Q and C079a 11167. 15551.

Surface and cytoplasmic irTllTMJnogtobutin is absent. Usually, BCl6 is absent. Activaton and plasma cell-related markers and a variety 01 non lineage-associated

antige ns such as HLA-DR, CD30, CD38. Vs38c, C0 138 and EMA are onen demonstrable. "Phe cell s usually lac k l IN K-c eil antigens . although abe rrant ex pression of T-cell markers may occur 1169. 254. 19 10 1. The ab errant phe notype frequently makes it difficult to assign a lineage with immunophenotypi ng. The nuclei of the neoplastic cells are positive for the HHVB-associaled latent protein lANA (ORF 73) 16281. This is very useful in establish ing a diagnosis. Despite the usual presence of EBV w ith EBER in situ hybridization. EBV LMPt is absentl58. 454. 963 . 21881. Solid tumours rep rese nting the extracavitary variant of PEL have a phenotype similar to PEL but express B-c e lt associated ant igens and immunoglobulins slightly more often than cases 01 PEL 13771. Gooetics Immunoglobulin genes are cl ona lly rearranged and hypermutated 11 4 19. 23531. Some cases also have rearrangement of

f- c eu rec eptor genes (so-called genotypic infidel ity) 1956. 19101. Rare cases di ag nosed as T·PEl have been reported {487. 1263 1. No rec urrent chromosomal abnormali ties have been identified. Compa rative genomic ana lysis has revealed gains in c hromosomes 12 and X 115371HHV8 viral genomes are present in all cases. Gene expression profiling of AIDSrelated PEL shows a d istinct prof ile with features of both plasma c ells and EBVtransformed Iymphoblastoid cell lines 11 1591. Postulated normal counterpart Post-qermoat centre Been. Prognosis and predictive factors The clinical outlook is extremely unfavourable. and median survival is less than six months. Rare cases have responoec to chemotherapy and/or immune modulation 17931.

Primary effusion lymphoma

261

Burkitt lymphoma

Definition Burkrtt lymphoma (BLl is a Ekeillymphoma with an extremely short doubling time that often presents in extrenodet sites or as an acute leukaemia. It is composed 01 monomorphic medium-sized transformed cells. Translocation involving MYC is highly characteristic bu t 001 specrtc. N o single parameter (such as morphology, genetic analysis or immunophenotyping) can be used as the gold standard for the

diagnosis of BL but a combination 01 several di agnostic techniques is necessary

ICD-Ocode Burkitt lymphoma. NOS

9687/3

Epidemiology Three cli nical variants of Burkin lymphoma are rec ogn ized , each mani festing d ifferences in cli nic al presentation, morphology and biology.

Endemic BL: This varian t occurs in equatorial Afr ica , rep resenting the most common c hild hood mal ign anc y in this area with an inci dence peak at a 10 7 year s and a male.female rat io of 2: 11301, 24471. BL is also endemic in Papua. New Guinea. In endemi c region s there is a co rrelation between the geographical occ urrence and some climati c fact or s (rainf all, altitude. etc.) which correspond to the geog raph ical dis tribu tion of end emi c ma laria 1301 , 656 ,2447 1. Sporadic BL: This variant is seen throughout the world , mainly in ch ild ren and young adu lts 1301,1 364,24471, The inc ide nce is low, representing only 1- 2% of all lymp homas in Western Europe and in the USA. BL acc ounts for 30 -50% of all ch ildhood lymphom as. The med ian age of the adul t pa tients is 30 years 1898 1. The mare.temaie ratio is 2 or 3: 1, and in ch ild ren it is even mo re common among males 12301. In some parts of the world, for example, in South America and Nort h Africa, both true sporad ic and endemic variants are seen.

262

Mature Been neoplasms

L Leoncini M. Rap h a~1 H , Stein NL Harris E.S. Jaffe P. M. Kluin

tmmunoaeticiencv-s ssoos tea BL : This vari ant is pr imar ily seen in association with the human imm unodeficiency virus (HIV) infection. often occurring as the initial manifest ation of the ac qui red immunodefici ency syndrome (AIDS) 118181. Etiology In endemic BL, the EBV genome is present in the majority of the neoplastic cells in all patients 12161, 24471 and there is strong e pidemiological link Wi th hoIoendemic malaria 15281. Recen t data provide insights into the emerging concepts of polymicrobial disease pathogeneSiS 118551. In pa rticular, the potential mechanisms, by which Plasmodium talciparum infections cooro impact on immunity and viral persistence. include the exhaustion of Epstein-Barr virus (EBV)-specific t-een resp onse and To ll-like rec eptor (TLR) 9mediated react ivation ottarenuv intec ted memo ry B cells 1203. 18551. This is in line with evi dence that EBV-po sitive tumours may de rive fro m memo ry B cells 11 80. 2232). However. epi demiolo gical studies suggest that malar ia and EBV alone cannot ac co unt for the d istribution of endem ic Bl in high risk reg ions (1807, 229 11. Arbov iruses and plan t tumour promoters are othe r possible local co tacto rs that cou ld exp lain suc h c harac teristics

Fig. 10.121 EI'Idemic Burkitt lymphoma, This Atncan patient presented witha Iwgejaw tul11Ol.l'.

122911. EBV may be detected in approx imately 30% of sporadic BL cases, howev er, a low sccio-economio status and early EBV infec tion are asso ciated with a high er p revalence of EBV-positive sporadi c BL In imm unod efic ie nc y-assoc iated c ases, EBV is identified in onl y 25-40% o f the c ases 18 77, 18181_BL is mo re co mmon in HIV than in other forms 01 imm unosup pression and BL appears early in the prog ressio n of H IV infection when CD4 . t-een counts are still high 11 301 1. This sug gests that immunos uppression per 58 d oes not exp lain the incre ased risk of BL A potential mechanistic link between ende mic and HIV-assoc iated BL lies in the polyclonat Been activation that occurs afte r mal aria and HIV infection. However, the oncogenic role of HIV itself cannot be

Fig. 10.122 Sporadic Burkitt lymphoma with lJj lateral ovarian tul1lOl.lf'S

Fig. 10.123 BlIaleral breasl fflolvemenl may be .. presentrng manrIesIaIion dln1g ~. n Il'blrlr. BL eels haYe proladIn receptOr$

rtg-10.124 &ni1l1ymp/lOma. loucl1 impmt. A The deeply basophilic cytoplasm can be appreciated as well as abI.n1riipd vacuoles II the C)1OPIaSm. B The cells II It'is case are relatively S1rri1ar kI{Al.e:«::ept !hey' havemore ~nudei.

nJed out 11781. In conclusion, one of the paradoxes in expla ining the etiology of BL is the occurrence of this tumour in many Oi!1erent populations and settmqs . II is posstse that drsuoct pathogenetic mecheusms exist among BL subtypes 11791. On tOO other hand . different and mult iple environmental exposures may converge II a corrvnon pathogenetic mechanism flVOMng the M YC gene at chromosome 8Q24 1201 41 .

Sites of involvement ExtrallOdal sites are most often involved 'Mth some variation according to the clinical variants. However. in all three clinical variants. patients are at risk tor cent ral nervous system involvemen t. In endemic BL.the jaws and other facial bones (orbi t) are the site ot presentation in about 50% 01 the cases (301, 24471 The distal ileum, caecum and/or omen tum, gonads, kidneys. lonq bones, thyroid, salivary glands and breasts may also be affected either w,th or without jaw involvement (302, 24471. Although loc alization may sometmes be found in the bone marrow (BM), manifestation of leukaemia in the peri. pheral blood (PB) is not present 1302, 24471. ln sporadic BL. jaw tumours are very rare 11612). The majority of the cases presents with abdominal masses 11 3641. The ileo-caecal region rep resents the most frequent site of involvement. SimiIar~ 10endemic BL, ovaries . kidneys and breasts are also frequently involved. Breast involvement totten bilateral and massive) has been associated with onset during puberty, pregnancy or lactation. Retroperitoneal masses may result in spinal CCH'd compression Wi th paraplegia, l'yfTlph node presentation is seen more ccmrnonly in adu lts than in chi ldren . WaIdeyet mg and mediastinal involvement ire rare. In invnunodelicieocy·associated

BL. noda l localization is frequent as well as 8M involvement 1877, 18 181. Clinical features Clinical presentation varies acCOfding to the epidemiologic subtype and the site of involveme nt. Patients often present With bulky c nsease.ano a high tumour burden due to the short doubling time of the tumou r. In the typical paediatric cases. the parents of affected children will report symptoms for only a few weeks. Paediatric 8 L palients are staged according 10 the system of Murphy el al.I15511. 70% of patients present at advanced stages (III and IV). Upon institutio n of therap y a tumour lysis syndrome can occu r due to rapid tumour c ell death /2381 1

Burl
--

The prototype of BL is observed in endemic BL and in a high percentage of sooadc BL cases . particularly in childr6l1 1898,24471 . The tumour cells of BL are medium-sized cells (nuclei similar Of smaller to those of histiocytes) and show a diffuse monotonous pattern of growth. Some tumours surround and invade otherwise uninvolved lymph nodes, The celts appear to be coh esive but sometimes exh ibit squa red-off borders of retrac ted cytoplasm. The nuclei are round with finely clumped and dispersed chromatin. with multiple basophi lic mecumsized , paracent rally situated nucleoli. The cytoplasm is deeply basophi lic and usually contains lipid vacuoles. These cellular details are better perce ived in imprints. The tumour has an extremely high proliferation tract ion (many mitotic figures) as

Fig.10.125 Burkitt IympIloma statned lor Goernsa ' AI and H&E (B) has lI'liform IumolJ" eels wdtl multiple smaI ru:leoli and Ii'oeIy ~ chrornabn II theirradii ,In hs &.nIa ~ slaIned b Giemsa (C)in! H&E (D). 1lere is !1Nternodear~

Burkitt lymphoma

263

...~ Fig. 10.126 BtnJn lymphoma. Imrnunohis1odlemistry shows a strong and homogeoeous stam.ng lor KJ67/MIBl (A) and C010 (Bl. C FISHfor MYC IIarmg probes {891"1. ~ one8Iellt..., ookx:aization aI bott1 probes (ted and greerl) a"Id oneallele WIth segregatJon aI boIh probes.

well as a high fraction of epootosis. A "starry sky· pattern is usua Uy present . which is imparted by numerous ben ign macrophages that have ingested apoptote tumour cells . Some cases may have a florid granulomatous reaction that may cause difficulties in the recognition of the tumour 189161. These cases typ ically present with limited stage disease and have an especially good prognosis 11973AI· In some cases, turnour c ells exhibit eccentric basophilic cytoplasm often with a single central nucleolus. Such cases, defined as BL with plasmacytoid differentiation , can occasionally be observed in children but are more common in irrmunodeficiency states 118181. Other cases of BL may show greater nuclea r pleomorphism and the nucleoli may be more prominent and fewer in number 18981. In the past. these cases have been referred to as atypic al BL However, these morphologica l variants share a similar gene expression profile, which suppor ts the evidence that the morphological spect rum of BL is relatively wide (509. 9941, Immunophenotyp e In Burkitt lymphoma. inclUding cases presenting with leukaemia. the tumou r cells express moderate to strong levels of membrane IgM with ligh t cha in restric tion and Bcen-assoc tateo antigens (e.g. CD19, C020, C022) , COlO, BCL6. CD38, and C043 ]15t . 898, 244n The neoplastic cells are usually negative or only weak ly positive (in -20% of the cases) for BCL2 and are uniformly Td T negative 1264. 890, 1104. 1307. 14381. Nearly too% of the cells are positive tor Ki67 18981. There are very few admixed t-eens. Cases with a more atypical phenotype such as BCL2-positlve, as seen in some adu lt patien ts. require s that the case otherwise has all the characteristic features of Burkitt lymphoma , incl udi ng

con

264

Mature B-eell neoplasms

IG:M YC trans locat ion without BCL2 or BCL6translocation.

Genetics Antigen receptor genes The tumour cells show clonal IG rearrangements with somatic hypermutation.

Cytogenetic abnormal/bas and oncogenes Most of the cases have MYCtranslocation at band 8q24 10 the IG heavy chain region , 14q32 or, less commonly, at the lambda. 22q1 1or kappa, 2p12 light chain loc i. Up to 10% of the cases may lack a demonstra ble MYC translocation by FISH, the explanation for which is uncertain 1890, 994 1. These cases may have MYC translocation demonstrated using other techni ques and must be otherwise completely typical to make a diag nosis of BL. Furthermore , M YC translocations are not specific for BL Most MYC/IG breakpoin ts in endemic BL originate from abe rrant somatic hypermutatlon. In sporadic cases. on the other hand , the transloc ation mostly involves the IG switch regions of the IgH locus at 14q32 1860, 20141. These d ifferences in MYC breakp oint may well be acc ounted for by the different maturational stage of the of EBV positive (mainly endemic) and EBV·negative (mainly spo radic) BL \1801. Mutations in M YC may enhance its tumourigenicity and some of these mutations may lead to decreased exp ression of BIM whic h binds and inactivates BCL2 1917. 24681. Other genetic and epigenetic alterations occurring in a subset of BL, involving p16""".... TP53, p73, BAX, pl3O!RB2and BCL6, may promole cell growth and/or inhibit apoptoee 1179, 5 17, 1158, 1314, 19251· Gene profiling studies have demonstrated a consistent gene expression signature tor BL, which is clearly distinct from that of DLBCL 1509. 994 1. Howeve r, intermediate cases were also found 1509. 994 1.

Postulated normaJ cou nterpart Germinal centre or post germinal centre BceUs. Prognosis and pred ictive factors In endemic and sporadic BL, the tumour is high ly aggressive but potentially curable . Staging is performed according to the scheme proposed by Murphy and Hustu (155 11 and modified by Magratt! 113631. Staging is largely related to til" mour burden , and identifies patients witt! lirmted stage disease and patients with extensive intraabdominal or intrathoracic tumour 123811. Bone marrow and central nervous system involvement. unresecteo tumour> 10 em in diameter, and a high LOH serum level are recog nized as poor prognostic factors, particularly in sporadic BL. Intensive combination chemotherapy regimens result in cure rates of up to 90% in pa tients with low stage disease 117081 and 60-80% in patients with advanc ed stage disease 11363, 20601 , The results are better in children than in adults 1591f. However, even patien ts with advanc ed stage disease, including BM and central nervous system involvement, may be cured with a high dose treatment program 13101 With high intensity treatment, most pa tients presenting with leukaemia also have a very good prognosis with 80-90% survival 12060, 238 11. Relapse. if it occu rs, is usually seen within the firsl year arter diagnosis 11363. 23811 , Recently it has been reported that rrtuxirnab may be a useful additional therapeutic agent 1531 . 22291 . Although BL is curable. many patients still die of the disease mainly in Africa 18921.

B-celllymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma Definition Bcetl lymphomas with features intermeoete between dutuse large B-cell lymphoma (DlBCl) and Burkitt lymphoma (BLl are aggressive lymp homa s that have

morphological and genetic features of both DLBCl and Bl, but for b iolog ical and clinical reasons should not be included in mese catego ries, Some of these cases were previously c lassi fied as Burkitt-like

lymphoma (BlL). The majority01 the cases in this category have morpholog ical features that are orermeotete between DLBCL and BL, with some cells that are smaller than typ-

ical DlBCl. resembling BL, and some cells that are larger than typical BL. resembling DlBCL. as well as a high prolif-

eraoon fraction. starry-sky pattern , and an

PM. Klu in

NL Harris H . Stein

L. Leoncmi

immunophenotype consistent with BL. Some cases may be morphologically

EpidemkJk>gy These lymphomas are relatively infrequent

more typical of BL but have an atypical immunophenotype or genetic features that preclude a diagnosis 01 BL The d iagnosis 01 this type of unctassifiable Bcentvrnoboma category should not be made in cases of morphologically typical DLBCL that have a MYC rearra ngement , or in otherwi se ty pica l BL in w hic h a MYC rearrange me nt ca nnot be demonstrated Some transformed follic ular lymphomas may fall into this category. This is a r eterogeneous category that is not consroered a distinct disease entity. bu t is use ful in allowing the c lassification of cases not meeting c riteria lor classical BL or DLBCL

and mainly diagnosed in adults.

ico-o code

-..,.""...

6L

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V.. No

Sometimes

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cormcn

V.. No

Sometimes Sometimes

Sometimes Sometimes

.,,,,,

No

8CL2expr..elon ~eg8tiVfl / weak

S".. Gtnetic Into,., WYC rearrallg8ll1el1l

YIS'

""Ye"o

V..

"'"1G..uvc-

No No

8CUbut no UYC reanangement 8Ct6but no UYC~ """" to!'

--

~ _ ooo

"""""""

No

No

V..

Prdiltrltion (KI61/MIB1) >00% and tIor'roopene
C

Iflte'

"""""" seeeeres

Only smaIo'mediUm-siZe cells

No No

.... Yo.

No

N,,,

--........ --...... , -.... ........ """"""

Sites of involvement More than half 01 the patients present with widespread. etten extranodal disease. Unlike BL , the re is no prefe rential localization in the ileocecal reg ion or jaws. The bone marrow (BM) and perip heral b lood (PB) may be involved as well. Clinical leatures Patients present with lymphadenopathy or mass lesions in extranodal sites. Some patients have a leukaemic presentation.

-ogy

968013

r.10.11 Iobpl'OClklgiCo. ~ and genetic Ieabns tlat may beusefIA .,
M. Rapha~1 E. Campo E.$. Jalfe

.... ....

""""""

"

• ~ 5'4 r:J 0ChlItwise dassicaI BL 'Wl a clel«table ILYC~ {891A. 994} I(;..,VYC juxtIposilioo of UYCIo oneof lhe IG loa: lGH@atl4q32./GL@al22q 11 or IGKO al 2p12. NoI'I JG..,\IYC ~ 0Dl\taIn a MYC rearratl{IlIIll but no juxtaplMon 10 oneof!hlllG loci. 'DO!Jlle hi! ~$afllain a AIYCIllq24 brlIakpoint lflcombination wiltl a BCt.2Il8q21 (by Iar most \'tQuenIl and/or BCL6J3q27 breakpoint. The partner of BCL2I18q21 breakpointmostty i5 ltle lGHiotus a114q32. nllQlllll cases a 1(8.14 t8) is presefl1 (132OA). ...SImplt karyotype noor ontv few cy10genllic or (array) CGH abnormalibe5O\t1er!han the MYe rearral'lgeme'!Jl. For.-ray CGHa lymphoma WIth 6 or ITlOfI abnormalities has beefl asslgned as "MYC-eomp~~-l994l.

These lymphomas are typically composed of a dilfuse proliferation of medium- to large-sized transformed cells with few adrTixed smalilymphocyles and 00 stranal reaction of fibrosis . Starry sky macrophages are typically present, as well as many mitotic ligures and prominent apootests. causing a resemblance to BL The cellular morphology is variable. In some cases, the cells resemble those ot BL, but with more varia tion in nuclear size and contour than is considered acceptable lor BL: some cases are co nsi stent with BL mo rpholog ica lly but have an atypical immunop henoty pe and/or ge netic features; othe r cases with an imm unophenotype that is consistent with BL have a variable nuclear size that is intermediate between BL and DLBCL. otten with either irregular nuclear contours or relatively large nucleoli. In rare cases the nuclei are relatively small and the chromatin is finely granular. resembling lymphoblastic lymphoma Some of these tatter cases have been classified as 'taestc" or blastoo-.lfl"lll.X'K)histochemistry lor TdT is required to exclude lymphoblastic lymphoma. Cases 01 morphologically Iypical DLBCL With a very high proliferation index should not be included in this category /44 11 . Irrmunophenotype These lymphomas express B-cell markers. CD19, CD20, CD22 and CD79a and

B-cell lymphoma , unclass ifiable . with features intermediate between DLBCL and Burkitt lymphoma

265

•

a.:

Fi~ 10.121 TI'nle ~ • •8.14~ .. T~ BL tJ)ll'I(X)SllCI 01 fI'IlidI.m-sizl. IloulolllOUS eels wGI ftUId rlld8i.1TUIIPt ru:leoIi. ;n:l a rTD:letaIe an'lOI.Ill 01 ~ wIid1 1m a ~ awe
typically 51g. but so-called double hit cases may be 51g negative. In general . cases will be placed in this category when the immunophenolype is suggestive of BL

(COlO. , BCLS+ . BCl2· and IRF4iMUM1or very weakly positive). Cases that morphologically resemble BL may be p laced in this category when BCL2 is moderately to strong ly positive. BCl2 positivity in a case that otherwise might be classified as Bl should suggest the possib ility 01 a double hit lymphoma with both MYC and BCL2lranslocations. The Ki67 lab eling index is usually high. again raising the d ifferential diagnosis 01 Bl, bu t in reported cases it varies between 50 and 100 % \26 4, 890, 1438 1. Rare tumours with a MYCwith or without BCL2rearrangement are TdT positive; classification of these cas es is con trove rsial , and the diagnosis of lymphob lastic lymphoma may be preferre d 11 561 , 2 19 11 .The use fulness of other markers rema ins to be estab lished 1922, 1858 ,2 179], Geneti cs IG genes are ctonauy rearranged. Ap proximately 35-50% of the cases have 8q2 4/MYC transiocatioos 1890. 994, 14381. However. whereas M YC in 8 L is juxtaposed to the one of the immunoglobulin genes (IG- MYC). many of these cases have other transiccauons (non IG-MYC). Approximately 15% of the cases have a BCL2 translocation, sometimes together with a MYCtranslocation ("double hitlymphoma"). Cases previously classified as Burkitt-like lymphoma may have a higher frequency 01 MYC and BCL2 trensrocatons as well as double hits 11104, 1359 1. Less frequently. BCL6 transiocanons are seen , sometimes together with MYC andJor BCL2. The relative incidence of double and triple hit lymphomas increases w ith age. 266

Mature 8-cell neoplasms

up to more than 30 % in elderly patients (http JIcgafJ.nci.ntl_gov~llel

man). Cytogenetic analysis of both the non-IG-MYC and double hit cases often shows a complex karyotype with multiple abnormalities . in contrast to cl assic al Burkitt lymphoma /12591 . Dependent on the algorithm used, gene profiling stud ies have shown that some double-hit cases have a profile intermed iate between BL and DLBCl\9941 or more similar to BL \509}. Cases of otherwise typical DLBCl with a MYC translocation should no t be placed in this cateqo rv Conversely. Iym· phomas with a IG-MYC rearrangement as the only ab nor mal ity likely rep resent Bl even if they are morphologically atypical.

Postu lated normal counterpart B-cell . most cases related to a germinal centre slage 01 differentiation.

Prognosis and peedlceve factors These are aggressive lymphomas, for which the most appropriate therapeutic approach is not established . The double hit lymphomas show frequent involvement of the 8M . PB and CNS; most cases are resistant to current therapies. which seems to be independent of the complexity 01 the other cytogenetic abnormaJ. ities 1501 , 994 ,1259, 14381.

Fig.10.128 Malepabent, 61 ~. WiCh a rapdy tJOlWlgCllltW3noda1lTli1SS. "DouI*t ht'~ . boIh8q24.urc lnl1 Bq21/BC1.2 breiIkp:lfIls A SlaJTysky paIlem. B ~ ~I showI'lg a IT"ixtIn d~ .. dei will Mtle pIto,o!i....l llU pIOTftnl ruiIoI, absence d ~ cM:maIrlln:l tTWlyrTltJlic ipes. C Strtrg 8Q2 staII'lI'9 is vety In.ISl.I3I b BL 0 Ki67 stanng Will ~ IU elseWtln flete M:!te doseto100'.4 poSIM __

B-cell lymphcma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma

E.S. Jaffe H. Stein S.H . Swerdlow E. Campo SA Pileri N L. Harris

DeIini1icn A B lineage lymphoma that demonstrate s

Imm unophenotype The lymphoma cells exhibit an immunop heno type With transitional features between CHL and PMBL (758 . 2265} . Neopla stic cells typically express CD45. In contrast to CHl . the B-eell program is often preserved. but is aberrantly expressed in concert with Hodgkin ma rkers. such as CD30 and CD 15. CD 20 and CD79a are frequently positive, and may be strongly expresse d on the majorily of the tumour c ells. C030 is pos itive and C015 is oosrtive in the majority of cas es. Surface or c ytop lasmic immunoglob ulin (Ig) is absent. The transcription factors PAX5. QCT-2 and BOB.1 are usually expressed, BCl6 is variably positive but C010 is generaHy negative. ALK is consistently negative. The background lymphocytes are predominantly C03+ . CD4+ . as seen in CHL In cases Ihat morphologically resemble oodular sclerosis classical Hodgkin rym. phooIa: (NSCHL). lSiform streng expression 01 C020 and other Be en markers and absence of CO 15 would favour the diagnosis of grey zone lymphoma. In cases Ihat resemble PMBL. absence of C020. expression 01 CD 15 or p resence of EBV would favour this diagnos is as welt. MAL. a marker associ ated with PMBL, is exp ressed in at least a subset of the cases presenting with med iastinal disea se 1472. 2265). Suppo rting a relationship to PMBl . nuclear c-REU p65 p rotein has been id entified in those cases tested [758. 1857}. In one series. p53 was expressed in Ihe

overlapping clinical, morphological and/or IfMl unophenolypic features , between

classical Hodgkin lymphoma (CHL) and onu se large B-cell lym phoma (DLBCL) ,

especially primarymediastinal large B-cell Iyrrt:lhoma (PMBL), While these lymphomas aremost commonly associated with mediastinal disease, similar cas es have been

respiratory distress. Another phenomenon which mayor may not be related to -grey zone lymphomas· is the occurrence of CHL and PMBl as composite lymphoma 1815}. or sequentially. at ornerent points in time 117271. While either lymphoma subtype may present first it is somewhat more common for the initial presentation to b e CHL with relap se as PMBL. often within the first few years 12487f.

Of

reported in pe ripheral lym ph nod e g roups

as a primary site. IC().()

code

959613

Synonyms Grey zone lymphoma 11895, 22651 , large Been lymphom a with Hodg kin features

175B1. Hodgkin-like anaplastic large cell ~ 12499. 25011.

EpidemoIogy These lymphomas are most common in young men, usually presenting between the ages 01 20-40 yea rs of age 1758. 22651. However, they have been reported tI Individuals as youn g as 13 yea rs of age. and in older adults beyond the age of 70 Most cases have b een reporte d

trem Western countries like CHL, they are less common in Black s and Asians. Etiology The etiology is unknown. Eps tein-Ba rr war sequences have been ide ntified in 20% or fewer cases.

Morpho log y The lymp homa is typic ally composed of a confluent, sheet-like growth of pleomorphic tumour cells in a diffusely fibrotic stroma 1758.22651. Focal fibrous bands may be seen in some cases . The cells are larger and more p leomorphic than in the typical case of PMBL. although some ceoucotastlike cells may be present. Pleomorphic cells resembling lacunar cells and Hoclgkin cells comprise the majOl'ityof the infiltrate . A characterisnc feature is the broad spectrum of cytological appearances with different areas of the lumour Showing variations in cytological appe arance. i.e. some areas may mo re closely resem ble CHL an d others ap pear mo re like diffuse larg e B-eeil lymp homa. There is usually a sparse inflamma tory infiltrate. although scattered eosinop hils. lymphoc ytes an d histocyt es may be p resent. Necrosis is frequ ent. but unlike CHL, the necrotic areas do not c ontain neutrop hilic infiltrates.

Sites 01 Involvement The most common p resentation is with a large anterior me diastinal mass. with or W1lhout involvement 01 supraclavicular trTllh nodes 1758. 22651. Other peripheral ~ node groups are less commonly 1'lYoIved. Theremay be spread to lung by Orect extension. as well as spread to liver. spleen and bone marrow. Non-lymphoid l)'Qans are rarely involved. in cont rast to

•

PMBl. CIncaI features A. large mediastinal mass may be associ-

ated with a superior vena caval synd rome.

••

Fig. 10.129 B-ceII ~ WlIh features I1lermediate be'- dI1Iuse large B-ce. ~ and dassicaI HodglIIrl lymphoma. Mediasbnalmass. A Lyrl'4Ihoma is composed of sheets 01 cells WJIh dearcytoplasm aoofine sderosrs. The appearance resembles that of primary rnediastinallarge B-ceRIyrT'4)homa (PMBL). BTurrour cellswere stroogIy COl 5 positiveandalso CD30positive {nol shown).

B-ce illymphoma. uncla ssifiable, with features intermedi ate between DLBCL and Hodgki n lymphoma

267

relationship between CHL and PMBL has been shown by gene expression p rofiling studies. but specific g enomic studies of "grey zone" or transitional lymphomas have not been performed 11 870.1 9441. Postulated normaJ coun terpart A thymic B-cell is the likely lor those cases arising in the mediastinum 122651. For cases ariSing in the pe ripheral lymph nodes. an alternative Be en origin is proposed.

fig . 10.130 Ik::eIIynlJ/lOma WIltIleallns inIemIe
majority of cases 17581. In instances of composi1e Of metachronous lymphomas. the venous components exhibit a phenotype charac teristic of that entity. either CHL Of PMBL Genetics Only a few cases of me tachronous CHL and PMBL have been studied at the genetic level; a clonal relationship has

268

Mature

a-cen neoplasms

been shown between the two components 122651. Specific genetic changes have not been associated with trenstormation of the lymphoma Of its components to either CHL or PMBL Because the mo rphological and phenotypic changes are reversible, it is likely that epigenetic rathe r than genetic alterations are responsible for the change in morphology an d immunophenotype 19331. A close

Prognosis and predictive factors These lymphomas generally have a more aggressive clinical course and poorer outcome than either CHL or PMBL There is no consensus on the optimum treatment, although in some series therapy lor an aggressive large B-celllymphoma has been proposed as effective 12265. 25011 Others have proposed use of a Hodgkin type regimen 13491. Among CHL patients. strong expression of CD20. as seen in this transitional lymphoma, has been proposed as a poor prognostic indicator in Hodgkin lymphoma trials 117741. However. other studies have reached an opposite conclusion 122751.

CHAPTER 11 Mature T· and NK-cell Neoplasms

T-<:eII prolymphocytic leukaemia T-eelliarge granular lymphocytic leukaemia Chronic Iymphoproliferative disorders of NK ce lls

AggressiveNK cell ktukaemla EBV-positiYe Pcell Iymphoproliferative disofders of childhood

Adult T-eeilleukaemialtymphoma

Extranodal NKIT cell lymphoma, nasal type Enteropathy-associated T-<:ell lymphoma

Hepatosplenic T-eelllymphoma Subcutaneous panniculitis-like T-eell lymphoma

Mycosis fungoides Sezary syndrome Primary cutaneous CD30 positive T-eeillymphoproliferative disorders Primary cutaneous gamma-delta T-eell lymphomas Peripheral T-<:ell lymphoma , NOS

Angioimmunoblastic T-eelllymphoma Anaplastic large cell lymphoma (ALCL). ALK positive Anaplastic large cell lymphoma (ALCL). ALK negative

T-cell prolymphocytic leukaemia

D. Catovsky H.K . Muller-Hermelink E. Aalfkiaer

Definition t -een prolymphocytic leukaemia (T-PLL) is an aggressive t-een leukaemia characterized by the proliferation 01 small to medium-sized prolymphocytes with a mature post-thymic T-cell phenotype involving the peripheral blood (PB), bone marrow (8M), lymph nodes. liver, spleen

and skin . ICD-Ocode

9834/3

Synonym t-een chronic lymphocytic leukaemia was used historically as a synonym to- some small cell variants

Epidemiology T-PLL is rare. representing approximately 2% 01 cases of mature lymphocytic leukaermas in adul ts over (he age of 30 I 1424 J; medi an age is 6S yea rs (range,

30-94 years). Sites of involvement Leukaemic t -eens are found in the PB. 8M, lym ph nod es. spleen. liver and sometimes skin.

Clinical features Most patients pr esent with hep atospl enomegaly and genera lized lymphadenopathy. Skin infiltration is seen in 20% 01pa tients, and serou s effusion s, c hiefly pleural , in a m inority ( 14241. Ana emi a an d thromboc ytopenia are co mmon and the lymphoc yte count is usually >100x 109/L and > 200x 109/L in half of the patients. Serum immunoglobulins are normal. Serology for HTLV-1 is negative.

coa. a

outlin e is very irregular and can even be cerebriform 117131. Irrespective 01 the nuclear features. a common morphological feature is the presence of cytoplasmic protrusions or b le bs. The 8M is diffusely mtnuateo. but the di agnosis is dllflcult to make by 8 M histology alone.

feature almost unique to T-PLL; 15% are C04-. C08+ 114241. The overexpression 01 the oncogene TCL' can be demonstrated by immunohistochemistry 19211 and this method is useful for detecting residual T-PLL on 8M sections after therapy.

Other tissues Cutaneous involvement consists of pe rivascular or more dilfuse dermal infiltrates without epi de rmotropism 11373, 1424 1. The spleen histology shows d ense red pu lp infiltration. whic h invades the spleen c apsu le, b lood vess els a nd atrophied white pulp 11663 1. In lymph nodes, the involvement is d iffuse and tend s to predominate in the oaracortrcat areas , sometimes with sparing of tourcres Prom inent high-endothelial venues may be numerous and are often infiltrated by neop lastic c ells.

Ge netics Antigen receptor genes t-een receptor (TCR) genes , TRB@ and TRG@, are clenatly rearra nged.

Cytoc hemistry T orotvmohocyt es stain stron gly with (I -na phthyl ac etate este rase and acid p hos phatase with do t-like stainin g in the Golgi region 114251. f--iov.Iever, cytochemistry is rarely used for routine diagnosis currently.

Cytogenetic abnormalities and oncogenes The most freq uent ch romosome aonomanty in T-PLl involves inversion 01chromosome 14 with breakpoints in the long arm at q 11 and q32 , seen in 80 % of patients. In 10% there is a rec iprocal tandem translocation t(14;14)(q11;q32) 1272, 13721. These tran slocations juxtapose the TRA@ locus w ith the oncoge nes TCL 1A and TeL 18 at 14q32 ,1 which are activa ted throug h the translocation (17181. The translocation t(X; 14)(q 28;q 11) is less common,

"'",p"o
Mature T- and NK-celt neoplasms

Immunophenoty pe

r-proiymonocvtes

are peripheral t-ceue which are TdT and CD1a negative while C02. C03 an d C07 are positive; the membr ane expression of CD3 may be weak. C052 is usually expressed at high density. and can be used as a target of ther apy 15351. In 60% of patients the cells are CD4+ . COB-, and in 25% they coexpress CD4 and

•

7

•

Fill- 11.02 T-<:eI proIymph:lcylic 1elNemia, P"" kiryotype s/'ll:MWIg ml 4q (q11;q32)

----l...

Postulated normal counterpart Unknown T-cell with a mature (pos tthymic) immunophenotype. Strong C07 and coexoresston of Co4 and COB and weak membrane C03 may suggest that T-PLL arises from a t-een at an intermediate stage of differentiation between cortical thymocytes and mature T lymphocytes.

f"i- 11.C3 T-<eI ~ IeuIo:.aemia " l~ node is ddfuseIy inIiIlrated, t:U: a IoIic:le is l.I\aIIeded. GIemsa B F'forrWlenl I'io;tI encIolheliaI verUe shorImg Iu!lloos cees in tile Unen , in I!le waI aIld the aqacent pnro1el Giemsa stall.

1QIl.

bu1 it also involves the TCAtJ locus at 14q11Wlth the MTCP7 gene. 'htlich is h0mologous to TCL I, at Xq28 120971. Both TeL I and MTCP7 have oncogenic prop etc e as both can induce a 't-een leuk aemia (CD4-IC DB+ ) in transgenic mice 1849. 23381. TCL 7 inhibits activationinduced death in the neoplastic t-eens. further contributing to the neoplastic process 15601. Abnormalities of chromosome 8, id ic (8p l 1), t(8;B)(p1 1. 12;q 12) and trisomy 8q are seen in 70-80% of cases 1171BI. Deletions at 12p 13 are also a featur e of T·Pll when studie d by FISH 19371.

Molecular and FISH studies also show deletions at 11q23 , the locus 101 the Ataxia Telangiec tasia Mutated (ATM) gene. and mutational analysis has shown missense mutations at the ATM locus in TPLL \2100 , 23441. T·PLL is not an uncommon secon dary neoplasia in patien ts with ataxia telangiectasia \2721. Abnor malities of ch romosome 6 (33%) and 17 (26%) have also been described in T-PLL using conventional karyotyping and CGH studies 1272,4831. The TP53gene (al 17p 13.1) is deleted with overexp ression of p53 protein in a number of c ases 12731.

Progoosis and predictive factors The course of the disease is aggressive with a median survival of usually less than one year. Cases with a more chronic course have also been reported \7541. Such cases may show an accelerated ccese after 2-3 years. The best responses have been reported with the monoclonal antibody alemtuzumab (anh-Co52) 1536, 11301. Both autologous and allogenei c stern cell transplants lor patients who achieve remission are being explored. in conjunction with immunotherapy. Recent studies have identified both high expression of Tell and AKT as poor prognostic markers 19231.

T-eeft prolymphocytlC leukaemia

271

_

.

T-cell large granular lymphocytic leukaemia

W C, Chan K. Fou car W G. Morice

Definition r-cea large granular lymPhocytIC leukaemia (T-lGll is a heterogeneous disorde r char-

of autoanti bodies. circ ulating immune complexes and hypergarrmaglobufinemia are also common 1390, 1247f. Cases that are CD4+ have been reported to be frequently (30%) associated with an underlying mali gn ancy 113031. Morbidity and mortality are mostly due to the accompanying cytoperaas or other accom panying diseases.

acterized by a persisten t (>6 months) increase in the number 01 per ipheral b lood (PB) large granular lymphocytes (LGl), usually between 2-20x 1()8i\... without a clearly iden tified cause.

ICD-O cod e

as lymphocyte reconstitution occurs 1732A, 14 14AI . Clona l populations of T-l Gl are also otten seen in association with low grade Bccell malignancies, inclu ding hairy cell leukaemia and chronic lym phocytic leukaemia. These are usually stabl e and d o not p rogress to clinically signilicant disease. They appear to represent a type of host respon se 182, 14031.

9831/3

Sites of invotvement Ep;demiology T·l GL leukaemia rep resents 2-3% of cases of mature lymphocytic leukaemias. There is an approxima tely equal ma le:lemale ratio with no clearly de fined age peak . The disease is rare «3%) before 25 years and the majority of cases (73%) occur in the 45-75 years ag e group _

Etiology The und erlying palho p hysiologic mechanisms for T-LGL leukaemi a are not well und erstood. This disorder is fairly unique in that the cl onal T-LGL cells retain many phenotypi c and functi ona l pr op ertie s of normal cytotoxic effector r-ceus 12201, One theory po stulates that T-LGL leukaemia arises in a selt ing of sustained immune stimulation. The frequent assoc iation of T-LGL leukaem ia with autoimmune disord ers sup ports this hypothesis 1220, 2428 1. Absenc e of homeostat ic apo plos is is also a feature of the T-LGL , as these cel ls exp ress high levels of FAS and FASL , lead ing investiga tors to pr opose ac tivation of pr o-survival pa thway s in T-LGL whic h p revent s FAS signaling [648, 1954 1. FASL levels are ele vated in sera of many patien ts, which may be impo rtant in the pathogenesis of neutropen ia 113231. Clonal expa nsions of T-LGl can be observed following allogeneic bo ne ma rrow (BM ) transplantation, usually reflec ting a restricted t-een reper toire. However, rare cases of T-l Gl leukaemia have also been observed as a torm 01 post-transplant Iymphoproliferative disorder 1103, 15731. A pitfall in diagnosis is the frequent d evelopmen t of oligoclonal T-cell populations following anooeneic BM transplantation 272

Mature T- and NK-cell neoplasms

T-lGl leukaemia involves the PB, BM, liver and spleen. lymphadenopathy is very rare . Clinical features Most cases have an indolent clinical cou rse 1390, 563, 1247, 16831. Severe neu tropenia with or withou t anaemia is frequent while thrombocytopenia is not; lymphoc ytosis is usu ally between 2-20x 1Q91l. Severe anaemia due to red cell aplasia has be en repo rted in assoc iation with T-l Glleukaemia 112471. Mod erate splenomegaly is the main physical finding, Rheumatoid arthritis, the presence

D. Catovskv

" "_

The predominant lymphocytes in PB and 8M films are lGL with moderate to abundant cytoplasm and fine or coarse azcrophi lic granules 1278, 390, 14411. The granules In the LGL often exhibit a characteristic ultras tructu ral ap pearance described as parallel tubul ar arrays 11441 1 an d contain a number of proteins that p laya role in cytolysis such as pertorin and granzyme B. There is no agreement on the level of lymphocytosis required tCJ" dia gnosis of T-LGL leukaemia 119921, but a l Gl count of >2x 1Q91l is frequently associated with a clon al proliferation. However, cases with l Gl lower than 2x10"n.

F"IQ.tt.G4 The various na phologic 'IlWla"IIs of LGl. in !he perVoeraI bk:lod (Wriltlfs slain).

-• . f.. l1,D5 Bone marrow lindn;Js in H.Gl.Ieukaerria. A ~ceIs ridlr.rte mrslibaly. as dernalstTaIed by 5lai1b TlA1. B,C ReadiYe ~ iJW'e9iItes.l~ lDUesin... bone marrow irnrIuIostainec wrth iII'l..cD2O (S) Md ri-C03 ie). !k:eIs in ltle nodule /If1I8O'Ined wrth C03 poS/lro'e T<eIs lNl predominate iIllhe~.

but which mee t all other appropriate crtene. are consistent with this dia gnosis. Despite the cvtopenlas. the 8M is norrrocellular or twoocenurar in about 50% of cases; in the remainder, the 8 M is typically slightly hypercellular 1152 1, 1662} . The granulocytic ser ies often show left s meo matu ration and mild to moderate -etccnn fibrosis is present 13901. The extent 01 8 M invo lvem ent is va riable and LGL usually comprise less than 50% of j-e cellula r e leme nts w ith inte rstitial/intrasinusoi da l infiltra tes which are d ifficu lt toidentify by mo rpho logic review 11 52 1). Non-neoplasl ic nod ular lymphoid agg regates containing many surrounded bya rim of CD4 + T-cells are also freq uently present 11662 1. Sp lenic invo lvement is characterize d b y inf iltration and exp ansco of the red pulp cords and sinuso ids by T-LGL with spari ng of the often hyperplastic white p ulp 116631.

express C08, the remainde r are C04/ COB-negative 11303. 1926, 19921. Abnormally d iminished or lost expression 01 COS and/or C07 is common in T·lGl leukaemia 11348, 15201_Co57 an d C0 16 are expressed in over 80% of the cases 11247 , 1520 1. Expression of the C0941 NKG2 and KIA families of NK-assoc iated MHC-class I recepto rs can be d etec ted in 50% or more of T-lGlleukaemias. KIA positive cas es usua lly sho w uniform expression of a sing le rsotorm and thi s finding can serve as a surroga te indicator of cronanty 11 348, 15201, The r-t.e t, express the cytotoxic effecto r proteins TIA 1, gr anzyme Band g ranzym e M. Bone marrow co re b iop sy immunohistoch emi stry using ant ibodies to th ese antig en s a nd COB can be used for c onfirmation of the diagnosis by revea ling the mainly interstitial o r intrasinusoida l T-l G l infiltrates 11519, 1521,16621.

Cytochemistry The granules are aci d phosphatase and ~ ~idase positive. However, enzyme cytochemic al stains are rarely used for rc:utine diagnosis.

Genetic s Antigen receptor genes Cases classified as T-lGlleukaemia are, as a rule, clonal. as documented by TCR gene rearrangement studies 11247f. The TRG@gene is rearrang ed in all cases regardless of the type of receptors expressed. The TRG@gene is rearranged in cas es expressing the TCfbP receptor, but the TRB@ gene may be in ge rmhne connquranon in cases expressing the TCR')'l5 receptor 123361.

a-ceus

~ RGL leukaemia is typically a disorder of mature CD3, COB and t-een receptor (TeA) o il-positive cytotoxic t-eens 1390. 16831. Uncommon va riants include C04 TCfbIl-positive cases and TCfTr,S-positive cases; approximately 60% 01 the ratter

Cytogenetic abnormalities Thefe is no unique karyotypic abnormality, but nume ric and structural chromosomal abnormalities have been described in a small number of cases 112471 _ Postu late d normal counterpart COB-positive t-een subset for the common type and a subset and T lymphocytes lor the rare typ e expressing the

'" TCA Prog nosis and predi ctive factor s The tvmobopronterauon is typ ically indolent and non- prog ressive and some investig ators feel that it is bett er regarded as a c lonal d isord er of uncerta in sig nificance rather than a leukaemia. Morbid ity is associated with the c ytopenias especially neutropenia, but mortality due to this cause is uncommon. In a series of 68 pat ients, median survival was about 13 years 15631 . Rare cas es with an agg ressive course have been described 1773, 22491. Patients who require treatment may benefit from cvcrosponne A, cyclophosphamide and corticosteroids, low dose methotrexate or pen lostalin 11247,

16641.

t-een large granular lymphocytic leukaemia

273

Chronic Iymphoproliferative disorders of NK cells

N Villamor W G . Moric e W C . Chan K. Fouc ar

Defin ition Chronic Iymphoprolileralive disorders of NK cells are rare and heterogeneous. They are characterize d by a per sistent (> 6 months) inc rease in peri pheral blood (PS) NK cells (usually ~2x 109/l ) w ithout a clearly identi fied ca use. It is d ifficult 10 d istinguish between reacti ve and neoplastic conditions. without hig hly specialized tecnoques. Chronic NK-ceU Iymphoproliterative disorder (ClP().NK) represents a proliferat ion of NK cells associated with a chronic c linic al course , and is co nsidered a provisiona l entity.

ICD-O code

9831 13

Synonyms Ch ronic NK-cell lymphocytosis , chronic NK-Iarge g ranular lymphocyte (LGL) tyroobopronterauve disorder. Nk -ceuuneaoe granular lymphocyte prolifera tive disord er, Nk-ceu LGL lymp hoc ytos is. indolen t larg e g ran ular NK-eeil lympho prol iferative dis orde r. Ep;dem;ology CLPO-NK occurs predominantly in adu lts with a median ag e of 60 yea rs without sex p redominance 11248, 1304. 1799 1. Unlike Epstein-Barr vi rus (EBV)-associated agg ressiv e Nc-ceu leukaem ia . there is no rac ial or ge netic pred isposition .

Etiology A transient increase in circul ating NK cells may be encountered in many conditions such as autoimmune d isorders Of viral infections 11248, 17991. NK-eell activation d ue to an unknow n stimulus, presumably v iral, is postulated to pla ya role in the early pathogenesis of chronic IymphoproIilerative d isorders of NK cells by selecting NK-eell clones, althoug h no evidence of direct NK-eell infection has bee n observed 113)4 .1340.1799.24831 , Agenetic susceptibility may be linked to haplotypes containing higher numbers of activating kille r immunoglobulin-like rec ep tor (KfR) genes (649, 1982, 2482),

274

Mature T- and NK-eeHneoplasms

Fig. 11.06 ChroniC tymphoproIifetative disorders of NKcells. Penpheral blood ftlms show the lymphocy1e 'Mth coarse azlJfOPhilic granulation(A), ~mphocyle withnumerous ftne granuiations (8), lymphocyte withscarce granlriaoon ;,,\IlI limit of~isi bility (e). 0 Intrasinusoidal marrow infiltrationby granzyme B positive cells, Note the bland nuclearcytology of the antigen ~ti l'El cees.

Sites of involvement Predominantly PB and bone marrow- (BM) . Cl inic al features The majority of patients are asymptomatic , but som e may present with systemi c sym p toms and/or cytopenia(s) (mai nly neutropenia and anaemia ). Lymphadenopathy, hepa tomegaly, splenomegaly and cutaneous lesions are infrequent 11304. 1661, 1799 /. Chronic Iymphoproli le rative disorders of NK cells may occur in associanoo with other med ical conditions such as solid and haemato log ic tumours, vasc ulitis, splen ec tomy, neuropat hy and autoimmune d isorde rs 11304, 166 1, 1695, 1799 1.

-

The ci rculating NK cells are typically intermeot ate in size with round nuclei with con d ensed ch romatin and moderate amounts of slig htly basop hilic cytoplasm co ntaining fine or coarse azurop hilic gr anules. The BM biop sy is ch arac terized

by intrasinusoid al and interstitial infiltration by ce lls with small. minimally irreg~ nuclei and modest amounts of pale cytoplasm , These infiltrates are difficult to de tect w ithou t the aid of imm unohistoc hemistry. Immunophenotype Surface C03 is negative. while cytoplasmic C03t: is often positive. CD16 is positive , while weak C056 expression is frequently observed 11304, 1519 , 1520. 1695. 236 11, Cytotoxic markers including TIA 1, gra nzyme B and granzyme M are positive , There may be d iminished or lost expression of C02, C07 and C057; also seen are aber rant cce xpression of CDS and abnormal uniform expression of CDS 11517. 15201, Expression of the KIA family of NK-eell receptors (NKA) is aboorrrl<4 in CLPD- NK ; eithe r restricted KIA tsoto m ex pression or a com plete lack of detec tab le KIA may be seen (649. 952, 1520 , 1695 , 2482, 2485 ) KIA-pos itive cases p referent ially e xp ress ac tivating

receptor tsotcrms 1649. 24821. Other abnormalities of NKR incl ude uniform. bright CD94/NKG2A heterodimer expression and diminished CD 16 1 expression 11304. 1520. 1982. 236 11.

Genetics Karyotype is norma l in most cases 11661. 1799. 21731. There are no rear rang ements of the immunoglobulin and receptor genes. as expected fOf NK c ells. In female patients. It is possible to exploit x-cnrorosome inactiva tion as an indi rect marker of c lonali ty. A skewe d ratio of

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x-cnromosome inactivation restric ted to is indicative of the presence of a NK clonal population, With such methodologies. cionantv is confirmed in some but not in all pat ients 11135. 1304 . 15 75 1. Unlike aggressive NK-eeil leukaemia. EBV is negative {1248 , 1340.24831.

cess

Postulated normal counte rpart Mature NK-cell. Prog nosis and p red ict ive factors In the major ity of pat ients the c linical course is indolent O'IIer a prolonged period

Disease progre ssion with inc reasing lymphocytosis and worsening of cvtocemas is ob served in some cases. The presence of cv tcoeruas. rec urrent infec tions and comorbi di ty may be harbingers of a wor se prognosis. Rare c ases with either spo ntaneous co mplete remission {1304. 1661, 1799. 2484 1or transtomaton toan ag g ress ive NK -c ell d isorder have been desc ribed 1990. 1628. 18781 · The p resence of cytogenetic abnormalities may imply a worse p rognosis and cou ld be related to ra re transformations reported in the literatu re 11628 1.

Chronic lymphopfoliferatlV8 disorders of NK cells

275

Aggressive NK-cell leukaemia

J .K,C , Chan

E.S. Jane E. Ra lfkiaer Y-H . Ko

Definition A systemic neoplastic proliferat ion of Nx-cens almost always assoc iated w ith Eps tein-Barr vir us (EBVj and an aggressive cl inical cour se .

ico-o eeee

9948/3

Syrooym Aggressive NK-ce ll leuka emiaJlymphoma .

El' derr1iology

~

This is a rare for m of leuka emia which is

•

other ethn ic populat ions 119011. Parents are mos t commonly young to midd leaged adults. with a med ian age of 42 years 1205 2, 2 128 1. There is no sex pred ilecti on or a slight male predomi-

nance 1381. 386. 1004, 1221 , 1223. 1659. 190 1, 1902,2052, 21281 . Elioklgy Little is known about the etio log y of ag gressive NK-ceilleukaemia . but the strong association with EBV suggests a pathogenetic role of the virus . Rare patients may mani fest features of hypersensitivity to mosquito b ites or ch roni c ac tive EBV infecti on 11020, 1021J, leading to overlap with EBV+ r-eef Iyrnp hcprohfera tive disorders of chi ld hood, Sites of involvement The most commonly involved sites are pe rip heral blood (PB), bone marrow (8 M), liver and spleen, but any organ can show involvement in addition, Since the number of neoplastic c ells in the PB and 8 M can be limi ted, the disease is different from the usual teukaemtee and thu s als o has been called "aggressive NK-eeilleukaemiaJ lymphoma". There c an be overla p wit h extranodal NKIT-eeillymphoma showing multiorgan involvement it is unclear whether ag g ressive NK-cell leukaemi a represents the leukaemic cou nterpart of ext rarooa t NKIT-ceil lymphoma 138 1/. Clin ical features The pa tients usually p resent with feve r, ccoeutunon et symptoms and a leuka emic 276

Mature T- and NK-ceH neoplasms

I •

.1. ..

much more prevalent among Asians than

~

...

)

•••

.••....

Fig.11.07 Aggressive NK<e/l leukaemia A In !his blood smear. the neopIas1ic cells are IIefY similartl normal large granular lymphocy1es, B In !his case, the neoplastic cells have basophiliC cyloJlIasm. and nuclei wiIh more open chromatin and disbnd nudeoli. AzurophiliC I13nules can be observed in the cylopIasm, C The neoplaslic cells are negative for s~ CD3 (leLl4), wtIiIe ee normal T lymphocytes are staifled. D The lleOPlastic cells show ~ illmunoreactivity lor C056.

blood p icture. The number of c irculating leukaemic cells may be low or high (a few percent to >80% of all leukocytes); anaemia. neut ropen ia and throm bocytopenia are c ommon , Serum lact ate de hydrogenase leve l is ofte n marked ly elevated Hepatospl enomegaly is commo n, sometimes acco mpa nied by lymphadenopathy, but skin lesions are uncommon. The d isease may be complicated by coagulopathy, haem ophagocytic syndrome or multiorgan failure {386 , 1004 . 1223 , 1515 , 1639 ,2052, 2128/. Rare cases may evolve from extra nodal NKIT-ceillymphoma or c hronic Iymphoproli lerative d isorders 01 NK cell s 1911 ,1628,1661 , 2049 1. While it has been sug geste d that ag gressive NK-ceil leukaemia may merely repr esent the leukaemic manifest ation of extranodar NKIT-cell lym phoma , the following fea tures are d istin ctive for the former: younger median age by more than a decade ; high frequency of hepatos plenic and 8M involveme nt; low freq uenc y of c utaneou s involvement : di sseminated

dis ease with uniformly fatal outcome irrespective of treatme nt; and freq uent ex· pression of CD 16 11582, 2128 1. Morpholog y Ci rcula t ing leukaemic cel ls can show a range of appearances from cells indistinguishable tram normal large granu lar lymphocytes to cel ls with atypical nuclei featuring enlargement, irregular fold ings. open c hromatin or distinct nucleoli. There is an ample amount of pale or lighlly besophilic c yto plasm con taining fine (X co arse azu rophilic granules , The 8M show s mass ive, focal or subtle infiltratioo by the neoplastic cells and there can be intermi ng led react ive tuenocvtes wilh nae rroonac ocvtoeis. In tissue sections the leukaemic c ells show d iffuse or pat chy destruct ive infiltrates. They often appear monotonou s, with round or irregular nuclei, c ondensed c hromatin and small nucleoli , but the y can sometimes show sig nificant nucl ear pieororphem There are freq uentty ad mixed apoptobc

More than 90% of cases harbour EBV, wh ich occ urs in a c lonal epi soma l form

1386.903. 11261.

A Ft.l1.oaAgpssMI NK<el IetAaema. A Giemsa-stained I'I\¥TOW asprate. The neoplasllccels show pleolnoqnc ~ b*l ru:IIi. prorrinenI ru:illoli lWId cytopla:stric 3lIftlPhIc granJes in ltle basoIt*~ , Bl~ IIlde. The neopIastJc eels appear mOlloD lOUS. and poss.e$$ l'OI.I'ld nudei. There are many inl~

--

bodies Necrosis is co mmon, and there

mayormay not be ang ioinvasion .

IrrmLllOphenotype The neoplastic ce lls are CD2 +, surf ace C03-. COOt: +, CD56+ and positive for ~ molecules. Thus . the irrmunopheoo-type is identical to that of exnenodet

cvto-

neg ative 1381. 1659 ). The neoplastic cells express FAS ligand . and high levels of FAS ligand ca n be found in the serum of affect ed pat ient s 11117, 1369. 2 156 1.

Genetics

NKIT-ceil lymphoma, except that C0 16 is

j-ceu receptor ( TeR) genes are in germline configuration . Clonalily therefore has to be esta bl ished by other methods, such as

frequently positive (75%) 121281. CD 11 b may be expressed. while CDS7 is usually

cytogenetic stu dies and patt ern 01X c hromosome inaclivation in female pa tients.

A variety of clonal cytog enetic abnormalities have been reported , such as d el{6){q 2 1q25) and 11q deletion 119021. An array -based com pa rative genomic hybr idizat io n study has shown signi ficant d ifferenc es in genetic ch anges between aggressive Nx -cenre ukaemta and extranodal NK/T-celilymphoma: 7p-, 17p. and 1q ... are frequent in the for mer but not the latter, while 6q- is comnon in the tatter but rare in the former 115671. Postulated normal counterpart NK ce lls. Prognosis and predict ive factors Most cases pur sue a fulminant cli nical course frequently complicated by mult iorgan failure . coag ulopathy and haemophagcx;ytic syndrome . The median survival is less than 2 months 1381, 1902,2052, 2 1281. Response to chemotherapy is usually poor, and relap se is almost lhe rule in patients ach ieving remission with or withou t BM transp lantation 12 128 1.

, , , j

s

,. Agg ressive NK-ceil leukaemia

277

EBV-positive T-cell Iymphoproliferative disorders of childhood

L. Ouintanilla-Martmez H. Kimura E.S. Jaffe

Two maiO' types of Epstein-Barr (EBV)-

extensive lymphadenopathy. and careytoc enta has been described in Japan {11 49. 1150. 21271. These patients have higher viral copy numbers in peripheral blood (PB) , and inste ad of or natura l killer (NK )-cells are EBVinfected. These cases frequen tly manifest monoclonal t -een populat io ns and prog ression to ove rt malig nant T-cell maliqnan cy is the rule. CAEBY with monoc lonal EBY+ r-eef proliferati on rep resents partct the spectrum of systemic EBY+ T-cell LPD of childhood 117971. and to avoid confusion should nOI be referred as to CAEBV.

associated T-cetllymphoprolilerative disorders have been reported in the paediatric age group . Both occur wi th

IC().() code The provisional code proposed for the fou rth edi tion of ICO-Q is 972413.

increased frequency in Asians. and in

Synonyms and historica l annotation

Native Americans from Cen tral and South America and Mexico . Hydroa vaceiniformelike lymphoma is a c utaneous ma lign ancy with an indolent c linic al cou rse, but it usu-

Historica lly this p roc ess has been d escri bed und er a variety of terms inclu di ng: fulminant EBY+ t-een LPO of chil d hoo d , sporad ic fatal infec tious mononuc leosi s (FIM); fulm inant haemophag ocytic syn d rom e in c hild ren in Taiwan 121151: fatal EBV-associ ated baemopn aqocvttc syn drome in Japan 11 144 1: an d severe CAE BV {1149, 1636,21271. The term fulminant or fatal haemoph agocytic syndrome has been used to describ e a systemic d isease secondary to acute primary EBV infection affecting previously healthy children . It has been shown to be a monoclonal COB+ EBVassociated Iymphoproliferative disorder. and therefore is now considered equivalent to systemic E8V+ T-celllPD of childhood

ally progresses over time Systemic EBV+ f-cemvmoro oronterauvedisease (LPD) of childhood t ies a very fulm inant clinical cou rse. It may be associated with ch ronic ac tive EBV·intec tion (CAEBV ). and in these patients is p reced ed by a p rodromal phase 01 ootycronat or oligoclonal expansion of EBV-infected T-cells .

Systemic EBV-positive T~II IymphoprolifBrativB disease of childhood

Be ene.t-eens

Epidemiology Systemic EBV + LPO of childhood is most prevalent in Asia . primarily in Japan and Taiwan 111 44 , 1149 .2115.21271 , It has been reported in Mexico and rarely in Western countries 117971. It occurs mosl often in children and yCM.mg adults. There is no sex predilection .

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l179n Definition

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Systemic EBV+ LPD of childhood is a hfe-threatening illness of children and you ng adults c haract erized by a c lonal proliferation of EBV-infec ted with an activated cy toto xic ph enoty pe , It c an occur shor tly after primary ac ute EBY infec tion or in the sell ing of chronic ac tive EBV infe ction (CA EBV), It has a rap id progre ssion with mul tiple organ fa ilure , sepsis and death, usua lly from days to weeks. This entity shows some overlapping clinico pathologic features w ith ag gr essive NK-cellieukae mia.

t-eens

278

Mature T- and NK -cel l neo plasms

The term CAE8V was coined to describe an infectious monooucleosis-like syndrome persisting for at least 6 months, and associated w ith hig h liter s of antibodies to EBY-cap sid antigen (VCA.lgG) and early antigen (EA -lg G) wit hout assoc iati on to malignancy, autoimmune d iseases or immunodefic ienc y 121071. These cases are mostly seen in West ern popu lations ; pr og ression to EBV-po sitive T-ce ll LPO ha s been rep or ted rarely in suc h patients 11069, 109 4, 17971. A more severe form of CAEBY ch aracterized by high feve r, hepatospl enomegaly.

Etiology Alt hough the etiology is unknown, its association with primary EBV infection, and the racial predisposition, strongly suggests a genetic defect in the host immune response 10 EBV 11 144, 1149, 1797, 21 15, 2127) , Sites of Invo lvement It is a systemic di seas e. The mos t commonly involved sites are liver and spleen followed by lym ph nodes, bone marrow (BM) , skin and lung {1 144, 1149 , 1797 2115,21271 ·

"_.1Ii

_ G .. .

Fig. 11.12 Systen"ic EBV. T<el lPO of childhood A The liver shows a subde sinUSOIdal lymphoid infiltrate Iac:U'lg cytOlogIc atypia EIyIhrqlhaglxyts is pronWIenl. BThe rlliIlrabng Iyl'npI'locyfes are C08-positive. C Nearlyall ~ in the S1llUsoids are EBER-posb'te.

CDcaI features

Mmphoklgy

Previously healthy patients present with

The infiltrating t-eens are usually small

acute onset of fever and general malaise S:.Jggestive of an acute viral respira tory illness. Within a period of weeks to months. patients develop hepa tospleno megaly and liver failure. sometimes

and lack signif icant cytologic atypia 117971. However, cases with pleomorphic med ium-sized to large lymphoid cells, irregular nuclei and frequent mitoses have been descri bed 121271. The liver and sp leen show mild to marked sinusoidal infiltration with striking baerroobaoocvtosts. The spl enic white pulp is dep leted , The liver has prominent porta l and sinusoida l infiltration. cr orestasrs. steatosis and nec rosis, The lymph nodes usually show preserved architecture with open sinuses. A variable deg ree of sinus histiocyt osis with erythrophagocytosis is presen t, Bone marrow biops ies show histioc ytic

I

eccoroaned by lymphadenopathy. tate-

t

rat(l(Y tests show panc ytopenia, abnormal Iver uncton tests and often an abno rmal EBV serology with low or absent anti-yeA 19M antibodies. The d isease is usua lly complicated by haemophag ocyl ic syndrome, coagulopathy, mulli organ failure ant! sepsis (1 7971. Some cases occu r in patients with a we ll-d oc umented his tory cfCAEBV infection 11 069. 10941.

hyperplasia with prominent erythrophagocytosis, Immunophenotype The most typical phenotype of the neoplastic ce lls is CD2+ CD3+ CD56- and TIA 1+ Most cases secon dary to acute prima ry EBV infection are CD8+ 11113, 1797, 21151, whereas cases in the setting of seve re CAEBV are CD4+ 11069, 1094, 1797). Rare c ases show both CD4+ and CD8 + EBV·i nfected T-ce lls 117971. EBVencoded RNA (EBERl is positive, Genetic s The cells have monociooauv rearranged t-een receptor ( f eR) genes. All cases

72 bp ·

TeRr ~ 11.13

lPO fA etill:tlOOd A The spleen sIJ:Ms depIebon fA tIM! ~e!up and prorninenl inMrales. The nodules are composed predomil'Iaolly DI CQ4.poWte eels I EBER inSCU ~ shcM t'lal 1tle C04-positiye eels are also positivelor EBV RNA. SysIerNc EBV.

-ada!
T~

~ ~

EBV-~il jve

Fig.11.1' Systemic eev- T<8I lPO DI ct*tlDod. PCR lor TRG@ gene. PeR derrmstrales an idenIicaI T~ etJne i'l h iYer. spteen n ~ nodes

T.celllyrnphoproliferatrve disorders of childhood

279

harbour EBV in a c lonal episomal form 11069. 1144. 1149.2 127 1. All c ases analyzed carry type A EBV. either with wildtype or the 30 bp deleted product of LMP1 gene 11 113. 1797,2 1271. In situ hybridIzanon for EBER shows that the majority of the infilt rating lymphoid cells are positive . No con sistent ch romosomal aberration s have been identi fied 1402, 11491 . Postulated normal counterpart Cyto toxic CD 8+ T lym phocytes or ac tivate d CD4+

t-eens.

Prognosis and p red ictive factors Most cases have a fulminant cli nical cou rse resul ting in death. usually from days 10 week s . How ever, some cases srow a subacute course of several months to a year.

Hydroa vaccinfforme-Iike lymphoma Definition Hyd roa vaccinnorrre-uke lymphoma is an EBV-positive cutaneous t-een lymphoma occurring in ch ildren, and associated with sensitivity 10 insect bites and sun sensitivity.

Etiology The neopl astic cells, usually T-eens. bu t sometimes NK-cells, are nanetoerrec by ESV. Patients exhibit hy pe rsensitivity to sunlight, and insect bites , often mosquito b ites, which precipitate cl inical symptoms 11582/. Sites of involvement This is a c utaneo us co nd itio n that p rimarily affec ts sun-expo sed skin, in particu lar the fac e 1596 , 10271. Clinical features It is characterized by a p apulovesicular er uption that generally proceeds to ulce ration and scarring. In some cases. systemic symptoms including feve r. wasting. lym phadenopathy and hepatosplenomegaly may be present. partic ularly late in the course of the disease {147 . 3991. Mmpoology The neoplastic are generally small to med ium in size w ithout sig nifica nt atyp ia. The infiltrates show extension from the ep id erm is to the subcutis , showing necrosis, angioc entric ity an d anqioin vasion. The ov erlying epidermis is freq uen tly ulcerated 11471.

cene

Postulated normal counterpart

ICD-O code The provisional code proposed lor the fourth ed ition oflCD-O is 972513.

Irrrnuno phenotype The cells have a cytotoxic Of, less often, NK-ce Uphenotype. with expression of CD56.

Epidemiology This co ndi tion is see n mainly in c hild ren and ad ole scents from Asi a , or in Nat ive Ame rica ns from Central and South Am erica , and Mex ic o. Like other Eb v- pos itive and NK-c eillympho mas, pred isposition for this cond ition ma y be related to a defec tive cytotoxic immune res ponse to EBV. It is rare in adults 11 47, 432 1.

Genetic s Most ca ses have clonal rearra ngements 01 the TCR ge nes Some c ases of NK· de rivation w ill not show TCR ge ne rearrangement 1399, 2455 1. EBER in situ hybri di zation is expressed in all 01the atyp ic al cells, but LMP 1 is generally neg ative . EBV is monocl ona l by term inal repeat analysis.

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280

Mature T- and NK-ceU neoplasms

Fig. 11.15 Hydroa vaccini!orme-like lymphoma. Sunexposed areas of the skin exhibit a papulO'lesiaJtar eruption. Many of the lesions are ulcerated WltIl a haemoo!lagic crust.

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Skin homing cyt otoxic T-cell Of NK-cell. Prognosis and predictive factors The clinical course is variable, and patients may have recurrent skin lesions fer some time , up to 10- 15 years . belore progression to systemic involvement. With systemic sp read, the clinical course is much more agg ressive {1600 1.

Adult T-cell leukaemia/lymphoma

Definition A peripheral T-cell neoplasm most ott en composed of high ly pleomorphic lymphoid cells. The disease is usually w idely

disseminated. and is caused by the tunan retrovirus known as human T-cell lelJ\aemia virus type 1 (HTLV- l).

roo code

9827/3

~

MJIt T-cellieukaemia/lymphoma (ATlL) isendemic in several regions of the wor1d. 11 particular Southwestern Japan, the

Caribbean basin and parts of Centra l Alrica The distribution 01 the disease is

Taillt 11.01 Clinical and morphoIogocai speclrum of

tffi.\Ll-4e1ated diseases. ~lit

difotd.rs

Pe/tlheraI ti:lod lleukaerlia)

-.."" ""'" "" -""

l~

reoe(lymphoma)

~ ikll type

Pleomorphic small celllype Pleomorphic (medium and large cells) type ArlapIasticlarge cell type

&,

P."". -,'''''''"

closely linked to the prevalence of HTLV-1 in the po p ulation . The d isease has a lon g late ncy, and affected individuals usua lly are exposed to the virus very ear ly in life . The viru s may be transmitted in breast milk. and through exposure to pe ripheral b lood (PB ) and bkx>d products. The c umulative inc idence of ATlL is est imated to be 2 ,5% among HTLV-1 carriers in Japan 121441. Sporadic cases are described, but the affected paIients often derive from an endemic region of the wor ld. ATLL occurs only in adults and the age at onset ranges from the 20s to the 80s , with an average of 58 year s. The male to fema le ratio is 1.5; 1 12462 1_

K. Ohshima E.S, Ja ffe M . Kikuchi

Fig. 1U 7 Adull T<elIleu kaemiahymphoma. A r3lio-

lrc'Ph shcIws extensive ¥ic bone lesions.

Etiology HTLV-1 is causally linked 10 ATLL, but HTLV-1 infection alone is not sufficient to resull in neoplastic transformation of infected cells. The p40 tall: vital protein leads to tra nscri ptional ac tivation of many genes in HTLV-1 infected lymphoc ytes 1726}. In add ition. the HTLV-1 basic leuc ine zi pper fac to r (H8Z) is thought to be impo rtan t for T-cell proliferation and oncogenesis 119401. f-iowever, add itional genetic alternations acquired ove r time may result in th e dev elopment of a ma lig nanc y, HTLV-1 also ca n indi rectly cause other d iseases, suc h as HTLV-1 associate d myelopathy /tropical spas tic parap a resis {21481.

Gastroilleslinal lraC!

'-

Ulcersfu!1

T"m. ..

"" .... """""

Portal orSinus inliltfation

IJ*traIion "Mill or Wllhout fibrosls

~ dilO rden

""""""

HTlV-l-woaa1ed myelopathy (HAM) HTlV·l-1UOCill!ed lIVefbI HTlV·1-associa1ecl tyrnpnadenrtlS

-

.......

HTllJ.l..as:sociB\ed ~(HAB) HltV-l~ 8l'thnlpIthy (liMP) IfTtV·l-a&SOCia1ed ,.eptwopaltly

Sites of involvement Most ATLL patients present wit h wid espread lym ph node involvement as well as involvement of PB , The number of cirdoes not correculating neopl astic late with the degree of bone marrow (8M) involvement, sug ges ting that ci rculating cells are recru ited from other org ans suc h as the ski n. In fact , the skin is the mos t common ext ralymphatic site of involvemen t (>50%). The distribution of the d isease is usually syste mic, involving the spleen and extranodal sites including skin. lung , liver. gastrointestoatnact and central nervous system 1298 1. Epidemiologica l differences occur in patterns of presentation. For example.

cens

Mao.........,...

fC.p.11.11 MAT-<8I ~. fir'odIngs of cutaneous lesions have been dassrlied as ~ (A). paplAes {Sl n:I nrxUes (e).

Adult T-eellieukaemia/lymphoma

28 1

•

I

T-celIeu~ . PeftpheralbIoodl*ns. A klttle acute vanant, the leukaemic eels are medlum-sazed to large ~ eels with inegular nuclei and basopIliIic cytoplasm . The dWaetensbc AduN T-cel ~ cellshavebeendescnbed as"1lower cells", with mallY ru:lear COI'IYCIIutiOnS and lobules. BMAl T-<::eI ~ eels in Itle etwonic varWit are generaIy small WIlh sJ9'IIl'I.Idea' abnormal",", sud! as nothng. indeoIation. and c::orrvoMIon

Fig. 11 .19 Adult

Fig. 11.20 -'dun T-cell Ie~ emiahy'mpholna eels trequenlIy eJPreSS FOXPJ. The roelqlreSSlOfl 01 fOXP3 and C025 is d'laraderiStk:oI ~ T<eIs(Treg).

PB involvement is much less c ommon in canents from the Caribbean basin than from Japan 112861. Clinical features Several clinical variants have been iden nfied: acute, lymphomatous , chronic and smoldering ATLL 1201 01 . The acute vanani is most common and is charac terized by a leukaem ic phase . otten with a markedly elevated while blood cell (WBC) count. skin rash and generalized lymphadenopathy Hypercalcaemia, with or without lytic bone lesions. is a common feature. Patients with acute ATLL have a systemic disease accompanied by hepa tosplenomegaly, constitutional symptoms. and elevated lactic dehydrogenase Leukocytosis an d eosinophilia are common . Many pati ents have an associated T-cell immun od efici ency, with frequent op portunistic infections such as Pneumocystis c arinii pn eumonia and Strongy loidiasis , The lymphomatou s variant is charac terized by prominent lymphadenopathy but without PB involv ement. Most pa tients pre sent with ad vance d stage d isease similar to the acute form , althou gh hype rcalcaemia is less allen seen. Cutaneous lesions are common in both the acute and lymphomatous forms of ATLl. They are clinically diverse, and inc lude erythematous rashes, papules and nodules. Larger nodules may show ulceration. The chronic variant is frequently associated with an exfoliative skin rash. While an absolute lymphoc ytosis may be present. atypical lymphocytes are not numerous in the PB. Hype rcalcaemia is absent. In the smol dering variant, the wac count is normal with >5% ci rculating neoplastic cells , ATll cells are generall y small w ith a normal appearance. Patients frequently 282

Mature T- and NK-cell neoplasms

,- _

Table 11.G2 lXaglW)Slic mlefia fordiniCal subt)1les 0( Ad~ T<8llIeu~, Moddied from Shimoya-na at ai. {2010}. Smoldering

N,

Bklod abnormal ~ LIlH

"""'" """'"

l~nopalhy

"'~

Bone marrow i'lliraIion

>" """" """"....... No No No

Clu"onlc

Acut.

have skin or pulmonary lesions, but there is no hyperca lca emia. Progression from the chronic or smo lde ring to the ac ute variant occurs in 25% of the c ases, b ut usually aner a long durat ion 120 101.

I.1o
morpholog ic al variants have been described, reflectin g this varied cytology and referred to as pleomorphic small , medium and large cell types, ana plastic , m a rare form resembling angiOirrmunobaste t-een lym p homa 116301. Use of sese variants is optional but they call attentoo to the spectrum of ffiO(phoIogical appearances Some cases exhi bit a e xeemc pattern of infiltration. with preservation or dilation of lymph node souses that contain malignant cells. The I'Iflammatory background is usually sparse. although eosinophilia may be present. The neoplastic lym phoid cells are typically medium-sized to large. etten WIth pronounced nuclear pleomorph ism . The nceer Chromatinis coarsely clumped with distinct. someti mes promine nt, nucleoli. Blast-like cells with transformed nuclei and dispe rsed ch roma tin are prese nt 11 variable propor tions 12010J. Giant cells w,th convoluted or po lylobated nucl ear contours may be p resent. Rare cases may be composed predomin antly of small ~phocytes, with irreg ula r nucle ar c onlours Cell size does not co rrelate with the clinical course 11036 ). with the exception of the chronic and smo lde ring for ms, in which the lymphocytes have a mo re normal appearance. Lymph nodes in some patien ts in an ear ly pease of adult T-cell lymphoma/leukaem ia may exhibit a Hodgkin-lymphoma-like histology 116321. The lymph nod es have expanded oaraco rt'ca t areas co nta ining a diffuse infiltrate of small 10 med ium-s ized tyTnphocytes with mild nuclear irreg ularities, indistinct nuc leoli an d scant c ytoplasm. Epstein Barr vir us (EBV)+ B tyTnphocytes with HOd gk in -like feat ures are interspersed in this back g roun d , The expansion of EBV+ B-ce lis is telt to be secondary to the underlying ewnuoooenciency seen in patients with ATLL In the PB. the poIy1obat ed appearance of ee neoplastic ce lls has led to the term bier cells. These cells have deeply base~ cytoplasm . mos t readi ly observed liI'Ilh Giemsa stains of ai r-dried smears. lrdallOW infiltrates are usually pat chy.

rang ing from sparse to mod erate. Os teoc lastic activity may be prom inent, eve n in the absence of BM infiltrat ion by neop lastic cells . Skin lesions are seen in mo re than 50% of patients with ATlL. Epid ermal infiltration wit h Pautrier-like rnicroabscesses are commo n 116301. Dermal infiltr ation is mainly pe rivas c ular. bu t la rge r tumour nodu les with exten sion to subcutaneous fat may be observed . Diffus e infiltration of many organs is indicative of the systemic nature of the disease, a nd presence 01 circulating malign ant cells.

Irrmunophenotype Tumour cells express r-cea-assocretec ant igens (C 02. CD3. CDS) . but usually lack CD7. While most cases are CD4 +, COB-, a few are CD4-, CD8+ or double posi tive for CD4 and CDa. CD25 is stron gly expressed in nearly all cases. The large trans formed cells may be positive for CD3Q, but a re neg ative for AlK 121 49} and Cytotoxic molecules. In ad dition, tumou r celts frequently express the chemoune receptor CCR4 and FOXP3, a fea ture of reg ulatory t-eens 11 112},

Fig. 11.22 Neoplastic eels Jlihrale Ihe epidemIis, pr0ducing Pautrier e microabscesses.

Genetics An tigen receptor genes T-cell rec e ptor genes are clonatly rearranged 116311. Oncogenes and other molecular changes Neoplastic cells show monoclonal integration of HTLV-1. No clonal integration is present in healthy carriers 122741. Tax, encoded by the HTLV-1 pX reg ion, is a critical nonst ructu rat pro tein that plays a central role in reukaerrcqenese. and activa tes a variety of c ellular ge nes {17221. Furthermore, enhanc ement of cyclic AMP response ele ment b ind ing transc ription fact or (CREB) phos phorylation by the

Fig. 11.23 Adu~ T-cee ietJkaemiaI1Y!ll1lhoma, A InItlis case, Itle infttlra le coessts of largeeens with anaplasticfealures, B The cells arestrongJ y C030+, ra i~ng the differential diagnosis ofarlaplasliG large eel ~

Adult T-cellleukaemiaJtymphoma

283

~ (~ )

•

._....

CI'ftnIc ('52} L.ymphomll ( 1&11)

. _

Col&5l

i

~

(fNl ilf*1l tr_form.w,,)

--...,

0

..

O'

"•

-

0

-.....

• No< ....ec

"

00

A

0

o

v....

B

Fig. 11.25 A &r.1vaI cJ paliln5 wiltIlOA T-<:elI~.Acute;nj ~1lluS Iorms I1a'o'8 l1l'i ~ ctilical 00U'Se. whe!'82S longer ~ i'I seen., paIIentS..etI ctwnic Of ~ disease. B MA T - a ' ~. HR\Ll proWaI ONA~ a"d cinicaI Sl.tJIype$

virus appears to playa role in leukaemogenesis 111481. Almost all ATLl cases have clonal chromosome numerical and structural abnormaunes. but none of them is soecitc.

Postulated normal counterpart Peripheral CD4+ t -eens. It has been suggested thai the CD4+CD25+FOXP3+ regulatory t-eens are the cl osest normal coun terpart 111 121. This finding correlates with the immunodeficiency cha racter istic of the disease.

284

Mature T· and NK-cell neoplasms

Prognosis and predictive factors Clinical subtypes, age . pertorrerce status, serum ca lcium and LDH levels are major prog nostic factor s 124641. The survival lime for the acute and lymphomatous variants ranges from two weeks 10 more than one year. Death is often caused by infectious com plic ations including Pneumocys lis carin ii pneumonia. Cry ptococcus men ingitis . disseminaled herpes zoster and hypercalcaemia 120101. The chronic and smoldering forms have a more protracted clinical cour se and better surv ival, but can prog ress 10 an acute phase with an aggressive course 11633}.

Extranodal NKIT-cell lymphoma, nasal type

Definition A predominantly ex tranodal lymphoma characterized by vascular damage and destruction, prominent necrosis , cytotoxic phenotype and association with Ep steinBarr virus (EBV). It is d esig nated · N KIT~ (1'lSlead of "NK") , bec ause whi le most

cases appear to be genuine NK-ceU neoplasms, some cases show a cytotoxic tee! phenotype,

97 19/3

J .K.C. Chan L Ouintanilfa-Martinez JA Fer ry

S.-C. Peh

Extranodal NK/T-ce ll lym phom as c an occur in the selti ng of immunos uppression , includ ing post -transp lant 198 1. 12221.

tissue, g astrointestinal tract and testis,

Some c ases may be accompanied by secondary lymph node invotveme nt 1381 .

386. 1137, 1220 , 1738,22481. Rare ex-

Sttes of involvement Extranodal NK/T-ce Ulym phoma almost atways shows an extranodal presentation . The upper aerodiq estive tract (nasal c avity, nasopharynx , parana sat sinuses , palate) is most co mmonly involved. with the nasal c avity being th e p rototyp ic site of invo lvement. Preferential sites o f exnanasat involvement incl ude the skin, soft

amples of primary lymph node disease in the absence 01 extranodaJ mvovereot have also been reported 1421 , 1082, 10051. Cli nical featu res Patients w ith nasal involvem ent present wi th symp toms of nasal ob struct ion or epistaxis d ue to p resence of a mass lesion. or with extensive midfacial destructive

Syrooyms AngiOCentric T-cell lymp homa; malign ant il'idIlI1e reticulosis; polymorphic renculoSIS: lethal midline g ranuloma: anqlocen rIC immunopro hlerative lesion .

Epidemiology Extranodal NKfT-c ell lymp homa is mo re prevalent in Asi an s. and th e n ative Amer-

can population of Mexico, Central America

lrIdSouth Ame rica (55. 104 , 38 1,17951 . ecccurs most often in ad ults, an d is more carmon in males than females . A low tre~ of HLA·A' 0201 allele has been rellOrted in patients with EBV·posihve nasal NrJT lymphomas 11094AI .

Fig. 11.26 E.x1rcn::ldaI NKIT-<:eI ~. nasattype. A fJparIsionol\tle nasal bIidge, B Cor!lMedlom:lp'n, The Uncu II \tie nasal caVIty edenCls upwMl no toe ortlil reSIAlrlg II proplosis

EIioIogy Li~ le is know n ab out the etiology of extram al NK/T-cell lymp homa , However, the ofJfY strong association wit h EBV, irreeecnve of the et hnic or ig in of the pa llents, suggests a prob able pathogenic Qeol the virus 170, 386, 389, 639, 1093 , '795, 22991 , The EBV is present in a IXrIaI episomal form 170, 389 , 639 , 944 , KOO. 1448, 1795. 2 130,2299J with type II lalency pattern (EBNA-1 + , EBNA-2-, IMP1+), and commonly shows a 3O-base pair deletion in the late nt membrane protein·1 gene 1415 , 589 , 639 ,1 205 , 2 143J Most stud ies sho w that the EBV is almost l tlays of subtype A 11 48, 639, 1717, 21)), 22481 . The d isease activity c an also te monitored by measuring Circ ulati ng EBV DNA; a high titer is furthermore corI!Iated with extensive disease, un'r.Q.jrable response to therapy an d poor s.tVival l1 OSI.

FIg. 11.21 ExtrarcdaI NKIT<.elI ~ ,nasaI-type . A F'!'ot!wlenI \k.efa1lon and necrosis 1\ ht nasal nu::osa B Thenasal rru:osa ill dlIMely rihlBd 1nI e~ by.. abnarmaI WlOId irIIinIIt . The rru:usaI gIIilnds ~ showa pecuIar dear eel cNnge . C,D ~ NKIT<eI ~ in Itle IestJS C There is a tifIlJse dense1ymphoid infiltrate. wilhprorrW1enl ooagt*l1rve oeaosis. D TheneopIiIstic eels a~ monoICInOuS and are mediuTl-lIized. Extranodal NKfT-ce lllymphoma , nasal type

285

lesions (lethal midl ine g ranuloma ). The lymphoma can extend to adjacent tissues such as the nasopharynx , paranasal stnuses. orbit, oral cavity, palate and oropharynx. The disease is often localized to the upp er aeroo'cesuve tract at presentation. and bone marrow (BM ) involvement is uncommon 124371. The disease may disseminate rap idly to various sites, e.g. skin. ga strointeSlinal tract , testis or cervica l lymph nod es during the clinical course. Some cases may be complica ted by a haemophagocytic synd rome 14 13. 12201. Extranodal NKIT-ceil lym phomas occurring outside the uppe r aerodigestive tract (often referred to as "extranasal NKIT-ceU lymphomas ·) have variable presentations depending upon the ma;or site of involvement. Skin lesions are corrvnonly nodular, often with ulceration . Intestinal lesions often manifest as perforation. Other in-voIved sites often present as mass lesions. The patients commonly have high stage disease at presentation, with involvement of multiple extranod al sites. Systemic symp toms suc h as fever, malaise and we ight loss can b e present 1386. 1137, 24381 . Lymph nodes can be involved as part of di sseminated disease. Marrow and periph eral blood (PB) involvement can occ ur, and such cases may overlap with aggre ssive Nk-ceure ukaernia. This disease is to be distinguished from a

Morphology The histological features 01 extranooar NKIT-ce ll lymphoma are similar irrespecuve of the site of involvem ent. Mucosal sites often show extensive ulceration. The lymphomatous infiltrate is diffuse and permeative . Mucosa l gland s often become widely spaced or are lost. An anqcceotnc and ang iode strucli ve growth pattern is frequently present. and fibrinoid changes can be seen in the blood vessels even in the absence of arqtonvasion. Coagulative

Fig. 11.29 Edrilnodal NKIT<el1ymphome in !he sUI. The ~ inNlrate in¥otves !he epidlIfrM, dermrs iI'ld Slb::utaneous tissue.

Fig.11.30 The cylWgic spednm 0I1OOrlwloda1 NKIT<eI nasal type, A.6,CThisnasal UIIlu is ~ predorrinantIy 01 small eels IfI'Ilh JregINr nudlIi (A). Medium-5ized cel5 1f1'1lh pale cytoplasm (B). large alll51C"' D Nasal typeextranodal NKIT<eII ~ 01 &kiloW'IIll pleoilOphic largeeels ar:mxed WI\tI smaller C8IS

286

Mature T- and NK-cell neoplasms

.'~ ' .$.' Fig. 11.28 ExtranodaI NKIT<eII ~. nasal type A The ~ nNrraIe shows infiltration and destr\I::tIon 01 ananery B In tis case irM:M'lgtleskrl. tie I'fn'4tOfSLus iniIImB has an II Ig1OC8lI1ric ~ quaIrty.

spectrum of EBV-associated t-een or NK-cell tympropronterative disorders such as chronic active EBV infection . systemic EBV+ T-cell lymphop rOliferalive disease of childhood and hydroa veccs»forme-like lymphoma , which occur predominantly in ch ildren 111 49, 16001.

necrosis and admixed apoctonc bodies are very common findings. These have been attributed to vascular occlusion by lymphoma cells . but recent studies have also imp licated other factors (such as chemokines. cytok ines) 121851. The cytological spectrum of extranodal NKIT-ceillymphoma is very broad Celts may be small , medium-sized , large or anaplastic. In most cases , the lymphoma is composed of medium-sized cells or a mixture of small and large cells. The celIS often have irregularly folded nuclei which can be elongated. The chromatin is gra~ ular. except in the very large cells. which may have vesicular nuclei . Nucleoli are generally inconsp icuous or small. Thecytoplasm is moderate in amount and often pale to cle ar. Mitotic figures are easily found , even for small cell-predominant

w-ana,

~

~,

J'

'. I

.'.

.

" '. •

11.31 Tcu::h pte9al'abOn 01 a nasal ~ (Gemsa 1tllIIl~ AzuroI:'oI* granules are eviclent 1"1 IIle pale qqlasm 1II h I)'!I1lhoma eels. fig

lesions. In touch preparations stained with Giemsa. azurophilic granules are commonly detected. Ultrastructurally, eieceoo-oeose membrane-bound granules

are present ExtrGrlOdal NK/T-celllymphomas, particularly those predominated by small or mixed cell populations . or those accompanied by a heavy admixture of muammalory cells (small lymphocytes. plasma cells, bstocvtes and eosinophi ls) may ll'IlITIiC an innarrmatory p roc ess 1381. 911 1. The lymphoma can some times be accompanied by florid p seudoep ithe jcn atous hyperplasia of the overlyi ng epithelium

Irrmunophenotype The most typical immunophenotype of emanooat NK/T-ceillymphoma is: CD2+ , CD56+. surface CD3- (as demonstrated on fresh or frozen tissue) and cytoplasmic CO&+ (as demonstrated on fresh, frozen or lixed tissues) {381 , 388, 1032, 1037, 22131. CD56, although a highly useful marker for NK·cells, is not specific for exlranodal NK/T-ceil lymphoma and c an be expressed in peri pheral f -ceu lymphomas. particu larly tho se tha t ex press the't6 l-cell receptor. Cytotoxic molecules (such as granzyme B. TIAl and perforin) are positive {639 1 Dlher T· and NK-cell associated antigens

expression 115901. On the other hand. nasal or other extrancx:iallymphomas that are CD3+ . CD56-, but negative for EBV and cytotoxic molecules should be diagnosed as peripheral r-eef! lymphoma. unspecified. A diagnosis of extranodal NKIT-celilymphoma should be accepted with some skepticism if EBV is negative {307, 389. 639.1205. 1590.2 1431. fnsiluhybridizahon for EBV encoded RNA (EBER) is the most reliable way to demonstrale p resenc e of EBV. with Virtu ally all lymphoma cells being labeled. Immunostaining for EBV LMP1 yields variable and inconsistent results. Genetics Antigen receptor genes T-cell recepto r and immunoglobulin genes are in g erm line configuration in most cases. In a small proportion of cases. the T-cell recep tor gen es show clonal rearrangement, p resumab ly c orrespo nding to the ca se s of cy totox ic T lymphocyte der ivation (1169, 1590, 21431.

Cytogenetic abnormaNties and oncogenes A variety of cytogenetic aberrations have been reported. but so far no specif ic chromosomal transiocatons have been identified The cornrnonest cytogenetic abnormality is del(6)(q21q25) or ~6)(p 10). but it is currently unclear whether this is a primary or progression-associated event {2028. 2029, 2238. 24401. Aberrant me thylation of promote r CpG regions of multi ple genes is common. in particular p73 120 271. Comparative genomic hybridization studies show that the commonest aberrations are: gain of 2Q: and loss of l p36.23-p36.33. 6q 16.1-q27. 4Q12. 5q34-q35.3, 7Q21.3-q22.1. 11q22.3-q23.3 and 15ql 1.2-Q14 {15671. A p roportion of cases exhibit partial deletion 01 FAS gene or mutation in TP53, a-catenln K-RASor C· KIT gene, bu t the signi ficance is still unclear 1959. 1796, 20021 . Postulated norm al c ounterpart Act ivated NK c ells and, less commonly, c ytotoxic T lymphoc ytes.

are usually negative. including CD4. CDS. CD8. TCAO, ~F1 . CD16 and CDS? CD43, C045RO. HLA·OR. CD25. FAS (COOS) and FAS ligandare commonly expressed 11589. 16341. Occasional cases are pesdivefor cm or CD30 {12051. Lymphomas that demonstrate a CD3&+, C056- irTYTIunophenotype are also classifed asextranodal NK/T-ceillymphomas if bcttl cytotoxic molecules and EBV are IX)Silive. since these cases show a similar ctncal disease as cases with CD56

I

•

Fig.1U3 ExtranodaI NKfT<eI~ , nasall)llI assodaled WIth prOO'Olfll pseudoeprlhelio ~ 01 the IT"UCOSaI epllheUn. Thrs can~ be Iilisit""peted as squamous c:ell3'CinlIlIa

Exlranodal NKIT-celllymphoma, nasal type

•

287

.,.'.

Fig. 11.34 Emnodal NKJT<elI ~phoma, nasa/type A,S The neoplasticcells show strong staining !ofcyloplasmic CD:k (A) and CD56 (B). C The neoplasticcells show s~ granular staining b granzyme B. 0 In situ hybridizabon!of EBV-eocoded RNA(EBER). InthiS rlasallumour, practically alilhe oeopIastic cells show nuclear labeling.

Prognosis and pred ictive lactors The prognosis of nasal NK{T-cell lymphoma is variable, w ith some patients respo nding well to therapy and othe rs dyi ng 01dissem inated disease desp ite aggressive therapy. Historic ally, the survi va l rate has been poo r (30-40%), but l he surviva l

has imp roved in recen t years with mo re intensive therapy inc luding up fron t radio-

therap y 11 48. 4 13. 4 14, 422. 493,1169,

288

Mature T· and NK-eell neoplasms

1220, 12931. Significant unfavourable prcqrostc factors include: advanced stage d isease (stage III or IV), unfavoura ble International Prognostic Ind ex (2), invasion of bone or skin, high c ircu lating EBV DNA leve ls and p resenc e of EBV+ cells in 8 M 141 4,422, 99 1, 1266, 1590 1, The prognostic importanc e of c ytolog ical grade is unclear; some studies suggest that tumours composed predominant ly of sma ll

cells are less aggressive. but most stoo. ies have not shown th is fea ture to be ot significance on mu ltivar iate ana lysis 1148, 413,943 ,12051. Extrano dal NKIT-ceillymphoma occurring outsi de the nasal ca vity is highly agg ressive. with short survival times and poor response to therapy 1381, 386}. Exp ression of multi-drug resis tance genes may contribu te to chemotherapy resistance 16121.

Enteropathy-associated T-cell lymphoma

Defin~ion

G, all H. Stein

t-een

Enteropathy-associa ted lymphoma (EATl) is an intestinal tumou r of intr aepithelial T lymphocytes , shcwv'ing varying degrees of transformation but usually presenllng as a tumour composed of la rge I)rnphOid cells. otten with an inflammatory background. The adjacent small intestina l mucosa shows villous atrop hy w ith c rypt hyperplasia, In 10-20% of cases, the lymphoma is compose d of monom orphic medium-sized ce lls . This monomorp hic variant (type II EATl) may occur sooraorcally. without risk factors for coeliac disease. ICI}{) cod e

PG Isaa cson A. Chon

97 1713

Syoonyms Intestinal I-ceaIvmonoma (with and with-

cot enteropathy), As a variety of Teen ~phoma subtypes c an p resent with inieennerdisease(extrancd at NK/T-eeli lymotona. )'Ii t-een lymphoma . anaplastic large cell lymphoma), the term Intestinal tcea lymphoma should be used only in re setting 01 incomp lete information regarding the precise diagnosis.

E,>demkllogy The disease is uncommon in most p arts al tha world, but is seen with g reater frequency in those areas w ith a high prevalence of coeli ac d isease , in part ic ula r Northern Europe . However, the monomorphic variant appears to have a b roader geographic distribution, and is encounin Asia and oth er regions whe re coeliac disease is rare .

eeo

Etiology In EATL, the association w ith coeli ac disease is borne out by positive serolog ic al iests. HLA 002 or Da B ex pression an d associated clinical findings suc h as d ermalltis herpeutormle an d hyposp len ism 1569. 1921, 23051. In the monomorphic form cI EATL, an association with coeli ac c! seese and othe r risk tacto-s is not prtM!O 15481. suggesting that the I1"lOflOrrorphic variant may represent a oistmct osease entity,

Fig. 11.35 Enteropathy-associated 1<8 11 lymphoma, Jejunum showing cill::lJm l~lI y-orien led ulcers.

Sites 01 involvement The lymphoma occurs most commonly in the jejunum ()( ileum. Presentation in me duodenum , stomach, colon or outside the gastrointesti nal trac t may occur but is rare , Clinical features In EAll. a small proportion of the patients have a history of childhood onset coeliac disease. Most show ad ult onset disease ()( are d iagnosed as having coeliac disease in the same clinical episode in which the lymphoma is diagnosed . Patients present with abdominal pain , often assoc iated w ith intestinal perforation In a p roportion of p atients, the re is a prod romal per iod of refractory coe liac d isease that is sometimes accompanied by intestinal ulce ration (ulcerative jej unitis), The clini c al

Fig. 11.36 Enteropathy-associated 1<811 lymphoma, deeply infillrabngintoad jacent enteropathic rTIUCOSlI,

presentation of the monomorphic variant is similar. with the exception that most patients do not demonstrate evidence 01 coeliac disease. Macrosco py The tumour usually p rese nts as multiple ulcerating raised mucosal masses. but may present as one or mor e ulcers or as a large exophytic mass.

-

The tumour teems an ulcerating mucosa l mass mat invades the wall of the euesure. The tumour cells exhibit a WIde range of cytological appearances POlS, 24481· Mo st co mmonly. the tumour cells are relatively monoton ous me di um-sized to large ce lls with round or angulated vesicular nuclei. p rom inent nucleoli and moderate

Table 11.03 f eatJns d entelQpalhy-asslXialed __ Ieslillal T<.elI Iymphoma (EAll) and lTl(ll1Ol11Olpl"ic WestrIaI T<eI lymphoma (Type" EAll~

-

EATl

Type liEAn

Mostly negative (20%+) Negatve (>90%) Positive (>90%)

Mostly positive (80%+) Positive (>90%) PosItive (3O-4O'It)"

F""""""

Immuoophenolype (437}

CO, C056

HLA-OQ2I-D08

GenetICS (543} + 9q31.3 or-1 6q12.1

._, + l Q322 -q41

+ 8q24

tUYCl

"" "" ""' ""

•Correspondmg to ee normal frequency 01 HlA.fJ02f.D08 among the Caucasian population. Ente ropathy-associated T-cell lymphoma

2B9

to abunda nt. pale-sta ining cytoplasm, Less commonly, the tumour exhib its marked pleomorphism with multinucleated cells bea ring a resemblance 10 anaplastic large cell lymphoma. Most tumou rs show infiltration by inflammato ry cells, inclu ding larg e numb ers of histiocytes and eosinopbns and in some cases these may be so abundant as to ob scure the relatively small number of tumour cells present. Infiltration of the epithelium of indiv idual crypts is present in many cases The intestinal mucosa adjace nt to the tumours, espe cially those in the jejunum, usually shows enteropathy comprising villous atrophy, cry pt hyperplasia, increased lamina propria lymphocytes and plasma cells and intraepithelial lymphocytosis {437, 4381. The degree 01 enteropathy is highly variable. however, and may consis t only of an increase in intraepithelial lymphoc ytes 1124}. In the monomorphic form of EATL (type II EATL), the neopla stic cells have med iumsized round, da rkly staining nuclei with a rim of pale cy toplasm, There is usual ly florid infiltration of intestinal crypt epithelium. The ad jacen t intestinal mucosa shows villous atrop hy and cryp t hyperplasia with striking intraepi theliallymphocvtosis involving both cry pt and surface epithelium. An inflammatory background is absent. and necrosis is usually less evident than in classical EATL Il1YTIunophellOtype In EATL, the tumour cells are COO+, CDS-, CD7+ , CDB-/+, CD4-, CD 103+. TCRI1+/-, and contain cytotoxic gra nule associated proteins, In almost all cases, a varying prop ort ion of the tumour cells express Co30 12064, 2448j The mtraeottbeuat lymphoc ytes in the adjacent enteroo attuc mucosa may show an abnormal immunephenotype, usually C03+ , C05-, C08-. 290

Mature T- and NK-cell neoplasms

C04 -, identical to that of the lymphoma. The monomorph ic form of EATL has a dig. uncnve immunophenotype. The tumour ce lls are C03+ , C04-, C08+ , C056+ and TCR6+ 14371 and the intraepithelial 1ympnocytes in the adjacent mucosa share the identica l immunophenotype 11241 . Genetics TR8@ and TRG@genes are cionanv rearranged 110 17, 1552J in allrrorpholoqica! variants, More than 90% of pati ents with coeliac disease have the HLAOOA 1"0501, 0081·0201 genotype, also seen in patients with EATL 19841 . In contrast to primary nodal PTCL. most EATL cases (58-70%) harbour complex segmental amplif ications of the 9q31 ,3qter ch romosome region or. alternatively, show deretcos in 16q 12.1. These features

are prevalent in both forms of EATL and form a COfTlTlOO genetic link between the 2 types . However, the class ical form 01 EATL frequen tly displays chromosomal gains in 1q and Sq , while the monomorphic variant is more often character ized by 8q24 (MYC) amplifications 1548. 2491 , 2494} Precursor lesions As indicated above, EATL may be precede d by refrac tory coe liac d iseases (RCD) with or without ulceration, In some cases of RCo , the mtrae otmenat lymphocytes (IEL) are phenotypically aberrant showing down-regulation of C08 Slmiar to the IEL in mucosa adjacent to EAlL These cases of ReO also show ~ clonal T-cell rearrangement 01 the IEl srn. uar to the clona l rearrangements that may

, f IJ 11.39 Type II enteropalhy-aSSOCl3led T-<:eI Iym-

>'Una aJII1l(lS8d IXsmaI FWldmoll()fT(llllhc eels.

be found in the enteropatnlc muco sa ,qacent to EATL (1241 . sugges ting that the irrm unopheno typic ally a berrant IEL constitute a neoplastic po pulation. In sese patients with RCD who sub sequently develo p EAlL. the IEl share the same monoclonal TRGG gene rearrangement as the subsequent t-een lymphoma 189, 358, 359. 5081 . Furthermore, the IEL in these cases of ReO c arry gains of

Fig. 11.40 A Sma. inlesbnal muoosa from a case of reIracDy coeiac diseasei'rnu'loslanId seqlllWlllaly lor C03 (alkaline phosphatase-blue) iW'ld C08 (peroldase~), Most ntraepIheiaII!ynl:tloc)1eS IIr8 COO.., C08-

The monomorphic form of EAll may also be preceded by RCD in which the im. munophenotype of the IEl is similar to that 01 the neoplasti c cell s in the subsequent lymphoma. namely CDa. and CD56• . This type 01RCD has not been well characterized

Fig. 11.'1 PCR of D~ extraded from enteropathyassocialed TGlI ~ . M.1I'OlecUa' weio;tIt rn
"""".

Postulated normal counterpart Intraepithelial t -eens 01the mtesnoe.

chromosome 1Q in common with EAIL 123321. Thus, RCO In which the IEL show these immunophenotypic and genetic features can be considered as examples of otraepnheliat T-cell lymphoma or, alternatively, EATL in situ. In a second group of

AGO patients 12332], the IEl express a normal immunophenotype and are polyclonal. These cases prob ably do not progress 10 EATL.

Prognosis and predictive factors The prognos is is usually poor with death frequentty resulting from abdominal complications in patients already weakened by uncootrolled malabsorption. Recurrences are most frequent in the small intestine . Both cl assic al EATl and the monomerphic form have a similar clinical cou rse.

Entercoamv-assocateo T-cell tympttoma

!

29 1

Hepatosplenic T-cell lymphoma

P. Gaulard

E.S. JaHe L Krenacs WR. Macon

Definition

Etiology

Hepalos plenic l-cal! lym phoma (HSTl) is

Up to 20% of HSTL arise in the seni ng of chronic immune suppression, most com-

an extrarooat and systemic neoplasm de-

rived from cytotoxic t-eens usually 01 }IS T-cell receptor type . 11 is usually composed of medium-sized lym phoi d cells. d emonstrating ma rked sinusoidal infiltration 01 spleen . liver and bone marrow (8 M). ICD-{) code

971613

Eoi_ HSTl is a rare form ct~. representing < 1% 01 all noo-Hodgkin lymphomas. Peak incidence occurs in adolescents and young adults. with a male predominance

(rreoen. -35 """'11176. 4651

monly long term immunosuppressive therapy for solid organ transplantation or prolonged antig enic stimulation 1176. 764 . 2322 ,245 11. In this c ontext. HSTL is reg arded as a late-onset post-transplantation iymoroorouteranve cnsoroer of host orig in. HSTL may also occur in patients, especially child ren, treated by azathioprine and infli ximab for Cronn'e disease (1355. 18721.

Sites of involvement Patients p resent with marked sprenomeg aly. usually with hepatomegaly. but

with no lymp hadeno pathy [672 1. Bone marrow is almost constantly involved 1176.465.23211 . Clinical features HSTl typically p resents with hepatosp lenomegaly and systemic sympt oms. Patients usually manifest marked thrombocytopenia. often with anaemia and leukopenia. Peripheral blood in\l'Qtvemert, uncommon at presentation . may OCCll" late in the clin ical cou rse 1176. 465, 232 11. HSTl is easily distinguishable IrtlTl other ')'6 t-een lymphomas wllich in\lCll\le extrarooauocanzetons (skin and scrcotaneou s tissue . intestine or the nasal region) 181, 22541.

Fig. " ,43 Hepaklspleric T-eel lymphoma A Cords and sinIsoids ofh! spleenareirlfillra1ed by a ~ plJpl.UtIon of neoplastic ~ eels wrth ITl9liI.rn-size ru:iI in! a mocIeraIe m.of palecytIplasm. B The neopIas1ic eels ddIuseIy in6IlraIe !he Ile9abc SirluSl::G C The bone marrow is usoaty tlypeft:eWar wilh neopIasbc OllIs inIInIrIJ 5nISOicIs. D NeopIas1ic caIs ~ wilh imrYulOhistx:totl,isty b CD3.

292

Mature T- and NK-cell neoplasms

""'phoIogyThe spleen is enlarged with diffuse involvement of the red pulp, without any gross lesions. Diffuse hepatic enlargement is present as well. Histopathologi cally, the cells of HSTL are monotooous, with medium-sized nuclei and a rim of pale cytoplasm 14651. The nuclear chromatin is loosely condensed with small inconspic uous nucleoli . They

involve (he cords and sinuses 01 the splenic red pu lp with atrophy of the white pulp. The liver shows a predominant sWlusoidal infiltra tion Neoplastic cells are amos! constantly present in the lhe 8M with a predominantly inlrasinusoidal disIJWion. This may be difficult to identify WI!tloul the aid of immunohi stOChem istry rx flow cytometry. Cytologic atypia w ith

large cell

Of

blastic changes may be

seen, especially with disease progression

1176. 1414, 232 11

""""""'-

The neoplastic cells are CD3+ and usually TCRiI +. TCf\4I·, C056+'-, C04., CO&/.

and CD S-. Most y6 cases express the VB 1 epitope {176, 17831. A minority of cases appear to be 01up type , which is considered a variant of the more common yO form of the d isease {1357, 21171. The cells express the cytotoxic granule-associated p roteins, TIA 1 and granzyme M, but are usually negative for granzyme B and perforin 1465 , 678 , 11911. They etten show aberrant coincident expression of multiple killer immunoglobulin-like receptors (KIA) .sotorme along with d im or absent CD94 115221. Therefore, the cells appear to be mature, non-activated cytow ith phenotypic aberrancy. toxic

t-eens

Genetics The cells have rearranged TRGO genes Cases of .,& origin show a brauetic rearrangement 01 TRGOgenes. TRBOgenes are rearranged in up cases: however, non-productive rearrangement of TRBO genes have been reported in some .,& cases 17641. Isoc hromosome 7Q is pre sent in most cases, and w ith disease prog ression a va riety of FISH patterns

equivalent to two to five co p ies 01 i(7}(Q1 0) Of numerical and structura l aberrations of the second chromosome 7 have been detected 127, 24251. Ring chromosome leading to 7Qamplification has also been reported 121541. Trisomy 8 and loss of a sex c hromosome may also be present. EBV is generally negative . Postulated normaJ counterpart Peripheral.,& (or less commonty o.(J ) cytotoxic memory t-eens of the innate irTYnune system 11035, 11911. Prognosis and predictive factors The c ourse is aggressive . Patients may respond initially to c hemotherapy, but selapses are see n in the vast ma jority of c ases . The median surv ival is < 2 years (1761_ Platinum-eytarabine 11761 and 2'-deoxycoformyc in have been shown to be act ive agents 1473A I.

Hepatosplemc T-eclllymphoma I

293

Subcutaneous panniculitis-like T-cell lymphoma

E,S, Ja ffe

P. Gaulard E. Ralfkiaer L. Cerroni C.J .L.M. Meijer

Definition Subcutaneou s pannic ulitis-like T-eeillymphoma (SPTeL) is a c ytotoxic t -een lymphoma, wh ich preferentially infiltrates subcutaneous tissue . It is composed of

atyp ical lymphoid cells of varying size. typica lly with karyorrhexis of tumour cells and associated rat necrosis. In contrast to the third ed ition of the WHO c lassifica tion. c ases expressing the )'IS receptor are excluded. and now reclassified as primary cctareous js T-eelllymphoma.

t-een

ICD-O code

970813

Epidemk>logy SPTel is a rare lorm of lymphoma, repre senting <1% of alt non-Hodgkin lym-

phomas. II is slightly more common in females than males and has a broad age range 11 202/. Approximately 20% of patients are under the ag e of 20 (median, 35 yea rs) 1240BI . Up to 20% of patien ts

may haveassociated autoimmune disease, most commo nly systemic lupus erythematosus (SLE) 124081. Etiology Aut oimmune d isease may p lay a role in some pat ien ts, The lesions may show ove rlap p ing featur e s w ith lup us profundus pann icu litis and in some patients a di agnos is of SLE ha s been documented

ru' A""'...... '<.::::n..

Fig. 11.'4 SlIX:ulaneous panniCulibiHike T-ceII Iymphoma, Infiltrate is conMed 10 ltl& subculaneous bssue wiltIoul invoIvemenl oI ltl& overlying demli:s orepidermis,

Fig. 1US Immunohistochemical stains highlighth rimming of individual Iat spaces by tumolJ" cess wrllI staining few coe lAo) and T1A1 (B).

11 365 , 1412j , In some pat ients, the early lesions may c losely mim ic lobul ar pannic ulit is. Whet her a benig n lobular pannic ulit is preced es the de velopment of SPTCl in pa tients w ithout SlE is not clear. Epste in-Barr virus is abse nt 11 202).

Sites of invo lveme nt Patie nts present wi th mul tiple subcutaneous nodules, usually in the absence of other sites of di sease . The most common sites of localizatio n are the extremities and trunk. The nod ules range in size from 0,5 em to several cen timetres in diameter,

Tlible 11 .04 Oilfaf&l1tia1 diagoosis of neoplasms expre~ng T<eUandNK<eUmarkers with frequent cutaneous involvement.

CD3, CD4, COl

CliniCalleatures

Disease

-.-, •

T-cell

Uneagt

reee... R

,....

R

r....

G

NK-oelI, somt-

Cytotoxic

' PTCt

T~ . extremities and

Primary Q.l\aneoUs y6 TCl

TUITllUS , plaques. uk::enlted nodules

...-

Extranodal NKIT<:eM

Nodules, tumours

+,', •

• • •

Primaty aJtaneous Ala.

Superftcial nodules -Md1 epidermali1'o'o1vement

+, +,-

•

Patches, plaques. tI.ITnn Iale in course

••.

Mycosis IqoiOes

-~

dendnbc eel neoplasm

......."""'"

. ~ pUHssoc:iaIed prolewl,

+,',

-1+

" +. -

CD56

•

•

•

R

•

_. """""'" ,....

Iines T.-

R

G

I;....

- '"

T1A1 itr'ldIorGranzyme Bat'Id1or perbin: SPTa.., subcWnecus~ T<eI~, TCL T<eI~ ; Al.Cl

~Jargeoel~.

294

trunk

EBV

moltculuo

Mature T· and Nx-cen neoplasms

Fig.11.46 A SlIbclItaneous panniculitis~ i ke T-cell lymphoma. Turrour cells are associated withabundant histiocytes containing apoplolic debris, B NeopIasticcellssurround fat cells, ~ witl1 some admixed histiocytes, C Neoplasticcells have round to oval hyperchromatic nudei with inconspicuous nucleoli and abundant pale cytOl)lasm.

larger nodules may become necrotic; towever, ulceration is rare 11202. 24081 .

CfnicaJ teanees Clinical symptoms are primarily related 10

me subcutaneous nodules. Systemic symptoms may be seen in up to 50% of panents. Laboratory abnormalities . including cytooenras and elevated liver Junction tests are common. and a frank haernopbaoccvnc synd rome is seen in 15- 20% (8141, Lymphad enopathy is usuallyabsent. Hepatosplenomegaly may be seen, but almost alw ays not due 10 lymphomatous involveme nt 112021.

-

The i1I~ trate involves the fat lobules. usu ally WIth sparing 01 septa. The overlying dermis and epidermis are typically uruo...::ived. The neoplastic cells range in size, bullfl anygiven case, cell size is relatively constant. The neop lastic cells have irregular and hyperchroma tic nucle i. The lymphoid cells have a rim of pale -stai ning cytoplasm , A helpful di agnostic feature is the rimming 01 the neoplastic ce lls surrounding individual fat ce lls. Adm ixed

reactive histiocytes are Irequently present. particularly in areas of fat infiltration and destruction. The hetocvtes are frequently vacuol ated , due to ingested lipid material. Other inflarnnatory cells are typically absent, not ably plasma cells. which are common in lupus panniculitis. Vascular invasion may be seen in some cases. and necrosis and karyorrhexis are common 114131. The tetter feature is helpful in the d ifferential diagnosis from other lymphomas involving skin and subcutaneous tissue[1202} . Cutaneous y8 T-c ell lymp homa s may show p anniculitis-like features. but com mo nly involve the dermis and epidermis. and may show epidermal ulceration.

Irrmmophenotype

t-een p henotype . usually COS-positive. with expression of cytotoxic molecules including granzyme B, pertonn. and t-een intracellular antige n (TlAl) 11202, 19191. The cells express I3 F1 and are negative for CD56. helping in the di stincti on from cutaneous 10 f-ceutvmpborna (8 1, 2253 ). The cells have a mature (I~

Postulated normal cou nterpart Mature cytotoxic a~ r-cea.

Genetics The neoplastic cells show rearrangement of t-een recep tor genes. and are negative for Ep stein-Barr viral sequences. No specific cytogenetic features have been reported. Prognosi s and predic tive factors Dissemination to lymph node s and other org ans is fare 181 4, 1175. 19191, The 5-y ear median survival ove rall is 80%; however. il a haemophagocytic syndrome is present, the p rog nosis is poor 11413. 24081· Combination chemotherapy has traditionally been used, but one study suggests thaI more conservative irmulosup pressive regimens (cyclosporine, prednisone, chlorambucil) may be effective {2273BI . A distinction Irom cutaneous -yO t-een lym phomas is impor tant. since SPTCL has a much better p rognosis 12254,2408 1.

Subc utaneou s panrncullt is-lill;e T-cefllymphoma I

295

Mycosis fungoides

Definition Myco sis lungoides (MF) is an eoioermotrooic. primary cutaneous t-een lymphoma (CreL) cha racterized by infiltrates

E. Ratfkiaer L. Cerroni CA sander 8 .R. Smeller R. Willemze

Table 11.05 CinIcaI stagIIg system lor mycosis UlpIes and S6zary syndrome. asrecenIIy propos.ed by\lle ISCL-EORTC {1642\. Stage I

Disease conlilecl kl tile skin with pa1dleslpapuleslplaQues <10% (5Iage IA) ex:>10% (stage IBI of the ski! Sl.dace; no ch:aIy abnom\aIlyn1tJ 1'IlXIe$.

Stage .

Skll'l~ WlltJ pa~BSSOOaIed 'II'lIh early(N1-N2)~ node rwotvemen! (Slage. AI ex skin irrIoOlvemel'll withone ormere un::us (:>l an) (stage 11B~

St.iJge III

Skin ~ witherytIVtlderma. no oreerty (N1-#Q) Ifnlih node IIWCWemenl am absenl: ex IcM blood Unc:u"bun:len «100G\d CI'OJlalI'lg seza,y eels)

Stage rI

!'to;;! t:bld UTn.r tud8tt (:>1000lt1 ~ SUary oeis l ard'or eXlerlsi'o'e ~ node ifflCIwment (NJ)orvisalrallll'Mllver'nel1 (Ml ).

of sma ll to medium-sized T lymphocytes

with cereontor m nuclei . The term MF should be used only lor the class ical cases characterized by Ihe evolution of patches , plaques and tumours, or for variants showing a similar clinical course ,

lCD-Ocode

970013

Epidemiology

TOIbIe 11.06

MF is the most corrmoo type of CTCL and accounts lor almost 50% of all primary c utaneous lymphomas 1240n Most patients are adults/elderly, bullhe disease can be observed in children and ado lescents. The mare.temaie ratio is 2: 1 124071.

~

Sites of involv ement The disease is. as a rule, limited to the skin,

staging lor dinicaIyabnormaIlyn1tJ nodes (:>1 .5 an)., mycosis!lJ1goides and 5ezary s.,..,.nme

ISCLreORTC (1642)

.,

DutchIystem (195aA)

NO clusifitation {lJ4(lA}

Categ«y 1, DL, no atypical CM(;

l NO. no atypicaIlymphocy1es LN l : oa:asionaI, isolated atypK:aIlyn1JIlocyIes lN2: ~ (3-6 oe1s ) d at)'piCal ~

Categ«y 2 Dl withearly lIIVOIvemen! with sc.anered atypical cue

.3

trac ted pe riod, Extraculaneous dissemi-

Category 3: parllal effacement 01 architeclll'e withmanyCMC

nation may occur in advanced stages. mainly to lymph nodes, liver, spleen ,

Calegory 4 wnpleteeflacemen1 of architecture

with widespread distribution. lor a pro-

lung s an d blood 12407). Involvement of the bone marrow (8 M) is rare 12407J Clinical features MF has an indo lent clinica l co urse with slow p rogression ove r years o r some times dec ad es, from patc hes to more infi ltrated p laques and eve ntua lly tumours. Patie nts with tumo ur stage M F c haracteristically show a combination of patch es. plaq ues and tumou rs, which often show ulceration

lN3 iIggI'llQates ofalypicaIlyrnphocyIes, bul

""''''''''-

l~ parllal ex complete eflacemenl 01 a~ lecture with manyatypical lymphocytes

Ol, dermatopathic lymphadenopathy; CMC, cerebriform mononlJdear cells with nllClei :>7.s...m ' N2 is divided into2 categories, N2a withoot donal!)'rearranged T-eellsand N2b with donaUy rearranged T-rels.

124071. Uncommonly. pa tients present with or develop an erythrcxiem1ic stage of disease that lack the haem atolog ic criteria of Sezary syndrome !23421.ln some patients, lymph node and visceral org ans ma y become involved in the later stages of the disease.

Fig.11.41 Myoosis blgoides A Early sageW!Ih palches. B DissenWlated plaQlJe stage.

Morpholog y The histolog y of the skin lesions varies with the stage of the disease. Early patch lesions show superficial band-like or lichenoid infiltrates. ma inly consisting of lymp hoc yte s and rnstocvtes. Atypical

Fig.1u a Eany MF W11h in6Itrates of CItypiCaI.1\aIoell ~ II the basal layer of epicIem'Is

296

Mature T· and NK-cell neoplasms

lmmunophenotype • The typ ical phenotype is CD2+ . CD3+ . TCRfl+. CDS+, C04 +. Coa- I1809I. Rare c ases ma y be positive for CDa 118091. Suc h c ases have the same clinical be-haviour and p rog nosis as CD4+ cases, and should not be consi dered a separate entity {24071. ACD8+ phenotype has been re port ed more commonly in paediatric MF. A lac k of C07 is freq uent in all stages of the d isea se 118091. Other alterations in antigens may be the expression of seen , but mainly occur in the advanced (tumour) stages 118091. Cutaneous lymphocyte anti gen (CLA) associated With lymphocyte homing to the skin is expressed in most cases. Cytotoxic granuteassociated proteins are only rarely expressed in the early patch/plaque lesions, but may be positive in a fraction of the neoplastic cells in the more advanced lesions 123331_

t-een

cells with small to medium-sized, highly irdented (cerebriform) nuclei are few, and rrostty conlined to the epi de rmis wh ere tt"ey characteristically colonize the basal layer 01 the epi dermis often as haloed cells, eithersingly or in a linear distribution 11411J . In typical p laq ues , epi de rmotropism is more prono unced. The p resence of intraepi de rmal collectio ns of atypical cells (Pautner mic roabscesses) s a highly c harac te ristic featur e. but is observed in only a mino rity 01 c ases 114111. With progression to tumour stage, the dermal infiltrates become more d iffuse and epidermotrop ism may be lost. The tumour cells increase in number and size, showing variable p rop orti on s of small , medium-sized to larg e c erebriform cells , blast cells with prominent nu clei and Intermediate forms 12407f. Histologic transformation. d efined by pr esen ce of >25% large lymphoid ce lls in the d erma! infiltrates may occur. ma inly in the tumou r stages 1361. 567. 23301. These large cells may be CD30-negative or C D30-positiye. Entarged lymph nodes from patients with MF frequently show dermatop athic lymphadenopathy w ith oaracor t'car ex pansion due to the presence of large number Ii renocvtes and interdigitating cells with abundant. pale cytoplasm. The ISCL-EORTC staging system lor cunlCally abnormal lym ph nodes (> 1.S cm) in tEm Sezarysyndrome 116421integrates se previous NCI and Dutch lymph node staging systems I 1940A. 1958AI . There ow-e 3 categories . essentially reflec ting no

involvement. early involvement (With no architectural effacement). and overt involvement (with partial or complete arct»tectural effacement). Recognition of the ea rly infiltrates can be d iffic ult and can be aided by T-ce ll rec eptor analysis 11642 1. N3 lymph nodes may simulate peri pheral lymphoma. NOS Hodgkin Iym.

f-ceu

pr oma.

or

Genetics T<ell rec eptor genes are clonally rearranged in a variable proportion 01 cases , possibly depending upon the number 01 tumour cells and the detection technique employed 11765. 23981. Complex karyotypes are p resent in many patients , in par tic ular in the advanced stages 11 381 . 2 1901. A vast number of

Fig. 11.50 MF!um()IJf stage (AJ wiltl histological translotmation toa large cellymphoma (8).

Mycosis fungoides

?37

12297f. Due to the deep localization 01 the neoplastic infiltrate. the d isease is less accessible to skin-targeted therapies, The disease-specific 5-ye ar-survival is approximately 70-80%, w hic h is significanny worse than that of p atients with classical plaque stage MF 1797. 22971 .

Fig. 11.$3 Mycosis l.npdes. A FoIo.*Jtropic myoosis foogoides Wlt!l atypic:al ~ irlfiltrabng a _bide B Hole O8lebllforrn nudIi , C The alypicaleels areCOJ.potsi\i'we. 0 The irM:llYed loIde shows IIlI.ICinOuS ~lion WIlh ~ of AIc:ian bkJe-positive matel'ial.

different structural and numerical alterations have been desc ribed . Constitutive activation of STAT3 and macuvauon of CDKN2A1p ltr" ... and PTEN have been identified and may be associated with d isease progression 11583. 1951,1952, 205 1, 24241. Ge ne ex p ress ion p rofi ling studies have srown tumour necrosis tactoe (TNF) antr-acootonc pathway activ ation in the tumouri ge nesis of MF 1226 11.

in patients with skin tumours andJor extracutaneous d issemination 12298}. Age above 60 years and eleva ted lactic dehyd rog enase are othe r adverse prognostic parameters 15681. Histologic transformation wilh increase in blast cells (>25%) is also an adverse parameter 13611.

Postu lated nor mal counterpart Mature skin-homing CD 4+ t-een.

Ponloulctroplc MF Fo lliculotro pic MF is c haracte rized by the presence of follicular infi ltrates of atypical (cerebri form) CD4+ T lymphocyt es etten with spari ng of the ep ide rmis 1797f. Most c ases sho w muc inous de ge neratio n of the hair fo llic les (fol licu lar mucinosis) bu t similar c ases with out fo llicular mucinosis have bee n reported {2297}. The lesions p referentially involve the head an d neck area and often present w ith g rouped follic ular papules associated with alopecia

Prog nosis and predictive factors The sing le most important prognostic fac tor in MF is the extent of c utaneous and extracu taneous d isease as reflect ed in the clinical stage. Patients with limited d isease ge nerally have an excellent prognosis with a simi lar survival as the general population 122981. In the more advanced stag es. the prog nosis is poor, in pa rticular

298

Mature T- and NK-ceU neoplasms

Variants

Pagetoid reticulosis Pag etoid reticulosis is characterized by the presence of patches or plaques with an intraepidermal proliferation of neoplastic t-eens 1870}. The term should only be used for the localized type (WoringerKoIopp type) and not for the disseminated type (Ketron-Goodman type) as cases corresponding to the latter category woUd currently most likely be classified as aggressive epidermotropic C08-positive CTCl or cutaneous y&-positive T-cell tyrophoma 124071. The atypical cells have medium-sized or large. sometimes hyperchromatic and cerebriform nuclei, and either have a CD4+, C08- or a CD4- . CD8+ phenotype. CD30 is often expressed. In contrast to classical MF. extracutaneous dissemination or disease-related deaths have never been reported 124071Granuloma tous slack skin Granulomatous slack skin (GSS) is an extremely rare subtype of CTCl characterized by the slow developme nt of folds 01 lax skin in the major skin fol ds (axillae. groin) and histologically by a g ranuloma· tous infilt rate with clonal CD4+ T cells. abundant macrop hages and multinucleated g iant cells 123001, In approximately one third of the repo rted patients. an assoc iation w ith C HL has be en observed, An association with c lassical MF has also been reported (2300 ). Mos t patients have an indolent clinical c ourse [12611.

I

Sezary syndrome

Definition 5ezary syndrome (SS) is defined by the reo ct erythroderma. generalized tym~lhy and the presence of CIOnaJIy related neoplastic with cerebriform ru::lei (5eZ8ry cells) in skin , lymph nodes and peripheral blood (PB). In addition. nc. moreof the foiloNing criteria are reIpfed: an absolute 5ezary cell count of aeasr 10CXJcelis per mm3,an expanded CD4+ t-een population resulting in a C04ICD8 ratio 01 more than 10 and/or

t-eens

'oss ol one 01 more t-een antigens.

-

9701/3

KDOcode

ThIs is a fare disease, which accounts for less than 5% of all cutaneous t-een Iym-

E. Ralfkiaer R. Willemze SJ . Whill aker

immunoperesrs associated with loss 01 normal circulating CD4 cells 19891. MOrpho logy The histological features in 55 may be similar to those in mycosis fungoides (MF). However, the cellular inliltrates in SS are more often monotonous, and epidermotropism may sometimes be absent. In up to one third of biopsies from patients with otherwise cl assical SS the histologic picture may be non-specific 122701. Involved lymph nodes cnaractenencanv show a dense, monotonous infiltrate 01 Sezarv cells with eff acement 01 the roemal lymph node archi tectu re 119591 _Bone marrow may be involved, but the infiltrates are oft en sparse and mainly interstitial 12018}.

eeree 124071_ II occurs in adults , char-

eiensncanv presents over the age 0160.

Fig. 11.54 sez.y S)'!Doole. Geoeralzed skin eseee lIIiltlerylhrOOenna.

M-Auorescence in ssu hybridization (FISH ) and comparative genomic hybridization (CGH ) tech niq ues have shown a high rate 01 unbalanced nansiccanons and associated deletions often involving chromosomes 1p, 6q , 1Oq, 17p and 19. suggesting a high rate of genomic msrability 113821. Inactivation of TP53 and p I(J"I'<'" are frequent 11 440 . 1583, 19511. Amplifica tion of JUNB, has been icenntied in Sezarv syndrome {13841. Gene express ion profiling stud ies have not yielded consistent findings 1239 , 871 , 1110 , 2296 1.

Clinical features

Immunophenotype Tumo ur cells are CD2+, CD3+ , TC RB+ and CD5+ . Most cases are CD4+ . Exp ression of CDa is rare . Sezery cells express cutaneous lymphocyte antige n (CLA) and the skin-homin g receptor CCR417031 and characteristically lack CD7 and CD26 1204 , 1571 , 2046}. T p lastin mRNA and protein have been shown to be enha nced in Sezary ce lls relativ ely 10 normal he lpe r t-eens 11110 , 2 1161.

Postu lated normal counte rpart Mature eoroermotrootc skin CD4 + T-cells.

Patients present wit h erythrode rma an d generalized lymphad enopathy. Other features are pruritus , alopecia , ect rop ion, palmar or planta r hype rkeratoses and OI1ychodystrophy. An inc reased pr eva e-ce of second ary ma lign anc ies, bo th cctareous and sys temic, has been reported in SS and attributed to the

Ge netics T-ce ll recept or genes are c lonally rearranged {1765 , 239 7, 2398) Recurrent c hromosomal ab norma lities have not been detected in SS, b ut com ple x karvotvpes with numerical and structural alterations are COTfT'Olandsimilafto MFl 161, 1381, 13821.

Prog nosis and p red ictive fact ors This is an agg ress ive disease with an overall survival rate at 5 yea rs of 10 - 20% 12407f. Most patients d ie of op portunis tic infections. Progn ostic teet er s include the degree of lymph nod e and PB involvement 11161. 2342 1.

and has a male predominance.

Sites 01 involvement SS isa leukaemia an d thu s b y definition a generalized disease. All viscera l organs may be involved in the te rmi nal stages. I"owever, there is often a remarkab le

&paring of the bone marrow (8 M),

homing

~

Ft ll j5

.-1""--

~d

sez.yC8b in Gi8msa ~ bklodIilms IA) arK! by lhastrucUal ellamllalion(B).

FIg. 1t .5& SUI iniItrates in SS wiIh epioermotll»C I'IflIlraIes of aIypl3, ceoeb"'''' ~

Sezarv syndrome

299

_

r

Primary cutaneous CD30-positive T-cell Iymphoprolif erativ e disorders

Primary cutaneousCD30-positive Iymphoproliferative disorders (LPO)are the second most common group 01 the cutaneous

years . Child ren are sporadically affec ted {172, 2407} . The M:F ratio is 2-3:1 11721·

T-eelilymphomas (CTCL), accounting for app roximately 30% of the cases. This group includes primary cutaneous anaplastic large lymphoma (C-AlCL), lymphomatoid papulosis (LyP) and borderline cases. These diseases tom a spectrum that may show overlap ping histopathologic and phenotypic featu res 124071. The clinical

Sites of involvement The most freq uently affected sites include trunk . face, extremities and buttoc ks .

appearance and coo-se are therefore critical lor the definite diagnosis. The term "borderline" refers to cases in which , de. spite careful clinicopathologic correlation. a definite distinc tion be tween C-A lCl and LyP cannot be made. However, clinical examination du ring follow-u p will generally disclose whether such p atien ts have C·ALCL or LyP {172 1_From a clinical perspective LyP is not considered a malignant d isorder , despite oemonstraton of monocionanty in many cases.

Primary cutaneous anaplastic large eel/lymphoma (C-ALCL) Definition C-AlCl is composed of la rge ce lls w ith an anaplastic, p leomorphic or immunoblastic cytomorphology that express the C0 30 antigen by the ma jority (> 75%) of the tumour c ells (2407 1. Patient s with C-ALCL should not have cl inical evid ence Of history of myco sis fung oid es (MF ); in this selling the diagnosis should be considered trans fo rmation of MF to tumour stage. whic h may be CD30-positive or negative 124071. The d isease must also be d istinguished from systemic ALC L with cutaneous involvement, which is a separate disease wi th different cytogenetics. clinical fea tures and outcome 16131. ICD-O code

97 1813

Epidemiology C-ALCl is the second most common type 01 CTCl 11721. The median age is 60 300

Mature T- and NK-cell neoplasms

E. Ralfk iaer

R. Willemze M. Paulli M.E. Kadin

Cli nical featu res Most patients present with solitary or localized nodules or tumou rs. and soretimes pap ules , and otten show ulceration 1172,2407). Mullifoc al lesions are seen in about 20% of the patients. The skin les ions may show partial or com ptete spontaneous regression as in lyP. These lymphomas freq uently relapse in the skin . Extracu taneous disseminat ion occurs in -10% of the pat ients , and mainly involves the regional lymph nodes 1172, 2407 1. Morphology Histology shows diff use , usually noneot cermotropic infiltrates with cohesive sheets of large CD30-positive tumour cells. In most cases the tumour cells have the characteristic morphology of anaplastic celf s , showin g round, ova l or irreg ula rlyshaped nuc lei, prom inent eosinophilic nuc leoli and abundant cy to p lasm 124071Less commonly (2Q-.-.25% ), they have a non-a nap lastic (p leomorphic or immuneb lastic) appearance (172 , 17 111. Reac tive lymphoc ytes are often present at the per ip hery of the lesion s. Ulcerati ng les ions may show a l y P-like histology with an abundant inflammatory infiltrate of reactive T-cells , hlstto c vtes. eosi no phils, neutrophils and relatively few Co30-posilive cells. In suc h c ases ep iderma l hyp e rp lasia may be prom inent . The inflammatory background is espec ially p romin ent in the rare neutrophil-rich (pyogenic) vari ant 12991. Immunophenoty pe The neo pl astic cells sho w an activated C04 + t-een phenotype with variable loss ot C02, C05 and/or C03 and freq uent exp ression of cytotoxic p roteins (granzyme B . TlA1 , pe rtonn ) {255 , 1204 . 24071 _ Some cases «5%) have a CD8 + phenotype_C03J is by defll'\ilionexpressed

t-oea

FIg.11.5a C-ALCl with conAuent sheets 01 large cell with anaplas tic ~.

by a majority (>7 5%) of the neoplastic cells 12407 1_Unlike systemic ALCl, most C-AlCl exp ress the c utaneous lymphocy te antigen (CLA ), but d o not express EMA or AlK (anaplast ic lymphoma kinase) (5 16 , 537 , 21821. Unl ike Hodgkin ano Reed-Sternberg cells. staining for CD15 is g ene rally negative, Coexp ression of C056 is observed in fare c ases, but does not appear 10 be assoc iated with a~ unfavoura ble prognosis (15811. Genetic s Most cases show c lonal rearrangement ci the t-een rec eptor (feR) genes 124071 However. TCR p roteins are often not expresse d 12381. Stud ies usi ng comparative genomic hyb ridi zation have revea led c hromosomal imbalances with gains of several puteee oncogenes 113831. However, specmc and consistent cytogenetic abnormalities have as yet not been identified. Unlike svstere AlCl, C-AlCl does not carry transccetions involving the ALK gene at chromosome 21537. 613 . 2182 1.

Postulated I'lQI"mal couterpart Transformed/activated skin-homing T IyrnphJcyte. Prognosis and predictive factors The prognosis is usually favou rable, with a l(}.year disease-related survival of approximately 90% 1'72, 13221. Patients :resenting with mounocarskin lesions and patents with involvement of regional tyrrch nodes have a similar prognosis to patients with only skin lesions 11721. No dlfl!fence in clinical oresentanon. clinical oehaviour or prognosis is found between cases with an anaplastic morphology and cases WIth a non-anaplastic (pletllTl()(phic CJ i'Tvnunoblastic) morphology 1172. 1322.17111.

Lymphomatoid papulosis Defr'lilion

l'lfTlPhomatoid papulo5is (LyP) is a ctvcoc. recurrent, self-healing skin disease comPlSEld 01 largeatypical anaplastic. irTTnJnoblaslic or Hodgkin-like cells in a marked lIf4arrmatory background. In some cases Ole pattern of cu taneous involvement may resemble MF (type B).

(;[}{) cod.

97 18/1

Epidomdogy lyP most often occurs in adults (med ian

age, 45 years). but children may also be affected. The male 10 female ratio is 2-3: 1 1172, 1322, 1996, 2303). Sites of involvement lyP isa skin-limited disease that most freq'Jently affects trunk and extremities 11721. Rarely, oral muc osal lesions may te present. tln ical leatures

lyP is characterized by the presence of papular. papulonecrotic and/or nodular skin lesions at di fferent stages of oeveropment[1721 . Individual skin lesions disappear within3-12 weeks, and may leave tlehind superficial scars. The duration of fie disease may vary Irom several months klrrore than 40 years. In up to 20% of pa\Ief'I1S. lyP may be preceded by. associaled with. or followed by another type of malignantlyrnphoma, generally MF, cutaIIlnJS anaplastic large ce ll lymphoma or ttxigkin lymphoma 1172,10791 .

Fig. 11.59 lYfl'lhomaDd papIbas, l p A..lDlSISling d atypicaIlyrnphoid eels adrriJced \MGl many nftarrmaDyeels (A). The alypical eels havea cerebriIorm or Hodglc.n-like ~y (B) and are strongty posrtiye forC030(el ·

-ogy

The histologic picture oflyP is extremely variable. and in part cor relates with the age of the biopsied skin lesion. Three histologic subtypes ollyP (types A, B and C) have been described, which represent a spectrum with overlapping features 1172. 2407j, In l yP type A lesions. scattered or small clusters of large, sometimes multinucleated or Reed-Sternberg-like. CD3Q. positive cells are intermingled with numerous inflammatory ce lls, such as histrocvtes. smal l lymphocy tes. neutrophi ls and/or eosinophile. LyP. typ e C lesions demonstrate a monotonou s popul ation or large clus ters of larg e CD30- posi tive T-c ells with relatively few admixed inflammatory c ells. l yP. typ e B is uncommon « 10%) and is c haracterized by an eprdermotropic infiltrate of small atypical cells with ce rebriform nuclei similar to that observed in MF.

Genetics Clonally rearranged T-een receptor genes have been detected in approximately 60% of lyP lesions 110791. Identical rearrangements have been demonstrated in LyP lesions and associated lymphomas 110791. No consistent abnormalities have been described The (2;5)(p 23;q35) translocation is not detected in l yP 1613. 614).

Postulated normal c ou1erpart Activated skin-homing T lymphocyte, Prognosis and predi ctive factors LyP has an exc ellent prognosis, In a study 01 11BlyP patients, only 2 patients (2%) died of systemic disease after a median follow-up duration of 77 months 11721, However, since risk factors for the deve lopment of a systemic lymphoma are unknown, long-term follow-up is advised.

lmmunophenotype The large atyp ic al cells in the l yP type A and type C lesions have the same phenotype as the tumou r cells in C-AlCL The atypical cells with ce rebriform nuclei in the l yP. type B lesions have a CD3+. CD4+ . COB· phenotype and do not express CD30 124071. Rare cases of LyP with COB and NK-cell phenotype have been reported 1709. 13661. Primary cutaneous CDJO.-posillVe T-eelllymphoproliferative disorders

301

Primary cutaneous peripheral T-cell lymphomas, rare subtypes

P. Gaulard E. Berti A Willemze E.S. Jaffe

Perip he ral T-cell lymp hom as (PTeLl not uncommon ly involve the skin, either as primary or secon dary manifestation of the disease. Within this group, three rare provisional entities were delineated in the

WHo-EORle classification lor cutaneous lymphomas. inc lud ing primary cutaneous -,fJ t-een lymphoma , primary cutaneous aggressive epidermotropic COO-positive cytotoxic r-ceu lymphoma and primary cutaneous CD4-positive smalVmediuffisized p1OOlTlOfphic t-een lymphoma The tarter two entnies are sntt c on sidered provtsicoar. It should be emphasized that a diagnosis of mycosis lungoides (MF) must be ruled out by complete c linical ex-

arrmanon and an accurate clinical history.

Primary cutaneous gammadelta T-calllymphoma

Fig. 11.60 Primary ~s -yI) T-c:el IympIloma. l esions are dinicaIy diYefse. alld consist 01 plaques. with or.... out lkeration (A,B), ortulTOUrs (C). The lesion may consisl 01 an indlrclled plaque. with subl::ul<wleous i'IMtrcIIicn(DI.

Definition Primary cutaneous rt'i t-een lymphoma (PCGD-Tel) is a lymphoma composed of a clonal proliferation of mature, activated yS T-eells with a cytoto xic phenot ype . This group includes c ases p reviousl y know n as subc utaneous panniculitis-like t-een lymphoma (SPTCl) with a y() ph enotyp e. A possibly related co ndition may pres ent primarily in mucosal sites. Whether cutaneou s and mucosal y(i TCl are all part of a single disease, i.e. m uco-cutaneous yO TCl , is not yet clear 11 040 , 24321. ICD-O code The provisional code p roposed for the fourth edition of ICD-O is 9726/3 Epidemiology PCGD-TCL are rare, representing approximately 1% of all cutaneous T-cell lymp homas 12254. 2407 , 24081. Most cases occur in adults. Thereis no sex predilection.

Fig. 11 .61 Primarycetaoecos -yI) epidermis is neaotic.

T~ llymphoma .

The

Impaired immune function associated with chro nic antig en stimulation may predispose to the developm ent of PCGD -TCL

[81,24321 .

Etiology

Sites of involve ment PCGD-TCl often p resent with generalized skin lesions. p referentially affecting the extremities 12254, 24081.

The d istribution of d isea se reflects the localization of normal ylJ t-eens. which are believed 10 p laya role in hos t mucosal and ep ithelial immune responses 12291.

C linical features The clinical presentation 01 patients with PCGD-TCl is variable. The disease may

302

Mature T- and NK-eell neoplasms

Fig. 11 .62 Primary cnaoeccs yO T-cell lymphoma In ltlis case the iI1filtrate is primarily dermal.

be predominantly eotoermotrootc and present with oatcnesroraques. Some patients may present with deep dermal a subcutaneous tumours. with or without epidermal necrosis and ulceration lS1 207, 1068,2254,2408,24321. The leeces are most often p resent on the extremes. but other sites may be affected as wei 11410.2254.24081. Dissemination tOrTlr cosar and other extranccar sites is frequently ob served, but involvement d lymph nodes, spleen or BM is uncorrm:n. A haemophagocytic syndrome may 0CCl1

Postulated normal counterpart Functionally matu re and act ivated cytotoxic yO T-cells of the innate ITrru'le system. Prognosis and predic tive factors

PCGD-TCl are resistant to mulliagent cll emotherapy and/or radiation and have a poor prognosis with a median survival of app roximately 15 months 12254, 2408]. Patients with subcutaneous tat involvement tend to have a more unfavourable prognosis as c ompared with patients with epidermal or dermal disease only 122541.

Primary cutaneous CD8-positive agg ressive epidermotropic cytotoxic T~1I1ymphoma

Fig. 11.63 Pnmary cutaneous yO T<811 tymphoma. H,slological penems arecverse. and maybe PiWlnicUitJs-like in the OemIaI lnMration is usualfy present and !tie overlying epiOenTis may be ulcerated.

IticlUIeous fat

in patients with pa nnicu litis-like tumours

12254. 24081. B symptoms, inc luding fever. night sweats and weight loss are seenin the majority of patients.

~ rnee ma)or histologic pa tterns of in'ldYement can be present in lhe skin: epillerrrolropic, dermal and subcutaneous. O'ten more than one histologic pattern is present in the same patient in different tiopsy specimens 01' within a single boosvsoeorren 1207,1 4 10,2254.24081. Epidermal infiltration may occu r as mild eccermotrocism to marked pagetoid reticulosis-like infiltrates 1207. 1540, 18111. The subcutaneous c ases may show rimmng of tat cells, similar to SPTCL 01 a ll cngn, but in addition usually show dermal

,

.•

•.

F, 1161 Plimary cutaneous aggr&SSive epidennolropW; cytoloxic T-cell lymphoma. te soes are _1IaemorltIagic, and llffl llSsocialed with ulcefalion IIItPdem'1a1 necrosis. ~ve

and/or epide rmal involvement (2254, 2408 1. Til e neopl astic c ells are generally med ium to large in size with coarsely clumped ch romatin 122541. Larg e blastic cells with vesicula r nuclei and prominent nucleoli are infrequent. Apootosts and necrosis are common. often with angieinvasion 12254. 24081 . Immunophenotype The torrocr cells characteristically have a JiF1-, C03+, C02+. CDS-, C07+/-, CD56+ phenotype with strong expression of cytotoxic proteins 11 040, 1410, 1919. 2254, 2408, 2432} . Most cases lack both CD4 and CD8, although COB may b e expressed in some c ases 12254, 2408) The cells are strongly positive for TCR6 with appropriate detection methods. If staining for TCRO cannot be performed , the absence 0l lJF1 may be used to infer a yO origin und er appropriate circumstances (1068 ,1919,2254.2408} .

Genetics The c ells show clo nal rearrangement of the TRG@ and TRO@genes. TRB@ may be rearranged or deleted, but is not expressed. Cases with predominant subc utaneous involvement express Wi2, but this has not been studied in other PCGD-TCL 117831. Epstein-Barr virus (EBV) is negative lB1. 1091, 2254,24321.

Definition This provisional entity is a cutaneous T-eelllymphoma (CTCll characterized by ponteraton 01 epioerrroncoc C[)B..positive cytotoxic t -eens and aggressive cl inical behaviour. Differentiation from omer types of CTCL expressing a COB·positive cytotoxic t -een phenotype is based on the cli nical presentation. clinic al behaviour and certai n histological features, such as marked eoioe rrrotroprsm with ep idermal nec rosis.

IClJ.Ocode

970913

Epidemiology This d isease is rare accounting for less than 1% of all CTCL 11 2. 209, 24071 . It occurs mainly in ad ults. There are no known predisposing factors. Sites of involvement Most patients present with generalized skin lesions. Clinical features Clinically, these lymphomas are cha racterized by local ized or disseminated eruptive papules, nodules and tumours show ing central ulceration and necrosis or by superfic ial, hyper keratotic patches and plaques 1209. 19341 _These lymphomas may disseminate to omer visce ral sites (lung, testis. central nervous system, oral mucosa), but lymph nodes are often spared (209, 1404, 17901. Morp hology The histolog ical app earance is very variable ranging from a lichenoid pattern with marked . pag etoid eproermoeocls m

Primary cutaneous peripheral T-cell lymphomas, rare subtypes

303

Genetics The neop lastic T-eens show clonal TeR gene rea rran ge ments. Specific genetic ab nor mali ties have not b een described. EBV is nega tive {174, 1410 1. Postulated norma l counterpart Skin-h omi ng. COB-positive. Cytotoxic t-eens of ~ type. Prognosis and predictive factors These lymphomas often have an aggressive clinical course with a median survival of 32 mon ths 12091. There is no difference in survival between cases with a small or large cell rTIOfphology 11741.

Pnmary cutaneous CD4-posmve smaJl/medium T-cell tymphoma F"IQ. 11.65 PmwyaDlllwsagps:siYe epdeoll()(r<4Jit

C()8...posltive C)1oloxiC ToOIlII lymphoma. The atypical lymphoid oeRs in~ ltra le in the superficial dermis and extend into the epiderrris in a pageDd Iashon.

Definition This p rovis ional entity is a cutaneous T-cell lym phoma characterized by a pre. dom inanc e of small to mediu m-sized CD4-positive pleomorphic t-eens without evi dence of patc hes and plaques typical of mycosis fungoi des. A majority of cases p resent with a solitary skin lesion .

teo-oro»

970913

Epidemiology This is a rare disease, accounting for 2% of all c utaneous T-cell lymp homas 124071. Fig. 11 .66 Primary wlarleOUs aggressive epidermotropic C08-positive cylotox ~ 'l-cell lymphoma, Skin section stained lor coe, highlighting the marked epdermojrcpism, with the majority of the neoplasticcells kxalized to the epidermis.

and subepidermal ede ma to deepe r, mo re nodu lar infiltra tes. The epi de rmis may be ac anthotic or atrop hic , often with necrosis, ulceration and blister for mation [ 12,2091. Invasion and destruc tion of adnexal skin structures are commonly seen. Angiocentricity and angioinvasion may be p rese nt 11 4 101. Tumour cells are smanmedium or mediul'T'l-large with p leomorphic or blastic nuclei 12091. Immunophenotype The tumour cell have a I3F1+, CD3+ , coa+ , granzyme B+ , pertonn- . TlA l+ , CD45AA+f- , CD4SAO-. CD2-f+ , CD4- , CDS-. CD7+f- phenotype 112. 174.209. 1410, 19341. 304

Mature T- and NK-ceU neoplasms

There is a predominance of small/mediumsized pleomorph ic t-eens 1174. 177. 734, 209BI. A small proportion « 30%) of large pleomorph ic ce lls may be present {1771. In some cases a consid erable ad mixture with small reactive lymphocytes and hisbocvtes may be ob serve d 11 9501. Eosmoptuls may be numerous in some cases 1754AI· The princi pl e drtterennar diagnosis is w ith a reactive lymphoid infiltrate in the skin . so-called p seudolymphoma or cutaneous lymphoid hyperplasia Immunophenotype By definition these lymphomas have a CD3+ . CD4+. CD8-. CD30- phenotype. sometimes with loss of pan T-cell markes 1174. 20981. Cytotoxic proteins are not expressed 11741. Adrrixed poIyclonal plasma and may be present, making distinction from a reactive process difflcUt in some cases

ceus

a-cens

Gen etics The TeR genes are cionanv rearranged 1209B. 234 11. Demonstration of an aterant t-een phenotype and clonality are useful cri teria to differentiate these smaW medium-sized p leomorp hic CTCL from pseudo T-cell lymphomas. which also may present wi th a solita ry p laq ue or nodule 11321 . Specific genetic abnormalities have not been described. EBV is negative,

Sites of involvement These lesions usua lly present w ith a sol itar y plaqu e or nodule, mo st co mmonly on the fac e, neck or upper trunk 1174, 754A l . Involveme nt of lower extre mities is rare . By definition , there shou ld be an abse nce of pat c he s ty pic al of mycos is fungo ides {174 , 734 , 2098 , 23411. Clinical features Patients are generally asymptomatic , with the detection of a single skin lesion being the sole manifestation of d isease {17 4. 754Af. A minority or patients may p resent wit h lar ge tumours, or multiple skin lesio ns {754AI. MoqJhology These lym phomas show dense. diffuse or nodular infiltrates within the dermis with tendency to infiltrate the subcutis. Epide rmotropism may be p resent focaUy. but if conspicuous. consideration should be given 10 the diagnosis 01 mycosis h.ngoides,

Fig. 11 .67 Typical presenIatlons of IlfIl*Y ausma&'medium ~ T<el 1yrllJIuna

I I

I

I Postula ted normal counterpart

Sc.in homing CD4-positive T-cell. Prtrgtosis and predictive factors r-ese lymphomas have a rather ~l'OUI'a ble prognosis with an estimated ).year survival of approximately 80% 1174 177, 706. 734, 825, 2098, 2341,

24071, Partic ular ly, cases p resenting with a solitary or loc alized skin lesions seem to

have an excellent prognosis 11741. In such patients surgical excision or radiotherapy is lhe preferred mode 01 treatment. Patients with multiple lesions or large tumours may have a more aggressive clinical course 1754AI.

Primary cutaneous per ipheral T-cell lymphomas. rare subtypes

305

Peripheral T-cell lymphoma, not otherwise specified

SA Pileri E. Raltkiaer D' D. Weisenb urger S, Nakamura I. Sng HK MOlier-Hermelink E.S. Jaffe

Definition A heterogeneous category of nodal and extranodal mature T-cell lymphomas. which do not correspond to any of the apectticeny defined entit les 01 mature T-celilymphoma in the current classification.

ICD-O code

9702/3

Epidemiology

These tumours account to- approximately 30% of "",,_aJ T-eel "'"""""'" (PTCll in Western countries 118491. Most patients are adults. These lymphomas are very rare

in children . The male:female ratio is 2:1. Sites of involvemen t Mosl patients present wi th peripheral lymph node involvement, but any site may be affected. Generalized disease is often encountered with infilt rates in the bone marrow (8M), liver, spleen and extranodal tissues 11849 1. Peripheral blood (PS) is some times involved, b ut leukaemic presentation is unc omm on. Extranodal presentatio ns may occur, with the skin and gastrointestinal tract represent ing the most co mmonly affecte d sites. Und er these c ircumstances, the diagnosis of periph eral t -een lymphoma , not ot he rwise spec ified (PTCL, NOS) sho uld be made only when othe r specific ent it ies have been excl ude d. Other less frequ ently invol ved sites inc lud e th e lung , sa liva ry g land an d ce ntral ne rvous system. Clinical features Patien ts most often present w ith lymph node enlargement and a majority have advanced disease with 8 symptoms {18491. Paraneo ptastic features such as eosinophilia, pru ritus or rarely haemophagocytic syndrome may be seen 118491. Morphology In the lymp h node, these lymphomas show paracortical or diffuse infiltrates with effa cement of the normat architecture. The c ytolog ic al spectrum is extremely broad, from highly polymorphous to m0nomorphous. Most cases consist ot numerous medium-sized and/or large cells With 306

Mat ure T- and NK-eel l neoplasms

Fig. 11.69 Periphelill T.e:en lymphoma. NOS. A Diffuse infillrates of large !yrrlIhoid cells WIth pIeomOi phic, ~ nudei and prcminent 1'IJCleoIi. B In between the neopIastlc eels, !here arescaneeed eosinophiIs andI'kJmetOUS vessA C Nutlei are marke
irregular, p leomo rp hic , hyperch romatic or vesicular nuclei, pr ominent nucleoli and many mitotic fig ures 1898, 10351. C lear ce lls and Reed-Stern berg (RS)-like ce lls can also be seen, Rare cases have a pre-

dominance of small lymphoid cells wi!:! atypical, irregular nuclei. Hig h endothelial venures may be increased 1898. 10351,A T zone patt ern may be observed, but is not specific for a d istinct entity, An inflam-

Table 11.07 Differential diagnosis of nodal penpteral T-Wli lymphoma, not otherwise specified , Disease

Immunophanotyplc fsaturlll

Peripheral T-cell "rmphoma. rot otherwise specified

C04>CD8, arltigen loss frequent (C07, C05, CD4IC08. CD52). C03(h1+. C056-/+,COlD-, CLCX1J.. POI-

~fTII1unob1a stic lymphoma

CD4+ or mi ~ed CD4I8. C010+/-, BCl6+1•. CXCl13+.P01+, hyperplasia 01 EBV+ C020+8 blasts

AdlAI T-cea IeukaemiaJlymphoma

CD4+, C02So , C07·, C03O-l+, COl5-l+, FQxP3+/.

Anaplasticlarge eel lymphoma

C030+. ALK+/·. EUA+. CO25+-. cytOtoxic glilnules+, CD4+/-, C03-l+. CD43+

acre..

roc.

I.¥ga C020+ bIasls m background of Coo+reactive T-<:e/Is Mixed awcD8. 1Iltad ard'liIecture. vanable C025andCD3O: scatlerlld

CO... _

+ . nearly a~ posiWe: oJ_.majOnly posrnve, .) +, rrirlOnCy pos.trve, FCC. kJIcuIitI' denlrtlic eees EBY. Epsleirl-8arT virus.

matory background is often present, lnckKllng small lymphocytes, plasma cells, la rge s-cene (that may be dOnal rresoecnve of EBV infection) 123591and clusters of epithelioid tusnoc:ytes. Epithelioid t nenccvtes are particularly numerous in the lymphoepitheliOid eel variant. The ortterennal diagnosis with rgoirrrnur"OOlastic T-cell tymphoola (AITL) may requireextensive im:nunophenotyping, rl one uncommon va riant, the neoplastic cellsselectively infiltrate the lym pho id follicles, and the resultant follic ular gr owth pattern may suggest a B-cell lym phoma dfollicular origin 15241 Extranodal involvement takes the form of use infiltrates composed of similar eels Inee skin, the lymphomatous popJalion lends to infiltrate the dermis and !LbcuIis. often producing nodules that -nay undergo central ulceration 117101. lcoerrceooism. anqccenmotv and adl'e1aI invotvement are at times seen 117101. In the spleen, the pattern is very variable fTtm solitary or multiple fleshy nodules to dl~use white pu lp involvement w ith c olorization of the periart eriolar shealth or in !tJllEl cases predominant infiltration of the red pulp13821.

eosmoonus.

the distinction from anaplastic large-eell ly mphoma (A lCL) and Hod g kin lymphoma 1149. 23901. Aberrant expres sion of C02Q and/or C079a is occasionally enc ountered 12359, 23901. Unlike AITl. PTCl, NOS usually lac ks a follicula r T helper (TFH) phenotype (C01O+, BCL6+, Po l+ and CXCL13+ ) with the exception of the follicu lar/perifollicular variant 199, 60S , 852, 2390 ). Prol iferation is usually high and Ki67 rates exceed ing 70% a re associated with a worse progn osis

123901.

Genetics Antigen receptor genes TCR genes are clonally rearranged in most cases 118491.

Cytogenetic abnormalities and oncogenes These are usually highly aberrant neoplasms with complex karyotypes 118491. In both conventional and array comparative genomic hybridization (CGH ) studies . recurrent chr omosomal ga ins have bee n observed in c hromosomes zq. Sq. 17q and 22Q. and recurrent losses in chromosomes 4Q, 5Q, 6Q. so. 10Q, 12Qand 13q . Dele tions in ch romosomes SQ. lOq and 12q are associated with a better prognosis 12233, 2492 1. The genetic imbalances observed in PTCL, NOS d iffer from those of other T-cell lym phomas. such as AlTL and AL CL 12233. 24921. Gene expression profiling studies have provided some hints for better understanding PTCl, NOS 1137, 494 . 1451, 1739AI. In particular, its gene signature d iffers from those of AlTland AlClI523, 1739A 1.

lmulophiberrant t-een phenotype with frequent

PTCL,NOS is usually char ac terized by an

OC!fI'!Vegulation of COS and CD7 123901. AC04+,coa- phenotype predominates in rr:daI cases. CD4/cD8 dOuble-positivity or lb..OIe-negativity is at times seen, as is COB. CD56 and cytotoxic gr anule ex[2390 1. T-c ell rec ep tor (TC A) oeIa-chain (I3F 1) is usually expresse d . aiIC\Img the differenti ation from "to t -een 'l'mphomas and NK -c ell lymphomas . COO2 is absent in 60% of c ases 1393 , '740. 18561. CD30 ca n be expressed, exceptionally with Co lS. but the global ;tl8'lOIypic profile and morphology allow

cesson

Rg. 11.11 Periplleral T~ lymphoma, NOS. A NoIe the marked pleomorphism ollhe neoplasticpopulation. B" Ki67Iabeling. C ~F l slall'lng. Peripheral

t-een lymphoma. not orrerwee specified

307

In comparison to normal T lymphocytes, it is characterized by the rec urrent dereg ulation of genes involved in relevant cell func tions. e.q . matrix oeposmon. cytoskeleton organization . cell adhesion, apoprosrs. proliferation. transcription and sign al transduction 11 739A I· The product s of these genes might have therapeutic relevance 1494 , 1739AI. EBV inte gr atio n has been reporte d in some cases 1632. 23901.

been developed 1749. 23901. Involvement of the bone ma rrow (BM) has been proposed as a negative prognostic factor. b ut this needs furthe r confirmation. EBVpositivity. NF",B pathway d ereg ulation. a high p roliferation signature by gene expression. and cytotoxic granule expression have been found to correlate with a poor p rog nosis 187, 494, 632 , 23901 .

Variants Postu lated normal counter part Activated mature T lymphocytes. mostly CD4+ ce ntral memory type of the ad ap tive immune svtem 1523. 769. 1739AI. Prognosis and pred ictive factor s These are hig hly agg ressive lymp homa s, with a poor resp onse to the rap y, freq uent relap ses and low 5-yea r ove rall survival and failure-free survival (20 -30%) 118491 . The only fac tors c onsistently associate d with prog nosis are stage and IPI sco re 11 849). New scoring systems have rece ntly

306

Mature T- and NK-eell neoplasms

Lymphoep ithel ioid (Lennert lym phoma) This variant shows di ffuse or, mo re rarely, interfollicular gr owth , Cyto logically, it consists p red ominan tly of small ce lls with slight nuclea r irregularities, confluent clusters of epithelioid histioc yte s and some targer, more atyp ical , p roliferating blasts, There can be admixed inflammatory c ells and sca ttered Reed-Ste rnbe rg-like ce lls (usually EBV+ ), High -end othelial venues are not prominent. In the majority of cases, the neop lastic cells are CD&positive 17701.

Follic ula r This variant usually c onsists of atypical dear celts forming intrafollicular aggregates (mimicking follic ular lymp homa ). small nod ular aggregates in a ba ckground of progressive ly-tra nsformed ger minal centres (mi mic kin g nodular Iymphocytepredom inant Hodgkin lymphoma) or enl arged perifollic ular zoneS/nodular aggreg ates surrounding hyperplastic follicles (m imic king nod al margina l zone 1ymphoma) 1524. 18941. Despite a FTH phenl> type, early stage d isea se, parti al lymph node involvement, lac k of enlarged follic· ctar dendritic celt meshworks and lack cJ prominent high endothelial veocies distngu ish it from typical angioimrnunoblasllC T-eelllymphoma. Recently. a 1(5;9) Iranslocation has been reported in a subset cJ cases with these featu res 121121. Other terms have been used for this variant, n. cluding per ifollicu lar. intrafollicular, paracortical nodular and expanded mantle zone 11002, 13581.

T-zone The T-zone vari ant is characterized by a pe rifollic ular growth patte rn throughout the lymph node 11894 , 23591. The ne0p lastic cells are p redominantly small wlll1 minimal cytological aty pi a, and the process ma y be mista ken for benign pa rac orttca t hyperp lasia. The cells express CD3 , CD4, and may show loss 01 CD5 or CD7, Some studi es have sug· ges te d that this variant may be associated with a more indo lent cou rse than other PTCL, NOS 11894, 2359 1. but data are limite d. Many PTCL can show focal residu al tomcures: this histologic al feature alone does not constitute evidence for the 'l-eone va riant.

Angioimmunoblastic T-cell lymphoma

A. Dog an P. Gaulard E.S. Jaffe E. Halfkiae r H .K, MuJler,Hermel ink

Definition Angloimmunoblastic t-een lymphoma (AITL) is a penpheral t -een lymphoma

Characterized by systemic d isease. a poIyrnorphouS inlil trate involving lymph nodes. with a prom inent pr oliferat ion of high endothelial venules and follicular deool'llic cells.

970513 ~ and historical annotation

AITl was previously tett to be an atypical reactive process . angioimrnunoblastic ~aclenopathy, with an inc reased risk fA progression to lymphoma . Cu rrently. tHerNhelming ev idence sug g ests that A1TL rises de novo as a peripheral t -een

""""""'" 15971. -kllogy "Ill occurs in the middle-aged and elderly, with an eq ual incidenc e in ma les and females 15971. It is one of the mo re com--

man soecmc subtypes of peripheral t-een ~,

acc ou nting lor approximat e ly

15- 20% of cases, or 1- 2% of a ll nonHodgkin lymphomas 11896).

a

E!K>kJgy The nearly constant association with EpsteinBarrvirus (EBV) has suggested a possible role for the virus in the etiology, possibly through antigen-d rive (6231. fbwever, the neoplast ic T cell s are EBV

regative.

Ft 11.74

-

Fig. 11.73 Angioimu'IobIasT-<:eI~. A T~ cytJklgy d ~ T-ceI:s wdtl~ rw.dIi iiW1d copious paieLIdeaf cylopIasm. BThe inNlriIte is CDIlp05ed of medUn " Iafge ~ eels wilh atIln:Ian:dNr

Sites of involvement The pr imary site of d isease is Ihe lymp h node and virtua lly all patie nts present with general ize d lymp hadenopathy. In ad d ition, sp leen , liver. skin and bone marrow (BM) are frequenlly involved 15971Cl inical featu res AlTl ty pic ally pre sent s with advanced stage disease, generalized lymp hadenopa thy, hepatosp lenom egaly. sys temic sym ptoms, and poivcionar hypergamm aglobulinemia 1597, 1234A. 1529A, 202 11Skin rash , often with prur itus, is frequ ently present. Other common find ings are pleural effusion, arthritis and ascites. l aboratory find ings inc lude c ircu lating immun e co mplexes , cold agg lutinins with haemolytic anaemia, positive rheumatoid fac tor and anti -smooth muscle antibod ies, Patients exhibit immunodefici ency sec ondary to the neoplastic proc e ss. In the

majOrity of the cases (75% ). expansion of B-cell s po sitive for EBV is seen , though t 10 be a conseq uenc e 01 underlying immune dysfunction 19 71. Mo rphology AlTl is c harac terized by pa rtial efface me nt of the lymp h nod e arctateciure. etten with perinodal infiltration but spar ing of the pe ripheral co rtic al sinuses . There is marked proliferation of arbor izing high endothelial venutes (HEV). There is predominantly paracortcat polymorphic infiltrate co mpose d of small to medium-sized lymph ocyt es, with c lear to pale cyto plasm and di stinct ce ll membranes and minimal cytological atypia, The neoplastic cells often form sma ll c luste rs a round the follicle s and HEV and are admixed with variabl e numbers of small reactive lymphocytes, eo sinoph ils, plasma cells and hatlocvtes. The polymorph ic infiltrate is frequently

~

patterns of angioimrru'lobIstic T-cel lymphoma. AAn early case 'lWilh hypefpIastlc IoIidn and paracoI1icaI e~ (Pallem 1). BAcase MIll JoIdes renWIscenl of cas1Ieman's disease MlI marked pcncorlicaI expMSion (Panem 2). C 0asSICiII1fuphoIogy WIll ~~ of normal ~ aM IWd ma& "II"""'atIol, assooaIed WI\h aggegateS d 8typicaI ~ eels (Pattern 3) ~

AnglOimmunoblasllc T-cell lymphoma

309

~'h v-lJ . • ' .• ~.,

pll'u .

...

1

'**

Fig. 11.75 AngioinYnlSIObIaslic T-ceII!yrr4tlcIna. A M~uclealed cells resermling Reed-Stemberg eels . B low poMf view of C02t imllllOOSlain h91191bng marbd dendntIc eel pI ~ aIJoI l eUb ilWlllQ tIigtl 8l'lCIOh!iaI wenJIes. C The c::h¥actenstic pheno(ypeof tumou' eels expressrog CO] {Cl. COtO(D) and CXCl..1] (E). F E8Y~ B-ceI proWerallon in angw:irmw.Jnotlslic T-<:elI !yrr4tlcIna
r...

associated with incr eased follicular d end ritic cell meshworks. Early cases may contain hyperplastic follic les with illdef ined bord er s an d the ch arac teristic histology may be lim ited to the perifollicular areas w ith predominance of clear cells 118281. The relationship between AITl showing limited caraccencar involvement and the follic ular variant of perip heral T-cell lymphoma . NOS rema ins to be cla rified . An ex pansion of B fmmunobrests is usually present in lhe paracort ex. The expa nsion of normal Bccetls and follic ular dendritic celts in the les ions ha s bee n linked to the functi ona l properties of the neoplastic cells as follic ular helper (TFH) of the normal follicle The expression of CXC l 13 mediates expansion of and , adh esion of follicul ar d endritic B-cell s to HEV with subseq uent entry to the lymph nodes. EBV-positive Be ene are nearly always present. They range in cell size and e xpa nsio n of B lmmunobrasrs may be prom inent 12377 . 2490J. The EBVpositive B lmrnunobrasuc pro liferati on may progress. either composite with AITL. or at relapse to EBV-positive diffuse large a-cen lymphoma 15, 99 , 24901. EBVpos itive Reed -Sternb erg -like cells of lineage may be present and may simulate classical Hodgkin tyrnphoo1a 117941. In advanced cases. the inllarrmatory component is diminished. and the proportion of c lear cells and large c ells is incr eased .

r...

Immunophenotype The neoplastic express most pan t-een antig ens such as C03. C02 and CDS and , in vast majo rity of the cases, C 0 4 a lthough nume rous reactive C08+

t-eens

t-eens

are often p resent. Cha racteristically. the tumour cells show the phenotype of normal TFH expressing COW, CXCl1J and PD-1 in 60-11)0% of the cases 196 523. 605 , 85 11. This phenotype is helpfLl

Paracorte x

t-eens

ceus.

a-ces

310

Mature T- and NK -eell neoplasms

't

Y

I

Gcnninal Center

J

Flg.1'.16 TheoretiCal model of angioimmunoblastic T ce~ lymphoma patllogenesis. EBY·positive 8-c:eIIs pr&Sel'll EFl proteins (e.g. EBNA-t) in assodalioo with MHC class II molecules. upregulaleCD28 ligand (BT). and ~ I:Co stimulatory SlgrWs lor TFH eel adMlllon. TFH cells uPf89Jlate CXCR5 and CXCl.. t 3. CXCl13 promotes 8<111 II' 0'\lItmenl 1O h! I'fr!1ltl flOde 1tlrouo;1l 8lIlefenO!I of !k:::IllIs OIl "'lfl endoltleliaI vetUes (HEV) and ~ gemWIaI centres. h:Jeased 8-ceIsexpand in 1hepar3COI'Iel and ~ adMlled.sere paraa::wticaI Ek:eII bea:ir'ne EBr translormed. CD21-positive dendri!(; cells expand from ee HEY Figure r&l'fOdtlCed with permission from 1623). viraj

in distinguishing AITL from atypic al paracortical hyperplasia and other peri pheral teen lymphomas 1631. 8521 as well as di-

Postulated norma l counterp art CD4+ follic ular helper t -een.

agnosing extranodal d issem inat io n 198.

Genetics t-een rece pto r genes show clonal rearrangements in 75-90% of cases 197, 2155,23781_ Clonal immunoglobulin gene rearrangements may be found in around 25-30% of cases 197. 21551. and correlate with expanded EBV+ Beene . The most frequent cytogenelic abnormalities are trisomy 3 , trisomy 5 and an additiona l X chromosome 1597,19611 and comparative genetic hybrid ization has srcwn gains of 22q , 19 and 11q 13 and losses of

156. 1656A1. B immunoblasts and plasma cells are polytypic : however, secondary EBV-positive a-ceu proliferations includfig diffuse large B-ceillymphoma . classical Hodgkin lymphoma or plasmac ytoma may be seen. Follicular dendritic cell 'I'leShworks expressing CD21. CD23. CD35 and CNA42 are expanded , usually Sl1I'OlXldII'lg the high HEY.

13q in subset 01 cases [2233 1 Gene expression prof iling studies have shown that the neoplastic cells show features of CD4+ TFH [5231. Prog nosis and predictive factor s The clinical course is aggressive with a median survival of less than three years. Patients ofte n succumb to infec tious c ompncauons. which makes del ivery of aggressive c hemotherapy d ifficult 11336 , !ynl:lhoma 202 11. Supervening large (often but not invariably EBV-positlVe)can occur 15, 99 , 135,24901 .

a-ces

I

"; Angioirnmunoblastlc

r-cea lymphoma

311

Anaplastic large cell lymphoma (ALCL) , ALK-positive

Definit ion Anaplast ic larg e ce ll lymphoma (ALC L), anaplastic lymphom a kina se (ALK)-positive

is a T-cell lymp homa consisting of lymp hoid cells that are usually larg e with abundant cytoplasm and pleomorphic , often horseshoe-shaped nuclei, wit h a translocation involving the ALK gene and expression 01 AlK protein, and exp ression

of CD30 AlCl withcomparable rrcepbologic and phenotypic features, bul lacking ALK rearrang ement an d the ALK protein, are considered as a separate category (ALCL. ALK-). A LCL, ALK + must also be d istinguished from p rima ry c utaneous AlC L and from other subtypes of T- Of B-ce ll lymphoma with anapl astic features ancsor CD30 expression .

ico-o code

-

-

-

-

-

-

Sites of involvement A LCL . ALK+ frequ ently involves bo th lymph nodes and extra noda l site s. The most commonly involved extranoda l sites incl ud e skin , bone , soft tissues . lung and liver 1285 . 668, 20871. Invo lvement of the g ut and central nervo us syste m (CNS) is rare . Mediastinal disease is less frequent than in classical Hodgkin lym phoma. The inc idence of bone marrow (B M) involvement is approximately 10% lNhenanaJyzed with H&E . but is inc reased significantly (30 %) when immunohistochemical stains are used 17241 . since BM involve ment is often su btl e. The small cell va riant of ALCL. AL K+ may have a leukaemic pre sentation with peripheral blood (PB) involvement 1164 , 11521, C linical features The majority of patients (70%) present with advanced stage III-IV disease with peripheral and/or abdom inal lymphadenopathy. Mature T- and NK-ceU neoplasms

-

- - --

-

RD. Gascoyne H Stein M C . Kinney

-

-

-

50 .1--• 40

5 '0 j

Male (n : 22 8) Female (n:158)

30

~

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Epidemiology ALCL, ALK+ accounts for ap prox imately 3% 01adult non-Hodgkin lymphomas and 10- 20% of childhood lymphomas 12OB71. ALC L, ALK+ is most frequent in the first three decades of lile 1188. 6681 and shcJWs a male pre dom inanc e (M:F ratio 1.5: 1).

312

60 .,--

E.S. Jaffe

G _Delsol B. Falini H K MOtier-Hermelink E. Campo

Fig. 11.77 Dlstnbution 0( anaplastic 1af9El oeIlymphoma (AlCL). ALK. by age (n=386).

often associated w ith extranodal inlilt rates and invo lvement 01 the BM 1285. 668. 2(9 1). Patients olten have B symp tom s (75%), espec ially high fever 1285. 668 ,

predominate. Five lTI()(phologiC patterns can be reccqneec . The "c ommon pattern" ac counts I()( fi(A;, of cases 1188, 6601 . The tumour cels

20911. Morp hology A LCL, ALK+ show a broad morp holog ic spectrum 1188, 383 , 55 1, 660, 898, 1033, 1 152, 1746 1. How eve r, all cases c onta in a variable propo rtion of cells with ecce ntric . horse shoe- or kidney-sha ped nuc lei often w ith an eos ino philic reg ion near the nucleus . These ce lls have bee n referred to as hallmark cells because they are prese nt in alt lTI()(phologic variants (1881. Although the hallmark cells are typically larg e. smaller cells with simi lar cytologica l leatures may be seen and c an g reatly aid in accurate diagnosis 11881. Depending upon the p lane of sec tion, some cells may appear 10 co ntain nuclea r inc lusions, but thes e are not true inclusion s but invagination s of the nuclea r membrane . Ce lls wit h these fea tu res have been referred to as doughnut cells 11 0331. Morphologic features of AlCL , ALK + range Irom small ce ll neoplasms to an oppo site extr eme in whi c h very large cells

Fig. 11.78 GeneralleaturesofALCL,common t)'pt , n. tynVI node an::Mecture is obliterated by ~ceII and fltrasinusoicIa eels are obsefwd ,

I

I

••

hiM! ebc-oent cytoplasm that ma y appear dear, basophilic or eosinophilic. Mu ltip le 'udei may occur in a wreat h-like pattern and may give rise to cells resembli ng ~Sternberg

cells. The nuclear cbro-

rarely 11881. Hallmark cells are always present and are often conce ntrated around blood vessels 1188, 11521. This morphologic varia nt of ALC L is ofte n misdiagnosed as per ip hera l T-cell lymphoma. NOS by

conven tional examina tion. When the PB is involved, atypical cells reminiscent of flower-like cells can be noted in smear prep arations, The "Hod g kin-like pattern" (3%) is characterized by morphological features mimicking nodular sclerosis classical Hodgkin lymphoma (NSCHL) 123161. More than one pattern may be seen in a single lymph node biopsy ("composite pattern") (15%)11881. Relapses may reveal morphologic features d ifferent from those seen initially 1188. 9461. Other histological patterns include tumours shOWing ce lls with monomorphic. rounded nuclei. either as the predominant populatioo or mixed with more pleomorphic cells. cases rich in multinucleated neoplastic giant cells or displaying sarcomatoid featu res 13831. Occasional cases may have a hypocellutar appearance. with a myxoid or edematous background 14101. Spindle cells may be prominent in such c ases and may simulate sarcoma in cases presenting in soft tissue 110341. In rare cas es, mali gnant ce lls are exceedingly scarce. sca ttered in an otherwise reactive lymph node . Capsula r fibrosis and fibrosis assoc iated with tumou r nodules may be seen, mimic king metastatic nonlym phoi d ma lignancy

Wolin is usually finely cl umped or ueoersed with multiple small, basophilic

nceolt In cases composed of larger cells, the nucleoli are more prominent , but eosinophilic. inclus ion-li ke nucleoli are 'ar~y seen. When the lymp h nod e arch itecture is only partially effa c ed, the wn:our characteristically grows within the

sreses and thus. may resemble a metastatic tumour, The "Iymphohisl iocytic pattern " (10%) is rtaractenzed by tumour ce lls admixed wm alarge number of reactive t nstccvtes 1188,660, 17461. The histiocytes may Mask the maligna nt c ells whic h are often !maIler than in the commo n pattern. The 'l!qlIaslic cells etten cl uster around b lood I'eSSE!ls and can be hig hlight ed by irnf!ktIOStaining using an tibo dies to C D3Q ~ AlK. Occasion ally. the histiocytes ~ signsof erythrophagocytos is. "'he "small cell patte rn- (5-10%) shows a pecmoant po p ulation of small to medll,m-sized neoplastic ce lls with ineguat' nuclei P88. 660, 1033 . 11521 . In e-e cases, the majority of the cells have palecytoplasm and centrally located nuteJs . referred to as "fried eg g cells". S!gnet ring-like cells may also be seen

Aoaoiasnc large cell lymphoma (ALCL). AlK-positNe

313

I Fig. 11 .13 Other tistological patterns of ALCl. (althese cases were positive lor ALK prolein). A AlCl shlWItng ~ large eels with round nucIel. B ALa. oonsrsMgd pIeoi,o.,nc: Prt cells CAla.1I:h n signet rilg eels.

lmmuno phenoty pe

The tumourcells are positive for CD30 on the cell membrane and in the Goigi region 120911. The strongest immunostaining is seen in the large cells. Smaller tumour cells may be ooly weakly positive or even negative for CD30 11881. In the Iymphohistiocytic and small cell patterns. the

strongest CD30 expression is also present in the larger tumour cells. wtlich etten cluster around blood vessels 11881. ALK expression is absent from all postnatal normal human tissues except rare cells in the brain 117861. For this reason, immunohistochemistry has largely supplanted molecular tests for the diagnosis of ALCl, ALK +. Note that tor AlK staining it is ad visable 10 use monoc lonal antibodies 3 14

Mature T- and NK-cell neoplasms

(mouse or rab b it ) instead of polyclonal anti bodies whic h may give false positive staining. In the ma jority of the cases that have the t(2;5)/NPM.ALK translocation. AL K staining of large cells is both cytoplasmic and nuclear l188, 660. 20871- In the small cell variant. ALK-positiyity is usually rest ricted to the nucleus of tumour ceus 1188. 660, 1785 ,20871 . In cases with va riant transiocenons. the ALK staining may be membranous or cytoplasmic 1188.660. 1785 .20871. Cases with t(2 ;5)1 NPM-ALK translocation show aberrant cytoplasmic expression of nocreoohosmin (NPM) , whi le ALCL. AlK+ carrying variant transiocenons show the expected nuclear-restric te d expression of NPM

16691.

The majOrity of ALCL , ALK+ are positiyefa EMA but. in some cases, only a proportioo of malignant ce lls are positive 1188, 5511 The great majority of ALCL. ALK+ express one or more t-een antigens [ 1881. HctNever, due to loss of severer pan antigens. some cases may have an apparent "nul cell" phenotype, but show evidence for a lineage at the genetic level 17221 Since no other distinctions can be found in cases With a versus a nutl-cel phenotype. T/null ALCl. ALK+ is ered a single entity {188. 8981_COO, the most widely used pan marker. IS negative In more than 75% of cases 1188. 2381. C02, COS and C04 are more usefu and are positive in a significant prooonco of cases (70%). Furthermore. most cases

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Fig. 11 .86 A HypocellularALCL B Malignant cells are h~hlighted by ALK staining

exhibit positivity for the cytotoxic associated antigens TIA 1, granzyme B, and/or

perforin 1722. 1192). COB is usually negative. but rare COB-posit ive cases exist. C043 is expressed in two thir d s of the cases. but this ant igen lac ks lineage specificity. Tumour ce lls are variably po sitive for CD45 and CD45RO and strongly cosisvefor CD25 15511. CD15 expression IS rarely observed and when present only

asmall proportion of the neoplastic cells is stained (188 1. Granu la r stain ing for scre entocoes reactive with CD68, such as KP1, may be seen, but other ant ibodies j rected aga inst the macrophagerestricted form of COBB, such as PGM1 , eereqative. ALCL , ALK+ are BCL2 nega:r;e 14841. ALCL are also consistently rapative for EBV (i.e. EBEA and LMP1) 12791,A number of oth er antigens are expressed in ALCL but are not of d iagnost ic 'ialue They include cnetenn (23831. SHP 1 p'osphatase 19621, BCL6. C/EBP 11798 1, serpinAt l12421and tascm .

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Differential diagnosis Arare distinc t d iffus e large B-cell Iym ptonawith immuno b lastic/plasmablas tic ezeres expressing the ALK p rote in m ay ll.perlicially resem ble ALCL, ALK+ d ue to freq uent sinusoidal g rowth pa ttern. These ftrl ptlomas exp ress EMA (as do ALCL) bLot lack C0 30 and sho w a characteristic Cjtcplasmic-restricted g ranular staining l:ntJe ALK protein 1553J, &me non-haematopo ietic neoplasms such eest oorr wosercom a 1660 , 8981 and in~arrnatory myofibrob lastic tumours 1843} may be positive fo r ALK but are mo rpho\:Jgically distingu ishable from ALCL and re recanve for both CD30 and EMA.

lJenetics Nltigen receptor genes "wroximalely 90% of ALCl, AL K+ show ctml rearrangement of the T-cell rec ep tor ITCR) genes irrespective of wh ether they

exp ress t- een ant igens or not. The remainder sho w no rear rangement of TCR or IG gen es 1722}.

Genetic abnormalities and oncogenes The gen es fused with ALK in variou s c hrom os omal translocations and the subcerlula r distrib ution of NPM-ALK and X-A LK ch ime ric p rote ins are shown in Tab le 11.08 . The most freque nt genetic alte ration is a tran sloc at ion , t(2 ;5)(p23 ;q35) , be tween the ALK ge ne on ch romosome 2 and the nuc leophosm in (NPM) gene on ch romosome 5 11244, 1407, 15251, Variant tr anslocation s involv ing ALK an d other par t ner genes on chromosomes 1, 2 , 3 , 17, 19 , 22 and X also occu r (469 , 669 , 93 1,124 1,1243,1408,1449 , 1868,2087, 2256,2258 , 2268 , 242 7) Th e t(2;5 ) can be detected by RT-PCR , but cases w ith

va riant translocations w ill be negative by standard AT-PCR us ing pr imers that are specific tor the ALK and NPM genes 1660, 17621. A ll these translocatons result in up reg ulation of A LK, but the subcellular d istr ibution of the sta ining var ies depending on the tran slocation, The ALK gen e encodes a tyrosine kinas e receptor be longing to the insulin recept or supe rfam ily, wh ich is normally silent in lymphoid cells 11525). In the t(2;5)(p23:q35), the nuc leophosmin (NPM) gene, a house keeping gene, fuses the ALK gene to pro duce a c him eric p rotein in wh ich the N-terminal portion of NPM is linked to the intracytoplasmic portion of ALK (1525j The particular cytoplasmic , nu clear and nucleolar stain ing seen in cases assoc iated with the t(2: 5) can be explained by the fo rmation of heterod imers between

Table 11 .08 Trans iocation s and fusion proteins inl'Ol'ling ALK at 2p23

ALK partner

MWtofALK hybrid protein

ALKstainIng pattern

% 01 eases

t(2;5)(p23:q35)

NPM

80

Nuclear. diffuse cytoplasmic

84%

t(l ;2){q25:p23)

TPMJ

104

Diffuse cytoplasmicwith peripheral intensification

13%

Chromosomal anomaly

Inv(2){p23q35)

ATIC

96

Diffuse cytoplasmic

1%

t(2;3j{p23:q21)

TFG Xiong TFG long TFG sholt

113 97 85

Dnfuse cytoplasmic Diffuse cytoplas mic Diffuse cytoplasmic

<1%

t(2;17kp23:q23)

cac

250

Granular cytop lasmic

<1%

t(2;X)(p23:q11-12)

MSN

125

Membrane staining

<1%

t(2;19)(p23:p13,1)

TPM4

95

Diffuse cytoplasmic

<1%

t(2;22)(p23;q11.2)

MYH9

220

Diffuse cytoplasmic

<1%

t(2;17kp23:q25)

AL017

NO

Diffuse cytoplasmic

<1%

?

?

Nuclear or cytop lasmic

<1 %

Others'

NPM, nucleophosmin gene; TPMJ and TPM4, non-musculartropomyos ingene: TFG. TRK-fused gene, three different fusion proteins of 85, 97and 113kO(TFG-ALKs , TFG·ALKl , TFG·ALKxL) areassociated with the 1{2;3)(p23:q35) which involves theTFG: ATIC, arnoc-terrrwoe of 5-aminolmidazole-4-carboxamide ritlooucleolide formyltransferasel lMPcyclohydrolase gene: c1alhrin heavy polypeptide gene; MSN, moesingene: MYH9. myosinheavy chain 9 gene; AL017, ALK lymphoma oligomerization partner on cororoscre 17, " unpublished series of 270 cases ofALCL, ALK+

cnc.

Anaplastic large ce ll lymphoma (ALCLj, ALK-pos itive

3 15

wild -type t;.l PM and the fusion NPM·ALK protein, On the other hand , the formation of NPM-ALK homodimers using cnmertseuoo sites at the N-term inus of NPM mimleks ligan d b ind ing and is responsible for the ac tivation of the AlK catalytic domain and for the oncogenic properties of the Al K protein 117851 . Compa rative genomic hybridiz ation (CGH) analysis shows that AlCl. AlK+ carry freq uent secondary c hromosomal imbalance inc ludi ng losses of c hromosome 4. l 1qand 13q and ga ins of 7. 17pand 17q 11923 1. In addition , th is study demonstrates that Atx-posmve and negative ALCl have a d ifferent representation of secondary genetic alterations. supporting the concept that they are d ifferent biological entities.

1,00 ALK1+ n=215

0,75

0,50

ALK1 ·

n-28 0,25 p= 0,001

125

250

Months Fig. 11.87 0veraI so.nivaI d AlK-po6ItiYe and negalive petlents.

Gene expression profiling Supervised analysis by class compa rison between ALC L. ALK+ and ALCL. ALKtumours p rovided d istinct molecular signatur es 11242 1. Among the 117 ge nes ove rexp ressec in ALCL . ALK+ . BCL6, PTPN12 (tyrosine phosphatase) . serplM 1 and QfBP werethe four top genes, bemg overexp resse d with the most significant p-value. This ove rexo ress loo wa s also confirmed at the protein level lo r CIEBP. BCL6 and serp in A 1, Postulated normal counter pa rt Ac tivated matur e c ytotoxic T-cetl. Prognosi s and predi ctive fact ors The international prognostic index (lPI) appears to be of some value in predicting outcome in AlCl, AlK+ . although less

316

Mature T- and NK-celt neoplasms

significantly than in other variants of 1ymp homa 1668, 7601. No differences have bee n found betw ee n NPM -AlK-po sitive tumours and tumours showi ng variant transiocanons 1658. 66 9 , 760. 20131. II might be that cases with small ce ll variant histolog y d o not have the same fav ourable prognosis as the other Al K positive tu mour s since these patients often present with di ssemi nated disease at d iag nosis. ALCl , AlK+ patients have a favo urable pr ogn osis compared with AlCl , AlK-I668, 760 , 20 131. The ove rall 5-year surv ival rate in At.Ct. . AlK+ ap proaches 80% , in c ontrast to o nly 48% in AlCl, AlK-. In the recent study by Savage and co- workers {1943AI, the overallS-year surv ival of AlCl , ALK+ pa tients is slig htly

lower (70%) due to the excicsoo of paed iatric pa tien ts. In the latter study, the 5-year la ilure free survival (FFS) of paIients with ALCL. ALK+ was 60% versus 36% lo r AlCL. Al K-. Relapses are not uncommon (30% of cases), but often remain sensitive to c hemotherapy ; alkr geneic BM trans pla nt may be ettecnve in refract ory cases {13191. Since it is now cle arly demon strated that AlK is essential for the p roliferati on and survival 01 the cells of AlCL . ALK+ . it can be expected that specific ALK inhib itors, c urrently tested in prec linical models , may be available in the near future for c linical trials

117631

Anaplastic large cell lymphoma, ALK-negative

DY Mason N.l. Harris

Definition

mimi c carcinoma Features such as sclerosis or eosinophils may occur, but when present shou ld raise the susp icion of CHL. The neoplastic ce lls show a similar morphologica l spectrum to AlCL, ALK+ . althOugh a osman ce ll variant" is not recognized. Biopsies typically show large pleomorphic cells. sometimes conta ining prom inent nucleoli. Multinucleated, including wreath-like. cel ls may also be present and mitotic ligures are not infrequent In addition , to a variable degree, "hall mark" celt s with eccentric . horseshoe- or kidney-shaped nuclei are seen . The neoplastic cells in ALCL, AlK- tend to be large r and more p leomorphic than tho se seen in cl assic al AlCl, ALK+ and /or have a higher nociea rcytootasmc ratio 1668, 1565 . 1762.20131 . The latter feature may suggest a diagnosis ot PTCL, NOS. but in the latter d isorder abnorma l small to medium-s ized lymphocytes are often admixed with a morphologically homogeneous neoplastic cell popu lation. and the sheet-like or sinus pattern of infilt ration typical of ALCL is absent.

AlK-negative anaplastic large cell tymjtana (AlCL. ALK-l is included as a proM1aI entity. and is defined as a CD30+ k:eI neoplasm that is not reproducibly disWlgUiShable 00 morphologica l grounds m AlK-positive AlCL (AlCL, AlK+). but tacks anaplastic large c ell lymphoma ki-ase (AlKI protein. Most cases express tcee -assoeateo markers and cytotoxic J<WlJIe-associated proteins. AlCL. AlK!T\lSI be distingu ished from primary cuta-

-eces AlCl, othe r s ubtypes 01 CD30+ f. cr B-cel1 1ymphcrna WIth anaplastic teaties, and cl assica l Hodgkin lymphoma

ICHl).

s

roo code

G . Delsol H . Stein

Sites of involvement AlCL. ALK- involves both lymph nodes and extrarooar nssue . although the latter sites are less commonly involved than in AlCL. AlK+ . Extranodal sites include bone, soft tissues and skin . Cutaneous cases must be d istinguished from primary cutaneous AlCl and cases that invol ve the gastrointestinal tract must be distingu ished from CD30-positive enteropathyassociated T-cell lymphomas. Clinical featu res Most patients present with ad vanced stage til to IV disease. with peripheral and/or abdom inal lym phadenopa thy, and B symptoms 121801.

9702/3 ",,,,,,hology

, v e d Y

,-

Is

9p'alyms and historical annotation "lCL ALK· was included in the third ecnlI:rI 01 the WHO crassincauon. together .1tIALCL. AlK + in the broader entity 01 'areplastic large cell lymp homa " 15541 . ltJwever, it was also recognized that ALCL, ALK· (mainly because ottneir older

In most cases the nodal or other tissue architecture is effaced by solid, cohesive sheets of neoplastic cells . When lymph node architecture is preserved. the neoplastic cells typically grow within sinuses or within T-ce ll areas , commonly showing a "cohesive" pa ttern that may

E. Campo M.C. Kinney E.S. Jaffe S. Falini

Median ageand more aggressive clinical course) are felt to be distinct from AlCl, A.LK+ (5541 . However, there are also valid arguments for excluding AlCl, AlK- from Tie category of pe riphe ral t-een Iymptpma (PTel), not otherwise specified INOS) 1659,1 034 , 2030 , 2431 ). Unforturately, there are few de tailed cl inicopathocqcal studies of AlCl, AlK- 121811 and 'llspecific oncogenic abnormalities (e.g. croaraoe to ALK gene rearrangement) rave been identified. Thus, the distinction beI~n PTCl, NOS, and AlCl, AlK- is 'llt always straightforward. The current 00 Classification considers AlCl, AlKt De a provisional enti ty within the spec11m of mature t-een lymphomas, distinct itrn both AlCl, AlK+ and PTCl, NOS.

-

-"Ie peak

incid ence of AlCl, AlK - is in

Wts (40-65 years), un like AlCl. ALK+ .

1tIdl occurs most corrmon ty in c hildren

young adu lts. a lthough c ases c an 1659. 208 71. There is a 'IOies1 male preponderance ( 1.5: 1).

;r(!

:ttiJ' at any age

Fig. 11.88 IrnmunostawlI1g lor COJO in cases of AlCl, AlK· shows ee coheSive and inIra$inuSOidaI !Towlh pattern of!le 1l.JOOU" and Ihe homogellllOUS eqJf9SSioo ofIt'iIIIllWter on 1l.JOOU" eels . Hole !le GoIgi- and ~ assodaled pattern of stanog Asteris.ls mcate ~ ~ lcIicies.

AnaplaS!lC large cetltymPhorna. ALK-negallve

317

although di ffuse cytoplasmic positivity is also common. Staining should be strong and of equal intensity in all cells. a feature that is important in distinguishing ALCL, ALK- from other PTCl , which can express CD30 in at least a proportion of the cells. and usually with variable intensity. AlK protein is by definition undetectable. Loss of markers can occur, with greater frequency than typically seen in PTCL , NOS . In this respect . AlCL, ALK· is sim ilar to AlCL, AlK-+ . However, OVel'all more than hatt of all cases express one or more T-cell markers. C02 and COOare found more often than CD5 , and COO is almost always expressed . CD4 is POSitIVe in a significant proportion of cases whereas COB-positive cases are rare Many cases express the cvtotoxcas sociated markers TIA 1, granzyme 8 and/or perforin. A substantial minority ~ cases is positive for EMA (on at least a proportion 01 malignant cells). a marker that is almost always seen in AlCL, AlK.. bul on ly occasionally in PTCL, NOS. In c ase s that lack all T-celVcytotoxic mark· ers. CHL rich in neoplastic cells or another large cell malignancy (e.g, embryonal ca rcinoma) should be ruled out, In this regard. slaining for PAX5 is useful ; CHL will show weak expression of PAX5 in ee majority of cases. whe reas it should be negative in all cases of A LCL, ALK· r:I ALK+. The demonstration of CD 15 sho.tI raise a suspicion for CHL. However, CD15 may be expre ssed in some cases 01 PTCL NOS, and such cases are ger.eraty strong ly C030-positive (1491. Whether periphe ral neop lasms expressing botl1 C030 and CO tS should be c lassified as ALC L, Al K- or PTCL, NOS, remains to be determi ned. Notably. these cases havea very poor prognosis, thus c linically more closely resembling PTCL, NOS. AlCL, AlJ(. are consistently neg ative for Epstein-Barr virus (EBV) (i.e. EBEA and l MP1). and the expression of these markers shoUd strongly suggest the possibility of CHL A single study has reported that AlCL AlK- and AlCL, ALK+ lack recece proteins. and in this respect tend to dille!' from PTCl , NOS 12381. Ctus terin is also commooly expressed in AlCL. ALK- and ALK+. bu t rarely in PTCl, NOS 11235, 1574. 1905 1; this marker has not ceeneamined extensively in CHl, but was neg. atrve in the cases studied 123831.

t-een

..

Fig. 11.89 ~ laalures of loll' cases d AlCl, ALK-. A Note \tie high nuclear 10 cytIplasmic rallo. B ~ (lll'I'llWSj ewe present (otten In ~l btA otherlealuresof IiCJ(lgU1 tymptIoma we absenC. C Typical m‫ס‬rph‫ס‬1ogicai and phenotypic fe.1IlIns of ALCl (a hallmark eel is arrowed) but arose in ee gaslrtllnleslNllrad (glanlUar 8pI\tleil.ITl is seen WI the upper Ieft.l. 0 Case Wlth more celkJIar ~

Emphasis should be placed on CD30 expression; If a large c ell lymphoma 01 roo-Been phenotype stows strong. forogeneous CD30 expression . especially if this is strongest in the Gotgi and rnembrane regions. and the ITlOfphologicallealures are consistent with AlCL , it should be classified as ALCL. AL K· , Fortunately the

distinction between AlCL, AlK· and PTCL, NOS currenlly car ries no major clinical implications. Immunophenotype All tumo ur cells are strongly positive for CD30. usually most strongly at the cell memb rane and in the Gofgi region.

r-ceu

t-een

Fig. 11.90 ALCl, ALK· s/lowing a IIigh nudear 10cytIplasmic ratio. A Some featlJ'es suggest periphefaI T<.eI 1')'rr4lIlomI. NOS Horweotef. eOlnsiw CDJOellPes5lOl'l in eYefy c:eI is ctIariK::teI.sticol ALQ..ALK.· (8). C l)'lT'9lOma eels exp!e$S COO (e l and (;Of {D). t«Jle a \IeSSel SI.I'IOI.I'Ided by normal. smaI C03+ T<8k

318

Mature T- and N K-cell neoplasms

r,~

a_

•

FiJ. 1U1 EJ+ression oflhe t)'t*lxiC TGI m.1I ef1 TlAt (A) and perfom (8) II OOterantial dlagnosis The principle dlfferenllal diagnosis of

Al Q.,ALK·.

arid phenotype are very close to those of ALK-positive cases. with the only cnsnnc-

Genetics The malOrity of cases shOw clonal rearrangement of the T-cell receptor (TCR) genes, whe ther or not they express t-een antigens. No recurrent primary cytoqenenc abnormalities occur with any fre quency. Two studies indicate a tendenc y of ALCl, AlKto differ (e.q. in terms of chromosome losses or gai ns) both from PTCl, NOS and from AlCl, ALK+, althoug h overlappin g fea tures can also be foun d 11923, 24921. Similarly, pu blished gene expression studies suggest that ALCL, ALK- has a distinct p rofile but these results do not p rov ide definitive evidence as to whether the d iseas e is more closely related to A LCL , A LK- o r to PTCl, NOS 11 37,1 24 2,

tal being the presence or a bse nce of

223 11·

ALa... AlK· is with PTCL. NOS. and CHL. HiSloncalty. many cases referred 10 as HOOgkin-like AlCl have now been recassneo as tumour cells rich forms 01 CHL With complete immunophenotypic a'Id genetic studies. AlCl. AlK· can be distinguished from CHL in virtually all cases, Bycontrast , the d istincti on between PTCL, NOS and ALCL, ALK- is nOI always cear-cu.and even experts may disagree CI'Ithis subject. In general, the WHO Clas-

sIlica!lOl"l advocates a conservative approach. recomme nding the d iagnosis of ALCl, ALK·, only if both the morp hology

ALK. ALCl, AlK- must also be di stin guished from primary c utaneous AL C L, ;{1~h can have a similar phenotype and rr«Pholog y, Clinical co rrelation with stagr,g ISot paramount importance in this d iflerenlial Primary cutaneous Al Cl has a rruch better prognosis than AlCl, AlK-,

Postulated normal co unterpart Ac t ivated mature c ytotoxic T-cell.

than that 01 ALCL. ALK+ 1668, 760, 21801, There is some suggestion that there is a plateau 01 long-term survivors (not seen III PTCL, NOS), but this remains to be confirmed . In a recent report by the Internahonal Peripheral Lymphoma Project {1943A} , the clinical features of the ALCL , ALK+ and ALCl, AL K- have been com pa red wi th each other and wi th PTCl, NOS. The results of this study further highlight the outcome differences between PTCL, NOS and ALCL, ALK-. The 5-year FFS (36% vs 20%) and OS (49% vs 32%) were supe rior in ALCL, ALKcompared to PTCL, NOS, Furt hermore , confining the analysis of cases of PTCl, NOS with high CD30 exp ression (>80% of cells), a g roup that can be d ifficult to d ifferentiate histologically from ALCL. A LK-, mag nified the d ifferenc e in 5-y ear FFS and 5-yea r OS ( 19% ) com pared to ALCL, ALK-.

t-een

Progn osis and predictive factors The cl inica l outcome of ALCL, ALK · with convent io nal therapy is c lea rly poo rer

Anaplastic large celt lymphoma. ALK-negatlve

319

Introduction

Definition Hod gkin lymphomas (HL) share the torlowing cha racteristics: (1) they usually arise in lymph nodes, preferentially in the c ervica l reg ion; (2) the majority 01 them manifest clinically in young adults ; (3) neopl astic tissues usu ally con tain a small number 01 scattered large rroroouciesl ed and multinucleated tumour cells (designated Hcx:Igkin and Reed-Sternberg celts or HA S celts) residing in an abun dant heterogeneous admi xture of non neoplastic inflamma tory an d accessory cell s ; (4) lhe tumour cells are often ringed by T lymphocytes in a rosette-like manner, Hodgkin lymp homa s account lor -30% of all lymp homas. Their absolute inci dence has not apparen tly chan g ed . in contrast with non -Hodqkln lymp hom as where there has been a steady increase in incidence.

H . Stein

Subclassificati on Biological and clinic al studies in the last 30 years have shown that Hod gKin lymphomas are c omprised of two disease entities 133 , 573 , 1406A. 16031: nodular lym phocyte predominant HodgKin lymp homa (NL PHL) and classical Hod gkin lym phoma (CHL ), These two entities drtfer in their clinical features and behaviour as well as in the composition of the ir ce rlular backqrouoo and -diagnostically most important- in the morphology. immunophenotype and the preservation or extinction of B-eell gene expression program. Within classical HL, four subtypes have been distinguished: nodular sclerosis, mixed cellularity, lymp hocyte-rich and lym phocyte-d eple ted , These subtypes differ in their sites of involvement. clinical

features, growth pattern, presenc e of fibrosis, composition of cellul ar background, numbe r and/or degree of atypia of the tumour cells and freq uenc y of Epstein-Barr virus (EBV) infection, but not in the immunophenotype of the tumour cells, which is the same in all four vanants A oetauec account of the historical evdJtioo at the suOClassification at Hodgki'l lymphoma is provided b y Mauch et al 114321 and by Anagnostopoulos et al. I331 Staging Treatment of HL is bas ed on clinical, and occasionally on pathological staging 01 the disease. The mod ified Ann Arbor slaging system {132OB} is used (Table 12.01).

r. ble 12.01 Cotswold revision (l 320B) oI1he Ann Afbor stagingdasslblion (337AI.

Synonyms and hist orical annotation This neopl asm was recog nized in the first half of the 19th century by Thomas Hod gkin 19471 and Samuel Wilks 12404 , 24051. The latter named it Hodgk in disease. The di sease was also c alled lymphog ranulomatosis, a term that is no longe r in use. Since the orig in 01 the Reed -Sternberg cell is known to be a lymph oid cell -most often 01 a-ce! typ e- the term Hodg kin lymp homa is pr eferred over Hodgkin's disease. The mod ern classifica tion of Hodgk in lymphoma is based on the Lukes-Butler scheme \1344, 13451

322

HodgKin lymphOma

Stage Deflnllion In'o'Olvemenl of a single ~ rooe regoo or IynllIloid structure (e,g. spleen, thymus, Wakleyerling). It

Involvement of two orrrorelymph rooe regiol'ls 0fI1he same Side of the diaphragm (the med~slinum is a sing~ site;hilar lymph nodes areIateraHzed): the number of anatomic sites shouldbe indiCatedby suffix (e. g. I!:y,

III Involliernent of ~h IXIde r&gion s or strllCtlJres0fI both sides of the diaphragm, 111 1 With or withoUt splenic, hilar, celiacor portal nodes 111 2 With paraaortic , iliac or mesentericnodes. IV

Involvement of extraoodal site(s)beyond thesedesignatedE.

E, involvement01a single extranodal site,or contigOO!Js or proximal 10 known nodal site of disease.

Nodular lymphocyte predominant Hodgkin lymphoma

S, Poppema G,oelsol SA Pileri H. Stein

S,H. Swerdlow R,A, Warnke E,S. Jaffe

DefirWon 'b:luIar lymphOCyte predominant Hodgkin ~phoma (Nl PHL) is a monoclonal B-ceI neoplasm c harac terized by a nodu1M, Of a nodular and diffuse proliferation rj scat tered large neoplastic ceus known !S poocom or lymphocyte predominant

eels (lP cells) - formerly called l&H eels for lymphocytiC andfor histiocytic Ud-Sternberg cell variants, These cells esoe in large spherical meshworks 01101k;.Jar j

dendritic cell processes thaI are

eo with roo-neoprasnc lymphocytes 01"(1 tastocv tes. One third of the cases

of

:lagnosed in the past has an NLPHl

<

.ere lymphocyte-ric h classic al HL. It is

e

QlITently not clear whether a purely dit-

use form of NLPHL exists. Most lesions dagnosed in the past as diffuse LPHL were probably r-ceu-ncn large B-eeillymecee (Te ASe l ). At present an overlap teween NLPHL and TeRSeL cannot be

ecaoeo.

roo code

9659/3

Fig. 12.01 Nodoor lymphocyte predorrln8rI4 Hodgkin IymJtlorna (NlPHL). A Thenodules are usually 1arger1hin 1tYJse present in follicular lymphoma andfollicular hyperplaSIa. and are closely packed and lack mantle zones. B Three popcorn cells(ai'TOWS) with !tie typically lobated nudei areviSlbIe in a background 01 smail lymph(id eels anda lew histiotytes. C TheCDlO staining revea ~ Itlalltle nodules oIltllsIymp/Ioma predomioarllty consisl of B-celIs, DAI hIifoer magnilicabon. the strong membrane slllilling oIlhe popcorn cellslor COlO is visib~ ,

-~k>gy ~lPHL represen ts appro ximately 5% of iiiKodgkin lymph oma s. Patients are prem inantly male and most freq uentl y in te30-50 year age g roup.

Sites of involvement ~L

usually involves c ervical, axi llary inguinal lymph nod es. Med iastinal. sjenic and bone marrow (8 M) invo lve 1TBl! are rare,

Cl

CfricaI features \\:lsI patientspresent with loc alized peri. ~"lefal lymphad enop athy (staqe I or II). 5-25\ of patients p resen t with advanced iQe disease 133. 20091.

~ -~ lymph

node architecture is totally or

I3"JaIy replaced by a nodular or a nodulr and diffuse infiltrate, predominantly IXI'lSISlII'lQ of small lymphoCytes, histio:yleS. epithelioid nlsuccvtes and interted LP cells. The latte r cells are large I'd usually have one large nucleus and

sc ant cytoplasm . The nuclei are often fold ed or mul tilo bated , often to such an extreme that the y have also been termed ' popc orn" cells. The nucleoli are usually mul ti ple. basophilic and smaller than tho se seen in cl assical Hodgkin and Reed- Stern berg (HRS) cells How ever, some LP cells may con tain one prominent nucleolus andior have more than one nucleus, and thus ma y be indistinguishable

from classical HAS cells on purely rroprological gr ounds . The d ill use areas are main ly composed of small lymphocytes with ad mixed henccvtes which are either single or in clusters. The proc ess is (arely totally diffuse . According to current criteria the oetecnon of one nodule showing the typicalleatures of NLPHL in an otherwise diffuse growth pattern is sufficient 10 exclude the diagnosis of a primary

Nodular lymphocyte predominant Hodgkin lymphoma

323

T-cell/hist ioeyte-rich large B-cell lymphoma (THRLBCl). Hetocvtes and some poly clonal plasma c ells can be found at the margin of the nodules . Neutrophils and eosinophils are seldom seen in either the nodular and diffuse regions. Occasionally, there is reactive follicular hyperplasia

with progressive trans formation of ge rmina l centres (PTGC) adiacent to the lesion or it may proceed or follo'N a diagnosis of NlPHll33, 8981. It is uncertain whether these lesions are preneoplastic . The vast majority of patients with reac tive hyperp lasia and PTGC do not develop Hod g kin

Fig. 12.04 Nodular ~ predominant Hodgki1Iy1f4lhoma (Nl PHl). A C~smc positMIy of the popcom eels lor J.<:haIn is seen, B Membrane and dot./ike stairWlg in the Go9region lor epdheIiaImembrane antigen (EMA) is .mtlle li the popcorn eels

lymphoma 1700. 16571. Sclerosis is infrequently present in prj. mary biopsies (7%), but can be found more frequently in recurrences (44%). Remnants of small germinal centres are infrequently present in the nodules 01 NlPHl, a finding more typical of Iymphc>cyte-nch c lass ical Hod g kin lymphoma (LACHL) 133. 6711· Immun ophenotype lP cells are posi tive for C020 1457, 1752, 17531. C079a, C075, BC l 6 and CD45 in nea rly all cases. J chai n 11771, 20891 is p rese nt in the majority of cases, and epithelial membrane antigen (EMA) in more than 5O'lb of cases 133. 4271 (Table 12.02) , In coonast to HRSceils from classical HL, QCT·2 , BOB .1 and acnvetcoinduced diaminase (AID) are coosistentty coex oressed in NlPHl. l abeling lor ~ munoglobulin lig ht and/or heavy chains is frequently strong 11 964 , 1965 , 20901. In 9-27% of c ases the l P ce lls are Igo. positive 1837A, 1777,20901. Tbe exoressco of IgD is more commo n in youn g males (17771, l P cel ls lac k CD 15 and CD30 in nearly all instances. However, CD3Q. positive large c ells may be seen : these are in most instances reactive immunoblasts unrela ted 10 the lP cells 1331. In. frequent ly, the lP ce lls show weal; expression 01 CD30. As revealed by thei nuclear positi vity for Ki67 . most LP cells are in cycle. Most of the LP cells are ringed by CD3 -+ T cells, and 10 a lesser extent by CDS7 + T cells. The arc hitec tural background in NlPHL is co mposed of large sp herical meshworks of follic ular dendritic cells, which are predominantly filled with small B ce lls, and nume rous C04+/C057-+ T cells /17721. These T-cells express markers like c-MAF, PO-1, BCL6 , IRF4/MUM 1 and CD134,
coa.

...

Fig, 12.05 NOOuIar ~e predominant Hodgkin lymphoma (NlPHl). A Non-oeoplaslicbyslander~ b1aslS stain lor C030 whereas the neoplastic popcorn teH(arrow) remains unlabeled. B Many non-oeopIastic bystander T-c::eIs are labeled lorCOS7. TheseCD57+ eels may be ifNolved II !he roselle-like bilding 10the popcorn eens wtIidl is pal'tIoAarIy pronounced in the case Iustraled here.

324

Hodgkin lymphoma

Afollicular dend ritic cell marker, such as CD21 , is esse ntial for recognizing these ~erent patterns. A prominence of ext ranodular lP cells is associated Wi th a propenSIty to develop a diffuse p attern resembling T-cellJllistiOCyte -ric h large B-cellym phoma (THRLBCL-like) . This is seen more frequently in patients with recurrence 167 11 . It is prob ably good practice to labe l cases 01 NLPHL that pattern as pcqress to a diffuse NLPHL, THAL BCL-like, an d d istinguish sesefrom primar y THALBCL. In me differential d iag nosis . p resence of small Beene and C0 4 +/CD57+ T c ells favours NLPHL. whereas absence of small scets. and presence of CDB+ c ells and TlAl + cells favours pr imary THALBCL

of ongoing mutations. The rearrangements are usually functional and IG mANA transc ripts a re detect ab le in the LP cells 01 most ca ses 113871. Latent Epstein-Barr virus (EBV) infection is consistently absent from LP c ells, but may be present in bystan de r lym phocytes 1331. IGH@-BCL6 translocations have been fou nd in 5/2 4 NLPHL cases as well as in the NLPHL ce ll line DEY 194,1 838 1and BCL6rearranga-ments (involving IG, lKA ROS, ABR etc) (48%) 12426 1 are frequent in NLPHL Abe rrant somatic hypermutat ions were found in 80% of NLPHL cases. most Irequently in PAX5, but also in PIM" RhoHITTFand MYC11 318 1.

t-een-ncb

of cas es (572, 573. 1603}. It is not clear yet whether immed iate therapy is nec essary to ach ieve this favou rable prognosis. There fore in some cou ntries (e.q. Franc e) stage I d isease is not treated , especially in c hil d ren, atte r the resectio n of the affected lym ph node {17201. Adv anc ed sta ges have an unfa vourable prog nosis {5731· Progression to large B-cell lymphoma-like lesions has be en reported in ap proximately 3 -5% of cases {425. 884 , 14761 . In some c ases OLBCL was found to precede NLPHL {67 11. The large Been lymphomas associated w ith NLPHL, if kx;alized. generally have a good prognosis 18841. A donal relationship between NLPHl and the associated OLBC L has been demonstrated 1838, 23991. Bone marrow invotvement is rare in NLPHL and raises the possibility of THRLBCL in particular if there are only C057-negative T cells and no small B cells in the bac kground. Cases of NLPHL with BM involvement were found to show ag g ressive clinical benaviour1 11411.

Postulated normal counterpart Germinal centre B cell at the centrob laslic stage of differentiation

Genetics LPeells have cio nauy rearranged immunoglobulin (IG) genes 1262 , 1387 , 1627l. The clonal rearrangemen ts a re usually ret delectable in who le tissue DNA but only in the DNA of isolated single LP cells, The variab le reg ion of the IG heavy chain genes (VH) c arry a high load of SO'llatic mutations , and also show signs

Prognosis and predi ctive fact ors This d iseas e develops slowly, with fairly freq uent relap ses. It usual ly rema ins respo nsive to the rapy and thus is rarely fatal. The progn osis of patients w ith stage I and stage II disease is very good ; with 10 year overall survival in mo re than 80 %

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Nodular lymphocyte predominant Hodgkin lymphoma

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Classical Hodgkin lymphoma, introduction

Definition Classical Hodg kin lymphoma (CHL) is a monoclonal lymphoid neoplasm (in most instances derived from B cells) composed of mononuclear Hodgkin cells and multi-

nucleated Reed-Sternberg (HAS) cells reo sid ing in an infiltrate containing a va riable

mixture of non-neoplastic small lym phocytes. eosinophils. neutrophils, tastocvtes . plasma cells, fib roblasts and collagen hbfes. Based on the characteristics of the reactive infiltrate and to a certain extent on the morphology of the HRS cells [i.e . lacunar cells). tou r histological subtypes

have been dlshnguished : Iymphocyterich CHL (lRCHL) , nodular sclerosis CH L

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(NSCHL) . m ixe d cellula rity CHL (MeeHL) and lymphocyte- depleted CHL (LDCHl ).

The immunophenotypic and genetic featu res of the mononuclear and multinu cle ate d cells are iden tical in these histological su b ty pes. whereas their clinical featu res and association with Epstein-Barr virus (EBV) show differences.

96SOI3

ICD-O code

Fig. 12.08 Classical HoclgkfI~ , Spleen.

E,>demJology Classical HL accounts for 95% of all Hodgkin lymphomas. with a bimodal age curve in resource-rich countries , showing a peak at 15-35 years of age and a second

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NlPHl. nodular IympilocyIe predominant Hodgkin lymphoma: TCRBCl, T~kid11arge 6-ee11 lymphoma:CHl, classical Hodgkin lymphoma: DlBCl, (li1l1JSe large B<eIlIymp!loma;ALCl, aflaplaslic large T-oeII lymphoma,

+an cases are posihve. +1· majOrity of cases positive, -1+ minoOty creases positive. - allcases arenegative, S strong elpression. ' Positive in rare cases, • PnJrninenI e~ III anaplaslic variant and variable expression in mediastmallargefk:8II subtype. s0lxaSl0I'IaI cases may show local positMIy. • Present in up1040% 01 ee cases but usuaIy expressed 01\ a rninonIyofturnourceis WIlh variable 111eoso1y, ~ Up 10 10'li.lT1lI1lt be negab...e ' The COfTVTJJIl posiIMlyb IgG and boIhIg IighI chalf1s reIIects upta ke oflhese proIeins by !he hJrnoIJ"ceIs rather ItIan S)flthe$i$ ' Slmng e.q)rMSion bJnd in - 10'J1, of tIWI cases. ' Rarecases (- 10'Ji,) may shaw scatIered 'lW8iI/I posIbvily. , any II minOrIty is negative II; W8ak e.qnssion may be seen in VnOur eels in 51. 01 !he cases. " Most ~ seen in DL.BCl wiII'I anapIask IfIOIllI'Dogy

peak in late hfe. Persons with a history d infectious mononucleosis have a higher inc idence of CHL 115351. Both familia l and geographical cl ustering have been desc ribed 115351. Etiology EBV has been postulated to p laya rote in the pathogenesis of C HL EBV is found in only a proportion of cases, pa rticula rly in MCCHl and lDCHL, but a sea rch for other viruses has been unsuccessful, loss of immune surveillance in mmu-cd efic iency states such as HIV infection m ay pr edispos e to the d ev elop ment 01 EBV-associated CHL. In tropical reg ions, up to 100% of CHl cases are EBV-positi~e !64 A, 1277A , 2369 , 2370 1. It is possible that EBV infection of a B cell replaces one of the gen eti c alterat ions ne cessary lor the d ev elopment of CHL. Sites of invo lvement Classical Hodg kin lym phom a most often involves lymph no d es of the cerv ical regio n (75% of c as es) followed b y the mediastinal, axillary and paraaotc regictls Non-axia l lym p h nod e groups such as mesenteric o r epitrochlear lym ph nodes are rarely involved Primary extranooet involvemen t is rar e . More than 60% ci patient s have localize d d isea se (stage I and II). Approx im ately 60% of patients. Ihe m ajority of them with NSCHl, have mediastinal involvement. Sp len ic involvem ent is not uncommon (20 % ) and IS associated with an inc reased risk 01 extranodal d issemination. Bone marrow (8M) involvement is much less corrmon (5'\)

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12.09 Classical Hodgkfl ~ A Mononuclear Hodgkrl eels (awws) and a rnbu:I8ated Reed-S1etlWg eel (lW1CI'tI!lead) areseee in a c:etiiIr ~ and tor\IaIIWIg hiStiocyIe$ and some eosirophis. B Onerrumified Hodgkil OlIIlamJw) rod w VItal Hodgkn eels can be seen.

As !tie 8M lacks lymphatics. 8M infiltration ooc ates vascular dissemination of the disease (stage IV). The anatomic distei:Moo varies among the histological sub~s of HL

120091.

Clir¥caI features Patients usually present with pe ripheral ~thy, localized to 1 or 2 lymph ~e-bearing

areas. Med iastinal involve-

ment is most freq ue ntly seen in the nodular sclerosis subtype, while abdominal and splenic involvement are more common in mxedcell ularity. B symptoms co nsistin g c tever. drenc hing night sweats, and signkant body weight loss are present in up1040% of patients.

Macroscopy Lymph nod es are enla rged , encapsulated

and on cut section show a fish flesh tumour, In NSCH L there is p rom inent l'JOdularily, d ense f ibroti c bands and a thickened ca ps ule. Splenic invo lvement usually shows scatte red nodules within tile wt1i te pulp . Sometimes ve ry larg e Masses are seen, these can demonstrate

fibrous bands in the nodular sclerosis subtype. Classical HL in the thymus can be associated with cystic degeneration and epithelial hyperplasia 113131. Aare cases can be confined to the thymus.

-logy The lymph node architecture is eHaced by variable numbers of HRS cells admixed with a rich in"arrvnalory background. Classical diagnostic Reed-Sternberg (AS) cells are large. have abundant slightly basophilic cytoplasm and have at least two nuclear lobes or nuclei . The nuclei are large and often rounded in contour with a prom inent, often irregular nuclear membrane, pale c hromatin and usua lly one prom inent eosinophilic nucleolus , w ith perinucle ar clearing (halo), resemb ling a viral inclusion. Diagnostic AS ce lls must have at least two nuc leoli in two sep arate nuc lear lobes. Mononucl ear variants are termed Hodgkin ce lls. Some HA S cells may have conde nsed cyto plasm and pyknotic red dish nuclei. These variants are known as mummifie d cells. Many of the neop lastic cel ls are no t proto typic HRS cells. The lacunar

~

rid! n

AS variant is characteristic 01 nodular sclerosisHL. The reccasrc cells typically represent only a minority of the cellular infiltrate With a frequency ranging from 0.1- 10%. The c0mposition of the reactive cellular infiltrate varies according to the histok:lgical subtype. Involvement of secondary sites (8M and liver) is based on the identification of atypical mononuclear (CD3J-pos;live Hodgkin cells with or without CD15 expression in the appropriate inflam matory bac kground ); thus diag nostic multinuclear AS cells are not required in a patient with classical HL diagnosed at anothe r site 11 8 19AI. Irrvnunophenotype H AS cells are positive for CD30 in nea rly a ll cases 11 97BA, 2088, 209 1/, and for CD 15 1987, 209 1, 2092] in the ma jor ity (75-85%) of cas es and are usually neg ative fo r CD 45 and co nsistently negative fo r J c hain, CD 75 and macroph age spec ific ma rkers suc h as the PG-M 1-epi lop e of the COB8 molec ule 1427. 662A ) (Table 12.02). Both CD3Q and C01 5 are typ ic ally present in a mem brane pattern with

Classical Hodgkin lymphoma. introductlOl1

327

accentuation in me GoIgi area 011he cytoplasm; C0 15may be expressed by only a minority 01 the neoplastic cells and may be restricted only 10 the Golg i area. In 30- 40% of cases. C020 may be detectable but is usually of varied intensity and usually present only on a minonty of the neoplastic cells 11964. 25071 . The 8 -cell-associated antigen C079a is less often expressed. The B-cell nature of HAS cells is further demonstrable in approximately 95% of cases by their expression of the s-een specific activ ator protein PAX5!BSAP 17231 - The immunostaining of HRS cells for PAX5 is usually weaker than thai of reactive B cells . a feature that makes the PAX5-positive HAS cells easily identifiable. The plasma cell specific transcription factor IAF4/MUM1 is consrstenny positive in HAS cells, usually at high intensity, In one study, BLiMP1, the key regulator of plasma ce ll differentiatio n, was expressed in on ly a small proportion of HRS cells in 25% of CHl 12941 . The plasma -cell -assoc iated adhesion molecule CD 138 is consistently absent 12941, EBV-infected HRS ce lls exp ress lMP1 and EBNA-1 without EBNA-2, a patt ern characteri stic of latency typ e II EBV

328

HodgkIn lymphoma

infection 15521. EBV-encoded LMPl pos sesses strong transforming and annapootonc potential. Expression (usually weak membranous or sometimes globular cytoplasmic) 01 one or more t-een antigens by a minority of HRS cells may be encountered in some cases 1504 /. This is, however. often difficult to assess because of the T cells that usually surround the HRS cells . Most of the T-cell antigen-po sitive classical HL cases have IG gene rearrangement in the HAS cells instead of t-een receptor gene rearrangement. so that the expression of t-een antigens is either aberra nt or artfactual \19871. Expression of epithelial memb rane antigen (EMA) is rare and usually weak if present. A further characteristic finding is the absen ce of the transcription factor OCT-2 in - 90% of cases and absen ce of its coactivator BOB,1 in the same frequency. Cases in which both OCT-2 and BOB.l are ccexpressed are rare 113281, The transcr iption factor PU,1 is consis tently absent from HRS ce lls 11328, 2250A). Most HRS cells express the proliferation-associated nuclear antigen Ki67 1775Cl. CHl cases rich in neoplastic cells may

resemble anaplastic large cell lymphoma (ALCL), a T-cell neoplasm. Their identJlication as classical HL is facilitated by demonstrating positivity for PAX5 and absence 01 EMA and ALK protein 1723, 20871. The detection 0 1 EBV-encodea RNA (EBER) or LMPl is indicative of classical HL 1992AI_The most difficult dillerenter diagnosis is with large B-cel lymphoma displaying anaplastic morphology and expressing CD3O. There may be a true biologic overlap between such cases and CHL (See Chapter 10). Cytokines and chemokines CHL is associated with overexpresson and an abnormal pattern of cytokines and chemokines and/or their receptors in HAS cells 1919, 962A. 1080, 1081, 11 08. 2293). which likely explain the abundant admixture of inflammatory cells P067, 21861. fibrosis 110801. and the predominance at Th2 ce lls in the infiltrating t-een population 122931. Genetics Antigen receptor genes HRS cel ls contain clonal immunoglobulin (IG) gene rearrangeme nts in more than

98% of cases. and clonal r-ceu receptor gene rearrangements in rare cases 11105, 1388.1553. 1987,20861 The clonal rearrangements are usually detectable only in the DNA of isolated single HRS cells. and not in wh ole tissue DNA. The rearranged IG genes of the tumour cells harbour a high load of somatic hypereuatcos in the vanaore region of the fG teavy chain genes (IGHVtI), usually wuhC'JI signs of ongoing mu ta tions. These tr1dings. in conjunction wi th the study of CO"TllQSIte lymphomas c on sisting of etasseal Hl and loIli cular non -Hodgkin lym:tuna . support the view that HAS cells of B-cel lineage are derived from a germinal cenlre BceU 1261A. 1387AI.

AL:notmaI gens expression Oespte their derivation from germinal centre B cells. HAS c ells have lost much j eeB-eett speci fic expression program and have acquired B-cell inappropriate gene produc ts [636A . 1205A . 1388A. 14 1M. 1977A. 2090 . 1047AI. ln addition . oeregulated transcription fac tors in CH L P"OITIOte pro nteranon and abrogate apopese in the neoplas tic cells. The nanscnoton fac tor NF"B is constitutively activated in HRS cells. and there is el\ered activity of the NFKB targ et genes. which regulate proliferation and survival 1938A. 9388 . 962Al. the AP-1 complex 11416A. 1416B) and the Janus kina se/SIgnal transducers and activators 01 transcrption (JAK/STAD signaling pathway 12030Aj. Mutati ons of the JA K reg ulator SOC- l are assoc iated with nuclear STAT5 accumulation in HRS cells . indicati ng a bockage of the neg ativ e feed bac k loo p cHheJAK!STAT5 pathw ay 11 070A, 1459A .

fig. 12.13 0assicaI HodgkIn ~ A EBV infected HRSceIs suongIy eapress!tle EBv~ 1alenI~ proIein 1fLMP1). B EBV4lf8ded HRS cells consistently ihow a 5trr6lg e~ of EBER il \llei' ~ as revealed by l'lOIHadio
observed in HRS cells in 17% of CHl

Genetic abnormalrlies and oncogenes Despite the frequent overexoreeecn of p53, mutations of TP53 are rare or absent in primary CHL tissue . although they have been observed in Hodgkin cen lines 1700A. 1504 1. Conventional cytogenetic and Al.Il> rescence in situ hybridization (FISH) stud ies show aneuploidy and hypertetraploidy. consistent w ith the multinucleation 01 the neoplastic cells; however. these techniques fail to demonstrate recurrent and specific chromosomal changes in classical HL 11935,19601 . Comparalivegenomic hybridisation, however, reveals recu rrent gains of the chromosomal sub-regions on ch romosomal arms zp. so. and 12q and d istinct hig h-level amplifications on ch romosomal bands 4p1 6 . 4q23-q 24 and 9p23-p24 11071]. Thetranslocalions t(14;t 8) an d t(2;5 ) are abse nt from HRS cells 1831. 12441 but 1(14; 18) may occur in CHL arisi ng in follicular lymp hom a 11561AI. In a recent study using interphase cytogenetics breakpoints in the IGH@ loc us were

cesesttaatzq. Postulated normal counterpart In more than 98% of CH L. the neoplastic c ells are derived from mature B cells at the germinal c entre stage of differentiation { 1105. 13881. In rare cases. they are derived from peripheral (post-thymic ) T cells 1514.1553. 1987 1. Prognosis and predicti ve factors Modern rad iation and chemotherapy have made CH L curable in more than 85% of cases 1462A. 571AI · Staging determ ines the mode of therapy. and both clinical and laboratory pa rameters are relevant to prognosis 19041. The response after two courses of ABVD as seen on FOG -PET imaging is an important prognostic ind ica tor 1748A] Histo log ic subtype is less important as a p redictive fact or 125. 10761.

23881 Epstein-Barr virus infection -he prevalence of EBV in HRS ce lls var ies according to the his tological subtype and epidemiologic factors . The highest fre~iJency {.75 %) is found in MCCH L. and ee cwest incidenc e ( 10-40%) in NSCH L 1992AI. In resou rce-poor reg ions and in pa:ients infec ted with the human immune delIClency virus. EBV infection is more p-evaIenl approaching 100% 164A, 1277A, 2369.23701. The type of EBV strain also enes among geographical areas. In resarce-rich cou ntries strain 1 p revails , i'ld in resourc e-poor countries strain 2. ~ 0081 infection by both strains is more c:onmn in resource-poor countries 1280. 00.23701.

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ClassiCal HodgkIn lymphoma. in troduction

329

Nodular sclerosis classical Hodgkin lymphoma

H . Stein A. von Wasiele wski S. Pop pema KA Mac l ennan

M. Guenova

Definition Nodular sclerosis classical Hod gkin lymphoma (NSCHL) is a subtype of CHL Characterized by collagen bands that surround at least one nodu le, and HOdgkin and Reed-Sternberg (HRS) cells with lacunar type morphology

ICD-Ocode

966313

Epidemkllogy NSCHL accounts for apprOl(imately 70% of CHL in EuroPe and USA ; rcwever. the rate varies greatty among other geographiCal reg ions: II is more common in resource-rich than in resccrce-occe areas . and the risk is highest amon g those with high socioeconomic status 14451. The incidence of NSCH L is similar in males an d females and peaks at ages 15-34 years 11 01 . 1525A I.

r'lJ. 12.15 Nol1JIa' sdetosis dassicaI Hodgkll ~ ACTscan shcM$ a Ia'ge
Sites of involvement Med iastinal involvement occurs in 80% of cases, bulky disease in 54%, splenic and/or lung involvement in 8-10%. bone involvement in 5%, bone marrow (BM) involvement in 3% and liver invol vement in 2% 1456. 20091. Clinica l fea tures Most pat ient s p resent with Ann Arbo r stage II d isease. B symptoms are encounte red in approxima te ly 40 % ot c ases

120091 Morp ho logy lymph nodes have a nodular g rowth pat tern , with nod ules surrounde d by collagen bands (nodul ar sclerosis). The broad fibroblas t-poor coll agen ban d s surroun d at least one nodule . This fibrosing process is usually associated wi th a thick en ed lymph node capsule. The lymphoma contains a highly variable number of HRS cells . sma ll lym phoc ytes and othe r nonneoplastic inflammatory cells. The HRS cells tend 10 have more lob ated nuclei with smaller lobes. less prominent nucleoli. and a larger amount of c ytop lasm than in other types of CHL In formalin-tilled tissues the cytoplasm of the HAS cells Ire330

HodgkIn lymphoma

fig . 12.16 Nodularsclerosisdassical Hodgkin lymphoma B 5everal lacunar cells (arrowed) are present.

quently shows retraction ot the cyto plasmic me mbra ne so that the cells see m to be silting in lacunae. These ce lls hav e the refore been de signa ted lacunar ce lls. lacunar c ells may for m ce llular ag gregates . whi ch ma y be associ ated with necrosi s and a histioc yt ic reaction. resembl ing nec rot izing g ranuloma s. When agg reg ates are very prominent. the term "syncyti al variant" has bee n used . Eosinephils, htsnoc vres. and to a lesse r exten t neutroph ils, are often numerous 117431· Gra d ing ac c ord ing to the proportion of HRS c ells or the characteristics 01 the back groun d infiltrate (such as the number of eosmo pbns) may predict prognosis in some settings. b ut is not req uired for routine c linical p urpo ses 1936. 1356,2307. 2341AI: it may serve a research purpose in protocol studies.

Immun op henotype The mal ignant cells exhib it the CHL ph enotype (see Introduction ): however. associ ation with Epstein-Barr virus (EBV) as demonstrated by EBEA or the EBV encoded lMP1 is less frequ ent (10-40%) than in m ixed c ellul arity CHl 1918A. 919A, 237 4A. 23 77AI. Prognosis and predicti ve factors NSCHl has a better prog nosis overej than that 01othe r types of CHl1251. Massive med iast inal disease is an adverse p rog noshc fact or 120621.

Mixed cellularity classical Hodgkin lymphoma

L.M . Weiss R. von Wasielewski

G Detsol S. Poppema H. Stein

Definition .,heel cellularity classical Hodgkin Iymecre (Me e HL) is a sub type of c lassic al Hodgkin lymphoma (C HL) w ith scattered classical Hodgkin-Read-Sternberg (HRS) cells in a diffuse Of vaguely nodular mixed ~tOfY bac kground without nod ular sclerosing fibrosis. C ases wh ic h d o not III Ino !he other subty pes are pu t in this cal"PY.

965213

-

•.

iology

The mixed ce llularity subtype comprises approximalely 20-25% of CHL. MeeHL is more freq uent in pat ients with HIV in'ecton and in developing co untries. A bimodal age distribution is not seen. The

reoen age is 38 years and approxi'Mlety 70% are male 120091.

Siles 01 involvement Peripheral lymph nodes are frequently evolved and mediastinal involvement is uncommon. The spleen is involved in m . 8M in 10%. liver in 3% and other opens in 1- 3% 14561.

Clir'l ical features Bsymptoms are frequ ent. Morphology The lymph node architec tu re is us ually Dbliterated although an inte rfol licular growth pattern may be seen . Inte rstitial

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_

.

Fig. 12.17 Milled celkllanly subtype of dassical Hodgklll~ . COJO.negatiYe ~, wrlh a prtIIIJUIICed epithelioid dilrerenbatlon forming cilsters. predominate. The CD30 imrTlJl'lOSlaifIing ~ ee presence d a large Reed-Slemberg cell and a sma. Hodgkin eel.

fibrosis may be present , but the lym ph node capsule is usua lly not thickened and there are no broad bands of fib rosis as seen in nodular sc lerosis Hod g kin l ymphoma. The HAS cells are typical in appearance. The bac kg rou nd cells consist of a mixture of cell types, the composition of whic h varies greatly. Eosinophils, neutrop hils, histioc yte s and p lasma c ells are us ually p resent. O ne of these cell ty pe s may predominate. The t ustrocvtes may show pronounc ed ep ithe lioid featur es pa rticu larly in Eps tein- Bar r virus (EBV)associate d cases 15521 and may for m g ranuloma- like clus ters or g ranulomas.

Immunophenotype The ma lignant cell s exh ibit the CHL immunoobenotyoe : however, the EBVencoded lMP1 and EBEA are expres sed muc h more frequently (approx imately 75% of cases) than in nodular scleros is and lymphocyte-rich CHL 133). Prog nosis and pred ictive factors Before the introduct ion of mod ern therapy, MCC HL had a worse p rog nosis than nod ular sc lerosis and a better prognosis than lymphoc yte-de pleted CHL. With current reg imens, these d ifferenc es have targely vanished although rot entirely [251.

F'i- 12.1. lobed ~ MtItype of dassicalliIldgUl ~_ AThe nixed teUJr I'llitrate does nolconlaIn fIbrotIC bends. IIIIIlld ceII.Mr rilltrate wiCI'I ~. IJIilO'OI)hageS and ~ is 'tiSibie

Mixed cellularity ciasscat Hodgkin lymphoma

331

Lymphocyte-rich classical Hodgkin lymphoma

Definition

lymphocyte-rich classical Hodgkin lymphoma (LRCHl) is a subtype 01 classical Hodgkin lymphoma (CHL) with scattered Hodgkin and Reed-Stenberg (HAS) cells and a roouiar or less common diffuse cellular background consisting of small lymphocytes and with an absence of neutrophils and eosinophils.

Epidemiology l RC Hl comprises approximately 5% of all CHL. in similar frequency to nodular lymphocyte predominant Hodgkin lymphoma (NLPHl). The median age is similar to NlPHL and signJlicantty higher than in other subtypes of CHL 15731. There is a male predominance (70%) 120091.

Sites of invotvement ICD-Ocode

332

9651/3

Hodgkin lymphoma

Peripheral lymph nodes are typically involved . Mediastinal involvement and bulky disease are uncorrvnon 1573, 20091 .

I. Anagnostopoulos PG, Isaacson H . Stein

Clinical'eatures Most patients present with stage I Of II disease. B symptoms are rare. The clinical features are similar to those of NlPHL with the exception that multiple relapses seem to occur less frequently 15731. Morphology There are two growth patterns: a corrmon nodular one 133. 901 and a rare diffuse one 1331. The nodules of the nodular vanant encompass most of the involved tissue so that the T-zone is attenuated

The nodules are composed of smail lymctocyl:es and may harbour germinal ceores that are usually ecc entrically located m relatively small or regressed . The HAS cells are predomina ntty found within the nodules but consrstennv outside of the germinal centres. A proporti on of the HAS cells may resemble l P ce lls or mononudear lacunar cells. This subtype can easily be ccofuseo with the NlPHL. In the past. approximately 30% of cases initially diagnosed as Nl PHl were lound to be LRCHL j33l. The demonstration of an immunophenotype typical lor classical HAS cellsisessential in making this distinction , Icsnopbus and/or neutrophils are absent from the nodules and if present they are located in the Inteetoutcurer zones and are low in number, In rare instances , the

.

lRCHl-typicaI nodules may be SlJJOlXlded by fibrous ba nds assoc iated with randomly distributed HRS cells in zones, Typ ing of these cases as nod ular sclerosis cla ssical Hod gk in lymphoma (NSCHl) mig ht be more appropriate. In some cases, seque ntial biop sies have shown NSCHl imp lying a possible relationship between the two subtypes 01 CHl and this is further inferred by the finding of HRS cells within expanded follicular mantle zones in some cases 01 NSCHl jl 01 1AI. A coe xistence oflRCHl and mixed ce llularity classical Hodgkin lymphoma (MeCHl ) occurs but is rare. In diffuse l RCHl ca ses the small lympho c ytes of the cellular background may be admi xed with histiocytes with or without epithelioid features.

t-een-nett

,.

1~100)

U'H.

••

00

,

..

~r 1W2 ."'~ )

00

.. ..

00

A

r,

-----

NSMCA.O (12$12....7)

J ..

00-

00-

1IlCK.1~100)

1.51

-

• • • • • • • • • •

B

-

• • • • • • • • • •

1~

The distinction 01 l ACHl Irom NLPHl is possible by immunophenotyping in all i~ stances 1331. The atypical cells in LRCHl stlCM' the sameirrYrulophenoty (CD30+. CD15+/· , CD20-/+ , CD75- , J cnein-) as the HAS cells in the other subtypes of CHL. The small lymp hocyt es present in the nodules display the features of mantle cells (l gM+D+). Thus the nodules predominantly represent expanded mantle zones . At least some of them cont ain eccentrically located . usually small, germinal cen tres which are highlighted by a dense meshwork of CD21+ follicular dendr itic cells, As intact germinal centres are infreq uent in NLPHl, this feature is helpful in differential diagnosis . CD15+ granulocytes are abse nt from the expanded mantle zones but may be present in low numbers within the otertoncuar zones. In the rare diffuse subtype the lymphocytes are nearly all of t -een type with CD15+ granul ocyt es and eosinophils being absent. These features fac ilitate the differentia tion of l RCHl from MCCHl. EBV lMP1 expression is seen more frequently than in NSCHl bul less frequently than in MCCHl j33 l. Prognosis and predictive factors With modern risk-adjusted treatment, survival and prog ression free survival are slightly better than in the other subtypes of CHL and similar to that of NlPHl exce pt thai relapses are more common in NlPHl than in l RCHll33, 573, 20091.

1121 A 0¥eraI suMYaI byMldogIc SIbyplt. B 0YeraI evenl-Iree SU'\'MI by Ii:skllogic ~ {2OO9}.1..RCHL.

~dassblHodgkrI~ :l.PH.,~~~ ,MC ,nued~ ,

\'S.1IXUar sdIllrosi$; LD, ~ depletion.

lymphocyte-rich classical Hodgkin lymphoma

.

333

Lymphocyte-depleted classical Hodgkin lymphoma

D. Benharroch H . Stein S.-C. Peh

Definition

If a nodular sclerosin g fibrosis is present, the disease should be assigned to nodular sclerosis Hodgkin lymphoma.

lymphocyte-depleled classical Hod gkin lymphoma (LDC HL) is a diffuse subtype of classical Hodgkin lymphoma (CHL) rich in Hodgkin and Reed-Stenberg (HRS) cells andlor depleted in non-neoplastic lymphocytes. The deflnitiorl 01LDCHL has

undergone several changes in the past few decades with the result mattre body 01 reliable clinical data on this SUbtype is limited , Since a proportion ollhese c ases have been reclassified into differen t 1ymphoma entities , the previously described clin icopathological coretatioos are 001 necessarily tenab le ,

ICD-O code

965313

Epidemiology This is the rarest CHL subtype « 1% of cases in Western countries). 60-75% of patients are male and the me dian age ranges from 30-37 years 125, 20091 . This subtype is often assoc iated wi th HIV infectio n and is seen mo re often in developin g countries {80S, 23 171.

Siles of involvement LDCHL has a pred ilec tion for retroperitone al lymph nodes, abdominal organs, and bone marrow. Clinical features l DCH L pr esents at a mo re advanced stage (Ill-IV) and with B symptoms than the other subtypes (1585, 2OO9}.

Mo
Immunophenotype The HAS cells show the same immunephenotype as in the other subtypes 01 c lassica l HL Most HIV + cases are EBV infected and stain positively lor lMPl 1932.2020.22761. Coexpression 01 CD30 and PAX5 is very helpful in differentia ting lDCHl from AlCl, ALK- . Prognosis and predictive factors Prior to modern therapy, the course 01 lDCHl was aggressive and it has remained so in some parts of Europe 125, 17821 and in developing countries . In the US and UK, the course is comparable 10 other CHl subtypes of similar stage , Poeprognosis is seen in Hrv-rerateo lDCHL patients.

Lymphoproliferative diseases associated with primary immune disorders

De finition Lymphoprouterauve diseases (LPD) associ ated with prima ry immune d isord ers (PID) are lymphoid proliferatiOns that arise as a result of illYTlune deficiency due to a pr imary immunodeficiency or immunoregulatory c nsoroer. Because the pathology and pathogenesis of the more than 60 PIOare hete rogeneous. the manifestations of the Iymphoproliferalive diseases are Ijghly variable. The PlD most frequently assoc iated with LPD are ataxia telangiectasia (AT), WISkOll:-AIdrdl syndrome (W~),

oomr<Jnvariable_(CV1D),

severe ccrooec rrm.n:xJeficiency (SClD), X-linked Iymphoproliferatrve disorder (XLP),

Nijmegen breakage synd rome (NBS) , hyper-19M synd rome and autoimmune Iymphoprohleralive syndrome (ALPSl·

Epidemiology Age -sp ecific mo rtality rates for all neoplasms in patients WIth P1D are 10-200 limes the expec ted rates lor the general po p utenon. Howev er, g ive n that PIO are rare disorders . the overall occurrence of PID· associated LPD is low With the exception of CVID . these di seases present primaril y in the paediatric ag e group . They are more common in male s than fema les, primarily because severa l of the primary genetic ab normalities are X-linked, e .g XLP, SCIO and hyper-lgM synd rome 110631, Etiology The c ause of the LPO is related to the underlying primary immune oetectl tsoa]. Epstein-Bar r viru s (EBV) is involved in the majority of PIO-associated lymp hoi d proliferations [23021, In these cases, defective T-ce ll immune surveill ance to EBV is believed to be the pr imary mechan ism 1935, 17881. The absence 01 T-cell control may be complete. resulting in fatal infectious m0nonocieosrs. or partial. resulting in other LPD

in the g ene for C040 or CD40 ligand . which affect inte ractions between and B-cells. and impair effective differenti ation of B-cefls into class-switched p lasma c ells 110081· In autoimmune iym onoprouteranve syndrome (ALPS). mutations in the FAS or FASL gene (and rarely other abnormalities) may contribute d irectly to lymphoid prolif. erations through the accumulation of lymphoid cells tha t fait to undergo aocotosrs. resulting in the accumulation of CD4 and COB dou ble negative cells in the penphefal blood (PS) and lym phoid tissues 11300. 20421. In AlPS, tile severity of the apoptotic d efect correlates directly with the risk 01 d eve lo pment of LPD 1104 11. The importance of FA$ mu tations in ca using LPO is supported by the tact that sporad ic FAS mutation s are associated with lymphomas in the absence of immune abnormali ties 16551. In AT. an abnorma l DNA repair mechanism due to mutatio ns of the ATM gene ca n co ntribute to the d evelopment of lymphoma . leukaemia an d other neoplasms 16381. In these patients, non- leukaemic t -een clones c an be d etected in the PB that have lranslocations involving the TeR genes similar to those seen in ove rt leukae mias. NBS also resul ts from defects in DNA repair du e to muta tions in the NBS 1 gene , resulting in many chromosomal breaks and transrocatrons. includ ing tho se in antigen receptor genes. In pa tients with NBS, LPD is

J,H. Van Krieke n M. Onciu K S.J . Erenrtcoa-Jormson E.S. Jaffe

t-eens

the mostcommonneoplasm 154,339, 23141.

hyperplas ia may occur in the lung and gastrointestinal trac t \1929\. a setting In which more aggressive LPD or overt 1ymp hom a may develop 15591. Sites of involvem ent Presentation is dependent on the underlying d isease. More often. LPD present in extranodat sites. most commonl y the gastrointestinal tract. lung and central nervous system (CNS). Clinica l features Patients often present w ith symptoms resem bl ing those of infectio n or neoplasia {i.e. fever. fatigue, infectious mononucleosislike synd romes), In some d iseases. such as ALPS and XLP, the lymphoid proliferation is the first sig n of the underlying immune d efect. but in most patient s, the d iag nosis of PIO has already been establish ed becau se of other manifestatioos.

In patients with CV IO. marked lym phoid

11042/ WAS is a complex immune d isord er. w ilh defects in function of tceas. Beene. neutrophils and macrophages. T-cell dysfunclion is significant . and tends to increas e in severity d uring the course of the di sease. Hypef-lgM syndrome results fran rTUtations 336

Fig. 13.B2 DiltLJse largeB-alIIymphoma II a pabenI WIth Ionp-slaodIng carmon ¥ariabIe InrTulOdefiOelq ~ A l~ eels ant seetl ll asates IUd nt show marked pleoITuptlisnl. B L~ eels are EB'V---poslIM t, EBER'" situ hybrWaticwl.

Irrmunodefic iency·associated Iymphoproliferative disorders

C Pa-ar::or1lCal T eels show

~ .I.s In other immune deficiency slates. n

,.

,.

~d prolifera tions in patents with pri-

rr.ary immunodeficiency inc lude reactive ~rplasias.

ia

polymorphous lymphoid (M/alessimilar to those seen in Ihe post1arsplant setting, and frank lym phom as tat do not differ from those in immunoerroeient hosts, The type and frequency «eech lesion differ among the PIO (Table

s-

1301),

,. ,h

a-

n·

,e b·

/lori-neoplastic lesions Crmary EBV infection in PIO may result in fatal infectious mon onuc leosis (FIM) , curacterized by a high ty polymorphous ~,iferation of lymphoid ce lls showin g ecerce of plasmac ytoid and immunetesc ditlerentiation . Reed-Sternberg-like ::etslllay be seen. This cond ition is prirrarly seen in patients with XlP (Duncan ~rome) [BOOI and SCID 11 7881. The noma! a.cell pr onteranon is systemic, 'ldYi"g both lymphoid and non-iymphoid ~. most corrmor"lly the terminal ileum, rlaer"cphagocytic syndrome is frequent, Rl 'SlT'OSt readily identified in bone ma r(BM) aspirates. In CV IO, waxing an d IymphoprOliferations ma y occur in rcoes and extranocar sites, with morphology including follicula r IflerpIasia, and paraco-ncat expansion

wi th m any EBV-positive cells. often including la rge atypical cells . that may res em bl e Reed-Stern berg cells. CV IO is c haracteriz ed b y nodular lymphoid hy per pl asia in the gastr ointestion al tra c t; VJ- PCR may detect clonal B-c ell populations tha t ar e self-lim ited 11 256 . 19291, In AL PS. expansions of double-negative (CD4-/CDB-) a lph a beta CD 45 RA +. CD45RO- T cel ls in PB . lymph no des. spleen and othe r ti ssues are the hallmark of t he d isease. T-cell expan sion can be ve ry ma rked, and the T-cel ls may hav e slig htly immatu re ch romat in, wh ich ca n lead to a m istaken diagnosis of T-c eil lym phoma especially when , as is usual , lhe patient does not c arry a pre exi sting d iag no sis of A LPS (13001. Follicular hy perplasia is often prcrn inent, and prog ressivel y transform ed g erm in al centres may be seen 113001. Hyper-lgM syndrome is c har ac terized b y c irc ulating PB B-cells that bear only Ig M an d IgO. G erm inal centres are absent in lymph rooes . Ig M-producing plasma cells often accumulate , most commonly in extranodal sites , such as the gastrointestinal tract, liver and gallb lad der. These lesions ma y be so exten sive as to be fatal, withoul p rog ression to clonal LPD.

Lymphomas Lymphomas occurring in patients with PIO do not genera lly d iffer in their morpholo gy from those occurrin g in immunocompetent hosts. Lym phom atoid g ranulomatosis (LYG). an EBV-driven proliferation of B-cells assoc iateo with a ma rke d t-een mtntratlon. is inc rea sed in fre q ue nc y in patients with WAS { 1003) (See Chap ter 10), The most com mo n si tes of involvem ent ar e lung, skin, brain and kid ney, Diffuse la rge B-ceillymphoma (DLBCL) is the mo st com m on type of lym phom a seen in PIO in general; Hodgkin and Bur kitt lymp ho mas 1224 11 an d peripheral r-celt lym p homas also occur [ 17291, In AT, and 10 a lesser ex tent in NB S, lymphomas an d leukaemias are mo re common than B-cell neoplasms 121641. Rare cases of lru e pe rip he ral T-een lymphoma have been se en in patients with ALPS 11729 . 21 08 1. Both T lymphoblastic Iymp homaaeukaerma (T AllJlBl) and T-cell p rolym phocyt ic leukaemi a (T-PLl) have been reported in PID.

t-een

Hodgkin lymphoma Hodgkin lymphoma-like Iymphoproliferalions resembling those seen in the setting 01 methotrexate therap y as well as LPO wilh all morphological and phenotypic

Lymphoproliferative diseases assocetec With pnmary immune disorders

337

•

fig. 13.05 Reactive ~ node from a pabenl with ALPS. A There is prominent parac:ortlcal expansion. B ALPS tynllh node. Reaclive geminaI centres eve present and tle C The ceb are slqllIy Ia'gerthanIIOITIIaI smallyrnphocyte$. wilh dispersed dYoma\Jl.

parac:or1eX is expMded.

features of classical Hodgkin lymphoma has been reported in patients with WAS, and AT 1638. 19091. In ALPS , nodular 1ymphocyte predominant Hodgkin lymphOma, classical Hodgkin lymphoma and t-eenrich large Bccel! lymphomas have been described 113001.

In cases showing evidence of plasmacytoid differentiation, monotypic cyloplasmic irrmunoglobulin (Ig) may be identified The immunophenotypes of the specnc B-and Teen lymphomas in PID do not differ from those of the same lymphomas in immunocompetent patients

Precursor lesions The underlying primary immune disorder is the principal precursor lesion leading to the development of LPO. This morphological spectrum is accompanied by an increasing dominanl ccoar poputanoo: from clearly poivcionel. to oligoclonal to mono-

Genetics Antigen receptor genes Since lPD in PID is a spectrum from reactive to aggressive Iymphoproliferalloos lhey can be polyclonal, oIigoclonal or m0noclonal. FIM is generally poivcionai: overt lymphomas such as OlBCl or Bunott 1ymphoma have clonal immunoglobulin heavy and light-chain gene rearrangement 1638, 1256 . 19291. Presently there is only limited expe rience with clonality tests in the selling of PID.

clonal. However, monoclonal expansions, particularly if they are minor clones. do not necessarily progress 10 major persistent

clonal lesions 112561.

t-een

tmmunophenotype Non-neoplastic proliferations In ALPS. there is expans ion of a d istinc tive CD 3 + CD4- CDB- CD45R A+ C045 ROnatve t-een pop ulation in the PB and BM, The T cells ma y exp ress C05? but not C025 Inc reased nu mbe rs of CD5+ polyc lonal B cells may also be seen ( 1300) Hyper-lgM syndrome is cha racterized by PB B cells tha t bear only Ig M and IgO.

Genetic abnormalities and oncogenes Genet ic alte rations may b e di rectly related to the p rima ry immune defect. suc h as FAS gene m utation in patients w ith ALPS , mu tations of the gene encod ing for SAP/SLAM in XLP, and ma ny c hromosomal b reaks in NBS {799 , 2t581 , Ot her abnormalities ma y occur in the course of LPO , In AT, in addition to mu tations of the

Neoplasms Most of the lymphomas in patients with PIO are of B-ceillineage, and thus express B-cell antigens co rresponding to their differentiation stage. EBY infection of B cells often leads to down-regulation of s-een antigens. Thus, C020. C0 19 an d C079a may be negative or expressed on only some of the neoplastic cells in EBY-positive LPD . Sim ilarly, EBY leads 10 the expression of C030 in most cases . In patients with EBY-positlve lPD resulting from defective immune surveillance, the latency genes including LMPl may be expressed.

Ftg. 13.06 Hypef-IgM syndrome. ", l ymph notle cootalns B C020 stan Iigt"ighIs oortIcaI areas

338

ImmunodeflClency·assoclated Iymphoprolileratlve disorders

ATMgene. inversions and nenccatcose the

t-een receptor genes on cbrcro-

somes 7 and 14 are common. Theseollen show breakpoints at 14qt 1-12. 7Q32-J5 and 7p15 , These nansiocanoos may involve the TeL I gene, leading to T-eel Iymphoproliferative diseases. inclUdIl'll; tom pre T-ALl./lBL as well as T-cell PLL Other chromosomal rearranoerrerse franslocations include inv(7)(pt3q35~ 1(7;7)(p13q3S), t(7; 14)(p13;q1 t), and 1( 14 .14)(q 11;q32 ). The immunoglobUin gene loci also may be involved 12t64).

Prognosis and predictive factors The prognosis is related 10 both the underlying primary immune disorder and ltE type of LPO. The immunological status d the host is an important risk factor {33tl The lymphoid p rolif erations in ALPS are often self-limiti ng , Lymphoid hyperplasas in CYIO may be indolent, Most 01 the ather LPO in patients w ith PIO are aggressive, However, g ive n the wide variety of uocely ing co nditions and ensuing lympboproliferative disorders , the prognosis rras be eval ua ted in each case ind ivid ually I pa tients with EBV-driven infectious rrceonucleosis. a hae mophagoc ytic syndrome ma y be the primary cause of dea th, usuatj

ro1e ~

wilh pnmary foldes, but Iacts gemWIaI ants.

,a

s

associated with ma rked pan cyt openia , liver dysfunction, co agulopa thy and fureer infectious com plications. Treatment is based both on the nature of the neoplastic process and the underlying genetic de tect. In gen era l. less ag gressive therapy than in pat ients without

PIO is need ed , Allog eneic BM transp lantation has bee n used in patients with WAS, SC IO and hyper-Ig M sy nd rome 1629, 8681, Since the EBV-d riven B-cell expansion in LYG is often not aut onomou s, it may resp o nd to immu no regulatory the rapy using inte rferon u -2b 124201·

TillIt13.01 ClinIcaI leatures 01 the pnmary inrnunoOefJoenc (PIO). Frequency

I"""'"

GIn.{.) or protein!.)

MOIl common abnonnal;ties

Mosl commonISsOCiated

Iymphoprolilerlliv. disortl~ {"loy

impkaled

dPlO"j

CorOled T.

-

9-1 6'Ji,

. . 1koI

-..nodefic:ienc:itt

....

1-5%

~1C)'

,sao,

VdlamofL·2R.Il.J.R. tl-1R, 1l-9ft1L15R, tl-21R, JAK3 lunase: Il ·l R, C045,C036 or

C03t . RAGll2. Al'tems. NJA

1-'"

C040 1ga1'ld (C04Ol. C0154J ~ C040

Reo.mntsevere bactefJai. fIIngai

EB'I-assooated lesions. fatalrnedIous

aM will t!fedions, ir'lcb)ng opptJrtunlSlic i1feclians, SU1ra:st1.

/l'lOI'lCI\UCie (!'l8al1y 100%)

--

EBV--astOOated lesions. (DlBCl. HodgloJn ¥'nphoma) granular ~e 1etJkaer!ia

haemolylic anaema. biliary tact andtver disease. oppor\Ilfll5lic

larve

i11ecbOns

Pndonlinantty IfIIJbody PIOJ

CcrrIIOlwnabit

21-3 1%

Badenal infecbons (king. GI). autoimmuf"ll cytopenlas. granOOmalOlJS dlSNSI (lung.liver)

..,..,lldeblrq

iClDl

EBV--assoaated lesions (Ol.BCl. HodgIlll'l lymphoma). exlJaoodal marginal zone

tympOOma. SII1a11 ¥'nphocylJc lym~. lyrnphoplasmacybc lymphoma, peripheralT-Gel lymphoma (l'afe~ 2-1%1

0lI'« welklefil'lfld

5--22%

iIIlmlmodtliciency 11l1 dro mes Wiskott·AAjricl1

13%

Thrombocykl~ , small platelets. eczema, aLttoimmune disease, bacterialinfections

EBV-asSOCiatlld lesions (OLBCl, Hodgkin Iymphoma. lympnomatoid granulornatosis)

ATM

Ataxia, telallgiectasias, increased AFP, increa sed sens ili~ity to ionizingradi ation

Non·leukaemic clonal 'r-eef proliferations. DLBCL, Burkitl lymp/loma, T·PLL, T-ALl. Hodgkinlymphoma (10--30'4)

NBSflNibrin)

Microcephaly, progressi ~e m&ntal retardation,sensitvity to ioniZing radiation. predispositiOn to cancer

OLBCl.peripheral T-<:eIllymphoma, T-lBLlALl, Hodgkin lymphoma (28-36%)

WASP

Ij"'O'oole (WASI

Ataxia·lslangieeta sia

2-{l%

:AT)

NffJe9E!" tlreakage l~ome (NBS)

OlMaMloflmmun.

1- 3%

<1%

SH2D1A

<1%

FAS {lype 1a). FASL (type

,-

1b). CASP10(caspase 10) (type 2a) or CASPS (caspase

aulOIlTlmune cytopenias. f8CII[8[lI

~ulatjon

x

~

WlO\Ji...liYe tfOtrne (XlP)

-~ .,........abve

"'-iAU'S.

CnI!--SrMh Syrd'ome)

8) (type 2b)

(3-9%)

EBV-triggered abnormalities (fatal 1M, twlpalibs. aplastiC anaemia),

EBV-asscOaIed lesions (Burtoll lymphoma, DlBCl) (nearly 100%)

Defective IynlII'loc)1e apop\OSis. splenomegaly. adenopatlly.

Nodulaf LPHodglurl lymphcma. Classical Hodgkin lymphoma , OlBCL BOOUII IyrnpIona. peripheral T<el lymphoma (rare}~CHl. 0l.6Cl and Bl may be EBV+ or·) (3-10%)

"'-.

repol1s 01 severalnalional and i1teInational registnes TCR. T-(eII anligen receplor; NI. normal; ADA. aOenosIfIe deamioase: B. B~, I T ~. !g, serum irmu'logIObI*l: AFP, e. fetoproleln. " "it where provicled n:licates appfOlUtTl8Ie %rJ pabenls II wtlom LPOdevelops.

' :W ~ !rom

tvmonopronteranve diseases associated With

primary IfTlmunedisorders

339

Lymphomas associated with HIV infection

M. Raphael J . Said

B. Bensch E. Cesa rma n NL Harr is

Definition

lymphomas tha t develop in HI V-posil ive pat ients are predominantly agg ressive B-eell lymphomas. In a proport ion 01 c ases they are con sid ered ac quired immunodeficiency syndrome (AIDS)defining conditions and are the initial mannestanoo of AIDS. These d isorders

are heterogeneous and include lymphomas usually diagnosed in immunocompetent pa tients. as wett as those seen much more often in the selting of HIV infection. The most common HIV-associatec lymphomas include Burkitt lymphoma

(Bl), diffuse large a-cen lymphoma (DLBCL) (often involving the central nervous system). p rimary effusion lym phoma (PEL), and plasmab lastic lymphoma. Hod gk in lymphoma (HL) is also increased in the setting 01 HIV

Epidemiology The incidence of all subtypes of nonHodgkin lymp homa (NHL) is increased 60-200 times in HIV-positive patients. In partic ular, be fore highly act ive antiretroviral therapy (HAART) was availab le , pr imar y central nervous system (CN S) lym phoma and BL w ere increa sed approximately 1000 times in co m parison with the general population 1193, 1283). Since the introduction of HAART. the risk of NH L declined dramatically (from 53 to 23 standardized incidence ratio): the risk dec reased cons id erab ly in 1996 and has remained sta ble ther eafter (646! Moreover. the d ecr eased incid en ce of most

Fig. 13.07 RadiaogicaI firdngs in HIV-assOOaled~ . A Nuc:le¥ magnetICresonance (NMRj lnagilg $I2lfll tile brain shows a Iiwge tl.molJ" mass in !he basal gangb. BMlIbple*'9 defects n seen in iYer

AIDS-associated NHl after HAA RT introduction is consistent with improved C0 4 cou nts 1211,2171. HAA RT is also associated wi th enhanced survival with a 75% decr ea se in mort alit y. although lym p homa s now contrib ute to a greater percentage of first A IDS-defin ing illness 1570, 6461. There has been an unexpected increase in the inci dence of HL since the advent of HAART therapy 1451! , Since HL incid ence is lower among pa tien ts wi th severe imm unos upp ress ion than among those w ith moderate immu ne d efect , the recen t increase of HL incid enc e co uld be possi bly related to improvements in CD4 coun ts (218!. Etiology and pathogenesis Lym phomas in HIV-patients a re heterogeneous. reflecting several pathog eneti c mechanism s: chron ic antig en stimulation,

Fig. 13.08 Dilfuse Ia'ge Ik$I "JnlIhoma. HI'..associaIed. AIiwge tun'lOls nvotves ee basal g
340

Immunodeficiency-associated Iym phoproliferative disorders

genetic abnormalities. cytokine deregulation , and the role of Epstein-Barr virus (EBV) and Human Herpes Virus 8 (HHV8) 1336 3371. However, EBV-positive lymphomas decreased in the HAA RT era 19411. HIVrelated lymphomas are consistently rroocclonal and are ch aract erized by a numbel of common ge net ic abnormalities of MYC and BCL6 genes, as well as tumour suppressor genes 1743, 22821. The recognition of a porv cionat or ono ocionar newe of some f-nv-retatec lymphoid proliferations suq qests a multistep lymphomaqeness B--cell stimulation, hypergarnmaglobulinema and persistent generalized lvmoreoercpa thy preced ing the development oi these lymphomas probably reflect the roe of chronic antigenic stimulation. Denotco of the c ytokine network leading to hign serum levels 01lL6 and IL 10 is a featured Hrv-rerateo lym p homas assoc iated wltn EBV or HHV8 . EBV is id entified in the reoplastic cells ot approx imately 40% of HIlirelated lymphomas , but the detectce d EBV varies consi d erably with the site ct presentation and histo log ical subtype EBV infec tion occurs in 80--100% 01 pi" mary CNS lymphomas 13251 and PEL 80% of DlBCl w ith fmm uoobtastc teatures and 30-50% of BL 1877!. Nearly
~.

2

:.8 0;

t

t.g. 13.10 Ii &r1utt lymphoma. eel ~ is urVIoon. B In arw;Jlher case of Burkill tymp/'lOma, eels show mud! great« vanaIion in size and shape. C BI.rtillIynllhoma'" pliI5trIaq'loid dItI8rentlation. eels have an ec:c:enbic rim rJ deepty stained cylopIasm

na.

11 11 Ii Prmary CNS lymphoma. dassIIied as liIfuse largeEk:eIIymphoma i'I an HIV-posiIiYe pabent. B Diffuse largeEk:eIIymphoma. irnrTulobIaslic variant. presenlIng in .. a:nnI nervous system. Thecellshaveprominentcentral nucleoli. C Cells extllbit marked pIasrnar;ybd ddIenlnIiabOn.

Sites of involvement These lymphomas display a marked

,e ,

,f

::ropensity to invo lve extranooat sites, in particular the gastrointestinal tract. e NS (less frequent since HAAAT ), liver and bone na rrow The peripheral blood is rarely incveo except in occ asional cases of BL presenting as acute leukaemia. Unusual eessuch as the oral cavity, jaw and body cavities are often involved . Many other exrenooal sites. e.q . lung. skin, testis, heart !rid breast, can be involved , lymph nodes are involved in abo ut one third of patients .t presentation (2131. but since the AAART era , nod al involvement account s \:Jr half of the cases 194 11.

h

,-

,-

,f ,f

,-

,-

," .n

·1 .

L.

of

.d

Clinical features \tIs1 patients present with advanced clincal sta qe: bu lky d isea se with a hig h

urccr burden is frequent. LDH is usually mar\(edly e levated There is a sig nificant '8ationship betw een the subty pe of Iymrtoma and the HIV d isease status . llBCl more often occurs in the selli ng of b'lg-stand ing AIDS and is associate d MU'I a trend towa rds a hig her rate 01 opXlrtunistic infec tions and lowe r CD4 + kell counts wi th a me an below 1JJx1()5/L In con trast , Bl occurs in less tmJOOdeficient patien ts, with a shorter lean interval be tween the d iag nosis of

HIV seropositivity and lymphoma and signilicanlty higher CD4 + f-cen counts (more than 200x 1CJ61l) 121 1, 3351.

Morp hology In HIV-positive pat ients, d ifferent ty pe s of lymp homa can occur. Some are the same ag g ressi ve B-c ell lym pho mas that develo p sporadically in the abse nce of HIV infection, wh ile others co rrespond ing to poly morph ic lymp hoid proliferations and unu sual lymphoma bistotvpes occur more spec ifically in AIDS patients, Lymph omas also occurring in immunocompetent patients Burkitt lymphoma : Burkilllymphoma accounts for 30% of all HIV-assoc iated lymph omas, One third of cases displ ay the spectrum of mo rp hologic fea tures descri be d in the Bl chapte r, with EBV be ing positiv e in 30 % of cases 11 8 191. Two thirds of cases show p lasmacytoid d ifferentiation, which is relatively unique to AIDS pa tients. They are ch aracterized by medium-sized ce lls with ab und ant basoph ilic cytoplasm, a nd an eccentric nucl eus , often with one c entrally loc ated p rom inent nuc feolus. The ce lls often cootain cytoplasmic immu nog lobulin. EBV is posi tive in 50-70% 01 cases 15 111

Diffuse large 8-cell lymphoma: The maJOl"Ity of these lymphomas contai n numerous centroblasts , vari ably ad mixed with immuno btasts. This type acc ounts for 25-30% of HIV-assoc iated lymphomas ; EBV is present in 30% of cas es, DlBCl containing more than 90% immunoblasts and usual ly exhi b iting p lasmacytoid tealures are cl assified as the immunoblastic va riant. They account for about 10% of HIV-assoc iated lymphomas, contain EBV in 90% 01 cases, and allen occur fate in the co urse of H IV disease. Primary ce ntral nervous system lymphomas are usually of the imm unob lastic type {325 f, Hodg kin lymphoma. Most cases co rrespond to either the mixed ce llularity or lymp hocyte dep leted forms 01 c lassical HL Some c ases of nod ular scle rosis Hl are also seen . HIV-re lated HL is associateo with EBV in nearly all cases: the cells express Ihe latent mem brane protein 1 (LMP 1) and are EBER-po sitive. Atypical forms with Hodgkin-like features may be observed in such con text 11 9091. Other lymphomas: Rare c ases of MALT lymphoma have been described in both paed iatric and ad ult pa tients with HIV infection 11436 , 2 1871. Rare cases of pe ripheral t-een and natu ral killer ce ll

Lymphc:WnaS associated WIth HIV Infection

341

Lymphomas associated with HIV infection

M. RaphaAI J. said B. Bofisch E. Cesarman N L Harris

Definition Lymphomas that d evelop in HIV-p ositive pa tients are p redominan tly agg ressive Bccef lym phomas. In a proportion of

c ases they are conside red acquired immunod eficiency syndro me (AIDS)defining conomons and are the initial mani fest ation 01 AIDS. Thes e disorders

are heterogeneous and include lymphomas usually diagnosed in immunocompeten t patients. as welt as those seen much more often in the setting 01 HIV inlec lion. The most common j-nv-assooateo lymphomas include: Burkitt lymphoma (BL), diffu se large a-ces lymphoma (DlBCL) (often involving the ce ntral nervous sys tem), primary effusion lymph oma (PEL), and p lasmablastic lymphoma. Hodgki n lymphoma (HL) is also incr eased in the setting of HIV.

Epidemiology The incidence of all subtypes of nonHodg kin lymphoma (NH L) is inc reased 60-2fXl times in HIV-positive patients, In particular. before highly active antiretrovirar the rapy (HAA RT) was available , primary central nervou s system (CNS) lymphoma and BL we re inc reased approximately 1(XX) times in compa rison with the q enere! po pulatio n 11 93 , 1283 ). Sinc e the introd uct ion of HAART, the risk of NHL declined d ramati cally (from 53 to 23 sta ndardized incidence rati o ): the risk d ec reas ed c on sider ably in 1996 an d has rema ined sta ble therea fter (6461. Mo reove r, the decreased inci denc e of most

Fig., 3.08 DilIuse I<wge Ik:eI ~, HlV-associated. A largeUnour irrYeIIves Itle basal gangia.

Fig. 13.07 RadIOlogical findings in HIV-associaled lymphoma, It Nuclear ~ rescoeece (NMR) imag'ng scan d ee bra,n shows a large tumour mass in 1Ile basal ganglia B Mufliple filling defects areseen in Mr,

AIDS-as soc iated NHL alte r HAART introd uction is consistent with improved CD4 co unts 1211, 2171 HAART is also associated with enhanced survival with a 75% d ec rease in mo rta lity. although lymphomas now contri b ute to a greater percentage of first AID5-defining illness 1570. 6461. There has been an unexpected increase in the incidence of HL since the advent of HAART therapy /4511. Since HL incidence is lowe r among patients with severe immunosuppression than among those with moderate immune defect, the recent inc rease of HL incidence co uld be po ssib ly related to imp rovements in CD4 counts 12181. Etiology and pa thoge nesis Lym phomas in HIV-pa tients a re hete rogeneou s, reflecting sev eral pathogenetic mech anisms: ch ronic antigen stimulation,

gene tic abnormalities, cytokine deregulation , and the role of Epstein-Barr virus (EBV) and Human Herpes Virus 8 (HHV8) (336, 33 7}, Howe ver, EBV-positive lymphomas decreased in the HAA RT era /9411. HIV· related lymphomas are consistently rro-oclonal and are characterized by a number of common genetic abnormalities of MYC and BCL6 genes. as well as tumour ~ p ressor genes 1743, 22821. The recogrtton 01 a polyclonar or otigoclonal nature of some HIV-reIated lymphoid proIiferam suggests a multistep Iymphomagenesis B-cell stirn,J1ation. hypergammagloblJlinemia and persistent ge neralized lymphadenopa thy pre c ed ing the develop ment 01 these lymphomas probably reflect the role of chronic antigenic stimulation , DisrupliOO of me c ytokine netw ork leading 10 high serum levels of IL6 and lL 10 is a reatoree Hrv- rerated lymphomas associated with EBV or HHVB. EBV is identified in the reoplastic cells of approximately 40% ot HIV· related lymphomas. but the detection ci EBV varies considerably with the site ci presenta tion an d histological subtype EBV infection occurs in 80-100% of prmary CNS lymphom as /3251 and PEL 80% of DLBCL with imm unob lastic teatu res and 30--50% of BL /87 7). Nearly a~ HL c ases in the setting ot HIV infection are associated with EBV P 07 , 20681, HHV8 is specifically assoc iated with PEL whic h usually OCCUfS in the late stagesof the disease. in the selling of profound immunosuppression 13721.

•

:. ~

l.

r,. 13,10 ABurtitl~ . tel Jl(lIdabon is t.IlIform. ~ lkIIereotiabon. CeIs

B In anothercase 01 &rtitl~ , eels show muctll1N1er variabon in size aid shape . haw an ecoenlric rimof deeply stained cytoplasm.

ens

~

Fig. 1111 A Pnrnaty lymphoma. dassifled as ddluse large8-cel1ymphoma in anHIViJosrtive patient . 8 Odfuse large 1k:eI IIIcenIraIlllIIVOUS s)'5lem. Thecells haw prominentcentral nucleoli. C Cells e d ubll. marked pIasITIacylllId dlflerentJalion.

Sites of involvement These lymphomas display a marked eropensrty to involve extranod at sites, in carncurar the ga stroin testinal tract, e NS (less frequent since HAART).liver and bone matrow. The periph eral blood is rarely in-

\'O wed except in occasional cases of Bl presenting as acut e leukaemia . Unu sual saes such as the oral cavity, jaw and body cavities are often involved. Many other 8Xtranodal siles, e .g. lung, skin, testis, heart and breast, can be involved. Lymph nodes are involved in abo ut one third of pal ients at presentation [2 131. but since the

HAART era, nodal involvement accounts tx half of the cases 19411. Clinical feature s

Yost patients present with ad vanced clincal stag e; bulky di sease with a high unour burden is frequent. lDH is usua lly markedly elevated . There is a significant relationship between the sub type of lymphoma and the HIV di sease status. DLBCL more etten occurs in the setting 0 1 l:lng-standing AIDS and is associated NI!h a trend toward s a higher rate of OJ)cctomsuc infec tions and lower CD4 + T-re11 c ounts with a mean be low lCKb: l lJ1lL. In con trast. BL occurs in less .rrmunod efic ient patients. with a short er mean interval between the d iag nosi s of

HIV seropos itivity and lymphoma and significantly higher CD4+ T-cell counts (more than 200x 1()6!L) 12 11, 335 1. Morphology In Hrv-oosmve patients. different type s of lymp hom a can occur. Some are the same ag gressive B-een lymphomas that d evelop sporad ically in the ab sence of HIV infec tion, wh ile others correspo nding to polymorph ic lymphoid prol iferation s and unusual lymphoma histotypes occur more specifically in AIDS patients,

Lymphomas also occurring in immunoco mpetent patients Burkitt lymphoma: Burkitt lymphoma ac counts for 30% of an HIV-associated lymph omas . One third of c ases di splay the spec trum of morphologic feature s d escribed in the BL cha pter, with EBV be ing positive in 30% of c ases 118191. Two third s of cases show plasmacytoid outerennarron. which is relatively un ique 10 AIDS pa tients. They are cha racterized by medium-sized c ells with abundant ba soph ilic cytoplasm. and an ec cent ric nucleus. often with one centrall y located p rominent nucleolu s. The cells often c0ntam c ytoplasmic immunoglobulin. EBV is positive in 50-70% of cases 15111.

~.

irm'UlotIlastic vananl. preseobng 1\

Diffuse targe B-eelt lymphoma: The ma jority of Ihese lymphomas contain numerous centrobl asts, variably admixed with immu nobtasts . This type accounts for 25-30% of j- nv-assoctateo lymphomas; EBV is p resent in 30% of cases. DLBCL containing more than 90% immunoblasts and usually exhibiting plasmacytoid features are classified as the immunoblastic variant. They ac count for about 10% of HIV-associated lymphomas , conta in EBV in 90% of case s, and often occur late in the course of HIV disease. Primary cen tral nervous system lymphomas are usually of the immunoblastic type 13251.

Hodgkin lym phoma: Most cases correspond to either the mixe d c ellularity or lym p hocyte d epleted forms of cl assical HL. Some cases of nodular sclerosis HL are also seen , HIV-relaled HL is associ ated with EBV in nearly all ca ses: the cells express the latent memb rane p rotein 1 (LM P1) and are EBER-pos itive . Atypical forms with Hodgkin-like features may be observed in suc h con text 119091.

Other lym phomaS: Rare cases of MALT lymphoma have been de scribed in both pa ed iatr ic and ad ult patents With HIV infec tion 11 436, 21871. Rare cas es of pe ripheral T-cell and natural killer cell

Lymphomas associated WIth Hrv infection

341

Iymphoma.can also occur 186. 213. 300. 330.801.863,956. 10571. Lymphomas occurring more specifically in HfV-positive pa tient s Primary effusion lymphoma (PEL). Plasmablastic lymphoma. lymphoma arising in HHV8-associat ed multicentric Castleman Disease (See Chapter 10). Lymph omas occurring in other immunodeficient states Polymorphic lymphoid proliferations resembling post -transplant associated Iympbo prouteranve disease (PTlD) may be seen in adults and also in children, but are much less common than in the posttransplant setting, representing less than 5% of Hrv-essocrateo lymphomas. These con form to the c riteria of polymorph ic

342

B-eell PTlO. The infiltrates contain a range of lymphoid cells from small cells. often with plasmacytoid features, to immunoblasts, with scattered large bizarre cells expressing CD30. EBV is oflen present, but some cases are EBV-negalive 111 51, 1399,1556 ,2160) Prognosis and predictive teeters Before the HAART era, the rate of complete remissions was abou t 50% for most of histological subtypes. The z-vear survival was sign ificantly lower for Dl BCl than Bl in univariate analysis. The International Prognostic Index (lPI) appeared to be a reliab le indicator. The degree of immunodeficiency also co rrelated positively with the IPI score 118741 . Some other adve rse prognostic factors were ident ified . such as age >35 years. intravenous

Immunodeficiency-associated lymphoproliferative disorde rs

drug use , stage IIlIIV and CD4 counts less than 100)(1CY'/L Despite dose adjustment, the outcome of patients with lymphoma and HIV infection was clos ely related to the severity of immunodeficien cy {2531 . Since the introduction of HAART. the overall survival of patients with DlBCl has improved. and outcomes are approaching those of patients with de novo lymphoma 113011. The achievement of complete remission is the most important prognostic teeter with respeclto the time of survival 124341. l ong -term survival can be achieved in approxima tely one third of patients with favourable prognostic characteristics. PEL usually has a very poor prognos is with a low comp lete remission rate,

Post-transplant Iymphoproliferative disorders

Definition Post-transplant IyrrVloproIrferative osooes

(PTLD) are lymphoid or plasmacytic oroIiferatoo s that develop as a consequence 01 immunosuppression in a recipient of a !did organ, bone marrow(BM) Of stem cel l

:lIIograft. PTLD compr ise a spectrum rang-

SH Swerdlow SA Webber A . Chad burn

J A Ferry

lymphomas in allograft recipients are designated as they are in the normal host and not considered a type of PTLO. Detection of rare EBV-positive cells in the absence 01 an appropriate Iym phoi dlplasm ac ytic proliferation is also not considered diagnost ic 01a PTLD

ng from usually Epste in-Barr virus (EBV)driven mtecucus mononucleosis-type

Ep idem iology

pelyclonal proliferations 10EBV-positive or uN-negative proliferations indistinguish-

The characteristic s of PTLO appear to differ somewhat from one institution to another, probably as a result 01 different patient populations, a llograft types and immunosuppressive regimens. A var iety 01 risk teeters have been id entified 1308. 309. 164 6 1. but the most important risk rector lor EBV-driven PTLO is EBV seronegativity at the time of transplanta tion 1309. 23661. Among adult sol id organ rec ip ients, the frequency of PTLO c orrelates. in part, with the intensity of the immunosuppressive regimen; patients rec eiv ing renal allografts have the lowest frequency of PTLO «1%), those with hepatic and ca rdiac allografts have an intermediate risk ( 1-2%), and those receiving heart-Iungll ung or intestinal allog rafts have the high est frequ ency (5% or g reater) 1133, 308, 309, 1646). In ch ild ren, the inc idences are very much high er 1562, 2367} , w ith the major ity of cases being associated with post-transplantation primary EBV infection 12367}. Per ipheral blood (PS), ste m ce ll and 8 M allog raft rec ipients in g eneral have a low risk of PTLO (- 1%) with the fis k of earlyonset PTLO « 1 yea r) highest w ith unrelated or HLA mismatched related donors, selec tive t-een depletion of donor BM, and use of antithymocyte globulin (ATG) or anti-C03 monoclonal anti bodies . The risk of PTLO in Ihese patients increases up to 22% for thos e with two or mo re of these risk factors 1499} . An unexpectedly high incidence of EBV·associated PTLO (17%) has been recently observed in patients undergoing unrelated umbilical cord blOOd transplants with a non -mveioabtanve preparative regimen containing ATG 12911 . PTLO -ljk e le sions are rare after autologous BMT; they may be associated with additional high-dose imnunosuppressNe

ilbIe from a subset of B-cell or less often teen lymphomas thai occ ur in irrvnunocorceteot individuals. The monomorphic m Hodgkin-type PTlO are further cate~ed as in non-immunosuppressed pasents. according the lymphoma they

resemble. Indolent B-cell lymphomas such as follicular lymphomas and MALT , . 13.02 CategaJeS d

POSl-tran~ Iymphopolifer-

1M esease (PTlD).

e.ty Itsi0fll1

9971/1

P1asm
PolymorphicPYlO

9971/3

llQrIOIllorphic PTL01 (classifyaccording to I)'mplloma lIMy membIt)

&t6# neoplasms Diffuselarge B-celilymphoma

Burkilllymphorna Plasma cell myeloma Plasmacytoma·likelesioo

"'"'"

T<eI fI60PIasms Peo:'iptoeral T-cet lymphoma, NOS HepatOSlllenic T-<;ell ~phoma

"*'

Clinical Hodgkin Iymphoma·type PTLD'

m

rnass-ll~& leslQr1S in the posHransplan1 may h&ve the morphok)glC appearance of Icn:I klIaAar hyptfpIasia orotherll'\8l1<.ed but lIlfI-I,I.lle Iy!npl'loId hyperplasias. Jm.o ccdts b' 1IlMelesions we the samt as tee b' IllIIeSI)8drve IyrnptIoId or p1asmacybc 1

~

-..

~ ~ IkeII ~.-.sMlg in trans. . ~ in not ~ among the PTlD.

regimen s and are best cons idered iatrogenic, rather than post-transplant, irTYn.Jno.. oencercy-associated LPO 115761.

Etiology The ma;ority of PTLO are associated with EBV infec tion (usually type A), and appear to represent EBV-ioduced monoclonal or. les s often, poIyclonaJ B-cell or monoclonal proliferations that occur in a setting of decreased immune surveillance 1376,450,699. 730. 1166. 1569. 21331. Up to 30% ot PTLO are EBV-nega tive with some series reporting an even higher proportion of ca ses and with about 213 of T-PTLO EBV-negative 1224 . 699. 1260. 1586.2 133 1. Furthermore. the proportion of EBV-negative PTLO appears to be inc reasi ng /15861 . EBV-negative PTLO are more common in adults. tend to occur later than EBV,poSit ive cases and are more likely to be of monomorphic type 1791. 1586 J. Human herpes virus 8 (HHV8)-associated PTLO are reported including post-transplant primary effusion lymphoma [606, 1106, 142 11; however, the etiology of the vas t majority of EBVnegative PTLO is unkno wn . Some may be due to ESV that is no lon ger detectable [2073J, some d ue to other unknown viruses and some due to chronic antigenic stimulation, includ ing by the transpl ant itself 1224) The EBV-negative cases are still co nsidered to repre sent PTLO and some may respond to decreased immunosuppression {15861. The majority (>90%) of PTLO in solid organ rec ip ients are of host origin and only a minori ty of donor origin . Donor origin PTLO appear to be most common in liver and lung allograft rec ipients. and frequently involve the allograft 178, 378 , 1255,2069, 23801. In contrast, the majority of PTLO in BM allograft reci pients are of donor origin, as would be expected. since successful engraftment results in an imm une system that is nearly exclusively of donor origin

t-een

t-een

125101.

Sites of involvement Involvement of lymph node, gastrointestinal tract. lungs and liver are common in all

Post-transplantlymphoproliterallve d soroers

343

allog raft types, whereas ce ntral nervous system (eNS) invo lvement is rare 1699, 1569, 1723, 23671. The e NS may be the only sile 01d isease or may be associa ted with multiorgan involvement 13431. In solid organ recipients, PTLO frequently involves the allograft and this may cause diagnostic con fusion since rejection and infection may result in a similar clinical picture. Allog raft involvement appears more common in earty-onset. EBV-positive disease 1133. 7911· The heart is the only organ in which allograft involvement is very rare. "Early lesions ' often present with tonsil and/Of adenoid involvement but may also occur at other sites. Overt BM involvement by polymorphiC aOO monomorphic PTLO is not comoon. and PB is rarely involved . Bone marrow auograft recipients tend to present with widespread disease involving nodal and extranccat sttes. including liver, spleen. ga strointestinal tract and lungs 11723. 1998. 2510 1.

Fig. 13.12 Intecbws rrDU'lUdeosis-ie(lM)Iesionfla D"ISiI ofan 11--year-<*l renal aIograftredpiert. lhefe ispesel· vatlon of cwertying epIlt1eiI.m and crypts. 1M normal tildes iJfI!I absenl and hire is a li1tuse ~ p1 oifelalo'L

Cflnical features The clinical features 01 PTLO are high ly variab le and correlate With the type of allog raft, and to some extent, with the morphologically de fined ca tegories. Almost all solid organ transplant recipients are currently managed with a carcmeunn inhibitor (cyc losporine or tacrolimus). With Ihese agents. PTLO frequently presents in the first year after transpl antation. earlier than tended to be obser ved in the pre-cyclosporine era 11 569. 1723}. EBVnegative PTLO and TINK-cell PTLO tend to present later (med ian time to occ urrence 4- 5 years and 6.5 years, respe ctively) 11260. 1586. 21331. The majority of PTLD in 8M allograft rec ipients dev elop within the first six months 14991. PTLO presentation may be non-specific with features such as malaise. lethargy, weight loss and Table 13.03 PathologicevaluallOn ofspecimens for !hediagnosis of PM.

Method of tvalualion

Necessity

-...._- ......... Histopathology

EBER in situ h)tlrWalion

EBV
PUrpoIie

Evaluate arthit6cture and cytologic features, requued lordaS$llicaboo il11t chatn classres\nCtlOl'l' and basic ~ subsets, requiredlor cIassofK:aIioo Uost senSltiYe method lor assessing ~ PTlD is EBV1J05Ilive, aidsII dIagnosrs and possobly prognostication. useful in dtIlerenbaI dl~ \WlIh f'eJlldIOn i1 aIografI (If positive) Detema ~,Iineage of clonal popuIation(s). d\I'or"nOSOOIaI and oncogene abnom'Ia\ItJes, may be needed klr dassificaboo IdellIJfIcation of minor c:Iones

Assess possible

"Pnllin section i1vru~ ddlen fall k1demr.f1Slrale ~ 8-<;eIpopuIaIions, eY8I'1lf jn'SeI'C, Lriess 1henl1S pIasmacytit~. ~1f!he less senWo'e EBV-lMP1 ~ is posiIi¥e. EBER in SlftsIlybrOZaIiOn is not rllQI,lO:l.

344

ImmunodefICiency-asSOCIated tymphoprolilerative disorders

.s

lever. Lymp ha denopathy and or gandysfunction are also common ceseotatcos. Obstructive symptoms such as enlarged tonsils are another type 01 presentation. Pres enta tion with disseminateddiseaseseems to be less COITIlTlOlI in 'he ccreot era. perhaps due to increasing aeeeress 01 the diagnosis and due to rooWle EBV viral load monitoring 01 seronegatve recipients in many transplant centres.

scecmc

Prognosis and predictive tactors Tne "early' lesions tend to reg ress with reduction in immune suppression. and if ns can be accomplished w ithou t g ralt eectoo . the prognosis is excellent , partie.Jarty in children {133O.2486 1. Polymor phic end less often monomorphic PTLD may aso regress wit h reduction in immune aocresstcn 12080, 236 71. Howeve r, reOOUnd acu te and chronic reject ion may be observed and c an lead to gr aft loss a"l{\ death 1236 71. A proporti on of poly -rrxphic and even mo re numerous mon oroorphic PTLD fail to regress, and require additional therapies suc h as monoclonal e acooes directed ag ainst B-cell antigens (roost commonly anti-CD20) 1435 , 6431. chemotherapy (436, 643 , 8561 o r co mbiretone of both . Several cen tres are also pe'forming phase I clinical trials of cellular nmunotherapy to restore EBV·spec ific cytotolCic T-cell immunity in EBV-driven 'l!lractory disease {46 1. 889, 1946 }. The ~tous lesions usually do not regress fllIh decreased immunosup pression , and T!NK-eell PTLD are also considered to be aggressive with the exception of those of rarge granular lymphocyte type {2 133} . 'eermerese. some T-PTLD do respond l:l reccosntu ton of the pa tients' imm une esen The plasmacytoma-like lesions Vt'8 a variable outcome {1074 1. EBV ~tivity in PTLD and even among the - K-eell PTLD, is also considered an

adverse prognostic inchcator, although not a ll studies document a survival difference

1435.21331· A number of additional prognostic factors associated with an adverse outcome include multiple sites of disease and advanced stage, older ag e at diagnosis. late onset d isease. high Internat ion al Prognostic Ind ex and elevated lactate dehydrogenase 1309, 435, 643, 792.22691. However. risk factors for adverse outcome vary g reatly between stud ies . Multi-site d ise ase may not be a risk fact or lor adverse outcome in paediatric patients 12367}. Overall , the mortality of PTLD is g reate r in BM allog raft reci p ients than solid organ allograft reci pients and may be lowe r in c hildren than adults.

Early lesions: plasmacytic hyperplasia (PH) and inf9ctious mononucleosis (IM)-/ike PTLD Definition The early lesions are defined as lymphoid proliferations in an allog raft rec ipient, characterized by arch itectural p reservation of the involved tissue , with preservation of the nod al sinuses or tonsillar c rypts. and

residual or sometimes florid ly reactive fol· tcies in some cases. In most cases. they form mass lesions . These lesions should be distinguished from lymphoid proliferation s with other known explanat ions or other non-specific c hron ic inflammat ory processes. Cases that have florid follicular hyperplasia but which do not fil into the PH or 1M-like c ategories have been sepa rately designated by some author s. Clinical featu res PH and 1M-like lesions occur at a younger age tha n the other PTLD and are often seen in c hild ren or in adult solid organ rec ip ients wh o have not had prior EBV infec tion {376, 1330 1. Case s described as post-transplant florid follicular hyperplasia also occur most c ommonly in children 12284 } The early lesions involve lymph nodes o r tonsils and adenoi ds more often than true extranodal sites 113301_ They often regress spon taneously or with reduction in immunos upp ression: however, 1M-like lesions ca n be falal. In some case s, polymorphi c or monomorphic PTlD may follow early lesions 11569 , 2453). Morphology Plasmacyte hyperplasia is characterized by numerous plasma cells, small

Post-transplantlymphOproliferatlYe disorders

345

lymphocytes and g ene rally infrequent bland-appearing immunoblasts, white the 1M-like lesion has the typi ca l morphologic features of 1M. with paraconcat expa nsion and numerous immunoblasts in a bac kground of T cells and plasma ce lls. Oth er non -de stru ct ive lymphoid hyperp lasias that either show fewe r immunoblasts or more prominent follicu lar hyperp lasia than typ ical c ases of 1M may also occur in the post-trans plan t setti ng and c ause ma ss lesions 122841. Criteria for the dis tinc tion of these ea rly. non-d estruc tive PTlD from othe r react ive lym phoid infiltrates are not well-defined and rest on the extent of the proliferation. clin ical correlations and the presence or absence of EBV

Genet ics Clonally rearranged immunoglobulin genes are not expected in PH. although small clonal pop ulations may be demonstrated with Southern b lot analysis using probes to the term inal rep eat regi on of the EBV. Some 1M-like PTlD may have small monocl onal or oligoclonal pop ulations, The siq nificance of oligoclonality or a small c lonal b and in these cases is unkno wn [ 1166, 24531. Flor id follicu lar hype rplasia (FFH) does not usually demonstrate clonal B cells b ut. as also repo rted in 1M-like cases. rarely demonstrates simple clonal cytogenetic abnormalities 122841.

PbIymorphic PTLD Immunophenotype Immunophenotypic studies shOw an admixture 01 pOIyclona/ B cells, p lasma cells and T cells WithOut phenotypic aberrancy EBV is present in many bu t not all of the cases of nodal PH and cases describe d as florid follicular hyperplasia 11 166, 22841. 1M-li ke cases are typic ally EBV-po sil ive with EBV-l MP1+ immunoblasts 113301. 346

Definition Polymorphic (P) PTlD are morphologically po/yrTk)rphiclesions composed of immuneblasts. p lasma ce lls and small and intermediate-sized lymphoid cells that efface the architecture of lymph nodes or form destru ct ive extrano dal masses and that

Immunodeficiency-associated Iymphop roliferative disorders

do not lulfill the c riteria for any of the recognized types of lymphoma described fl immunocompetent hosts. Distinction ci some P-PTlD from more -monorrorohc' (i.e. lymphom a-like) lesions that show pasmac ytic di fferentiation is not well-defined, Clinical features The frequ ency of P-PTlD var ies from en! institution to another, rang ing from 20%10 over 80% of the cas es 1450, 699, 735 110 7,1 166 ,1 569 ,1 586 1. ln c hildren ltlis is the most common type 01 PTl O 123671 and frequently follows p rimary EBV intec· lion. The cl inic al p resentation of lhese cases is not distinguishable from PTLO general. Reduction in «renuooeuooessian leads to regression in a variable po portion 01 cases ; others may progress.rd require neenreot for lymphoma 11t 6f. 1569,2080,23671 .

Morphol ogy In con trast to early PTlO lesions. P-PTlO show effacement of the underlying tssce architecture 1735. 8871, Unlike most tyrn. phomas. however, they show the lull fange

of a-cea meunauon . from immunoblasts to plasma cells, with small and mediumsized lymphocytes and with irregular nuclear contours. There may be areas of geographic necrosis and scartereo large, bizarrecells that not infrequently resemble Reed-Ste rnberg cells (atypical immunooIasts ); numerous mitoses may be present . Some cases have areas that appear more rronomorp hic in the same or other tissues ; eos. there may be a cconnoous spectrum between the se lesio ns and the moool"'O'J)hic PTLD. Other P-PTLO have features nat more c losel y resemble Hodgkin lymphoma. Some of these cases have been referred to as "Hodg kin-like" in the past. Variably sized . but usually small . lymphoid aggregates wi th or wit hout p lasma cell ekJslers are seen in the 8M in some patients with P-PTLD (and occasionally in \WTl O) 111731. They are more com mon nmldren than in adults . The c linical sig wcance of these aggregates, that are n:x always EBV+ , is uncertain .

cens

mnunophenotype mmunop henoty pic studi es demonstrate cells with or without lig ht c ha in c lass restriction and a variable proportion at 'eieroceneous T cell s that sometimes ceoonoete 1625. 1569J. light c ha in class restrict ion , when present , may be ttal. and some cases may demonstrate OOIerent clona l populations in the same or dferent sites 115691. Cases with cleercut 911 chain class restriction are recog ~IOO but this observation mus t be noted fl the diagnos tic rep ort, as some of these cases could also be cl ass ified as a rrooornorp hic OLBCL-like PTLO w ith resmecvttc d ifferentiation, a DLBC L-like P'lDwith significa nt polym orph ism or as I plasma ce ll neop lasm w ith inc reased rsstormeo cells . Aeed-Stern be rg-Ii ke :~I s when p resent a re often C030+, [120. but C 0 15-{4061. Most cases of ~.pTLD contain numerous EBER·positive :ellS. Detec tion of EBV by EBER in situ ~dization is a uselul tool in the differr.a l diagnosis of PTlO versus reject ion allografts.

a

n ,I

,j

,e 10

5.

lis i7 1

ecse

I

in

3S.,0-

,od 66.

""""

;JlllD are expected to demonstrate etralty rearranged irTYnunoglobulingenes

,LD sue

ymnge

'IOJgh the c lones are less predominant l8'Inrra 1Q1IOphic PTlD 1449 , 1107, 1166. WI . EBV terminal repeat analysis is the sensitive method lor demonstrating inaI population s in the EBV-positive

cases. In some repo rted c ases , tumou rs at d ifferent sites in the same pat ient may b e clonalty distinct 13 75 1. Seventy-five percent at P-PTLO are reported to have mut ated immu nog lo bulin gene va riable regions (lGVj wit ho ut ongoing muta tions and the rema ind er are unmutated 1334J. Sign ificant I -cell clones are not expected. Clonal cytogenetic abnormalities may be present although less commonly detected than in monomorph ic B-ce ll PTLO (593, 22841 . Comp arative g enomic hyb rid izat ion studies also demo nstrate abno rmaut ies in some P-PTLD incl ud ing some rec urrent abnorm alities also seen in monomorphic PTlO (17641. BeL6 soma tic hype rmutations may be present as well as aberrant promoter methylation, but other oncogene abnormalities are not detected 1334,37 11 .

Monomorphic PTLD The group of monomorphic (M) PTLO fulfill the criteria tor o ne of the B-cell or TIN K-<:e ll neoplasms that are recognized in the immunoc om petent host and scr ibed elsewhere in this monograph. The only exception to this is that the small B-<:elllymphoid neoplasms such as follicular lymphomas or MALT lymphomas are not designated as PTLD even though

oe-

anention has been drawn to the occurrence of MALT lymphom as arising in the posttran sp lant setting 1986 1. The M-PTLO should be des ignated as Ptl.D in the diagnostic line of the pathology report. and then further categorized based on the clas sification of lymphomas arising in the immunocompetent host. Although the term M-PTLO reflects the fact that most cases are composed of a monotonous proliferation of transformed lymphoid ce lls or plasmacytic cel ls , the re may b e sig nificant p leomo rphism and va riab ility 01 ce ll size within a g iven ca se. In addition, because polymorph ic and monomorphic PTLD of B-cell orig in for m a spec trum , their dis tinc tion can become b lurred . Currently, their distinction in problematic cases is usually based on a subjective assessment of whether there is a predominance of large transformed ceusnrrmurobrasts. The presence of abnormalities in oncogenes and tumour suppressor genes may also favour the diagnos is of M-PTLO {11661. Monomorphic B-cell PTlD

Definition

The monomorphic Been PTLD are fT'IOr'Il)clonal transformect B lymphocytic or ptasmacyt ic prol iferations that fulfill the criteria for a diffuse large Been lymphoma. less

Post-transplant Iymphoprollferative disorders

347

•

even thoug h only a minority are CDl38 positive, whereas the EBV negative cases are more likely to hav e a germinal ce ntre type phenotype (C OlO±, BCl 6t . IRF4/MUM1 -, C0 138-: 60% of ca ses in o ne stu dy) 1106 11. The myelomatous or plasm acytoma-like lesion s, which may be EBV-pos itive 01 negative, are phenoIypicaty' simi lar to those in immunocompetent patients {2 1651_

often a Burkitt lymphoma or a p lasma cell neoplasm. The latte r may have alt the fea-

monomorphic PTLO - some cells may be bizarre and multmucleated and even

tures of plasma cell myeloma or of an

resemble Reed-S ternberg-like cetls- and there may be plasmacytoid or plasmacyte differentiation. Thus. the term. m:)l')()ITl()I'ic, does not mean com plete cellular mono tony, only that most of the c ells appear to be transformed or more uniformly p1asmacytic.

ext ramedullary plasmacytoma with involvement of the g astro intes tina l tract . lym ph

nodes or other extranodat sites . Clinical features The c linical presentation of patients with

monomorphic B-PTLD is not distinctive and is, in genefaJ . smilar to the presentation of the IympOOmas or plasma een neoplasms that the y resem ble.

Morph ology Monomorphic B-PTLD fu lfill the co nve ntional criteria for DLBCL Bu rkitt lymphoma,

plasmacytoma or myeloma 18961. This is in contrast to the full range 01maturation seen in polymOrphic PTLO. II is important 10 recognize , however, that me re ma y be p leomorphism of the transform ed c ells in

Table 13.04

Cr ~eria

Immunopheno type

The oon-p1asmacytic lesions show B-cellassociated antig en expression (C0 19 , C020, C079a), with demon str ab le monotypic immunoglobulin (of ten w ith expression of g amma or alp ha heav y c hain) in about half of the c ases. Many cas es are CD30 + , with or without anaplasfic mor phology. Mo st M-PTLO are of non-GC type based on irrmunohistochemistry 1332, 10611. The EBV-p:)SitIvecases usually have a late germinal centre/post germinal centre phenotype (C0 1O·, BC l6±, IRF4/MU M 1+)

used in the categorization of PTLD.

'"""'"

Hisl~thoIogy

......... """"""'" ......

,oty . . . .

Pdymorphic PTLD

MollQl,lOIptic PTlO

Present

"""" .....

Hodgkn IymptIoma

"''''''

type PTLO

Genetics

"""_ ..... ._Major findings

eels, :l irJm.IlDblasts,

Immu~

In sifu hybriciution Pd B ails & a:lmiled T eels: often EBVt

...

fu~ spectrumof lymphoid maturation

Pel (l( mel B cells & admixedT ~Is: often EBV+

FtAs aRenaIcf a NtI.

(OUlef than one of the jn. doIefII !kelt neoplasms) (I" lMsma eel nec¢lsrn

Varjes based ontype01 neoplasm they resetmle. EBV lOO"e vaRable than n other&ategories

FuffiRs l7itefialor CHl

Similar tootherCHL;

19tt wiD not be eaSily

EBV+

der'nonslraled.

= = Pd, polycIooal; Md, m‫ס‬n‫ס‬c1onai: NK. nalufalkiller OIly: TeR,T-wl anbgen recepIor. ~

348

Genetics Clona l IG gene rearrangement is present in virtually all ca ses, and the major ity conta in EBV genome s, which, if pre sent. are in clonal episomal form 1449, 450 , 11071. Most cases hav e somatically mutated IGV with a minority showing ongoing mutations 13341. However, some cases have IGV loci inactivation related 10cripp ling mutations as seen in Hl l333 l . Asio non-PTlO DlBCL, on cogene abnormal~ ties (RAS or TP53 mut ati ons and MYC rearran gements) may be found , and BCL6 gene somatic hypermulation IS c ommon; however, BCL6 trensiocatcos are uncorrmon 1371, 11661. Cytogenetic abnormalities are cornrnon, and are mere freq uent than in the early or polymorphic lesions 122841_ While some recurrent abno rm alities are reported in PTlD such as breaks involving lq ll -q21 region, 8q24.1, 3q27, 16p1 3, 14q32, l 1q23-24 and trisomies 9, 11, 7, X, 2 and 12, differert studies find different conrnon abnorTnalles 1593.22841 . Comparative genomic hytnd ization studies demonstrate additional gains and losses, althou gh no ind iviCUI

~

~

Irrvnunodeflciency-asSOC18ted Iymphoprolileralive disorders

Md Bcells, norK:IonalT celts

Some have BCl 6 soeatc hypefmutalions

!\ ~.

-:r ~~c:.::c'~_~~:iZ~

Fig. 13.19 HodgkJHype PTLD 1l52-year«l male(post renal transpIanl). The Read-5tentlerg eels _ lJClSIq:Ns, ~ 0Ih WIlh C03O+ ellpfflSSion (B) n Golgi-Iype C01S expression Ie).

aboofmality is very common; some are shared with DLBCL in immunocompetent tosrs 11764. 18471 EBV·negatlve mononnphic PTlO frequentty lack expression of the cyclin dependent kinase inhibitor CDKN2A (pltJ'"1.-) 11397/. Abe rrant promoter hypermethylalion and aberrant

somatic hypermutation also occur in

EBV+, AReed-Stemberg eel WfCU'ldedbysmaI~ and some

Clinical fea tures Clinical presentation depends on the type of T/NK-celloeoplasm. Most cases present at extranodal sites, sometimes with associ ated lym phadenopathy 12133I.The more COlTV1lOO sites of involvement include the PB or BM, spleen, skin, liver, gastrointestinal tract and lung

M-PTLD 13341. Mo"","_

Moncmorphic

TIN K~ I

PTL.D

Definition Monomorphic PilO of l IN K-ceil type IT/NK-PTLD) include PTLO that fulfill the criteria lor any of the T- or natural killer (NK) cell lymphomas. They include almost !he entire spectrum of T- or NK -eell neoplasms, with the larges t group being oeripheral T-eeillymphoma, not otherwise specified type. followed by bep atoeolenlc Icelllymphoma. Other typ es of liNK-ceil PTLD include T-cell large granular ~phoc yl8

leukaemia.

adult

T-cell

leukaemia/lymphoma, extranod al NKIT-cell ~phoma , nasal type, mycosis fungoide sl sszarv synd rome, primary c uta neo us e-epiastc large cell lymphoma and other anaplastic large ce ll lymp homas. In North America and Western Europe, they ma ke Jp no more than 15% of PTLO. In some rserces PTLD have occurre d with, e soosequentto, ot her types of PTLD,

t-een

The morphologic features of T/NK· PTLD do not di ffe r from those of the same T/N K-cell lymphomaSin irTYT1llOCXXllT1petent hosts.

fmmunophenotype T/NK·PT LD show express ion of panand sometimes NK -associated antigens. Depending on the specific type, they may express CD 4 or COB, CD30, AL K an d either ali or·to T-cell rec eptors. A bout 1/3 of cases are EBV-positive .

t-een

Genetics Cases of or igi n hav e c lonal T-ce ll recep tor ge ne rearrang ement. Chromosomal ab normalities are commo n and similarto those seen in TIf\JK-cell neoplasms in the immunocomp etent host suc h as i(7)(q1 0 ) and +8 in mo st of the neoatosplenic lymphomas 1593, 21331. TP53 and othe r oncogene mu tations are also reported in a high p rop ort ion of T/NK - PTLD 19801.

r-ceu

r-ceu

ClassicalHodgldn lymphoma IypePTLD Classical Hodgkin lymphoma (CHL), the least COlTlTlOl1 ma,or form of PTLO, occurs in the post-transplant setting . roost often in renal transplant patients, is almost always EBV-positive and should fulfill the criteria for CHL as described (See Chapter 12) . Because Reed·Sternberg-like celts may be seen in early, polymorphic and some monomorphic PTLD, the diagnosis of HL must be based on both classical morphologic and immunophenotypic features, preferably inclu ding both CD15 and CD30 expression 11 570 , 18871. Although CD15-negative cases occur. caution is advised in maki ng the d iagnosis of CHLtype PTLD as these cases must be disting uished from Hodqkin-Hke lesions, in which the EBV+ Aeed -Sternberg-like ceas areCD45 +. CD 15-, CD20 + and where one may find small and intermedi ate-sized EBV+ lym phoi d ce lls as well 1406, 609, 823, 1570 , 1759 , 18171, Rare c ases may fo llow other typ es of PTLO. Although the d istincti on of Hodgkin-l ike P·PTLD from true HOdgkin type PTLD may be d iffic ult in some cas es, the former are bett er characterized as eithe r a polymorph ic or monomorphic PTLD. depending on their overall morphologic features 11759,18171,

Post-transplant lymphoprolilerative disorders

349

Other iatrogenic immunodeficiencyassociated Iymphoproliferative disorders

P. Gaulard SH Swerdlow N.l. Harris E.S. Jaffe G. SundstrOm

Definition The other iatrogenic Iympho prolile rative d isorders (L PD) are lympho id prolifera tion s

or lymphomas that arise in patients treated with immunosuppressive drugs for au toimmune diseases or conditions

other than in the euoqran/auroqratt transplant setting. They comprise a spectrum rang ing from polymorphic proliferations resembling polymorphic post-transplant Iymphoprolilerative disorders (PTLDl to cases that fulfill the criteria for diffuse large Be e nlymphoma (DLBCL) or other s-een lymphomas. periphe ral l INK-ceil lymphomas or classical Hod gkin lymphoma (CH L). Iatrogenically-related lymphomas supe rvening on naematoiogncat malig nancies are not co vered here l4]

Epidemiology The freque ncy of these disorders is not well known, and it is dlfhcult to determine how many are directly related to the iatrogenic immunosuppression rather than the underlying disorder, Of to chance alone . It is likely that the risk and type of LPO that develop in this setting varies depending on the type of irrmunosuppressive agent and on the nature of the unde rlying disorder being treated (e,g rheumatoid arth ritis (RAJ. inflammatory bowel disease (IBO]. psoriasis and psortasc arthritis or other autoimmune disorders) 13171, Methotrexate was the first reported immunosuppressive agent associated with LPD in this

rug ~ule

setting 11089. 1709, 1920). predominantly in patients being treated for RA. In one survey. 479 lymphoma cases were recorded among 101,589 patie nts treated with methotrexate and/or anti-TNF therapy for RA {24351. Many 01 these patients received a combination of several immunomod ulators. complicating interpretation of the role 01 any specific agent. Among the TNFu antagon ists (inlliximab , ada hmumab and etanercept), patients with Grahn's disease treated with infliximab have been reported to have a lymphoma prevalence higher than in a healthy age-ma tched population { 1355}. A striking associ ation between nepatosplenic t- een lymphoma (HSTL) and young patients with Crotm's disease receiving infliximab in combination with azathioprin and/or e-mercaotoounne has

U~ng di$Ofdel

ThefaJ1Y duratiOn

Type of LPD

~ diseases,

3 year.i (0.5-5 ~l

OLBCL. If. PoIymorptIIC LPO. PTCL

6 weeb (2-44 weeks) 1- 56 rronth$

OLBCl. ottlerlype$ HSn.olIlertwes

psor1aSlS

Antagonists 01 TNFo:

InfIIIlITI3b (MAll)

~d lseases

CtdIn's disease (young

patients) Adalimuf1lilb (MAll)

Autoimmune diseases

NA

Altftype

Etarercept (fusion protem with p75)

Autoimmune diseases

8 weeks (2-52 wee ks)

AJly type

NA, rv>l available: MAll. monoclonal antibody: TNF. tlll'llOtlr necrosis faclol': DLBCL. dlfllt$lliarge B-ce~ 'Ym~. HL.1"lodgUl tymphorna; LPO, /yf1'lpI'qlroIOOrabYe disoI'def', PTCL, peripheral T<ellyn1lnoma: HSTl, hepatospl&ric T<ellymphoma (reported only in pabenls eeeteo WIIh InlWnab. not with other drugs)

350

Immunodeficiency-associated Iymphoproliferahve disorders

been reported 11355. 18721, Cases eX large B-ce ll lymphoma and Hodgkin lymphoma have been reported in RA patients treated with TNF inhibitors. although it is not clear whether there is a signdicart increase in incidence 1284, 24351. Etiology Although some of these other iatroger.:; LPD are associated with EBV. like rr'\iI1y PTLD, the frequency of EBV intectot IS very variable 1982, 19201· Overall. atxxA 40% 01 lPD in RA patients treated W1Il methotrexate are EBV+, with EBVdetected more frequently in Hodgkin lymphcrna (-80%) than in OLBCL (-25%) or olhe! a-ces lymphoma types, It is almost con stantly found in polymorphic lPD and In lPD with Hodgkin-like features in this se. ting {982, 19201. EBV is not seen in Hsn. The deg ree and duration of i~ suppression likely plays a role in ee development of EBV-positive lPD. H0wever, the presence of inflarTrnation anQia chronic antigenic stimulation as well as ee patient's genetic background may be important determinants of the risk and type ol lPO 11221. For example, oanents we RA are estima ted to have a 2- to 2O-Idd increased risk of lymphoma even in the absen ce of methotrexate therapy (122, 2230). and may have an altered EpslenBarr virus (EBV)-host balance 13161.lnaddition, HSTL -a lymphoma that tvoce affects young men in the non-lnmcrcecpressed popu latioo- is common in)'OUl"\l

l

men receiving inlliximab for lBO, but not in older patients or in patents with RA receiving this agent.

Cl inical featu res These do not appear to differ from those of imm unocompe tent patients with similar appearing lymphomas.

Sites rJ involvement M10ng the cases reported in patients receiVIlg methotrexate, 40 - 50% have been enrercoat. inclUding the gastrointestinal sect, skin, liver and spleen, lung, kidney, Ilyroid gland , bone marrow (BM) and soft tssoe 1982, 19201, As with HSTL in other sermqs. spleen. liver and BM are the COOII'TIOIl sites of involvement of HSTL in Crohn's disease pa tients receiving inflixrreb 11355. 18721·

Histopathology The d istr ibution of histologic types of iatrog enic Iymphoprohferation s in nontransplantation sett ings appears to d iffer from that seen in other immunod eficienc y settings, with a probable increase in the frequency of Hodgkin lymphoma and lymphoid proliferations with Hodgkin-like features. Among patients treated with methotrex ate . the reported cases are most commonly OLBCL (35- 60%) and CH L ( 12-25%). commonly of mixed

TJbIt 13.06 Charactensbcs of melholrexate-assoeiatedIymplloprolileralive disorOers (135 cases withdetailsfeported). Tolat

jpt

EBVt

EilfanOdal

Rtgr . n "

rsse

15/27

.,

7141

'"

keff Iymphoprolif.raliv. disordersllymphomas

.,

~BCL

64

Ptl/ymorphicl1 ymphoplasmacytic LPD

11

FoIIbJlar lymphoma

s

'18

' /5

&r'o.itt lymphoma

3

1/3

0/1

!,IlL/MALT lymphoma

,

0!3

"

Lrmp'loplasmacytic lymphoma

3

casu

., 012

Tail lymphoprolil. rallv, dlsordtrsllymphomas

.,

.,

3/5

0/3 1/1

a. 01

EOlodaI NKIT lymphoma. nasal type

••1/1

1/1

1/1

etrw R PO

1/1

1/1

1/1

10/12

2119

5118

PTCL··

7

lbtgUI lymphornato 1Iod{I k~i ••

tI:GI

lnlons M

28

3IS

5

515

214

515

135

4011 06

32169

2&'90

•r IlW. hal oIlhestCil9M. fle t1.rabCrl oIl1!lT1SS1CJ'1 was short 11- 10 mcnlhs) and c:hendherapy washfl reqlIIlld. -n:ludes PTa.. notOlherwise s.pealiedand ~ T<eI ~. 1I.n. dIIIuse Iargt Ek:eIIymphoma; MZl.IUALlll'lill'glnal zone ~rnlCOS3-associated ¥nphoid!issue ~ CLlISU.. d1roIic/yll'lphlXyliCleukaemaIsmaII ~~: PTa.. ~T-
cellularity type. with less frequent cases of follicular lymphoma (5-10%), Burkitt lymphoma, extranooat marginal zone lymphoma of muc osa-associated lympho id tissue and PTCL [982. 1086, 1392, 19201. Polymorphic or Iymphoplasmacytic mfiltrates resembling polymorphic PTLD have been described in up to 15% of the cases in this setting. Lesions conta ining ReedSternberg-like cells but not fulfilling lhe c riteria for Hodgkin lymphoma. that in the past were referred to as Hodgkin-like lesions . have bee n repor ted in all these settings {10901. The HSTL in patients who have been treated WIthinlliximab is indistUlQuishable from HSTL arising in irTYn..o:lcompetent or post -transplant patients.

Immunopl1eoolype The irrmunophenotype of the LPO does not appear to d iffer from those of similar histologica l types of lymphoma in ronirmlunosup pressed hosts, I~ type is a usefu l tool in the d istinct ion between LPO with HL-like features - that should 001 be considered to representHLand CHL . the large cells being C02O+! CD30+iC 0 15- and C020-iCD30+! CD15+ respectively, EBV is variably positive. Genetics The genotype of these immunodeficiencyassociated LPD does not appear to differ from lymp homas of similar histological types n01 associated with immunosuppression. Prog nosis and pred ictive fact ors A significant p roportion of pat ients with methotrexate-assoc iated LPO have shown at least pa rtial regr ession in respo nse to d rug withd rawal (Table 13.06): the majority of responses have occurred in EBVpositive cases 1982, 19201 A variab le proportion of OlBCl (up to 40%) and CHl (up to 30%) have reg ressed. while most require cytotoxic the rapy: overall survival of OLBCL is approximately 50% [982 . 1088 . 1089, 10901. Some pa tients whose LPO may initially regress after discon tinuation of MTX. regrow at a later date and require chemotherapy {9821. Regression after discontinuation of drug seldom occurs in patients who develop LPO following the administration of TNFn blockers. Like in other ind ividuals without overt immunodeficiency. cases of HSTLin pat ients treated with infliximab appear to be fatal 11355. 18721.

Omer Iatrogenic lrrenorooetcencv-aseoceteo tymphoprohferative o.soeoers

35 1

Histiocytic and dendritic cell neoplasms, Introduction

R. Jaffe

SA Pileri F, Faccberu O.M , Jone s

E.S Jaffe

Hetlocync neopl asms are derived from mononuclear p hagocytes (macrophages and dendritic cells) or tnsuccvtes. Dend ritic cell tumours are related 10 seve ral d ifferent linea ges of accessory antigenpresenting cells (dendritic cens) that have a role in phagocytosis. processing and presentation 01 antigen to lymphoid cells. Peucuiohis tocv tos is and Rosai -Dorfman disease. which are covered in the WHO Classification of TlJT1QUrs 01 the Skin, will not be included in this chapter. Epidemiology Tumour s of tusuocvtes are amon g the rarest of tumours affecting lym phoid tis sue s, p robabl y repr esenting less than 1% of tumours presenting in lymph nodes or soft tissues 1673. 17451. As several of these tumou r types were poorly recognized until recently, their true inci dence remains to be determined. Historic ally, some large cell lym phomas of Been or were though t to be histioc ytic or reticulum cell sarcomas on p urely mo rphologi cal grounds, but only a sm all num ber

r-cenrspe

prov e to be of true macrophage or dendritic ce ll o rigin, Some of the reg ulator y disorders such as macrophage activation or haernophagocytic syndromes may have large numbers of hetocytes but the se are roo-recotastc. No sex. race or geographic predilection has ye t been described Histogenesis The cellular counterparts of this group of neoplasms consist 01 myeloid-derived macrophages, rnyeloid-derived oeodnnc cells and stromal-derived dendritic cells , The myeloid-derived macrophages and dendritic cells constitute divergent lines 01 d ifferentiation from bone mar row (B M) precursors, althoug h traneortterennauon or hyb rid di fferenti ation states likely occur.

Monocytes. macrophages. his tiocytes Me tch nikoff is consi dered me father 01 the macrop hage and in 1883 coined the term · phagocytosis·, postulating a central role for the process in the bodys innate defense against infe ction 1821A, 146 7AI . The histiocytes/m ac rophages are derived from

~LT3L

•• •

OIll~5f

._~- -

•
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.. -- . -- -----

"," ••

•• '. •

OM-esl'

~

c::::;co,..

. ,

•

•

-

.' !.~

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, ...~...... ,, .J.L(~

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, • • •

Fig.14.01 Sdlemabc diagram d!he 0f9II- Bolh maaopllages and dendritic eens (Mligen presenIilg eels) are ~ from a canmon bone marrow preanor. In contrast tokuIar deOO1IJc cells are Ihougt'4 m be d ~ origtn. - . rrost 4 I'lOl: III oeII poSItMt: ., aI eels negabve: ~+, a rrinorily of cells pos4Mt, 'I. vanabIe 1Jl18nsity,

354

Histiocytic and oeoonn c cell neoplasms

BM-derived monocytes and ton migration/maturation in tissues participate in the innate response with pro- and SI1Iinflammatory cytokine effects as weN as particulate removal and tissuerecoosaen 1821A. 82 1BI . They are derived large!'{ from the circulating peripheral blood (PS monocyte pool that migrales thfOl.9l blood vessel walls to reach their SIte ~ action. but local p roli feration also cootributes 118161. Histiocyt ic tumours are closely related to the roonocytic tUI'l'M:U5 from which their precu rso rs are derIVed The distinction between a ieusaenc ilti trate of monocytic ori gin and nrstocrtc sarcoma can sometimes be difficult (II morphologic grounds alone. Mac rophages display phagocytosis lnler some conditions 01 activation and. at ths stage, there is hei gh tene d exp ression ~ lysosomal enzymes that can be demonstrated by netocnemlstry including ~ specific esterases and acid phosphatase Phagocytic activity is not a prominent feature 01 histiocytic mali gnancy but is a cardinal feature of the haemophagocybc synd romes, The naemopbaqocvnc macroph age activa tion syndromes are an in-;. potent group of ron-neoplastic prolileratrve di sorders tha t need 10 be dilterenliated from true histiocytic neoplasms, and are far more co mmo n, The haemophagocytic sy nd romes are the result of genetic or ac q uired di sorders in the regulation of macrophag e activa tion. The primary familia tvmonobienocvnc d isorders are due to genet ically dete rmined inab ility to regulate ma crophage killing by NK and /or T ces becau se of mu tatio ns in perform, Its pa c kag ing , export or release. AcquiredlX seconda ry causes of the naemoonacccvtrc ma c rophag e ac tivati on syndromes follow c ertain infections, most nola Epstein-Ba rr virus (EBV) and a wide varl8':Y of other infectiou s agen ts, as well assere malignancies. rheLmatic disorders and mJ. npie organ failure 11 04 51. The characteristic cvtopentas of the haemophagocyoc syndromes are most like ly du e to BM ~ pression by the cytoone storm since t"le BM is often twperceuoiar at the outset

Tlblt 14.01 Trufl histiocytic malignancy, a vanishingdiagnosis.

Original diagnosis

Currently considered

HisIr::q1ic lymphoma, nodular anddofl1Jse

Diffuse largelX:e1l lymphoma Folicularlymphoma, grade 3 PenpheraI T-cee lymphoma

HrstJocyte-rich variants 01 B-oeI. T-cell and Hodgkin lymphoma Anaplastic largecellympIloma (ALCl)

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FCR, Fe IgG receptors (include C016, C032, C064 onsome cells); LC, la ngerh ans cell; IOC, interdigitating dendriticcell; FOC, follicu lar dendritic cell: POC, plasmacytoid dendritic cell: Mia, macrophage: DIOC, dermal/interstitial dendriticcall: c. cytoplasmic: e. surface. Expression is semiquanlitatlvelygraded 0 thrOlJQh H , + present, ++ high, +/-Iow or varies wilh cell activity.

Myeloid-derived dendritic cells Dendritic c ells or antigen presenting cells are found in various sites and at different Slatesof act ivation , and no single marker foil identify all de ndri tic cell subse ts {138, 1816,2094/. Langerhans cells (LC) a re soecanzeo dendritic cells in mucosal Sfe!:Jskil that upon ac tivation become specialized for antigen presentation to T cells, and then migrate to the lym ph node nrough lym ph atics. Lymph nodes also

conta in a paracort ical d end ritic ce ll type, the interd igita ting cell (lOG) wh ic h may be de rived in part from LC 17711. This classical dendritic cell lineage is believed to give rise to Langerha ns cell t sstccv tosrszsarcoma and to IDC sarcoma. A third, poorly-defined DC subset, de rmaVinterstilial dendritic cells, are found in the soft nssue . d ermis and in most or gans, and can be inc reased in some inflammatory states 11381. Plasmacytoid cencrtnc cells (POC) (also

known as p lasmacytoid mooccvtes) are a distinct lineage of dend ritic cells, which are be lieved to give rise to the blasticplasmacytoid dendritic cell neoplasm (See Chapter 6) 19201. The histogenetic origins of POC are controversial but are likely 01 myelomonocvtic lineage. Interferon-a-producing PDC prec ursors, which are not strikingly dendritic in appearance, circulate in the PB and have the capacity to enter lymph nodes and tissue through high endothelial veouies 113251.

Stromal-derlved dend ritic ref! types Follicular dendritic cells (FOe), which are resident within primary and secondary B-cell follicles, lIap and present antigen to B cells FOe can store antigen on the cell surface as IITrnune complexes for long periods of time 123041. FOC appear to be closely related to BM stromal progenitors with features of myofibroblasts 113601. They are a non-migrating population that forms a stable meshwork within the follicle via cell-to-cell attachments and oesrrosomes . Fibroblastic reticular cells (FAG) are invotved in maintenance 01 lymphoid integrity, production and transport of cytokines and other mediators. In lymph nodes, they ensheath the pos t-capillary venuies {1 115. 23201. They are of mesenchymal origin and express smoo th muscle acti n Hyper plasia of FRC (i.e. stromal overgrowth) may be seen in Castleman's d isease (1028, 1309 1. and tumours of FRC arise in lymph nodes and have features of myofibroblastic tumours and closely related neop lasm s 144). Prog nosis and pred ictive fact ors Because there are few phenotypic markers uniq ue tor the dend ritic or macrop hage tusuocvtes. the investig ator should use a panel appropriate to the ce ll in qu estio n and rigorously exclud e other cell lineages (T cell, B cell. NK cell but also stromal, meranocvuc and epith elial) by immunophenotypic and molecular means. It is also worth mentioning that some reueaemtas and anaplastic large cell lymphoma can be ac com panied in lymph nodes by an exuberant histiocytic response that may obscure the neoplastic cells.

Introduction 1

355

Histiocytic sarcoma

1M. Grogan SA Pileri J ,K ,C . Chan L.M , Weiss C.D .M. Retche r

Definition HistiOCytic sarcoma is a malignant pronteration of cells showing morphologic and

immunophenotypic features of mature tissue histiocytes. NeoplastiC prOliferations associated with acute monocytic Ieuka~ are excluded

ICD-O code

9755/3

Epidemiology Histioc ytic sarcoma is a rare neoplasm with cxty limited runbefs of reported series of bona fide cases 1473. 886. 964.1087,

1745, 23451 . There is a wide age range. from infancy to elderly; howeve r. most cases occur in adu lts (median age , 52 years) 1964. 1745 . 234S1. Ma le predilection is found in some studies 11745. 2345} b ut

not in others 19641.

..

Etiology

Fig. 14.02 Histiocytic sarcoma. Ditluse etlacem&nl 01 arctlitectln is seen by a large eel prokIeraboo N iI irdsmgiWlable from a diffuse latge Ek:eII lymphoma by c:onvenlionalllistopalhology

The etiology is unknown. A subset of cases occurs in patients wi th mediastinal ge rm cell tumour, most co mmonly malignant teratoma, with Of without yol k sac tumour

intestinal tract, skin and soft tissues . Othe rs

component 15551. Since teratocarcinoma

present with I;-mphadenopathy. Rare patients

cells may differentiate along haernatopoietic line s in vitro 14951. histiocytic neoplasms

have a systemic presentation , with multiple sites of involvement , some times referred to as "malig nant histiocytosis" 1347, 1745 , 24 19).

lesions to innumerabl e tumours on the trunk and extremities. Patients with intesllnal lesions often present with intestinal ocsnucnon. Hep atosplenom egaly and associa ted panc ytope nia may occur. The tooe ma y show lyti c lesions (964, 1745,23451,

Clini cal feature s Patients may present with a solitary ma ss, bu t sys temi c symptoms are relatively com mon, e.p. fever and weig ht loss 1964, 1745, 2345 1. Skin manifestations may range from a benig n-ap pearing rash to soli tary

Morphology The tum ou r co mp rises a diffu se roocohesi ve pro lifera tion of large cells (>20 IJm), but a sinuso idal distribution may be seen in tymph node, liver and spleen. The prolife ratin g cells may be monomorphic

may arise from plurip otential ge rm cells, Other cases may be assoc iated with malignant lymphoma , either pre ceding or subseq uent. o r with my elodysp lasia and leukaemia 1677 . 964 ,1745, 2345 1.

Sites of involvement The majority of cases present in extrarodal sites {964, 1745 , 23451, most co mmonly

356

HistiOCytIC and

cenontc cell neoplasms

or. more commonly, pleomorphic. The individual neoplastic cells are usually large

and round to oval in shape; however. local erees or spindling (sarcomatoid areas) may be observed The cytoplasm is usually abundant and eosinophilic, often with some Ire vacuoles. Haemophagocytosis occurs occasionally in the neoplastic cells The nuclei are generally large, round to oval or rregularty folded, and often eccentrically placed; large multinucleated forms are corrmonly seen . The chromatin pattern is usually vesicular, and atypia varies from rrjd to marked . Irrmunostaining is essentia l lor distinction from other large cell neoplasms, such as large cell lymphoma, melanoma and carcinoma. A variable number of reactive cells may be seen, including small lymphocytes, plasma cells, benign ntsuccvtes and eosi"Klphils. SometimeS the neoplastic cells are obscured by a heavy inflammatory rilltr ate including many reueoonns, mimdUng an inflarrmalorylesion; this feature is partICUlarly corrmon in histiocytic sarcoma IrlYOIVing the central nervous system 1411}. Ultrastructure The neoplastic cells show abundant cvtoplasmwith numerous Iysosomes. Birbeck granules and cellular junctions are not seen. Irrrnunophenotype

lir Fig. 14.1)4 HIstiocytic sattOI\"Ia, AHIstiocytic satO:llNI iNCM'lg tie bowlt B Nole tle al::u'ldarC cyt;)pIasm. wI'ich stans stn:lf9Y b' C068 (e) and tysozyme (Dl·

expression of CD 15 occurs 11745 1. In addition , CD45, CD45RO and HLA·DR are usually positive. There may be expression of $. 100 protein, but this is usually weak or focal 117451, There is no positivity for specific B-eell an d markers . CD4 is often positive. These tumou rs are devoid of HM B45, epithelial memb rane antigen or keratin. The Ki67 index is variable 117451.

t-een

By definition, there is expression of one or rrore histiocytic markers, including CD163, CD68 (KP1 and PGM1 ) and lysozyme WIth typical absence of Langerhans cell (C01a, langerin) , follic ular dend ritic ce ll (C021 , CD35) a nd myeloid cell (CD33 , CD13, myeloperox id ase ) markers 1964, 1745, 2345 ) Both C D68 and lysozym e show granular cytop lasmic staining. The ~zyme staining is accentuated in the Goigi region. CD 163 staining is in the ce ll membrane and/or cyto plasm. Rarely. weak

Genetic s Histiocytic sarcomas usually lack clonal Ig H or TCR rear rang ement s 1473), bu t rare cases have been reported to show ant ig en receptor ge ne rearrangements. most likely repr es enti ng exa mp les of transd ifferentiation 1886. 1810,23451.The rare c ases a rising in med iast inal ger m ce ll tumou r show isoc hromosome 12p . id entic al to the gene tic c hange in the germ cell tumour 115941.

Postulated mormal counterpart Mature tissue histiocyte.

Prognosis and p red ictive factors Histiocytic sarcora is usuaJly an aggressive neoplasm, with a poor response to therapy. although some exceptions have been reported 19641. Most patients (60 -60%) die of progressive disease reflecting the high clinical stage at presentation (stage III/IV) in the majority (70%) of patients 11745 , 2345). Patients w ith clinically localized disease and small p rima ry tumou rs have a more favourable long-term outcome (964, 1745).

HISllocytlC sarcoma

357

Tumours derived from Langerhans cells

A. Ja ffe L.M , Weiss F. Faccnetn

The tumours discussed in this section originate from Langerhans cells of which they maintain the phenotypic p rofile and ultrastructural features. According to the

degree of cytolog ic atypia and clinical aggressiveness. they are divided into two main subgroups: Langerhans cell histio-

cytosis and Langemans eel sarcoma. There may be rare cases that can be difficult to assign to one or the other category; these cases need further clmicopathologic studies to clarify their nature.

LangarfJans cell histiocytosis Definition Langerhans cell histiocytosis (lCH) is a clonal neoplastic proIiferaticrl of Langerhanstype cells thaI express COla. Iangerin and S 100 protein , and stowe Bubeck granules by ultrastructural examination.

ICD-O code

975 113

Synonyms Histioc ytosis X, eosinophilic granulo ma (if solitary lesion). Hano-Scnuner-Chnsnan d isease (if multiple lesions), Lette rer-Siwe d isease (if d isseminated o r viscera l involveme nt). Epidemiolog y The inc idence is about 5 per m illion po pulation pe r yea r, with most cases occurring in child hood. There is a pred ilection for males (M:F ratio 3.7:1) 117451 . The d isease is more common in whites of northern

B f ig. 14.05 I..angemat1s celllIstJotyklsls, A Radioo;1aph from a paten! WIth eosrIOptilic ~ cl bone ..... a discrete ~ lesion. B Agalun SC8l1 sI'lOWS high uptakei'llytic bone lesion.

European descent and rare in blacks. Fam ilial clustering has shown a high concordance rate for identical twins but not dizygous pairs and no vertical inheritance {761. Primary Langerhans cell hetocvtoers of the lung is almost always a disease of smokers, usually non-clonaf and thought to represent a reactive process 1502, 24791.

Sites of invo lvement The disease can be localized to a single site. multip le sites within a single system, usu ally bone, or more disseminated and multisystem 11480, 22421. The dominant sites of involvement in the solitary for m are bone and adjacent soft tissue (skull . fem ur, ve rte bra, pelvic bones and ribs ) and, less co mmonly, lymph node, skin and lung . The mu ltifoc al lesion s are large ly c onfined to b one and adjace nt soft t issue. In mu ltisystem d isease , the skin, bon e, liver, sp leen and bone marrow (8 M) are the preferential sites of involvemen t. The gonads and kidney appear to be spared eve n in disseminated forms ,

Cl inical features Patients with unifocal disease are LlSI.latf older childrenor adults wOO rmsl: lXlrTJTUtf present with a lytic bone lesion , eroong III cortex. Solitary lesions at other sites peset as mass lesions or enlarged lymph nodes. Patients With unevstem momtocar disease are usually young chil dren who presem with mulliple or sequential destructive 00'Ie lesions often associated with acaceot sdt tissue masses. Skull and mandibular involvement is common. Diabetes insipidus follows cranial involvement. Patients witt'; multisystem involvement are infants whJ present with fever, c vtooenras. skin and bone les ions and bepatcsplenomeqav 175, 14821· Pulmonary disease in childl'c«j is c linica lly variab le {16 19l. There is an associatio n between lCH and T lymphob last ic leukaemia, with the leukaem ia-associ ated T-cell receptor gef1l! rearrangement p resen t in the LCH cells: this has been considered a transd ifferentiation phenomenon (6761.

Fig. 14.06 Langemans celMIiOC)1O$IS. A Numerous lange!t\arJS eeas are seen. wiItI scattered eosinophiIs and smallymphocy1es. S Ni*ll'oe typical cytlIocjit leau.d I.Mgernans eel$. WIfl many nudei contaIIWIg IneargtOOYe$ CEosI'lophic microabscess.

358

HistIOCytIC and dendritic cell neoplasms

•1 Fl;. lUI langertIans eel ~...-aslruclln A typical BII'bect granule is seen.

~ Tne key feature is the identification of the l CH cells. These are oval, about 10 - 15 .m, recognized by me« grooved. folded. tdenled or lobulated nuclei with line ctvomatin, inconspicuous nucleoli and thin

can be confirmed by tangerin expression. The Birbeck granule has a tennis racquet shape. and is 200-400 nanometers long and 33 wide. with a zipper-like appearance.

Immunophenotype

lCH consistently expressesCDla, langem and 51 00 protein 1418. 1191AI . In add ition . the c ells are positive lor wreren. C068 and HLA-DR. CD45expressonand lysozyme con tent is low. B- and

t-een

ncear membranes. Nuclear atypia is rwlimal, but mitotic activity is variable and

,

, j

I j

,

e e

."

can be high without atypical forms The cytoplasm is moderately abundant and s~ghtly eosinophilic . Unlike epidermal Langerhans cells or dermal pe rivascular eens. l CH cells are ova l in shape and de\'Old ofdenonnccell processes. Thecharectensncmilieu includes a variable number of eoslnopnns . hrsnocvtes (both multinuceeieo l CH forms and osteoclast-type cells especially in bone). neu uoonns and small lymphocytes. Plasma cells are usually

sparse Occasionally, eosinophilic abscesses with central necrosis, rich in Oarcot-tevoen c rystals , may be found . In early lesions, the l CH ce ll p redo minates along with eosinophils and neutroobus. In Ia'.e lesions, the lCH cells are dec reased n number. with inc reased foamy mac rop'lages and fib rosis, Il'MlIved lymph nodes have a sinus patte rn Mtt1 secondary infiltration of the paracortex. ~ showsnodular red pulp involvement. liver involvement has strong pre ference 'cf intrahep atic biliary involvement with ~ressi ve scle rosing cholangitis . Bone lI'arrow biopsy is prefe rred to aspi rate for «c crrentatlon of BM involvement [14811. -arge clusters or sheets ollCH cells ac::cmpanied by eosmoprnrs can be found • other lesions , lymphomas and sarmas. It remains to be clarified whether rese represent a local reactive phenomeroo 01 a trenscntterentlaton process 14401.

•

lIJastructure -"IE! ultrastructural hallmark is the cyt o:mmic Birbeck granules whose presence

A ~ Fig.1U9 langerhans C&l1 hist~os~ . A,B This lymph node biopsy ~ extensive inwlvementof !he sinuses and paracoucal regions.

...

Fig. 14.10 la'lge!tIar<s rei histloI:pJsis. A Connst!he bland I'IUl::lN' mor~wifl lhatol1he sarcoma (Seef ig 14.11 and 14.12). B ~ is !loCh I'IJderar and cytopIasnic W'IIh 5100. C COtastai'WIg is lA'lIofrnly SU'1ac:e WIlll a ~ dOC 0 L.angenn slaInilg is rrwn grarWr and cytlJlla$rTiC.

Tumours oeovec from langerhans cells

•

359

lineage mqrkers (except for CD4 ). CD30 and follicular dendritic cell markers are absent. Ki67 is high ly variable 11745 1. Genetics LCH ha s been shown to be clonal by x-unkeo an drogen rece ptor gene assay (HUMARA), except in saneadult pulmonary lesions 12418. 2479 . 24801. No consisten t molecular genetic defect has bee n identified 115421· Postul ated normal counterpart Mature Langerhans c ells. Prog nosis and predictive factors The clinical course is related to staging of the d isease at presentation, with 99% or g reater survival for wutocat disease and 66% mortality lor young Children with m...iltisystem involvement whO do not res pon d promptly to therapy 1740. 1480. 22421 Involvement 01 8M . liver and lung are regarded as high risk fac tors 11480 . 22421. Prog ression from inilial focal disease to multisys tem involveme nt can occur. most usually in infants. Age. per 58. is less important an indicator than extent of disease /1480,2242 1, System ic and (rarely) multifocal disease can be complicated by haemophagocyt ic synd rome 16741.

Clinica l features Most instances are extra noda l involving skin and bone an d muttltoc al. hig h-sla g e d isease (III-IV) is seen in 44 %. Only 22% are primarily nodal. Hep atosp lenomeg aly is noted in 22% and pancytopenia in 11%.

Morphology The most pro minent feature is the overtly malignant cytology of a pIeom::lrphic turour. and ooIy the phenotype and/or ultrastructure w ill revea l the Langerhans cell de rivation . Ch romatin is clumped and nucleoli are conspicuous. Some cells may have the COfT'4)Iex grt:lCNeS of the LGH cell. a key due to the d iagnosi s. The mitot ic rate is high. usually more than 50 per 10 high power fields. Rare eosinophils may be admixed

Langertrans cell sarcoma Definition Langerhans ce ll sa rcoma (LCS) is a highg rade neoplasm wi th ove rtly mal ignant cytologic featu res and th e Lang erhans ce ll p henotype. ICD·O code

9756/3

Synonyms Dendritic/histiocyti c sarcom a , Lanqernans cell type . malignant histiocytosis X. Epidemiology La ngerhans cell sarcoma is rare 1183, 232 . 1745 1. and almost all repo rted cases are in adul ts. The median age is 39 years (range. 10 - 72 years). A female p redominance is described (M:F ratio 2:1) 117451. Sites of involvement Skin and underlying soft tiss ue are the most conrnon. with rrultiorgan involvement that includes lymph nodes. lung . liver. spleen and bone 1232. 696 . 1745 1.

360

HistIOCytiC and oenonuc cell neoplasms

Ultrastructure Birbeck granules are present, ~ile d esmosom es/j unc tion al specializations are absent 117451. Immunophenotype The immunophenotype is identical to thai of Langerhans ce ll histioc ytosis. amJough the staining for the indivi dual markers can be focal and pa tchy. Postu lated normal counterpart Mature langerhans cell. Prognosis and predictive factors Langer'hans cell sarcoma is an~, tigh-grade malignancy with > 50% rrortaIti' from progressive disease

Interdigitating dendritic cell sarcoma

L.M. Weiss T. M. Grogan J .K.C. Chan

Definitioo

power fields) . Necrosis is usually not present. There are often numerous admixed lymphocytes, and less commonly, plasma cells. The histological appearance is soretimes indistinguishable from a follicular dendntic cell sarcoma and phenotyping is necessary for precise d iagnosis.

Interdigitating dendritic cell (IDC) sarcoma is a neoplastic proliferation of spindle to ovoid cells with phenotypic features similar to those of inte rdigitating dendritic cells.

roo coda

The nuclei also appear spindled to ovoid , and may show indentations; occasional multinucleate cells may be seen . The Chromatin is often vesicular, with small to large, distinct nucleoli . Cytologic atypia varies from case to case. although the mitotic rate is usually low «5 per 10 high

Inlerdigitaling dendritic

cell sarcoma

975713

E,;demOOgy nterdig itating dendnlic cell sarcoma is an extremelyrare neoplasm. With most Studies

representing single case reports or very

small series 144. 68 1, 1343. 1475, 1563, 1564,1745. 1881 .23751. The largest series IO date have consisted of four cases 1741, \745, 17481. The repo rted cases have occurred p redominantly in adults, although

paedia tric series has been repo rted 117481. There is a slight male predomi-

CI'Ie

nance Occasional cases have been associated with low-grade B-ceillymphoma

and rare cases have been associa ted lIIith t-een lymphoma 174 11, Sites of invo lvement

Fig. 14.13 Interdigitating dendriticcell serccna Tumour is YilQuetylobulatedin fymph node, and firm in con SiSterq

The presentation has shown wide variation. Solitary lymph nod e invo lveme nt is most common, but extranodal p rese nta tio ns. oarticularly the skin and soft tissue , have been report ed, Clinical feature s

Pa'ients usua lly present with an asvrr otosere mass. although sys temic symptoms. SlJ:h as fatigue, lever and night sweats, have been reported. Rarely. there may be generalized lymphadenopathy, splenomegaly or hepa tomegaly,

-y

TN! iesonar tissue in lymph nodes is eesent in a paracorticar distribution lIIlh residual follicles . The neoplastic prolif. eexn usually forms fascicles. a storilorm estern. and who rls 01 spindled 10 ovoid Sheets of round cells are occasionay 1cLnd. The Cytoplasm of the neoplastic eels is usually abundant, slightly eosine• . and often has an indistinct border. InterdigItatIng dendntlC cell sarcoma

•

361

Ultrastructure The neoplastic cells show comple x interdigi tating cell processes, but well-formed desmosomes are not present. Scattered lysosomes may be present , but Birbeck granules are not seen. Immunophenotype The neoplastic cells consistently express S100 protein and vimentin with CO1a and langenn being negative . They are usually positive l or fascin and variab ly. weakly positive for CD68 . lysozyme and C045. Strong nuc lear staining for p53 may be present. They are negative 104' markers 01 follicular dendritic ce lls (C021 . C023 and COOS). nwecoeroxoase. COO4. specific B-cell and T-cell associated antigens. C030. epi thelial memb rane antigen and cvtosereuns. The Ki67 index usually ranges between 10 and 20% (med ian 11%) 1681). The admixed small lymphOcytes are almost always of T-cell lineage, with near absence of B cells

Genetics The irrvnunoglobulin heavy chain gene and the beta. delta and gamma chain genes of the T-cell recep tor are in a germline con-figuration 123751. Postulated normal counterpart Interdigitahng dendritic cell . Prog nosis and pred ict ive factor s Theclinical course is generally agg ressive. with ab out one half of pat ients dy ing of their disea se, Viscer al organs that are commonly attected includ e the liver, spleen , kid ney and lung . Stage may be an impo rtant prognostic factor, however histologic features have not been correlated with clinical outcome.

362

:D:' •~ . ~

. ~

Fig. 1.4.16 Inlerd~ ilaling dendritic cell sarcoma. A Nole ttle paraooctical pattern of tulTlOUf growth in the ~m ~ root B There are scattered sma~ Iympllocytes througlloullhe lesion, CThe CD21stain is negalive on !he lurT'lOlX cek tu: labels follicular dendritic cells in residual follicles. 0 In contrast. the slain for 5100 protein is strongly posili'le J\!tII tulTlOO r cells.

HIstIocytIC and oeocnnc cell neoplasms

Follicular dendritic cell sarcoma

J .K ,C . Chan SA Pileri G. Delsol C.D .M, Fletcher LM , Weiss

K L Grogg Definition Follicular dendritic cell (FDC) sarcoma is a neoplastic proliferation of spindled to ovoid cells showing morphologic and immunop henoty p ic features of foll icular dendritic cells.

975813 EpOdemdogy Follicular dendrrtic cell sarcoma is a rare 144.385. 1501. 1591, 1724 , 1745, 23751. There is a wide age range, with an ao:1Jt predominance (meanage, 44 years)

reooasn

11591, 17451. The sex orstntxnon is about even, but there is marked female preoneclIOn for the inflammatory pseuoorurrourke variant 1409. 1745.23131 . Follicular

dendritic cell sarcoma occurs in associebon with Castleman disease in a small proportion 01 cases, usually the hyaline-

vascular type \3871. In these cases, either ee Castleman disease precedes the follicular den dritic celt sarcoma or the two

esoos occur simultaneously, Ebology tnere is no known etiology lor most cases, The inflammatory pseudo- tumourI I~e variant of follic ular dendritic cel l sarcoma is consiste ntly associated with Epstein-Barr vir us (EBV) (7 1), wit h EBVencoded RNA (EBER) being d emonstra ble in virtually all the neop lastic sp ind le cells, and Southern blot stud ies ha ve ::Iemonstrated the virus to be p resent in a rooccronar episomal form 11991)

Ft.l•.1, FoicUar ~eeI • • ~locaIlon.

sartlCII'l'I3.

Precursor les ions In rare c ases of Castleman disease, there is a proliferation of fol licular oenontc celts outside of the foll ic les form ing clusters and small sheets {1893 1· Follicular dendrit ic c ell sarcoma may evolve in this setting of foll icular dendritic cell hyperplasia eoc overgrowth. Sites of involvement Follicular dendritic cell sarcoma presents as lymphadenopathy in one half to two thirds of cases, w ith one of the ce rvical lymph nodes be ing most often affected The tumour can also present in a wide variety of extranodal sites, such as the tonsil, oral cavity, gastrointestinal tract. soft tissue, skin, mecnastmom. liver and spleen 1957). Comnon sites for metastasis include lymph nodes, lung and liver 14341. Clinical featu res Patients most often present with a slow grO'Ning, painless mass, although patients with ab dominal disease may present with abdominal pain . The tumou rs are often large, with a median size of 5 ern. Systemic symptoms are uncommon in conventional follicular den dritic ce ll sarcoma, but are common in the inflammatory pseooo-tcrroclike variant I409 }. Rare patients have paraneoplas tic pemph igus 11 265,1 405. 23571. Morphology The neoplasm com prises sp ind led to ovoid ce lls formi ng fascicles, storifo rm arrays, who rls (at times reminiscent of the 360 0 pattern o bserved in mening ioma ), d iffuse

.

Fig, 14.17 FokUaf llerO'CiC eel satCOTI3. This mass oco.ned n the soft bssues .
'"""'"

sheets or vague nodules. The individual neoplastic cells generally show ind istinc t cell borders and a moderate amount of eosinophilic cytoplasm. The nuclei are oval or elongated, with vesicular or granular finely dispersed chromatin, small but distinct nucleoli , and a delicate nuclear membrane . The nuc lei l end to be unevenly spaced, with areas showing clustering. Nuc lear pseudo-inclusions are common. Binucle ated and multinucleated tumou r cells are often seen . A lthough the cytologic features are usually relatively bland. significant cytologic atypia may be found in some cases. The mitotic rate is usually between o and 10 per 10 high-power field s, althoug h the more pleomorphic c ases can show muc h higher mitotic rates (>30 per 10 high-power field s). easily found atypical mitoses and co ag ulative necrosis, The tumour is typically light ly infiltrated by small lymphocytes, which can sometimes be aggregated around the blood vessels

ASprde eel proWer.lliOn.

Fol lic ular oenccuc cell sarcoma

363

. '1' •

'6a,'tof' ,..(.:,,.' \ . , ...:;, . . ..

. ... .

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Fig. 14.20 Fojlicular dendriticcej l sarcoma This&lectron miCrograph shoo.Ys nOOlel'OUS cytoplasmic processes. do one weI-formed desmosome presenl lnee Cflfltre as well (3841, Less common morphologic features include: epi thelioid tumour cells with hyaline C')1OpIasn, clear cells. oncocytic cells. myxoid stroma, fluid-filled cystic spaces, prominent fib rov asc ular septa and admixed oeteoctastc giant cells 1384, 385, 1724 , 17251. In rare cases, the large neo plastic ce lls are scattered singly in a bac kg round of small lymphocytes, mimic king Hodg kin lymphoma. Rare cases may also show jig saw puzzle-like lob ulation and perivascu lar spac es , mimi c kin g thymoma or ca rcinoma show ing thymu slike element (CASTLE) 14341. The inllammatory pseudo-tumour-like variant of follicular dendritic ce ll sarcomas occurs exclusively as primary tumours in the liver or spleen 171. 409, 19911. The reoplastic spindled cells are dispersed within a prom inent lym phoplasma cyt ic infiltrate. Theruclei usually show vesicular chrornallO patten and disflnct nucleoli. Nuclear atypia is hig hly var iable: usually many cells are bland-looking. but sere cells with enlarged. irreg ularly-fo lded or hyperchromatic nuc lei are always found. Some tumour ce lls may even resembl e Reed -Sternberg c ells 1199 11. Necrosis and haemorrhage are often present. The b loo d ves sels frequently show fibr inoid deposits in the walls .

364

Ultrastructure The neoplastic cells have elongated nuclei . often with cytoplasmic invaginations. If-ere are characteristically numerous long, slender cytoplasmic proc esses , often con nected by scattered , mature desmosomes. Birbeck g ranules an d numerous Iysosome s are no t seen. Immuno phenoty pe Follic ular dendritic cell sarcoma is positive lor o ne o r mor e of the follic ular dendritic marke rs, suc h as C02 1, C D35, C023, KiM4p and CNA .42 1159 11. Clus terin is almost always strongly positive, while this marker is usually neg ativ e or only weakly positive in other dendritic cell tumours lB53. 8541. In addition, thel1.mour is usually positive for desmoplakin, vimenbn, tascn, epidermal growth factor rec e ptor and HLA -OR 1384, 21221. It is variably positive for epithelial membrane antige n, S l00 protein and C068. Exce ptionally. cytokeratin, CD 45 or C020 c an be expressed . Staining for C0 1a. lysozyme, myeloperoxid ase, C034, C03 , CD79a. C030 and HMB 45 are neg ative. Ki67 labeling range s from t to 25% (mean, 13%). The ad mixed small lymphocytes are pr edominantly B cells in some cases.

HisllOCytlC and dendritic cell neoplasms

predominantly T cells in some , and mixed Band T cells in others 1385,17451.

Genetics The immunoglobulin and

t-een receptor

genes are in a germline conligJ'ation 123751 Data on genetic changes are c urrently very limited 119271, Postulated normal cou nterpa rt Fo llic ular dend ritic cell of th e lymphoid follic le . Prog nosis and predictive factors The behaviour is usually indolent. much like a low or intermediate-grade soft tissue sarcoma 13851. Most patients are neater by complete surgical excision . with Of without adjuvant radiotherapy or therapy. Local recurrences occur in rTli7l! than 50% of cases, and metastases OCCU' in about 25% of pa tients: SLJCh occurrences may be delayed after many years 1384 1725 , 2054 , 23131. At least 10-20% 01 patient s ultimately d ie of the d isease. often after a long period of time Cases showing high -g rade features (significant cvtoccc atypia. ex tensive coa gulative necrosis and a high oroseranve inde x), large turro.I size (greater than 6 em) or intraabdooll'lal location can pursue a rap id ly fatal course 1365.17451 .

crerc-

Other rare dendritic cell tumours

L.M . Weiss J.K.C , Chan C.D.M. Fletche r

There are rare types of dend ritic cell tumour other than the better-delineated entities covered in the previous chapters. These may be derived either from myeloid-derived dendritic cells, such as ooetermmate dendritic cell tumour ; or from stroma-oenveo dendritic cells, such as fibroblastic retic ular cell tumour. Some dendritic c ell tumours may rema in unclessifiabledesp ite extensive work-up or show hybrid features, and such cases may be tentatively designated "dendritic cell tumur, not otherwise specified".

the alleged precursor cells of Langerhans cells . These neoplasms are extraordinarily rare 144, 203, 236. 391. 11n, 1859. 1865. 2019,2315.2325,2441 .24501 . There may be an association with low-grade a-cen lymphoma 12315 1. Patients typically present with one or, more commonly, multiple generalized papules, nodules or plaques, Systemic symptoms are usually not present. The lesions are usually based in the dermis, but may extend into the subcutaneous fat. The infiltrate is diffuse, comprising cells resembling Langerhans cells, with irregular nuc lear groove s and clefts. Cytopla sm is typica lly abundant and usually eosinophilic. Multinucleated giant cells may be present. In some cases, there may be spindling of the cells, The mitotic rate varies widely from case to case . An accompan ying eosinophilic infiltrate is usually not present. By defin ition, these cells lack Bsbeck granules on ultrast ructural examination . There can be complex interdig itating cell processes. but desmosomes are lacking. The proliferating cells consistently express atco protein and COla. Langerin has been negative in one studied case . They are negative for sp ecific B- and t-een markers. CD30 , the histiocytic marker C0 163, and the follic ular dendritic cell markers C02 1, C023 and CD35, They are varia bly positive for C045 , C068, lysozyme and CD4 . The Ki67 index is highly variable. One case has been shcM'n to be clona l by human androgen receptor gene assay The dinical coese has been tvgtVy variable , ranging from spontaneous regression to rapid progression. There are no known prognostic factors. One case has been associated with the deve lopment of acute myeloid leukaemia 12325},

RbrobIastic reticular cell tumour ICQ.{)

code

The tumour is histologically similar to follicular dendritic cell sarcoma or interdigitating dendritic cell sarcoma, but lacks the irrmunophenotypic profile of these tlXT1ClU'" types. There are often interspersed delicate collagen hbres . Ultrastructu rally, the spindle cells shaw delicate cytoplasmic extensions and featu res reminiscent of myofib roblasts (filaments with occasional fusiform densities, well-developed oesmosomal attachments, rough endoplasmic reticulu m and basal lamina-like material), The tumour cells show variable immunoreactivity lor smooth muscle actin, desmin, cvtoeeratm ( in a dendritic pattern) and CD68

975913

Indetermina te dendritic ce ll tumour Fibroblastic retic ular ce ll tumour is very rare, and the entity reported as 'cytokeratinpositive interstitial reticulum ce ll tumour" probably rep resent s the same entity 144, 3001. Thistumour can occur in lymph node, spleen or soft tissue {44, 380, 822 , 10651. The clinical outcome is variable, with some patients dying 01 the disease.

ICD-Ocode

9757/3

Indeterminate dend ritic ce ll tumour, also known as indeterminate cell histiocytosis, is a neoplastic prolifera tion of spindled to ovo id cells with phenotypic features similar 10 those of norma l indeterminate cells ,

Other fare dendritic ceutcmours

365

Disseminated juvenile xanthogranuloma

Def inition Disseminated juvenile xanthogranuloma (JXG) is characterized by a proliferation of histiocytes similar to those of the dermal JXG . commonly having a loamy (xemromatous) component with Touton-type giant cells. There is evidence 1Q( clonality

in some instances.

Synonyms Deep JXG (if soft tissue involvement). Benign cephalic histiocytosis. progressive nodular histiocytosis or generalized (nonlipidemic) eruptive histiocytosis (cutaneous disorders wi th multiple JXG but withou t systemic mvotverrenn . Xanthoma disseminaturn (if skin and mucosal lesions). Erdhesn-Chester disease (possible adult form with bone and lung involvement) 12488A.238 1AI.

Epidemiolog y Solitary dermal JXG is vastly more common than other forms and does not progr ess to more d isseminated forms 1538Al. The majority 01deep, viscera l an d d isseminated forms occ ur by age 10 years, ha lf within the first yea r of life, except for the adult Erobem-Cbester form 110458 1,

Etiology There is a know n association with neurofibr oma tosis typ e 1 (NF l); pa tient s with both are at slig htly high er risk of juvenile myelomo nocytic leu kaemia (J MML) 125 1OAI. Patient s with bot h Langerhans cell d isease (LCH ) and JXG are encountered. Sites of Involvemen t Skin an d soft tissues are most common, and, in disseminated terms. mucosal surfaces es pecially upper aerocnoesuve tract . The central nervous system, dura and p ituitary stalk can be affec ted as well as eye , liver, lung , lym ph node and bo ne marrow (8 M). Retroperitoneal and pe riaortic involveme nt is noted in ErdheimChester d isease 1538A, 733A . 104581.

366

A, Jaffe C.o.M . Fletcher W. Burgdorf

Cl inical features Skin lesions other than the common papular solitary fo rm are small (1-2 mm) and multiple. Soft tissue lesions can be large. and the lesions present as mass effect. Optic lesion s can cause g laucoma , CNS and pituitary lesions, like LCH. can c ause diabetes I1sipidus, seizures, hydrocephalus and mental status changes 1538A, 733A . 104S8 1. In contrast to LCH . liver involvemen t does not target the b iliary system Of lead to sclerosing cI1oIar'Qrtls 11042A1. There is some ca pacity lor lesions to slowly regress. While JXG appears to be benign, a concomitant macrophage activation syndrome can lead to cytocentas. liver damage and death in the system ic forms . Morphology The JXG cell is small and oval , sometimes slightly spin dled with a bland round -toov al nucleus without g rooves and pink cytopl asm. Touton cells are less common at no n-derm al sites. The cells become progressively lipid ized (xanthomatous) . A mixed inflam matory component is invariable, Varia nts include epithelioid cells with g lassy cy topla sm , The ultrastruct ural feat ures a re histiocytic without otstlngu ish ing features 124BBAI. lmmunophenotype ln co mmon with macrophages, ce lls express vimentin, surface C0 14, C0 6B (PG M 1) in a co ars e gr anu lar patt ern , C01 63 in surfac e and cytoplasmic pa ttern and Staoiun- t (MS- l antige n). Fac tor Xnta stain ing is common but not unive rsal. Fascin stai ns the cell cytoplasm and 8 100 is variab ly pos itive in less than 20% of the ca ses; however, none of these ma rkers is specific lor JXG. C0 1a and Langerin are negative 1392A, 118BA, 193 1A,24B8AI . Genetics No consistent cytogenetic or molecular genetic change has been identified. B and 't-een receptor gene rearrangement are qe rtruire. An association with NFl is known in some. There is evidence for clonality in some instances 11045AI.

HIShoc yhC and oenontc cell neoplasms

Fig.14.24 A Radiograph ofa case of Erdheim-ehesler disease showing a lytic and sclerotic lesion in the ~ femur and theproximal tibia, There is destrudioo ti the antttrior femoralcortex, with an impactedpatllolo:9c fracture through the lesion and an aote~ateral s.oII--tissue mass extending from the destroyed femur (arrow) Reprinted from {187lA}. Courtesy of Or SuS¥! ~ ram, B Abdomioal CT from a patient with ErcIlet1IChester disease showmg a soft tissue infflm! SUrroundll'lll lhe aortaand kidoeys (wtVte arrows), is a sclerotic lesion in the veteea (blaet. arrow), Reprinted from {1479A}. Courtesy 01 Dr. RGdbE!l1O Gl:JI.

n-

mo..

Fig. tUS Systeri: JXG inYoMng Mr. A The nfiltrate is portal in natJSe but spares ee bi& duct. FewToulon cells n p-esenl. 8 Faco Xilla There is d1ltuse stailing of the portal hJStJocy1eS.

Postulated normal counterpart The celt of origin is debated , In spite of macrophage prerotvoe. it has been sa id 10 be a defmaVinterstitial dendritic cell on eebasis of shared Factor Xllla and tascn immunostaining. but these have limi ted specificity 11 188A1.

Prognosis and predictive factors All clinical forms are benign. though multiple lesions in brain , dura. or pituitary c an cause local consequences and even death. Systemic teems tha t involve liver and 8 M have been treated with lCH-type therapy

Dtsserranated juvenile xanthogranuloma

367

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m

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31. ~ JR ",,"1Iige W_tug&< 00 (1998). E~ flOfl-Hodg'Il" lymphomas d~ rI major &.ubtypn diIIef by g80Vr~

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MoltM TJ (2lXXll· Pr()yll(l$lio; SlQnkanoe 01 su",,,,,i" .'pression in di1'l'1,>S\I latglI S-al 1ymp/\otIIQ 1lb:ld 96 1921·HI2S. II. AdrJlUln J, ~ R. au:.VoGa

S, 1Illl'itUM1 E, Mtnanli SP, Meani N, D. Bernard L. TlUOIli L VoIoOO S,LUl'i L, CoiorTtlo E Lo Coco F, IAecoo:i C. FiMli S Ptk:o f'G (2005) ~ ~ .... I.emis

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ar>aemillll B! J liaematol 116

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Eng! J Med 3012 998-1008 la. ArtI'IIlt JE, Mgul P Sou1IlIy lAC, Battaglia Sf R(U Be. JonB AM VanlIr OJ (19B4). L~1li¥e dO-. 01 donor origin artting On pabBfIlI lilt... ~ MIl' lranoplentatinn Canca< 14 2431).2441 n, ,t,,mtage JO, Wei:$Ilnbo.tgli' 00 I' 99!l1 New HpIlroach 10 r;lIlSo;d'ying r)(ln·HOOgkin', I y m phorn.a ~ . clinical ~tUffl!l oT tho major histolog~ $ubtypel Non·Hodgl. ,n'l Lymphoma ClaSlolfication Projoct J Clm Oncoi t8 27802795, 80, AfIrn!Tmng SA, Kung AL, Mabon UE, Sillo9ml8l1 LB, Slam AW Clan Boer~ .. f>Jeters 11., I(~ JH. Sal.an SE. F1elttlar JA, GOOb Til. Griff", JO Kll<smeyer SJ (:?OO3) Irr.
n . As'IIon-KfIy Lt, Diu TC. PM L lllllAO lSiIiICIon PG (1991) t.loiecuIw anaI,- ri T· celldonalttyII uIoaraTi>e ~ lWId lJIlIllropI>!M~ T-oell Jymphomll. Am J pafIaj 151493498 90. AsIlIoM(ey 1.4, Thorpe PA, AAtn JP, ISlliCIOn PG 119951 FoIKlJlar Hodgkin'! iii&_ , Am J Svr(l Patl'ol19, 1;/94·129'< 91. A$OU H, Sad m, Yang R. Ltuokor A, PaM< DJ, Klmada N, Koeffler HP (199BI ~ 0I!}'tlWfl conlroI d KlIll('):'....S sam>~ted I'Mlo'p!'S 'MJs--associatlld pnrnlIi)' eIkIsoon IyrnpIloma cells. BIooc:I91: 2415-2481 92. Assaf C. GeHr;ctl S, Wh,~aker S, Robaon A. C8tronI L. Massone C KeI1 H, RO$II C,CM A, CI1imenti S, Hallermanl1 C, Peh4la T, W......,... J, BagoI M. HI.Il'\n"I8l M, &aan.

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Mlot DA ~ TI(2005j, Bone """~I bjo non--Hodgi
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ElIOOd !l4. ttiO-~ 8.lhief OW I'1nclzole .lA. S'ofIIffdIow Sti (2002). SpIetw:: m.rglnal lOI'llI ~ appear l(l ClnglMlIImm 6dlererlI B ell typet..

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References 39 1

Wesll!m ~ '" ~ '" ~ ~1Illllogy

37 5($.512

Sl*Ik WI<Wll

622. l>..i.l.. ~ V(1990) ,., 1I'9I...-wIl aoo:I ~lion ............ ~ ~lhe'1ll ~ ....,.biodIt~_

Res 156:9-18: g..18. &36A. E'*tr$ A. OllerE. IlartIIi1I; S. l8nle D.

bon ProcNil! AQd So USA 87 813!l-&U9 m . Ounltriy K 'M10I 'Ml JIfle ES

SIIIn H. HurnIIleI M (2008), H,$lone ~ ...., DNA ~ aI celI$ fed: ., •

(2007)~Tc:elI~ ~ ir49lI5 IJ1d ch:aI ~ __ CurrQpn 341-3S3

!tldIl1;""'" fIl'IInCIYfle l-..nia 22-8J.5-6' 1

HInlIlol' " Ok. IIo.or.- L

l:JurII.~

5201. J ~

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an

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.......... ~~~lIIllof . . C)bIlIInC _lIUjIletdW-'llll"_ ~ of . . . . . mollOC,-. "'" J ~ 1'310 122" 1!lll5-lI7$ 627. ~ ~ OU TL I\IIFI P T.-.z M Ow MQ Scanl O....... IV.. PG

ea.dI C 20001 t.f4\I-I. - - . , . . . bW' -....l 01 e-..r.. ...... .,.15 ..... III ~

m.

MlN~

....

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~

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Tua-l M Fr.wl< N """ WI/dI E 0 Gom I, E-.II .'/P. IV. AlIlIlo K

w-

8oItIoII C (19lil91

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of ....... ,..

~ IMIntt ~ ~ II ~. un:;ome ~ CaIlernen. dlMlIH

and prlI'IlaI"/ . - - . lympllOl'na

Prot

N"

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~~'·". ""~:RP ~ tiD. ~ K ,t.lR Good RA (2001)

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MuIef·Hermeiln' HK (20001· Hekooact&r pybi ., 9"$lnC mtJ(:o,,;HIS5Ol)!Ited tyrnpl'od .... !We IylTIf:tm\a Rea!Ill RestJts Canoer

IrrmJnoIoglc ioIootIWIg bone..... _ ~ lor X-hed I\'fPO!IIlr,oM..,nlIrtYre,ClnlmrlM.llOl98 31)-318 Dupnaz l.b8I P Demory Jl, lei JL SirnoI1 M. f'laMI.., I Baul. ... F (1996). PrOl}'lOlIM; Iaclors.. '9f'109lnC In)'elcIld

m.

e,

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plasia I report 00 195 01_ WIth 1 . - SCOIing$\'1tom'l BIoodSll 101;)..1018 631. ~ J, Boye K M¥tJn N ~

lkIfgman C, PIorIQuel A, Fabioln' e, Baglio AC H3OJI'l C, D!l«MU-Llrue MH. G3uI¥d P (2006) Expr9$8ioo 0' CXCl13 by hllOpIilItic cells iM ar,giol!'mmoblastlC T-o&iIlymptloma {"'IlL)". .....

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392 References

SSO , ~ L Orillo A, ViIImIboiI J. [Ul·A.gl/*Ie e:.-oC RICI5A. v...ooJl.. Co.dId J Nr4tro JL Sen "'9JII JF (19981 ~~of"""" tIone l1l/I,",* lIWIl cell A """ cyIDm8tnc

*'Y r:A llOlI'ftII ana ~ llQnrf ~ ~ AnalCtI PefO'6 151-159 651.

E~

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Fit'nghI

L. ...... S

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filii M Ruct8nIr R Os 'llI,,:imaI>'" ~ Am J Trano>ptanI6 569-576 6U. Emanuel PC. 8lltllS U, CastletJeell RJ, Z
Selecl~

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Blood 88. . . .

Ra ~ ReusdI R. 0fl0n8l G lAnZG 1 ~M SIl*Ill 1_ .....,rJlIe~

...

References 393

ValOrprolein il RMO-SIBmt>erg tell ~ d8Itical l-lodgkr1's ......' llI'QVI08s ......,. ..... dfw;e b' ,ts 6-aIII 0l19"". Blood 94 31Qll.31 13 724. Fffg.ll lIf. Bruuue l P, Schlaofel D, Payeo C. Robetl A. Rublt H, Hugutt RIvIl r Delsa G (1995) £kq fI*1OW ~ on ......tic IafVe ctlI Iympho!'ll
n s.

Frag. .... s..chR·Verdt L. fOl1lU J ~

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1........"*"th.1 21&.229 126.

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73M, FroNing S, Sr:toienk RF. B.-ooiINdo; J. Benne< A t(~ S 100s K. Donner Ii. Clonow K (2002}. Prognostic ~ of .a.villng Flf31l'l1ta1oo!11'l ~~(16 kl 60 ~l ",til aculII m)elood ilYl.Pmll an; ncrlIIII~ .• ""'" of the AlAL S100y Group um. Blood 100: 43n-4JilQ 737. Flllhh"'il S. ScI>len ~ RF, Slotte I, 8it*rII¥r J B.YIlIl' A, Kr~ S Tobi!> K. 00ttlIr H Clo:Jrr.- K (2004; CE6PA muIiIJonS II'l 'fOIo"'VIf idIAl5 IfII'IIl aculIlTJl'llbd ........ 1IICl1l(ll'lllll~,progn;lSIIc 'e<e.-a In:l ...,.. of CllOlIOlf*'lI ....1aIIOll$ J CIrt

0nc0I22 112~3 738. Fu It ~ 00. Go:wolo" rc. c... S. W"Jhl G RoserrwIk! A, CI'IOaUI M. IqbIl J G.k S, s.ber1 R De Jcrtg D .11III ES WIIon M; tleGIbII J. 011 G, Daoe 8J .s.rtgeo- WG Srrd'I Uol RM!sa L, 6rnDIII RU ................. >it< Campo E Gasl:l:¥lI RD

we

Sload LM 0.... (2005), C)o::Ir1 D1""ll1P" MI . . . . DIll ~ & lil~ -.cly bIIId on ~ e~ prdMg Ilklod 1at 4315-4321

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73211 , Frt rd> Dl Lasko. R, S<.h1O'ff "'0 ' 1 ~1. The roit IlIl10milbc ~i\iof1 on !tie generalion 01 ..,bbodV ~ &ler.oIl

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t.bl1'lhll19 1101·1101 lU Grogg KL lM ME K..-. I' J MM:an WR ~ QIIaIr'Il....- ~ lolIoAa' ~ 011........ tern Ill.- ... elf« O!II ~ "IllI'l oll """" . . . . . ~ c:elIllWlIe< arcl ...... ~ ~ 11 IdCIillonaI tokIAIr cliIIllnc 011 &mln Ifld 6 addIbIIl ~ o:IllIIlt* 011 V'Iln AnIJ Surll PII'd 28 . 154. G
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M1 jPallIoI158, 11)43·I BSQ 930 , H8m1Mez t, Ilea S, I'ioyol M, OU G

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LB (2001) Stcor>d "ncar IlItIdence and eause--speak IIUIiiIy ....:>rog 3100l pIller'Ib .... '*'Y c.I 1tul<errIlo. a llOPUlIIIIorKli_

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(

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m

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t64.4, IiorTwIg SJ, Roserberg 5" (1984' ' " I'lIUIl I'IIsD'y ol iroIiIIy lI'4fMlI(I ~ Mfl.Ho:IO./kil' ~ Ii EngI J ..... 31'

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1471·1415 965 HOrny HP KlI MlI'ling E I l~""IIllI""_llIIIsol _~"~II_'-I

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M7. Ibl'Iy t-t> IJIIIi'Ig pl;asmIcylOId ~ lIndirqs !rom I case 01 CD56' d\roI ~ 1lIu_ Ell' J HIIIflIIlOI54

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1'loI11"\lsworth He . 5tetler·5te llel'iOI1 Gagoet8l' 0 l
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Three caYI slloomg

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35ol.2. 1!l-2.:lO. 994A Hummel M, Tama,," J. KaIY8Iaqe B Stein H (1994) MantH. cell ipreVlOlJSly crtnlrocyOC) ~"~ VH (l!!l'1eS WltI't no Of ~9I) .1lIe somallC mut8tio1ls I'Ke the ptly&dog. lC oalkI of ~ trAde mantI<; Blood 84 403-407 995. HuogneSl 51 , A,in C 120071 MastOC'/tosls. actI~nces in dlagnosi~ and lJ'e~t·

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~T,~I'{;,~JE,

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J (19931. The teSjlOf"6e of (lII9 from

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Har9
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ae.

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CA SOilIer R r.,lrIo.fIto R. SIOnI' RM (1995) A Iyndrome of 1\'ft\II~ ~mpI'>llma ~, and myeloid h)1lefPla· si&lmMgoan<: , .lIOeilIted I\',th ~8,H~p1 1,Q \')

descri ption rJ a ~ Blood 85' 1$81-11>81

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lil KIl(I l1yper

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1020. isIlItliri S, 0hIIlirna K Tolwra VtbW R ImWIo H 'NalogIDi H. ~

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e-. RaM' 62-81

1021. I9hh
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lily rea«:led p I IItIII!'engclma Ie5ion D tile !hOf1QC ea.,tyJ N'Pllllfl 0()'Obu a.o. GarMi laritlhi 35. fl<8.-532

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plotsms MoO P1lItloI 19. 1555-1562 1052. ~ A. ~ 'I, Ward E "'u"ll)' T, ~u J. T!ul MJ (2007l- ca~ statIStics, 2007

CA Cancer J 01157 4:>-66.

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_ UoclPaO'lol3 4~1 1123. ~ J"~ R$ ~. "lllll! J'" I(,ta AA 2005 ~

..11>".... rJ ~ "IAII ~ "' I9t l:I..-n .-,s In drQl lIldI» CIo'I 0..... 51 87B-.Wl 1124. ...,....., JA Clwlo IU ,..... VS

n

"..,.. ~ l!luI:e<noI Ie 1879-1M2 112li, ~ I( ~ S, Nncnwya T V....... y~1< tWaJ ~ ~ T_ ... '*ai K (1i89 c::D3--oagaIM ~ . ~".

_ _ dll'llfllJlr~<XlI1laIhnQ

E~vnIDN.A JC1I'I"-'&ol 5155 11V . ~ t; (2006' "tIeR dlMIop-

"*'lIaI ~ tIlitWW>. . ~ IfICl ~~I

~C

".'"

~t;"U~lIft.l,ZiIIlit1Jli

BIoodl~3076-3019

t113 .

.

1 1 3 ' 42~26

Ok~ zaKI 1.4, OIl-is h, T .... Wang F, T~ G 11996) ... synQ<(l(IllI III ptlipIlolrlII DIood T-<»It Infection ... Eps-...a.r ViM IEBV}Iollowec by EB", pO$Ill" . T-
C Dr8dlJ (2004] 801> IGH ~ and etvlll/lOlOmll 13Q deIaIionI_ M1y _ _ .. ~ ~ of l.AlIIlermrllId sqIliblo! IfICl ee not II!'KM lluMg r--.n 10

~&'ldell'loc;ll~d~ ~ tbls~5
1107. Ks!>,an MA, Ferry JA. Hani. Nl , Jawbson JO 119!l4). Clonal analysts ,j post.

S,

V....... S ~ H TIII:eIhllI ~ KlIo:.m M NatalllUra N TaI:.IIu 0 ............ f T89i""'8 H Sftl I.4. ()hVIinIa I( (1Ol)n COlO. MlNI . k*:uW lymphomlIllJcb IlCL1 Qll'li ~ and I/loWli ~ 00I0gc

1099 Kant JA, H...tWrll SU LOfl9O DI. SrncII'I ~. OeWol VT ~ ES ll 9ll6 ~

"_75 167·

JaI~~.lab

m

Kanada H, WI(\B T, Vad\Ill ... Se«i 11 Nil T ~add;,m

K:;1e R$ (2003), Moooc:lorlaI ~ Ioghl ctIIinB IfI S51ii!rotn tI8iIlIt' indiOOuals f LC MGUS. a.n Ch8m49 pAJ4 1US, Kaufmann H. Acketmanrl J Ilaldia C ~ T W_ R Sad S SagaslII V

1112. ICarI.tla I( CJlalwna I( TIllChlya T V~ T Kawano R Sulunrfa J ~ A.. Harada M I«(qd'o M (21)>11 hptBMIOII 01 FotP3 • ~'Y In C04CD'<'5 ~ T oak 1'1 T-
1094, Kanegl nll H. Bhatia K, Gubllrrez M

Klglmoto

dIclion ct ~ ......III PlIliantri ~ \hi! !eJl;amoC phaw d cutaneous T eel 1ymptIotna J E.~ Mad197' 1471-1488 1111. ~ba K G..to V ~ J Sugu V. Nomunl V Vama/l1OtCl K. S/wrnIzu I(

m""

-

hIllgas T,ends lIrlmInlI27 169-115 1121. Ka-ano S. r _ E. VllM:II N v...-gadv N Go;J ~ H . . . T , . . . " M ClIranv.II A.. ~ 0 (19951 """"'-.......: ~...,~~ __ slIgiI d ,..,. ~ ~ ~ !iImIlll Drecl lJ ' 11 un KI
..... '*" \ -.

It ~ T L...,...- W lIIblIf B t.lao4*' T "" K T~ G. B8batiIo iii IklNIo t.l t1nilPf2OO2'l

~lti

~ ..........,.......,.. III

dT41

PIIIt* lot lIllh:lma

"'lltlIprUa.,iClII'.-3P1~_~

J C1I'I 0rclII2O' 2r6-213 1131, I(eaIl; JJ. ror-:a It a.. t.l SdqI R. e....- A.. CIIlg 'l'fJ .... W. $ TIIld8rlwIn R SI'Ii Cx s.:.g M Brao»o E. ......., T Zhu U RlgIif H f'ncao. TrosIe noncanonocal w: . kappee ~ II ~ rnyaIDmI c......Cell12 131·144 1132, I(N" JJ. Reiman T, lotatlOSll CA., Ta)'lor BJ, Lamltt l M ld.lnl MJ, Elek::t1 "'R, Pilar~~ 1

LM (2003). In

mu~ ipIa

myeloma,

U4:14}!p16;Q:l21i!; .., adwr$8ptOgnlJ$Iic flClOr II'I'KpIICti>5 of FGf R3 e.prassion, Blood 101' 1520-1529 113l , l(aegM ,"" , GI8.W 5L Clari
RF t.Ian~ RB, ~, Rf 12005). EpslHlBarr WlJ$ as a marl<e' of "'NN,I Bfler Hodgk in's Iymplloma: a ~puIalion·ba sed study J Clit1 0nccM 23 76(14·7613 113>4, 1(_ P, Mendel
~ ~ daWmlrw:l

!It'

POl ~ lr.........., AJCia5 J Oro PIlhol

" ""'"

113S1.. ~L.U. GiIilnl 00 (2002 GsneIcs ~ 18Uf<_ .w.. ~ Geroncs

fJ

Muma.-ll7tl--lllll 11)6. ~ Go' I(ay Ttl -'*-' O'to I1awIllyCM 56 IIblIi NI.I . . . . P CorJ"cII l't GI 0 C
ean.ua

Reference s 40 1

Pall1oklgv)4.2b3·2fj6 1m. Kern Wf' S\llIf C~ ~ EH, Moler TP, r.lIllnIf M, GI'IlQ*1 I'M il~), Ne'nIC8ll~~,. ~

. . 1<*1 ~ 8'''' _11Mlt1. propemoly lor ............ 01 ~ Blood 19 2432 2437 mao KIIIIodl HS. IlrY"* ~K t.lIdIMoI U. 0Iq KL SlDva Ul ~ OS. MItr OA 119llB) ne ~ III bItsl ~ f
M MeMo T. YoI
101 4660-4666 1163. Kion -'0. Robl'l J. AAi~ C. Noel P Brown M, Law t.l, ~ 00, OYrttilI C NuttrlJn Ttl (mol) ~ _ ancl flMIISIl0/ myWJlboM WI feIpIJ'llle kl ~

"'"I'W ~ In PI\IIIU wII\

SOOlirlI LR. Wood tv. 1<.&1.0, RafIeId '" .lII1fll ES (1WIll, l-Vade lTI()n(lI;;iona ~

drwolI1llooll103 473-478. IIW. Kbn-NelWnInIHC.IludlG

~1yrIIp/'oCIp~~oI

S~Se...nooH8.F ~JH

l.1IIewood T ...... p. 8erelorll 0 "M'l dar LH Grefn AR. Rooundul K.J M.... AE

........l<JpOIIIlIc ~em cell ~

o.rq~~ ct'*I ..... aar.-d ~ ~

... syn·

Art:n PIII'loI UO hIW 123' 8J.tlT

CI\apm8rl

~

(S.

P

(2(lO6l

~ ~

01 ~. ~~~II-.

1152A. ~ 1J (19llS) Tre C05 e-.a.I Mol

~aI""l'fIIOO"'~1llCl Yryol)C1lC IbIl(l111'" II 210 ~ n

-...0147 117·1~ 1153. i<JPllI TJ (2003).

11~_

AlIIJClnP-.ollll

Kh:uy H 0IIIl

eom..tr

EI. ...... TJ

~

DE 8aIllIll ....,

~

JO loa Cl.

~ Ii.)

fA.

"1~1fi

~

OE

Stj 120031 AwIt ~ ~"'.8~1,......"""'oIlll.ol· ~

oc_lllCII""'...... l ...

l~

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171).1718

1141. KJooour, JO _ 0 V-.:l ~ UarPIg JT Jt AIIn.LI:lo LV. ~ Fa MedwoI W (200( 8DnI_ ~

1152. I\n'Iey Me CoIrIs R!) Gr.- jP WIllock .II\. SwIos N I(aQn UE j1!193) ~

1 1iS

" essese

em.-

rJ _~ _ CUll" Opon

~

........-olIO" 31.-318 1154. ~ AE

~-MMdou

do .............,... ~ ms.1 III 35 cmes

HIst:ll HIsIoPaitooI n ~5J9. 1155. I(iIlIlt NI!Iio.aee !<.. MPwa H l.Ia5"J'8 l.! It uma N TaAaoUl1ll N 0tsW '" S~ S. IJed;l T '" Ii (1992) PIlenotroJiC* eM.... rJ ilCl*' ~

..

~ t'(IWIIIC ~

a

IN*l " IIl')'lIloIro'l lIuI<emiII ~

942401-2106

1143. K.... O ~A. KItlenDIIrgIIl T,011 G ~ E ~TF ...... P,&enntrA, ~A.""~HK.IlenaI.l, lichIlll' P 000- 11, ~ S (20031 ..,., ~

slalla IIIld VOJ 1!lilIllII~~ WI.c-

lin III ~ ~

* lympno;:.m,

CQrIWIoon 'MIn

aberrallorl5 clIno;8I ch8rllCllt/lt1leS

tlnll~,

BOllj 102 3OOl-3009 1144. KiIu.Jlj 11, $akryamll V. Matsumol<> S. O!I-tlillo T, NMaoo T, ~ma T, Ok, T. Hil'mRk8 T, ""81 K j19'l:i1 f Ataj E~...,.1lan' virus.a~ttd ~mop Mooc yl";

syndrome

8Iood 82: 3259-3264 1145. Killl,k S, M31Utlll E Powln RL. Hamblin hi. Swanr;(l\H')' J, rrn lf8v~n JG. lunas A, Alra A, Coloogj.,y D (1m ) OuluJmt ol bo(lhenoIypic "CUlt iI<J
&4. 69l<- 7()f; 1146. Kim BIt Sur;, lJ. PlIrld;o. A, Cohen J RIIl",~ "' S, Sw..-OIow SH 120051. ChnK:op.tiIoklgJc. Ill'>/lIIJnophtrIotyplt, In(I moiewIIr CytogeneliC IIuofeIce!lc. III "Iu ~ybncIIl.alIon"""olp"",,1I)'" MlCCl'Wy ~ ~

-"...,

ly'lnOhomn fvIo J

U47 . KIllY weilILN.CtltnYV

Sur9

~IV

(20071 o.ln:l ~ 0"llIIftlI olsrt'*!'C ...... ~ Itlll INOI»lId IkaI ~ l"'R4II~l 174~17~

114. KIm Vt.l R-. JA. ~.IE G*llat HA.V.. )P. NyI;Ior; JI( (2007 hIolaaA!J" d\II'. acIflrlUJllOn ol 1ht 1.'~1IlIllll HflY.l eoIWlCeI" CO'IllIe< -ala. ptlIIIIIWt fQla /or CREB~ .. T.. ~ J BooIa.n282. 187:;0.18751 114. . .......... Ii HoIlII'Cl Y ~ H TSOIgtJ ~T ~I( ~T (2001 QrIQI.-.o W!lI(Vl: ~ 01 ctrvnoc _ ... EPSlBot>-Ban IIlIadIon

6Iood!lll 280-2t!16

402 References

~ N,

C t-.a R a..-g U 1200R ~ 01 ~ Ill-. III rwhcby _ and

.............

~~ ~ poaOo;ls . . ~ CIAl:aN. lfIl# Res

32: 13-37 11M, Kr..- OU e-..... E a.run A.. fnawa G JR.-fA. !oIIo;tIW RE 119!15) ~~_~

c:n.

~

~

....'o.1lH __

dIsarcl

~ol~."",,,,,,,~

poIiarII"" aIYflICIIl mroooe myeloid . . . .

Ilc:q ~ T ~ 34 1047-1050 1179, KoIMl$u H YfJIIIloOI tl SeIO t.l Il:iI ......... 1. ueda R C (1

S

Oriwxpieswn 01 ~1 II lIN tyqtonI j)iIlIInI . . . a q1122~1l13.1l1 .~erJ~86.4'1 "'2'iI

11nA. i'D'llo T Kinl H ~ N Yt*IGII R. To*i Ii. ~) .... W R:lut H ~A

'*_..

F..-T.IUI(l989}.Aga-_

.... am.-..

olATUb HTl.Y-larrton" JC8n:er4J 101il·1~ 1110. ~R.~J O".uH m,.N,~E ~E.u GiIaInII- H. ~ s. ~ R ~ K ,... H. Qrar:tl J (2lXlI3~ o.aaa ~ cno... _ 1Jq II "OllXb'lII1JIlI" ......., ol ........ ~ ~ lA*emiI U 1915-1i"l 1111. KorIgstlerg R. za,. N ""-"-'" J(ror,. E KlIW H FnIz E ~ ~ ~TRieI:IL~H • SInOlIIdI I HeN R. J.utMg H. ...... K ~ J (2lXXll PnKkM ... ol ...",..

KJ)'OUQ K (19961 EosnophII13 a!o!OOal8O ..,'" proliIIrnlIoool C0l3- i't.(ll-) aIQIla bela' T c.eIs willi c/ImmOsOme 16 anomiileS 8, J

Genes Qlromosomllii Cara< & 11~213 1169. Ko YH RflI HJ, K-n WS. Choi WH

~92

~NS

hi If'ft-loIIt:<jo Ulo call ~ ....

p"ewr»' IympI'lot'n
11M . Koltaridrs PO, Gale- RE, LII'dl DC (<003) flU ITl
~8.2 1j(q22.q22J~ ~

(II"

~ e

H El'nuglIdi All (:2004 0I*una oj

IMI't ~ 01 Il'IllII!kI!tI B-o:8I llllIlglrl CD19 ~ """ .... oeII rigIn COl' Illood 80 47~n 1156. KlWlo K ld1I<_ No MaIlIkb 8 ueoo t.l ~ 1. SfliIllOOil/il S Kodlwa H. ~ F, Kd;JayWI H S8IlD H QluJ:)O Y Enoi
"*"

IIa'II t1tllIgIIoIn

I loU. KholIy.lO. ~ LJ. ~ JT. So*k LE e.-HlaInDI C ~ 0 12002) Cl>!J6<.) TdT('1 t*Ut ...... ~ OiIIIlumor

K"ll(l S

~B SchaIn"'~A..1d

~

BIoocI86!iS2-5E6 1167. Klll.M6II [It.l , . . . . . G. I..lbt*XJ A. CMla-f-. R \1989 ~ geneDc ....,. ol It-. ~ II8(llllIIIN rJ _ ~ den............. e.-e.lI
'"

....."

~,

~ VA.. ~""inlo R RI.ol~ R 12lIl7) ~ II dIo1rdnln

II pIIInlS ...... ~ ~ ~

AmJ s...g PIfloI28

~

the /:Qn ~ as r>Jman ~

lOO:~15

aduI~

Un. KoIClIr G. Bnxl<er E8 (1986).

Am kad 0erm.II1ol 15, 591-597, 1178. KoloahoII t.l,IleeIenDW T~~ S~" f'iK, Peceny R. Dilsd*"""', N

lie-

~~olpnmaryl(,.l

s..-...,

~""' .... ~ansong...'"

no::etlIlflg CI'Jloo Mod PdIoI12: 739-743

sUlll,oml)"'$ol~cebllanIll1ll.J

(COX)}> 1<11I ~ Am J S
ltut_

TfOI\illIInl:ZO 111·173 1116, ~M.N.aWnu1 T (199Qi 1.lasl0lli

prdlferaM .¥I&'lI ol h~ $)\'I.

lhe rnyeb-

liS CIWIg KL ~ u Ilrtr- RK so.-. "" ~ JL ArtIer OA 1999~ Al::vIe ~ ~

wlolis. Bone M_

llwt'''''''''''ff.o:lion JirlIllcl0is181 521-533 1151. I\XIgmI D".... I.iueIer BU. f*1:o I(

olloooo-dOlt ...~ ~ II dYmic: Ill'JI'bCI lIu_ll"OIllICM .............,ol3,.. WI. . 0, ... loIRe nl HOVOH IJOI4lI 9Iood

1131.

•

1, 5Il, KlITl\lla H, I.4onsilIlTl8 T, Kaoegaroe Ii, CA'lga S HoshIIlo y. M8ed8 A lma S, Ql..ano

1157.

.... ,,~

~

W'lh

lhe

floe.

315-311

~S,Husl.>yG,SlblIenKi2006)

T"- anwlO aad !IIlQU8fICE e heart of a pa111l1l1 WIlh

_~

'*

~ - . - ~ . and ~S. !41

KIm Sf< (2£00) ~ and ~ SlUC!y ol e>:tranodal naUl·fypI:t ro>hJIlIIlUIlII,'T.qI ~ Me! natuIJI ..... .-rDIQ

K OflII:trlS

c..nc.

WIlIl:Ienslroms macrogIObulinerria Itlll llffl\'1Oidosi&, Amyloid , 3 260-262 1158. KWIg~ U, ~an I, Magnussorl KP, W,~ M, llml P, Wiman KG 11995) p16ilNK4a and p15ilNK4P gene rnet~l y!>l lion lIn<1 l1ll18nct of p15JINK4a mRNA and proIeIn e~ p«!ssion in Burkltt s Iympt.oma, Biood 91 1680-1 687 1159. Killin U, GllJIl hinl A, GaidallO G, CIl8

um A, Cf&armll~ E. Dalla·Fa\'ela R, C8ttlone ~ (20031 Gene expr!lS>ion plollie

89' 2106-2116

anaIyM 01 AIDS-flllillOiC1 P"'N' IY effuSlQl\ Iympfloma IPEl ) Wgo:)I!M~ a p1alffi3l>las!ic deIi , atioIl and lCl8nlrileS PEl·speclfic IIll11~c~pts

fiodo;Jk,ns I,mphon" Blood 90 4075-4091,

lIood101.4115--(121 1160. KleIl U, Tu V. SIlJIo\.1tz+:y GA. Matlicll M. Cattoretu G Husson H F'WCIlllao A, ~ G, CIO l 8aIdi"o L NenA. ~ A.. O~aY8llI R \20011 Gena el<;lll'SSlOO profiln;l 018 tel d"ro1C ~ Ie;.r '~ Ill'iMls • ~ phenOtype >elated to 1!lIIIlOIY8011lla J E..,1dea 194 162>1638 1161. KJemq CO ~ U. PolIMl N. ~ E GoerdI S (2005) PfOIJ'lOSbC fKtDrs and jQOIdlOII of ll'ogroo5I5 by It>e eTU Sf.,..,., InGex

myw'lfS iunQoi.- T8 Nl

<003 Elfv_ _

~

a-. IiermI't

....... ol ~ YIIfl a ilIJlIk4JoIlIlo_ .....,. 01 ~ nl"peIleoili!Ol"'* 'l'"llrtwr'e ~ ior:JsIs poor _ """ IISoSUe_ _ Illood ~,ano

~

Chon~,

Metze

D, Ker!Ii, CIJrrorj L 1<0(5), ~ cular.eous elirucrJpMtllOlogoc fee· tLKl:t5, d88!1ltlCaliclll , and progII05tlC f8Cl()tl ill a ~ge Bo(lIlII fyl r~ :

l1l ,qe lIe1"iIS of p!l [Illi\Ia, Blood 106· .4 91·2497, 1171. KOduru Pk, Raju K v eomal V, ~ZIl5 G. Shah S, SU5ir1 M. Koiitz J, B,OOIIllI JD 11997). Correiation belween I'lIUlalion ffl P53 p5J e,pr_ . c;1og&rlt1tic1, hlllologie

typa. &00 s
nor>-

1172. Kpel'ilarI:.IlS M, Spa rkl:tS RS 11960) ChronIC ",yelocybc lIJyl;em.a ~ II1volw
oII~. J

CIn 0nc0I 15 80«112

l In KoI5 ....

wer..n 'M).

~ L I # 9 *....

~

AA IiKtIoII PW 1

lJillPloll.bd ~ . ~ lo!IIC sU11 ol42P'*fIII. ~ 18 283-2lIlI 1113. KoeIer A. 1A:lflt1!'lA, RasniI:tlIn M BorIn Gf. Hebeda K. ~ w.., .....

KrlMnJHl
~~.~92IS4-\iO.

KMm"1oI ' 22.52:J..5J8

1110. !<.Cld¥rIIK, t.la!lSOllt C

I'l8

~bw-..val()i~""

NSIl

IfIIIhII'WOIIteftlenl ol ~ Am J Sur;

Pdloll1 .41-248 1175. J'.oa""" K s...-. K ......, t.l !<.IIl9" E f ....... J F1AIda 'I T....... 1 "«*lofa A. S/wIIzu T AOI' R:. ~ H

1185, Kooldes PA. BI~ne~ JM 119961 Morphology and c:laGsif~lion ol tIEl myekxiy5pIa!!>c lyndr0trJe5 and !heirIl'lthologic ~ $eII\I1 Ii8matol 33 95-1 10. 1186, Kralol/lCS R, Pasaamonb F, Buw ,l,$ T&O SS, Tiedt R, O'!lSsW!!g JR. Td>eIi ~, Cau ole M. S~oda RC (2005), A ga;. bon mulalion of JAK2 ill m~eloproliflll8~~ dl OldaM JH. De.loogD, KiIA' PM119961, Cncal Slgrtlicanc:e oIlld2 and p53 proleIn IIXpm$Sl(IIl '" difluse Iar\II B-QIII1jolIphoma ·aPQllY~slIn;

JClwI~

14 2131·21311 1188, K . - MH, Henn;ons; J. W'lli<"9 E. PllIlWo K. Geelen E VI'iIl Kr8.en JH Da.klll o. Maar1I:tnrie E. ScIv.Jmg E, 10ooPl.4 (1 9lJII CIrlIcIj _ vance of BCU, IlCL6 anc Ill'C l_lgllfIl8ll1s In

(io/IuSII

largII B-QIII 'll""

Illood 92 3152·3162. 118lA. KrousW , Haley JC RrMR ~L Mor!In Co\. FItIl:M'CO 12001~ ".llMnla" ...

pIloma

~

..

~aq

"'IlI'l.~d-.._A'tl ~23

104-111

1189. ~ A.. Butt. G GI*l:lIilrIli T F~ T.~ CJ (20051 The d!InoI ol ....,........,. II _

II'!'

KooklIT(1!l97 E~~~· ~ lly .......,. ~ DlOoC:I _ Q!III . . . . ._ 1I.I*oINMIl",

~~_tn:I

~

aw--.nol~~~

101 ol

~~a ",''''''''' ~

_

tooI:t - - . . . . . .lda

f1aerlI3tOj

mo.

11) 131·1.3

K_ M, S(lI!m" M, ~Web« S. S _ K, SChmidt e, Hohr H. OI.-ltan&t/dlWli'ltl' t. F.,.;l r (2Q)31 0iI00rdanI _ lIWTO'* tnWIvelTllWll III ~ lIfge II-oIIIym;YIomI' 03I'IllIQM l~lJtlI.4IrJ~ l...Wl""'-t

moMQ.llIf"""".......

83101-114 1" ' . l<.rtI\ICS l. S
pl""'''.

12112. Kvmaf S, Kr&f\3CS, l , Mlldllir05 J, ElenI!I:JbrJoIvo KS, G _ tc. SoriJara t. K'ngtI\II DW, Raneld M, ;aile ES (1996) ~ pamiMllC T..::eIl'f!'1Phoo1.i ISa

32: 362·311 121'. Kv.SI'1<"'" HI>I. Tnie~ J (2001) Cias$thC/IlIan 01ph.negalr.ie ~ m~

tlJmor 01C'f1ol':'.:M 29 397..((lJ 1203. I(I>'!\If S Kreoacs L. 0Isukl T. Kcrnif O. Han" CA. W\lIlmiwIn A.Jaffe £S. ~ M (1996) Dd·l f$lmongeme
I/l<;llrl~ P~ ~74 .63-71

dIIIl;liaIrJ(Xl1AIllIQIII'l in~-.d..cl

CloUtlIIOuI CD~ ~ clIlUders _ I ~ ~ ToQII pr.not~ J In¥elIl DerrnalI 109 636-040. 1205 " - rr. $IlIl tv. TSlI'Ig NY (2llOoI) lQNI ~ llII~ in Ta'0N3n.'dnic:o(:IIIlDIDgIc: !Ilucty rJ 22 ta!I8S ,.." ~ rJ

llIIiIfIl ~ ....

IaI1lIIogoC

~lI19931~

..::tooftI"_

~ ~ WIJS

CbWIIl'Mlod1010 J PIhI111 "'001 lIn. K.reo8s l. w.Irnnl A. ~ l

lJ,lP.l ~-.ociak:Il.IIllI~~If1l J Surg PIhII12 37So387

. . . . - III . . . . . . . - W - r J T. • fd. 0IIl rw- IIllI ~ . . . . . . .....,.. b"

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,~,

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PlIll'K> 2000; 113:411-.4 18

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1191. Krotowslu M, $ollar K, Krauth MT. FodH1gllf 1>1, VI~ t p. Humy HP (2005). ~ 01 [ldemI 01 bone ~ . , . 0IIl nfiIIrallOn II lyMemoc mnloo;tolis v..... 01 C025. correIIloOn ~ wb-.tlrJ a. 0.-

1212, KUSSId< SJ WC>:Jd BL (2003). f O\Jf. cob" now <;yb'mlIy iO/I;'Ibfies vl:1uall)' at cy1ogeoa1lQlty abnormal bonll rYWfO'/ll ~I in !toe "O"lwp 0/ oon-Clotl m~ern!Ml dr$-

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1213, KUZII!I T, Nakamura N. HMiWmIo '1', s.-. y ~ 1>1 (2000). Tl'le dl
257·260 1231. Kyle RA.

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n

IQoIle ~ ........ ..re.. l1p dIIiIIonNo ~ d\n::lIInlIlCl by . . . ..,.... lc(Jo:.- nl a "'" IldderaI rJ PS3 __ lIeN teuatrr119: 37(1..381

1231. La It AlberDA CNrJgKl.. N&on CS, (1998) F~ rJlid-2 IUP*

we. Lll

...... non--HOOgiuo.:; ~ • IWy 01 718 caMe ..., <:tlflIP'I'lSOl rJ lflII9hlII lillie ~nl~8-ceI~

Mod PJlhgI 11 ll64--ll69 1239, La R. w.s l M CIwIg IlL AstIer DA (1999) FrequerqrJC04J~ rlllJdIo Hods,loin~.A~rJ742CiA1n1

funhet ~ rJra-e C04J.

**"-

...... J can PavIOl 1I1 -1&6-494 1240 l.aoo5I (;oJ. SIiIddeld M, GrIll T (200S). Determ'nal\li of I~d"""'lelood ItMage ~

~ AInl!lev1rrlro.lr()l241Q5.738 1241. t..vnarII l , Oasn.gue N PIAlord K, DenoI:G, IAanameB (1999), A .--t.oIk:Of't~ TI'loU-ALK '" ~ ~ CIIlI ~ Cf$;jt!ld b~ a 1l.2)IQ25.p231 t'ansloclbofl, !lkxId93, 3Oll8.3095, 1242, Lamant L d8 ReyT"liei A, Ovplenlllf MM , Rickman DS. Saboord)' F. Gil.nalo S, BrllglllfeS L, GauIard P, Espino$ E. 06lI0! G 12OO7j. Gene ~. pn! !lSIJdl profiling 0/ systemoc: itrI8plaslic: lar\lHllll iympl'loma rIlVllai5 dI!et'. erns bllsed on AlK status and ~ (llslJrld r'I\OI'?hOlO9lC AtK+!oUbll'Jl'\Ii Blood 109 2156,,~

1243. taman! l , ~ RD , DupIwi\lef r.u.l. Arml;lroog F. R~ A. CI1hIrIat:t\ai 101, Raji;ln-Se(JarovlC E, Ragnab J 0elI0l G. Espnos E (20031 ~ ml'OS'~ IJee'v)' ttJaon (MYH9): a Mw pWNf fuIed 10 AtK '" lIIIiPiasllc lafge ceH l-;mplloma. Genet ~~JT· 427~32

l24oC. l ilTlint l. I.Iegge\b f. aI SaIIl T.

Bruo- t.

de P"elS 68. ~ N Bam"""'" A Rvboa I. TerriM-\.aIXon'bII IIIJ Robert A. RwIl F SctialtIlf O. ShoJt.iII.I Uon S DeboI G (1996!.....h inc1dfIlDt rJ lie ~2 5~,p23 Q3S1 . . lIIocIIionil anapiISIc '-91 tell ~ end '" lIO< 01 0IIlId00l'I I'l

1tldgo;"1~.~ol~ ~.

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dIaI'l 'eadIon, and

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1246.

~I ·S5 ~

l'f"hPlDrna 8

G, OtoW A

References 403

lu~td'l

R Mnlloro C

0 (1991)

~

~eyndranlt"'" ~IIW'

fUoM a dIIlincl tWmIIOI 78 161·166 1247. Larny T. LOUIl"ran TP Jr pf199

fOIl

~_

Iv BrJ

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tuIClI(8 IIrge

~

pa.V

- . . - Illood Rt¥ 13 2JG-2"O 12.... l - r r l~ TP .Jr 12003 CtrGII . . . . 01 ~ pUir ~ ....... s.r-~'-O-l8>'!lI5 12 !..In 0 Zlwr1g T ~ 5 2lwll; 'f S/wl Wq SS e.Jd $I bhn SH Hi;lIlotI:l ~ lMcMo9 B y~ M. WIIk:h R ~ 0

~ P I'IoIlIIWI N (200S) Ger-.c _ _ 1'1 tnl*egeresillfld~

litMIitI

__ HOdQ_,n

10

Iymp/IOrfta

319-418

125t, le GooI S Talmarol p. T~ C. t.IorMu A Gar8nd R Jug~"" N ~ f GaIlmI T UipIed N. Uor-.. P ~.11. A~-I.cneau H (2lXl1) The '*"tlIl "'_....., -:I ~ 01 doIlJM "9" Ik:eI IyfI'I(l/IOIft; willi 18l and 81;2. ·lIIYC . . . .."..,." Hw-*lflOl

Il'.

'll" 1l)S.13oCl

lao.

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lJIC*)rId

R. a..r

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W\IS

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CInoxIl16 2052·2059 1261.

LeBootPE(19901).~siId<

WI ClennftII c.. 12: 37So389

~,,=

m 9, ~ O. Grdey G llAS50ll I, CIporakl NE ~ til.. 0 F~ TR Hl:XMIf' Rtol, toni! t.lS 12(06) RisI.. of IIlOflI)doneI ~mmoptltl)' of urodeMmined SlgMI.

1261 A.LlIBoo1 PE Burg G WllflOOtl D, ~

~ (t.lGUS)

12&2. LeBrun DP 12OO:l) E2/l. basic lleIi.·

a.rs

ma amoog

and ~ muttiple m~

African AmerIcan IlIId

...mote _ .

arllin ee UnitedSlams Blood l Or 904·906 1249A Lj rds 511. MUfTay T. Bold~n S, WIngo PA(H199) Canoer "BtISIICS. 1999 CA ~ Jc.,498-11 mo. l.JnO" 6J, Kobmsl
DiAno:lMl~, blcllogy

ar>d

OUIro.... 01 .cu~ myeloicI leu ~_ and rnyoelodflPlls'lt syndrOme ... dlIlhn ..... [»,on lyndr'onllI Cl\iGrer1' e-- Gfo"p SUIII5 2lIlll nl2891 IlIood 91 flO8.815 1151. l.IngItnke C o.Azq U ~ 0 200$ ~ aI no.r. ~

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of ~b'llumo<J'J lARe . l)'ll!'l

loop·l'lell~ IraMSC"ptiO/1 factO'S 'M human M8rT'lI.lI Fn>nl Iliosr"8 s20&2Z2

1263. l echapt·Zalemoo E, Chail,f'leD, M au· ll''''' MH, HlIioun C. De!;Vll\J ' D, Glulard P (2001), Ahooiatiol'l of primary ple!J!'81 elfuskw1 Iyn'ViomI rJ T~ origI1 al'ld hu"""" hArPMWuI 8 ., II"IumII1 rrtI"OJllOdt'ftcilny WIll· ~ men Arr11 Pall10llAb Mad 12$

1?"6-1:l48 126' llwHI ~E.Mn'lA.~.Jl1C P!Xt\II'I P &..w F !lolngoja D, ~ J L-vne A GarlIo:ro.J Berdle P GoIIeYWI L l.ortJJIIfy 0 f2OOl) lrmlu ..... "*"**",..~

~

J""

,.... N Er'III 3SO 239-2'8 1265. lMU KillS(; Kfl,KS,~D Yq WI .lu'lg \1M Cl'li HS (1999l ~

IJI'I'Ilh9US

c.I_~ trorn~l_

~R ~F.~G(2OOJ)

1M, lei J SlII C P-. Yl-l !Co YIi e".g SJ.llel.llLMOtl Hl,nJ OhSY.l(_HC l(JfIHJ ltllSi Kim.ll.f'arlcJ OIISJ K""l( .u.g C PI<> iii l(JfI WS 12006) E~

. . " . . . " II CIWO'.: ~ ....",..

Blood 101 1087.1093 12Sl l.BrOII P BcdJnan UA. $In:lBeo J. Lmgo 01., J8tIe ES 1'990) L~ lymphome of Irolermed181e <:iI!ll,... baloon

J

AI'l'l~~.&Oc29ol·297

..... ~. . T
1255. Lnoo RS, Soot! WI. McCurIIIy n. V~·JCw'ttICl. (1996). ""cfIJ'Sa!llllle ..,I/y. lis d PQIllrItl6O!lMI lyTnprq:ltoli!efillMl (ljsor· den dIlImin;Jiotl 01 dorlof.l19ClPeMI ~ and icIInIibIorl Qi ~ ~ ~ c..c:. R80s 56 AJ78-4381 12~ . laawIIIj Mj, KemO JD. GoekM JA.

lIlrl!ud)" J CIi'l 0r>r0I2~ ij12.ij18 1266A Lit 11'. Inf'lI!5 OJ. WIIilIm ME SlQu!II'ltial 1>d·2 aM c·m'lc oncogene 'Hfl'lInge"'lflls Rssooaled "rir1 &Ill dirloelll IrIr'lll!ormlllioi" r1I noo-Hodgk,n's tymptIoII\a J c-. in_t 198\1: /l.t 1~54 , 1 ~59 1267. ltg rand 0, Perrot JY, SimoniM G, B3udarll M, CadlO\l M. Blanc C, Rarr10fId 5, Vrguiol F, M ~rM1 JP. littOOM R (1998l· Adu ll tIlp/'ler'lotypoc .cute W."".M: an ~t
. . FA. PIIlz 0: 0ICt FH (1990) ~

.........., Cl (1999' fJ8lllJe"lCY and cIOciIl "U"

~lII"lt-lge<TIell""'" ~ ~ of h giW... _ . I'Id ~ "C1CIIMUl~

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",,"'ibxrt--'> Ao ~ ollht flIIunll courw II'ltlIdIIg Nrly SGIglI!. Br J ........... 100 1~

1171 lllll'llf1 K fed!) (1978). ~ t)"'lPllOmls oIher than HodgtirlS oIrialI. SprIngIlr VtlIIag 8@rIin

0.,.. UJ CIiIMlOOii 11111 .. 8--ceI ~ ...-.- Blood S8

1m . ''''"'''' IhoW

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l ~nnert K, PalWamsdl MR (t97q) Ma'll ~k and mast 0IlII ~asill a re,,*w Hrslop;lthology 3 349-365. 121&, leonetlK,Sleo'1 H Kaisetlmgf(19 751 C~ ..." and fundiQ-lll 0'lI!II'lI b !tle clIAifo;:abOn of maliglml ~18 Br J Career 31SUPPl. 2"29-43

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References 405

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oe !euH""'.a, -.d mY81oftbros<5 ~" an ~vaa,Anly AmJ Pll!hal157, 1~19 1:Ma. LllI>GIil R. Hart~ng l. HoIl S, Pet1ocyll Ieuk_ have muIlicllI lNnotyPio: ~ irMlMng P'f\oT-eeI . . . . . 1ro1

lorI.lHC IllOiKlJIa Am J

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P.-:JI18 235-2.(7 13&6. Magro CW Ctt'JlO!Q'l AN. t.b'nsoo C . . . K, Pm;u P. WrIght EO (21X161 C06~ ~ 8Il:l iIs

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J CinOrlcol15. 1664-1671 1369. Makl,nima H 110 T, Mom~ K, NR'aurwa H, 5nlrr\Ol.laira S, KamiiO Y, Nal
31 1237-1 245 1370. MRlco'vali L, Gllrming U. KuandgM A De~R

PCl/la MG, Pascutto C, I ~ Y a r n lll:; R, ~ idl5 A, Hildebrandt e, Bernasconi p. Kroipp S.StruppC, Lalla/irlQ M. ALJI C Cnlola M (20071, h ne-dependMt prognosllC srorir>g sysl<Wn !or predatlg suMial a<'O::l IwI<erniC evOOIlon in ~tic synd«l"1eli, J CM Oocoi 25' 3503-3510 1371. ~ l, Porta I.!G Paseutto C, In'MlllUi R flooj

M. Tra.-agino E Pa!lS8lT"Cltlb

F. "'elmi L. t.tallioli 1,4, Bemascon, P l.Immo M, ~ M (2005). Pro Oocoi

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1310. .......,." E SNrron I(t.I SlIger DA F....... J CtwIKW ~ JM SnIlet ES (1999) 1~ ""l)IIOIClIIl7: a C8iiI _ n ct6nn iII'Id....- oIlI'e .... U'W e-.8:.'i. 26M-2Ml 1381. ~ X 1AngIcn 0 Scan1/>ID JJ WtMI 1 . ~ , S, R~ R. Young B, WIob'ft SJ «002) ....,...., t'P> QMf!bC ~s 01 eutaf'IeOW T-cell Iym. phcwna<. iOtnbllcaOon d canmon lI"'I!c aIIIr· Ibon1 II Sazary s~ iltld rnVCOM fI.Ill. qoi
1383. Mao X. O,,:hard G, LillingtOl1 OM RU61" "·J(ln8Il R, Young e o , wniltaker S (2003) Go'lnebC alte,ation5 ill primary CUIII· 000U!i CD30+ anaplastic 18flJ' celi lymplloma ~"" Chr~

Cltn(eI' 37 116·165 1384. Mao X. O'cnard G, l jlll1OCl8IId w

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LeuQrnia ~ B sU!y J ~ 0rUlI2'l 57l)$.$717. 139OA. 1lIwcutd G BIiIdI.e CO ~ AS en;I ~r.().~K ~SPll.CMl JE., Eltwwds CG V _ IN POMI a, a- 1olR. I.loore JO P8m:O D. Caigu! "" CImJI AJ li\I"SOI'I RA. de iii 0..-. CoS, ~ CO !2OOSl, CMnlll'filD' cJ lit ET5-releled 1I"'fI. ERG, fR(Ida. lOOIW UCOITJI '" 8Ql\e myeloid ~ _ I'lI;IInII katyOlytlol: • CarlCIt a'ld l .... emiI Gmuo B ItUdY J ~ 0n00I23 9234·'l242 1)1ll B. Marc.oct;! G l,\¥larry K, WMn\ln SP, 1I.,1,osallljevic T, Pasdlt1 P, larlQIr c, '*Ozek K, Baidus CD, earrtf AJ, Poooei SL KohtlJE llN)/\ RA. Bloomfield CO{2001) Hq1 elPfIf' 1ioo l!N'lMs of It>a erS-related gena. ERG, prtdiet ad\1!r!;I oolcoma and improve moltcuiIr ri<;H>a'lO!Cl dassiflC8lio1' 0/ eyt"\l'l!"llltlcalv rlCf· mal acl!t @ myeloid !eui(en1a: e CarIcar iIrId leu kemia Group B Study J Clin Ontoi 25 3:137-3343 '3" , Mane I. Rooyn J, Maltalf! DO. F'I' tdP C-"" M. Wi ISOrl T. Fu 1/;, Sloddwd J S<Xltt l Hart5a~ M, lOrsnenbaum A, Akin C, N.J\mlJI rB,N oeIP, Klo::I'l,l,[l (20011 K IT oeW'~ tiattld I Vlltemoe ~ witn ~ snd FIPILI /POGFRA-assodated dltonoc ~ leul<emhud N, Slliie J I2IXl2 ll""\llhOmls in meumaiold ertmIis . . . . ~ .... I\'II!lhotreI:a a 3-,..- ~ sU!yIll FfBflCI BIood99 J9J9.)915 1393, Ma1IDn P K8IWlg '" KMUqlIn M PIIlt:e S. 01lnen S F..-.:h EJ. E..,. E (19951 C~ and dinieIII rorr.llile1.. 1M, .......... atJI..., [ II 01 dlIlIIII- .,..,. 16 lIui.enII9 96>911 1394. uPIIIMP.~ N.~V lAo A. Peen R Msnru:a R I s T Ilol N Rawn:nIo F. .$plIt:cN G NiroIeltI I ..... w. F_sr2OOll' AbsernIoI~ ......-c ...... II B a'ld T lrllnI AM. ., '* .... ,.",,1 ........, . . . . . . b''' 01 0I'9fl d NPI,lc.. AM. l _ 12 1\15. 1395, M~1\l GE. Raw~lfOl1 .4C Gt1i11 P, HiImeI1 p. +i:J.IIslon RS, Kay N, SdlIewl/Iz T,., ~ N120051 ~lo;c:n-.!ofmor>­ ~lk8I~BrJ~ 130 J2S.3.'U 13H . WiWtIllt P, Mlehau, Jl RodIl"n J (1991) PlIilacllll"~ 1Ptl-1 chronic I\'lyeloId leulc_ (CMl) ~....." 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R. 58, J051-Hl62 a-g 101M , ~ GV. ~ A ~ ~JJ, JWioIS TuM R3Wrta"8fl'f DIhI G. W8nlliill HJ l20CIfi ~ ~ Iolud¥ 01 lIB ....,. hIslory d ,,~ l'IdeJ: ....,.,. to dIIlct "'" 10 aneu~ III PtdtM1C IQlUt to,m. pllctiMi: ...._ a PIcIIh: Qrc:cIcM}v Gn:lup L (2005) 11IaIopa~ /6iIll.Qs ~ c"oo,_ • tlJctf J ~ HImIiIoI 0nc0I II 1130121 1401A ....,io-Slbero JI KIacII:* W ~ A caIltt-BooudIu E, HIfllIt L. a.IaIl:I C Sclwnt1 R~S,~J RlemkeJ IlMI'I TF, Berge!' F. e.md HW ~A.. S, Frank GA, K3p1ant>klyB IB M6llw P "-wareadl RM ROdIgiir T, S\IM1 H KUppm '*"' Hat15mann Ml Siebert R Dt R Medlaoi,m l ... M'*Il~ l ymphomH (20061 brBAkDOlntl ~lfKtl rtg omrT1IJnoglob<Jtn loci IrlI IWQmenl If' fm::jgkm ilrTd R8&d-St8fflbolrg C&IIof d'I!~ Hodgk;" tympt1or'na, CIInoef RN 66' 10332-10338 1402. MAl1inel ·CitrTl&nt JA., Vizcarra E. Benet I, M3r1J9ilI1 I Tem! MJ, S<;OAno C, ArOO<\& C, Tormo M, ComN AM. Gilrda-Conoe J (1M). Chromoscm~ CI"'OQ8I1'ltIC rll'flOl'lili inclUClld b~ onteff9l'OO a!ph.a In ~ m\'floPtOli!etalive dIaorder \Il'IIl'l ~, T IyrnpIlon\lIIfId lne C!1fOmO. IOlNII ~ 1(8 I 3Hp l 1:~12), lBUkBlTlli I2 999-HlOO 1403. I.larnz A, P.ltIluiji S Vilamor N, COOIne< 0, RonMn M IWIIlkl M, ~ E. ~ E. ~ £S (200041 CklnII T- '* CII~"~LJ*ienII'~ lc9c_ ,*""lWld~..alyaI Am J s..g PIhlI 2lI1M9--858 I~ , ~A.V ~Iol e>.>IIU C3pJlO R ..... E. e... £ {2005) F.- coe. ""lllIl'OPiC~ pr'lII.-y ~ T. cal IympIIorI'II iIIIIl ~ ~ ~21l281--2l1$ 1405, MarutIo AV VeuoIl P , . . . . f Bonnch V Caclula R. B.r\I E 120051 POG-\l481 8lood 101 ~ll 1 ~ TO. " ' - C. ChocI A. JAeuoe O. K.-t 1(. CilnIa L Vall E Kerl H CePcJlIj ll2004l ~b8ak-.-al"'(l«l.Ni{T· 11lP35 tall . Maasclna C ~ K. KII'l H Cetrorw -'Y (pKtI1 In10nl d III'\'WSIS lui'iQOlOeS- ~ fI'O'. ~ IlIdy 00 745 biopsy Sl)eCimenIIrom .:17 """"'" Am J Surg f'afloI29' 5-50-560 1~12. Iola5aoro& C, KodBma K, ~ W, Abe R S/IunIzlJ H, PII'Od, A Kert H CerrQni l lUP<J5 erythemil10sus PilnnlallillS prOOJndu!;) t:llric81 hl$1~ and moloK:l.Wr analysis rJ rJI'Ill uses, J Cullin Pal~:12, 396--4G4 l a13. MassoneC LOlZ1Gf' ,EgtlertsF FFnlo:P...ct'4lI Fl, Cola C, K&r1 H Cl'/l'O/ll l (2006\ T~ ll'QI$an spectrum 01 'IOe m.YnliO IrlWlspl¥1ta-lioo Blood 87: 789--199 1415. ""'~ S, Nal 1 ~1 1 , MilIto M. UoIejo '" Vtuenaas R Algar. P Serd'ez&alO lol. MarIInal P PlIiI lolA. 11m) 1031-32 aIIk lois 15 B hQOflll l'wIOOg III Denil: ""'9"'al ~ ""'~ Am J P8ltd 1~ 1583-1589 (2005) l\uIlu5 c--.IlIJ~15J21"'215 14111. . . . . 5 JanlIol.H........... f Mumma! .. WoIarI·W\llI B LUi8IoS S. ~ I LIWA ~lil. .lIftIIF..ICIIltl!I' 1__ LladIak H GeoIgi A ....... V w.- Iol. 8IrIMc:Ir K K...- YG ChcdI: lot """lI Pill• ..,...... ~..-x:.-a." icUlI dWol:I'iIoc CII _ n c...... **" 104l).1111~ we, ~A~A.~DM l1995l Of _ ~ nl RlctMr" "I'lOO"""'' :e...,_.BCfII,.... ~"lI"~~ AmJFWlIll 147 207·216 "'-UIIl:wtIIar.-- 011 and""'~~~fIe III e mDIpiUogK: ~ and f'IlOIlic. "-1U:l¥ ~ 50 ~ Am J Swg PaIJ:lI2lI' ~ 1417. ~ P Telletl A. o-.kl GW God:wg SL &0 J IQglBnd He Jioal P (1993) Thll Sqo~. , IIMl¥ of 43 ~ ~ Blood el ~~--. ncI reQUftICI for ~ Iratlli~ 85 31571-3618 1401. ..... PI. took AT SCtnIII s.... lie. PIlIWo J. $IWAW JJ ~ AJ ~ loU flmPNP9ll6) ~ ~ ~ III rr,t:lrOlIbtrl cybJII'eIIC ~, .., "*' K~mem l.Iecl'ola-Gn9O"OO f Steln H DOotBn B ~ C (20021 ~It; B>:tI'MIlId eAin lWld ......B . . a 1laIrniIn. or HodIJIon ¥'Ap/IooN e-h I/lmu.te prokilIorl8lld s)'IW' p ..... NF~B EmboJ21 ~10A""13 "1'. ~A. ~RG e-....E I\rlowIB [)l,l (1M\ ~ ~ gan. ......... m/111 necr\lIles . . . 00J,0n s~ lOS! Qikhn, ()lCClIDgy Gtta(llCOG) ....,., v.. .... 1 207·215 HrllM ~t 0 L>B\Z A Jundl f. ~ II. 1 4168. ~ S K.....- I,IJ 8l*ir tH, l..arniI f H:BIIIlol to1 311-31 7 10&00, ...... Ail ~ DO 0IaI'I ~ ~ EI ~ JA 8IIrmalI PJ IlMt lolA. ~ MfIII9I JO 11995 Pn:qlauc ...... ~ ~ ~ '"" '"**9C pdt III llIIIa*r ~ Illoo:l or phon-" N~ Onmunoi sa.n ~ A£lF.1 n Id2 . - ~ ~ ~ 6 <::eb III /to:lOgUl ,.... ~ ... dIrioIlrom 5UII" 01 6011 ......... ArnJPaI'CIIIS3 "'ltl4 1'20, ~ A.. Gemwog U ...... _~ ~",\IulIU ~ A ~C. ~ Y, T..-- H Y llIItho Iol s-. ~N ...... C T~1ol 2001) ~, .... 01 CMIIlt b""""" C-"j'IClPDI ............. ~ ~ t o ... Rems1efll EO. SIIIlr A, Sole r. SlillTllltllpOOJlr)a K Thlfblemoot C, TfI,-e~~ A, ~ A. GmIier 8, Pina I,IA 120081 $pleoc ~irlilllon8lymp11omapropotaIab a reVlIOl d diagoo5lie, ~ and. . - . . lie ~ L..... emiiI 22 481495. 14:10. r.IMbJleI E OoovsIJ.,A,ni;onlIIo '" MediI R. Gwaa MJ. tt:IuWm A.. QJt 1ll ~ D (199011 ThlllftlltUlOlDglallJ'olil orlkeldilordin and pI'l.lCIOIOlI rJ ~ 5Cllmg s,sl8mb tie ''''''''1U3. ~ N """ M ~ L 8MUOI R ..... T ~ l a,r.n J ~ U. NiIISal PG MI!*rlaIl F.,.... l JdwI5sclII B (2002 1"l:Ioltll...". ~ *QI ani ~ laaIoIllS III 1Wli•• f , . . tel a'lll cl8 _ idII Xl*' "'l"bd ___ r - I an. d. 7tl1 ~ 0'1 5098 ~ ~ tie - . . . . 197"'2001 l . . . . . ~ ~ lWld """* _ 197f>.1993 _ ~ /8llIRIll fIl 1t12:J66.23T!l "'*'*..... 14.)01 IolaU blian ~ 21 I7S--6lI6 lUl . ............ A.Y ~JA LelG SogwJo E H.- fE lIT 8ur1Iain 0 l(8I\'lIiI 0 Uo .-s IIIldec! tI¥ iT'UIJcI ~ ~IO~-.ove­ n 2llllA-2813. WHO~.-tO'l~,.,.... anaol .... p1(11ogo<;:11 ......... 'tbcIory _ 8CUIIOng ID lit FAij ~ w.. K8Pt*t ~ , ce"" Mr· _ _ AlII J SlJq P8floI23 1Jll3-.1-400, 1.f22. ~u- T R _ P, ! raellMl H DatlaiIay R, Coatandou S Xadara A.. RJdIBu A Bens P 12006) ~ paI/IophyllCllc9Cll mecIl8rBre rJ ~ IItIl aetuIrIUilllM fIl ~ aocI ~ aidIrttiIIII: II'MIIIIiI ~ by miklchondnII DtIA dIIiIlIon ......-.:I to E....J~n, lllS-tN 1.21 MlI1ule1 E 12006) lrrmJnopharlOl)'Piflg lIfId ~!iagnoIiII 01 hairy eel ~ ~maIoI Onool C'n NortrI AA1 2U' 1051·1063 1.:1• . "Mute" E, 6nlo-B.bapulle V, SWllI'lSbI.o"y J, Ell, J, I.loriII R Dt>ortlan C, Sfmpwa A CiltOYlky D p99 11 CIk'1o;BI ;oM laboralOr'y fl'lllur8l 0178c-. 01 T·profrnph four rtOd h\'llroUl sel HlStodllwn J 15695--909 142ii, MatutB1l E. G~ rClii TJ. O'Brtff1 M CatovaI ~ ~ .....-.odoolII B--cel1Pl8I"O' 1435. Me lornarI DP PM:y MJ Jonaa AV CIOII NC Me W (2005), cmnc ..... ""'*' ftJllI* - . . - WIllI In - = - t V617F JM2~ ~_""-' ' ' '_1llii:JgQ 90 1696--1697 1<4Jli. McClai'I ilJ. lM:h CT, JarIKIII fill JoIhIW. Pc*U 8M. Hi.*tli!cI'I R£ IollolJlh¥S6 12000) ltilcUarn\'lllb)c~rJ ~ ~ '" tNi:lr8n """ AllS J Atxlui' ImrTU18 Detc Sj'IKt 23 \52·'59 1431. McClure Rf. Dew8k! GW. Ho\'er JO, IiarIson CA (1 999) 1$OlII8d i$ol.:t'IomOIOm I1q a ~isliod type or mo ~lld myaloplolilllratl.. doaon:lerlP'l'lyelod'ysPlstJc 5yrodroma *'til an aqgreMIW <:*nical~. !If J Ha!lmaIoI 10li ~ ... ~ McCkJ re RF, Rem&ool ED, Macon 'Ml lWwaid GW, Habermann TM, f-lollnng A, Kwtm PJ (~) Adull l3-ceIl)'rnp/lOmaS WIth bullun· 1~J8 . ~ke morpt1oklgy am p/'ooII'IoIypicy and geno. ~ het8roge11l1011$ with ~ oiIr\IcIl t>eha\l1Ol'. AA1 J Surg Palhol29: 16!l2·1680, l.uBA McOooneI TJ, oe_ N, Nurez G,.hlegef U. Md<eam JP, SJ (1989) bcl- 2.+mrnunogiob\llln Ifanagooic: ~toI64111.'2A mIC!I 1427. ""'lute, E, M iJllioJIal'~.C1ll 57 (19971 OehM.an or 1ClI1tI blphenotypic ""'..... ~82.f>t-ti6 1421. MaOJIeI E r.b1II R ~ K ~Ihan A.. CalO","-y 0 {TWA) Tht ........ ~ ~ IlpIwoe II""QIlomli ..... I/lIhjI ~ lWld ill ..-....ce ID" drf· . . . . ~.OIholir!k*l~ 8lDoxl83 15M-1562 l a. """'" E a. J o.c. 0 ~ ~J A. ~ R IiantlIrl T L_O ~ G J c.o-y 0 (111116) TNonty 12. . . . 'lllNI ~ CU -1il'ftOCIII ~:~--~ cliIeII '"" lalu*wy ....... ~ J*ienII BrJ~12 382_ c 1U9A ..... E 0.:. 0 ..,.......,. Iltt9" ~ GaIIl.aNhl E ~ A. F.... P.FranooV . . . . E loIoIItIOy ~T I'\iIn FM Kor5mejW derrmSlfatf exlaMad B elllI "",,"V(M and n.a8 143', McE""- S. MvIogan C GroaI J SproBIi 101. Rir\aIdI A.. Oenyel G Menaa/l A.. ea...... S. Billdo C, Dilgna-&c.-llIi ~. IWnnI, Sa.., G. Cotter FE N'l ebc 0 110001\ /.Iic:nwr8t"~~ ~ . . ~ Irtm lne lKllE type 01 ......,. lJ.l1}'" DorM!s ~ apack \Mail._1Q rrwl<ar, BrJ HaolmiIIlOI12S' 129-142 1440. ~ JIA. Crook T F_. AnIlrwws. EA ROl)':U Iol CroaIInclS Btoob L Wh"'-" SJ (1999) ~ ~ p53 9"" "lIlIl*n 1lll)gl!tlS I poIItJIir b- ....-...0'" <JdI*III III . . IWI""",,_ 01 8ltfanc:e:I ~ ~ J m.as.l:llimlftII1'1 \llllaItIc ~ ........-.g PRJ,ME .. e "* 317-321 1"1. McMmiI 1M PaiI (11m ClrInc .......'''''''''. . . References 407 WI1t1~<*1it1j,rIOOl~ ~. aI and merrtIr_ 9l,lI'taoe nm. c:tIarac:8lI. bel M1 J IAed 112' 58&-!l86 1442. I.l(:MMa RW, WM/W1g1(lll LT. ~ DB PorJo:er U, I(fOIl SM (2001) 01 ~ ... ( ~ lllecu'lll:Ql III 862 lXII\MCl,llM I;lOre IIWlIM ~ by okdor b c.,t:wn~ llloocl96 2496-2501 1«1 ~ P. f_ LM y~ itnnlIlIr>phto~ ~ WS!kJlleo'.JJlol. . . . . FBs..~ JA. DuCWI 00 "987~ SlIge IH loIcuW Iylnpi-.. dInlllt , _ ..... ~ t:t.1....~icliuIl• .". 1'19"'*" J ClIn ~,1lIood1l94514~ '45<1. McIloN(l996) TII8d'oers.l,olBCR· AIll. fuu;wl prolen and !her IWlJOt>5hlll 10 ............ p/lllAOI'pl , Bbld lIB 2375-2384 '455. Iolekl N. 8a"les OJ (20011 Ctro'lic myeloid lIuilJelnl8 III I Il'I(l(/ejol _ _ .....,. IuIioIIII'I tunan~ NalRev 7 «1· ean::. , 456. '" *-' !J1I"'lOtj18s ~ ~ ~ il t:If _ _ _ """ IIrge ~ J tin PaI'IoI40 1445. MctUn Mf, 8Mbd 0 ~ p, GIwe AA ........ C lUll 8 0.- 0, &4'~1 PoIleyloAl ~JT ~~.~I( M (1980\1 PNnon TC HIIIM B 2OlX> ~ .. ~ ......,.....n ......,...( ~ foI lI~rhut,-- BrJ~ 130 174-195 1416. McHiIJU Coca- 0 PI.. T_, G e.-:tl J HoM G r- C«II't RN 1M LY"~~ol"''''''''' Ulg. An ~ T- AIdlOlnlllllcll 132 14ij.t "" fir J tWmall63 311-387 ttIlgde ]V, ~ 00lMn ~.,. ~ 1ll'Il:liann'-a~_e.or­ ItIII pl'tlgI'IOM NIl n 1'3 ...,... *""'" ~,,~"""""myebd ~. 8Iood I III 1262 1270 144S. ........ U 'l'1IlKl T ~ ~ SC Elwood L 1,1, .)MIll ES (1981) MgoacenlnC ~ IeSoOl'lS. • ~ .....,... 01 w,,1Il oatS, tUn Pilhi U Parrtw1l .... lAc ~y D (1)61 ~ B c:el1'J'rnpI'o1li will ~ ....,. '4sa ..... ]V, . . . 1i,"*"'0A,~ P1~R-A&. c:I1fllnc IIJ'IIbO Ihe IIISIlfIg .... ...., t!'trtnC "',....... «yk~ll~8 2!J8.. '459, MIlll* I B.nr AJ. ~ S. C a.tI1F ~ F. Dcndl j{ r.- sacs- . . . . P \2(105) EIilIlIek -..on of 1 -.pan IN(2 . . . . , . . , and _ _ pho&pflo-JAA2 Ktol ., he MedB-l ~ IwmJl/'IalllI kwI llIood 11>5 :IS35-2Sl2 ' 459A. 1oIelZnef t 1447. Iotill.o AI lIl'dI DC. RK.. ~ K IUnelI AI( GlIIt RE12007f FlO ~ _ "*"l. ~ '" w..- t.IA. t.konl. CK ..... P /20(6) ~ Q/ he JAK2 ~w: """'*'U ......... 11'I CIasSQI tiodgo' iy'nphDr'lII anll pmwy ~ B-oeI tyro>. DbonIa ~20 157.15li I.... t.IIrt;,e DU ItoIn't HP. Gr>e"'>MII' H 1........ 1<1. Kaumarm JJo ~II,ng E ~ R. K~ RA (2001 ~ P!'In8ty ~ noda pllIwnacytom.Js (pla6"\ilC)ilc I~m· 1II'cln*) Am J Gin FalhOI115 119-126 t 4 1. Merdler T Coma' M8 Moon; R UI~tte M. Nguyen KF, G'ess'" L. F LelliIncT, Dasll1',1Jt r., llerger R. :n-1I~'157 ~ 1449. WIIeciI SJ ~ L. O BemBrIl 0.'1 (2001) InvolMMnl of a IIuman gene ~ to!he 0r0s0pr0IasPerl ~ 11\ In. IropCIlllyOIin 4-ani1>u~ ~ 'IrI3H ~!woon 6100(I96 12Qli.\216. 1450. Meektr Te Hardy O. W"mIln C, Hogen T, AbnlmI J (11190) kll_oI\IOI'1 of ltv! ont9!loo1<",·J ~ by ~ Irlln$lOCa· !'()11 Blood 76 285-289. 145OA, MeleA. ?\lIIo Andnzz' C PusM S Don! F, I.\arftclI 1<1 , RapIOtllll 1<1, l Maot:I!IIl F F~ S (2Oi'JJ) HoIpe~tis C OIirulIlIflCI fkeI nor>- Benilaz J 120041 GeN .~..,.~~~ .., gaon or_ t:J ganMIC_ _ daKa:l bI' lXllI"4*~ ~ ~ GetIft Ctwan:!somes: e- 4' 35J..J&5 ,0452. lHkld; .... l.Jc,tJI; JO (1999), ~1""~"Wm trod....., , * . , IIIl ~ ......._ d *'*' IMI~"""'" llIoodiJ 3111. rlJCUr'enl It1;22} tran$loCallOn 01 aeulll .....eryoc'jticlB\JKemia. ProcNat! kad Set U S A96 5176-5779 1462. Merlin; G. SlorlIl MJ 120061 Osngerous tmatI EkeI~ . Blood lOll: 2520-2530 1463. Mesa RA 1ian5Ol' CA R~i ,u m;lf SV SdlrlJtde< G, T~tten A 120001 E,alUIlliOfl and c:I~ corre!atiorl!l of boIle "''''lTOW angi rnyelofi tvoSl~ "" Ih m ~ rMt apla~ia L~ ",ero.~ ,*-,1,(2001 ~fIndII'Ig tJ . . "F'1L 1·PDGfRA IuwOll Il"'II II ___ = 1rNInlInt{IWG-MRn LtlUI< Res J\ 7J1·7~ 14S. ~ DO (1991) 0ats0/IcaIr:fl and _ _ or mastIIcy1oSIs. ~ 'iIaIlla- J IrMIIl DennatlI96: 2S- J ~ t:lIrm*' 96' 45S-C6S l t11. ~ E leGS.j (19b8) l.ecUe t63. ..,.. It. Rodr9Jaz It. P\ql we F (19iTl E...-and,.. ~ ~ l ~ c' ' • •, al'" or !QIpmI or . . 1893 EfIlIIiItII!llll!iIlIioll ,... ~"'*Ql-...at:J~ 1461"- .......... E 11863) ~ pahJII;:yt ~ ~ IQlII .~ IIY'IbCI ........ anll~T-{lIII~ ~'1 In... 62 31(1.312 1479A ""If; J at a112008i, A 44-~-oId ..... ""ltl fBlio;lua Illd lawn, III II'oe pdUI1I1'y .", ce-ebIIum N EngjJ!.led (" PAlSII 1180. Mri.o_ "', Grots N I1ailgar " f'oIId'llI' U ~ T. GaGnIt H (2002 ReepotlII 10 ... ba1 ~ 01 l!UbsySIIm ~ eel IvsIlocyIIslS an ~ ~ nicalOf Ued Pedollr Or>::d 39' 58'''' 14n Uinkov M. Potschger U Grois N o..::.rza WIl (2001) Bone_ ~ ., ~ 011I !'IiIIocraiI ~ 8Iood eanc. 4g. ~ GMt...- H ElInIU H. ,..., L DII V_ F, AuIIIa.~ WE wm_y G SdwI'IItz N ~ C 1oluIII· . . - 1\. HOOgII E. ~ SJ 0 - . F OOIV'III' H SdUd I' ......, R ~ 118).\1. I t&2, ~I ..,. . . . . F'elIIaI' BIooa CIocar45 1483 ""'*' GO. ao2~1 O"FaIon JR. 1*r kJ (1992 ' ~ dyIo-. ~ JllPiII» The ~ II POOlS ~ N ErojJWI ~ W lfjS1.!. SyoIIn; _ CII MIl ~ m i . we.,.. C Sdw...- B JalIoD S, SnN _ S. ~ ,. SdwIl\gIf S Sdlocn C, ...... 1M _ 0rlngIrI JJ 0. Boar IlL . . . . . . . ~PllIIoI25 721-130 ' 415, LlIuI~" ~S P\aMIIt R E_ t.lG. ~ E KoIN U GI-' J ~ F lJIl SlId U ErJoItt C SzezeparlSlu 1 NIOgIJ f+( ~ BW ;<;M 4*' H BrmyHJ lurIIJ TI' ""'*_ myeloilYiplaslc Of """""'. . . . . .'t'e ..".. ~1leU1L\'flIfIlOfIIlI9J5.t1 1412. r.IIo.1IIlI5 SO.!.4cK¥N RW. "-'ltU" DC, 6n.ming RD "'Yl'bd ('~J ~ ~ IIuk_ and nIyIbl\'lPllJllC ~ dt'tmlI a etoW:aI arld fI'lI'.lI'P/'IC IIuay t:J S5 BIooa &5 1173. M>ch.... Lm(lflllH.... J, Eryohomelage tIleS 1J1i,1l·1312 JJ, _In GIMI'&n FJ, .an VllIl HH (1996) lhrorr'll:dic and ~ rna~.Il50CI8ISof~ ltl(llllymphoma22Sl1pll1141-56 '41 4. ~ Ichor F (20011, C~mr1k; myeloi-ll WBmII blasl C1\III ...-- from pI1)9IfliIclr; SlamCeh251 114·1118 CO. LawlI J (lWJ ), Trve hl">oeytl~ Iymplloma 01 !mal 1..15. Mlllttiren M. F~tc!lI< mtesllne, An1ll1!115 ollwo S·l00 pmt&ll1·po6Jt,..,. 0011ur(;l)ll1~, Am J Cion (2007) PmTlal'y~(f'MF).POSlpcly­ eythetnIf _I ~ 1posl-PV I1g ~ for ~O$IS ,~ trod J ClIrI t .t6i. MIIIlgIroIhG Wall. C Score J SIIbeo1 R ~ S IiIltr*tl C Popp ~ ~ 1 Eiben I' ... . J IlUer t.IC easel IlarOf,j G. ReIlly JT. Dupriez B Lelll rle R, IlolMe-Kerdiln r.IC. 'Nar:IletgIl M, Campbell FJ. Sil.al RT, Varvlll()Ch, AM. Deeg HJ, GisIIInget H. Thomas O. Odet\ik.e 0, S<::>tlIIl'\l LA.GOIlib J.Hel/lO:l< E N;merSO. Kan!at).an H, OriW A. VM'dirJlan .NI. TrneIe j Tf/Itln A s..o. Clog ~36 Blood!l6 3374-3380 '''' CabnIIas 408 References 0"llXII3 14«. Me9.a RA, Vtnlo\'&ek S. ClllVilllleS F, ,.. among CIIIIgIIOMS I coIlaIlorlb.. Ilud'I IhlI ~ ear. andl'lllhcJt,gy Pn b" ~~"""'.~~ .15 1216-1. _arl8bo 11 or phomiJ The....",~ ~ . . . . . . gftllCl P ~~orfoaaMrlym­ MelD N. CMo..-r. ctwlllic Iyrwpho<':)o1Jc ....1:HfllIIl and prolymphocy1Ic IiIuUIni8 1 CloniaII • ..., Iiob ' 451. ubi! die 1l1~lIQ'I4ki..-e Verdauung bill witbelto&en 1t1i9lllll , Alb~ Inll U""" Wo«! 5 141 1461. t.IIIIII C£ NaI'r«llrI BN. a...u 15, WirlDllrlI CO,!,lam RB. e.t:oI M ~ CR.~CC [honDO MoIIITP(19115) 118malopa~ 0na:II5 861~74 1444. t.IcMIrAa OT ~ Mo\. e-,. PO CllItIIfl RJ ......... If) 200'~ 1.1.1(. poIII'" dA.- lqe lklII ~ 01 ... , • I)9Il ill S60 <;lISe'S 01 aggll59M! ~ ' I Wltn faalu"" 01 inllfd.lgllillllg l1I!lCUlum FM~ 100' 285-292. 1476. M!ettln&n M. Fl1If1S1i1a KO. Suen E (19tlJ), HodgIun'. ~, Iymphoeytit pIfl. dOn\i1 ~be ~ io:NolwJmelIl" ~ ..... ~ ~ 1 8lld f'AIlI\Jl'*1l ~ 0IS0rCle01 6lcxxI p<~ ~ RO Var'lg B F.- WG. ""' Ell 120021 Prmwyaa-ulotollir ~ .. - . . . n I 01 cinoc.aI ~0JfIlt0. _W;(lI,.,d"", lIrld~""" ClIrI 0n00l20-&41-655 1486. ...,.,. J ~.-:. f'IIfI)' JA (19ll1 Fokit cerlIW ~ t:J .. II t:J '1'_ ~ ..... julda fWPlJId. c-. AIn J s.,gPllIIoI21 .48U88 1411. ".....,., F 11993) The ~ Il:8Ila'lO or ctIllnc ",j'I/oIl ........ L"" SIIfIfII l' 11·15 1_ UIIIIIrI8fl F Levwl G. Helsol PG hdL(1916) Non-!;nJom~'" kin ~ dIroroc myeIuo:IleukImia. .. J e.l ~ 11 1624-:J';I '489. MI15lildes CS t.Idd.... OW KlrWII S ~ T Ctoau/larl 0 RdIn10n fIG """'!ho He Anienon KC l2001) Tha". 01 Ih8 boolI ll'I¥TtlW mi(:roe,wir(lMlllll .., ... ~yliology of my9klma and I~ IIgIlII canc:e ill IhlI dlll9lopment of rruI eIII<;Ii.. lhlnpiel fiemfloI Onco! Chn Nt'tVl Am 21 1001·10:).tVII-1Illi '490. MltliIl K, N9I1 A, Feine< H, Sdl"* II. AIIonIIO F ( 19lJOIl~ ~Ior'na\;). toll In till aCQ ulled irnmunodefK:iency I~ droma, Eildence ot E ~\eIn·Barr w~.,fecti;ln and 6-c" " cklnal se le<:llon w , t~OUI m'lt 'earrangemeol. Cancer 65: 1345-1349, 1491, Millis ilJ, StainR, Rappl?Olt JM, IvU:r JH, W"'Il5kW1 HJ. AIpeI CA. Smilll6R 11989 ~Bncl~~(l\,* bone rnatfQIofi "58 1492. lIa'1spiaI1lalo1 6loud 74 27,* MrNI H. Ta! gene ., pyoI'IoIa>:'M«>:Ir 000:I0gy62.241·250 10 3. ~ V Kunyarn.a K. ~ S ClnlaMI s. SaI:afnajQ H, MItIuo T. En'lI N IYIT"(lhornI 118 <4Jl«J20 ~l~T~~ '41& ...... TP Grog.! 1M 0IIibI0v S. Ohno R T0lll0lIBgIl '" (20031 C~ '~ ~ acute ~ . . . . \N.IL ~ CI ~ I'tllgrnIc ~ or ... K>o61~ llfOIrleo-.v.e Mb9'" ., . . - non,~ a ~ ~ Onculogy ~ ... ~ 83 1400-1-'66 1419, .... TP lJIlpman SM, ~ Ct.I SI¥"'*' OJ Gqan 1ltI 1988) fV,.OR ~l _ jl/'IIllo(ypt lftllK;O llIItconII for 1iodgIk"'. ~_ _OII~.J()n witI ~ d)1llll$oa Jap8fl ' - - ' _ Stuely Gn:tJp-AM. 92 sll.C; a- Haen1at11120- 56-62 t f N . ~ G f't:Ipcw SW 8 ~ S, Reel P F1ssokI N Sd\nltJIli. R RJIz O..... I' L....- F (2OOIj AID ~ I(lenIiIIl$ orI!IltlIIl:UIr lqIll 11 ~ ptI(:UIICf5 ~ I'IIUI IkeI ..... ~ 107: 24ro-2H3 l oWS, ......... Loft8'd C, 00nkJn T co GollIITR. Shw1Ml2005) MoIea.IIIr profiWlg 1521 . M(ll'Il;I WG Kco1lI\ PJ. Te"eo /I., IIIld ~ GI di111JalI ilIfVll 5-a11i !ymphoma lde ~ k l M II . prim;Ny ",trtvascuilrl~)~ Cancer66·474..0419 lll.lIl ~ 'Sil9O"tll, Blood 105 18510 Hanson CA 12002) Distinct bone mBffOW!;oIjIn\l$ In T-QlI ~ ranular IympI'IocytJc lBulcerroa ~ DyP1W,,"1I sectioo~liOatll Ooo:lnwl RF (19'XlJ. lmmu~,ic:8I IIWoes Il'IdK:ale 1Ilal mMgnirl 1495A. ~ M AIgiIrt P Matell MS, ~J.PlfIIQlIlE FfWlOMF.c..d'lo u.g.&alI~ ~ Fl Pn ..... (2OOJ1 -*'liI1I rae , III dIIIerenI J Suri P.-o ~ condolIOnI 27:1l'J5.i02 1496. M~IeJO M. Algar. 1". Mateo MS, Sandlez·E!ee1o M. LIorwl E. MOOtn,'I MT, Pins WI (2002). ~ $ITlIII B..::elIIym(lho/I'IfI WIIh p'eodonJo ... ~ red ~ ~ • diIUse __ rJ ~ "*\,WW zont ~7 ~~060:22·30 raobust SlJbtypet indud~ 0I'Itl dlSfa<:terillld by "" 1501. sIiln 1orC08.lIA_l trld lP'~ B Illooxl ~ S. ue-l~ toa-D,E-..J .... F fit.. ~_A. WImor N Menno C CImpo E. ~ E (2003) ~ aro;l drIociIl ~ 1II bcl-21IgH I'NITIU'lQllf1'lIII\llI in !olloculer IytnpIloma.leukl~44 11·76 1509. MotItMrral E Vll.amQr N. Re\l&!'l&i'./C. ~ RM, Tases 0, Bolch F, / .268--21. 1522. Monca 'fIG IlIealn ~ 00gIn .... ....... '" K..-. PJ(20061 NI(~ "'~tt..-.prfttll)'lI'l~T.(lII ~, "'igh\ ~ inlO pamogeneti$ Laulcamia 20 883-8&6. 1523. Mo!U WG, ROOngllllz FJ, Hover JD. Kurt>n PJ12005) CWIuselat9' B-c:elI~ ""II 6*IChYe peIIIems II spIent Ind bone "*"OIO~do~""" ~~-"'-"~or oINoDCISe$ MrxlPard18 495-502 1524. lbrII E. e-.a C l(IeBy C V...... JHaern&ll93: 111_116 15l0. ~ AV. RidIrh SM. RoOonton HM, St",fford JC, Gibson BE. , Klnse~ SE, loon TO, IIQra A,J, Mtlo:hel CD. HatTison CJ 12007) 1491. MoIlI,o M. ~z J UorII E, s..d'ez I" CImpo E . . P CnHbIl E. ~ E. Pm W. 119%1. ~ ~ zone 1ympIlomB, I distinclr;e typeof ~rade B-ceII lymphoma. A dillol:opalhoklg~ Iludy of 13 C8S8t Am J SurgPIlIhDi 19 1146-1151 1498. .... P I1BrTmIr1lB ~G. tIops(! Ar;amplII'_ sae, II 258lMNf* Br PrognDSO$ 01 o::hihMl.... a:ulB ~ lalkemia (AU) n MId'InvroscmII ~ ... Id e..-.aLCanai8 T~E.~ l. LauBMO Id(0'0031 ~"" V3I18t>IM lor mill'9flNlI ll'artliformation tn 452 p>W9nts WIf1 as, mplofnalic IgM rnonodonil ~lI'ry Sen-in 00r;0I 30' H2. ttt. 1525. t.lorriI SW UN V_ _ ldEI ~ F i1987) 0Il0I0cM '''P''I'iOn III lllHC ~ I. . . . 1'1 &oaIIlym- """""01 c)loOl'lOUn. 2110AMP21~ 5Iood 109' o...-KG ShIl:wcON. ~ [l. lOOllAT 2327·23lO. 119!'itl F\IIim 011 ~ 0iIN ALII.. tl. ruc;lelU' pr-.. gttfllI NPld in non--Hodgl<Jl t ~ Saeonat263 1281.1284, 152M. Morton lid. 'N3 ""*' ~1lI~~.InlJe-:er " 32-39 14". "tlIIf p.lMmInlIr B, Eblr1eI'I.(;ooska M, F9K:tllIIr GE.!'lofmam WJ. SdlfTHttadett H. Otto HF (1988) Pri rrlll'y ~ cIMr I;llij Iym(tlO'l\II 01 8--cII type V~ Arch A PIf'CII Arwl HiAJpalrO Q 1M2 1500. UoIIr P ~ G. Iobro.J1 F LatMllel' B ~ M. K.iIIeI S. 0Irtan B (Ullin ~ 01 do!er CIIIIl)'llt " ' _ correspondl:'lg tllBr· IJlflII sIBpS 01 B eel ~ Blood 69: 1081·10ll!i, '501 , UonOB l, Warn>:" R. Rosao J j19ll6) A IP'*Y ~ nodB ~ .-ill fMlures . . . . . . III ~ 011I dIIIarwe114 _ Am J PIh:Il \22 w.... '*'*" *' A ,.., "'.." 1502. e s.nu. A Beng D. Re«nlo e, ~ 1 c...,. JL dif At9'I' e M, ~ ~C ~2001) T~o(low~adll\jllsttlC Iyrnphood !issue Iyrrlp/'lOnla in srage I wIIh HIlia;ttao;l.- pyIoti trPcabcn l.ln£lB'I1I ~ . . MQl.-aI t'IIlliogIc ~ ted ...." ..., ~ ~ 86. 1501 ~.fl:07IgII'I M 1\l 4'l*' R, StNuIBr 0 ~ T,Vtrl Roos! D. Sd1IIIIrC, ~G, WoesliefOO QeI;:qn--$dlkJler M (\ 999). Pnmar; atrltfal rlllI'o'OIIS S/'S*!' Iymp/I(lmaS are dlln>'e'd from I1"<'ml'lllklenler B c:eIlaana IIlllM a~ o.JSagll 01 .... V" ,.. J.l ger-. ~ Am J PIllhoI 1S5 2On- 15ll4. ~llI"II'fI " - I" lot ~ R ~yK ~"'11f1991 "-'talm 1II .... p53gana II nol a ~ IMUe 01 Hod9~Jl If1d RfltIl.S\1I(nberg ctHt '" Hodgloo's dlsBaSll, Blood ~· 17 5 5- 1760, 1505. ~or'IgIIl M. VW1 Roost O. So::NIe< C. w..- 00. ~ M (2004) PmIary ~ _ 8-alI ~ II . . c.n...-..",...... ~tIi1 ..... toor-=~ BIoodw.l1_1B75 1506. ~ fit.. s...... E PIw s, Bllatt M 8ertl:lo'ulII Me, M V,vo A. 8nPomalit A, Roncador G. Fan; B, PIlen SA (1995), 80rlI marmw IindlfIgs further support .... hypolheeo, It\D1 _ t", CI)'OIIk.>tluo Inernull'fpe " II ~ Dy iI IIIOIlO(:lcrI- ,.,..".j 118-al1~ lIIilL~20: 119- ,~ 15G1. Warlc S Savq l(J KIAok JL F....miII<. F. 1<""'" P Woiwn .. Wu 8. F'IsquaIu(;o l. NotWerg D.~ RC. Cloll t;., P. Ladd C, Pd..,. G$, Silas G. Ham. NL Da'la-fll'l1lfll R. liab8mlBnn TM. Allar JC. 1511. 8, lMII.- E.. Altern RP. ~ RM, Owr.t.&I-AnkolUl KA. ~ ..".. ~ s.or. SI< ~yO('997).~ol the chronic lymphocytic ,",ukemia scoring 5yS11m "-'lh the monock>n.1 antobody SN8 (CD19b) ......J c.. Paf'd 108 3n--3821512. McnlP.l~E.&aP ~B 6""'" W ~ p Gc:8IIn S. 6auIn F GiMIItlredll C ll992l ~$ ana ,.. """"ol~~II"a rwpor1 on 80 pMen15 J ClI'I Oneal 10 1078- toes ""*' H;vtgIl P, Weisenburger 00, uret MS (2006), Ll'fIl"\M1a incideoc1! ~ ~ WHO tOOtype ....... lhIItd $blIe$, 1992-2001 8lot:xl lor· 265-276 152t . ~ 01, Zeltr>ea Ii) di~ In Hr:lOgU'I. 0 . - I.Iaur:tJ P ArrnIIage JO. DlttN v lids l-ClPfICOII W.... & Nn "p;o.mlol"\ly ()! IiodQ kin', ~pp61 MI cenle< "lft/J9 nongIIfmI'III cenII!f. deter· 1531. MuIaMy BP. Ng Vl, Hl!mdIet IlG McGrath MS, PallB_ic! nl MG (20001 1511. ~ P, Bb:ld 106 338J-.-33M G.oJdon F. ~ III '--IJIr~V Dollol6ant~. LeaonJC. ~ ~A~~,~Y C. Berro C Hem'ooueII S. PnD.. V (2004) llIlq>o9Io: .au r:J tefU'l'I ~ ehn Ie~ in pallBr1t~ witllllbscMulll erylhnxyIo';5 HaematologiUI 69. 11\14 .1196 l $2B. Mouroer N, Brin J, GuttIbrechI C, Emilo! JF. llldlo'n P SebbIn C !Ierg8r F 8c*y'" t.llnI P, TJIy H 8ouIIldIIIIf> R ~ F ~ P, Co6r B (2llCl3). ~_ KqlInB H ~ T l2000l l~jll&\lS "lures 01 iIWM"" NI( cell ~ wrth ~ 1IllOWis. ~0I<1i and lB VINS irlllK:lion CMOP (R-otOPl ~ Dd-2-.&Oa1ltid rl'Sl5lanc;1 10 cl'ltmothfrlpy 1'1 ekltrly PltienII wiIIl d'fIuse Iwgtl B-aoII ~ IDLBCl). Blood 101: 4279-4,84. IiIlliXl8ttdogy 37 363--371 1516. MOO N. Y.llalleY ~ t.I, Koba)'lll'h T. Aui J (1M) F')'oIIlcn>~ tym. 1529, Moun....- N, Br~ J, ~ C, RttyM F Glullrd P CQIlflOtr B (1006). EAonIlIlg . . ompecr 01 nklunab 0'1 bd-2· IISOOIIed ~ to CHOP i'l tIderly ~ "'" ..... IlI'gt ~ ~ ~91715-716. 1529A- MoirlIcI N,......... N.he J. ~ E. DflImef A, FelIBr A. ~ CJ E_ JF, BoualJdaliah R. BnsIy A DIebold J. HaioI.IO C, CWII&f 5, GlMlbrechI C. G&u'ard P (2006) Oncal bo:lIogll;aIlnd Pl1hoIoQic8I ~ in 151~""'~T- "*' ....,fAdlAl .. ~ db.IdiI GeLAl'" ..... C8I~ lblIIklill~ !h:lwrlg _1IICD5an:l ~1II COlO AmJClnPllllOl122 122-127 ~ 151' , Monee 1'fG, ~ D.HI..", CA (M11, The e~ 01 !he ~ cyklloxic prolein granzymeM by largll l1anlkr Iympl'lotyIiC ~ ol lXlll't T-ttl iIOd ~I( ~ ~ aage' .. ,,",ll*18d &ndIng -.nil ~ JtIlliIIlIirlg , . ~ II line doeOl\Mf1 lit J Haeo'rlIloI137 237_239 152(1. ~ 'NG. K.IIWl PJ. tlliOlon PJ, 15Jll. Mf6«9, K Htmnen K. (III II ~ A llbJrMBld CO 11991) CloricaI sign,ficance of c)'logeneticll iM IK:U I ~ mytlold leul.emitl Semirl0n<Xll2( 11·31 1531. M,llZf'k I( HeinoneI'I K. lawfara D, CImlI A,J, Kodur\l PR Rao KW ~ I.IP ~ RE, MoOlt JO. ..,.. RJ Sd'ofIer CA. lJloorr1fIeId CO 119911 AlUI p8lier8 .... (III 110"'O acW rny@IoId ....... JI'hiI Ind l{ll. l1J(p22: li23) ...... a ~ llI/lD)nlt to p.et,ents ..11I1 ottIei' tran'lklcetlOl1 5 Irl'iCli'Mjj band 11q23. a cancer !Iflllleukl'fl'lia group B leIJka6mia, Br J Haema loll 20: 1026-1 036 1535. Mueller NC. Gruffllrman {l999), The IO'I,trld~ol~~ 6IIIl Prad ReI; CiIl ~ 11 MJ.557 .......... .... .5 '1)!q33-pl1 2) eano. Res64. 2'6ol9-265' TIIlen A.. ....... CAl20(3) o.roiiili",01 lr-'ormabon 01 chlor.: ~ . . .1._ dntaI. morphologic. Iro;l cytogenIli: r.alule'. Am J CW1 Patllolll2 \-14, HoIAd-"J.OII/Ia'lA CIlegriR N... S. Ttrvyt-Feio:ltI.-. J (2005). CeI 01 <:ngI'I, \II"T"-' """'OIliJCY'C tOoIm1nI T-alii Il'lCI naIJ,Ql luItr --co'JI rigen t~., iI!I cases 01 gr.-.ul3r IyfnjlhocYlIc JIOfTTlaI cytog9h8llc5: are we ready for I PfOll' ~~ pnoritiZed m(Iler;. doi~? Blood 1(19 ( 31..u,&. 1531 uroz"k II( Pnor 1Vf Edloirds C IlIllfcuI:g G. Carrol A,J Sr¥ltr PJ KotUIl PR ThIIKS I'elItnII t.Ll An::hef lY CIigo.rI r.&o\ V~ JoN. Koltz JE ~ RA.1lIoorr'iWl CO (2001) ~1II~1flll rf¥:IlBQ;lar gentIJ: de\edl(ln (If 1(6,11 rtd 1(1\'(16) in a prllSPlldll'1l senn of adults \\'l!tl clB rlOYO ICl. 1535. .... GJ(2004· mined hy ornmunoh;,;tochemI91!'j Clf1 tlSSUOl O'I'IICI1lI'Tay. does not C(lI'1'l9Iaif ..rlh l)JlOOrrlIl1 palJrjnIS IO'ilh rellPeed Ind rUaclory Dl8CL ~M""""~""'~ _ _ _ lilT ..0 5 0lIk Am J SI.-g PlIIaI 20 7llO-7(,6. 1511. MoncaWG(2007f The~ typic It!Itlvtet 01 NI( (:>lIs and NK~ linage 1)'fflllhollroI,IellllIVe dlSOl'def!i, Am J 010Pathol 127 881-886. 1511. Morice WG. ~ Jt.I. KI>'\I'I PJ. l-W'IIonCA(2OOoIJ M caMoI-......: reIr4nOe 01 II'IIAIIonI; n ~presII(IIl d\llnget 10 llOIJIlOAIt m~ llMJ ~/!rTlilI ..., ~T~P~S. 1513. Moreno C, kq..... M, Rmancla C, ~ A, 0uf0lIr C ~ F. MaSllflli E. Pasquai F, Prertlo C (2004) HCMOGT·l is • nowi ~ partner Ib POGFRB II ~ 151• . IobIH COrnanSM.x.oZ.fOlll~, HeIIy LE. ClonIIchon C. Howl .1M, ~ C, GreallM M (2002) Cl1roroosornt lI'Bntloca· ItonlI llfId ooverllWk&mOC ckJ !IlullY Blood 9lf 4532-4538 1531A.MrOzt k K. Bloomfield CD 1:10061, ChrornosGmB lberrntions, gene mutations and • ..,.-euOn (l'IangM, and pto;:9'lOSI5 on ado'! XlIIe myeIOO........-na ~ "'" Soc ....... E<1It f>ro,pn 16S-77 1532. Ikliz8I: K, ~ G Pa:tU P " ' - sP. IlIoorNieId CO (2007) Ch:II _ l~ (III BIooclll1:~70 ~.~ ~el)lll'lOll"ic~(lfpovnr;. . . ~ ArdlPaIloIlib Med12(.~ ea. 1531. IUr,Jlrl SP, w.u. E. 0I000r.-. C e...-.y 0 (1991) ~ ~ ..... 1o.‫ס‬I ~ IlIkAI hIIIbry Iro;lIllSPCQl tI ~ III 50 ~ Br J HaIrnIr:lI7B' 2Q6.2(lI. 153i , MuJlIghan CG, I<ennedy A, Zhou X, RidtkeI, PNlOpt LA. S/'IIJ M!eff SA, Downir'o;l JR (lOOT). Pedilln: 8CUW m~ ....k _ W'lh NPldl IIIUIabons II ~ by i 91"1 ~ pro6It...... ~ I10X gIflt t.~ doslnc:I !rorII r.ILl.~ IIluIoerRa ~21. 200).2009 IS4Cl. MI,onn Sf. ~ Jt.I. .ltJnItt A. AmlotP, RuSlin Wi. R.-I JR WNt!liIer S {1M), CjntClli sncl Pl't~ IHltoln:>genelty 11 cul~ garTlfTll-deolta T-;;eIlymphoma', reporI r:J "'M ~ iIrKI a ...... lIIl11t li6Ior lur. Br J DotrmmI 13!l 916--llll I I~ I,fun$N rfC ~ S ~ A12OO!1 e- 'l-JOOB - '" '/NI oIIl ~ ..... "*'"'IIDid ...... end ",. 1"'*IIi~~ Nl"lJl J U!1C1358 183$.\848. 15011. Munoz l NomdedeIJ JF VI&emor N, Guard.. R, Celom..- 0 , Ribet'l Jr.t, TDlTB9 JP, ~ JJ, F..... no:taz C, llonWlll A, ~ Of llin:l ",", $IncNl N. erur.r S sen.·J (2003) -'aM myeIood ' - - .." ldll '.'.lgtnlll'll$ c1W~ . . . P'flll'lO* rf1llEl _ .... 01 b ~ II , . o:\IItedul 1II resoduII ~ - . leuI<8rnIio 11. 16-82 1542. MUlliMmi I, Go9Jsev J FtlUmttl.!C, G/()r1lJll C, JaubM F 12002i Q.,1"c!ion 01 rI'I *' ...'" 15013. IoU--..I,l ~T.~N Ohnll H Fllkuhlr. S 00..- 101 il997i RtlII'.'9tr,.. elIIh BCl61i1""41'1 e.OIII ryrnpI'ol;l ~ Leul<1mia 11 St.clPl3 31&- 320 15014. MlJQSlIT, Nl k.amura S KawaUChi 1(, References 409 Ma\:iIuZ.e" H SaQo C. I...... T, N It Sl.om T, Silt) H(20001. AA ~ K. TMl'iolQ _ d lqt &all 1yTnphoma' <:iInieaI paIloIogoeal" ~ ~):) 11Iru. l8fgI B<:ell WlOmIl .uodIled d1 ~ J.,rwtomI 9r J HMmIIoI 111. 826-8301 1S4S. I.V.e T. y~ t.l SuzUa R. ~ 1.1, SIIkI V TIn*U J, llqI.... t.l I, Mon Ii- YOi/lIlo T. ~SI2OOT) lnIr..-a,W ~ (M.9Ct.j ur.n .,..8-011 lIdo~ SluO)'d96~"'", l:ilIl,.......kl . . ~ h e W o o IJIfIIllY of a>5 8Iood 1011 t~ . YI.rII: JJ e--.n SA, Vol W ..." Iioul:tIlS, ~ JA. VIII ~'" JH ,M NM, ....., PM, 1QwI........... He. .'&-485 ~ GJ Gundy C. . . . . CJ. ~JJ 12!Xl&l lrNu~ lIfO" tIng 01 c...- '9'*1l -......,. prUo:b dnieII /lMOOIlM II) ~IIOP III ~ ~ ...... ~ Ik:eI ~, EIlood 105 2916-2'!I21 1541. """'" JJ ..... CJ VOl W VIII I *. lIiofl~riU.~IIl~'" ~ nodiI _ _ 1II9' B CIII ~ Paro:i 20lI 71 04-723 1541, ~ ~ S 1191l8\ J u-. n~lIl~tw"""R_ .......OI.OX,...,.. 5tmIl~:llI 9>13- 1549, ~ S. ~ P IlIlId H lalIo J (l WTl. ElPIlW"CII rt... ~ V. . Sl4y Gto.oo""" ,.... trill "llO'I on dlIiQnoIlIc _ ...., .......-.c lI'..-...on by tr~ Sen'Iin -~,.,. ,... 1S5G. Murphy se (197&) 0IIIdh0al 1'0'>- !iodgklll', ~ NEr9 J UId 299- 14016- sa, Hl.oPI p9&:l~ A ranclorrOled .... of oomtonId rnodIIl'I "*." fA ISS'. ""-'flhy • HO o::hoIdhood I'lO,\·Ho(lgl"n'. ~ c.nc.~ 6JO.tl37 1552. M~,,'Y ", C....... EC .lorIo. DB, wr>1'l OH 119%) Sl~ 01 tht ""mll'lll/lisllr dlemtslry &'Id T 0»1 dorIak)o of _lIPIf\y. 8ISSCIl:8Ifd T teII lymphome, 1Vn J Patr'lol 146. ...." 1553. Muadler! M,R.....,y K, Bri Ul'lirlgllr A. Baur "'5, OudeJarw JJ. ROW& A, H ~n R&IlI O(lQIrrel'ICe of da95ical Hodgk in', dilWlallll as a T cell Iymp!'orl\II, J hp Mt61n 387·3\14. loll, KllflP(l(t R (2000) 15M, NilCM'lan JB, ~ NA. Sa!h&r H CamitIII e, FOfllSt>er E, HIlIrisof1 CJ, Da6lugue N, Sdlrlppe 1.4, PuI CH, Bam G, Si lvfrman LB, Jria·Sd\IILJb GE (2Q071 OulOOl'l'oll oj ~l in d1idtlll\ ril ~ lKlJtlI ~S/lc lt\JI<emiII, BlOOd ' 10 "'2·1' 15 S KumarA. O!"ond S. y~ B. Sapre R CIIougule A. "d¥9ll1 s (19951 · Immune-pI'IerlOlytIe and ullre ugIClIl ...... b IlOII--HodgkI1 ~ ~ -.n(:lT(n(~~d l1c-.woII~~ , ~92 K)OJbuGeU ~Znh~ 1511. NHaIllln F Tats""" E. T.1Ii K KiJ'IIagiIo S, ~ Y Saroo K. Naka....,. Ii ,..... N, Abe T, K_ 0 (1996) Cot~ 01 oekii18oce ~ ltlg) ~ lr8IlSfer-.e (TIlT) and ' 0 _ ' a<.:liv*",l gene 1 (RAG-- 1) two QI5Cl$ tnd !lefrooed CIII Io'llIs t _10: lt59-1163 1511A. ~a N 0IlIIl_ K Aliil 101. ~ Yl2OO1l ()emcn,ntion ollHlNn: DNA ollld-2 nI ~ '-Y d>lIiil .. 1uIIt:o..-~n1~~ ~ t\:IoI'l hl _ paIiIrll J EJp !iamIlDp.' 9-13 1552_ 5 ~ cr... ~ s...- H ~ K. FUl\4OI U. T Y80 T $.aio;lIiY. AJ, casa... A f ur"9 JJ, LOd<..- J (19931 altar l~ ~ Hodc)l<J" ~ pos~llllymJlllopolllericr4 dmtdllr '". reciplenl cancer 12 25$&- ""'" trln5llltnl un. "" tardut:Cl MG, sea... E, B..."n " E, PItd'Iio t.IC. Rtmolli D. R;,gone G, Natom f fl'OnWl M. N!JaI 0, V. . S. Lorrtlirda GA. B-... G. N8poIItno M. RiMo G (1OlI6f Skrrllloming 01Sal¥y fAIl....,.... SOF·l.cX~ tigNIng and ~ ol co~ IV Blood 101 Ctpv'oi H(l8.1115 1m. !WlnIalaII H, OtaY Il.-ri M. TaklludI K SuzuIlJ R u.uo K MIlliumIn T. Y", K KJIlI Y,........ T SaWII:Ia U. UrytIlI S, s..o T. T~K 1(Ao. . . . IrII UedlI R. N........... AtMa y T...uY S (2001) On;co. ~ lMUaoI 01 pyoIIof..- - - . : I ~ ............. .....,-1lI\OOhfIng llll ~ At-lOncolla 122·121 tm. 'tIrIniH ~ K loIIIu;IY,haD ,.,.T,8rGJS ~H ~ H, ~ K 31.·366 1565. Nakarru3 S, SIiola lA, ~ A, Yatalle Y, Ko;m<1 N , Motoo1 T. Su4J" R. I'lJogitrnj Y, 0QlI'aI.l, lh;II'i.rlima Y, Mizogo.K:lli Y, OkitfOOll:! I.l, Sekl I.l, Koshikawa T, I.lori S StICIlI T (1'1971, Ar!8PlilSbc liIrge cell Iympl\ormI . a dislil\cl moiectJlar p.athologlt: eIllilr a reappraisal w,th speCial relereflCll to p8()( NPMJALK) e.pressiO<1 Am J Surg P"UlOI ~ 1 14W.'4l2. 1566, Nillcamuf1l S, 1'80 T. Aoyagi K. lIla 1.4 , f UjlIhtmaM, TS(JrIIlyosfllM (199n I1eIicobactllr pj'lorl al'ld primary gastnc lymphoma " ~thcJIogjc ilI1d~ ear..:. alla/y· SOl 01 131 patients. 79 3--1 1. 1561. Noil ~). CUIInI • _ _ b' tnIlPI&k *ge hllllaPOC _ ~ AmJ~"'aIIoI121 MeS-,. 1>. i2003) ElI'\eII'I-8M vinowMoci8l8d poll' lraMplantaOOfl 1yfr>phoproIof_.. d'lOI"der after ~r..oo.a ~ "*1I\lY and~I~~ l1em r.eII lra\spIIlnlatiofl fol _ . 8I.J1Oim. lTlurlll , , _ Ild Blood Mam;rw T~ II 583-59' 1m . NiltlWani BN AnderIoro JR, ArrnItage JO, C"'aIi F, Oklllokl J, Drllct'oenberg MR. ~ NL, lMctflfl(lan KA, M uIIer·Hllrme~n~ HK, Ullrich FA. l'I'eke"tlurger OD (1999) C~nlcal tign,!lcaflCll ol JoI loculw lymphoma with rTIOl'IOC)IlOid 8 ceAI, Nl)r\.HOOgkin·1 Lyrnp/lOma Cla!'&ifiC<1tlOfl PI'OjtCI Hum Pathol30 263·268 1518. Nllhwalli BN, ~ JR Armill 9ll JO, C..aII, f , 0ie00ld J. Oract>art>erg MR, HarTili NL, Mld.ennan KA, M uller-HemWi'1~ HK, Ullrich FA, W~Mll~uf9"r DO (1999) Mdlgf\Ill zone B<:eI tympI10ma A cinicll corn. PB'*'" 01 ~ llrId ~Ied tympIlood ~_ ~. Non-liodgkill 'l LY"'CJh0m8 ClaI"'1lOO Pfoted:. J ClIll 0rl00I 11, 2486- lSM . NaOOr RG, C".eIarmtll E, O\edbum A, 08. ......, MO, StId J, K ~ DU (19961 Pfimar'y tIIIMon lym~, • dtttind Kamtn S, Karube K. 0IlsI'tmil K. lAula K. IWwa\i H, Morishoma Y, Na+;amura S, $Ilrl lA ~,.;,jfl atl'a'f-b3sed comparatJve 2492 ~ """" ~ wilI1 .... ~ ~~ oI!\3llil'<e I<jlkl< celilym- 1511. Nalllw..... BN uener GE, WIer W ~ 1(apoI;', saroorna-anoolIc.d hwpn ",/IfW, Blood 88 &4~ 1S56. ~R(; CNodblmA.~G, c...... E SaId JW K- ' I I OM (2O(lJ] HumIolITl'fll,l.J....o.i1cy ~ ~ -:I ~ ~ <Jopdn Nn J s..q PI1lIOl 21, m-J02 l ID. Nagtlt Ii WOflltItc: ,1,$, Oh CK o-.:tvy SA 1 - - . . . S, SuNu y WIlaIIlII DO (1995) Idoii.......' 01 • p;lIf1l nIAJIii)n ., fit ctUt-,1il; ~ 01 ... pro. ~t>.laI"'~blooO_ tINr cell 01..,.. ....., ' - ~ . . . . . ~ l ~. . . . . ~ ,.... olaIl SOIJ 5 A 92, 10Sfl0.105601 155.. ~ C CI'q:q Ii Shnle 5 BallI8yI (20051 a.n.JS. ...,"Re,~ ... ,~ CR p/lorrIftuk.m dlfter9n1 gerotrW:. ~ ~ ol ~ NK-a!I lllul;emiII tnd lItIrtnOO!Il N~-all ~ . lIasaI Iype [).oon Genes~ ~cJ~~'Bbxl68 00, w...berg CO. "",100mb CC (1986. *"*' !loI1ht llIlJlllIlOIogo ~ lor lhe C8nelJr". 241·255 1561. Nak.ltl<,ita S Y80 "I. Hosll,da Y. WN1 Yamamoto S, Iuchi K Aousa K (2002) ~.-asaooalad !ymllllonlol • JlMN of 106 ~ J CIrl 0nccI20 .2S5-4260 1511. NIIe6nit 1rAA. Jaffe R S1arzl 1£ ~ AJ PorW K. 9.ml\atll JA. Mal.OWQ L 110 M Lt)Cie< J (l!lll8l. The paIhology 01 post, " ~klr.lM dioorlJerf 0CQ6Mg ., $lllIIIlg of tyCia;(loMI ~ _ ~ A,onJ I>iIlhoI 133' 173-1112 ISIlI l M. ZIIIiO S PohIIrlIn 8. ~N. Baal: "I. ""9dor A.Sdq-G. NIlgIer A, 81""1 GE, Ltvy R. ~ RD. IS (2lXl8) u«)2 lI'OliIIll UJft*lf' Pf1ICIl1I......a In P*'*'" -119 1m . ........ t st1. ....... Y. ""~P~ S33 1513. IUwIIlC. Orv~ Pl. va..s. R, Mnrm P, ~ C GoJmal E. ~ .l., GatiI O. ~ F IgIlJIias L, PwlI Mol AIgln P f2llOOj p1611HK4) ~ • • ., Iiasiln 01 ~ ...,. J P1h1156' '565-1512 lS101. N....:l F. ~ AD. HNd OR !lcn:Mllz MJ c.rct AJ. lltIn:I JI,l lr'l< t.IP RQlWII """. ~ GA Sc:I-.. t.lIl. S/ialdI OJ v.e. TJ, OJ 1191l9'1 AQ.tt lIlilN _ ~ 0QICleS Moo p/laklqy ~Af,PlI* .. .l..~GS tnd'o...,........... ...-llgnInl 108-111 1$75. NMh R. M<S UI\tJ P ZtfllbeIo R ~ G LwgInrl TP ¥, (1ill3). Cb'III -.0. 01 coo. W""'oIlIoII.. . - - 01 ~~ BIooclal·2363-23llll 1ST6. '-II RIo. D.lMy R, Ston!l J Georgta GE. 8cMtrl JD Ho:*rWg LA KrJII GH, .... MD. IoIcOoNgh llJ, 0... CS I)perw J. lema'Wll Cf. Pa-MOC S SulI¥8ro 1< 101 SunclarNuI J. furst DE tympIl .-.odeletiorIs '" Iot.r case5, Palhol llll 4 12003. He~ T~ ""'" ptona ill. paIierf'" Crohrl'I~lrlllIlId ..... ~ L.eul L~ ~ 531· T~33·.,0, 15R F.,.,.. .. (IMi lk:eI i1..... illdo;nIly pI'8-~ III ~. 01 g:JSh: MALT tym. pIlclrN ., ~1oA:i::W.18I ~SSOOil8ddlf'Or>. 1l; . . .,,IfiIJ~ 1.')2'1211-1219 1511 NNron S. Hin K. Su:rlI T IklM I~'" H. ~ma .. Na_ayatnlI A ~ A ~ H Asai J t1988) 1r'IIerlIg0llrlg c:et s;ycoma A 1l'IlJI1""'CJlogIc. f!lCIf1hlID9lc llrId 1l1TlJ"'*9C ltuay at 1512. NmI VE. JaIIeES 121X!5), Tile pallO. 01 NK-aIll ~5..:1 .......... Mv 4nal PathoI1Z: 21-301. 1S82A. HavllO'O JT Rlbll<. Jt.l. Mate JI. Granada I Jurcl J Balle M . . F. hiu E tJgf (a, 1.KCi2•. Q321 rao~, etI~_~~., (XlI'Illl. • pm>ary ~l.Ibon II ee sk", d;rucopa!tlologic. ,mmmolllSlooIlllmocel and IIlOIaclJBr alllliy$es 01 """"" ~ J Q.tlWl PaIhol 27 392-399 pI'ii:iinaI _ T,YIiwIhjrI Y 5ai F\Od'IgaIIIi T V--*' L Tv>eyosIii lot ....... ~ . a n d ~ -.t¥ c.....61 ~·568 15M. ~ S. Kosnika.. a T, K~ II. l Su LO, I.e 80iI PE, Kim YH, Kci1Ier S (20001, Co--expre&SlOO 01 C056 eni COJO ill IyrfI. !l31~5 u- e. oaI~RalId"'~ ~""and~ ~ ..... ....mJ 0nc0I26 441... Sol vvw...- RA. ItIilt9"8 ~ "*' 1ll IilIltl ". IlId f AllU IIU· ~ ... ~ ~ ' Iht I"edlolMc Oncology Grlluo~ L~13.1)5.141 ISIS, ~ R5. ROW! PJ. t ..... FlJ (1913) t~ ItodqUlI ... _ A ............... _1 NEr9JMed 2M. 15,.,55, ISM. ~ BP. ,....., NA IWIIllr ow locI<... J Fung JJ. S-roloov SH (2OOll EpsleirI·Barr .-.ua-<>egaWe poIH'~ ~ lk$OrCIIlI$; I arIIIy'l kro J s.,g PalO 24 315-385 .-..a lsa7. ......... A. 1'hIedt C t.Io9'* -.. AIpen B. RJIItr 1rII, NeINuar B. ~ r EIiiWlgIrG. SIOlle 101, Bayerdorfler E (1991) Con oIlie1ocd1ac1llf PY'cn riecboo'IalO 01.2 C3Se'I '" SirlQallore. Mod PaIh(J 1T H197.' 101. 1591. Ngu~ DT, 0iM100d LW, ~ study ML, HllI II. f i!lcherR (19941 rollit:ul8r ~ ir; CllIIaI'CO'N. ~tiotI by moroclorIII .nliboOiM il1 J)llI"alfm wdlons, "PPl irnrnJrlc:Inlodiilm 2' 6Q.6ol 1592. hI~. Baosi G RorodfII; O. Hol'lmiIl R (2005] Studies oIlhl1 Ille an:llbbilJJliotl (J COlof' cell '" iOOp!Ilhic ~ "'" J CIon PtIlOI 123c833-839 Isn hIdds PI( SWlIey", 12000I TIll ~ .. ~ . . pmwy 9""'" aIII...-.n to EngJ'" m 1.25--1429 19 5. Nltme\'f' C"I. N1CO M 8-.0 G &ord A ear.. FlA. CreuIz9 U ' - ' 0 I-WboII J, ..... H. ~ G toc:IliaI ~ ...... G ~ 8,V_-llaI'iilf ET.... Wtr'IIIlI E. z.r-- .. (11181) 4 10 References 7 C!Iroricm~*,l 89 35)4·3543. 1595A.Nie""Y" e M Be..-.o 112OOl11 ~ 'ynctolnIlI \:I'IIldNn iIIld ..",. ~ SenW'I HemIlcJ 45 llO-70, s.... 1596, .....,... CM r_ H ........ G. Star)' J. ... W....-.g E \1.) ~ ' 0ilIeremia*>g ~ m-,.lDfnoliOCl'1ie _ _ IIun I'IItcIouI ~ 8Iood 91 ""'" 1517 A. ~ 8. blIWl P. 011 101, lot. '*-"It v F~ L. Cocm PI.. s.iIIt A, ~ M. WIC! l VNPH. GiIIiI . .*"*"Il, 131' EPI- 1m1. , . NDoN ~ M .. Nlk..-. H.AollIS, ~M I(2l107j f'mDr'i* ~ al d 3cl27 011 . . . B-oI ~ QlIIlIlIIon .. a'o-.' ~.~.~. ~ 0Ilk:0mI II 32'9 ~ " . . . . I.UAoIII311191-1 197 1595. IWliu M rOlOllll v ........,.. S r....-T liNIiI N ~Y lkedIJ Ilo::I>o K. Y~ R. ~ V. Aozat K (20011 DIIn:t ...... allll'le ~ II ~~IPAl.I.'1ym­ ptvn,lI ~ II ~ ......... bl Sa 95 Q-.83oI c.n:. K.KmnH ~ S k. 00110 T (2005) f ...... UI1I ~ 0II1y1r'(l1lomi1-*'9" ' ~ . . • aop d ~ ~ diIIor· don Eur J 0lIrrM1Il 15 503-506 1• . '"*'Y, cveec myelogetnJs n: leIJ ~emia fflllIeruIif S9- i'IIllUr1t, ~ 3952·3963 1609. I+..oo::II JP, Konlt1WI'fllt SJ \l9901 0erag0..iaIed Bd-2 gene e. pIWSoItIfI ~ fIIl)loror,;s $UrYi\-. oI1'OW\1'! fIdor· depoNed ~ cellnts J lrrm:lnDl1" 3602·)610 1&10. N'ffI*l H AdO& .... ~ ~ ..... Tew... M BergUld M, ""'" fW ~ C. Enblad G \.epplI 5 (2(07). ~...-aol~ d*oId grrwIlIIII cenler ~ '" ~ iIr9" 8-OIlI ~ P'ilIenlS lreaIecl ... -~lIPY IlIDod 109'4930-4935 16U . OBr.l OS KPWBl'f MJ. o.ty PA. O"~ M. T _ WA, R<:Jgn P L-v E \1.) ........ ~ ~ o l l l e . . . . . . . . . nd. A ch:opiII....,....,. iIIWd\IIt bin 01 ~'. 'JfnI:tIomI d 8-OIlI ~ fJP8 Nn J s.,g I1Ilol 13 ,,,- 1111. 0'C0f00r GT P963} ~ iISI*:li 01 cMIald ~ 1\ Ah:a """'"' Rill 13 1514·1518 1611. OP. Km YS. I'MolnI SL &.Idnclge t JuMr 8£. Oran A (20051 0-......,. ~lI'Qrmu""oaxJllI!"IICiII~ bl ~ ptOilBr_ in naopasliit nI bIIigfI ~ Mod ~ d.-: 18 156G-t561 leC12. NcG1 L.1liINer OW, .JiIc.(U s.A. Lock.. J S~ SH (2003) 11'ICloIiInI"... . 011 ~ WI!h oodiII ,,~ encI mutillild ""muflOgloblllin hellV'/ cMm geMI Mu m PiIIho)'34 1 0~10 :W 1&03. Nog.o,. L R,irlllke T, 8r~l.nl C, ~ M, Rud iget' T, Joa~ A, Ilr8cienlllld M, Skflpnitc/'I..nko R. Muller RP, Muller· ~k HK, Diehl V, El'Illert A (2008) Lymphocyte.predomlnlnl ~nd classlClI l 1614. 0......., OP VInCe GH, Orazi A (20051 Chrtnc: -tympl'loey1lC Ieuk~srr.­ ~ ~ ""'" 1rlSOfIIy 12 and b:Il cydirI d1 e.~ • poIe<$II ~ k poIlalI AtdI P8ID Lab r.4ed t29: 92-95 1615. ONei J, SharIk J CussOI1 N. ~e C. K..... M{20041. TIoL1''SCl indIK:eI Wen'III b~ ,nh'bibrIg lIle (tanSOl~ aetiv"Y 01 E47/HE8 ~ Cell5, 587-596 1116. O'S~e JJ Jafft ES, lane tlC, MiK:OermolI RP, FlIUC:i AS(1987). Petl>f'rtnI T OIIlyrnptlomli pl'WS&nllng as ~flOSImphU ...Ilh ,ll&ClIlIliI, Cliflical, patOOlCi9'C, .rq dele· Uoo '" Wlldenstrorn mBcrc>IJlobu l,"em l~ ,s Hodgk,"'1 Iymphoml • oomp<eIlen... \'II _ ISsodaled w.1h 1ealUteS toIOI1IhIlIa T.T leCl1 . NIla H CogIiMlI 58 __ SctI6r9 C F.... A(; , liIMIIt K (11191) t.kn:qIoid B-OIlI ~,mCIl~Vilrillrllsilhll~ lhp 10 ~. . lkiIlI ~ 01 lilt muco.....u lOeltt ild I)-mp/lold 1'_ ~ ll1'~14 Iy. SIS /rom 1hll Gefl1'llln HodQkln Study Group J of BdVSWJ prognosiS 1.. NcIroodiI UO. ~ p. Fmw T. Sf J Haemalol !36: 80-88 1618, Oo1 uetuu M, Ortao A, Almeida J, Blade J Gonzaiez M. GafClll-Sanz R, Lopez· Berges C,Moro MJ, Hemandel J, EsmllaOO L, CBbMen:l D. Ro,anan M San ~igJel JFj1998) lnvnunop/'letlolypic ctllUIClef',zatioo 01i>asma tell from monodonaI !}8nomopaltlyolUf'IdaW· miled ~ petillnls ~icB\iotIs forlhe difIerenliIl ~ ~ MGUS lW1d tiple myeloma Am J P~!l'oi 152" 1655·1665 1119. Od._ I, l, P, Yu l, Dod. W NoseioootIhy M. Ilabyll P W$tlmarl S (2OOIl1 ~ l.ingertIwIs0!!I11slioc';tosis, • ~ . . \liMI$e In ctlildtlOOd Ped,alr Blood CiItIcer 41 889-89J 1m . 0IIl: K, lo CF. t o:U!l DC. ~ N2 tu>q 0 ~ e. Ye 61'1. LitIa f. FiliPl>' OA, Rosar-.m A (1~1. Rearrarogemenl rJ thI ~ lII'le as.1l'tlll"'J5IIt 1IliIfIl'" II o:ilt.t&e ~ ~ N Eng! J hIllcl331: 74-«1 11l21. 0IIl: K f'aoy HZ. GIIida'lo G. ~ DA.. LouiIO. "-'0 " - - SC, DaIlI.f_. It Ch"9ri RS\19931 ~cIeIetIott5def1'l1lo'" ~ dnc:o.~ subsels 01 tlO!'HoajkIl'.. ~ EIIood 1l2: 2151-2162 ~ ,.,22. CliI!0nc0I26:43"-439 161W. NonaIl1l A. Yokoy.ma T, TIk ItIhIlB 1-1, O!lstMmil K, Kubota A, OkB"""f' 5 11004). HUflWl htrpes W1JI 1I~ pnmlIf)' effu. !IOfl 1ymplloma lPE.l. l plbenl.fIer flIP'lIl. ell d1}'bus ilSdtes If'Id d1}'loltl(ltU Intern MId 43 Z,lI;.242 1&05. NotIon Aj, l-I, lllItlIo, J PiIIJl)Il V, SIwMItI J, low S. ~ 1>Z.lidIr TA (1 995), "'-'II 011 ~. nAItIll'lodry dIrIred II • .....-yIllopIied p(IpI.iIIoon _ • ~ I*iod Am 0n00l6 24902'56 1606. "'o,l1...1IjIIIo l, e-.- Jl., COI1ley ME Ctoil* H f .... A. PIId< J Roifr,., e. Seger R GehI RS (XKl!Il PmlIrt' ~ licillrIey dlMMft. ... ~ from !he ~ Lhonal~ SOOMoM In, DBN_ OIaIIIt*li, COrrwr-... ""*'lllIlluclIpMt. 2005 J AIIrllJ Qrl1rMulol117. eeJ.8IllI. Pnmary Im~le, l eC17. ,..",... PC ~ DA (196Ol A ........ a'o _ ,IlI " ....... dV\lnIC w1llc)Ic . . . . . 'SO-:' 132. 1.97.1500. G "'~, T SIootsID T (2003l, m" ~K.~Y,$lrtle, T_ H, 0.. K, Hoy. . A (2006). ~ . . . !iond!'ow e,bneIic ~ d CV34+ 011I ., kJ,rt.grllde ~lc I~ llk.«I lOS 1037-1044. 1623, 0gatiI K, N.l "" 0II'r'itle K OCt J lledI M. l eu, u.no 5, 't'0Ihijm It. YlIIf\IIIMII Y, K"*J K, ~ S N_.V.SIiIoK.~t.I,~K ~ Y. ~ N Oz.- K, MIno H (2001) ~oI"~lIt1'1ft1t'to ~ -....- by ow. "lImllI"WY .... ~.,~ _ CIk ~ 20" 8249-8<'57 1125.. ~ H. ~ K. ..... Y ~ lot. WOlIbt T 1200rI av- e PlJ"iIed ~ -...... 'MIl FP1Ll-KlGf'RA IuIti:rIII'Id 76141 ""*"en hll'\llf\llllllrtJoo, ~OII~"'~ . .d......., &'J ...... ,)4 547-5019 1621. 0M0 H FU'1Nn 5 (19911 01 d '" IlCl.6 ~ II 8-aII f'\o'!lPlloill ......- l.M l\'mCllloonl21 5J..63 1m , QtwIo T SItieJ JA W\I G. ~ SH. WMerlllurVe' 00. we (1991} S9*-» CionIity '_'9"'__ "*' Ifl ftOlUIt ~ HO(l9"'" " - . NEnsIi J....., 331 4~ 1628. QtwIo V. ~ R FuIlLNnl S, ttIa'"9 CR ICarT-"a H Anw10 H ~ T. 71k:N1t'O y """ y ~ T (19891 Aa.ile ~ 01 cmnc: llII'gt ~ ~1IuiWrie~~a1diIitr'IItI d>oomoaornell!lllorrnllity c.w:.64 63-67 1m . OhuftIol.TomDY,~H,I\.dlIK KIwDbI V, ~.... Y Koro'IIIIu H "-'Ui K, StwnoyarM t.I, AouN K (1995) Flole 01 ~,,",lirlP*IfIl~llJIiI lolod PllllOl8 84S-35J 1m. O!lshiml K (20071 ~ -. klrft of d i _ I!lIOCiBlBd WIIh ".",..., T-OII ~ Wustypt I. Car'Ieet SCi 98'112·778 1631. Oh~ h,trnl K, loM Bi Y, Shita, i H, Suzumi)' J, 7astW\l K, K+k..ctli M (1997) Clonal inteogralion IrId "preISIOn 01 human 7· r-ltil ~ mphotrOlJlC ""uS type 1in (;llI'I'lIfI deled' Ad by potymetl-;e cha ," rNt;!lOn ~ncl fMlnlI PeR Am J Hematol54: 3(1&.312 1632. Ohsnlma K, Suzum l~a J, KakJ A, ra~ lro K, Klkudll M (1997), CJonaI HTLV·~ In*,ted COol ' T.jyrnphocyt", If1d non·do'~ nQt1.HTLV·I"nlected gi8l1( cells in lnc CMCfJf n 592-598. 1633, O!ls!lomll K, SulumoyI J, SaTo K,KII'ldI ~. Sim.uk> T, K.I"-Bsal Su"",. PIlIU 189 5390545 1134, OtlIllimII K SUl\I'l'W'f1 J ~ K, KaIO -., TIINQ T, KoIndiI 1-1. ICilwd'o III 11997j IiISIIl TI!IIK c.I ~s OJfIlIl'IOf"Iyeqllftl I*1oM and F. liQIllit lmporIan1 !IllllSIlOrI tJ n-lWr'o1gI ~31·«4"50 oumur. 1m. T ~. N N,no v IIlIZOgl.d'l H (2001) ~ ctwono: ""l"'k:lIbo'llln cIoitaI.ro:l ~ ~ .. 336 '--/IIliII'IlIInIJ!WIaki73194-19l1 1636 Okiiroo III ~ S. 0MI0 T s...r,..... V It"Olile GIol PInIo OT 11991) Sowwt dV\lnIC ..... ___ ~ bl syrodrome 0Il1ollc:Ja:liol Rt> 4 In-l3$ 1637. c.V,~"',ZI'clu,l(,CoItIIJ FlICltft S v......... S, O'&wt S. Kt*r C. !lEnn '" 8NIlt SI<j, PWct S 1"'- O. R-.I F. 't'I'inI WG. GilII f, ~ A. JabbOll E. ~ MJ, Ilueso-Flamos CEo e.y E. ~nettl G (2006) Adult XUII ~ie«i.""'lif'~0131 paloenls Iteated lit I,l.D Ai'IdetIoo c.ooer CenlIIf Ilb>d 107 88IJ.lIlI4 163l. Or.sertlelderE, Ilou\afIgef E GBic>Bt L. DJ MQ ~ N 0Iss TC tia"Dlllo R 0...... MY, AgbIIil:,a F, BoshoII CIIlNeI JP -..:aon PG.""""'" V(2002}.Hogh ~ tJ KIposo ~ hetpeswuI*-d ~ Iympnomi" . . . . . . . . tw ~ a'ld ~ CasIItrnIrl _ 9IoolI99:2331·2336, l ID. Okuda T SIi.IrnoIo S 0t9Jtfli T e *' ........S~KY~T~ S HtliS ImMI1uIwS(I99t) ~ ~ IhCICIOliIIld WIlJl . - tlIV1l kJef*~ AmJ ...... 3e 321·323 1640 Ok"" De T.... KR 11m) l~"""'~1#nJ"'" 4 29l-29fI 1641. Oi-oey 'iJ Le s-. ,... f2007 E _ o I recwmg~~ "1\1le~oI~~ ~ l d Res 31 ''17-'~ I":' CIwlE V ~ E ~It ~ R, Kim V lVlOlIIBr R ~ H lNwic '" EsndI 7, l.ItIW9 S. Wood G R. R-*' A 8'JIi G, ~ P, ~ M ~ MG. S1BlI'y W l..w!ld'It L 7r;Ur'ig1tF. 'MIilIiAer S12OO7l. RfI\oalr;Q 10 roe ~"~ rJ""¥X* ~ P * II'Id s.nr, SJ"'lIf'C'I'IlI. , pt'CIPOelIIl a111lt NmnotIeI Sooety b euc-ous lyrn~ (ISCl.) and . . o.a-ous ~ ph:rna task ll:lrtIoIllWI ~~ tJ R-.d'I IrId TreaPerli aI c.ar evo-. (E~TCI 8Iood 110- 171l-11n 11043. 0.-... H. Woi"ll HY Cliett W RW. I'.......mdoklr NJ 1rImJ~ der.~ tJ McKenna (2007) lIgI>-nsk monodoNl gaorwnopaItIy oI ...\(IlltlIlmollod !l9" ....FU L40lI P'1hoI20, ~ 1644. 0rK:>u 101, Be"'" FG. OowwrM19 JR SIuIeff SA. RamOI1dI SC. Mil Z, t.briI SW, """rI8dy W ..mes sc, ~ JT (20031 ALK1XlIilrI'II ~ B-cet !yrnltlomll \Mltl fxpressq'l 01 !t'If NPt.l-ALK fusion !rIIt>1(:I'ip!.~ of2_ Blood 102' 2642·21)44 1645. ()loda F, ~ HM. Smith ft. Boil G,KeaIflg MJ, ElteyEH,GIasS/lllfl AB Aillitllf t.l. Kw m 1647. Orali -. (2001), HistrJpa!holo9Y III the diagnosis aM classllicl~ of IQJle m)'tbll beul<emia. myeIDdyljllDsti\: syfldromt&" aM m~eIOd)'llllas~clmyelopr'olill!fltiw ~. Pilttloboology 74 91.1 14 1641. Orali A. -.Itnlaf 1-1, H_ NA tiIIki:'II S, Ne!IlIIn RS (1997j Hypoplntic: ~plM.l+c syndromel GlIfl be ~ gUillled trom 8COJOfed IpIao.IH: . _ OJ COOolIf'od PCl'IA ~ol bOIle ....· """ ba\)sy ~ Am J 011 PIlIloI 101 ...m 16f9 0rNI A. 0. R. 0 ...... DP Clai:IIJ M. "'" $I.. An C V.-ote GH (2OO6l CM:Ilie ~ ThI tole tJ I8:IlI ~~~.LlodPIlflol 19 1536-1545 1651. Orazt A. Newrwl RS. C"*'lI H tW..-.NA..kmkI19'iM) CD34~ ,.dlxN_biopI'; ~ . . . . . . ..,. ~ tIIIiIIl)o . . ~ d d'IlnI; fI".al .............. J ~ PiJltd 'til 426-42e ' 651. Orazi A. O'~ DP .-ng J V_ References 41 1 GH, ~ J, Cudtr M, F.,-,g wAlle. B.d's PM {2OO!l1 .-.cute p8M1)'IMoIiI; wllh ~. aI1 _wry dll~nd !rom meQdl<aryoDIatIie ....Mni6 I.locI PIiIItool HI 603-614 1665. OIsuki T, KlImiII' S, Ensoli S, 1<1f1l1ll8 OW, Yano '. StetI6r·Sle'vensoo .... Ja~e ES RatIeId III (1996) tleIedIoo 01 HHV-a,'K SiW DNA MQUllf10llS Il'l A.lD5-assOOaled eru-aroodal !yn'(lIlQid ~ l."'e"llll 10: 1M ~d J Gatllld R. 0..... Z, Babbige G. SMlotI 5, _ _ e ~ 0 1666. 011 G, KallI J. 011 UM. Sd")'en B. iW. 1651. Tr.;;mas PW....~~ H 0.- 0 (2003) ... SlA:ItIlcrl~l' 141~"'''''''oeI . . . . . dilplIryt; llIUIIlilltt lQVH ~ .., ~ pMIeinIs .... good progIIOIla nom0(11I ~ IlloocI 101 491>4Qll1. 1&53. 0rcNrl:l JA. Ibllo*In RE 0.... Z. W....... ... RoMrMoIId A. Thornu PW. HIfrtilrI TJ S1adI LU 0.- 00 (20001) 1»·10 ~ .., ~ Il'l d'Iltnc ~ ~J63 1(.15.111 1~ . 0fI0 A. CtlIon llIC IllnIIua AM lllpe:l--8etglol llIC, ~ R. Go:Il'lm.l: "T_loIl~W.~ s.. ""9*' "., ~ T 1Il.... .!G. l.Uef~ IiI\ 1'991) llinlod varianl$ of mantlet:eIIly"'" ~ ~ bd-l rUTlllgilfnel1ls aI ' " l'lIIP' b.'IIlociiIu, CIuS$If,\lQOO'1 ;IIrId lelJaplOid d"l'O'h"_I>edonn IlalclIl9 ,421·1.29 IM7. 011 G IC.IlzIIrltlerg T GrllJ>er A.. 1"..* J ~ A. HeO'ndl U, 011 MhI ...... r« (1997). n:e 1(11;18j(Q21;q21) ........... rJVuIrcaJi'>e bai .........., IS ;I ~ ind ~ --.:Il'l i'I ~ b.JI not highp;lI .....-1ICIIl-Ho:ld\Ib·s ~ d lie na:. •• - ' Iyrrclho«l'-..e (loW. T· )MIe CarorRes57.~ G Kallenberger T. l(lhr oa ~-RrM J JF P9ll9) n._."....~dC034 CDl~_ 166&. COl) . ~ Il'l ecult ~ ........ IS , . . , 0 ........ d . . j:Wa..... d PM.~O--'_t."".llI ~ AI 11a&4....... 84 ""12. 1&55. 0rlIn A. ...-.rue. J. S ( I . ADoo~~ OIls ~ nom-' a'ld ~ tJone _ ~ l. e.- C CIUOIlI J. ,...,.." ..... v-eo s.. d ~ , . . . .. .........-, ..,....--... ""'J P1Ilal149" 149}1499 1656. 0rtI0 A. ~ N:, SaolCM.L l fsoo;n) l (20(1) ~ 1Ct4'II* . . . . \lOIdInUllling d ~ . . rdI d I(IT ........ IlrJ~ 13812·)0 1656A ClnoMt N ~ J Plonclu-l A ..... N ~ C. 8Igol" l.M\IIt MM. Geuw A. I1IIou'I C, w.etIIIiIf J. GIlII.rd P (2001) ChIrIdInabOn 01 Oct13' fIeOPIKDc: I 0IlII III ~ """'oI~T~~ lAm) Am J Swll Pl1IlOI31 106&-1016 1651. 0Ib0rre 8M. e....- JJ Grell. "'" o.w.u. {199Z)~~d~ cenIeIs, ~$(Il'l III 23 '*''*'' '**'" 10 !hI1ll"'~bOn.ModP.llhol~ ow- 1~140 1658. 00. Tl\ompMn A. Zl\II D. SlIwosQrI ~K (1991), OifWenb.1 ra* QI SOflIa1ic hype.-rT1\MIiOrl ;" V(li) geres iImOIl!l SlIQ$ollS of cl'IIOnl( Iymphocybc OIu'emoa lIefinlld b\' ~ IJbnormIl 1659. OMi'ni K ( 1996) lymphoprol if9l ~ 63. 279-290 1660. Oshm K 12001), ProgruM m under· ltaodfig and managing naturel . ,IIar..cell maI!Q' nanotl, Br J Ha&rnot04 13~ ~32·S44 1661. Q!,himi K. YitITilICla 0, K.ne'o T, NMorIIIKa 5, lIzu'" Y. UtabB A.. lnamon T, AslIno 5 Tal a.w.. E.l~G~yO,~A {ZOO7) Chlnc:tInIk ~"lC8Id'" bot-. I'IlIfI(M- '" T lIfVI 9'.... Jymp/'ccyIe leui 1663. ~ N MalutM E, CalovtIly 0 lMlIpen I ~ A (2005) HollO~ d . . apleIrIll'l T~ .... plUIW ~-'-a'ldl s..v IIilJk_ • ~aIJ" _ Nfl J PaIIol ;?9- 93s.9ol I 1664. OWo,N _ _ E T~G.Gr8;1I tI 011 G I. 'NohlJJlOCll' A. c.o.os., 0 ~ ~ JG. (2006) T<11II ...,. WIlUIr Iylfto _ _ A "PQI1 on.. . - . . d 29~and.,....()l",.~ c.nc. 11)1 5ro-~73 412 References A.. ..... JG. 011 WoI......... HI< (2002). C~ ................,..... n l ~ ~ d 1l*UiIt~. 2lypesof ~ ~ I"UM 9'3de 3. &:Iod 99' 3lD6--J812 OI:tAL~A..~T, 16M. ~ W I J. Gmt..- A.01: G, .........- HImoIh. If( (2OOJ~ IlliIlIgNIltIl'lll 8-aII ~ (iolZSl) IfISO'lljl aI ~ s-. ~ ~ bdogieal er'IlIIIM Gel-. ChomDlllllleS 28:J!lO.Jll£ 1671. ~ CH TlDRp&elI Aft ZtII N\I;Il'l$ s--../N. s-...- FJ( (1998) """'01 VH ~ Il'l loIiaJrar.., dIlIuM lymphomll 'flaIrS 0fIlICWl9 somatIC naIIon anr:I nApIIl ~ ~ I'l -.ty 0 _ ~ d\arQ8S ~ oiseasep-o- c.nc. o as. ~,1lIood 91:.292..(299. o-o.n TM. 1 1611. EJwm N. RoberIs Gl (2006j, ~ ~. and ~ dlaradens1lCS 01 1lI~ ICUIe ~ oienIiIied by '" EGll scomgsyslem letJkerrliI 2l} 620-626 l&n Owen I'IG, BarnJ"s Sl, R.chards 5..1, O'CDfIl'lOI' SJ, CIWd JA Par3PII LA Morgan GJ, Jado. AS (2001) WaIlIenslrom macrogkJbu_ _ OoN&Iopment of ~oe cnlOpoukJ. lolA 12(03). Clinicopalld<'\lifal clefitllOOn of Waldooslrom's rTIllCtogio-bul'lemia oonMlflIllJS panej recommenda!lons fmm !he StcofId In terr;~ tlon~ 1 Workshop on Waldensuoofs Macroyklbolinemia Sern ln 0n00I 30' 110-115 1674. OyarJ\il T, Icnimura K, Suzuki R. Sul\J",,~a J, ~ K. Yatabe Y, YoIyama Y. Kar!Iya It ~ T. ~ 5 /2001) ~ E8v--.oalled IkelIlyTnpro:lpro. . . . . disorders e:tWlSIill*l • un Kojwna". '*' can ~ ec ~ AaM...,..,... d)'spIIrIIIa .., R Yeaeoros U ~ ~ of tl3 a-- ~ (2Ol'I~ WIll t.6.9)(P2J,Q34l. a Iw,tt hq,ot MI J ~ (2004) PIIbII 122 Adlva~ng FLT3 mutaliool In CDll1i1C.IT(~) T-«II ....c. Iymfl/>Oble6loe IeuI<er!lA Illooll lOol S58-SOO 1&7' . PailIIlli E. Gciol.tJto4 O. Nel.tlerv D. llemd JM, ~ R RaorNJs J. DIAd G W-..k PH. TaInwl MS{2004l A-.mgaII m.t.- ~ b' F't.IlJR,I,R ~ .~ IC\IlII~ **-1lId ... .__. bood~~_,...... pIlI;ltlgle and IfIdIQ.iII ~ C,unevy 8 Cylom 59. 1-9 1&79. P3IIlII E, R...vA J, NIlbIirlI D. 16!lO P.... S, lee J. Ko YH, Hat1 A, JU'1 HJ, lee $C. Hwar'lg IG. P.... YH. Am $, JuI1ll CW, Kwn K. AM vc. Ka-lg Wt<. P.... K !C,Q WS (2007). lhe 01 E~ WlA ItalUl 00 cIrlOll WlDJmlI in ddluIe Iqe ll-oIlI ~ Blood 110.972-978 169l1A. Parl "'*' eanc. ee menl. ~ /II'ICl ~ l:hnc- an .-...a.. 81‫ס‬0O 60 Rorooe..IN GoIdIIoreAti ....... PH p997, ~ 01 CD2S ("*"'-Il'l-2 ree.pb I8sh JC . . . . ~)Il'l . . . . . . ~ and QIlI cvIIure sII*S ia ~ ............ B!' J "-tIItlI62. 6S9-a'ii ' ' '3. pany-. .... N. Ma-. E WDItr. R. ...._ A. ~S.~I."""''''.",*J. ~ aa-ase 1617, PiIIetIa E. FItfTllrdll M. ~ 0, Be.....l1JM. Raoe'$JI J l.4zaruI H. 0ew8Id G. R~JLI. W«r;k PH,T..-.- US.lool pnIdds b""'~ d llCRAIll. ~~ . . . . d.~1stIo­ ...,.~ofECOG"ARC~SloI:ly Em] COoparaM ClrlI:Uo;y ~ R-m Co.A:i ~ e........ 11 1811·11/190 1321.1331 r __ de tIitJtIII'I j,I, w.eus RE. 8apAI VB Sp-y CJ 1692. P....... l ~JW e.-,D(\986~awo.r­ ~" WoI'eSPOQftA. ~ GJ. CalcI$, 0 (2007) ~ ........ tIM Illc*lnilI tl "11.1., oon-.. diu !IlIlIl.o'.s"~~d"'" 16S0. Pal 5 S<-.l OG KIn 5 ~ j(f( KM J. COIIl' SJ. e..t.1 RL. Jt Woocl Bl. IUtt d60caes t1I' FISH !If J !--.oIlY QIllan Pen.n.c.~ORl2006) of hipIIlII C .... Il'l . . . . " . . 16M. "--:tl1llR, I1Dmy 14'. ~ ~ .... 1I'I_~dHCV~ (1985) T_"'cellll'llleIIItn~ __ GMlM....",.,,» 1107·1116 1611. PIkI!l<e" T"*:.D ~ResP!1r:::l179'.4~1 PYollucM"" '-'~ar>cl-r~~' 117.124 1695. "-:lllV.saw.aN 8rInlC RMl '*-'II'*" c:eII ........ca.g 5 &mil E.t..fal9aX.T..... 1rt IlIr.-O ~ JF ldoreaoi Jf. ~ ....... BlIrtc:o p....... .,II'!. 5MIpaI J v- E 16tI2. P.... AD(2006~ C~ WIdi'Igs Gec:wge F. PU P (2OGol) ~ . . . . 01 Nl( c:eII subsel I'l ~ pIIMntI .... pt"",""8IWlcl_ilfgr...-~ ...... a'ld ~ e-:.- 48. 2041.20SS - * " I'WtrTtlo- C\'II8Ilia.1n VMJ 20 3tl1-3&l 16U PIfIdoIIi F loug/lran o-r o.e- ~ TP Jr. EurJ lrmUIOl 304 29J0.294G 1696. P.:N a.buiT,cr....WC, r.tozellit Chen H. KilIes RA. V~ T ~JC.DlRoMoC ~RW,SeiIMo F (199(1), ClnQIl toIQe a'Ml prt9'lOIIS d !hi Pwtol\I O. V~ JIN. c.roI"l KatIz.IE l.-.:ln RA. !lIoorTI\ekl CO (2006) ""'- ~"""~d'1anularlyrlVooo Pfil\1'OSbC ~G C'/IM.AII'lllbl::enW SUl1 CanoIr&S 341-348 16&4, ~ F, Fngeri F A.. SondooI M, Ilrlg/llII F. ~ V Luciano l. Sthn C Del Veo:too L, RokllI B ~alore F (1996). CornplIlI pI-.noIyplc lIf"(l ~ ~""'llI SWtIdI ill ;I ~ ~lXl5'ti,e acute tymplloblaSIIC: 18;.01<_ l .... emia 10 741.745 1685. Pent F. Frigen F, SondonlI lA, Lu<:iarn L. fermra F, C>mtIlCl R. Melon i G, ~ G, Sat;alCfe F. Rot<.>M B (19961· N&Utroprnlic. c:hronoe my&iQid 1tU1.emi;l a dlSllnct disease With a specdk: moIecUw markar {BCRiABl With C3IfV. JIInctlon). Illooll 88.2410-2414 \686. PIlQUlllIll Rl. llJnclaw EM, P....re RV, l<1lt1an J, LlbberI ..., LeZaKlO 0, 1$3il<. G, Mo:;C¢rmIdo; F. KCMllllef HP{19931 N... mula· lioos art ~ IfI'Itt1 pooO' ~0ljIl0Iis and incre3Sltd nso III leukema '" ~ e.-. synOro...... 6Ioo:l82. 59G-~99 1687. p~ A, Allin C. VllienlP {20061 P3I"ogerwIM. dncaI tuhnt. and lreIt\'lllflI Idv8tlcft Il'l ~ 8ftl Prad R~ ClII 1iaemIlt:ll19: fl9!>.615 161&. Pardarlanl A IlrQafl\ll'l 5R. P.l8rIlo.Ier SF. Fiyrtn He, ~ RP. I.a$/lO TL HoCL U cr. 0ewaId GW TMlwi A \2O(l() FIP1L1.roGFRA Moon prw;tallnot /II'ICl di~ CXfTllI*It 1l'l1l9 CU'ltlIQ;live PIIloe .,..,. . "'YlIlIJd cllIoIllIrt.' a Iludy d 1182 ~. 8lood 108 30472·3,47& ~ d KIT moIaIIoos -e)A Ik:\llIt myeloicI .......,..... ""'" i'Iv(\6;1lId .8.2\): a Cancer anr:Il-.1<errU CtOI4l Bsw,J can Qlo;.oI24 )9()4·3911, 1696A. Pedlka 1', Mareuco G, R1WIfI AS Whitman SP, Mrozek K. MaIIerr; It l.angIr C. 8aldut CO. lhiIO W, PoweI BL Baer UR Camlil AJ, Caig&;ri MIl, KoIiU Jf:, l;JfS<)!1 AA BIoomf.eld CD (2006). Wims tumor I II" mutations independenttv pr~ poet out:orr. ,n III)J lts With cytogenoltlCally i\OI'ITIlII acuII Iwkemia. A Cance, and L&Ul< emia Grwp 8 stud\' J ClHl Oncoi, in press. 1697. Pa&q""letti P. Festuccill V, ~ II Casale R{1991) The oatLJr.ll Nsloryilf mooodooaI III"'1rrJOl13Ul'1 01 undetemwned ~ ~, A 5-lQ 2O-vear I(fuw~ 01263 c-. Ada I1aemaloj 97: 1,4·119, 1698 Pasql.l3luOOl,lI$O AMa '* R (1998) 8Cl-6 "**"IdIr9 B 101\ ~ I'lIlOl'l\il QiWIMlIII alb ~ d KIffIaIIl: h)'I*IIIAoulI-de Ig Ix> Proc toiall Acad ScI lJSA95.11816-11821 1699. "-qualucci r-. l ~ 1. ~ G. P ChI9ri RS KullP"'$ R. OlJIlI·FaW!tll R l2001 ~d"",~" Ek>III 00It.M ~ ~ .'2 J,.Il·)16 1100. "-n:lnli F. l.WINrtla l. 0!tInII E e..C, e...v.t A.. ~ E ElarA::hi 101 An:wi L CaberkJn S PaKllltI C.1..a1:zalWlo 10112003 ~,.. . . _1'1 rtU'll ~ f IlIlly 011 . . ~ ,.. 01 ~ ..,..... . n ...... ~M 1).1' 1m. P - . I I F, ~ ....... E "'tani L ~ C L~ '" Bem8sconi P ~ 0Ik Pt,I CoUIilo 101 , PaIcuIo e CC'Ille III ~ 'II 12005,1. ~ • • •,...., fA llCJl'Iqt"."Ml a 1IirIljlt SM)y fA 23 pIlift'IlI Cancer 104 1ll32· '**" "'" ~ F.RtmE 17m. ~ E ~ L Bwlamn P V...... M Orl:ant\ E M:to"" L, BruumolnJ E, Pa$CtJllo C. c:.zzot- ,"" Morra E. Lazz.n'lO '" I~) Lilt expecl8t'Iql ~ prognosllc Iacbs lor _at "p!JlIenV. WI!h ~ ';ffiI aridll$$f1I'I101l1 I1rombocylhemia Nn J Mod 117: 755-T6 1 1703. PllIIa'TlOnt, F, Vane,I L, Mal!l~ L, Rum, E, PUf\QdIM E. Makxr ClwtsMIs JM ~ H, IW'tI Ir,I, ~ P,," Stile! CA [2(03), Pllldillnt ~1IslIc syndromn and ~ "'J'lOo..:..:x,.tc~ 1'1III ~ p_. of nXI8nc:e 1l1d,.,..121 7!l8-767 . ~ Illdy .... ~J~ 1715, $..I, HIm 11,1. SliIlIr CA.. ~ P s......., GJ, Gtilo:n S Rwvw llRChaaeIIM(1!l961 ~ ~ . . a ..... dee~ww:ta_ll't'9" 'UIlC1COTIiI~ Blood!lS 1U2-175O 1711. PaIII Il8 '*"*-l AN 5ct*' CA °Aculil ~ ........ "-' 1006' ,............ Ool. bIlIIl CJ1Ii!l t.o_ ~drN(16)'l(16.16Iand.~d. . .· ..... LU RoM 3D- 22S-2'32 1701• ....... AD G. Hedge U,.... J GIInI 101, ""'" £S. ~ A.. PalnlnIS NJ. MaorI 'Ml (20051 L~ gta'Il.lbIIIIlllIII: ...." • • • rJ!he brain at MRIIMg- "* MerJ4&W8<:eIlympto'na a SUjy d !IS l'i5lomoIptloIogIc IPIt*\.m based on 109 c;Ilift t+.Jm PIll'O 30 118--187 1713. " ' - R MaLoIes E IlrJIo--Bat4cUI v UIIi- H HIdges l.I ~ J. D¥er '" ~ 0 (1991l. So!l8ty all . . . . . . , dItIncl T0IIII ...... 01" a_lorII'lolT lIfO" ~ 1BuI<_~ leu~ 11 1009- W" 1714. " ' - - 1olG. NtI le 8eIu ..,. ~ Xl, ~ S. Kernwl St.. COIWI ...., ~ EW. ~ El y~ (1985) IncJ..-l nutnllen 01 _ . . , . . .....,. till I6IOCIiIIed .., a 116:9) 11'1 AM.L Ml J i"lWnM:lI18, ~ 1715. PelnonTC wet>erIey-Mell'l G \1919) TheCllUIIII . . , ~ 01 'o:l1OlllllhJC eryItwocyaI& c-.1.lIb H.....,. 1 189--196 1716. P8<1f1rser1-6I"rgaatd J. em.lill_ DH, Deslogeoosis of therapv'lIlated m~.Iody5plaSia ar'l<1 acute mtolOod ~~1lI'ni!I L.uk~mia 20, 1943-1949 1711. Peh SC, Kom lH Poppema S 120021 FrKlUflllt pre1flnce of !IUblype A VI' UI in Ej»I'"".!larr '<'II'IIS-omIaIo!JeS aI Uq32 I 11'1 T eel ~ irMJM two orocogenn Pruc,... AcId SciUSA 96 ~9-2961 171' ~ C B"rIIe $ ./ego G........ D RobAarl:IN.?r-D RawMJ ~ RPM] A.'ftd III ~ rJ al56 /NCAl.I) on ~ cell II a !IIa'nwt of ~ cell ..... _ .., of ...... JUbseI of "'lAIPe mNIar!'4. l.eU The '*""'* 1120. ~ B Temer-laooorft MJ, 0bIm 0 lIlilInc T. PM! Y. ~ Y. C. EdIn C, $dltniII. C, ....... D. e-c ~H.V_JP.t~e. CoAIult G. 1labo~·EloiIeklt A Thuret I. ~ ~.~G Del"G.~ P8n;. J f"OO,] L~e-pred~ HodgIunI ~ 1'1 chklren ......... ~ __ .... lymph r()(ll! re&ICIOtI---e SIUdy rJ the FreI'Ch SocifI!)" of Pediatric ~~2312M-2n 0nc0I0gv J ClIl DnwI21 2948--2952 170l1. PalIe C, Auperm A, GItrrafd Iol, Mochort 1721 , PeIlIl P, Berger R llerrfflm A, Srooet JC, TSllPI A (969) Mok!obr aMlysis of a 1191. Hpl t qJ2) hnsk:x:aliu1 occumng ,n • CMe of h'Ulnan alpIla herJ\"f chai!1 dl"l!ls e J, PrtkMon R, Spoalo R, W'lS1oo C, RapI\aeI 'd, ~ms SL ~ K. Caoro MS (2007) Aesult5 01 the randomized inwna tiooa l FABil.M696 "'II lor inlllrmediare risk B-(OlII r'(;"N·!odgl.lfl lymphoml in children and adolll$011'15' ~ ia POS5 ". I nt, P-.l C, Lfl T~ A.. Cayuela JM, llMja A. ROOIrt C MoIne V, D\.tIlutrtll l (19'11)~~~ ~ cnuse dImg melhl*e,* !henl- lW b f*lI1MII A/ttI 0fIrmII::j 133: 861-371 1110. PM M 8wI' E (2l)Ot) ~ T~ ronc:ludlng ..e !UbIypes) lMr'W'IlXlI'QIIlL _ ...........".... 89 un· ". 1711, .... y Ilt'lo E, Rogj) R. ee- E Kl..... S IOn', e LMzarnl '" Ban:nr G, .......... ~ Sww:ci "(199S) ~1· ~~"""_~rJ" -....dtoiCllJPllW*YC ~ .., sliIlt5I>011 ...,. d 86 e.- '!I'UIicolr*ic: 'IIlIlly toft III E ~ Drpiz&lrl b" ~ IIId T..........-.t of Cance< eutanflous L~ Prlo::Iject Gm;p J Cllrt Ono:d 13 1343-13So1 1712. PIuIl.I, Slr*r J, Gollnali U, fbJsMt NT ~ LJ~ M, QrIi1f'l(\i E Klfisy C T. Morra E ManegoIo:l C. lamnno Y , Ltagnni U, IoloIler ? (1'199). ~ 4' 653-M 1 1722. Pelopone$l:l jM, Jr , Kinjo T, Jea"ll KT 120011 Human T-<:eI leukemill vius !;'p411 Ta ~ and t8!Ull1r IraI1s1ormatioo, In! J Hematol 86. 101.106 1723. Pam]( I!l91). The~peIlemof ~ ~ TllIf'Sfiant Pruc 23 1101·1103 (1_" '124, Perez..Qrdonez S, f<1andson IV..Rowi J FtIIoaAat ""'dnIIc <*I vmr- ~ (II 13~,*"of.9 J (l'i9l1J f*"-~cl!iltumor _01111_ Ml J S"ll PaIloll0. 116-191 1721. ~ E. 0fI S V PiAl! A P~ A.~ r,I~C,UItldII F. ElMn CD, te ceec r (1997) P............ an.1 cMi:lII ~ rJ 8cU Il1d Bd-2 ~ oonIo'p... '" noxlBl dAM IWglI B-aII .,..... ~ J P..-a 163 281.2@6 1729. "'"" Ar,I ~ot"ofri B ......... ~ '" ~ J ('i9it ~ ~ due t:I a poIIl 1I'IUlItIIiDrl1l'l ....... ~ofC095-.o­ ...................... Iyo~. . . . . . qn. _ T-ClII~. and HolIr;;orII di&~ F, Wcw;nann e. • LC 6loorntIeld CD flr\JrI*Ig AD (1918) 8IllIl CNlI as an inlIiltI ~ \IIfItIqI .....oileIloon rJ cIwtlfIIC ~ A ft!l2Y0124poolIenIs. NtI J Uedlll)- m220 1731, PfIllnon lC Brown SA, CrouoII r,lladtnCWlc J 1191l6) Appicatoon of tilt ~ led\nic 10 bone I'I'IlII'1OW l'ephtroe tliop6ie!in !he clas5i1icalion aI pel>enll ....lh monodonaI gammopa!hie:l Am J C.,-, Pathol4~; 644-693 1732, flelflrson le. Park ,~ JL. IIrtlM DC, e", nomg RD 11991), Acut~ basoptriuc ifIIJ,nmia A clirocal. morphoiogic. and cylot;Jl>n&lic stud';rJ fli9hlcases Am J Clon flitlhol96' 160-110 17$3. Pelerl<;ll'l If. Zhang Of (20041 ThB 811 in levkemog_ _ _EIIP~21,~1 mo, ~ laJ._ rr. ~_locabon ()rc:(lqerlII2J .2!l5-4262 17M ~ 8, JIrllil f. JoIy B MnI- Gama N. TIIy H. PICfll.*d.ll4.Ilr.-e J, 08neI C Mehaol S Abd-AJ.s.nad 1 ~ C, 0tIl'....urue M... Gaulowd P (2OO2l ~ • ~ ~~enIIy~~e . . . . . PyoI'o:n<...-:ilMd _~ot""''''''rand'''oa;:aaillf'lII . . . . . . . . B- nI T<:eIlNtU~ "'" J ~ P..-a 26 rn-732. 1735. ..... T. 9agol 101 Wileonle R 8e)toI-8arry '" v.,.. B 0elBtrey M .... CJ. ~ P JoIy P Gr3nII" F (If A MadlM L 00mcJm;nt A.. llosQ J. Dtnch A Benowd p. 0IliJc S 0echeIaIle P D'h:an '" WectwiIr J Ttillol Mo\ (20051. BlIIIsk NK-QII ~ llI\1l1'Uar CD.l hemaIo- dame neoplasms). a IllYie'w Ml J can PllhJI 123' 662~7!l 173$, ~ T, Comeau "'R, Mayn.1d_ '" Cou~ G. de Muret A, MallSZllllrSl Dsl>te 5, Our!fl(:h II, (;ali!lef\ L 12002) 'AQrBn ular CQelI IympllorMl Mglnatl5 from • population of CD56_ procIlrSOf ce ~5 'lIJal>Jll to plasmacytoid mooocyles. Am J Surg PI!lt>ol 28 852-862 1137. P-et,~I~ ~l ~ , T, Daloc 5 M~ynadol r,I Thc:mnI'l E. CouMle I' JoIy P, ~ 6 MlOUld l WedlSifIr J. El'IJOl '" Rleu> C 80"< J, Ami"". Bernheom A.. T. ""*" A. DeItat-Larue r,I.... GaUaId P D (1999) C04' CD56. eutanIOl4 ~ ~ ~. , d ~ ri!Y' Gt!qlfI FfW'ICIS ll fhJde lIM l~ e - (GfElC" Am J Suo;/ PaihlI2J 137- .. ' I't Se!tWl o.gn PIIlhlII IS 144-1504 1731 . . . . T. Oebu-l.wue ...., CIlIul O. 1121, Perw~ E. ~ I,Ill Mailio G ~Senz R W, de Coca fIG GlIIrcleJ ~ G Ab>soJf,I,. t. ~... 0 I'orIifIrIi G.Wwnf P, Fan:eI ... Arno:Ud L 11996) " - "'*'" e--.a.-. ~ ~ ~....-.c.b'1 m iderlIty rlIk 01 prtll)"MSiorIlr' 1'!lOI"lOdonaI II*"mopeIlofof~~and smcbr· on; muIIiPI rnyeIoma bas8d on rMJIIipW. . . . law cyIOmeIy ~ rJ bone mar>o'W pIaanw 17)1. ....... T. 1.4e'fe'" CJ 0alIc S R Milynad.. Y. Mad\e( l e.-rov. 0 V~ B. T. . IdA (2004) TCL1 ....:l eLA ~ '" itgrenullr cell Blood 110 2586-2592 nauII kJIIr 0lIl <;ngI' w,-.- COoIiCD56 rw'i0lvOeil'l'OC ~-ClIII Med~ CIinPathol 122" 301·'13 a«u" ~ lymphoma IM!h C052 .. ~ T-oef ",....... I. . ......,.... 92 566-561 1741. ~!'P, " - ' " S ...,... C I'aoIniS ~C.P~C"""" G v.-. G, ~ L4 PlIan SA \20071 IltyeIo::ad _ _ d ' " an ........ CI\IIIi dI jlIlnice Reportof me CIIIIS and . . - dI ........ ~5O;802.a 1712. Piltri SA. Aseani 5 eo-. IIC CampjdeIi C.Bacei f Pia:ir::' M. PlaaJge pp AgoiIJnelIt C, A!Joli S, NoYero 0 ~ r,I Pon:ltIni '" GfIntie A. RI\IIdt P, F....-.xl V, VrIceIi D, PiIen A .1", Galbolrra R, f.1Ino e, ZlnlerilPI. 6fIcciuni '" (2007).Myeloid W(l)o mac ck>M::n-pethologic, pheoolypIc and cytogt- l'HItic _ 1)'SIs of 92 Ill!OI)IisrIl5 (~ tymphomasl ar 1739A. ~ ?P Agostir'ofIlIIC,~A. adJ ~ pllt>l!lllll. lluhme 21: 340-350 1143. P!1i E Zonzano pt , PlccekJga PP, I'W1 A, Jr. GU1ti M. faMi 6. Solis Ga. StooIi (20021 1io:Id9kin'1 ~. lh~ P1~1 ..... ~ J ClI'II'aI'd 55 11;2· flti 17". Pfter, SA. GaldanoG bIzanoPl. F_ G.ullwd p. ZUox:a E PllII'I F I*ta E. SabIIn £ ~ $, Pll::ci:llIM JoI'tlton PW, Gi8niini R, Pe1carmone £ ~ D e F'IrX:a.'IJll!'P t.t..-"T,AklnkI"'CMIl~ (2003) """-'Y mecinW4I 8<.IlI ~ ,.., ~ of BCl.~ _ancIlD'MlII'ite~rJ"~oon""" ot DCT·2 EIOB I. and PU1 . . . . . . . . . J ~'62' 2.3-253 174S P*Ili SA.. Gmgatl ~ +WIll M.. '**P C*'¥IO E cr...,.J( ~ _ R. o.d G.Oa WdA PC. Fain S ~ RO G.iWd P GaIllr KC ~ PG .bills ES IO¥'l P Knowles OM ~ OY. IoloIl $ ......... Henr'**- HI( Pa;& WI.. ~ E M Su lJ. wa-e It\. WIlissLM (2OO2l TlmlfS dI hoIliocytes Il1d l1CC89OI"Y derIIiIlk: CIk Ato ~,.,. ss. ommuod ncaI ~ t) <:InIMr.:aiKln !rom ~ l~ SIlJCt,t Group biIsIKI on 61 C3SIS ~ .1 '" 1746. I'Iltn SA PuIfoo:l K, MOO S, "'iISOf1 DY, Saba",ri E, Rorw:adOf G. PIceioIi M,CfIccareIi C. Pla:aluge f'P, 5ant".. D, lMone 0 , 5t.", H, Faijni Il 119911 FIllQUIn! el prlSlioo rJ !!Ie ~ Pr,I . "I.I( d11'T'1ll1lC!uWf1 protein In ."ap.-.stiC ....gfI-ClllI lymphoma. ~t!Ol)tJC ~ Am JPatlloI l50' 1201·1211 1m . I'>ldlowska ME, FlaIow1g IMJ. ~ .... Pm40us GS (2007) C04'ICD56· hemM> detn*: flIICIPIestn fblM/IC flIII.QI ~ cI!iI"""" phome"l flIIOIlIe*cellfI'pn!S5I11~ dIo"4r1lo: osI ~ar 8OCA--2 and ll'OCk.Ice ~ AmJc:..Pakill211 «5--I.s:l 17.... ...., K Sdorroon R, D!Iubw'*llI .IJ SinclIor-StnII CC 12004) ~.dyI*i .... dnlIc oalI!IlI!tO'lI a fllPOI"I rJ tu ....-..c ~ III'ICl ~ of . . IIIrIbW I ' ~ « 283-2'11 17.'. PIom E. M.a!r.ttwlnI5nI. t«. F.e ~ e FdW C, Gtonst K 'NwIIoaIl J (199ll\ Ger'4 1'1 T-oel ¥""UIItdIot: 1127. PerrorllI T. f rizzera G, Rosa J P 986) ~ A ~ic sll. ~ PaIlof 27 121- W'i.~JW "'-'n A..lopel~C ()fao A.. s.t ~ JF (2007) Nl!w aoIet4 t:I FlO!BIl.I. Bas:so K Zl4'O S Wen! p. Klwl U ZI'\aII PI. BlICl.:arIro M. DellI F _ R SA(2OO7j GeI>e e~.....,.. 01 PI'lf'>. . T oalI ~ lII'IspfICIIialI . . . . . . WlCt ~ and _ paIInIiIIIlw,,** •. oats J ClirIIn>tIel 111 123--8305 1740. ~pp ~C ~S Z - Pl.. ~ SA 1200'1 u;r- rJ "'""" mo _,.+ •• ~ JParo 1M ~ E PUiotr:l Il ,JcrIea '" 1dltlIIt· tterrnMrIk ..:, f .,; B R.....- E P6Iri S PuztII F, Wdf-f'eeIers C MJet 0 S\IIi'l H t.Iaon D GaIlef K (1998) Co-fI~ 01 CD19a (JCB117) and COO by ~h~ l'tmotlomI J Pe!IIOI 186 l M}-l.tl 1751. PinkelD 11998) IMlfllnliallnll ~ References 413 m~ _ leuI Blood 91' ~367 1752. Pinl<usGS.SIiclffl(19851 ~'. lJII-., ~ ~ fVpt, r<Jdu. 1Ir-ll dIIIrld S'lIily? lJrlq.le5lWWl9 profilelor l&li VIIW1lS of ~ cell ...., by !1IClI'IOClI;ql-*'Odoel1O lIul .,.., ..... and 8AJro JP.rD 118 1~ ancet '" PQSttrilis~ tuIlcalego<1ft InCl EBV SIa\lJS Transplanlatiol1 ll(l11\>- 184. 1715. Ptw1ll R. ~oo P, ~ M. Ferro L4T, COfI'ltSNtti /10, Pef(M'lO /10, ll Iltrrler9J lAG (2005) T-cef fllCeQIOI' glWIYl\1I li gnt ctli-Ifl I;lepo$r6. Am J Kidnev 0.. 42 11501-1163 1m . P..... S, FcunIlIine T, RBtIekl 1.4, .leiit' E5 , I'lRiIlugI 5 (2006) IQD plltIb .. llM ceh ~ • umque IUbtel 01 f'O:llIWIr IvmpI'icq-1B preclorlwIInt ~In Iyrrclhoma. Am J s....g PIlhoI30 ~Z 1153. F'wlusGS s.JNI(l9ll8J.~·' lII08 rearra'lg(!mer>l ~ fTII/bPe>: ~ ct\iIl~ '~II'IP*r1l5 1MIh ~I T~ lymphoma i\'l¥Xl5l& .... lli&ua.~pliOb' ...... ~ >Ulu- godBII5eZ8ry srncwomel MId ~ ..,... BOIII"..,.liIlIOn L8 pciyI::".,iiC tIIlicn:Itn. Semon 1tiItnIlllI38, 11). mIb'V"'" ~ """ dncaI, !IIII)lr.JgQl.-.a ~ fnd-.. Br J 1m , P.-.ud Hcnwne Jl, 0Irm8JI1S3 56!>-513. 1766. PonD:n M, ~ G, GWd VE. Del Clft) B. ~M. ~A., Pdoo S [Mnoroy l Cogne Iol (l9i4l l.4onodonII ~ doI(loMon dII-. (RnII cekpea6c;~ 1Ir~"-":'lor • H ...... oI~ctII~ 126.• I*\BOIII....... AmJ F' m PInIo "- ~ RE, Grtnt 1I1. TIWeIWI Ct.. 8eIa-Il ON (1990) ~ 17~ ~II~"" l£lIl.)13 Mod PIh:Il 3: e.. S PIll Rtqg 1/ eo.; ..... P(2001). 01 RBl II IIWlII-ClII ~ l7S5. Pw.,a'" J,~"-~E ~ ~by~,.RHA~ ..., ~ " /IICfOII'f~ . . . , . IIood 109:s.tZHoI2e 175'. PwlpOI Ill. CollO F. 811I 5 __ P frWyIdI I F~ I'l ~ . E. A.,CIfIPll E {19!lI~ pl6(1NI(.oII11l"'t c..-. ~bydllllDnl,"""""Il'ICl~­ CISIISII A., P - . C (2lXXl~ lid< of co 29 (bItIl "*'PJJ...:J co Sol (lCAM-1) ~ onolecuIe5 WI ....iJIWl¥ ~ HuIII PIIlDI 31. 220-226 11f 7. Ponroni M Bergef F. ~ CitlIwlt C Tif9IIIf' ''. n- "- FIl'Ttfl AJ 0II"0rv 5 T"","" ... 00gIIcn C, W. J Cer1Ili t.I lIMWi M LmlinD P. . . . . T, ~ "- "-"it E. Sandlez J. !llRy .!'f RIll III CO'lalri "'- ElInorl F. ZUoca E e-.I F IknKri B (2007~ Rea:;INe ~ T· otlI..... ~ ~ iIll"lWY cenhI _ _ sysIBm B-cel IympI:lomM. Br J l. c:aLOIII Ill. 1WMlilol1311: 316-323 1718, PonZOI"' U FemI!I AJ /2006), ..-..~ .. ~0I'tor. . . ~ ? ....,..,... ()lwi 1<4. 1«'- 1lII:Ii't "'..... P ~I'l.~ E Car!lIslI "- lqm.()lrl C. ~ E (199n 11ft. Ponrono "'. Ferren AJ. Campo E ~. - . . . : I " ""'*"'*l1nCl ~ ...... of~WI'tym. ~ 1757. 1lIood11 Zlln.15l&l Pt¥J "- ~ o..o.lnCllOM 01erp-_ 01 p161N1(4 III'IlI pZlW;I!1 III"'" lit MIOOIMd .iII . . . . . _01,....CIII~ Blood llll 1758. PlnI M. llrO\OI'I OC G.- KC, U DY(1990) COJO IXJIIWSOlll'l i'O'I-HodgkIll ~ l l'*'i*!-*'QV17: Z11·118 17$9. Pllrnw1 SO H.-.g a. ~ cw ~ EH. CIo JD, 8IfliItI JG, w.u lM Wang J (2ln'» t-Il.>dgIm~. pott. hriIPInI ~..... l:borOtIlHl'" PTlD) ~ ~ 5-cIlI pnD bom eh:tlIy MId ~ AIft J Ssg Patholll . 7~76 1760. Plltalugt S A~ TA, WIrJdarska I, 5~ M, Clltin'llWl JJ, t.IIlcucci C, I/IIro Otn SM, VBn Of VIIn WJ. Wo/t- PIII.1l C 11~) Bel· m.zeo 6 e1preuoon ", fu cli Vlt tymprlOId t_ IIIId WI 8-c&Il oon-Hodgkln', ~", J Pa!hoI179 145-150, 1761. Pltt.1uge 5 , VlJtIoefG, Criej A. MIIlII A, Nuytl J. ~6 M, De Woll PC (1996) P~noslic Mgnl fiClllCe of bon-e mar'uw trephine and ptI'Ip/lerIJ blOOCl ' "*,,I in 55 patltnts w.1h rTIIt/1Jle cell lymp/lOmI leuk Ll'f'lPI\omiI 21:115-125. 1762. P\tI8Il1,lol 5 , W...,..sb I, Pullotd I( CInW E. ~ SW. VII'I din 8M WoII· PMlBlS C (19911, The m:lOCJdorIBj ~ AlKI . .~.... ~ ~ IWlype 01 ~lil; ltrQt 011I aI!Id WIth 2;l23iAlK -» ~ _'.~1II, Am J PIoh:ll151' 313-351 1163. PMI R PtIIgnno E. r.laadiM. ApI l. lllll'b8llli l,lloc:aIIllI F Colla G, Ruggeri SA et.lg M. O'itllt R p~ G. ~ A. inpwII G (2006) F...aiontI ~ 0111I ~ ~ ~ IIgnlIIlon IllIntI. . CEBPB tn:l BCl2Al • 0'llJetl Urge! ~ JCliIItI_ 116 3111-3182 17601. Ptnl HA '*""-" "- SdNidIr A Medl:ItC M Choq.iII 5 ~ v C1ItrIr.IM F. ON F e - D . ~ E "'-"-BrI.nIII IoIF HntfI I. ~ 0 .... It. Co"...H .• ••rt P p..,- M. TOIM"iOt 0, "'-!y .... 0..0. P ~ U f2lXl!l1 ~""'01~""" 414 References H2. F~ F. Mauurxhelt l YO!tIIOO T. Mula!lll T. PWi s,A, 00gI0II C. Zucca E Ci.iilI F ~ 5 (200n 0eI<W0n ....,raboi. mo. i1'IBe1il9 J Clti DncoI a:nsenIUI 25 3168-3113 ~ e. ZhIng B, Grf!9Olre MJ. ~.P ~"', BOnba\mD. PfbusQI.o& MJ (1999). The ~6.8XllZl·pll) nnllocaDoo in II slenl eel m~iI\I'Ill dIIOnllI¥ ~ II i'lO\'eI gene, FoP, III fillroDlatl facIor recepIOr 1, Blood 93, 1381· 13ll9 I'llpperTlilS( l960) Thelli\rlll"iilVoIitIo 'mm~ noh lst(llo9icil l sl. ini"ll pattem 01 ~ 1m. Sttrnberg-Reed 28 l aa-19t. ~, J Hl5lcchem Cyloctlem 1112. PO\IPIIffiiI $ 11:/89). The rl8IUrll oIlhf! lymphocytes surrCKKldingRew.sI!llnOOrg reI~ In ncdulllr ~ mphccyte pre 13S. :151·351. 1773. Porw P. Noonan RS, OraLi /10 {1m) , Spito&ctomy in agno<}lII1it myeloid me!'pl&si.I 8k>od 93 2132·2134 1774. I'QrIlcd< CS, DcrneiIy Ga, 0r1 J. 5traus D. ytflal<)-n J.l.eiBnoll A. No)' A. O'Came:> 0, """""'ll. 5, c, F'wa 1771, P1dIIl JTi1OO1f· ~ mer;tw. __ . - . d ~ _01~ " TOWWd G ~ P. SWbrl.~ M.RoecIA. type) p .1l~"~"'~"'IlJl"I.11 of ~ l.'I'..-. KdIty h "6. 965- on 1710. ~ e. • C. 60IMiIl N, x. ... TiQIUIll. lit Bolon S. noRIIoulI E. L-.lil C, e.t.qlI 5 F _ P.~H11OO2) FlIIOlIbltlJfOV'O*tID" r*ra! of CfBP/Io...,.. ill ~ . . . de IQIIO xuIII ~ IIUItme: ",..,. 01 ~ &.rtIt'11l'IlI~'" B 011 ro>-8lrtII'1 ~ for ~ ""'" gtflOlIIIt . . . . il .... ~ Elr J H.-:JIIJO 21·32 1181. Pra SK jlW)f Irmu.......... srnII I ""'1 01 13 c.Bt . . . . . . ~ . . . . I......."*':N 11 1_11 1782. ~M E1C*\IP ..... 1.ytbnl M. SII'Ichu N::.. lit '- rA.,1kolIII F. ~ CA. de l~'" (2004) F'fognotIc lIdorI" Hor)g"" ~ LM ly:tlllllomll45 1133- "'. 1183. Prlyb'fiskl GK, Wu H, UlICOI'I WR, f illllfl J, ltoltllWd 00. FelgwRE ~ jA, NoftII PC.s-tllcM- SM. KIdn ME. 'II. MA, SII\aIly KE (200)). ~ end IIUllcu~ partllCUllhl-lol<. garnrnl'diIltI T eel I)'mp/'Ior¥'IM iII'e Oe"v!'d from d.fIa Jr.klIDilg n2: 11·j9, 1784. Pui CH, &~ rllp~ lol, Ribeiro RC, N'llffift)'\'" eM (2004) C~iklhood a'od Ido4HCM t Iympllcld and m ~e lcod l&ukelTllll, HerlIQtclogy Am SOc liemetul Educ PrOlplll '118·45,118·145 1785. PtJlfool K. Lamant l, Espinos E, JIs"ll Q, Xu« l. Turturro F, Delsol G, Morris SW (20041 Thtl - 91119 normal Iod ~_ rel.ated roIet of anapj;l!IIIC ~ ",¥\ale, ~I Mol Life Sci61,1\13fl-2953 1188. Pulto DA (20041, (1997i O&IktlOn 01 ....pIal;lic 1.,mphcmI ,,",-~~dC DZO~ kinMt (AlK) and riIO:leOIIr proleiIl n~ mill (NPtol)·AlK proIeiIlI .. nonnIl lind p*uc .".. ..,;m the morlOdontiI ,"hbodv ~ll. RleG-S~"" dBsslc=lI Hod1'inIa. Br J HaemllIoIl25: 101-1013 _ inS. PtJrwo~3k:l /10. J.OO$!;Y G,Ivay K, S'tmky 0, ~ R ~ K. Walkei' H TurtM A GoIdI«lOe N-l e...>ett /10 (1996) ~~ ~ idenlified by ~ b~. IV CO:W iM!rU' IftIS'OO II awlI ~ leuI<efl'lilo U2 ~U82') 8kIod81 1162-1169 m!lA. PouaIo G, MImiro C. CtooallCl M, t.IodaIo MI.. Ceselli S. IMzzI G SullMI S F _ F. T.... P. Morell "'11!l9() la.· P'e ~ ~ , nec;aIM C VIM ....... ana ""ell ~ 8kIod Il4 30017·3053. 1m PIlUI C DAmoco Ill, F~ GB, C\nlIlI 5 1'. ...-0 F. ~ S ~ G. ~ e ~ S. I.O(;JMIi F (2003\ '*'" /loL KI Bloocl89 13901-1-404 1787. f'lAs;p/leI MA. -'d.ml RH /lo$dl J. PlI_ _ fB (2004) ~ ~ 01 JMloll ~ .. h~ IM'ftIaIed IIogenIIiI; ~'" 10IIh cyttq;ludoi loIotoId ~ 01.1 IllCl ,,~ . .....-.oe for. p ...... ---...:_ e/IIIel rI ~7 JUr.lL, &q t.lanow TI'8I'II(lIInl 33 113-115 1188. PttIIoDT.S,o_tlR$.Oka'lOIol 0.... JR(lm ~ m . .... W-O~ ditti'CIIn. L&I ~ 67: 5-23 U8l. QIIlI Y. G _ /lo. TiIIt" MJ ~ B, 01 MM 1A*......... 11K {1995}. So:J'I1IIk ~ .. ~ ......",..11 cc~~~1k:II ~ 1lIood1l6' ~ mo. Quarterman MJ, LeSher Jl., .It.. 0... l5. Ptoo\illisCG, t.lulim 5 (1995) R8!Jdy~ ~'" CD61llls*ve 0Jla080us T-eel ~ phcl¥l\il WIth Ion9W irwoI'<e.... nl /10m J O....1IIOPatool17. 281·1\I1 I1U 0utIn ER CllIn CH. '*lIoct KG Fot.ng SII, FiirII M, levv 5 (20011. The B-otlI ~ d II tllIpllIIli5 C WIlt (1'IC1/)-llstociiIild nan-HcdgkiIl ~ bQIs Iht ... E2 ~ prlll8ll, IfI\IllicJ\Ing HCV 11'I ""'" phcli'..... _ Blood 96 37-6-3149 m2. ~ PG.1(3jIIdie SB. 8ehlIr OW .Jc:flnSoo JT, s-do;M st1 (1997) SIt*l' gltnI:llyn¥lhoid IIIiInIes ~ .... ~ ~lnKInI.ll~ _""4Il_(Ilj'lllC. an:i ~ 1Ildv· I1YIII PIif'oI26 850-a61 1111 0uIi..........18Z l. lR.--HII T FerdF ~W""'J,~L~E .IIIlt es, RBtIekl t.I {2003}. _ _ rJ p111t4l1 ~ ~ cr:*' 01 "1)1llCiI1IIll till~ ...... 01 011 ~ (t.1C4 "** ~b'~_ilIolIIll01'3'81­ 31" H94. ~ l FtrIll F. "" lR ~l.~tM.Kl9ntDW ~ .. JaIIESjl9llll1 ~T-1:IlI~ IiIIII\ ~ 011Io of 1k:II"", l'IQlInlgtrlill'flli! _ _ ee-.!lin' _1Ileaion Mi J SI.rg PIifII;t Zll1»- '''' 1115. ~ l Frankln'" I. KIwI8cs l.!9'eih l(N ~ C. Br'IIIie K. Fla/Iei;l M.. ....., IT 11. ~ ~_~lI'OIIltrJ ..... NKIi CII ~ km f'w' ~ pnwIIBrICe 01P53 ~ HIn P1IIoI ''''''55 1798. OuIrlarIiIla-Uarllnez l. ~ III KlIer G ~ lol Gimboa-OoInngut "'" " " - A., lur>a-CcntrerllS l, CIllrw A I1oe/Ier H, ldohIr /10 fltlld f (2001) p53 MuIIbOnS ., nI$8i natural lA!irIT-011 Iptphorna lrom MeJia) assooalIon... 1Irgtl:eI morprdcg~ I:tId advanced distasI. /10m J Palt1cl 159 20*-11(15, 17111. OuonIllfiIoII-Milnnez l KII/lI;I'S FltIIl F. RlI)'eI E. T8IU)';;--fflilj$llWl J, KirqrM OW Sf JafIe ES 110001 FUI¥lllrlllnl EBV(.) T~ iympIloproIIIr. at,ve d,~r klIowl'"il llCUttlctlrortic EBV inte<.1Icn a <:bIinct ~Ihologic s)'TlCtoole Sorbitra L, Rattald M. Str_ Blood 96, «3-451, 17118, OUlntan.lla·lolartinez L, PmBl uga 5 MielNng C, Klier M. RudeiitJl M; DaI'leS-HJJ T, An;r;lasoy N, lolartinez A. Vive«) A, Duj'IW J, Jaffe ES, Fend F, Raffeld M(1006), NPM-AlK· depIInOenl e. press>oo cf the lr1lnsaipllcn lIaor CCMTienhiJl\Ce1' ~ prolIin beta in AlK· ~lO$l1p..t anaplastic large C$I lymphoma Illoocl 108: 2029-2036. 17M. Rabbani GR, PlIj'likv Rl. Talfwj "'(1999) A Ioog-Ierm stud)' of palientl ..... dIronoc NlIInl kiler eel ~ Bt J ~ 106 96lHI66 1800. RtdteIi f . Mau.BR e.rtn E, On A. I'omBb lol. MaICIlo AT 12002) AoJle,....,.... 0XVk........".,--.~ .......... ~? ElI'JHaemttII69 1~111 lllOl. ~T,Or3gosOB.BaArP (19ll1l GIsIl..llMfIill1l ~ ~ oIlll1lll1oaJEllllJOIItId ~ - . . ‫ן‬10­ m ,..... XI ~ Gwotl_OIOIJ 102 10163$ ~ M.. $hubel B. Wolrnr S PwIp:IeIc "- ~ U. F"",,**- M Ch:II A WI paIierS _llW. T ~ .-raIlI& IiIeIoog ~ CIiI 18111. l200Sl High . . . . _ c.anc. Res11' ~ 111I). RIaIi:Il JP, 0.. H w.n r.t, 0elllIr v. SchtI.- J, DrI.*a' B. ~ C. SllIII II SbJi W ....... ct. 1'.-..:1 $, U1IIloI' PS ~'1Ip1I$SIOrI (20061 d\aII9" ~ .... PflllIItsSIOII and NIPOI'8t on dwtIIIIt ........... P!uc ..... Ac.-I SCi U 5 .. '" 1m""W, WrIltIl JJ, tClbll E, !II • IIt3A ~ ~ 01 lI'UBl toIocl.- .,.... ~ (iIomol>$WloIIId ~ ~ C10AeI geran . . ,1!Il;21 ....... ~ . . . . e- ReI 1987 412!lJ7-2!>0'2 11104. ~ A. ReidIafd l ...... 1&05. Rao KR. Sawllsk ~ A Cronkit. EP, ChfrIroB M) Le'W)' RN, PfSlfm8cIo BS11975), ClrocaI IlIg><>g 01 dtronoe lympllOeJ1i<; ..~ BIood~ 219-2301 1 .. R.nondo SC, PIlI CH. tIfncod< I.l., 8fMI FG Filatov L RIVlII'I GK P996) ~...,a1~ (51~nCfllltlood IClM' ~ - . - l.flNriI lit 1107. "'"'" T-celI ..oIpb' ~ ~ ~ 7-cel1 ~ ~ on . . . . . . drI- ell '-*JgICIl end ~ acly Ea:I 0ImII0I I ' 31.)ll 1111 Rnat 8, Stllll'IrI ..., IUIit JJ (HIM) ~ 1)"llIIOOIf" ~ 01 SIlIIII ......... .. Iludy 01 13 ~ .. "led J 47' 221.22ll O::mil*ln ... cases ftWodl SUty G cum... en... cancer .. _ ~ ~ p!IInoI eel 8lood 105 311-323 1122, RaIIer* lZ. ,..."... L Toy T1. ChInL ~ fW W GrtilIn Ra KR. ~ w- A.1 M) S/IlIlh WJ IIuaon PG ! I ~) T~Ek:lII~.Am JSoJf1l ~ 12 43J..« 3 1514. RandaHRE. Wibmeon we, MulliN~ F, Tl'1Q MY, Sb!1WJ 11976) "",rlile sl/l!ions of 1~)ghI cIl>lon dIIlpo5ition, Am J I-ded 60' ",."" 1115. RarOMl , PU\llt,lC FIbnI F, Si\lMlI l . l, GII:Un'i A (2lXlO) F-..rtIIo 01 ~ on d1i1dhood' I SWy 01 ... ~ Il< J 1'\-.01106' 86M 1"1.. RIIIdolpII GJ, ""'9fI V s-u w. ~ ~"*,"",,IO""" IilIloql ~ . . . . NIl ~ In"vlol 5 611Q 1117. ....... Rai _ . h.~.' S. WwtlbIf 5 ....... 5. .... R(2(lDt). Hr:xlgUI--lM lQhl",-' lytIIditoIoer II d*lrIn. dOlI • dIIII frnoII P'*QrI$pIlonl HoGglun ~? P.-. 0.. Pah111 34a-J6O 1"1. RaplIael t,I. Gen\IIlomme 0, Tl.6tl t,I IIvron PA 000ID0lcl J (1991) Himpel!loloyic fHlorK of Iligh--g rade non·~ k",'5 Iym· oI'o<>mlI5 1'1 EteQU ~ed immunodtd'c:'lfllC)' ' yr'!. <J'omfl The ,rencn SluO~ Group 01 Palhology I:lr HLIIMIn Imllv lodefid .ncy \ll r~ed T~1l'(II1 NrJo Pill td lab Ued 1t5 15-20, 1111 Raphael t,It,I AIJdot.on J 1.11""" t,I. 0IIIduNI HJ Vuollilumtl t,I, l.enoor G.... CiIIItJrtdIt C. lem.'\1< CliIrlo:*l J (l9rHf, II"'."........ )G. NeuboJrg OS. ~ ~ 'OE Grw-o-. A. JC. TJ t2004). lN'·1O COfllPI'W3 ....... ~~~ ­ lIOI'I SlfU • • ~ of dis&a$e progr. . IjICflln ctJooic Iyfrcnxy\ic leukenlla , N £1'lgI J I.led 351:893-901 1823 ~ AC, GIeeI1 MJ. Kw:md.' .., Keronedy F...,tQl1 JA. Eyoos PA, O'Coonor SJ, RlChenls SJ . Morgan GJ. ,Jack AS, Hillmen e P {20021. r.Ionoclooal B Iym~&~ W1tn trill d1l1fllct9fl$tiCl of .~ dlroni<; ~k: ~.milI ... p~ in 3 5%01 adults...~ 11«. mel bIOQ(\ ~ Bloo:ll00: 635-639 1&24. RallI A, 1lucN"'ICiS LU. L. Tilw S. ~ II I on ~ I'Il¥Ibd~ SInwl 00'lC0l 3U59--J6ol 1m ReoI8r A. Will C. W~ A. SchocIl C.lllII u I. Sd1~ 8, IlergerU,TeIorII N,Arullah S,Yin JA,V~ D. BarMf HI', TaylorPC, 0'0ntc0II "'. IlenedIlb F. R~ C. Koib HJ, f-Iochh3lJ' "', Hv/lImllM R, Chase Res 28 7i1-l103 ~ CA, HarI5O!l CA. ~0Ih .....um.a c.-.oern 1526-1~ . 1826. Redaelh A, Bel C, Casagrandoo J. Stephens J, Bon.rnan M Li 5k,n B, Palho\lC (2004). Cinlcll and epidemkJlogic bUfl1en 01 d1ronic m)'llklgenouli leuKemia. E~pert Re. AnlicancerTr.4,85-96, 1827, R...... A, 1.II&k1tl Bl, SIep/lIrts JI,l, ElonemarI t,lF, P~ CL(2005), A s~ iterllure _ a/the cirU and 01 IlunJIIl 01 IICIM tymprotliasloc ......... lAl.l.l fur J ear.:iEngI) 14 S3-62 1121. R. KJ Kadol LIE K."uch: t,I. Ko Yti. Go JH. Sulunwy.t J KtfI\ OS 119981 ~ ~ ,:Alt!). ~ T· 011 tyn'Vo'IIIl """ ~ QIIrnWlIl tl8I'to WI. Am J ~ PIfloI22. tw:w;5 l&2IA.Reed JC (20081 Bd-2-1alMy proBns ..a rw.,..-...,.c "*9.IOeS. hairy and fulA pIOICIIl:lI lllood 111:3322·30. 1829. Rf9l'" A Slarl< P. BldsIeJl D. L8Iao "''"'*'lr c.e ... (1997). 11vombocIc compk:a~ in _ _ tiiO ~ ~Sl reIIItioaly low lJl8telel c::ounts, Am J Hem.alol 56' 163-172, 1830, RIlid"oarO KK, Burh EJ, Fouell MK, Wil$on CS,VllWolfIHth. OS, IiozierJC, Larson RS (2OO!i) C04I+j C05ll{+) lirreage-oog.'lb\'e mahgnllrOltl ar. JllfI futI'IOr1! 01 .mrnw:ylcllO dendn\iC . . . Am J Surg Paf'oI 29. 12741283, 1831. ~ llJ( UcKennil RW I e-",*,* 1141. FlIrllIDI Ul . Rober1s RA u.w TP J/Il. le8WIc ... !lrantI RW. _1&_ "",,00 OIIflWC ""*~ lIngtf ceee HIt JIIII ES. ~ RD. E FudlI Do\. $pIIrUt, F,*" R!,o-.J. RotPMkl .. SIIOOl LW. c;rog.. TN120011 Loll of I.lHC .... " QIOIIIld ll"*""'~ II difIII!,e "'9l' Ik:eIIy!1'Icl/lomIl is r1lllIIed 10 dIa8llsed lu'not m-nu1lOSJ~ IIld poor palienl &I,uYioai r&gIIdless01 other PfllQIlOSIic l&Clors: ~ foIlow-· up stUdy trom tne Leul.lIfTll~ arid 21·JlI I147A. R<J!l .lA.. I.OIIll DC c...W.~H Potoca CS {2002}. T-<:eII tidl Ik:eI tyIr>- 1135. ~M,~$PugtlG , EAYI C. sna ." Car'IIlI C. A _ A 12006) Or.:l:umn:lt 01!'II JNQ V6lJ'f ....... 1m on lie WHO ~ enIit)' rnyeloo:IyspllSllCl"'yelolltokler~ .. d1seaw. 1.OldassIll. ~iIClOry ¥!el'I1il1 ..... ringed ~ '5110C",100 OIilt1 malted lhromblxytos;$ ~tolog,;a9 1 71fJ.no 183ti, Remstein ED, Do9~n "', £1OOfSOO RR. PatenloM",. SF, Fink SR. L... M, Dewald GW. 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KaI>s P (2000) Lowo- ~ polInIiIII a/ bCflI ~ ~ IrJr ~ . . - 8ClIIrI choomolll4".posnM aeul!I tym- ~ ~ ..... !.,.......... ~ ~ 1832A RetIlr JT (200S) Cy1ogenet>c IIlCl IfCIIllI:Uir genMic .... 0" MS, 'IlIIOolIIo» 1&25. (2l)O1). ALK~ . . . . IIJ9t Ek:lII tyrllpr.:ma. ,ep;lIt 01 low ClMlIIIl.- 0( \l'lI 1Il!nln. Mud PIIloI llolALT 1yIl1JhJmII) ., NorII ~ Am J Burg »: 1546--1543 1137. ~ ED, ....... CD. K..-. PJ (<000) n:idIrIOt IIld IUblypI ~ a/ APt2-1U.LTl Uion ~ ........ ill u:hnodIl nclli3I n IllItnC ~ lUll lyonpIlornIs. "'" J P.a 156 11&3-111l8 1831. '<~ C ~SlbIIo .ll HlnmaIWl I.l.. Soebet1 R (2006) MoIIoJlIJ ~ -'Yf8S 01 ~ 100 ., noot4f tym. LI D. ......... t,I CllIudary NI, ~i11 H. ~ .lA. ~ t,l1. "'umtu t,I Geztl' 5 ~ p. RPIy p. Gall N. Ca-ldono A. Sf>ger J. ~ G (2004). AnerOc ~ Caslle VP (1994) 1113. Remsay lMw;o JUI~'. ~ ~ ...... on )ll l./tP(lf$ RinIy.lJ ~ O. s..otra PO. liloomIPINA Rodlbd R, wteon .... l1OO71 SC*oII ~ aI !IfII3WIlI(; BuroA. ¥n~1I",-~01~ WJ c.ar 120" 121-127 1101. 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VeIllsquaz WS Iti.aqoifl P s-..F~"""'~fB.F. 0.::0- bCflI_ 1MIhoI.... in dA.- lIfVe-<:IlI~' • derCI LJ,l (1991) ~ IrluWI Jl5k "*Y -.::oIIId....,.eon- 01 ..... J Gin0nctlI9 236-242 PO. Neonlan RS S, .kion1<, Orazi " (19\171 013 (C099) ~ '" IwImalOlogiC proIIer.lions COfT1IIlItes ""lh TdTposltr ~ lympllomt wiIh ~ e-.ctI proillfHon' moIIcuIara-.em of lie <*lntl 'III81lonIhI&l ~ lie Ic:AcuIar and II'Of"OClCYD:l Ek:lII lXWl"()OI'lfI'l. lIb k'rYesl 8(t 1593- 159!l IIS4 Robyn J L.-y 5 IkCo't JP ~ J. K-.. YJ, PId< S ~ Tll Clunba- C, Qon AI) (20061 .......... ~ollllllllllon9fIlI ..e on flPl lI!POGFRA~ ",. . _ IOPI* ~ Sf J ~ 132 286-192 liS!. RoctQd '< . 1olJ. ~ ~ (<005) ~ 1lo.AaIr"' ~ .• c..r.r.:n .....,,1ItI\bII dIIMse? , . !lew t.lIattJaI 3 162·181 lISe. Rodog SJ. Abr'an'«In JS. PI!lO... GS Treon SP. ~ OM. ~ HY, Sr rlI:KJlll3Iims ~ !lOlls 01 HlJ\ elKS II genes in II-eel lyrnpllomas nng '" i"'~1eged """ Bloai 96 bona lor the 1158 0( alemtulUfTlIb (CAMPA TI11H). C~n c.r.c:et ReI; 12:7174·7179 1m. ROOo;j SJ. Sawge KJ, LfCasce AS, Wq /\P, ~ lolL SloW MA, Hs ED, e- Stabilics~. 1'17~2001. NabonIl TAAF1 endllUdl9r c-Rei ~ ~ C¥lCIfNiUe. BefwlIda. t.IO ~ ","'On 1844. Rles LA 81 1/ (ells) (20041 SEER ~RO,II.ulOIIJl(2lXln E~oI Ita'9I r.elI W-- rn:.n lIIII.- References 4 15 lypft 1:1 dIboI lItge 8-a11lymplloma . ...", J p/lcfTl&. fl EngI J Med 346 Suf9 PlItlo131 106-112 H.rbQmg • MYC 1~ Am J PahlI 32 113-122 1859 ll.~z.JtQ60 II. Vidlutli-dt II 18711 , R06tfll\'ald A. Wright G, le CtuzH.~C, RllIl~R nt. F.... RI....... TP l l/Bbl'lC M. C/lIorelZl 1858. Rodig SJ, Verglio JA $IIaIlMl ... A, ~OM(2006) ~E~ PatIems t;J TCU. C038, lW1d C044 k:\IwllIly W- l~ s..rv (2003) ~odIlIo"." c.lI ~ ChcIIl -.cl~~I'1'~~.lid! ~ 186CI. lab Med 127 74-751 ~ J P Ucl.IugIIIIn ~ F8F~l~Mol sn-go lll . . . M c........ ~J F (199ll11 F~ IIrVI c.lI ~ .. . . . . . . ~""oIlIn~..., llP.orZIt ~ ...... Blood t3 2202· 2'" 193 7·1~7 . genas lfomllpl 1 tT-'ocabons CIroc:erCel5' M. ZhIo H. 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Iar• Il.c.l d lid T "lIIUNn 1M3. RoB!ICM ltlP w..u~e.-.C WidII'o$ LJ (2001 l~ ~ ~ 11604. RouI 5 I«ll II. Xu F ~ E, le e- 101M. lncI'I 11., V~ JW (1996) ~~..., ~dyIptt­ Ila UtI'« ~aID'I d III ~ able' ~ syndltvll8 LllUkemiilll) "". 11165. ROItIMg K3, Morga/! MIl (2001) CtAIneous ordNfmflllle 011 ~ • new Il:'rlI:It c.lI >1Wiarlt ~ GendnliC celsarcoma JCuI3nPalhol28 531·537. 1866. ROMf'lhe 9'" 1867. RCl$fJl\wald A, Allzade-h /lA. W>dhoplG, Simon II. o.Wi RE, YU X,YHng l. PIckeral OK RHSMIl~ LZ. PoweM J, BolIt"fl 0, Byrd JC. G<ever 1.111. Ch/lIo(I BD , cr.iofaUt N W~ WH, K~ TJ, Brorwn PO 5t,udI LM (2001) RfIlatlOO of lj&1lf! np'" J,!OO p-henolyp4 10 ~ mlJllotioo 98"CJ1ype ., B ceo! <:tItono:: ~".me J EIll '.led 1~ 1~g.1M7, 1S&t. ROMI1Wald A, Oll G. f'lJlIoril K ~ T, l Id.cn OY,~~ !of{ilggg) ~1,2l(q21,p23) arcl ~2 3l(p23:q211 1"0 ~ ..-....t tr.'IIloce. . . t;J lht .2.5~p23q35) i1 ~ atlI~ Bloocl9ol Jll:i!.3&f 1869. ~ A. WnghI G Cormrs,ll.l, Campo E FW. RI. ~ RO I.Wer.HermIlinl< If!( SmelIncl E8 ~JI.l '-'rtEI,l ZIl;oH ......ell Y.-.g l, WiIIoorl 'Mi .WI8 E5 $HncI'I II. ~ RO POMIII J. DA,o Pl lllO9l 01. G<.....TC ~ 00 SIrp WG 8J l)'l'dl X, V~ J ,."".... JO ~ E wv- cr.n we. e- llCfIy l.esoms iI1d ,tqaoenl SoIl· T N E"IJI .I Med3012 87s-aJ 1m. RoiIc8ch HC (20015). F¥IllIaI inIi!I'lIiIe myeloItlrosr:IIS an au1l;lS(llnalll!ll':eS$iw dt!J(lf· del' ~.-nang d*Iren lrtm Saudi Arabie PelIil* Henli!IlOI Oncd 23' . ~ 1674. RosII G. Ocnsi A Ca&ar1 S, Re A. Cadeo G. CaroIi G 11999) The irllernal>OMI ~ lrIde. ca'I be used lIS a gOOe to WIllI Ir8atmerll deosiolls f89MdIFlg patoenlS W>It1 ~um a n ImmlJ'IOdefioerlCYfflls.-retiltlld systemic non ·Hod~ k;n Iymplloma Car.oer 86' 2:m ·2391 1175. RO'ltil!J'1O A, Fril lefil G, Ylagan l. Kun'la< A. 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HI( ~.JO (19n} leW" "- ... 001>- ~~ my~ ~ 1Iuk_ .. dVtri: by o:;tenWied ~~IrlClc.n.~. ~ 2.(3' 290-293 l A S. Rowlty Xl (1988) ~ Itudits ill Ie nofl-HoclgIUn'slympl'cma:s . . ItIII 01 lPle 1.(;18 IrII'Isb:a\iorI J ClI'I Oncd 6. 919- m 1&86. Rowley JO. OIl'4y MJ (2002) 0 ."1 "'qed. ~ Oncd 13 1<10-1 49 1897. Ruggen M. TMelIO " Fr-enetl 101, ~ F (2OOl1 The . . o I ~ 10 ~ 'oOfi or 8SSlf1IIaI ItroorWc,fltma i1 ~ ... ~ III ~ Nfl Meo:l 139" 41O-f ~ IIge . RW: A RMdII U. SwenlIow SH ~ M. S1reIbel 8 Proc:clp G TuID RIl. Cook JR (2007J E>hro?dal ~ zone 8cellymphornlls oIl1lll ot:JJIar il\IIICIto l~ f "*'" adnt., ramelef llIll!Il5 ~ "... phBr.e ~ ~ lW1d PCR b' C ~ ~ . AmJSoIy P3!hol31 m· ~~onl'te~cA ." poor Itlerapv In bIBnced c:tlrllmoeome ~ bons in "*,,py_tflCl ~ s)'1\~ Ind acuIt ltuI'OI LB, Kfl9mlI JaHa ES, Soilocinsk. KA, Iion:AIone marrow transplantation . J C'in 1899. Ruro:l O. K~ y S Bw--oCol'1lIfl S ~ fl, Kedmi U IoI<JW< E, Gural "SMfran.TikVllS, Ben Neriah S Ben Yi!hOOa O (2005) ~-rnIaled leuk&ml9: dI1itaI~. aclnties and analysis of i'I6W moIeo.ilaI risl Iactors fn 96 adlJ ~ patie!11s LllIJ.e ow Onrol17: 3122·3127 188l1, Rozm!n C, Mo-nt~rr't E (1995). Chrl>nic; Iymphocyti(: iflI 333. 105.2·1057 1169, RubensWn )l, Fridlyarod J, snen A AIo<1pe I( Giru.ingM 0 , !l8tCflelor T,Tf-'!f P ller9"f M. ~ M, PnldoI l01I, Kan:t1 J. Okao:ta C, Hyo.fl w. P"; kl1 S. ~ C, SIunen 1.1 (2lXl61 Oene • •pr8MIOfllWld 1I~1n ll'f'llWY Cf-jS ~ 8100d 107 3716- 3m 1690, Ry~ F. Clm!nl J So!btr1 R. Pins MA, u.lIl-Subefo JI. tMlInclII' I• G.Yt>I-ConOe J. 0...- MJ. T8f(II W F'I1ka1 O. MIrbne.!-CIment (20051 MenIt-oII Iyrn- J" 98rloI'IP" r:l8nWliecl . . CGti tJ !lAC ptIOfIllI ~ 330-3~ 1893. RllCO lP. .....".,.;iyS dllII'It• III.II 1171 ldaklI9S E, Calovsl<~ 0 (2ClO4\. 8--flttJl~ leukaemi.a with ~ I U 4) f8~isit!(l I ~ form d m&'111e cell lymphoma tvo/YI'Ig wrttl leukaem.... 8< J ~ 125 t\'lle U r'(lWJI~$lepl'lowly~ le8lIrc l01I 011 G. 1<"*1 5, o.IItitJ HoII8H KrIld P S**V T, SQu(!I LM (2002 The ... ~ F, ~ E, GlIr8rld 11. , T~ P, l.e\>IItY P Ui JL. CaP8flO'llS O. MByt\IdIt M. . . . J EIll Meo:l203 2.f2S-2431 1712-17" 1m . ~ S K!ause OS, ~ Co' i)nWI CA. AIIllt\I F Crtlss NC. VlIflE!lI!In RA 12ClO4) o.liind ... cell m~ l.oclez--&.*mo 287.2'18 \ 880. Rwnillf C, Edactle V. ~ l01I , Q3v; ... "'~ 11tt1. Il.\tlniU .IE, RWnord SC. Tong X ~ Ql( RazzU 81. S/lurtIIfl SA e.rvn ,m 1900. RlJ$kooe.f' O\WIl1eSlraux A, 0eIn'er ,., LaYefllnll ,,", MoItna T, Broosse N "'udouIn d. Rambaud JC (1991). Multiple lym ~' polyposis of tile gaslrointeslinallract. PfOSllllO" 1M! d1nio:Jl>8t1lo1ogic study of 31 QlSl}S, ~ O'etude de! l vmphomll! D;g.,.tik GaSlJ'Oe<1tellllogy 112 7·16 1901 . Ruskol'a A, ThUll R, Chan G (2OC>l1 Aggfessil'll Na\1Jf3i KIII6r.ee.llookema I.,-t ,." 191)3. S!cdI S. Yintl G G YIIIllie "*" 1lieIoP'''''''-.e CroricteiGMIC ~85 492 "95 s.z ~ JR: PuI CH Rt.o RC FC (2002) F...,.. ompecl rJlelt9'11) in CflIdIlood .,..1nyllIold IIukamll J CfII 0r0lI2lI 1,... AI Seel!oJ MIglI hIJ Pwaz. RllISIdo A e-aCflo Fl DiN A GtIu. Jf F...,;a U 80Idl 11. , R~l"""" S/oI 2302-2300 1m. R ~ R Pwoy-.Jones ". ~ 8IbIpl* V Aa*lD I WolherIpocn AC ~ I,l RomeroC ~·Ven»l l01I PriI", 12llO41 8olIlIi "*' Nn J PallD 164 613-022, 1905. s.~ H. WiQd A.. Ra&.la1Jl GZ. ~ U (2002) ()nw,n ••. . . - III "'Iligoa'tI ~ • ~ 01 266 c-. Mod Palhol15 1221.122l! 1 ~. Salle'; Nol. ~tian S. CQIilI TS, T,roiOOu", SlInzeI TT. GeniI JZ,Gooo:lnwn BI( (2004) II'lll C)109Il'IIlIc chnttIlI· ... ~"~I at za1D'l lt42211ll'oOMn\l !lie ~ ~ "lI'O" " pIMaIeldIlri*l grooo9I facIor ~~ geneI" • . . . . ..., IIypoCII chn::JnIt mytIoi:l......... ~~Clnc.-40"-50 1907. S90G.~F,~E FngtnF. Eluor1MAo 101Ft ~ A.. F (199ll) I ~ ~ 01 ...... "",""Pl909CRJAElL-.:* by chrI;lnol: "'~ •• l.qnued ............... ~Blood87,'07S. ",., , . s.n r.-..nD It, K. 1. . . . 1(, 'illlcK, t1nW.Oroo T r&lftllf.- S, __ II( CltrOtII K 0I'n0 R r.-s N, _...... QOO21 ~ ~ .., IlfOlI"O'IIC 01~...,.. ~B<J~l'l882-1&5 1901. s.l M (20071 ~ ~ Hoo:lglIMl~..,a ~ Mo MIl PaI'lDI U 1.194 ' 9" . Slid IN. sr..u iP ...... H ~ S. eo- J. ......, G.e-- E NIdOr R. KoelIIIrHP(I999i ..,......"..~Il prIIWy . . . . . ~-~(lli~ _ "'" T~ ~ t.Ied 121 151·260 1911. SlId HI T.... T H AIth PIId UtI T~ S AIou dlV05S.e-E.~OM ~HPt '9Q6) ~~~ III _ . ,..., fA!IMJ etMI 01 K.Ip3II1 ... l:lII'IlI /Illrll" wus ... '..-0 ~ ~ III I'uIWl rnrrullllleicJlllC1 ........ I'lII98IMt -.on'*l. B~ 8ll 3121-3128 1912. s-l W CIiIWI K, T-....:tu S, laMb T Aioo H. ~ SK, e-m.n lllO:'6 in 8 celI~. Cancel Cell12 zsz 2ao- Wl<eml35 'eflecI !hi ~ d ~ 11M· N, Oka T, Y06/Wl<J T(20081 gtI~ ~ stIIlIll TCfl\llffimldelta~ T-ceils I+.Im PafloI36 tifi&.672 lUI. Saolde lMOA. ~ fA. WoW\llm GT- . t.lalNws loll, Mak\dl RW. flldw!lalwl AS ~ (2006~ ~~ Y...c T Fernandez dS. Romagosa II, ~~&t:8 E. Pe A. .. ,...... 0II1ympo'n1: • ~ dI>oc. erdoKoP0:.. and ~ 5luItf. Am J 5..rg PatloI:rt 1274-128D 1t17. SMwmI I, Pe ..... ~ aro rrdiIaAar pIlrICq8l_ e -~~~ (.eul;emll20 505-513 1927, S;;UIde' a, Middel P, Guna"'311 8. Schhn HJ. 8Ium f. GolM. MM, Sd>uIze f, G!allt.- E. ~ R fuzw; L (2001) fOlilW! denclIik c..I ...a:wnI of IIlll tpIIen. ~k!lJ&.gPltlol16 ~ c.a.. MIdeJ'oI U 1929. S¥lclI< Weu Ll.l. Me. JIfI. ~ ES (1992) LY""*"""'''.......,,'''' ......... ~ ...... CXlI't'tflCII'l 'IIIiIblt -"'''''''''lCJ ~ AmJ So.rg PIlIlOI I6 111(l.1182 113(1. Sano* YIIlD T. CII<>. 11M ...... C. UlIlgo OL ..... ES RIlIakl" ll9113j. ~ c.a.. ~ .. -..,,-~.. It;j. kYBr~ 9lDod82 1.20001 1J31. ~ CJ 1199.2) .........11>-6, 91- \1·16 191'- ~I.ZeaA.6NS,~V J. ~ E. on G, 'Nirip. G l.ll(le.l. ........,ard. . . 8laod7'9 3101-3109 ~ 00 <>-:o,ne RD,GrllI)Wl TW. DeutIIlI J, .ale ES ~ E, ...... HK, Sta<.oIlld ~ A, ~ E (2007;. SOedIc __ M a.b-.l.f1119ll5l ~ ~ . . . .:.1 drlocII ~~and _ _ /lISIodwIIaI1lody J P-.oi 22 )21. ~ ~ - * ' I s in ~ oeI . . DhomI pro.odlI ~ . " , . " . P»PIIldInI 01 .... 9ll"' ~ proIlIr~ J GIn Oral 25 1216-1222 1932. \1_ Go.lIIrlrlo A, "*" we. ""'""'*'" *'" 1119. ~ «e. F. WiICOtl Wi'!:. Ct\OI JI( tJ3 1 "- ~ Of' SIIBlon JK I'ltoII CR c.. aas U5 A 103 120-125 GP. Gal.- Al-, e..m _ 01 lymph ~JcWQI~~~ a ~ da5sIcaIior' $yIltItII'l "UIl PalhoI16: 1091-1109, OG &ycIo RU 0 - A. M (11197) Bor'I ,,*1000' '~1Iblln lor cIIflQc .....,.od _ _. , . IIIlecb of dIIImIIlMIlI b clIirw"ll dYInc ~ 011 ~ 01 .... _ nllWiapM Br J ItIeal*lIllll »35 1!M2. S3wgt OG Sl)do Rt.I. ~ AI 11!/91). ClN:3l .II diIgmM ~ Ul d'ro'Il: m,elOId _ .Ila cerh_a16-,...~ BrJ lj41 . ~ ~ S ~ ~ ~ --..ct ~ &JlIIh C<Jo.orbII 'I, ~ ~. DI VItI S ~ 8clDc:dlo M 0MvnIr.c0 f e.t:Ion _ ~ 0 1 " " ,C (11l96~ proIIIlI ... Iylnph ~ of .... !)PI • 111>«1 ~ nlllllplllllc or ~ ~ ...." Blood 88 «iJ8.4645 It». SIIllJca t.I. ~ Po NgtIIlinI l <*ItymcII'IQIlIII~~ ~ f t genotypIC analysis of aI~ (1991) ~~IklIII~.I UOlQUlI I'fPlI low-9'tIdt 01 ~ IIld ga'l'I'IIlW(lII $lII:lIypeS Ivn J s...g Palh:lI 22 861-393 1920. s.Ioum E, CooJ>er OL ~ G.1..acy J, T.... G CItI\Id'I J. &:to.ollz M. t.Ulen J (1996). ~ regessoon of~ ... CIolO:lPi*dCyc an:I imnu'dllQlc ItUdy of &3 ~ Caro:er 67: 2311·2326 1U1, SInIul;Q Id. ~ "". ..... O. t ~ dOSOfd8n 1Il pa\ien15 lINIed """ llemeogoMG, CeKwe!l'\3lufll . illt< c:eII o;ylaneool ~m­ eo pnm3l'J'-----va ~ AnrI ~ 19Uf.. S3w. t<J 18n5P\LV<8eM ~ F. . . . ES. COmer.; M, R,mw l, PIIti SA ~ III GaiImyne RD ArnIgI JO W~ 00 ~3!ICl~~hII!I ~noI~~' KcB, K. Qhara A. .... E, KornaaI Y, HO S. l)3IiI!rIt$ _ N~ ~ 8 2.•1"'9 1,. ~ Cl NItrt ~ IeYkamia ~llOa~~. dFoieloIlfld phero- twc ~sbcs 01 11 palienb 8lood 76 15M62 1914, $Ionly 0, L-o II, ~~ A, A. FlInctInG (2(001 A _ InG';I/loIogIc _ 5y ' - lor ~.. promyoeloc~ - - - dlslIngulIhIf ,.", un(Iellylng PW RARA ~ -lII'l\J8'I** Groo4le FlWlCIISdeC~~.UK ~ GrOI4l nl BlCIolED 1 ..... ear.. EI.I'OCl8II'I .......... ~~ ~~ 1DQoaII~ "'*'" saez AI. NaVll$IC. AIp'.I P. Sol Mid, VIUloclas R Camacho f, s.nd'IeL-AQI.*w.l A Sandlez E. PUis MA (2001) o..aI ~ .. ~ 8-eeII 8 c:* "1lIlXUd br 9Cl61J1l" .....- Y. Va",.,. H, ! '*"1 Ea proleio oodN' ~ 2 on P)'OlIlO!a.-3IIOCIllled lyTnp/IomB EpsleitI-8arT \'1I'U$ AmJ Palha 143 1280-1285 1837. Sulki H, r.canT~ t.l, ~. KopmI S. Hayalhi Y, lkUC.I K ~ I, T (2001) M)'eb:IpplNIic syndro're in d'okIlood .I ~ Skldy Ii 189 paberlD 1Il Japan. l.&«emolI 15 1713-1720 lUI. Sashodl G, T....... u 11 ShOjI r. J '--"- j,l ~ J. GonzaIel 101, e-.n. P ~ T, GasIeI-Iolal on.o A. ~ ~>N (20061. TCAjooil''''' ' iarge Il"lIl'JIif ~ ~ Jr. It) Y ~ I( t Clhy-... Jtl, Clfrtnh'u K {2O(l3J ~ _ _ of~1)"'- EJ. WIld H. ~ A. ... 00ngIn JJ. ~ Sa....-na H".... K I,bi S Pll93i Hog" e.Pf"SIOIl ollha ~ OIII-F-a R 120(7) ~ ~ ~,pp,1£1S 1136. ~ IS depenClIII OlIN ~ lS9c 205-213 1m . Sandbetg Y. I9l*'ll 1835. Sams A. Jhanwa' 5, Cabanlllas F (1999). C)'1'9E""'tlC5 fA ~1;1Il'1 di'>lllse In' Hodgkll''' 5 0iM&sa. Mauch P, "'mlllgl JO, Oiehi V. /Id$, L4JI>inr;:otI W6iltTlI & Wile"",,' oI"""""lIlp53 p16.1!ldp27 IvnJP3IloI 1lIood96 1287-1296 111U. S8IlO Y. Gao J e.- k.1lJlIgIq Y SrnIl PM. Bnaga G. Ptrrit A. ~ L. ...-.,g ~ 0I9Cl6.1JInl"I Sunl PlIItlclI ln pro" c::n:o. - ~ • .-.:I~ ". .. eI*Y " . I ........., lIMnbIe P't9'lll_lela l~"'. 653«18 1831. $aIg Y ~ Il T.-a T T. . it Uor*l T Slm Ii lClJnclll E Y_ 101, 0Iwa reoort-..n .... InIemiIIorlII PeemIarm T QW.fiMfa R, rtamli NL, ~ JC, Goktl TR.ShippJ.lA (2003) The molIclIIar !I\lflBlUl'll of mediaslJrlll Oi!ge lH:elIlyr\'>pIIoIlW <JHell from that of lllhot" diffuse large B~ lymphcJmils IOd $hares rl'iltlJl'e$ ",'Ih ct3uicaI Iiodgl"n lymphoma, 6I0o:I102' :l671·:l679. l j4 5. $3vllo E. Gan'lp(l E, MoIit1i I t H , SiOt;:tlel~ M. (1990), A va,iant bm of (2006) flwt'eso;ern;t ommur,ophlootypic aoo inlmphaSll cylogenetlc char(lCl&nzat,on g! rlOOai lympt'<Jplaln\aCytlC lymphoma, Am J ALK~ (In. brllIl Al.J(-p)SIlMI ALCl an:I ~ T-OIII .me.- *! Reporl GI EORTC CUtantoul 1~) 3I'\IPIISliC lllrge cell ~ (AlCl ) If Reed-SW:nbetg ceII5 01 HodgI<J'l $ d~ will ~ Blood 75 13·16, Ramai 5, de o.-~ MP, Rani S, Lampert lA, C~lovM:y 0 phomils l)'l'll/loma T3Ill Fa-c. WO!kVlol> Caf'qr 97. 61Q.B27 19 34~. Sllrgenl Rl, Cool< JR. Agu,le.-a NI. Sut'\l U. Abbondanzo SL, GoIifl SM, SWll'd1ow SH 17 In.l3(1 ~of~5~RHAin llemonw abon 01 hefP'5V~UI 1/'1 ~ eels Biood 87,4:l37....9olJ 1913. Sild,... T. AdviI'II S, Da'llUplll A, ...... orrOJ!\ 01 GrmlooadeO.~ Id.~ 1'.iIPl*'.' herpeswu, IKS~ 01 HHV8) io1 i>f'lIlWI e/IusIon ~ .,Ilr8SlNd...ral ~ ~ 1'-'*1 go:; 111-116 1t41. Swajja KJ AI Rap ,,", Yo. H. PIlIIl C. KlMI R. ~ Co s-orm 0 ElIrIIIII$ R.lesUl SR. RE. 'MIotI OM. "'~ GK. l.Js1Il" J, W~ l.tA. s-dbIr $It (1996). SubaAinIws ~ T_ rI>Iu'rellc di:seasM. J Oin 0r0:0I P~ """*\1965, .. gtlIOeSJSe:a Head 0, Moniconaa;1 MJ. ~~!et C, BenlllW L. f ...... S, Manc:n j,l, OudliI)'I'!I E, Mallon FX GY..., N, 90rg F, 8O'ldI A.. ~ loIII:..W 202·200 1916. Sai8f A. JwI1peQ N. BeIosIllo B, ~ E. ES\Wle1 B. SlIoef-. A, Romagosa V, G;nzaIez-8art:a E, p..... A. !>No C, NiBtJ M, AbeIi E. Sole F, Mn A. F"'*'ClIu.soMle A. B8Aes C StrTatlO S 1915. Oom~"" rneIhoIrelll1e lor I'l'IIIumatoid ~ and clhe< 14, 19431949. lU1. SalmI n. CoIn P, Kco'ponay-Szabo IR, L.IIunIa K, PaftY1etl J, HlIlIaI3 H, KiriWy R. l.orInd L, Rw roala T, lIIaki III KillJl" nen K (200)) ErIdomySl>ll MtJI;IOdy-nega\IW o:>eMc d_se, cIrlaI dlaracleflStlC5 aoo il>leslMl it\Jlo.i llefmo A. La$pif1el II, Pt~yci III. M I'I3lllt e , ll'Il1Wll l. Zatl1 A.. fior5rnan 0, G"lsroroe R,OIlG, Sieber! fl, ~ G, CiI«IlxI E (2006). Genom\: p'oIi~ "lliI1.-rIs dIl!erlIrtl geneIic abelrnlKloll in sys. IllIl"oe AL K~ 3IIdALK- E. ~ oommoo dla!3c:I!lIisli WlIh muww·assooale ~ facIO! gene mRNA IUW'J'I$~ of adIA. T c..IlII/I;lWIU ceI5 Pnx f'C!Il Aca:l Sci ~ 'eapiell~ ·Mltl ~ EJ)5lerl Ba!l "t G.w ~ (1999) QvtlIlic llll"bll --..a. NEng! J Mad 340. 133lHWO lj41. Scaran .... Boxnri P CamnlrojjI J,Nr1WSO\20021 T~Iacb,,*­ .. .ICUa ...._ ......... OIl .I '*"" Ont:ogere 21' )(22-3(.M 1~, SC:lllIIbeIo A. L. . . . B. """uO Id ~ A. file< w:, Kerl H. CoMfO'Ill (2002) C*IllOIII~_~pUl­ lIlIIlOu5 . . . - .I polenIlItI fIIdaII ... lie ttiitlpBl....".. cMgnclM of _ _ T- and References 417 Ek;$ll ~ Am J S""l P8IhQj 26 1259- "" 1951, Scan$bfti. JJ, WooIIold "-I, C8lonJe E, f'ho4loy A, F«Ten S, Qrchard G, R....... .lonts R v.t1~ SJ (20021 Fr8QUllll abn(lr. ofltle pl5 and p16 gw-oM r11llyOOSl1 fl.lngoodl5 and r.u"'y syll(lfOlllt J In...c "'*'" Dermat:Jl118 49J..4911, Scnbtd JJ. W<dorlI "-I. ~ JoneI R ~ SJ (2000) LOllI II "". 1951. Ii"" ~()I'I1OQand 11I._mIIlbiIy rI acl'4nced ",of~~ T-cil Iympllon'Ia all(l poatI6e ISSOCUIion IIrIlh ~~oIPTEN 1llood95 2937- "" notmal acute , NEJM358'1909·19 18 cylogen"'~cally IlI63 , Sdienl E, Elooso-Raml.lS C. Gills F A. Mar- K, MedeitQ& U i200IJ M..tln ~ leoJlmid C. Pan t. Diss T. I s - . PG (1991), E.qnWon of B-oaI l ilIigInS b'/ rtodgkin I *'Ill RiMd-Sl~ eels Am J PaIloIl39-701-701 IMS. SdIn;l C. Sa-venI C. Ii.-on PG (1991) L -.d Ii oelIs d ~ ~ ~ ToclIIIdJnG F (l9lllll MoImlIar fMUes 01 ~ ktiI lyon~ IlMlhtonIInl 01 pl6INk4A.163 and 0ft¥. ~J~107 101>113 1154. ~ AE WIodats&I WI ~ JP (2OOe PIltqIl'~y ..,bot....-.:l~~lJIIII­ ~,"'".oIJo11l(·STAT ""POK~ II . . . . IIlgIIJIrUif ¥'"",u,. c.lI Cjda 5 2571·25U 1955. SChaIar AJ (200'1 T~ N EngIJw.d3:50 121M219. 1951. ~C._I o.:m.r ~ pIoIu • lcI*ir P (2000 ATW~ ,m by ilI'IOIVlOIJIOb ~ _ _ mged SO!ftIIlI8sIs. a ~ d ~ Dul.".,. ~ a ....-v •• ,iIIlCibJt:IS7. 392-399 1Mi'. $ctiIrIitt C, ElIIogIl B. GtundI A IIutttUIl C lIQ A. Boemer A. Itom!Ji .... HI) ~ L.o E (2006~ The bd·2'JgI-! """'lgIIIllIlC .... ~ d 204 heaiIrl)' ~ 1lCClI'IIn(:8. 111&'" ~ ~ twtoak· pGI'1lI.In! dMIaO'l melra! ~. Leut ReI 7~750 u, Wc:CUe rs. ue CEo PiNl .11., Btumong RO ~5 1968. SdwMz ~ OIl ~ ~ V.WMo:bf OJ. (199ol~ ~ R ~ !se PIhlIl39 1281.1289 196&, $l::tlmill-Gtaeft A. Thela J Z". I IC~ i1M 120(2) EIWI'IbIl 1llrombo- JO d", Prt.:NIIAcadSciUSA~72m ~1CIIl1ZIId show ~ 'e!ft1lOn Am J HOdgl predonwnar>I 1953. ~ A, Moore PS. RogfUd G IrqwJmi G Ilb'lIrMor N ~llZl 1,1 , ~ d'IaIIges II btIod RIIWfOlI CllII i:IIoooiIg lJOIi'I' ltc· A",JClnPalholl(ll·67.7!> 1968, ~ S. Ba<:/'Ier U, HalerIad> C 0angIIt A, Krober A. Kern W Ha/emd'l T (2lXl81 0Bteaim01 an LlPLW5 15 mulallC1l\ln a 1Ct~ 1ts7. Sd""* C SMgartIII.- 5 RiIJlll*I GA. ~ H l.idlIIr P P999) SoR.Iic AlLl lIlIA;iIiDnI indka. ~ " . of ATYII 8-011 d'foolc ~ - . . . - Blood ~ 743-753 1ts8. $dleet 0, Horny HP Ruck P, S<mllIIzIe fl, Kai6ftIg E (1967) St*tIIoy,.... ~ 01 !hi eylIlid. A caM IfIIXlI'l MIh... i)iIIl'8Ierer'IaIlo ... ~ 01humIItI '* ..., oftlllllnlure Vi'clIcMs N d> A PIhlI Anal HiIIopaIt>oi 412 &uIi mat I _ ".,. liS&-'. Sd'eIIer E, .... CJ, ~." V1o;Iten WA (1'l8O). Dermiklpatillt ~"""~Ih)' aro;l ~ oode ~ 'II my<.OIII MIgoidaa, e-:a.- 45: 137-148 1959. Schell., E, Met;ar CJ, _ Il\ol." WA, 1WIeml& R l1~l A ~ 5luc!)' 01 lymph roooes from plIt>enl! \'11th lilt S8.1:l ry ~J'""rQl1\!l 57: 2375-23l1O, 11l6C, SchlegtlbetO"" B Wt!baf·M.lltuIMn """* I( HlmmJer A, aartel& H. $onoon R, KuM fl, F . AC. GfOle W (19941 CylQglnellc fin >ng and karyotyping '" Hodgkm'a d._se Leuk.mOl 8. 12 ~ l Ml, ootc;om. on myelood_ _ ~ B, ZhiIng Y, W&Oer' MatlhieIan K, G,olB W ( 1~) Ott«*ltl 01 ~ elones in ~ all e-n 01 ~ munoblalll<: !'t m~ lI1y .. ith dyIpro~ T-<:ell ~ bot COII'itlrIed ~ .-.d mIlap/'IaM C)"toganelic:l Blood 64,264Q.264a 1962. ~." . flf Bennet A, KtllO.lW J, &IlMilrT ~C.E~G ~ ".MorYB NoedItw_O, "' R. P..., R Ckmer 1(,<>-- A. Dohrw H G (200'1 nNr:IuII dIilI-eu.l ~ of paIIn5 aged 16 10 60 '1M"I. , an brding .......... myeklid lauo.-.• """'Y rJ til ~ MY'ICJid ~ IrlIIrgrucl J '**" "'* 0ralI22. 37.1-3T50 ..,... c-. ..... re.auea. II boll ~ II'I ~ -.oj ..ncDy IIIe'Il\iI ....th mged ~;lI'ld~,l.eul<_22 lK9A. s.:m.g. S. KotI TM. Ii3Iellach 1. KIm 'N, I-liddefrwon W SpiI!l<ermar>n K. Scnoch C (2006) KIl--D816 ~5 III Atdl.l-ET().posilMJ AM. are associaIed 'OJI'IIh i/lll)iII'8(lllVlll'll-1me lJnd o-aI suM~ a! Blood 101: 1791·1799 It70. ScMiItge< 5, Schoch C, Kern W, Mtcl>co C, Tschulk C, ~ MF. Ha!ellach T, litddilmann W, Falini B { of re~ progl'lO$ia in acut", myelogerloos ieII k~ m ia ..-i1l1 1 noonaI karyotype. BkJo(Il06' 373J.J739 1971. &/looIey RT, Flaum"lA, GroInick HR. FeudAS(1981 I, Aclinicopalhologic oonelatioo ot the IdlOPllthlC hypereoslI\ophillc syndrome II. Clinical menifeslatiOl'ls. BlOod 58. 1{}< 1 _1ll<~ 11112. ScOOp RF, lIan WlfJ' SA, Xu A, GhOOnIII, AtvniI nn GJ, G'&ipp PR, Kyle RA, ~i&ti A, l..cy MO A(ljlu.mar SII, Ger!z MA, fcmeca R (2006) 6q . .lion ooomr'l3tel Walclanstrum ~~ !min 19M lI'IOf'O:XiOna! gar>rmpall1y of u.-.delem'Oned III\lniblce Cancef Genet Cyloi;jenel 169' 150-153 1971. $dIra:;IIn "I, De Jong 0, K...... P, KrIaen H (20051 LoJd; ofBdIoktAar JympIloma ~ be cau.:l bot IIlllIkltls on lh& ElCU !)Il!>i!I 0( by IlIterQ oIN 1(1.,18) nnstocabco J P4ltloI ~ 2 P, _ .~ in ""= 00hnar IC Kra4er J FrtlIlIing S ~ A. 9uIIInger L t1iIIldft; N ~ 0 ....,., 1,1 A, ~9'" B. iW G.~ A.llCI-.-. H. l mA. Sd>ragar JA PlIlall'IllI 5 RatlItl N. .IIllt ES 12(05) GrarUomaD..s ~ II IlI.IUI ~ t::rJI'I8Ibon EBV IlOS*'iiIy and dncIi ouK:ome J Surg Patio! 29:111>1116. 191. , So:tWberl S bDef III Ro- SL lloI S. "'.... C, BoIag G 'IIfl dB I. MusaMe L ""*'- V. WtmIr LE ~ H. west B GemW!·Au..... AcuII ..."..... L.a."..... SUI)" Grtl4ll2OOll) ,........, ........ CU, SIwWUl It. Knta CP !2OOl) Ger"*- ~ 1962A.SdIllIn' Rf a.- 418 References ZhlngI(Y,~E ~ A.~ KAAS m"labonlcause Noonan syndtoml Nat Geoat3a. SJl·336 1975. Schultz KA. bman P, S1aylOn WB AJtdo r.. 0lo0o. M. SiNo' H, Botowilz MJ, ~S Tngg M. PItUlB.JM.IIllD,E~ 1, Bur. .. L Wang C. R...... R. ~ P Cwl'I)I A. HN<ema N. WII\ir.Io: N. IUlget S WL. CatriIlI B (200n ImptMMl E., E..... Frea $urvMiI (EFSI in CNIdrM ..... Philadejp~.. Chr~~ (Ph.1 e-:. AD,i1l L~ L"'. ..... (All) ..... ~ In-.I) ~ ~ WrII HIgh ~'P)' ChIld<er'-s 0nc0I0lw eo. ~ n, (COGI SD.od1 MUOOJI 9ICIod 110 1m Sd>I.«l kR ~ OJ SaIw +fII. snu. JJ. 0avdII N. ~ Ir,lJ c.roI "-I, tWemJ NA. RJblI.l:.IE ltII'll4. R-.u EA.l'Moc):kJ c--. H~SP,CMcIWI. e>.,noot PS, 8U (2007) R*- and . . . . . . l..-l" ....... ' d ~ ~ XlM ~ ....._ • COII"bnad ~ 01 Il"CJll'lO'k ....'" Iroon .... ~ (POGI II'Ill CIlilthn's e- Grtl4l ICCGl 6iood 1119 ".." 197U.. ~ A, ~ J ~ H. FaIN 8 P.lIn S. SMI H 11_1 BfR·H2, I . - anl-fG.l lCOJOl ~ .-body 0n0i:lblY PlIdialr>c ~ . I ~'I*JpI.1llood7.' 1818--11;89 11m. SdI'*lltI2' L8 sa. K er.tbtl 01 R.... S.Z_B.~AS . . . . . 00 (199S1 n.1fllN Ionnd " - "YIJ'III. III ~ IYll'll'8WlI ... btIod • tIaIIIo-. ... lIOm'olII aJb,ecb and • * ' - l on ........... sylWT'ic ~ JOn InWII ~ 2702- 2710 19n A w-ong I ~ A, IUeon U. D.nI v. ~ "'L, DallI--F_1 R Ra;ewsly K. Ko.iPl*S A (2003) LOllI rJ III ~ ~ expttlllOl'l progo-am in filldgkin and RwclStetrCer9 cella rJ HocJ;jIo'" ~. Blood 1011505-1512 197& $ctowyz9f A. S/len'rIMn GG. C::ton RJ, ~ B. Tonguely 1,1. POOII JE,Wilem P (1996) GranulDc:jot1c SIlO)- rna in ~ ..-il!1 aeu1. m\'floblalbC lauI:&mia ~8:21). Meoj Pediatr Dnoli31 144·1.g 111111. SconI J. CurtIs C, Wwpom It Slakler 1,1, .Joll.,ancl 1,1, Gtancl FH, Cross "Ie 12(06) identifICAtIOn rJ a 1lO'I1!i imIllinib r~ KIF 5B-~DGFRA f-.ion 1I""'lI 1oIow0r'0g ~. 11'19 lor PD(lFRA olltrtllj>fflS1ion in pali&nts .-.d withhyperern;rophIlJlI L... . _ <0 821-83< KJ, App&lbaum FA. Theil KS, G..... MR, ChIln1M, Whl1la,er MH, Gr.fflfh BB, l.ldlt JO (1 C056>, C018· myeloidlNlluraj . iller ~ acute ltu kamlll: I pre. "lOUiI'I ~ torm of aeuII """&mia poIef\llaty ~ .. frenc!l-Amen::ll Br1~sh acuII myeloid leoJ ~_-M ~ Blood 64' 1980. Scott A.A. H&tel DR , Kopel;~Y 244-255. lMl , SooIl lJ,l Tong '1'1, Le\Wle RL, Soon MA, BeerPA, S/nlIIon MA. FutrMI PA Erber 'Mi, r.u.lA'I Mf , HamIon CN, W..- M GiIilnl 00 , lOiWl ~ Aft (2OOJl, JAK2IXOfl 12 ~ ... ~ "llI1i lJnd ~ erylhnxykIM to Eng! J Mecl '* "'- ltn ~=-> E T.-.no A. t.locm 1,1, Faec:o N, PIIuI F, ,.,... r T...... L ~ C. z.rilaIo It Stmenz8lo G (20011 Gerol)pIc lII:e ~ ~ .. rJ liiIIIr IIlfIUlllllIr:l HI(-m>e tylilph:lpl. . . . . . . ~0I~~L-..-21 10liG-l069, llll:l. ( 1 995~ ~-W" lJ,l s.on , . , . A. II AbliOT lSI' 01 3Q21 and 3Q26 ... illjJIbd ~ Ilk-.l ~ ear~l3fol$"""" 8rJ~1l1 490-501 lllN. SecMf·Wall<1lf LM, t.\ol:WTl\ilnA". Baon BJ" Mehta AB 1'998) 5&tOOd1ry acute .......-.a and myeloi:!yspIlIlK 1ynclrome IWIfI 11'123 abnonMIIIIIs. EU Coocer1tId Ac!loII 11(123 Wcn1lqll8<Jl:;_ 11" 84{l.844 19BU. S«IeIies KA. S¥<s TJ. Eda'MIi KM Cllen W, ~ DG, Godh.,- 01, TIapaIlI JA (2(m) ~ f9QUlIlion ol9'~ H Illd 9¥\l)'Il'II B ~ II runan ~ cyIeI. J BooI Cham 26581-2M81. 1. 5. s.tln LH. e.r, B ~ III FiIZgIlfJId C. GIl I( Hl:>IU>s P IIJIIIa R ~ IU Sl>enI:oer T. SUlllIrIIrId J m Ga:oyneRO . CtrroorToM (2007). Tte~ ~~nie 'IR~I •• beIIr prUdor 01 ~ INn til ,PI tr PfIIar* .... ~ . . 8-OIlI ~ ...-:I'" A-otOP Blood 109: ll1S7_1881 19M. SeIar T Dcmer M ~ S 120061 ~ *"lIIiciIIICfl1l thtnc ~ It . . . . . . . SalIIi'I0ra:lI)3, 186--194 1!lf7. SIICz V, IiIJrInIl .. ........ T Allf9OO1lOp01A01 I Asi:II C. s.n I-; (2OllOI o.c- rJ ebIII T-QII f1ICOlClb' ~ ctIIIl!llN ..-raogeo-w ~ ~ 0IlIIi 01 dluc ~ ~ . !ltrId 9S ,m••,,, 1918. ~ 101 (19151. ~ '-kIdWiiGt.....-.., PiiflOklgaI"'" rJ ~ cNon--.. Yael n ,.., Nd'i"'" 1989 St6gmann 101. u.r-co E PrIUlrHomme ...., D8non F. BrouetX (19791 Hahy dWl lIBuieI· CUlT'" lInl;Inga _ tIlI'IC1iPlS ~A .... 48 14$.167 lMO. SeIIck G5. Lubbe SJ MIMtI E. ~~ D. Hco..IIIton RS12(07) r.lIaouIIIII ~ irlckaIi¥t01dMeds... N map_ mak;fI ~ gao-. i5 rafll in paIIM& ...., BQIIlI cmnc Iymp/locyIic ....".. E.......... YfIIl1 dr:wMlse Slag& ..., /at'I>Iy t-osklry. IN: L\'I1lPIlOma 48 1320-1322 I"" ~J,MeggeaoF.Bm..sIeIP \ioigI JJ, Praoiere B, GrasitI 0, ~ J. "'""- B Knect>1 H DMd G (1996), IlllIarrlfl'lilOr\' ~rJ!hI twr. E-..Jence 1rJl ~ clendri!lc relicWIn cell f>'l*Ier3IIoo lISIOciIleIl wtlt1 olonaI EpsI&OI1-Barr WlJS Am J Sur9 P!lhol20: 147_753. 19920 SemenLalo G. Zambtlo II, Starkebaum G, Ds/IImj K, LCWJ9h Y.... y.twmba M. fl9112I·GetIe_.... manl and ~ 01 PAADl !lOfttnIllignancy . i1h tll114~QI3Q321 0nc0gane7' 1-01·14(16 1M . ~ L Ker1 H Cerrtn L plIOoll ~ (20001) L~ ~ ttIifCICAIIl d ... ~~lIlddlllib­ aon "'t) I\bIyCleS A. B .-.d C hd> ~ 140"441-«7 1991, Shamton KM. O'Q:rnell P, .... GA P8IiIIInga D. C*OI'I K, QInIorl p. ~ F(199ol1l.olsoftlilOlM~1"'~" bone IT*row <:I chIIdrlln WIllllypt 1 ~ "..,... and ITIIlignIrIt ~ dlIordef1 N EI'Ql J Utd 110.5li7-OO ' 1• . S/IapnJ RS, t.\tC1IIl 1<, I'fiUenI G. ~ l<J. !{ffwy JH. BlIur BR. ArltoJr OC, P;1Ilon 01'. ~ JS, flI.o'q B 11911111 fpllei'l-8itr \WUI ~ B e.I ~ foborIg to'IlI '""'l(Jfloprolilllo..... _~.8loocl71123(.1213 I" '. S"-Pe RON. 8IhII l<J (20(1&) HWy .- ........... difI110Ik ~ ..... zo- 0raJI CIrl tbIIl AlII 1013-100 2000. ~J,.lKdlulJ.~J. IlIcCoy J, ,,_ A. ~ I' ~ 1(, EPIIIiII J " ' - f . . . . S v.-O.SIIgelO, 0.0.. R. .......,. N, ~ ..... n.. E ~ M TfICCIlG CrorMIrJ.~B I2OO3l ~ ~ (II ~ ""~IllI~J~(II 13 ..., I\yJIOdIJIb(lJ ...... ~......w.III ~ """"..-d n.., ... T"... I, , In . . 00f>lui d globIII lI"'t ~ Blood '01 ....... 2tlt1. ShIugMMIy ..0 JI n- F. IIomgtII BE, t"-'g Y COllI S " ' - - I s - t Jl>, I<~ ....... OR K-.Y,!(uH E. ~ C, ~J, ........ B, SCi c..w.Fo.o 0VliI'i\a 1,1 , ~ It ~A.~M.TfICCIlG, .... J. ~ Y......... R. ~ Y. CrowltyJ 8Ir1OIJot B (2001j. A...... dilId lI"'t ~ ...,.. d I'qwlsO """ ~ RIoet I' . . Ifty4OIOrnI • ~ by ~*l ~ d lI""" lIlIClP'"U III dWt#I_'. 1 8bId 109: 2:27'&-22&4 :lllO2. sr... L.l.iIn\I 1oC. LuL A.J W'( K-.ong n. I...-.g RH, Sriv-. G QOO2) F~ ~ d F. lI"'t ~ .-.codlng ~ IIld ~ .. _,Ib ... dorl'IIInI i'I !InIl rIilInI UI8IfT -<;'181 ~ Am J PIltd 161 2123-2131 2IlllJ. ~d j,gs7). PC a.-. TS, <:>.1m 1M ~ ~ gI . . dn'nc my8IIlld '-"---., 8lIlliBrft Cln ~,. 887·806. 2000t, gj G, Wrll IoIJ, [).Men U Z.... W, I10MIIItI OK (1997), 00twr0I0mII 8bnLYmIIIIIy ffl(3XIl2'(l26) ~ • ~ 10.. ,,,*,,,,,,* prog!II"IIU _ In ,.,.oIkJPOO* ~, GeMICyklgenel 96, 58-63 2005. Shi.a J Teruy.Ftk!'ltein J. Pan 0, f1egde A. K~""IIt r8 OS Chll\l8"ll RS, Qin J, ~ es, FIIWI DA 120021, Primar)' folliw· IIr lytllPIIomi of lhe ga;trool$J/JMI lrllGl U donK.:iJ l and Piltt"dog1c &tud'1 of 2l!C8118S, Am J SurlI P. tho/2l! 211).224 2Ollll. $IligMada K, ¥M dol S!uII B, l ill PP f2OO(), MechlIISm of I&u. emogene~ by trle IW(16) ct'!r'I'Itno: ~ CBFa--F'EBP2B-MHYll ~ 23' 4297~»7 2007. SlIih LY. Lee CT (1994) Idenl!licMlon 01,*"ed ~ ....... ! e- 1~ Y(2006). KIT mvlation&.llfId flOl FLn I1IlIml1I taroetn ~Wl, 8ro S!lOngly ""tIcilMd ,.,tt> a poorpmgroosis In ped ~a;21). a sWdy of 1M ..Iapat.- Chi:Ihood IW( ~ Siudy GnJuo Ilb>d 107 1806-1809, Haym ~10 , ~M(19911.Oiagno&lr:;t:!IIe­ .. ar.d ~ d dI'iraI Sl/bIyfIIII <:I ICUlT-celI~, Al'e(O'1frO"l the LyqJIlOma Study Group 11964-81). 8r J 1tIemaMll19 42&.431 2tl1. ShiInoy.- Y ()ylwna T. AYlO N OI/Ii'o ..... Suzulu R. Kaprj Y. Iobahi1IIo Y. " - v a S 120061 Sene ~...,. -.-l1k.ell1ymtllqw",re. 201,. ~ B. 8ani9a I' ~ J. JIln A.. ClIIa.F.-a It N!Jq "- GlAlere.t 1,1 L _ p, ....... 1119911 f'3Ilems of c:rwoIl'OUTIII tnIIIo:p(linIlIleaIons i'I B..loIh foJ<'lI-DfOM '*"-'ce kl ~ ar.d E~ 8a'f""~ 81:0077 1516-1!>26. 2OlS. ~ M Kilaga*l 0'I'¥'b dI'IJmo5ome 5 abllQl'II aliM& ~_Lymptwlma48 21011·21 .... 2016. Shiv.Il'erJe la'y01ypie abnormaIlOO5 of lI'ie c-myc iocll& associaled wrIh c--mye !t)'steguialioo IIIld .... rno< pt(>llftlU'O" .. multiple myeIom;J Proc Na~ AclId So US A 91 22e-Z33. 2011. SibJud V, Bey4oI.flarry M, Tnleb;M Fl P~ ..., Vergier S, Detauna y M. ~t C, Cl'IeNl G. Ferrer J de M.5C1!fe! A, Dubus P MeOO JP (2003) 8orol marrow nislOPatrdoglc and moIooullI; stuging in epidafmolropo:: T-<:ell tvm~ Am J ClinPathel 119: 414-42l. 2019, Sidoroff A,Zeiger B, SteinerH. Smdh N (1996 ). 1r1Ck!t&mllnale ce~ hktlOCyloS'9-iIl c1i1ll. oopaltlological en ~ly with Ie. tures of llottl )(. and non-X Ilt$~s 8f J Dermatol 134 525-532. 2020, SieOOr! JO. flF, Nilpoji \1M, Banks PM. G\Iey t.1L Arnbiro)ef 0u~8!IlOOZ L, (1995), HI.onan IlM"OJnodeficE<'tcy ,;,uw~ alec! Hadgl<.if'f$ diseasIl ear>tains Iate<1t not ~ E~ Wus Hum PiIl\hol2l! .A.mencM SaOef\' of ~ Blood 94 1517.1536 2023. Shefn\"" LB. saa.n SE(2003). NeMv dilillnased cIlildl>ood 1OJ1Io I~sti(; upc\Ile (Jl prognaAC Ian and lMoIIlme"t Cur CfJIlll Htmelol 10:290-29l!. 20.21, 51""", HU !'loU SG OUll'Wllltl' R. !lIllMr K (1999) ~ dorles 01 T 0IlII pnxh.Icng i'lWliIoJkll'I-5 ... odol:JpIh;....-.opIli•. N 8lgI J IolItd 341 1112.1120 20.25. ~ C. SPINI lol, Cltlf!lll R T...... R TIdMdloR.lJlottwiA.~£ CarbcN A. Tni U (20031 CIo'lQI ...... and 00Ae0me 0I1lf11'*Y ...... ~ In ""'emiI· HIV-Pedfd pII8lIS • ~ '*"Y J Or! 0nl;:aI21: 3:94-3&64 2026. Sn1' IN, HuO 0 SW. KMIiKIn T. Lt ~ e.. ...... vam,...... .N; (2001) ~ .,."..,., '*" t J SniIl L.nlI'I AA ~ jiiOl~ !1Ib- mlI'/ lilt bt dnc:IIIJ ....... Am Jan".... \21 197·205 2e21. Slu 11 ChwlJK. Wong l(f. K-...;I YL (2002) S!**~dgllllt ~ II ,..... ... e.I~ 1113.~ .... ......, Mo J PIhJI fflO S9-tI& 2021. wu. CllF V 0.. .,IIl;, 'o'Ion\J I(f '--"iI R. KIlIOIllI YLl2000t ~~ 0I.-..e IC* II""" dlrOll ~ Mo J~ 157 1803-1~ 2021 Sill U. Wang Kf Owl.,lll; KtIOII; n l~. 1419-1425 2030. SIurndIf IIF. CcIlncn ..... SI.dIIt SB ~ RO(1999) ~ Ilrv- e.I IympFloma a ~IC WlII/ysIJ I-lerMloI Clno:II17 137-10&8 2OlllA.$kmdBr 8F, e./U. ~ flO. PaIlanall B. f n.nw L K'llP U """ 1W (2002). S.gnII ~ and adIY8Ior 01 .... taipIioll 6 1$ lr8qutn1ly IIm'IIed '" HOO2"i" and Reed ·Slernberg 0IlII 01 HoOgkNl fytnp/lOmlo Blood 99" 618-26 2031. Skomil:ler BF, EIioI /U, Ga$ccVf'lll RD, I IVlT1* LH. \/00 800IIl f KlIPP U Pomerson B Snow BE, loW< TW(2001), ~ 13 IIld I n le rle u k~ 13 receptOO' . r. Irequ""lly elpf8Ued by llOOgkin end reed·Jlem berg 0llIJ of i'Iodgl:irllymprIoma. Blood 97: 250-255 2032. Skode R, Prthel Jf (2005) L...""" !fOOl femillai myeloprolileMi., d,lOfders, SIImitlHtmalol 42 268·213. 2033. Sloand E"', M.!I1waorlg L. FUM:lf M, Flamlossoon S. Risitaroo AM , K&Y'Ieoafar K, Lu J. 6a!>lJ A. 6arre ~ AJ, YO\Ing NS (2005). Preferential supf)felisioo 01 lIioomy e QOmtlltrlld wilI'l !1CtfI\;I1hemalopoiMc cell ~ t>y ilIItologou. i~ i\ pa!lenls WllI'1 lnIi:my 8 mylllod)'Slllesbc S'f'ldrome. Blood lOll' 1!.41. A Wrlg$ II ~. GtClCl n-e Koellymo/"(ma OncoIS, 65S-664 SlI1y P HtiI G, Eidl HT. StloIl H 0iIN V .IO*lIl A (2OOSJ L~ ~ H(l(IgIun'. flT. Woof $H, ~ R. I\r> ~ cIrItII Ill_"*", 1Ild ...... ~i'I100 peIenIIl'MIId"'" ~ ~ . SlICt¥' ~ ..... J l> Orc:d 23 5mSt45 2OISA.. ~ A.. HcJa K. T f.T. TIbutft K, T_A. Y, ~ R TIUIirIldJ I. 2022. Am ~ "P\*blKJrn FR. ~ in ....,...., an-al _ e- c-. ..... )51 _ ~ _ _ NEI9J ... 2ol(ll.2«l7 g",.r, SU, re 8eal """. Huo 0 KimIarI T SoDD;s RtI. AresIiiIIi J, ~ 2041. ~. Lnall AA l2OO3l- CIIIal~~il306~" .IN Ro-Iey ~~ar.d"""" W ~LA.(;/'I(IY.~TA.lJmMS. sr- Sf. (lWi'}. an:.l.IIW'II.JI'Ctlgc. and ~,.. Ull$ rJ 11\ ~ 1JrrlIlMpl...... _ .~ ~".,." abromII ~ MltIOOl*Joll$. 8loacI89 1141-l~ 2013. SalIn SK Ju1g rr. KWn OIl. Kill .Ill K_ EK. "-" T sr.t 00. SdIn l(fl l_KB f2OO3) Pr-ocpaPc sign6carce of bd-2. t.. ItllI p53 ~ ""diII\lse 1If91fk'*I tym. phamI AmJ Hemat:t 101·101, 2G4lA. 5olka OK. ~ YI-1. Fewell OJ (2006) Mel:hao1t5ms t:J reg.Alllor'; T-cell ""ll" pno$&IOn • I ~ ~ b • rroving 1tn}tI. l""""""'*'!y' 24 13-22 204' . SobI JE. Cot EB, Baa:arar. 'I Tura S, Gomez GA. floOOrtSOll ..1£, Tao CY, BrJuIl TJ, C13mo-. BD, Cervanlss F. ll! 111. (1964). ProQroosoc dlscfimitlalionin 'good-Ils~' ctImnoc gra~tic leukemlll 8!<xld 63, 789-799 2G45. Sokal JE, SMerin KA (l \}!lfj) OtCfe.sed , teinable rMfTOIIJ ifO/1 ill d1fOn4c grnm.»ocyiJc ~u k~m;a Am J MeOat 395-399 :HIlS. Sc>kol~ka·WOjd ylo M, Wenl~ oJ, Ga ~al E, Steill J. R=k>ewicl J. 8ieber T, TulI'Ig T (2005) ~ of C02l! e<prelSlon n 00 siull-IIoming ClA. C04. T lyn'opnocyles in ~ai llbxI i& a highly~ "'Illcer lor eerty ~ ;nl ~ oTlOI\lb"ing rJ Chas1a'lg C. Am¥ M. VfQdMs M, N MandllI F. Reroou~ .... Bemarll JF (19841 Chronr: m,«li'oor«Y1iC 1toJ ~8OTiI.-x:on:II'Ig 10 c . . U 3J9..394 2035. Sloor.lk ..... Go.o~ H. BloamAtld CO. o..l G, ,fqJelbIum FR. Lnall AA T.......... loIS, Ilerwlfll JM. $lIreoqIt Ol. IoleIlwIltl S. ~ CL. Raww:nnIlh y o\Ior'UIJ TA CIrnlI AJ. R-.:nli SC. Ii8lIr8mro ~H,EnglrtA ~l,~ a.oIlr .Y&*tm ~ Blood 101. als-321 :Hm. SIr*l lIlA. ~ lA ~ .Ill II • (td&.) (19951 e-. IlClCltlD I"d IloI'o"QI ..-.::r'IV lHOrwIarl1. . . . . t.ntId SlIIII SEER ~ '9JS.1995 Nali7III ~ SEER~. a.r-lI. MO 204ll, ~ t.I.. -XJ. L.-' TA FIll;IIlDoll j 12004', ......., 01 CfSPA II petients witll Sezary Sl"'QIOIM 0. " Exp Den!IilklI30: 702-706 2034, Slo';ak Ml , !ltdelI V, ~ l. Attlfr" 1M. Sd'oad> C. SIll*" R 00021 21022 blianc:ed CIYOn'otOmt tbttflllln i'I lhtrIPY. M. ~ G. ToemannM . Lerllll!l'l K.HI.Ivl O I AlLOj-lylle T<.81 lyn'¢ooNo. progrmtiC ~ of cInI:al obIeri E.-01~~l (CXCL13) by ~ ~ and ... ." 11995),~~ MLL 2037. StNlh 08, HllmsM.Gowlallcl E.ChIng J. s.:-tI8 JH (1!l8lif ~ mulIopIt "'J'OllIma a ~ 0113 CIS8&...... _ 01 . . ~ I1tmml 0rIlXIl4 307·313 2113&. s.no.. oR. BrmeI RM , p.... s. LcJ9 III iJgIIcaaoI ... ~ rt (20031 . . . fS ll\d; ......, l _ t.U. '*' ~'-- Reo:9*IIgI~paI. UicIl pn. 9I"l8I"" 114 ""'''' myeloid ltuk~ «ea IImJ 01gill*: _ _ Mo J PlIO flJlIted ~~: fepor1/fon'l "" ......bcIIlIl -"shop, Genes ChoOl'll:*l',ots _ 1M GlCQIOg'f groop SlIIOy 8bId 96' 401S. ......,.. .... ~d~_ Ilload 102 43-52 2OQ. SntllIr NC. W~ J 0. JI( saoo. 1191.1195 2021. Soegerl 'N. Neo1 C AgIhe ..... Engelh _'9M*'I. l . . . . . 20 21&-223 2009. SJ'limIrlvI;uro-VOITIMgen awe a SOOAI-.tonoolOgy ~~ caopera. (1.) ~ genotIlIC ~ .-..IyJiI of "1Iutal ..., ~ 2Ollll. SIllILY l*'Il DC, Fu JF. Wu JH. W¥I\l PN, til TL Dum P.Kuo we, T8I'I\1 TC. lJl TH. L1i CL (2OOl'I1 ~ d '***...,"'" de SJ. Awetlaum I'R (200')1, ~ aoat(JiI ptfI(lids CitJICOO'Ie 01 pnlRI"'5&ionand ~ ilSIOll Ihtrapy in lId.m)'Sloid ltoJi<enWI teA00(6) A ~ P.ody 01641 ...... ..... 1(69~.p231l34) AM. ~ Itrf IIMd Iot.~.~""'b .... poor proglIOtII.' "'Y'bd ~.o.s l .._20.1m.1291 2IIl1. SIooIk lol., I a.. ..., :HIlT. ~ p,~e,~. A, I'Aa ~ 63 634-638 aro.- ~ <:I 3!>l3SIlI. 8k)ad ~ p. flay P ~ P WhIltJ. ""'wlage JO,"-u:-S-: R Au W'( B40Iai lol. Bme P ~ D. CooIW B, ~ E ~ C. Fean:o 'I, FtIte' 2048. RI.~Jf Gugiiei!!lC.~ ..... Htioull C le8IIfW; M !AI.- AT lopw' GuIIarnIo ..... IlId.a.9*l P. ~ N. Ur:n! P, ........ N. ProcD SJ. R,*,-*- "- ~ P ~ P TIIy H. V'IoIo U, ~ PI. ZlJD E, ~iI E~; F~.". pI'r:mi ~ PItI'7'O* nlel. BiDod t04 1258-12'65 References 419 _.. 204t, see- J, Bordel R, Ort.mo F, ldo!Ugud "'. ~ J Pon. C. ~ J. lopez· Lopez.lJ l'r.tJ.RlanIIll(I\l904I~ IlllU1Il kIar '*l ~ in two paban15 wi1h I8Ilal Il1lI:IInt \ll'anuloma Br J ....., 2050. ~O. DelIIO,ClnatlIA, c.ItnIliG craz. A, twd V OYilci N Otl*n Gl (1991) ~ of CO).t. <*II in nomIlII WId ~ bona_~by Qe£N010 ~ ~ ~ 5 1026-100(1 205l. S<:r'rYr-. VH. o.mrr- OJ ......., W. . . . l-oYalo P a-dar C E.-.n KW. W _ A. K-"I CG.""-' Wi Ropq C SkcJ'I'S.DdurnN(2OOf11n_ ....... of ST"13 III tulaneous T-ul ~ . Evdarlce lor ... ~ ~ of STAn L u - l' 12M-129$ 2OS2. Sor9 I(rn WS Kll YH Ila Il.. LM o sr. MH ~ K (2002) . - . . . . . . , . .... e.I ........ ~ ....... ..,..-... (dXJIne 1"''"**9W81 1Jo1).lJo15 2053. ScIOllIIb I'P. B, Kclznf B ev- t.Id* Y ~ P l19l12) l,..\I01IiIIkJIIIl ~ ... ~dcn:al'" - - * 9 C ~ e.-.9 2010- 2616. 20501. SarIn:) N:J ~...-.. .ro.-'ll .If F_LE.~N.j ~ E . ~, ..... FB. PloS (2007\ RlIo.JIIr'.-oIlI;eeI-. "tWUldl._.-.:I._ of........ Am J ~ 8:2: 12!>-n8 lOss. SOlar NA l20001 ~ and . . HamlIa:ll 0rllXIl CIn Pbtl Nrt 1. 531· ... s.w 2056. It. F"lh':ft C Mil A. JIuMI R 8uIlmaon S, Valent P Homy HP \20(2) DetadIon of o-M poi'II Asp-816 -" V... ~ pooIiMI rnIal 0IIa Fid lau<erTIIC <ell in II ~ s\'*IIC muIocyloais end COIIQ)II'O\aIII t!lrorl"= ... ~ lItlk_ leu. Res 26 919- 2051, SoII.r K. Horny HP, S'mo',,1ICh I, Kroll.,.." Ill. ~ KJ, ~ Y, Pmtz 0, Fntach G,ValarIl P (2OOol), C025.... ClIIllS IflI! IMlOpIaslic phenoIypa rJ mast cab • ooveI i'r1rrIvrloht'toctlfmlcllI tor t"'~ of s~ molslDcy101iS ISM)11 IOU- _rk., lonety pIOCllUIllI 000a ....ow bocilla'; specimen&. Am J SuryPalholZ8 1319-1325 2058. SoIbier MJ. DuboII JJ. Sauvene 8J 119941 POEMS IYf\dfClrne: a study of 25 casll'l and a " - rlf the! Iilerotvr. Franch STL>dy Group 011 POfMS Syndroo1e Am J Mild 97 'i43-M3 2059, ~ V, Liu VJ 12006) From plas. macyDd to dendn lic call' rnorphologiclll BOO !UnctIOIlal $WJlrtIeI OOftllg plnmac/'bd predef\df$C call (I ,~t s.... A.Bin:l J.lOVto E s.- 0 (2OOf) dlll)llO&'$ ancl IIIa'I8\JiIlI'* ~ of bone .1Id on !he GiadeIrlllI ullOlilrt dIIry .~~BrJ"""'­ 12. 717·]26 2062. SI*hI: t, H~ 0 (1!l99) ~ !kiln of Hodgk,,'S ~ III ~$ Mao:n p ......... .10, 0Ia/lI V, _ I.ippn:d: ' ~ & YMIin$ c-.. ~~m lOU SjllIli ""- GIIIiIIircl OG 12002 bnlIng **n " ~ 420 References c.:r. .., 1eUI<.lemil. Nal Row Cancer 2:502·513 20604, $penc:ef J. Ceo1-8er't1l1!;SiIn N, Jatfy A, Br0U5M N, Guy-Granoma (ma~ ~ rJ !he irlKl$lintjl$ ~ by I II'lOIlCJdon.:l body (HMl.·ljlhal ~ a memtl'ane mole· CVIe on Ilurn.vl mucosal ~ Am J "'*" P.thoIl32c 1-5 2064A. SpenaI' J. Fm T, PullDfd KA. Ma$Qn OV IUatJon PG (1965) The!'olman gJ lDIlao-. a I'lO'4I ~ fJ B IympItcqIes Irnrnun:lI 62 607~12 2llU Sparr WR. Orac:tl J. ~ AW Ao:::Wmnl J. MiIItBrtraJaf .... ~ ~ G ..., FonaIxhe.~1 KIh P V-. P 12(05) h I ~ - . . . - ewIar'Ioe lor Ille 0IlQi'I of ....... __ "~done.-.:l'-"'bV. gtII8C . , . Rsll (;IJI ~ 01'1 e-. 6787~ lON. Sperr WR W~ S, Iiomy tiP, ~ hi SnorobdII, F ~ R, $cllwM"llf'lI"" I T~ E SoIabar e, Ha9II1 'II GeiI8Ir I( 0'10I A. l.ecInlr K. V'-'Pl19Elll) Srsseme~_ _ - . . . . iIClM ~ leY~' feport of . , e - n dIItIidio-I fJ .... e .../osD.I!161O VlIl& J ~ 103:7"1).1.9 2017. SpiIn AS Ball BJ T_.£ fl!l17) T1lB ~ bbld .. tIvurit ~ ""*-- sw,. of50. - - , ~ ~ Cll'SlS $o2llI J HM1IalDI18 ?>-38 20M. SpwIaM V~E NaAG. TnlIU l2lXXll. t1.mlln ~W\.IH54OC>­ alad 1blgUI', lMMIe Samin cn:oI21 ~ '" 206S. Spiro U. Yandel OW li C SainI S. Ferry J. PooNlson J. Kan."" 'M'l eas.m. AS (1993). llnef ftIP(lIt Iyn\pr'IomlI of doru IlrigIn lIl:l;I.mIll'nlhe por18llep9\1$ 01 1 ~~nted ..... NErqJMed329. 27-i:'J 2070. SI*i H. Lanoer U PhiI>ps.lf (1~). ~ of human T and OllhKal klIlIf ellu Blood 85: 2654·21)70 207l1A. Sp\$ H, 6lom 6 .JaIeto N.'., Wei,.er K Versd'll r8f\ Me, van Ooogen JJ Heemskerl: MH. Res PC(199111 £arty stagas In !tie deveIC(lfTIIlf1t gl human T, natural XlI... Epstein-Barr "f1J5 reao:;tivallOl'1 " • BUf1 201.. StaaI·V,tiaf1l A. LaTIIe'-CaMa,d V. RIIAl JP, DOon J, G~ MJ, ~ S, Witz B. .lon-ieaYx P, l.erornpte T. RIoV(2006) IAe- fJ de I1'.MllltlJlll basllptMk leukaemll ~ (tileria and 1l'!'Iiew of!lle ~J (199J i· CloMltty 01 d1lO11it neutroph,lIc lau'-"'ill aSSOCliled \11m ..ng ,.. ~. 8l'IB/y1IS X-lrol<ed probe 1.127 !leta. J CIIfl P!IIIU 46· 297·M 2011. $WIley ". tdcKema RW , E...... G. Bn.ming RO (19651 CIauilaboo 01 3!>8 ,*"of AQ.llt Ml"bd l u - by FA8O*- na ~ofdnl;alllfl(l~.,· .... In: Chrtnt llfl(l """lIuMmilII "DJItI. BIOOII'IhIlcl CD Pubnhars· 9oIb:l, (td.) "'lIrtlnus Nifhof' ~ 1.1.11•. 201IA. SansfIkl AG 0Iab0Id J Noel H eI • ~ K* C*1':aIior, lor ~ tAnc:aI 1 292-293 2071. SUrt B.~J P ~ hi lJ.Illl O. • 0..... S ShIlO.l(odlIwI y ~ R. NIl S (1995~ " ~ ~ of Uol-U5 a<x.- If~ . . . . . . aaem.d _t816)ipl1.p13) 11 • . . . " . _ , . ..... ~ 19)(plll113~~an:l_of,. _ _ I.U All 19 367-379 201V.. SlrfJ, Ba-.l o...cz;g U "'MIoI J, IoId\liIoA K ~ C ~ Gl*'ll" ~ Ih9tfl ~ l.IOS ~ of S w.-.l hI ........ S ~BP,RowftlJT ..... TR, 51-. BW, /II HarlIasly Rl (19&41 ~of~and lyi,ijIqii.... - . ........ ~InlllI~ Mod t>npy l.nlIl: 1 583-587 2081. OP.CadI JS. PwdIrwlI A Mr:Qn RF Ut!ltW) 1..... A (2006) r.FI. s-.r. n. W51S.-.:I JAIQ '1617 ....- ....,. " ..... ....." ....-.:uv -. mgad .., ... ....-.:I Haer''"**9W 91 EC~1 ~ ~ tQIrt 2012. s.-OP.o..:IGW ~Tl Po.eI ..... lAl;:Q.Ife RF. l . - RL ~ 00, TtIIeri A (2005) Tilt JAK2 Wl1F llCIJdI. '"II ¥t*lf knelt mulItIiOn • ~ '""~ hetlI'nbolh .aIypot::l(~....... den iIIld ~bc syndftIrrla Blood lOll t207.1209 2GI3. S18eflSmII OF', Hanlon CA. l.-.c!I1I L, TtlWi A (2001) I.IyelodyspItai Mlto Itlrcu B (lislirltl tntlty? Lu "" 25 e29083a 2084. SIHo9me Of', HKkM14 IV\. Porchaf JC, l .she Tl (2007) c..do:1ate ~ ""talIon ilMIj'Iis fn ~ lCQuored ~ anemia (rafraclory IIlfmi9 \11th ringed!lderOO- 2(116. SInlen GR. JitwrI B, W ' " M, W~ CA {19!lO) Chronic r>eulroP'*; lOn. SlIro:Ian GR SIW'5 FJ . Jones l ~ . . darI'Md &om ~ ~ ails 8IoolI 66 """ ee 2OIll. sa.. M, l.Il:t>iinIb-ZIaglar B,GtoliIIJ l"lll* A. W-..el MOOglI'l and P (1962) ~ OIIa~~SOfClIIt 101M c*a ~ Inl J e.-- 2t ",.'" 20tl s.n.z FIG Ga)ron PS. . . . . . .JC et.rtooo M. ~ "'l, ~ ,,$;, .kmIt;Irlt HS. SiiIIllf'" Trigg WE ~ R ~ O. Bley.- WA (H1fI61 C~.-.:I~ ...... .".. ~"""""~of...,. ,..-row fWItllOMll tep;lfI kft . . ca-.:.- Grolcl. J On ()UJI 1. 211M. s--- 38S-l9ll RIol. ~..... H 12006 Oandnllt '*- ranaiI*lg ~ m.... iMvoq. Cu'r Top t.IoIUoI~ 311 11· se ~ F, Solar K. BaIaMn L ViIllInI P Ho:tny HP (2lI(Wj 1lcnI_ .... lOCyIOM lltSIOC:iIled IgM ...,.. pi-. 2Ot5. .nen eel rnyeIorna L.U; 209f,. ~ L~ ~ K. w.- 601-< hi ~ KA. Maruy_ K. E__ PO It a-. ShImon KM (2006). lnIarsIUI ~ IMII ~ at <':lI*Irtll tnakpt)il'll ......... fraquenI mectwiIrn rJ NF 1 i\adJvBtioII " III'1'lbd~ Blood 108. 16801-1689 2091. Slam I.IH. SouIitr J, ~ M No» ~ma1Plt T '*l ~ ~delta ilx:us "' IIlIlIn T cal ~ 0I'It;0ger;e 62475-20461 2098. Slefry W, SlIlIlel A. MoelI.II V (1992) HTlV· '~w pIeomorpho: T-all ~ gllhe $Iun.lhe ~ ~ aro:lMTlnI h1slory el1 5 pabefllS, Bf J l:IerrYIm 121).56-46:1, 107 113·\22, 206\1, Sttin H, 0i!l!lI V, MaraftOti l Jo. A W~f J. Hummel Mll 9991 Tha lIah.o'e of R89dStfl Kyle RA, Ra] 'Umaf SV. Fonseca R (20011 A pract>:al guodol to OOf,ning higl-fllk fTl)IIIoma k>r <;krx(;!II h1aIs, paIiItnt ~ and ~ Haem~ tol disease, In HodgkiO" Arm Oi:Maw Mauch P edt..l~ 'M~ &W~ ~. ppI 21 "'.", '" c* ..., lIIItIOq'ft 209t. Stewa~ AK, Be EJ, 182-1•. d ........'• • q22·2. Ht.m PalhoI 38 940- Blood 91'.96-501, Cross NC It oo:l), Myaloproliferat'.... diliOl'Olln wdh lfanslocali:onl of chromosome 5q31·35 roitI 0Ilt>e p1aT9M. oo,ivlld growth (actor rltC8Plo, 6ll1~ Acta 2085, Steer 1Io.-na_ ......... ~ An--.on ... ~ Ii1t d1arI Ull'\'IIIOI Cane.- 66' (2007) AnaplaW:; ~ ~ <M...e IlIr\Je 8-<eII ~ ..... B compiex ~ and aypIi:; 3' AU< 9'JfIlI rnr.et'OfI 8) ~~ lOt1. StNI H, Mn on OV. Gerl!taI J, O'Connor N, Wanteoal J. Palasen G. G.K. Fiillni B Oaisol G. lernU> H (1985) 1'hI .ltP"II'OIl rJ!he 1bIgbn', lBeaIt--.:t ........ l kl6l!i), Ltc ' ROl't 31' £23-626. 20117. S1aon H, Foss 110, D.lo13O(.) ~ ~ (;IJI ~. t ........ rJa~ ~nlcifl. caI!alIlInI ElIoOO 96 3681-Jllll5, lOla , S1ltin H. ~J. 1(rdV1tfH. Sc1I;IIdI III l'/IeIlI V (1981~ I-t;IdQUI n ~ ReId eel anIogItI(s) '*'ttfd by ~ .-..n.on III iI (;IJIhlL.28)......., lrllIII HodgUI's ... _ lnI J c...c. 28 .~29 lOIt. S1aon H, M. LerwWI I( ~ P KC DY (1.). ~.-.:I+blgl.aI_ III ~ evltiJIadoI'••• ~ s cIiaMM 01 ~ ~ lDllain J ~ AlII J (.:III Paf'I(lI 86 ""' 50 ~ (Pans) 64 361·365, 2015. ~ o. ~ PM. Al Hor'nII S. HI*:hr6on l lee HN. WIlda B. Wang SA H. Hoovnel M. ~ r. W..... T. Demel G, F"1Ii B (2001). ~T1on or 908 IIOBF.l a->d 0ct2 1Il d'** Hadg!<" dIMasa but not in lympllocyle pradonlfln H(xlglun d~ eateIallIs ..... ~ aa. 2090 s.ton M...... T Fa. HI) laImtn leId8oru~t SR. (MgJi D, Roode< ca, Roy V 01 tt-.rapy l aul;erri09 21 529-5304. 20991..Stewart BW, le1 P (20031 Wtri:l Ca'lCIIf Re9M IAAC PIll$S. 2100. Stilgerobauef S SdIal!Il&f e, lJIIaAt A. L.itOotd'l P, GiIad S. 8 Ud'tler P. 00hfIIIf H (19971 BiaI9lic!Tt NlIl t.Ied 3. 1155-1159. 2 101. (19904) s.... CA. 0!eas0lItf, .J,I, F1Id'IIIll Id NeutofilIrorniI10S1s and crildhood 1eu~i1~ e-- Br J 70 969-9n 21ll2. Sbroolo NA. "loIona,- we, ~ OS. e.;,. BennetI JhI (1990) C/lrQno: m,elon'o:lllCiCyK *"'- L . . - . 1660UKCCSG!UIy c. no a. J, lae BIt. COOII J Ci*nD.CoIu!I A. Moore SA. Owr 91, ~E,~J TEl.f'OGF~ inl F!Pll1.p()Gf~ i'lII'O It'IOi in OM,I. 8lood 106' 3206-5213 2104 StnllIm 6, loeallllW F, BadIf P. EI1lBfT K, Kfe<"ltn e, llI'AI F, F\lIAr M. Slaot>'leI 0, s~ t(W StcIIcek P, 8at.mannl. '""""'" eM (2001) RnacI II'lIlInMV ~ to ~ ClOn:lf ~ 0 ~ cylopIflilI In ~lIclhood Bone Marmor 1~~3n.J33. SV-·WelclfJI It StiIvw t.l. K_ 211)5, ~ F. TanlIow ~ 00rm0W 5 t.l. F~ M Snlonbch-Klupp 1 Z . N. GouIongef H l.IoMg H (2006/, . . &'ld ~ lIMIl ~ ...... ~ dral progrlOSit pnInIItnlll~"'~ '*ocIuclIon fA i ~ ll'l'9'O* 1O';ln, I.aokL~41 ""1-450 21116. ShucMIl JA (2001) IndcIeo'Il T-¥npIlt.OIIIIc~ ..,011 ~ • • 11.,..- '-kIIy A'ld ~ .... ~ .. _ Am J SuIll PIfloI1!l 411"'15 tl07. 5__ SE 098ll) Tht o:fInnc _ _ _ _ . . . - J InIIIa 0. 1ST ...." tlOl. sa..se J*es """,*M 0..,1( ElriOn KiI ~l'IIt« A ~ MI. ~ we ~ CW, Wa'lll J FiIdw M. ....... CM Lil"'V a.".. C SiIv-1 E. IWl ~ V_ _ AA Grolmcty T ~ To\ l..--lD lIlJ (20011 The dr._i•• al ~III"""'''''---'''"" P.............. ~ • lII"'*'e F. ~ &'ld liII1It*we ~ 'JIOl*- BtxxI 98 19'·200 tlO9. RR sw..w ~ CA. R..-l/wd E 917} l'rt9lOIllc~oI"UriItloc,.,. . . . odopIIflI; ~ - " . Blood 50 .,,.~ 2109A. S~ 8, Hober 0, WoI'W.- S. 010I A.~ M(2004J F~oI~ ... aIlerI'aIior-. inwtmg MALTl on auoc:iItad IyfnphoId _ _ IIIUlXU- ~ if! .... ...... s;:.;,..', sJ'I'i't>M Clrl tAnoIr Re!lO 4~ 2110, Slreulle1 8 Su'llOlli1ld\ol{t..w I, ~ l ~ A. fMw' D. Sl8bflI1 ~, S)Jlle t.l. TI'9Uli1gW F LuI:as J, PI.-pok ..., FllIIIWlel< t.l. "'*'-- T, ...... -HtfmIW; ttK Cem:ini l Rar.llIrer t.l, Ct10lI ... (2Ol.\oI/. Vil/IIltlle fr8Quenciefi of IMl T 11~!IC'o CMftj genetic lIbemIlkq in MAL T ~ ~dll'Jnrl! silll$ 2111, Str~ LI\Jkemi8 18. 1122·1126 B, VlnllU tr U, lllfT'4)f'9Cht A ~III' 1.4, O>oll A (2005) T(3 ,14)(p14.1:q32) involwlg IGIt ano FOXP1 II ~ rICMll r9O.IfI'8I1t cMl<no5omaI ~beml hon in M"'LT ~mphoma LeuI<emIa 19 652-658 2112 , Stl'e\JbtI B Vinatzer U, W,lIheim M, R~~", M, ~5:9HQ3J,qZ2) ~ ". ChoU A 120061 Novel fu5es ITK to 5YKIII IIIspee;118d T-eelilymphomi l.&uO;emlll?O 31l- 2m.... St1rWWI BW, KlIOIIueI P (2003). WOl1ll Cane« Rl!(lOlt IARC PI. . 2113. Strom 55. Gu Y, Gn.«N<....5K, PIeroI SA "-",,,,81(20051 RitklKlcnolmytlod~ pINk l\'fIdromM 1 e:ate-<:or\trol study t.e....... 19. 1912·1918 2113A. ~ 58, VeIez&l'olo v EIIty EH (20081 Epidemialo<,ry fA ~ tyn~ s.rw. .........45 SoIl 2114, SWwp C. ~ N ~ ,. AU C HiIdlItJI3ldl B R Gefmrlg U 120031 Rt!lrIttcry - . . fAbII8II .......... ,. . . .11: .....,.. 01 ':.' iCl:OIlIIIg ~ lie WHO ~ I.euk Res 7T "''''' 2115. Su U Cte'l RL lIII OT, lfl KS 0..... 0:; !l99'l ~ Wus (ElM inI8aI T ~, III d'oldhood EBV·~ ~~IIIT_""'J .....,. ' '''' 1219-1225 1111 Su lIN . ee.oor.z I, ~ WH. IiO 1/ 1I G. Voss ,", Gasooyne R. Zhou v (20031, Aberrlllll .~ ot T-plastWl in Senty CfIIs. Rts 63: 1122·7127 c....... 2117. Suat6z F ,WkxlonI ~ t.l, Ua1ln-Ga'tia N. F:net .lf' Do*ll GNtrd p (200)1 H~ ~l 111& 8uIJn'o'o K. Hnno N. T(IyO$IImI Ii, CtDS. M.-.oH Tai Uol1 H, Sugmon H. l{iIWII K, Qs/I;mi K(10041 ~ nalInl kiler<*llaoJ~emia fll't'ilhd ~ gr.u.lym~...._ 01 c,fC*llI. Ie HI( call ~ 18. 163-nO 2U' , SlJZ\jki R. VII1'\alIIOlo K, SeIo M. ~ YOgln lll '!'$be Y SudoT,KIXIIrI Y, t.b:ishma Y. T~ T, SMJ Ii, I.led3 R. Nal<8mu!11 S (1991) COT' and COS6' mytloldlllMllnll killt. eel pt«Vl'» ecule ""*- a dlIIinct ~ __ entlIy 8Iood llO-l'17.2>42t1 1130. ~ J, 0IWirIlII K. T....... M ~IIl,~C~ N.T-.raK K*\ldIIldI1991l) ,....~ ......:a nigh ~ aI ~ Wl,II I)'Pt A A'ld0lllCi0n ...... N .... .....a98'11 Leuk l~ 36.567-578 2131. s..t 01., Golortt> HM ~..o. '"*'" "" V~ Jill (1~1i) AaM ~ ...... &'ldtwOllDx,..... . - - . . , .... IIlIlltlon!llllly d d.""....... Ill) 3 .. 1 IlIPM d lJ9lI CiIIK Br J ~ ''1 11·\6 112OA. K s:...sJ ~l. ~ I,l SIIlIIl u. ~ F. ~ J 80rnll 0 V~ BO.lalel' TA.. ~ J Mnos'...... __ GerllIl ~ 1 33--JT 2132. ~SHOOl)4l 2f29. SoIIIrI C . . . F. Imtel lol ,...,. F If1l81).~~'/lIIIl~ s..rm.. l200n 1 ~ "*" ~ .... Fl.T)-fTO &'ld 01 slindIflI ~ aIIlOI ,. .,..., 2123. SutiIlI M.J snusw JJ Sollhllr .... c.ntlll BM, PuIenJ ScWlz KR , l3clrooIiIz t.lJ "'ema ,. ." Ga\'OOft PS Carroll AJ (2005) ItgtI ronconJente from I/IIieperIder'lllllJdles b)' ll\e CNldre~'. C3nee< Gtoop ICCG) 8tlCl Ptdosis With romtooed trisomIeS 4 10, and 17 lI'I tfIi!dren ""ith NCI Standafli-R.",k B-prllClnOl I\cule l Y"'lf'hol.'l3-'t>c Leu ke'l'lla , ~s 0n00I0gy Group (COGI inrtiati've l ......erro.a 19. 734-740 2124. SUVllfdllC N. MatlSllv1jlivic 0 Krag uljac N PanllC M, Dj<>rdjevic 1/, Ja~~ovic G. CarTlllrik,c-ManillOvlC 1/. CoIO'I'ic M (2004) Acute penmyelosis WlIh myelo!i)rQ,;i!;: dtnical, ~typIC IIfld cytogenetIC study rJ ~C3S8S levk Lymnhom;l 45: 1873-1879 2'2 5, Suzuk.awa K, P~as E, Gajjar A, Abe T, T~S, TallIK. Asano5 Asoo It, KIITIada N. VO~(l/3 J, 1/ !I ,Yl94j 1denIilicabon of ~ bfeaIo+Klonl dIMer '''9(\11 3'of !he rtlopIlom I gene at ~1 a<,soda!ed With l!le 1I'aMCtiQtioI\al aetivabon 01 tneEVIl gene ... .cot. m~109efIov9 invIJI(Q21Q261 I~~emias ";I~ 8lood84 2S81·2ti8$ l U6. Suzuko H "'sano H Ohasllt H I\onQsIVla T t.!urMI T. SaiIo H, Holla T (19991. C1con*y analysis 01 refi"atby.-.nil ..,.,., nng IicilIrobIKlIl MniItaneous study or cIonaily I'1d ~ fAbone ~ progenIltn laJk_n lJG.l34 2127. Suzu~i I( ~ K . Kan.obe K SuN....,. J Ohga S Ishii'lara S T,.,.",.a K. KJ1thrl &'ld I'Ol"'lI In!J 0n:0I24 116$-'17' 2121. SuMi R, SuzuIIWya J, ~ 5, Mill S ~ A 0nMi S. Gondo Ii H.ro N pIIOpo(lifeo . . . au. e- ~1oItuIIr ~, . . . . . . ZllNI ~ 8'ld _ ~ Ivfl J PIft;I a.. ~ 122StW .101 1131 ~SHI2OO1l T- It..,... ~1IId~~"'''''' ~ SlIdt' d 18 _ 8ld ..... ""'Jf'IIIOll13 18'-191 2135. s-odbo SH IJIz GL ~ IdE ('993) 9d-2l1fOW1l11 CIn'OCylC ~ • f*3lIn .... -..:ty l.....- 1 1456- .... 1136. S\oer'ltIovo 511 WWIerll5 ME (2002) FJtIfI\ CWIlnlcyk k! tI'8nIIt ctII ~ • etil~ &'ld ~ _ aI 3 de<:.-JM ...... PdloI33 1·20 2m, Amoi:I ..., Wlleml Me ('995) 01 ptoINl '" 0ri'llcyI~ r.ell lymptcmois . .." .-.d -.ihloJl r~ rJ !hi Bel.' !cydon D1 gene Hum P&!hoI26 999-1004 213a. Szt.z~1 T. PIJtIQ8ff"WillarnM MJ LllIlglIoI'a~ "''1'1 , ~ WA Wrjkrn>js 0\.1 , van WerirJo;l ER. • ~n I':longoln JJ {l9gel 19 flIavy d\,)in genu tU"tlll9""'ll"1I in T-oeII aeutelym· phob!llIlt!c leu~ema 1.~ibt1 pr9dominant DH6· 19 and DH7.<1g_lISIIjlfl , tar1 rewll to rom· p1ete I/, [).J ttlan-i/l98fTIll!'15, and alll raffl in T. 0lMl recllll!Ot "lpt1a t>!lla ~ fllIll{l8. 8lood 93 4Q79-4OS S 1139, Srpurka It, Tiu R MUlugaun G. AtxIo«lI a 5, H5I EO, TMeli KS. Sel<_ MAo MBOIjewsI:i JP 12lXl61 Raltacsory -.NI ""'" MQ'ed 1dMobliI&ls ilUOCIBled ....tIl IlI/Iriced Ih~ (RARS·T), IIlOlhet~· ~~' e condillon charadlinlOO by JAK2 \l617f 'lIIIIalion Blood 108 2173-2181 21400. Tadatt....Htath l, Pillalug8 S soo.. l. &Me)' M ~ 1,1 , JIllf ES H&tri$ NL E.(pI§Iioo of ~ (2003/ ~ ztnIll-oIIl~ .. (:hi. d.en atl(l JCUt'OII IIl).oIl5 Am J Sutg PaIIoI 11 522·531 1141. T~ A8 ItIlIl O.811 M) Cwtly ... Cwrtnifts 0 Banr.- NIl I2OO5l ~ ~ j«.:qund ~ IIlOnlIIIy) CM.aId tIy gandtlOW T"ii4IlIIl-.,1KJ IV· ". Suguro t.l. TIW"', S ~ K 0I<arll0ID t,I ~ Y ~ S, Stlo 1.1 (2(IOSl ~ d IJI'O"e pI'OlIIf b "*'IIicf. kill 01 do5lIIIel ~ aI cIlluIIllf9llk:e1 Ii 5 ~,lllDall06 177fl.lnl 1141 T. YC """ t Ho P8h SC QOOIiI .soc.. 1I'\lIIlIaIIic~.~~ .... . . Vwch:lws1>ldl441 1000-1006 2146. T__.....a T, Ham 1M' luo WJ ~ S l::lIImIa I,l, AlllMI I( I100S lois 01 •• pr9$SIOrI fA ~ __ ....... 1NgIf>-2 ~ ~ 1 ilOOf P'O'1" rtOIIisllle:-d~~t,& p/>olnI h Je.ut 118 2182·21119 2141. T _ T. Luo WJ "-" IE ~ 101, IudlI I( ~ I( QOO3I E4iU .... 1Ild~0I""'0II~""" lfom l'\'OIlOti'"""""'*"d ~ 0IfldI 0I¥Il0ps on ~ ~ ~ • ~~-~­ riIcl .... lli5IIrOWI """'" ....1iirIUDgoelII A'ld cIricaI Ito1' S»-S46 ~I>cs ~26 2150. T N. SokoIoIl L BarIh I'If p9STj E.n ary tvmphoid a~normalrlie5 III s,;.gr.,'~ s-dIootStl,V~Wllu~LR, 21C2. T Maul K IrlMlUllflC'l' at EBY associaIion a'ld ~ __ lion'" !he lMP·l gar-.if1C056 ~al h >JWfIl" aenxJigl!$IM'I lrlIct Palhol 1m 54 \58-166 21"". TIjoNI It IiroImII Y (19911 ~ d HTlV-lIlI .. ./aI)in and l!le WOtIcl In· ~ on AdIJl 1-(AI ~ and Hnv~ ReseilIdI lGirro ~ OIl CIncef Res8¥ch1. TakilIUar'* !'tm. To/I)'O. pP 129-149 2145. TlIkiNslI E ~ K. "..... T Y~ 101. Ema T NaUmIn S i2OO5 lnn~ 19t9t' T- W"drome (ralKUum C8II _ _ ~·~I"'"'J Mod 43' 50-65 1151. T8Iao.Ib D, ~JE. SI>lcIloI B. iIld'OiWIn ~ , Iltoom6eId ..., PwlcoeI< M (2001). C/eI.:uIl bcq marrtllIt in _ _ with difluM large B-eeI ~rnpIx:.ma. ffilJI:s fA. piIoI ltudy P~!floIQgy 39 580-585 2152, Tallman MS ~ RI, Sd>/IIIf CA.. A/lpebl Benflllil JM. 0e>0tId G, Ca-Wleth PA. W_i~ PH, Rowe JM 12004) "'wt a nlQrlOCytlC 1$oJi<_ (Ft9IIch-ArnerIca-BriMh eIasIifa. lion M5) does tI(JI tIav!l a *'tl'SII prognosis I\ifl ol!Iet Sro:m;>. ~ 1 an IIOdVomoioomll 7q eQlOIWaIInI ~ III dlromosomII abMrrion V-u-s M:h 449" "'..., 11S5. TII'I BT W...,., RA.. ....,., [),A (2OOSl n.~dB-anrlT-OIllI~~ rte1llI IIId ~ ....... III T-OIllI rym.. p/IorrllI$ 1 ~ ~ artgollO'Il~ T-OII ~&'ld Ie'tIIlnI T· (JII ~ . ~ .... ~ ~ ",*"lIIOnI """. .-.d WIIIO\ll J I.Ial 019 8 2151i. T...ai Reference s 421 N. . S ('9llfi) F_1gilncl1l hI.rnin.-um "'" Utd 2 317·322 2157. r.-.v K..., U TogIIlI'I K F,.. H.w-.btN ..-oeA ~ II: Sd II T, r T (2tXlIiL CNtnit 1lOIftIP* . ._ fit f1P1Ll· PIIiIn Il~""'m,..od~ IltJ A. ~ S {lOO1) Curr8r4 __...., "....,....1 ~ peIll> opi'IICII ~. ElIood R8w 15, 121·131 2171. TIIIIIri A, 1'IKIInalI'-' (2OOl) CIJIocIII, ~ lII"*- r4 IlIrao8uIC 111II1* II'IlO ~ .... 0IIlI---' Oprl ttIm1Illl\ 5ll-04 83: t52·t$ 2151. r. . SG ~ JH, u... LL P6ctds KE 12000) f..-dlOnll ~ b" SAP" 2St~~d human .... ....... ~ . ~111" X-lr>kecI ¥n- pllapo........ "".""r.... syndromll J lmmunoI 165 2159. p ~ F. vn., O. IsaK S, loQ II. Conl... JF 8efger F (1998). L~~~on leu _ lviclInce lor B pherIotype oj lhlI 1lIi'n(lIaIeeIt, f ur RespirJ 12 102-106 21&0. T80 J VitkIerrarna E P 999) EpU8IIla.r 'o'II'~ poIymorpIlic B<.eII ~ ~lMl (I1!Of'dMl l/\ II1e Illngr; of ~ drIor1 wlm AIDS: a repon o1 lwo cases, Am J Surg PalttOl23. 560-566 2\61. Tf<J a RolllIl1$Oof1 KD, Maoo& II, H~ A. ~ Rf 11998). Epsl8frl. BiIIT ";fIJI iEElV) '" ~ 6I.rtitt's lymphoma rmiKlJlIr ~ d P'inla)' WInOI' !I$. _ Blood 91137]..1381 2162 r.,.". M, N~ CL4 F!39* .... Song x.. ~ J. JufllJ A. IUIMrI K,'" H,lJctIJO GIoII80(2003f, Sa!NllclMalOli II PTPNll II ~ myeIornonocylC " " " ' _ " ' ~ sytlCItarftllS . , _ III)W.:od - . . - Nil GenIl 34 1"8- '"" 2161. T-.u 101, ~ It ~ M, GcJbl ... ~ I(, ~ N ,:2006L ~ II'lIIyM d etItOI'1IC ~ 1Il*-'" .4,101 s/lorllooII;I goal1'NJl(Nl a... 7.... A. 1bIIt J, caa A.K....,.. T. H8tW'l CA e.os. G, ~ S. ~ G Mesa R. Rely Jr. 21n. HM s.w ~ H V..-.ucm AM, ~ ..... _bal1hrtlmbocyll'le, ard pnnlIry ~: ,~ from .. ad hoc wrllmlborlal e.perl I)droel 8Iooll 1101092-1097 2111, Tlhnl rd'll R. Irrvemiz.zl R. Gr3ndien A, Z hl votov sk ~ B, Fadeel B, Fon;tllom AM , TrevagllooE, SamCl8lss.oo J, Hast R. N,lwon L. CluC>13 lA, Wibom R, Helistrom-Liodberg E (2005~, Ablrri!lt rrYIOCtlotIdrial ~oo d,sviDullOO I/lCl n'IIhI\IllI:In arrest dIaracleru:e \'J8/1)' err- ~WG.c.oM5.SlidJWI2005) T.ffotrI A( ~1 The doitgl'lOSis ol poly' c)'lhemil WIoI'll: new IiIt/$ a --- ..... 815530563 2ITI , T..,. A ~ He. T,*,,-, TM, "*"- RV llflell) CIvllnot m~ .,...,"~~. _ _ Mllyo Qrl Prot 64; 12-46-t25ol 2171. T A LMho n GlIIlinIG 120061JNi.2 II...,........_ ....... Irl E'9 J )53 141f>-t-411 21n. T A. lMtIo ~ SN. s..- oP. . . RA. li CY. WadlIqllol Grt GO l2OO51 TIll JNQMi17f) ~ . . - . . . " , II """,,*,,_ IIlIl "'l'IbCI n.. lIlICfIPlMiI: ."..".. ~ and drlal CX)t. st. TO,.l 124 56$-675 2110. ... 8el9t RL. dI!I 8tuIl PC ~ JJ ~ GJ. ..., d. V,... CJ (2llll31 Al.K~ IflIIPIa* iargI-oIIlyrIIptonI ".............. pool ~ 10 ~T 43 ot62-4S9 Ilet9I Rl. ...s,-nc 0ucIetans JJ. CJ (2OOJ) PfOIl'"CI'lic MjleCb- . _ J PIlhol200: 4-15. 2112. \Ittl 8ergll RL CluO&ja'Is JJ ~ GJ. F'IlIbll K 'MlIIIl'IltI R. F_ 8, Qlgn A. Uo!otef CJ(2000f AlI("",", IlcrI in utrInodllI .-.apl&sllc Iar~ cal lymp/lomIlIvour\ syslemlc~ wilfl (pr'mary) 00ClIll ~ arMi a good ~ ard octUl'1 beIOte dls....naaoo, J CIIl Pathol53 445-4 50 2113. Terre C, NgoJyen·Khac F. Barln C. Mouil.Onll;cl MJ, ECiache V, Leonard C. Cnap;ro E, Famal H. Booyo<1 A, RouS>llol p. Choquel S, $(ltn tct1i¥l M. DWr.1JIi p, L~ V. Caslaqll S (2006), Tnsomy 4. a new et1fOmosomal iIl)rlOtmal,!y In WaldenslrO'lfl ~lmtmoa .• allldy of 3'9 CoISlI. l..II.QrrA20 1634·\6)6, 21M. T.....,...FIIOslIlirI J. CtlIIO E. FiIppI ~ ~ 0, R. Coie..... l.l, I'llrIoct. C. Hoy It (2l»Il ~ lIrve-<*l ryr. c..o.r-m pIlOII\II-'" ~ ~ • dInl:aIy ~ IP'CNII .. bclf> HIV~ . . , ~ ~ -'"' ()ICd 15, 1673- "" T~1klsIM1 21as. B. JIlIe E5 {1995\ s.. ~ J .IIftI ES, 1M! PR H. ~ r:Ni 'flIiIrlCIn WH LMgc 01.. TOIII:) G {1'il'}7j The roll rJ ~ fie IIUO.nI ~ b y ~ , .., If-Ill " ~ p r o l I & ~ '*'* .., ¥3SCUIr Ga1IilII fI'III9Ii" Iy!II- phomI 0IIft<:ol3 ..,.,..,.. IyqftJcI ..... (MALn &"ISIf'IlI ill • pedIaITc HIY~ ~ AnIJ SI6i PIIhlI 19 357·363. 211.. TlfUP4'tItlI*l J. z..ow P. ~ JE EL ~ L ~ M TOIIIO G. JIll E5(1998) E~oI _ _ "', s.r-. ~~andcylr.ll;nt~ .... H 1 V ~pebenl .... 1IUIic4'lIit a..M .., I"'W1lA4iof1lp>~ lItllr>olsllll: 1~1-1642 21M. TnbJ hi 8o:nanJ G........ G CIrtu'I C. R"iJ}IIl O. ~ E. F'tIIo::IlI S c........ RUl P, P3SlIllO R .- v..... G ~ A. T.... S (1999). 3Q21 100 3Q26 ~ aI;irIor. ........ 11 aeuw mJ'8lOblasbc Natroa: bioIagQI Irid diIIcaI JeMJ.ns HIlOlI'l'Iakllog 84 2190. Tl\lIf'9 2m . l.I Tha~ M. 0klpIde O. Beet..,." ~ TW, 8eIu MM R.,..,. JD(l99Jl. Clnc.Il. lllOf· ~ ~ rJ lyrI¥IIOid ~ cn..:w. Il«l by both 1{14,18HQ32.q21j IllCl 1(814XQ24 (32) 01 1(822)(q24 qll) ~ phoIogc. ¥Ill pe** Oloo"..,."aCan::er 2 ' 41-158. 'l, ~ S {2005~ ...... 011 ""'" ~.., donII ~ Vll'l~21 r_I.""'I""~' e'dlbll ~ IlIII"l-= II'tIIlIraI .... ....- eel ~ \llIIIZ. "'II Ohf ~ V{H) lIII"I UoIl Pehllll: 331-3J9 2113. TI'IItJIIno:lrl C. 8asaOI'I 'I, 8IrglIr F. RiIu. C. G. ()urnaNt C, F-....n p. CothIrB(l997j ~ ~ .... 1JI'tI(lIO..brtal MId l'lOI'lgII$Io:Iil........ lympllllmil be/lIM;Ir Nysis rJ 1M peDelllI J s... CIIl0000l 151624-1630 21 t4. T~C,6e<~F,Oumc:nlelC, ~ I, Ilw8Aa F, Felman P, Sa .... G, Cootr.. B (2000).Mocos3-a:;sooated tymprlOod lissIIe Iyrnpr.;.rna 1$ a dl$Semfr\alfld d i _ III OIl! thifd of 1S8 palll!(1ts anal)'zoo Bklod 95 !lO2·806 2195. ll\ieblelnOtl t C, Felm.Y1 P, !lerl)II F, Oumonl!ll C. AmIud P. Hequet 0. Artad1I J, C"e1-81ucllll E, Sali&$ G. COdfltll' 8 l2002l, TI'83blW1I of 5PIeooe troargO'lal ZOl'ilIk:ell ~ p!>om. 111 ansll'SiS of 81 palllnls, CIIl l~3,4147 21M. ThoIblImorII C. FIlma!I P. CItlIt· 8IuChJ E. T'_rw·Glehe!> A. SIIIes G IleIgIr F. COftIr B /2llll3). SpiInic II'lIJgII'IIo .... ~ • liIiIr>d. cb::II IIIIl peIlo1DQaI-*J I.MIoeI()ICd 4' 9S-1G3 21' 7, 1hIblIrnonI C. " - V, FIlIna'I P. ~ K, <>-ao S. ,*&m. E. LClIiocl B, ~ 5. GIulinl P, f9Q.IfI C. T _ CJIIlI!l A. L Betl.co F. e.orrt.mD, ~ F. MIIOWIi!III 5 ,1,- .....-, H. SIIII G. Coder B. Berger F ~ R l2OO4i· SII\IlI ~~, IftlI9lIIIl e.wo tr.... lUI"*,,etI~.~cIIrIt­ ~ 21... rtwdI C Koeh S, er.rtz,g E SIIudIl c:al1lullY BIoorl &4 2121-2125 2174. T.... A. I.IIu RA. ScIlroed8r G, fI'I'lIIoerllJf 11...- CA 1I CY OewaOi GW (20011, bllfl C. l*IlII' T, Sdlaich '" Eh/'IngII G (2OOl5~ P<e.1iI!lCI arod iY09rooslic Il1*l rJ hiPl,lI rr'IUlIloOrlI in 1485 I(loJI ~ with ICM 422 References III ~ ficlopllhl:) 261-2t16 221M! n..J.K-.-..nt1M(2003lo.mc 1ItfiIlOp"""*,, diSl.lflltn ..... ~ cyIlIIriI' • ~ SIll1Y lit IlIO ~ syswns\PVSG. WHO) Ofl aJ6 pIWIl Am tWnIluI 82' 143-152 22111. ThJelI J. Kv,lSr.cu 11M (2003) ~ ~ lit -.bal blJlIbo. '*'" eylhaemalrom~~ ..... dlrQric idoopi1lhic myeloIibroIiI by liIl:fMrl. ....1I1r11l'/1is of 00ne "'Wll7IfI' ltat.......... dIfI. ocoplIthl:*:lgi<;ll lludy ('Ill 272 patilll" l1iilO1 MlopIthoI \8 93-102. 2202, Thllie J. Kmrvck. HM (2004) Pfe/lbrotic cllrwic idiopalt\le mye~ ~1ll"IigTIa? fom Halmatol 1 11' 1$1 511 2203, l h'dIlgIind"lmcodloplhc ~. Orocxll J2 J80.~ s.rr.. 2205. Thotle J. K.WId.a HM (2008) ao~ C1tetII b" difterInIIIa.,. _ rJ III _ _ fIl)'IIl> ~ ~ SetrIn TIltarrtt I1IIIIIlIl 32 21i-2Jll, 22Ol. 1lIotII J, K"4$ftd.I HM (2007) ...,....... . -W!W·s.. a 1 e-- scr.lIrlJW{2OO:lf ~..,~ of~lIgIIfOIlg~fIlDI­ ......... IIogen!oc lkIlII lIWI'CNI _ _ ......... c:hrtne~~ e>.periIrIoI 011 160 peMrG, IlonI lAarrow llilflSPlril26 21!)-281 22lI8. ThieII J, K~ r+IoC, CZlIIId C {2002l, COl4. progeIIIIor c* '" ~ (pllr!\iIf'j) myelo/lb ...'*'* Borlll ma rrow CDJ4' prOlllln,tOl CIl IIs in PMId. l p~lII ehromoSOi'!le·''IeQ'Ulv' chrook: ~flIfatl\ll! d'~~ loggj SWd~ 01' 575 paIlel1lS lllUi. L)lI1to'nI 46 709-715 2211. ,"-"J.K~ ~.DiIhIV(2Q05l 1IJNI (lIlInIl poIycy1helIIIa \'If3 Mlh Ilto'r\tIl). CflOeIs I1IImdn;J - * I I I 8YOmOOq1I\IllII -",*!"IIImIld \13 213-219 2211. T'-le J. K~ ..... DoeN V (20051S1IndIlWIIIOfl 01 w. . . - ...,... doeIl 'iOO'\ ""'I~ b ~ ..........., of diIIferI . . . . ~ ? ~ ~ 20:633-6U 2212. TIIIII J KI ~II"fIrD.I!"",*"","""" 2213. n.Mo J. K-...-:lw HM o.tcrl H StIIrl G,,...,. lol. KMlw'IslJ A. flaIl\JIll N ... tV.. Beelen OW lloIscN.owskl 1.1, ZIr"o6II A. KrOt9l" hi (2005). Oynlmes of bonI _ eIIIo"9M l/\ paIoInlS Nlth ChrotllC ~ '*-II BIoool90: 4(I!l').<41115 211l6. T.-uye-f~ J. .IIfflI E5. 8urll PR. Ho(lgkirlilisease' dna cor<eII01 tiO\a)I.in •• p,_ ..,n .~ lIs'lIt ~ otIIo",**"c:es rmuoth:itXl.'iU1 IIlIl .oprol.... ....-..onof~~ of ~ n ~ ClIl*ltf of ~ IfllCN,l,. _ KHl7 ~ ~ 1m>8 CelPIfO'rolk4 ~64 2137. 2113. tt/llllA.li C'I. Willig 1E ~ lItI. (llloJrIQ Sli. Prr,M;y RLl19ll4f,CM:nc ~. OW, StlIi.dI JE Tosato G (1999). ClIf'lIrwJbal chImokN'll eopteSSlOll II II!$f,IM 2111. 1bIIt J. 8fIq-.z Fe Be dIoRlntrr~,"""'·I_ylllll ...... Ilt J......-cJ 131 320-328 ~~tvm- """ ZO'lI k:II ~ . .J/Id nw-.e 011 ~ pho(liWd~ prolIIts ~1'lIllItIclllIr~ 8IoocllG3.2727· 10 1IIOC8Md pI'oOplOlllli m)'lllocl ......... jNol.f Blood 101: 4011· bonuJl:;~ 21.2. '......,.H WMshSll, ThorwIuIM. ....... A.~O,t.ars&onC ~ gre AlJ(~ 1ilf9ll0ll~ ~ ~..., BIooclIl3. 2463-2470 2117. T~1IC:Is1lJrl J. TtIIIIId< BK. E. VIllMIIll.HI, I..arson RA I«lQS!lOll and E~ \'IUS SlIlM in pedIIrlt ~ ~ ~ J CJ,n PiIIloI 2111. ... "" ~ Blood lOll 247·253 2179, Tlilell w.. lo ~GJ 2168. klw-m.. s~, 1Il-.b~ lnlJ~&3,.3J..43ll """"* ........... "'**"' F, rllAUl G. HlJIonaoI R. ~ OG 8Ioom6IIkI Ni (2007). PrCIllQSIIls and IMIOn8It lot ......-on 01 lhe World H...." ~1lOn dlagOO$lJC cnt_ lor poly. 21", T* AM ....... JA Tllio:* J. UI* YF (19ll61 ~ a'ld ~ II .... ....".... IlIoolI 61 423-'38 211S. Tl1WrQ WY s.l J. ""-I T I>l" " - $, ~ M F.;j Sot. I200lll Pos4-tr-. plInl II • priIInc renal PdK PttiaIr 8lo<xI Ca'lcer -47 218-:123 2161. TeGeIdlI .... Barate C, IolIrdil E ....".,. E (2007), ~_ Illood RIlV 21 1&3-200. 2167 . re!leli A (2000). Myelo/ibrOSIs .. ill'l ",ye\:)i(l rTIllliplKja. N Eogi J Mell 342: '25~ c.r-- CD. Verdtnlin l!lrolrj Pf'Q,IlI(llt In ~ MM KIlgmI OW ~ M. P-. HI........ ~113 76).m 217S. T POGF~ ~ ll'I"II II I Will ;I ~ d .........". Inl J Nslor)' d • ~~andtleirdll"oit8llM~ ~ fI-orn bone....".. ~ LMJ~ L ~ 33' 201·218 "yeIo~ /oIowIng allogeneic !tern t8l ~ . HistQj H1~ 20 87~. 221~ ThotIt J. KvllOldo.l HM, F8CChettl F, f.atlGO V v"" _ WJ, Oruo A (2005/ e~ ~ on~ bonel!WlOW ibroI" and _SfllIIIII 01 OI~ulan ly ~90"'28-"J2 2215. ThoIle J K. aII1Q.a HM f..,;l'ler R (lm~!loot.-.oor ~~ on oYonc: lII'fIloIIIonou ...._ lCMl.~ 01 .....,... ,........, lfrQI ~ .... ~ ,,,. 12<11.125ll. 22't6. Thiele J. Kv~ 11M 0rJlJ A I~ Bone _I~ III "'7'Ib~~d~ llIlIWOidI SerrwI",,"2 l&.t-lllfl 22't7. n-. J. K-.:u .... sa-~ A. c.hI V (2003) 80nt _ r............,,, ~ ~ .. 111~ IwfIPI' il dW'/lI'IIt dO- 1_ _....",. .tl "71). .~ 22't1 T... JK....... HI.. ~ A o..n. V (20031 O'l-.:t 01 IrlII.- il tmnc ldIopIlIic ~ .., . . . . w· "'......, • ~ ~ on 30i Il*IllI LML~.t04~~ 22lt. TI*J K~Ht,l, ~ A. " - S EngIlt K. SCIII> P,' - ' ~ III I\"IIw CF. 00 ........... r.m.tl ~ 01 ... l'fI'*'llI a- n'lCIU -*' ..... ISTl511) on bont - . . . lIIIlft!Ion ~ ... dWllNC ~ iIuUmllI mo. ~ 1tIlopIIhol19 1277.1. ~J. K-.:uIf.l.S<:Mw~ 11.. lriow:tI R CWII V /20021 FlIIcloHc> ~OII(UIong ......... bont_ ~I'I-*11~(m. ~ l i l ~ RAy 01 120 - . I I AmJ~70'28H91 T""" J K~ HM, Sctma~ A. at. TK, 80mbun F. ""--'n C, YIlguim-Gflh"..., Iol frCk"'Po/ll H, ml. ~ C.1.edar LD, OlIN '1.lricMttl R Sc:hIIIllr HE, NIIllIrlI 't, frSd'* R (2000) Bona marroor IeriJlurM &rill cInc.IIlrOr9' on ..'" (/VtI'IIC~~~w.. ,muI­ IIc.riIr ~~..-.rl~ Sb1\' on 61 . pailIKlll Lauk L~ 36, 2222. ThoIII J. K~iWIrlII 'Inman J on tt-. ~ aI Cl\l'GnlC myeklprallleralMr dotot'. dars a klrgoften pear1. e.st PrIcI R.. Cill 12OOll) Iloot HM, ITl<MTl:HI' hlst~ ,nterferon ltl-efapy...... ncceesceoce in ! itu ltybridIz'aIlon study 011 l1ell/1.... bio\lSi8$ J Pattvol191! 33' -335 mao TlIIlI J, WiMlld<er R. KI'a$/lId "'2m. "" Thomes OA. FlKIerI S. 08ne... S. ..., ~'jtJIIQIIe tytI(I,_ (I.IOS)" In ........ unoo~1I: ~ 01 bont _ _ . . . . . tiopty IPIllfI'I!ft J CIon PIklI ... "',.. 2227. It.11e J SdwrIll 8 F\lCflf R. ~-oa 1AI. 1..otwInn J. F.... R (199ll~ o.a.on oil'll lXJllbI gent '" bont _ ~ .. CMI.&'ld"""~ lIrve 8 on Rdlwl"oorom.. lIo.ol._ 18 J.26.3JO V~ R. r.u.- E. ~~CC, ~J l.MMo 80nIctl 8 (1*1 1iOdgUI'1 ~ c-.FJ.V~S.WiwI1aWG.~SA. ~ ........ ~ on PllW'I\I MIl ShIn J 8r.nlI ... H1l1l8ll__ Fe KeaiI'Ill I,lJ ~ F. ~ H (2006), ~ ....... nyper-CVAO .,... b" III r--.. 01 ;J(UI1lcnoIt WId 8urUI-typa ~ (r aculI "" .... KbIaMit ~ -...-. c..c.- 106' 1~1580 U30 1 _ E, ~ Oit. s--. RJ WllcfIr\Iflll GJ l20001 R.sk of ~ nong....-awill ~ ~ lr( J cane. 68 497_502 2211. ~ w.. SUrd1 J. IilIrtOson SE.. ~ A Worog a, CIscr> S. I!raI'Itt SJ, ~ J, Zlwlg X. St¥ Y. IC"onney we ('2(Xl5;. ~gIttlle....- on ...... lie ~ ~ "'l If\lIPllJk ~~~lIfVecel ~ Hi,m i>lIfO 36 "94-504 2232. ~ DA. G c.ar ,, ~ s.won,... 22).1. 1l'onIon PO. BellBsC, ShIh G. Pooock C, Woe palllogene&! oIheiry·ceIlN-OO, Nat Rev C¥JCer 5. 437· ... 2236. TOtco E, Pileri S, OrIeth A, PaQrli R. lIbamni A,Frengi.'lllli F, LISQ A- Di,llIi Cooxl F, Falor< 8 (2004). PAX5 expression In 513·5:(1 2226. 1.... J. Qullmann H Wagntr S, f ' " R (1991) ~ il B. AngsIer C, floc1>¥ A, s.up. A, I( opper l. UlIOIt'lly A (2C04) R~ ' * - the fhJlIlonIl stalwol VH~&rIll ~ o/dIllYM ». lICIJM Ieu,_s, higher 8~ioeage speaficity than C079a and seloct i~e assoaallOO wdh t16:21)-.1oJle m~nous lau,emill, Ca'lCtll' RIlS64 7399-7404 ""*' $lud)'. Aro'1 ~C~J~.....-.oG. 227:3. ThIIle J. K~3!lnd<1 11M Zf,tH-o" l . Hlemlt ologo:.l 85: l t26-113<1 2221. ThiIIIt J, Kv.~ HM, Zlf, koW::/1 R, De'I V (2001 1, The v.... 01 boI'lIl rr'\IffOW n. IIllogy .. ~I,O\I bf!lwIen 8lIIly ~ ~ ...-a aM MWldIry (...ell...) ~ ~1l631i8-J7.. ....' • dinIcal, 22U TrlQUIly M. ~ 1 9 .~1 3-43 7 2225. 1lwlII J. Koand.! HIol. Zam.-n G. Va-diNIl J, Oiehl V, luetIi:IeIt U. SdmI1Gr3eW A l2OO.t) .\cult ~ ... tIl ~. 'lilIcXIPartOOgocll A4y on.t6 tJilIenIs. n:iJdong ~ 01 bont ....· ~ /oIooI,o"'4l Ann HIln8lll 83' . . . 01 dlrorroIomIl abllormalo!ial in Iolkvltr i~ 8iled!l.t 1O.t3-10.t9 22.ta. T~ B,Fuloll Z.C _ 2231iA. Tiemann M, Riener "10, Cla,;"l A, MeYlll' U, Dotffei W, ReIlIlr A, PEllW3I"esdl R {20051 ProO!eration rate and ou!oome .n ctWdItln With T~ ricI1lke/1 iymp'lotna. I din.:»pa!hologlC study from the NHl-I!eraIIon iI'\dO;tl! and c:lPciIl CIJt:XlmI! on 30f . . . MIllllllllle QII ~ (UClr • ~ SlJlly from the fll'OPl!¥' UCl toeIwort< 8r J Hatmala 131' 29-38 2211. Tlen 1iF. Su U. TII'li Jl..lJu "'C, i.lle FY, Chen YC, o..-g SN (1997) CIoNIi dIft>. moIOII'lIl ~;III and ~ b" don*; il nasal TInat\QI k/lIef OIl !ym. ~8rJ~97 621-615 tnt. r.y H. R(\50S, It. $lamalcUlas 11.. L~ 8, iltgDIgnt C. I(ur*l 11.. hlonanluif .. 8llItard C illl9.tl. ~ PllclIll"Onc:d37 1[18.114 2243. Tollil G (2007) lhe ~ llll"" ~...,~ .. lhoI\c """" pIo:yIIc ....... IN L ~ q. 1081. ",. 224.t. Toc;n G ~ U, ~ Alton l. ~ 0 l-WOI'I ". Ilof&olg J ~G,~J.~C'CJolIG ~ A (2llQ2) ~!IlIAIilld III V(tf)3-2ll11"'1 ~ I ,..IIItIIII<:I ctwora: ~ ......... 8lood \lit 22t\2, "" T~ I( J ~ Y."", Y. s...;.K. ~ IoU'III( (1001~ 0 - . ; IlIqJiIIic"'t"l'Jlltl.....'~'~l)Illlolm· POGFR8 cll",,_. reIPOfICle 101. ~ U """"'~LU_21 190-192 1246. Tobdorl G. sw.n H.lImIrt I( \19101 ~n~llIInobIoI. ~ ~ ~ /rom genrwlllI- C8'h oellI '"" CItll'<'8d rudII ~I, 41 168-182 Br J c..c.- 2241, TotnIlIS./olonKL Sal.alnS,OIIwnIK 12003),8-0lIl marI.. ~ lcor+, COl~) E~ wu......., P'f')IhorI.·IIIIOallI· ''''II9*''*'' il the JH \)lJ'IIl,Leu.lyrnp/lomll .t04 121·730 ell ~ WI!Il 224.6. Tomrhl Y Clhww. '" Oi ~ II Has/limolo 1>1, YiIO\I WI. K.m Gf, Aolilll I( (1997) EPliteon·81uT \'INS il ~ live l i - . 1'1 me SlI'Il:>-naIIi regKln, doH 8ssociatron WJIh CD56+ irlIn>J~ and l'Oiymo rv~k;·'et'culos 22.9 . T()rdjman R. Matintyre E, Em"" Jf, Vaillns, F, Ribreg II, 8u~1n ML, Vare! S, Broosse N, Ht<mine 0 1'996). AggmSlW! acute CD3+. Lallioemia 10 1514-1519, USlI, TOtI3kCl'o'IC E, Nilll$en S, Vyberll r.4 12(05) M loIl ~ on rtW:Wf ~led MId ~ 1ICIionI. • ~ ~ ~..., 8-oII1nIllM. Am J PaIlol2'li' s..v 1ln·mO. 22U. TorIikcNII: EE ~ HV. Hwn S (2006~ A rr.-gnlllInt phInoIype on fokUllr IympI'IorIIiI _111418)" -..lId __ orGfy C)'IlgenIIc typQIl 01 _ . g.llllOI'II ~ J P-.oID 25&-26.t, 1251. 1~ .Jt e.t)' ". So:wtn l, T _ ~ .... ....,.J KnpIDW.~IIl"ES (2000\. U-- dIIlI T_ ~ of". MId ~ 136. 1024-1032 2254. ToroJR L~OJ,I>abbv 't,Sort>.1I L, Rat\eId 1.4, Sleinberg SM, .Ide ES (2003) Glmma-della T~ ptleno1ype • assoo»lell ,,;m ~ demlased ~ .. 1lIOI41"""'~ eo-. 8loocll0l, 3oW7·3 2255. l ortF. CImIciloE. BosdlF,H.ns 'tL. lobttsetral E. Campo E (2OO.t1 F...... IyrnphtI(I neopIasrn! III paIIents .... m.l8t CllI tvrmhomI. ~ 89:31"-319 2256. 1011 F Pr>yoII.l. PIlllml K. Rotadcr G HenwocIftl l ~ I. KI.Ift., . tiC, IOuon P. louro:ll C, ~ G D. ~E(2001) UoIetuIIr~oI "LK \r.II>9llCiIklI. ""'Ili'IIIlg _ • _ (\lSJoMLK) il ~ llo-gIr CllI ~ L-lIbbft61 "19-.126 2257. Toully EA 1I920) 1IliIl1Oln8\lll, .... A c.- 01 ~ _ ,,~"-"JMedSDllil)­ 16-25. 2251. T delio.,"'''''' lMrVy Ii ~ (I\lI'qIII ~ 2p2J 11\ "l.K~~. 2 _ Il~ A!.I( fuHd kl Clla. (cWnl dlW' ~ I l . Blood Il5 3204-l2Q7. a... 2251. 22"5. lo1.l11 K. .... mICftIeOJlIic. ~ T~ O. Sarb 00 Xu L I(ati J 1. YT. til GoA S. CIIeI' L I-MIIr Z. IlrIn9n AA Iloya J1, ...... ... ~ KC TrtoOn SP (£006). Walt OIls on W8klenslrorns ~ SI4lllO'1 ~ eel growVI ~ Am ()r(;oI C015ol1CD40 IllrouQII 17 127!l- "" mo. T...,....K. Ot,.-. K.YCJIIIl8 Y, Itbe T, Asan:> S, l'fr8i H. ~ K, I-da 1, ~"'~S(199:11 ClncaI ....... ~ . 0 "....... -lQl palMI!; Ii ....,~~a~ lIludy il . . . LeuiIamiI1: 4~ 2281 . TrJl;ll)' L. W1-.dll1 R. DoV AN, 5>*"1, Ortiz P Gam-lI.If, ~ano.A..lBIer M PIlls UA «'003) MycosIs MgoideI . . - . COOOi~1 ~lIIat>on 01 rnulr!jlle ~ II'lVO!wd In lhe lNF sign;lIng pathway 11'1 Ilxprfision pro6Ie stud'f, 8klod 102, lOt2- ,.., 2a2. Tr 8 ~ A 8a~ L. C 111: 2253-2260 22&3 , T~A , ~.,F. Ben Smon E. CalIeI.&oc:I1<J E, Felmen p. ~ L, G3Uo S, rn..oa.:.mont C, CI\IfIoI C, Col!fi«B, 8ergef F. Salles G (2005). AnIIy!iI<:I VH margNl rooe IyIr(lOOma re'oWIIi m8r>:ed ~~ betwMn ~ ..., nodal tumors and ~ lhe exiIlenoe 01 <*nil &eledQI tiaElmaIJIogio: 90,..7Q.4 78 2264. T~ 1\. Felmen P, ~ 8alChu E. Gal20 S. 8ll!eggoo L Bryon PA. 1hIItIklmonl C. Codfier 8, Sallas G, !IerlI'l" f (:10061. A cil~ study 01 nodal ~ rore 8-0lIl ~ 1\ rtPort on21 genii in C8S1&.~.t8.162·173 2265. 1 ra_Giehea '" PldIlugI S GUirll P. So:wtn L I\b'lIO w.. ~ u JllIle ES r.'OO5). ...,...,. gqy mr.- .,.... pIloIM !he rnrssong .... ~ '*MI: ~ 1 ~ &'ld IIllIlAIlINlIlIl'ge 8c:eII ~ .lin J S\,rg PaIrd 29" 1411· 1421 22li6. TrenlPlll P, ~ C, Uut'IIll: G. ~f.OoiIIIloI-G ~ ~ IlnlUlIlIlP References 423 (2003) C~ m~~ ....... "'lh f1l8...-.g«lW11 0/ the plal<Mt-(jen.ecl IIowIl !«:to< IiIl'Ia moe¢r • ,.. ctroc.ll.-. ~ for STl~n'GMc 0nl:::cqIne 22- 5702· . " 2261. T_ $P HunIIr ZR. ~ A.. EMIl EP, "' . . - S L.. C StnQ 00 ~ E XU l. L.elIu Il. T~ 0 Pau.rJM CJ. IoWwng R 8rI"-llln ,I,R Momn Ct: i2OO61 ~ olllmtll W3IdlrlWonl5 ~ AM Onml 17 43lIof91 226l. Tnr-. PuIoo:l K ~ ~ (2lIOOI ... , . . __ c.rc» l E DV P*o fIG. F... 8 IALK~ ~ <-'.,.. jATJC.AlK) II , c-. ~ ALK~""-':_ c..e. R-.lIO" 7'il3-798 2:26t. J !IuIII.# 8Mllt N, ~ MJ. F", LA ~ RH, Gl!u fG Sl.ccap P WQo:dIt ES (200§ .....,.. 01 ..", ... "*-a ~ ~dIDdIr ..... . . . lit iIraIl FwI'I ~"j,*,. T.......... lilliill' ~~, AlII J TIIf1ICIlIrC 5 pIl(I'II;L r_ n.", ChIll<en's GenoerGftl\IIl Blood 90: 26·35 1271. \Jeda C. N;,;MOtl M. K;liIwaki T UCh,yama T, Ohno H (200-1, eoe l ;st&r\l ~ 01 ..-MYC, BCU, lIIld Bet6 gtIIIM II 11 d64e IW9" B- Hematll79:52--5ot 2279. 1JroIe JM(2001l CliIgnoIIIc~ of ~.• lhll\Ul8$lhcallOl'l oonsetI"" propoul. l.e<Jk Res 25:603-625 2291. . ilII den!lol(h 0. j2O(l.t1 ,,~ MilIl ~ . , alIenoI ~ ...... II'IIectionlI .nd • U'noof tIftIInCW? L.-at 0n00I 5.738-746 22U Q'l den .........ElwW< MM l2OO1l PavoytnlIII nodtInaI ~ II tH,. MIn ~0n.99 11.16 1293. van dill e.g A .."... L ~ 5 11Ml Iigh e~ d tht CC dIIrnokN TARe II ~ celli A ~ lllIPIInIkII for tie d . . . . . . . T-eel .,.. ..... HodgkIl'Jyrl'iph(I'IllI M1J FWrlI1S'" 1685-1691 8Iood 8ll ~A.P:-m5.~ '*- MaDr1OnQl'lI:lsioo IU'nPal'd3$31!>-325 %285. Vailluetlil JR MedeI'tIS W, Ra!Sldakis W~mze R T",1IeI'l CP (2OOtl AbeffBnt e.preswn ol the lyfOIioI kifll6e ~ EphM Irld lha ~ Iacb' twill ... SezarysyodfOrne ~lJ1Ied by 9"'8 e.Pfll$SKIfl ~ Caocef FlIS 60', 557&-5586 ... ~ ~* " '" co.if tom ~e-.Ilb.xl ~ aooe). Gero3ri: ~ -.wus status 20 2205-m' GZ HaG S Wy co, ""'" L, lin P (2006), ExprlIMIOIl or 8 celHlpeclfrc lICtivalor prtr leI'IIPAA5 irt llCUW myeloid leI!lo.emNI \O,1h l(8:2 1~tI22;q22), Am J Gin P;l!hol 126 23~ '" 2286. V:tIent P,AA'" C.ESOlOO!>o L, Fooi!1glll" "I, I-WtmaM K, 8rod<"", K, c..steb M, SpIl e.... '" In~ 37' 1~ ~: ~ 1)81·1_ 127l. l.lct.R 5, r.bwdo F ~ '" Gr.......... ~ Ml FlIggICW "'. MIlIIIlI V v.gDL ~G RuooLP (I~) i"lIgIl ~ rj ~ --Il"'O"'l ~ bOll II ~ ;.u ~ 01 HIV~ _ InI J c.ro:-.e. 581-585 l2T7. t..ldr¥I FM s.t. tiN Gt,tnI PS. MuOC TnwlllE J ~ T~OG,~ PO, SenIeI l,IG R....., GH 111J'}7l CIIa . . . . IfIl:I ....... OIAtOIIW 424 References 00n0;IIn JJ Stnu T Panzllf· ~ ER. IlIlnt '" ~"..". MJ 2297. van Doom Fl SchItIer E. WIlemze R (2002) FDIIo.iIar rI'lyl".OSIt 1~ a disIIfrcl diseaSllentity \011h Of Wltl\oo! M60d '" 2293, •..., Doom fl, "'an HaseiellCW, V()Qfl;1 ...1IdM PC Geert. ML He<JIa F. de Flill M. Steljlen PM, Del.. ... SK. •en Vlot"n WA Wil8mze R (ZOOO) MyW511 fI.IflgoIdfll dl!Plllltfl evolution arld prognosiI d 309 0u\d1 palilf1ts Arm Dermal:ll 136 504·510. 2293........ n C 5'11, Oelabill J. CoolevtlS L.DeW<JH·PMIefI GOO V~ p. e...wens Jl (19971. (CDIl6) E.~ of 87-2 moIaculeI by Ree Hodgkfl'1; deeasI, leukaefnll 11 a.6--851 2299. va'I Gort> J WIIpIlg l . ./Io::I:lbw K l.io.I YH l.JFY.OeWegt(RA.LJG(l99041 EpslIln- (.!003) IMp:lIis .nd lrN\fIIefrt at s;Wlmie 9 ~ 8arT"""inlmal T<:e4I~I~· pI-.e ~ ~t rtlia*lM) on Id, ledToef K.llemett JM. I,IeII:lJIle 00 ,.... 00 (2002) SnouId!!nng ITIlSlIJCylo- ....... 0lI\l J PltIollnel~1 23OG. II H8IeIen CN. TlIOnIlnI J ... <Mf Pula SJ tklr'1gIn JJ• ..., liMa Q. VIoIen '11-' (199ll1 ~ IlId< _ . . 11 ncMl !AlbIype 01 sysIPmI: IIIllSkqkIIiI .......... PfOll.-r> lit ArdI AIIeryy ~ or In. 895-717 rille art 8t J IiaelMlD 2m. VaIetIlP,AlunC SoerrWR.HomyHP, 127 137·13lil, 22M. .... . . P Horny HP, EscnbaI'o l. LoM BJ, l.J C'f SdwIrW LB. r.wone G. '-aJ: R ...... C ScJIar K. SIll!!T WR. Wdtlf K. 8Iwlrong 1m P . - - t l ~, ........ K.F L......... II DO, ~NI, 80ImIIII ""'** ~ IlIKIy d .....e e.n Aclli wa-- 2307. ..,~OJ YfI'ItslW.HolJhG Cronwnelo'! lUI. ~.IN IlfWCl YIP 119'17) ~ ol ~ M»- a.saIHOOgkll~ .~ '* "., L. . . . . 18 1911· 22M. Vale QI stu:fy rj 119 ~ ~ c.w. • l,lRO-PCR W9Il Ind .....,. _ _ am .... 2295. leorIc masklcylo$lS E....J COn 1275. Tz..-a. ..... Krvgmann J. Fend F, F~ ~. GtW R ~ S (20031. PmgnosIoe ~ of C02l:l.~ II ~ (~) ~iI"''IlIeolClllillc~1l olal ",RNA • e~ allcM- ..... P21~ po:l!IIhedwtnc ~ nl atllII lie ........... Blood 87 521),5211 _9"'*_ 2(),202·21 0 22T3A.Tsiri\I01J6 __ PQqI H,I, _~Senin...........a14751~ 2305. VS'! OvertJe;:e L Edtn It Tp J ER. KtlIlllI ... .., [lQngIn JJ 12Q(lt). TCIltI9""lI II ctIlltlDo4" .... cncv--8-ALL' ~ ~ ~ 1131.1733 2296. vanDoorn R. [);Io...... R, V _ Wi OIlt-l.""'nu JJ, van dtf Rllit-Helmer EM 21738. TIUkarrw:M Y. Kat>.unoiltl Y. Omura y , ~ I, Iiir1lt lot, TnI1imlI H, KoniIhi Y12006) Subcu!llrollO\le ~ T~ lymphoma ~~ fliIaIlrlltlmlont wHl1 ~ and cycIo5.ponn II I"!emMIld ~5, 2 1-~ 2274. TI'JkasIokl 1(, T8U!W'1 Im,1 H, Y"""'........ !d, IilIta T, l.Uata K, Matda T, ~"" 5 Sohda H. Idomlla S. IdedI S. Kala...... S, yatMda '1", ~ 5 TomotII\)lI ~ ~1997) IoMgtMlOO ~ Ql HTlV-4 pIlM'\It ill __ kin 10'" dIflic.Ij COUflllI 01 .... Tl. freQuent don- a.-- 2'-' .... FlheeF.~A,lIIF r.IIIo N. GokrTwI .... CttlII NC0996l p11101ICR· S. "lW'IPIInl lymphoproIiIafaions vlllicl3le$ ... WCllId HaaIIh 0rgInizaII0n d&ss6:alioo Ifld IUg9ISIs n:luso:Il olllond IoIcWr ~ 1J '257-~ , 2J03. V.. Neeo' FJ. ToonsnJ. VOOflilVldef PC ~ R, .... \IIoIen W'" (2001) ll"'....o,lIIkiicl~fld*nn .Adylll 10 dWchn ~ by" D.IIdl l ~ Wtw1<Jrlg Gn:lup 8t J OeoIr-.Il~ 351-3601 DIM. .... '-op 1<.. de GrooI C (2OO2J ........ loIa.oW tIIifU*; 0.11 UQon origrl T. ..., w.ng lln-l182 e. .. ..., PO RaIl T ~ J RaoMl Onml BooI Phys 50: 1tl-1211 2273. TMIlg WI' CI\al JI( NIl CS Pal l,rI (1996) UliIIy 01 • pInIIn ~ CD5ll ~ 112)CJ1 lor ~ arid CliIgnc:8I 01 ~ Am J Surg P8lhol '/11th dilllJse - \Ill B<elI Ijrl1phoIrla Onoology SIud¥. Hum PaIhol20- 321).32!> PO lSi tt'jQi(lna)Jt Corral L SIIll: f Sdnpp& Id . . . . . G ~ WA Gtlcher H van Wwrog ER Luchoog we 8aa:l G. lSi lNin hIA. CaangI G IieIgor K. .., 0.- oo-..n din e.g, Hop we. RiIlwn H, s.nm CR (1998) ProgooaIl; value ol mnnIiI resd.JaI ~ II acuIlI !I'mphOlll;ls1lC""'" In ctIlltlDo4 LancII 352 mspo;mIllCl!nlltmlllll, ..........al lWId ~rison ¥nPh nodI." ... ...,.....,...and~ ~ Nt KloIn PIoI (l!l96'1 Dred:visu*alion of dis- 1213. ~ UN. UohaypocipIoody 8t J HaemIlDIl15 66--6fI 22M, VaQlrIi E.Nln:kAaSV. ~ S, I(eIe< CEo AJolleid e, Murty \IV. 8haga1 G (2OOn, CylDgeroiIlic arBysis 01 B--uI post- ~D~J,~ ~.lOI-. ~ Raap _rJl"'WY~80l11~ E, Bo/la& G, M,ntzios G K~iJ 0, Kot!nlIna'loo A, RapbI S (200 I). T-atI-ndI Beet tympI'Iorrul, ..... tyalI of dinICII /ealu'es, 5!lle'lt fllIiIled oelI5 1'1 \hi PWIr H, GJ. _II~~~"" T. I'M . l - . t K {1989!, ~ lAd " - " : e II Jill ()rmIen RIPlMII t,I P, EconomopouIos MI J Clin Palhol In SopJIl, 5122·5127 2302.\. .... , KfIIf.en JH, .... Sd*l\lC.lGJIn .... oat~ b'f ~ DNA hi' Q'l 25291 2271. T-.g P e-E.a..unA 1M 'l'f. Kr.- OU (1el161 lIbIo:UIr tfWIttIfto /2OOn SoIdIry plllijllK~""'''' ~ defiaerlcyIn ctlldllfl a-o.. . 8eIg 68 419-423 HC ~~T"-dolfJ~PIN ~rrc-td......,,_on~ 120(4) II'" ~ nodi ~ "-"0121:1 1~1221 22M . .., 0.- VtIcIIn VH e...p.,••, M ~ •. . . . . . 15 F.~5,s.tIE.OawI F.~J. Nt. JH llMa$e 3$SOdIJI!ld ""'" per-' 1\.. 13 ~ "~II %281 . V...".. JW. Sc!'o.ulr9 E. Zw!ksh E 0. 80Ir CJ. ~ KK. Villi 1("""", ..f'l ~.,...,:lIIlIIlI.*'1d41_"'1 2Z71. Tsang RW ~Y(, PI* Y. Be$k A.. Well w, tbIgpt OC S"-' Kneken ll"'lt..........."l...e ~~~?A_ 0."',........ " .... Z212. VIljltAP Am J PIIhlI l48 2017·2025 4135--4142 2302. Van 2293A van elM Oon:l JJ. WaIl~ C• 0esnIIl VJ (lll16l, The ",*gIlII zore II I'of '-"~ IIlll1a MI J C*l1Wlol 116' 4~1'9 22t38 van .... in tAa.- ~ u$A'lg ll<eakpo:Jftt.rUIg pIOOa GrIne CIncer Z271. TtC*r W, ~ SJ. ~ GE g",..""il9lJ7l ~ ~ o l 1~ • 01 etttdten wrtIl m ~ llnligen pos;IJ\I!l 1lOJIo! lymphOOjasbc !eYkllll'U' a repon !rom ee v" Reportoltlfee~ ... . , ~ _ ~196.382-3111 2lD1 . IInIdl (J#I 80ennI EJ .... <Mf H8. 5ctluuring E VIIfdonct LF, KJuin. .......... HC, lOuin PIoI 120081 ~ iIIIpId d gerrrnII _ . . . . - d prfAeM Ifld e1 .............,., tttIlpOIllIlI pocw_ til- ... III;Ja 8--<:tI ~ J ~ 0na:lI 2. I9l6- ewaor~~ol~ sdIrosinlf H",.-,-s ~ b" ...-edId 197M2 8t J ~ 96 322-321 2J01. VMlde"'barglla E ~ C._ den 00n:I J WloclIrsU I 0eIIIl0I J SU Id Thor.- J.~. JL, Mecuca C, ~ e.- JJ, (1991) TranslI:lcilIaII11:14) 11~ It if"O'lltIy ~ WI\Il 8--ceI Iyn'Ip/lOrI'MiI !:sf I'OI-ddI ~ eel ~. J PiMhDl163 1~18 2309. "'andenbergroeP WIodar!.QI. t.IK:!IuI L ~ P, EIoogaaf1s ... 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N (20051 H,1lOIogiCII o.l5kaliofl 01 U'2~ . - of HcldgI!;01'. !ymImma from . . SIMI t:/ s.J PUa. SU Sao PNo !.led J 123 1)(.- '" 2311, V......... H, 'lit OS Sd>uh MJ. ~ UM,""" J,~.(;q,aI A12007) ~. ~famo' bllf· ".-ge fk:aI ~ II ~ Ul'ldar. ~ ctincaI . .....-:l '*IP'I', AM 0rl00I 18931·;39 231', Vega f CIIang ce. Medeoros tJ. lJdcl!rl ..... Ow>v.ga ~ lIu ce F"rdl CJ 'v'Ii:I'Ial AA t.lc:GMgorO,~"'(2IlO51 ~ ~ ard plaai'iiIl:lIIIIk ..... ..•", ~'-.-.,~ ~ 2321 ......' IoIad I'ahJI 18 \Ia9I F. e-e. 1C.F1. n-zv VA. !'WI K.l..-.g W Jonaa 0 l2OO5l, * ...... r. . . . 01~~~'*»­ llnc:als P~ n- Tl .e , . ZIl1 , VIOl F IMdaaaIi U, ~C .u. 0 ~ R t.utn A AMIau tv f2OOl~ l~liC~T-OII~1I !lOlII ~ A IRlIOIIaI ~ ..,;tI blaI- Ie ~ . . . . . NIt J (»l Patd l1e· '1~19 nn V. F MedIll'Ol lJ GauIanl I' (2007) •........,.p.... aM of.- 'iI8"""IICiI T-<:eI ~ Am J can PaIhaII27 . . '"e.n 2323. ....... MM, ~ BN ScHuu l.A. Arbtr CIA. SIl;:wak 1.1.. W-lM (1999) IrIdDlerrr r-tyi'~"*"-* proIilerakln ~ 01 a C3III .... a 1~ COUItI MI\tJUl o:yIOIO.« lha M.I ~angemen15 detecled '1'1 a iIlJbM>! oIlJ11l'1111'\' ClJIaneouI foIIode ¢e!1Ie< ~ ~. /to.m alli4lly or pallfll'll! \\itll1hll l(6.8 ~q27.p1 2 1 atlI:l FGf"R10f'.f GFRl fuaIon: Iwi:I !urtf\fIr UMI J So.og P1II\Ol28, 748--755 2»0 Veog« S, de M\JlJt A, ~-s.ry t.l Villani L E ~ D. Chene G CatIotll A, Hem8IoI J 5: 5~5J7 2341 . 'o'OIl defl DrllIIdl P. COcn EA (20021 l.ocaI1ad OJIIneoo!I smIlI 10 !IlIdI.o~ pIe(lrI\olJlIli T-QIllI ~ a NpOrt d 3 CUM $tlIbiI for -,.n. J "'" AcId l:IermIklI-46 Franck N Oedlelotle P. Souteyrand 1', CcuviIe P ~ 1', Delal.f1ay M. Bagot 101, cnnge- F, Frailag S. &lsq J, Pe/fW T, CUlIoct'I A. de MaIl*1ll A.. ldfwlolI .-.. Wechaler J{20001 T~ of mytO!ilS ~ ~ arid pmgnosIIC Jeal.res of .5 ~ Frerd> Stud,' G~ d CuIaneiouI Lvrnof'omas. 8Iood9!l. 2212-2218 2331. Vem.w RG. Goudsooaanl CS van w. at lolA Sa'Iders 1M HugeeffIrvQrabie I"l9' rak ~ 8Iood106 3747-375ot 2m V RmlIlN SP, CeIier C, AsrWI V JJ. 8arbe U ~ S, ........ 0 ~E ~N Cef1~ N. Fladbd--WfliM I (20031 ~ ~ ....., lq22~ II dcnII . . . . . . . . ~ in tM-adl:ry 0llIIc "*" _ e--0lJ_'*'91 ' 2S ~ 212.. V..... A, Dal PoeIa G, Ilutl:::.eno F r...,.",.., A, eo.·FrllrlCIIo t.lC. Nooica G, Ilrooo A. 011I UortIe, Epocano~, Ilallaght A. Fn l, P!:Jatomo M Cordero V, $aroIIntI $. ArMdorI $ (19911). Prognosbl; 0I1tle e. _3f'IClI '''' 2325, VenerC, SoIogo D. Berti E, Gt8llfli U. 5erYida F, C&r~ E. Ca pulO R. PasWllll E, Larrtber1Mghl DG (2007). Indetilm'lin,1te C8II tIisliocytoeis in "500etiot'1 witll later ClCe\J1> renee of awle m~sbl; leukaemia 6r J Dtrma~ 156 1357-1361 2326. Veoen D. Aqel H, Fr~ i'ICI\onl M, Meneglol'li V, KramP&fl M(2004) Prev>tI6nee of ilI!patltl! C \Ilf\III it1fllCtlOO '" IgM4ype!llOllOf:lcNI llIImmop;IltlY 01 ~ """'ftCal'lOl inl Wa!deo:Wrom ~ Am J Iter!lIIlQj 71 421 2327. Vertlorgh E A.c~len R lou," VJ, BI\l...."." C DeIlotgt 1.1 Boogaens M ~ A Vm;lenbetghe P, Ver!loel G (1(107) A ~ _ _ ealegOnZIlIOn t:/ low· !P:le~Iic.~lJIIIIl(Ionltle e~oI~...,~l'Iona . . . . "'1ft NIl one IIllIaQ8 ~ on ll'wl __ 21 668.f1n 2328, VettIuIgh E Adllen R MaM 8, M ~ Iloo\IMI'IS 101 WoIl'~ C. \IelTloeI G 120031 AddIIionIl ~ ..... ~ A d boN _ _ ~ II ~ IUllc*III'ell ~ III 1Ilf ~ . .,.-oo... f'rl:9loIlic seomg S.,....., lor ~ IY'" ~ J ()wi 0rl00I21 2T3-282 v..., 232t B 8Mod-R~ 1.1" 8lMIsy MH, Bt~ ... DubuI P. o..-, U ~..I:. Tlilltl f2l»Il 'oIeCPII* 011I 00 PlOt QIty beQ..tl Mallo' 01 chrmic myllloprolIIeraliYe ~ 9fIl'lll"l' ad by ~ d !he plIIllIeI.oen.ad growIl fIctor ~ !leI(I gene. I.... ' ~ 92' 531 ·5J ~ ,6l-169 2J,f1" >'OIl WlMIIoo'!J 2356, WrdI H. SdIakel U, KII:.«hnIky F WaiIIlewtkI R (2003) ~ ~ "'II Iil'XIQI A._ *""" Searr 011 (2OO6f. aDIeO.IS progr(l(OI auIlI II . ~ T-QIllI tympto.I ......... b' ItIgng lM lyll'lpl'Dnll .7: ..a 1SC1.l~ nu ~ PM. CWIr I(A. 5rTIf\ SV, A,.... lH, RID KW. ~ ~ ~I ..-....x. FoIicUar ~ ... I ~ ~ ~<:IrIcalCOUltl . I eat fIP(lIl nl _ d ... ...-- AItIl "'Ill PllI'd YIl!.led 128 210-213 23U VonKhoYIlo, t luo l. ey.. MJ. e-wy 0, Ntid Pl. Vadly JC Futn t. " ' - _ L W - AD, v_ . . . (199nCl.ll*-rogd_~II"" ~~.G.Mr;k8,ThledeC ~ .Ii U SouceIl S. SdIM:h M. EtvwllIW G (2OO!I1 WIIneege ~ IOCXlOrding III lie WllrId HeIIfl ()gareaIIor> {WI«)1 dele II S ..... m~ W_ IAMLI"" I'I(l ~ kltI "'" • and ~ I'I(l .ldepIllldeo~ ~ lISnfyslld i1'1171i61Jl*rG 8tod 111 1l!S6-1861 :zm. Wang J, Bu OF U T. lhiIrIg R 2hMe 8X, OWl xx. Zhu XJ 12005) ~ ~floo't¥IU'Ia""a"""'_ drtIc ..... ~~ ... ~ pIaIIic~8rJ~l53~ 2351. W ... ~~ ..... bor1 JNQ _ and sIIOWS ~ myeklj:o........ iW"CI ~ _ ~ 1&tl·1~ 2333. V - lolH, Ge*n FA.1 ( _ JJo . . . . . .gec:lIIilI ganell a IlJ(O:IIc T-llII '"" ..... CJ. ~ ........ NatGen8l17'96-99 2345. Vol JA. ~ Sl. ~ Cl. Andl'il 23SIA. W8ng SA. ()soo N zu-belgL ..... A (1m!. ~ d tylDb!1C ~ by tlIOQle5lic T 'J!lIs Ii m,co- "" ~ irll;7.- ""'" ~ Irtm ~ D}e 10 UIo sIiIge dIsoliilse ...., J PaIId 1501121»-1210 2134, veeee- 101'" Geelen FA. V.. HiIStilMI CW. Voont VIdet PC Geer!$ U1.. ... VIolefi WA. 'oWamze R (1996) Primary 0JIinI0IA '-9! Ik:eI ~ or . . 1019>. A dIsIiI'Icl: lYIle of ~ lkeI ~ \IIIIIh .. irlWmedIale prognCIS15 DlIIdl CU13fleOUS l)""lhJma WorUlg Group M:tI [le<m-'Oi 132: 1))&.1 308 '" 5dlm,U--Graftff A. Fab&llU5 A. HBg"" V. PfurMw 0, RM S. Hehlm¥1n R, ~ A, CrossNC. Reil@f A(20071 Ol~ or tmoe .-- imlJlinob.NSPCIlM Iuso1 ~ 2m. VMIli W Faccheta F, Rosati S Velli 0 Gngo!aIO p, Muserllli G, Frtuera G !2OOol), Nodal and e>hOOd8llUmOr./om'ong iIOOJITIJl9lJon of pin- easel n1JdIIg .... IlI$IluCylI ,..... COl!S3 Mod PIIhoI 18 693-1001 2346. Vase .1M e.- PJ. lynctl .!C. ~ DO, Ktsair9W A Chan we ~ TC, Arnilage IicUIeriIy 00 J() 1'9981, Ellad '" n. ~ iMOIOgOu' ~ /or ~ 1lOI'I-HoG9~ Iy!T'¢oma J ~ ClncoI16 ~9 2J,f7. Vyas1', CnapIlO JO (2OOTl- t.IoIIcuIIor lI.oglrtJ ...,., Oowrl tyndlQrllll"lSodaled IIokerrill, CJ.o'r Opin Peo:Ntr 19 ~ ,. 2348. WaggolI W, OreIIoIG, ~ FIF. MIl_ DY, ~ KC. ~~J, W~I ~ .....,;yI:od mO"ocyle$i~OOng cells as5OO;lle(l wittI myeloOd dosor~ Am J Surg (1991) NF'U-AlJ( gene fuaIon ..., P3IhoI 28 5l!5-595 2349, 1'1.",... SO, MerMel V, LllU~lIo L 119941 Similar pattllmll 01V I 2335",. V!dal AU, Gol,sa,n A, Yc>shtda 101, lMhieu. R. Nrlt>ioka K. Tehia F, ROOIlI1 l, De The G (1994) Molecular ep.demioIog'y (If HTl V type 1in Japan IlViderlQi for!M) Oi'stll'iCl ance,· trallOneagill with a particular geographical dill· tnooboo. AIDS Res Hum Retroviruses 10 1557·1566, 233e, VOl H, Chevalilor S. Garand R, Motsan JP. Pralooln V. ~vilOOr ~C, I.Ioreeu Jr . Soohoo JP (1989). Clonal e.~ oliymp-hocytllS bearlllg The gamma delta T-oell reoepIor .., I palimt wiII1 large ...,..,.,laI lyrnpIlo<;yle d*""". Blood 14 285-290. 2337. 'lifoll A, Gertz MA (20071. Walden!;lrom ~. Blood 109 5096--5103 2»1. VI"}IkIl. laueri C, 8dli R. NbJ K. NII'duccI MG, Russo G, Roli>steon JL. Croce CM (1998) ~laled erpression of TCll canon Tcellau kernia in mr;:e. Pmc NalIAcId USA 95. J88S.3869 lm. V*"o U. Gaidan:I G. BolIO 8. ~ G Al.dIio E, Bettn M. CaM R. FIllib'le FI Nowero D. Or!uc:ci L ~ G. Caplt> 0 p.w; G. Satco C, ZagoneI V Cwbone A. UWa U. P""*tl G, Sagloo G. R~ L (1998) ~ogemeo0t5 or bd-6. bQ.2. c-myt IIllI liq tlelelIon n Il-- sa ~. haory 0llI leukemill. proIyrnpI\o(:yt 1e\"emtIl, Weldemlrom'. fT18CrOIllobvIintmil and myekr rna Blood 83 364 7-J65J mo. Wahner·RoedlN DL, Kyle RA ~ '99 2) Mu·heavy d'1!\1n di_ preseollllioo I S " b-en lgn monoc lonal Qarllmoplllhy Am J ~malO' 2351. 40. 56-60 W"~roe1"·RDed4er 01. , Kyk! RA. l19!lB1 HllI'o')' d\3In clisea-. In M ~lomII BIology nl ~ n l Malpes JA.. 8ergsageI DE.Kyle F1A , Aodet1or1 KC. edt a . lord U_ity PrN' New YOlt. pp 6Q.t-938 2352. Wlhner·F1oec1laf D1., Wrlrig TE, l.oetow II I(~ RA (7Ol)31 ~ d\;lrri 6M_ _ or 23 CIIM. Medb:e lBal1i1'1we) 82 2J&.2S0 2353, WallSA.E,~ulP SaodJW{l990l· DiIgrooaIlI d ~ Iymln)ma II efIuIiln frMI ll*nIS .... AIDS by ganI ~ men! Am J CItl PtIfloI ~ lro.,7S 23~, W~ C. Curll. C. SdwwlIger S Schullhel1 8 l,Ielz geroth G SCIlorJI C, L~E.ErtlenP ..... Ha/erW:tiT, ~ "- HII*TIam R en. HC RlllW A (2llO8~ T _ ......... III l'I'IIInib II I cIlrtno': ~ ......,. - - ' "'" ue ClncoI9 5&--61 1lS(9 4', 2~. ~ \fIzlr-.s.J. ~ R, \ImI M.I ~ MJ CldiItll,., M.Pl J "-'OiInaz loll c.anz loll, 0t8I He (20001). CR::aI .... ~In" Blood 90: 1712· 1713 ..., I CDKSRAF'2· luIlon 11'I'" Gerw Cl.on_1'III$ ~ 5 95l»5lS 2355, Wltl C ~ G, ~ C. e-. q33,q'2q2~1 20. HI. (20061 S!JIerwe ~ lI'lI'lt ~ ...... ~ T-oel nell!k:ell ~ Nn J s..gPaIloI 30" 128-132 23588. W~ SA. Wang l HodlbIrg EP MlllIU'I5ky A. t-llVn$ HI. IiassarJIIft RP 120051 t.o. ~ grade k!IIcuIIr Iyft>~wrfl'9'~me . ~ ~ /eetlRs. Am J Su'g Pah3I 29 1491)."96 23S8C. Wang 55, Colen W Cerhel'I JR. ColI JS. Morton Ul. Ell9I'S EA 0... S ~ RK, RoImwI N C/Ia'loci SJ Har1ge P ~2(01) Immune med\ar!iims II ~~,n tyro. p/'I(lrIIa: prrt tIJe<;Is ~ Ihlt TNF G308A..., 1.10 T3575A ~,.;m ro>-Hodgkil't 'l"Iphco'I'l8 ..... tocIors. C¥IcefRes 67: 5OoI2·5OSol 2359. WlM"flIle AA Jones 0, ~ ED 120(7) MorphologIC -.d ~ YMianIIri ~ T-<X!I ~as nl T<:elI1ymp/'on mtmic!l. Atn J CIion Pethel127: ~1 1·527 It " 2360. WiII1Ike RA. Kim H, Fuks l , DorfmBn RF (1977). The r;oemlenceoj IICIO.riftr and (if. l\I1fI plInems .., nod!Jlar oon-HodgkOn's ~ phomes ",," lflCill\Cl! arid ~ cor· relation Carl{:f!I' 40' 1229-1233 2361. War'l!fl HS, Chn5b~nserl FT, WIll CS (2003). FUIlCliorIal inhibilort h\lman ieIJooc)'If "'ligen ctass I receptors 00 natural Uler il'K) ceIlIIln pallfln19 with chronic NK ~ Br J H"""",-,~ 121 793--<1()4 2362, Wm.nglon I T, Dl;ilerty D. Gllossmlll A.1.WrIIl5 J, IbraIWn S, t.. R (200n UyeloId ~ -.11'I delfboo ri 5q III Ihlt sole litotypic aI;In(mlaIiIy !he dncaI and p;llhologic IQ8ClrUm leui< l~.3 161.765. 2343 , WI!&'IabeO. l.lIIlJyama l. Annua K ~ I. Anlvll H. I1.-i U, Uelao K MsalDT,Osame t.4 (19981 ~d YI5ClAIr endo:JIheliaIllfI'MIIllacW1va:5I::ul;w per. ~ fac::b 15 ~ II ero.F,*- (POEMS) syrd'ome ...... ~ 211m "". 23501, Watanuk,.YIyauchl R. Kop"" Y, TlUVI'I H. HIII1I T GolD N. KaI8IWa S, Saio M Mon References 425 Chtld FfIlSj Neonatal E.d 92 F50J.F507, 2:J.6fi. Webber SA {1m) Po.Hranlopia"t lymphoprQll!etlI~ .. 0iI00lerI, a ~ oomplocaIm of tQkj 1lIg.l ll~? Peooll T~ 3, lI5-99 23fi7. w.obet SA NafItoI DC. f""*« FJ. 0IIIr>eW::h p, Il'Jrne EO. AddotI on:lIt$" ~..,., lancIlJ67.23J.239 2361. W.... T Weber RG. ~ It Act:lf B. MljW-PulIU B. ~ S. 8uIodlget R ~ R 0t0erl~ M SdwoIdIk P Redent>et9w G. LithW P (2000) CIlirilansloc ~ ~ II pn. "*'1 cennI.-.rwouIo IiI'*Il ~ ~ ,. ~IW9f!k:lll1ype s..nP..u 10:73-84 230. 'Nfittwtb M. oa,. PJ. Nwi F, ~ Ell.. NJOIlf o ltD. ~ HA. ~ MS ~F ~JRl1996) Tht~ --.on '*"'-' E ~ ..... .-.cl t1DdgI<.., " ' - I I ~ III~' I!IIuod 81 382$-38Jli 2371. W....c .E u o.y PJ Noggll F PooooII ~F~P9~1N I-WltyPS T ~ F ~ ER. ~ A. El SIfo, UR Widaw F. N 1.1. ~ C ~ T, R-'Ii R. T * , - K, W..... I{[) e.n-..... JC, N'/O"lP "- RI)'IIlI.lS JR ll9961 ThefIIIt sr.nm w.w. ~ ~ .... II HorlgkIl'. ~ lronl ditIInnI: AId! 0. a.:t 14 ~ 27·31 2371. Wtir EG AI ""-H.an U 8Ilr:sli DA. GnIIn Col.. F.... S SnofI eo IlllIoooI!l MJ (2007). AalIe~ ........... m... ...., lIOOf o:wur. l.IoNru 21' 2264-2270 2372. w. EG K Lee-. P, !loI'tMllz UJ /1999) A..,.. aFlIlbud~ can ~ 61;reana aeuII ~ Ie IIt.oUmilltom IlOIlJIIt B ~ """ lev COb' /low ~ ~ lor ~ e- ** or-dItIdoon L ~ 13. 566--567 w~E,uanleyPW.eo..MhlKcb 2373, SW, I'tldIhiuI A, GrrfwI Xl (2007) SIanl ill"l"1lion I'lhbIorI rJ ElCR..ABl. "" Iht 1r8II. merit of Imaliflob. re"~\lInl tlYonoc m~eIOId Cln:eI' 1: J.4S.:l66 2374. W_ nbur\l&' DD. Ande,son *,"-nia, NatR.. J, Armllage J. el aI (1996), Gr.ld.ng 0I1oII1tl.OII ~ diagnootoc KCUtIlC; , ~ ty a.nd dirlr..) l ltIevllfl(;e. Mod Pathol11. 14211" 2314A, Wai$i LM (2000), EPioIflirl.8IIl" >'iruI a.nd Ho'!9I" n'l dilMl.lMI.CurT 0nc0I R'P 2, 1!l\>. "" 2315. Wel5l LM. !l&rry GJ, Dorfman RF . Batlkl P, Ka'Sllrl ing E, CUrtl~ J, ROSll' J. Warnke RA 11 9901 Spll>dle oalI neopW.-n, of lympIl rodel 01 proOabliI M iculurn (;flllinMge Twe ~m celI lIIf'COrT\lI ? Am J Surg Palhol 14' 4()S.414 2376. Weiu LM. Bind! JM, Pi<Xlui VJ, Lir>< MP, W~mII. RA 119661, L ~ 1ymphoma: atl iITImurIopheooli'Pf shldf 01 2£ CilSlIIS....,~riec)"lIoT"*l~ Il""" Blood 61 47....18, ES Uu XF Cheo '(y, Shballl D. l.4edwoII U (19911 OtIlec!IllI1lftl ~ ~ 23n . 1'1_ LM. _ mil ~ II ilI'9'J"l\IIlunob'-lic lymplladenop;iltly and aryoommunobleslJC 1y!nplII(llonop, t IQo';Mlalm ~ 01 E~'" Blood 19 11l$.IM 23nA W- LM, ~ LA. 1'1. . . . RA sc.- J (1i89) DMeclo:1 01 E~ ¥IllI genorneos II R*-SlerrtIerg t * 01 HocIgl.ll', NEJU320 502·506 nn. W_ LM. SIrIcQr.!G. DorImIn RF. I1CfIWIg SJ warru RA. Sder J p986) 00nII T-<;tiI~II~"" ~""~1ynI­ ~"'~AmJPtIQ 122 392·)9' 426 References 2319 , Weest LU. Wilmoe RA SIJaI J, Oea')o ML (1987) MoleoJ~ _ I\'lis 01 the 1(14;18) ch'oo>osomaI troll1slota11ll11 II malignanl ~ ~ NiOnglJ Med317; 11B>11M 2380. ~n OJ, Farry JA, ~ NL Louis ON Oelmonittl F. ~(J I (1995) ~llon ~le'iIIlivt: disof· dlIrlI"solI:lOfVlll'l~arepr~­ ly agg~ llI<nors Ii 1m! ongWl. Am J CIi'I PiIIIlaIl03 7~755. 2381. 'o\IerIzmIn S. Gteenberg ... n.or- P (1991) T,. . . . . of ron--I1cJdgulllymflloma II d1Ildhood. by PH~ GPc.I8b RA Kyll. SdvlI!< CA 1 .al 2nd eel, NlM YllIiI 1~1 In 6i5e '*'D"lbc: ~ NN YIlIi 1».75-3-168 23S1A.WtIUmiIn S. JiIIfte R l20(6). Uncommon IUbOCybC dOiorl2el5 1Ile r>llIl. ~ 011I I~ Peci.- 8lDool eano."5 25Wt>4 l3I2. w.. PF. 8 peh: trypeoeowo:ljll" syrDoone Blood B3 2759-2179. 23U. ~A.~C.~ S SiN A. Jell! ES. Soaber! P. Ra\IeIIo 1,1 l2lXXIl ~ 01 ilIIafrialy e ~ lII"- II ~ USI'l\l eDNA . . . . eeeIIlk:akln 01tMIm as ill . - ~ ..-t. . b ' ~ ~ W -Blood ........ 2314 Wencln D. ~ C. GaaMl P Coiffler 8, Tily H. CuiIis D 60ehn A. RO ~ R. .... bowI J DielKIld J de uascaret A GInebedlC C (t99n FIlkIAa' BrgoKelI,.... F....-.t A jtlome Duled willi ~~1.1Il ~ 0189tIM5 n:llded II !he U "" 2385. "'eng,.p. Fee.z·Inu'l)' C. Biadio¥rr SC tooll AT.~ JC 1'2004/ Acli'. M.blIlarol JM. Yaslu~ Ohtanl Y ArQlngel ML, Lau A. Wa C. Doll 6'anco C, R~~ CG. Sai H, Tobiai J. U y, Wolle MS. ShachafC, Felsher D, Blackbo SC, Pur WS Aster JC (2006i c-Mv<; is an irrlp¥. lilnI dirlld targe( 0/ Notdl I in T--cell iltUla Iym. ptloblasbt leukamil!i' ymphom ~ Ganas De_ 2ll 2096-2109 2387. Wanlger MA,Gesk S. EhflIch S, MartrrJ. SlJ btIro JI, Dyer MJ, S>eberl R. MoI~ P, 6a ~ h TF(2007). Gai nsofREL In ",nmary mediastinal B-<:&Il ~ r;oincida with l'II.ICiear <>tOUm<Jlillion of REI. protein, Genes Cho"on"osomts Caoc&r 46. .4(l6.415 2388. Weniger MA, Melzne< I, Menz CK. w....- S, &ct.- /IJ Dorscl1 K, Matlflllm. T. BlInt1 TF. ~ P l2006i Mutations (J/ the Uoor eupprelSOl" gene SOC$-1 i1 diUeal HocIgI . . - . . i1 pnrna')' ~ EkellymltlDma ~ 20 1880-1882. 2310. wn .. ~ C GIIilmn A. ~ PP A&Qri S. SabawlI E F, F... B. t.IrAa T. PM M. .&l\.<sl T, Pu:iolI N, bIzero PI. Pel SAi2006l. t.tner e~ a.ca ,"~alT-<:eI:~,i~C» ~ ~ ~~II~~B--oII ~ ~ ~ 0 / 3 7 _....... uSIIQ ~ ~ P'I*ni lllTi'f" CGH) t _ 21' 246).20169 2394. ~ ~, a.uw..w.t.ooo IoN. "--CE, D*tlCf. ~ Nt ~ lIJ tail\III A ~ UF, "-tan Te 12OCOl TIlt I'OOIAl:.s 01..-.,. 8 ~ 8 .-.d 020SI08 -...on II ~...-. an ~ 0/ 1*IOll~ .......... ~ ~ I 1. . ~ ~ & J ~IIO'a»846 l3ML ............ $P, NthIf KJ, FIl'Oll L 8alo1oI C. 8«:J:rlIIII 8 CMItt> so c.ro.-'J M Ger.vge SL l\oICl: .E ~RA.~CO Caflgul lolA (2001) ADIIIu rJ til """f>tpe . . . j)'IdcI!I P'JO'" Pf1¥'OSIS on idI.4I e.-v.. 24.2"12-2"19 2391. Wtt>t P, AIt¥li S, Stn:lm E, ~ Sit MU$IO M.ZIfIUrlII>L, raj... s, l:lomhoIw S. PilerI S (2004) Nodal~l;OOlI IymD/lOma iI5$OCiIIted "'" monoc:lorItl ~-dIain and huv)' san. J ClIl 0n00I e..e. =mo 2395. .1"II"oIIrwI $P. RJJPl*I-'S, u.o..to G. ~ I( Paec:t&a P. la'lger C Bildus CO. Wen J. \/I4;OSll"1lYit T PoooelI B1.. Carrol AJ KoIitz JE.lI'$Oll RA. Ciilgun lolA. BloomieId CO j2(07), tong--lerm ......trw ~ with ty!09""btaily rI(JITl"III KIlle mylllDool IIul\erIQ a'ld MU ~ III'Il)tnl d ~ il earc. iI\d L",*- GlOOD B tIu(!¥. IlIood lO!l,5164-5161 2396. "-"'ltmil1 SP, RUOI*'! AS, Radlllld'llr MD P-oIrOltlc K, Pilsd'1l 1552.1558. 2397. Whitta kllf SJ, Smith NP (19921, Diagnostic viJue 0/ T-<:ell reoevtClf bela gene rtil rTatlQfmenl i/IiIlyM llI1 pilnphenl blood ~ 0/ DlItitlnt1 wtlh \lfYlhrodttmI J 1tWe$l Oerrn.tb< 99' )61·Jli2. 2398. Wh we ew.. (2000). I;et-*'Y ~ •• ~ ~ drIooole<, e~dullon of TPO andMPL In I'M) Iamiies WI\II ~ ,., ~ Bf J Haemrtlol110 1ll4- 2011)2, W..... A. RClsenwajd A. 6IIrry rs. Wngtt G, 0.- RE, HemtUllI1 Sf, D1IO Ii IbboIIllI1 RE. 0ttIar\l JA, 0.... Z, Sl1IIlIfSIe-.-on M, RallfIkj U. AI1hI.r DC. Utrli GE w.-.. WH, /WftlIrl TJ. Oea..- 00, StIulltLM (2003). ZAP-70 e.pres5ItII oOIf1IiieI. ctIO'lE SIltllYflI ... lIl'II'..-.cI ~ I'MIlIlll\JlOOU ~. i1fIrIor cIrloaII (d. rome ..., dIsWlC:\ 9lIfllI IXp'llMIOIl ilklod 101 ~951 2.103. Wider RB. Ha CS eo..o w.o.- n PIQIe 0e/alaIe K. Alt_ R (2002) p. . . . . . 0/ ~ proleirl b .......... llIlI,.. . . aa..w prugnosIt lIdor II d tole c..o.- 9Il ,. . . . .""" .. Sl IOIiIIf)' ~ 1!lJ2·1S31 24M, \WIo.s S l1856} e- 0/ ....... dilr;nH WIll _ _ aIecl lWPIaI'\s, .. ~ Gut"'s ~ Il8cl 11 103. 2405-. WIIl$S(I856~ ~d"~ pI>IIic gMnds..., ~ lOt', ~ .... _ I ' " III'Wtl Gut-'s HoslI Rtp II 56 2_. w.Iern$e LIJ Seov T, ~ K d"AnlIIkI E. Hap "-'~ ER. we 6uldI A. ~ u. ~ WA. ..... G Ga '*-" T-ALl.lIld preanor B--IO.I. ilklod 99 .3S6-.q,,) 2407. ~ R JiIIe ES. &.l} G. CIrI'\II L ilIrI E. "-'*'""St-t. ~E, awS.DilIz~Jt.~LU.~f..... Nt. l':.tmPI W Ked Ii Kwrw U KrcbIIf R AmprleIi hi Sandllr C, $lIlD.oa:i U SWy'li 11_ _ UH. "Ned\lIItil J. "'-II S ""'" CJl2005l WI1O-EORTCd=f -.,ba.lltympIlomIS. lIIood 1135.3768--3185 rtlO.lS e- 2• . Willemle R........ PM. L Ile<1I E. ~ U, AssaI C. Carfwlslit-VIIl 0,0 MR. ClrctlJ A, GearIs Mt, IWItllI S, HI.t'nmosIl.I, JesbnerI L K~ W, l.IM&onIC. Ortiz.flO'nllfO PI. Paulli U. PelralllT, Raniu A. ROOng\l6Z P8raIIo JL, Robson "- Sen« I\J V..- UH. Wet/lsler J, VvhiItalcer S, MeiIIf CJ (2007). SubOJtaMOuS ~t""'e cell ~ ryrnpllorn.a defwlrtillII, T· MId prognosllc !acto ~ . An EOFl TC UJ t~1'IIOl4 Lymphoma GrouP 5tooy 01 83 caSfi. Bi<xId 111 838-845, 2408. WillelllUl Fl, Karl H. Sl&1T)' W, Berti f , ~ L, Chomenb S, Diaz--Pel'lll JL, GeIrtt MI., Goes M, Knoble'R, RllIfklaef E. SaI1ll,ll;(i P-oI. Smdl\ N, Wachsle< J.,.;IIl VlotenWI>.. ~ CJ (HI91). EDRTC claSSlflt.iltlor1 lor PlIT1iI)' wtaneous l)mphoma 5 il pItIllOlal from itWI Cu\afIeQus L~ SlUdf GrOl4' (J/ hi EUfopeal1 Of\lan,zation for Ra5e¥dl IIld TrHlmenI 01 earx:. 8Iood 00' 3,54·371 2410. WliamsME. Swt«lklw 511, Ro5enbelv CL.Arnol. (19931, C1lnlmlll(rne 11 ~ C3lrJn biwlcpoif 72.'·245 2411. wasms UE. . . .mem-n CO ~S Hllm~~~ 0/ ten1rotrbt 1ymph<Jma: lrequn lhe tI'rtrnOI;Onle 11 bd-l loa.- Blood 76: 138J.1391. 2412. w....-. UE M"iIeieId t.I S-** SI'l (1997). AneI\'liIo of lnt ~ lion _~ ~ IQr,.. P1bItn p18 oJfIl D19 II . . . . . . . __ ~oJfIlcbmc~ Ann ()lC(Il8 SuPllI2 7\-732113. ~!.IE ~ D F....... SO. s-tIow SH il995) UTS1"fTS2 (JI15i1'16lllaltlor:J1s II'ld p6J INA*Ils 11I_ "OIlI~)~BIooda6147 .. Subject Index sq- synd rome, 90 . 102 Bp l 1 myeloprolife rative syndrome. 72 8pl 1 stemcel~ S)T'ldr'()'T'l8. 72 Bp t l stem cell syn d rome. 72 Ac ute myeloid leuka emia (AMl), 15, 18 , 19, 21 -30, 38 ,43,4 7, 50, 52, 53, 57, 59,62, 68-73,77,79, 81 , 88 ,9 1,93,95, 97,1 00, 10 1, 104 , 11()'1 22, 115-1 17, 124-1 44 ,130,132,137, 140, 142,145, 146, 150-152, 155,100.178,365 Acute myeloid leukaemia with abnormal marrow eosirconns. 111 Acute myeloi d leu kaemia with gene mutations, 118-123 A ABL1, 15,24-27,32,35.36.39, 44, 48. 65,69.80,65.86. 15 1, 171 Abnor mallocalizatioo of immature precur sor s, 91 , tOO ABA, 325 Accelerated phase . 25, 32. 43. 46 Aci d pho sphata se. 135, 136. 138. 177, 270,273.354 Activ ation-induced draminase. 32 4 Acu te (malignant) m yelofibrosis, 138 Ac ute (malignant) myelosc lerosis. 138 Ac ute ba sophilic leukaemia. 29. 13 7-138 Acu te eryt hroi d leukaemia. 2 1. 22. 27-30, 121 ,125, 130, 134 -135 Acute leukaemia, NOS. 151 Acu te leukaemlas. mixed p henotype , 22. 23,35, 72, 14 1, 150· 152, 173 Acu te leukaemias, mixed ph enotype . S/myeloid , NO S, 152-153 Acu te leu kaemia s. mixed phenotype , NOS. 154 Acute leukaemla s. mixed phe notype, T/m yeloid , NOS, 153- 154 Acute myeloid leuk aemia with inv(3)(q2 1q26.2);RPN 1-EVI 1, 116-117 Acute myeloid leukaemia with 1"ro.i(16XP13.1q22); C8FB-MYHl1 , " '-',2 Acute m yeloid leuk aemia with maturation, 13 1-132 Adult T-cellleukaemia;1ymphoma, 163, 28 1-284.306 AF9, 115, 172 AFP.339 Age-related EBV + Iymphoproliferalive disorder, 243 Ac ute mye lo id leukaemia w ith mut ated NPM1 ,120-122 Aggressive systemic mastocytosis, 54, 57 nwero- Acute my eloid leukaemi a with dyspIasia-related changes, 29, 124- 126 Ac ute myeloid leukaemia with rec urr ent ge neti c abnor mali ties , " 0-123 Acute myeloid leukaemia with t(1;22)(p 13;q13): RBM1 5-MKl1 , 117-118,136 Acu te myeloid leu kaemi a w ith t(3 ;3)(q 2 1;q 26 .2); RPN 1-EVI1, 116· 117 Ac ute myeloid leukaemia w ith t(6;9)(p23:q34); DEK·N UP214 , 115-116 Acute leukaemiasot ambigl.O.JS lineage, 150 Acut e m yelo id leukaemia with t(15;17Xq22;q12); PML-RARA, 112·114 Acute myeloblastic leukaemia with matura tion . 110 350 Aggressive NK-eeilleukaemia. 276-277 Ac ute myeloi d leu kaemi a with t(9;1 1)(p22; q23); MlLT3-MlL, 114-1 15 Acute monocytic leukaemia, 133-134 Acute undifferentia ted leuk aemia, 151 Adalimurnab, Ac ute m yeloid leuk aemia with mu tated CEBPA, 122-123 Acute leukaemias, mixed ph en otype with t(v; 11q23); MLL rearranged, 152 Acute mooot::lIastiC 1eIJ Acute promyelocytic leu kaemia with t(15;17XQ22;q12); PML-RARA, 112-114 Aggressive eptdermonopc COB positive cytotoxic lym phoma, prima ry cutaneous, 303-304 Acute leukaemias, mixe d ph enotype w ith t(9:22)(q34 ;q11 .2); BCR-ABL 1, 151-152 Acute megakaryoblastic leuk aemia. 29, 30 ,115-1 17,125,1 3 1, 134 .136-737, 139,1 42 Acute panmyelosis with myelofibrosis, 29. 138- 139 Acute myeloi d leukaemia With minimal d ifferen tia tion , 130-131 Acute mye loid leukaemia with t(8 ;21 )(q22;q22): RUNX 1·RUNX 1Tl , 110-111 Acu te lym pho bl astic leu kaemi a, 23, 52, 104,1 15,130,1 42 , 150, 165, 168 , 176 Acute myelomonocytic leukaem ia, 20, 2 1, 29, 112, 115,11 6 ,132-133,134 Ac ute myeloi d leukaemia with t(16;16Xp13.1;q22);CBFB-MYHl 1, 111-112 Ac ute my elo id leukaemia withoul maturation, 116 , 131,132 Acute m yeloid leukaemia with 11q23 abnormali ties , 114 t-een AggessM>NK_ """"""" """""'" Zl6 Agnogenic mye loid met aplasia, 44 Ag ranular CD4+ nat ural kille r cell leukaemia, t 45 Agr anular C0 4 +C D56 + haematodermic neoplasm , 145 A ID, 25 1, 324 AKT, 27 1 Alem tuzumab , 27 1 ALK, 163 , 234 , 254 ,255 , 267, 283, 300 , 30 1,306 ,31 2-319,326,328,334, 349 ALK -po sitive, anap lastic large cell lym phoma, 31 2-316 ALK positive large B-ce li lymphoma, 254-255 ALK -posjtive ptasrnebrasnc B-cel1 lym phoma, 254 ALL,35.104, 115, 128, 130, 13 1, 135 , 136, 138, 142 , 151).155, 161 ,165,168171,174 ,178,337-339 ALL with favou rable trisomies, 173 All-trans renroic acid, 113 AL0 17,3 15 Alopecia. 298 Acute my eloi d leukaemia, NOS, 130-139 c -catemn. 102 Acute myeloid 1etJ(aemia, therapy-re!ated, NOS. 127 u heavy d'lat1 disease, 100, 100-199,214 Sub;ect index 4 29 a naphthyl acetateesterase, 21, 78, 83 (J naphthyl butyrate este rase, 21, 78 ~ltu'(JTt)l'xYloperia. AML, see Acute myeloid 100. 107 leukaemia AML (megakaryoblashcl with 1(1;22)(p 13;q 13). 29, 30 A plastic ana emia in c hildhood , 106 Basket ce lls, 181 Arsenic trio xid e, 114, 117 BCl 2. 14, 15, 159 , 160, 163, 186 , 195, 219,223-227,23 1,235, 236,238,241 , 242 .250,25 1,264-266,315 Artemi s, 339 As ympto matic (smol de ring ) plasma cell myeloma , 202 Ataxia-telang iectasia. 27 1. 336. 339 A ML with bal anced Iransloc alio nsl inversions, 110 ATM (ataxia telangiectasia mutated ), 182 , 231 , 27 1, 336 . 338 . 339 AMLWlIh cytoplasmic ruc:IeophosmIn, 120 ATAA. 30 , 113 , 114 A ML with inv(3)(q21q26.2), 29 . 30 , Aty pical chronic myeloid leukaemia, 26. 38. 52 , 7 1,85 116-117,125 A ML with 1( 15 : 17)(q22;q 12), 112 A ML1 ,36. 104. 111, 131, 170. 172 Atypical ch ronic myeloid leukaemia. BCRAB L 1 negative , 8lJ.81 AuernDds. 78 ,83.89,91.92.97.100, 10 1.11 0 .11 2-115. 1»1 33 .1 35 AM M,44 Amyloidoma .2 10 Amyloidosis. primary, 200 . 2Q9.21 1 Autoirrvnune Iymphoproliferative synd rome . 165.336.339 Ana plastic large cell lymphoma. ALKnegative. 317-319 Anaplastic large cell lymphoma. ALKpositive, 312-316 A nap lastic large cell lymphoma. 'common pattern", 312. 313 Anaplastic large cell lymphoma. 'composite pattern", 313 Anaplastic large cell lymphoma. "Hodgkin-li ke patt ern ", 3 13 • Anap lastic large ce ll lymphoma. hypoce llular, 3 13, 3 15 Anaplastic large cell lymphoma, "lympfohisticc ytic patt ern ", 3 13 Anaplastic large ce ll lymphom a, "small cel l pattern ", 3 13 Anap lastic large ce ll lymphoma, p rima ry cu taneous, 300-3 0 1 Ana plastic lym phoma kinase , see A LK Anne xinA 1, 192, 193 Angiocentrc ilTm.JnoproIiferative lesion, 285 Ang iocentric T-cell lymphoma, 285 B acute lymphoblastic leukaemia, 150, 16&170 Bilinealleukaemia. 150 B lymphoblastic leukaemia, 26 , 165 , 168 ButlE!d<. grarule, 357, 358,300. 362. 364. 365 B lymphoblastic leukaemia/lymphoblastic lymphoma, not otherwise specified, 168-170 Blast phase, 23 . 24. 30. 32, 65, 112. 117, 138,151 ,152 B Lymphoblastic leukaemiaJIymphoma w ith hyperdi ploi dy, 173-174 Blastic NK-cel1 lymphoma, 145 B Lymphoblastic leuk aemiaJIymphoma with hypod iploidy, 174 Blastic p lasmac ytoid den dr itic cell neo plasm. 29. 15, 141 , 1450147 Blastoid mantle cell lymphoma, 229 , 233 B08. 1, 251, 267, 324 , 326 , 328 Borrel ia bu rg do rferi, 166 , 214 8 Lymp hob lastic leukaemia/lymphoma with t(5;14Xq31;q32): 1L3-IGH, 174- 175 8 Lymp hoblastic leukaemia/lymphoma with t(9;22Xq34 ;q11.2): BCR-A8L 1, 171 B Lymp hoblastic leukaemia/lymphoma with 1( 12 :21) (p 13;q22); TEL-AML 1 (ETV6- RUNX1), 172-1 73 B-ce il lymphoma , unclassifiable, With features intermediate be twee n DLBC L and Bu rkitt lymphoma . 234 . 265-266 4 30 BIasOC nattxaIkiller~, 145 B Lymphobla stic leukaemia/ lymphom a w ith t( 1;19 ) (q 23:p1 3.3 ); E2A- P8 X1 (TCF3-P8X1 ), 175 Angiotropic large cell lymphoma, 252 Annexin A 1 (ANXA 1). 160. 186 . 189 . 190 Biphenotypic leukaemia, 150 , 151. 154 B Lymphoblast ic leu kaemiall ym phoma w ith recur rent genetic ab normalities, 17 1-175 Basic leucine zipper fac tor. 28 1 API2/MALT1 .163 BDCA-2ICD303, 146 Bence Jones pro tein , 197,205 BF1, 287 , 304 Angiolymphoid hyperp lasia , 52 Ann Arbor staging system, Cotswald revision, 322 BCR-ABl l , 15,24-27,32.35,36,38,39. 43 , 44 ,47.48, 5(}.53 . 64> 65. 69-7t . 76. 79-86,138, 151. 152. 171 B B Lymphobl astic leukaemiallymphoma with t(v:11Q23); MLL rearranged, 171-172 Ann Arbor staging system, 322 BCR , 15.23--27 ,32.35,36,38,39,43, 44 ,47,48.50-53,64.65.69-71 .73,76. 79-82,84-86,138. 151, 152,171,180, 182, 237, 251 Benign monoclonal gammopathy. 200 Angio immunob lastic r-eef lymphoma . 162, 163 , 166 , 177, 196 , 283 , 30 7, 308 , 309-3 11,351 Anisopoik ilocy1osis,45, 100, 105, 138, 143 BCl l 0 , 195,217 Benign cephalic histiocytosis, 366 Anaplastic large cell lymphoma, 162, 163 . 234.255,289.290.294,301 .306,3123 19.328.349.355 BCL6 . 159, 160, 162. 163, 186,219,223, 224.227,23 1.235-237 .241,242.244, 250 .251,261 .264-266.307,3 15,316, 324,325,340.347.348 B-ceil lymphoma. unclassmabre. with featu res intermediate between DlBCl and cl assical Hodgkin lymphOma, 234 , 267-268 B-cell prolymphocytic leukaemia. 181. 183-184 BMI1 , 231 Bod y ca vity ba sed lymphoma , 260 Bud d-Chia ri synd rome , 41 , 48 Bullous mastoc ytosis, 55 Burk itlleukaemia variant, 263 Burkitt leukaemiaJlympho ma , 168 Burkitt lymphoma, 141. 160 , 163 , 165. 166 , 176, 233, 235, 262 -264, 266, 337340 ,343,348,351 Burkitt-like lympho ma, 265, 266 C CIEBptJ. 315 . 316 CA E, 2 1. 57 , 79. 130 , 132 , 134-136, 138, 140 CAlM-AF10, 178 Campyfobacter ieiuni. 166. 198 , 214 Canale-Smith synd rome , 339 SubieCl index 7 Carcinoma showing thymus-like element (CASTLE). 364 castleman disease. 213, 258.309. 355. 363 CBFA, 111. 112 CBFB, 28, 29, 111, 112 CBFB-MYH1 1,29, 111, 112 CCAAT/enhancer binding protein , 118 cCD22. 131, 151 cCD79a, 131 . 151 CCND1, 14. 186. 195, 206, 229 . 23 1 CCND3,206 COla. 161, 177,270.355.357.358.362, 364-366 C02. 56, 57. 62. 70. 72, 79, 112. 113, 131.132.1 46.154.161 .163.177,246. 270.274,277.279.283.287.297,299. 300.303,304,3 10.315.318.326 coo. 23 . 146. 150. 154, 158. 161-163. 177. 224.238.246.248.254.267,270,271. 273.274.277,279.283.287.290,293, 294.297 ,~30 1 ,3O3 ,304 .3O6,308 , 3 10,31 4.318.324.326.338,343,364 CD4.79, 112, 114. 131-134. 140. 142. 144,1 46.161-163,177,224.246,248. 255,262.267,270-273.279.280,283. 287.290.293.294,297,298.300.301 . ~08 .3 10.31 1 ,3 15 .318.324 .325 . ~338 .340. 349.355 ,357 .360.365 C0 4 positr ve. primary cut aneous smalV medium T-eeillymphoma. 304-305 C05. 79. 146. 154. 158. 160-163, 177, 180.1 81.1 83.1 86. 189,192.195. 197, 216.2 17.2 19.223.227.23 1.234-236, 238.253.273.274.283.287.290, 293. 297.299, 300. 303, 304,306-308, 310. 315.318.338 CD7, 23.101 .116.122.125,1 28,1 31134,137,142,144 .146.1 54.161, 163, 177, 246, 270, 271. 273, 274. 283.287, 290,297 , 299, 303, 304, 306-308 CD8. 161 · 163, 177. 237. 248, 270,271 , 273, 274. 278, 280, 283, 287. 289-291. 293-295, 297. 298, 300. 301 . 303, 304. 306-308,310.3 15,31 8,324, 325,336338, 349 131-134.141 .142.144 .1 50. 366 CD15. 61,79, 101.1 10. 112, 113, l 16.122. 131-134. 142. 144. 152,1 72. 238. 244. 248,250, 267.300,306,307,315,319, 324.326,327.333,347,349.351,357 C016,61. 146. 155, 161. 163,273,274, 276.277,287,355 C01 9, 110, 131, 132, 146. 150-152. 169. 17 1. 174. 18 1. 183. 195. 201. 205. 223. 235.250.261.264,266.338.348 C020. 15, 146, 153, 160, 169, 173. 181. 183,186,189.190,192,195.199.205, 208.216.223.227.235-237,241. 242,244,246,248,250,254 .255,259, 264 .~268 .306.307 .324 .326 .328, 333.338,344,347-349.351.364 C02 1. 162.216.220.221 ,224.227,311 . 324.333.355.357.362.364.365 C022. 138, 150. 152. 100. 181, 183. 189. 100. 1ro, 195, 223. Z35. 241. 250, 264 .266 C023. 70, 160. 180-182. 186. 192. 195, 216,219,221 ,224,231 ,250,311,362, 364.36S C025, 56 , 57, 60-62, 70. 72, 138, 163. 171,1 89,1 90, 192, 195, 283, 287, 306, 315,338 C056,23, 79, 101,11 1, 113. 114. 122. 125,1 28,1 3 1, 132,134 ,1 40, 142, 144146, 155,1 58, 16 1-164, 177. 201, 203. 205,257,274,277,279,280,287,28929 1,293-295,300,303,306, 307 C057, 161-163 . 224, 255, 273. 274. 277, 287,324.325.338 COOl . 23, 101. 105. 106, 116, 117, 136, 139, 140. 142. 144 CD64 . 79. 112-114. 116, 122, 131-134. 150.355 C068. 61, 79. 121, 133. 134. 140. 146.238 . 315,327.355,357,359 .362.364~ CD71,92, 135, 142, 144 C077,264 CD79a. 110, 146. 150-152, 160, 169, 177. 181.183.186, 195.205.216.223.227. 235,241,242,244.246,250.251 ,254. 256,259.266.267.307,324.326,328, 338, 348, 364 CD94/NKG2 . 273. 275 CD99, 140, 177 CD103 . 160. 186, 189. 192. 195.290 CD27,259 C0105.92 C030, 140, 163, 164,235,238.244.246. 248,250.254.255,257,261,267,283. 287,290, 297,298,300,301,304.306, 307.312-3 15.317-3 19.324,326-328, 333,334, 338.342.347-349.351,355. 360,362,364, 365 CD 117, 57, 59, 61, 62, 92, 101, 107. 112114.11 6.1 31-135,1 38, 140-142,144 . 146, 150. 153. 171, 177,205 C0 30-positive Iymphoproliferativ e disorders, primary cutaneous, 3O()..30 1 C0 138. 160. 195. 197, 201, 204, 205. 235.238,246. 254,256,259.328,348 C033, 23, 61, 79, 101, 110,11 2- 114.1 16, 117. 121, 122. 125, 128,131 -134,1 37, 138, 141.142, 144.146,1 50,1 53,169 , 171. 177,357 C0 161, 155, 275 CD34, 20, 23, 34, 44, 45, 47, 65, 79, 92, 96,100.101 ,105-107.11 0.11 2-114, 116,117.121 ,122,1 25,128.1 30-135, 137,138,140,142,144,146, 151,169, 173, 175,362,364 COK6, 186 CD35.216, 227, 311, 355,357,362 ,364. 365 C038, 101 , 116. 125. 131, 146. 151, 160. 169.182, 192, 195. 20 1, 205. 235. 256. 259, 264 COO. 23. 61,138.173,175 C04O, 160, 336 , 339 COto. 150-152. 159, 160, 162- 164, 169, 171.174. 181. 186. 189, 192, 195, 197, 205.216.217.219.223.225.227.231, 235.236.241.242.244,250.253.264, 266,267.306.307.31 1,348 C04OL, 324, 339 C014. 23. 6 1. 79. 81, 112.1 14.121. 122. C054, 250, 253 CD26,299 COB positive cyto toxic T-eeill ymphoma, rimary cutaneous agg ressiv e epidermotropic. 303-304 C011b, 23.101 ,1 12-114, 121. 122, 131134. 138. 277 C052, 205. 270. 271, 306,307 CD41. 105. 100, 116.1 17, 136. 139.1 42. 144 CD43 . 79. 146. 160, 181. 186. 216. 219. 223.224.227,231 ,255.264 .287,306. 3 15,318,326 CD45 , 61,1 17.1 37.1 69.173. 254. 255. 261,267.315,324 ,326,327,339.349. 357,359.362.364 .365 CD123,79. 138. 140. 146, 189. 192. 355 CD134,324 COl 63. 79, 133.134.141.355.357 .365,366 CDK4, 178, 231 COKN2A, 178, 228. 241, 242,298, 349 CDKN2B, 228, 242 CEBPA. 23, 28-30, 118-120. 122. 123. 125. 126 CEl , see Chronic eosinophilic leukaemia Ceutvoes. - dou ghnut. 3 12 - clear, 306 - flame, 205 - Gaucher-like. 205 - hallmark, 312, 3 13. 3 17 - hand-mirror, 169 - Hodgkin, 238 , 247, 326 , 327, 329 - l&H . 323 Subject index 431 b • Lacunar. 267, 326, 327, 330 . 333 - Lancenans. 35 5. 358. 360, 365 • lP, 238. 323·325, 333 - morula. 205 • Motl . 205 • plasmac ytoid dendritic, 78, 79,140, 145-147, 151, 155,294,355 - popcorn, 323 • Pseudo-Gaucher. 33 Chronic rnyelomonocytic leukaemia with eosinoph ilia as soc iated with t(5:12). 71 Cyclin 01 , 18 1. 183. 186, 189. 205, 217, 2 19,231,235 Chronic neutrophilic leukaemia (CNl). 23 , 25.38-39 Cytokera tin, 254, 364 , 365 Cvtokeraun-oosinve interstitial reticulum cell tumour. 365 Chronic NK-celilymphocytosis, 274 Chronic NK-Iarge granul ar lymphoc yte lym pho proliferative disorder, 274 Chronic pha se. 26, 32, 70, 72, 73, 85 , 137 o Chymase, 57,59,61 ,62 Dacryocvtes. 42, 47, 138, 143 • Reed-Stemberg. 182,234.247,250,261 , 300.3 10.313.322,327,337,347,364 CIMF, 44 Darter's sign. 54, 55 CLA, 146,297,299,3OO DBA.44. 189. 190-193 • Reed-Stern berg-like, 243, 306, 310, 337, Classical Hod gkin lymphoma. 164. 165, Deep juveni le xanthogranuloma , 366 347,348,349 1 82, 25O , 267, 31 1 , 31 2, 31 7 , 322, ~ 334.338,339,343,349 DEK.29. 115. 116 - Sezary. 299 - Touton, 366 CereOOIorm nJCIeus, 270, 296, 297, 298 , 3)1 Classical t-t:O:j DEK-NUP214, 29, 115 Clattvin-AlK, 255 Dendritic/hisliocytic sarcoma . Laroerhans cell type, 360 Cnarcot-tevoen crystal, 52, 70, 359 ClL Chediak-Higashi granules , 90, 92, 100 Clock-face. chromatin pattern, 205 Childhood mverodvsorasnc syndrome. 27, 104- 107 Cl TC, 254 .255. 3 15 Chlamydia pneurromae. 166 Chlamy dia psnta cr. 166 . 214 Chlamydia uacromans. 166 Chlorom a, 140 Chronic ac tive EBV infec tion, 278 Chronic eosinop hilic leukaemia (CEl). 23, 25,26.51-53.59. 6&71 ,73 Clear cells. 306 see Chronic lymphocytic leukaemia CLTC-AlK, 254 . 255 Clusterin, 3 15 C-MAF,324 CMl, see Chronic myelogenous leukaemia CMMl, see Chronic mveiorronocync leukaemia CMMl with eosino phili a. 27, 7 1, 77 Chronic eosinop hilic leukaemia with F1P l ll-PDGFAA, 69 CMMl- 1, 76, 78 Chronic eosinop hilic leukaemia. not otherwi se spec ified. 5 1-53 Coeliac disease, 289, ?90 CMM l -2, 76. 78, 91 Chronic granul ocyti c leukaemia. 32 Collagen fibrosis, 42, 44. 46, 48, 49 Chronic id iopathi c myelofibrosis, 44 Common variab le immunod efici ency, 336 Chronic lymphocytic leukaemia(CLl). 15,159,164, 180- 182,183 , 186,191, 194, 196,197 , 229, 233, 270, 272. 351 Core binding factor, 111, 112 Chronic Iymphoproliferati ve d isord ers of NK cells, 274-275 CREB,283 CoREl . 228 , 267 Crohns disease, 292, 350, 35 1 Crosti's disease, 227 Chronic myelog enou s leukaemia. 18, 2327,32·37,39.44.50.53,65.7 1, 79, 104. 112, 117,137, 138, 150-152, 171 Cryoglobulinemia, 166, 194. 195 Chronic myelogenous leukaemia, BCA ABl l positive, 32-37 CTNNA1.102 Chronic myeloid leukaemia, 32 Cutaneous anaplastic large lymphoma. 300 Chronic myeloid leukaemia, atypic al, BCR-ABl 1 negative, 80-8 7 Cutaneous ma stoc ytosis, 54, 56, 57-58 Crow-Fuka se syndrome. 2 12 Cryptococcus meningitis, 284 Cutaneous yO T-cell lymphoma . 162 Chronic myelomonocytic leukaemia, 26, 27,32,35,52,56.71,76-79. 8 1.82. 85,91, 128,133,134 ,145 CXCl13, 162, 224, 306. 30 7, 310, 31 1 Chronic myelomonocytic leukaemia with eosinophilia, 26. 68 Cyclic AMP resco-se element bI'ldIng. 263 432 Subject index CXCA5, 162, 189 Cyclin D, 160. 206, 231, 235 Oeodnnc cell sarcoma, follicular 363-364 Dermatitis herpetiformis, 289 Dermatopathic lymphadenopathy, 297 Diamond-Blackfan syndrome, 88 o.fIuse cutaneous mastocytosis. 54. 57, 58 Diffuse follicu lar lymphoma. 222 Diffuse large B-c eil lymp homa (DlBCl). 141, 160, 182,195, 198,216-2 17,220, 222-223 .233-237.238,240,242,245. 248-250 .252,256, 267,310-311 ,315. 326, 336. 340-34 1, 343, 348, 35D-351 , 355 Diffuse large B-c eillymphoma. activated B-cell-Iike, 235, 236 Diffuse large B-ceil lymphoma. anaplastic variant, 234 Diffuse large B-ceil lymphoma assoc iated with chronic inflammation, 234. 243, 245-246 Diffuse larg e B-cell lymphoma, cen troblastic variant, 234 Diffuse larg e B-cell lymph oma , EBVpo sitive. of the elderly, 243-244 Diffuse larg e B-cel1 lymph oma, immu noblastic variant, 234 Diffuse large Bccetllymphoma, germinal centre Bc eu-uke. 234, 236 Diffuse large B-celilymphoma. not otherwise specified, 233-237 Diffuse large B-c eillymphoma, primary cutaneous, leg type, 242 Diffuse large B-c ell lymphoma. primary. 01 the cent ral nervous system, 240-24 I Disseminated intravascular coagulation . 112,1 14 Dissem inated juvenile xanthogranuloma . 366-367 DLBCL associated with chronic inflamma tion, 234, 243, 245-246 Ervmroreukaemta. 29, 134-136 Follicula r dendritic c ell sarcoma, 363-364 DNA tooorsonerese II, 127 Essennarttuomoocytnaemta. 18,23,25, 39,4 1, 44,48-50, 64,85,104,139 Follicular dendritic cell sarcoma, inflammatory pseu dotumour-like variant. 364 Dohre body, 95 ETV6-PCX3FAB, 71, 72, 79 Doughnu l cells , 312 ETV6-AUNX1,172 FOllicular lymphoma, 160, 165, ~226, 351,355 OaNnsyndrcme, Xl, 104.117, 136, 142,144 EVI-l ,36 Follicular lymphoma, diffuse, 222 Dutcher body, 195 EVI1-AUNX1, 117 Follicular lymphoma , extranooai. 225-226 Dwarf megakaryocyte, 32 Extracut aneous mastocytoma , 54. 57, 6 1 Follicular lymphoma, in situ, 222, 226 Extramedullary haematopoiesis (EMH), 40, 43-48, 50 Follicular Iyrnphc:ma , intrafOllicular reoptasia. 226 Extramedullary myeloid tumour, 140 Follicular lymphoma. paediatric, 225 Dyskeratosis conaenua. 88 , 106, 107 E E2A-PBX1, 175 E47,il-iEB.178 EBEA,1 46.236,246,248.256.257.259. 279 ,280,287,315,319,328,330.331 . 341 ,346,347 ,363 prmary ntestJnaI, 225 Extranodal follicular lymphoma, 225 Follicular Iymptloma, Extranodal marginal zone (B-cell) tym.. phoma of mucosa-associated lymphoid tissue , 214-217 FOXP1,227 Extranodal NK/T-celilymphoma. 146, 163, Fried-egg appearance. 188. 189,313 166,248 ,276,277.2~287 .349 EBNA-1. 245. 328 Extranodal NK/T-celllymphoma, nasal type, 285-288 EBNA-2. 244-246. 285. 328 Extraosseous plasmacytoma, 208 FOXPJ, 163,283 Franklin disease, 196 Fulminant EBV+ t-een tymphoproliferative disease 01 childhood, 278 Fuloronln_syncl<are,278 EBV. see Epstein-Barr virus EBV positive T-ceillymphoproliferalive disease (LPD) of childhood. 166, 278 EBV positive T-ceillymphoproliferalive diso rders of childhood, 276 , 278-280 EBV-associated Bcenlymphoprouteretlve disorder of the elderly, 243 G F Faggot cells , 112, 113 Fanconi anaemia, 88, 106, 107 F~. 107, 165,272,277,287,336,338,339 Gamma heavy chain disease, 195-197 t-een lymphoma, Gamma-delta ("to ) primary cutaneous, 163,302-303 GATA1. 142. 144 EBV-encoded small nuclear ANA, 146 Fascin . 3 15, 362, 364, 366 Gaucher-like cells, 205 EBV-positive diffuse large B-ceillymphoma (DLBCL) of the elderly, 243-244 FASL, 272, 336, 339 Generalized (non-lipi demic) eruptive histiocytosis, 366 Ectropion. 299 Fatal EBV-assoc iated haemophagocytic syndrome. 278 EGR1. 102 Ferritin, 44, 48, 96 EMA, see Epithelial membrane antigen Embryonal carcinoma, 3 18 Ernpenpolests . 49 Endomyocardial fibrosis, 51, 69 Enteropathy-associated T-cell lymphoma, 289-29 1 Eosinophilia, 15,23,25,26,27,32,51-53, 55,57,60,62,63,68-73,76-79,8 1, 174, 196,219,282,283 ,306 Eosinophilic granuloma, 358 Epidermotropism, 270, 297, 299, 303, 304 Epithelial membrane antigen (EMA) , 163 , 238,254 ,257,26 1,300,306,314,315, 318,324,326,328.357,362,364 Epithelioid nrsuocvte. 185. 307 FGFA1, 15, 23,25, 26,39.5 1-53,64, 68, 72, 73, 85, 150, 177 Glycophorin, 23, 92, 135, 136, 139, 140, 142, 144 Glyco protein, 106, 117,1 37 Gout, 38 FGFA3/MMSET, 205, 206 Graft versus host disease, 165 Fibrob lastic reticula r cells, 355 , 365 Granulocyt ic sarcoma, 140 Fibroblastic reticular c ell tumour, 365 Granulomatous slack skin, 298 FIP1L1-PDGFRA, 51, 52, 62, 68-71 Rame c ells, 205 Granzyme B, 79, 146,1 63,272-274,287 , 293-295,300,304,3 15,318,326 Rorid follicular hyperplasia, 225, 343, 345 Granzyme M, 162, 273, 274, 293 Rower c ells, 282 Gray zone lymphoma, 165, 250, 267 Rower like c ells, 3 13 FLT3, 14,23,28-30,1 14, 116,1 18, 119,122, 125. 126, 131, 147 FLT3-ITD, 14, 114, 116, 118, 119, 122 FLT3-TKD, 116, 118, 119 Epstein-Barr virus (EBV), 82, 145, 166. 182,233,240,245.247.260.274.276, 285.294.303.306.322.329-33 1.336. 340, 343,350. 354, 363 FMC7. 181. 182. 193 Erdhern-Chestee disease, 366 Follicular oen onnc cell meshwork. 159 Follicula r dendritic cells , 159, 216, 219, 222,223,227.231 ,238,306,308-311 , 323,324,333,355.357.360.362-365 H Haemog lobin, 23, 40, 41, 44, 48, SO, 65, 82,84 ,94 ,98, lOS, 122, 135, 136, 139 Haemophagocytic syndrome. 163, 252, 276-278,286. 295,313,.D3, 339, 354 , eeo Hairy cell leukaemia. 44, 59, 158, 160, 186 , 188·190,191 , 192 ,272 Hairy cell leukaemia-variant. 192-193 Subject index 433 Hairy cell leukaemia, prolymphocytic variant, 192 Hodgkin lymphoma. nodular lymphocyte predominant, 322 , 323-325 In situ follicular lymphoma . 222 Hallmark c ells, 3 12, 313 . 31 7 Hodgkin-like anaplastic large c ell lymphoma, 267 Indeterminate ce ll t ustlocvtos's . 365 Hand mirror c ells, 169 Hand -SchOller-Christian disease, 358 HQX l1 , 177. 178 Hashimoto thyroidi tis. 165. 215, 216, 219 HQX11L2, 177. 178 Heucobacter pylori, 166, 214 , 217 Heucobacter pylori gastritis , 216 Hepat itis C vir us. 166 . 194,218 Hepatosple nic t-een lym phoma. 162 . 163, 166,292·293, 343 Hereditary x-nreeo sid erobiasnc anaemia, 96 HES6.147 HHVB. see Human herpesvirus 8 HHVB-assoc ialed multicentric Castleman d isea se, 254-259 HHV8 positive rn.iticentric Castleman disease, 258 HHV8 positMl_ t-een leukaemia HTLV-1 associated myelopathylt rop ica l spastic paraparesis. 281 Indolent systemic mastoc ytosis , 54, 57 Ineffective 88 , 92 haematopoesis. 15.26,40, Infec tiOus mononuc leosis . 243-244 , 278, 326 .336-337, 339 . 343 HTLV-I associated arthropathy, 28 1 intec tcce-rrcoonucieose-uke PTLO. 34S HTLV-lasso::::iated ~, 281 Inflammatory bowel d isease . 6 1,350 HTLV-I assoc iated lym phaden itis . 28 1 Inflammatory myolibrobl astic tumour. 3 15 HTLV-I associated nephropa thy, 28 1 Infliximab . 292 . 350. 35 1·~"­ HTLV·I associated uveitis , 28 1 Interd ig itating dendritic ce tl sarcoma , 367 -362 Human her pesvirus 6 (HHV8) , 166, 2 13, 234.257-260. 340.343 loreteco-c dependent molecule MxA, 146 Human irrvnunodeficienc y vi rus (HIV) , 101 ,165,166, 247. 255 , 257-260.326, 33 1. 334 ,340, Interferon-a ,37 Hig h hyperdip loid A LL. 173 Human r -cenieukaemra virus type 1 (HTLV-1), 166 ,270,26 1,263 Intestinal T-eeil lymphoma. 289 High.grade MALT lymphoma, 2 16 Hydroa vac ceutorme-ree lymphoma, 280 Intravascular large B-cel11ymphcma 234. Histiocyte ric h/T-celt -rich la rge B-cell lym phoma. 238 Hydroa vacciniIcmle-like T~II Histiocytic cyto pa thic panniculi tis , 355 HypercalcerTia. 163, 200-203, 200 Histiocytic medullary reticulosis . 355 Hyperdiploid ALL. 173 tynVona. 258 Hgl eodotheIiaI venJIe (HEY),n-31 ' , 355 • Indeterminate dendritic cell tumour, 365 Indolent large granular NK-celllymphOproliferative d isorder. 274 HRX, 114 HTlV-1 , see Huma n virus type 1 In situ Me L, 229 , 230, 232 lntestmat malig nant histiocytosis , 355 Intrafollicular neoplasia. 226 252-253 ~homa , 166 inv(3 )(q21q 26 .2). 30, 50, 93 . 110. 116, 117. 136 inv( 16)(p 13 .1q 22), 29 . 30 , 104 . 110-112. 118 ,119,1 22, 129 HistiOCytic sarcoma, 35&35 7 Hypereosinophilic syndrome. 51 Histiocytosis X, 358 Hyper-lgM syndrome, 336 , 339 HIV, see Human immunodeficiency virus Hypodiploid AL L, 174 IRF4!MUM1. 160, 223 ,227, 235,236,241 , 242 ,244.246,250, 253. 255, 266,324. 328, 348 HIV infection. 247, 256-258, 260, 262, 326, 331,334,340-342 Hypo plastic MOS, 92 Isochromosome 17q , 27 , 79, 81 HIV-related mye lopathy. 101 J HLF, 170, 175 HMB45, 357, 364 Hodgkin ce lls, 238, 247, 326, 327, 329 Hod gkin disease, 322 Hodgkin lymphoma , 15. 52 , 164 , 165, 166,180,182,190,19 1, 195,229,233, 238, 248, 250, 267, 268, 292, 29 7, 30 1, 307 -309 ,3 12,3 13,321-334 ,337-340 , 347 ,349-351 ,355 ,364 Iatrogen ic immunod eficienc y-assoc iated Iymphoproliferative disorders, 350-351 JAK2, 14. 19 , 23-27, 39-41, 43- 45. 47-50, 53,62 ,64,65,76,81,85,86, 102,251 Id iopath ic cytopenia of undetermine d significance, 94 JAK2 V6 17F, 24 , 25, 27, 40 , 41 , 43·45, 4750 ,62, 64 ,76,81 ,85,86. 102 Idiopathic hypereosinopnilic syndrome , 26, 5 1,52 JUNB, 299 Idi opathic myelofibrosis, 44 J uvenile myelomonocytic leukae mia (JMML), 18 ,26,71 ,82-84. 104.366 Hodgkin lymphoma , cl assic al, Iymp hoc vte-c epreteo. 322. 334 Id iopathic paraproteinemia, 200 Juvenile xanthograruloma, disseminated. Hodgkin lymphoma. cla ssica l, lym p hocyte-rich , 322, 33 1, 332-333 IKARQS, 325 Hodgkin lymphoma. classical. mixed cellularity. 322, 326. 330, 331, 334, 341, 35 1 lL·3 A, 142, 144 Hodgkin lym phoma. c lassical, nodular sclerosis , 165 ,267. 313. 322.326,327, 330, 331. 334 ,341 434 Subject inoex 366367 Id iopathic throm boc ytosis. 48 IL3 , 52. 72 , 174 IL6 , 189. 195. 245 . 259 . 340 IL10 , 245 . 340 lmatinib.1 5.36.37.39.62.68-72, 152, 171 K Kapo si sarcoma. 258 , 259 Kapos i sarcoma herpe s virus (KSHV) pos itive ptasrrebrastc lymphoma . 258-259 Keratin , 357 LM 0 2, 177,236 Mastoc ytosis, systemic, 58--81 Ketron-Good man type, 298 LMP1, 244, 248, 257 , 26 1, 280, 285, 287, 315,319,328,33:1,331 ,333,334.338. 341,345,346 MOS with myelofibrosis , 92 Ki6 7, 186 , 224. 229, 232. 235 . 237, 257 , 264 ,265.266.307,324.328.357,300. 362,364,365 Killef' irrm..n:Jg1obul1l'Wi<e receoto- (KIR), 161. 2 73 . 274. 293 lobular pann icu litis , 294 LP cells, 238, 323-325, 333 Lupus profundus pan nic ulitis. 294 MOS, see Mveroovsorast'c syndrome MOS/MPN , see Myelod ysplaslic/m yelop roliferative neop lasms MOS/MPN, unc lassifiable, 85 MOS. uncrassltebre. 89. 90 , 94 . 98. 103 KiM4p ,364 LYl1, 177, 178 KIT, 23, 25 , 28, 56, 60-62, 111-112, 118119,287 f...1ecflastJnal germ cell tl..mC:U", 136, 356, 357 Lympho bl astic lymphoma. 15,68,70 ,72, 73 ,141, 168, 176, 265 , 266 Mediastinal large B-cell lymphoma, 164, Lymphocyte-dep leted classica l Hod g kin lym phoma, 334 Med ullary plasmacytoma, 202 L L&H cells, 323 Lymphocyte-rich cl assical Hodgkin lymphoma. 332 -333 165 , 236 , 250-25 1 Meh::Mexate, 24 1. 273, 338, 350, 351 MGUS , see Monoclonal g ammopathy of undetermined significance lymphocytic lymphoma simulating hairy c ell leuk aemia , 19 1 MICrocephaly. 339 lymphoepitheliallesion, 199 , 214-217 MItogen activa ted protein kinase, 24 Lac unar ceHs. 267. 326-327,330, 333 lymphoepitheliaJ sialadenitis, 165,2 15,216 LANA- 1, 259 lymphoepithehoid ,308 Mixed cellularity c lassica l Hodgkin Iymptona. 322. 326. 33), 331, 334 , 341, 351 ~ lymphogranulomatosis. 322 Lactate dehydrogenase (L DH ). 44. SO. 63 , 122 . 178.207.246235,264.276. 282.284.298.341 . eel ""<>eyt<>;is, 355, 3S8.J8) Langerhans cell sa rcoma, 358, 360 L~ asso::iated WIth HIV rlecticrl, Langerh ans cells. 355 , 358. 360. 365 Langer in, 355 . 357 , 358 . 362 . 365, 366 Large 8 -eell lymphoma arising in human her pes virus a-assoctateo multicentr ic Castleman d isease , 258-259 l arge 8 -eell lymphoma . AlK pos itive. 254-255 l arge 8 -.c ell lymp homa arising in HHV8associated rnncennc Castleman disease. 2S4-2S9 l arge 8 -c ell lymp homa exp ressing the AlK kinase and lack ing the t(2 :5). 254 lyrrV'onatoid granulornatosis, 234 . 247249.337 Lymphomatoid pap ulosis . 3IXI, 30 1 Lympho plasmacytic lymphoma , 59, 160 , 166,186, 191, 194- 195, 196, 200 , 2082 10,219.339.35 1 l arg e B-cei llymphoma rich in t -eens an d simulating Hodgkin's d isease, 238 large B-ceillymphcrna with Hodgkin's features, 267 l arge gra nular lym phoc yte leukemia. 339 LAT, 137. 140 , 146 Mixed p henotype acute leukaem ia, 22, 23 ,35,72,1 41 ,150- 152,173 Mixed p henotype ac ute leukaem ia, B/myeloid . NOS, 152-153 MIxed p/"lerK:1ypeacute~. NOS. 154 Mixed pherUype acute ~, TJmyeIoid, NOS. 153- 154 t ymobop ronteranve di sea ses assoc iated with primary irmune disorders. 336-339 Mixed phenotype ac ute leukaemia with t(9;22)(Q34;q 11.2); BCR-ABL1, 151-152 Ly ~p hoprol ife rativ e Mixed phenotype ecute leukaemia with l(v:l lq23) : Ml l rearranged . 152 l ysozyme, 79 , 134 . 355 MLL·ENL, 115, 172 dis orde rs , iatroge nic Immunodeficiency-associated , 350-351 Ml LT1, 115 large 8 -cell lymphoma , intravascular, 252-253 large 8 -c elllymphoma, primary medi astinal (thymic), 250-25 1 Mixed myeloproliferatiVe/ myelodysplastic syndrome, unclassifiable , 85 Ml LT2, 115 M MLLT3 , 29, 30, 114, 115 Maculopapular cutaneous mastocytosis, 57 MLl T3-MlL, 29 , 30 , 114 Ma lignant histiocytosis, 356 , 360 MLl T4 , 115 Malignant histiocy tosi s X, 360 MLLT10 . 115 Malignant mid line reticu losis, 285 Monoc lonal B-ce l! lymphocytosis, 180 MALT lymp homa, 160 , 163 , 166, 198 , 209 .214-21 7, 2 19.341 ,343, 34 7, 351 Monoc lonal gammopa thy of undetermined signi ficanc e (MGUS), 200-202. 206.21 1 latent po lycyth aemia vera, 4 1 Mantle cell lymphoma. 160, ~232 LATS2, 147 MAPK, 24 , 26 , 82, 84 , 195 lCK, l77 Mast cell d isea se, 54 Lennert lymphoma. 308 Mast cell leukaemia, 54 . 57 , 6 1 Lethal midl ine granul oma . 285 , 286 Mast c ell sarcom a. 54 . 57, 61 Lenerer-Siwe disease. 358 Mastoc ytoma , cut aneous, 57-58 Leukocyte alkaline phos phatase , 6 1 Mastocytoma.ecrecuereccs. 6 1-63 teokoerymrobreetose. 44 , 45 . 46 Mastoc ytoma of skin . 58 LM01, l 77 Mastoc ytosis, 23 . 25 . scet. 62 Monoclonal ga mmopathy, unanribu tedl unassociatec. 200 Monoclonal immunog lob ulin deposition d isease, 209 Monoclonal lig ht and heavy c hain oeoosnon dis eases , 2 11-2 12 Monoc ytoid 8 -eell lymphoma . 218 Mor'Iornorphic B-ee ll PTlO, 347 Monomorphic PTlO, 343, 347-349 Subject index 43 5 ~phic T/NK-eell PTLD. 349 Morula cells, 205 Mott cells. 205 MPL, 23. 25, 44. 47, SO. 64. 86 MPN, see Myeloproliferative neoplasms MPO, see Mye1operoxidase M-protein, 200-203, 205 , 207-213 MSN. 315 Mu heavy chain disease. 197-198 Myeloid and lymphoid neoplasms with FGFAl abnormalities, 26, 72-73 Nod al margin al zone lymphoma, paediatric , 219 Myeloid and lymphoid neoplasms with PDGFRA rearrangement. 26. 68-71 Nodular lymphocyte predominant Hodgkin lymphoma, 322, 323-325 Myeloid and lymphoid neoplasms with PDGFRB rearrangement, 26, 71-72 Nodular sclerosis classical Hodgkin lymphoma , 165,267 ,313,322,326,327, .w,331 ,334,341 Myeloid leukaemia associated with Down syndrome, 29, 143-144 Myeloid proliferations related to Down syndrome , 29 , 30, 142-144 Myeloid sarcoma, 28-30. 47, 73, 110.111 . 118 , 122. 140- 14 1 Multicentric Castleman disease. large Bceu lymphoma arising in HHV8- Myelomastocytic leukaemia , 56 NOTCH1.178 Myelomatosis. 202 f'S'Ml .23,28-3l.114, 118-122, 125.126.141 associated. 234 , 258 ¥ I ipholllltWs polyposis. 229 Mu ltiple myeloma. 38 , 202 Myasthenia gravis. 196 MYC, 14, 36. 177, 178,206.224,225. 231 ,235,237,241,242,251,262-266, 289.290,325,340,348 Mycosis fungoides. 294 . 296-298 Mycosis"-"goides, ldO:Uolropoc """",,, 296 Mycosis lungoides, ISCL-EORTC staging sYSlem .296 Myelodysplasia , 24, 28-30 . 34 . 43. 49, 65 , 76,81,9 1, 101, 104,106. 115 .124 , 125, 128, 130, 131, 136, 138, 145,356 Myeloperox idase (MPO). 20, 21. 23, 35. 57.83.107.110,112-11 4,116,117 , 121. 122. 130-132. 134· 136, 138, 140, 141.144.146,1 50.151 .1 55.169. 357.362,364 19. 22. 23. 25·30 . 39 , 43. 44 , 48-50 , 53.57,59.71 ,76,77,79,85.86,87108, 110. 116 . 118, 124, 125, 127·129, 135.1 36,139-141 , 143,144,1 50 Myelodysplastic synd rome with 5q deletion, 102 Myelodysplastic syndrome with isolated del(Sq), 27, 102 Noonan syndrome, 82 NPM-AlK. 254 . 314-316 r-R.1c+ M1L. 120 ~,23,2),2B,81 .B4. 111.118. 201 ,200 Nuclear matrix associated gene , 114 Myeloproliferative disease , 23, 25, 38, 82 Nucleophosmin, 114, 118, 120, 314, 315 MyeIoproIiferalNe neopIasm,lIldassdiable, NUMA1 .114 64-65.85 Myeloproliferalive neoplasms (MPNj. 23, 31-66 NUP214 , 115, 116 Myeloproliferative varian t of the hypereosinophilic syndrome, 69 o Myofibroblasts, 355, 365 OCT-2, 25 1, 267 Onychodystrophy, 299 Myelod ysp lastic syndrome (MDS) , 15, 18. .. Non-secretory myeloma. 200, 203 Non-specificesterase,20,21 . 112-114,122. 132-134.136, 138, 140, 169,354 Mu'Iicentric CastlErrmdisease. 166, 234,200 M.itipIe • Non-myelomatous gammopathy, 200 Osseous plasmacytoma, 208 N Osteosclerosis, 42 Naphthol-ASD-chloroacetate esterase , 21,33, 34, 41, 45, 49 ,57 ,76,78,83, 105,11 2.1 30,140 Osteosclerotic myeloma. 200 , 212·213 on, 117 Naph thol-butyrate esterase, 145 Nasal typ e t -een lymphomas, 146 p Myelodysplastfc syndrome,NOS, 103 Natural killer ce ll lymphoblastic leukaemia/lymp homa, 155 p16N\"", 36. 224,241,251,264, 298, 299,349 Myelody splastic syndrome, therapy related, 127 NBS1,339 Myelodysplastic syndrome, unclassifiable, 27, 103 p 18'N~olc , 206, 231 Neurofibromin, 84 P190,32,35, 79, 171 Neutrophil alkaline phospha tase , 35, 39 p210 , 35, 79, 171 Myelodysplastic/myeloproliferative neoplasms (MDS/MPN), 18, 19, 22, 23, 2530,75-86,79,85,86 ,91 ,102,124, 127· 129,1 40 NFl , 23, 26, 82, 84, 366 p230, 35,39 NFKB, 162, 163,206,329 Paediatric follicular lymphoma. 225 NG2, 114, 172 MyelodysplastiC/myeloproliferative neoplasm, unclassifiable, 85-86 Nibrin, 339 Paediatric nodal marginal zone lymphoma, 219 Nijmegen breakage syndrome , 336. 339 Pagetoid reticulosis, 298 MyelodysplasticJmyeloprollferative neoplasms, therapy-related , 127 Nc-ceuteusaemta. aggressive, 276-277 Pancytopenia . 89, 94,103,106,115,124 , 138,188,252.279,339,356,360 NK-ceHLGL lymphocytosis, 274 Myelofibrosis, 19,24 ,37,42,44 ,46,48, 64,65.71 ,86,92,101 .137.138 Paornyelosis. 42 NK-cell lineage granular lymphocyte proliferative disorder. 274 Pappenheimer body, 98 Myelofibrosis, primary. 44-47 Nodal marginal zooe B-ceI tyrrV'ona, 218 Myelofib rosiS/sclerosis with myeloid metaplasia , 44 436 Sub;ecl index NodaImarginalzroe~ 219,3l3 166,218- Paratomcutar B-ceillymphoma. 2 18 Paraneoplastic pemphigus. 363 Paroxysmal nocturna l haemog lobinuria, 91.106.107 Partial nodal involvement in follic ular lymphoma. 222 Parvovirus 819. 91 Pautrier microabscess, 297 Pautrier-like microabscesses. 283 PAX5, 23 , 110, 169, 192, 195.225,235, 256 .267,318,319,325,326.328,334 PBX1,175 PD-1,162,311,324 POE40IP-PDGFRB , 71 PDGFRA . 19,23.25,26, 39 ,51-53.57. 6O ,62~ .~70. 73 , 76 , 78 ,80,81 ,85 PDGFRA-FIP111 .23 PDGFRB, 19. 23. 25-27. 39 , 5 1-53 , 64 . 65 . 68 .71 -73 .76,78.80,81 .85 Pearson (marrow-pancreas) syndrome. 96 , 107 Pelger-Huet anomaly. 80 . 83 , 90 , 92 . 93 . 98, 100, 105. 106. 110 Pelgeroid oenropnne. 114 Perlonn . 79. 146. 163 .255 .272.287.~ 295,300,304 ,3 15,318.354 Peripheral T-ceillyrnphoma, follicular variant, 308 t-een Peripheral lymphoma , Iymphoepi thelioid variant . 308 Peripheral T-cell lymphoma, not otherwise specified. 163 , 165 , 166, 177,287, 297, 306-308 Peripheral t-een lymphoma, primary cutaneous. 302-305 Plasm acytoid monocvtes. 78, 145 . 355 Plasm acytoma , extramedullary, 208 Prima ry effusion lymphoma, 166, 234, 243, 259, ~261, 340,342, 343 Plasm acytoma, exuaosseous. 208-209 Primary intestinal follicular !'ymptx:ma, 225 Platel et derived growth factor fl, 19 Primary intraocular lymphoma, 240 PML-RARA, 29 , 30,112-114 Primary mediastinal (thymic) large Bceu lymphoma , 234, 250-251 Pneumocyslis carinii, 282 , 284 Pneumothorax, 245 Primary myelofibrosis (PMF), 23, 25, 27, 39, 44-47, 48-50, 52 , 64 . 65, 86 , 139 POEMS syndrome, 200 , 212-213 Progressive nodular histiocytosis, 366 PoIydonaI hypergam"l8Qlobulina-nia, 162 Progressive transformation of germinal centres, 324 PoJycythaem ia rubra vera , 40 Polycythaemia vera , 23 , 40-43 Primary thrombocytosis, 48 Po/ycythaemia vera. po/ycythaemic phase. Proliferation centre. 181, 183, 195 40-42 PoIycythaemia vera , postpolycythaemic myelofibrosis. 42-43 Polycythaemia vera , prepolycythaemic phase, 40-4 1 Potycythaemia vera, spent phase, 40-41 ProJymphocytic variant of hairy cell leukaemia, 192 Protoporphyrin IX, 96 Pruntus . 38 , 41 , 51 , 55 , 69. 299 . 306 , 309 Pseudo-Gaucher cells, 33 Polymorphic PTlO, 343 . 346-347 Pseudo-Pelger-Hullt anomaly. 27,105. 116,124 Polymorphic reticu losis. 285 Psoriasi c arthritis, 350 Popcorn cells, 323 Psoriasis, 350 Post-essential thrombocythaemia myelofib rosis . 50 Post-polycythaemic myelofibrosis, 40 , 43 Post-transplant Iymphop roliferative disorders (PTLD), 166, 272, 343-349, 350 Precursor B lymphoblastic leukaemia! lymphom a, 68, 73 PTEN.298 PTGC , 219 , 322 , 324 PTLO, see Post-transplant Iymphoproliferative disorders PTlD. cIassicaJ _ ~ type . 349 PTLO, otecuous-mooonucleosle-uke. 345 PrecurscrT~~,68,337 PTLO, monomorphic, 343, 347-349 Perip/"erat T-eel1 tymptnna, T-zone variant. 3)3 Pre-p olycythaemic phase, 40 PTlO, monomorphic B-cell, 347-349 Pesticide, 166 Primar y amy loidosis, 200, 209-2 11 PTLO, monomorp hic T/NK-ce ll. 349 Philade lp hia (Ph) ch romosome, 24 , 35 . 36 ,39, 43 , 47,52,53.65,69 ,76,80, 82 , 85 , 15 1,1 52,1 71 Phosphotid ylinos itol a-kinase. 24 PICALM-MLLT10, 178 Plasma cell g ranuloma , 210 Plasma cell leukaemia. 200, 203 Plasma cell myeIcma, 100, 161,20:),202207,343 Plasma cell myeloma, asymptomatic, 202-203 Plasma cell myeloma , non-secretory, 203 Plasma cell neoplasms. ~213 Pesta eel variant d Castleman disease. 212 Ptasmablastic lymphoma. 166 . 234 . 243. 255, 256-257. 258 . 340 , 342 Ptasmacytic hyperplasia, 345 Ptasmacytoid dendritic cells, 78 , 79 , 140 , 145-147 ,151 ,155,294.355 Prima ry CN S lympho ma , 240, 340 PTlO , plas macytic hyperp lasia, 345 Primary cu tane ous ag g ressive epioermotroorc C0 8 po sitive c ytotoxic T-c ell lymphom a , 303· 304 PTPN 11, 23, 82, 84 Primary c utaneous anaplastic large cel l lymphom a. 3O()...301 PU. 1, 25 1, 328 PTlO, po lymorphi c, 343. 346-34 7 PTPN 12,316 Primary cu taneous C030-positive t-een Iympho p roliferative d isorde rs, 300·301 Pure id iopathic ery throcytosis, 41 Primary c utaneous diffuse large B-cell lymphoma, leg type , 227 , 228,234,242 Pyothorax-associated lymphoma, 245 Primary cu taneo us follicle centre lymphoma, 227-228 R Primary cut aneous gamma-delta ()'O) lymphoma, 163, 302-303 Primary cutaneous peripheral phoma. 302-305 r-ceu t-ceuwm- Primary cutaneous smalilmedium CD4 positive lymphoma, 304-305 j-ceu Primary diffuse large B-cell lymphoma of the central nervous system, 240-241 Pyothorax, 245, 260 Radioulnar synostosis, 106, 107 RAEB. see Refractory anaemia with excess blasts RAEB with fibrosis, tOO RAE~1.89 ,93 ,94 . 100, 10 1, 104 RAEB-2, 89, 91, 93 , 98, 100, 101, 104. 139 RAG112,339 Subject index 43 7 • Randalldisease. 211 RPN1-EVI 1, 30,1 16 RARA, 28, 30. 113 . 114 RUNX1,23,28,29,62, 110,11 1, 112, 126, 131, 172 RARS. see Refractory anaemia w ith ring sroerobrasts RUNX 1-RUN X1T1, 29 , 110 . 111 RUN X1Tt (ETD), 111 RARS- T. see Refractory anaemia with ring srderobtasts and thrombocytosis RUNX2 , 147 RB1 , 36. 147, 206, 231 Russell body. 205 , 2 10 RBM l 5-MKL1 . 30 , 117 S RCe , see Refractory cytopenia of childhood S1OO.355,358,362,364-366 Sclerosing cholangitis, 359 , 366 Sea-blue t ustccvtes. 33 347-349, 364 Seckel syndrome, 107 94-97 ,99. 103. 104. 124, 125. 132 Splenic red pulp lymphoma with numerous basophilic villous lymphocytes, 191 Senile EBV-associaled B-celilymphopro liferative disorder, 243 278 Stabibn-f, 366 Starrysky pattern, 78. 169, 176.214.229, 264-266 STAT, 24, 251, 329 Stem cell acute leukaemia . 151 Strongyloidiasis, 282 SubCutaneous pan nicu litis-like T-cell lymphoma, 163,294-295,302.355 Refractory anaemia of ch ildhood. 104 SerpinA 1,315,316 Refractoryanaemia with excess blasts Severe combined immunodeficiency. 336 Syncytial variant. nodular sclerosis classica l Hodgkin lymphoma, 330 Sezarv cells, 299 Sezarv syndrome, 296 , 297 , 299. 349 Syndrome of ab normal chromatin cl umpi ng, 81 Sezary syndrome, ISCl -ED RTC staging system, 296 Systemic EBV+ T-ee illymphoproliferative d isease of ch ildhood . 278-280 SHP1 ,3 15 Systemic lupus eryth ematosus, 196,294 SHP2,82 Systemic mastocytosis, 25 , 52-55 . 57 , 5861, 70 (RAEB), 23, 27 , 89-94. 96, 98-99, 1OD- 101,104 ,136.139 Refractory anaemia With ring sideroblasts (RARS), 27,49. 65.85. 86, 88. 89. 94. 96-97,104 Refractory anaemia with ring srderobrasts an d thrombocytosi s (AARS-T), 26 . 27 , 49. 65. 85-8$ Refractory anaemia withL.Jrjlineage dysplasia, 88 • sCD23,182 310.313.322.326 .327.330.331.337. Refractory anaemia, 27 , 49 . 65 , 85. 88-91 , Splenic marginal zone lymphoma, diffuse variant, 191 Sporadic fatal infectious mononucleosis. ABTN2,177 244.247.250.261 .300.301 .306.308. Splenic marg inal zone lymphoma, 160. 164, 166. 183,185-187,189-191 Spoke whee l, c hroma tin pattern, 205 ABTN1,177 Reed-Sternberg cel ls, 182,234 ,238,243. Splenic Iymphoma/leukaemia. unclassiliable, 19 1- 193 Refractory cytopenia 01 childhood (RCC),27, 1M 107, 143 Shvv-actYnann-Diamcfld sworcrre. 88. 107 Signal tra nsd ucer and activator of transcription, 24 SjOgren synd rome , 196 , 215 , 2 19 SlE , 196 ,294 Refra ctory cytopenia w ith multilineage dysplasia, 89, 90, 97, 98-99, 100, 103, 100 sivi. Refracto ry c ytopenia with unilineage dy splasia, 89-90, 94-95, 100 , 103 Small lymphoc yt ic lymphoma. 180-182 216,2 17,229, 233. 339 , 351 Refract ory neutrop en ia , 89, 90 , 94 , 95 Small round ceutomours. 14 1 Refractory thromboc ytopenia, 27, 89-91 , 94, 95 Smu dg e ce lls, 181 Regressing atypical histiocytosis, 355 SOCS1, 236. 251 Restrictive cardiomegaly, 51 Solitary mastocytoma of skin, 54, 57 Restrictive car diomyopathy, 69 Solita ry plasmacytoma of bone, 200, 208 Reticulin fib rosis. 33 , 44. 48, 49 , 59, 50, 100.101 ,189,193,273 Somatic hyper mutation . 158. 159, 182, 186,190,192,195.197,201 ,205,207, 2 17,228.231 ,235,241 ,250,258.264, 325 ,329.347,348,349 Reticulin/collagen fib rosis , 60 aetcuiomsuocvtona of the dorsum, 227 Bencuiotnsuocvtosis. 354 Retinoic ac id receptor (1 , 113 Rhabdomyosarcoma, 137, 3 15 Rheumatoid arthritis . 196.245 ,350 Riluximab, 190, 193, 236 . 255 Bosa-Dofman d isea se, 354 438 Systemic mastocytosis with associated haematoioalcer c lonal non-mast cell d isorder, 54 185, 186 SOC- 1. 329 Sorafenib . 70 Splenic B-celi lymphoma with villous lym p hoc ytes. 191 Splenic diffuse red pu lp small B-ee ll lymphoma. 191-192 Sp lenic lymphoma w ith ci rculating villous lym phocytes, 185 T T lymphob lastic leukaemia/lymphoma, 161 ,1 65 , 176-178 T-be l, 189 , 190 T-cell ch ronic lymphoc ytic leukemia, 270 T-cell large g ranul ar lymp hoc ytic leukaemi a, 163 , 2 72-273 T-cell proIymphocytic leukaemia, 163,270271, 337 T-c ell ric h large B-ceillymphoma. 238 , 323 ,326 T-cell/histiocyte-rich large B-celllymphoma , 234, 238-239, 325 T-cell rec eptor (TCR), 112, 13 1, 146, 151, 158.161-164, 169,176-178,249.261 , 270 ,273,275,277,279,280,283,287, 290 ,293-295,297,299-301 ,303,304. 307,311 .315.318,319,328,329,336, 338 ,339,348,349,357,358.362,364 , 366 T-cell-rich B-eeillymphoma, 238 Sub ject index $ v TCF3-PBX1, 175 1(3;5)(p2 1-25;q31-35), 71 TCL1, 146, 270, 271, 338, 355 1(3;2 1)(q2 6,2;q22), 93,1 17 Vein Ihrombosis, 41, 48, 65 TCR, see t-een receptor t(4;11), 128, 172 von Willebrand teeter, 106 Teardrop-shaped, red blood cells (dacryocytes), 42, 44, 45, 49 1(4;22)(q 12;ql1),70 t(4;14)(p 16.3;q32) ,201 TEL·AML1, 170, 172 1(4;5;5)(q23 ;q31;q33 ),71 W Terminat deoxyn..cleottdyl transferase (TdT), 34,110,1 16,117,125,131 ,1 37,138, 140,146,147,151 ,161 ,169, 171, 177. 264-266, 270 t(5;7)(q33 ;ql1 .2).7 1 WDR48-PDGFRB.71 t(5;10)(q33 ;q21), 71 Wiskolt-A ldrich syndrome, 247. 336 1(5;12)(q31 -33;p12). 71, 72, 79 Woringer-Kolopp type , 298 Thalidomide. 102, 117 1(5;12)(q31;p13),72 WT1 , 118, 119 Therapy-related acute myeloid leukaemia, 127 t(5;12}(q3 1-33;q24),7 1 1(5;14)(q33 ;q24), 71 Therapy-related myeloid neoplasms, 29 , 30, 127- 129 1(5;14)(q33;q32 ), 71 x Tresaurocvtes. 205 t(5 ;15)(q33;q22 ),71 Xanthoma disseminatum. 366 Thrombocyt openia wilh absent radi i. 107 t(5;16)(q33;p13).71 Thymic (mediastinal), primary large B-cell Iymphoma, 25(}25 1 t(5;17)(q33 ;p13), 71 X-linked Iymphopf oliferative Syndrome, 247, 339 1(5;17)(q33 :Pl1 ,2), 71 Thymoma, 364 TlA1. 79, 146. 163,273,274,287, 293, 295.300. 304,315, 3 18 Tingible body macro phage s, 220 , 227 TLX1 ,l77 t(8;21)(q22;q22), 28, 30. 104, 110, 112. 118.123,1 41 ZAP-70, 182. 23 1 t(9; 14)(p13:q32), 192 TLX3, 177 1( 10:11)(p13;q1 4).178 Toll-like recep tor, 162,262 1(11 ;14)(q13 ;q32), 163, 231 Topoisomerase II, 128 1(1 1;16)(q23 :p 13,3),93 Toulon cells, 366 t(11;19)(q23;p1 3.3).11 5 TP53, 14,36,93, 182, 187. 192,206.207. 224,225 ,231 ,237 ,246, 25 1,264,27 1, 287,299 ,329,348,349 1(1 4:16)(q32;q23),201 1(14:18),1 60, 163,164,186,217,222. 224, 225, 228,235,241,242,329 TPM3-PDGFRB,7 1 t(15;17Xq22;q 12j, 30, 104, 110, 112, 114, 118, 129 TPG-R , 142, 144 TRAF1, 250 t(16;1 6XP13,1;q22j, 28, 30, 104, 110112,118, 129 Transient abnormal myelopoiesis, 29, 142-143 transiccauoos z 1(9:11)(p22;q23 ).30, 110, 114, 115, 128 T-LBl, 68-70, 73, 176. 178,339 Transientmyeloproliferative disorder, 142 t(6;9)(p23;q34), 93, 110, 115. 116, 118, 125, 138 1(17;19), 170, 175 TRAP (Tartrate-resistant acid phosphatase), 189, 190, 192,193 1( 1;3Xp36,3;q21.2), 93 Triphenotypic leukaemia, 152 t(l ;3;5}(p36;p2 1;q33), 71 Trisomy 12, 184,231 t(l ;5)(q21;q33), 71 Trisomy 21 mosaicism . 142 t(1;5}(q23;q33),71 t( l ,14 ), 163, 178,217 t(1;22)(p13;q 13). 30,1 10,117,136 t(2;11)(p2 1;q23), 93, 115, 125 u 1(2;5), 163. 164, 254, 255, 3)1, 3 14-316, Ulcerative jejunitis. 289 329 Urticaria pigmentosa, 54-56. 57-58 1(3;3)(q21;q26.2), 29. 30, SO. 93 , 110, 11 6, 117, 125, 136 Subject index 439 Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues (World Health Organization Classification of Tumours) Read more Who Classification of Tumours of the Central Nervous System (Who Classfication of Tumours) Read more TNM Classification of Malignant Tumours Read more WHO Classification of Tumours of the Central Nervous System Read more Histological Typing of Odontogenic Tumours (WHO. 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