Dermal Tumors: The Basics

Dermal Tumors: The Basics

 

Dermal Tumors: The Basics

Bruce R. Smoller Department of Pathology University of Arkansas for Medical Sciences Little Rock, AR, USA and

Kim M. Hiatt Department of Pathology University of Arkansas for Medical Sciences Little Rock, AR, USA

Dr. Bruce R. Smoller Department of Pathology University of Arkansas for Medical Sciences Little Rock, AR 72205 USA [email protected]

Dr. Kim M. Hiatt Department of Pathology University of Arkansas for Medical Sciences Little Rock, AR 72205 USA [email protected]

ISBN 978-3-642-19084-1 e-ISBN 978-3-642-19085-8 DOI 10.1007/978-3-642-19085-8 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011929931 © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is ­concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant ­protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

In this fourth, and final, volume of the series on dermatopathology we conclude our framework which students, at all levels of learning, can use to continue building from in the classification and diagnoses of cutaneous diseases. This volume is focused on lesions arising from dermal-based processes. The format is structured, like the previous volumes, as a bullet-point outline of the main clinical and histologic features with an atlas of quality images to demonstrate these points. This format provides a small-sized reference that is easily accessible to the sign out microscope and provides a foundation that is elaborated on in the already published excellent larger texts available to the student. Little Rock, Arkansas, USA Little Rock, Arkansas, USA

Bruce R. Smoller Kim M. Hiatt

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Acknowledgment

These volumes could not have been made possible without the dedication of the dermatopathology laboratory staff at the University of Arkansas for Medical Sciences. Their commitment to provide high quality histology allows us the opportunity to share the numerous images in these volumes. As always, Bruce Smoller wishes to acknowledge his wife, Laura, and two (now adult) children, Gabriel and Jason, for their constant enthusiastic support and love. He would also like to acknowledge the entire Department of Pathology at the University of Arkansas for Medical Sciences for the honor of having worked with them over the entire duration of this project. And, Dr. Hiatt would like to thank her husband, Jim, and her children Stephanie, Nicholas, Kaitlyn and Natalie for their support.

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Contents

1  An Overview of Cutaneous Lymphomas . . . . . . . . .

1

2  Vascular Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37

3  Histiocytic Proliferations. . . . . . . . . . . . . . . . . . . . . .

59

4  “Fibrohistiocytic” Proliferations. . . . . . . . . . . . . . . .

73

5  Tumors of Fat, Nerve, and Smooth Muscle . . . . . . .

103

6  Cutaneous Metastases. . . . . . . . . . . . . . . . . . . . . . . . .

123

Further Reading. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

131

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 1

An Overview of Cutaneous Lymphomas

• Classifications of cutaneous lymphomas –– Two recent systems both had problems °° Revised European-American Classification of Lym­ phomas (REAL) °° European Organization for Research and Treatment of Cancer (EORTC) –– REAL classification °° Uses classification of systemic lymphomas and applies them to cutaneous lymphomas °° Classification based upon pathologic, genetic, and clinical features and adds immunohistochemical criteria °° Cutaneous involvement accounted for in clinical features –– EORTC classification °° Recognized cutaneous lymphomas as a distinct entity °° Organ-based classification system °° Only system that has been clinically validated for this group of diseases; classified as indolent, intermediate or, aggressive –– WHO-EORTC classification °° Consensus conference in 2005 incorporated features of both systems to acknowledge particulars of cutaneous lymphomas B.R. Smoller, K.M. Hiatt, Dermal Tumors: The Basics, DOI: 10.1007/978-3-642-19085-8_1, © Springer-Verlag Berlin Heidelberg 2011

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–– WHO 2008 classification °° Integrated the WHO-EORTC classification of cutaneous lymphomas in the general classification °° Only minor changes in terminology, except blastic plasmacytoid dendritic cell neoplasm, previously CD4+/ CD56+ hematodermic neoplasm, previously blastic NK cell lymphoma • Overview –– 3% per year increase in incidence of cutaneous lymphomas every year since 1970 –– Cutaneous lymphomas represent a very heterogeneous group of diseases with very different clinical presentations, courses, treatment programs, and prognoses –– Second most common (after GI tract) site of extra-nodal non-Hodgkin’s lymphomas –– Large groupings include T cell lymphomas, B cell lymphomas, and Hodgkin’s lymphoma –– Overall incidence estimate of 1:100,000 –– 75% of cutaneous lymphomas are T cell lymphomas, 25% B cell lymphomas –– Hodgkin’s lymphoma is exceedingly rare in skin –– 5–10% of T cell lymphomas are not mycosis fungoides • T cell lymphomas (Table 1.1) • Mycosis fungoides (MF)/Sezary syndrome –– Epidemiologic features °° 0.42 cases/100,000 population °° Overall, more than 50% of all cutaneous lymphomas °° Incidence rapidly increased in 1970s–1980s, but now stabilized Table 1.1  T cell lymphomas Mycosis fungoides/Sezary syndrome Primary cutaneous CD30+ lymphoproliferative disorders Subcutaneous panniculitis-like T cell lymphoma Extranodal NK/T cell lymphoma, nasal type Blastic plasmacytoid dendritic cell neoplasm (Peripheral T cell lymphoma)

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°° Twice as common in African Americans as in Caucasian Americans °° Twice as common in men as in women °° Associated with 3.3X relative risk for second, non-­ cutaneous malignancy –– Clinical features °° Usual onset in middle age (mean 55–60), but can appear at any age °° Starts most commonly as erythematous, slightly scaly patches on flank and buttocks °° Progress to plaques and ultimately tumors (in a minority of patients) °° Poikilodermatous variant – uncommon °° Involvement of lymph nodes, spleen, liver only late in course –– Histologic features (Figs. 1.1–1.4) °° Epidermotropic proliferation of hyerconvoluted, hyperchromatic lymphocytes in clusters (Pautrier’s microabscesses) and as single cells within epidermis

Fig. 1.1  Early lesions of mycosis fungoides show an epidermotropic lymphocytic infiltrate. Single atypical lymphocytes are seen lining up along the basilar epidermis

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Fig.  1.2  In more evolved lesions of mycosis fungoides, small clusters of atypical lymphocytes and increased single lymphocytes are present in the epidermis which also shows only minimal spongiosis and no dyskeratosis

Fig. 1.3  This case of mycosis fungoides shows only a mild dermal infiltrate but numerous Pautrier’s microabscesses

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Fig.  1.4  Variable number of eosinophils and some plasma cells are often present in the dermal infiltrate of mycosis fungoides

°° Difficult diagnosis to make in early lesions °° Later lesions with less epidermotropism and more cytologic atypia °° Variable number of eosinophils and some plasma cells –– Immunologic features (Figs. 1.5 and 1.6) °° Mycosis fungoides is defined as a neoplastic proliferation of CD3+, CD4+ T helper lymphocytes °° CD8+ tumors are rare but are now classified as MF °° Loss of CD2, CD3, and CD5 often seen °° Clonal rearrangements of T cell receptor is ultimately detected in most cases, but only 50% of early lesions. –– Molecular features °° T-cell gene rearrangements seen in 50–80% of patchstage lesions, nearly 100% of tumor stage and Sezary cases °° When same clone is present in two separate locations, worse prognosis is reported

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Fig.  1.5  The epidermotropic lymphocytes in mycosis fungoides most commonly express CD4

Fig. 1.6  Loss of normal T-cell markers such as CD5 is common as in this case of mycosis fungoides

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–– Treatment protocols °° °° °° °° °° °°

Topical steroids Topical nitrogen mustard Electron beam irradiation Interferon Chemotherapy Photopheresis

–– MF – Prognosis °° Excellent, overall °° Patients presenting with stage I disease have the exact same 30-year survival as age and sex-matched controls without MF (97–98% 10-year survival) °° Generalized (>10% of skin surface) disease – 83% 10 year survival °° Tumor stage disease 42% 10-year survival °° Nodal involvement usually with less than 1-year survival –– MF variants (Figs. 1.7 and 1.8) °° Folliculotropic – characteristic morphology; 70–80% 5-year survival – less responsive to therapies –– Myxoid degeneration may be seen –– Folliculotropic MF replaces MF-associated follicular mucinosis °° Pagetoid reticulosis – localized patches, very epidermotropic; excellent prognosis °° Granulomatous slack skin/granulomatous mycosis ­fungoides – rare; responds to radiation, but with rapid recurrences °° Sézary syndrome –– Triad: erythroderma, generalized lymphadenopathy and neoplastic T cells in skin, lymph nodes, and peripheral blood: 3 (>1,000 cells/mm , CD4/CD8 ratio >10, loss of CD2, CD3, CD4, and/or CD4) Clonality of cells in blood

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Fig.  1.7  Folliculotropic mycosis (A) shows an atypical CD4+ (B) lymphocytic infiltrate with a predilection of the follicular epithelium. Myxoid degeneration may be seen

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–– Mean survival 2–4 years –– Treat with photopheresis • Primary cutaneous CD30+ lymphoproliferative disorders –– Primary cutaneous anaplastic large cell lymphoma –– Lymphomatoid papulosis • Anaplastic large cell lymphoma (ALCL) –– Epidemiologic features °° Primary cutaneous ALCL occurs primarily in adults (non-cutaneous in children) °° Most patients with solitary or localized skin lesions at time of presentation –– Clinical features °° One to several nodules or small tumors °° Ulceration may be present

Fig.  1.8  Granulomatous mycosis fungoides shows sarcoidal granulomas in the dermis and typically lacks an epidermotrophic lymphocytic component

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°° <10% with lesions extending beyond one area of skin °° Spontaneous regression of lesions may occur °° Minority of patients develop nodal disease but recurrences of skin disease are common –– Histologic features (Figs. 1.9 and 1.10) °° Dense dermal infiltrate of large lymphocytes with round nuclei, one or multiple nucleoli and marked pleomorphism °° Minimal epidermotropism °° Abundant necrosis °° Often an abundant reactive, inflammatory infiltrate with eosinophils and neutrophils –– Immunologic and molecular features (Fig. 1.11) °° Defined as >75% of cells expressing CD30 in skin biopsy °° Lymphoma cells also express CD3 and CD4 in most cases

Fig. 1.9  Anaplastic large cell lymphoma shows a dense dermal infiltrate of large lymphocytes

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Fig. 1.10  The nuclei in anaplastic large cell lymphoma are round with one or multiple nucleoli and marked pleomorphism. Scattered reactive lymphocytes are also present

°° CD2, CD3, and CD5 may be absent °° CD15 negative (unlike Hodgkin’s disease) °° B cell variants of CD30+ lymphoma have been described °° t(2;5) translocation common in children but not seen in adults with ALCL °° Clonal rearrangements seen in most cases –– Treatment protocols °° Radiation is preferred mode of therapy for limited ­cutaneous disease °° Chemotherapy reserved for patients with generalized cutaneous disease or systemic involvement –– Prognosis °° Excellent for patients with primary cutaneous ALCL °° 10-year survival >90% °° Much worse prognosis for patients with nodal disease

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Fig.  1.11  The large cells in anaplastic large cell lymphoma express CD3 (A) and CD30 (B)

• Lymphomatoid papulosis –– Clinical features °° Chronic, recurrent, self-healing papulonecrotic process °° Mostly in adults (median age 45) °° Lesions at different stages simultaneously

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°° Process may last from weeks up to 40 years °° 20% of patients with LyP have associated lymphoma (MF, Hodgkin’s or ALCL) –– Histologic, immunologic, molecular features (Figs. 1.12–1.14) °° Large, atypical CD30+ cells interspersed with a brisk reactive inflammatory infiltrate (type B variant looks like MF and cells do not express CD30)

Fig. 1.12  Lymphomatoid papulosis shows a dense dermal infiltrate (A) with scattered atypical large cells (B)

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Fig. 1.13  This case of lymphomatoid papulosis shows an exuberant dermal infiltrate attenuating the overlying epidermis (A) and showing numerous large atypical cells (B)

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Fig. 1.14  The extent of large CD30+ cells in the dermal infiltrate of lymphomatoid papulosis varies from scattered (A) to numerous (B). Diagnosis hinges on clinical presentation

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°° CD3+, CD4+, CD8− °° T cell clonality seen in 60–70% of cases –– Prognosis excellent • Subcutaneous panniculitis-like T cell lymphoma (SPTCL) –– Epidemiologic features °° Previously known as histiocytic cytophagic panniculitis (at least some cases) °° Occurs primarily in adults (median age 37–56 years), but reported in children °° Rare neoplasm –– Clinical features °° Multiple red to violaceous cutaneous nodules °° No overlying epidermal changes except tendency to ulcerate °° Not painful °° Legs and arms most common sites, followed by the trunk °° Systemic symptoms present at time of presentation in most patients, but nodal involvement usually only late in course –– Histologic features (Figs. 1.15 and 1.16) °° Dense, diffuse infiltrate of small to medium-sized lymphocytes in deep dermis and subcutaneous fat °° Fat necrosis with extensive lobular involvement °° Rimming of adipocytes by neoplastic T cells helpful, but not specific °° Hemophagocytosis usually prominent, as are necrosis and karyorrhexis –– Immunologic and molecular features °° °° °° °° °°

All cases represent T cell lymphomas a/b+, CD3+, CD4−, CD8+, CD30− Clonal T cell gene rearrangement EBV not seen in these cases CD56+, l/d+ lymphomas are similar, but much more aggressive clinical course (different classification now in new system)

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Fig.  1.15  Subcutaneous panniculitis-like T-cell lymphoma shows a dense, diffuse infiltrate of small to medium-sized lymphocytes in deep dermis and subcutaneous fat

Fig. 1.16  Rimming of adipocytes by neoplastic T-cells is seen in subcutaneous panniculitis-like T-cell lymphoma. Karyorrhexis, shown here, is also common

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–– Treatment protocols °° Systemic chemotherapy °° Corticosteroids (systemic) – often control disease for long periods of time °° Radiation therapy –– Prognosis °° Generally favorable – 5  year survival of 80% with frequent recurrences but rare systemic involvement • Extranodal NK/T cell lymphoma, nasal type –– Epidemiologic features °° In this case, primary vs. secondary not important for prognosis or treatment °° Skin second only to nasal cavity in terms of frequency of involvement °° Neoplastic proliferations of NK cells or less commonly, cytotoxic T cells have been implicated °° Most common in Asia, Central and South America °° Male predominance –– Clinical features °° CD56+ lymphomas have a predilection for nasopharyngeal region (used to be called “lethal midline granuloma”) °° Multiple skin lesions may be present on trunk and extremities  – subcutaneous nodules with ulceration commonly °° Systemic features including fever, weight loss, lymphadenopathy, splenomegaly and anemia may be present °° Hematophagocytic syndrome also common –– Histologic features (Figs. 1.17 and 1.18) °° Superficial and deep dermal infiltrates of atypical lymphocytes °° Epidermotropism is present but not extensive °° Angiocentric and angiodestructive infiltrates are the characteristic finding with secondary necrosis °° Panniculitis-like infiltrate also present in most cases

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Fig. 1.17  Extranodal NK/T-cell lymphoma has a superficial and deep dermal infiltrate of atypical lymphocytes

°° Neoplastic cells often accompanied by heavy mixed inflammatory infiltrate –– Immunologic features °° Neoplastic cells express CD2, CD56, and cytotoxic proteins such as TIA-1, granzyme B, and perforin and are CD3 negative °° Almost all are EBV+ °° CD56 negative-type very rare, with much less association with EBV infection

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Fig. 1.18  Angiocentric infiltrate with complete necrosis of the vessel is seen in this extranodal NK/T-cell lymphoma

–– Molecular features °° Gene rearrangements usually not seen –– Treatment protocols °° Aggressive chemotherapy (cytoxan, vincristine, adriamycin, and prednisone in one series) °° Radiation –– Prognosis °° CD56+ lymphomas have less than 12  month median survival °° If presenting with only skin lesions, survival is 27 months, compared with 5 months if they also have extracutaneous disease °° Most patients develop systemic disease and bone marrow involvement • Hematodermic neoplasm (NK blastic lymphoma) (Fig. 1.19) –– Newly described

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–– Similar cells morphologically to NK/T cell lymphoma, nasal type –– Express CD4, CD43, CD56, and CD123, but not CD3 or CD20 –– EBV always absent –– Not angiocentric or angiodestructive –– May be derived from plasmacytoid dendritic cells • B cell lymphomas (Table 1.2) • Primary cutaneous marginal zone lymphoma (MZL) –– Epidemiologic features °° Slightly more common in men (1.5:1) °° Mean age 50  years – >50% are in fifth and sixth decades °° May represent 15–20% of all cutaneous lymphomas °° Cases previously called immunocytoma included in this category °° Part of MALT lymphomas – mucosa associated lymphoid tissue –– Clinical features °° Single or clusters of red-brown papules or nodules that usually do not ulcerate °° Upper extremities, back and lower extremities are most common sites °° Face involvement uncommon °° More than one region involved in 25% of cases °° Systemic symptoms are very uncommon but cutaneous recurrences common –– Histologic features (Figs. 1.20 and 1.21) Nodular dermal infiltrates involving dermis and subcutis No epidermotropism Reactive germinal centers with mantle zones present Lymphoplasmacytoid cells present in all cases but may represent the minority population °° Often with monotypic plasma cells at periphery of lesions °° °° °° °°

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Fig.  1.19  CD4+/CD56+ hematodermic neoplasms show a diffuse, non-­ epidermotropic dermal infiltrate (A) atypical and mitotically active cells (B) that co-express CD4 (C) and CD56 (D)

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Fig. 1.19  (continued)

Table 1.2  B cell lymphomas Marginal zone lymphoma (MALToma) Primary follicular center cell lymphoma Primary cutaneous large B-cell lymphoma of the leg Intravascular B cell lymphoma

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Fig. 1.20  Marginal zone lymphoma shows a nodular dermal infiltrate, without epidermotropism

–– Immunologic features (Fig. 1.22) °° Neoplastic cells express CD20, CD79a, and bcl-2 °° CD5, CD10, bcl-6, and CD43 negative °° Monoclonal immunoglobulin distribution in 75% of cases; these plasma cells also express CD138 and CD 79a °° Many CD3+ T cells present in infiltrate –– Molecular features °° Trisomy 3 is seen in 70% of cases °° Trisomy 18 and rearrangement of chromosome 1 also seen

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Fig.  1.21  Reactive germinal centers with mantle zones may be present in marginal zone lymphoma

°° t(14;18)(q32;q21) involving IgH gene on chromosome 14 and the MLT gene on chromosome 18 –– Treatment protocols °° Local excision and radiation are therapies of choice for primary lesions and local recurrences °° European studies emphasize antibiotic therapy and stress relationship with Borrelia burgdorferi infection (not seen in USA) – in these cases, antibiotics should be tried first °° Chemotherapy only for recurrent and widespread disease –– Prognosis °° Recurrences common °° 100% survival in one study with 5-year follow-up (median 24 months)

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Fig.  1.22  Neoplastic cells in marginal zone lymphoma express CD79a (A) and bcl2 (B)

• Primary cutaneous follicular center cell lymphoma (FCCL) –– Epidemiologic features °° Occurs in middle-aged to elderly patients (mean age 58.5) °° 1.6:1 male predominance

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Fig.  1.23  This case of follicle center lymphoma shows a dense nodular ­dermal infiltrate

°° When on back, previously known as “reticulohistiocytoma of the dorsum” or “Crosti lymphoma” –– Clinical features °° Usually presents as one (or several) grouped, erythematous to violaceous papules or nodules without surface changes in a localized distribution °° Head and neck are most common locations, then trunk °° Will gradually increase in size over years without disseminating if left untreated –– Histologic features (Figs. 1.23–1.25) °° Dense, deep dermal infiltrate of lymphocytes with no epidermal involvement and a frequent grenz zone °° May be nodular (more common on scalp) or diffuse °° Neoplastic follicles of lymphocytes may be difficult to find °° Eosinophils and plasma cells are not present °° Mixed cell type of FCC lymphoma most common in skin, then large cleaved type; small cleaved is least common

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Fig. 1.24  This case of follicle center cell lymphoma is composed predominantly of small centrocyte-like cells with cleaved nuclei and inconspicuous nucleoli

Fig. 1.25  This case of follicle center lymphoma shows a mixture of small and large centrocyte-like cells with scattered centroblast-like cells that show large nuclei and prominent nucleoli (arrows)

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–– Immunologic features °° Predominance of CD20+ or CD79a + cells in infiltrate with scattered reactive CD3/CD43+ lymphocytes °° Either kappa or lambda restriction in many cases °° Bcl-2 expression uncommon in primary cutaneous FCC lymphomas (common in nodal based lymphomas) °° Bcl-6 expression helpful in confirming follicular nature of cells °° CD10 expression seen only in follicular pattern, not in diffuse growth pattern lymphomas °° CD5 and CD43 are negative –– Molecular features °° Clonality can be established in most cases, but t(14;18) is not seen in primary cutaneous FCC lymphoma –– Treatment protocols °° °° °° °°

Orthovolt radiation therapy to local lesions Surgical excision has been used (less desirable) Radiation also effective for recurrent lesions Chemotherapy indicated only when noncontiguous regions are affected

–– Prognosis °° Local relapses present in 25% of cases (disease-free interval was 27 months (mean)) °° Systemic spread of disease in <5% of cases °° 5-year survival >95% independent of growth pattern (nodular vs. diffuse), multi-focality vs. localized, or percentage of blasts °° Strong bcl-2 expression and a diffuse large-cell growth pattern may be associated with less favorable prognosis • Primary cutaneous large B-cell lymphoma of the leg –– Epidemiologic features °° Only in elder patients (median age 76) °° 85% greater than 70 years of age °° 3:1 female predominance in one study

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Fig.  1.26  Primary cutaneous diffuse B-cell lymphoma of the leg has a ­non-epidermotropic infiltrate filling the dermis

–– Clinical features °° Large blue-red tumor nodules appearing on lower legs, mostly multiple °° Almost always confined to lower leg at time of presentation, but associated with rapid dissemination °° Has been associated with lymphedematous leg –– Histologic features (Figs. 1.26 and 1.27) °° Dermis filled diffusely with large cells including centrocytes and immunoblasts °° High mitotic rate, abundant necrosis °° No epidermotropism

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Fig. 1.27  The dermal infiltrate in primary cutaneous diffuse B-cell lymphoma is composed of large cells with centrocyte and centroblast morphology

–– Immunologic features (Fig. 1.28) °° Cells express CD20 and CD79a (pan B-cell markers) and strongly express bcl-2 (unlike most FCC lymphomas in the skin) °° Bcl-2 expression cited as evidence in favor of classifying as a separate B cell lymphoma (not follicular center ­cell-related) °° Usually bcl-6 positive and CD10 negative –– Treatment protocols °° Usually starts with local radiation as first choice therapy for patients with single, small lesion °° Systemic chemotherapy for relapses, more extensive disease –– Prognosis °° 50% relapse rate °° Median survival is 28 months (range 8–97 months) °° 2-year survival 77%, 5 year survival 55%

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Fig. 1.28  The neoplastic cells in primary cutaneous B-cell lymphoma of the leg co-express CD79a (A) and bcl2 (B)

°° Patients with multiple lesions at time of presentation with significantly worse prognosis than those with a single lesion °° Considered an intermediate prognosis lymphoma in EORTC classification

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• Intravascular B cell lymphoma (malignant angioendothe­ liomatosis) –– Epidemiologic features °° Also known as angiotropic lymphoma (not angiocentric) °° Usually in adults ages 50–70 but can occur at any age °° No gender predilection –– Clinical features °° Most commonly involves skin, lungs, and central nervous system at time of presentation °° Skin findings may appear as telangiectasias, panniculitis, or erythematous nodules, most commonly on trunk and lower extremities °° Constitutional symptoms including fever and myalgias are common °° Hematopoietic tissues are rarely involved °° Mild anemia –– Histologic features (Figs. 1.29 and 1.30) °° Ectatic vessels in dermis and subcutis occluded by noncohesive proliferation of large, cytologically atypical lymphocytes °° Lymphocytes are hyperchromatic with prominent nucleoli and abundant mitoses °° Fibrin thrombi may be present °° Small- and medium-sized vessels are involved –– Immunologic features °° Most cases express CD20 and CD79a (rare cases are CD3+ T cell lymphomas) –– Treatment protocols °° Aggressive chemotherapy and radiation therapy °° Lymphoma responds poorly to both regimens °° Some evidence that better results occur with aggressive polychemotherapy early in course

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Fig.  1.29  Intravascular B-cell lymphoma shows dermal vessels distended with large atypical B-cells

Fig.  1.30  The cells filling the dermal vessels in intravascular B-cell lymphoma have irregular nuclei, prominent nucleoli, mitoses, and apoptosis

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–– Prognosis °° Very poor °° 13-month median survival after diagnosis °° Patients with only skin lesions have a 56% 3-year survival °° Patients with other organ involvement have a 22% 3-year survival

 

Chapter 2

Vascular Tumors

• Vascular tumors (Table 2.1) • Telangiectasias (Table 2.2) • Port wine stain –– Clinical

°° Presents at birth or shortly thereafter °° Progressively darkens, thickens, and becomes more °° °°

nodular with age Associated with Sturge–Weber syndrome, Klippel– Trena­unay syndrome, and Cobb syndrome Progressive ectasia believed to be caused by abnormal autonomic regulation – decreased nerves present in lesional skin

–– Histologic (Figs. 2.1 and 2.2)

°° Ectatic, thin-walled vessels in superficial to mid-dermis °° Vascular ectasia becomes more prominent with increas°°

ing age Difficult to diagnose in young children (without clinical history) – appears virtually normal

• Hereditary hemorrhagic telangiectasia –– Clinical

°° Autosomal dominant inheritance °° Nosebleeds in children °° Telangiectasias appear on mucosal surfaces and diffusely on skin

B.R. Smoller, K.M. Hiatt, Dermal Tumors: The Basics, DOI: 10.1007/978-3-642-19085-8_2, © Springer-Verlag Berlin Heidelberg 2011

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38 Table 2.1  Vascular tumors Telangiectias Intravascular papillary endothelial hyperplasia Hemangiomas Lymphangiomas Non-hemangiomatous tumors Table 2.2  Telangiectasias Nevus flammeus (port wine stains) Hereditary hemorrhagic telangiectasia Angiokeratoma Venous lake

Fig.  2.1  Port wine stain demonstrates vascular ectasia but no increase in numbers of dermal blood vessels. Original magnification 40×

–– Histologic

°° Ectatic post-capillary venules °° Thin-walled vessels °° No inflammation

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Fig.  2.2  Widely ecstatic vessels are present in the papillary and superficial reticular dermis in port wine stains. Original magnification 100×

• Angiokeratoma –– Clinical

°° Acquired telangiectasia °° Epidermal hyperplasia is secondary °° Mibelli type – multiple telangiectasias on dorsa and sides °° °° °°

of fingers Fordyce type – multiple telangiectasias on scrotum Associated with Fabry’s disease – multiple angiokeratomas, renal disease Angiokeratoma circumscriptum is probably a true hemangioma (not a telangiectasia) – is probably misnamed

–– Histologic (Figs. 2.3 and 2.4)

°° Dermal papillae expanded by dermal capillaries °° Epidermal acanthosis with elongated rete ridges engulf°°

ing ectatic vessels Deeper vessels may rarely be involved

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Fig. 2.3  Ectatic vessels are located high in the papillary dermis and surrounded by acanthotic epidermis in angiokeratoma. Original magnification 40×

Fig. 2.4  The superficial, ecstatic vessels in angiokeratoma are usually congested and often thrombosed. Original magnification 100×

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• Venous lake –– Clinical

°° Slowly enlarging ectatic vascular lesion usually in elderly men with marked sun exposure

–– Histologic (Fig. 2.5)

°° Dilated vessel, usually filled with erythrocytes and often thrombosed surrounded by marked solar elastosis

• Intravascular Papillary Endothelial Hyperplasia (IVPEH) –– Clinical

°° Also known as Masson’s lesion °° Tender-painful red-blue dermal nodule, often sudden appearance and growth

–– Histologic (Figs. 2.6 and 2.7)

°° Proliferation of endothelial cells confined to lumen of °° °°

larger, thrombosed vessel Papillary infoldings may resemble angiosarcoma, but no mitoses or cellular atypia Represents a recanalized, thrombosed blood vessel

Fig.  2.5  A venous lake consists of a single ecstatic vessels in the superficial dermis, often surrounded by marked solar elastosis. Original magnification 40×

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Fig. 2.6  Intravascular papillary endothelial hyperplasia is a proliferation of endothelial cells confined to within the lumen of a vessel. Original magnification 40×

Fig. 2.7  Higher magnification demonstrates a florid proliferation of endothelial cells forming interanastamosing channels and extravasated erythrocytes in intravascular papillary endothelial hyperplasia. Original magnification 200×

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• Hemangiomas (Table 2.3) • Acquired capillary hemangioma –– Clinical

°° Small, red lesions acquired in adolescence and later in life °° Associated with increased estrogens, liver disease –– Histologic (Fig. 2.8)

°° Proliferation of dilated capillaries in the superficial dermis Table 2.3  Hemangiomas Acquired capillary hemangioma Infantile capillary hemangioma Cavernous hemangioma Verrucous hemangioma Lobular capillary hemangioma (pyogenic granuloma) Arteriovenous hemangioma Acquired tufted hemangioma Targetoid hemangioma (hobnail hemangioma)

Fig.  2.8  Capillary hemangioma is characterized by a proliferation of bland appearing blood vessels in the superficial portion of the dermis. These vessels may be fully congested with erythrocytes. Original magnification 100×

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• Infantile capillary hemangioma –– Clinical

°° Usually present within days of birth and grow rapidly for °° °°

up to a year May involute in up to 75% of cases, usually starting at about age 5 Usually in area surrounding parotid gland, but can grow to involve airways and to be life-threatening

–– Histologic (Fig. 2.9)

°° Early lesions – marked cellularity, may have jig-saw °° °° °°

puzzle-like appearance at low magnification Difficult to find vessels – very small Mitoses are abundant Older lesions with less cellularity and more prominent vessels

• Lobular capillary hemangioma (pyogenic granuloma) –– Clinical

°° Rapid onset of exophytic red nodule

Fig. 2.9  Juvenile (infantile) capillary hemangioma demonstrates a markedly cellular proliferation with scattered blood vessels that are often devoid of erythrocytes. Original magnification 200×

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°° Usually ulcerated °° Most common on fingers, mucous membranes, but can occur anywhere

°° Increased numbers associated with pregnancy °° Can occur in any age patient –– Histologic (Figs. 2.10 and 2.11)

°° Collarette of rete ridges surrounds proliferation of wellformed small vessels

°° Feeder vessel at deep margin ramifies into many smaller vessels

°° Endothelial cell mitoses and mild cytologic atypia may be present

°° Infiltrate of inflammatory cells most prominent at surface where ulceration is common

Fig. 2.10  Lobular capillary hemangioma (pyogenic granuloma) is characterized by an exophytic proliferation of small blood vessels surrounded by an epidermal collarette. Original magnification 40×

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Fig. 2.11  Lobular capillary hemangioma demonstrates many small blood ­vessels with a proliferation of spindle-shaped cells between the vessels. Inflammatory cells may also be present. Original magnification 200×

• Acquired tufted angioma (angioblastoma) –– Clinical

°° Benign, progressive angiomatosis most common in chil°° °°

dren and younger adults Slowly enlarging erythematous macules Usually on trunk and upper extremities

–– Histologic (Figs. 2.12 and 2.13)

°° °° °° °°

Cellular lobules dispersed throughout the reticular dermis Ovoid or spindle-shaped cells without atypia Cleft-like luminal spaces Masses of cells protrude into and distort surrounding thin-walled vessels

• Targetoid hemosiderotic hemangioma –– Clinical

°° Most common in young to middle-aged men °° Usually single, on trunk and proximal extremities °° Central papular area with centrifugal areas of bronze discoloration

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Fig. 2.12  Acquired tufted angioma demonstrates a lobular pattern of dermal involvement. Original magnification 20×

Fig.  2.13  The lobules consist of angulated blood vessels surrounded by ­spindle-shaped cells in acquired tufted angioma. Original magnification 100×

–– Histologic (Figs. 2.14 and 2.15)

°° Vascular spaces lined by plump endothelial cells with °° °°

papillary projections into lumen Abundant hemosiderin deposits, especially laterally Poorly circumscribed and infiltrative growth pattern at periphery

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Fig.  2.14  Targetoid hemosiderotic hemangioma demonstrates thin vessels with prominent endothelial cells and surrounding hemosiderin. Original ­magnification 200×

Fig.  2.15  Targetoid hemosiderotic hemangioma (hobnail hemangioma) ­demonstrates prominent endothelial cell protrusion into the lumen in a ­hobnail-like pattern. Original magnification 400×

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• Lymphangiomas (Table 2.4) • Lymphangioma circumscriptum –– Clinical

°° Grouped vesicular papules, often on flank and thighs °° May appear fluid filled or dark (if hemorrhagic and thrombosed)

–– Histologic (Fig. 2.16)

°° Indistinguishable from angiokeratoma except if vessels °°

are devoid of erythrocytes Epidermal collarette surrounds ectatic vessels in papillary dermis

• Non-hemangiomatous tumors (Table 2.5) Table 2.4  Lymphangiomas Lymphangioma circumscriptum Cystic hygroma Acquired progressive lymphangioma

Fig. 2.16  Thin-walled vessels, often containing serum but few cells, are present in the superficial dermis in lymphangioma circumscriptum. There is often an epidermal collarette. Original magnification 200×

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Table 2.5  Non-hemangiomatous tumors Angiolymphoid hyperplasia with eosinophilia (ALHE) Spindle cell hemangioendothelioma Glomus tumor (glomangioma) Hemangiopericytoma

• ALHE –– Clinical

°° °° °° °°

One or several erythematous papules, nodules Most common around ears and on face Young to middle-aged adults Synonymous with epithelioid hemangioma

–– Histologic (Figs. 2.17–2.19)

°° Abundant small vessels with swollen endothelial cells, °° °°

often occluding lumen – difficult to identify as vessels in some cases Dense inflammatory infiltrate of lymphocytes and eosinophils surrounding vascular proliferation Often completely filling dermis, may be germinal centers present

Fig. 2.17  Angiolymphoid hyperplasia with eosinophilia demonstrates a marked inflammatory infiltrate at lowest magnification. Original magnification 40×

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Fig. 2.18  At high magnification, swollen endothelial cells may make vessels appear to be small granulomas in angiolymphoid hyperplasia with ­eosinophilia. The percentage of eosinophils present in the infiltrate is highly variable. Original magnification 400×

Fig.  2.19  In some cases of angiolymphoid hyperplasia with eosinophilia, there are many eosinophils surrounding the thickened blood vessels. Original magnification 400×

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• Spindle cell hemangioendothelioma –– Clinical

°° °° °° °° °°

May be reactive, and not neoplastic 50% of cases in people <25 Single or multiple, but multiple confined to single region Hands and feet most frequent Local recurrence after removal

–– Histologic

°° Three major components Thin-walled cavernous vessels that may contain thrombi Solid area of spindle cells with slit-like vascular spaces (like Kaposi’s sarcoma) Plump endothelial cells in groups or lining vascular spaces – intracytoplasmic vacuoles

°° Minimal cytologic atypia or mitotic activity • Glomus tumor –– Clinical

°° Erythematous to blue nodules, most common on extremities

°° Tender/painful –– Histologic (Fig. 2.20)

°° Normal blood vessels surrounded by proliferation of °° °° °°

bland, uniform appearing cells with central dark nuclei and relatively scant cytoplasm Cells express smooth muscle actin “Glomangioma” is variant with concomitant proliferation of vessels and glomus cells Glomangiosarcoma – very rare

• “Malignant” vascular tumors (Table 2.6) • Kaposi’s sarcoma –– Clinical

°° Four subtypes Classic – men – fifth to seventh decades, E. European Jews, lower extremities, long chronic course

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Fig. 2.20  Glomus tumors are characterized by a proliferation of monomorphous, cuboidal cells with small, dark, central nuclei surrounding small blood vessels. Original magnification 400× Table 2.6  “Malignant” vascular tumors Angiosarcoma Kaposi’s sarcoma

African (endemic) – marked male predominance, can resemble classic type or involve nodes, also frequent EBV infection in these patients Immunosuppressive – younger patients, no male predominance, tumors appear with treatment and abate with cessation, more aggressive than classic – may result in death from GI hemorrhage HIV associated – intravenous drug abusers and homosexual men, 10% of AIDS patients, widespread lesions, mucosal involvement, not usually cause of death

°° All associated with HHV-8 infection –– Histologic (Figs. 2.21–2.24)

°° Patch – irregular vascular spaces surrounding pre-existing vessels, around appendages, between collagen bundles; lymphocytes and plasma cells

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Fig.  2.21  Patch-stage Kaposi’s sarcoma is characterized by a sometimes subtle proliferation of endothelial cells forming slit-like vascular spaces in the superficial to mid-dermis. Original magnification 100×

Fig.  2.22  Normal vessels are often surrounded by the slit-like vessels and increased numbers of endothelial cells in Kaposi’s sarcoma. Extravasation of erythrocytes is commonly seen. Original magnification 400×

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Fig. 2.23  In nodular lesions of Kaposi’s sarcoma, the proliferation of endothelial cells may be quite dense but there is little cytologic pleomorphism, often despite brisk mitotic activity. Original magnification 400×

Fig.  2.24  Degenerating erythrocytes may appear as small pink globules within vessels or in the surrounding dermis in Kaposi’s sarcoma. Original magnification 600×

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°° Plaques and tumors – dermal proliferation of interlacing bundles of spindle cells and poorly defined vascular spaces; variable nuclear pleomorphism, rare mitoses, extravasated erythrocytes, hyaline globules

• Angiosarcoma –– Clinical

°° Head and neck type Elderly patients, M > F Single, blue – violaceous nodules and plaques 15% 5-year survival

°° Arising in lymphedematous limbs (Stewart–Treves) 12.5 years post-surgery

°° Post-irradiation 10–20 years post-irradiation

Fig.  2.25  Angiosarcoma is characterized by a proliferation of angulated, interanastamosing channels throughout the dermis. The early lesions may be subtle. Original magnification 100×

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Fig. 2.26  The interanastamosing channels are lined by prominent protruding endothelial cells in angiosarcoma. Original magnification 400×

Fig. 2.27  In some cases, the proliferating endothelial cells may be markedly spindly in shape. Original magnification 100×

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Fig. 2.28  In other cases, the endothelial cells may demonstrate pronounced atypia and have an epithelioid morphology, making it difficult to determine the nature of the malignant process. Original magnification 200×

–– Histologic (Figs. 2.25–2.28)

°° Poorly circumscribed proliferation of interanastamosing °° °° °° °°

vascular spaces Vessels lined with atypical endothelial cells May be solid areas Dense lymphocytic infiltrate in some cases may obscure vascular proliferation Well-differentiated can resemble benign angiomatous process, poorly differentiated can be difficult to identify as vascular

Chapter 3

Histiocytic Proliferations

• Histiocytic proliferations −− X-histiocytoses – Langerhans cell histiocytoses (LCH) −− Non-X histiocytoses • Langerhans cell histiocytosis −− −− −− −− −−

Letterer–Siwe disease Hand–Schuller–Christian disease Eosinophilic granuloma Congenital self-healing reticulohistiocytosis Indeterminate cell disorder

• Langerhans cell histiocytosis −− Proliferation of Langerhans cells −− Distinction between subtypes is not sharp (nor important) −− Letterer–Siwe °° Clinical Infants Fever, anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy 80% with cutaneous lesions – first sign Papules and petechiae – may be scaly Extensive, involving face, scalp, trunk Resembles seborrheic dermatitis or Darier’s disease Poor prognosis B.R. Smoller, K.M. Hiatt, Dermal Tumors: The Basics, DOI: 10.1007/978-3-642-19085-8_3, © Springer-Verlag Berlin Heidelberg 2011

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−− Hand–Schuller–Christian disease °° Clinical Diabetes insipidus, exophthalmos, bony defects Other organs may be involved Cutaneous lesions in about 30% of cases Plaques with ulceration mainly in mouth, anogenital region, axillae Rarely, xanthematous, yellow lesions May resemble Letterer–Siwe clinically (rare) 30% mortality without treatment

−− Eosinophilic granuloma °° Clinical Least severe form Lesions are few or solitary Mostly bone lesions, diabetes insipidus may be present Skin only rarely involved – lesions resemble other subtypes

Fig.  3.1  Langerhans cell histiocytosis showing a dense papillary dermal infiltrate of histiocytosis with marked epidermotropism

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Fig.  3.2  The dermal infiltrate in Langerhans cell histiocytosis is accompanied by numerous eosinophils in this case

Fig. 3.3  Langerhans cell histiocytosis showing diffuse expression of CD1a

−− Histologic (Figs. 3.1–3.3) °° Proliferative lesions Abundant infiltrate of Langerhans cells close to epidermis with marked exocytosis and spongiosis Cells may be atypical Variable numbers of eosinophils in infiltrate

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°° Granulomatous lesions Seen with infiltrated plaques Aggregates of Langerhans cells extending deep into dermis and subcutis Giant cells may be present Variable numbers of eosinophils −− Xanthomatous lesions °° Only in Hand–Schuller–Christian subtype °° Abundant foam cells seen in conjunction with other patterns °° Can also be foreign body or Touton-type giant cells • Congenital self-healing reticulohistiocytosis −− Clinical °° °° °° °°

Present at birth or within weeks Multiple scattered papules and nodules Rarely solitary lesion All resolve within 12 months (usually within 2–3)

−− Histologic (Figs. 3.4 and 3.5) °° Abundant large giant cells with extensive eosinophilic cytoplasm °° Can see “ground glass” cytoplasm °° Admixture of lymphocytes, neutrophils, eosinophils °° Occasional foam cells °° Exocytosis and spongiosis °° Mitotically active −− Histogenesis °° °° °° °°

Langerhans cell proliferation Cells express CD1 and S100 Demonstrate Birbeck granules on electron microscopy Clonality demonstrated in many cases

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Fig.  3.4  Congenital self-healing reticulohistiocytosis shows epidermotropism and spongiosis

Fig.  3.5  Giant cells with eosinophilic cytoplasm with “ground glass” appearance are seen in the dermal infiltrate in congenital self-healing reticulohistiocytosis

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• Indeterminate Cell Proliferative Disorder −− No characteristic clinical or histologic features −− Previously regarded as “nodular non-X histiocytosis” or “generalized eruptive histiocytoma” −− Dermis filled with S100+, OKT6+ cells that do not contain Birbeck granules – incompletely developed Langerhans cells? • Benign Non-X histiocytoses (Table 3.1) • Reticulohistiocytosis (multicentric) −− Clinical Cutaneous nodules associated with polyarthritis Usually in middle-aged women Lasts for about 8 years Destructive arthritis, mostly in interphalangeal joints Skin-colored papules on head and hands 50% with oral lesions Underlying malignancy in 25% of cases, thyroid disease in 15%, hypercholesterolemia in 33% °° May be solitary (reticulohistiocytoma) – no systemic associations

°° °° °° °° °° °° °°

−− Histologic (Figs. 3.6 and 3.7) °° Dense infiltrate of multinucleated and mononuclear histiocytes in superficial and mid dermis °° Histiocytes with pale, ground glass eosinophilic cytoplasm

Table 3.1  Benign non-X histiocytoses Juvenile xanthogranuloma (see Chap. 4) Reticulohistiocytosis (solitary and multiple) Xanthoma disseminatum Benign cephalic histiocytosis Verruciform xanthoma Sinus histiocytosis with massive lymphadenopathy (Rosai–Dorfman disease)

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Fig. 3.6  A dense dermal infiltrate fills the superficial reticular and papillary dermis in reticulohistiocytoma

Fig. 3.7  The infiltrate in reticulohistiocytoma is composed of large cells with pale, eosinophilic cytoplasm

°° °° °° °°

Plasma cells and eosinophils may be present Overlying epidermis thinned Fibrosis in late lesions Cells are S100 negative

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• Xanthoma disseminatum −− Clinical °° Adult onset °° Red-brown papules and xanthomatous plaques °° Symmetrical, flexural surfaces and intertriginous regions °° 40% with mucous membrane involvement °° Normolipemic °° 40% with diabetes insipidus °° Good prognosis −− Histologic (Figs. 3.8 and 3.9) °° Dermal histiocytes with foamy cytoplasm °° Inflammatory infiltrate admixed with occasional eosinophils °° Numerous Touton-type giant cells °° Indistinguishable from JXG histologically • Benign cephalic histiocytosis −− Clinical °° °° °° °° °° °°

Onset during first 2 years of life M = F Many small yellow-red papules on face, neck, ears Trunk and extremities involved later May regress by age 4 without scarring No systemic anomalies described

−− Histologic °° °° °° °° °° °°

Well-demarcated, superficial infiltrate Atrophic epidermis infiltrated with histiocytes Histiocytes with pale, glassy cytoplasm Eosinophils not prominent Cells are S100 negative Comma-shaped bodies in 5–30% of histiocytes on EM – not specific

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Fig. 3.8  The xanthomatous plaques of xanthoma disseminatum show numerous histiocytes in the papillary dermis with a sparse inflammatory infiltrate consisting of lymphocytes and scattered eosinophils

Fig.  3.9  Multinucleate Touton-type giant cells and cells with abundant foamy cytoplasm make up the infiltrate in xanthoma disseminatum

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• Verruciform xanthoma −− Clinical °° Solitary verrucous lesion, most common in oral cavity or on genitals °° Also occurs as secondary lesion in association with conditions with marked epidermal hyperplasia (epidermal nevus, ILVEN) −− Histologic (Figs. 3.10 and 3.11) °° Elongated rete ridges °° Papillary dermis distended with foam cells pushed up against the dermal epidermal junction °° Uniform population of cells – minimal associated inflammation • Sinus histiocytosis with massive lymphadenopathy (Rosai– Dorfman disease) −− Clinical °° °° °° °° °°

Benign condition Massive cervical lymphadenopathy 10% of cases with skin involvement Most common site for extranodal disease Multiple papules, nodules

Fig. 3.10  Verruciform xanthoma shows an acanthotic epidermis with elongated rete. There are numerous foamy cells filling the papillary dermal tips

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−− Histologic (Figs. 3.12–3.14) °° Polymorphous dermal infiltrate with many histiocytes, some with foamy cytoplasm; Touton giant cells °° Emperipolesis (lymphophagocytosis and erythrophago­ cytosis)

Fig. 3.11  The papillary dermal tips in verruciform xanthoma are filled with cells with abundant foamy cytoplasm

Fig.  3.12  Sinus histiocytosis with massive lymphadenopathy shows a vaguely nodular dermal dense mixed infiltrate

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Fig. 3.13  Higher power of sinus histiocytosis with massive lymphadenopathy shows collections of histiocytosis with foamy cytoplasm accompanied by a dense lymphohistiocytic infiltrate

Fig. 3.14  Perivascular plasma cells are a characteristic feature of sinus histiocytosis with massive lymphadenopathy

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°° Plasma cells collaring blood vessels lined with swollen endothelial cells °° Histiocytes are S100+ • Malignant histiocytic proliferations −− Histiocytic cytophagic panniculitis – better known as subcutaneous panniculitis-like T cell lymphoma (at least in the majority of cases previously diagnosed as histiocytic cytophagic panniculitis) – see Chap. 1

 

Chapter 4

“Fibrohistiocytic” Proliferations

• Fibrocytic lesions –– Scar °° Normal scar °° Hypertrophic °° Keloid –– Fibrous papule °° Angiofibroma • Hypertrophic scar vs. keloid –– Clinical °° Initially identical °° Red, raised plaques with firm surface °° Hypertrophic scars flatten within years and do not extend beyond the original scar °° Keloids persist and enlarge beyond original scar • Keloid –– Clinical °° Familial predisposition °° More common in African American than Caucasian population °° Rubinstein–Taybi syndrome – spontaneous keloids during adolescence associated with microcephaly, mental retardation, breaking of nose, broadening of terminal phalanges of thumbs and great toes B.R. Smoller, K.M. Hiatt, Dermal Tumors: The Basics, DOI: 10.1007/978-3-642-19085-8_4, © Springer-Verlag Berlin Heidelberg 2011

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–– Histologic (Figs. 4.1–4.4)

°° Hypertrophic scar vs. keloid: spectrum on microscopy °° Whorls and nodules of thickened collagen bundles – scant in hypertrophic scar, majority in keloids °° Collagen bundles are thickened, more hyalinized °° May be perpendicular to skin surface – unusual in normal scar formation or in unaffected dermis • Fibrous papule (Table 4.1) • Fibrous papule of the nose –– Clinical °° Most common on nose, but can occur anywhere (mainly face) °° Almost always single °° Dome-shaped, skin-colored papule up to about 5 mm

Fig. 4.1  Hypertrophic scar shows a dense collagen deposition in the dermis

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Fig.  4.2  Hypertrophic scar on higher power shows the thickened collagen bundles arranged in haphazard array

Fig. 4.3  Keloid, similar to hypertrophic scar, shows dense collagen ­deposition. However the collagen is thick and eosinophilic

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Fig. 4.4  This higher power image of keloid shows the comparison of the thick eosinophilic collagen compared to the adjacent normal dermal collagen Table 4.1  Variants of fibrous papule Fibrous papule of the nose Angiofibroma (adenoma sebaceum) Pearly penile papule Subungual fibroma (Koenan’s tumor)

–– Histologic (Figs. 4.5 and 4.6)

°° Papillary dermal fibrosis (appears as if reticular dermal collagen is overgrowing the papillary dermis) °° Concentric perifollicular fibrosis °° Ectatic blood vessels °° Stellate fibroblasts °° Occasionally slight increase in overlying epidermal melanocytes °° Dermal dendritic cells express factor XIIIa • Angiofibroma –– Histologically identical to fibrous papule –– Part of tuberous sclerosis constellation

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Fig. 4.5  Fibrous papule is composed of ecstatic superficial dermal vessels with concentric collagen deposition around the follicle and in the papillary dermis

Fig. 4.6  Many fibroblasts in the dermis of a fibrous papule show stellate forms

–– Tuberous sclerosis

°° Autosomal dominant °° Triad of mental retardation, epilepsy, and angiofibromas (adenoma sebaceum)

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°° May also see fibromas of face, scalp, subungium °° Shagreen patches – collagenomas °° Ash-leaf macules – often earliest manifestation (at birth or shortly thereafter) Ash leaf macules – normal numbers of melanocytes with decreased melanin production

°° Gliomas (calcified) in brain and retina °° Rhabdomyomas of heart °° Angiomyolipomas of kidneys (tend to be bilateral) • Pearly penile papule –– 1–2 mm papules along corona of penis –– Histologically identical to angiofibroma/fibrous papule of the nose • Miscellaneous fibrous conditions –– Fibrous hamartoma of infancy Acquired digital fibrokeratoma Recurrent infantile digital fibroma Myofibromatosis Nodular fasciitis

–– –– –– ––

• Fibrous hamartoma of infancy –– Clinical °° Presents within a year of birth °° Slight male predominance °° Occurs on shoulders, axilla, upper arm °° Rapidly growing 3–5 cm nodule –– Histologic (Figs. 4.7–4.9) °° Poorly circumscribed proliferation with three components Cellular fibrous tissue with spindle-shaped fibroblasts arranged in an organoid pattern Loosely arranged bundles of collagen with rounded, immature appearing fibroblasts resembling neural tissue Variable amounts of mature fat cells

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Fig. 4.7  Fibrous hamartoma of infancy is composed of a poorly ­circumscribed proliferation of fibroblasts and mature fat cells

Fig. 4.8  This section of fibrous hamartoma of infancy shows a cellular fibroblast proliferations surrounded by loosely arranged collagen and immature fibroblasts resembling neural tissue admixed with mature fat

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Fig.  4.9  Both the cellular and less cellular areas of fibrous hamartoma of infancy are composed of spindled cells lacking significant atypia and mitoses

• Acquired digital fibrokeratoma –– Clinical °° Solitary, round, firm, hyperkeratotic projection on finger or toe (rarely palm or sole) °° Usually in adults °° Differential diagnosis of supernumerary digit –– Histologic (Fig. 4.10)

°° Hyperkeratosis, acanthosis °° Thick, interwoven bundles of collagen oriented perpendicular to skin surface °° Only thin, scant elastic tissue fibers persist °° Loss of cutaneous appendages • Recurrent infantile digital fibroma –– Clinical °° Single or multiple nodules on fingers or toes °° Usually occur during first year of life or rarely later in childhood °° Rarely exceed 2 cm in diameter °° 75% recur during childhood

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Fig.  4.10  Acquired digital fibroma shows acanthotic acral-type skin with a vaguely papillomatous epithelium. Lack of adnexal structures and thick ­collagen in bundles perpendicular to the surface are seen in this lesion

–– Histologic (Figs. 4.11–4.13)

°° Numerous spindle-shaped cells in dermis °° Collagen in interlacing bundles – may extend into subcutis °° Eosinophilic cytoplasmic inclusion bodies in fibroblasts – often perinuclear °° Inclusions resemble erythrocytes – best seen with Masson’s (purple) or phosphotungstic acid-hematoxylin (PTAH) (deep red) –– Immunostains

°° Stains with smooth muscle actin antibodies °° Cells are myofibroblasts °° Infantile digital myoblastoma has been suggested as a name for these tumors

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Fig.  4.11  Recurrent infantile digital fibroma shows a dermal spindle cell proliferation

Fig. 4.12  Interlacing fascicles of fibroblasts is present in the dermis of this recurrent infantile digital fibroma

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Fig.  4.13  Eosinophilic perinuclear cytoplasmic inclusions (arrows) are ­characteristic of recurrent infantile digital fibroma

• Myofibromatosis –– Clinical °° Superficial – nodules confined to skin, subcutis, skeletal muscles, and bone – good prognosis °° Generalized – visceral nodules obstruct vital organs – 80% mortality within first few months °° Nodules appear at birth and continue to appear °° Spontaneous involution of superficial and deep lesions within first year –– Histologic (Fig. 4.14)

°° Well-circumscribed proliferations of spindle-shaped cells without atypia °° Arranged in short fascicles °° Collagen not abundant, areas with mucoid stroma °° Virtually all cells are myofibroblasts • Nodular fasciitis –– Clinical

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Fig.  4.14  Myofibromatosis is composed of a relatively well-circumscribed nodule of short fascicles of spindled cells, lacking atypia

°° Most common in young adults (10–50) °° Male = female incidence °° Most common on forearm, but can occur anywhere °° 75% with rapidly growing lesion (<4 weeks) °° Tenderness may be present °° History of trauma in minority °° Nodules, usually <3 cm °° Do not recur, even if incompletely excised –– Histologic (Figs. 4.15 and 4.16) °° Occur in subcutis or fascia – subcutaneous ones are wellcircumscribed °° Spindle, plump, or stellate fibroblasts with vesicular nuclei and prominent nucleoli – some multinucleated cells °° Vaguely storiform pattern with myxoid matrix °° Proliferation of small capillaries and intermixed inflammatory cells °° Zones with increased cellularity °° 1–2 mitoses/HPF in myxoid areas – no atypical ones

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Fig. 4.15  A hypercellular area of nodular fasciitis showing scattered mitoses and myxoid stroma

Fig. 4.16  A less cellular area of nodular fasciitis showing plump and stellate fibroblasts

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–– Variants (Figs. 4.17 and 4.18)

°° Proliferative fasciitis – abundant giant cells °° Proliferative myositis – intramuscular analog °° Cranial fasciitis – infants and children, on scalp

Fig.  4.17  Proliferative fasciitis shows areas of increased cellularity, as in nodular fasciitis

Fig. 4.18  Numerous large cells with abundant eosinophilic cytoplasm, resembling ganglion cells, are seen in proliferative fasciitis

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Table 4.2  Benign Fibrohistiocytic proliferations Dermatofibroma Sclerotic fibroma Fibrous histiocytoma Angiomatoid variant of fibrous histiocytoma Juvenile xanthogranuloma Giant cell tumor of tendon sheath Atypical fibroxanthoma

°° Paraosteal fasciitis – arises from periosteum of long bones °° Intravascular fasciitis – arises from walls of small- to medium-sized arteries and veins • Benign fibrohistiocytic proliferations (Table 4.2) • Dermatofibroma –– Clinical °° Single or multiple red-brown indurated nodules °° Usually in adults °° Mostly on extremities °° Characteristic dimpling sign °° Rare on palms or soles °° May persist or rarely involute –– Histologic (Figs. 4.19–4.22) °° Epidermal hyperpigmentation and elongation of rete ridges in 80% of cases °° Spindle-shaped cells coursing singly between collagen bundles °° Storiform pattern °° Poorly demarcated °° Clumped collagen (appears keloidal) at periphery °° Located in central reticular dermis, may extend into septa of subcutis °° Often a Grenz zone °° Paucicellular in center of lesion, more cellular at periphery in well-developed lesions

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Fig. 4.19  Dermatofibroma showing a cellular dermal infiltrate with an overlying grenz zone and epithelial hyperplasia with increased basilar pigmentation

Fig.  4.20  The cellular infiltrate of a dermatofibroma intercalates and traps collagen fibers at the periphery of the infiltrate

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Fig. 4.21  Cytologic atypia and mitoses may be seen in dermatofibroma

Fig. 4.22  Large multinucleated cells, such as these, may be seen in dermatofibroma

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°° Occasional “monster” cells (large multinucleated) in atypical dermatofibromas °° Old lesions may be fibrotic, much less cellular • Sclerotic fibroma –– Clinical °° Controversial if this entity is distinct from sclerotic dermatofibroma °° Associated with Cowden’s syndrome °° Firm, dome-shaped, skin-colored papule °° Usually 3–5 mm –– Histologic (Fig. 4.23) °° Dermal nodule comprised of thick bands of hypereosinophilic, thickened collagen bundles in whirled pattern °° Also known as “plywood” fibroma referring to microscopic appearance °° Slight increase in dermal fibroblasts

Fig. 4.23  Sclerotic fibroma shows paucicellular collagen deposition in a pattern reminiscent of wood grain

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• Fibrous histiocytoma –– Probably identical tumor to dermatofibroma –– No distinct clinical features –– Increased numbers of histiocytes, often lipid-laden –– Multinucleated cells common • Angiomatoid fibrous histiocytoma –– Clinical °° °° °° °° °°

Intermediate biologic potential Extremities of children and young adults Slowly growing Recurrence may occur 1% metastasize

–– Histologic (Figs. 4.24–4.26)

°° Unencapsulated, well-circumscribed °° Spindled to ovoid cells °° Blood-filled cavernous spaces

Fig.  4.24  Angiomatoid fibrous histiocytoma is a well-circumscribed ­proliferation of spindle and ovoid cells in the deep dermis

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Fig.  4.25  Cavernous blood-filled spaces are characteristically seen in angiomatoid fibrous histiocytoma along with a lymphoplasmacytic inflammatory infiltrate

Fig. 4.26  Cytologic atypia and mitoses in angiomatoid fibrous histiocytoma are not associated with biologic behavior

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°° A mild to brisk lymphoplasmacytic infiltrate may also be present. °° Pleomorphism and mitoses may be seen, but not associated with behavior • Juvenile xanthogranuloma –– Clinical °° Often in children, but can occur at any age. Hence the proposal to drop “juvenile” from the name. °° 30% present at birth °° 2–5 mm red-yellow papules °° May be multiple, retro-orbital °° Unclear if this entity is extensively lipidized variant of fibrous histiocytoma or has some other pathogenesis °° May be associated with neurofibromatosis and café-aulait macules –– Histologic (Figs. 4.27–4.29)

°° Superficial reticular dermal accumulation of histiocytes °° Many Touton giant cells with lipid at periphery of cytoplasm

Fig. 4.27  (Juvenile) xanthogranuloma is a polygonal infiltrate in the superficial dermis

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Fig. 4.28  Many Touton-type multinucleate cells are seen at the periphery of (juvenile) xanthogranuloma

Fig. 4.29  Partially and completely lipidized cells are typically seen in (juvenile) xanthogranuloma

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°° Admixed lymphocytes and eosinophils in most cases °° Early lesions may not display Touton giant cells (or lipid) °° Late lesions – mainly fibrotic °° Histiocytes are S100 negative • Giant Cell Tumor of Tendon Sheath (GCTTS) –– Clinical °° Subcutaneous nodule attached to tendinous sheath of fingers, hands, wrists °° 1–3 cm °° Relatively asymptomatic °° Benign –– Histologic (Figs. 4.30 and 4.31) °° Accumulation of histiocytes with intracellular lipid °° Osteoclast-like giant cells – usually abundant °° Hemorrhage and hemosiderin often present

Fig. 4.30  Giant cell tumor of tendon sheath shows a proliferation of polygonal cells with bland nuclei extending from a fibrous band or tendon

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Fig. 4.31  Numerous multinucleate osteoclast-like giant cells may be seen in giant cell tumor of tendon sheath. Hemosiderin is also present in this case

• Atypical fibroxanthoma (AFX) –– Clinical °° Head and neck of elderly patients °° More common in men °° Rarely occur in sites of previous x-ray therapy °° Probably histogenetically related to fibrous histiocytoma °° Do not metastasize if truly confined to dermis –– Histologic (Figs. 4.32–4.34) °° Very cellular tumor extends up to overlying epidermis, may ulcerate °° Markedly pleomorphic, atypical cells – resemble both fibroblasts and histiocytes °° Centered in upper half of reticular dermis °° Abundant mitoses °° Label with histiocyte markers and focally with smooth muscle actin

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Fig. 4.32  Atypical fibroxanthoma shows a pleomorphic spindle and polygonal cell infiltrate in the dermis, abutting the overlying epidermis

Fig.  4.33  Numerous mitoses, including atypical forms, are seen in atypical fibroxanthoma

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Fig.  4.34  Striking pleomorphism and variably lipidized cells characterized atypical fibroxanthoma

• Malignant fibrohistiocytic proliferations –– Dermatofibrosarcoma protuberans (DFSP) –– Malignant fibrous histiocytoma • Dermatofibrosarcoma protuberans –– Clinical °° °° °° °° °° °°

Slowly growing, indurated plaque with nodular component May ulcerate Most common on trunk, then extremities Rare on scalp, neck, face; not reported on palms and soles 10% in children – has been reported as congenital 5% of cases metastasize, an average of 6 years post initial excision

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Fig. 4.35  Dermatofibrosarcoma protuberans is composed of a bland dermal spindle cell proliferation extending into the subcutaneous tissue

–– Histologic (Figs. 4.35 and 4.36)

°° Resembles “grade 0 fibrosarcoma” °° Uniform population of spindle cells with minimal collagen formation °° Grow in storiform pattern °° More cellular than dermatofibroma, but minimal cytologic atypia

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Fig.  4.36  The spindle cells in dermatofibrosarcoma protuberans intercalate around individual adipocytes in the subcutaneous tissue

°° Mitoses relatively slight °° Extension into fat lobules (not just septa) °° May de-differentiate with foci of frank fibrosarcoma °° Tumor cells express CD34 • Malignant fibrous histiocytoma (MFH) (Figs. 4.37–4.39) –– Unclear if this tumor exists or is simply an undifferentiated malignant mesenchymal neoplasm –– Most common on thighs and buttocks

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Fig. 4.37  Malignant fibrous histiocytoma shows a dermal tumor with striking cytologic atypia

Fig. 4.38  Areas of malignant fibrous histiocytoma show fascicles of spindled cells with striking pleomorphism and mitoses

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Fig. 4.39  Some areas of malignant fibrous histiocytoma show polygonal cells with striking atypia, multinucleation, mitoses, and lipidization

–– Same histologic features as atypical fibroxanthoma, but extends deep into dermis and subcutis –– Subcutaneous tumors – 65% 5 year survival –– Deeper tumors – 40% 5 year survival –– Metastasize to lungs and regional nodes

Chapter 5

Tumors of Fat, Nerve, and Smooth Muscle

• Adipocytic tumors (Table 5.1) • Lipoma –– Clinical °° °° °° °°

Most common on trunk and upper extremities Usually in middle-aged to elderly patients 1–4 cm asymptomatic nodules Associated syndromes: Madelung’s disease – benign symmetric lipomatosis Dercum’s disease – adiposis dolorosa – multiple painful lipomas Familial multiple lipomatosis

–– Histologic features (Fig. 5.1)

°° °° °° °° °°

Sheets of encapsulated fat separated by thin fibrous septa Adipocytes are fully mature cells Mitoses are not apparent No lipoblasts or cellular atypia Lipomas often display cytogenetic abnormalities in 12q13-15

• Angiolipoma –– Clinical °° Earlier onset than lipomas °° Painful B.R. Smoller, K.M. Hiatt, Dermal Tumors: The Basics, DOI: 10.1007/978-3-642-19085-8_5, © Springer-Verlag Berlin Heidelberg 2011

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Lipoma Angiolipoma Spindle cell lipoma Pleomorphic lipoma Liposarcoma

Fig.  5.1  Lipoma demonstrates an encapsulated proliferation of mature ­adipocytes. Original magnification 100×

°° No associated cytogenetic abnormalities °° Subcutaneous nodules –– Histologic features (Fig. 5.2) °° Encapsulated aggregates of mature adipocytes °° Variable numbers of clustered, well-formed blood vessels °° Thrombosed vessels commonly found • Spindle cell lipoma –– Clinical °° Occurs on shoulders and back °° Mainly in middle-aged men

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Fig. 5.2  Angiolipoma has an admixture of small blood vessels (many of which may be thrombosed) and mature adipocytes. Original magnification 100×

°° Slowly growing, asymptomatic subcutaneous nodules °° Tumors demonstrate monosomy 16 or partial loss of 16q –– Histologic features (Fig. 5.3) °° Circumscribed, but not encapsulated °° Arise in subcutis, usually °° Mixture of mature adipocytes and spindle cells °° Spindle cells poorly organized °° Minimal nuclear pleomorphism °° Mitoses not abundant °° Lipoblasts NOT seen °° Spindle cells express vimentin, CD34 • Pleomorphic lipoma –– Clinical °° °° °° °°

Subcutaneous nodules usually on shoulders, back Up to 5 cm in diameter Most common in elderly men Loss of 16q, similar to spindle cell lipomas

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Fig. 5.3  Spindle cell lipoma may demonstrate minimal fat differentiation and is characterized by “ropey” collagen. Original magnification 200×

–– Histologic features (Figs. 5.4 and 5.5)

°° Circumscribed growth of adipocytes, spindle-shaped cells, collagen and myxoid matrix °° Multinucleated giant cells and lipoblasts present °° “Floret” cells (overlapping nuclei) are characteristic °° Rare mitoses °° Spindle cells express CD34 and/or factor XIIIa • Liposarcoma –– Debatable if these occur in the skin –– Semantic – tumors with the appearance of liposarcomas in the skin do not metastasize so many advocate avoiding this term –– May extend into subcutis from deeper tissues – mainly in thighs and buttocks • Neural tumors (Table 5.2) • Traumatic neuroma –– Clinical °° Results from severing of a nerve °° Occurs at sites of trauma and in scars

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Fig.  5.4  Pleomorphic lipoma demonstrates large, atypical cells that may resemble lipoblasts. Original magnification 200×

Fig. 5.5  Multinucleated forms and atypical adipocytes are present throughout pleomorphic lipoma. Original magnification 400×

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Traumatic neuroma Neurofibroma Schwannoma (neurilemmoma) Palisaded encapsulated neuroma Myxoid neurothekeoma Cellular neurothekeoma

°° Firm, oval nodules in subcutis or deeper °° Often painful –– Histologic features (Fig. 5.6) °° Irregular proliferation of nerve bundles surrounded by fibrosis °° May resemble onion skins with concentric circles of nerves and fibrous tissue °° Multiple axons present in these bundles • Neurofibroma –– Clinical °° Solitary or multiple skin-colored papules °° More common on upper trunk

Fig.  5.6  Traumatic neuroma demonstrates lobulated whorls of neural ­elements. Original magnification 100×

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°° Soft and may have “button hole sign” – invagination with pressure °° Often do not appear until puberty °° May be associated with neurofibromatosis, but vast majority are not °° NF-1 gene is on long arm of chromosome 17 –– Histologic features (Figs. 5.7 and 5.8)

°° Epidermis often flattened °° Proliferation of spindle-shaped cells coursing in a light pink matrix °° Minimal cytologic atypia °° Mitoses not apparent °° Differ from dermatofibromas: Less eosinophilic stroma Less nuclear pleomorphism Lack of epidermal hyperpigmentation and no elongation of rete ridges

°° “Plexiform” designation used with great caution on cutaneous neurofibromas

Fig.  5.7  A proliferation of spindle-shaped cells, often coursing in myxoid stroma is present within the dermis in neurofibroma. Neurofibromas are not encapsulated and rarely demonstrates overlying epidermal hyperplasia. Original magnification 40×

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Fig.  5.8  Spindle-shaped cells with tapered ends are present in a myxoid stroma in neurofibroma. Original magnification 200×

• Schwannoma (neurilemmoma) –– Clinical °° Slow growing, usually solitary °° Up to one-third are painful °° Usually are 2–4 cm. °° Can be seen with neurofibromatosis °° Also occur within viscera –– Histologic features (Figs. 5.9 and 5.10) °° Encapsulated dermal proliferations of spindle-shaped cells °° Cellular areas admixed with more myxoid regions °° Pseudopalisading regions very characteristic °° Mitoses very rare °° No cytologic atypia • Palisaded encapsulated neuroma (PEN) –– Clinical °° Slow-growing painless nodules °° Usually on face of middle-aged people

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Fig. 5.9  Schwannoma demonstrates densely cellular areas admixed with less cellular areas with myxoid stroma. Original magnification 100×

Fig.  5.10  Verocay bodies with pseudopalisading are characteristic of ­schwannomas. Original magnification 100×

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°° About 0.5 cm in diameter °° May be identical to traumatic neuromas –– Histologic features (Figs. 5.11 and 5.12) °° Single nodule in dermis °° Well-developed nerve fascicles coursing in myxoid stroma °° No fibrous sheaths like in traumatic neuromas °° Loose myxoid stroma may cause resemblance to neurofibroma on superficial aspects of tumor nodules • Neurothekeoma –– Clinical °° Most common on face and upper extremities °° Not associated with neurofibromatosis °° Two types (histologically): Myxoid Cellular

Fig.  5.11  Palisaded encapsulated neuroma is not truly encapsulated, but ­demonstrates a sharply circumscribed proliferation of neural elements. Original magnification 20×

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Fig.  5.12  Mature neural elements in a lobulated and whorled pattern c­ haracterize palisaded encapsulated neuroma. Original magnification 100×

°° Myxoid type occur in older aged patients than the cellular variant °° Dome-shaped nodules up to 3 cm in diameter °° Unknown etiology – myxoid may be related to schwannomas; cellular variant still unknown –– Histologic features

°° Myxoid (Figs. 5.13 and 5.14) Multilobulated, not encapsulated Located in reticular dermis and may extend into subcutis Spindle-shaped and stellate cells in swirling pattern Concentric layering Myxoid stroma °° Cellular (Fig. 5.15) Nests and fascicles in multilobular pattern Hyalinized stroma between lobules Concentric pattern to nests of cells Mitoses may be present Cells may be hyperchromatic

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Fig.  5.13  Myxoid neurothekeoma is characterized by lobules of mucin ­containing spindled and epithelioid cells. Original magnification 40×

Fig. 5.14  Myxoid neurothekeoma demonstrates large pools of mucin containing cells that are not easily characterized based upon morphology. Original magnification 100×

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Fig. 5.15  Cellular neurothekeoma is characterized by lobules of spindled cells with ample eosinophilic cytoplasm. It is difficult to classify the nature of the cells on routine histologic sections. Original ­magnification 200×

–– Immunostains °° Myxoid S100 (and vimentin) positive EMA often positive °° Cellular S100 negative May stain with smooth muscle actin and/or neuron-­ specific enolase NKI/C3 (melanocyte marker) also positive sometimes • Additional neural crest neoplasms –– Granular cell tumor –– Meningioma –– Merkel cell carcinoma (see separate Chapter in volume 3)

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• Granular cell tumor –– Clinical °° °° °° °° °° °° °° °°

Frequent on tongue and in oral mucosa More common in women More common in non-Caucasians Usually arise in fifth to sixth decades but can appear in children Asymptomatic, skin-colored nodules up to 2 cm 10% multiple Multiple rarely associated with neurofibromatosis 1–3% malignant – >5  cm, vascular invasion, necrosis, rapid growth

–– Histologic (Figs. 5.16 and 5.17)

°° Pseudoepitheliomatous hyperplasia °° Sheets of large cells with abundant, eosinophilic, granular cytoplasm °° Granules are PAS+, diastase resistant °° Displace dermal stroma and surround dermal appendages

Fig. 5.16  Granular cell tumor demonstrates sheets of large cells with abundant granular cytoplasm throughout the dermis, with overlying epidermal hyperplasia. Original magnification 200×

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Fig. 5.17  The cytoplasm is eosinophilic and contains prominent granules in cells that comprise a granular cell tumor. Original magnification 400×

–– Immunohistochemistry

°° Almost always strongly and diffusely S100+ °° Also stain with PGP9.5 (neural) and NKI/C3 °° Negative for myoglobin and glial fibrillary acidic protein (GFAP) • Meningioma –– Clinical °° Scalp, forehead, and paravertebral °° May be present at birth or appear in adulthood °° Rarely associated with neurofibromatosis –– Histologic (Fig. 5.18)

°° Involve subcutis and less commonly dermis °° Irregular strands of meningothelial cells set in fibrous stroma °° May also have cellular whorls and even psammoma bodies

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Fig.  5.18  Meningioma is characterized by a lobular proliferation of banal appearing epithelioid and spindle-shaped cells with ample cytoplasm and the occasional psammoma body (see arrow). Original magnification 400×

• Malignant neural neoplasms –– Malignant peripheral nerve sheath tumor • Malignant peripheral nerve sheath tumor –– Previously known as neurosarcoma, neurofibrosarcoma, malignant schwannoma –– Rare –– Probably arise from malignant transformation of neurofibromas –– > 50% of patients with this tumor have neurofibromatosis –– 2–3 year mean survival –– Histologic (Fig. 5.19) °° Spindle cell proliferation with wavy bundles °° Alternating areas of dense cellularity with more myxoid areas °° Can be cellular with abundant mitoses and pleomorphism °° Can show divergent differentiation with other sarcomatous elements °° Express S100, neuron-specific enolase, neurofilament

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Fig.  5.19  Malignant peripheral nerve sheath tumor demonstrates a spindle cell proliferation with abundant, pleomorphism and bizarre, atypical forms. Original magnification 200×

• Smooth muscle proliferations –– Smooth muscle hamartoma –– Leiomyoma °° Angioleiomyoma °° Piloleiomyoma –– Leiomyosarcoma • Smooth muscle hamartoma –– Clinical °° May present with hyperpigmented patch with irregular surface –– Histologic features

°° Poorly circumscribed, diffuse proliferation of perfectly mature smooth muscle bundles °° Usually localized to superficial portion of reticular dermis

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°° No mitotic activity of cytologic atypia °° Often associated with enlarged terminal hairs and epidermal hyperplasia and hyperpigmentation (Becker’s nevus) • Leiomyoma –– Clinical °° Occasionally painful/tender dermal nodule with overlying hyperpigmentation and superficial dimpling (pseudoDarier’s sign) °° Most common on extremities –– Histologic features (Figs. 5.20 and 5.21) °° Poorly circumscribed, diffuse proliferation of perfectly mature smooth muscle bundles

Fig. 5.20  Leiomyoma is characterized by a proliferation of eosinophilic fascicles coursing in bundles throughout the dermis. Original magnification 40×

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Fig. 5.21  Spindle-shaped cells coursing in fascicles, with little nuclear atypia or pleomorphism characterize leiomyoma. Original magnification 400×

°° Usually more cohesive and circumscribed than smooth muscle hamartoma, but often difficult to distinguish based on histologic changes –– Angioleiomyoma °° Bundles of smooth muscle (eosinophilic with “cigar shaped nuclei”) surrounding large dermal blood vessel °° Usually in deeper dermis °° Well circumscribed °° No cytologic atypia °° Mitoses infrequent –– Piloleiomyoma °° Bundles of smooth muscle more diffusely scattered throughout the superficial portion of the reticular dermis °° Not obviously centered around arrector pili muscles °° No cytologic atypia °° Mitoses infrequent

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Fig.  5.22  Leiomyosarcoma demonstrates marked nuclear pleomorphism, bizarre atypical forms, and abundant mitoses within the proliferation of smooth muscle cells

• Leiomyosarcoma –– Histologic features (Fig. 5.22) °° Controversial as these tumors rarely, if ever, metastasize when dermally based °° De-differentiation with recurrence of leiomyoma has been reported °° Infiltrative growth pattern °° Bundles of smooth muscle cells demonstrating nuclear pleomorphism °° Abundant mitoses (exact numerical requirement not as clearly defined as leiomyosarcomas in other organs) °° Necrosis may be present (unlike in leiomyomas)

Chapter 6

Cutaneous Metastases

• Carcinoma metastatic to the skin (Tables 6.1 and 6.2) –– Occurs in 0.7–9.0% of all patients with cancer –– Most frequent sites on the body for metastases to appear:

–– –– –– –– ––

°° At sites of incision of primary tumors °° Three-fourths of metastases are on head and neck, despite only one-fourth surface area °° Extremities uncommon site for metastases Most common presentation is that of a painless, skin-colored, freely mobile cutaneous nodule; ulceration uncommon Indurated plaques, erysipelas-like patterns also seen Survival: 1–34 months following identification of cutaneous metastasis One-third of patients develop cutaneous metastases within 6 months of initial diagnosis One-half develop metastases within 1 year of initial diagnosis and >90% within 5 years

• Metastatic breast carcinoma –– Clinical °° Seen in 23.9% of patients with breast carcinoma °° Presenting sign in 3.5% of such patients °° Different clinical patterns: inflammatory (resembles erysipelas), en cuirasse (resembles morphea), telangiectatic pattern, nodular metastases, alopecia neoplastica, Paget’s disease B.R. Smoller, K.M. Hiatt, Dermal Tumors: The Basics, DOI: 10.1007/978-3-642-19085-8_6, © Springer-Verlag Berlin Heidelberg 2011

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Table 6.1  Most common carcinomas metastatic to skin in women Most frequent primary sources in women

Percent of total cutaneous metastases in women

Breast Colon Melanoma Lung Ovary

69 9 5 4 4

Table 6.2  Most common carcinomas metastatic to skin in men Most frequent primary sources in men

Percent of total cutaneous metastases in men

Lung Colon Melanoma Oral squamous cell carcinoma Stomach Kidney Esophagus

24 19 13 12 6 6 3

–– Histologic features (Figs. 6.1–6.4)

°° Inflammatory – tumor cells confined largely to dermal lymphatics °° Telangiectatic tumor altering blood flow leads to widely dilated and congested blood vessels °° Alopecia neoplastic – blood vascular spread to scalp °° Nodular-type most likely to be confused with primary eccrine adenocarcinoma °° May be separate nodules or diffusely infiltrating entire dermis °° Atypical cells prominent at low magnification °° Ductular differentiation may be present • Metastatic renal cell carcinoma –– Clinical °° Hemorrhagic tumor nodule °° Scalp is most common site (28% of cases)

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Fig. 6.1  Inflammatory breast carcinoma shows dermal lymphatics distended with tumoral cells

Fig. 6.2  Metastatic lobular breast carcinoma shows individual tumor cells in a single file infiltrating between collagen bundles

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Fig. 6.3  Cutaneous metastasis of ductal breast carcinoma shows nodules of tumor cells with ductal differentiation

Fig. 6.4  The ductal differentiation in metastatic ductal carcinoma can be so extensive as to mimic a primary eccrine carcinoma

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°° More common in men °° Ulceration uncommon –– Histologic features (Figs. 6.5 and 6.6) °° Highly vascular neoplasm °° Clear cytoplasm, some mitoses and cytologic atypia °° Differential diagnosis includes pyogenic granuloma which has spindle-shaped cells in surrounding stroma and less cytologic atypia. –– Immunohistochemical features °° RCC stains with EMA and cytokeratin cocktails, as does pyogenic granuloma °° RCC often S100 positive °° RCC stains with renal cell carcinoma antibodies and with PAX-2 –– Prognosis

°° Metastatic renal cell carcinoma – rarely can spontaneous regress with cure °° 5 -year survival with known primary RCC and a single cutaneous metastasis is 35%

Fig. 6.5  Metastatic renal cell carcinoma is characteristically highly vascular

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Fig. 6.6  The tumoral cells of metastatic renal cell carcinoma are often clear, or vacuolated

• Metastatic neuroendocrine carcinoma –– Histologic features °° Identical to Merkel cell carcinoma (Fig. 6.7) –– Immunohistochemical features °° Cytokeratin 20 (and CAM 5.2) stains almost all MCC with either punctate cytoplasmic pattern or membranous pattern °° Less frequent, but similar pattern can be seen in neuroendocrine carcinomas °° Thyroid transcription factor 1 – not seen in MCC, present in most metastatic small cell carcinomas from the lung and other sources • Melanoma – primary vs. metastatic –– Clinical features °° Individual lesions may be identical °° Primary lesions identified in >95% of cases, so history is crucial

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Fig.  6.7  Metastatic neuroendocrine carcinoma is histologically identical to primary cutaneous neuroendocrine carcinoma (Merkel cell carcinoma) with small cells having open chromatin, minimal cytoplasm, and numerous mitoses

°° Multiple lesions favor metastasis over primary °° Proximal spread along cutaneous lymphatics also helpful °° Diffuse melanosis another pattern (rare) –– Histologic features (Fig. 6.8) °° Usual histology is a dermal nodule, often well-circumscribed without epidermal changes °° Differentiation from primary melanomas usually relatively straightforward °° Epidermotropic metastatic melanomas recently described °° Intraepidermal atypical melanocytes do not extend lateral to the dermal involvement in most cases – some exceptions reported °° Nesting pattern and Pagetoid invasion °° Inflammatory response often pronounced in these types of metastases °° Involvement may be limited to superficial dermis in nesting pattern °° Small size to these types of lesions also reported

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Fig. 6.8  Metastatic melanoma has cytologic features and immunohistochemical staining consistent with melanoma. An in situ component is not present in the overlying epidermis

°° Often vascular and lymphatic invasion seen °° May see thinning of epidermis or epidermal hyperplasia °° Can be seen in lesions <3 mm in diameter • Metastatic squamous cell carcinoma –– Clinical features °° Usually not the presenting sign of cancer °° Nodal involvement often present °° Direct extension from underlying nodes often seen –– Histologic features °° Only diagnostic feature is lack of connection to overlying epidermis °° This can be seen with some primary cutaneous lesions (sampling) °° May see tumor spreading up to epidermis, making it look primary

Further Reading

Chapter 1 Lymphoma classification systems Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009; 523–531. Kempf W, Sander CA. Classification of cutaneous lymphomas – an update. Histopathology 2010; 56: 57–70. Robson A. Immunocytochemistry and the diagnosis of cutaneous lymphoma. Histopathology 2010; 56: 71–90. Weaver J, Mahindra AK, Pohlman B, Jin T, His ED. Non-mycosis fungoides cutaneous T-cell lymphoma: reclassification according to the WHO-EORTC classification. J Cutan Pathol 2010; 37: 516–524.

Mycosis fungoides Diwan H, Ivan D. CD8-positive mycosis fungoides and primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphoma. J Cutan Pathol 2009; 36: 390–392. Duvic M, Foss FM. Mycosis fungoides: pathophysiology and emerging therapies. Semin Oncol 2007; 34(suppl 5): S21-8. B.R. Smoller, K.M. Hiatt, Dermal Tumors: The Basics, DOI: 10.1007/978-3-642-19085-8, © Springer-Verlag Berlin Heidelberg 2011

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Guitart J, Kennedy J, Ronan S, Chmiel JS, Hseigh YC, Variakojis D. Histologic criteria for the diagnosis of mycosis fungoides: proposal for a grading system to standardize pathology reporting. J Cutan Pathol 2001; 28: 174–183. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, Burg G, Cerroni L, Dreno B, Glusac E, Guitart J, Heald PW, Kempf W, Knobler R, Lessin S, Sander C, Smoller BR, Telang G, Whittaker S, Iwatsuki K, Obitz E, Takigawa M, Turner ML, Wood GS; International Society for Cutaneous Lymphoma. Defining early mycosis fungoides. J Am Acad Dermatol 2005; 53: 1053–1063 Smoller BR. Mycosis fungoides: what do/do not we know? J Cutan Pathol 2008; 35: suppl 2: 35–39.

Sezary syndrome Kim EJ, Lin J, Junkins-Hopkins JM, Vittorio CC, Rook AH. Mycosis fungoides and sezary syndrome: an update. Curr Oncol Rep 2006; 8: 376–386. Klemke CD, Brade J, Weckesser S, Sachse MM, Booken N, ­Neumaier M, Goerdt S, Nebe TC. The diagnosis of Sezary ­syndrome on peripheral blood by flow cytometry requires the use of multiple markers. Br J Dermatol 2008; 159: 871–880.

Mycosis fungoides variants Boone SL, Guitart J, Gerami P. Follicular mycosis fungoides: a histopathologic, immunohistochemical and genotypic review. G Ital Dermatol Venereol 2008; 143: 409–414. Gerami P, Guitart J. The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides. Am J Surg Pathol 2007; 31: 1430–1438. Kempf W, et  al. Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous ­Lymphoma Histopathology Task Force Group of the European

Further Reading

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­ rganization For Research and Treatment of Cancer (EORTC). O Arch Dermatol. 2008 Dec;144(12):1609–17 Lee J, Viakhireva N, Cesca C, Lee P, Kohler S, Hoppe RT, Kim YH. Clinicopathologic features and treatment outcomes in WoringerKolopp disease. J Am Acad Dermatol 2008; 59: 706–712.

Anaplastic large cell lymphoma Guitart J, Querfeld C. Cutaneous CD30 lymphoproliferative disorders and similar conditions: a clinical and pathologic prospective on a complex issue. Semin Diagn Pathol 2009; 26: 131–140. Kadin ME. Pathobiology of CD30+ cutaneous T cell lymphomas. J Cutan Pathol 2006; 33 suppl. 1: 10–17. Kempf W. CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants and simulators. J Cutan Pathol 2006; 33 (suppl 1): 58–70.

Lymphomatoid papulosis De Souza A, Camilleri MH, Wada DA, Appert DL, Gibson LE, el-Azhary RA. Clinical, histopathologic, and immunophenotypic features of lymphomatoid papulosis with CD8 predominance in 14 pediatric patients. J Am Acad Demratol 2009; 61: 993–1000. El Shabraw-Caelen L, Kerl H, Cerroni L. Lymphomatoid papulosis: reappraisal of Clinicopathologic presentation and classification into subtypes A, B and C. Arch Dermatol 2004; 140: 441–447. Guitart J, Querfeld C. Cutaneous CD30 lymphoproliferative disorders and similar conditions: a clinical and pathologic prospective on a complex issue. Semin Diagn Pathol 2009; 26: 131–140. Kunishige JH, McDonald H, Alvarez G, Johnson M, Prieto V, ­Duciv M. Lymphomatoid papulosis and associated lymphomas: a retrospective case series of 84 patientss. Clin Exp Dermatol 2009; 34: 576–581.

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Subcutaneous panniculitis-like T cell lymphoma Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009; 523–531. Lozzi GP, Massone C, Citarella L, Kerl H, Cerroni L. Rimming of adipocytes by neoplastic lymphocytes: a histopathologic feature not restricted to subcutaneous T-cell lymphoma. Am J Dermatopathol 2006; 28: 9–12. Willemze R, Jansen PM, Cerroni L, Berti E, Santucci M, Assaf C, Canninga-can Dijk MR, Carlotti A, Geerts ML, Hahtola S, Hummel M, Jeskanen L, Kempf W, Massone C, Ortiz-Romero PL, Paulli M, Petrella T, Ranki A, Peralto JL, Robson A, Senff NJ, Vermeer MH, Wechsler J, Whittaker S, Meijer CJ: EORTC Cutaneous Lymphoma Group. Blood 2008: 111: 838–845.

NK/T cell lymphoma, nasal type Schwartz EJ, Molina-Kirsch H, Zhao S, Marinelli RJ, Warnke RA, Natkunam Y. Immunohistochemical characterization of nasal-type extranodal NK/T-cell lymphoma using a tissue microarray: an analysis of 84 cases. Am J Clin Pathol 2008; 130: 343–351.

Hematodermic neoplasm Herling M, Jones D. CD4+/CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic cells. Am J Clin Pathol 2007; 127: 687–700. Martin JM, Nicolau MJ, Galan A, Fernanxez-Izquierdo A, Ferrer AM, Jorda E. CD4+/CD56+ hematodermic neoplasm: a precursor haematological neoplasm that frequently first presents in the skin. J Eur Acad Dermatol Venereol 2006; 20: 1129–1132.

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Marginal zone lymphoma Ferenczi K. Primary cutaneous marginal zone B-cell lymphomas: are they different from other extranodal marginal zone B-cell lymphomas? J Cutan Pathol 2009; 36: 715–717. Gerami P, Wickless SC, Querfeld C, Rosen ST, Kuzel TM, Guitart J. Cutaneous involvement with marginal zone lymphoma. J Am Acad Dermatol 2010; 63: 142–145. Takino H, Li C, Hu S, Huo TT, Geissinger E, Muller-Hermelink HK, Kim B, Swerdlow SH, Inagaki H. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathological study of cases from Asia, Germany and the United States. Mod Pathol 2008; 21: 1517–1526.

Follicular lymphoma Bogle MA, Riddle CC, Triana EM, Jones D, Duvic M. Primary cutaneous B-cell lymphoma. J Am Acad Dermatol 2005; 53: 479–484. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009; 523–531. Kerl H, Cerroni L. Primary cutaneous B-cell lymphomas: then and now. J Cutan Pathol 2006: 33 (suppl 1): 1–5.

Primary cutaneous B cell lymphoma, leg type Senff NJ, Willemze R. The applicability and prognostic value of the new TMN classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome: results on a large cohort of primary cutaneous B-cell lymphomas and comparison with the system used by the Dutch Cutaneous Lymphoma Group. Br J Dermatol 2007; 157: 1205–1211.

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Wiesner T, Obenauf AC, Geigl JB, Vallant EM, Speicher MR, FinkPuches R, Kerl H, Cerroni L. 9p21 deletion in primary cutaneous large B-cell lymphoma, leg type, may escape detection by standard FISH assays. J Invest Dermatol 2009; 129: 1149–1155.

Intravascular B-cell lymphoma Eros N, Karolyi Z, Kovacs A, Takacs I, Radvanyi G, Kelenyi G. Intravacular B-cell lymphoma. J Am Acad Dermatol 2002; 47 (5 suppl): S260-262. Kong YY, Dai B, Sheng WQ, Yang WT, Wang CF, Kong JC, Shi DR. Intravascular large B-cell lymphoma with cutaneous manifestations: a Clinicopathologic, immunophenotypic and molecular study of three cases. J Cutan Pathol 2009; 36: 865–870.

Chapter 2 Port wine stain North PE, Mihm MC Jr. Histopathological diagnosis of infantile hemangioma and vascular malformations. Facial Plast Surg Clin North Amer 2001; 9: 505–524. Smoller BR, Rosen S. Port-wine stains. A disease of altered neural modulation of blood vessels? Arch Dermatol 1986; 122: 177–179.

Hereditary hemorrhagic telangiectasia Braverman IM. Ultrastructure and organization of the cutaneous microvaculature in normal and pathologic states. J Invest Dermatol 1989; 93 (2 suppl): 2S-9S.

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Angiokeratoma Hunt SJ, Santa Cruz DJ. Vascular tumors of the skin: a selective review. Semin Diagn Pathol 2004; 32: 506–511. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part III. Malignant neoplasms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as ­vascular neoplasms. J Am Acad Dermatol 1998; 38: 143–175.

Venous lake Requena L, Sangueza OP. Cutaneous vascular anomalies. Part I. Hamartomas, malformations and dilation of preexisting vessels. J Am Acad Dermatol 1997; 37: 523–549.

Capillary hemangioma Kalof AN, Cooper K. D2-40 immunohistocyemistry –so far! Adv Anat Pathol 2009; 16: 62–64. North PE, Waner M, Buckmiller L, James CA, Mihm MC Jr. Vascular tumors of infancy and childhood: beyond capillary hemangioma. Cardiovasc Pathol 2006; 15: 303–317. Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997; 37: 887–919.

Infantile hemangioma North PE, Mihm MC Jr. Histopathological diagnosis of infantile hemangioma and vascular malformations. Facial Plast Surg Clin North Amer 2001; 9: 505–524. North PE, Waner M, Buckmiller L, James CA, Mihm MC Jr. Vascular tumors of infancy and childhood: beyond capillary hemangioma. Cardiovasc Pathol 2006; 15: 303–317.

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Cavernous hemangioma Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997; 37: 887–919. Tsang WY, Chan JK, Fletcher CD. Recently characterized vascular tumours of skin and soft tissues. Histopathology 1991; 19: 489–501.

Verrucous hemangioma Tennant LB, Mulliken JB, Perez-Atayde AR, Kozakewich HP. Verrucous hemangioma revisited. Pediatr Dermatol 2006; 23: 208–215.

Lobular capillary hemangioma (pyogenic granuloma) Demir Y, Demir S, Aktepe F. Cutaneous lobular capillary hemangioma induced by pregnancy. J Cutan Pathol 2004; 31: 77–80. Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997; 37: 887–919.

Arteriovenous hemangioma Enjoiras O. Classification and management of the various superficial vascular anomalies: hemangiomas and vascular malformations. J Dermatol 1997; 24: 701–710. Garzon MC, Huang JT, Enjoiras O, Frieden IJ. Vascular malformations: Part 1. J Am Acad Dermatol 2007; 56: 353–370.

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Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997; 37: 887–919.

Acquired tufted hemangioma Prieto VG, Shea CR. Selected cutaneous vacular neoplasms. A review. Dermatol Clin 1999; 17: 507–520. Tsang WY, Chan JK, Fletcher CD. Recently characterized vascular tumours of skin and soft tissues. Histopathology 1991; 19: 489–501.

Targetoid hemangioma (hobnail hemangioma) Prieto VG, Shea CR. Selected cutaneous vacular neoplasms. A review. Dermatol Clin 1999; 17: 507–520. Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997; 37: 887–919. Vion B, Frenk E. Targetoid hemosiderotic hemangioma. Dermatology 1992; 184: 300–302.

Lymphangioma circumscriptum Bauer BS, Kernahan DA, Hugo NE. Lymphangioma circumscriptum— a clinicopathological review. Ann Plast Surg 1981; 7: 318–326. Heller M, Mengden S. Lymphangioma circumscriptum. Dermatol Online J 2008; 15: 27.

Angiolymphoid hyperplasia with eosinophilia Garzon MC, Huang JT, Enjoiras O, Frieden IJ. Vascular malformations: Part 1. J Am Acad Dermatol 2007; 56: 353–370.

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Spindle cell hemangioendothelioma Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997; 37: 887–919. Tsang WY, Chan JK, Fletcher CD. Recently characterized vascular tumours of skin and soft tissues. Histopathology 1991; 19: 489–501.

Glomus tumor/glomangioma Mentzel T, Hugel H, Kutzner H. CD34-positive glomus tumor: Clinicopathologic and immunohistochemical analysis of six cases with myxoid Stromal changes. J Cutan Pathol 2002; 29: 421–425. Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997; 37: 887–919.

Hemangiopericytoma Fletcher CD, McKee PH. Sarcomas—a clinicopathological guide with particular reference to cutaneous manifestation. III. Angiosarcoma, malignant hemangiopericytoma, fibrosarcoma, and synovial sarcoma. Clin Exp Dermatol 1985; 10: 332–349. Hardisson D, Cuevas-Santos J, Contreras F. Solitary fibrous tumor of the skin. J Am Acad Dermatol 2002; 46 (supple case reports): S37-40. Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997; 37: 887–919.

Angiosarcoma Abrahamson TG, Stone MS, Piette WW. Cutaneous angiosarcoma. Adv Dermatol 2001; 17: 279–299.

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Fletcher CD, McKee PH. Sarcomas—a clinicopathological guide with particular reference to cutaneous manifestation. III. Angio­ sarcoma, malignant hemangiopericytoma, fibrosarcoma, and synovial sarcoma. Clin Exp Dermatol 1985; 10: 332–349. Hunt SJ, Santa Cruz DJ. Vascular tumors of the skin: a selective review. Semin Diagn Pathol 2004; 21: 166–218.

Kaposi’s sarcoma Goh SG, Calonje E. Cutaneous vascular tumours: an update. Histopathology 2008; 52: 661–673. Hunt SJ, Santa Cruz DJ. Vascular tumors of the skin: a selective review. Semin Diagn Pathol 2004; 21: 166–218. Wilkins K, Turner R, Dolev JC, LeBoit PE, Berger TG, Maurer TA. Cutaneous malignancy and human immunodeficiency virus disease. J Am Acad Dermatol 2006; 54: 189–206.

Chapter 3 Langerhans cell histiocytosis Hussein MR. Skin-limited Langerhans’ cell histiocytosis in children. Cancer Invest 2009; 27: 504–511. Singh A, Prieto VG, Czelusta A, McClain KL, Duvic M. Adult Langerhans cell histiocytosis limited to the skin. Dermatology 2003; 207: 157–161. Stefanato CM, Andersen WK, Calonje E, Swain FA, Borghi S, Massone L, Kowalski JV, Bhawan J. Langerhans cell histiocytosis in the elderly: a report of three cases. J Am Acad Dermatol 1998; 39: 375–378.

Congenital self-healing reticulohistiocytosis Kanitakis J, Zambruno G, Schmitt D, Cambazard F, Jacquemier D, Thivolet J. Congenital self-healing histiocytosis

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(Hashimoto-Pritzker). An ultrastructural and immunohistochemical study. Cancer 1988; 61: 508–516. Ricart J, Jimenez A, Marquina A, Villanueva A. Congenital selfhealing reticulohistocytosis: report of a case and review of the literature. Acta Paediatr 2004; 93: 426–429.

Indeterminate Cell Proliferative Disorder Manente L, Cotellessa C, Schmitt I, Peris K, Torlone G, Muda AO, Romano MC, Chementi S. Indeterminate cell histiocytosis: a rare histiocytic disorder. Am J Dermatopathol 1997; 19: 276–283. Rosenberg AS, Morgan MB. Cutaneous indeterminate cell histiocytosis: a new spindle cell variant resembling dendritic cell sarcoma. J Cutan Pathol 2001; 28: 531–537.

Reticulohistiocytosis (multicentric) Lutz FB, Gaspar TAP, Kalil-Gaspar N, Ramos-e-Slilva M. Multicentric reticulohistiocytosis. J Eur Acad Dermatol Venereol 2001; 15: 524–531. Lutz FM, Kurizky PS, Ramos-e-Silva M. Retculohistiocytosis. Dermatol Clin 2007; 25: 625–632. Tajirian AL, Malik MK, Robinson-Boston L, Lally EV. Multicentric Reticulohistiocytosis. Clin Dermatol 2006; 24: 486–492.

Xanthoma disseminatum Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M, Bucsky P, Egeler RM, Elinder G, Gadner H, Gresik M, Henter HI, Imashuki S, Janka-Schaub G, Jaffe R, Ladisch S, Nezelof C, Pritchard H. Contemporary classification of histiocytic disorders. The WHO Committee on Histiocytic/Reticulum cell proliferations. Reclassification Working Group of the HIstiocyte Society. Med Pediatr Oncol 1997; 29: 157–166.

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Newman B, Hu W, Nigro K, Gilliam AC. Aggressive histiocytic disorders that can involve the skin. J Am Acad Dermatol 2007; 56: 302–316.

Benign cephalic histiocytosis Jih DM, Salcedo SL, Jaworsky C. Benign cephalic histiocytosis: a case report and review. J Am Acad Dermatol 2002; 47: 906–913. Zelger BW, Sidorof A, Orchard G, Cerio R. Non-Langerhans cell histiocytoses. A new unifying concept. Am J Dermatopathol 1996; 18: 490–504.

Verruciform Xanthoma Nowparast B, Howell FV, Rick GM. Verruciform Xanthoma. A Clinicopathologic review and report of fifty-four cases. Oral Surg Oral Med Oral Pathol 1981; 51: 619–625. Philipsen HP, Reichart PA, Takata T, Ogawa I. Verruciform xanthoma—biological profile of 282 lesions based on a literature survey with nine new cases from Japan. Oral Oncol 2003; 39: 325–326.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol 1990; 7: 19–73.

Histiocytic cytophagic panniculitis Craig AJ, Cualing H, Thomas G, Lamerson C, Smith R. Cytophagic histiocytic panniculitis—a syndrome associated with benign and malignant pannicultiis: case comparison and review of the literature. J Am Acad Dermatol 1998; 39: 721–736.

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Chapter 4 Hypertrophic scar Liu B, Connolly MK. The pathogenesis of cutaneous fibrosis. Semin Cutan Med Surg 1998; 17: 3–11. Sahl WJ Jr, Clever H. Cutaneous scars: Part I. Int J Dermatol 1994; 33: 681–691. Sahl WJ Jr, Clever H. Cutaneous scars: Part II. J Am Acad Dermatol 1994; 33: 763–769.

Keloid Bran GM, Goessler UR, Hormann K, Riedel F, Sadick H. Keloids: current concepts of pathogenesis (review). Int J Mol Med 2009; 24: 283–293. Murray JC. Scars and keloids. Dermatol Clin 1993; 11: 697–708.

Fibrous papule Bansal C, Stewart D, Li A, Cockerell CJ. Histologic variants of fibrous papule. J Cutan Pathol 2005; 32: 424–428. Jacyk WK, Rutten A, Requena L. Fibrous papule of the face with granular cells. Dermatology 2008; 216: 56–59. Kucher C, McNiff JM. Epithelioid fibrous papule – a new variant. J Cutan Pathol 2007; 34: 571–575.

Angiofibroma Fletcher CD. Distinctive soft tissue tumors of the head and neck. Mod Pathol 2002; 15: 324–330. Zelger B. Connective tissue tumors. Recents Results Cancer Res 2002; 160: 343–350.

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Pearly penile papule Agrawal SK, Bhattacharya SN, Singh N. Pearly penile papules: a review. Inti J Demratol 2004; 43: 199–201. Ferenczy A, Richart RM, Wright TC. Pearly penile papules: absence of human papilloma virus DNA by the polymerase chain reaction. Obstet Gynecol 1991; 78: 118–122.

Fibrous hamartoma of infancy Carettto E, Dall’lgna P, Alaggio R, Siracusa F, Granata C, Ferrari A, Cecchetto G. Fibrous hamartoma of infancy: an Italian multi-­institutional experience. J Am Acad Dermatol 2006; 54: 800–803. Grynspan D, Meir K, Senger C, Ball NJ. Cutaneous changes in fibrous hamartoma of infancy. J Cutan Pathol 2007; 34: 39–43.

Acquired digital fibrokeratoma Kint A, Baran R. Histopathologic study of Koenen tumors. Are they different from acquired digital fibrokeratoma: J Am Acad Dermatol 1988; 18: 369–372. Kint A, Baran A, De Keyser H. Acquired (digital) fibrokeratoma. J Am Acad Dermatol 1985; 12: 816–821.

Recurrent infantile digital fibroma Grenier N, Liang C, Capaldi L, Ney A, Lapidus C, Schappell D, Katarincic J, Robinson-Bostom L. A range of histologic findings in infantile digital fibromatosis. Pediatr Dermatol 2008; 25: 72–75. Laskin WB, Miettinen M, Fetsch JF. Infantile digital fibroma/ fibromatosis: a clinicopathologic and immunohistochemical study of 69 tumors from 57 patients with long-term follow-up. Am J Surg Pathol 2009; 33: 1–13.

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Myofibromatosis Larralde M, Hoffner MV, Boggio P, Abad ME, Luna PC, Correa N. Infantile myofibromatosis: report of nine patients. Pediatr Dermatol 2010; 27: 29–33. Matthews MR, Cockerell CH. An historic perspective of infantile myofibromatosis. Adv Dermatol 2006; 22: 279–305.

Nodular fasciitis Krasovec M, Burg G. Nodular fasciitis (pseudotumor of the skin). Dermatology 1999; 198: 431–433. Nishi SP, Brey NV, Sanchez RL. Dermal nodular fasciitis: three case reports of the head and neck and literature review. J Cutan Pathol 2006; 33: 378–382.

Dermatofibroma Yamamoto T. Dermatofibroma: a possible model of local fibrosis with epithelial/mesenchymal cell interaction. J Eur Acad Dermatol Venereol 2009; 23: 371–375. Zelger B, Zelger BG, Burgdorf WH. Dermatofibroma- critical evaluation. Int J Surg Pathol 2004; 12: 333–344.

Sclerotic fibroma Gonzalez-Vela MC, Val-Bernal JF, Martino M, Gonzalez-Lopez MA, Garcia-Alberdi E, Hermana S. Sclerotic fibroma-like ­dermatofibroma: an uncommon distinctive variant of dermatofibroma. Histol Histopathol 2005; 20: 801–806. Lo WL, Wong CK. Soitary sclerotic fibroma. J Cutan Pathol 1990; 269–273. Requena L, Gutierrez J, Sanchez Yus E. Multiple sclerotic fibromas of the skin. A cutaneous marker of Cowden’s disease. J Cutan Pathol 1992; 19: 346–351.

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Fibrous histiocytoma Billings SD, Folpe AL. Cutaneous and subcutaneous Fibrohistiocytic tumors of intermediate malignancy: an update. Am J Demratopathol 2004; 26: 141–155. Luzar B, Calonje E. Cutaneous Fibrohistiocytic tumours—an ­update. Histopathology 2010; 56: 148–165.

Angiomatoid fibrous histiocytoma Billings SD, Folpe AL. Cutaneous and subcutaneous Fibrohistiocytic tumors of intermediate malignancy: an update. Am J Demratopathol 2004; 26: 141–155.

Juvenile xanthogranuloma Dehner LP. Juvenile xanthogranulomas in the first two decades of life: a Clinicopathologic study of 174 cases with cutaneous and extracutaneous manifestations. Am J Surg Pathol 2003; 27: 579–593. Hernandez-Martin A, Baselga E, Drolet BA, Esterly NB. ­Juvenile xanthogranuloma. J Am Acad Dermatol 1997; 36: 355–367. Moschella SL. An update of the benign proliferative monocytemacrophage and dendritic cell disorders. J Dermatol 1996; 23: 805–815.

Giant Cell Tumor of Tendon Sheath (GCTTS) Ciattaglia G, Filossa G, Bugatti L. Giant cell tumor of tendon sheath. J Am Acad Dermatol 1991; 25: 728–729. Rustin MH, Robinson TW. Giant-cell tumor of the tendon sheath— an uncommon tumour presenting to dermatologists. Clin Exp Dermatol 1989; 14: 466–468.

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Atypical fibroxanthoma (AFX) Gleason BC, Calder KM, Cibull TL, Thomas AB, Billings SD, Morgan MB, Hiatt KM, Smoller BR. Utility of p63 in the differential diagnosis of atypical fibroxanthoma and spindle cell squamous cell carcinoma. J Cutan Pathol 2009; 36: 543–547. Luzar B, Calonje E. Cutaneous Fibrohistiocytic tumours—an update. Histopathology 2010; 56: 148–165. Luzar B, Calonje E. Morphological and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls: a review. J Cutan Pathol 2010; 37: 301–309.

Dermatofibrosarcoma protuberans Mendehnhall WM, Ziotecki RA, Scarborough MT. Dermatofibrosarcoma protuberans. Cancer 2004; 101: 2503–2508. Sundram UN. Review: Dermatofibrosarcoma protuberans: histologic approach and updated treatment recommendations. Clin Adv ­Hematol Oncol 2009; 7: 406–408. Tardio JC. CD-34 reactive tumors of the skin. An updated review of an ever-growing list of lesions. J Cutan Pathol 2009; 36: 89–102.

Malignant fibrous histiocytoma (MFH) Billings SD, Folpe AL. Cutaneous and subcutaneous Fibrohistiocytic tumors of intermediate malignancy: an update. Am J Demratopathol 2004; 26: 141–155. Kamino H, Salcedo E. Histopathologic and immunohistochemical diagnosis of benign and malignant fibrous and Fibrohistiocytic tumors of the skin. Dermatol Clin 1999; 17: 487–505.

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Chapter 5 Lipoma Challis D. Atypical subcutaneous fatty tumors. Adv Anat Pathol 2000; 7: 94–99. Mentzel T. Cutaneous lipomatous neoplasms. Semin Diagn Pathol 2001; 18: 250–257.

Angiolipoma Requena L, Sangueza OP. Cutaneous vascular proliferations. Part III. Malignant neopalms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol 1998; 38: 143–175.

Spindle cell lipoma Billings SD, Folpe AL. Diagnosticlaly challenging spindle cell lipomas: a report of 34 “low fat” and “fat-free” variants. Am J Dermatopathol 2007; 29: 437–442. Duve S, Muller-Hocker J, Worret WI. Spindle-cell lipoma of the skin. Am J Dermatopathol 1995; 17: 529–533.

Pleomorphic lipoma Mentzel T. Cutaneous lipomatous neoplasms. Semin Diagn Pathol 2001; 18: 250–257.

Liposarcoma Dei Tos AP. Liposarcoma: new entities and evolving concepts. Ann Diagn Pathol 2000; 4: 252–262.

150

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Val-Bernal JF, Gonzalez-Vela MC, Cuevas J. Primary purely intradermal pleomorphic liposarcoma. J Cutan Pathol 2003; 30: 516–520.

Traumatic neuroma Argenyi ZB, Santa Cruz D, Bromley C. Comparative light­microscopic and immunohistochemical study of traumatic and palisaded encapsulated neuromas of the skin. Am J Dermatopathol 1992; 14: 504–510. Kossard S, Kumar A, Wilkinson B. Neural spectrum: palisaded encapsulated neuroma and verocay body poor dermal schwannoma. J Cutan Pathol 1999; 26: 31–36.

Neurofibroma Barbagallo JS, Kolodzieh MS, Silverberg NB, Weinberg JM. Neurocutaneous disorders. Dermatol Clin 2002; 20: 547–560. Requena L, Sangueza OP. Benign neoplasms with neural differentiation: a review. Am J Demratopathol 1995; 17: 75–96. Roos KL, Muckaway M. Neurofibromatosis. Dermatol Clin 1995; 13: 105–111.

Schwannoma (neurilemmoma) Reith JD, Goldblum JR. Multiple cutaneous plexiform schwannomas. Report of a case and review of the literature with ­particular reference to the association with types 1 and 2 neurofibromatosis and swchannomatosis. Arch Pathol Lab Med 1996; 120: 399–401. Requena L, Sangueza OP. Benign neoplasms with neural differentiation: a review. Am J Demratopathol 1995; 17: 75–96. Roos KL, Muckaway M. Neurofibromatosis. Dermatol Clin 1995; 13: 105–111.

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Palisaded encapsulated neuroma (PEN) Argenyi ZB, Santa Cruz D, Bromley C. Comparative light­microscopic and immunohistochemical study of traumatic and palisaded encapsulated neuromas of the skin. Am J Dermatopathol 1992; 14: 504–510. Dover JS, From L, Lewis A. Palisaded encapsulated neuromas. A clinicopathologic study. Arch Dermatol 1989; 125: 386–389. Kossard S, Kumar A, Wilkinson B. Neural spectrum: palisaded encapsulated neuroma and verocay body poor dermal schwannoma. J Cutan Pathol 1999; 26: 31–36.

Neurothekeoma Fetsch JF, Laskin WB, Hallman JR, Lupton GP, Mettinen M. ­Neurothekeoma: an analysis of 178 tumors with detailed ­immunohistochemical data and long-term patient follow-up ­information. Am J Surg Pathol 2007; 31: 1103–1114. Hornick JL, Fletcher CD. Cellular neurothekeoma: detailed characterization in a series of 133 cases. Am J Surg Pathol 2007; 31: 329–340.

Granular cell tumor Rejgi B, Jambhekar NA. Morphologic spectrum, immunoshistochemical analysis, and clinical features of a series of granular cell tumors of soft tissues: a study from a tertiary referral cancer center. Ann Diagn Pathol 2010; 14: 162–167. Suster S. Tumors of the skin composed of large cells with abundant eosinophilic cytoplasm. Semin Diagn Pathol 1999; 16: 162–177.

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Meningioma Hussein MR, Abdelwahed AR. Primary cutaneous meningioma of the scalp: a case report and review of literature. J Cutan Pathol 2007; 34: suppl 1: 26–28.

Smooth muscle hamartoma Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol 2002; 46: 477–490.

Leiomyoma Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol 2002; 46: 477–490. Smith G, Heidary N, Patel R, Rosenman K, Meehan SA, Kamino H, Sanchez M. Cutaneous piloleiomyomata. Dermatol Online J 2009; 15: 10.

Leiomyosarcoma Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol 2002; 46: 477–490. Hornick JL, Fletcher CD. Crieteria for malignancy in nonvisceral smooth muscle tumors. Ann Diagn Pathol 2003; 7: 60–66. Pipe J, Broers GH, Plaat BE, Hundeiker M, Otto F, Mastik MF, Hoekstra HJ, van der Graaf WT, Berg ED, Molenaar WM. The relation between histologic, tumor-biological and clinical parameters in deep and superficial leiomyosarcoma and leiomyoma. Sarcoma 2002; 6: 105–110.

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Chapter 6 Cutaneous metastases Hussein MR. Skin metastasis. A pathologist’s perspective. J Cutan Pathol 2010: 37: e1-20. Lookingbill DP, Spangler N, Sexton FM. Skin involvement as the presenting sign of internal carcinoma. A retrospective study of 7316 cancer patients. J Am Acad Dermatol 1990; 22: 19–26. Pipkin CA, Lio PA. Cutaneous manifestations of internal malignancies: an overview. Dermatol Clin 2008; 26: 1–15. Sariya D, Ruth K, Adams-McDonnell R, Cusack C, Xu X, Elenitsas R, Seykora J, Pasha T, Zhang P, Baldassano M, Lessin SR, Wu H. Clinicopathologic correlation of cutaneous metastases: experience from a cancer center. Arch Dermatol 2007; 143: 613–620.

 

Index

A Acquired capillary hemangioma, 43 Acquired digital fibrokeratoma, 80 Acquired progressive ­lymphangioma, 49 Acquired tufted angioma, 46, 47 Acquired tufted hemangioma, 46 Adenoma sebaceum, 76, 77 Anaplastic large cell lymphoma, 9–12 Angioblastoma, 46 Angiofibroma, 73, 76–78 Angiokeratoma, 39–40 Angioleiomyoma, 121 Angiolipoma, 103–104 Angiolymphoid hyperplasia with eosinophilia (ALHE), 50–51 Angiomatoid fibrous histiocytoma, 91–93 Angiosarcoma, 56–58 Angiotropic lymphoma, 33 Atypical fibroxanthoma, 96, 98, 102 B Blastic plasmacytoid dendritic cell neoplasm. See Hematodermic neoplasm Borrelia burgdorferi, 25 C Cranial fasciitis, 86 Cystic hygroma, 49

D Dermatofibroma, 87, 91 Dermatofibrosarcoma protuberans (DFSP), 98–99 E Erythroderma, 7 Extranodal NK/T cell lymphoma, 2, 18–20 F Fibrous hamartoma of infancy, 78 Fibrous histiocytoma, 91 Fibrous papule, 73, 74 G Giant cell tumor of tendon sheath, 95 Glomangioma, 52 Glomus tumor, 52 Granular cell tumor, 115–117 Granulomatous slack skin, 7 H Hemangioma, 43 Hematodermic neoplasm, 2, 20–22 Hereditary hemorrhagic ­telangiectasia, 37 Hypertrophic scar, 73, 74 I Infantile capillary hemangioma, 44

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Index

Intravascular fasciitis, 87 Intravascular papillary endothelial hyperplasia (IVPEH), 41–42 J Juvenile xanthogranuloma, 93 K Kaposis sarcoma, 52–55 Keloid, 73 Koenan tumor, 76 L Leiomyoma, 120, 121 Leiomyosarcoma, 122 Lipidized cell, 94, 98 Lipoma, 103–105 Liposarcoma, 106 Lobular capillary hemangioma (pyogenic granuloma), 45, 46 Lymphangioma, 49 Lymphangioma circumscripta, 49 Lymphoma intravascular B-cell type, 33 primary cutaneous follicular center, 26 primary cutaneous large B-cell lymphoma of the leg, 29 Primary cutaneous marginal zone, 21 Lymphomatoid papulosis, 12–16 M Malignant angioendotheliomatosis, 33 Malignant fibrous histiocytoma, 100–102 Malignant peripheral nerve sheath tumor, 118–119 Meningioma, 117–118 Metastatics breast cancer, 123–126 melanoma, 128, 130 neuroendocrine carcinoma, 128, 129

renal cell carcinoma, 124, 127, 128 squamous cell carcinoma, 130 Multinucleate cells, 91, 94, 95, 102 Mycosis fungoides, 2–7 folliculotropic, 7 granulomatous, 7 Myofibromatosis, 83 Myxoid, 113, 114 N Neurofibroma, 108, 109 Neurothekeoma, 112–115 Neurothekeoma, cellular, 113–115 NK blastic lymphoma. See Hematodermic neoplasm Nodular fasciitis, 83–84 P Pagetoid reticulosis, 7 Palisaded encapsulated neuroma, 110, 112 Paraosteal fasciitis, 87 Pearly penile papule, 78 Piloleiomyoma, 121 Pleomorphic lipoma, 105–107 Port wine stain, 37–39 Primary cutaneous CD30+ lymphoproliferative disorder, 2, 9 Proliferative fasciitis, 86 Proliferative myositis, 86 Pyogenic granuloma, 45 R Rubenstein–Taybi syndrome, 73 S Scar, 73 Schwannoma (neurilemmoma), 110, 111 Sclerotic fibroma, 90 Sezary syndrome, 2, 7–8 Smooth muscle hamartoma, 119 Spindle cell hemangioendothelioma, 52 Spindle cell lipoma, 104, 105

Index Subcutaneous panniculitis-like T cell lymphoma, 2, 16–18 Subungual fibroma, 74

Telangiectasias, 37 Traumatic neuroma, 106, 108 Tuberous sclerosis, 77

T Targetoid hemosiderotic hemangioma, 46–48

V Venous lake, 41

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