Shimizu's textbook of dermatology

Preface Welcome to Shimizu's Textbook of Dermatology. This is an upgraded edition of Japan's best-selling dermatology textbook. I spent 5 years completing the Japanese-language edition, which sold more than 10,000 copies in the first one year after publication in 2005. The popularity of the Japanese edition owes to its coverage of all the basic information necessary for dermatology practice, presented with clear descriptions and accompanied by more than 1,000 high-quality clinical photos. This is not a color atlas, but a complete textbook of dermatology for dermatologists, medical students and educators, and other medical workers. There are many similar dermatology textbooks of similar size and weight. But the unique point of this textbook is that I have included all major diseases seen in dermatology practice, while minimizing the book's size and weight by avoiding vague or excessive descriptions. I hope readers will bring this textbook with them to the clinic and the classroom. Thanks to the Internet, anyone can read any chapter as a PDF file for free. Those who wish to buy the hardcopy, with high-quality clinical photos, can order the textbook by Hokkaido University Press I hope you enjoy and appreciate Shimizu's Textbook of Dermatology as a tool for education, everyday reference and refining your dermatological expertise.

Hiroshi Shimizu July 2007

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Structure and Function of the Skin

The skin is the human body’ s its largest organ, covering 1.6 m2 of surface area and accounting for approximately 16% of an adult’s body weight. In direct contact with the outside environment, the skin helps to maintain four essential bodily functions: ① retention of moisture and prevention of permeation or loss of other molecules, ② regulation of body temperature, ③ protection of the body from microbes and harmful external influences, and ④ sensation. To understand cutaneous biology and skin diseases, it is very important to learn the structure and functions of normal human skin.

A. Skin surface The skin surface is not smooth, but is laced with multiple networks of fine grooves called sulci cutis. These can be deep or shallow. The slightly elevated areas that are surrounded by shallower areas of sulci cutis are called cristae cutis. Sweat pores fed by the sweat glands open to the cristae cutis (Fig. 1.1). The orientation of the sulci cutis, which differs depending on body location, is called the dermal ridge pattern. Fingerprints and patterns on the palms and soles, which are unique to each person, are formed by the sulci cutis. Elastic fibers also run in specific directions in deeper parts of the skin, with the direction depending on the site. Some skin diseases, such as epidermal nevus, are known to occur along specific lines distributed over the body, the Blaschko lines (Fig. 1.2). These lines are thought to be associated

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Fig. 1.2 The Blaschko lines. Many dermatological disorders appear along these lines, such as epidermal nevus and linear scleroderma (Bolognia JL, et al. J Am Acad Dermatol 1994; 31:175-90).

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crista cutis

Fig. 1.1 Appearance of the skin surface. a: Cristae cutis (triangle) and sulci cutis (arrows). b: Nevus-cell nevus along the cristae cutis. c: Sweat pores fed by sweat glands open to the cristae cutis (arrows).

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Structure and Function of the Skin

hair

arrector pili muscle sweat pore apocrine sweat gland horny cell layer

epidermal rete ridge papillary dermis subpapillary dermis epidermal basement membrane eccrine sweat gland

epidermis

dermal papilla

infundibulum

reticular dermis

dermis

sebaceous gland hair bulge

hair follicle dermal hair papilla hair bulb hair matrix

subcutaneous tissue

subcutaneous fat

muscle

fascia

Fig. 1.3 Structure of the skin. (Nakagawa H, editor. Dermatological disorders. In: Symphonia Medica Nursing (Vol.19). Nakayama-Shoten; 2001. p.3).

with the direction in which the differentiated cell clones extend during fetal skin development. Skin generally consists of a three-layer structure: the epidermis, dermis and subcutaneous tissues (Fig. 1.3). At the boundary between the epidermis and dermis are finger-like projecting structures (the dermal papillae) that project into the overlying tissue (the epidermis) (Fig. 1.30). The portion of the epidermis that projects into the dermis is called the epidermal rete ridge, and the portion of the dermis that projects into the epidermis is called the dermal papilla.

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B. Epidermis a. Structure and cells of the dermis horny cell layer (10-20 layers)

The epidermis is on average about 0.2 mm thick, and 95% of the cells composing it are epidermal keratinocytes that proliferate and divide in the epidermal basal layer and move up to the upper layers as they mature (to form cornified cells). In the epidermis, epidermal keratinocytes at different stages of maturation are arranged in layers that can be divided into four levels (Figs. 1.4 and 1.5). The period between the production of daughter epidermal cells and their exfoliation from the outer surface of the epidermis is called the turnover time, which is approximately 28 days in normal skin.

granular cell layer (2-3 layers) suprabasal cell layer (5-10 layers) basal cell layer (1 layer)

epidermal basement membrane

100 mm

Fig. 1.4 The four layers of the epidermis: basal cell layer, suprabasal cell layer, granular cell layer and horny cell layer.

1. Basal cell layer The basal cell layer is a single layer consisting of basal cells including the epidermal stem cell subpopulation. Basal cells vary in shape from cubic to columnar. They contain basophilic (or darkly staining) cytoplasm and an elliptical nucleus that is rich in chromatin. The basal cells have desmosomes (for cellcell attachment), gap junctions (for cell communication), and

cell nucleus suprabasal cell layer

basal cell layer

dermis

epidermal basement membrane

Fig. 1.5 Ultrastructural anatomy of the epidermis.

desmosome

gap junction

basement membrane

hemidesmosome

Fig. 1.6 Intracellular positions of desmosomes, gap junction and hemidesmosomes.

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Structure and Function of the Skin

horny cell layer

hemidesmosomes (for connection with the extracellular matrix and underlying basal membrane) (Fig. 1.6). Cell cytokeratins (keratin filaments, tonofilaments) are abundant in the cytoplasm of many epidermal keratinocytes and are distributed in bundles at the periphery of the nucleus, from where they distally connect with hemidesmosomes and desmosomes to form a rigid and robust cellular cytoskeleton.

2. Suprabasal cell layer horny cell layer

cornified cell envelope

keratin pattern

granular cell layer

The suprabasal cell layer is composed of five to ten layers that appear connected to each other by prickle-like structures. Suprabasal (prickle) cells are polygonal in the lower layer and flattened in the upper layers. They are larger than basal cells and contain a small amount of chromatin in their circular nucleus. The part that gives the appearance of a prickle corresponds to the desmosome (a form of intercellular bridge).

3. Granular cell layer

Fig. 1.7 Horny cell layer. horny cells

The granular cell layer is composed of two or three layers of cells containing basophilic keratohyalin granules. The cells and nuclei in the granular cell layers are even flatter than those in the suprabasal layer. Spherical lamellar granules, each with a diameter of approximately 300 nm (also known as Odland bodies or ketatosomes), can be observed in the granular cell layers by electron microscopy. The main component of lamellar granules is released into the intercellular space of horny cells as stratum corneum lipid.

4. Horny cell layer Fig. 1.8 Ultrastructural image of the epidermis between the granular cell layer and the horny cell layer, with cornified cell envelopes and lamellar granules (arrows).

The horny cell layer, also called the stratum corneum, is composed of about ten sub-layers. Enucleated dead keratinocytes become membranous and multilayered, resembling fallen leaves, and exfoliate sequentially, beginning with the outer layer, in what is commonly called grime. The horny cell layer is very thick in the palms and soles. Horny cells are flat, and their cytoplasm is filled with aggregated keratin fibers. Directly above the granular cell layer, the horny cell structure appears as an eosinophilic layer. The horny cells gradually change into membranous structures in the upper layers. By electron microscopy, the contrast between electron-dense interfibrous substance and the low-electron-dense keratin fibers is clear; this contrast is called the keratin pattern. The cell membranes are thicker in the horny cell layer than in the other layers. The lining structure is called a cornified cell envelope or a marginal band (Figs. 1.7 and 1.8). The protein, component of the cornified cell envelope, is extremely stable against physicochemical degradation.

B. Epidermis

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5. Other cells Keratinocytes account for 95% of the cells within the epidermis. The remaining 5% are melanocytes, Langerhans cells, adendritic cells and Merkel cells, which are involved in melanin formation, antigen presentation, and sensation, respectively.

b. Adhesion of keratinocytes The epidermal basement membrane plays a key role in dermalepidermal adhesion. Even when normal skin is rubbed, the epidermal basement membrane keeps the epidermis and dermis from separating. The epidermal basement membrane zone, which lies immediately under the epidermis, stains by periodic acid Schiff (PAS) under the light microscope. The complicated structure of the basal membrane includes the lamina densa (LD) and the lamina lucida (LL), which are observed by electron microscopy (Figs. 1.9 and 1.10). The lamina densa is 60 to 80 nm thick and consists mainly of fibronectins, heparan sulphate proteoglycan, type IV collagen and laminin 5 (including laminin 332). Under the electron microscope, it appears to be an electron-dense lattice network structure. Hemidesmosomes play an important role in adhesion between the basal cells and the lamina densa. Although the hemidesmosome resembles a desmosome that has been cut in half, the molecular components of hemidesmosomes and desmosomes are very different. Keratin fibers within basal cells link hemidesmosomes, to maintain and anchor the structure of the cell (Fig. 1.11). The lamina lucida includes the component laminin 332. Type XVII collagen (BP180; 180kDa bullous pemphigoid antigen) bridges the lamina lucida to connect hemidesmosomes directly with the lamina densa. Anchoring fibrils, which form semi-circular loop structures, form firmly connections around type I and III collagens in the dermis linking it to the lamina densa.

1. Adhesion between keratinocytes Epidermal keratinocytes adhere to each other by desmosomes and structures such as adherens junctions, gap junctions and tight junctions. The desmosome is composed of an attachment plaque (comprising inner and outer plaques), a structure that penetrates membranes to connect cells. The attachment plaque is mainly composed of desmoplakin, to which keratin fibers connect, to strengthen the cytoskeleton. Transmembrane proteins such as desmogleins and desmocollins are homophilically connected to the same molecules by a calcium ion dependent mechanism, which makes connections between cells possible (Fig. 1.12).

Fig. 1.9 Ultrastructural anatomy of the basement membrane zone. TF: tonofilament. HD: hemidesmosome. LL: lamina lucida. LD: lamina densa. AF: anchoring fibril.

MEMO Blister formation caused by congenital change or autoantibody deposition A congenital change or attachment of an autoantibody to the peripheral basal membrane may weaken the dermal-epidermal junction, leading to blister formation. When autoantibodies are produced against BP180 and BP230, which comprise hemidesmosomes, the disease bullous pemphigoid occurs. If a congenital abnormality is caused in K5, K14, BP180, laminin 332, or collagen type VII by genetic mutation, then epidermolysis bullosa occurs (Chapter 14). Blisters easily form after weakened epidermal intercellular adhesion resulting from production of autoantibodies against desmogleins, which are structural proteins of desmosomes; this is an autoimmune bullous disease called pemphigus.

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Structure and Function of the Skin

keratin 5/14 basal cell hemidesmosome

enlarged BP230 integrin a6 basal cell lamina densa (LD) type I/III collagen

plectin integrin

b4

lamina lucida (LL)

BP180 laminin 332 N

N

N

N N

N

basement membrane

lamina densa (LD) anchoring fibril (type VII collagen)

type I/III collagen

Fig. 1.10 Microstructure of the basement membrane zone.

keratin intermediate filaments plectin

BPAG1e erbin

a6b4integrin

BP180 CD151/PETA-3

laminins fibrin 2 NC-1 NC-1

NC-1

laminins type IV collagen nidogen fibronectin type I or II collagen in the dermis

type VII collagen

Fig. 1.11 Electron microscopy of the basement membrane zone.

The gap junction which is composed of connexin subunits, mechanism, has a structure in which cell plasma membranes associate with each other such as to leave a 2- to 3-nm space. Connexin is involved not only in connecting cells but also in transporting small molecules and ions between cells (Fig. 1.13). The cell membranes of keratinocytes in the granular cell layers are connected to each other by a tight junction network characterized by membrane proteins called occludins and claudins, to prevent bodily fluids from leaking between cells in that the layer (tight conjugation).

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1 electron micrograph

c. Keratinization The horny cell layer acts like a film of plastic wrap, allowing the body to retain moisture and protecting it from invasion by foreign substances. If the horny cell layer is lost or defective, a human being can survive for no more than 24 hours due to loss of liquid components leading to dehydration. The layer comprises various substances such as keratins, produced by the epidermal keratinocytes, and lipids. The epidermal keratinocytes divide in the basal layer, produce keratins and differentiate, and migrate to the upper layers as they mature. This process is called keratinization. Recent studies have proved that epidermal keratinocytes secrete various cytokines.

plakophilin Ca2+ desmoglein 1

desmoglein 1

Ca2+ desmoglein 3

desmoglein 3

Ca2+

1. Keratin

keratin fiber

Keratin forms tonofilaments that act as a cytoskeleton to maintain the structure of the keratinocyte. Keratins are classified as type I (acidic) or type II (neutral to basic). Type I and type II keratins bind to each other in pairs to form intermediate filaments. Pairs of keratins with characteristic molecular characteristics form, depending on the keratin pairs and state of differentiation of the keratinocytes. For example, K5/K14 pairs in basal cells and K1/K10 pairs in the suprabasal cell layers to form the cell cytoskeleton (Table 1.1, Fig. 1.14). When keratinized, keratin fibers in the granular cell layer aggregate with help from the protein called filaggrin to form the characteristic condensed keratin pattern. Profilaggrins, abundantly found in keratohyalin granules, decompose into filaggrins by the action of the protease peptidylarginine deiminase during keratinization (Fig. 1.15). Released filaggrins aggregate keratin fibers in the horny cell cytoplasm and keratins decompose into amino acids, for example, in the horny cell upper layer. The

desmocolin desmocolin

keratin fiber

desmoplakin cell membrane

Fig. 1.12 Ultrastructural image and illustration of the desmosome. cytoplasm

cell membrane

cell membrane cytoplasm

connexon

connexin

Table 1.1 Expression regions of main keratin pairs, and congenital disorders from mutations of keratins. Keratins

Main area of expression

K1, K10 Keratinocytes in the suprabasal cell layer and granular cell layer K2e

Superficial epidermis

Genetic disorder Bullous congenital ichthyosiform erythroderma Ichthyosis bullosa of Siemens

K3, K12 Anterior epithelium of the cornea Juvenile epithelial corneal dystrophy (Meesman) K4, K13 Mucosa

White spongy nevus (on tongue)

K5, K14 Keratinocytes in the basal cell layer

Epidermolysis bullosa simplex

K6, K16 Nails

Pachyonychia congenita

K9

Keratinocytes in the suprabasal cell layer and granular cell layer on the palmoplantar region

Palmoplantar keratodsis (Vörner)

N

C

second messenger, ion, etc.

Fig. 1.13 Molecular components of the gap junction.

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Structure and Function of the Skin

horny cell layer

type of keratin:

decomposed filaggrins, which function in moisture retention and ultraviolet absorption are called natural moisturizing factors (NMF).

granular cell layer

2. Cornified cell envelope

suprabasal cell layer

K1 & K10

basal cell layer

K5 & K14

Fig. 1.14 Expression of keratin types in the epidermis. profilaggrin calcium binding domain filaggrin domain N-terminal leader

The cornified cell envelope (marginal band) is an extremely large and strong, insoluble structure lining the horny cell membrane. It appears under the electron microscope as an electrondense structure at the periphery of the horny cells (Fig. 1.16). The main structural components of the cornified cell envelope are involucrins, produced in the lower keratinocyte suprabasal cells, and loricrins, produced in the granular layer keratinocyte cells. The cornified cell envelope forms when these proteins are successively cross-linked by enzymes such as transglutaminases during keratinization. Transglutaminases are calcium dependent and are activated by the influx of calcium ions into the cells accompanying cell death after keratinization.

linker

3. Horny layer (stratum corneum) intercellular lipids

phosphorylation of serine / threonine residue C-terminal decomposition

keratin fiber keratin fiber

dephosphorylation

keratin pattern

decomposition natural moisturizing factor: small molecule peptide

Fig. 1.15 Keratohyalin granules. Profilaggrin is composed of linearly arranged filaggrin domains that connect with each other by linker proteins. These filaggrin domains have many serine-threonine residues, which are kept phosphorylated. During keratinization these domains are cut by proteases and are dephosphorylated to form filaggrin, which aggregates (hence:“fil”for filament, and“aggrin”for aggregate) keratin filaments. The filaggrin degrades into small peptides, which act to moisturize and to absorb UV rays (quoted from; Iizuka H. Hyperkeratosis. In: Arata J, editor. General Dermatology. 7th ed. Igaku Shoin; 2004).

More than 50% of the lipids in the horny cells are ceramides, followed in decreasing order of abundance by cholesterols, free fatty acids and cholesterol sulfates. Lamellar granules are abundantly found in the cytoplasm of the granular cell layers. These granules are released from cells when the cells become apoptotic, forming horny layer intercellular fat. The enzyme ABCA12 plays a significant role in the release of lipid from lamellar granules from granular cells. Ceramides are released from lamellar granules, and free fatty acids are secreted from granular cell membranes. Cholesterol sulfates connect and stabilize the layered cornified cell envelope horny layer intercellular fat loricrin

involucrin horny cell layer cell membrane

keratin pattern

granular cell

Ceramide and its moisturizing function

MEMO

The ceramide content in the horny cell layer is reduced in patients with atopic dermatitis. Ceramide is thought to relate to dry skin and to disorders of skin barrier function.

lamellar granule

nuclear keratohyalin granule

Fig. 1.16 Cornified cell envelope.

B. Epidermis

lipid structures between horny cells. The horny layer intercellular fat is important in preventing excessive transepidermal water loss.

4. Exfoliation of horny cells As horny layer intercellular lipids move upward with the horny cell layers, they gradually get more decomposed by lipases, a group of catabolic lipid enzymes, and steroid sulfatases. Subsequently, adhesion between keratinocytes is disrupted by proteases from the upper skin surface, which causes gradual exfoliation of horny layer cell.

d. Melanocytes and melanin synthesis 1. Form and distribution of melanocytes Melanocytes (pigment cells) are neural crest (ectoderm)derived dendritic cells found in the basal cell layer and hair matrix (Fig. 1.17). Since their cytoplasm contracts during the processes of dehydration and fixation in light microscopy, such as in HE staining, melanocytes, as well as Langerhans cells, are called clear cells. Melanocytes stain a characteristic brownish black in DOPA (Fig. 1.17). Approximately 1,000 to 1,500 melanocytes are seen per square millimeter of skin. Dense melanocytes are found in sun-exposed sites of the body, such as the face, and in physiologically pigmented sites, such as external genitalia. The Golgi apparatus develops in a cell and contains various melanosomes in various formative stages (stages I, II, III and IV). Melanin is produced from the amino acid tyrosine in the melanosome. Mature melanosomes are packaged and transported to the neighboring basal cells and suprabasal cells. Basal cells that are provided with melanosomes aggregate them in the upper part of the cytoplasm over the nucleus, forming a melanin cap to protect their DNA from UV rays. Racial differences in skin color are determined by the number and size of melanosomes. There is no difference in the distribution or density of melanocytes between races.

Ichthyosis caused by enzyme deficiency

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MEMO

Transglutaminase is an enzyme that connects the cell membranes to protein molecules such as loricrin, involcrin, cystatin-a, and small proline-rich proteins. Without this activity, normal cornified cell envelopes do not form. When ABCA12 is lacking, lamellar granules are not normally produced, and formation of intercellular lipid is incomplete, resulting in the onset of harlequin ichthyosis. The mechanism of onset is thought to be thickening by a compensative increase in number of horny layer cells or by inhibition of the normal exfoliative process. A lack of steroid sulfatase, which restores sulfate cholesterol to cholesterol, inhibits normal exfoliation of horny cells, which causes sex-linked recessive ichthyosis (Chapter 15).

MEMO Vitamin A inhibits cholesterol sulfotransferases and decreases cholesterol sulfates, which is considered to stimulate exfoliation of the horny cell layers.

Activities of vitamin A

2. Biosynthesis of melanin Melanin is a generic term for a group of polymer pigmented molecular phenolic substances. The melanins in human skin are various indole compounds synthesized from tyrosines through polymer formation (Fig. 1.18). Melanins in humans are roughly classified as eumelanin, which is black (intrinsic melanin), or pheomelanin (yellow melanin). Melanins in human skin and hair are complexes of these two types, and their ratio determines hair color. Tyrosines, supplied by the blood, are oxidized by tyrosinase, which contains copper, and are metabolized into dopas and then

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Fig. 1.17 Melanocytes. Melanocytes are seen as clear cells (arrows) under hematoxylin and eosin staining, because the cytoplasm of melanocytes shrinks during the process of fixation.

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Structure and Function of the Skin

HO

into dopaquinones. Tyrosinase is the enzyme that catalyzes these two reactions. This metabolism is the rate-limiting reaction in the synthesis of melanins (Fig. 1.18). Dopaquinones are automatically oxidized to become indole compounds that are connected to each other to synthesize eumelanins. If cysteins are involved at this stage, dopaquinons connect with cysteins and change into 5-S-cysteinyl dopa (5-S-CD), which polymerizes to synthesize pheomelanins.

N COOH H2 tyrosine tyrosinase

HO N COOH H2

HO

dopa

3. Melanosome

tyrosinase O O

N COOH H2

dopaquinone

dopa chromium

cysteine

5-S-cysteinyl dopa

indole derivative eumelanin (black)

pheomelanin (yellow)

Fig. 1.18 Biosynthesis of melanin.

Causes of enhanced pigmentation

MEMO

ACTH (adenocorticotropic hormones), MSH (melanocyte-stimulating hormones), thyroid hormones, estrogens, ultraviolet rays, and Xrays are known to increase pigmentation of the skin.

Association of tyrosinase with albinism

MEMO

A child that has a congenital lack of tyrosinase is born with pale skin, from the lack of melanins (oculocutaneous albinism). In patients with Menkes disease, there is an extreme deficiency in copper, which causes tyrosinase activity to decrease and these patients to have less pigment.

MEMO Increase of 5-Scysteinyl dopa (5-S-CD) in serum Generally in malignant melanomas, pheomelanins are vigorously synthesized, and 5-Scysteinyl dopas in the blood and urine increase. Therefore, the increase of 5-S-CD in the blood indicates metastasis of a malignant melanoma and its degree of spreading.

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The melanosome is a subcellular organelle, enclosed by a lipid double membrane, in which melanins are exclusively produced. When tyrosinases, which are synthesized by the Golgi apparatus. are carried to premelanosomes, which are isolated from the agranular endoplasmic reticula, melanin synthesis begins. As the amount of synthesis increases, melanosomes enlarge. The formation of melanosomes is divided into stages I to IV by the degree of melanin deposition (Fig. 1.19). A melanosome in stage IV is 500 nm to 700 nm along its major axis, football shaped, and supplied from the dendrites to the neighboring epidermal keratinocytes.

4. Functions of melanin The most important role of melanin is protecting the skin from UV rays and preventing the occurrence of malignant tumors and sunlight injury to the skin. The darker the skin of a particular race, the lower is the incidence of skin cancer caused by UV light. Exposure to sunlight darkens the skin. This darkening may occur immediately after exposure and may be temporary, when melanins are oxidized temporarily, or it may occur after several days of exposure, when there is an increase in melanin synthesis and mature melanosome formation. Melanins can also act to absorb harmful active enzymes, metals and drugs.

e. Langerhans cell The Langerhans cell is a bone marrow-derived dendritic cell specific to stratified squamous epithelia such as the skin. Langerhans cells are frequently seen isolated in the middle and upper suprabasal cell layers (Fig. 1.20). The cells are distributed at a density of 400/mm2 to 1,000/mm2. They lack tonofilaments and cell attachment structures, such as desmosomes, and they migrate. By electron microscopy, a few fibrillary components and Birbeck granules, whose cross-section is a characteristic tennis racquet shape, are observed in the cell cytoplasm (Fig. 1.21a). Birbeck granules are known to be Golgi-apparatus-derived or membrane-derived, and carry antigens in the cells.

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B. Epidermis

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Langerhans cells present antigens to T cells (see Chapter 3 for immune reactions in the epidermis). Since the Langerhans cell is ATPase positive, CD1a positive and S-100 protein stain positive, it is easily distinguished from other kinds of cells.

f. a-dendritic cell The a-dendritic cell is found in the epidermis. It resembles a Langerhans cell because of its lack of adhesive intercellular structures such as desmosomes; however, it can be distinguished by its lack of Birbeck granules. Although the origin and function of a-dendritic cells are unknown, these cells may be precursors of Langerhans cells or otherwise related to Langerhans cells.

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Fig. 1.20 Langerhans cell (immunostaining against CD1a).

g. Merkel cell The Merkel cell is a tactile cell found in the basal cell layer. Greater numbers of Merkel cells are seen in the fingers, oral mucosa and trichodis areas (the hair roots). With angular plasma membrane projections, Merkel cells are connected to adjacent keratinocytes by desmosomes (Fig. 1.21b). Multiple dense-core granules called Merkel cell granules are found in Merkel cells, to which the sensory (free) nerve endings are connected by synapses beneath the cell. After physical stimulation, neurotransmitters are secreted from Merkel cell granules, and the tactile information is transmitted to the sensory nerve. a

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melanin cap epidermis

neural crest cell migration

dermis melanoblast migration of melanosome to a horny cell differentiation

melanocyte

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nuclear division

Ⅳ Ⅲ

Fig. 1.21 Histopathology of Langerhans cell and Merkel cell. a: Birbeck granules of Langerhans cell (arrows). b: Dense-core granules of Merkel cell (arrows).

Ⅱ

mature melanocyte

stageⅠ

Four stages of melanin in a melanosome, divided by melanin pigmentation

formation of melanosome

Fig. 1.19 Maturation of melanosomes.

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Langerhans cell histiocytosis (LCH)

MEMO

This used to be called histiocytosis X, a disease in which a malignancy occurs from excess proliferation of Langerhans cell histiocytes.

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C. Dermis a. Structure of the dermis The dermis is the structure beneath the epidermis, and the two are separated by the basal membrane (Fig. 1.3). The dermis is approximately 15 to 40 times as thick as the epidermis. It consists of three layers. Papillary layer: The dermal area that projects into the intervals between the epidermal ridges. The fiber components are thin and richly supplied with capillaries, sensory nerve endings and cytoplasm. Subpapillary layer: The area underlying the epidermis, containing the same components as the papillary layer. Reticular layer: Accounts for the largest part of the dermis and has dense connective tissue comprising fiber components. The

cellular components lymphatic vessel blood capillary

nerve

mast cell

fibroblast

histiocyte

plasma cell basement membrane

Meissner corpuscle

epidermis papillary layer subpapillary layer

reticular dermis

dermis

subcutaneous tissue

Pacinian corpuscle

collagen fiber

elastic fiber dermal matrix

Fig. 1.22 Structure of the dermis.

ground substance

C. Dermis

lower part comes into contact with the subcutaneous fatty tissue. There are blood vessels and nerves in some parts. The components of the dermis comprise the fibrous tissue and the dermal matrix formed by cells in the interstitial components (Fig. 1.22). The major components mainly consist of collagen fibers (mainly types I and III), with smaller amounts of elastic fibers, reticular fibers and matrix. This matrix generally comprises the extra-cellular matrix and ground substance made up of proteoglycans and gelatin. Fibroblasts, macrophages, mast cells, plasma cells, vascular channels and nerves are common cellular components.

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b. Interstitial components 1. Collagen fibers Collagen fibers account for 70% of the weight of dry dermis (Fig. 1.23) and appear white to the naked eye. The collagen fibrous component is poorly extensible; however, it is extremely tough and especially resistant to tension parallel to the fibers. This characteristic is important in maintaining the dynamic strength of skin. Collagen fibers form from aggregations of thin fibrils. The more fibrils there are in the fiber, the thicker and stronger the fiber. Thin collagen fibers are sparsely seen in the papillary layers and subpapillary layers; however, collagen bundles, with fully developed thick collagen fibers, are densely distributed in the reticular dermal upper layers. In light microscopy, the proteinaceous collagen fibers stain well in eosin solution; they stain red in Van Gieson and blue after Mallory staining. The fibril is observed by electron microscopy as being very long, 100 nm to 500 nm in diameter with cross striations that repeat at intervals of 60 nm to 70 nm (Figs. 1.23 and 1.24). Fibrils become collagen fibers by aggregating with glycoa proteins. A thick collagen bundle can reach 2 mm to 15 mm in diameter. Collagen fiber molecules are produced in the rough endoplasmic reticulum of fibroblasts. Helical procollagens with three achains are secreted and the molecular ends are cut by procollagen peptidase to become tropocollagens. The molecules are crosslinked to each other with a regular gap that forms the striped collagen fiber (Fig. 1.23b). Twenty subtypes of collagen molecules with a-chains of different molecular structures are known to exist (Table 1.2); however, type I collagen accounts for 80% of the collagen fibers that make up the dermis. Reticular fibers, which distribute in the perivascular regions as thin argyrophilic fibers and do not form thick fiber bundles, are type III collagen, and these account for about 15% of all fibers. Most of the remainder is thought to be type V collagen. Types IV, VII and XVII are mainly found in the basal membranes, associated with epidermal keratinocytes.

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Fig. 1.23 Histopathology of the dermis. a: Collagen fibers (stars) and elastic fibers (arrows). b: High-power magnification of collagen fibers. Stripes approximately 60 nm to 70 nm in width are seen. 60~70 nm

tropocollagen molecule

Fig. 1.24 Stripes of collagen fibers. Fine fibrils (tropocollagens) have cross-links, giving the fibers a striped appearance.

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Structure and Function of the Skin

Table 1.2 Types of collagen fibers. Fiber

Type

Fibrillar

I, II, III, V, XI

Basement membrane

IV

Anchoring fibril

VII

Network forming

VIII, X

FACIT

IX, XII, XIV, XIX, XX

Microfibril

VI

Multiplexin

XV, XVIII

Other

XIII, XVII

FACIT: fibril associated collagen with interrupted triple helix

2. Elastic fibers The elastic fiber is not as tough as the collagen fiber; however, it is extremely elastic and found abundantly in the dermis of the scalp, face and the extensible organs such as arteries and tendons. In the dermis, the deeper the elastic fiber, the thicker it is. In the reticular layers, elastic fibers are scattered among collagen bundles running parallel to the skin surface. The closer the elastic fiber is to the papillary layer, the thinner it is and the more perpendicular it is to the skin surface. It forms an arch shape in the papillary layer from which thin fibers are produced that perpendicularly reach the lamina densa. Elastic fibers are also connected to the lamina densa of glands, sweat ducts, smooth muscle, nerves and blood vessels. Elastic fibers are 1 mm to 3 mm in diameter. They cannot be differentiated from collagen fibers by HE staining. Elastic fibers stain dark blue to black in Weigert resorcin fuchsin, red-violet in aldehyde fuchsin, and brownish black in orcein. In elastic fibers, the characteristic striped pattern of collagen fibers is not observed by electron microscopy (Fig. 1.23). A skeletal fiber is 10 nm to 15 nm in diameter and its main content is fibrillin. The homogeneous substances are highly elastic structural proteins called elastins.

3. Ground substance, Matrix

Abnormality in elastic fibers or collagen fibers

MEMO

If elastic fibers are decreased, lost or denatured, dermatolysis or senile cutis rhomboidalis nuchae may occur. If fibrillin molecules are congenitally abnormal, Marfan syndrome results (Chapter 18). Abnormalities in collagens, which are components of collagen fibers, may lead to Ehlers-Danlos syndrome, which causes skin fragility.

Ground substance, a gelatinous amorphous substance of sugar and proteins, is observed in between fibers and between cells in the dermis. The components of ground substance are principally proteoglycans and glycoproteins whose molecular weight is 150,000 to 250,000 and whose sugar content is 2% to 15%. The molecules stabilize the fibers to give flexibility to the skin. Fibronectin, one kind of glycoprotein, contains a domain that connects fibrin, heparin and collagen; and binds integrin receptors on the cell surface are involved in cell proliferation, differentiation and wound healing. Besides these components, blood and lymph-derived tissue fluid forms the remainder of the ground substance that is involved in the transport of substances essential to cellar activities and metabolism. Proteoglycans are a massive molecules with a molecular weight of 105 to 106 or more and a composition of multiple glycosaminoglycans (mucopolysaccharides) connecting with backbone proteins. Glycosamine, mostly produced by fibroblasts in the dermis, is rich in hyaluronic acids, which are associated with moisture retention.

C. Dermis

15

c. Cellular components 1. Fibroblast Fibroblast differentiates from the mesenchymal cells and produces collagen fibers, elastic fibers, and glycosaminoglycans. Fibroblasts appear as thin spindle-shaped cells sparse in collagen fibers (Fig. 1.25). By electron microscopy, multiple Golgi apparatus and granular endoplasmic reticuli are seen in the fibroblast. When collagen fibers are produced and the dermis matures, fibroblasts stop their activities and become fibrocytes. At this point, the cell nuclei shrink and have fewer endoplasmic reticuli. Adrenal cortex hormones and thyroid hormones are involved in this process.

20 mm

Fig. 1.25 Fibroblasts (arrows).

20 mm

2. Histiocyte The histiocyte, a kind of macrophage, is broadly distributed in the connective tissue and intermingles with fibroblasts on the outside of endocapillary cells (Fig. 1.26). A small circular nucleus and a large spindle- or star-shaped cell structure is seen in a histiocyte by light microscopy; furthermore, concave nuclei and the formation of psudopodial protrusions are observed by electron microscopy. Histiocytes contain Golgi apparatus, smooth and rough endoplasmic reticuli, and lysosomes. Lysosomes contain hydrolases and active acid phosphatases. The histiocyte releases collagenase and lysosomal enzymes containing elastase to digest the interstitium. It is involved in organ repair. The histiocyte degrades and phagocytoses mainly foreign substances and presents them as antigens to T cells (Chapter 3).

3. Mast cell The mast cell is found in the dermis around capillaries and in the periphery of subcutaneous tissues. The shape is roundish or spindled, and the diameter is 10 mm (Fig. 1.27). Mast cells produce and maintain various vasodilatory and hyperlucent chemical mediators. Mast cell granules stain red-violet in toluidine blue and methylene blue, and present with metachromasia. Cutaneous mast cells resemble basophils in form and function; however, their characteristics differ slightly from those of other organs, because they differentiate in skin during intrauterine life. A mast cell intracytoplasmic granule appears as a circular structure with a diameter of 0.3 mm to 0.5 mm under electron microscopy. Multiple mast cell granules are evenly distributed in the cytoplasm. Chemotransmitters in the granules are released outside the cell under various stimuli, such as in type I allergic reactions (Fig. 1.28, Chapter 3). The main components of the released substances are histamines and heparins, followed by

Fig. 1.26 Histiocytes (arrows)

Histiocyte, Monocyte, Macrophage

MEMO

Large phagocytic cells in the living body are called macrophages. There are two kinds. -- Free macrophages: e.g., monocytes in the blood, migrating macrophages in granuloma -- Fixed macrophages: e.g., histiocytes in the dermis and subcutaneous tissues, Kupffer cells Histiocytes and monocytes are kinds of macrophages.

MEMO Melanin granules that have exfoliated from the epidermis to the dermis are often phagocytosed by histiocytes. Histiocytes that become brownish-red after repeatedly phagocytosing melanin granules are called melanophages.

Melanophages

20 mm

Histiocytes, the key to pathological diagnosis

MEMO

Epithelioid cells, Touton giant cells, xanthoma cells and foreign-body giant cells in an epithelioid cell granuloma are histiocytes that pathologically present in an atypical form.

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Structure and Function of the Skin

various enzymes, including neutrophil chemotactic factors (NCF), eosinophil chemotactic factors of anaphylaxis (ECF-A), tryptase, chymase and tumor necrosis factor (TNF)-like substances. The mast cell may produce and release inflammatory substances such as prostaglandins, leukotorienes and plateletactivating factors.

4. Plasma cell

20 mm

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

The plasma cell is a differentiated B cell that has been stimulated by an antigen. It produces antibodies and is involved in humoral immunity. The shape of the plasma cell varies from circular to pear-shaped, and the diameter ranges from 8 mm to 14 mm, which is twice as large as a leukocyte. It has a wheel-shaped nucleus with peripheral chromatin (Fig. 1.29).

5. Dermal dendrocyte 20 mm

a

b

c

d

e

g

f

h

Fig. 1.27 Mast cells. a: Hematoxylin and eosin staining. b: Metachromasia is seen by toluidine blue staining. antigen

d. Vascular channels and nerves 1. Blood vessels

second exposure of the antigen nucleus

nucleus histamine

sensitized mast cell

vasodilation vascular permeability itch

Fig. 1.28 Sensitization by mast cells.

20 mm

Fig. 1.29 Plasma cells (arrows).

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is m found in upper layer (inr p q j i The dermal kdendrocyte l n the dermal o and between the papillary layer and the reticular layer). It is thought to be an immunocompetent cell (Chapter 3), and it is characterized by containing clotting factor XIIIa.

Multiple branches of arteries distributed in skin (Figs. 1.30 and 1.31) are connected with each other in the dermal deep layer to form a horizontal network (subcutaneous plexus). With numerous branches ascending from the subcutaneous plexuses, the arteries form a second network in the papillary lower layer (subpapillary plexus). The arterioles ascend through the papillary layer, forming capillary loops in the dermal papillaries before moving to venules that connect to each other to form two kinds of plexuses, whereby the blood flows into the cutaneous veins (Fig. 1.30). There are also characteristic plexuses in the periphery of the cutaneous appendages. The peripheral regions of the eccrine glands are particularly rich in vascular networks, which control blood flow volume and body temperature by perspiration. Moreover, hair follicles in the anagen (growth) stage are also richly supplied with blood vessels, present in the surrounding dermal tissue. There is another apparatus that circulates the blood directly from arteries to blood vessels: This is the arteriovenous anastomosis, which is controlled by sympathetic nerves. The arteriovenous anastomosis controls the peripheral blood flow and is involved in body temperature regulation. Glomus apparatuses, which have spherical anastomotic branches, are seen everywhere in the skin. They are particularly well developed in the fingers, at apical ends of the toes, and below the nails. Many layers of

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17

C. Dermis

epidermis

50 mm

rmis

Fig. 1.31 Blood vessels (hematoxylin and eosin).

50 mm

Fig. 1.30 Distribution of blood vessels in the dermis.

smooth muscle cells (epithelial cells or glomus cells) cover the peripheral walls of the endothelial cells. Under the electron microscope, endothelial cells, pericytes, and the multilayered basement membrane (lamina densa) in the peripheral interstitium may be observed in the capillaries. The stick-shaped Weibel-Palade granule, which has a diameter of 200 nm and a length of 1 mm or less, contains factor VIII associated with histamines and blood coagulation. It is found in the endothelial cell. Pericytes have a vasoconstrictive effect, and they are seen on the perimeter of the walls of the endothelial cells.

Fig. 1.32 Lymphatic vessels (hematoxylin and eosin).

Discriminating between MEMO blood vessels and lymph vessels The important points in discriminating between these are tabulated below.

2. Lymphatic vessel Lymph vessels are distributed around the subpapillary layer region and extend through the postcapillary lymph vessels to the dermal and subcutaneous lymph vessels. The endothelial cells of the lymph capillaries are thin, without pericytes or lamina densa. They are partly ruptured and are surrounded by loose collagen fibers and elastic fibers (Fig. 1.32). The closer the endothelium is to the dermal deep layer, the more continuous it becomes with the valva in the lumen. The structure of lymph vessels is not as regular as that of the blood vessels. Aggregated cutaneous lymphatic fluid passes through the regional lymph nodes and flows into the blood vessels.

Lymph vessel

Item

Blood vessel

Factor VIII

Positive

Basically negative

Basal layer

Extended and multi-layered

Intermittent

Intercellular connection

Developed

Weak

Lumen shape

Round

Irregular

Elastic fiber stain

Arteries: positive in the internal elastic layer veins: negative

Negative

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Structure and Function of the Skin

3. Nervous system

50 mm

a

b

c

d

e

g

f

The nerve fiber bundle is covered with a membrane in the dermal lower layers. The nerve fibers change from being myelinated to non-myeliated where the nerve bundle branches into many fibers in the dermis, and these branched fibers are distributed within the superficial dermis and peripheral appendages (Fig. 1.33). The sensory nerves transmit tactile, pressure, pain and temperature sensation. The autonomic nerves control the blood p q j h isweat glands k other l appendages. m n o vessels, and

1) Sensory nerve

100 mm

a

b

c

d

e

f

g

h

h

i

myelinated

nonmyelinated nerve

b

c

d

e

f

g

Fig. 1.33 Nerve fibers. a: Myelinated nerve fibers. b: Unmyelinated nerve fibers. c: Electron microscopy.

The sensory nerve structures include free nerve endings sensing pain, Merkel cells (described above) that perceive tactile sensation in the epidermal basal layer, and nerve end bulbs that accept tactile, pressure and vibration sensation. p q j i k l m n o r ①Free nerve ending The free nerve endings are distributed in the dermal upper and papillary layers. Some of them adhere to Merkel cells in the dermal papillary layer, whereas others infiltrate into the dermis directly. Nonmyelinated nerves transmit pain sensations. ②End corpuscle The end corpuscle is a specific sensory nerve terminal covered with a membrane. Various end corpuscles are described below. Meissner end corpuscle: The nerve fiber spirally ascends through the Schwann cell (inner bulb cell) in the dermal papillae of the palms, soles, lips of the mouth, and external genitals, perceiving tactile and pressure sensations (Fig. 1.34). Pacinian corpuscle: It is seen in the dermal deep layer and subcutaneous tissue of the palms, soles, and external genitals. The central nerve fiber is multi-layered with concentric membranes. It p be clearly q r isj oval, kwith a lmajor maxis ofn1 mm,o and can seen by light microscopy (Fig. 1.35). It reacts to vibration.

2) Autonomic nerves The autonomic nerves are principally distributed in the sweat glands, arrector pili muscles, blood vessels and glomus apparatuses, to control the functions of these organs. The cholinergic nonmyelinated sympathetic nerves are distributed in the eccrine sweat glands. Mitochondria, and dense core and non-core vesicles containing chemical substances are observed. The adrenergic sympathetic nerves are distributed in the arrector pili muscles and blood vessels.

50 mm

Fig. 1.34 Meissner corpuscle (hematoxylin and eosin).

Sympathetic nerves distributed in the eccrine sweat gland

MEMO

The sympathetic nerve is generally adrenergic; however, that in the eccrine gland is exceptionally cholinergic.

r

D. Subcutaneous fat tissue

19

100 mm

Fig. 1.35 Pacinian corpuscle (hematoxylin and eosin).

D. Subcutaneous fat tissue The subcutaneous tissue is the layer between the dermis and the fascia. The fat tissue acts to preserve neutral fat, cushion against external physical pressure, retain moisture and generate heat. The subcutaneous tissue is largely composed of fat cells. Assembled fat cells separated by the connective fibroid fat septum are called fat lobules. Fiber bundles produced in the dermis and firmly connected with the fascia and periostea through the subcutaneous tissue are found throughout this region. These fiber bundles are called retinaculae cutis, and they strengthen the connection between the dermis and deeper tissues. The main component of the fat droplet is triglyceride, composed of olein acid and palmitin acid. Since a large droplet accounts for most of the contents of the cellular cytoplasm in the fat cell, other cellular organelles are pushed to the edge. Multiple smooth muscles called tunicae dartoses are characteristically seen in the dermal deep layers and subcutaneous tissues of the scrotum, penis, labia majora and nipples (Fig. 1.36). The boundary between the subcutaneous tissue and skeletal muscle is called the musculus cutaneous. It is not clear in sites with muscles of expression, such as in the face. The thickness of the subcutaneous tissue depends on the body site, age and other factors. It is particularly thick in the cheeks, breasts, buttocks, thighs, palms and soles; it is thin in the eyelids, dorsal nose, lips of the mouth, and labia minora; subcutaneous tissue is absent in the foreskin. Subcutaneous tissue tends to develop and enlarge in newborn infants and in children at puberty. In embryos and newborn infants, heat is produced at a rapid rate by brown fat tissue in the dorsal region, which contains multiple fat droplets.

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Fig. 1.36 Tunica dartos in the skin of the scrotum.

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Structure and Function of the Skin

E. Appendages hair shaft

a. Hair apparatus

infundibulum

epidermis

The hair apparatus plays a role subsidiary to that of the sensory nerves in protecting the scalp from external forces and light, and in moderating heat in the head. Eyelids protect the eyes from dirt, and armpit hair and pubic hair absorb mechanical friction. The number of hairs on a person’s head averages 100,000. The hair apparatus is found throughout the skin except on the lips of the mouth. It consists of hair and hair follicles that enclose the hair.

keratinized outer root sheath sebaceous gland hair medulla hair cortex hair cuticle hair

isthmus

hair follicle

hair root lower part hair bulb

1

arrector pili muscle hair bulge inner root sheath fusion sheath cuticle inner root Huxley’s layer sheath Henle’s layer outer root sheath hyaline membrane connective tissue sheath melanocyte hair matrix

1. Hair follicle The layer of tissue that encloses a hair is called a hair follicle. It is aligned obliquely to the skin surface. Part of the hair follicle is slightly enlarged to form a hair bulge to which the base of the arrector pili muscle is connected (Figs. 1.37, 1.38-1 and 1.38-2). Dermal stem cells reside in the hair bulge. Sebaceous glands are seen above the bulge stem cells, and apocrine glands open further above. The bottom of the hair root during the growth stage bulges out spherically; it is called a hair bulb and contains a hair group of cells known as the hair papilla. The hair follicle opens in a funnel shape (hair infundibulum). The hair follicle is double-bounded with two layers, with an epithelial interior and connective tissue component on the exterior.

blood capillary

Fig. 1.37 Longitudinal section of the hair follicle.

outer longitudinal connective layer tissue sheath (CTS) inner circular layer

connective tissue sheath (CTS)

basement membrane

outer root sheath (ORS)

outer root sheath (ORS) Henle’s layer Huxley’s layer

inner root sheath (IRS)

inner root sheath (IRS)

cuticle of the root sheath / sheath cuticule

cortex of hair shaft

cuticula of hair shaft

papilla

cortex of hair shaft melanocyte

anagen metaphase

100 mm

hair matrix cell hair papilla

anagen early phase

50 mm

Fig. 1.38-1 Structure of the hair follicle (longitudinal section).

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E. Appendages

The epithelial components are the inner and outer root sheaths. The connective tissue component is called the connective tissue sheath.

connective tissue sheath (CTS) basement membrane ORS

1) Connective tissue sheath (CTS)

IRS cortex of hair shaft hair shaft

The connective tissue sheath (CTS) covers the outside of the hair follicle and is a layer connected with the dermis. Collagen fibers run circularly inside the connective tissue sheath and longitudinally outside of it. Several elastic fibers can be found among these collagen fibers. a

b

c

d

f

connective tissue sheath (CTS) basement membrane ORS Henle's layer Henle’s Huxley's layer Huxley’s cuticle of the root sheath/ sheath cuticle cuticula of hair shaft cortex f of hairgshaft h medulla connective tissue sheath (CTS) basement membrane ORS

d

e

2. Hair shaft The hair shaft is composed of a three-layered structure. From innermost to outermost, the layers are the medulla, cortex and

h

i

hair h papilla i

j

IRS cuticula of hair shaft cortex of hair shaft (medulla)

c

d

e

f

100 mm

g

Fig. 1.38-2 Structure of the hair follicle (cross section). a: Hair follicular isthmus. b: Lower part of a hair follicle. c: Hair bulb (see Fig. 1.37 for the crosssection position).

4) Hair bulb The hair bulb is the bulge of the hair follicle, with a dermal hair papilla at its center. The keratinocyte follicle enclosing and covering the dermal hair papilla semi-spherically is the hair matrix layer, where hair and inner root sheath cells grow and extend upward. The outer root sheath forms the outermost layer of the hair bulb. Melanocytes that provide hairs with melanins are also found in the hair matrix.

g

hair

b 100 mmc

3) Inner root sheath (IRS) The inner root sheath (IRS), found inside the outer root sheath, consists of capsular layers, Huxley’s layer (a double layer of cells), and Henle’s layer (a single layer of cells). The capsular cuticles anchor and entangle each other, with the differently directed apical tips functioning as hooks to stabilize the hair. The Henle’s layer is connected with the outer root sheath by desmosomes. a inter-b Keratinization occurs in the inner root sheath close to the follicular epidermis. IRS has the appearance of trichohyalin granules. These granules, often found in Henle’s layer and Huxley’s layer, stain eosinophilically. Keratinization finishes at the height of the sebaceous gland opening, and it is followed by exfoliation.

100 mm

e

IRS hair follicle

2) Outer root sheath (ORS) The outer root sheath (ORS) is the outermost part of the hair infundibulum (inner two layers). It is keratinized and comprises keratinocytes that contrain a light cytoplasm without keratohyaline granules. The outside of the outer root sheath meets the connective tissue sheath at the basal membrane. The inside of the outer root sheath is connected by desmosomes with the Henle’s a layer, the outermost layer of the inner root sheath.

1

Unusual keratinization of the outer root sheath

MEMO

When cells in the outer root sheath denucleate and keratinize without passing through the granular layer or becoming flat, it is called trichilemmal keratinization.

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Structure and Function of the Skin

cuticula. Tonofilaments align in the direction of the axis in the cortex, and a pattern similar to that observed for keratin by electron microscopy is observed at the tips of the tonofilaments. That is, keratinization is seen in the cortex; however, unlike in the epidermis and inner root sheath, no formation of keratohyaline granules or trichohyaline granules is seen. Unlike the keratins found in other epithelial cells, the keratins that are produced in hair cortex are rich in cystines, glycines and tyrosines. Such specific keratins are called hard keratins, a general term, and they are also found at other sites, including the nails. In the hair cuticle, the cortex is covered by flat cells in a scalelike pattern, and they are attached to the capsular cuticles of the inner root sheath. This connection becomes the outermost layer of the hair shaft, protecting the shaft. The cuticles may be injured and the natural glow of hair lost if there is excessive physical damage to hair, such as over-brushing, or excessive use of chemicals such as hair dyes or permanent solutions. Hair color differs according to the size and number of melanosomes: Large and/or multiple melanosomes are seen in dark hair, and red hair contains large amount of pheomelanins.

3. Hair cycle

fixed part

hair bulge hair papilla

anagen (6-8 years)

The part deeper than this point recedes.

catagen (2 weeks)

Fig. 1.39 Hair cycle.

growing part

telogen (3-4months)

The hair has a regular period of growth (anagen), transition (catagen), and rest phase (telogen) (Fig. 1.39). Head hair grows for several years after it sprouts (anagen: about 80% of all head hair), after which its growth rate slows for 2 to 3 weeks (catagen: about 1% to 2%) and then stops. The hair remains for several months after it stops growing (telogen: about 15%). As a new hair is produced, hair within the same follicle in the telogen phase falls out. Hair in the catagen period grows 0.3 mm to 0.5 mm per day. When hair follicles in the anagen phase repeat cell division and transition to the catagen phase, they begin to contract and cell division stops. The hair follicle cells lose their ability to divide in the telogen phase and ascend to the elevated part of the hair. The hair root presents a stick-like shape called club hair. In the telogen phase, macrophages phagocytose melanin pigments and cell fragments in the hair papilla. As the anagen phase comes around again, cell division begins at the surface of the hair follicle. A hair papilla forms and a new hair grows in the hair matrix. It pushes out the club hair, which exfoliates. Only the part of the hair with stem cells below the hair bulge expands and contracts in the hair cycle. That area is called the fluctuation area, and the upper area is called the fixation area. The human hair cycle differs for each hair; however, the overall quantity of hair remains roughly constant.

E. Appendages

b. Arrector pili muscle The arrector pili muscle is a smooth muscle bundle between the outer root sheath and the dermal upper layer. The hair stands vertically after contraction of the arrector pili muscles. This slightly elevates the peripheral hair follicles (causing goose bumps). Controlled by the adrenergic sympathetic nerves, the arrector pili muscle is contracted by cold stress and emotional stresses including fear and surprise. The formation of goose bumps may accompany shivering that occurs to raise the body temperature.

c. Sebaceous gland The sebaceous gland produces sebum (Fig. 1.40) that mixes with moisture such as sweat and is emulsified on the skin surface to form fatty acids that coat the skin. The coat is an acidic bactericide with a pH of 4 to 6 (acid mantle). Sebum and sebaceous glands prevent invasion and infection by pathogens and toxic substances. Additionally, the sebaceous glands control water loss from the skin and maintain moisture in the horny cell layers. The sebaceous glands are widely distributed throughout the skin, except in the palms and soles and some mucous membranes, but most of them open to the upper hair follicles at hair follicle sites. Sites where multiple individual sebaceous glands congregate are called sebaceous zones. They are seen in the scalp, face (the “T zone,” which includes the forehead, regions of the glabella and the nasolabial groove), sternal regions, armpits, naval, and external genitals. The seborrheic zone is very densely distributed with sebaceous glands (400/cm2 to 900/cm2). Sebaceous glands open directly to the skin surface at hairless sites, which are distributed in the lips of mouth, buccal mucosa, areola

acrosyringium straight duct coiled duct sebaceous gland

secretory unit apocrine sweat gland hair

free sebaceous gland

eccrine sweat gland

Fig. 1.40 Sweat glands, hair follicles and sebaceous glands.

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Structure and Function of the Skin

mammae, vagina, labia pudendis, glans penis and foreskin inner plate. These glands are called free sebaceous glands, because they are not attached to hair follicles. Meibom glands in the eyelids are a type of free sebaceous gland. The sebaceous gland is composed of sebaceous lobules and a duct that carries sebum to the hair follicle. The daughter cell, produced by cell division, migrates into the lobule as it matures, to produce fat droplets. As they migrate, sebocytes are filled with fat droplets and the cells rapture, resulting in secretion of the cytoplasm and fat, which is called holocrine secretion (Fig. 1.41). The amount of fat secretion changes with age. Large amounts of fat are produced in newborn infants, and small amounts in children. Production begins to increase again from puberty. The secretion of fat peaks in women in their second and third decades of life, and in men in their third and fourth decades of life, decreasing thereafter. The amount of fat secretion is controlled predominantly by sex hormones: testosterone in men, and adrenal androgens in women. Hormones derived from the mother are thought to be important in newborn infants.

exocytosis (eccrine secretion)

apocrine serection (beheading secretion)

d. Sweat glands Human sweat glands are either eccrine, distributed throughout most of the body, or apocrine, found at specific sites of the body and producing and discharging sweat to the body surface. Both are hair follicle-associated glands consisting of a secretory part and a sweat duct. The secretory parts are coiled and surrounded by fat tissues in the deep dermal layer and subcutaneous tissue (Fig. 1.40).

holocrine secretion

Fig. 1.41 Types of secretion.

1. Eccrine sweat glands

100 mm

a

b

c

d

e

Fig. 1.42-1 Errcine sweat gland. a: Cross section.

f

g

Eccrine sweat glands are found over the entire body, especially in the palms, soles, and armpits, at a density of 130/cm2 to 600/cm2. They are known to number approximately 3 million. Perspiration is enhanced by thermal stimulation, which is associated with body temperature control, but it may be stimulated by mental strain or gustatory stimulus (gustatory sweating). The total amount of perspiration in a day is controlled by acetylcholines and is known to average 700 ml to 900 ml (in adults). Two-layered secretory cells with a circular nucleus and peripheral flat myoepithelial cells are observed in the secretory area by p con-q j (Fig.k 1.42-1). h i l Cellsmon thenbasal-layer o light microscopy side tain few subcellular organelles and a large amount of glycogens. Since these cells secrete large amounts of serous sweat by eccrine secretion (Fig. 1.41), they are also called serous cells. Cells on the luminal side secrete mucus. The myoepithelial cell is a smooth muscle cell that pushes the accumulated sweat out of the lumens to the sweat ducts by contraction. The sweat duct ascends perpendicularly in the dermis (straight duct) through the coiled duct that extends from the secretory area

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E. Appendages

25

1

(Figs. 1.40 and 1.42-2). The sweat duct contains two cell layers, consisting of intraluminal cells and peripheral cells, and it lacks myoepithelial cells. The sweat that is produced in secretory areas (as precursor sweat) is slightly hypertonic; therefore, sodium ions and chlorine ions are re-absorbed by intralluminal cells in the coiled ducts, and hypotonic sweat is finally secreted.

2. Apocrine sweat glands Apocrine sweat glands, which number fewer than eccrine glands, are degenerated pheromone-producing mammary glandsa found in the armpits, external ear canals, areola mammae, external genitals and anus. They develop in conjunction with hair apparatuses, temporarily slow in development after birth, and accelerate with development again during puberty. Perspiration from these glands is considered to be adrenergic and is caused mostly by emotional stimulation. Mammary glands and Moll’s glands are kinds of apocrine sweat glands. Although sweat is viscous and odorless, its components such as glycoproteins and fat are broken down by microbes resident on the skin surface, which produces odor. Glandular development is associated with sex hormones; the glands are thought to be involved with sexual function. The secretory portion of the apocrine gland is larger than that of the eccrine gland. Secretory cells are aligned as a single-layer epithelium surrounded by myoepithelial cells (Fig. 1.43). The part of the cytoplasm that faces the lumen of the sweat duct bulges, blebs and separates from the cell (apocrine secretion; Figs. 1.41 and 1.44). a The sweat ducts do not open to the skin surface directly, butb open on to the upper parts of the sebaceous glands (Fig. 1.40).

e. Nail

100 mm

b

c

d

e

f

f

g

g

h

i

i

j

100 mm

c

d

e

h

Fig. 1.42-2 Eccrine sweat gland. b: Longitudinal section (epidermis). c: Longitudinal section (dermis).

The nail is a portion of keratinized epithelial tissue and composed of the nail plate, nail matrix, nail folds and nail bed. Each of these parts comprises several more detailed structures (Fig. 1.45). The nail differentiates from the epidermis in the third month of fetal development. Recent studies have shown that the nail has characteristics of both dermis and hair. The fingernail grows 0.1 mm per day, and it takes about 6 months to re-grow an entire nail plate. The growth of nails is slower in the elderly, whose nails tend to be thick and brownish. Nails are important in protecting the digits and in assisting subtle sensation in the fingertips. 100 mm

1. Nail plate The nail plate is a rectangular horny plate on the dorsal tip of the digits consisting of top nail, middle nail and undernail. In the proximal area, the nail plate is ingrown and covered by the

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Fig. 1.43 Apocrine sweat gland (cross section).

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1

Structure and Function of the Skin

proximal nail fold, where the nail matrix exists. Cells that proliferate are keratinized in the nail matrix to form the nail plate. Keratohyaline granules are not involved in this keratinization. An opaque white half moon shape (lunula) may appear at the root of the nail plate from inadequate keratinization.

2. Nail matrix Keratinocytes are produced in the nail matrix. The cells that differentiate and proliferate in the nail matrix extend and keratinize to form the nail plate; however, the undernail of the nail plate is considered to form in the nail bed. Fig. 1.44 Apocrine secretion of the sweat gland.

3. Nail fold

nail bed

The nail folds are the skin lesions that cover both sides of the nail plate and nail bed. The cuticle is the horny layer that extends and partly covers the nail plate.

nail matrix

1

nail plate

lunula

4. Nail bed nail groove

lateral nail fold

The nail bed is seen at the bottom of the nail plate. Its components are the same as those of the epidermis, except that it lacks a granular layer and is continuously keratinized to connect with the nail plate.

proximal nail fold cuticle

Fig. 1.45 Anatomy of the nail.

MEMO Hemorrhagic punctums in the cuticle may be found in collagen diseases (e.g., systematic lupus erythematosus, dermatomyositis, scleroderma). It is thought to be caused by the mechanism of angiitis in the microvessels. It may be a risk factor for systemic angiitis.

Bleeding in cuticle

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Histopathology of the Skin

Skin biopsy is the most frequently used and important test for dermatological diagnosis. In a biopsy, a sample of skin is collected for observation under the microscope. There are many cases in which it is impossible to make a diagnosis based only on the clinical symptoms. A blister, for example, may be caused by various pathomechanisms, including viruses, bacteria and autoimmune diseases, or by heredity. It is often difficult to diagnose a blister just by naked-eye observation and disease history. To specify the cause of the disease and reach a final diagnosis, dermatopathological examination is essential.

A. Skin biopsy In skin biopsy, a biopsy site is selected, a skin specimen is removed, and the sample is fixed and stained. It is necessary to select a site that is without secondary changes and that is cosmetically acceptable. In inflammatory diseases, it is recommended to include the peripheral normal skin for comparison with the lesion. When a disease presents various lesions, it is preferable to collect multiple skin samples from different stages of inflammation. After local anesthesia, a biopsy specimen is removed (Figs. 2.1-1 and 2.1-2). The main methods for removing a sample are punch biopsy (clipping of a round sample), incisional biopsy (removal of a spindle-shaped sample with a surgical knife), and excisional biopsy (removal of the entire site). Shave biopsy (sample excision by razor blade) is another method for observing a lesion in the epidermis. The removed sample is fixed immediately with 10% formaldehyde to avoid secondary degeneration. The sample may be divided for cryo fixation or 2% glutaraldehyde fixation for an immunofluorescence test or electron microscopy. A skin specimen is prepared for hematoxylin-eosin (HE) staining. As shown in Table 2.1, various staining methods, known collectively as special staining procedures, are often used in combination. Immunostaining using monoclonal antibodies is also effective for diagnosis.

MEMO Skin biopsy may scar the site to varying degrees; therefore, the site and biopsy method should be chosen carefully, especially when it is performed on cosmetically important sites or on patients with a keloidal tendency. It is essential to record clinical conditions by photographing the biopsy site, as well as to obtain the patient’s informed consent by thoroughly explaining the necessity of the biopsy.

Preparation of a skin biopsy

27

Fig. 2.1-1 Procedure of skin biopsy. Punch biopsy.

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Histopathology of the Skin

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Table 2.1 Specific stains used in dermatology. Stain

Stained material

Hematoxylin and eosin Entire skin (HE) Elastica van Gieson

Fig. 2.1-2 Procedure of skin biopsy. Incisional biopsy with a surgical knife.

Stained color Blue (nucleus), magenta (cytoplasm, etc.)

Collagen fibers

Red

Elastic fibers

Black

Azan Mallory

Collagen fibers

Blue

Masson trichrome

Collagen fibers

Green

Periodic acid-Schiff (PAS)

Basement membrane Red

Toluidine blue

Glycogen

Red

Neutral mucopolysaccharides

Red

Fungi

Red

Mast cells

Purple (metachromasia)

Acid mucopolysaccharides Blue Alcian blue

Acid mucopolysaccharides

Blue

Sudan III

Fats

Orange-red

Congo red

Amyloids

Red

Dylon

Amyloids

Orange-red

Berlin blue

Hemosiderins

Blue

Kossa

Calcium

Black

Grocott

Fungi

Black-purple

Ziehl Neelsen

Mycobacteria

Red

B. Dermatopathology When observing a pathological specimen, it is necessary to identify the abnormality in the specimen by comparison with normal findings (Figs. 2.2-1 and 2.2-2). This section introduces fundamental terms for skin pathological changes and diseases.

a. Epidermis 1. Acanthosis (epidermal hyperplasia) a

b

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d

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Fig. 2.2-1 Normal skin (hematoxylin and eosin staining). a: Normal skin of the forearm. A basket-weaved horny cell layer is seen. Gaps between the stained horny cell layers are lipids that dissolved during fixation. These gaps indicate that the skin is well protected by moisturizing lipids.

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Acanthosis describes thickening of the epidermis. It is classified into flat (the entire site thickens moderately; e.g., in chronic eczema), proriasiform (epidermal protrusions are extended), papillomatous (the epidermis projects upwards; e.g., with viral warts or seborrheic keratosis), and pseudocarcinomatous (pseudosquamous cell carcinomas project irregularly downward; e.g., chronic ulcer margin, deep mycoses) (Figs. 2.3 and 2.4).

2. Epidermal atrophy (epidermal hypoplasia) Epidermal atrophy (epidermal hypoplasia) is caused by reduction of keratinocytes (Fig. 2.5). It leads to thinning of the epidermis. As a result, the papillary processes are diminished or lost. It

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B. Dermatopathology

29

2 normal

flat

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psoriasiform

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papillomatous

pseudocarcinomatous

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Fig. 2.3 Patterns of acanthosis.

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Fig. 2.2-2 Normal skin (hematoxylin and eosin staining). b: Normal skin of the sole. A thick horny cell layer is seen. c: Scalp. Many follicles can be seen. d: Face. Sebaceous glands are abundant.

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Fig. 2.4 Acanthosis. Chronic eczema.

is often found in senile skin, discoid lupus erythematosus, lichen planus and actinic keratosis.

3. Hyperkeratosis The horny cell layer becomes abnormally thick. This is seen in psoriasis vulgaris, ichthyosis and callus (Fig. 2.6). In ichthyosis, hyperkeratosis is due to detachment and exfoliation of the horny cell layer, a process called retention hyperkeratosis. Keratinization associated with hair follicles is called follicular keratosis.

4. Parakeratosis Parakeratosis is caused by incomplete keratinization in which nuclei remain in the cells of the horny cell layer (Fig. 2.7). In normal skin, keratinocytes denucleate when they reach the horny

Fig. 2.5 Epidermal atrophy. Dermatomyositis.

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cell layer; however, keratinocyte formation in inflammatory diseases such as psoriasis vulgaris or in tumorous diseases such as actinic keratosis and Bowen’s disease takes place so quickly that most of the nuclei remain in the horny cell layer. It is frequently accompanied by hyperkeratosis and hypogranulosis. The nuclei remain physiologically in the mucous membranes. Wedge-shaped or columnar parakeratosis, called cornoid lamellae, is observed in porokeratosis (Chapter 21).

Fig 2.6 Hyperkeratosis. Chronic eczema.

5. Dyskeratosis Dyskeratosis occurs when some keratinocytes keratinize abnormally before they reach the horny cell layer (Fig. 2.8). The keratinocytes become apoptotic and necrotic. The nuclei shrink and contain eosinophilic cytoplasm. Since intercellular bridges between the peripheral keratinocytes are lost, the cells become round. Dyskeratosis is often found with inflammatory diseases and malignant tumors. It is termed “grains” in Darier’s disease and “individual cell keratinization” in Bowen’s disease.

6. Hypergranulosis Fig. 2.7 Parakeratosis. Psoriasis vulgaris.

Hypergranulosis is a thickening of the granular cell layers to four or more layers from the normal one to three layers (Fig. 2.9). It is often found in lichen planus, viral warts and congenital ichthyosis.

7. Granular degeneration, Epidermolytic hyperkeratosis

Fig. 2.8 Dyskeratosis. Bowen’s disease.

In granular degeneration, numerous vacuolated cells containing large keratohyaline granules appear in the granular cell layer and suprabasal cell layer (Fig. 2.10). It is characteristic of Vörner palmoplantar keratosis and bullous congenital ichthyosiform erythroderma (Chapter 15). It may also be found in epidermal nevus and even in normal skin.

8. Spongiosis, Intercellular edema Spongiosis occurs when the spaces between neighboring keratinocytes are enlarged by intense edema. As a result, the intercellular space becomes extended and distinct (Fig. 2.11). When aggravated further, intradermal blisters (spongiotic bullae) form. It is found in eczemas and dermatitises such as contact dermatitis, atopic dermatitis and acute eczema.

9. Intracellular edema (ballooning degeneration) Fig. 2.9 Hypergranulosis. Parapsoriasis.

Intracellular edema is the infiltration of cytoplasm into keratinocytes (Fig. 2.12). As the swelling develops, the cells deform

B. Dermatopathology

31

2

and become spherical (ballooning degeneration). If the cytoplasm swells even further, the cells break and the membranes remain in a network pattern (reticular degeneration). It is found in eruptions caused by viral infections such as that of the herpes simplex virus.

10. Acantholysis Acantholysis is the dispersion of keratinocytes resulting from the dissociation of keratinocyte intercellular adhesion, particularly that of desmosomes. Intercellular spaces and blisters form, with acantholytic cells (spherical keratinocytes that have lost their intercellular adhesion) floating inside. Acantholytic cells have a tendency to become dyskeratotic (Fig. 2.13). The phenomenon is found in pemphigus, Hailey-Hailey disease and Darier’s disease, and it may also be found in part of the lesions of actinic keratosis, keratoacanthoma, warty dyskeratoma and squamous cell carcinoma.

Fig. 2.10 Granular degeneration. Bullous congenital ichthyosiform erythroderma.

11. Blister, Bulla Blisters, whose contents are cytoplasm and infiltrating cells, are divided into intraepidermal and subepidermal, according to the histological findings (Fig. 2.14). Intraepidermal blisters are classified by formation mechanism into severe spongiosis (eczema/dermatitis group), prominent acantholysis (e.g., pemphigus vulgaris), reticular degeneration (e.g., herpes infection) and basal cell degeneration (e.g., burns, epidermolysis bullosa simplex). Causative diseases of subepidermal blistering are autoimmune bullous diseases such as bullous pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis (Duhring) and epidermolysis bullosa, and burns (Chapter 4).

Fig. 2.11 Spongiosis. Acute eczema.

12. Pustule A pustule is a blister containing purulent components (mainly neutrophils). A small pustule below the horny cell layer is called Munro’s micro-abscess, which characterizes psoriasis vulgaris (Fig. 2.15). A multilocular pustule, also called a spongiform pustule, is caused by damage to keratinocytes from neutrophilic infiltration in which intercellular junctions are retained. It resembles the network formation that is found in pustular psoriasis (Kogoj’s spongiform pustule) (Fig. 2.16). Pautrier’s microabscess is produced by infiltration of tumorous lymphocytes and is not a genuine pustule (refer to the following section).

13. Exocytosis (cell infiltration into the epidermis) Exocytosis is the infiltration of inflammatory cells and

Fig. 2.12 Intracellular edema. Herpes simplex.

Fig. 2.13 Acantholysis. Pemphigus vulgaris.

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Histopathology of the Skin

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Fig. 2.14 Bulla. Bullous pemphigoid.

erythrocytes into the dermis. It is mostly found in spongiotic space. Infiltration of lymphocytes is seen in epidermal inflammatory diseases such as contact dermatitis and atopic dermatitis. Infiltration of multinucleated leukocytes is observed as a pustule in impetigo contagiosa, palmoplantar pustulosis and psoriasis. In cutaneous T-cell lymphomas such as mycosis fungoides, tumorous T cell may infiltrate into the epidermis forming a mass that does not become spongiform; it is called Pautrier’s microabscess for its resemblance to an abscess (Fig. 2.17). Langerhans cells infiltrate into the epidermis in Langerhans cell histiocytosis.

b. Dermo-epidermal junction 1. Vacuolar degeneration (hydropic degeneration)

Fig. 2.15 Munro’s microabscess. Psoriasis vulgaris.

Fig. 2.16 Kogoj’s spongiform pustule. Pustular psoriasis.

Vacuolar degeneration occurs when the dermo-epidermal junctions become vacuolated and ill defined as a result of basal cell degeneration (Fig. 2.18). It is often accompanied by edema and lymphocyte infiltration, and the basal membranes are lost at the site. It is an inflammation that mainly occurs at the dermo-epidermal junction. When further aggravated, subepidermal blisters form. Melanin granules contained in basal cells may permeate into the dermis, a condition called incontinentia pigmenti histologica. The macrophages phagocytose melanin granules. Dyskeratosis caused by necrotic keratinocytes is seen in erythema multiforme, lichen planus, lupus erythematosus and graft-versushost disease (GVHD). An eosinophilic Civatte body with a diameter of 10 mm may be found immediately beneath the dermis (Fig. 2.9).

2. Melanin synthesis abnormality Production of melanin pigment in the basal epidermal layer is increased by exposure to ultraviolet radiation. When pigment is lost, leukoderma is observed. Generally, to diagnose melanin synthesis abnormality, a DOPA test or an immunohistological test is performed. Albinism: A congenital abnormality of melanin synthesis. Melanin loss can be identified by Fontana Masson staining, for example. Idiopathic guttate hypomelanosis: Melanocytes experience functional reduction by aging. Nevus of Ota: Ectopic melanocytes are found in the dermis. Chloasma: Melanocytes and melanin pigments increase. Freckles: Melanocytes experience functional increase.

Fig. 2.17 Pautrier’s microabscess. Mycosis fungoides.

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2 c. Dermis 1. Inflammatory cell infiltration Inflammatory cell infiltration occurs when inflammatory cells such as neutrophils, eosinophils, lymphocytes, plasmacytes, macrophages and mast cells infiltrate around the blood vessels (perivascular infiltration). There are several infiltration patterns, such as lichenoid infiltration (the cells infiltrate in a band resembling that in lichen planus), vasculitis (the cells cause fibrinoid degeneration, blood clots, or bleeding in the blood vessels), and nodular infiltration. The principal infiltrating cells and the causative diseases are shown in Table. 2.2.

2. Granuloma A granuloma is a thick aggregation of histiocytes (mostly macrophages) that form focal chronic infiltration. The macrophages in granulomas are called epithelioid cells. Besides macrophages, in granulomas one can observe lymphocytes, fibroblasts, degenerated connective tissue, and blood vessels. Granulomas are classified according to the distribution patterns and subtypes of inflammatory cells, as below. Sarcoidal granuloma: The main components are epitheliod cells

Fig. 2.18 Vacuolar degeneration. Graft-versus-host disease. Dyskeratosis is also seen, from the apotosis of the epidermal keratinocytes.

Table 2.2 Diseases with inflammatory infiltration into the skin. Infiltrated cells Neutrophils

Disorders early-stage inflammation; irritant contact dermatitis, erythema nodosum, etc. infections; impetigo, candidiasis, etc. disorders associated with reactions of immunocomplex and complements; cutaneous small-vessel vasculitis, Sweet’s disease, Behçet’s disease

Eosinophils

early inflammation; incontinentia pigmenti autoimmune diseases; pemphigus, bullous pemphigoid, etc. type I allergy malignant diseases; mycosis fungoides, Langerhans cell histiocytosis

Lymphocytes inflammations; allergic diseases, etc. Plasma cells

infections; syphilis, lymphogranuloma venereum deep fungal infection actinic keratosis, syringocystadenoma papilliferum, etc.

Histiocytes

granulomatous diseases; sarcoidosis, granuloma annulare, etc.

Mast cells

inflammations; atopic dermatitis, chronic eczema, lichen planus, etc. other; wounds (especially during healing), neurofibroma, etc.

Fig. 2.19 Sarcoidal granuloma. Cutaneous sarcoidosis. In sarcoidosis, epithelioid cell granuloma is accompanied by few inflammatory cell infiltration, which is also called “naked granuloma.”

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Histopathology of the Skin

2

and giant cells. It contains a few necrotic foci and slight lymphocytic infiltration. This is the typical epithelioid cell granuloma observed in sarcoidosis (Fig. 2.19). Tuberculoid granuloma: Epithelioid cell granuloma with caseous necrosis in the center and abundant lymphocytic infiltration at the periphery is observed. Palisading granuloma: The granuloma contains degenerated collagen fibers and mucin deposition in the center, with peripheral macrophages in a palisade or circular pattern. It is found in granuloma annulare and rheumatoid nodules. Suppurative granuloma: An abscess (neutrophilic infiltration) surrounded by macrophages and lymphocytes, it is found in deep mycoses. Foreign-body granuloma: Macrophages, neutrophils and lymphocytes accumulate around an extrinsic body (e.g., glass, suture thread, animal hair, plant fiber) or an intrinsic body (e.g., elastic fiber, calcium deposits, cholesterin crystal). It is a normal reaction to foreign bodies (Fig. 2.20). Giant cells that have phagocytosed a foreign body are often observed; however, the foreign substance becomes buried in fibrous tissues over time. Fig. 2.20 Foreign-body granuloma. Cholesterin deposition (arrows).

foreign body giant cell

Langhans giant cell

Touton giant cell

Fig. 2.21 Giant cells originating from histiocytes.

3. Giant cell Giant cell is the general term for cells that contain a characteristically large nucleus. Most giant cells derive from macrophages and are multinuclear from the fusion of macrophages or repeated nuclear division (Fig. 2.21). Ballooning observed in viral diseases and Reed-Sternberg cells found in Hodgkin’s disease are types of giant cells. These are other types: Foreign-body giant cell: Macrophages grow large by phagocytosing foreign substances The nuclei are irregularly arranged (Fig. 2.20). Langhans giant cell: Syncytial macrophages with regularly arranged nuclei in a circular or horseshoe-shaped arrangement. These often found in tuberculosis, sarcoidosis, and lichen nitidus. Touton giant cell: These macrophages phagocytose fat tissue. The eosinophilic cytoplasm at the center of the cell is surrounded by a nucleus that is further surrounded by foamy light cytoplasm. Touton giant cells are found in juvenile xanthogranuloma and xanthoma.

4. Changes in connective tissue Fibrosis (irregular proliferation of fibroblasts and collagen fibers such as in scarring and dermatofibroma) and sclerosis (decrease of fibroblasts, swelling or homogenization of collagen fibers, radiation dermatitis, scleredema) are observed in changes of collagen fibers. Elastic fibers decrease in size and number, fracture, and degenerate in senile skin and pseudoxanthoma elasticum. Edema with detachment of connective tissue and accumu-

B. Dermatopathology

d. Subcutaneous fat tissue

subcutaneous tissue

Substances that deposit in the dermis include amyloids (e.g., in macular amyloidosis, lichen amyloydosis), mucins (e.g., myxedema, lupus erythematosus), calcium (e.g., in carcinosis cutis, pseudoxanthoma elasticum, CREST syndrome), hemosiderins (e.g., in bruising, angiitis, hemochromatosis), uric acid, porphyrin and hyaline.

dermis

5. Deposition of foreign substances

2 epidermis

lation of serous fluid (scleredema) and dermis elevation caused by projected dermal papillae (papillomatosis) are also changes of connective tissues.

35

septal panniculitis

Lipogranuloma, lipoatrophy, liponecrosis, lipolysis, lipoma and liposarcoma are other changes of fat tissue.

subcutaneous tissue

2. Other changes in fat tissue

dermis

Panniculitis is an inflammation of the subcutaneous fat tissue (Figs. 2.22 and 2.23). It is categorized by the site of inflammation. In septal panniculitis, inflammation occurs mostly in the septa of the subcutaneous fat tissue, such as seen in erythema nodosum. In lobular panniculitis, inflammation occurs in the lobules of the fat tissue, such as seen in erythema induratum. Panniculits can also occur in acute pancreatitis from the fat necrosis that occurs as a complication.

epidermis

1. Panniculitis

lobular panniculitis

Fig. 2.22 Differences between septal panniculitis and lobular panniculitis. Black dots are the infiltrated inflammatory cells.

Fig. 2.23 Septal panniculitis. Erythema nodosum.

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C. Immunohistochemistry Table 2.3 Monoclonal antibodies frequently used in dermatology. Marker

Positive skin component/ disorder

cytokeratin (CK)

epithelial cell

CAM 5.2 (CK8, CK18, CK19)

sweat gland, mesothelioma

cytokeratin 20

Merkel cell

epithelial membrane antigen (EMA)

epithelial cell

vimentin

mesenchymal cell

desmin

striated muscle, smooth muscle

a smooth muscle actin (SMA)

striated muscle, smooth muscle

neuron-specific enolase (NSE)

Schwann cell, melanocyte, cartilage

S-100 protein

nerve fiber, paraganglionic cells, melanocyte

Immunohistochemical techniques are used to identify substances in tissue by marking them with specific antibodies. They are widely used in dermatology for identification of antinuclear antibodies, autoantibodies of autoimmune blistering diseases, and infiltration of malignant lymphoma cells. The methods of labeling are immunofluorescence using fluorescent pigments, and an immunoenzyme method. Antibodies frequently used in dermatology are listed in Table 2.3.

1. Immunofluorescence (IF)

HMB45, MELAN A malignant melanoma carcinoembryonic antigen (CEA), CD66e

sweat gland

Ki-67 (Mib-1)

proliferation marker of tumor cell

factor VIII

endothelial cell of the vessel

factor XIII

endothelial cell, dendritic cell

gross cystic disease fluid protein (GCDFP)-15

sweat gland

CD1a

Langerhans cell

CD3

T cell

CD4

helper T cell

CD8

cytotoxic T cell

CD20 (L26)

B cell

CD30 (Ki-1)

Hodgkin’s disease, anaplastic large-cell lymphoma

CD31

endothelial cell, fibrous tumor

CD34

endothelial cell, hemangioma, dermatofibrosarcoma protuberans

CD56

natural killer cell

CD68

macrophage, myeloid cell

CD79a

B cell

cyclin D1

mantle cell lymphoma

Immunofluorescence (IF) is an immunological staining method that uses antibodies labeled with fluorescent material such as fluorescein isothiocyanate (FITC) to detect the molecule connected to the antigen. It is used to detect antigens, antibodies, complements and causative factors of diseased tissues and to examine serologic reactions. IF techniques are classified by the labeled antibody reactions into direct fluorescent antibody test, indirect fluorescent antibody test and complement fixation test (Figs. 2.24 and 2.25).

1) Direct IF A fluorescent-labeled antibody is used to detect the antigen. When the labeled antibody detects the tissue, fluorescence appears at the site with the target substance, and that fluorescence can be observed by fluorescent microscopy. This type of test is used for detection of the autoantibody in vivo, mainly in autoimmune diseases such as lupus erythematosus, pemphigus vulgaris and bullous pemphigoid. Direct IF is also used for detection of pathogenic microbes in tissues.

2) Indirect IF Indirect IF is a two-phase technique whereby an unlabeled primary antibody reacts against a target substance, and a labeled secondary antibody is reacted against the primary antibody. In dermatology, it refers to detection of an antibody, especially in the patient’s blood. In bullous pemphigoid, for example, an IgG antibody circulating in the bloodstream reacts directly with the basal membrane of the patient. Direct IF is used to detect the antibody reacting in a patient’s skin in vivo. In indirect IF, a patient’s serum is reacted against normal skin, and then a labeled anti-IgG antibody is reacted. If the IgG anti-basal membrane antibody is present in the serum, fluorescence is observed on the basal membrane zone. Indirect IF is widely used not only in dermatology but in other fields for various tests, including detection of antibodies and

37

C. Immunohistochemistry

2

A. direct IF

＋

antigen

labeled antigen-specific antibody

fluorescence

B. indirect IF

＋

antigen

＋

antigen specific antibody (IgG)

anti-IgG antibody labeled with fluorescent

fluorescence (+)

C. complement IF ＋

antigen

＋

antigen complement specific antibody

＋

labeled anti-complement antibody

fluorescence (+)

Fig. 2.24 Mechanisms of the immunofluorescence technique. (Ueki H, et al, editors. Atlas of immune tissues in dermatology. Nankodo; 1996).

syphilis FTA-ABS tests (Chapter 27) using normal skin as the substrate.

3) Complement IF An unlabeled primary antibody is reacted against the target substance and is provided with complement components. Then a labeled secondary antibody (labeled anti-C3 antibody) is reacted against the target substance.

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2. Immunoenzyme method In the immunoenzyme method, an enzyme rather than a fluorescent material is labeled with an antibody. Antigens, immunogloblins and complements can be detected using the enzyme reaction. Enzymes such as peroxidase are labeled with an antibody to react against the target molecules in the tissue in the same way as in the IF technique. The presence of the target substance and its distribution are indicated by the presence and a distribution of the pigments. Immunoenzyme method has the following advantages over IF: the enzymatic reaction makes electron microscopic observation possible, the reaction is easy to observe and has a high detection range, and the samples can be stored longer than those of IF. It

Fig. 2.25-1 Examples of immunofluorescent staining pattern. a: Epidermal basement membrane (bullous pemphigoid). b: Intercellular space of the keratinocyte (pemphigus vulgaris).

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Histopathology of the Skin

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b

can also be used for electron microscopic section.

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Fig. 2.25-2 Examples of immunofluorescent staining pattern. c: Perivascular area (anaphylactoid purpura).

D. Electron microscopy (EM) and immuno EM

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The electron microscope is a device that generates enlarged images of a specimen by emitting electron beams instead of visible light. Electron microscopy (EM) and immuno EM achieve magnifications of 1,000 times and greater, so they can be used to observe fine intracellular and intercellular structures (e.g., Birbeck granules in Langerhans cells) that are not visible by light microscopy. The transmission electron microscope exposes an ultra-thin specimen possible magnifip q h i to anj electron k beam. l It is m n to achieve o cations of 500,000 times. Immuno EM, a combination of immunostaining and electron microscopic observation, has greatly contributed to the development of dermatological science, such as in the identification of autoantigens in autoimmune blistering diseases (Fig. 2.26). In scanning EM, electron beams reflected from an exposed object are detected. It is effective in revealing three-dimensional structure; however, the magnifying power is not as high as that of transmission EM. p q j i k l m n o r

Fig. 2.26 Immunoelectron microscopy of the bullous pemphigoid (BP) proteins in normal skin. a: BP180, a transmembrane protein in the basement membrane zone. NC16a, the most important domain of BP pathogenesis, is in the basal cell membrane. b: BP230 is immediately inside the basal cell membrane, a component of the hemidesmosome.

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Immunology of the Skin 3

The recent rapid progress in immunology has had a great influence on dermatology. Many diseases are now understood thanks to increased knowledge of immunology. Furthermore, it has come to be known that the skin itself plays a major role in the immune system. This chapter introduces the fundamental mechanisms of immunology and the pathophysiology of various skin diseases.

A. Basics of immune reactions hematopoietic stem cell

a. Immune system Immunity is crucial in protecting the human body from pathogenic microorganisms. Skin physically prevents foreign microorganisms from invading the body. The human body coexists with microorganisms on the surface of the skin, in the intestines and in mucous membranes. It thereby maintains a balance; however, if the balance collapses for whatever reason, the microorganisms begin to harm the body, and the immune system is activated. The immune system performs the following functions: ●Distinguishing between “self” and “non-self.” ●Excluding “non-self.” ●Remembering what has invaded (immunologic memory).

multipotent progenitor cell

common lymphoid progenitor cell

B cell

T cell

These functions are performed by the immunocompetent cells, such as lymphocytes and antigen-presenting cells, both of which are derived from bone marrow (Fig. 3.1). How these cells act against various pathogens is briefly described below.

NK cell

macrophage granulocytes

b. Reaction pattern Foreign substances (antigens) including bacteria, viruses, transplanted organs and certain proteins are distinguished as “non-self” by the immune system. The receptor, also called the major histocompatibility complex (MHC), plays a critical role in identifying whether a substance is self or non-self. In humans, it is called HLA (human leukocyte antigen), because it was discovered in leukocytes. HLA is classified as class I (HLA-A,B,C) or class II (HLA-DP,DQ,DR)(Fig. 3.2). Every human has a different HLA pattern that identifies what is non-self. Some diseases that are thought to occur in individuals with specific HLA have been revealed (Table 3.1). A cell or a protein recognized as non-self is phagocytosed by a histiocyte (macrophage) or a dendritic cell, such as a cutaneous Langerhans cell. The phagocytosed substance is processed, and 39

common myeloid progenitor cell

cytotoxic T cell

helper T cell

neutrophil eosinophil basophil

plasma cell

Fig. 3.1 Myelogenous cells composing the immune system.

40

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Immunology of the Skin

#6 chromosome

HLA

3 DP

DQ

class II antigen

DR

B

class III antigen

C

A

class I antigen

Fig. 3.2 HLA (human leukocyte antigen) genes on the short arm of chromosome 6. Genetic recombination causes the HLA pattern to differ for each individual.

part of it is recognized by lymphocytes as antigenic information associated with MHC class II molecules. The cells that actively engulf the foreign substance and transmit the information to T cells by MHC class II molecules are called antigen-presenting cells (APC). Cells infected by latent viruses degrade the virusderived proteins and transmit the information to T cells by the function of MHC class I molecules. The information of the antigen is conveyed by the combination of a T-cell receptor (TCR) and MHC, resulting in immune activation and reaction (Fig. 3.3).

c. Humoral immune reaction 1. Antibodies The antibodies, proteins produced by B cells, react against infectious agents or pathogenic proteins (antigens) to inhibit infections and neutralize protein toxicity. Numerous specific B cells and antibodies corresponding to the antigens exist in the body. There are five immunoglobulins in descending order of concentration from IgG, IgM, IgA, IgD, to IgE (Table 3.2). IgG, produced at the time of infection or in the late stage of infection, accounts for 75% of immunoglobulins and plays a central role in the humoral immune reaction (Fig. 3.4). IgM appears preceding IgG at the early stages of infection and strongly activates protein complements. IgA is seen abundantly in exocrine secretions, such as mucus, where it prevents invasion of causative factors. IgE reacts to basophils and mast cells to evoke type I allergy.

Table 3.1 Association between HLA complex and skin diseases. Disorder

Associated HLA in ethnic Japanese

Associated HLA in Caucasians

Behçet’s disease

B51

B51

11

Systemic lupus erythematosus

A11, B40, DR2, DRW9

B8, DR2, DR3

12

Neonatal lupus erythematosus

DW12

Chapter

12 DR3, DW3

12

Rheumatoid arthritis

DR4

DR4

12

Pemphigus vulgaris

A10, DR4

Sjögren syndrome

A10, B13

14

Herpes gestationis

A1, B8, DR3

14

Epidermolysis bullosa acquisita

B8

14

Dermatitis herpetiformis (Duhring)

B8, DW3

14

B27

15

Cw6

15

Pustular psoriasis Psoriasis vulgaris

Cw6

41

A. Basics of immune reactions

MHC class Ⅰ

MHC class I molecule CD8

T-cell receptor

3

perforin apoptosis of the infected cell

Fas-Fas L B7 CD28 infected cell cytotoxic T cell

MHC class Ⅱ

Fas

macrophage Th1

B7 CD28 antigen-presenting helper T cell (Th) cell

delayed hypersensitivity reaction against infected cells, etc.

IFN-g

MHC class II molecule T-cell receptor CD4 IL-12

IL-2

IL-4

cytotoxic efffect cytotoxic T cell

Th2

antibody production (kills pathogen)

IL-4 B cell

Fig. 3.3 Immune reactions classified by MHC class. Each class of MHC presents antigen information to different types of T cells.

2. Complements The complements, proteins contained in serum, are classified into nine types from C1 to C9, and can be subclassified. In the classical pathway, C1 reacts to IgG or IgM antibodies, followed by continuous reaction of complements, and finally the pathogens and infectious cells are penetrated. In the alternative pathway, the reaction is evoked mostly by bacterial components, which directly activate C3, factor B and factor D.

antigen binding sites N terminus

3

3

Antigen type of heavy chain

g

m

a

d

e

Transport across the placenta

(+)

(-)

(-)

(-)

(-)

Activity of complement fixation

(+)

(+)

(-)

(-)

(-)

hinge

ＣＨ２

Fc

ＣＨ３

proteolysis by pepsin

6

ＣＬ

proteolysis by papain

5

ＳＳ

21

ＳＳ

0.00005

ＶＬ

ＳＳ

Ｓ Ｓ

0.03

ＳＳ

3.0

ＳＳ

1.5

ＳＳ ＳＳ

12.0

ＳＳ

ＣＨ１

ＳＳ

184,000 188,000

Fab F（ab´）2 L chain

Ｓ Ｓ

160,000 (390,000)

IgE

ＳＳ

Half-life in blood (days)

150,000 970,000

IgD

ＳＳ

Serum concentration (mg/ml)

IgA (secretory)

ＳＳ

Molecular weight

IgM

ＳＳ

IgG

H chain

ＳＳ

ＶＨ

Table 3.2 Basic characteristics of immunoglobulins.

C terminus

Basic structure

(monomer) (dimer) secretory piece J chain

J chain

Fig. 3.4 Basic structure of human immunoglobulin (IgG). Fab: Fragment antigen binding. Fc: Crystallizable fragment. VL: Variable light chain. CL: Constant light chain. VH: Variable heavy chain. CH: Constant heavy chain.

42

3

3

Immunology of the Skin

MEMO Clinical symptoms resulting from abnormalities of complements Various skin diseases, including those with systemic lupus erythematosus (SLE) like symptoms, Raynaud’s syndrome, angioneurotic edema and opportunistic infections, may be caused by congenital abnormalities and deficiencies of complementary proteins.

B. Immunocompetent cells a. Immunocompetent cells in general 1. T cells T cells express T-cell receptors that recognize the antigen information associated with MHC molecules (Fig. 3.3). T cells are produced in the bone marrow and develop in the thymus. T cells are classified by function into CD4 positive helper T cells (helper T lymphocyte; Th) and CD8 positive cytotoxic T lymphocytes (Tc). Th contains CD4 on the cell surface, by which Th adheres to MHC class II. Therefore, Th reacts against antigen-presenting cells and B cells, which contain MHC class II. Th differentiates into subtype Th1 or Th2, depending on the surrounding cytokine environment (Fig. 3.3). Th1 secretes cytokines such as IL-2 and IFN-g , activating histiocytes (macrophages) primarily, and it induces cellular immunity by evoking various inflamatory reactions. Th2 secretes IL-4 and IL-5, activates antibody production in B cells, and inactivates foreign substances (humoral immunity). It is known that Th1 is involved mostly in type IV allergy while Th2 is involved in type I allergy (atopic diseases). Tc contains CD8, by which Tc is associated with MHC class I to initiate cytotoxic immunity (Fig. 3.3); in this way, non-self cells and virus-infected cells are destroyed. Tc is important in transplantation immunity, tumor immunity and viral infections. Recently, the presence of another subtype – regulatory T cell (Treg) – has been identified. Treg is considered to be involved in immune control, including suppression of autoimmune disease onset. It is also known that some Th and Tc circulate in the blood after an immune reaction to guard against re-infection.

2. B cells B cells derive from hematopoietic stem cells in the bone marrow, after which they differentiate. They react against foreign antigens in lymph nodes, the spleen, and peripheral tissues to differentiate into antibody-forming cells (plasma cells); B cells produce antibodies in this process. B cells contain MHC class II and

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B. Immunocompetent cells

activate T cells as antigen-presenting cells. Immunoglobulins expressed on the surface of B cells react to the corresponding targeted antigens to convey information to T cells. When activated, most of the B cells differentiate into antibody-producing cells that provide antibodies against the antigens and die in the course of time – except for some that differentiate into memory B cells so that they are able to produce antibodies immediately upon reinfection.

3. Histiocytes (macrophages) Histiocytes (macrophages) are bone marrow-derived cells that have intense phagocytic reactivity. There are dermal-originated histiocytes and monocytes circulating in the blood. Histiocytes degrade phagocytosed antigen proteins into peptides and present the antigen information to T cells by MHC class II (Fig. 3.3). In inflammation, histiocytes proliferate, migrate to loci, leave various cytokines, and induce phagocytosis of causative factors and injure the infected cells. Histiocytes may fuse to form enlarged cells. They are the main cells to form granulomas in chronic inflammation (Chapter 2).

43

MEMO Th1 is involved in cytotoxic immunity, including apoptosis; Th2 is involved in humoral immunity, including type I allergy. Th1 and Th2 release mutually inhibitive cytokines; it is thought that this maintains a balance between the two (Th1/Th2 balance). In recent years, various allergies and malignant tumors have been explained by the concept of Th1/Th2 imbalance. For example, atopic dermatitis and type I allergy are thought to be caused by a Th2-dominated immune reaction, and organ-specific autoimmune diseases and arterial sclerosis are thought to result from a Th1-governed immune reaction.

Th1/Th2 balance

4. Mast cells Mast cells play a central roll in type I allergy. They contain high-affinity IgE receptors (FceRI) and considerable amounts of histamines. When binded with IgE and further cross-linked by an antigen to react to IgE, mast cells are activated to release inflammatory cytokines that lead to dermal edema in erythema or urticaria. Mastcytosis is caused by tumorous proliferation of mast cells.

5. Eosinophils Eosinophils have phagocytic and cytotoxic functions. They are associated with atopic diseases (type I allergy), autoimmune blistering diseases, and parasitic infections. Eosinophils are activated by Th2-derived IL-5. Morphologically, they are characterized by having multiple eosinophilic granules (Fig. 3.5). They do not usually exist in normal skin.

20 m m

Fig. 3.5 Eosinophil. The cytoplasm is eosinophilic (stained red in Hematoxylin-Eosin). Note the multiple nuclei.

6. Neutrophils Neutrophils are phagocytic and play a large role in fighting bacterial infections (Fig. 3.6). They are hardly ever found in normal skin. They are also activated in inflammatory diseases. Neutrophilic infiltration (pustule) is observed in psoriasis vulgaris and Sweet’s disease.

20 m m

Fig. 3.6 Neutrophil. In skin, cytoplasm of neutrophils is less eosinophilic than that of eosinophils. A neutrophil has a multiple segmented nuclei.

3

44

3

Immunology of the Skin

7. Basophils

3

Like eosinophils and neutrophils, basophils are also granular leukocytes, and they contain multiple basophilic granules. They contain histamines in the granules and have FceRI on the surface. They are involved in type I allergy. The functions of basophils are similar to those of mast cells.

b. Immunocompetent cells specific to skin 1. Langerhans cells

Fig. 3.7 Langerhans cell electron micrograph.

Langerhans cells are bone marrow-derived cells and appear as dendritic cells. They contain the characteristic racquet-shaped Birbeck granules in the cellular cytoplasm (Figs. 3.7 and 3.8). Langerhans cells are antigen-presenting cells that are specific to the skin. Langerhans cells adhere to the epidermal keratinocytes by E-cadherins, functioning as sentinels against foreign antigens. When presenting an antigen to T cells, Langerhans cells are known to detach from the epidermis to reach the regional lymph nodes through the lymphatic vessels (Fig. 3.9). On the surface of the human Langerhans cells are MHC class II, CD1a, and S-100 proteins; this is useful for identifying them. With stimulation by antigens, they express CD80 and CD86 by the functions of GMCSF and TNF-a secreted from keratinocytes to strongly activated T cells. Langerhans cells disappear in lesions in graft-versus-host disease (GVHD).

2. Keratinocytes

Fig. 3.8 Birbeck granules (arrows). High-power magnification of Fig.3.7. Birbeck granules look like tennis racquets in sectional image.

Keratinocytes are involved not only in cornification but also in skin immunity. They produce and secrete various cytokines to stimulate immuno-incompetent cell activation (Table 3.3). IL-1 a is particularly abundant in keratinocytes. When keratinocytes are destroyed by inflammation or injury, IL-1a is released to evoke activation of lymphocytes, histiocytes (macrophages), and vascular endothelial cells, which induces an inflammatory reaction.

3. Dermal dendrocytes Dermal dendrocytes are bone marrow-derived cells found in the upper dermal layers. Since dermal dendrocytes are characterized by expressing the factor XIIIa on their surface and have antigen-presenting ability, dermal dendrocytes are considered to be Langerhans-related cells in the dermis. They increase in number in inflammatory diseases and Kaposi sarcoma.

C. Immunity, Allergic reactions

45

Table 3.3 Main cytokines secreted by keratinocytes. Classification, cytokines

Main functions

Multifunctional cytokines IL-1a IL-6 IL-7 IL-12 IL-15 IL-18 TNF-a MIF

Induction of secondary cytokines

6444447444448

Interleukin (IL)

Modulation of adhesion molecules Modulation of activation and migration of T cells, B cells and macrophages Activation of endothelial cells and fibroblasts Modulation of activation and migration of Langerhans cells (IL-1a, TNF-a)

Induction of fever and acute inflammatory proteins

Chemotactic factor: associated with leukocyte migration IL-8

Activation and migration of T cells and neutrophils

Colony stimulating factor: associated with leukocyte proliferation GM-CSF

Activation of granulocytes, macrophages, T cells and Langerhans cells

G-CSF

Proliferation of granulocytes

M-CSF

Proliferation of macrophages

Growth factor: associated with local cutaneous reactions TGF-a

Proliferation of keratinocytes

b-FGF, PDGF

Proliferation of fibroblasts and endothelial cells

Suppression factor: modulates immunity TGF-b

Suppression of keratinocytes and endothelial cells

IL-10

Suppression of immunity through Th1 cells

IL: interleukin, TNF: tumor necrosis factor, MIF: macrophage migration inhibitory factor, GM-CSF: granulocyte macrophage colony-stimulating factor, G-CSF: granulocyte colony-stimulating factor, M-CSF: macrophage colony-stimulating factor, TGF: tumor growth factor, b-FGF: basic fibroblast growth factor, PDGF: platelet derived growth factor

C. Immunity, Allergic reactions Skin is a major organ where immune/allergic reactions occur. Various skin diseases have been increasingly understood by the concept of immunity and allergic reactions, which are generally classified into the four categories established by Coombs & Gell (Table 3.4).

1. Type I allergy Type I allergy is caused mainly by mast cells. Since a reaction occurs 5 to 15 minutes after an antigen (allergen) is administered, it is also called an immediate hypersensitivity. Mast cells with IgE on the surface react to antigens, and chemical mediators such as histamines and leukotrienes are then secreted by the mast cells (Chapter 8). These chemical mediators enhance vascular permeability, to produce edema; in addition, they induce migration of

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3

46

3

Immunology of the Skin

eosinophils, to evoke inflammation. Therefore, nasal discharge, pruritus, and bronchial asthma are induced, and blood pressure is decreased, by vascular dilatation. A patient with these symptoms may undergo anaphylactic shock in serious cases. The symptoms are transient and usually subside within several hours. Typical skin diseases caused by type I allergy are urticaria and certain types of drug eruptions (urticarial reaction). Other factors are involved in atopic dermatitis; however, IgE plays a pivotal or even solo role in the pathogenetic process. Additionally, allergic rhinitis (hay fever) and allergic bronchial asthma are common diseases caused by type I allergy.

3

2. Type II allergy In type II allergy, antibodies are produced against the antigen on the cell surface to which complements and cytotoxic T cells have been activated, thereby injuring the cells. Type II allergy induces cutaneous diseases such as autoimmune blistering diseases. In bullous pemphigoid, autoantibodies bind to BP180 (BPAG2) in the basal cell hemidesmosomes, and the basal cells are injured by Type II allergy, resulting in blisters (Chapter 14). A drug may function as a hapten to bind with epidermal cells or blood cells to cause Type II allergy. Drug-induced hemolytic anemia, thrombocytopenic purpura, and toxic epidermal necrolysis (TEN) occur by this mechanism. Table 3.4 Classification of allergy. Coombs classification

Type III

Type IV

Immune complex reaction

Cellular immunity (delayed hypersensitivity)

Type II

Type I

Type of reaction

Anaphylaxis (immediate Cytolytic reaction hypersensitivity)

Associated antibodies

IgE

IgG, IgM

IgG, IgM

-

Associated immune cells

Histiocytes, basophils, mast cells

Cytotoxic T cells, macrophages

Multinuclear leukocytes, macrophages

Sensitized T cells, macrophages

Complement

Unneeded

Needed

Needed

Unneeded

Target tissues/cells

Skin, lung, intestines

Skin, erythrocytes, leukocytes, platelets

Skin, vessel, joint, kidney, lung

Skin, lung, thyroid gland, central nervous system, etc.

Disorders

Urticaria, drug eruption, Bullous pemphigoid, hemolytic anemia, idiopathic asthma, pollinosis, thrombocytopenic purpura, TEN, anaphylaxis transfusion incompatibility

Illustration of reaction IgE FC receptor

antigen

cytotoxic T cell IgG or IgM

IgE cytolysis

Allergic contact dermatitis, Cutaneous small-vessel vasculitis, serum sickness, erythema induratum, GVHD glomerulonephritis

immune complex complements

IgG complements

secretion of chemical mediators such as histamine

surface antigen

phagocytes tissue

antigen effector T cells

APCs

secretion of cytokines such as IFN-g

activated macrophage

C. Immunity, Allergic reactions

Blood group incompatibility from transfusion, autoimmune hemolytic anemia, and Goodpasture syndrome are also Type II allergies.

3. Type III allergy Type III allergy occurs when antigen-antibody complexes (immune complexes) deposit in the blood vessels and specific sites of tissue. An infection or a drug induces immune complex deposition, where an allergic reaction causes fibrinoid degeneration and neutrophilic infiltration; this is called cutaneous smallvessel vasculitis (Chapter 11). Serum sickness disease, glomerular nephritis and lupus nephritis are also type III allergies.

MEMO Phagocytic cells engulf antigens that contain proteins of 10,000 molecular weight or greater (complete antigen) and carry the information of the antigens to lymphocytes. That is, non-protein substances of small molecular weight (e.g., carbohydrates, fats, organic compounds, metallic molecules) cannot be antigens themselves; they are called haptens, or incomplete antigens. Although antibodies react to haptens individually, lymphocytes produce such antibodies only in combination with other proteins.

Hapten

4. Type IV allergy Type IV allergy is inflammation caused by a reaction between an antigen and the corresponding T cells (Th1 in particular). There are two stages in type IV allergy: sensitization, and an effector phase. After an initial invasion, the antigen is engulfed by antigen-presenting cells to activate T cells in the regional lymph nodes. At this time, memory T cells along with effector T cells are produced in order to enable them to respond promptly to the secondary invasion of the antigen (sensitization). In the secondary and later invasions, memory T cells are activated by the antigen-presenting cells, and inflammation is evoked that peaks 48 hours after antigenic challenge (effector phase). Since it takes a long time for the reaction to occur, Type IV allergy is also ② contact with the same antigen (challenge phase: 24-48 hrs)

① first contact with antigen (sensitization: about 1 week) allergen (antigen)

papules, vesicles

spongiosis cytokines

Langerhans cell migration to lymph node T cell

antigen presenting by Langerhans cell

memorization

presents antigen information lymph node

Fig. 3.9 Mechanism of allergic contact dermatitis.

effector T cell (Th 1)

47

edema inflammatory-cell infiltration telangiectasia

3

48

3

Immunology of the Skin

called delayed hypersensitivity (Fig. 3.9). Typical lesions caused by type IV allergy are allergic contact dermatitis and graft-versus-host disease (GVHD).

3

D. Immune abnormality 1. Autoimmune diseases Immunity is a mechanism whereby self is distinguished from non-self to exclude non-self. Therefore, autologous proteins do not usually induce immune reactions. If there is a disturbance in the body, antibodies (autoantibodies) are produced against autologous proteins and the immune mechanism tries to exclude self; this phenomenon is called autoimmunity, and the diseases caused by it are called autoimmune diseases. Autoantibodies are thought to appear by the following mechanisms. ●Organs that have been isolated from the immune system since the embryonic phase are exposed to the immune system for an unknown reason and are recognized as non-self (e.g., sympathetic opthalmia, azoospermia). ●Normal tissues are degenerated by viruses or bacteria, and antibodies are produced against the degenerated proteins (e.g., mycoplasma pneumonia). ●Antibodies that have been produced against specific bacteria react with similar self antigens (cross-reaction) (e.g., rheumatic fever). ●Immunologic homeostasis becomes dysfunctional somehow, and lymphocytes that react against autoantigens (forbidden clones), which are excluded in a normal state, are not excluded (some autoimmune diseases, including systemic lupus erythematosus (SLE)). ●Regulatory T cells suffer reduced function for some reason, and immune reactions to self become uncontrolled (some autoimmune diseases, including SLE). The major autoimmune diseases that are treated in dermatological practice include SLE, systemic sclerosis (SSc) and autoimmune blistering diseases such as pemphigus and pemphigoides.

2. Immunodeficiency Immunodeficiency is subclassified into congenital and acquired. In congenital immunodeficiency, the immune factors are congenitally lacking. In acquired immunodeficiency the cause is secondary – the result of a disease or treatment. Different factors are dysfunctional in each disease, resulting in immunodeficiencies such as hypogammaglobulinemia, lymphocytopenia and the decrease of compliment titer. In congenital immunodeficiency diseases, the infection is often

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D. Immune abnormality

by bacteria, viruses, or fungi. The infection tends to become serious. Specific cutaneous findings may be present in each disease, such as the eczematous lesion observed in Wiskott-Aldrich syndrome, and the oculocutaneous albinism and photosensitivity reaction distinctively observed in Chédiak-Higashi syndrome. Secondary immunodeficiency is caused by collagen diseases such as SLE, malignant lymphoma, immuno-proliferative diseases such as leukemia, HIV (human immunodeficiency virus), HTLV-I (human T-lymphotrophic virus 1), and immuno-suppressive treatment (e.g., by anti-cancer drugs, steroids, radiotherapy). The main symptoms are opportunistic infections, including bacterial and viral infections. In patients with AIDS, besides these symptoms, seborrheic eczema, psoriatic rash, purpura, tumor masses and Kaposi sarcoma may also occur (Chapter 23).

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4

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Skin Lesions

4 The most fundamental and important methods of medical examination for skin diseases are visual inspection and palpation. The recent development of biochemical and immune system examination methods has made diagnosis more accurate. However, naked-eye and dermoscopy inspection and palpation are always the most important in acquiring information on the nature of skin lesions, including their distribution, form, color, shape and firmness. A skin lesion is generally called an eruption. Eruptions are divided into primary lesions, which occur in normal skin, and secondary lesions, which are caused secondarily by other eruptions. This chapter briefly discusses the terminology for describing the characteristics of various types of eruptions.

A. Primary skin lesions

Clinical images are available in hardcopy only.

An eruption that occurs in normal skin without any preexisting eruptions is called a primary lesion. These include patches, where the only change is color; papules, nodules and tumors, which are elevated; blisters, cysts and pustules, which contain serum, keratinized substances, pus, etc.; and urticaria, which is temporarily elevated.

1. Erythema

Fig. 4.1 Erythema. Annular erythema in a patient with Sjögren syndrome.

Erythema is patchy redness produced by vasodilation and hyperemia in the dermal papillae and the subpapillary layer (Figs. 4.1 and 4.2). In erythema, although the blood volume increases in the dermal blood vessels, there is no blood leakage into the extravascular dermis. Thus the bloody color fades under the pressure of a glass plate (diascopy). Erythema produced at the periphery of other eruptions such as papules, bullae and pustules is described as a red halo.

2. Purpura Purpura is purple to bright red hemorrhaging in the skin (Figs. 4.2 and 4.3). The color of the blood does not fade in diascopy, erythema

Unusual erythema and purpura

purpura

pigmented macule

leukoderma

MEMO

Bleeding may occur in the superficial epidermis, making the epidermis appear red. The red does not fade by diascopy, unlike in the usual erythema. Vasodilation may occur in the dermal deep layer, making that layer appear purple.

telangiectasia extravasation melanin deposition

Fig. 4.2 Skin lesions. Macule colors and their respective changes.

50

decrease of melanin

A. Primary skin lesions

because hemorrhage causes blood leakage into the dermis, which distinguishes it from erythema. A purpura of 2 mm or less in diameter is called a petechia. A purpura that is larger than a petechia is called ecchymosis, and an even larger elevated purpura is called a hematoma. The red of a purpura is fairly bright shortly after bleeding begins (from the hemoglobin) but becomes brownish (from hemosiderin) over time. When macrophages phagocytose and decompose the leaked blood cells, the color fades.

3. Pigmented macule A pigmented macule is a patch of brown, yellow, blue or other color, depending on the deposited substance (Figs. 4.2 and 4.4). It is most commonly caused by deposition of melanin, the next most common causes being deposition of hemosiderin, carotin, bile pigment, drugs or other foreign substances (e.g., metal, charcoal). The macule color changes from brown to blackish brown with increased melanins in the epidermal basal layer, and ranges from gray to purplish brown in the papillary dermis. It becomes blue with deposition in the deep dermal layer. The sites of melanin pigmentation in various diseases are listed in Fig. 4.5.

4 Clinical images are available in hardcopy only.

Fig. 4.3 Purpura. Henoch-Schönlein purpura.

Clinical images are available in hardcopy only.

Fig. 4.4 Pigmented macule. Senile freckle. a

b

c

d

e

epidermis dermis

Site of melanin deposition and disorder Site of deposition

Color of lesion

Disorder

a) Intraepidermis~ dermo-epidermal junction

Black

nevus-cell nevus (compound), malignant melanoma

b) Basement membrane

Deep brown

Melasma, nevus spilus, café-au-lait spot

c) Basement membrane~ Brown to black the middle of the epidermis

Clinical images are available in hardcopy only.

nevus-cell nevus (junctional)

d) Dermal papilla

Violaceous to brown Lichen planus, incontinentia pigmenti, fixed drug eruption

e) Deep dermis

Bluish

Mongolian spot, blue nevus, Ota's nevus

Fig. 4.5 Association between the site of melanin deposition and the color of the lesion.

51

Fig. 4.6 Leukoderma. Vitiligo vulgaris.

52

4

Skin Lesions

keratotic papule

serous papule

solid papule

perifollicular papule

4

Fig. 4.7 Various papules.

4. Leukoderma Clinical images are available in hardcopy only.

Fig. 4.8 Papule. Lichen nitidus.

Leukoderma is a white patch produced by depigmentation or local anemia (Figs. 4.2 and 4.6). Depigmentation is caused by abnormal production of melanins, such as in vitiligo vulgaris (Chapter 16). Nevus anemicus causes local anemia leading to leukoderma (Chapter 20). Leukoderma in the periphery of an eruption is called a white halo.

5. Papule

Clinical images are available in hardcopy only.

Fig. 4.9 Nodule. Dermatofibrosarcoma protuberans.

A papule is a localized elevated lesion of 10 mm or less in diameter (Figs. 4.7 and 4.8) with a hemispheric or flat shape. It is characterized by a surface that can be smooth, eroded, ulcerative, hyperkeratotic or crusted. It may be caused by a proliferative or inflammatory change in the epidermis, or by dermal edema. Papules are distinguished by naked-eye observation as serous (with a vesicle on the top; e.g., eczema and dermatitis), solid (without blistering; e.g., neoplastic lesions, dermal edema), follicular (associated with hair follicles) or non-follicular (not associated with hair follicles).

6. Nodule, Tumor A nodule is a localized lesion that appears as a papule with a diameter of 10 to 20 mm (Fig. 4.9). It can have various causes, such as tumor formation, granulomatous change, inflammation or edema. An intensely proliferative nodule with an elevation of 30 mm or more in diameter is called a tumor.

7. Blister A blister is a skin elevation of 5 mm or more in diameter enclosed by a membrane and containing transparent fluid that is mainly plasma and cellular material. A small blister with a diameter

A. Primary skin lesions

intraepidermal bulla

subepidermal bulla

53

vesicles

4 Clinical images are available in hardcopy only.

Fig. 4.10 Blisters.

a

of less than 5 mm is called a vesicle (Figs. 4.10 and 4.11). A hemorrhagic blister containing serum mixed with blood is referred to as a bloody bulla. A blister with a flaccid covering (flaccid bulla) breaks easily. A flaccid bulla is often produced by exfoliation of the suprabasal cell layer (e.g., in pemphigus or impetigo contagiosa). A bulla with a thick, tight covering formed under the epidermis is called a tense bulla (e.g., pemphigoid, dermatitis herpetiformis). It does not break as easily as a flaccid bulla. During an infectious episode, a variolar bulla is observed; this is a bulla with a central a concavity. Blocked by the thick horny cell layer, a blister on the palms or soles does not elevate, but presents a droplet-like appearance. Such a blister is called a pompholyx. When it occurs in the mucous membrane, the covering of the aphtha breaks spontaneously. Pompholyx with painful erosion and peripheral erythema are included in aphthae (Fig. 4.21).

b

c

d

e

f

g

h

h

i

Clinical images are available in hardcopy only.

b

c

d

e

f

g

Fig. 4.11 Blisters. a: Bullous pemphigoid. b: Insect bite.

8. Pustule A pustule is a yellowish blister with purulent contents (neutrophils) (Figs. 4.12 and 4.13). It may be produced by bacterial infection or by leukocytes that migrate for some other reason (sterile pustules). Diseases that produce multiple sterile pustules are generally called pustuloses (Chapter 14).

Clinical images are available in hardcopy only.

Fig. 4.13 Pustule. Palmoplantar pustulosis (localized pustular psoriasis). pustule

cyst

neutrophils

Fig. 4.12 Pustule, cyst and wheal.

wheal (urticaria)

edema

54

4

Skin Lesions

9. Cyst

4

Clinical images are available in hardcopy only.

Fig. 4.14 Cyst. Epidermal cyst.

Clinical images are available in hardcopy only.

A cyst is a closed tumorous lesion covered by a membranous lining, which does not always elevate above the skin. The covering consists of epithelial tissue or connective tissue containing keratinous substances (observed in epidermal cysts, for example) or fluid components (e.g., in eccrine and apocrine hydrocystomas) (Figs. 4.12 and 4.14).

10. Wheal, Urticaria Urticaria is localized edema that disappears in a short period of time (usually within several hours, and always within 24 hours). It usually appears light pink with a slightly flat elevation. It is accompanied by itching and heals without scarring in most cases (Figs. 4.12 and 4.15). “Wheal” and “urticaria” are often use synonymously, although the former is the name of an eruption and the latter is a condition presenting these eruptions.

Fig. 4.15 Wheal. Acute urticaria.

B. Secondary skin lesions A secondary lesion is an eruption that occurs secondarily after a primary or other skin lesion.

Clinical images are available in hardcopy only.

Fig. 4.16 Atrophy. Widespread striae atrophicae.

1. Atrophy Skin atrophy is when skin becomes thin or has a smooth or finely wrinkled surface (Figs. 4.16 and 4.17). The secretory function is reduced, and the skin surface dries. Aging leads to skin atrophy, including subcutaneous lipoatrophy, striae atrophicae caused by steroids (Chapter 18), kraurosis vulvae and macular atrophy.

epidermis dermis

subcutaneous tissue

atrophy

hypertrophic scar

Fig. 4.17 Atrophy and hypertrophic scar.

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B. Secondary skin lesions

55

2. Scaling Scaling is the abnormal thickening of the skin surface and formation of scaly white lamellae from the accumulation of horny cell layers. Detachment of scales from the skin surface is called desquamation. Since the normal horny cell layers exfoliate individually, individual desquamation lamellae cannot be seen by the naked eye. Scales are observed when multiple horny cell layers pathologically exfoliate in diseases such as psoriasis (Fig. 4.18). Fine scaling is called pityriasis, slightly larger scaling is simply called scaling, and even larger scaling is called large lamellar scaling. Thick silver-gray scales, called micaceous scales, visible in psoriasis and fish-scale-like large scaling, are called ichthyosiform scales. There are two mechanisms of scale formation: retention hyperkeratosis and proliferation hyperkeratosis. In retention hyperkeratosis, such as in ichthyosis, horny cell layers are too cohesive to exfoliate normally; they exfoliate only after accumulating abnormally. In proliferation hyperkeratosis, such as in psoriasis, the epidermis exfoliates abnormally from over-proliferation. Blisters and pustules may become scales secondarily.

4 Clinical images are available in hardcopy only.

Fig. 4.18 Scaling. Psoriasis vulgaris.

Clinical images are available in hardcopy only.

3. Crust Crust is solidified keratin and exudate that forms on an erosion or on ulcerous skin (Fig. 4.19). A crust of clotted blood is called a bloody crust (commonly called a scab).

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4. Callus, Tylosis A callus (tylosis) is localized, proliferated, and thickened epidermal horny cell layers. It is commonly called a corn (Chapter 15).

5. Clavus

a

In clavus, the horny cell layer becomes wedged into the skin by prolonged physical stimulation, such as pressure produced by wearing shoes for long periods of time. It is commonly called a corn (Chapter 15).

Clinical images are available in hardcopy only.

b

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d

e

f

Fig. 4.19 Crusts. a: Epidermolysis bullosa simplex. b: Psoriasis vulgaris.

6. Scar, Keloid A scar is the reactive proliferation of dermal collagen after the skin is injured (Fig. 4.17). Healing usually leaves a flat scar. Sometimes the scar is hypertrophic, or thickened, but confined to the margin of the wound. A keloid, by contrast, starts some time after the injury and extends beyond the wound site (Fig. 4.20). This tendency to spread into surrounding areas that weren’t injured distinguishes keloids from hypertrophic scars.

g

Clinical images are available in hardcopy only.

Fig. 4.20 Keloid.

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Skin Lesions

7. Excoriation

4

Excoriation is partial damage to the epidermis by injury or rubbing (Fig. 4.24). The symptoms vary by the depth of excoriation. When it occurs within the horny cell layer, it heals by scaling. When it occurs in a deeper site, blood or other fluids may be exuded. In both cases, healing is without scarring.

Clinical images are available in hardcopy only.

8. Erosion Fig. 4.21 Erosion. Bullous pemphigoid.

Erosion is epidermal excoriation down to the basal cell layer. It often develops after breakage of a blister or pustule (Figs. 4.21 and 4.24). It appears red and is infiltrated with serous fluid in most cases. It frequently forms in the lips and oral mucosa, from their lack of keratinocytes. Healing is without scarring. It frequently occurs in diseases that cause intraepidermal blistering, such as impetigo contagiosa, pemphigus, epidermolysis bullosa and herpes simplex, and in diseases that cause subepidermal blistering, such as pemphigoid, burns and spontaneous intensely itchy eruptions (e.g., Duhring dermatitis herpetiformis, atopic dermatitis).

Clinical images are available in hardcopy only.

9. Ulcer Fig. 4.22 Ulcer. Chronic radiation dermatitis.

An ulcer is the complete deficiency of tissue at sites deeper than erosion, reaching from the dermis to subcutaneous tissues (Figs. 4.22 and 4.24). In healing, an ulcer is repaired by granular tissue and scarring is left. The bottom of an ulcer often has bleeding, serous exudation, and a crust that includes part of the previous lesion. Ulceration occurs secondarily in many cases after blood circulation disorder (e.g., stasis dermatitis, collagen disease, vasculitis, blocked arteries, diabetes), infection and malignant tumor.

Clinical images are available in hardcopy only.

10. Fissure A fissure is a thin linear cleavage running through the deep epidermal layer and the dermis. It is commonly called a crack (Figs. 4.23 and 4.24). It may accompany another lesion, including chronic eczema in the hands and feet, psoriasis and angular

Fig. 4.23 Angular cheilitis (perlèche).

excoriation

erosion

Fig. 4.24 Excoriation, erosion, ulcer and fissure.

ulcer

fissure

D. Lesions with elevation of skin

57

cheilitis. It tends to occur in the hands and feet, joints, intertrigo, and mucocutaneous junctions.

C. Enanthema

4

An enanthema is a lesion of the mucous membranes, such as the oral mucosa, conjunctiva and external genitalia. Specific types are listed below. Clinical images are available in hardcopy only.

1. Aphtha An aphtha is a painful, sharply circumscribed, round erosion with a diameter of 1 cm or less in the mucous membrane (Fig. 4.25). It is accompanied by peripheral inflammatory flush. Healing is without scarring. Deep ulcers are not included in aphtha. Major diseases that cause aphtha are viral infections (e.g., herpes simplex, varicella, hand-foot-and-mouth disease) and Behçet’s disease.

2. Leukoplakia

Fig. 4.25 Aphtha. Patient with Behçet’s disease.

Clinical images are available in hardcopy only.

Leukoplakia is abnormal keratinization of the mucosal epithelium. It appears white (Fig. 4.26) and may be benign or precancerous (Chapter 22). Fig. 4.26 Leukoplakia. Squamous cell carcinoma with leukoplakia at the center.

D. Lesions with elevation of skin 1. Lichen Lichens are multiple aggregated papules of 5 mm or less in diameter that persist longer than one month without progressing to another type of lesion (Fig. 4.27). Lichens are classified into lichen planus, lichen nitidus, lichen pilaris, lichen spinulosus, lichen amyloidosus, lichen sclerosus et atrophicus, lichen myxedematosus, lichen scrofulosorum and lichen striatus. Atypical lichen-like skin lesions are called lichenoid eruptions

Clinical images are available in hardcopy only.

Fig. 4.27 Lichen. Lichen amyloidosis.

2. Lichenification Lichenification is the thickening and hardening of skin that results from chronic disease. The sulci cutis and cristae cutis are clearly observed (Fig. 4.28). Lichenification is found in chronic eczema, lichen simplex chronicus and atopic dermatitis.

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58

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Skin Lesions

3. Plaque

4

A plaque is a broad, flat, elevated skin lesion with a diameter of 2 cm to 3 cm, sometimes more (Fig. 4.29). It presents as flat or papillomatous, according to the type of elevation; moreover, the shape is described as round, oval, atypical or circular. These descriptions are useful not only for individual lesions with a flat elevation, but also for flat, elevated lesions of aggregated fused papules.

Clinical images are available in hardcopy only.

Fig. 4.28 Lichenification. Atopic dermatitis.

4. Papilloma A papilloma is a papillary tumor that is covered by epidermis and mucosal epithelium. Connective tissue containing capillaries is present. Since it is protrusive, papilloma is susceptible to injury and infection. Elevated lesions on the glandular epithelium are usually called polyps.

Clinical images are available in hardcopy only.

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b

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5. Condyloma

Clinical images are available in hardcopy only.

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A condyloma is an aggregation of soft nodules with a papillary or granular surface (Fig. 4.30). It is mostly seen in the mucous membranes, such as those of the external genitalia. Typical condylomas are condyloma acuminatum caused by human papilloma virus (HPV; Chapter 23), and condyloma lata (caused by syphilis; p q j Chapter i k 27). l m n o r

Fig. 4.29 Plaque. a: Extramammary Paget’s disease. b: Mycosis fungoides.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 4.30 Condyloma. left: Condyloma aquminatum. right: Condyloma latum.

E. Lesions associated with hair follicles 1. Acne Acne is an inflammatory change, such as an erythema or pustule, at a hair follicle (Fig. 4.31). It is usually accompanied by

r

F. Lesions with color changes

black-headed papules (comedos). It frequently occurs in seborrheic zones of the skin. The term acne usually refers to acne vulgaris; other types of acne are oil acne, iodine acne (the follicle is blocked by iodine secreted after chronic ingestion of iodine) and steroid acne (from prolonged chronic use of topical and systemic corticosteroids) (Chapter 19).

2. Comedo

59

Clinical images are available in hardcopy only.

Fig. 4.31 Acne. Acne vulgaris.

A comedo is a black-headed papule that results from the blockage of a hair follicle by sebum (Fig. 4.32). The hair follicle at a site with a comedo is open. A plaque of multiple aggregated comedos on the face is Favre-Racouchot disease.

Clinical images are available in hardcopy only.

3. Sycosis Sycosis is the formation of a nodule or pustule in a hair follicle, found as a plaque at sites with terminal hair (Fig. 4.33). The main types are sycosis vulgaris and sycosis trichophytica.

Fig. 4.32 Comedo. Solitary giant comedo.

Clinical images are available in hardcopy only.

Fig. 4.33 Sycosis. Sycosis vulgaris.

F. Lesions with color changes 1. Erythroderma, Erythrodermia Erythroderma (erythrodermia) is the condition in which the skin has a systemic flush on more than 90% of the body surface (Fig. 4.34). Often accompanied by scaling, erythroderma may also be called exfoliative dermatitis (Chapter 9).

2. Melanosis

Clinical images are available in hardcopy only.

Fig. 4.34 Erythroderma. Patient with Hodgkin’s disease.

Melanosis is large, vaguely margined pigmentation, including Riehl’s melanosis and friction melanosis (Chapter 16).

3. Livedo (livedo reticularis) Livedo is a large network of reddish lesions caused by hypotonicity of the venous network and overactivity of the arterial network in the junction of the dermis and subcutaneous fat tissues (Figs. 4.35-1 and 4.35-2). Livedo is mainly classified as cutis marmorata (physiologic livedo reticularis), idiopathic and

Clinical images are available in hardcopy only.

Fig. 4.35-1 Cutis marmorata (physiologic livedo reticularis).

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Skin Lesions

4 Clinical images are available in hardcopy only.

Fig. 4.35-2 Idiopathic livedo and primary livedo reticularis on the dorsum of the feet.

primary livedo reticularis, and secondary livedo reticularis. The most frequent type, cutis marmorata, occurs as a rosy network of persistent erythema in a shape of a closed ring, mostly in the knees. It is mainly caused by cold and is often seen in otherwise normal women and children. It tends to disappear when the outside air temperature rises, without leaving pigmentation, or when pressed by glass (diascopy). Idiopathic and primary livedo reticularis occurs in the extremities as peach bloom dendritic persistent erythema in the shape of an open ring. It tends to accompany systemic organic changes such as vasculitis.

G. Lesions accompanied by multiple blisters and pustules 1. Herpes Clinical images are available in hardcopy only.

Fig. 4.36 Herpes. Herpes zoster.

Herpes is a lesion in which there are aggregated vesicles and small pustules (Fig. 4.36). Presently the term usually refers to herpes simplex or herpes zoster, which are infections caused by the herpes virus. In other cases, herpes may be observed as lesions of vesicle aggregation, such as in Duhring dermatitis herpetiformis and herpes gestationis. Aggregated pustules are found in pustular psoriasis and pustulosis palmaris et plantaris (PPP).

2. Pemphigus

Clinical images are available in hardcopy only.

Fig. 4.37 Impetigo. Impetigo contagiosa.

Pemphigus produces acantholysis in the epidermis. The mechanism is autoimmune. The typical types are pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus and pemphigus erythematosus (Chapter 14). Bullous pemphigoid and dermatitis herpetiformis are considered to be separate diseases; they are excluded from the category of pemphigus.

3. Impetigo Impetigo is a combination of pustules and crust, which may be accompanied by erythema and small blisters (Fig. 4.37). Impetigo contagiosa and bacterial dermatitis are typical of impetigo (Chapter 23).

H. Lesions with a change in the horny cell layer 1. Pityriasis Pityriasis is characterized by fine scaling caused by abnormal keratinization (Fig. 4.38). It includes pityriasis rosea (Gibert),

I. Lesions accompanied by other changes

61

pityriasis simplex and pityriasis circinata.

2. Xerosis Clinical images are available in hardcopy only.

Xerosis is dry skin whose surface is rough and muddy. It is caused by diminished secretion of sebum and perspiration. Pityroid scales and shallow cracks may develop, giving an ichthyosis-like appearance and mild itching. Hereditary xeroderma pigmentosum and secondary xeroderma, both of which occur after the onset of a preexisting eruption, are included in xerosis (Chapters 13 and 19).

Fig. 4.38 Pityriasis. Pityriasis rosea (Gibert).

3. Ichthyosis Ichthyosis is thin dry scaling on the skin that resembles gluedon fish scales (Fig. 4.39). Various types of ichthyoses are known, including congenital and acquired (Chapter 15).

Clinical images are available in hardcopy only.

Fig. 4.39 Ichthyosis. Lamellar ichthyosis.

I. Lesions accompanied by other changes 1. Poikiloderma Poikiloderma is a lesion that shows the combined features of atrophoderma, pigmentation, depigmentation and telangiectasia (Fig. 4.40). It is often observed at the terminal stages of various lesions. Poikiloderma occurs in dermatomyositis, scleroderma, systemic lupus erythematosus (SLE), mycosis fungoides, chronic radiodermatitis and xeroderma pigmentosum. Congenital poikiloderma is called poikiloderma congenitale (Chapter 18).

2. Sclerosis Sclerosis is thickening of the skin caused by proliferation of connective tissues such as collagen and extracellular matrix (Fig. 4.41). It is found in scleroderma, scleredema adultorum and scleromyxoedema. Pathologically, the number of fibroblasts decreases, and collagen fibers become swollen or uniform in size.

3. Seborrhea Seborrhea is a condition in which sebum accumulates on the skin surface in great amounts, as a result of increased secretion. This tends to lead to bacterial infection, acne, eczema infantile and seborrheic dermatisis (Chapter 7); however, seborrhea itself

Clinical images are available in hardcopy only.

Fig. 4.40 Poikiloderma. Dermatomyositis.

4

62

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Skin Lesions

4 Clinical images are available in hardcopy only.

Fig. 4.41 Sclerosis. Morphea.

does not present inflammatory symptoms. Sites that are densely distributed with sebaceous glands, such as the head, face, precordial region, center of the back, armpits and external genitalia are called seborrheic zones. The severity depends greatly on genetic factors and predisposition. Androgens are known to enhance sebum discharge. Physiologically, seborrhea occurs in newborn infants and in adults from adolescence.

4. Alopecia Alopecia is a condition in which hair grows sparsely or not at all (Fig. 4.42). The major types of alopecia are alopecia areata, alopecia totalis, alopecia universalis and ophiasis.

5. Pruritus

Clinical images are available in hardcopy only.

Pruritus is itching without eruptions. Pruritus is also called pruritus cutaneous, and it may occur secondarily in various systemic disorders and local lesions, such as urogenital diseases (Chapter 8).

Fig. 4.42 Alopecia. Alopecia areata.

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Chapter

5

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Diagnosis of Skin Diseases

In dermatological diagnosis it is most important to correctly identify the nature of the skin lesion by visual inspection. Skin lesions are often diagnosed only by naked-eye observation or by dermoscopy. Besides visual inspection, diagnosis is verified by detailed history-taking (oral consultation), palpation, and olfactory examination in some cases. Various additional tests are conducted according to the symptoms. History-taking ・ Chief complaint ・ Present illness ・ Family history ・ Past history

1. General diagnostic methods 1) History-taking (Fig. 5.1) Diagnosis begins with questioning on previous diseases, that is, medical history-taking. The inquiries that should always be included in history-taking and reminders for history-taking are listed below. ①Chief complaint ・What is the main reason for the patient’s visit? ②Present illness ・Are there subjective symptoms? Is there a presumed cause? ・Are there systemic symptoms (e.g., high fever, fatigue, aching joints, muscle pain, insomnia)? ・Were there precursory symptoms? ・How has the lesion progressed? (Has it generally become aggravated? Does it worsen at night?) ・How has the lesion spread? (Is it spreading? Does it occur and disappear repeatedly?) ③Family history ・Have any family members had similar symptoms? (Check the hereditary and allergic background of the patient.) ④Past history ・What diseases and medical treatments has the patient had? (Have topical or oral medications been used?) In addition, the patient is asked whether there are people with similar symptoms at home or school, or in the workplace, to determine whether the condition is infectious or environmental.

2) Inspection and palpation Physical examinations should be conducted in a bright room. It is preferable to examine not only the site of the complaint, but the entire body skin and visible mucous membranes. It should be remembered that an eruption may show its distinguishing features secondarily by fusion or rubbing. For accurate identification, it is important to find and examine an eruption that has not been influenced by any changes (individual eruption). Terms used to describe the nature and feature of eruptions are listed below. Eruption type: e.g., spot, papule, nodule, blister (Chapter 4) 63

Inspection and palpation ・ Dermoscopy (see Appendix) ・ Diascopy

Olfactory examination Other tests ・ Photosensitivity test ・ Allergy test ・ Skin biopsy ・ Etc.

Fig. 5.1 General diagnostic methods.

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Diagnosis of Skin Diseases

round

oval

polygonal

irregular

map-like

linear

circular

serpiginous

5

band-like

star-shaped

araneous

Fig. 5.2 Shapes of lesions.

flat

pedunculated

acuminate

dome-shaped hemispherical

umbilicated

linear

verrucous

papillomatous

Fig. 5.3 Shapes of elevation.

aggregated (localized) disseminated (widespread)

arcuate

beaded

serpiginous

linear

intermittent

lemniscate

Number of eruptions: single or multiple Eruption shape: e.g., round, oval, polygonal, irregular, maplike, linear, circular, serpiginous (Fig. 5.2) Eruption size: Numerical values (millimeters and centimeters) are used in this text to describe the sizes of eruptions, thereby avoiding ambiguous expressions such as coin-size, egg-size and finger-size. Shape of elevation: e.g., flat, domed, hemispherical, pedunculated, linear, umbilicated (Fig. 5.3) Eruption surface: e.g., smooth, rough, warty, papillary, markedly uneven, granular, lichenoid, shagreen-patch-like, oystershelllike, dry, moist, exudative, hemorrhagic (bloody, bleeding), scaly, crusty, erosive, ulcerated, cracked, atrophic, shiny, necrotic, elevated Eruption color: e.g., colored, depigmented, hyperpigmented, pale, anemic, congestive colored Eruption texture: e.g., soft, firm (stiff), fragile, tense, elastic, undulated, movable Eruption distribution: e.g., localized, widespread, aggregated, plaque-like, diffuse, centrifugal, beaded, serpiginous, linear, symmetrical, asymmetrical (Fig. 5.4) Eruption site: e.g., face, head, extremities, hand, sole, fingertip, toe, extensor surface, flexor surface, exposed, unexposed, areas with pubes, mucocutaneous junction, intertrigo Subjective symptoms: e.g., itching, pain (tenderness), numbness, crispation, hyperesthesia, hypoesthesia, alganesthesia, burning, cold Eruption progress: e.g., rapid or gradual, with or without recurrence, progress of an individual eruption, progress of spread, with or without precedent eruption, treatment effect Other: e.g., with or without mobility between the eruption and the skin surface or the base of the eruption, sharply circumscribed, mildly circumscribed

3) Olfactory examination Osmidrosis axillae are examined by the smell of absorbent cotton or gauze with which the affected site has been swabbed. In infectious diseases, each microbial species has a distinct smell. Fluid and color of pus in the eruption may be keys to diagnosis.

Unfamiliar terms used to describe eruptions MEMO

Fig. 5.4 Eruption distribution.

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Some terms are more frequently used in dermatology than in other medical fields. They are described here. Shagreen patch: The surface is leathery, such as seen in tuberous sclerosis. Oystershell-like skin: The surface is thick with rough and uneven crusts that resemble an oyster’s shell. It is seen in severe psoriasis and Norwegian scabies. Beaded skin: Multiple circular eruptions fuse to form an irregularshaped eruption that resembles a map-like eruption.

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2. Photosensitivity test (Chapter 13) Various photosensitivity tests are conducted by examining the reaction to irradiation. Ultraviolet radiation is divided into ultraviolet A (UVA) (operative wavelength of 320 to 400 nm), ultraviolet B (UVB) (operative wavelength of 290 to 320 nm) and ultraviolet C (UVC) (operative wavelength of 100 to 290 nm). UVA, UVB and visible light are most frequently used.

5

1) Photo test The degree of photosensitivity and suitable operative wavelength can be measured and determined by the amount of radiation that causes cutaneous reactions such as pigmentation and erythema. By testing the operative wavelength on patients, it is possible to know which particular radiation exposure should be eliminated. The most widely conducted photo test is exposure to UVB irradiation in the minimal dose that causes erythema in 24 hours (minimal erythema dose; MED). The average dose for ethnic Japanese is 60 to 100 mJ/cm2 (Fig. 5.5). When the MED is low, involvement of a photosensitive disease is suspected. Diseases of photosensitivity to UVA are rare, occurring for example in some cases of chronic actinic dermatitis. Pigmentation (suntan) is caused by UVA exposure; it is called the minimal response dose (MRD), in contrast to the MED. The normal MRD for ethnic Japanese is 5 to 15 J/cm2. The result is determined 48 hours after irradiation. Chronic actinic dermatitis and some cases of porphyria cutanea tarda are diseases in which there is sensitivity to visual light. There is no standard technique for measuring MRD for photosensitive diseases; they are generally observed in the cutaneous reaction induced by exposure to slide projector light for 15 to 20 minutes. A photo-provocation test of exposure to 2 to 3 MED for 3 consecutive days may be performed in the case of photosensitive diseases to observe the reaction.

2) Photo-patch test The photo-patch test is conducted to examine the influence of rays when a chemical substance is placed on the skin. Twentyfour to 48 hours after a material that is suspected of causing photosensitive disease is pasted on the skin, the site is exposed to UV rays. If reddening or swelling occurs within 24 hours, the test is considered to be positive for such disease.

3) Photo-drug test The influence of radiation in the presence of a chemical substance can also be examined by photo-drug test. A drug that is

Fig. 5.5 Photo test to measure minimal erythema dose (MED). Erythema appeared at the site of 60 mJ/cm2 irradiation; the MED for this patient is 60 mJ/cm2.

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Diagnosis of Skin Diseases

suspected of causing a photosensitive disease is taken orally instead of topically. The photodrug test is generally used for diagnosis of drug-induced hypersensitive diseases.

3. Allergy test

5

The tests for allergic reactions to a specific antigen are largely divided into those for type I allergy (immediate) and those for type IV allergy (delayed). A scratch test and an intracutaneous reactivity test are conducted for type I allergy; a patch test and an intracutaneous reactivity test are conducted for type IV allergy. ELISA and Western blot test are performed to detect the antibody in autoimmune blistering diseases.

1) Patch test

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Fig. 5.6 Patch test. a: The antigens are spread on adhesive plasters that are then stuck to the back of the patient. b: In 48 hours, various allergic reactions (edematous erythema and papules (arrows)) are seen if the patient is allergic to the antigen.

The patch test, for detection of the antigen of contact dermatitis, is conducted by applying the antigen to normal skin to observe the reaction. The antigen that is suspected of causing p q j h i k l m n o allergy is mixed in a vehicle of a topical agent such as white petrolatum and spread on an adhesive plaster or put in a Finnchamber (a plaster to which an aluminum plate is affixed). The plaster is adhered to a site of normal skin (usually the back or the upper inner arm). After 48 hours, the patch is removed, and the test result is determined in about 20 minutes when stimulation caused by the plaster has subsided. If reddening, edema, papule or erosion is produced, the test is considered to be positive for allergy (Fig. 5.6, Table 5.1). The site may be observed after 72 hours and 96 hours for more reliable results. A series of diluted p q j i test substanceskis usedl for themtest. Inn casesoin which the result isr positive only when the test substance is diluted to a certain level

Table 5.1 Readings and interpretation of patch test reactions. Japanese criterion − ±

ICDRG criteron −

Faint erythema

Doubtful reaction; faint ＋？ erythema only

Erythema ＋

Fig. 5.7 Prick lancet.

Negative

Negative

＋

Weak positive reaction; palpable erythema, infiltration, possibly papules

Edematous erythema

Strong positive reaction; erythema, infiltration, papules, vesicles

Infiltrative erythema, papules, vesicles

Extreme positive reaction; intense erythema and infiltration and coalescing vesicles

Coalescing vesicles

IR

Irritant reaction of different types

NT Not tested ICDRG: International Contact Dermatitis Research Group

r

3. Allergy test

or higher, it is considered the primary irritant (Chapter 7).

Table 5.2 Readings of scratch test reactions. Reading

2) Scratch test The scratch test is a simple test to detect an immediate allergen (type I allergy). The flexor surface of the forearm is scratched with a needle or a needle-like tool without drawing blood, and one drop of antigen solution is applied to the forearm (Fig. 5.7). If the patient is allergic to the allergen, reddening or swelling is produced on the spot. The diameter of the reddening or swelling along the minor axis is measured 15 to 20 minutes after application for identification of the allergy (Table 5.2). A scratch test may cause shock in patients with a history of anaphylactic shock. Therefore, the antigen solution should be tested first on normal skin to see whether urticaria is produced in 30 minutes (open test). If the result of the open test is positive, it is unnecessary to perform a scratch test or an intracutaneous reactivity test.

3) Intracutaneous test (type I allergy test, type IV allergy test) Type I allergens can be detected by intracutaneous test 1. In this, 0.02 ml of a solution containing the suspected substance is injected intradermally, and if an urticarial lesion or pseudopodialike projection occurs within 15 to 20 minutes, the test is determined to be positive (Table 5.3). Since there is a risk of causing anaphylactic shock in the intracutaneous reactivity test, it is desirable to perform a scratch test in advance to determine the severity of the reaction. Intracutaneous test 2 is conducted to examine the strength of cellular immunity against an antigen. Forty-eight hours after intradermal injection of 0.1 ml of the solution containing the suspected substance, if the reddening or swelling along the minor axis averages 10 mm or more, the result is generally considered positive to allergy. Common intracutaneous tests are listed in Table 5.4.

4) Drug-induced lymphocyte stimulation test (DLST) The drug-induced lymphocyte stimulation test (DLST) is known to be useful in identifying drug-induced eruptions associated with T cells; however, the involvement of a drug cannot be ruled out even when the results are negative, because of the low sensitivity of the test. DNA synthesis accompanying a lymphocyte proliferative reaction can be determined by 3H-thymidine after peripheral blood lymphocytes are cultured with a drug.

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Wheal diameter Erythema diameter (mm) (mm)

Negative (-)

＜5

＜15

Positive (+)

≧5

≧15

Table 5.3 Readings of intradermal test reactions (in 15 minutes). Reading

Wheal diameter Erythema diameter (mm) (mm)

Negative (-)

＜7

＜15

+) Doubtful (-

＜9

＜20

Positive (+)

＜15

＜40

Strongly positive ( )

≧15

≧40

5

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Diagnosis of Skin Diseases

Table 5.4 Typical type IV allergy tests.

5) Drug challenge test

Tuberculin skin test (PPD skin test)

5

A tuberculin skin test is used to detect delayed hypersensitivity to tuberculosis, by injecting tuberculosis antigen intradermally. 0.1 ml of tuberculosis antigen (purified protein derivative; PPD, 0.05 mg/ml) is injected into the inner side of the forearm. The long diameter of the erythema 48 hours after injection is used for interpretation: less than 10 mm is negative, and more than 10 mm as positive. Positive reaction is sometimes categorized into weak (only erythema), moderate (erythema and induration), and strong (erythema with vesicles and necrosis). Tuberculin skin test is specific to tuberculosis. However, patients with measles, sarcoidosis, Hodgkin’s disease, severe tuberculosis, and serious malignancies may show weak reaction or false negative. Trichophytin reaction An antigen derived from trichophyton (trichophytin antigen) may be used to test intradermally for trichophytid and tinea profunda. Sporotrichin reaction Sporotrichin antigen is injected intradermally for diagnosis of sporotrichosis.

The drug suspected of causing allergy is administered to the patient to determine whether the eruptions will recur. One onehundredth to one tenth of the usual dosage is given orally. In serious drug eruptions, there is a high risk that a drug challenge test will cause anaphylactic shock. The drug challenge test is the most reliable allergy test.

4. Skin function test Tests for measuring various skin function, such as temperature control, secretion, and vascular regulation, are as follows.

1) Measurement of skin temperature and thermography Thermography, which uses an infrared-camera-equipped emission pyrometer to express the distribution of skin temperature two-dimensionally, has become widely used for diagnosing diseases of the blood vessels, and nervous system disorders, inflammations, tumors, and other disorders.

Ito’s reaction

2) Transepidermal water loss (TEWL)

Haemophilus ducreyi antigen is used for diagnosis of chancroid. Frei reaction Frei reaction is an intradermal test for lymphogranuloma venereum. Lepromin reaction (Mitsuda reaction) Lepromin reaction (Mitsuda reaction). Antigen derived from leproma is intradermally injected for diagnosis and classification of leprosy. Kveim test Diagnosis of sarcoidosis used to be done by a skin test whose antigen is derived from another patient’s spleen and lymph nodes. Kveim test is rarely done today.

Transepidermal water loss (TEWL) from the skin surface is measured by electric hygrometer (Fig. 5.8). This test is effective in determining the clinical condition of keratinization. The TEWL value usually is elevated in dyskeratoses, such as in ichthyosis.

3) Skin capillary resistance test The fragility of skin capillaries can be determined by measuring ecchymosis produced in artificially pressured blood vessels. In the Rumpel-Leede test, the upper arm is pressed by a blood pressure manchette to congest the blood vessels. Two minutes after pressure between the systolic and diastolic pressures is applied to the patient’s upper arm for 5 minutes to constrict the blood vessels, hemorrhagic spots occur. When 10 hemorrhagic spots or more produced, the test is positive for dysfunction of vascular regulation. It may also be positive if there is abnormality in the capillaries or platelets, such as Henoch-Schönlein purpura or thrombopenic purpura.

5. Fungal examination Potassium hydroxide (KOH) is used for observation and detection of fungi and mites. Scales or blister contents are swabbed (Fig. 5.9) and applied to a glass slide onto which 20% KOH solution is dripped, and a slide cover is placed on top. The slide is

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10. Cytological diagnosis (Tzanck test)

69

heated on a hot plate at 70 ℃ to 80 ℃ for 5 to 10 minutes. The components of skin such as the horny cell layers are hydrolyzed, and the fungal components become easily Fig. 25.1. By similar procedure, animals such as mites are observed. Recently, KOH solutions to which dimethylsulfoxide (DMSO) has been added have been frequently used, due to the short dissolution time and the fact that there is no need to use a hotplate.

5

6. Dermoscopy (see Appendix for details) Dermoscopy is a test to observe the skin surface in detail under a magnifying glass with a magnification factor of ten (Fig. 5.10). Use of jelly for echography and a bright light source reduces scattering light and makes it possible to observe the lower dermal layer as well as the horny cell layer. The technique is particularly useful in distinguishing between and diagnosing pigmented lesions (e.g., malignant tumors including malignant melanomas and nevus) and subcorneal bleeding. Unlike skin biopsies, dermoscopy is not invasive; it is essential and greatly useful for dermatological examinations. Digital images of dermoscopy can also be saved.

Fig. 5.8 Electric hygrometer for measuring transepidermal water loss (TEWL).

7. Diascopy In diascopy, a site with a skin lesion is pressed with transparent glass to see whether the coloration of the lesion disappears (Fig. 5.11). If so, the diagnosis is erythema. Otherwise, the diagnosis is purpura. A light brown spot is characteristically seen in a granulomatous nodule such as lupus vulgaris. The test is also effective for distinguishing between nevus anemicus and hypopigmented macule. In the case of the latter, the whitish macule remains visible under the pressure of diascopy.

Fig. 5.9 Diagnosing tinea pedis: Scales or swabbed blister contents are sampled from the interdigital area. Microscopic examination is made with potassium hydrate.

8. Needle reaction test When the skin of a patient with Behçet’s disease is stuck with a needle, an erythema, papule or pustule appears in 24 to 48 hours. The needle reaction test is positive for about 70% of patients with Behçet’s disease, which reflects the skin irritability of patients with this condition.

9. Wood’s lamp test When skin with erythrasma, pityriasis versicolor, tinea capitis or porphyria is exposed to Wood’s lamp, a 365-nm UV light, the fluorescence has a characteristic color (Fig. 5.12, Table 5.5).

10. Cytological diagnosis (Tzanck test) Cytological diagnosis (Tzanck test) is conducted by applying a slide glass to the bottom of a broken blister and staining the adhered cellular components in Giemsa (Fig. 23.8) for observation

Fig. 5.10 Dermoscopy. Observation of skin lesion by dermoscope.

70

a

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Diagnosis of Skin Diseases

c

d

e

f

g

under a light microscope. Acantholytic cells called Tzanck cells are observed in pemphigus. In blisters of herpes simplex and herpes zoster, ballooning cells produced by viral infection are p q j observed. h i k l m n o

11. Dinitrochlorobenzene (DNCB) test

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fd

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hf

The strength of cellular immunity is measured by dinitrochlorobenzene (DNCB) test. First, a patch soaked in a 1% solution of DNCB acetone is adhered to the upper inner arm of the subject for sensitization. After 2 to 3 weeks, a patch soaked in 0.1 to 0.01% of the same solution is adhered to a symmetrical site on the other arm as a provocation test to observe the reaction after 48 hours. If erythema, papule or small papule is produced, theg test is positive; that is, the subject is consideredpto haveq cellu- p jh i ki l j mk nl om r n o lar immunity. Immuno-compromised patients with cancer may not always be sensitized by this test.

q

12. Dermographism

ca

db

ec

fd

ge

hf

ig

jh

Fig. 5.11 Diascopy. a: Transparent glass plate for diascopy. b, c: Erythema disappears with pressure from the glass plate. d, e: Purpura does not disappear with such pressure.

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Some reactions of skin rubbed by something dull such as a fingernail maybe observed. If the rubbed site becomes red and elevated, it is called (red) dermographism which is a diagnostic finding of physical urticaria (Fig. 5.13). If the site becomes white, itl jis called white dermographism; this seen in r pn qo is usually q ki mk nl om rp patients with atopic dermatitis (Fig. 5.14).

13. Darier’s sign When dermography is performed on a pigmented area of a patient with mastocytosis (urticaria pigmentosa (Chapter 21)), mast cells are degranulated and the site becomes markedly elevated to form an urticarial lesion. This phenomenon is called Darier’s sign (Fig. 5.15). Urticarial lesions are usually produced shortly after rubbing. Mastocytosis can be distinguished fromq p j h i k l m n o other pigmented lesions by Darier’s sign.

14. Sensory test Sensory tests on touch (stroking with a brush), pain sensation (sticking with a needle), and temperature sensation (touching by tubes containing warm water or ice water) are conducted on a blindfolded patient. It is useful for the diagnosis of dissociation disability in Hansen’s disease and neurological disorders.

Clinical images are available in hardcopy only.

a

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Fig. 5.12 Wood’s lamp. a: Wood’s lamp. b: Photodynamic diagnosis of extramammary Paget’s disease. Wood’s lamp reveals the area of the lesion, after delta-aminolevulinic acid ointment is applied in occlusive dressing.

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21. General internal medical tests

15. Nikolsky phenomenon In Nikolsky phenomenon, although the skin appears normal, blistering is produced by rubbing. The result is positive in pemphigus, epidermolysis bullosa, staphylococcal scalded-skin syndrome (SSSS), and toxic epidermal necrolysis (TEN) type drug eruptions.

Table 5.5 Fluorescence under Wood’s lamp. Disorder

Fluorescence

Pityriasis versicolor

Yellow-orange

Erythrasma

Coral pink

Porphyria

Red

Tinea capitis

Yellow green-viridian

16. Köbner phenomenon From stimuli such as rubbing or sunlight, a lesion is produced in normal skin; this is called the Köbner phenomenon, which is seen in psoriasis and lichen planus.

17. Auspitz phenomenon Auspitz phenomenon is the occurrence of small droplets of blood in skin. In psoriasis, when scales exfoliate, petechia is quickly produced (Chapter 15). However, the patient may also test positive for Auspitz phenomenon in cases of eczema; it is not necessarily specific to psoriasis.

Fig. 5.13 Dermographism. Artificial urticaria.

18. Enzyme-linked immunosorbent assay (ELISA) Enzyme-linked immunosorbent assay (ELISA) is a method for measuring the amount of specific proteins, using enzymes and antibodies that are associated with fluorescent substances. For pemphigus diagnosis, it is necessary to identify whether there are autoimmune antibodies to desmoglein 1 and 3. For bullous pemphigoid diagnosis, it is necessary to identify whether there are autoantibodies to BPAG2 protein (Chapter 14).

19. Western blot Western blot is a method to measure the amount of specific proteins using proteins that are extracted from the epidermis to be electrophoresed and reacted to the specific antibody (Fig. 5.16). It is used for detection of autoantibodies.

20. Diagnostic imaging Diagnostic imaging using X-ray photography, CT, MRI, ultrasound, and scintigraphy is important for diagnosis of skin tumor and lymph node metastasis of a skin tumor.

21. General internal medical tests A general blood test, bacterial culture and urinalysis are general internal medical tests.

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Fig. 5.14 White dermographism. Atopic dermatitis.

Clinical images are available in hardcopy only.

Fig. 5.15 Darier’s sign in mastocytosis.

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Diagnosis of Skin Diseases

22. DNA analysis 230 kD

With identification of the causative genetic mutation, accurate diagnosis and classification of diseases are possible for hereditary skin diseases caused by single-gene mutation (Fig. 5.17, Chapter 29). The characteristic configuration of DNA in tuberculosis and atypical mycobacterial diseases is detectable by magnifying the DNA extracted from the lesion or reproducing it by PCR.

5 180 kD

patient

normal control

Fig. 5.16 Western blotting. Serum of bullous pemphigoid patient reacts against skin antigens (molecular weight of 180 kD and 230 kD).

Fig. 5.17 DNA analysis of type VII collagen in a patient with epidermolysis bullosa. Point mutation (C6761G, exon 86) causes nonsense mutation; stop codon (TGA) occurs at 2261 amino acid instead of arginine (CGA).

Photodynamic diagnosis MEMO (PDD), Photodynamic therapy (PDT) When d -aminolevulinic acid is applied as topical occlusive dressing therapy or when it is locally injected or orally administered for lesions such as those that occur in extramammary Paget’s disease, basal cell carcinoma, and actinic keratosis, there is accumulation of protoporphyrin IX that contains red fluorescence. Taking advantage of this, non-invasive diagnosis (photodynamic diagnosis; PDD) and treatment (photodynamic therapy; PDT) is possible. In PDD, by irradiation of Wood’s lamp 4 to 6 hours after topical application of d -aminolevulinic acid, red fluorescence is observed (Fig. 5.12). In PDT, irradiation is by 100 J/cm2 630-nm excimer dye laser instead of by Wood’s lamp.

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Chapter

6

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Treatment of Skin Diseases

Dermatological treatments are largely divided into external application of drugs, systemic therapies (oral administration of drugs, injections), physical therapies, laser therapies and surgical therapies. Among these treatments, topical therapies are the most important treatments in dermatology. Physical therapies, including irradiation and warming/cooling of affected sites, are also frequently applied. It is essential for dermatologists to have full knowledge of various therapies and combinations of effective treatments.

A. Topical therapies Topical therapies involve the application of a topical agent on affected sites of skin. Topical agents are compounds of a main agent and a vehicle (base). The main agent acts on lesions, whereas the vehicle acts supplementarily to increase absorption of the agent. The horny cell layer in the outermost layer of skin is waterrepellant and dense. It prevents water from evaporating from the body, which means it is the strongest barrier for the topical agent to overcome (i.e., the rate-controlling step). The water-repellant horny cell layer generally has a thin sebum membrane on the surface that also functions as a barrier. The site below the granular cell layer is characterized by hydrophilicity and ready absorption of agents. ●Topical agents more readily permeate places where the horny cell layer is thin, such as the face and scrotum, than places where the horny cell layer is thick, such as palms and soles (Table 6.1). ●The smaller the molecular weight of an agent, the more efficiently the agent is absorbed. Generally, substances whose molecular weight is 1,000 or more do not permeate normal skin. ●The absorption of a topical agent increases at a site whose horny cell layer is injured by erosion, ulceration or the like. Oleaginous ointments are fairly slow to show effects on these types of lesions. ●A topical agent’s absorption tends to increase with duration of contact. This characteristic is taken advantage of in occlusive therapy. The type of vehicle and the consistency of main agent are chosen according to the conditions and site of the eruption. Various vehicles and main agents and their characteristics and application on eruptions are described here briefly.

a. Vehicles for topical agents Vehicles help main agents permeate the skin. The agents have various actions, including hydration, cooling, lubrication, drying (removal of exudate), protection, softening, purification, and itch 73

Table 6.1 Relative absorption rate of topical steroids by skin region (forearm=1). Region

Relative absorption rate

Plantar area

0.1

Palms

0.8

Flexor side of forearm

1

Back

1.7

Scalp

3.5

Axilla

3.6

Cheek

13

Scrotum

42

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Treatment of Skin Diseases

oil

water

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a．w/o emulsified ointment

relief. A vehicle can be applied without a main agent in many cases. Vehicles should be non-stimulating, colorless and scentless, stable (non-denaturing), able to retain the main agent evenly, moderately viscous, appropriately firm, and moderately absorbable. The same main agent may be mixed into various vehicles for various types of topical agents with different applications (Figs. 6.1 and 6.2, Table 6.2). Typical vehicles and their characteristics are listed below with brief explanations.

oil water b．o/w cream

Fig. 6.1 Illustration of water in-oil (w/o) emulsified ointment and oil in-water (o/w) cream. a: W/o emulsified ointment. Water granules are dispersed in oil by emulsion. b: O/w emulsive cream. Oil granules are dispersed in water.

MEMO Vaseline (petrolatum) is a semisolid compound that is refined from petroleum. It is often used as a vehicle for topical agents. It comes in yellow and white, the latter being yellow Vaseline that has been bleached. There is no essential difference between the two.

Vaseline, Petrolatum

1. Ointments Ointments are the most frequently used topical agents. They are less stimulative than other vehicles and are highly protective. They are transparent or translucent semisolids.

1) Oleaginous ointments Various oils such as olive oil, vaseline, paraffin, and plastibase are the most frequently used vehicles for oleaginous ointments. These ointments are free of water, absorb little water, and are insoluble in water. They are also called water-repellant ointments. The vehicle itself protects and softens the skin and works as an anti-inflammatory. Oleaginous ointments are the least stimulative, and are applied on all kinds of eruptions. (Examples: white petrolatum, zinc oxide ointment, various steroids)

2) Emulsified ointments These are water-in-oil ointments containing emulsifiers such as polyethylene glycol. Because of the cooling sensation they bring with application, emulsified ointments are commonly called cold creams. They are more protective and less sticky than creams (see below) and are easily washed off with water. They are mostly applied on dry lesions.

Table 6.2 Characteristics of vehicles. Vehicle Ointment

Characteristics

Oleaginous Least irritating, superior in skin protection Emulsified

Drawbacks Greasy feeling, not water absorbant

Less protective, contact dermatitis Less greasy than oleaginous ointment, readily penetrates the skin may occur due to adjunct materials

Target skin lesions Any skin lesion Lichenified lesions, nodules, etc.

Cream

Readily penetrates the skin, feels soothing after application

More irritating than ointments, contact dermatitis may occur due to adjunct materials

Chronic hypertrophic lesions, acute-phase lesions with slight oozing

Lotion

No greasy feeling, easy to apply to the scalp

Irritant, possible to overuse

Eczematous lesions on the scalp

Tape

Strong protective effect and drug penetration

Unable to apply to wet lesions and scalp, possible to cause folliculitis and miliaria

Nodules, lichenified lesions

A. Topical therapies

75

2. Creams Creams, also called oil-in-water emulsive vehicles, are semisolid mixtures of oil suspended in water containing emulsifiers. Creams are less sticky than ointments, and the color disappears when they are applied thinly (vanishing cream). Since they do not stain clothes, creams are readily accepted by patients, and compliance with application is ensured. However, they may be irritating, and less protective than ointments. Although creams are useful for erythema and papules, they should not be used on eroded or moist sites.

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3. Lotions Lotions are liquids (usually water) with an agent mixed in. When applied topically, the liquid evaporates, bringing cooling, astringent and protective effects. The agent remaining on the skin acts pharmacologically. In addition to water, the following are often used as liquid vehicles for lotions: alcohol, propylene gly-a col, glycerin, and zinc oxide oil (a 1:1 mixture of zinc oxide and olive oil). Some lotions require shaking prior to application. They are known as shake lotions.

1) Emulsive lotions Emulsive lotions are emulsions of oil in water. They are more permeable in skin than are shake lotions (see below). They are used for non-moist lesions and are often applied on the a hairyb scalp. (Examples: various steroid lotions)

Fig. 6.2 Topical agents with various vehicles. a: Oleaginous ointment. b: Cream. c: Lotion.

2) Shake lotions Shake lotions are liquids with powdered agents mixed in. The powder settles, so these need to be shaken before use. When applied, a cool sensation is produced as the liquid evaporates; shake lotions are effective on lesions that are accompanied by fever and evaporable moisture, such as erythema and papules. They are unsuitable for intensely exudative lesions, such as erosions, because they may cause irritation. (Examples: sulfur camphor lotion)

3) Other topical agents Tinctures: agents dissolved in alcohol or in alcohol and water Aerosols: vaporized liquid agents

4. Gels Gels are transparent agents that are solid to semisolid. Gelatine is dissolved in water or acetone, yielding a gelatinous product.

MEMO “Ointment” in dermatology usually refers to an oleaginous ointment. However, some water-in-oil emulsive creams (cold cream) and oil-in-water creams (vanishing cream) may also be regarded as “ointments” by patients. Care should be taken in prescribing ointments and in explaining their use to patients.

Ointments

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Treatment of Skin Diseases

After application, it dries to become a thin adhesive film on the skin. Gels with high solvent content are called jellies. These are used on mucous membranes to protect lesions from friction.

5. Powders The main ingredients of powders are zinc oxides, talc (magnesium silicate), and starches. Powders dry affected sites by absorbing moisture. They also cool the skin, reduce friction, and smooth the skin surface. They are effective in preventing miliaria and intertrigo.

6

6. Liniments Liniments are mixtures of water and zinc oxides, phenol or glycerin. They dry fast on the skin. They are effective in cooling the skin and relieving itching. Carboric acid liniments are used for erythema and papules of, for instance, varicella; however, they must be avoided for lesions with moist surfaces, because of their water solubility.

7. Pastes Pastes are highly viscous mixtures of oil-based substances and microparticles of powder. In this they resemble oleaginous ointments; however, pastes contain more powder than oleaginous ointments do.

8. Plasters Plasters are cloth, paper, or plastic film spread with topical agents. One example is 30% salicylic acid plaster. They are applied to lesions such as callus and clavus (Fig. 6.3). Adhesive plasters containing steroids are also useful. Adhesive plasters with nitroglycerine or fentanyl are used for systemic administration in non-dermatological medical departments, utilizing the transdermal absorption of the skin.

9. Other vehicles for topical agents These include compresses, soaps, shampoos and bath additives.

b. Main topical agents The main agents are the components that have therapeutic effects on skin. Frequently used main agents are listed below.

1. Corticosteroids (steroid) Fig. 6.3 30% salicylic acid plaster.

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The main purpose of steroid topical application is to fight

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A. Topical therapies

77

Table 6.3 Topical steroids. Brand name and form

Corticosteroid

Potency

Betnovate cream/ointment/lotion

Betamethasone valerate 0.1%

Very strong

Betnovate RD cream/ointment

Betamethasone valerate 0.025%

Strong

Bettamousse

Betamethasone valerate 0.12%

Very strong

Cutivate cream/ointment

Fluticasone propionate

Very strong

Dermacort cream

Hydrocortisone 0.1%

Mild

Dermovate cream/ointment/scalp application

Clobetasol propionate 0.05%

Strongest

Dioderm cream

Hydrocortisone 0.1%

Mild

Diprosone cream/ointment/lotion

Betamethasone dipropionate 0.05%

Very strong

Efcortelan cream/ointment

Hydrocortisone 0.5%, 1%, 2.5%

Mild

Elocon ointment/scalp ointment

Mometasone furoate 0.1%

Very strong

Eumovate eczema and dermatitis cream

Clobetasone butyrate 0.05%

Strong

Eumovate cream/ointment

Clobetasone butyrate 0.05%

Strong

Haelan cream/ointment/tape

Flurandrenolone (fludroxycortide)

Strong

Halciderm cream

Halcinonide 0.1%

Strongest

Locoid cream/ointment/lipocream/scalp lotion

Hydrocortisone 17-butyrate 0.1%

Very strong

Metosyn cream/ointment

Fluocinonide 0.05%

Very strong

Mildison lipocream

Hydrocortisone 1%

Mild

Modrasone cream/ointment

Alclometasone dipropionate 0.05%

Strong

Nerisone cream/oily cream/ointment

Diflucortolone valerate 0.1%

Very strong

Nerisone forte oily cream/ointment

Diflucortolone valerate 0.3%

Strongest

Propaderm cream/ointment

Beclometasone dipropionate 0.025%

Very strong

Stiedex LP cream

Desoximetasone 0.05%

Strong

Synalar cream/ointment/gel

Fluocinolone acetonide 0.025%

Very strong

Synalar 1:4 cream/ointment

Fluocinolone acetonide 0.00625%

Strong

Synalar 1:10 cream/ointment

Fluocinolone acetonide 0.0025%

Mild

Ultralanum cream/ointment

Fluocortolone

Strong

(Adapted from; http://www.netdoctor.co.uk/skin_hair/eczema_corticosteroids_003762.htm).

inflammation. Vasoconstriction, diminution of membrane permeability, liberation and inhibition of inflammatory chemical mediators, arachidonic acid reduction by phospholipase inhibition, immunosuppression, and cell division inhibition combine to inhibit inflammation. Steroids for topical application are classified by strength: strongest, very strong, strong, mild and weak (Table 6.3). Steroid topical application may have side effects. Particular care should be taken in facial application, because of the high absorptiveness of the skin there. As long as the dosage and usage of steroids are appropriate, systemic side effects are rare. However, when strong steroids are applied on a large area for a long period or when they are used in occlusive therapy, side effects similar to those caused by steroid systemic administration may be produced. Moreover, special care should be taken in administering steroids to infants, since the effects tend to be systemic. Topical corticosteroids induce and aggravate cutaneous atrophy, striae atrophicae, telangiectasia, purpura, hypertrichosis, steroid acne, rosacea-like dermatitis and infectious diseases (tinea

6

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Treatment of Skin Diseases

Table 6.4 Side effects of topical steroids. Systemic Suppression of adrenal gland function Local

6

Atrophy Steroid purpura Rosacea-like dermatitis, perioral dermatitis Steroid acne Hypertrichosis Infection (bacterial, fungal, viral) Contact dermatitis Rebound (exacerbation of disease after sudden cessation)

Potency and strength of topical steroids

Potency

Potency Class

Strongest

Very potent, super potent

class 1

Very strong

Potent

class 2 class 3

Strong Mild (medium)

Moderate class 4 (mid-strength) class 5 Mild

Weak

2. Immunosuppressants Tacrolimus (FK-506: molecular weight=822Da), a topical calcineurin inhibitor, selectively inhibits T-cell functions, making it effective against atopic dermatitis as an immunosuppressant. It is also useful as a treatment for chronic actinic dermatitis and lichen planus.

MEMO

Topical steroids are classified into several groups according to the potency of preparation. In Japan, the clinical activity is expressed in terms of strength, which is categorized into five levels: strongest, very strong, strong, mild and weak. However, the English-language literature uses the term “potency.” This table ranks the strengths and potencies. Note that the correspondence of strength/potency is not determined strictly; it can change with changes in the concentration of the drug and the vehicle. Strength (Japan)

incognito and candidiasis in particular) (Table 6.4). Intralesional steroids are used for recalcitrant dermatoses, such as alopecia areata, keloids, scars, prurigo nodularis and lichen simplex. Triamcinolone is often used, but dermal atrophy and leukoderma may occur.

class 6

3. Antifungal agents Various types of topical antifungal agents, such as those containing imidazole, benzylamine or morpholine, are used. They act by attaching to the cellular walls of fungi and inhibiting biosynthesis. These agents are used topically (as creams, lotions, or ointments) for superficial mycosis; however, they may be used orally for tinea unguium and deep fungal infections.

4. Antibiotics Topical agents containing antibiotics are used against superficial bacterial infections. Antibiotics should be effectively antibacterial against the targeted bacteria and have transdermal sensitization capability. Macrolide or new quinolone antibiotics are effective against folliculitis, including acne vulgaris. As antibiotic resistance among bacteria has been increasing in recent years, ointments containing antibiotics are not always effective in treating superficial infectious diseases.

class 7

5. Vitamin D analogues Activated vitamin D3 is used to treat hyperkeratotic and proliferative diseases such as psoriasis, ichthyosis, and palmoplantar keratosis, because of its ability to induce differentiation of the epidermis and antiproliferation. It is the first choice of treatment for psoriasis. Nevertheless, a prolonged large dosage of activated vitamin D3 may lead to hypercalcemia; the dosage should be carefully decided.

6. Urea Urea is used as a moisturizer for its water retentivity. Hydrophilic ointments containing 10% to 20% urea are frequently used to treat senile xerosis, ichthyosis, palmoplantar keratosis, keratodermia tylodes palmaris progressiva, and atopic dermatitis. Urea may produce irritation on cracked or moist sites.

A. Topical therapies

79

7. Zinc oxide Zinc oxide is frequently used not only as a vehicle but also as a main agent for its actions of desiccation, astringency, anti-itching, cooling, and radiation blocking. Zinc oxide spread on cotton lint is available commercially (Fig. 6.4).

6

8. Sulfur, Resorcinol Sulfur and resorcinol are antibacterials and antifungals with keratin-exfoliating action. They are effective in treating acne vulgaris. Fig. 6.4 Zinc oxide sheet.

9. Salicylic acid Salicylic acid is keratolytic and is used to treat keratoderma in the soles. A plaster containing 30% to 40% salicylic acid is used to soften and remove callosity and clavus.

10. Phenol Phenol has anti-itching and antibacterial effects. Because of its corrosive effect, it may also be used in treating verruca vulgaris and ingrown nails, and for chemical peeling.

11. Tars Tars such as coal tar, wood tar and Glyteer have been applied topically on moist eruptions and lichenified lesions. Because of their peculiar odor and color, and their carcinogenicity if used for long periods, they are rarely used now. Tars may also cause photosensitive diseases. As tars have a cellular antiproliferative effect, they have been used in the past in combination with ultraviolet rays (UVB) against psoriasis; this treatment is called Goeckerman therapy.

12. Other agents Antihistamines, retinoids (isotretinoin and adapalene), antitumor drugs, sunscreen, psoralen, vitamins, sex hormones, and nonsteroidal anti-inflammatory drugs (NSAIDs) are used as topical agents.

c. Application Topical agents are applied as described below. Care should be paid in the application of agents for which there are restrictions on dosage and use frequency. For agents whose dosage is not specified, it is necessary to determine the daily dosage for each patient.

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Instructing patients on the MEMO daily dosage of external medicine

6

For oral medicines, it is easy to specify the precise daily dosage in the prescription. For topical medicines, it is not. Dermatologists must give careful instructions not only on the daily dosage but also on how much of the topical medicine (e.g., the number of grams, how much of the tube) should be applied according to the severity and size of the lesion.

Direct application: A topical agent is applied directly to a skin lesion. This is the most common application method. Plaster: A cloth spread with the agent is applied to a lesion. It is effective in removing crusts and protecting erosions and ulcers. Occlusive dressing therapy (ODT): A topical agent is directly applied, and the site is tightly sealed with polyethylene film. Steroid adhesive plasters are sold commercially. They are useful for treating infiltration, acanthosis, lichenified plaques, and hyperkeratosis. However, ODT is much more absorptive than other topical agents; therefore, the patient should be monitored for side effects such as systemic symptoms. Chemical and mineral bath: Chemicals and minerals are dissolved in warm water, for systemic or topical soaking. The bath may also be used for disinfecting burns. Hot spring water is rich in minerals and has a thermo-therapeutic effect. In UV therapy, the patient is radiated with UV rays after a chemical bath of psoralen (PUVA-bath therapy).

B. Systemic treatments Table 6.5 Common antihistamines. Non-sedating Acrivastine (Semprex) Cetirizine hydrocholoride (Zirtek) Fexofenadine hydrochloride (Telfast) Loratadine (Clarityn) Mizolastine (Mistamine, Mizollen) Terfenadine Sedating Alimemazine tartrate/trimeprazine tartrate (Vallergan) Azatadine maleate (Optimine) Brompheniramine maleate (Dimotane) Chlorphenamine maleate/chlorpheniramine maleate (Piriton) Cinnarizine (Stugerone) Clemastine (Tavegil) Cyclizine (Valoid) Cyproheptadine hydrochloride (Periactin) Hydroxyzine hydrochloride (Atarax, Ucerax) Meclozine hydrochloride (Sea-legs) Promethazine hydrochloride (Phenergan) Promethazine teoclate (Avomine) (http://www.bupa.co.uk/health_information/html/ medicine/antihistamine.html).

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1. Antihistamines There are several types of antihistamine agents that bind to histamine receptors to inhibit their functions. H1 receptor inhibiting drugs, widely used in dermatological treatments, are extremely effective in treating inflammation and allergic reactions. Second- and third-generation antihistamines, which also inhibit the release of a chemical mediator from mast cells, may also be called antiallergic drugs. Third-generation antihistamines such as Loratadine, Cetirizine, and Fexofendadine have a mild depressant action on the central nervous system (Table 6.5), and have a long serum half-life: Only one or two doses per day is effective in relieving itching from urticaria, eczema and dermatitis, pruritus, and prurigo. Drugs prompting anticholinergic action must be avoided for patients with glaucoma and enlarged prostate.

2. Corticosteroids Corticosteroids afford anti-inflammatory and anti-immune effects. They are administered orally for long periods in collagen diseases such as systemic lupus erythematosus (SLE), and in autoimmune skin diseases such as pemphigus and pemphigoid. Short-term oral use of corticosteroids may be given for extensive drug eruptions or autosensitization dermatitis. However, systemic administration as a treatment for chronic diseases including atopic dermatitis, chronic urticaria, and psoriasis should not be performed without careful consideration. Oral use of steroids may cause a wider variety of side effects than topical use. Oral use should be performed with care,

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B. Systemic treatments

particularly for patients with an underlying disease such as diabetes or high blood pressure; steroids may aggravate these diseases. The typical side effects of systemic steroid administration are shown in Table 6.6. The initial dosage of steroids is determined according to the severity of the disease. This dosage is reduced to a maintenance dose or stopped with the gradual diminution of symptoms (Table 6.7). If necessary, steroid pulse therapy (500 mg to 1,000 mg of methylprednisolone intravenous injection per day for 3 successive days) is performed.

3. Nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, antipyretics and other anti-inflammatory drugs

81

Table 6.6 Side effects of corticosteroids. Severe

Relatively mild

Secondary adrenal dysfunction Sideration and exacerbation of diabetes Sideration and exacerbation of hypertension Hyperlipidemia Psychiatric effects Muscular atrophy Cataract, glaucoma Gastric ulcer Osteoporosis Aseptic necrosis of bone Susceptibility to various infectious conditions

Moon face, central obesity Hyperphagia Leukocytosis Skin streaks Subcutaneous hemorrhage, purpura Steroid acne Hypertrichosis Alopecia Edema Insomnia

Most analgesics and antipyretics also have anti-inflammatory effects, which occur from inhibition of prostaglandin synthesis. Aspirins inhibit thromboxane A2 (TXA2) synthesis-synthesis that is necessary for platelet aggregation. Therefore, besides antiinflammatory and analgesic effects, aspirins are used for thrombotic diseases. Gold preparations, colchicines and potassium iodide are applied exclusively for specific inflammatory diseases. Gold preparations that are engulfed by macrophages inhibit the functions of macrophages; additionally, those preparations are thought to inhibit cellular immunity, a characteristic that is used in treating rheumatoid arthritis and pemphigus. Colchicines act to inhibit neutrophil chemotactic and cell division, making them useful in treating gout and Behçet’s disease. Potassium iodide is effective against erythema nodosum.

4. Immunosuppressants Azathioprines, methotrexates, cyclophosphamides, cyclosporines and tacrolimus are known to be immunosuppressants. When it is difficult to reduce the steroid dosage, such as in treating SLE, dermatomyositis, pemphigus, bullous pemphigoid and Behçet’s disease, immunosuppressants may be used in combination with steroids. Cyclosporines may be used alone in intractable psoriasis; however, they tend to cause dose-dependent kidney disorders and high blood pressure. Therefore, blood concentration Table 6.7 Various corticosteroids: comparison of the duration and dose for the same effects. Duration of action

Drug

Short (within 8 hours)

Hydrocortisone

20 mg

10 mg

Moderate (1 day)

Prednisolone

5 mg

5 mg

Methylprednisolone

4 mg

4 mg

Dexamethasone

0.75 mg

0.5 mg

Betamethasone

0.6 mg

0.5 mg

Long (2 days)

Dose needed for the same effect as 5 mg prednisolone

(Adapted from; Wallace J, et al, editors. Dubois’ lupus erythematosus. 5th ed. Williams & Wilkins. 1997).

Dose per tablet

6

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Treatment of Skin Diseases

monitoring is necessary when cyclosporines are administrated.

5. Antifungal agents

6

Antifungal agents for internal use, such as potassium iodides, Griseofulvin, amphotericin B, nystatin, flucytosine and miconazole, were formerly administered orally or by injection. They have a narrow antifungal spectrum, and side effects. Recently developed itraconazole, terbinafine and fluconazole have a broad antifungal spectrum and fewer side effects; therefore, they are widely applied in many types of diseases. Highly keratinophillic, these drugs are known to concentrate in a skin lesion. Moreover, they are administered orally to patients with kerion celsi, sycosis trichophytica, or mycosis profunda. For tinea unguium, pulse therapy of itraconazole (400 mg per day, 1 week per month for 4 cycles) is also effective.

6. Antibiotics Antibiotics are used to treat cellulitis and infectious skin diseases such as impetigo contagiosa. Most infectious skin diseases tend to respond to internal use of antibiotics; however, drugresistant bacteria such as MRSA have been frequently found in community-acquired infections in recent years. For that reason, before administration of antibiotics, cultivation tests (on exudate, pus or the like) should be performed. When antibiotics are not effective enough, the drugs may be changed according to the results of laboratory culture test. History-taking is necessary to avoid allergic reactions. For patients with severe liver disorder or kidney dysfunction, the dosage and times of administration should be reviewed in consideration of the metabolic pathway of the drugs. Types of antibiotics and their mechanisms of action are shown in Table 6.8.

7. Antiviral agents Aciclovir and Ara-A (adenine arabinoside) are effective against herpes viruses, including herpes simplex and varicella zoster. Aciclovir may be administered orally or by injection; it is used in outpatient treatment. Since antiviral agents are metabolized by the kidney, in patients with kidney disorder the dosage should be controlled based on creatinine clearance. Other antiviral agents are ganciclovir, which is effective against cytomegalovirus, and some kinds of anti-HIV drugs.

8. Retinoids Retinoids are A vitamins and their derivatives. They control the proliferation and differentiation of epithelial tissues, processes that are promoted by retinoic acid, a metabolite of vitamin A. The only retinoid permitted in Japan is etretinate; however, in

B. Systemic treatments Table 6.8 Common antibiotics and their mechanisms. Antibacterial effects

Classification by drug structure

Biocidal agents b -lactams

Mechanism

Penicillin Cephalosporin Monobactam Carbapenem

Inhibition of cell wall synthesis

Penem Fosfomycins Aminoglycosides

Inhibition of protein synthesis

Polypeptide antibiotics

Inhibition of cell wall synthesis

Synthetic antibiotics

Bacteriostatic agents

Quinolone

Inhibition of DNA synthesis

Sulfamethoxazole/ trimethoprim

Inhibition of folic acid synthesis

Tetracyclines Chloramphenicols Macrolides

Inhibition of protein synthesis

Lincomycins

other developed countries, acitretin, isoretinoin and all-trans retinoic acid are permitted. Vitamin A works to decrease sulfate cholesterols, constructional components of the horny cell layers; that is, exfoliation of the horny cell layers is increased by vitamin A administration. In light of these effects, retinoids are useful against various disorders of keratinization, such as ichthyosis, palmoplantar keratosis, Darier’s disease and severe psoriasis (Table 6.9). Nonetheless, etretinate causes serious side effects (teratogenesis and bone defects), and contraception of 2 years for women and 6 months for men after the administration of retinoids is strictly advised for patients of reproductive age. In Europe and U.S., etretinate has been withdrawn from the market because of its undesirable pharmacolcinetics. Today acitretin is commonly used. Care should be taken in deciding whether to administer retinoids to children, because of the possibility of premature closure of the epiphyseal line. Other side effects are epidermal exfoliation, nail fragility, liver disorders and abnormal lipid metabolism. In Europe and the United States, retinoid creams are externally applied to treat acne and psoriasis.

9. DDS (4,4’-diamino-diphenyl-sulfone, diaphenylsulfone) DDS (dapsone), a sulfa drug that inhibits folic acid synthesis, was originally used to treat Hansen’s disease. Since it was found to be effective against inflammatory skin diseases whose main symptom is neutrophilic infiltration, DDS has been administered to treat Duhring herpetiform dermatitis and other bullous

83

Table 6.9 Major retinoid-responsive skin diseases. Disorders of keratinization Ichthyoses Darier's disease Psoriasis Pityriasis rubra pilaris Malignancies Basal cell carcinoma Squamous cell carcinoma Mycosis fungoids Other Acne Cutaneous aging

6

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Treatment of Skin Diseases

diseases, erythema elevatum diutinum, subcorneal pustular dermatosis, vasculitis, granuloma faciale and pustular psoriasis. The side effects are hemolytic anemia, methemoglobinemia, leucopenia, liver disorders and kidney disorders; regular blood tests are necessary. Eruptions, fever and liver dysfunction may be present as so-called hypersensitivity syndrome in rare cases (Chapter 10): These particular symptoms are known as DDS syndrome.

6 10. Vitamin preparations Skin diseases caused by vitamin deficiency are ariboflavinosis (vitamin B deficiency), pellagra (niacin deficiency), and biotin deficiency (vitamin H deficiency). Vitamin replacement therapy is administered. Vitamin C is given in cases of melasma and postinflammatory pigmentation.

11. Anticancer agents Anticancer agents may be administered for skin diseases such as malignant melanoma, squamous cell carcinoma, Paget’s disease, and cutaneous lymphoma, depending on the stage of the disease. Combined use of various types of anticancer agents is conducted; however, the various anticancer agents and their dosages should be thoroughly discussed before administration. Most anticancer agents have more serious side effects than drugs in general, and they can even be fatal (Table 6.10). Nausea, vomiting and leucopenia are diminished by anti-serotonin and G-CSF drugs. CHOP therapy (for lymphoma) and DAV-feron therapy (for malignant melanoma) are frequently administered in dermatology (Chapter 22).

12. Biologic (molecular-targeted) therapies Biologic (molecular-targeted) therapies, in which monochrome antibodies such as infliximab, adalimumab, etanercept Table 6.10 Main side effects of anticancer agents. Drug

Side effects Myelosuppression

Nausea/vomiting

Alopecia

other Hemorrhagic cystitis, SIADH

Cyclophosphamide

+++

++

+++

Cisplatin

++

+++

+

Renal dysfunction, hypacusis, neuropathy

Dacarbazine

+

+++

++

Flu-like syndrome, hepatic vein dysfunction

Methotrexate

++

+

+

Hepatic dysfunction, renal dysfunction, neuropathy

Fluorouracil

++

+

+

Diarrhea, aphtha, cerebellar ataxia, myocardial infarction

Doxorubicin

+++

+++

+++

Cardiac dysfunction

Bleomycin

+

+

++

Interstitial pneumonia, fever, allergic reaction

Vincristine

+

+

++

Neuropathy, constipation, SIADH

Etoposide

+++

++

+++

Allergic reaction, hepatic dysfunction, neuropathy

Docetaxel

+++

+

++

Edema, eruption, allergic reaction

C. Laser therapies

85

Table 6.11 Biologic (molecular-targeted) agents. Drug

Target molecule

Indication

Rituximab

CD20

B-cell lymphoma, pemphigus vulgaris

Infliximab

TNF-a

Crohn’s disease, rheumatoid arthritis, psoriasis

Etanercept

TNF-a

Crohn’s disease, rheumatoid arthritis, psoriasis

Alefacept

CD2

Psoriasis

Efalizumab

CD11a

Psoriasis

6

and alefacept are administered, have recently been developed to treat lymphoma, collagen diseases, autoimmune bullous diseases and psoriasis (Table 6.11). In contrast to anticancer drugs and immunosuppressants, there are fewer and less severe side effects with biologics. Particularly beneficial effects on severe psoriasis and psoriatic arthritis have been reported, and widespread use of biologic therapies is expected in the future. However, secondary infections such as tuberculosis have occurred in some cases. These therapies should be applied carefully.

C. Laser therapies 1. Basics and theory of laser therapy “Laser” is an initialism for “light amplification by stimulated emission of radiation.” Molecules are excited in a xenon flash tube or by electric discharge. When they return to their base state, the molecules emit light. The light is amplified in the resonator. Laser beams are distinguished by their monochromaticity, directivity, and high energy density. Light energy is absorbed in tissues by heat transfer, and cells and tissue are destroyed as a result. The part of a visibly colored molecule that absorbs light in the visible range is called a chromophore. It is found in melanins and hemoglobins of normal skin. The application of a laser with a wavelength that affects melanin- or hemoglobin-containing cells causes the temperature to increase and thermal diffusion to be produced, which in turn causes the cells to burn. In this way, blood capillaries are cut off, and the unwanted color tone of the cells fades. To prevent degeneration of the skin surface by thea destructive heat, apparatuses equipped with cooling systems may be used. As a cohesive theoretical understanding and trial results have been accumulated, it is now possible to determine the most effective wavelength for each case. The main laser therapies are summarized in Table 6.12. Examples of laser therapy are shown in Fig. 6.5, and the laser apparatuses that are frequently used are listed in Fig. 6.6. The wavelength that is most effectively absorbed by each lesion is selected for irradiation. O 2 -hemoglobins absorb

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a

b

c

d

e

f

g

h

b

c

d

e

f

g

h

i

Fig. 6.5 Laser therapy. a: Dye laser for vascular lesions. b: Alexandrite laser for pigmented lesions.

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86

6

Treatment of Skin Diseases Table 6.12 Common lasers.

6

a

b

ac

bd

ce

eg

df

Laser

Wavelength

Absorbed by... (chromophore)

Carbon dioxide

10600 nm

Water

Dye

577-585 nm

Hemoglobin

Ruby

694 nm

Melanin, tattooing pigments

Alexandrite

755 nm

Melanin, tattooing pigments

Nd: YAG

1064/532 nm

Melanin, hemoglobin, tattooing pigments

lights most effectively at 418 nm, 542 nm, and 577 nm. Light with a wavelength of 577 nm reaches the deep area of skin (Fig. 6.7). For melanins, the proper wavelength varies depending on the depth between the pigmented site and the epidermal layer. Moreover, the of irradiation need to be changed accord-oq gi duration j l may fh hj ik km ln mo np ing to the color of the targeted lesion. Lasers with a pulse on the order of nanoseconds (10-9 second) or shorter are used to destroy melanosomes; lasers with a pulse on the order of microseconds (10-6 second) are used to destroy the cells completely. Heat damage to the epidermis may result in adverse reaction such as blistering, scarring and dyspigmentation. To reduce the risk, some lasers have cryogen spray cooling equipment (dynamic cooling device).

pr

2. Laser therapy on pigmented skin lesions Ruby laser (694 nm) and alexandrite laser (755 nm) are used to ac

bd

ce

eg

df

gi

fh

Fig. 6.6 Lasers. a: Carbon dioxide laser. b: Dye laser. c: Alexandrite laser. d: Ruby laser. molar extinction coefficient (X105l / mole・cm)

b

1.4 1.2

Hb (H2O) HbO2 (H2O)

1.0 0.8 0.6

bilirubin (CHCl3)

0.4 dopamelanin (H2O)

0.2 0 300

400

500

600

700

pigmented lesions.ln Lightmoat those pr is notq j j l skin km htreat ik np wavelengths oq absorbed by hemoglobins, and it reaches the depth of 1.5 mm. The Q-switched ruby laser has a 20- to 30-ns irradiation duration, and its beams can be concentrated on melanosomes effectively. Reduction of pigmented cells is observed in 80% or more cases with nevus of Ota, a kind of dermal melanocytosis. Laser therapy is effective only against pigmented lesions in nevocellular nevus and blue nevus. The color tone of nevus fades in proportion to the number of irradiations; however, the therapy does not work on elevated, slightly pigmented skin lesions. Basically, laser therapy is not performed in such cases; if necessary, the possibility of pathological malignancy should be ruled out. Laser therapy is performed on ectopic Mongolian spots, senile lentigo, and nevus spilus. It is also used to remove tattoos; nonetheless, the effectiveness depends on the depth and the pigment color. For multicolored tattoos, a different laser should be applied for each color.

wavelength (nm)

Fig. 6.7 Optical absorption spectrum in human skin. (Anderson RR et al. The optics of human skin. J Invest Dermatol 1981; 77: 13-9).

3. Dye lasers for vascular lesions Dye lasers (577 nm to 585 nm) are used to treat hemangiomas. With hemoglobins targeted, the vascular endothelium is destroyed by destruction of erythrocytes and subsequent emission of heat. These lasers are effective in treating hemangioma simplex,

r

D. Physical therapies

87

strawberry marks, and telangiectasia. Photodynamic therapy (PDT) is also conducted. In this therapy, a tumorous lesion is exposed to red fluorescence with application of d -aminolevulinic acid, and then it is irradiated by laser.

D. Physical therapies 6 1. Phototherapies Phototherapies are largely divided into those using ultraviolet rays and those using infrared rays.

1) Ultraviolet (UV) light Ultraviolet (UV) light is classified into three wavelength ranges. From longest to shortest, they are UVA (320 nm to 400 nm), UVB (290 nm to 320 nm) and UVC (200 nm to 290 nm). The shorter is the wavelength, the lower is the penetration and the greater is the energy of the light. UVC light that affects only the skin surface is chiefly used for sterilization lamps, because of its high cytotoxicity. The UV phototoxic reaction of UVA and UVB light are used in dermatological laser therapies. UVA and UVB directly or indirectly damage DNA by exciting UV absorbing molecules, or they produce free radicals that injure cells. ①Psoralen-ultraviolet-A (PUVA) therapy Psoralen-ultraviolet-A (PUVA) therapy (Fig. 6.8) is a typical UV therapy that uses UVA, which is deeply penetrative but has little energy. After oral or topical application of psoralen, a phototoxic substance, the site is irradiated with UVA. The patient is given radiation in combination with 8-MOP (8-methoxypsoralen) or TMP (4,5’,8-trimethylpsoralen). This treatment is applied in cases of psoriasis vulgaris, vitiligo vulgaris, mycosis fungoides, palmoplantar pustulosis, atopic dermatitis, alopecia areata and prurigo nodularis. As a side effect, sunburn may be caused by excessive irradiation of long-wavelength UV rays. It should be performed carefully, so that successive irradiations over a long period of time do not cause cataracts or cutaneous malignant tumors. ②UVB therapy UVB is known to be immunosuppressive by inhibiting the functions of Langerhans cells. Currently, UVB irradiation therapy is performed to treat atopic dermatitis, pityriasis lichenoides chronica, and pruritus in dialysis patients. For patients with psoriasis vulgaris, frequent sunbathing is strongly advised, as the UVB in sunlight is expected to be beneficial (heliotherapy). ③Narrow-band UVB therapy Narrow-band UVB has a wavelength of 311 nm ± 2 nm. It is thought to be more effective than broadband UVB as a treatment for skin diseases. It is effective against psoriasis, atopic dermatitis, the early stages of mycosis fungoides, and vitiligo vulgaris.

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Fig. 6.8 UV irradiation instrument (narrowband UVB).

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Treatment of Skin Diseases

④UVA1 therapy UVA with a long wavelength of 340 nm to 400 nm is called UVA1. It is applied mainly to treat atopic dermatitis. It is effective against scleroderma.

2) Infrared (IR) irradiation The patient is subjected to infrared (IR) radiation at a wavelength of 760 nm or longer so as to raise the temperature, improve blood circulation, and achieve anti-inflammatory action. The transmissivity through skin is high, with a reach of several centimeters in depth from the skin surface. This allows the therapy to act directly on blood vessels, nerves, lymphatic vessels and other tissues. It is effective in treating frostbite, chilblains, and ulcers of the lower thigh.

6

2. Radiotherapy Radiotherapy was once used to treat benign diseases such as chronic inflammatory diseases. In consideration of its side effects, which include carcinogenesis, it is rarely performed for this purpose nowadays. Instead, linac ultrahigh X radiation, 60Co g radiation, or electron radiation generated by linac or betatron are the main forms of radiation used for therapy. These forms of radiation strongly ionize molecules, and the generated free radicals damage DNA directly or indirectly, leading to cell death. The proper type of radiation should be chosen in suitable dose for each case.

1) Electron beams MEMO

Skin types

Reaction to sun exposure differs for each individual. Some people sunburn easily, whereas others tend to suntan. Fitzpatrick classified human skin into six types according to such differences. Japanese skin falls under type III xanthoderm. Fitzpatrick type I （pale white） type II （white） type III （white）

Japan sunburn

Japanese skin type falls within this range of type III.

type IV （light brown）

type II（70%）  reddening  suntan（＋）

2) Soft X-rays Soft X-rays are low-voltage, low-energy X-rays (about 20 kV). A device called a dermopan is used to generate X-rays in dermatology. However, their application is limited to superficial lesions (e.g., intraepidermal carcinoma, malignant lymphoma, hemagio blastoma) because of the low energy. Soft X-rays are rarely used nowadays.

3. Cryotherapy, Cryosurgery type III（15%）  suntan mainly

type V （brown） type VI （black）

type I（15%）  reddening（＋＋）  suntan（−）

These are b rays generated by betatron or linac. They evenly irradiate lesions to a certain depth, and the energy is not attenuated in the superficial layers. They are used for treating lymphomas and keloids.

suntan

Cryotherapy is a method of freezing cells using a cryogenic source such as liquid nitrogen. It is frequently used to remove warts, and it may be used to treat nevus, hemangioma, alopecia and other diseases. There are several methods of cryotherapy,

E. Skin surgery

89

including the swab method (a cotton swab dipped in liquid nitrogen at -196.8℃ is brought into contact with a lesion (Fig. 6.9), and the spray method (liquid nitrogen is sprayed on a lesion at a pressure of 0.1 kg/cm2 to 0.5 kg/cm2 (Fig. 6.10).

4. Thermotherapy, Hyperthermia In thermotherapy, a lesion is warmed to 42 ℃ to 47 ℃ with warm water, a body warmer, a medical exothermic sheet or the like. This is effective in treating sporotrichosis, chromomycosis and infections of atypical mycobacteria. It may be performed as a treatment for malignant skin tumors in conjunction with chemotherapy or irradiation therapy.

6 Fig. 6.9 Cryotherapy (using stype).

5. Hyperbaric oxygen (HBO) therapy The aim of hyperbaric oxygen therapy (HBO) is to increase oxygen dissolved in the blood and to increase the partial pressure of oxygen in the tissues. It may be used for peripheral circulatory disorders such as ischemic anaerobic infections (e.g., gas gangrene), or postoperatively on skin grafts. Fig. 6.10 Cryotherapy (using spray).

E. Skin surgery Skin surgery may be performed to treat various types of nevus, benign and malignant tumors, burn scars, intractable ulcers, chronic pyoderma, and tattoos. Before operation, medical indication for surgery should be carefully evaluated (particularly as to whether the lesion is malignant,). Also, the physical capability of patients to tolerate surgery should be thoroughly examined. It is important to conduct surgeries for satisfactory functional and cosmetic results. Before the use of local anesthesia, the complete medical history should be taken, and an intracutaneous test may need to be performed. Sufficient explanation about the surgery should be given to the patient in advance; moreover, it is essential to gain the patient’s written consent. Practical techniques of suturing, skin grafting, and dermabrasion are introduced briefly below. Refer to textbooks on dermatological surgery and plastic surgery for greater detail.

1. Excision and suturing A comparatively small lesion is removed and the periphery is sutured (Figs. 6.11 and 6.12). The basic method is spindleshaped excision and suturing (Fig. 6.12). If the long axis of excision is not long enough, the ends may rise in what are called dog-ears, from their shape. This is a cosmetic problem. For that reason, the long axis needs to be at least triple the width. In the event that a lesion cannot be sutured in one operation, it may be

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Treatment of Skin Diseases

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Clinical images are available in hardcopy only.

6

excised in two or more operations (serial excision). The skin may be extended using silicon prior to surgery (skin expansion), or skin graft may be performed. Excision is basically performed along the line of a wrinkle; however, excision lines are decided carefully, according to cosmetic concerns, especially when the excision is long or in the face.

2. Skin graft Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

When a lesion is too large for excision and suture, a skin graft is performed. Skin grafts are roughly divided into free skin grafts and pedicle grafts. Free skin grafts: Skin grafts are removed from the donor site (Fig. 6.13) and fixed (tie-over method, Fig. 6.14). The removed skin remains ischemic for approximately 4 or 5 days, until blood flow returns. Depending on the thickness of the dermal area, grafts are full-thickness (the epidermis and all of the dermal layers) or split-thickness (the epidermis and partial layers of the dermis) (Fig. 6.15). In a split-thickness graft, removed skin is processed into a mesh to raise the graft survival rate (mesh skin graft). Since skin is one of the organs that are most likely to produce immunologic rejection, the patient’s own normal skin is the only possibility for a permanent graft. Allogenic graft, dermatoheteroplasty, and biological dressing of freeze-dried pigskin are sometimes performed to temporarily cover the body. Pedicle flaps: Skin and subcutaneous tissues are not completely separated from the living body for a graft. The flaps themselves supply the blood (Fig. 6.16). Although local flaps are usually used, distant flaps may also be used.

3. Dermabrasion, Skin abrasion

Clinical images are available in hardcopy only.

Dermabrasion is a method of scraping away the skin surface with a high-speed grinder or dermatome. Depending on its depth, dermabrasion may produce keloids, recurrent lesions, or pigmentation; therefore, skillful performance is required. Instead of a

Fig. 6.11 Excision of keratoacanthoma. Skin defect was closed by V-T flap.

B A

B

A

B

Fig. 6.12 Various incisions and flaps.

A

91

E. Skin surgery

6 Fig. 6.13 Split-thickness skin graft was obtained using silver knife.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 6.14 Skin grafting and tie-over.

With application of chemicals (e.g., salicylic acid, glycolic acid, trichloroacetic acid) to a lesion, the surface of the skin exfoliates. In many cases, cosmetic effects of chemical peeling are expected on lesions such as acne and senile lentigo. As the penetration depth can be varied so as to limit the treatment to the horny cell layer or to apply it to epidermal layers, the method most suitable for the disease or purpose should be chosen according to the chemical and the duration of activity.

5. Electrosurgery, Iontophoresis The main electrosurgeries are electrocoagulation, in which heat generated by an electric scalpel coagulates tissues (Fig. 6.17), and electrolysis, in which blood and tissue fluids are degenerated by direct-current electricity applied to the body. Iontophoresis is the process of introducing salt ions in solution through the skin into the tissues, and it may be effective in treating palmoplantar and axillary hyperhidrosis. Several iontophoresis devices are commercially available.

dermis epidermis

4. Chemical peeling

split-thickness skin graft (STSG)

flap p

subcutaneous muscle tissue

high-speed grinder or dermatome, a carbon dioxide gas laser is often used to treat epidermal nevus, seborrheic keratosis, tattoos, lichen amyloidosis, porokeratosis, Darier’s disease and HaileyHailey disease.

full-thickness skin graft (FTSG)

Fig. 6.15 Skin thickness and various graft procedures. B A

120° 60° C D E

G

B E A

C

F D

G

F

Fig. 6.16 Pedicle flap (Limberg flap).

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Treatment of Skin Diseases

6. Laser knife Laser knives cauterize tissue using heat produced by laser. Carbon dioxide gas lasers are the principal lasers used for surgery. The advantages of surgical lasers are that there is no direct contact and that they can be used without electricity, thus making them applicable for patients with pacemakers. A surgical laser is useful for treating seborrheic keratosis and epidermal nevus; moreover, the depth is easily controlled, and injury to normal tissues is minimal.

6

Fig. 6.17 Electrocoagulation.

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Chapter

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Eczema and Dermatitis

Eczema and dermatitis are synonyms for a disease that is the most commonly seen in dermatology practice. Eczema/dermatitis has the symptoms of itching, reddening, scaling, and edematous papules, and the condition progresses in a specific inflammatory reaction pattern. Eczema/dermatitis is histopathologically characterized by intercellular edema called spongiosis, which can be caused by extrinsic factors, such as irritants or allergens, or by intrinsic factors, such as atopic diathesis. These factors interact in complex ways, and extrinsic and intrinsic factors are seen together in many cases. There is no international agreement on the subcategories of eczema. If the cause is not identified, eczema may be called acute, subacute or chronic, depending on the clinical and pathological features.

Eczema Synonym: Dermatitis Outline ● Eczema

and dermatitis are synonymous. eczema is accompanied by itching, reddening, scaling, and edematous or serous papules. ● Histopathologically, it is characterized by intercellular edema (also called spongiosis). ● It accounts for one-third of all dermatology cases. ● Extrinsic and intrinsic factors are simultaneously involved in its onset. ● The first-line treatment is topical steroid application. ● Pathologically,

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Clinical features Itchy edematous erythema forms, on which papules and serous papules are produced. After the formation of vesicles, pustules, erosions, crusts and scales (Fig. 7.1), the condition begins to subside. The progress of eczema is illustrated in the chart (Fig. 7.2). In the acute stage, these symptoms are present singly or together. In the chronic stage, acanthosis, lichenification, pigmentation and depigmentation are found, in addition to the symptoms of the acute stage. Pathogenesis Both extrinsic and intrinsic factors are involved in eczema (Fig. 7.5). When an extrinsic agent such as a drug, pollen, house dust, or bacteria invades the skin, an inflammatory reaction is induced to eliminate the foreign substance. The severity and type of reaction vary according to intrinsic factors such as seborrhea, dyshidrosis, atopic diathesis, and the health condition of the patient. Pathology Eczema is characterized by intercellular edema (spongiosis) (Fig. 7.3). In the acute stage, it is accompanied by exocytosis of lymphocytes and spongiotic bulla. In the chronic stage, hyperkeratosis, 93

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Fig. 7.1 Eczema. 16-year-old Japanese woman with acute eczema on the legs. Scaly erythema with scales, papules and vesicles are scattered, partly forming oozy crusts and pustules.

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extrinsic factors

acute eczema

chemical agents bacteria other allergens drugs

pustule

vesicle

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wetness

health condition sebum secretion sweating existence of allergy

chronic eczema lichenification, pigmentation

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scaling

Fig. 7.5 Various factors causing eczema. Extrinsic and intrinsic factors interact, resulting in eczema formation.

Fig. 7.2 Course and symptoms of eczema.

parakeratosis, irregular acanthosis, and elongation of rete ridges are observed. Spongiosis and spongiotic bulla are less severe in chronic eczema than in acute eczema.

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Classification Eczemas are generally classified by cause (Table 7.1). These causes interact in complex ways and are not always clearly idenp j tifiable. ofk the disease may differ from toq h i The name l m n o country country.

a. Eczema with unidentified cause When the cause is not identified, eczema is simply called acute, subacute or chronic, according to the clinical findings, the course of the eruption, and the pathological findings. There is no clear definition of eczema. Lesions in various stages often exist a

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Fig. 7.3 Histopathology of eczema. a: Acute eczema. Spongiosis (arrows) has formed from intercellular edema. Lymphocytic infiltration is also seen. b: Chronic eczema. Hyperkeratosis, regular acanthosis and elongation of epidermal rete ridge are noted. Spongiosis is not severe (arrows).

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Fig. 7.4 Acute eczema. Itchy edematous erythema and infiltrated small papules are seen. Small vesicles also appear.

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Table 7.1 Eczema classified by pathogenesis. Contact dermatitis Housewives hand eczema Keratodermia tylodes palamaris progressiva Diaper dermatitis Atopic dermatitis Seborrheic dermatitis Nummular eczema Lichen simplex chronicus，lichen Vidal Autosensitization dermatitis Stasis dermatitis Other Pompholyx, dyshidrotic eczema Pityriasis simplex faciei Perioral dermatitis

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together on the same individual. Eczema with unidentified cause is usually considered contact dermatitis with the involvement of an extrinsic substance. Topical steroids and oral antihistamines are applied as the first line of treatment for eczema at all stages.

1. Acute eczema Acute eczema is accompanied by exudative erythema, edema, and sometimes vesicles (Fig. 7.4). It is newly produced eczema only several days after its onset. Intercellular edema (spongiosis), intense dermal edema, and inflammation occur. Acanthosis usually does not.

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2. Subacute eczema Subacute eczema has a severity between that of acute and that of chronic. Such eczema is accompanied by erythema and edema, and it is slightly lichenoid. Mild edema is produced in the epidermis. Acanthosis and parakeratosis are observed.

3. Chronic eczema Chronic eczema is characterized clinically by lichenification. When acute eczema continues for more than one week after onset, it is likely to appear lichenified, and the diagnosis is chronic eczema. Acanthosis and parakeratosis are noticeable histopathologically (Fig. 7.6); however, there is less infiltration of inflammatory cells into the epidermis than with acute and subacute eczema.

b. Eczemas with more specific names according to their distinguishing features

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Fig. 7.6 Chronic eczema. Hyperkeratosis is severe, as in tylosis. Erythema and fissures are seen.

1. Contact dermatitis Outline ● Contact

dermatitis is localized to the site of extrinsic stimulation by foreign substance or allergic reaction. ● Eczema reactions such as reddening and blistering occur at the contact site. ● There are specific types of contact dermatitis, such as diaper dermatitis and housewive’s hand eczema. ● The causative substances include certain plants, chemical agents, and nickel, mercury and other metals. ● Patch testing is useful for diagnosis. Topical steroid application is the first-line treatment. The causative agent should be eliminated.

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Fig. 7.7-1 Contact dermatitis. a: “Ginkgo nut dermatitis.” This patient touched his face without washing his hands after gathering ginkgo nuts.

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Clinical features Erythema, serous papules, vesicles, erosions and crusts are localized at the contact site of the causative agent (Figs. 7.7-1 to 7.7-3). The eczematous lesions are relatively sharply circumscribed and are intensely itchy. Although only localized areas are affected, erosive lesions may become widespread when the causative agent is spread by rubbing and scratching. If the inflammation spreads over the entire body, systemic symptoms such as fever may arise. When the causative agent is highly stimulative, it may cause necrosis of the skin and ulceration.

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Fig. 7.7-2 Contact dermatitis. b: Contact dermatitis from a bra. c: From allergenic plants. d: From an unknown cause, probably soap. e: “Shiitake dermatitis.” When eaten raw, shiitake mushrooms sometimes cause very itchy, systemic contact dermatitis.

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Atypical cases of contact dermatitis ①Pseudoatopic dermatitis: When the skin is repeatedly stimulated by a causative agent, symptoms closely resembling those of adult atopic dermatitis may appear. ②Melanosis Riehl: Ingredients of cosmetics are converted by light into allergens that cause pigmentation without noticeable inflammation (Chapter 16). ③Systemic contact dermatitis: When an individual is sensitized by contact allergy and inhales an antigen, a systemic allergic reaction is induced. Mercury is well known as such an antigen. ④Gold dermatitis caused by earrings: Readily ionized metals such as nickel often cause dermatitis. In recent years, the number of cases caused by gold earrings has increased significantly. They are characterized by intractable induration where the p q j l A lymphoid m n follicle-like o r form ear isk pierced. structure may (Fig. 7.8). Pathogenesis Primary irritant contact dermatitis is an inflammatory reaction caused by lysosomes or various cytokines that are released from keratinocytes when the keratinocytes are injured by substances in the causative agent. With a certain level of irritation, contact dermatitis may occur in anyone from the very first contact. Allergic contact dermatitis basically occurs as a type IV allergic reaction (Fig. 3.9). The causative agent invades the body perp q k l m is captured n o by Langerhans r which are cutaneously and cells, epidermal antigen-presenting cells. It moves to the regional lymph nodes and transmits information about the antigen to thymus-derived T cells. Those T cells proliferate in the lymph nodes (sensitization). If the causative agent reinvades the body after sensitization, the sensitized T cells become activated to release various cytokines, which leads to a prompt inflammatory reaction that causes dermatitis. This reaction is not produced by the first contact, but it is produced in previously sensitized persons even p l contact m withn a minute o amount r by ofqthe antigen (that is, there is no threshold amount of a causative agent that causes contact dermatitis). Almost anything, from plants to cosmetics to detergents to chemicals in workplaces and homes, can be an allergen (Table 7.2).

1. Contact dermatitis Table 7.2 Main allergens in allergic contact dermatitis. Heavy metals

Chrome, nickel, cobalt

Plants

Poison oak, primrose, orchis, ginkgo, chrysanthemum, aloe

Foods

Tomatoes, lettuce

Hair dyes

Paraphenylendiamine (PPD)

Perfumes Medicinal agents

Ointments, disinfectants

Preservatives

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Synthetic resins

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Table 7.3 Contact dermatitis: locations and main causes. Cause

Location Dcalp

Shampoos, hair dyes, hair restorers, hats

Face

Cosmetics, medicinal agents, perfumes, eyeglasses, plants

Neck

Necklaces, cosmetics, perfumes, medicinal agents, clothes

Body, extremities Clothes, cleansers, metals, medicinal agents Hands and feet

Rubber, leather, plants, medical agents, cleansers, cosmetics, metals

Genital region

Clothes, cleansers, condoms, contraceptive devices

Laboratory findings, Diagnosis Each causative agent causes a particular distribution of eruptions; the agent in each case is easily identified by the distribution and history-taking. Substances that frequently cause contact dermatitis are listed by the location on the body in Table 7.3. The causative substance is determined by patch testing (Chapter 5). Treatment The irritant should be avoided. Topical steroids and oral antihistamines are the first-line treatments. Although desensitization a b c d e therapy is performed at some institutions, the efficacy varies from case to case. Note There are more specific names for contact dermatitis according to types of patients and particular locations on the body. ①Diaper dermatitis: This occurs where the diaper comes into contact with the skin (Fig. 7.9). ②Housewive’s hand eczema: This affects the hands of those who frequently work with water. Keratodermia tylodes palmaris progressiva is included in this category. ③Dyshidrotic eczema: Small vesicles (also called pompholyx) and desquamation occur frequently on the palms and soles, and they often worsen during the summer.

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Fig. 7.7-3 Contact dermatitis. f: Contact dermatitis from tattooing. Red pigment is thought to be the allergen.

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Fig. 7.8 Contact dermatitis from gold earrings.

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MEMO Contact dermatitis may be diagnosed as ginkgo nut dermatitis, rhus dermatitis, mercury dermatitis, or shiitake dermatitis. The diagnosis depends on the allergen.

Varieties of contact dermatitis

Fig. 7.9 Diaper dermatitis.

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2. Atopic dermatitis Outline ● Atopic

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General information In atopic dermatitis, chronic eczematous/dermatitis lesions are caused by various acquired stimulative factors, under conditions in which the skin barrier function is congenitally low and IgE is easily produced. The Japanese Dermatological Association defines atopic dermatitis as “a disease whose main lesion is itching eczema with recurrent remissions and exacerbations, and most patients have some atopic condition.” Type I allergy (an atopic condition, such as asthma, allergic rhinitis, or conjunctivitis) and type IV allergy are involved in most cases.

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dermatitis is chronic eczema/dermatitis caused by an atopic condition (allergic asthma, rhinitis, conjunctivitis). ● Exudative eczema occurs on the face and ear pinna. It is characterized by eruptions of dry pityriatic scales. ● The patient tests positive for white dermographism. The IgE value is high. ● Filaggrin gene mutation is a key predisposing factor for atopic dermatitis. ● These complications can occur: Kaposi’s varicelliform eruption, cataract, and retinal separation. ● Topical steroids, topical immunosuppressants such as p q j h i k l m n o tacrolimus and pimecrolimus, oral antihistamines, and moisturizers are the first-line treatments.

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Clinical features Atopic dermatitis is classified into three age periods: infantile (age 2 months to 4 years), childhood (early childhood to puberty), and adolescent/adult. Different eruptions characterize each period (Figs. 7.10-1 to 7.10-3). Atopic dermatitis is accompanied by intense itching in all the periods, with recurrent remissions and exacerbations. It tends to worsen when the skin is dry and during the summer. Although it most frequently occurs in infancy, its incidence in patients beyond infancy, including adults, has been increasing greatly in recent years.

1) Infantile atopic dermatitis In the early stage of atopic dermatitis in infancy, erythema, b

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Fig. 7.10-1 Atopic dermatitis. a: In childhood. Widespread eczematous lesions with severe excoriation. b: Adult man. Edematous, infiltrated plaques with exudation are seen on the face and neck. c: Adult woman. Lichenified papules are seen on the face.

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MEMO Atopy is the word for a concept that Coca et al. proposed in 1923. The term means “abnormal hypersensitivity.” Atopic patients tend to suffer congenitally from bronchial asthma and hay fever. Atopic dermatitis is often hereditary.

Atopy

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scales, and serous papules are produced on the head and face and these gradually spread to the trunk. The condition becomes exudative: erosions form, with crusts and scales attached to the surface. It resembles seborrheic dermatitis. Thick crusts on the head and ear notch, and lesions around the mouth and lower jaw (produced by causative agents in baby food) are also observed. The trunk and extremities become dry, and follicular papules aggregate, appearing as goose bumps. Scaly erythematous a b atopicc plaques form on these lesions and progress to childhood dermatitis.

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2) Childhood atopic dermatitis In childhood atopic dermatitis the skin becomes dry. Lichenified plaques occur on the cubital fossa and popliteal fossa. Cracks are often found in the auricle area (ear notch). Multiple follicular papules occur on the dry skin of the trunk. This dermatitis is accompanied by intense itching, and it progresses quickly to eczematous crusty lesions. a

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3) Adolescent and adult atopic dermatitis The symptoms are similar to those in childhood dermatitis, but the lichenified plaques progress and enlarge. Rough, dry, dark brown atopic dermatitis occurs all over the upper body. The lesions are more severe and widely distributed than those of childhood dermatitis. Thinning of one-third of the lateral eyebrow is present (Hertoghe’s sign, Figs. 7.10-1b and 7.10-1c). In serious cases, diffuse erythema occurs on the face, and a mottled appearance is seen on the neck and upper chest (poikiloderma lesion, dirty neck, Fig. 7.10-2d).a Atopic b prurigo c may d occure repeatedly on the extremities. Pathogenesis There have been many studies on skin physiology and immune function in atopic dermatitis; however, the pathogenesis has not been fully clarified. Abnormality of skin physiology: A defective skin barrier is important for the pathogenesis of atopic dermatitis. Filaggrin gene mutations have been shown to be a key predisposing factor for atopic dermatitis. Abnormality in vascular response can be tested by white dermographism (skin with atopic dermatitis becomes white when scratched, whereas normal skin becomes b c d e f red) (Fig. 7.11). Dyshidrosisa and decreased content (particularly a decrease in ceramides) of lipid in the horny cell layer, facial pallor, dry skin and multiple small follicular papules are present (atopic skin). The atopic skin is vulnerable to extrinsic irritation; intensely itchy eczema is easily produced by slight irritation, or even by perspiration or contact with animal fur, wool or chemicals. Immune function abnormality: Atopic conditions such as allergic

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Fig. 7.10-2 Atopic dermatitis. d: “Dirty neck.” Poikilodermatous pigmentation is seen on the neck and upper chest. e: Adult atopic dermatitis. Severely excoriated plaques are seen. f: Erythrodermic atopic dermatitis. g: Prurigo will occur as a result of longtime scratching.

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asthma, allergic rhinitis, conjunctivitis and atopic dermatitis are found in the family and patient’s history. Patients with atopic dermatitis readily produce IgE antibodies. When there is a high IgE value and positive intracutaneous reactions to various allergens, a congenital immune abnormality of some sort is regarded as being involved in atopic dermatitis.

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Laboratory findings The serum IgE value is high; IgE RAST for mites and house dust is positive in most cases. There is an increase in eosinophils in the peripheral blood. Although white dermographism is highly sensitive in detecting atopic dermatitis, it has low specificity.

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Complications Eye diseases such as cataract (in 10% of severe adult cases), keratoconus, and retinal separation develop as complications of p q Eye-rubbing atopic dermatitis. from the itch and prolonged oral o r steroid use are thought to be the cause; however, this has not been confirmed. Infectious diseases including Kaposi’s varicelliform eruptions, molluscum contagiosum, and impetigo contagiosa may also be caused. Patients with atopic dermatitis may be hypersensitive to drugs and insect stings.

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Fig. 7.10-3 Atopic dermatitis. h: Atopic dermatitis with severe hand eczema. i, j: Severe erythema is sometimes seen on the flexor of the lower legs.

Diagnosis When there are the clinical findings described above, atopic p q is easy r to diagnose. In diagnosis, it is also important to dermatitis consider any family history of the condition. Atopic dermatitis in adolescents and adults has been increasing in recent years. Infant seborrheic dermatitis closely resembles infantile atopic dermatitis. Treatment Topical steroid application is the primary treatment for the intense cutaneous symptoms. The application method and dosage of steroids are chosen according to the degree and course of the lesion. Ointments containing immunosuppressants such as q tacrolimus r and pimecrolimus have become widely used dermatological treatments (Chapter 6). These drugs are not used for erosions or ulcers; however, they are helpful for systemic lesions including those on the face, and they are frequently used internationally as first-line treatments. Moisturizer is helpful in treating mild symptoms. Oral antihistamines are effective at preventing

MEMO Patients with atopic dermatitis have become the target of commercial ventures in recent years in Japan, not all of which are medically justified. This is called the atopy industry or atopy business, which has become a social problem. In light of this, some medical institutions such as university hospitals are providing educational hospitalization for atopic dermatitis, so that patients can learn correct knowledge of the clinical state and its treatments.

The “atopy industry”

2. Atopic dermatitis

the eruptions from becoming aggravated by rubbing and scratching. Oral steroids are usually unnecessary for mild symptoms of atopic dermatitis. Besides these medical treatments, improvement of the living environment (e.g., removing carpeting, keeping the temperature and humidity low to reduce perspiration), and skin care (avoiding contact with causative agents, keeping the skin clean) are important. Prognosis Atopic dermatitis tends to be chronic and recurrent. It mostly resolves spontaneously by the time the patient reaches age 10; however, the symptoms do not improve in some patients until they reach adolescence or adulthood. The incidence of adolescent and adult atopic dermatitis has been increasing in recent years.

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3. Seborrheic dermatitis Synonym: Seborrheic eczema Fig. 7.11 White dermographism in a patient with atopic dermatitis.

Outline

Seborrheic dermatitis occurs on sites of skin where sebum is actively secreted. It is characterized by erythematous lesions accompanied by yellowish scales. ● This is one of the most common skin diseases, occurring in infants, adolescents and adults. ● Pityrosporum fungus resident in the skin is a factor in the occurrence. ● Skin care and application of topical steroids and antifungal agents are the main treatments. ●

Clinical features There is some controversy as to whether seborrheic dermatitis in infants, adolescents and adults is the same disease, because there are minor differences in the clinical courses (Fig. 7.12). Dermatitis appears as follicular eczema on seborrheic sites or intertriginous areas in the head, face, axillary fossa, neck and external genitals. The main features of the lesions are oleaginous scales and erythematous plaques that may be slightly itchy. In infants, yellowish crusts begin to form on the scalp, eyebrows and forehead. In infants, scaly erythematous plaques may also form 2 to 4 weeks after birth. In most cases they resolve 8 to 12 months after birth. In adolescents and adults, pityroid scales (commonly called dandruff) increase and scaly erythematous

MEMO Partially hypopigmented macules accompanied by pityriasis scales are produced on the face in later childhood. It is most commonly observed in boys and may appear as a symptom of atopic dermatitis. It heals naturally in several years, in most cases.

Pityriasis simplex faciei

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lesions form on the eyebrows and nasolabial groove. Seborrheic dermatitis is chronic and recurrent.

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Differential diagnosis Dry seborrheic dermatitis closely resembles psoriasis vulgaris. It is also important to differentiate seborrheic dermatitis from pityriasis rosea and parapsoriasis en plaque. In infants, differentiation from atopic dermatitis is essential.

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Fig. 7.12 Seborrheic dermatitis. a: Scalp. Erythema with thick white scales. b: Scaly erythema on the chest.

MEMO Eczema tends to occur in infants 2 to 3 weeks after birth, or sometimes up to several months after birth. It can generally be referred to as infantile eczema. Infantile eczema includes the diseases listed below. Differentiation among these diseases is difficult, especially in newborns. ①Seborrheic dermatitis in infancy: See text. ②Early-stage atopic dermatitis: In intractable cases of infantile eczema. ③Contact dermatitis: e.g., lick dermatitis (dermatitis caused around the mouth by saliva and food), diaper dermatitis. ④Food allergy: Eruptions caused by baby food or by changes in breast milk from health problems including nutritional imbalance in the mother. ⑤Other disorders: Tinea, candidiasis. WiskottAldrich syndrome, Netherton syndrome and Langerhans cell histiocytosis are rare; however, it is necessary to distinguish infantile eczema from these diseases.

Infantile eczema

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Pathogenesis Triglycerides in sebum are decomposed by microbes resident in the skin to produce free acid. The free acid reacts to cause seborrheic dermatitis. It has been reported that over-proliferation of Pityrosporum fungi such as Malassezia furfur aggravates seborp q j h i k l m n o rheic dermatitis.

Treatment with and hairo washing p withq sham-r j facialk cleansing i Proper l m soap n poo are basic for keeping the seborrheic regions clean. Regulating daily life is also helpful. Middle class topical steroids are applied. Topical antifungal agents and antifungal shampoos are effective at resolving seborrheic dermatitis accompanied by dandruff in adolescents and older adults, which is often caused by overproliferation of Pityrosporum fungi.

4. Nummular eczema (eczema nummulare) Outline

Round, relatively large eczematous plaques are produced. ● Nummular eczema may occur at any site on the body, and it tends to progress to autosensitization dermatitis. ● Topical steroids are the first choice of treatment. ●

Clinical features, Epidemiology Nummular eczema is frequently seen in the winter. Multiple round eczematous lesions occur, mostly on the extremities (particularly on the extensor surface of the lower extremities), trunk, hips and buttocks (Fig. 7.13). At the periphery of the lesions, serous papules aggregate, in the center of which exudative erythema is produced with scales on the surface. Most cases are accompanied by intense itching and multiple scars from rubbing and scratching. As the lesions progress, they may produce dispersal eruptions (id dermatitis) to progress into autosensitization dermatitis. Pathogenesis Scratched insect bites may develop urticarial lichens that, when rubbed, progress to nummular eczema. Or nummular eczema may result from asteatotic eczema in the elderly, or it

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may appear as a symptom of atopic dermatitis. Treatment Topical steroids (containing ODT) are effective. In cases in which infiltration and exudation are intense, the application of topical zinc ointment sheets is also effective. Oral antihistamines are helpful in relieving the itching.

5. Lichen simplex chronicus

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Synonyms: Lichen Vidal, Circumscribed neurodermatitis Lichen simplex chronicus is chronic eczema in which round, intensely itchy lichenified plaques form on the nuchal region and extensor aspect of forearms and lower legs of middle-aged women. Pigmentation or depigmentation is present in many cases. Warty eruptions may proliferate (Fig. 7.14). When skin is repeatedly stimulated by the friction of clothing or by metal allergens and the site is rubbed and scratched for a long period of time, it leads to the occurrence of chronic eczematous lesions. Topical steroids and oral antihistamines are first-line treatments for the itching. Clinical images are available in hardcopy only.

6. Autosensitization dermatitis Outline ● Multiple

small papules and erythematous lesions accompanied by itching occur systemically. They are caused by sudden aggravation of a localized lesion. ● This dermatitis is caused by endogenous allergic reaction (id reaction). Clinical features Reddening, swelling and acute aggravation of exudation occur in the lower extremities as primary lesions of autosensitization dermatitis (in 50% to 60% of cases). Two weeks to several weeks after acute aggravation of reddening, swelling and exudation, dispersed eruptions appear. In most cases, the eruptions (id dermatitis) are erythema, papules, serous papules, or pustules of 2 to 5 mm in diameter dispersed symmetrically on the extremities, trunk, and face. These are often accompanied by intense itching (Fig. 7.15). Systemic symptoms such as fever and fatigue may occur. Pathogenesis Autosensitization dermatitis arises from endogenous allergic reaction (id reaction). Decayed proteins, bacteria, fungal components, and toxins produced by injured tissues in a primary lesion are considered to be the antigens. These may spread through the entire body such in blood flow from the primary lesion, or they

Fig. 7.13 Nummular eczema. Round patches of eczema, 1 cm to 3 cm in diameter, are disseminated on the trunk and legs.

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Fig. 7.14 Lichen simplex chronicus (lichen Vidal). Long-time friction from clothes is a cause. It is a chronic eczema.

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may spread by rubbing or by an accidental dose of the causative substance (orally or intravenously). Autosensitization dermatitis is caused by sensitization against the antigens. The primary lesions can be nummular eczema, stasis dermatitis, contact dermatitis, atopic dermatitis, tinea pedis, or eczematization of a burn.

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Treatment Topical steroids are applied and oral antihistamines are administered, in addition to whatever treatment is given for the underlying lesion. In severe cases, oral steroids are also administered.

7. Stasis dermatitis Outline ● Edematous

erythema or eczematous plaques form on the lower thighs as a result of varicose veins or congestion in the lower extremities. ● This disease tends to affect those who work standing, the elderly, and obese women. ● It may progress to autosensitization dermatitis. ● Elastic bandages and varicose vein phlebectomy are effective in reducing congestion. Clinical images are available in hardcopy only.

Clinical features Edematous erythema occurs on the lower third of the leg, particularly at the upper ankles. The site gradually presents a dark red, scaly, eczematous plaque, pigmentation or whitish atrophie blanche (Fig. 7.16). Minor trauma may induce ulceration. Treatments for stasis dermatitis may induce allergic contact dermatitis as a complication, from the application of an antiseptic or a topical agent (lanoline, antibiotic agent, preservative). Aggregated serous papules often progress to autosensitization dermatitis.

Clinical images are available in hardcopy only.

Fig. 7.15 Autosensitization dermatitis. Disseminated eczematous eruptions are seen.

Epidemiology Stasis dermatitis is frequently found in those who work standing for long periods of time. Pregnancy may trigger stasis dermatitis as a complication of varicose veins. Pathogenesis Congestion in the cutaneous blood vessels is caused by impairment of venous outflow, which leads to bleeding from the capillary vessel loop in the dermal upper layer. Hemosiderins deposit in tissues, and the skin takes on a blackish-brown appearance. The keratinocytes are injured by further impairment of blood flow. Atrophy and scaling occur in the epidermis and there is tendency of ulceration. The skin looses its function as a barrier and becomes more reactive to extrinsic irritation, leading to eczematous lesions in many cases.

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Laboratory findings, Diagnosis Stasis dermatitis is easy to diagnose from the varicose veins and the characteristics and distribution of the eruption. A Doppler test and angiography are performed on the varicosity to examine the physical potential of patients for surgical treatment. A patch test is performed if allergic contact dermatitis is suspected. Treatment Topical steroids are effective in treating eczematous lesions. When there is ulceration, it is cleansed and dressed. Induced allergic contact dermatitis is carefully avoided during treatment. Intravenous circulatory impairment is treated to prevent stasis dermatitis from progressing. Pressure that is greater than that of elastic bandages and socks should not be given to the patients. They should take bed rest and keep the lower extremities elevated. Surgery such as sclerotherapy, ligation, and removal of varicose blood may be necessary for cases with severe varicosity.

Clinical images are available in hardcopy only.

8. Asteatotic eczema Skin dryness (asteatosis, xerosis) occurs when sebum decreases as a result of aging or excess washing. When the horny cell layer is destroyed, the skin is vulnerable to extrinsic irritation. When asteatosis becomes inflamed and eczematous, the condition is called asteatotic eczema (Fig. 7.17). This mostly affects the lower extremities of elderly in dry seasons, especially winter. For those who have a habit of excessively washing or rubbing the body with a towel, lifestyle guidance to avoid such behavior has therapeutic effects. Use of moisturizer prevents skin dryness. Eczema is treated with topical steroids. Skin care with moisturizer is helpful afterwards (Chapter 19).

Clinical images are available in hardcopy only.

9. Wiskott-Aldrich syndrome Outline

The three major characteristics of this disorder are immunological deficiency (T-cell dysfunction), thrombocytopenia, and intractable eczema. ● It is hereditary (X-linked recessive). ● There are decreased levels of immunoglobulins. ● Bone marrow transplantation may be performed. ●

Clinical features Wiskott-Aldrich syndrome is characterized by eczema or purpura that occurs in newborn babies within 6 months after birth. The eczema that occurs on the head, face, buttocks and extremities appears similar to atopic dermatitis and seborrheic dermatitis (Fig. 7.18). Purpura is caused by thrombocytopenia. Immunedeficiency-derived infections occur repeatedly as the patient grows. Infections are caused by various factors including bacteria,

Fig. 7.16 Stasis dermatitis. Edematous, darkred erythema with scales. Chronic vein insufficiency is a pathophysiology. Ulcer formation is also seen.

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Eczema and Dermatitis

viruses, fungi and protozoa. Impetigo contagiosa (Staphylococcal infection), pseudomonas infection, herpes simplex, varicella (herpes virus infection), and candidiasis are particularly likely to accompany this syndrome, and they tend to become aggravated and persistent. Systemic symptoms such as bloody diarrheic stool, internal organ hemorrhage, infection (e.g., tympanitis, paranasal sinusitis, pneumonia) are seen recurrently. Clinical images are available in hardcopy only.

Pathogenesis Wiskott-Aldrich syndrome is caused by abnormality of a WASP gene at Xp11.22-11.23. The function of the WASP protein is unknown; however, it is thought to be associated with the cell viability and functional activation of T cells and platelets.

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Fig. 7.17 Asteatotic eczema.

Treatment, Prognosis Born marrow transplantation may be conducted as a treatment. Treatments for atopic dermatitis are given for skin lesions produced by Wiskott-Aldrich syndrome. Patients with the syndrome may not survive, because of bleeding and infection in infancy (until about age 10); nevertheless, long-term survival is possible if the patient survives this period. In long-term survival cases, autoimmune disease and malignant lymphoma may arise as complications.

Clinical images are available in hardcopy only.

Fig. 7.18 Wiskott-Aldrich syndrome. Eczematous eruption on the scalp.

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Chapter

8

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Urticaria, Prurigo and Pruritus

This chapter discusses urticaria, prurigo and pruritus cutaneous, which have severe itching in common. Each condition has its own mechanism, clinical features and histopathological findings.

Urticaria 8 1. Types of urticaria Outline

Urticaria is transitory localized erythema or wheals accompanied by itching. ● Acute urticaria occurs in episodes shorter than 6 weeks; chronic urticaria occurs in episodes of 6 weeks or longer. ● Vascular permeability increases. Edema forms in the dermal upper layer. ● In factitious urticaria, dermographism is positive. ● Oral antihistamines are the first-line treatment. ●

Clinical images are available in hardcopy only.

Clinical features A slightly elevated, sharply circumscribed wheal or reddening with a circular, oval or map-like pattern suddenly appears, accompanied by intense itching (Fig. 8.1). Edema, the primary event in the dermal upper layer, may occur at any site on the body, especially at sites subjected to rubbing or pressure. Wheals may occur not only in skin but also in mucosa. When formed in the pharyngeal region, urticaria causes hoarseness and breathing difficulty. Urticaria usually begins to subside within several hours and usually disappears within 24 hours. In some cases, erythema and slightly infiltrative lesions remain for several days. Pathogenesis, Classification Chemical mediators such as histamines released from mast cells enhance vascular permeability, which causes edema to form in the dermal upper layer (Fig. 8.2). Even thorough examination is unable to detect the cause of urticaria in about 90% of cases (idiopathic urticaria). For that reason, urticaria is often classified by duration of episode. Urticaria in episodes shorter than 6 weeks is called acute; that in episodes of 6 weeks or longer is called chronic. When there is an identifiable cause, the urticaria is named after that cause (discussed later). Diagnosis, Examinations It is easy to diagnose urticaria by the clinical findings. Historytaking on suspected causative agents of urticaria, such as 107

Clinical images are available in hardcopy only.

Fig. 8.1 Typical eruption of urticaria. It is characteristically itchy, with slightly elevated erythema and wheals.

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wheal epidermis plasma dermis

physical stimuli

allergen

IgE

8 mast cell

mechanical stimuli, the cold, foods and drugs, is helpful. Since urticaria sometimes accompanies systemic diseases, including collagen diseases, determination of the primary disease is necessary. Dermographism is positive (when the skin is rubbed, the site turns red; Fig. 8.3). Tests such as that for serum IgE levels, IgE RAST (radioallergosorbent test), intradermal allergic test and drug-induction test are conducted.

chemical mediators (histamines)

Fig. 8.2 Mechanism of urticaria. Chemical mediators such as histamines from mast cells induce vascular hyperpermeability, which causes intradermal edema.

Treatment Antihistamines are the first-line treatment. When the cause is identified, it should be removed. Oral or intravenous steroids are effective in severe cases, such as glottic edema. Urticaria resolves in several days in most cases; however, it may progress to chronic urticaria. Types of urticaria Typical types are described below.

1) Acute and chronic urticaria Urticaria is divided by duration of episode into acute (less than 6 weeks) and chronic (6 weeks or longer).

2) Contact urticaria Clinical images are available in hardcopy only.

Contact urticaria occurs at sites where a foreign substance comes into contact with and permeates the skin or mucosa. It is classified into allergic contact urticaria and nonallergic contact urticaria. Patients with allergic contact urticaria have had previous contact with the substance and are sensitized to it. Nonallergic contact urticaria is caused by the first contact with a substance (MEMO).

3) Physical urticaria

Clinical images are available in hardcopy only.

Physical urticaria is an eruption caused by physical stimulation. It disappears in 30 minutes to 1 hour. It is divided into several subtypes according to cause. Factitious urticaria, also called mechanical urticaria, is produced by rubbing. Dermographism is positive in factitious urticaria. Solar urticaria is caused by sunlight. Cold urticaria is caused by exposure to the cold, such as cold water or wind.

4) Cholinergic urticaria

Fig. 8.3 Dermographism. Mechanical stimuli such as rubbing cause wheals (urticaria).

Cholinergic urticaria occurs when the body perspires after the body temperature rises from exercise or bathing (Fig. 8.4). The cholinergic nerves are thought to be involved.

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Urticaria / 2. Angioedema

MEMO

Allergic reaction as a disease name

The diseases listed below cause urticarial eruptions; however, they are often described as kinds of allergies. The tests and treatments for these diseases are the same as for urticaria. For cases with severe respiratory symptoms or anaphylactic shock, epinephrine administration and systemic management are necessary. ◆ Food allergies Food allergies are reactions (mainly type I allergy) to certain foods, such as eggs, milk, chicken, rice, wheat, soybeans, fish, shellfish, buckwheat flour, peanuts, chocolate, kiwi fruit and papayas, or to antigens contained in the additives of these foods. They frequently occur in children, causing edema in the oral mucosa. Digestive symptoms (nausea, vomiting, abdominal pain, diarrhea), respiratory symptoms (bronchial asthma, nasal discharge, glottic edema), and migraine are also found. They cause anaphylactic shock in severe cases, which can be fatal. ◆ Latex allergy Latex allergy is caused by contact with products made of natural rubber. Latex may have cross-reactions with certain kinds of foods, such as bananas and avocados; latex allergy is also called latex-fruit syndrome*. The symptoms, which have various severities, include erythema accompanied by itching at the contact site, mild wheals, urticaria on the whole body, wheezing, and anaphylactic shock. ◆ Insect allergies IgE reacts to histamines and phospholipases, which are the main components in the venom of bee stings and which are the allergen in moth bodies; type I allergy is induced. Insect allergic reactions are most often triggered by bee stings, followed by respiration of substances from moths, and stings/bites from mosquitoes, gnats and, more rarely, fleas, ants and centipedes. Besides the main symptoms of urticaria and flushing on the whole body, there may be systemic edema, edema of the larynx, bronchial stenosis, abdominal pain, diarrhea, and shock that may lead to death. Generally, insect allergic reactions develop within 15 minutes after the sting/bite or other exposure to the allergen. The sooner the symptoms appear and the older the patient is, the more severe the symptoms tend to be. ◆ Occupational allergies Occupational allergies are caused in workers with specific occupations by exposure to antigens. For example, beauticians, pharmacists, buckwheat noodle-makers, and workers at oyster shell crushing sites, factories, sawmills and egg farms are likely to develop occupational allergies. The main symptoms are eczema, dermatitis and urticaria. Allergic contact dermatitis and solar photosensitivity may also be caused by various workplace drugs, chemicals and materials. Bronchial asthma and allergic rhinitis are frequently produced by various kinds of dust.

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*Type I allergy predominates among in food allergies. Specific IgE antibodies are sensitized against specific foods by oral ingestion, and food allergic reaction occurs. Recent study has identified another type of food allergy in which a specific antibody can be sensitized by food intake through non-oral routes; the cross-reaction occurs with a wider range of foods (class II food allergy). Latex allergy and oral allergy with the involvement of pollen allergen (oral allergy syndrome; OAS) are typical class II food allergies.

2. Angioedema Synonyms: Quincke’s edema, Angioneurotic edema

Clinical images are available in hardcopy only.

Outline ● Angioedema

is caused by increased vascular permeability in the subcutaneous tissue at sites deeper than those of urticaria. ● The pathogenesis can be hereditary or nonhereditary. ● The eyelids and lips of mouth are the most frequently affected. ● The treatment for nonhereditary angioedema is the same a as for urticaria. Clinical features Localized edema suddenly occurs and remains for several

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Fig. 8.4 Cholinergic urticaria. a: Small, multiple wheals are seen. b: Sweating test reveals that wheals appear at locations of sweat glands.

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8 Clinical images are available in hardcopy only.

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hours to several weeks. The size of the angioedema varies, with the diameter ranging from 1 cm to 10 cm. It is sharply circumscribed, and itching is not usually present. Although it may occur at any site on the body, the most frequently affected areas are the eyelids, lips and genitalia (Fig. 8.5). Angioedema may be produced not only on the skin surface but also in the glossopharyngeal areas, nasal cavity, bronchial mucosa, gut mucosa, p q j intracranial region, heart It can be h i k or kidneys. l m n fatal.o Pathogenesis, Classification Angioedema is produced by the increased vascular permeability in the subcutaneous tissue that results when histamines are released from mast cells in the dermal lower layer or the subcutaneous tissue or when some hereditary factor comes into play. Angioedema is divided into hereditary and nonhereditary. Nonhereditary angioedema is thought to be deep-seated urticaria. angioneurotic edema, caused by absence p q j i Hereditary k l m n o congenital r of C1 esterase inhibitors (C1INH) is autosomal dominant in most cases and is rare in Japan. Because of the absence of C1INHs, there is activation of C1, kallikrein, Hageman factor (antihemophilic factor XII) and plasmin, which results in the production of C2 kinin or bradykinin. Angioedema is caused by a resulting increase in vascular permeability. Diagnosis

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p q j Andioedema k l is easymto diagnose n o medical r clinfrom history and

ical features. Serum C1 inhibitor activation assay is effective in diagnosing hereditary angioedema. Treatment The treatments for nonhereditary angioedema are the same as those for urticaria. For hereditary angioedema, the following are administered: C1 inhibitor; androgen, which enhances expression of the C1 inhibitor; or C1 inactivator, which strongly inhibits the action of C1.

Clinical images are available in hardcopy only.

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Fig. 8.5 Angioedema. a: Severe swelling on the right palpebra. b: Severe edema on the lower lip. c: Edema on the upper lip, particularly on the right side. d: Angioedema on the right side of the tongue.

Prognosis Nonhereditary angioedema may heal naturally. Hereditary angioedema rarely subsides, and it may beqaccompanied by disp k l m n o r orders such as those of the vocal cords.

3. Urticarial vasculitis Urticarial or erythema multiforme-like eruptions that persist for more than 24 hours recur and heal with purpura or pigmentation. Urticarial vasculitis most frequently occurs in women. Systemic lupus erythematosus (SLE) like symptoms and decreased complement value are seen. Leukocytoclastic vasculitis is found histopathologically in many cases (Chapter 11). The etiology is unknown. It is divided into idiopathic urticarial vasculitis and secondary urticarial vasculitis, the latter of which occurs secondarily

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to a primary disease such as SLE, rheumatic arthritis or hepatitis B. Unlike in ordinary urticaria, type I allergy is not involved in urticarial vasculitis. However, the immune complex that indicates the involvement of a type III allergy is present.

4. Food-dependent exercise-induced anaphylaxis (FDEIA) Physical stress – from exercise, for example – 1 to 4 hours after ingestion of certain foods may cause anaphylaxis and urticaria simultaneously. In Japan, food-dependent exerciseinduced anaphylaxis (FDEIA) is most often caused by wheat, followed in frequency by shrimp, oysters and celery. Since exercise or ingestion of specific foods alone does not cause FDEIA, an induction test is necessary to confirm and diagnose FDEIA.

8

Prurigo Outline ● Prurigo

is a condition in which there are independent itchy papules or small nodular eruptions. ● It is induced by insect bite, allergy, or atopic condition. ● It may be aggravated by rubbing, whereby small intractable nodules form. Clinical features, Classification In prurigo, papules or small urticarial nodules are accompanied by intense itching that becomes chronic. These nodules are called pruritic papules (Fig. 8.6). There are various etiologies and clinical features; however, the condition is thought to be a specific inflammatory reaction. Prurigo is characterized by exudative inflammatory lesions (Fig. 8.7) and by its failure to develop into the other types of eruptions that are seen with eczematous and dermatitis lesions. Prurigo remains as chronic papules and nodules. It is often categorized as acute or chronic. Pathogenesis Prurigo is exudative inflammation that occurs in the dermal upper layer. It is accompanied by lymphocytic or neutrophilic infiltration. It is thought to be induced by specific inflammatory reaction (pruritic reaction); however, the causative agent is unknown in many cases. Insect bites, mechanical or electrical stimulation, certain kinds of foods, and chemical stimulation such as by histamines are thought to be causative factors. Prurigo may also accompany malignant tumor, leukemia or Hodgkin’s disease. Atopic dermatitis can also cause prurigo.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 8.6 Prurigo nodularis. Small, severely itchy nodules of 5 mm to 20 mm in diameter are noted. Excoriation is also seen.

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1. Acute prurigo Synonym: Strophulus infantum Clinical features Urticarial erythema or wheals appear and become exudative papules, usually in small children. Secondary infection may be caused by rubbing and scratching brought on by intense itching. Although acute prurigo tends to last only several weeks, it tends to recur. Symptoms do not appear after the patient reaches a certain age.

8 Fig. 8.7 Histopathological findings of prurigo nodularis. Acanthosis and inflammatory cell infiltration in the upper dermis are noted. Excoriation induces even more severe acanthosis.

Pathogenesis Atopic condition and hypersensitive reaction to insect bite or certain foods (e.g., eggs, soybeans, pork) are known to be associated with the occurrence of prurigo. Children under age 5 are mostly affected in the summer, when insect stings are common. Treatment Topical steroids and oral antihistamines are the first-line treatment. Insect bites and intake of causative foods should be avoided.

2. Subacute prurigo Synonym: Prurigo simplex subacuta Clinical images are available in hardcopy only.

An urticarial papule accompanied by intense itching occurs on the extensor surface of the extremities or the trunk. When it is rubbed and scratched, erosion or crust forms. Subacute prurigo is intractable and may become chronic. The etiology is unknown. A primary disease such as atopic dermatitis, diabetes, liver dysfunction, lymphoma, leukemia, Hodgkin’s disease, internal malignancy, polycythemia, gout, uremia or pregnancy is often involved. Mental stress has also been pointed out as associated with onset. The clinical features are intermediate between those of acute and chronic urticarias. However, acute and chronic urticarias may be found simultaneously in the same patient. In addition to treatments for the primary disease, topical steroids and antihistamines are administered as needed.

Fig. 8.8 Prurigo chronica multiformis.

3. Chronic prurigo Clinical images are available in hardcopy only.

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Fig. 8.9-1 Prurigo pigmentosa. a: Chest lesion in a young male patient.

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Classification Chronic prurigo is subdivided into prurigo chronica multiformis, with aggregated individual papules that tend to form a p q j h i lesion; l nodularis, m n with o lichenoid andk prurigo large nodular papules that form sparsely and individually.

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Pruritus cutaneus

Clinical features Prurigo chronica multiformis occurs most frequently in the trunk and legs of the elderly (Fig. 8.8). Exudative or solid papules aggregate to form invasive plaques. The lesions are rubbed as a result of intense itching, and exudate and crusts form to present intermingled pruritic papules and lichenoid lesions. The condition is often chronic, with recurrences and remissions. Prurigo nodularis most commonly affects adolescents and older women (Fig. 8.6). Papules and nodules occur in the extremities, accompanied by intense itching. When rubbed they developa erosion and bloody crusts, resulting in dark brown solid papules or nodules. These are isolated and do not coalesce to form plaques. They persist for several years. Treatment Topical steroids or ODT is applied as a local therapy. Application of a zinc ointment sheet over topical steroids is effective. Oral antihistamines are helpful in relieving itching. Oral steroids and cyclosporines may be applied for a short period of time in a severe cases. Local injection of steroids and phototherapy areb also conducted.

4. Prurigo gestationis Prurigo gestationis appears on the extremities or trunk of women in their 3rd or 4th month of pregnancy and subsides after delivery. It is increasingly likely to occur with each successive pregnancy. Differentiation between prurigo gestationis and PUPPP (pruritic urticarial papules and plaques of pregnancy) is controversial; however, the former occurs in the early stages of pregnancy, whereas the latter occurs in the later stages of pregnancy.

5. Prurigo pigmentosa (Nagashima) Prurigo pigmentosa (Nagashima) is urticarial erythema accompanied by intense itching. Pruritic erythematous papules recur and heal with reticular pigmentation (Figs. 8.9-1 and 8.9-2). It most frequently occurs on the back, neck and upper chest of adolescent women. The pathogenesis is unknown. Minocycline and DDS (dapsone) are extremely effective treatments.

Pruritus cutaneous Outline ● In

pruritus cutaneous there is no obvious eruption; only itching is present. ● It is often accompanied by dry skin (xerosis). ● Eruptions, lichenification and pigmentation may be

Clinical images are available in hardcopy only.

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Fig. 8.9-2 Prurigo pigmentosa. b: Prurigo pigmentosa in a female patient in her 20s. Fresh-red erythema are mixed with old lesions, which are seen as reticular hyperpigmented macules. c: Erythematous macules (arrows) are seen at the center of reticular hyperpigmentation. It is a recurrence of prurigo pigmentosa.

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Table 8.1 Causes of pruritus cutaneous. Diffuse pruritus cutaneous

●

Visceral disorder

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Endocrinological dysfunction

Diabetes mellitus, diabetes insipidus, thyroid disorder, parathyroid disorder

Metabolic dysfunction

Hepatitis, cirrhosis, carcinoid syndrome, biliary atresia, gout, etc.

Renal disorder

Chronic renal failure, uremia

Hematological disorder

Erythrocythemia, iron deficiency anemia

Malignancy

Various carcinomas, multiple myelomas, malignant lymphoma (in particular, Hodgkin’s disease and mycosis fungoides), chronic leukemia

Parasitosis

Ascariasis, ancylostomiasis

Neurological disorder

Myelophthisis, thalamic tumor

Environmental factor

Mechanical stimuli, dry conditions, spicy foods

Drug

Cocaine, morphine, bleomycin, and drugs to which the patient has hypersensitivity

Food

Seafood (mackerel, tuna, squid, shrimp, clams, etc.), vegetables (aroids, bamboo shoots, eggplant, etc.), pork, wine, beer, chocolate

pregnancy

In the third trimester

psychogenic factor

Excessive stress, compulsive neurosis and other psychogenic disease

skin dryness

senile xerosis

Clinical features, Classification The disease is classified by distribution into pruritus universalis and pruritus localis. Pathogenesis Pruritus cutaneous occurs secondarily to various underlying diseases, including liver dysfunction and renal failure (Table 8.1). Scarring, thickening of the skin, lichenification and pigmentation often develop secondarily by rubbing and scratching. The disease is accompanied by dry skin (xerosis). It tends to occur when the skin is sensitive to external stimulation, especially in winter and at bedtime. Differential diagnosis Systemic examinations such as blood test and renal function test are necessary for diagnosis. When the genitalia are affected, pruritus cutaneous should be differentiated from scabies and candidiasis. Treatment Treatment focuses on the underlying disease, if detected. Application of antihistamines and moisturizer, and UV irradiation are conducted as symptomatic therapies. It is also important to eliminate pruritus-inducing factors such as alcohol, coffee and spices. Bathing to keep the body clean, wearing cotton clothes, avoiding dryness, and eliminating emotional stress are also helpful. Topical steroid application is effective against secondary eruptions; however, it is ineffective against pruritus itself.

1. Pruritus universalis

Localized pruritus cutaneous Pruritus on the Genital region

Prostatic hypertrophy, urethral stricture, vaginal trichomoniasis, etc.

Pruritus on the perianal region

Constipation, diarrhea, anal prolapse, hemorrhoid, etc.

(Adapted from; Miyachi Y. Minimum dermatology. Bunkodo; 2000).

produced secondarily by rubbing and scratching. Oral antihistamines and psychological counseling are helpful.

Itching is present on the whole body surface. As shown in Table 8.1, it usually accompanies other diseases. In the elderly, pruritus may be present without a disease because of dry skin and age-related processes; this is called senile pruritus.

2. Pruritus locaris Itching appears locally in the anal region or genitalia. Pruritus locaris in the anal region, which accounts for most cases of pruritus, frequently affects young and middle-aged men. It may be caused by constipation, diarrhea, hemorrhoids and anal prolapse. Pruritus localis of the genitalia is commonly found in middleaged women. The labia majora and minora are most commonly affected. Pruritus localis needs to be differentiated from parasitic infection.

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Chapter

9

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Erythema, Erythroderma (Exfoliative Dermatitis)

Erythema is caused by telangiectasia or hyperemia in the papillary and reticular dermis. The color disappears with application of pressure. Erythema is a component of a very large number of cutaneous diseases including eczema, urticaria, psoriasis, infectious diseases, blistering diseases and lymphomas. This chapter is devoted to well recognized patterns of erythematous eruptions, with a focus on erythema multiforme, annular erythema and erythroderma (exfoliative dermatitis).

Erythema 9

A. Erythema multiforme and related diseases 1. Erythema multiforme (EM) Synonym: Erythema exsudativum multiforme (EEM) Clinical images are available in hardcopy only.

Outline ● Multiple

circular edematous erythema of 5 mm to 20 mm in diameter occurs multiply and symmetrically on the dorsal hands and the extensor surfaces of the joints. ● EM may occur in patients of all ages, but it occurs predominantly in adolescents and young adults. ● Infection by the herpes simplex virus or mycoplasma pneumoniae is the dominant causative factor of EM, but drug-sensitivities are also an important cause. ● Topical or oral corticosteroids are effective for the treatment of EM. Recurrence may occur.

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Classification Erythema multiforme (EM) is largely classified into localized cutaneous lesions (EM minor) and mucosal lesions with systemic involvement (EM major). EM major is thought to be the same as Stevens-Johnson syndrome. Both EM minor and EM major are transitory. These prototypes are well defined, but their distinction may be difficult in practice because of their overlapping features. Clinical features, Epidemiology Eruptions occur symmetrically on the extensor aspects of the joints (e.g., the dorsal hands, elbows, knees) as erythematous papules or edematous erythema, and they spread centrifugally in about 48 hours to form sharply circumscribed, round or irregular-a ly shaped erythema (Figs. 9.1-1 and 9.1-2). The center of the erythema is concave, presenting either as a target lesion or iris formation, also called exudative erythema. The affected area simultaneously shows new and old lesions that may fuse into 115

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Fig. 9.1-1 Erythema multiforme (EM). Well-demarcated edematous exudative erythema disseminates on the dorsal hand (a) and elbow (b). The size is up to 2 cm. Note the central concavities.

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map-like patterns. EM may be accompanied by blistering (bullous EM) and erosions of the oral mucosa. EM frequently occurs in the young and middle-aged, and it tends to appear during the spring and summer. Infectious symptoms including high fever and pharyngodynia may precede the onset. In cases caused by herpes simplex infection, EM tends to occur 1 to 3 weeks after the onset of the herpes simplex symptoms (post-herpetic EM).

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Clinical images are available in hardcopy only.

Pathogenesis As shown in Table 9.1, EM is caused by various factors, such as viral or bacterial infections (by herpes simplex or Mycoplasma pneumoniae), and drugs and malignant tumors. It is estimated that EM is a cell-mediated immuno reaction leading to the destruction of keratinocytes expressing various antigens. However, the underlying pathomechanism is not known. Pathology In the early stages of epidermal EM, there is lymphocytic infiltration into the dermo-epidermal junction and vacuolar degeneration of basal cells. As the disease progresses, lymphocytes (CD8+T cells) infiltrate into the epidermis, and necrosis of epidermal cells and subepidermal blistering are found (Fig. 9.2 and

Table 9.1 Conditions associated with erythema multiforme. Fig. 9.1-2 Erythema multiforme (EM). The central concavities give a characteristic irislike appearance.

Cause

Details

Infections

Virus (e.g., human herpes simplex virus), bacteria (Streptococcus, Mycoplasma, Mycobacterium), tinea, Chlamydia, Rickettsia

Drug reactions

Antibiotics, NSAIDs, anticonvulsants, antineoplastic agents, etc. See Chapter 10.

Collagen diseases, Insect bite, disease (especially systemic lupus erytheAllergic disorders matosus (SLE)), sarcoidosis, Crohn’s disease Other

Physical stimulation (e.g., cold), hematopoietic malignant disorders, pregnancy, etc.

Table 9.2 Histopathological classification of erythema multiforme. Classification Main histopathological findings

Fig. 9.2 Histopathology of erythema multiforme (EM). Necrosis of epidermal cells (staining strongly red by eosin), vacuolar degeneration of the basal layer, inflammatory cell infiltration and edema in the upper dermis are noted.

Epidermal

In the early stage, lymphocytic infiltration and ballooning degeneration in the dermo-epidermal junction. As the disease progresses, infiltration of CD8+ lymphocytes into the epidermis, resulting in keratinocyte necrosis and subepidermal blistering. Decrease of epidermal Langerhans cells and overexpression of ICAM-1 on keratinocytes.

Dermal

Perivascular monocytic infiltration in the upper dermis; edema in the dermal papilla. It is now said that erythema multiforme is always accompanied by at least some change in the epidermis.

Mixed

Epidermal changes (vacuolar degeneration of the basal layer, satellite cell necrosis); dermal changes (perivascular lymphocytic infiltration).

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Erythema/A. Erythema multiforme and related diseases

Table 9.2). Laboratory findings Because of inflammation, CRP may be positive and the erythrocyte sedimentation rate is elevated. The herpes simplex virus antibody titer, Mycoplasma antibody titer and antistreptolysin O (ASO) titer may be elevated in some cases. In cases involving bacterial infection, there is an increase in neutrophils. Diagnosis, Differential diagnosis EM is relatively easy to diagnose by its characteristic clinical features and by the distribution of the eruptions. History of previous diseases, such as infectious diseases, supports the diagnosis. Refer to Table 9.3 for differential diagnosis.

Table 9.3 Erythema multiforme: differential diagnosis. Disorder

Difference from erythema multiforme

Urticaria

Itching is more severe. Each lesion usually disappears within 24 hours. Dermographism rubrum occurs.

SLE

Systemic symptoms occur (renal, arthritic, etc.). Laboratory findings of antinuclear antibodies, etc. Erythema multiforme sometimes occurs in association with SLE.

Bullous Direct/indirect immunofluorescence pemphigoid reveals antibodies against basement membrane.

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Treatment, Prognosis Identifying the pathogenesis is important not only for treatment but also for prevention of recurrence. The underlying infectious disease should be treated. Topical steroids, oral antihistamines, NSAIDs and potassium iodides may also be used. Severe cases need the application of systemic corticosteroids. EM regresses spontaneously within 2 to 4 weeks. When caused by herpes simplex infection, acyclovir administration may be effective; however, EM tends to recur.

Clinical images are available in hardcopy only.

2. Stevens-Johnson syndrome (SJS) Synonyms: Mucocutaneous ocular syndrome, EM major Outline ● SJS

is a severe acute mucocutaneous reaction with systemic symptoms such as fever and arthralgia. ● It may develop into toxic epidermal necrolysis (TEN). ● When the symptoms are severe, systemic corticosteroids is administered. Steroid pulse therapy and systemic management may also be adopted. Classification Stevens-Johnson syndrome (SJS) is EM major with oculomucous lesion and systemic symptoms including liver and renal dysfunction. Nevertheless, well-defined findings on the differences between EM major and SJS have not been obtained. Drugs are clearly the leading causative factor of SJS. The disease occurs 1 to 6 cases per million population per year. It is sometimes difficult to draw an absolutely clear distinction between SJS and toxica epidermal necrolysis (TEN) (Chapter 10). Clinical features EM occurs suddenly, with systemic symptoms such as high fever, general fatigue, arthralgia, myalgic pain, chest pain and gastrointestinal distress (Figs. 9.3-1 and 9.3-2). Intense edematous

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Fig. 9.3-1 Stevens-Johnson syndrome (SJS). a, b: Erythema multiforme rapidly spreads on the entire body. Some lesions overlap to form large plaques on the back. A bull’s-eye pattern, characteristic of erythema multiforme, is seen at the border of a plaque.

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Clinical images are available in hardcopy only.

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Pathology Refer to the section on erythema multiforme. Necrotic degeneration is found mostly in the epidermis. Vacuolar degeneration of the basal membranes and dermal edema are also present.

Clinical images are available in hardcopy only.

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Fig. 9.3-2 Stevens-Johnson syndrome (SJS). c: Large plaques. d: Erosions and ulcers are seen on the oral mucosa and tongue, with severe pain.

Differentiation between SJS and TEN

MEMO

Both Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) produce necrotic lesions over the skin and mucous membranes on the whole body. When the area ofepidermolysis is 10% or less, the disease is called SJS; when it is 30% or more, the disease is called TEN.

EM major, accompanied by blistering and bleeding, develops and tends to be severe. The extensor surface of the extremities and the entire body surface including the face and trunk are affected. Mucosal sites are involved and may be severe. Erythema, hemorrhagic bullae, and erosions accompanied by pus and bloody crusts occur in the eyes, oral cavity, nose, perineal regions, and genital mucosa. Patients sometimes cannot eat or excrete because of severe pain. Systemic treatment is essential for cases with involvement of hepatopathy and renal dysfunction. Conjunctival inflammation, adhesion, corneal opacity and ulceration occur in p q j eyes. the aftereffects, k Whenl it heals, m SJS nmay leave o serious r such as loss of eyesight. Dense fibrous adhesion (symblepharon) between the conjunctival linings is also seen. Ocular involvement in SJS requires early consultation with an opthalmologist.

Diagnosis, Differential diagnosis lesions in p q the mucocutaneous k SJS isl characterized m n by severe o r junction, erythema over the entire body surface, blisters, erosions and systemic symptoms, and histopathologically by epidermal necrotic degeneration. A detailed medical history is needed to identify the cause. Antibody titers of HSV, Mycoplasma, pharynx culture and chest X-ray are performed. Sudden enlargement on the entire body suggests progression to TEN. Treatment Early diagnosis and treatment are important for improving the prognosis. Systemic steroid administration (orally or by pulse therapy) is especially important in the early stages. The causative drug should be discontinued immediately. The skin and mucous membranes should be protected by ointment application. Prognosis Unless the patient is treated appropriately, SJS may develop into TEN, and the patient may die of pneumonia or renal dysfunction. In severe cases, it leaves corneal opacity and conjunctival adhesion.

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3. Sweet’s disease Synonyms: Acute febrile neutrophilic dermatosis, Neutrophilic dermatosis Outline ● In

Sweet’s disease, painful erythema with elevated borders occurs on the face and joints. ● Fever, neutrophilia and arthralgia appear simultaneously. ● Histopathologic features are edema of dermal papillae and dense infiltration of leukocytes in the dermis. ● It is associated with hematologic malignancies (commonly acute myelogenous leukemia and myelodysplastic syndrome (MDS)). ● The treatments of systemic corticosteroids, colchicines and potassium iodides are effective. Clinical features Sweet’s disease occurs most frequently on the face, neck, forearms and dorsal hands of middle-aged women. Several days to 4 weeks after upper respiratory tract infection, multiple painful and sharply circumscribed dark reddish edematous erythema 10 mm to 25 mm in diameter occur suddenly, accompanied by high fever (Fig. 9.4). The surface of the eruptions is rough and granular, and the eruptions are surrounded by vesicles and pustules. Central clearing may lead to annular or accurate patterns. When Sweet’s disease occurs on the lower thighs, it resembles erythema nodosum. Differentiation from Behçet’s disease may be necessary if oral aphtha is found. Pathogenesis Hypersensitive reaction occurs against Streptococcus and other pathogens in certain circumstances, such as the presence of a hematopoietic malignant tumor, solid tumors, or various autoimmune disorders. Sweet’s disease is caused by abnormally activated neutrophils; the details of the pathomechanism are not known. Complications Sweet’s disease often accompanies the diseases listed in Table 9.4. 10% to 15% of the Sweet’s disease is reported to be associated with hematologic malignancies. Pathology The main and most striking feature is a massive infiltration of neutrophils in the dermis and dermal edema (Fig. 9.5). Changes on the epidermis and vasculitis (fibrinoid necrosis) are not observed. In the chronic stage, lymphocytic perivascular infiltration occurs instead of neutrophilic infiltration. Laboratory findings, Diagnosis Peripheral leukocytosis with neutrophilia is the characteristic

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 9.4 Sweet’s disease.

Table 9.4 Disorders associated with Sweet’s disease. Disorder type

Details

Hematological Myelodysplastic syndrome (MDS), leukemia, myelofibrosis, etc. Autoimmune

Sjögren syndrome, rheumatoid arthritis, subacute cutaneous lupus erythematosus, ulcerative colitis, etc.

Other

Other malignancy, pyoderma gangrenosum, etc.

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laboratory finding. An elevated erythrocyte sedimentation rate and high CRP levels are also present. Sweet’s disease is often associated with an underlying disease. It is necessary to determine whether the primary disease is lymphoma (myelodysplastic syndrome, leukemia), malignant internal-organ tumor or autoimmune disease. Treatment Oral administration of corticosteroids, potassium iodides, NSAID and colchicines are the main treatments. Antibiotics are ineffective.

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Fig. 9.5 Histopathology of Sweet’s disease. Dense neutrophilic infiltration on the entire dermis without apparent vasculitis.

Prognosis Without treatment, the eruption may persist for weeks or even months. Patients with cancer may see frequent recurrences.

4. Palmar erythema Clinical features Palmar erythema is observed in several conditions. Pathogenesis Palmar erythema is a vascular acrosyndrome with multiple etiologies. Best known in pregnancy, liver diseases and collagen diseases (e.g., erythematosus, dermatomyositis, rheumatic arthritis), it can occur in a variety of other systemic disturbances. Palmar erythema may be related to elevated serum estrogens and related 17-cetosteroid hormones. In rare cases it occurs hereditarily in otherwise healthy people. Refer to Chapter 18 for erythema nodosum and erythema induratum.

B. Annular erythema Annular erythema is a general term for diseases in which small erythema appear and then spread centrifugally. It begins with small erythema that enlarge centrifugally while resolving in the center, resulting in a ring shape. It may involve an underlying disease, such as an infectious disease, malignant tumor, drug eruption or collagen disease. Annular erythema is classified according to the underlying disease and the clinical features (Table 9.5). Refer to Chapter 12 for Sjögren syndrome and the annular erythema associated with LE.

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Erythema / B. Annular erythema

Table 9.5 Classification of annular erythema.

1. Erythema annulare centrifugum (EAC)

Eythema annulare centrifugum

Synonyms: Darier’s erythema annulare centrifugum

Annular erythema associated with infection ・Erythema chronicum migrans

Clinical features Erythema annulare centrifugum (EAC) most commonly affects young middle-aged adults. Infiltrated papules slowly enlarge and form a ring as the central area flattens and fades (Figs. 9.6-1 and 9.6-2). The disease may persist for many years.

Annular erythema associated with collagen disease ・Annular erythema associated with Sjögren syndrome ・Neonatal lupus erythematosus ・Subacute cutaneous lupus erythematosus, annular/polycyclic ・Erythema marginatum rheumaticum

Pathogenesis It may involve interaction among inflammatory cells, their mediators and ground substances, as foreign antigens diffuse through the skin.

Annular erythema associated with neoplasms ・Erythema gyratum repens ・Necrolytic migratory erythema

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Pathology The vessels of the upper and mid-dermis show dense perivascular lymphocytic sleeving. Treatment A search for the underlying cause is the primary goal of treatment. The systemic or topical application of corticosteroids and oral antihistamines may help.

Clinical images are available in hardcopy only.

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2. Erythema marginatum rheumaticum Clinical features, Pathogenesis Erythema marginatum rheumaticum occurs in 5% to 30% of patients with active rheumatic fever. It begins as an erythematous macule or papule that extends outward while the skin in the center returns to normal. The edge of the eruption elevates slightly. The eruption is symptomless. The lesion fade in a few hours, or at most in 2 to 3 days. Recurrent crops may appear at intervals for many weeks. Deposition of antibodies and complements on the blood vessel walls suggests an association with immunoreaction. Although children are the most commonly affected by erythema marginatum rheumaticum, there are cases in adults. a

Treatment The treatments for rheumatic fever (systemic administration of antibiotics in very large doses) is effective. Prognosis The eruptions disappear spontaneously. The prognosis of rheumatic fever depends on coronary damage.

Clinical images are available in hardcopy only.

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Fig. 9.6-1 Erythema annulare centrifugum (EAC). a: On the abdomen. b: On the trunk. Edematous, slightly elevated erythema 1 cm to 5 cm in diameter. These sometimes expand centrifugally to 5 cm to 20 cm in diameter. The margins are usually elevated. Erythema annulare centrifugum presents one or more lesions on the entire body.

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3. Erythema chronicum migrans (ECM) Clinical features Within 1 month after a tick bite, a papule or erythema occurs on the bitten site. It quickly enlarges centrifugally to form a characteristic ring-shaped eruption: The edge is scarlet and may elevate, and the center partly or totally fades. It is asymptomatic. The eruption may reach 40 cm in diameter. Erythema chronicum migrans (ECM) is the cutaneous hallmark of Lyme disease (refer to Chapter 28 for other symptoms and treatments of ECM).

Clinical images are available in hardcopy only.

Pathogenesis ECM can be attributed to infection by Borrelia burgdorferi, a spirochete whose usual hosts are ticks of the genus Ixodes.

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Fig. 9.6-2 Erythema annulare centrifugum (EAC). c: On the upper arm.

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4. Erythema gyratum repens Cutaneous eruptions of concentric raised erythematous bands move in waves over the body surface in a “wood grain” pattern. Accompanied by intense itching, they enlarge quickly (Fig. 9.7). The eruption is associated with internal malignancy. Immunoglobulin and immune complex deposit in the dermo-epidermal junction, suggesting the involvement of immunoreaction.

Clinical images are available in hardcopy only.

5. Necrolytic migratory erythema

Fig. 9.7 Erythema gyratum repens.

Necrolytic migratory erythema is a marker for glucagonoma. It typically involves the face and the intertriginous areas. There is a cyclic pattern in the course of the eruption. Vesicles and pustules tend to become confluent. Irregular centrifugal expansions of the annular lesions coalesce into a map-like serpeginous pattern.

Erythroderma Outline ● Erythroderma

is the term applied to any inflammatory skin disease with erythema and scaling which affects more than 90% of the body surface. ● The causes are various. Clinical features, Pathogenesis Erythroderma is often of sudden onset. Patchy erythema which rapidly generalizes may be accompanied by desquamation (Table 9.6, Figs. 9.8-1 and 9.8-2). The underlying dermatologic disorder is often impossible to identify, but in some causes, patients have the specific clinical features of the original causative disorder. Intense itching is present. When the palms and soles are affected, erythroderma may cause acanthosis,

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Erythroderma / 1. Eczematous erythroderma

hyperkeratosis, and fissures in the horny cell layer. The scalp hair may be shed and the nails become ridged. The skin becomes shiny and pigmented in the chronic stages of the eruptions. These may be accompanied by fever, shivering and malaise. Pathology There are no characteristic pathological findings for erythroderma, because the findings vary depending on the underlying disease. In most cases, histopathologically, there are hyperkeratosis, parakeratosis, acanthosis and chronic inflammatory infiltrates. The submission of multiple biopsy specimens from a patient enhances the accuracy of histopathologic diagnosis. Laboratory findings In cases in which the underlying disease is not identified, laboratory findings are referred to for diagnosis (Table 9.7). Treatment Oral antihistamines and topical steroids are useful; nevertheless, side effects from topical agents tend to occur as a result of enhanced skin barrier function, which accelerates percutaneous absorption. Systemic corticosteroids are needed in severe cases. Treatment in hospital is advisable for cases with systemic symptoms, including protein or electrolyte imbalance.

1. Eczematous erythroderma Eczematous erythroderma accounts for about 50% of all erythroderma cases. Although it most frequently affects elderly men, it may occur in patients of other ages with atopic dermatitis. Atopic dermatitis and various types of eczema generalize to become erythroderma under the influence of intrinsic or extrinsic factors. Intrinsic factors include dysfunction of T cells, liver or kidney; paranephros; and autonomic dystonia. Extrinsic factors include inappropriate treatments for eczema, home remedies and environmental changes. Edematous redness and scaling are present over the entire body skin. This is accompanied by intense itching and, sometimes, indolent lymphadenopathy, particularly of the inguinal lymph nodes. Systemic symptoms such as fever, dehydration, protein loss, body temperature instability and opportunistic infection may be found. Skin atrophy, pigmentation, pityroid scaling and skin glossiness become noticeable as the eruptions become chronic. Eczematous erythroderma is often caused by atopic dermatitis, contact atopic dermatitis, seborrheic dermatitis and autosensitization dermatitis. Topical steroids are extremely effective as a treatment. Antihistamines are useful. Oral administration of steroids should be avoided as much as possible.

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Table 9.6 Causative conditions of erythroderma. Inflammatory disorder Eczema, atopic dermatitis Drug eruption Psoriasis Erythema multiforme Viral eruption (measles, rubella) Pityriasis rubra pilaris Reiter’s syndrome Congenital ichthyosiform erythroderma Bullous pemphigoid Pemphigus foliaceus Dermatitis herpetiform (Duhring) Hailey-Hailey disease Lupus erythematosus Dermatomyositis Sarcoidosis Fungal infections Scabies Staphylococcal scalded-skin syndrome Ofuji papuloerythroderma Graft-versus-host disease HIV infection Neoplasm Mycosis fungoides Sézary syndrome Adult T-cell leukemia/lymphoma Leukemia Malignant lymphoma, especially Hodgkin’s disease Multiple myeloma Other malignant disorder

Table 9.7 Examinations for diagnosis and severity of erythroderma. Examination

Points

Complete blood count, blood picture

Essential for the diagnosis of infections, malignant lymphoma, leukemia and Sézary syndrome. In atopic dermatitis, drug eruption and eosinophil levels are elevated.

Liver function

Liver dysfunction suggests drug reaction or collagen disease such as dermatomyositis.

Skin biopsy

Underlying disorder (mycosis fungoides, psoriasis, etc.) may be found by repeated skin biopsy.

Bacteriological examination

Bacterial culture and potassium hydrate (KOH) from scales/ pustules may reveal underlying disorders.

Plasma protein fraction

Indicates hypoalbuminemia from scaling and skin metabolic dysfunction.

Renal function, Indicates dehydration and cardiopulmonary edema. function, electrolytes

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2. Drug-induced erythroderma Drug-induced erythroderma accounts for about 10% of all erythrodermas. It is most frequently caused by antibiotics, antiepileptic drugs and NSAIDs (Table 9.8). After intake of any of those drugs, the disease starts as erythematous papules. These spread rapidly until bright red erythema affects the entire skin surface. Causative drugs should be discontinued. Oral steroids and pulse therapy are effective at the early stages. Although most cases resolve relatively soon after the causative drug is discontinued, lichenification may continue for a long period. Druginduced hypersensitivity syndrome (DIHS, Chapter 10) is a persistent severe drug eruptions with organ failure; the disorder may also cause erythroderma.

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3. Psoriasis erythroderma Clinical images are available in hardcopy only.

Psoriatic exfoliative dermatitis can occur in association with the use of steroids, and phototherapy, alcohol and stress. Typical psoriatic eruptions often partly remain in erythroderma. Nail deformity frequently occurs. The treatment of oral cyclosporine or etretinate (a vitamin A derivative) is required as treatments in many cases.

4. Tumorous erythroderma T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), adult T-cell leukemia, Hodgkin’s disease, or chronic lymphocytic leukemia may occur as the primary diseases of tumorous erythroderma (Figs. 9.8-1 and 9.8-2). Systemic examination is necessary to detect internal lesions. Erythema with intense itching spreads over the whole body surface, and the lymph nodes swelling. The primary disease should be identified and treated.

5. Other potential cause of erythroderma

Clinical images are available in hardcopy only.

Fig. 9.8-1 Erythroderma associated with Hodgkin’s disease. Flushing and marked scaling are seen on the entire body. The severity of the skin lesions mirrors that of the Hodgkin’s disease.

①Bullous dermatosis: Pemphigus foliaceus (and erythematous), herpetiformis dermatitis may progress to erythroderma. A histopathological examination and a direct immunofluorescent antibody test are useful for diagnosis. ②Hereditary keratosis: In nonbullous congenital ichthyosiform erythroderma, diffuse erythema, scaling and hyperkeratosis occur at the time of birth or within several weeks after birth. Keratotic follicular papules are produced on the extensor surface of the joints in pityriasus rubia pilaris, and these may diffuse and progress to erythroderma. ③Infectious disease: Erythroderma tends to occur in immunocompromised patients, such as those with AIDS. Scabies (Norwegian scabies, particularly), tinea, candidiasis, and viral infections such as of measles and rubella may also produce erythroderma. In children, staphylococcal scalded-skin syndrome

Erythroderma / 5. Other potential cause of erythroderma

(SSSS) sometimes progresses to erythroderma. Graft-versus-host disease: Erythroderma may occur as a symptom of graft-versus-host disease (GVHD) after transfusion. It is fatal. About 10 days after transfusion, edematous erythema, fever, diarrhea, liver disorder, pancytopenia and edematous erythema occur and become erythroderma. Postoperative erythroderma can be prevented by X-radiation of blood products before transfusion. Ofuji papuloerythroderma: Ofuji papuloerythroderma is an uncommon entity of unknown etiology, characterized by a pruritic eruption of flat, widespread, reddish-brown papules that progresses to spare skin folds. Some cases may be associated with an internal malignancy or T-cell lymphoma.

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Clinical images are available in hardcopy only.

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Fig. 9.8-2 Erythroderma associated with Hodgkin’s disease. With regression, normal skin areas appear on the abdomen and shoulder (arrows).

Table 9.8 Causative drugs of erythroderma. Antibiotics NSAIDs Allopurinol Lithium Phenytoin Calcium channel blockers Carbamazepine Cimetidine Gold Quinidine Other

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Drug-Induced Skin Reactions and GVHD

10

Skin and mucocutaneous lesions induced by a drug or by its metabolites are called drug eruptions. Some cutaneous drug reactions present a specific morphological pattern. However, most drug eruptions can present the appearance of any cutaneous lesion. It is necessary for dermatologists to take a detailed patient’s history of medication use as well as a medical history. It is clinically important to differentiate drug-induced skin reactions from viral rash and graft-versus-host disease (GVHD); this differentiation is sometimes difficult.

A. Drug-induced skin reactions 10 Outline ● Drug-induced

skin reaction or drug eruption is a general term for eruptions in the skin and mucosa induced by a drug or its metabolites. ● Drug-induced skin reactions show various morphologies. Clinical images are available in hardcopy only.

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General information Maculopapular or morbilliform eruptions may be the most common of all cutaneous drug reactions. It is also known that cutaneous drug reactions present the specific morphological patterns. (Figs. 10.1-1 and 10.1-2). In diagnosing skin diseases, it is essential to consider drugs as a possible cause of any eruption, because drug eruptions can take the form of any skin lesion. Drug eruptions may be accompanied by general symptoms including fatigue, porgansq j h i k l disfunction m nof the internal o fever, lymph node enlargement, such as liver, kidneys or bone marrow, hypotension and shock. Classification, Pathogenesis Drug eruptions are roughly divided into immunologic and nonimmunologic. The pathogenesis is unclear in some cases. The eruptions are often classified by their clinical features (Table 10.1, Figs. 10.2-1 and 10.2-2).

Clinical images are available in hardcopy only.

Treatment It is essential to discontinue the causative medication. In serious cases, such as anaphylactic shock, systemic management using steroids in large doses including antihistamines, epinephrines, and steroids in large doses, including by pulse therapy. a

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Fig. 10.1-1 Drug-induced skin reaction. a: Diffuse edematous erythema on the back. Each eruption is an erythema multiforme-like erythema of 1 cm to 2 cm in diameter that gradually enlarged and tended to coalesce. b: Edematous itchy erythema coalesced into a large plaque.

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A. Drug-induced skin reactions Table 10.1 Drug-induced skin reactions and their typical causative drugs. Type of eruption in druginduced reactions

Causative drugs

Maculopapular

Iohexol, iomeprol, ampicillin, amoxicillin, carbamazepine, mexiletine, tiopronin

Photosensitive

Sparfloxacin, fleroxacin, lomefloxacin , piroxicam, ampiroxicam, griseofulvin, mequitazine, ketoprofen

Fixed-drug eruption

Allylisopropylacetyl urea, mefenamic acid, ethenzamide, barbital, minocycline, sulfamethoxazole, piroxicam, fluorouracil

Erythema multiforme

Iohexol, carbamazepine, amoxicillin, tiopronin, phenytoin, diltiazem, mexiletine

Lichenoid

Tiopronin, captopril, interferon a, cyanamide, oxatomide

Urticarial

Cefaclor, minocycline, iohexol, aspirin, cetraxate, mefenamic acid

Toxic epidermal necrolysis (TEN)

Cefzonam, penicillin, phenobarbital, chlormezanone, carbamazepine, methazolamide, acetaminophen, allopurinol, diclofenac

Stevens-Johnson syndrome

Penicillin, chlorpromazine, sulfamethoxazole, sodium aurothiomalate, phenytoin

Erythrodermic

Carbamazepine, sodium aurothiomalate, cyanamide, allopurinol, ampicillin

Vesiculo-bullous

D-penicillamine, tiopronin, captopril, bucillamine, alacepril

Eczematous

Penicillin, chlorpromazine, chlorthiazide, promethazine

Purpuric

Sodium aurothiomalate, sulfamethoxazole, penicillin, aspirin

antigenic, causing a drug eruption that results from immunological processes. That is, a drug eruption occurs in specific individuals whose antibodies and lymphocytes react against specific antigens. Although type I, II, III, and IV hypersensitivities are thought to cause drug eruptions (Coombs and Gell classification), the details of the pathogeneses are unknown. IgE mediated type I allergy: Within 2 hours after exposure to an antigen (e.g., penicillin or some NSAIDs), urticaria or anaphylactic shock occurs. Type II allergy: Complements are activated by an antigenic drug that connects with tissues, resulting in hemolytic anemia and thrombocytopenia. It is observed in some cases of purpura-like eruptions. Immune complex-associated type III allergy: Immune complex deposits in tissues, causing disorders. Vasculitic eruptions are thought to be caused by this mechanism. Type IV allergy: A delayed hypersensitivity reaction is induced by T cells that have been sensitized to drug antigens. It isa knownb that many types of drug eruptions, such eczema-like eruptions, are produced by type IV allergy or by T-cell mechanisms that resemble type IV allergy.

Clinical images are available in hardcopy only.

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2. Non-immunologic drug-induced skin reactions Drug-induced skin reactions without an immunologic pathogenesis may affect anyone, regardless of whetherathere has b beenc sensitization.The pathogenesis of drug-induced skin reactions can also be classified pharmacokinetically. Pharmacologic effects: Drug-induced skin reactions may be produced by essential pharmacological action of the drug. Hair loss

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Fig. 10.1-2 Drug-induced skin reaction. c: Drug-induced erythema enlarged and coalesced to form erythroderma. d: Drug eruption caused by tegafur.

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Drug-Induced Skin Reactions and GVHD Table 10.2 Drug-induced skin reactions classified by mechanism. Immunologic Type I hypersensitivity (via IgE antibodies; acute onset within 2 hours after drug intake) Type II hypersensitivity (eruption caused by thrombocytopenia and hemolysis resulting from complement activation) Type III hypersensitivity (immunocomplex deposition in skin components) Type IV hypersensitivity (reactions caused by activated T cells)

Clinical images are available in hardcopy only.

Non-immunologic Pharmacological effects Accumulation Drug interaction Patient-specific conditions

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caused by anticancer agents and exfoliation in palms and soles caused by retinoids are examples. Accumulation: A drug accumulates in the skin or mucous membranes from prolonged use (arsenic melanoderma and argyria are examples of accumulation disorders). Drug interaction: One drug may inhibit another drug’s metabolism or excretion, or it may influence protein binding, leading to the same symptoms as those in drug overdose. Specific condition of patients: Inherited enzyme deficiency may p j i k l m reaction n o cause drug reactions; excessive occurs against a qminuter amount of drug (intolerance). An unexpected action of the drug is caused (idiosyncrasy).

b. Classification of drug eruptions by characteristic skin features Although maculopapular eruption (multiple edematous erythema on the extremities and trunk) are the most common; drug-induced skin reactions can appear as any kind of cutaneous lesion (Table 10.1). When seeing patients with any types of eruption, dermatologists should always carefully consider the possibility of precedent drug reactions.

Clinical images are available in hardcopy only.

c. Methods of identifying the causative drug b

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Fig. 10.2-1 Various types of drug-induced skin reaction. a, b: Erythema multiforme-like. Although uniformly colored erythematous plaques are mainly seen, newly formed erythema is seen at the periphery, some parts of which show the targetlike appearance that characterizes erythema multiforme. c: Purpuric. Dark red macules up to 1 cm in diameter are observed. These do not disappear by diascopy pressure, which indicates that the eruption is purpura.

History is taken on drug-induced skin reactions and on exacerp j k remission l n influenced o r bation or ofmeruptions by useqor discontinuation of a drug. If the eruption is suspected to be drug-induced reactions, tests listed below are conducted for identification (Chapter 5). ①Skin test (scratch test, prick test, intradermal test) ②Patch test ③Drug lymphocyte stimulation test (DLST) ④Rechallenge test (absolutely contrainidicated in severe forms of drug reactions)

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d. Specific types of drug-induced skin reactions 1. Fixed drug eruption (FDE) Definition Fixed drug eruptions (FDEs) are eruptions that recur at the same site each time the same drug is administered. They frequently occur at mucocutaneous junctions. Clinical features FDEs frequently occur at mucocutaneous junctions, such as in the perioral area, lips and genitalia, and in the extremities. They are characterized by a single or a few sharply demarcated red or purple patches (Fig. 10.3), with a diameter of 1 cm to 10 cm. Multiple patches may also occur. They may appear as blistering or erosion. Itching and pain are common. The lesions appear seva b of thec eral minutes to several hours after the administration causative drug. They heal in 2 to 5 weeks, leaving pigmentation. If the same drug was administered repeatedly, the dark brown pigmentation intensifies from inflammation in the basal layer, and subsequent melanin deposition in the dermis (post-imflammatory pigmentation).

Clinical images are available in hardcopy only.

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Pathogenesis FDEs are caused by the activation of cytotoxic T lymphocytes in the basal layer by drugs. Common causative drugs are NSAIDs, tetracyclines, sulfa drugs, phenacetin, hypnogenics and food additives.

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Diagnosis FDEs are diagnosed by detailed history-taking on drugs and the course of the eruptions. A patch test performed on the site where an eruption has occurred is positive with high frequency; it is diagnostically meaningful. Treatment a The causative drug should be discontinued.

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2. Adverse drug reactions in skin that can result in death There are several specific clinical types of drug-induced skin reactions that may lead to death. Toxic epidermal necrolysis (TEN) has the highest mortality (30-35%); Stevens-Johnson syndrome and transitional forms correspond to the same syndrome, but with less extensive skin detachment and a lower mortality (515%). Hypersensitivity syndrome, sometimes called drug-induced

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Fig. 10.2-2 Various types of drug eruption. d, e: Urticarial drug eruptions. Edematous erythema resembling urticaria is seen on the trunk and palms.

Generalized bullous fixed drug eruption

MEMO

Blistering may be present in some fixed drug eruptions, and it may spread on the whole body surface, becoming severe. Generalized bullous fixed drug eruption may be categorized with toxic epidermal necrolysis (TEN), which is described in the following section.

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Fig. 10.3 Fixed drug eruption (FDE). a: Early FDE on the right eyelid. Early lesions are edematous erythema without pigmentation. b: FDE on the abdomen. Repeated intake of the causative drug results in a severely pigmented FDE lesion. c, d: FDE on the thigh. The center of the lesion shows characteristic pigmentation caused by chronic inflammation. The periphery is erythematous, which suggests recent intake of the causative drug. e: FDE on the interdigital area. Erythema and bullous lesions are seen.

hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS), has a mortality of about 10% or less.

Clinical images are available in hardcopy only.

1) Toxic epidermal necrolysis (TEN) Synonym: Lyell’s syndrome

Clinical images are available in hardcopy only.

Fig. 10.4-1 Toxic epidermal necrolysis (TEN).

Clinical features, Classification Toxic epidermal necrolysis (TEN) is one of the severest drug eruptions. It is accompanied by fever, and erythema and blistering on the whole body surface. It leads to marked epidermal necrosis and exfoliation (Figs. 10.4-1 and 10.4-2). It is closely related to Stevens-Johnson syndrome (SJS) (Fig. 10.5). TEN is classified into several types according to the clinical course. TEN developing from SJS: Most cases of TEN develop from SJS. Vaguely outlined, small, dark red edematous erythema sparsely appear on the whole body and gradually spread. They subsequently increase and form blisters and erosion. Typical primary lesions are characterized by so-called target lesions with dusky centers. Severe erosion develops in the oral mucosa, and systemic symptoms such as fever and fatigue are seen. SJS is characterized by the transformation of erythema into blistering

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A. Drug-induced skin reactions

fixed drug eruption (FDE)

generalized FDE

TEN

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Fig. 10.5 The pathogenic association of fixed drug eruption (FDE), toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS) and erythema multiforme (EM).

and erosion with dark red patches at the periphery (Chapter 9). Rapid extensive type: This is the type that Lyell first reported. Two to 3 days after intake of the causative drug, erythroderma and extensive erosions occur on the whole body surface without preceding macules, and the skin exfoliates easily; it is similar to a large burn (second-degree). This type accounts for several percent of all TEN cases (Fig. 10.6).

Fig. 10.4-2 Toxic epidermal necrolysis (TEN).

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Pathogenesis It is widely accepted that the cellular functions of cytotoxic T cells are abnormally enhanced by certain drugs, including sulfa drugs, penicillin, barbituric acids, aspirins, pyrazolone drugs, and anticonvulsants, and epidermal necrosis and subepidermal separation occurs as a result. Fas-Fas ligands, which induce apoptosis in epidermal cells, are thought be involved in the occurrence of TEN. Treatment Use of the causative drug should be discontinued immediately. Systemic glucocorticosteroids in high doses, including pulse therapy, are widely known to be useful in the early stages of TEN, but not in the late stage of the disease course. Intensive care with topical treatment and body fluid management similar to the patients with burns are essential. Plasma exchange may be conducted, and large doses of immunoglobulins may also be applied. The causative drug must not be readministered.

Clinical images are available in hardcopy only.

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2) Drug-induced hypersensitivity syndrome

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Synonyms: Drug hypersensitivity syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS) There is still controversy on the naming of this newly proposed concept of the disease condition, but each different disease namea may indicate the same or similar condition which is induced by drug. Drug-induced hypersensitivity syndrome (DIHS) is proposed by a group of Japanese dermatologists which holds that skin lesions are caused by a combination of drug allergy and reactivated latent viral infection, specifically human herpes virus 6 (HHV 6) infection. Two to 6 weeks after administration of a specific drug, fever

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Fig. 10.6 Diffuse erythematous toxic epidermal necrolysis (Lyell's syndrome). a: The causative drugs here are antituberculosis drugs, which were used for tuberculosis associated with AIDS. Generalized shedding of the epidermis on the whole body is seen. The dermis is pink where the skin exfoliates. b: Severe erosions and ulcers in the oral region.

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Drug-Induced Skin Reactions and GVHD Table 10.3 Diagnostic criteria for drug-induced hypersensitivity syndrome (DIHS).

Clinical images are available in hardcopy only.

1. Maculopapular rash develops more than 3 weeks after starting a certain drugs. 2. Lymphadenopathy 3. Fever (>38˚C) 4. Leukocytosis (>10 × 109/L) a. Atypical lymphocytosis b. Eosinophilia 5. Hepatitis (ALT >100 U/L) 6. HHV-6 reactivation The diagnosis is confirmed by the presence of five of the six criteria above. (Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpes viruses and antiviral and antidrug immune responses. Allergology International 2006; 55: 1-8).

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Fig. 10.7 Drug-induced hypersensitivity syndrome (DIHS).

and generalized maculopapular erythema occurs (Fig. 10.7), which results in erythroderma in some cases. Enlargement of superficial lymph nodes, liver dysfunction and hematological abnormalities (leukocytosis, appearance of atypical lymphocytes, increase of eosinophils) occur. There is also a report that suggests the involvement of cytomegalovirus and human herpes virus (HHV7) in DIHS. The diagnostic criteria are listed in Table 10.3 (also refer to Chapter 23 for viral infections). Drug reaction with eosinophilia and systemic symptoms (DRESS) is thought to be the same or similar syndrome, which is mainly used by European dermatologists group. The important point is that dermatologists should be aware of these systemic drug-induced reactions in association with marked eruption, and that routine laboratory examination is necessary when a drug eruption is suspected. The treatements include systemic corticosteroid and termination of the causative drug.

B. GVHD and viral eruptions 1. Graft-versus-host disease (GVHD) Outline ● After

bone marrow transplantation, other organ transplantation or transfusion, donor lymphocytes are stimulated by major and/or minor histocompatibility locus antigens and subsequently target host tissues for cytotoxic damage. ● The skin, intestinal tract and liver are the main affected organs. ● In acute GVHD, erythematous macules occurs on the palms and spread over the whole body. In chronic GVHD, lichen-planus-like and scleroderma-like eruptions are found.

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Definition, Pathogenesis When donor-derived blood cells circulate in the patient’s skin after transplantation, the immunocompetent donor, T cells, may recognize the foreign hosts histocompatibility locus antigens (HLA). Subsequently, an immune reaction against the host’s organs occurs. It may also be caused by general blood transfusions. Classification As shown in Table 10.4, graft-versus-host disease (GVHD) is categorized by the onset. The skin, digestive tract and liver are the main organs affected, and the symptoms are mainly seen in those organs. Post-transfusion GVHD occurs about 10 days after a transfusion and has a poor prognosis. Congenital GVHD occurs after birth, and intractable dermatitis, diarrhea, opportunistic infections, and disturbance in growth are caused by lymphocytes transferred from the mother. Clinical features Acute GVHD: In most cases, 10 to 30 days after a graft, edematous erythema appears on the extremities and trunk. It may be accompanied by slight itching. In severe cases, the eruptions coalesce and may develop into erythroderma, blistering or erosion (Figs. 10.8-1 and 10.8-2). Symptoms of acute GVHD may remain longer even after the first 100 days or more after transplantation, as a result of recent improvements in immunosuppressive drugs. Chronic GVHD: This includes lichenoid forms and sclerodermoid forms. The lichenoid forms multiple purplish-red plaques resembling lichen planus, and the sclerodermoid forms sclerotic lesions resembling scleroderma. The severity of GVHD is classified according to the severity of the skin lesions and other organ disorders (Table 10.5).

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Pathology GVHD pathologically presents a lichenoid reaction. Intradermal lymphocyte infiltration, necrosis of the epidermal cells, and Table 10.4 Classification of graft-versus-host disease (GVHD). Type of GVHD

Duration after transplantation/ transfusion

Symptoms Fever, diarrhea, erythrodermic skin eruption, pulmonary edema, heart failure

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7 to 14 days

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a b Up to 100 days Triad (fever, diarrhea and liver dysfunction). Poorly demarcated erythema seen on the face and palmoplantar area. In severe cases, TEN and erythroderma.

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More than 100 Various skin lesions like those in collagen diseases and lichen planus. Liver dysfuncdays tion, oral symptoms, ocular symptoms.

Transfusion- About 10 days associated

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Resemble those of hyperacute GVHD. Prognosis is poor.

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Fig. 10.8-1 Acute graft-versus-host disease (GVHD). a: Diffuse erythema on the back after bone marrow transplantation. Differential diagnosis from drug eruption is almost impossible clinically. b, c: Severe acute GVHD. Severe exfoliation similar to toxic epidermal necrolysis is seen.

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Drug-Induced Skin Reactions and GVHD Table 10.5 Clinical staging and grading of GVHD.

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vacuolar degeneration of the basal cell layer are found (Chapter 2). The number of Langerhans cells decreases. Differential diagnosis GVHD needs to be differentiated from drug-induced skin reactions, eruptions of peripheral lymphocyte recovery accompanying a graft (generally 10 to 14 days after transplant), and viral infections.

Clinical images are available in hardcopy only.

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Fig. 10.8-2 Acute graft-versus-host disease (GVHD). d, e: Diffuse small erythema coalesce into red plaques.

Treatment Immunosuppressants (cyclosporine, tacrolimus, azathioprine, cyclophosphamide) and steroids are administered orally, Posttransfusion GVHD can be prevented by irradiating the blood to p q l m n o r be transfused.

2. Viral eruption When maculopapular erythema appear abruptly on the whole body of a febrile patient who has been adiministered NSAIDs or any other medicine for that condition, a drug reation or a viral infection are the two most likely diagnoses. In those cases, differentiation between drug-induced eruption and viral eruption is often difficult, even with thorough examination. Drug-induced hypersensitivity syndrome (DIHS) is thought to be caused by causative drug as well as re-activation of latent viral infection. Refer to Chapter 23 for details on viral infections.

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11

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Vasculitis, Purpura and Other Vascular Diseases

Vasculitis is divided into several types according to the diameter of the artery or vein at the principal site of inflammation (Fig. 11.2). In cutaneous vasculitis, there is frequently purpura or ulceration. Purpura may be an early sign of vasculitis. Purpura is a general term for reddish-purple skin lesions produced by bleeding in the dermis or subcutaneous tissues. It is classified by the size of bleeding into petechia (diameter up to 2 mm) or ecchymosis (diameter larger than 2 mm). The major causative factors are ① vascular abnormality (from vasculitis or mechanical injury), ② blood flow abnormality (e.g., hypergammaglobulinemia, which often accompanies a systemic disease), ③ decrease or functional abnormality of platelets, and ④ coagulopathy (e.g., DIC). However, the etiology is unknown in many cases. This chapter discusses diseases with the symptoms listed above and diseases caused by circulatory disorder of the arteries, veins and lymphatic vessels.

Vasculitis

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A. Vasculitis in small vessels 1. Cutaneous small-vessel vasculitis (CSVV) Synonyms: Leukocytoclastic vasculitis, Necrotizing vasculitis, Allergic vasculitis, Cutaneous allergic vasculitis Outline

is a group of diseases that are characterized by neutrophilic infiltration into the peripheral small dermal blood vessels. ● Various clinical features, including erythema, purpura, papules, blistering and ulceration, may be present, depending on the depth and severity of the vasculitis. ● Henoch-Schönlein purpura is a variant of CSVV.

Clinical images are available in hardcopy only.

Definition Cutaneous small-vessel vasculitis (CSVV) is a general term for diseases that present pathological features of leukocytoclastic vasculitis, i.e., diseases with pathological perivascular neutrophilic infiltration and fibrinoid degeneration of the vascular walls (Fig. 11.1). Henoch-Schönlein purpura and urticarial vasculitis are included under a broad definition of CSVV; however, they are usually treated as distinct diseases. In its more restricted sense, CSVV is considered to be a disease caused by small-vessel vasculitis in the dermis (in and between the middle and deep layers of the dermis).

Fig. 11.1 Cutaneous small-vessel vasculitis (CSVV). The skin lesion presents a mix of purpura, papules, nodules, pustules, blisters, erosion and ulcers. It is accompanied by sharp pain.

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Clinical features Purpura, urticaria, erythema-multiforme-like erythema, 135

MEMO Allergic vasculitis, Vasculitis allergica cutis (Ruiter) Cutaneous small-vessel vasculitis that occurs mainly in the upper and middle dermal layers and is rarely accompanied by systemic symptoms is called allergic vasculitis. Although the term is frequently used in Japan, it is not known internationally. For that reason, the term allergic vasculitis is not used in this textbook. Instead, the term cutaneous small-vessel vasculitis is used.

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A-1：cutaneous small-vessel vasculitis (CSVV) A-2：Henoch-Schönlein purpura (HSP) B-1：polyarteritis nodosa (PN) B-2：allergic granulomatous angiitis (AGA) B-3：Wegener’s granulomatosis

Fig. 11.2 Cutaneous vasculitis and the depth of the affected vessels.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

papules, nodules, pustules, blistering, erosion and ulceration occur, mainly in the lower extremities (Figs. 11.3-1 and 11.3-2). Nephritis, pulmonary infiltration, pleuritis, acute abdomen, cranial nerve symptoms, convulsive seizure, headache, myocarditis and epicarditis may accompany CSVV. Pathogenesis An immune complex of an antigen (e.g., bacterium, virus, drug) and the antibody against that antigen deposit on the arteriolovenular walls. These activate the immune system and cause vasculitis (type III allergic reaction). Penicillin, sulfa drugs and other drugs, chemical substances, hemolytic streptococcus bacteria, or viruses may be the foreign antigen. Collagen diseases and antibodies against malignant tumors can also be causes. Pathology In the upper and middle dermal layer, fragments of nuclear debris and leakage of erythrocytes are found in the peripheral arteriola. Neutrophilic infiltration occurs in the arteriolovenous small blood vessels and capillaries. Thickening of the blood vessel walls and fibrinoid degeneration are also found in many cases (Fig. 11.4).

MEMO When diagnosing purpura, it is important to distinguish between purpura caused by vasculitis and purpura caused by other factors (e.g., thrombocytopenia, capillary fragility). Purpura caused by vasculitis tends to be accompanied by palpable infiltration (palpable purpura), whereas in purpura caused by factors other than vasculitis, infiltration is not usually present. However, infiltration is impalpable in mild vasculitis.

Palpable purpura, Non-palpable purpura

Fig. 11.3-1 Cutaneous small-vessel vasculitis (CSVV). The disease presents various cutaneous clinical features including purpura, erythema, bloody blisters and ecchymosis.

Vasculitis / A. Vasculitis in small vessels

Laboratory findings Elevated erythrocyte sedimentation rate, increase of leukocytes and hypergammaglobulinemia may occur. The serum complement titer often decreases. Tests for immune complex are sometimes positive. When CSVV immunocomplex is accompanied by systemic symptoms, renal lesion tends to occur, and proteinuria and hematuria are found.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Diagnosis CSVV is diagnosed by skin biopsy. Since there are many diseases that cause CSVV, special care should be taken in diagnosis. Treatment, Prognosis When the cause is a drug or infection, those should be removed. For a lesion in the lower extremities, the legs should be raised and kept warm and the patient should get bed rest. Oral application of NSAIDs and DDS (dapsone) is effective in relieving symptoms. Systemic corticosteroid therapy and immunosuppressants are useful for severe cases with systemic symptoms.

2. Henoch-Schönlein purpura (HSP) Synonym: Anaphylactoid purpura

11 Fig. 11.3-2 Cutaneous small-vessel vasculitis (CSVV). It presents various cutaneous clinical features from palpable purpura to deep ulcers, depending on the depth of the affected vessels.

Outline ● It

is a specific type of cutaneous small-vessel vasculitis. The cause is IgA immune complex deposition on the vascular walls. HSP is a type III allergy. ● It is a leukocytoclastic vasculitis in which there are scattered nuclear fragments (nuclear dust), mainly in the subpapillary vessels of the dermal upper layer. ● Arthritic symptoms, abdominal pain, and renal symptoms occur. ● Bed rest and systemic steroid administration are the major treatments. ●

Definition Multiple palpable purpura occur mostly in the lower legs, and they are accompanied by arthralgia, digestive disorder and kidney disorder. Henoch-Schönlein purpura (HSP) is in the pathological category of cutaneous small-vessel vasculitis (CSVV); however, it is localized in the dermal upper layer, and there is IgA deposition on the vascular walls.

MEMO This is deposition of eosinophilic amorphous material on the vascular wall, and it appears in the early stages of vasculitis; the immunocomplex may be identified by fibrinoid degeneration (Fig. 11.4).

Fibrinoid degeneration

Fig. 11.4 Histopathology of cutaneous small-vessel vasculitis (CSVV). Fibrinoid necrosis of the vessel walls in the upper dermis, hemorrhage with neutrophils, and nuclear dust (arrows) are present.

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Clinical images are available in hardcopy only.

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Clinical features, Classification The most severely affected organs and locations are the skin, joints, digestive organs, and kidneys. Although children are most commonly affected, HSP may also occur in adults. It may be preceded by a headache, pharyngeal pain, and symptoms of the common cold. Disseminated palpable purpura of several millimeters to 10 mm in diameter occur, mainly in the lower extremities and dorsum of the foot, but sometimes on the thighs, upper extremities, and abdomen (Fig. 11.5). Blisters, ulcers, and old and new eruptions may be present together. In some cases there is transient edema with slight pressure pain. Arthritic symptoms in the legs, knees, hands and elbows, sharp pain in the abdomen, and gastrointestinal symptoms such as nausea, vomiting, hematemesis, and melena are found. HSP may be accompanied by renal symptoms including acute nephritis that progresses to nephrosis. Renal symptoms are closely related to the prognosis. Pathogenesis In children, the onset is mostly after upper respiratory infection; association with hemolytic streptococcus has been pointed out. Drugs (penicillin, aspirin) and certain kinds of foods (milk, eggs) are known to be antigens. These antigens combine with antibodies (mainly IgA) in the body, and the immunocomplex deposits on the vascular walls. Immunoreaction is induced to cause vasculitis and purpura. Pathology Leukocytoclastic vasculitis accompanied by fibrinoid degeneration is seen on the vascular walls in the upper dermal layer. IgA deposition is observed by direct immunofluorescence (Fig. 11.6). The histology of the kidney in HSP patients often shows crescentic glomerulonephritis.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 11.5 Henoch-Schönlein purpura. Palpable purpura may be accompanied by bloody blisters in some cases.

Laboratory findings When HSP is caused by hemolytic streptococcal infection, antistreptolysin O and antistreptokinase values increase. In half of the patients, serum coagulation factor XIII decreases. In cases with renal lesion, hematuria and proteinuria occur. Differential diagnosis When the purpura described above occurs in youth, HSP is suspected. History-taking should inquire into not only HSP but also other diseases before examinations and histopathological tests are conducted. It is necessary to differentiate HSP from other purpura, polyarteritis nodosa, Goodpasture syndrome, nephritis after infection caused by hemolytic streptococcus, and systemic lupus erythematosus (SLE). In adults, differential diagnosis from polyarteritis nodosa is important. Treatment Bed rest is the first-line treatment, followed by the administra-

Vasculitis / A. Vasculitis in small vessels

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tion of a vessel-strengthening drug and hemostatics, and systemic administration of steroids. When the disease is caused by hemolytic streptococcus, antibiotics are used. Administration of factor XIII may be effective. Prognosis HSP generally has a good prognosis and resolves within several weeks in most cases; however, it may recur. Serious complications may occur in other organs, such as nephritis with IgA deposition in the mesangium area, enterorrhagia, intussusception, intestinal perforation, or cerebral hemorrhage.

3. Urticarial vasculitis

Fig. 11.6 Direct immunofluorescence of Henoch-Schönlein purpura. IgA deposition on the vascular wall in the upper dermis is observed.

When an urticarial eruption remains for more than 24 hours with purpura, urticarial vasculitis is suspected. It may be accompanied by systemic symptoms such as fever and a decrease in complement titer (Chapter 8).

11 Clinical images are available in hardcopy only.

4. Erythema elevatum diutinum (EED) Erythema elevatum diutinum (EED) frequently occurs in men and women of middle age and older. It is a skin lesion that is accompanied by symmetrical infiltration on the extensor surface of elbows and knees. Although the pathogenesis is unknown, an immune reaction caused by deposition of immune complex in the blood vessels is thought to be involved. Appearing as soft, slightly elevated, purplish-red erythema at first, the eruptions gradually become fibrotic and keloidal. There is an atypical type with blistering (Fig. 11.7). Leukocytoclastic vasculitis occurs in the dermis. It is nearly asymptomatic, however, it recurs repeatedly and persistently. Oral ulcer, arthritis, lung fibrosis, IgA myeloma, and viral infection may accompany EED. DDS is an effective treatment.

Fig. 11.7 Erythema elevatum diutinum. A specific type of erythema elevatum diutinum produces not only erythema but also vesicles.

5. Granuloma faciale Granuloma faciale, a soft, infiltrative, reddish-brown plaque with a sharp margin, occurs on the face. It is known to be a chronic leukocytoclastic vasculitis. Deposition of immunoglobulins on the vascular walls has been reported, from which the possibility of an immunoreaction resembling that of EED has been pointed out. Granuloma faciale is intractable. Liquid nitrogen cryotherapy, local injection of steroids, and dye laser treatment have been used in recent years.

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B. Vasculitis in medium-size and large arteries 1. Polyarteritis nodosa (PN) Synonym: Periarteritis nodosa Outline Clinical images are available in hardcopy only.

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affects muscular arteries the most severely. PN is classified into cutaneous (only the skin is affected), systemic (systemic symptoms occur), and microscopic (renal symptoms caused by affected arteries occur, and respiratory symptoms occur). ● Histopathologically, it is inq p j h i k l leukocytoclastic m n ovasculitis small and medium-size arteries. ● Cutaneous findings include subcutaneous nodules, livedo reticularis, and erythematous ulceration. Clinical features, Epidemiology Polyarteritis nodosa (PN) most frequently occurs in men and women in their 30s to 60s. There are no significant differences in cutaneous manifestations between systemic PN and cutaneous PN, and cutaneous symptoms are seen in 10% to 60% of systemic PN cases. Palpable subcutaneous nodules of 1 cm to 2 cm in diameter, purpura, livedo and ulceration occur mainly parallel to the superficial arteries (Fig. 11.8). Tenderness may be present. PN becomes chronic with repeated recurrences and regressions. Urticaria and transient erythema may also occur. Livedo reticularis (livedo racemosa) p q j i k l is commonly m nfound. o r Systemic PN may be accompanied by fever, fatigue, weight loss, arthralgia, and visceral symptoms such as renal failure, cardiac infarction, cardiac failure, pericarditis, high blood pressure, abdominal pain, neuritis and myalgia. The kidneys are the most commonly affected organs, and death from renal failure is possible. Patients with microscopic PN may develop acute progressive nephritis, interstitial pneumonia, and pulmonary hemorrhage. The disease is highly associated with MPO-ANCA. Pathogenesis The etiology is unknown. The hepatitis B virus, bacterial infectious diseases (e.g., streptococcus), and drug hypersensitivity are known to precede or induce PN.

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Fig. 11.8 Polyarteritis nodosa. a: Nodules with palpable, severe infiltration. b: Coalesced purpura. c: Advanced polyarteritis nodosa accompanied by ulceration.

Pathology PN is leukocytoclastic vasculitis that is accompanied by swelling in the tunica media of small and medium-sized arterial p q j k l degeneration, m nand neutrophilic o r walls, fibrinoid cellular infiltration (Fig. 11.9). As PN progresses, thromboembolism, aneurysm and bleeding occur, leading to the formation of epithelioid cell granuloma. In cutaneous PN, these symptoms occur in the arteries in

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Vasculitis / B. Vasculitis in medium-size and large arteries

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the deep dermal layer and subcutaneous fat tissue. Lesions occur in almost all the nutrient arteries in systemic PN; nevertheless, the lungs are rarely affected. The thickness of the blood vessels and the depth from the skin surface for PN and other vasculitises are compared in Fig. 11.2. Laboratory findings Immune complex deposition may be found in the area with eruptions. ANCA is generally positive in microscopic PN. Aneurysm is frequently observed by angiography. Diagnosis PN is diagnosed by the clinical features, laboratory findings and skin biopsy. It is necessary to differentiate it from systemic lupus erythematosus (SLE), cutaneous small-vessel vasculitis, erythema nodosum, erythema induratum and cryoglobulinemia.

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Treatment Cutaneous PN with mild clinical severity is treated by bed rest with the lower extremities raised, and administration of vasodilators, NSAIDs and DDS. Steroids are temporarily administered orally during acute aggravation. For systemic PN, steroids and immunosuppressive drugs are necessary in high doses. Prognosis Cutaneous PN has a good prognosis. The eruptions heal in several weeks; however, they are persistent and recur for years. In contrast, the prognosis of systemic PN is poor, because of various internal-organ disorders (e.g., renal failure, intracranial hemorrhage, cardiac infarction).

Fig. 11.9 Histopathology of polyarteritis nodosa. Thickened vessel walls of medium-sized arteries, fibrinoid degeneration, and leukocytoclastic vasculitis are accompanied by neutrophilic infiltration.

2. Allergic granulomatous angiitis (AGA) Synonym: Churg-Strauss syndrome Outline ● AGA

is a vasculitis syndrome. Allergic symptoms such as asthma, fever, and increase of eosinophils and IgE precede AGA. ● Necrotizing vasculitis in small and medium-sized arteries and the formation of granuloma are the primary diseases. ● Interstitial pneumonia and lung granuloma occur. ● P-ANCA is positive. ● Oral or pulse administration of steroids is the main treatment. Clinical features, Differential diagnosis In most cases intractable bronchitis and other allergic diseases occur for several months to several years before the onset of allergic granulomatous angiitis (AGA) (Fig. 11.10). Infiltrated

Clinical images are available in hardcopy only.

Fig. 11.10 Allergic granulomatous angiitis. Infiltrative subcutaneous nodules, purpura and erythema.

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Table 11.1 Main clinical symptoms and findings of Churg-Strauss syndrome (based on classification criteria proposed by the American College of Rheumatology). Symptoms and findings

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Details

Bronchial asthma

Expiratory wheezing or high-pitched rales

Eosinophilia

Eosinophils accounting for 10% or more of the fraction of peripheral leukocytes

Neuropathy, mono or poly

Numbness accompanied by pain, with glove-stocking distribution

Pulmonary infiltrates, non-fixed

Migrating or transient pulmonary infiltration (X-ray)

Paranasal sinus Sharp pain or tenderness in paranasal sinus, or abnormal abnormality findings in X-ray Extravascular eosinophils

Extravascular eosinophils in the skin and lung, observed pathologically

（Adapted from; http://www.rheumatology.org/publications/classification/churg.asp?aud=mem）.

subcutaneous nodules, purpura and erythema frequently appear. Peripheral nerve disorder (usually mononeuropathy multiplex) and gastrointestinal lesions are also found. Lung involvement is common; migrating polymorphic interstitial pneumonia resembling Löffler syndrome is observed by chest X-ray. In comparison with PN, prodromes are common and renal dysfunction is rare in AGA. The typical symptoms of AGA are summarized in Table 11.1. Pathology In AGA, as in PN, there is leukocytoclastic vasculitis in small and medium-sized arteries and small veins. Granuloma occurs in the vascular or perivascular walls, and there is marked eosinophilic infiltrate in the tissue. Laboratory findings Notable increase of leukocytes, eosinophils and serum IgE are seen. The patient often tests positive for P-ANCA (MPOANCA), a kind of anti-neutrophil cytoplasmic antibody (ANCA). Treatment With systemic high-dose application of steroids in the early stages, AGA subsides in a relatively short time. Their use in combination with immunosuppressants is recommended in intractable cases.

3. Wegener’s granulomatosis Outline ● This

rare vasculitis syndrome is preceded by upper respiratory symptoms such as paranasal sinusitis. It is accompanied by fever and systemic fatigue. ● Leukocytoclastic vasculitis and granuloma are found in the upper respiratory tract, lungs and kidneys. ● Cutaneous symptoms are the same as in PN. ● C-ANCA is positive. Multiple lung lesions are observed by chest X-ray. ● The prognosis is improved by combined use of steroids and cyclophosphamide. Clinical features, Epidemiology Wegener’s granulomatosis most commonly occurs in men and women between the ages of about 25 and 55 years. Necrotizing granuloma lesions in the upper and lower respiratory tracts cause foul-smelling rhinorrhea, mucosal erosion in the upper respiratory tract, nasal hemorrhage, paranasal sinusitis, ocular proptosis, hemosputum and breathing disruption. As the lesions progress, saddle nose may be caused. The lesion gradually spreads to the kidneys, leading to rapidly progressive renal failure. Cutaneous symptoms are found in approximately half of all

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cases. Various eruptions, such as gangrenous papules, blisters, erythema, purpura, pustules, nodules and ulcers, are produced symmetrically in the extremities and buttocks. In the early stages, a skin lesion resembling pyoderma gangrenosum may be found; it may be useful for early diagnosis (Fig. 11.11). Pathogenesis The etiology of Wegener’s granulomatosis is unknown; however, an autoimmune mechanism is suspected. Autoantibodies called C-ANCA (PR3-ANCA), which are anti-neutrophil cytoplasmic autoantibodies, are thought to activate neutrophils and monocytes, causing Wegener’s granulomatosis. Pathology Leukocytoclastic vasculitis in the upper dermal layer and granuloma formation in the periphery are found.

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Treatment, Prognosis Systemic steroids and immunosuppressants (cyclophosphamide in particular) are used. Wegener’s granulomatosis was once regarded as having a poor prognosis and usually leading to death from renal failure or other disorder within a year after onset. Currently, it may subside as long as it is treated in the early stages.

4. Temporal arteritis (TA) Synonym: Giant-cell arteritis Outline ● TA

is a vasculitis syndrome. The superficial temporal arteries and ophthalmic arteries are affected. ● It occurs in elderly women. The typical symptoms are

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Laboratory findings Elevated erythrocyte sedimentation rate, increases in leukocytes and platelets, and elevated levels of human immunoglobulins are found. Skull fracture may be observed by head X-ray. In a chest X-ray, there is shading that closely resembles that of pulmonary tuberculosis and pulmonary metastatic tumor, and cavitary circular shading with a thin wall is seen in 30% to 50% of cases. C-ANCA is useful for diagnosis as a specific antibody and is associated with disease severity. The antibody titer decreases during the course of successful treatment. Differential findings It is necessary to differentiate Wegener’s granulomatosis from sarcoidosis, lymphoma, Goodpasture syndrome, malignant tumor, PN, AGA and cutaneous small-vessel vasculitis. Diagno-a sis follows the diagnostic criteria of the American College of Rheumatology (Table 11.2).

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Fig. 11.11 Wegener’s granulomatosis. a: Necrotic papules. b: Ulceration in the oral cavity.

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Table 11.2 Criteria for the classification of Wegener’s granulomatosis. 1. Nasal or oral inflammation Development of painful or painless oral ulcers or purulent or bloody nasal discharge 2. Abnormal chest radiograph Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities 3. Urinary sediment Microhematuria (>5 red blood cells per high power field) or red cell casts in urine sediment 4. Granulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)

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For purposes of classification, a patient shall be said to have Wegener’s granulomatosis if at least 2 of these 4 criteria are present. (Leavitt RY, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990; 33: 1101-7).

unexplained fever, throbbing headache, and visual impairment. ● Cord-like induration occurs in the temporal region, and muscular pain develops (polymyalgia rheumatica). ● Oral steroids are the main treatment. Clinical features, Pathogenesis Temporal arteritis (TA) most frequently occurs in persons over age 50, with a ratio of 1 male to 3 females. Temporal arteries are mainly affected. Cord-like thickening of the temporal arteries, reddening, pain and swelling are present. Throbbing headache, difficulty of opening the mouth, blistering, ulceration, necrosis in the scalp, and hair loss occur. When the lingual artery is affected, the tongue becomes red, swollen and erosive. When the ophthalmic artery is affected, visual impairment results, with blindness following in 10% of cases. A temporary visual disorder (amaurosis fugax) may also occur. When an artery in the brain is affected, bulbar palsy and dementia occur as well. The pathogenesis of TA is unknown; however, the involvement of viral or bacterial infection, or drug allergy is suspected. Since HLA-DR4 is associated with TA, genetic factors may be involved in the occurrence of TA. Laboratory findings Elevated erythrocyte sedimentation rate and increased CRP are observed. Autoantibodies are absent. The serum complement titer and myogenic enzyme are normal. By biopsy, TA appears as granulomatous inflammation accompanied by cellular infiltrate mainly caused by mononuclear cells and production of giant cells. Treatment To prevent visual impairment, steroids are used systemically in the early stages of TA. If the symptoms subside, the medication may be discontinued.

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C. Other diseases related to vasculitis in small and medium-sized blood vessels 1. Behçet’s disease Outline ● Recurrent

oral aphtha, eye symptoms (uveitis), ulceration in the genitalia, and cutaneous symptoms (erythema-nodosum-like eruptions) typically occur. ● Behçet’s disease is an inflammatory disease with an unknown cause. It occurs mostly in middle-aged men. Severe thrombophlebitis is induced. ● A distinct, severe clinical type that involves nerves, intestines and blood vessels has been reported. ● Its occurrence correlates highly with HLA-B51. It occurs more frequently in ethnic Japanese than in people of other ethnicities. ● Needle reaction test is positive. ● Administration of colchicines and immunosuppressants are the main treatments. Clinical features Behçet’s disease first manifests in men and women in their 20sa and progresses over a long period of time (Figs. 11.12-1 to 11.12-3). It occurs slightly more frequently in ethnic Japanese than in Caucasians, and in men more than women. The typical cutaneous symptoms are ① erythema-nodosum-like eruptions, ② thrombophlebitis, and ③ folliculitis and acne-like eruptions. The erythema-nodosum-like eruptions most commonly occur in the lower extremities and forearms and are accompanied by pressure pain. They subside in about 1 week; however, they tend to recur. Thrombophlebitis appears as palpable painful subcutaneous linear cord in the extremities, and it often migrates. Folliculitis and acne-like eruptions produce multiple follicular sterile pustules; they are presumably caused by increased irritability, and they produce a pustule where a needle has been inserted, 24 to 48 hours after insertion (needle reaction test). The disease is also characterized by ulceration in the genitalia. Deep ulcers with sharp margins form in the scrotum in men and in the labia majora and minora in women. These are painful, and they leave scarring when they heal. Aphthae in the oral mucosa form sharply margined ulcers that are persistently painful. They heal in about 10 days and then recur. More than 60% of patients with Behçet’s disease experience oral aphtha as an early symptom; this has diagnostic significance. In addition, uveitis accompanied by hypopyon often occurs; there is a high risk of blindness. Fever, fatigue, arthritic symptoms, gastrointestinal symptoms (in the ileocecal region, in particular), epididymitis, vasculitis symptoms, and central nervous

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Fig. 11.12-1 Behçet’s disease. a, b: Recurrent aphtha in the oral cavity accompanied by sharp pain.

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system damage may also occur.

MEMO

Human-leukocyteantigen (HLA) complex

Pathogenesis The primary disease is thought to involve increased neutrophil activity; however, vasculitis plays a central role. Behçet’s disease is strongly correlated with the HLA-B51 allele, and abnormality in immunity is known to be associated with the occurrence of the disease. The involvement of bacterial allergy (especially hemolytic streptococcus) is suggested as an initiating factor. Antiphospholipid antibodies and autoimmunity are thought to be involved in the formation of thrombi.

This is known to be a gene cluster that influences histocompatibility and is involved in the strength of immunoreaction. It is thought to have a strong association with autoimmune and other diseases (Chapter 3).

Pathology In erythema-nodosum-like eruptions, neutrophilic or lymphocytic cellular infiltration is found in the peripheral blood vessels in the deep dermal layer and subcutaneous fat tissues (septal panniculitis). Unlike in erythema nodosum, vasculitis may be found. In thrombophlebitis, thrombus tends to occur in the small veins of the subcutaneous fat tissues.

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Fig. 11.12-2 Behçet’s disease. c, d: Deep ulceration in the genitalia.

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Laboratory findings Needle reaction test is positive in 70% of cases, from enhanced pis alsoq an important j irritability k of the l skin. m Positive n HLA-B51 o r finding in diagnosing Behçet’s disease. Increased erythrocyte sedimentation rate, positive CRP, increased immunoglobulins, and leukocytosis (particularly neutrophilic) are seen from inflammation. When the disease progresses, complement activity increases. Diagnosis Criteria for diagnosis of Behçet’s disease have been made by Health and Welfare Ministry of Japan (Table 11.3). When the four typical symptoms present during the course of the disease, it is called complete Behçet’s. In recent years, complete Behçet’s has rarely been seen; in incomplete Behçet’s there are three main symptoms or m a combination and one main p symptoms q k l n o of eye r symptom. Treatment Specific and severe types of Behçet’s disease and ocular symptoms, if any, are given priority in any treatment. When colchicines, which inhibit neutrophils and NSAIDs, are ineffective, immunosuppressants (cyclosporine A, tacrolimus) are useful. Anticoagulation therapy is performed on thrombosis.

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2. Kawasaki disease Synonyms: Mucocutaneous lymph node syndrome (MCLS), Acute febrile mucocutaneous lymph node syndrome Outline ● The

etiology is unknown. Kawasaki disease has six characteristics: 1 fever continues for more than 5 days, 2 edema, erythema and scaling occur in the distal fingers and toes, 3 eruptions of various shapes appear on the trunk, 4 hyperemia occurs in the bulbar conjunctivae, 5 reddening in the lips and oral cavity, flush, and strawberry tongue are present, and 6 non-purulent lymph nodes enlarge. b c ● It is most common in children age 4a and under (80% ofd cases). ● Aspirin and human immunoglobulins are the main treatments. a

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Clinical features Kawasaki disease occurs in 3 boys for every 2 girls. Prodromes are not present. It begins with a fever of about 39 ℃. Sharply margined erythema occurs in the fingers and toes. Reddening or blistering at the site of BCG immunization appears. b occur c on the d whole e body.f Shortly after that, irregular aeruptions The eruptions are mainly erythema, followed in frequency by urticaria and by scarlet-fever-like or rubella-like eruptions in some cases. So-called strawberry tongue is present. The distinctive facial features of strawberry tongue, and eruptions and firm edema on the hands and soles are seen 3 to 5 days after the onset of Kawasaki disease. Non-purulent cervical lymphadenopathy also occurs at this time. Scaling occurs in the tips of the fingers and toes 10 to 15 days after onset (Fig. 11.13). Joint pain and swelling, and nail deformation are found. Myocarditis, pericarditis and coronary vasculitis occur as complications in 70% to 80% of all cases. Pathogenesis It is unknown. There is a theory that superantigens of hemolytic streptococcus and chlamydia infection are involved. Laboratory findings In the peripheral blood, leukocytosis (increase in neutrophils and platelets, and left shift of white blood cells), platelet increase, elevated erythrocyte sedimentation rate, positive CRP, and increased a-2 microglobulins are seen. These findings are helpful for early diagnosis. Diagnosis Children with a persistent high fever that does not respond to antibiotics may have Kawasaki disease. The diagnostic criteria are those of the Kawasaki disease Research Group of the Health

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Fig. 11.12-3 Behçet’s disease. e: Nodular erythema-like eruptions. f: Folliculitis-like eruptions. g: Folliculitis-like eruptions.

Clinical images are available in hardcopy only.

Fig. 11.13 Kawasaki disease. Firm edema and scaling in characteristic pattern.

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Table 11.3 Diagnostic criteria of Behçet’s disease.

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1. Major symptoms 1 Recurrent aphthous ulceration in the oral mucosa 2 Cutaneous symptoms (a) Erythema-nodosum-like skin lesions (b) Subcutaneous thrombophlebitis (c) Folliculitis-like eruptions, acne-like eruptions; helpful finding: enhanced sensitivity of skin 3 Ocular symptoms (a) Iridocyclitis (b) Retinouveitis (chorioretinitis) (c) Symptoms that suggest past occurrence of (a) and (b), such as posterior synechia of the iris, pigmentation on the lens, chorioretinal atrophy, optic atrophy, complicated cataract, secondary glaucoma, or phthisis of the eyeballs 4 Genital ulceration 2. Minor symptoms 1 Arthritis that is not accompanied by articular deformity or rigidity, 2 Epididymitis, 3 Gastrointestinal lesions such as ileocecal ulcer, 4 Vascular lesions, 5 Moderate or severe central nervous symptoms 3. Diagnostic criteria for types of Behçet’s disease 1 Complete Behçet’s disease 4 major symptoms during the course of the disease 2 Incomplete Behçet’s disease (a) 3 major symptoms, or 2 major symptoms in combination with 2 minor symptoms (b) A typical ocular symptom in combination with another major symptom, or a typical ocular symptom in combination with 2 minor symptoms 3 Possible Behçet’s disease 1 or more major symptoms that do not meet the criteria for incomplete Behçet’s disease, and recurrence or aggravation of typical minor symptoms. 4 Rare symptoms of Behçet’s disease (a) Gastrointestinal Behçet’s disease: Abdominal pain should be investigated, and occult blood test should be conducted. (b) Vascular Behçet’s disease: Impairment in large arteries, small arteries, or both large and small veins is noted. (c) Neuro Behçet’s disease: headache, paralysis, and encephalomyelopathy. Investigation should be made for neurological symptoms. 4. Helpful laboratory findings (not essential for diagnosis) (1) Needle reaction of skin: negative/positive (2) Skin prick testing (SPT) using Streptococcus vaccine: negative/positive (3) Inflammatory response (enhanced ESR, serum CRP positive, increased WBC, and elevated complement titer） (4) HLA-B51(B5) positive From the Japan Intractable Diseases Information Center (http://www.nanbyou.or.jp/top.html).

and Welfare Ministry of Japan. Treatment Aspirin is administered orally, to prevent thrombus. Human immunoglobulin preparations given in large doses are effective in shrinking coronary artery aneurysm in the early stages (less than 7 days after onset).

3. Pyoderma gangrenosum Outline ● Small

pustules and papules rapidly appear to form ulcers with an elevated edge. These mostly occur in the lower body. ● The etiology is unknown. It is frequently associated with primary diseases such as chronic ulcerative colitis, aortitis syndrome and leukemia. ● Steroids and oral DDS are the main treatments. Clinical features Pyoderma gangrenosum occurs most commonly in the extremities, lumbar region, and abdomen of women from about age 10 to 60. The eruptions progress through four stages. In the first stage, blisters, pustules, and small hemorrhagic papules occur. In the second stage, many of them coalesce into ulcers that enlarge centrifugally. The periphery of the ulcer is elevated in a riverbank shape. The ulcers have undermined edges and are accompanied by palpable infiltration. The bottom of the ulcer contains brownish-yellow necrotic substances with mulberry pigmentation at the periphery. The ulcer is painful and secretes pus when pressed (Fig. 11.14). In the third stage, the center of the ulcer begins to heal and papillary granulation proliferates. In the fourth stage, the ulcer heals with scarring. The scars have the surface roughness of fabric. These eruptions recur chronically in a cycle of several months. Pathogenesis One theory is that vasculitis is the cause, with autoimmune response as the etiology. Another is that bacterial allergy is the cause. However, no definite cause has been identified. Injury, bruise, or skin biopsy may also induce pyoderma gangrenosum. Pathology Nonspecific neutrophilic infiltration and fibrin deposition are the major findings of pyoderma gangrenosum. Since necrotic vasculitis is not seen, it is thought that vasculitis is not involved. Complications Aortitis syndrome, ulcerative colitis, rheumatoid arthritis, leukemia, Crohn’s disease or IgA deficiency may appear as a

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complication. In pyoderma gangrenosum, various complications develop in 75% of cases. Laboratory findings, Diagnosis There are few specific diagnostic findings. As a result of inflammation, CRP is positive, the erythrocyte sedimentation rate is elevated, and there is an elevated level of neutrophils. As pyoderma gangrenosum is sterile pyoderma, bacteria are not detected in the lesions. Nevertheless, various bacteria are released by secondary infection during the course of pyoderma gangrenosum. Therefore, it is diagnosed by clinical features and complications. If pyoderma gangrenosum is suspected, there should be a thorough investigation for complications.

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Treatment Systemic administration of steroids and DDS are the main treatments. Pulse therapies of steroids or cyclophosphamide, and cyclosporine are administered in intractable cases.

4. Buerger’s disease

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Synonym: Thromboangiitis obliterans (TAO) Clinical features Buerger’s disease most commonly occurs in male smokers in their 20s or older. It is caused by arterial obstruction and contraction of small arteries, and contractive ischemia. At onset, Raynaud’s phenomenon appears; that is, the skin color changes from white to purplish blue or red and sharp pain occurs in distal fingers and toes, cool sensation in fingers occur, and cyanosis is observed. Over time, a minor injury may trigger ulceration in the fingers, toes and peripheral nails. When a relatively large artery in the extremities is affected, weakened arterial pulse, intermittent claudication, and pain during rest may occur. It is accompanied by migrating thrombophlebitis in 20% to 30% of cases (Fig. 11.15). a

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Pathogenesis Most patients with Buerger’s disease are male smokers; the disease is strongly associated with cigarette smoking.

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Laboratory findings Multiple segmental blockages are found in the main peripheral arteries of the lower extremities (popliteal arteries) by arteriography. Pathology a b c Thickening and inflammation are seen in the tunica intima of arterial walls in the medium-sized and large arteries. Accordingly, stenosis and blockage are caused by thrombosis. Necrotizing of the vascular walls does not occur.

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Fig. 11.14 Pyoderma gangrenosum. a: Ulcer with inflammation is seen (2nd stage). b: These ulcers are replaced by blood crusts and granulomatous tissue (3rd stage). c. The lesions heal with scarring (4th stage). d: 4th stage (scarring stage).

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Differential diagnosis Differentiation from arteriosclerosis obliterans is important. In general, Buerger’s disease is differentiated by the age of onset, sex and other factors (Table 11.4). Treatment Smoking should be discontinued immediately. It is important to keep the body warm, to maintain blood circulation in the affected sites, and to avoid external injury. Vasodilators, anticoagulants, and prostaglandins are administered. Revascularization or sympathetic nerve block is performed as a surgical treatment.

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5. Mondor disease

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Clinical features, Epidemiology Subcutaneous linear cord with a diameter of 3 mm to 10 mm appears on the chest, upper abdomen and upper extremities (Fig. 11.16). Mondor disease is usually characterized by obliterative phelebitis, and it most frequently occurs in women between the ages of 30 and 60. However, it may also occur in men at the root of the penis and in the coronal sulcus. The primary disease is thrombophlebitis or lymphangitis in the subcutaneous fat tissues. Iti is induced byk external chest, orr p q j l injury m or operation n oin the upper by infection. It may be accompanied by spontaneous pain. There may be some tenderness or discomfort, but there are often no symptoms until the patient discovers a red linear cord running from the lateral margin of the breast.

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Fig. 11.15 Buerger’s disease. a: Bluish discoloration (cyanosis) of the first toe. b: Progressive ulceration of the first toe. c: Necrosis of the first toe caused by impaired blood circulation.

Treatment The disease usually resolves naturally in several weeks. Clinical follow-up is fundamental.

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Table 11.4 Differential diagnosis of chronic arterial occlusive disease. Thromboangiitis Arteriosclerosis obliterans obliterans Age of onset

30 to 50 years

over 50 years

Most common site

Small arteries

Large or medium-sized arteries

Habits, complications

Smoking

Diabetes, hypertension, hyperlipidemia

Arteriosclerosis

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Mobile phlebitis

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6. Malignant atrophic papulosis Synonym: Degos’ disease Multiple rose-pink papules occur in the upper extremities. Several days after onset, they form peculiar eruptions with atrophy or telangiectasia at the center. Pathologically, lymphocytic infiltration is seen in the periphery of the blood vessels. Malignant atrophic papulosis has a poor prognosis, and it is known to cause cerebral infarction or perforative peritonitis several years after onset. Since eruptions that are pathologically similar to malignant atrophic papulosis are seen in SLE, systemic sclerosis, rheumatoid arthritis, dermatomyositis and Crohn’s disease, it is neces-

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sary to examine the eruptions thoroughly to determine whether there is an underlying disease. There is controversy over whether malignant atrophic papulosis is an independent disease.

7. Thrombophlebitis Concept Thrombophlebitis is a disease in which thrombi form in the small and deep veins as a result of various factors.

Clinical images are available in hardcopy only.

Pathogenesis Most cases of superficial venous inflammation treated by dermatologists result from damage to the veins by IV line placement, or from administration of vasodilators or antibiotics. Thrombophlebitis often develops in the lower extremities when there is infectious disease (e.g., tuberculosis), Behçet’s disease or chronic venous insufficiency including stasis varicose vain. Clinical features Thrombophlebitis occurs mostly where IV lines are placed and in the lower legs. Cord-like induration parallel to the veins occurs, accompanied by tenderness and itching. Reddening is often present. Ulceration may occur in severe cases. The lesion may change by the week depending on the pathogenesis. It may progress and recur. Diagnosis, Differential diagnosis Thrombophlebitis is easily diagnosed by the distinctive clinical symptoms. History-taking on drug administration and detection of Behçet’s disease and tuberculosis may be necessary. Particular care in differentiation should be taken for diseases in which there is linear cord, such as Mondor disease and gnathostomiasis.

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Fig. 11.16 Mondor disease. Subcutaneous, cordlike induration is observed.

Treatment Bed rest is most important, followed by cooling of the affected sites. NSAIDs are necessary in many cases. When the symptoms are severe, oral steroids may be administered.

Fig. 11.17 Histopathology of Mondor disease.

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Purpura 1. Thrombocytopenic purpura

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Definition, Classification Thrombocytopenic purpura is the general term for purpura that accompanies a decrease in platelet density. When that density is less than 100,000 per microliter, subcutaneous bleeding is easily produced by bruising. When it is less than 50,000 per microliter, bleeding becomes marked and causes purpura. Thrombocytopenic purpura is classified by pathogenesis into idiopathic thrombocytopenic purpura, which is caused by auto-antiplatelet antibodies; symptomatic thrombocytopenic purpura, which accompanies drug-induced purpura, leukemia, bone-marrow cancer, SLE, infectious diseases and DIC; and hereditary thrombocytopenic purpura, which accompanies Wiskott-Aldrich syndrome and Fanconi syndrome.

1) Idiopathic thrombocytopenic purpura (ITP) Clinical features Idiopathic thrombocytopenic purpura (ITP) occurs in children during recovery from infectious disease; in adults it develops without any particular pathogenesis. Its main symptoms are cutaneous petechia and ecchymosis, which are followed by bleeding in the oral mucosa, nasal mucosa and gingiva; hematuria; melena; and menorrhagia. Splenomegaly is not found. Pathogenesis Platelets are destroyed as a result of production of plateletassociated IgG (PAIgG), which leads to ITP. The mechanism of production of these autoantibodies is unknown. Pathology Decreased platelet density (100,000 per microliter or less) and an extended duration of bleeding (3 minutes or longer) are observed. PAIgG is found in the blood in more than 90% of cases. In a bone-marrow biopsy, the megakaryocyte count is found to be elevated from consumption of platelets. The coagulation system is normal; the prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen value are normal. Diagnosis, Differential diagnosis Bone-marrow biopsy and detection of PAIgG are essential for diagnosis. ITP should be differentiated from symptomatic or hereditary thrombocytopenic purpura listed below (Table 11.5). Henoch-Schönlein purpura and hemophilia are also differentiated

Purpura / 2. Cryoglobulinemic purpura

from ITP. Henoch-Schönlein is distinguished by relatively localized purpura in the lower extremities that results in systemic symptoms other than cutaneous symptoms, such as arthralgia and abdominal pain; hemophilia causes deep bleeding in the joints and elsewhere.

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Table 11.5 Causes of symptomatic thrombocytopenic purpura. Decreased productivity of platelets Disease

Aplastic anemia Paroxysmal nocturnal hemoglobinuria Leukemia, lymphoma, cancer invasion

Treatment Oral steroids are the treatment of choice. Immunoglobulin is administered in large doses for severe cases. Immunosuppressants and temporary platelet transfusion are also helpful. ITP subsides in 80% of cases by drug therapy. For chronic cases that do not respond to these treatments, splenectomy may be performed.

2) Symptomatic thrombocytopenic purpura Drugs, leukemia, metastasis of a malignant tumor in the bone marrow, SLE, viral infectious diseases, or vasculitis (KasabachMerritt syndrome; see Chapter 21) cause reduced production and enhanced consumption of platelets, leading to decrease of platelets and the onset of purpura (Table. 11.5).

Hereditary thrombocytopenia Causative Drugs, radiotherapy therapy Enhanced consumption and destruction of platelets

Disease

Diseases associated with collagen diseases Disseminated intravascular coagulation (DIC) Thrombotic thrombocytopenic purpura (TTP) Hemolytic-uremic syndrome (HUS) Viral infection

Causative Drugs, blood transfusion therapy

3) Hereditary thrombocytopenic purpura Wiskott-Aldrich syndrome (Chapter 7) and Fanconi anemia (congenital aplastic anemia accompanied by malformation) are classified as hereditary thrombocytopenic purpura.

2. Cryoglobulinemic purpura Clinical features Cryoglobulinemic purpura most frequently occurs in middleaged women. The purpura may be accompanied by petechia, hemorrhagic papules, ecchymosis and subcutaneous nodules. There may be necrosis. It occurs mostly on the lower legs, and may spread to the thighs, lumbar region, and lower abdomen; it seldom appears on the trunk or face. Raynaud’s phenomenon is found in fingers. The disease typically causes renal symptoms such as proteinuria, erythrocyturia, nephrosis syndrome, high blood pressure, acute or chronic renal failure, arthralgia, liver disorder and polyneuritis. Pathogenesis Cryoglobulinemic purpura is caused by an increase in the level of cryoglobulins in the blood. Infectious diseases (viral hepatitis in particular), multiple myeloma, macrogloblinemia, collagen diseases (e.g., SLE, rheumatoid arthritis) or malignant tumors may occur as complications. The elevated blood viscosity results in inadequate blood flow and in deposition of protein on the blood vessel walls to induce necrotizing vasculitis, which causes purpura. Cryoglobulinemic purpura may appear without a primary

MEMO Immunoglobulins (Ig) and similar substances (e.g., Bence-Jones protein) are the essential components of cryoglobulins. Cryoglobulins are heat-labile proteins (readily changing or denaturing at high temperatures) that precipitate at 37 ˚C or cooler and denature when the temperature exceeds 37 ˚C. Cryoglobulins are divided into three types. Type I: The main component is monoclonal Ig. It is observed in multiple myeloma and chronic lymphocytic leukemia. Type II: The main components are monoclonal Ig and polyclonal proteins. It is observed in collagen diseases and various infectious diseases. Type III: It is associated with polyclonal Ig and complements. It is observed in collagen diseases and various infectious diseases.

Cryoglobulin

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disease or known cause. Pathology Necrotizing vasculitis caused by cryoglobulin embolization in the lesion is found in the skin lesions of cryoglobulinemic purpura. However, when type I cryoglobulin is involved in the onset, vasculitis tends not to occur. Cryoglobulinemic purpura is characterized by membranoproliferative glomerulonephritis in the kidney. Clinical images are available in hardcopy only.

11

Laboratory findings Cryoglobulin is detected by processing the blood at 37 ˚C to isolate the serum. Rheumatoid factor and HBs antigen are often positive, and hypocomplementemia and hepatitis C virus antibodies may be found. M proteins in the serum and Bence-Jones proteins in the urine protein electrophoretogram may be observed. Treatment Systemic administration of steroids and removal and inhibited reproduction of cryoglobulin by plasma exchange therapy are the main treatments. Any underlying diseases are treated.

3. Pigmented purpuric dermatoses Synonyms: Idiopathic pigmentary purpura, Purpura simplex, Chronic capillaritis, Purpura pigmentosa chronica

Clinical images are available in hardcopy only.

Clinical features, Classification Pigmented purpuric dermatoses occur most frequently in the lower extremities of middle-aged men. They are characterized by orange/brown pigmentation (from hemosiderin deposition) that Table 11.6 Differential diagnosis of pigmented purpuric dermatoses. Schamberg’s disease

Clinical images are available in hardcopy only.

Pigmented purpuric lichenoid dermatosis of Gougerot-Blum

Sex distribution

Slightly more More common Slightly more in men common in women common in men

Age of onset (yrs.)

20 to 59

30 to 49

30 to 49

Rate of Onset Gradual

Gradual

Rather acute

Most common site

Lower legs

Lower legs

Upper and lower extremities, trunk

Symptom

Irregular Enlargement of coalescence of petechiae, petechiae formation of circular lesion

Venous congestion

Fig. 11.18 Pigmented purpuric dermatoses.

Majocchi’s disease

Pigmentation Itching

Hemorrhagic brown papules, aggregated coalescence of lichenified papules

＋

＋ (sporadic)

−

＋＋

＋

＋

−/＋ (mild)

−

＋

Purpura / 5. Steroid purpura

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occurs after the onset of petechia. Pigmentation shows both clinical and histological features. There are no significant systemic symptoms (Fig. 11.18). These dermatoses are classified by distribution of eruptions into three main types: Majocchi’s disease, Schamberg’s disease, and pigmented purpuric lichenoid dermatosis of Gougerot-Blum. However, the main three types are the same in essential (Table 11.6). Pathogenesis The etiology is unknown; however, there may be the involvement of venous circulatory disorder, focal infection, or druginduced factor. Pathology Lymphocytic infiltration, vascular dilatation, and bleeding are found in the perivascular area in the upper dermal layer. Idiopathic pigmentary purpura is chronic hemorrhagic inflammation. Hemosiderin deposits are seen in old lesions (Fig. 11.19). Treatment Topical application of steroids and bed rest with the lower extremities raised is the main treatment. Agents to reinforce the blood vessels (e.g., vitamin C) are administered, as are hemostatic and antiplasmin agents.

4. Senile purpura

Fig. 11.19 Histopathology of pigmented purpuric dermatoses. Perivascular lymphocytic infiltration in the upper dermis and deposition of hemosiderin.

Clinical images are available in hardcopy only.

The vascular supporting tissues weaken from age, and purpura is easily caused even by stimulation so light the patient can scarcely feel it. Senile purpura occurs mostly in the dorsal hands and the extensor surface of forearms, producing sharply margined subcutaneous hemorrhagic spots.

Fig. 11.20 Steroid purpura.

5. Steroid purpura When the vascular supporting tissues are weakened by prolonged topical or oral use of steroids, the capillary blood vessels are readily broken by mechanical stimulation, leading to purpura (Fig. 11.20). Steroid purpura occurs most frequently in the elderly. Mechanical stimulation should be avoided, and steroids should be used appropriately.

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Other vascular diseases 1. Arteriosclerosis obliterans (ASO) Clinical images are available in hardcopy only.

11 Clinical images are available in hardcopy only.

Fig. 11.21 Raynaud’s phenomenon.

Concept As a result of arteriosclerosis in the extremities, distal ischemia, skin pallor, pain and ulceration occur. The patients often have diabetes and high blood pressure as primary diseases. Clinical features Symptoms caused by ischemia and poor circulation appear. The Fontaine classification of arteriosclerosis obliterans (ASO) is well known: In Grade I, a cooling sensation appears at the ends of the extremities and there is mild numbness; in Grade II, there is intermittent claudication (inability to walk more than a certain distance); in Grade III, there is pain even during bed rest; and in Grade IV, ulceration or necrosis occurs at the ends of the extremities, which are prone to ulceration. The lesion becomes enlarged and white or purplish-red from ischemia. Pulse in the peripheral arteries in the lesion is impalpable. Diagnosis, Differential diagnosis Pain and ulceration are present at the ends of the extremities in both Buerger’s disease and ASO; nevertheless, Buerger’s disease occurs mostly in young male smokers. Pulse is often palpable in Buerger’s disease (Table 11.4). Lumbar spinal canal stenosis is also known to cause intermittent claudication. Treatment Conservative therapies using vasodilators and thrombosis inhibitors, and physical therapies such as exercise and hot spring bathing are the main treatments for mild symptoms of Fontaine Grades I and II. For severe cases of ASO, surgical treatments such as stent placement and revascularization are performed. Amputation of the extremities may be necessary at the terminal stages.

2. Diabetic gangrene With a microvascular disorder or arterial sclerosis as the primary disease, ulcers form in toes, soles and fingers. They are accompanied by sharp pain (Chapter 17).

3. Raynaud’s phenomenon Synonym: Raynaud’s disease Definition Fingers and toes suddenly become bluish. After several min-

Other vascular diseases / 4. Stasis dermatitis

utes, they progress to a purplish-dark-blue hue from cyanosis and then return to normal color through a diffuse flushing phase. Raynaud’s phenomenon may be induced by frigidity without a primary disease (primary Raynaud’s phenomenon), or it may accompany a primary disease, such as a collagen disease, particularly systemic sclerosis (Raynaud’s syndrome, secondary Raynaud’s phenomenon). Clinical features Fingers and toes become white and there is a cool sensation, sharp pain, numbness, edematous sensation, and hypoesthesia (Fig. 11.21). Cyanosis heals with a diffuse flushing and burning sensation. The ends of the extremities are constantly cold, with or without an attack. Pathogenesis The potential causes of Raynaud’s phenomenon are shown in Table 11.7. Circulatory disorders are closely associated with it. A bluish tinge is caused by reduced blood flow resulting from arterial constriction. Cyanosis results from dilation of capillaries or small veins and stasis. Diffuse flushing occurs as reactive congestion.

157

Table 11.7 Causes of Raynaud’s phenomenon. Disease, Causes Primary Raynaud’s disease Raynaud’s phenomenon Secondary Physical stimulation in people who Raynaud’s work with vibrating machinery phenomenon (vibration syndrome or vibration white finger), pianists, typists, and food industry workers （meat industry, fresh fish industry） Drugs: ergotamine, tryptamine, bblockers, oral contraceptives Collagen diseases: e.g., mixed connective tissue disease (MCTD), systemic sclerosis (SSc) Blood disease: cryoglobulinemia, cold agglutinin disease Neurovascular disorders: arteriosclerosis, Buerger’s disease, thromboembolism, thoracic outlet syndrome Other diseases: malignant tumor, hypothyroidism

Examination Antinuclear antibody test is performed to rule out the involvement of secondary Raynaud’s phenomenon. Other useful tests for Raynaud’s phenomenon are a cold provocation test (soaking fingers and toes in 4˚C water for 10 seconds) and thermography. Treatment Causative factors should be eliminated, and the body must be kept warm. A vasodilator (calcium channel antagonists are the first choice), prostaglandins, or sympatholytic agents are applied. Smoking cessation is effective.

4. Stasis dermatitis Synonym: Chronic venous insufficiency (CVI) Clinical features Stasis dermatitis usually occurs in the medial aspects of the lower legs or ankles of obese elderly women, but it may be widespread. It may develop as a complication of impaired venous return from the lower legs. Superficial varicose veins are a frequent predisposing factor. These lesions are often seen around chronic stasis ulcers, and they are itchy, scaly, often swollen, and hyperpigmented. Superficial veins of the lower legs including the greater saphenous veins and lesser saphenous veins enlarge in hose shape, nodular shape, or saclike shape and take on a serpentine appearance. The skin surface appears dark blue (varicose veins in lower legs, Fig. 11.22). As the varicosity progresses, subjective symptoms appear. Fatigue of the lower extremities,

Clinical images are available in hardcopy only.

Fig. 11.22 Varicose veins. Superficial veins of lower legs enlarge in serpentine, nodular or cystiform patterns.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

sharp pain, edema, pigmentation, eczematous lesions and skin induration (sclerosing panniculitis) occur. In the last stages, a minor external injury in the lower legs may induce ulceration. Stasis dermatitis shows the epithelial changes of spongiotic dermatitis and a characteristic lobular pattern of superficial and/or deep dermal neovascularization. Pathogenesis The pressure in the superficial veins is elevated, and veins are dilated and serpentine from congenital fragility of the venous walls and venous peripheral supporting tissues, stenosis and obstruction of deep veins, hyperplasia of superficial veins, pregnancy, standing for long periods, and venous valve dysfunction.

Clinical images are available in hardcopy only.

11

Clinical images are available in hardcopy only.

Diagnosis Stasis syndrome is easily diagnosed by varicosity. History-taking on occupation and pregnancy is helpful. When surgical treatment is conducted, venography is also performed. Treatment Standing or walking for long periods should be avoided. The patients should be protected from extrinsic injury and infection, and they should keep the lower extremities elevated and use elastic bandages. When the condition progresses to stasis syndrome, besides these treatments, topical steroids, oral antihistamines, and vasodilator drugs are administered. Surgical therapy including removal of the superficial vein, ligation and sclerotherapy may also be performed.

5. Livedo reticularis Fig. 11.23 Livedo.

Livedo reticularis is a generic term for purplish-red to purplish-black discoloration with a characteristic network pattern caused by stenosis in the veins of the dermis and subcutaneous fat tissue junctions (Fig. 11.23). Although it can be divided into several subtypes, the classification is not standardized. The color deepens with exposure to cold. The condition is largely divided Table 11.8 Livedo (reticularis).

Clinical images are available in hardcopy only.

Cause

Symptoms and diseases

Physiological Cutis marmorata (without an underlying disease) Secondary

Thromboembolism: e.g., cholesterol embolism, cryoglobulinemia Impairment in blood circulation: e.g., heart failure Disorders in vessel walls: vasculitis (polyarteritis nodosa) Systemic diseases: collagen diseases (e.g., rheumatoid arthritis, SLE). Infectious diseases (syphilis, tuberculosis)

Fig. 11.24-1 Lymphedema. Marked swelling occurrs secondarily in the lower leg.

Pancreatitis, lymphoma, hyperparathyroidism, hypercalcemia Unknown

Livedo accompanied by ulceration (livedo reticularis with summer/winter ulceration), Sneddon’s syndrome

Other vascular diseases / 8. Lymphedema

into cutis marmorata, in which there is no particular primary disease, and secondary livedo reticularis, in which there is a primary disease such as collagen disease. The former transiently appears in infants and adult women without subjective symptoms and disappears when the body warms. The sympathetic nerve is thought to be involved. Livedo that is found at birth and that is often accompanied by combined malformation is thought to be caused by angioma-like abnormality; this condition is called cutis marmorata telangiectasia congenita (Chapter 21). When cutis marmorata occurs intermittently, the involvement of underlying diseases such as blockage of vascular cavity, circulatory disorder or vascular disorder is suspected (Table 11.8).

159

Clinical images are available in hardcopy only.

Fig. 11.24-2 Lymphedema. A skin lesion with extremely hypertrophic changes resembles elephant skin.

6. Erythromelalgia Synonym: Erythralgia Erythromelalgia occurs in the extremities. It is characterized by three main symptoms: paroxysmal burning sensation, flushing and skin temperature increase. The pathogenesis is unknown. It is extremely painful and tends to appear when the body is warmed by exercise or bathing. It may also be caused by a primary disease such as erythrocytosis, primary thrombocytosis, or collagen disease.

Erythema ab igne, Thermal burn

MEMO

These are livedo caused by repeated heat exposure at the same site for a long period of time. Vasculitis is not found pathologically; however, livedo-like eruptions are present.

7. Lymphangitis Concept, Pathogenesis Lymphangitis is an inflammatory change in the lymphatic vessels, usually those in the extremities. The spread of various infections (e.g., various secondary infections, cellulitis, trichophytic infection), malignant tumor (e.g., breast cancer), and parasitic infestation (e.g., filariasis) are known to cause lymphangitis.

Clinical images are available in hardcopy only.

Clinical features Painful, linear, soft, palpable, cord-like reddening accompanied by tenderness occurs in the primary lesion and the nerve area. Systemic symptoms such as fever (may reach 40˚C), fatigue, and poor appetite are seen in many cases. As chronic lymphangitis recurs, lymphatic vessels become obstructed, which may result in lymphatic edema or elephantiasis. Treatment Antibiotics and analgesic drugs should be promptly applied systemically. In the event that an abscess forms, an incision may be required.

8. Lymphedema Lymph fluid volume increases locally from lymphatic vessel dysfunction. Soft edema is often produced in the lower extremities

Clinical images are available in hardcopy only.

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Symmetrical lividity of the MEMO soles This is edematous erythema produced in the footpad and sides of the feet in young people. It is associated with hyperhidrosis.

and it gradually moves upwards. Soft tissues become fibrotic or stiff. Papillary thickening of the epidermis and follicular dilation are seen in the terminal stages (Figs. 11.24-1 and 11.24-2). The causes of lymphatic vessel dysfunction are largely divided into congenital (e.g., hypoplasia of lymphatic vessels) and acquired (e.g., metastasis of a tumor into a lymph node, lymph node dissection, filariasis, deep-lying thrombophlebitis).

9. Ataxia telangiectasia (AT) Clinical images are available in hardcopy only.

Synonym: Louis-Bar syndrome Outline ● AT

11 Clinical images are available in hardcopy only.

is an autosomal recessively inherited disease involving functional abnormality of the DNA repair mechanism. ● The three main symptoms are progressive cerebellar ataxia, telangiectasia in the auricular region and bulbar conjunctiva, and T-cell immunodeficiency. ● IgA deficiency and high a-fetoprotein level are found in the serum. Clinical features Telangiectasia in the skin and bulbar conjunctiva occurs in patients 4 to 6 years old, and it extends to the auricular region, eyelids, cheeks and extremities. Ataxia telangiectasia (AT) may produce lesions that resemble xeroderma pigmentosum. As the patients age, severe bronchiectasis and malignant lymphoma occur as complications. Pathogenesis Disconnection or translocation of the AT gene on chromosome 11 (11q22.3) influences T cells and the Ig gene region, leading to T-cell immunodeficiency and decreased production of immunoglobulin. Pathology Peripheral blood T cells are reduced in number and function, and serum IgA and IgE (sometimes IgG2 and IgG4) are absent or markedly reduced. The serum a-fetoprotein value is elevated. Brain CT and MRI show significant atrophy in the cerebellar vermis. Histopathologically, denaturation of Purkinje cells is observed. Diagnosis AT is diagnosed by the pathological symptoms and laboratory findings. Diagnosis can also be made by AT gene analysis. Treatment Symptomatic therapy is the main treatment.

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Collagen Diseases

Collagen diseases share certain similarities with autoimmune diseases, because autoantibodies specific to each collagen disease are produced. Multiple organs may be affected, and the site of the main lesion often differs from case to case: Diagnosis of collagen diseases is mainly based on the criteria established by the American College of Rheumatology, which include cutaneous lesions. Dermatologists play an important role in diagnosing and treating collagen diseases.

A. Lupus erythematosus (LE) Definition, Classification Lupus erythematosus (LE) is a diagnostic name for diseases that cause various systemic changes including those in the skin, such as systemic lupus erythematosus (SLE) and neonatal lupus erythematosus. The term is also used for localized cutaneous lesions such as those seen in discoid lupus erythematosus (DLE), lupus erythematosus profundus and subacute cutaneous lupus erythematosus. Cutaneous LE is subcategorized as acute, subacute or chronic, with each subcategory having characteristic features (Table 12.1). Since acute LE usually occurs as a manifestation of SLE, it is discussed in the SLE section. Subacute (cutaneous) LE and chronic LE are usually localized on skin, and most cases do not meet the diagnostic criteria of SLE. These two diseases are discussed in another section of this chapter.

12 Clinical images are available in hardcopy only.

g

h

g b c d e f h Fig. 12.1-1 Systemic lupus erythematosus (SLE). a: Butterfly-shaped erythema and edematous erythema that is symmetrically spread from the dorsum of nose to the cheeks of a young woman in her teens. The skin lesion does not usually spread to the nasolabial groove and lips. b: “Butterfly rash” from the recurrence of SLE in a woman in her thirties. As SLE worsens, such rashes may recur.

i

a

b

c

d

e

f

1. Systemic lupus erythematosus (SLE) Clinical images are available in hardcopy only.

Outline ● Multiple

organ failure occurs. The kidneys, heart, joints and central nervous system are affected. SLE is an autoimmune disease whose cause is unknown. Young women are most commonly affected. ● Typical mucocutaneous manifestations are butterfly rash, a

Table 12.1 Lesions of cutaneous lupus erythematosus. Acute

Progresses in a few days Butterfly rush, alopecia, palmar erythema, aphtha

Subacute Progresses in a few weeks to a few months (SCLE) Chronic

Papulosquamous and annular-polycyclic lesions Progresses over a long period of time DLE, lupus panniculitis, lupus profundus, nodular cutaneous lupus mucinosis

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DLE, oral ulceration, solar photosensitivity and alopecia. laboratory findings are antinuclear antibody positive, anti-dsDNA antibody positive, anti-Sm antibody positive, LE cell positive, biological false positive serological reaction for syphilis, decreased complements, and pancytopenia. ● The diagnostic criteria are those published by the American College of Rheumatology. ● The main treatment is oral corticosteroids. ● The

Clinical images are available in hardcopy only.

Epidemiology The onset tends to be between the ages of 10 and 30. Women outnumber men 10 to 1. Therefore, the majority of patients are women of childbearing age.

b

c

d

e

f

g

h

i

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Clinical images are available in hardcopy only.

c

d

e

f

g

h

i

j

Clinical images are available in hardcopy only.

d

e

f

g

h

i

j

k

Fig. 12.1-2 Systemic lupus erythematosus (SLE). c: Skin lesion on fingers caused by discoid lupus erythematosus. Tenderness may be present. d: Diffuse erythema on the sole and toes. e: A large ulcer in the pharyngeal region. Large oral mucosal ulcers may be caused by SLE.

Cutaneous features Various cutaneous findings are observed in more than 80% of cases. The of oSLE, which are in p q included j k fourl mainmsymptoms n r the diagnostic criteria (Table 12.2), are erythema on the cheeks, chronic DLE, oral ulcers and photosensitivity (Figs. 12.1-1 to 12.1-3). The frequencies of occurrence of various symptoms in SLE are listed in Fig. 12.2. Erythema on the cheeks (Fig. 12-1-1): Also called butterfly rash, this is the most characteristic eruption. It is seen in about 90% of cases. Edematous erythema spreads symmetrically on cheeks with the dorsal nose at the center, forming a butterfly pattern. Generally, it does not extend beneath the nasolabial groove. The margin of the erythema is relatively distinct, with slight elevation. Blistering present. The p patients q are rasymptomatic k l m is rarely n o or have mild subjective symptoms, such as a slight burning sensation. It heals without scarring. DLE: Discoid lupus erythematosus is sharply margined discoidal erythema. It is seen in 30% of patients with SLE, occurring on exposed sites such as the face, lips and ears. Scales and crusts often form. It gradually progresses into scarring atrophic lesions and causes alopecia when the scalp is affected (described later). Palmar erythema: This is seen in about 50% of SLE cases. Diffuse erythema occurs on the palms, the thenar and hypothenar in particular. The lesions are hyperkeratotic and often accompanied by scales. Alopecia: It occurs rapidly and diffusely in the head hair. The occurrence of short, thin, broken hairs at the front edge of the scalp results in uneven hair length (lupus hair). The severity of the alopecia is considered to reflect the degree of SLE progression. p q l m n o r Enanthema: This is seen in about 40% of SLE cases. Small hemorrhagic lesions with a red halo and small ulcers appear on the lips, oral mucosa, pharynx and pharyngeal mucosa. They may be found in DLE of the mucous membranes. Subcutaneous nodules: Nodules form on the face, hips and upper arms. This is from inflammation of fat tissue, also called

163

A. Lupus erythematosus Table 12.2 1982 Revised criteria for classification of systemic lupus erythematosus. Criterion

Definition

1. Malar rash

Fixed erythema, flat or raised, over the malar eminences, but tending not to appear on the nasolabial folds

2. Discoid rash

Raised erythematous patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions

3. Photosensitivity Skin rash from unusual reaction to sunlight, revealed by patient history or physician observation 4. Oral ulcers

Oral or nasopharyngeal ulceration, usually painless, observed by physician

5. Arthritis

Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling or effusion

6. Serositis

a) Pleuritis ―convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion OR b) Pericarditis ―documented by ECG or rub or by evidence of pericardial effusion

7. Renal disorder

a) Persistent proteinuria greater than 0.5 g per day or greater than 3+ if quantitation is not performed OR a red cells, b hemoglobin, c d e b) Cellular casts ―may be granules, tubules or mixed

8. Neurologic disorder

a) Seizures―in the absence of causative drugs or known metabolic disorder (e.g., uremia, ketoacidosis, electrolyte imbalance) OR b) Psychosis ―in the absence of causative drugs or known metabolic disorder (e.g., uremia, ketoacidosis, electrolyte imbalance)

9. Hematologic disorder

a) Hemolytic anemia ―with reticulocytosis OR b) Leukopenia ―less than 4,000/mm3 total on 2 or more occasions OR c) Lymphopenia―less than 1,500/mm3 on 2 or more occasions OR d) Thrombocytopenia―less than 100,000/mm3 in the absence of causative drugs

10. Immunologic disorder

11. Antinuclear antibody

a) Positive LE cell preparation OR b) Anti-DNA: antibody to native DNA in abnormal titer OR c) Anti-Sm: presence of antibody to Sm nuclear antigen OR d) False positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome

The proposed classification is based on 11 criteria. For clinical studies, a person is said to have systemic lupus erythematosus if any 4 of the 11 criteria are present, serially or simultaneously at any time during observation (Tan EM, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7).

lupus erythematosus profundus (described later). Other cutaneous symptoms: These include palmoplantar keratosis, purpura, Raynaud’s phenomenon, erythema multiforme, and ulcers in the extremities.

Clinical images are available in hardcopy only.

f

g

h

j

i

k

l

Fig. 12.1-3 Systemic lupus erythematosus (SLE). f: Diffuse alopecia caused by SLE. In this case, discoid lupus erythematosus (DLE) is present on the sites with alopecia.

malar rash

72

Raynaud’s phenomenon

51

alopecia

51

hyperesthesia optica

43 41

oral ulcer 16

discoid rash 0

20

40

60

80％ 89

arthritis fever

78

lymphocytopenia

73

skin lesion

72 65

leukocytopenia thrombocytopenia neurologic disorder proteinuria hemolytic anemia pleuritis

29 20 17 12 10

seizure

8

pericarditis

7 5

coma 0

20

40

60

80

100％

Fig. 12.2 Main eruptions caused by systemic lupus erythematosus (SLE) and their frequency (% of cases). (Hashimoto H, Miyamoto A, editors. Systemic lupus erythematosus. Clinical allergology. 2nd ed. Nankodo; 1998).

m

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Table 12.3 Factors associated with onset of SLE. Factor

Finding

Genetic

Familial prevalence, especially in monozygotic twins

Type C viral particles are detected in the SLE Viral infection patient’s kidney, skin and lymph nodes. The virus is persistent and forms an immunocomplex, resulting in onset of SLE. SLE frequently occurs in women of Sex hormone child-bearing age. Endogenous estrogens and androgens are associated with the onset of SLE. The SLE symptoms in model mice are improved by androgen.

12

Extrinsic Procainamide, hydralazine, isoniazid, hydantoins and other drugs may cause skin/systemic symptoms and serological findings that are similar to those of SLE. If these symptoms are improved by discontinuation of these drugs, the condition is called drug-induced lupus. Otherwise these symptoms are thought to be idiopathic SLE that was triggered by drugs.

Fig. 12.3 Lupus band test. Normal skin in the unexposed area of a patient with SLE, observed by direct immunofluorescnce. There is linear deposition of IgG (fluorescent green) in the epidermal basement membrane. The nuclei stain orange.

Differences between SLE MEMO and DLE SLE is the diagnostic name of a condition in which various lesions appear on the whole body. DLE and LE profundus are the diagnostic names of eruptions. Therefore, DLE and LE profundus may occur in patients with SLE, or they may occur without underlying diseases associated with SLE.

MEMO Nuclear proteins that are soluble in a buffer solution are called extractable nuclear antigens (ENA). Anti-ENA antibodies include anti-RNP antibodies, anti-Sm antibodies, antiSS-A antibodies, and anti-SS-B antibodies.

Anti-ENA antibody

Systemic symptoms The symptoms of SLE are significantly various (Fig. 12.2). The onset is an attack of fever, systemic fatigue, arthralgia and edema, accompanied by the cutaneous symptoms described above. Renal symptoms: Lupus nephritis is the most critical lesion. It relates closely to the prognosis. It affects various sites and causes proteinurea, hematuria, nephrosis syndrome and renal failure. Arthralgia: This is seen in more than 90% of SLE cases. Multiple or single arthralgia occurs, transiently in many cases. Proximal interphalangeal joints, knees, legs, shoulders and elbow joints are most frequently affected. Cardiac symptoms: Libman-Sacks endocarditis, pericardiac inflammation and cardiac tamponade occur. Mental and neurological symptoms: Central nervous system (CNS) manifestations such as convulsions, impaired consciousness, depression, schizophrenia-like symptoms or cognitive deficit occur in about 20% of cases during the acute active period. It may be difficult to differentiate CNS lupus from similar symptoms caused as side effects by corticosteroids. Blood abnormalities: Hemolytic anemia (mostly autoimmune hemolytic anemia), leukocytopenia and thrombocytopenia are present. Pathogenesis Hereditary predisposition, viral infection, sex hormones and other factors are thought to interact in complex ways to cause immune abnormality and SLE. However, the pathogenesis has not been identified (Table 12.3). It is known that antinuclear antibodies, anti-DNA antibodies and anti-Sm antibodies are produced and destroy tissues directly (type II allergy) or form immunocomplexes to destroy tissues by complement cascades (type III allergy), which results in inflammation in the systemic internal organs. Complications SLE may present symptoms that meet the diagnostic criteria for collagen diseases such as rheumatoid arthritis, scleroderma, Sjögren syndrome and dermatomyositis (overlap syndrome). Viral infection, such as by herpes zoster, and mycotic infection result from decreased cellular immunity. Pathology Pathological findings are various, and each eruption presents different cutaneous clinical features depending on its stage. Cutaneous atrophy, keratotic plug formation, vacuolar degeneration, edema in the upper dermis, mucin deposition, and perivascular and periadnexal inflammatory infiltration of lymphocytes are found. IgG, IgM and C3 may be found deposited in the basement membrane zone of eruptions in unexposed normal-looking skin, which can be identified by skin biopsy and immunofluorescence

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A. Lupus erythematosus

(lupus band test; Fig. 12.3). Laboratory findings Anemia, leukocytopenia, lymphocytopenia and thrombocytopenia are found. The erythrocyte sedimentation rate is elevated as a result of the systemic inflammation; however, CRP is only slightly increased. human immunoglobulins and IgG increase and complements (C3, C4, and CH50) decrease. SLE is an autoimmune disease; various autoantibodies, such as anti-nuclear antibodies, anti-DNA antibodies (especially antidouble-stranded DNA antibodies; dsDNA) and anti-ENA antibodies are detected in the serum. When antiphospholipid antibodies are positive, biological false positive (BFP) is observed in serological reaction for syphilis. Diagnosis Skin biopsy and direct immunofluorescence (IF) are necessary for diagnosis. The diagnosis of SLE can be made when four or more of the 11 diagnostic criteria are satisfied (Table 12.2). Even when four criteria are not met simultaneously, the other symp-a toms often appear later. Therefore, careful observation is required.

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2. Discoid lupus erythematosus (DLE) Definition Discoid lupus erythematosus (DLE) is the name of an eruption, whereas SLE is the name of a clinical condition with systemic involvement. Some but not all patients with DLE may meet the criteria for SLE. In other words, in many cases of DLE, the skin is the only organ involved. Patients with SLE may have

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Treatment The primary treatment is administration of immunosuppressants such as steroids, cyclophosphamides, azathioprines and cyclosporines. Steroid pulse therapy may be performed in intractable cases. Psychiatric treatments are also conducted for CNS lupus. Lifestyle guidance is important; stress caused by direct sunlight exposure, over-fatigue or the cold should be avoided as much as possible. It is known that SLE tends to become aggravated during pregnancy. Prognosis SLE progresses chronically with repeated aggravation and remission. It used to have great influence on the prognosis of renal disorders. However, the mortality rate has been reduced by dissemination of dialysis therapy (the 5-year survival rate a nowb exceeds 90%). The number of deaths from central nervous system damage and cardiac failure has been increasing. Infection resulting from steroid treatment can be fatal.

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Fig. 12.4-1 Discoid lupus erythematosus (DLE). a: The affected dorsal nose of a man in his 20s. The skin lesion is a sharply demarcated macule with a reddish-pink center. The periphery is brownish and accompanied by scaling. b: A sharply margined skin lesion accompanied by dilated hair follicles on the cheek of a woman in her twenties. The lesion is partly erosive. c: A skin lesion spread on the whole of the right cheek of a woman in her thirties. Multiple DLE eruptions of 1 cm in diameter occur and gradually enlarge or coalesce into large plaques.

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DLE eruptions.

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g j e f h i k Fig. 12.4-2 Discoid lupus erythematosus (DLE). d: DLE on the lips. Erythema and purple eruptions are present. It should be differentiated from lichen planus. DLE of the lips may induce squamous cell carcinoma. e: DLE on the dorsum of hand and fingers. There are thick scales and thickening of the skin.

Clinical features Multiple, round to oval, sharply demarcated rose-pink lesions accompanied by scaling and follicular dilation occur on sunexposed sites (Figs. 12.4-1 and 12.4-2). These tend to occur on the face, scalp and auricular region and, rarely, as individual eruptions Scaling and ulcerative p q k l at sites m lower n than o the neck. r lesions may occur on the lips of the mouth. When DLE is produced in the head region, scarring alopecia may result from the destruction of hair follicles. These eruptions are aggravated by sun exposure, and they heal with scarring and pigmentation at the center. Multiple DLE eruptions that occur at sites lower than the neck region are called widespread DLE (Fig. 12.5), and these may progress to SLE accompanied by systemic symptoms. Pathology findings pare ① qformation l The characteristic m n o r of horny follicular plugs, ② flat atrophy of the epidermis, ③ vacuolar degeneration of the basal layer, ④ dense focal infiltration in the periphery of the appendages and blood vessels, and ⑤ mucin deposition in the dermis (Fig. 12.6). Linear deposition of immunoglobulins is found in the skin basement membranes of the lesion in most cases (lupus band test is positive; Fig. 12.3). Laboratory findings Lesions tend not to occur in organs other than the skin. General laboratory findings are normal. However, in some cases (widespread DLE in particular), antinuclear antibodies and anti-DNA antibodies may appear, accompanied by hypocomplementemia with progression to SLE.

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Table 12.4 Differential diagnosis between DLE and SLE. Patients with DLE eruption only Difference between sexes Almost none

SLE patients with DLE eruption Women outnumber men

Common site of eruption The face, head and auricles The whole body surface Clinical features of eruption

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Fig. 12.5 Widespread discoid lupus erythematosus (DLE). Large areas on the trunk and arms are involved.

Poor, sometimes fatal

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Differential diagnosis Patients with DLE eruptions only are compared to those with SLE accompanied by DLE eruptions in Table 12.4. Other eruptions that should be distinguished from DLE are polymorphous light eruptions, lichen planus and cutaneous sarcoidosis. Treatment Patients with DLE should avoid sunlight, which tends to aggravate the condition. Topical application of steroids and tacrolimus are effective.

3. Lupus erythematosus profundus Synonym: Lupus panniculitis Definition Lupus erythematosus (LE) profundus is a subtype with major lesions in the subcutaneous tissues. It is characterized by nonspecific inflammation of fat tissue. Clinical features Lesions occur as subcutaneous induration of normal color or rose pink, most frequently on the face, shoulders and hips (Fig. 12.7). DLE may be produced at sites with those lesions. Concave lesions may form in the course of LE profundus, and these heal with concave scarring. LE profundus may occur independently; however, more than half of all cases are accompanied by SLE and DLE. Pathology Perivascular infiltration of lymphocytes, mucin deposition and dense lymphocytic infiltration are found in the subcutaneous tissues. Interlobular inflammation gradually becomes fibrotic. Deposition of immunoglobulins and complements may be seen on the blood vessel walls and at dermo-epidermal junctions. Treatment Topical or oral corticosteroids are the main treatments.

4. Subacute cutaneous lupus erythematosus (SCLE) Definition Subacute cutaneous lupus erythematosus (SCLE) is characterized by eruptions whose course and duration are intermediate between those of chronic DLE and those of the acute LE seen in SLE. Clinical features Multiple eruptions appear symmetrically on sun-exposed sites

Fig. 12.6 Histopathology of discoid lupus erythematosus (DLE). There is vacuolar degeneration in the basal cell layer, lymphocytic infiltration in the blood vessels and peripheral skin appendages, and severe edema and mucin deposition in the dermis. Neutrophils and eosinophils are rarely seen.

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Fig. 12.7 Lupus erythematosus profundus. Large panniculitis in the skin of a patient with SLE. DLE eruptions are present on the skin surface.

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of the body. There are two types of SCLE: annular-polycyclic SCLE, with erythema whose center tends to have color degradation (Fig. 12.8), and papulosquamous (psoriasiform) SCLE, with eruptions resembling psoriasis. Both types heal without scarring and are recurrent. About half of patients with SCLE meet the diagnostic criteria of SLE. The disease may be accompanied by mild systemic symptoms, such as arthralgia and fever. Severe renal symptoms and central nervous system manifestations are rare.

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Characteristic findings of lupus erythematosus include epidermal atrophy, vacuolar degeneration in the basal layers, and perivascular and adnexal lymphocytic infiltration. Laboratory findings Antinuclear antibodies are positive in more than half of all cases. Since anti-SS-A antibodies and anti-SS-B antibodies are frequently found, a correlation has been reported between SCLE and HLA-B8 or HLA-DR3.

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Treatment The main treatments are corticosteroids applied topically or administered orally in small doses.

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Fig. 12.8 Subacute cutaneous lupus erythematosus (SCLE). a: Annular polycyclic SCLE on the back. The center of the lesion is healing centrifugally. This condition resembles the annular erythema of Sjögren syndrome. b: Papulosquamous SCLE. Psoriasis-like papules and scaling are present.

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g a b c d e f Fig. 12.9-1 Annular erythema in neonatal lupus erythematosus. a: Annular erythema on the cheek of an infant with neonatal lupus erythematosus. It begins as erythema of 5 mm to 10 mm in diameter and gradually enlarges. The center of the lesion tends to regress; however, marked edema and elevation occur at the periphery.

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Definition Annular erythema occurs in newborns whose mothers have SLE or Sjögren syndrome with anti-SS-A and/or SS-B antibodies, even when the mother is asymptomatic for both diseases. The face is most frequently involved. Neonatal lupus erythematosus is a specific type of lupus erythematosus. Clinical features Neonatal lupus erythematosus resembles the annular erythema that accompanies Sjögren syndrome, or DLE-like annular eruptions in newborns in the first month after birth (Figs. 12.9-1 and 12.9-2), and it heals with abnormal pigmentation within 6 months. In addition to systemic symptoms associated with SLE (fever, hepatosplenomegaly, anemia, thrombocytopenia), congenj is found h cardiac i block k l m o blockpis irre-q ital in some cases. Asn cardiac versible, it requires full attention. Pathogenesis Placentally transmitted anti-SS-A antibodies and anti-SS-B antibodies in newborns are thought to lead to neonatal lupus erythematosus. An anti-SS-A antibody against 52kD antigen is strongly suspected of being involved. The cutaneous symptoms subside in 6 months, when placentally transmitted antibodies disappear from the newborns, which implies the involvement of the

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B. Scleroderma

antibodies. Treatment Symptomatic therapies for the eruptions and the systemic symptoms are the main treatments. A pacemaker may be implanted in patients with cardiac block. Clinical images are available in hardcopy only.

6. Nodular cutaneous lupus mucinosis Papules and nodules occur on the back and upper arms. Nodular cutaneous lupus mucinosis is a subtype of cutaneous LE. These lesions are caused by deposition of mucin in large amounts in the dermis, and they often accompany SLE.

7. Bullous lupus erythematosus

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Fig. 12.10 Bullous lupus erythematosus. Bullous LE in a patient with SLE. Vesicles form not only on the LE erythema but also on the normal looking skin.

B. Scleroderma Scleroderma is characterized by sclerosis of the skin that follows a course of edema, sclerosis and atrophy. It is divided into systemic sclerosis (SSc) and localized scleroderma. In SSc various lesions occur in the internal organs, whereas in localized scleroderma the internal organs are not involved.

1. Systemic sclerosis (SSc) Synonym: Progressive systemic sclerosis (PSS) Renaming from PSS to SSc

Outline ● Generalized

cutaneous sclerosis, fibrosis in the synovium and small arteries, and Raynaud’s phenomenon are found.

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Fig. 12.9-2 Annular erythema in neonatal lupus erythematosus. b: Two annular erythema on the face.

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Because progressive systemic sclerosis (PSS) is not necessarily progressive, the disease has come to be called systemic sclerosis (SSc).

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affects multiple organs, with unknown etiology. antibodies and anti-centromere antibodies may be positive. ● Penicillamines and nonsteroidal anti-inflammatory drugs (NSAIDs) are the main treatments. ● Anti-Scl-70

Classification There are two classification systems for systemic sclerosis (SSc): Barnett’s, and LeRoy and Medsger’s. Classification is done according to the degree of hardening of the skin. These classifications are used to describe the severity of SSc (Table 12.5).

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Clinical features SSc frequently occurs in adults aged 30 to 50. The incidence is greater among women, with a ratio of 3 or 4 women to 1 man. The onset is Raynaud’s phenomenon or arthralgia that becomes aggravated in winter. The affected skin gradually hardens, beginning with the peripheral skin. Skin lesions demonstrate characterp j h clinical i k differ l according m o istic features that tonthe affected site. Theq course is usually edema, sclerosis and atrophy. As SSc progresses, the skin becomes impossible to pinch, resulting in impaired finger extension. When it progresses further, the fingers become pointy or crooked, and swollen like sausages (sausage-like fingers). Small ulcers form on the finger pads from circulatory failure, which results in intractable, concave, worm-eaten scarring (Fig. 12.11-1). These symptoms spread from the fingers to the upper arms (proximal scleroderma). Table 12.5 of systemic sclerosis (SSc). p j Classification i k l m n o

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a. Barnett Classification Type I Cutaneous symptoms are Raynaud’s phenomenon and hardening of the fingers. Type II Hardening of skin occurs on the extremities and face. Type III Hardening of skin spreads to the trunk. b. Medsger & LeRoy Classification Limited Hardening of skin is seen only on areas distal from the elbows, cutaneous and lesions in internal organs are mild. The prognosis is good. Most cases with anticentromere antibody-positive are classified as this type.

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Fig. 12.11-1 Systemic sclerosis. a: There is intense sclerosis and impaired movement in the fingers. b: Sclerosis leads to impaired extension in the fingers. c: The ends of the fingers, particularly the index finger, are lost or shortened due to necrosis from blood circulation disorder.

Diffuse Hardening of skin spreads to proximal sites, including the trunk cutaneous and upper arms. Visceral involvement quickly progresses to conditions such as interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement. The prognosis is poor in many cases. Cases with anti-DNA topoisomerase I (anti-Scl-70) p q j k antibody l positive m tend nto be classified o r as this type. c. Other classifications CREST syndrome: A subtype of SSc, it is characterized by five symptoms: calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactylia and telangiectasia. Anti-centromere antibody (ACA) positive is serologically present. This syndrome may be used as a synonym for limited cutaneous SSc.

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Telangiectasia, pigmentation, depigmentation and calcium deposition are also found. ①SSc in the face (Fig. 12.11-2) Mask-like face: Wrinkles on the face disappear from edematous hardening. The nose becomes characteristically pointy. Microstomia: There is difficulty in opening the mouth, which makes the mouth appear small. Miscroglossia, tongue-tie: The tongue is difficult to stick out. ②SSc in other organs The main symptoms found in other organs are arthralgia (swelling), decreased esophageal peristaltic motion, dilation of a b c the lower esophagus, lung fibrosis, cardiac symptoms (arrhythmia, conduction disturbance), maldigestion syndrome, renal symptoms (manifesting as malignant hypertension; severe cases are called sclerodermatous kidney), and chronic thyroiditis (Hashimoto’s thyroiditis).

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Pathogenesis The fundamental etiology is unknown. SSc rarely runs in families. Environmental predisposition: Patients with are a silicosis b c proned to SSc. SSc-like symptoms may be found in workers who handle polyvinyl chloride or epoxy resin and as a side effect of the antitumor drug bleomycin. A type of SSc called human adjuvant disease occurs in half of those who have received silicon or paraffin injections or implants for cosmetic purposes. The disease appears 10 years or more after the operation. These substances are no longer in use. Pathology In the early stages of SSc, collagen fibrils are swollen in the middle to lower layer of the dermis. Interstitial edema, hardening and lymphocytic infiltration are present. As the lesions progress, atrophy in the epidermis and appendages, deposition of collagen fibers parallel to the epidermis, and deposition of acid mucopolysaccharide (the major component is dermatan sulfate) are observed. Unlike in SLE, the deposition of immunoglobulins and complements is negative in many cases. Laboratory findings Anti-Sc1-70 antibodies are frequently seen in diffuse cutaneous SSc. Anti-centromere antibodies are frequently seen in limited cutaneous SSc and CREST syndrome. SSc findings are similar to those of other collagen diseases: Rheumatoid factor is positive, there is biological false positive serological reaction for syphilis, and antinuclear antibody is positive (macular or nucleolar). Nonetheless, unlike in SLE, the patient tests negative for LE cells and anti-DNA antibodies, and the serum complement titer is normal.

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Fig. 12.11-2 Systemic sclerosis. d: Mask-like face. e: Microglossia.

Table 12.6 Preliminary criteria for classification of systemic sclerosis (SSc). Major criterion Proximal diffuse (truncal) sclerosis (skin tightness, skin thickening, non-pitting induration) Minor criteria 1) Sclerodactyly (only of the digits) 2) Digital pitting scars or loss of substance of the digital finger pads (pulp loss) 3) Bibasilar pulmonary fibrosis The diagnosis is given when the patient meets the major criterion or two of the three minor criteria. (Adapted from; Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581-90).

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Diagnosis, Differential diagnosis Various diagnostic criteria are consulted. In cases with typical symptoms, the cutaneous symptoms are sufficient for conclusive diagnosis. Otherwise, skin biopsies and the characteristic autoantibodies are used for diagnosis. SSc in the edematous period should be carefully differentiated from mixed connective tissue disease (MCTD) and overlap syndrome. The diagnostic criteria established by the American College of Rheumatology (1980) are shown in Table 12.6. Treatment Moderate doses of oral steroids are administered against hardening of skin at the early stages. NSAIDs are used for arthralgia. Various vasodilators (e.g., calcium antagonists, prostaglandin E1) are applied for Raynaud’s phenomenon. For patients with severe systemic symptoms, immunosuppressants and hematopoietic stem-cell transplantation are also used. Bed rest, and warming and massaging of the extremities are effective against cutaneous lesions.

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2. Localized scleroderma

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Prognosis SSc tends to be chronic. Hardening of skin usually progresses p q j h i k l m n o gradually. The prognosis depends on the severity of lesions in the kidneys and lungs. Infection may be caused during treatment, and it is fatal in some cases. Sudden death may be caused by heart failure.

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Fig. 12.12 Localized scleroderma morphea. a: A sclerotic plaque of 10 cm in diameter on the extensor surface of the forearm. The center of the lesion appears ivory-colored and glossy. A lilac ring and erythema of light color are present around the lesion. b, c: Morphea on the precordial region.

Definition Localized scleroderma is sclerosis of the dermis, which occurs only on the skin. Unlike in systemic sclerosis, there is neither p q j i k l m n o r Raynaud’s phenomenon nor lesions of internal organs. Clinical features Localized scleroderma occurs most frequently in adults aged 20 to 40 and sometimes in children. The proportion of male to female patients is 1 to 3. Raynaud’s phenomenon is not present. Systemic symptoms are mild, if any. Localized scleroderma includes variety of conditions. ①Morphea (circumscribed plaques) q silvery j Localized round or m oval indurated k l n olesionspthat are r at the center occur on the trunk (Fig. 12.12). These may be surrounded by a purplish-red halo called a lilac ring. Morphea is further classified by the size and number of eruptions as localized, guttate or generalized. Generalized morphea is multiple morphea or morphea accompanied by other localized sclerodermatous lesions. ②Linear scleroderma (linear morphea) This may be accompanied by facial hemiatrophy. Linear or band-like indurated lesions resembling morphea occur on the

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body. When the forehead is affected, it is called sclérodermie en coup de sabre; this spreads to the scalp, leading to alopecia (Fig. 12.13). Linear scleroderma generally penetrates to deep sites. Lilac rings are rarely seen. Pathogenesis The pathogenesis is unknown. The disorder may be induced by external injury. Involvement of Borrelia infection has been reported recently.

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Pathology, Laboratory findings Localized scleroderma has a histopathology similar to that of SSc. The abnormal laboratory findings that are seen in SSc are not usually found in localized scleroderma. Rheumatoid factors and antinuclear antibodies may be present in generalized morphea. Treatment Steroids are topically applied or locally injected. Oral steroids may be administered for severe cases. If no spreading tendency is observed for a certain period of time, surgery may be considered.

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Prognosis Patients with localized scleroderma have a good life expectancy; however, the condition is usually chronic. Indurated patches gradually shrink, and abnormal pigmentation appears.

Fig. 12.13 Linear scleroderma with facial hemiatrophy. Alopecia and sclerosis on the head. It resembles the slash of a sword. Atrophy occurs in the hypodermic scalp.

C. Other collagen diseases 1. Dermatomyositis (DM) Outline ● Heliotrope

rash, Gottron’s sign and unique erythema and poikiloderma appear, and there is telangiectasia in the perionychia. ● Muscle weakness begins in the proximal muscles. Elevated levels of CPK, aldolase and urinary creatine reflect myositis. ● Malignant tumor commonly develops as a complication. ● Interstitial pneumonia may aggravate rapidly. The prognosis is poor.

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are the main treatment.

Epidemiology There are fewer patients with dermatomyositis (DM) than with SLE or scleroderma. It most commonly occurs in adults aged 30 to 60 and in children, with a male to female ratio of 1 to 2. DM that does not cause cutaneous lesions is called polymyositis (PM). Clinical images are available in hardcopy only.

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Fig. 12.14-1 Dermatomyositis (DM). a: Diffuse, edematous erythema accompanied by itching on the trunk. b: Itchy erythema on the back. c: An atrophic, erythematous plaque on the knee.

Clinical features Cutaneous symptoms: Edematous purplish-rose patches on the face, especially the eyelids (heliotrope rash), and flat elevated papules with scaling (Gottron’s sign) on the extensor surface of fingers and joints are diagnostically significant (Figs. 12.14-1 and 12.14-2). Seborrheic dermatitis-like erythema on the cheeks and scalp often progresses to butterfly-rash-like skin lesions in children itching dermatitis-like pdiffuseq h i (Fig. j12.15).k Intensely l m n o edematous erythema appears on the neck and trunk, which sometimes shows linear distribution on the trunk and extremities (linear dermatitis). These eruptions cause abnormal pigmentation or depigmentation, skin atrophy, scaling and telangiectasia over time; they present as poikiloderma. Erythema in the perionychia and hair loss are also seen. Panniculitis resembling lupus erythematosus profundus may be produced. Muscular symptoms: Muscle pain (spontaneous pain, tenderness, gripping pain) and weakness occur symmetrically in the trunk, the proximal regions of the extremities, and the neck. Disorder of the proximal muscles causes difficultiesp in ascending q j i k l m n o r and descending stairs and other walking. Weakness of the pharyngeal muscle group may lead to dysphagia, dysphonia and respiratory disturbance. Other symptoms: Raynaud’s symptoms, multiple arthralgia, subcutaneous calcium deposition, pulmonary fibrosis, myocarditis and sometimes interstitial pneumonia occur. Dermatomyositis in children: It may be caused secondarily after a vaccination or a viral or bacterial infection. Muscular symptoms are preceded by cutaneous symptoms (Fig. 12.15). Subcutaneous and muscular calcium deposition is found in 10% to 20% of all cases, frequently causing dyskinesia. It progresses rather chronically. Myoatrophy, contracture p q and rsubcuj k l m n articular o taneous calcium deposition are seen. Fever and muscular weakness may occur. The patients may die from multiple ulcers of the gastrointestinal tract. Classification, Pathogenesis Viral infection, autoimmunity, and allergy to malignant tumors or infection are known to be involved in DM; however, the pathogenesis is unknown. Complications Malignant tumor of the internal organs is found as a complication

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in 30% to 40% of adult cases. The incidence is even higher when severe edema and intense itching are present. Stomach cancer, breast cancer, lung cancer and malignant lymphoma are frequently caused as complications. Malignant tumor is rarely seen as a complication in children. Clinical images are available in hardcopy only.

Pathology Edema in the upper dermal layer and mild thickening of the basement membranes (staining positive in PAS) are major findings in the early stages of erythematous eruptions. As the lesions a of the b basalc progress, cutaneous atrophy, vacuolar degeneration cell layer, mucin deposition, telangiectasia, swelling of collagen fibers, lymphocytic infiltration and increase of histiocytes in the tissue are found, and these resemble the erythematous histology of SLE. Immunoglobulins and complement deposition on the skin are rarely seen. In muscle tissue biopsied from a painful site, myositis symptoms are present. Laboratory findings a b c d Nonspecific inflammatory reactions such as leukocytosis and

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Table 12.7 Classification criteria for DM and PM. Criteria 1. Skin lesions (a) Heliotrope rash (red-purple edematous erythema on the upper palpebra) (b) Gottron’s sign: purplish-red erythema accompanied by hyperkeratosis and atrophy on the dorsum of finger joints (c) Erythema on the extensor surface of extremity joints: slightly raised red-purple erythema over elbows or knees

a b c trunk) d 2. Proximal muscle weakness (upper or lower extremities and

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3. Elevated serum CK (creatine kinase) or aldolase level 4. Muscle pain on grasping or spontaneously 5. Myogenic changes in EMG (short-duration, polyphasic motor unit potentials with spontaneous fibrillation potentials) Clinical images are available in hardcopy only.

6. Positive anti-Jo-1 (histadyl tRNA synthetase) antibody 7. Nondestructive arthritis or arthralgia 8. Systemic inflammatory signs (fever: more than 37˚C at axilla, elevated serum CRP level or accelerated ESR of more than 20 mm/h by the Westergren method) a b c d e

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Patients presenting no items from the first criterion and at least four items from the second through ninth criteria

Differential Diagnosis Myositis caused by infections, drug-induced myopathy, myopathy resulting from endocrinopathy, muscular dystrophy, other congenital myopathies (Tanimoto K. et al. Classification criteria for polymyositis and dermatomyositis. J Rheum 1995; 22 : 668-74).

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Fig. 12.14-2 Dermatomyositis (DM). d: Poikiloderma on the neck and cheek. e: Intense edema and purplish eruptions on the eyelids (heliotrope rash). f: Multiple, scattered, sharply margined, keratotic erythema several millimeters in diameter on the extensor joints of DIP and PIP of fingers (Gottron’s sign). g: Telangiectasia of nail folds.

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elevated erythrocyte sedimentation rate are the only symptoms in the early stages. Rheumatoid factors and antinuclear antibodies are positive in 60% to 80% of cases. Myogenic enzymes such as CPK, aldolase, GOT and LDH in serum are elevated, and creatine in urine and myoglobin are elevated by myositis. Specific antibodies such as anti-Jo-1 (histidyl tRNA synthetase) antibodies and anti-PL-7 (threonyl-tRNA synthetase) antibodies are found (Table 12.9). Skin and muscle biopsy findings and myogenic changes in electromyography are also important for diagnosis.

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Diagnosis DM can be easily diagnosed by the characteristic cutaneous manifestations, muscular symptoms and laboratory findings. However, in early stages it is difficult to confirm the diagnosis only by the eruptions. The major diagnostic criteria are shown in Table 12.7.

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Fig. 12.15 Dermatomyositis (DM) in children. a: Diffuse erythema accompanied by scaling on the face and trunk. b: The cheeks are most commonly show with diffuse erythema. The skin lesion clinically resembles butterfly rash in SLE.

Prognosis If steroid therapy is given in the early stages, reduced muscular symptoms and decrease of serum CPK are observed in about 80% of cases, which makes a normal life possible. However, prolonged steroid treatment is required in many cases. Life expectancy depends on the severity of malignant tumors and on q withr heart orj lung complications. i k l mThe mortality n orate ofp patients the complication of interstitial pneumonitis is particularly high. Patients whose onset is in their youth tend to have a good life expectancy.

2. Mixed connective tissue disease (MCTD) Outline ● Symptoms

Amyopathic dermatomyosis

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Dermatomyosis without myositis (proximal muscular weakness and laboratory evidence of myositis) but with typical cutaneous symptoms of dermatomyosis such as Gottron’s sign and heliotrope rash is called amyopathic dermatomyosis (ADM). Systemic symptoms may occur rapidly; therefore, careful observation is required.

of SLE, SSc, and PM/DM are seen; nonetheless, it does not meet any of the diagnostic criteria of these diseases. ● Anti-U1RNP antibodies and Raynaud’s syndrome are positive. Sausage-like fingers are present. ● Pulmonary hypertension may develop as a complication, and this greatly influences the prognosis. ● It is internationally controversial whether MCTD is an independent entity. Clinical features Mixed connective tissue disease (MCTD) most frequently

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C. Other collagen diseases

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occurs in women in their 40s. The typical pathological features are Raynaud’s phenomenon, multiple arthralgia (inflammation), and swelling in the dorsal hands (sausage-like swelling). SLElike symptoms such as erythema and fever, SSc-like symptoms such as lung fibrosis and esophageal reduction, and PM- and DM-like symptoms such as inflammatory myositis and muscular weakness are seen. Renal disorders and central nervous disorders are not usually present. From these symptoms, collagen disease may be suspected; however, most cases do not meet the diagnostic criteria of SLE, SSc or DM/PM. Laboratory findings MCTD is characterized by high titers of anti-U1RNP antibodies in serum. Collagen disease conditions cause positive rheumatoid factor, reduction in pulmonary diffusing capacity, elevation of myogenic enzyme, pancytopenia and hypergammaglobulinemia. Diagnosis There are various diagnostic criteria. Those published in 1996 by the research division of the Health and Welfare Ministry of

Table 12.8 Guidance for diagnosis of mixed connective tissue disease (MCTD). Concept MCTD is a disease in which the symptoms and findings of SLE, SSc, and polymyositis are present. Anti-U1RNP antibodies are serologically observed. I. Common findings Raynaud’s phenomenon Swelling in fingers and dorsa of hands II. Immunological findings Anti-U1RNP antibody positive III. Mixed findings A) SLE-like findings 1. Thrombocytopenia 2. Lymphadenopathy 3. Erythema on the face 4. Pericarditis or pleuritis 5. Leukopenia (≦ 4000/ml） or thrombocytopenia (≦ 10,0000/ml） B) SSc-like findings 1. Hardening of skin in the fingers 2. Pulmonary fibrosis, restrictive ventilatory defect (%VC ≦ 80%), or decreased pulmonary diffusing capacity (%DLco ≦ 70%) 3 Diminished esophageal peristalsis, or esophageal enlargement

Diagnosis 1. Positive for one or both of the common findings 2. Anti-U1RNP antibody positive 3. Positive for two or more items in A, B or C of III, and at least one item in A , B, and C MCTD is diagnosed by all three items above. Additional note 1. Anti-U1RNP antibody is detected either by double immunodiffusion (DID) or by ELISA. If DID is positive and ELISA. is not, the DID result has priority. 2. Diagnosis of MCTD is carefully made when the following labeled antibodies are positive. 1) Anti-Sm antibody 2) High titers of anti-dsDNA antibody 3) Antitopoisomerase I antibody (anti-Scl-70 antibody) 4) Anti-Jo-1 antibody 3. Cases of pulmonary hypertension with positive anti-U1RNP antibody are likely to be diagnosed as MCTD in the future, even if other symptoms do not meet the criteria.

C) Polymyositis-like findings 1. Muscle weakness 2. Increased myogenic enzyme (CK) 3. Electrographic finding of myogenic abnormality (Tohjo T. A diagnostic criteria for MCTD. In: Torikai K, Kashiwagi H, Tohjo T, editors. MCTD studying group in the Ministry of Health and Welfare in Japan. A guideline for treatment of mixed connective tissue disease. 1996: 4-9).

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Table 12.9 Major specific autoantibodies in collagen diseases and diseases related to collagen disease. Disease

Autoantibody

SLE

Anti-dsDNA antibody Anti-Sm antibody

SSc

Anti-Scl-70 antibody Anti-centromere antibody (ACA) Anti-Mi-2 antibody

DM/PM

Anti-Jo-1 antibody Anti-PL-7 antibody Anti-Mi-2 antibody

MCTD

Anti-RNP antibody (Anti-U1RNP antibody)

Overlap syndrome

Anti-dsDNA antibody Anti-Sm antibody Anti-Scl-70 antibody Anti-Jo-1 antibody Anti-Ku antibody

Sjögren syndrome

Anti-SS-A antibody Anti-SS-B antibody

Japan are shown in Table 12.8. There is international disagreement on the diagnostic criteria of MCTD. They require further deliberation and discussion. Treatment Systemic steroids are fairly effective. Vasodilators such as calcium antagonists and NSAIDs are the main agents used for Raynaud’s syndrome and arthralgia. Systemic steroids, oxygen inhalation, and vasodilators are helpful for pulmonary hypertension. Prognosis The kidneys and central nervous system are not affected, and steroids are highly effective; MCTD generally has a good prognosis. However, when pulmonary hypertension is involved as a complication, the prognosis may be poor.

3. Overlap syndrome

12 Outline ● This

is the name for SLE, SSc or DM/PM whose symptoms meet diagnostic criteria for 2 or more collagen diseases. The collagen diseases do not need to occur simultaneously. ● Many cases meet the diagnostic criteria of both SLE and SSc. Clinical features 92% of patients with overlap syndrome are women. When patients have both SLE and SSc, they frequently have fever, Raynaud’s phenomenon, polyarthritis, ulceration of the fingertips, and pericarditis. Vascular lesions frequently occur, resulting in poor prognosis. Pathogenesis The pathogenesis is unknown. Hereditary factors are thought to cause overlap syndrome, in conjunction with environmental factors; however, the influential hereditary factors are unknown. Antibodies that are detected specifically for each collagen disease (labelled antibodies) are found independently or simultaneously. Laboratory findings Elevated erythrocyte sedimentation rate and polyclonal hypergammaglobulinemia are seen. SLE-specific antibodies (antidsDNA antibodies, anti-Sm antibodies), SSc-specific antibodies (anti-Sc1-70 antibodies), and PM-specific antibodies (anti-Jo-1 antibodies) are positive. Anti-Ku antibodies are positive when SSc and PM occur simultaneously (Table 12.9).

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Diagnosis The symptoms of overlap syndrome meet the diagnostic criteria for various collagen diseases. When anti-U1RNP antibodies are positive and the diagnostic criteria of MCTD are met, the disease is often diagnosed as MCTD. Treatment As a general rule, the most significant symptom is treated according to the treatment guidelines for each collagen disease.

4. Anti-phospholipid antibody syndrome (APS)

Clinical images are available in hardcopy only.

Outline ● This

disorder is caused by antibodies produced against phospholipids whose antigens are various. It tends to accompany SLE. ● Anti-phospholipid antibody is a general term that includes anti-cardiolipin antibodies and lupus anticoagulants. ● Thrombosis, habitual abortion, ischemic heart disease, distal cyanosis, ulceration in the lower legs, and livedo reticularis are caused. Clinical features Livedo reticularis, purpura, subcutaneous nodules, fingertip ulceration and gangrene are caused by thrombotic vasculitis in the cutaneous blood vessels (Fig. 12.16). Cutaneous vasculitis is pathologically seen. SLE-like symptoms (e.g., butterfly rash, DLE, photosensitivity) may appear. Thrombophlebitis is often found. In addition to cutaneous symptoms, the thrombosis can cause pulmonary embolism, transient ischemic attack, cerebral infarction, Budd-Chiari syndrome and myocardial infarction. Another typical symptom is habitual abortion. Thrombus formed in the placenta is known to cause the inadequate placental function that is frequently seen in the fifth or sixth month of pregnancy. About 20% of habitual abortions in the absence of obvious underlying disease are thought to result from anti-phospholipid antibody syndrome (APS). Pathogenesis Anti-phospholipid antibodies, often abbreviated as a PL, contain anti-cardiolipin antibodies (antibodies to b -2 glycoprotein I) and lupus anticoagulants. b -2 glycoprotein I plays a role in anticoagulation, such as by inhibiting prothrombinase activity and the formation of activated X factors. Accelerated blood coagulation is thought to be caused by disruption of these functions. From recent studies it has been widely accepted that a complex of b -2 glycoproteins I and phospholipids (cardiolipin) accelerates blood coagulation by connecting with a PL.

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Fig. 12.16 Anti-phospholipid antibody syndrome (APS). Intractable skin ulcer and purpura on the lower leg of a middle-aged postmenopausal female. This ulceration results from circulatory disorder caused by angioma that is induced by anti-phospholipid antibodies.

MEMO Anti-phospholipid antibody syndrome (APS) Lupus anticoagulant, an immunoglobulin that prolongs the activated partial thrombolastin time (APTT) without inhibiting coagulation factor activation, and biologic false positive of syphilis are frequently observed in APS. This has been recognized since the 1950s. In the 1980s, extensive examination showed that cardiolipin is the only antigen of the disease, and the name was changed to anti-cardiolipin antibody syndrome. From further examination, it has become clear that the antigens are various phospholipids; the disease is now called APS.

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Clinical images are available in hardcopy only.

Laboratory findings Anti-cardiolipin antibodies and lupus anticoagulants are positive. The anti-cardiolipin antibody titer increases when patients are infected with syphilis. In serological test for syphilis, the most reactive antibodies are anti-cardiolipin antibodies. Biological false positive is observed. Lupus anticoagulants inhibit phospholipid-dependent blood coagulation reactions, leading to prolongation of the APTT; however, the thrombin time is normal. Since APS has a thrombotic tendency, thrombocytopenia is often seen. Positive anti-cardiolipin antibodies in the absence of syphilis infection is biological false positive. Treatment Anticoagulant therapy using heparin and warfarins is effective for cases with thrombosis. Small doses of aspirin and simultaneous use of steroids are helpful in preventing abortion. It has been reported that plasmapheresis, megadoses of human immunoglobulins and megadoses of steroids are useful.

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Clinical images are available in hardcopy only.

5. Sjögren syndrome Synonym: Sicca syndrome Outline

This is an autoimmune disease which mainly targets exocrine glands, including the salivary glands and lacrimal glands. ● Annular erythema and purpura due to vasculitis are characteristic skin features. ● Xerostomia, keratoconjunctivitis sicca and distal renal tubular acidosis occur. Tooth decay is frequently caused by dryness of the mouth. ● Anti-SS-A antibodies and anti-SS-B antibodies are positive. ● Hashimoto’s disease (chronic thyroiditis) and B-cell lymphoma occur as complications. ● Symptomatic treatments and steroid administration are the main treatments. ●

Clinical images are available in hardcopy only.

Fig. 12.17 Sjögren syndrome. It begins with elevated, edematous erythema 1 cm in diameter. The erythema gradually enlarges and becomes ring-shaped. It occurs multiply in most cases. The center of the erythema tends to heal, and there is severe infiltration at the periphery. Sjögren syndrome resembles the skin lesions seen in neonatal lupus erythematosus.

Classification When there are only the characteristic symptoms of Sjögren syndrome unaccompanied by any other collagen disease, it is called primary Sjögren syndrome (sicca syndrome). Cases with other collagen diseases such as SLE are diagnosed as secondary Sjögren syndrome. Clinical features Sjögren syndrome most commonly occurs in adults in their 30s to 50s and affects 9 females for every 1 male. The characteristic cutaneous symptoms are annular erythema and purpura accompanying vasculitis. Punctate hypergammaglobulinemic

C. Other collagen diseases

purpura is recurrently seen in the lower extremities. Extended macular purpura may also occur (refer to the section on clyoglobulinemic purpura in Chapter 11). Annular erythema, either edematous or urticarial, that is sharply margined and 1 cm to 5 cm in diameter is seen (Fig. 12.17). There is a close relationship between anti-SS-B antibodies and edematous annular erythema. Annular erythema frequently occurs multiply on the face, healing spontaneously in about 2 weeks or sometimes persisting longer. Dry skin, telangiectasia, hair loss, butterfly rash, chilblain erythema and nodular erythema also occur. Eye symptoms: Keratoconjunctivitis sicca, photophobia, pain, itching and lacrimal disorder occur. Oral symptoms: Dryness of the mouth, dysphagia, and sharp pain in the mouth are caused by affected salivary glands. Tooth decay, angular cheilitis and oral candidiasis occur secondarily. Other mucosal symptoms: Lesions are found in the nasal cavity, pharynx, larynx, bronchial tubes, external genitalia and alimentary mucosa. Other symptoms: Raynaud’s phenomenon, arthralgia, fever, fatigue, myalgic pain, lymph node enlargement and interstitial pneumonia occur. When B-cell lymphoma is produced, the prognosis is adversely affected. Pathogenesis The pathogenesis has not been identified. Complications Sjögren syndrome tends to accompany SLE and rheumatoid arthritis. SSc, polyarteritis nodosa, polymyositis, idiopathic thrombocytopenic purpura, Hashimoto’s disease, autoimmune hemolytic anemia, primary biliary cirrhosis, renal tubular acidosis and malignant lymphoma may occur as complications (Table 12.10). Pathology Annular erythema shows pathological features similar to those of SLE and SCLE. Typically, the secretory glands are densely infiltrated by lymphocytes and plasma cells. Labial biopsy of minor salivary glands has prognostic value. Skin biopsy of the purpura shows involvement of vasculitis in the small blood vessels. Immunoglobulin deposition may be found in the blood vessels. Laboratory findings Schirmer test, Rose-Bengal test and fluorescent dye test are ophthalmologically performed to identify lacrimal tear gland abnormality. Otologically, apple-tree appearance is observed by parotid gland radiography, and salivary gland dysfunction can be detected by parotid gland scintigram. Serologically, antinuclear antibodies, anti-SS-A antibodies, anti-SS-B antibodies and antiRNP antibodies are positive. Elevated levels of immunoglobulin,

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Table 12.10 Complications of Sjögren syndrome. Other autoimmune diseases

SLE, SSc, PN, PM/DM, annular erythema, ITP

Joints

Rheumatoid arthritis

Thyroid

Hashimoto’s disease

Blood and lymphatic system

Autoimmune hemolytic anemia, lymphoma, hypergammaglobulinemia, hypermacroglobulinemia

Lungs

Interstitial pneumonia

Stomach

Atrophic gastritis

Pancreas

Acute pancreatitis

Liver

Primary biliary cirrhosis

Kidneys

Renal tubular acidosis

Table 12.11 Revised version of the European classification criteria for Sjögren syndrome (2002). I. Ocular symptoms: a positive response to at least one of the following questions: 1. Have you had daily, persistent, troublesome dry eyes for more than 3 months? 2. Do you have a recurrent sensation of sand or gravel in the eyes? 3. Do you use tear substitutes more than 3 times a day? II. Oral symptoms: a positive response to at least one of the following questions: 1. Have you had a daily feeling of dry mouth for more than 3 months? 2. Have you had recurrently or persistently swollen salivary glands as an adult? 3. Do you frequently drink liquids to aid in swallowing dry food? III. Ocular signs - that is, objective evidence of ocular involvement defined as a positive result for at least one of the following two tests: 1. Shirmer’s test, performed without anaesthesia (≦ 5 mm in 5 minutes) 2. Rose bengal score or other ocular dye score (≧ 4 according to van Bijsterveld’s scoring system) IV. Histopathology: In minor salivary glands (obtained through normal-appearing mucosa) focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score ≧ 1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing mucous acini and contain more than 50 lymphocytes) per 4 mm2 of glandular tissue V. salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result for at least one of the following diagnostic tests: 1. Unstimulated whole salivary flow (≦ 1.5 ml in 15 minutes) 2. Parotid sailography showing the presence of diffuse sialectasias (punctate, cavitary, or destructive pattern), without evidence of obstruction in the major ducts. 3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer VI. Autoantibodies: presence in the serum of the following autoantibodies: 1. Antibodies to Ro (SSA) or La (SSB) antigens, or both (Vitali C, et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8).

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salivary amylase and rheumatoid factor may be present. Anti-SSA antibodies tend to show high sensitivity in Sjögren syndrome, and anti-SS-B antibodies tend to show high specificity for Sjögren syndrome. Diagnosis Currently, Sjögren syndrome is diagnosed by clinical features according to diagnostic criteria established by European diagnostic criteria (Table 12.11). Treatment The main treatments are symptomatic therapies, because no effective pharmacologic therapy is available. Mouthwash, treatment for periodontal disease, and administration of artificial saliva and of artificial tears for protection of the cornea are the main therapies. Large doses of internal steroids and immunosuppressants are administered in severe cases in which systemic angiopathic lesion or malignant lymphoma occurs as a complication.

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D. Rheumatic diseases with arthritis 1. Rheumatoid arthritis (RA) Outline ● This

Clinical images are available in hardcopy only.

Fig. 12.18 Rheumatoid vasculitis.

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collagen disease causes sharp pain and swelling in the joints. ● Rheumatoid nodules and cutaneous lesions accompanying vasculitis are found. ● Chronic inflammation occurs in the synovial membranes of joints. The articular cartridges and bones are destroyed by synovial proliferation. ● Diseases closely related to RA include juvenile rheumatoid arthritis, adult Still disease, ankylosing spondylitis, psoriatic arthritis and Reiter syndrome. Clinical features The primary disease of rheumatoid arthritis (RA) is symmetrical arthritis. In dermatology, RA is characterized by rheumatoid nodules and cutaneous lesions that accompany vasculitis (Fig. 12.18). Rheumatoid nodules are found in 20% to 25% of patients with RA. The nodules, 0.5 cm to several centimeters in diameter, are painless, solid, subcutaneous nodules frequently produced on sites where the skin is subjected to pressure, such as the knees, hips, Achilles tendons and occipital region. They persist for a long time, sometimes rupturing and causing secondary infection. Ulceration on the fingertips and elsewhere, gangrene, purpura, blistering, and livedo accompany rheumatic vasculitis. RA is usually accompanied by extracapsular symptoms, such as pericardial

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D. Rheumatic diseases with arthritis

inflammation, interstitial pneumonitis, peripheral neuritis and uveal inflammation. Pathology Three-layered palisading granuloma is found at sites with rheumatoid nodules. This granuloma is fibrinoid degeneration of collagen fibers surrounded by histiocytes, which is further surrounded by inflammatory cells such as lymphocytes and plasma cells (Chapter 2). In rheumatic vasculitis, immunocomplex deposition is seen on the vascular walls at sites where lesions have occurred, and obstructive changes are often caused by thickening of endothelium and leukocytoclastic vasculitis. Laboratory findings Inflammatory findings such as elevated erythrocyte sedimentation rate, leukocytosis, thrombocytosis, CRP positive, and increases in human immunoglobulins and complement titer are seen. Rheumatoid factors (mainly IgM antibodies that react against abnormally produced IgG) are positive in 80% to 90% of RA cases. The degree of progression of RA can be determined by diagnostic imaging. Diagnosis The diagnostic criteria are listed in Table 12.12.

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Table 12.12 1987 revised criteria for the classification of rheumatoid arthritis. 1. Morning stiffness lasting at least 1 hour 2. Arthritis of 3 or more joint areas 3. Arthritis of hand joints (at least 1 area swollen in a wrist, MCP, or PIP joint) 4. Symmetric arthritis 5. Rheumatoid nodules 6. Serum rheumatoid factor 7. Radiographic changes For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she meets 4 of these 7 criteria. Criteria 1through 4 must have been present for at least 6 weeks. (American college of Rheumatology Classification Criteria of Rheumatoid Arthritis [1987]).

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Clinical images are available in hardcopy only.

Treatment Besides pharmacologic therapies such as NSAIDs, treatments for RA include disease-modifying anti-rheumatic drugs (e.g., DMARDs such as gold preparations, D-penicillamine, methotrexate) and steroids. Biological agents such as infliximab, adalimumab and etanercept are now covered by health insurance in Japan. Rehabilitation and lifestyle guidance are also important.

2. Adult Still disease Synonyms: Subsepsis allergica, Wissler-Fanconi syndrome Outline ● The

three main symptoms are salmon-pink rheumatoid eruptions, intermittent and remittent fever, and arthritis. ● The laboratory findings are elevated erythrocyte sedimentation rate, leukocytosis, rheumatoid factor negative and marked increase in ferritin. Clinical features Adult Still disease most frequently occurs in young women aged 16 to 35. Fever, arthritis, and specific cutaneous symptoms are found. Cutaneous symptoms: Salmon-pink rheumatoid eruptions occur on the trunk, extremities and face (Fig. 12.19). Itching is not usually present.

Clinical images are available in hardcopy only.

Fig. 12.19 Adult Still disease.

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Other symptoms: Intermittent fever persists for more than a week, rising in the evening and at night and falling in the morning (evening spike). Arthritis occurs in the large joints (hands, knees, feet, elbows) in all cases. Splenomegaly, lymph node enlargement, epicarditis, and myalgic and pharyngeal pain also occur. Laboratory findings Elevated erythrocyte sedimentation rate, strong positive CRP, anemia, leukocytosis and increase of complement titer are caused by inflammation. Negativity of antinuclear antibodies and rheumatoid factor differentiates this disease from other collagen diseases. Adult Still disease is characterized by elevated levels of serum ferritin, which may be ten times the normal level. The ferritin level indicates the disease’s degree of activity.

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Treatment Mainly oral steroids and NSAIDs are administered. Antibiotics are ineffective. The effectiveness of treatment is measured by the CRP and serum ferritin values. Prognosis The life expectancy for adult Still disease is good. Amyloidosis may occur.

3. Juvenile rheumatoid arthritis (JRA) Juvenile rheumatoid arthritis (JRA) is thought to be the same as Still disease when the patient is under age 16. The pain is relatively mild. It is the most common pediatric collagen disease. Chronic synovitis, morning stiffness and rheumatoid eruptions are found. Since the rheumatoid factor is negative, JRA is thought to differ in etiology from RA. JRA is divided into systemic (Still disease; the main symptoms are extracapsular), polyarticular (accounting for 30% of all children with JRA; five or more joints are affected), and pauciarticular (accounting for about half of all children with JRA; four or fewer joints are affected). In systemic JRA, intermittent and remittent fever precedes rheumatoid eruptions or arthritis. Lymph node enlargement, splenohepatomegaly, pericarditis and pleuritis may also occur. Arthritis is the main symptom in both polyarticular JRA and pauciarticular JRA; other symptoms rarely occur. Elevated erythrocyte sedimentation rate, positive CRP and leukocytosis are present as findings of inflammation; however, there are few findings that are specific to JRA. Seventy to eighty percent of patients with JRA heal without any serious disorders. Pauciarticular JRA has the best prognosis of the three types.

D. Rheumatic diseases with arthritis

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4. Reiter’s disease Outline ● Men

aged 10 to 30 are most frequently affected. After prodromes such as diarrhea, the three characteristic symptoms of polyarthritis, urethritis and conjunctivitis occur. ● Erythema, pustules, and hyperkeratosis occur in the palms and soles. Balanitis circinata is produced. ● Reiter’s disease is closely related to HLA-B27. ● It heals spontaneously within 6 months in most cases. Clinical features Men in their 20s are most commonly affected. The incidence is 20 males to 1 female. Inflammatory symptoms such as urethritis (or uterocervical inflammation; most cases are sexually transmitted) and bacterial diarrhea precede Reiter’s disease. When the prodromes subside, arthritis, conjunctivitis and cutaneous symptoms appear. Erythema or papules are produced in the palms and soles, coalescing to form hyperkeratotic nodules. The lesions are accompanied by pustules. Balanitis circinata (painless shallow erosion) and keratosis in nails also occur. Laboratory findings HLA-B27 is positive in 90% of cases. The disease cannot be pathologically differentiated from psoriasis. Calcification is observed in the calcanei, fingers and phalanx regions by X-ray. Sacroiliac articulation and ossification in the vertebral ligament may be found. The lesions caused by Reiter’s disease are unilateral; differentiation from ankylosing spondylitis is possible. Treatment NSAIDs are used primarily. Steroids and immunosuppressants may be administered in severe cases. Prognosis Arthralgia recurs; however, most cases subside in about 6 months.

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Physiochemical Injury and Photosensitive Diseases

An important role of the skin is to protect the body from extrinsic stimuli such as sunlight, heat and cold. Melanin pigment and intercellular bridges in the epidermis prevent DNA from being damaged by sunlight and ultraviolet rays. Perspiration and blood capillaries work to maintain the body temperature. The horny cell layer and intercellular bridges protect the body from mechanical shock. Nonetheless, skin barrier functions can be destroyed when extrinsic stimuli exceed a certain level, resulting in injury such as electrical burn, chemical burn, frostbite, radiation damage and solar dermatitis. This chapter introduces skin disorders and photosensitive diseases with physiochemical causes.

Physiochemical injury 1. Burns (Fig. 13.1) Outline

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● Burns

Clinical images are available in hardcopy only.

Fig. 13.1 Burn. Second-degree burn. Mix of superficial dermal burn (SDB) and deep dermal burn (DDB), caused by hot water.

are injuries to cutaneous tissues caused by high temperature. The damage is divided by depth into first, second, and third degree. ● Burn size is measured by “the rule of nines” or “the rule of fives.” ● The basic treatment is cooling. Systemic intensive care or escharotomy may be necessary for severe cases. ● The first infusion, if necessary, is lactated Ringer’s solution, whose amount is decided according to the extent of burn (e.g., by the Baxter method). Clinical features, Classification Burn severity is evaluated by depth, size and patient’s condition. ①Classification of burn by depth (Table 13.1) The depth of a burn depends on the temperature of the heat source and the contact time. Burns are classified into first-degree, second-degree and third-degree. However, the severity is difficult to determine immediately after a burn. A burn may deepen with time after the burn incident.

Table 13.1 Diagnosis of burn by depth and clinical features. Diagnosis

Synonym

Clinical Findings

Treatment

Aftereffects

First-degree burn

Epidermal burn

Painful erythema, edema

Application of ointment

Scarring (-)

Second-degree burn

Superficial dermal burn (SDB)

Painful blisters with clear fluid and red blister bottoms

Application of ointment

Heals in about 2 weeks, scarring (-)

Deep dermal burn (DDB)

Hypalagesic blisters with white bottoms

Débridement, skin graft

Heals in 3-4 weeks, scarring (+)

Deep burn (DB)

Grayish-white or brown carbonized skin Pain is usually absent.

Débridement, skin graft

Scarring (+)

Third-degree burn

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Physiochemical injury / 1. Burns

First-degree burn (epidermal burn): Painful erythema and edema occur, healing in 3 to 4 days without scarring. Second-degree burn (dermal burn): Intense burning sensation is present. Erythema is followed within several hours by tense blistering (Fig. 13.2). Second-degree burn is subclassified into superficial dermal burn (SDB) and deep dermal burn (DDB). SDB presents as painful blisters whose bottoms are rose pink; there is mild damage to the dermis, which heals without scarring in about 2 weeks. DDB affects the deep dermal layer and heals with scarring in 3 to 4 weeks. The bottom of a DDB blister is white and has reduced sensation. DDB often progresses to third-degree burn. Third-degree burn (deep burn): All cutaneous layers and sometimes even deeper areas are damaged (Fig. 13.3). The skin appears gray-white. Blistering is not present, or the skin is carbonized to appear brownish. It becomes necrotic: Eschar forms and autodestruction occurs. Proliferation of the epidermis around the burn is the only spontaneous recovery; skin graft may be necessary. A needle is sometimes used to examine the severity. The needle is stuck gently into the skin of the affected area; if it is painful, the diagnosis is second-degree burn; otherwise, the diagnosis is third-degree burn. If hairs come out when pulled gently, the diagnosis is DDB or third-degree burn. ②Estimating the burn extent “The rule of nines” is generally adopted to determine the extent of burns in adults; “the rule of fives” or the Lund and Browder chart is used for children (Fig. 13.4). a ③Evaluation of burn severity Systemic intensive care is conducted in cases of second-degree burn on 10% or more of the body in children and on 15% or more in adults. Cases with 15% or greater burn index score (Fig. 13.4) are treated as severe burn. Pathogenesis Burns are caused by high temperature. They are extremely common in infants and children under age 10. However, lowtemperature burns caused by prolonged use of electric pads and air heaters have been increasing among patients with cerebrovasa b cular disease or diabetes (Fig. 13.5). In severe burns, histamines and cytokines are secreted from damaged tissue, leading to an increase in systemic vascular permeability. Accordingly, leakage of plasma proteins and extracellular fluid loss occur, resulting in burn shock. Renal disorder, pulmonary edema, disseminated intravascular coagulation syndrome (DIC), and multiple organ failure may occur. Respiratory failure may also occur in patients with tracheal edema from inhaling hot air from a fire. Extensive burns are prone to infection (sepsis), and they tend toa induceb pepticc ulcer (Curling’s ulcer) within a week after the burn incident. After epithelization and hypertrophic scar formation or a prolonged course of burn, squamous cell carcinoma may be caused.

Clinical images are available in hardcopy only.

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13 Clinical images are available in hardcopy only.

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Fig. 13.2 First- and second-degree burns caused by explosion of a cigarette lighter. a: Face. b: Back. c: Palms. d: Dorsum of hand.

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Clinical images are available in hardcopy only.

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cke

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Fig. 13.3 Burns. a, b: Second-degree burns caused by hot water. Marked blistering is present. c: The epidermis has exfoliated with the stripping of clothes that were wet with scalding water. Third-degree burn is also present.

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（Lund and Browder chart） ＊ Add 5% if breast or two legs are burnt. 1 ×（area of second-degree burn）＋（area of third-degree burn） burn index ＝  2

Fig. 13.4 Calculation of burn index score.

jr l

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Physiochemical injury / 2. Chilblain (perniosis), Frostbite

In cases with hypertrophic scarring of the surface of joints, contracture may occur. Treatment ①Local treatment The primary treatment for burns is cooling with running water for at least 30 minutes to relieve pain, inflammation and edema. In second- and third-degree burns, it is important to prevent infection. Blister puncture may be performed. Appropriate antibiotic and incarnative ointments are chosen according to the skin condition. Affected sites of DDB and third-degree burns are removed (débridement), and a skin graft may be performed. The burn depth can be more clearly determined about 2 weeks after the time of the burn, which often makes it possible to determine whether the affected site should be treated for conservative preservation or whether surgical treatment is necessary. In the case of extensive burns, mesh skin grafts or fresh homografts are applied. In the event that severe edema disturbs the blood flow in the extremities, escharotomy is necessary to prevent necrosis. ②Systemic treatment Airway management and infusion are primarily performed on patients with severe burns. The Baxter method is a widely applied infusion therapy (Table 13.2). Infusion fluid is controlled by monitoring urine output, central venous pressure, and serum sodium and potassium concentration. Antibiotics or other drugs are applied systemically under observation if there are signs of sepsis, peptic ulcer, cardiac failure, pulmonary edema, or renal dysfunction.

2. Chilblain (perniosis), Frostbite

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Outline ● Chilblains

and frostbite are cutaneous disorders caused by exposure to the cold. ● Edema-like and erythema multiforme-like eruptions are caused by local vascular constriction. ● Avoidance of the cold is the basic treatment. It is important not to warm the affected sites rapidly.

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Fig. 13.5 Third-degree low-temperature burn. a: This burn was caused by adhering a heated pad to the skin for a long time during sleep. Although the burn seems small and superficial, it is deep and third degree. b: Third-degree burn caused by a hot-water bottle during sleep. The patient has diabetes and diminished sensation in the peripheral nerves.

1) Chilblain, Perniosis Clinical features Chilblain (perniosis) occurs most commonly on the hands, fingers, feet, heels, auriculae and cheeks of schoolchildren (Fig. 13.6). Chilblains are localized, usually tender, inflammatory, erythematous, often itchy lesions that may blister or ulcerate. Abnormal hypersensitive reaction is thought to be the cause; however, it is not clear why some people have this reaction while others do not.

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Table 13.2 Parkland (Baxter) formula. Lactated Ringer’ s solution [4cc x %TBSA (total body surface area) x weight (kg)] is given for the first 24 hours after the time of burn. Half the amount is given in the first 8 hours. The rest is given in the subsequent 16 hours.

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Pathogenesis, Epidemiology Chilblains are caused by exposure to low temperatures. Small arteries and veins become congested by repetitive exposure to cold, and the congestion causes inflammation. The condition occurs more often in early winter and early spring than in midwinter, and is seen even in regions with warm temperatures. In addition to low temperature, moistness from perspiration and heredity factors are closely associated with chilblain occurrence. Treatment Exposure to the cold should be avoided. The affected sites are warmed and dried. Massaging is helpful. Vitamin E preparations, topical steroids, and orally administered peripheral circulatory dilators may be given.

2) Frostbite

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Clinical features Frostbite is acute freezing of tissues from exposure to extreme cold. Even just a few seconds of exposure may be sufficient to cause it. The fingers, ears and nose are most easily affected. It tends to occur in those who are not accustomed to the cold, and in the elderly. A few severe cases of frostbite in winter mountain climbers and in drunken persons, and from occupational accidents, have been reported. The skin becomes white to purplishred, and reduced sensory perception is accompanied by hypoesthesia. As it progresses, blistering, necrotic ulceration, and mummification occur. The depth classification for burns is used to determine the severity of frostbite (Table 13.1).

Fig. 13.6 Chilblain, Perniosis.

Pathogenesis Inadequate blood flow and thrombus formation (circulatory disorder) is caused when skin is exposed to the cold, leading to intercellular dehydration, destruction of cellular membranes (from tissue freezing), and blood vessel constriction. Frostbite most frequently occurs at or below –12°C. The length of exposure and the wind speed are factors in the occurrence and severity of frostbite. When the entire body surface is exposed to the cold for a long period, lethargy may set in and freezing death may result. Clinical images are available in hardcopy only.

Fig. 13.7 Chemical burn.

Treatment The affected sites are warmed gradually as an emergency treatment. Rapid warming and strong friction should be avoided. The sites are warmed with 40˚C water for 20 minutes and kept clean and protected. Surgical removal and care to prevent infection and necrosis are necessary. Intravenous vasodilators are useful in cases where the frostbite is related to circulatory disorder.

Physiochemical injury / 5. Radiodermatitis

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3. Chemical burn In chemical burn, cutaneous tissues are damaged by acidic, alkaline or other escharotic chemicals (Fig. 13.7). Acid induces coagulative necrosis. Crusts appear, and their color depends on the causative acid (brown for sulfuric acid, yellow for hydrochloric and nitric acids, and white for hydrofluoric acid). The affected sites should be flushed with running water immediately. Neutralizing agents are not applied. The treatments afterwards are the same as those for burns.

4. Electric burn In electric burn, cutaneous tissues are damaged by the passage of electrical current (Fig. 13.8). These burns, called “flash burns,” are caused on sites that come into contact with an electrical current. They result in ulceration and necrosis. Flash burns spread to become electric burns with dendritic reddening and ulceration. Lesions are caused by metal contained in electrodes that melts and fuses to the skin. The treatments are basically the same as those for burns.

Clinical images are available in hardcopy only.

Fig. 13.8 Electric burn.

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5. Radiodermatitis Synonyms: Radiation dermatitis, Radiation-induced dermatitis Outline

radiodermatitis, cutaneous lesions are caused by radiation. The condition is divided into acute radiodermatitis, in which lesions occur immediately after exposure, and chronic radiodermatitis, in which lesions occur later. ● The treatments are the same as those for burns. ● Actinic keratosis and squamous cell carcinoma (radiation cancer) may develop. Surgical removal of the affected site is also chosen as a treatment.

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Clinical features ①Acute radiodermatitis Acute radiodermatitis is caused by a single large exposure of radiation. The symptoms vary depending on the amount of irradiation, the site and the patient’s age. With a comparatively small amount irradiation (up to 5 Gy of gamma rays), erythema occurs several minutes after irradiation and disappears in 2 or 3 days, followed by edematous erythema, pigmentation, atrophy and telangiectasia. Blistering and erosion are caused by radiation doses between 5 Gy and 10 Gy (Fig. 13.9), and intractable ulceration and burn symptoms are caused by irradiation greater than 10 Gy. ②Chronic radiodermatitis Chronic radiodermatitis is commonly caused by a small

Fig. 13.9 Acute radiodermatitis. Blistering occurred after electron beam irradiation.

MEMO This dermatitis is caused by prolonged contact with kerosene. Kerosene dermatitis readily occurs when kerosene clings to clothing for a long period. Characteristic fresh red erythema, edema, blistering and erosion are seen at the contact site, and the symptoms are similar to those of shallow second-degree burns. Steroid application is a highly effective treatment. The treatment is the same as for burns with blistering and erosion.

Kerosene dermatitis

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Pathogenesis Radiodermatitis is caused by exposure to X-rays, radioactive materials, or corpuscular radiation. All kinds of radiation cause cutaneous lesions of different severity. Radiation injures intercellular genes by DNA degeneration and DNA synthetase inhibition, which impairs cellular functions.

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amount of fractionated radiation. It often occurs on the site where a malignant tumor has been produced and radiation therapy has been repeatedly performed. It is also seen in the hands of medical professionals who deal with radiation (Fig. 13.10). There are four stages of chronic radiodermatitis: atrophy (atrophy, pigmentation, alopecia, and telangiectasia, occurring 6 months after the irradiation incident), keratinization (proliferation of horny cells), ulceration (intractable), and canceration (squamous cell carcinoma or basal cell carcinoma, occurring 15 to 20 years after irradiation). p q j

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Fig. 13.10 Chronic radiodermatitis. a: Chronic radiodermatitis on buttocks exposed to therapeutic irradiation for uterine cancer. There is atrophy of skin, pigmentation, telangiectasia, and ulceration in some areas. The skin lesion could become the site of origin for squamous cell carcinoma. b: Chronic radiodermatitis in a man in his fifties. Chronic radiolesion-inducing actinic keratosis is present on the flexor of a DIP joint. This patient was diagnosed with tinea manus about 30 years ago and had been treated with therapeutic soft X-ray irradiation.

Fig. 13.11 Areas most likely to be affected by pressure ulcer. The sacral region, ischial tuberosity, and the bony areas of the skin, including the ankles, which tend to be subjected to pressure from the body weight during bed rest, are most frequently involved.

Treatment The treatments for acute radiodermatitis are the same as those for burns. For chronic radiodermatitis, the affected site is protectp q j i l m n o ed by ointmentk application and bandaging. Extrinsic stimulationr should be avoided. Ulcers and tumors are removed and the site is repaired with tissue that has good blood circulation, such as by pedicle flap procedure.

6. Pressure ulcer Synonyms: Decubitus ulcer, Pressure sore, Bedsore Clinical features Pressure ulcers mostly occur in the sacral division, ischial tuberosity, and ankles (Fig.13.11). Erythema, edema and induration are produced in areas subjected to constant pressure, and ulceration develops. Ulcers may be as deep as the bone, or spread to joints, rectum or vagina. The periphery of the ulcer is erosive and the lesion is often larger inside than it appears from the outside. The bottom of the ulcer is moist and covered by necrotic tissue and accumulated pus. Secondary infection such as by anaerobic fungi may result in sepsis. Treatments and skin care are chosen according to the state of the affected site; therefore, stage classification is important (Table 13.3). Pathogenesis Circulation disorder caused by persistent pressure leads to necrosis of skin and subcutaneous tissues. It most commonly occurs in bedridden elderly and patients with spiral cord injury who are not able to change position by themselves. Thin persons and those who have underlying diseases such as under-nutrition and diabetes are also prone to pressure ulcer.

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Table 13.3 Stages of pressure ulcer. Shea scale (1975)

NPUAP (formerly IAET) stage 1988

AHCPR guidelines (1994) Non-blanchable erythema of intact skin, the heralding lesion of skin ulceration.

Stage I

In lightly pigmented skin, lesion appears as a defined area of persistent redness. In darker skin tones, the lesion may appear with persistent red, blue, or purple hues. Lesions occur within the epidermis.

Reddening persists for more than 30 minutes after pressure is removed. Damage is within the epidermis.

Stage II

Partial-thickness skin loss involving epidermis, dermis, or both. The ulcer is superficial and presents clinically as an abrasion, blister or shallow crater. The ulcers spread to the dermis and subcutaneous fat.

Partial-thickness skin loss involving Partial-thickness skin loss involving epidermis, dermis or both (e.g., the epidermis dermis or both. The ulcer is superficial and may appear as abrasion, blister, or shallow crater). an abrasion blister or shallow crater.

Stage III Full-thickness skin loss involving damage to, or necrosis (death) of, subcutaneous tissue that may extend down to, but not through, underlying fascia (the sheet of fibrous material overlying muscles). The ulcer presents as a deep crater with or without undermining of adjacent tissue. The muscles are involved.

Full-thickness skin loss involving damage to, or necrosis of, subcutaneous tissue, which may extend down to but not through underlying fascia. The ulcer may appear as a deep crater with or without undermining of adjacent tissue.

Full-thickness skin loss involving damage to or necrosis of subcutaneous tissue that may extend down to, but not through, underlying fascia (deep crater with or without undermining). The ulcer presents clinically as a deep crater with or without undermining adjacent tissue.

Stage IV Full-thickness skin loss with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures (tendons, joint capsule). Adjacent tissue undermining sinus tracts (an abnormal cavity in the tissue) may also be associated with this stage. The ulcers spread to the skeletal tissue. The bones and joints are damaged.

Full-thickness skin loss with extensive destruction tissue necrosis or damage to muscle bone or supporting structures such as joint capsule.

Full-thickness skin loss with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures (e.g., tendon or joint capsule).

Treatment The primary treatment for pressure ulcer is quick removal or reduction of pressure to alleviate the impairment of blood flow. The affected site is locally cleansed, incarnative and antibiotic ointments are applied, and dressings are applied for protection. In the chronic stages, the affected site is cleaned with water and the necrotic tissue is removed. Disinfectant tends not to be used unless there is apparent infection. It is most essential not to worsen the condition.

7. Dermatitis artefacta Synonyms: Multiple neurotic gangrene, Hysteric gangrene Clinical features Erythema, erosion, gangrene and ulcer occur suddenly, mostly at sites within reach of the hands (extremities, chest and face). Right-handed patients tend to have dermatitis artefacta on the left side of the body. Eruptions may present different appearances according to the cause (e.g., fingernail scratch, knife injury, misuse of drug). Pathogenesis, Diagnosis In dermatitis artefacta there are factitious lesions. Patients with mental stress, hysteria, depression, mental disability or schizophrenia injure themselves in the skin, nails or mucous membranes. Most patients deny that the injury is self-inflicted. The specific types include trichotillomania (Chapter 18) and onychotillomania. Akatsuki disease (Fig. 13.12) and navel stone (Fig. 13.13) resemble dermatitis artefacta; however, they are

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Fig. 13.12 Akatsuki disease in a woman in her twenties. There is marked deposition of keratin. This patient hardly ever washed her nipples for fear that she would contract a skin disease.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 13.13 Navel stone. This is so-called bellybutton lint. The patient consulted a doctor on what seemed to be a black tumor in the navel. When it was pulled out, there was a grimey mass of keratin. This patient had believed the superstition that the navel must not be washed.

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caused by chronic poor hygiene. Treatment Cutaneous symptoms should be treated appropriately. If necessary, treatment for mental imbalance may be necessary with cooperation from a psychiatrist.

Photosensitive diseases 1. Solar dermatitis, Sunburn Erythema and blisters are produced by prolonged exposure to sunlight (mainly UVB). Pathologically, sunburn cells (apoptotic epidermal cells), epidermal spongiosis, edema in the dermal blood vessels, inflammatory cellular infiltration, necrosis and subcutaneous blistering are present. Erythema occurs several hours after photoradiation on the exposed site, and it gradually becomes edematous (Fig. 13.14). Solar dermatitis is most severe 12 to 24 hours after irradiation, after which it gradually resolves. Exfoliation and pigmentation occur in several days. Pigmentation is left after healing in some cases. Application of sunscreen is helpful for prevention. Cold compresses and steroid ointments are effective. When blistering is present, the same treatments as those for burns are applied.

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2. Photosensitive dermatoses a

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Fig. 13.14 Solar dermatitis, Sunburn. a: Solar dermatitis caused by sleeping for 3 hours on the beach. Blistering is marked. The cutaneous symptoms are equivalent to those of firstdegree and second-degree burn. b: The normal skin, which was under the swim trunks, differs distinctly from the site with solar dermatitis, which was sun-exposed.

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dermatoses are cutaneous diseases that are caused or aggravated by sunlight exposure. ● Both extrinsic factors (e.g., drugs) and intrinsic factors (e.g., inherited diseases, metabolic disorders) may be involved. ● They are caused by direct action of drugs (phototoxic dermatitis) or by immunological mechanism (photoallergic dermatitis). ● Xeroderma pigmentosum is a hereditary photosensitive p q j i dermatosis kthat is linduced m by intrinsic n ofactors. r Pathogenesis The two main causative factors of photosensitive dermatoses MEMO The skin is darkened by exposure to the sun. Oxidation of melanin occurs in the epidermis (primary tanning), and there is enhanced production of melanin (secondary tanning).

Suntan

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Table 13.4 Main drugs that induce photosensitive dermatosis. Drug Classification

Drugs

Psychoactive

Chlorpromazine, promethazine, diazepam, carbamazepin, imipramine

Muscle relaxant

Afloqualone

Antihistamine

Diphenhydramine, mequitazine

Antibacterial agent

Nalidixic acid, enoxacin, ofloxacin, ciprofloxacin, lomefloxacin, sparfloxacin, fleroxacin, tosufloxacin, tetracycline, doxycyclin

Antifungal agent

Griseofulvin, flucytosine, itraconazole

Antiinflammatory

Ketoprofen, tiaprofenic acid, suprofen, piroxicam, ampiroxicam, actarit, diclofenac, naproxen

Antihypertensive agent

Hydrochlorothiazide, trichlormethiazide, meticrane, clofenamide, tripamide, metolazone, furosemide, tilisolol HCl, pindolol, diltiazem HCl, nicardipine HCl, nifedipine, captopril, lisinopril

Antidiabetic

Tolbutamide, chlorpropamide, glibenclamide, carbutamide, glymidine sodium

Antipodagric

Benzbromarone

Antitumor agent

5-FU, tegafur, dacarbazine, flutamide

Lipid-lowering drug

Simvastatin

Prostatomegaly therapeutic agent

Tamsulosin

Photochemistry therapeutic agent

8-Methoxypsoralen, trioxypsoralen, hematoporphyrin derivative

Vitamin

Etretinate, pyridoxine, VB12

Antirheumatic

Sodium aurothiomalate, methotrexate

(Based on: Kamide R. Photosensitive dermatosis caused by extrinsic photosensitizing substance. In: Tamaoki K, editor. New Dermatology Vol. 16. Nakayama Shoten; 2003: 293-300).

Table 13.5 Classification of photosensitive dermatosis. Classification

Cause

Drug Extrinsic photosensitive dermatosis

Diagnostic name Phototoxic dermatitis

Chapter 13

Photoallergic dermatitis

Chapter 13

Pellagra Accumulation Intrinsic photosensitive of chromophore Porphyria in skin dermatosis DNA repair defect

Described in...

Xeroderma pigmentosum (XP)

Chapter 17 Chapter 17 Chapter 13

Cackayne syndrome Bloom syndrome Decrease of melanin

Albinism

Chapter 16

Phenylketonuria

Chapter 17

Unknown

Hydroa vacciniforme

Chapter 13

Solar urticaria

Chapter 13

Polymorphous light eruption

Chapter 13

Chronic actinic dermatitis (CAD)

Chapter 13

are extrinsic chemicals and intrinsic factors (Tables 13.4 and 13.5). This section describes photosensitive dermatoses that are caused by extrinsic factors. Extrinsic photosensitive dermatosis is inflammation of skin caused by the excitation of chromophores by daily exposure to radiation (mainly UVA). Chromophores reach the skin either from outside (skin lotion, perfume, fruit juice, tar) to induce photocontact dermatitis or from within the body (drugs, food). The mechanisms of inflammation are phototoxic

Photosensitive drug eruption

MEMO

In addition to phototoxic condition or photoallergy, drug intake may induce intrinsic photosensitive diseases (e.g., porphyria, lupus erythematosus).

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sunlight (UVA)

chromophores ②Chromophores convert into photoallergens.

①Contact is made with a causative substance, or there is intake of such substance.

photoallergens ③The photoallergens connect  with biologic proteins. biologic proteins ④Macrophages and Langerhans cells phagocytose the conjugates of photoallergens and biologic proteins. in the lymph nodes or intradermal area

intradermal area

lymph ducts

⑤The photoallergens in macrophages and Langerhans cells are presented to T cells, and sensitization occurs.

regional lymph nodes

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①Macrophages and Langerhans cells recognize photoallergens themselves.

primary intake of causative substance (sensitization)

②The photoallergens are presented to effector T cells, causing inflammation that peaks 48 hours after presentation.

secretion of various cytokines, localized inflammation secondary and further intake of the causative substance

Fig. 13.15 Mechanism of photoallergic reaction. Table 13.6 Phototoxic reaction and photoallergic reaction. Phototoxic reaction

Photoallergic reaction

Incidence

May occur in anybody

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More than one exposure to agent required?

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(the excited substance itself becomes toxic) and photoallergic (the excited substance becomes an allergen that induces inflammation by immunoreaction) (Fig. 13.15, Table 13.6).

1) Phototoxic dermatitis Outline ● Phototoxic

Onset of reaction hours to 1 after exposure to day agent and light

24-72 hours

Dermatitis

Clinical features

Exaggerated sunburn

Distribution

Sun-exposed Sun-exposed skin skin

Spread to unexposed areas?

No

Pathologic feature

Spongiosis, Necrosis of epidermal cell eczema (sunburn)

Yes (possible)

Almost never Yes Cross reaction (sometimes) caused by similar compounds? Amount of agent Large required for photosensitivity

Small

dermatitis may occur in anyone by the combination of a certain dose of drugs and sun exposure. ● It may occur even at the first irradiation (usually by UVA), without any latency. ● The main causative drugs are psoralen, coal tar, thiazide drugs, and tetracycline. Clinical features Sunburn-like symptoms are mainly seen. That is, erythema and edema are followed by exfoliation and pigmentation. Perfume may cause both allergic contact dermatitis and phototoxic dermatitis (Berloque dermatitis) on the neck, especially the sides. MEMO The skin comes into direct contact with the causative agent. Subsequent exposure to light of a certain wavelength causes photocontact dermatitis. It is classified by onset mechanism as phototoxic or photoallergic.

Photocontact dermatitis

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Photosensitive diseases / 2. Photosensitive dermatoses

Pathogenesis Drugs that accumulate in the skin absorb light at a certain wavelength. Exposure to light at that wavelength causes phototoxic dermatitis. Each drug affects a particular site.

1. A test substance is adhered to the back for 24 hours.

Treatment Intake of the causative substance should be discontinued. Sunlight is avoided by sunscreen and a hat. The treatments are the same as those for contact dermatitis.

2. Half of the patch site is exposed to a slightly smaller amount of UVB than for the first MED exposure (about 70% of MED). If the not substance is not a exposed cause of to UVB photoallergic dermatitis in the patient, no skin lesion or erythema will appear.

exposed to a small amount of UVB

2) Photoallergic dermatitis Outline ● Photoallergic

dermatitis is photosensitive dermatitis that is caused by a type IV allergy reaction, which is induced by sun exposure after topical application or intake of a drug. ● Erythema and blistering are the main symptoms. ● Chlorpromazine, thiazide drugs and oral antidiabetics are the main causative drugs. Clinical features Erythema and serous papules occur on the sun-exposed site, progressing to edema blistering, and erosion. Pathogenesis Chromophores that somehow attach to the skin react to exposure to light of a certain wavelength (mostly UVA, sometimes visible light) to become allergenic, or they may convert into haptens, connect with biologic proteins and become photoallergenic. After sensitization, the causative substance is re-exposed to light when it reaches the skin surface, where it induces type IV allergic reaction (Fig. 13.15). This reaction does not occur without sensitization; that is, inflammation is not caused by the first exposure, nor does allergic reaction occur in everyone. A person who has been sensitized is prone to light-induced inflammation even from a minute amount of the substance. Laboratory findings, Diagnosis Photo-patch test: The test substance is patched as in the usual patch test. The minimal erythema dose (MED) of the patient is also determined. After 24 hours, half of the patch site is exposed to a slightly smaller amount of UV than that of the first MED exposure. The other half is left unexposed. The result is determined 48 hours after exposure (Figs. 13.16 and 13.17). Photo-drug test: Application of the suspected drug is discontinued for at least 20 days. A normal dose of a test drug is applied for 2 days. The diagnosis is photoallergic dermatitis if an eruption is produced by exposure to light.

3. The patch is removed after 48 hours. The site is examined after a short time passes.

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Fig. 13.17 Determination of minimal erythema dose (MED). UVB from 0 mJ/cm2 to 100 mJ/cm2 is irradiated in increments of 10 mJ/cm 2 on areas of the patient’s back where no eruptions have been produced. The MED in this case is 30 mJ/cm2.

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Treatment Intake of the causative substance and sunlight exposure should be avoided. The treatment is the same as that for contact dermatitis. A photosensitive disease called “persistent light reaction,” which is categorized as a chronic actinic dermatitis (CAD), may remain after discontinuation of the causative substance.

3. Solar urticaria

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Definition, Pathogenesis, Clinical features An allergen is intrinsically produced in skin by exposure to light, against which type I allergy is induced. Several minutes after light exposure (mostly the visible spectrum, but also UVA and UVB in some cases), extremely itchy urticaria occurs; however, it disappears in several hours. Anaphylactic shock may be p q j h i rare cases. k l m n o caused in Diagnosis, Examinations Solar urticaria is generally diagnosed from the recurring eruptions caused by exposure to sunlight or to artificial light. However, wheals may be produced or aggravated by light shielding in some cases; certain wavelengths in the light are thought to inhibit wheals. In young patients, differential diagnosis from erythropoietic protoporphyria may be necessary. i

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Treatment The patient is shielded from the sun, and antihistamines are applied as a symptomatic treatment. PUVA treatment may be performed as a desensitization treatment. Immunosuppressants and plasma exchange have been reported to be effective in severe cases. Clinical images are available in hardcopy only.

4. Chronic actinic dermatitis (CAD)

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Fig. 13.18-1 Chronic actinic dermatitis. a: Intractable eczema presents as lichenified plaques that progress slowly. b: The skin lesion improved significantly after topical application of tacrolimus for several months. c: The skin lesion recurred after sun exposure.

Clinical features, Pathogenesis Chronic actinic dermatitis (CAD) most frequently occurs in pchangeq whoser main j k l intractable m n eczematous o adult males. An symptom is slowly progressing lichenoid plaques occurs on exposed areas of the body and becomes chronic (Figs. 13.18-1 and 13.18-2). In some cases, the lesions progress to erythroderma, leading to cutaneous lymphoma-like subcutaneous nodules, thickening of the skin, or facies leontina. It is hypothesized that intrinsic antigens are produced by light exposure for some reason; however, the details of the onset mechanism are unknown. Photosensitive diseases used to be called “persistent light reaction” “actinic reticuloid” or “photosensitivity dermatitis.” Now these are categorized as forms of CAD.

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Pathology Eczematous lesions are the main symptom of CAD. As CAD progresses, lymphocytic infiltration and atypical cells are seen in all dermal layers, and Pautrier microabscess-like lesions may occur in the epidermis (actinic reticuloid). Laboratory findings, Diagnosis, Treatment The minimal erythema dose (MED) for UVB is greatly reduced. The MED for UVA and visible light is also reduced in some cases. For differential diagnosis, the skin is subjected to repeated UVB exposure and if eczematous lesions appear then the diagnosis is CAD. Topical steroids are helpful. Complete a b c light shielding is essential. Tacrolimus ointment is also useful. Oral steroids and immunosuppressants are effective in severe cases.

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5. Polymorphous light eruption Clinical features Polymorphous light eruption occurs most commonly in women between the ages of 10 to 30. Itchy erythema and papular eruptions appear at sun-exposed sites. They become chronic and tend to gradually worsen. The condition also worsens in summer and subsides in winter. Pathogenesis, Diagnosis Polymorphous light eruption is thought to be an allergic reaca bdiseases c withd tion to light. In practice, all photosensitive unknown causes and without specific symptoms of other photosensitive diseases are considered to be polymorphous light eruption. It requires reconsideration as to whether it is an independent disease.

6. Hydroa vacciniforme Outline ● Hydroa

vacciniforme is a rare intrinsic photosensitive disease seen in infants. ● Blisters with concave centers form at sun-exposed sites on the face and dorsa of the hands. ● Epstein-Barr viruses are involved. The disease resolves naturally at puberty. ● Sun shading is important. Clinical features, Pathogenesis Hydroa vacciniforme first appears in infants 2 to 3 years of age and resolves naturally at puberty. It occurs more often in males. Erythema and blisters with concave centers are produced by exposure to sunlight or UVB, and crusts form later on. These

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Fig. 13.18-2 Chronic actinic dermatitis (CAD). d, e: Chronic eczematous skin lesion accompanied by intense itching on the occipital region and dorsum of hand of a man in his 50s. It worsened with exposure to the sunlight. Oral cyclosporine improved it markedly.

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leave atrophic scarring when they heal. They mostly occur in the face, auriculae, and dorsa of hands (Fig. 13.19). The lesions are sensitive to light and tend to worsen in summer. When the EB virus is involved, the condition may progress to lymphoma. The onset mechanism is unknown, and hereditary predispositions are not usually found. In cases with the involvement of the EB virus, natural killer-cell lymphoma may develop. Diagnosis, Examinations, Treatment Hydroa vacciniforme is diagnosed by laboratory findings. The symptoms may resemble those of porphyria; however, the porphyria level in hydroa vacciniforme is within the normal range. Direct sun exposure is avoided. Sunscreen is helpful.

7. Xeroderma pigmentosum (XP) Clinical images are available in hardcopy only.

Outline ● XP

13 Fig. 13.19 Hydroa vacciniforme.

Clinical images are available in hardcopy only.

Fig. 13.20 Xeroderma pigmentosum (group D). Pigmentation on the face of a woman in her 20s. The cutaneous symptoms are mild.

occurs in persons with congenital failure in the DNA repair process. The cells are easily damaged by UV. Sunburn frequently occurs. ● All types are autosomal recessive inherited. ● A malignant tumor may occur as a complication with age. ● Complete shading of light is an effective treatment. Classification, Pathogenesis Patients with xeroderma pigmentosum (XP) have a congenital failure in repairing and eliminating DNA that is damaged by UV exposure. The failure results in severe photosensitive symptoms. UV causes a replication fork bypass of a pyrimidine (thyminethymine) dimer. XP is classified by unscheduled DNA synthesis (UDS), a classification index, into 8 subtypes: groups A to G, and a variant group (Table 13.7). Group A is the severest, and the variant group is the mildest. In the variant group, UDS is normal; however, there is failure in DNA modification after synthesis. Group A and the variant group are the most frequently occurring in Japan, together accounting for 80% of all XP cases. All groups are autosomal recessive and occur in 1 person out of 100,000 to 1.5 persons out of 100,000. About 30% of patients with XP are born from consanguineous marriages. The main genes responsible for XP have been identified (Chapter 29). Clinical features Abnormalities are not found at birth; however, intense and delayed sunburn in 1- to 2-month-old infants may be recognized as the onset of XP group A. Extremely intense and persistent sunburn recurs on sun-exposed sites such as the face and dorsa of hands and forearms. As sunburn recurs, the skin dries and coarsens, presenting an unwashed appearance with ephelides-like pigmented patches, exfoliation, hypopigmented macules and

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Photosensitive diseases / 7. Xeroderma pigmentosum (XP) Table 13.7 Comparison between types of xeroderma pigmentosum. Severity of skin manifestation

Neurological manifestation

Average age of skin cancer development

UDS (%)

Onset

Reduced

<5

Babyhood

Reduced

3-7

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C

Normal

10-25

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Severe

None

10.5

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Reduced

25-50

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Moderate

Sometimes

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E

Reduced

40-60

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Mild

None

41.0

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Reduced

10-20

Early childhood

Mild

None

47.7

G

Normal

<25

Early childhood

Mild

Sometimes

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Variant Normal

100

Early childhood (about 5 years old)

Moderate

None

41.0

Group

MED

A B

Severe, carcinogenesis Appears at about 1 year old

telangiectasia (Fig. 13.20). Seborrheic keratosis, small tumors, and ulcers occur in succession at the base of these lesions in childhood. Basal cell carcinoma, squamous cell carcinoma, keratoacanthoma and malignant melanoma occur subsequently. Eye symptoms such as photophobia, blepharitis, dacryorrhea, and conjunctivitis occur in childhood and progress to ectropion, blindness, and malignant tumor in the terminal stages. Progressive neurological symptoms occur 6 months after birth, leading to articulatory disorder, gait disorder and intellectual impairment. Disturbance in growth, such as dwarfism and spondyloschisis, also occur. Groups E, F, and G are often overlooked due to their mild symptoms. The carcinogenic period is the third decade of life. Eye symptoms and neurological symptoms are rarely found in these groups. Nevertheless, cutaneous symptoms and neurological symptoms in some cases of groups E, F, and G closely resemble those found in group A (Fig. 13.21). In the variant group, MED is almost normal, but ephelides gradually appears after childhood. Although eye symptoms and neurological symptoms are rarely seen, basal cell carcinoma or squamous cell carcinoma occurs in adulthood.

9.2

Sometimes

Severe

MEMO UDS (unscheduled DNA synthesis), a test for xeroderma pigmentosum (XP), shows the potential degree of recovery from DNA damage under UV exposure, expressed as a percentage compared to normal controls. Cells are scattered in a petri dish and exposed to UV. When cultured in [3H] thymidine solution, damaged DNA is repaired, and the cells absorb [3H] thymidine. The amount of [3H] thymidine is measured by autoradiography for comparison with normal cases; patients with XP have reduced UDS values.

UDS value

Clinical images are available in hardcopy only.

Laboratory findings, Diagnosis XP diagnosis is confirmed by the MED level, DNA and RNA syntheses after UV exposure, measurement of UDS, and gene test. Treatment Sunlight should be thoroughly avoided by limiting outings in daytime, wearing clothes that cover the body thoroughly, keeping the hair long, wearing UV-screening eyeglasses, sticking UVscreening film on windows, applying shades to fluorescent lamps, and applying sunscreen. Early detection and treatment of cutaneous malignant tumor are important. Neurological disorders are treated by regular listening-comprehension tests, speech training, and motor ability retention training.

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Clinical images are available in hardcopy only.

Fig. 13.21 Xeroderma pigmentosum (Group F). Basal cell carcinoma on the dorsum of the nose of a man in his 20s.

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Chapter

14

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Blistering and Pustular Diseases

In the strict sense, blistering and pustular diseases do not include physical injuries (e.g., burns and frostbite) or infections (e.g., those by bacteria or by viruses such as herpes). Diseases that are associated with blistering are divided into inherited congenital ones and acquired ones. Congenital blistering diseases such as epidermolysis bullosa are caused by mutation in the gene that codes for epidermal basement membrane structural proteins. Ultrastructural molecular sites where the genetic mutation is expressed become fragile, which results in blistering. Since the causative gene of epidermolysis bullosa was identified, accurate diagnosis of disease subtypes, genetic consulting and prenatal diagnosis have become possible. Acquired blistering diseases such as pemphigus and bullous pemphigoid are autoimmune diseases. Autoantibodies against epidermal structural proteins are produced, which leads to fragility of the epidermis and blistering. Pustular diseases are those in which multiple sterile pustules are produced.

Blistering diseases

A. Genetic blistering diseases 14 a. Epidermolysis bullosa (EB) (Fig. 14.1) Synonym: Epidermolysis bullosa hereditaria Outline ● It

Clinical images are available in hardcopy only.

Fig. 14.1 What is epidermolysis bullosa? Epidermolysis bullosa is a group of hereditary diseases, in which blisters, erosions and ulcers easily occur by slight mechanical stimuli. This photo shows recessive dystrophic epidermolysis bullosa.

is caused by a mutation in structural molecules of the epidermal basement membrane. ● Shortly after birth, blisters, erosions and ulcers form at sites of friction in newborns, whose skin is congenitally fragile (Nikolsky’s sign). ● It is divided by the ultrastructural site of cleavage into EB simplex (in the epidermis), junctional EB (in the lamina lucida junctions), and dystrophic EB (in the dermis). It is subdivided into 10 to 30 subtypes by clinical features, inheritance patterns and causative genes (Table 14.1, Fig. 14.2). ● Identification of genetic mutation by immunofluorescence (IF) to determine protein levels, and electron microscopy of the cleavage site are important for diagnosis. ● There are no effective treatments, only symptomatic treatments.

1. Epidermolysis bullosa simplex (EBS) Outline ● The

three main types of EBS are Dowling-Meara EBS

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Blistering diseases / A. Genetic blistering diseases

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Table 14.1 Classification of epidermolysis bullosa (EB). 3 major types EB simplex (EBS)

Junctional EB (JEB)

Dystrophic EB (DEB)

Main subtypes

Causative protein and gene

Inheritance pattern (autosomal chromosome)

Clinical features

Dowling-Meara (severe)

Keratin 5/14

AD

Blistering on the whole body surface

Köbner (moderate)

Keratin 5/14

AD

Blistering spread to sites other than the palms and soles

Weber-Cockayne (mild)

Keratin 5/14

AD

Blistering on the palms and soles

EBS associated with muscular dystrophy

Plectin

AR

Late-onset muscular dystrophy as a complication

Herlitz JEB

Laminin-332

AR

Blistering and erosion on the whole body at birth. Death within 1 year after birth

Lamina lucida blister, absence of laminin 332

Non-Herlitz JEB

Laminin-332

AR

Type XVII collagen (BP180)

AR

Poor development in teeth and nails Alopecia Good prognosis

Lamina lucida blister, reduced laminin 332 or complete absence of Type XVII collagen.

JEB associated with pyloric atresia

a6b4 integrin

AR

Blistering on the whole body Congenital pyloric atresia Poor prognosis

Lamina lucida blister. Absence or reduced a6b4 integrin.

Hallopeau-Siemens recessive DEB

Type VII collagen

AR

Recurrent blistering on the extremities and trunk. Fusion of fingers and toes in club-shape.

Non-Hallopeau-Siemens recessive DEB

Type VII collagen

AR

Milder than Hallopeau-Siemens recessive type

Autosomal dominant DEB

Type VII collagen

AD

Comparatively mild

Immunohistochemistry and immunoelectron microscopy

Intraepidermal blisters, aggregation of keratin fibers

Intradermal blister. Hypoplastic anchoring fibrils

14

(AR: autosomal recessively inherited, AD: autosomal dominantly inherited). tonofilament (keratin 5/14) basal cell hemidesmosomes lamina lucida lamina densa anchoring fibril (type VII collagen) type I and III collagen

abnormal tonofilaments

abnormal hemidesmosomes

abnormal anchoring fibrils

intraepidermal blisters (epidermolysis)

blisters in the lamina lucida

subepidermal blisters (dermolysis)

epidermolysis bullosa simplex (EBS)

junctional epidermolysis bullosa (JEB)

dystrophic epidermolysis bullosa (DEB)

Fig. 14.2 The mechanism of epidermolysis bullosa.

MEMO Are epidermolysis bullosa hereditaria and epidermolysis bullosa different? Epidermolysis bullosa may be called “epidermolysis bullosa hereditaria” to distinguish it from epidermolysis bullosa acquisita; however, the name “epidermolysis bullosa” is now widely used for all hereditary bullosas.

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Blistering and Pustular Diseases

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

14 Fig. 14.3 Epidermolysis bullosa simplex, Dowling-Meara type. Blisters form ring shapes and heal without scarring.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 14.4-1 Epidermolysis bullosa simplex, Köbner type. Blistering occurs on the whole body surface. The clinical severity is between those of the DowlingMeara and the Weber-Cockayne types.

(severe), Köbner EBS (moderate), and Weber-Cockayne EBS (mild). The disorder is caused by keratin gene mutation (K5 or K14). It is autosomal dominantly inherited. ● Blisters form at sites prone to friction, beginning at birth or early childhood. ● The prognosis is generally good. It subsides with age. ● EBS with muscular dystrophy (EBS-MD), a rare type of EBS, is caused by a plectin gene mutation. Inheritance is autosomal recessive. Clinical features Shortly after birth, blisters of various sizes form at sites that are prone to friction: hands, feet, elbows, knees and so on. Blistering is observed by rubbing a normal site on the skin of a patient with severe EBS (Nikolsky’s sign). EBS heals without scarring. It tends to aggravate in summer, from the high temperature. It subsides with age and generally has a good prognosis. EBS is dermatologically divided by severity into three subtypes; however, there are intermediate subtypes. EBS with muscular dystrophy (EBS-MD) is rare (MEMO). ①Dowling-Meara EBS: Ring-shaped blisters form. When it occurs in newborns, systemic erosions and fatality may occur. This is the severest subtype (Fig. 14.3). ②Köbner EBS: Blistering is present on the whole body surface. The severity is moderate (Figs. 14.4-1 and 14.4-2). ③Weber-Cockayne EBS: Blisters form only on the hands and feet. It is the mildest subtype (Fig. 14.7). Pathogenesis Basal cells collapse from mutation of either the K5 or K14 gene, which codes for cytoskeletons of basal cells (intermediate filaments). Cleavage occurs, resulting in blistering. Epidermolysis bullosa simplex (EBS) is autosomal dominantly inherited. The severity depends on the type and location of the mutation in the K5 or K14 gene. The severity of clinical symptoms is measured by the location of genetic mutation and the amino acids produced. Pathology Separation occurs within the cytoplasm of the epidermal basal cells, which leads to intra-epidermal blistering (Fig. 14.5). Clumping of degenerated keratin fibers in severe Dowling-Meara EBS is clearly observable by electron microscopy (Fig. 14.6). Treatment Symptomatic therapies are the main treatments. Friction and warm temperatures should be avoided. Local therapies (e.g., drainage of blisters, application of antibiotic ointments) are helpful. The cutaneous symptoms subside with age.

Blistering diseases / A. Genetic blistering diseases

205

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 14.7 Epidermolysis bullosa simplex, Weber-Cockayne type. Blistering is localized on the hands and feet. Blistering is induced by mechanical stimulation, such as from long walks. Fig. 14.4-2 Epidermolysis bullosa simplex, Köbner type on hands.

MEMO Epidermolysis bullosa simplex associated with muscular dystrophy This specific type of epidermolysis bullosa simplex is associated with late-onset muscular dystrophy, a disease caused by plectin gene mutation. Plectin is a protein found in the epidermal basement membrane, hemidesmosomes and sarcolemma of muscle fascia. The mutation is autosomal recessively inherited. Epidermolysis bullosa simplex is accompanied by muscular dystrophy in the fingers and toes, and muscle atrophy.

☆

☆ Clinical images are available in hardcopy only.

☆ Fig. 14.5 Electron microscopic image of epidermolysis bullosa simplex. The arrows indicate lamina densa. The cytoplasm of the basal cells (indicated by stars) on the basement membrane is damaged, leading to blistering.

aggregated keratin fibers

Fig. 14.6 Aggregation of keratin fibers seen in Dowling-Meara type.

14

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Blistering and Pustular Diseases

MEMO Epidermolysis bullosa simplex with mottled pigmentation Blistering is almost the same as in WeberCockayne epidermolysis bullosa; nevertheless, there is the atypical presence of small pigmented patches 2 mm to 5 mm in diameter on the lower abdomen, axillary fossa, and extremities. Epidermolysis bullosa simplex with mottled pigmentation is caused by P25L missense mutation in the V1 domain of the keratin 5 gene. Epidermolysis bullosa simplex-like blisters and pigmented patches are found on the trunk and axillary fossa.

2. Junctional epidermolysis bullosa (JEB) Outline

Clinical images are available in hardcopy only.

occurs at dermo-epidermal junctions. The disease is caused by dissociation of the lamina lucida in the basal cells. ● All JEB subtypes are autosomal recessively inherited. The majority patients with Herlitz JEB die within 1 year after birth. Non-Herlitz JEB has a better prognosis. ● JEB with pyloric atresia, an atypical type, is caused by genetic mutation in the integrin a 6 or integrin b 4 gene. The prognosis is poor. ● Symptomatic therapies are the main treatments. In recent years, genetic counseling and prenatal diagnosis have been conducted.

Clinical images are available in hardcopy only.

Clinical features In Herlitz JEB, there is systematic blistering, erosion and ulceration in newborns after birth. The lesions do not heal, but recur and enlarge. Mucosal lesions and growth insufficiency of teeth and nails are seen. Herlitz JEB is fatal, causing death within 1 year after birth in almost all cases (Fig. 14.8). Non-Herlitz JEB has a better prognosis, and patients may survive to reproductive age. Non-scaling alopecia, palmoplantar keratosis, nail deformity, and aplasia of dental enamel are present (Fig. 14.9). Nikolsky’s sign is positive.

14

Clinical images are available in hardcopy only.

Fig. 14.8 Junctional epidermolysis bullosa, Herlitz type. Intractable, erosive ulcers on the whole body surface. The ulceration gradually enlarges.

Lethal Herlitz junctional epidermolysis bullosa

MEMO

The disease, once called “lethal Herlitz JEB,” is now simply called “Herlitz JEB,” because some patients have survived for more than 1 year.

● Blistering

Classification, Pathogenesis Herlitz JEB and non-Herlitz JEB are the two main subtypes of JEB. They differ in prognosis. Herlitz JEB is caused by the complete absence of laminin 332 (laminin 5). Non-Herlitz JEB is caused by reduction of laminin 332 or complete absence of type XVII collagen (BP180). It has a better prognosis. JEB with pyloric atresia is caused by a genetic mutation in integrin a 6 or integrin b 4 in the membrane ligands of hemidesmosomes. Complications associated with the disease are systemic junctional bullosa and congenital pyloric atresia. It is fatal soon after birth in many cases (Fig. 14.10). Pathology JEB presents as subepidermal blistering under light microscopy. Blister formation is observed between the basal cell plasma membrane and the lamina densa. Electron microscopy shows the separation more clearly (Figs. 14.2 and 14.11). Treatment Symptomatic therapies are the main treatments for JEB. Friction should be avoided. Local therapies and symptomatic therapies including nutrition management, topical application of ointments and antibiotic administration are conducted. Prenatal diagnosis is also made in severe cases, such as Herlitz JEB.

Blistering diseases / A. Genetic blistering diseases

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 14.9 Junctional epidermolysis bullosa, non-Herlitz type. Blistering and pigmentation occur on the whole body surface. Nonscarring alopecia also occurs on the scalp.

14

Clinical images are available in hardcopy only.

☆

Clinical images are available in hardcopy only.

Fig. 14.10 Junctional epidermolysis bullosa associated with pyloric atresia. Aplasia cutis congenita-like ulcer of skin and congenital pyloric atresia occur as complications.

Fig. 14.11 Electron microscopic image of junctional epidermolysis bullosa. A blister (star) forms in the lamina lucida, between the plasma membrane of the basal keratinocytes (purple arrows) and the lamina densa (black arrows).

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3. Dystrophic epidermolysis bullosa (DEB) Outline

Clinical images are available in hardcopy only.

● There

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g

Clinical images are available in hardcopy only.

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①Hallopeau-Siemens recessive DEB (HS-RDEB) Hallopeau-Siemens recessive DEB is the severest DEB. At birth or shortly thereafter, blisters and erosions appear recurrently on the extremities and trunk, with or without external influences. They heal, leaving milium and scarring, which results in the clubp Lesions q j shaped coalescence ofl fingers arer i k m and toes n (Fig. o 14.12). mostly seen in nails, oral mucosa and esophageal mucous membranes, and there is a tendency for esophageal atresia and dysphagia to occur. The symptoms do not subside with age. When patients reach adolescence or older, a malignant tumor (squamous cell carcinoma, in particular) often occurs. Expression of type VII collagen is completely absent. Recessive Hallopeau-Siemens is extremely serious and may cause death in young patients. ②Non-Hallopeau-Siemens recessive DEB (non-HS-RDEB) Type VII collagen is reduced, but not completely absent. The q Hallopeauj k symptoms l m lessnsevereo than p r clinical are those of Siemens (Fig. 14.13). ③Autosomal dominant DEB This DEB occurs in newborns and infants. Multiple blisters form on the extensor surfaces of the extremities. The disease may cause esophageal atresia, or papules on the trunk. It heals with scarring (Fig. 14.14). Deformation of nails is present. It tends to subside over time. k

l

m

n

o

p

q

r

Pathogenesis Dystrophic epidermolysis bullosa (DEB) is caused by a mutation in the gene that codes for the type VII collagen, a main component of anchoring fibrils that is essential in connecting the dermis and the epidermis. Subepidermal blistering occurs from hypoplasia of anchoring fibrils (Fig. 14.2).

Clinical images are available in hardcopy only.

d

are several subtypes; however, all are caused by a mutation in the gene that codes for type VII collagen, a structural component of anchoring fibrils. Subepidermal p q j h i k m n o blistering is present over l the entire body. ● DEB can be autosomal dominantly inherited or recessively inherited. Nikolsky’s sign is positive.

k

Fig. 14.12 Dystrophic epidermolysis bullosa, Hallopeau-Siemens type. a: Blistering and ulceration are relatively mild at birth. b: Intractable blisters form as patients grow. c, d: Marked blistering is present on the whole body. Adhesion is seen in the fingers and toes due to recurring scarring. e: Hypoplasia of teeth is present.

Pathology Subepidermal blistering (dermolysis) is present. Dissociation isl observed immediately below theq lamina p m n o r densa by electron microscopy (Figs. 14.15 and 14.16). It is characterized by hypoplasia of anchoring fibrils. Laboratory findings, Differential diagnosis DEB is diagnosed by findings obtained by clinical examination, electron microscopy and immunofluorescence (IF). DNA tests are conducted to determine whether it is autosomal

r

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Blistering diseases / A. Genetic blistering diseases

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 14.13 Dystrophic epidermolysis bullosa, non-Hallopeau-Siemens type. Scarring blisters, crusts and adhesion occur in the fingers; however, these are milder than in the Hallopeau-Siemens type. Expression of collagen type VII remains.

14

Clinical images are available in hardcopy only.

Fig. 14.15 Light microscopic image of dystrophic epidermolysis bullosa. Typical subcutaneous blistering and slight inflammatory cellular infiltration are present.

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a

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Fig. 14.14 Dominant dystrophic epidermolysis bullosa. a: Blistering and scarring occur on areas subjected to friction, such as knees. b: Deformity in the toenails.

Fig. 14.16 Electron microscopic image of dystrophic epidermolysis bullosa Blistering is observed immediately beneath the lamina densa (arrows).

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dominant or recessive. For Hallopeau-Siemens recessive DEB with severe clinical symptoms, prenatal diagnosis is made by fetal skin biopsy, amniocentesis and chorionic villis biopsy. Treatment Synthetic type VII collagen therapy has been attempted on DEB patients in recent years. Friction is avoided and topical therapies are applied. Fluid therapies, nutritional management and genetic counseling are conducted for recessive DEB.

Clinical images are available in hardcopy only.

a

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p

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1. Skin fragility syndrome Skin fragility syndrome, an autosomal recessive inherited disease, is caused by abnormality in the gene that codes for plakophilin 1, a desmosomal structural protein. Epidermal fragility, painful hyperkeratosis in the hands and soles, and abnormalities of hair, nails and perspiration are found.

Clinical images are available in hardcopy only.

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2. Hailey-Hailey disease Synonym: Familial benign chronic pemphigus

14

Outline ● Vesicles

Clinical images are available in hardcopy only.

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i

Fig. 14.17 Hailey-Hailey disease. a, b: Vesicles, erosion, impetigo and pustules form in the groin. c: Blisters may appear, although only rarely.

aggregate on an erythematous base in areas exposed to friction. The appearance resembles that of impetigo. ● It is autosomal dominantly inherited and occurs in adults in their 30s. ● It is caused by a mutation in the ATP2C1 gene that codes for a calcium pump in the Golgi apparatus within p q j k l m n o r keratinocytes. ● The pathology is acantholysis and villi formation. It is somewhat similar to Darier’s disease. ● Topical steroid application is the main treatment. Clinical features Hailey-Hailey disease is inherited. It tends to manifest in adults in their 30s, appearing as aggregated erythema and blistering in areas that are exposed to friction, such as the cervical regions, axillary fossa, inguinal regions and anus. On an erythematous blistering base there are crusts, pustule formation and pigmentation, and secondary infection produces impetigo-like lesions (Fig. 14.17). Itching is usually present. Although it heals without scarring, it leaves abnormal pigmentation and is recurrent. The disease worsens in summer, and subsides in winter. It is worsened by external friction, perspiration, infection and UV radiation.

Fig. 14.18 Histopathology of Hailey-Hailey disease. Intraepidermal acantholysis.

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Pathology Acantholysis of the epidermis leads to intradermal lacunae

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r

Blistering diseases / B. Autoimmune blistering diseases

formation immediately above the basal layer. The dermal papillae, which are covered by basal cells in the single layer that is left in the lacunae, protrude and resemble villi. Dyskeratotic cells are occasionally found. Acantholytic cells in the lacunae are connected loosely to each other by a few desmosomes (Fig. 14.18). Autoantibodies to the epidermis are not detected by immunofluorescence. Diagnosis Hailey-Hailey disease is diagnosed by the clinical symptoms and pathological diagnosis. As it is autosomal dominantly inherited and frequently occurs within a family, it is important to take a thorough family history. Genetic diagnosis can identify the mutation in the ATP2C1 gene.

211

Hailey-Hailey disease and MEMO haploinsufficiency Both Hailey-Hailey disease and Darier’s disease are autosomal dominantly inherited. Mutation occurs in one of the allelic genes. In most cases, cutaneous symptoms do not appear until adulthood. Haploinsufficiency has been proposed as the mechanism of onset of these diseases. That is, the amount of protein produced by one allelic gene is sufficient in childhood, but shortages that emerge with age cause the later onset.

Treatment Topical application of steroids and antibiotics ointments is useful. Oral etretinate (a vitamin A derivative) and surgical ablation may be performed in intractable cases.

B. Autoimmune blistering diseases 14 a. Diseases with intra-epidermal blistering (pemphigus group) Outline ● Middle-aged

and elderly people are the most commonly affected. Intra-epidermal blistering with flaccid blisters occurs. ● The two main pemphigus groups are the pemphigus vulgaris group and the pemphigus foliaceus group. ● They are an autoimmune diseases. Acantholytic intraepidermal blistering is produced by autoantibodies against desmoglein (intercellular substances; MEMO). ● Anti-desmoglein antibodies are detected by ELISA. In vivo IgG deposition and IgG antibodies are observed by immunofluorescence (IF). Nikolsky’s sign and Tzanck test are positive (i.e., for acantholytic cells). ● Oral steroids and immunosuppressants are mainly administered.

Adhesion of keratinocytes MEMO Keratinocytes are firmly adhered by desmosomes. Transmembrane adhesion molecules in the cadherin superfamily, such as desmoglein 1 (Dsg1), desmoglein 3 (Dsg3), and desmocolin cadherin (DC), are important to intercellular adhesion. In pemphigus, autoantibodies are produced against Dsg1 and Dsg3, some of whose molecular functions are disturbed. This causes acantholysis. keratin intermediate fiber

desmosome

Ca2 ＋

Dsg1 Dsg3

Dsg3

Ca2 ＋

DC

keratinocytes and desmosomes

DC

mucous attachment plaque membrane

Classification Diseases with intra-epidermal blistering (pemphigus group) are divided into two groups according to pathogenesis: pemphigus vulgaris and pemphigus foliaceus. Pemphigus vegetans is a type of pemphigus vulgaris; pemphigus erythematosus is a type of pemphigus foliaceus. The characteristics of each type are summarized in Table 14.2. Pemphigus vulgaris accounts for 60% of

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Dsg1

Ca2 ＋

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Table 14.2 Types of pemphigus groups. Pemphigus vulgaris Pemphigus vegetans

Pemphigus foliaceus

Pemphigus erythematosus

Age of onset

Middle age to elderly Middle age to elderly

Middle age

Middle age to elderly

Frequent site of skin lesion

Whole body skin, oral mucosa

Intertriginous areas (e.g., axillary fossae)

Whole body skin

Oily areas of skin (e.g., face)

Blisters, erosion

Blisters, erosion, papillary acanthosis, pustules

Erosion, lamellar exfoliation, crusts

Erosion, butterfly rash, seborrheic dermatitis-like skin lesion

Clinical finding

Skin

Mucosal lesions Nikolsky’s sign Pathological finding

＋＋

＋

−

−

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Skin Tzanck test

Intraepidermal blisters (acantholysis) ＋

＋

Site of acantholysis Lower epidermal layer (directly on basal cells) Targeted antigen ELISA Immunofluorescence technique

Direct (skin lesion)

14

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Only Dsg3, Dsg3 and Dsg1

Only Dsg1

Dsg1(＋/−), Dsg3(＋)

Dsg1(＋), Dsg3(−)

IgG(＋) in the epidermal intercellular space, C3(＋) positive

Indirect (serum)

Treatment

＋

IgG (＋) Steroids, immunosuppressants, plasmapheresis, human immunoglobulin therapy

horny cell layer granular cell layer suprabasal cell layer basal cell layer lamina densa

Dsg1 is distributed in all epidermal layers.

Dsg3 is predominant in the lower epidermis.

damaged Dsg1

damaged Dsg3

Fig. 14.20 Direct immunofluorescence of pemphigus vulgaris. Intercellular deposition of IgG is observed in the epidermis.

pemphigus foliaceus Acantholysis and blistering occur in the upper epidermal layer through lower horny cell layer.

pemphigus vulgaris Acantholysis and blistering occur immediately above the basal cells.

Fig. 14.19 Distribution of desmoglein 1 and desmoglein 3 in the epidermis and pathomechanism of pemphigus. Diseases with intra-epidermal blistering are classified according to the desmoglein molecules that are impaired (see also Fig. 14.23).

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all pemphigus cases. Pathogenesis In pemphigus vulgaris, autoantibodies against desmoglein 3 are produced. Because the basal cell layer is rich in desmoglein 3, the action of autoantibodies against desmoglein 3 causes keratinocytes to lose adhesion: The basal cell layer erodes and blisters. In pemphigus foliaceus, however, autoantibodies against desmoglein 1 (and not desmoglein 3) are produced. Acantholysis occurs in the upper epidermal layer. Because the basal cell layer is not rich in desmoglein 1, the action of autoantibodies against desmoglein 1 has little adverse effect on basal cell adhesion: The basal cell layer remains largely intact. (Fig. 14.19). Pathology Dissociation of intercellular connections in the epidermis is called acantholysis. As dissociation progresses, epidermal cleavage and blistering occur. Keratinocytes deform to become spherical from loss of intercellular connection within the blisters (acantholytic cells). Tzanck test is positive. In pemphigus vulgaris, acantholytic blistering occurs immediately above epidermal basal cells; in pemphigus foliaceus and pemphigus erythedermatosus, blistering occurs in the superficial epidermis, such as at sites immediately below the horny cell layer. In pemphigus vegetans, besides the findings of pemphigus vulgaris,a acanthosis and papillomatosis are found, and eosinophil-filled pustules form in the epidermis. Laboratory findings Epidermal intercellular in-vivo-bound IgG in lesions are identified by direct immunofluorescence (IF). IgG anti-intercellular antibodies in the serum of patients are detected by indirect IF and ELISA (Fig. 14.20). Autoantibodies against desmoglein 1 and 3 are detected by ELISA. Tzanck test is also useful, in which the bottom of the blister is smeared and labeled to investigate the presence of acantholytic cells by Giemsa staining. Elevated levels of eosinophils may be found in the peripheral blood or a in theb blister contents.

1. Pemphigus vulgaris Outline ● Acantholytic

blisters form immediately above epidermal basal cells. ● The disease is caused by autoantibodies against desmoglein 3, which is a desmosomal adhesion factor in keratinocytes. ● The pathogenesis involves anti-desmoglein antibodies. ● When there is the involvement of autoantibodies against desmoglein 1, pemphigus vulgaris becomes systemic.

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Fig. 14.21-1 Pemphigus vulgaris. a: Edematous itching erythema and blister on the trunk. b: Intractable erosion on the lips and in the oral cavity. c: Erosion on the membrane of the genitalia (glans penis).

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When anti-desmoglein 3 antibodies are exclusively involved, an oral mucosa type of the disease develops. ● The disease most frequently occurs in the middle-aged and elderly. It tends to manifest as oral enanthema. ● Nikolsky’s sign is positive. ● Oral steroids and immunosuppressants are the first-line treatment. ●

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Fig. 14.21-2 Pemphigus vulgaris. d: A mix of blisters, erosion and crusts is present on the trunk. e: Blisters appear on normal skin.

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Clinical features Pemphigus vulgaris most frequently affects the middle-aged and elderly. Erosions and ulcers develop acutely in the oral mucosa in 70% to 80% of cases. Subsequently, blisters of various sizes occur on normal skin (Figs. 14.21-1 and 14.21-2). This blisp q k l m n o r tering may occur anywhere on the body; however, it tends to appear at sites prone to pressure and friction, such as the back, buttocks and feet. The blisters easily rupture to form large erosions and crusts. They are painful when touched. Blistering can be artificially produced by rubbing normal skin (Nikolsky’s sign). When the blisters are pressed without breaking, the fluid contents extend to the peripheral normal skin around the blisters (blister diffusion phenomena, sign). p q l mor false n Nikolsky’s o r Erosions form in the oral cavity and esophageal mucosa, causing dysphagia. When the eruptions are widespread, electrolyte abnormalities resulting from loss of body fluid or hypoproteinemia are found; this can be fatal when there is secondary infection. Complications include thymoma or myasthenia. Pathology, Laboratory findings Acantholysis causes intra-epidermal blistering. Blisters often form leaving one basal layer at the bottom; such blistering is described as “tombstone-like” (Fig. 14.22). Highly eosinophilic infiltration occurs in the blisters and the dermal upper layer. Anti-desmoglein 3 antibodies are detected by ELISA.

Fig. 14.22 Histopathology of pemphigus vulgaris. Acantholysis is observed on the basement cells.

Diagnosis In diagnosis, it is necessary to identify intercellular in vivo IgG deposition by immunofluorescence (IF), and to detect antidesmoglein antibodies by ELISA. The quantity of antibodies in Table 14.3 Autoantibody against desmoglein detected by ELISA, and confirmed diagnosis ELISA Diagnostic name

Anti-Dsg1 IgG antibody

Anti-Dsg3 IgG antibody

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Pemphigus foliaceus

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Normal or Non-pemphigus

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Dsg1

Dsg3

Dsg1

Dsg3

horny cell layer granular cell layer suprabasal cell layer basal cell layer lamina densa mucosa skin Expression of desmoglein 1 and desmoglein 3 in skin and mucosa of a healthy person. The differences in expression of Dsg1 and Dsg3 in the skin and mucosa explain the pathogenesis of pemphigus. Dsg1

Dsg3

skin

Dsg1

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mucosa

Dsg1

skin

Dsg3

Dsg1

Dsg3

Dsg1

mucosa

Dsg3

Dsg1

skin

When only Dsg1 is inhibited, skin lesions occur only in the upper dermal layer.

When only Dsg3 is inhibited, mucosal lesions occur. Skin lesion may also occur.

→ pemphigus foliaceus

→ pemphigus vulgaris  (mucosa-predominant type)

Dsg3

mucosa

When both Dsg1 and Dsg3 are inhibited, both skin lesions and mucosal lesions occur directly in the basal layer. → pemphigus vulgaris  (mucocutaneous-predominant type)

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Fig. 14.23 Mechanism of pemphigus, according to the expression of desmoglein 1 and desmoglein 3 (see also Fig. 14.19).

the serum is known to reflect the pemphigus condition. When only desmoglein 3 is detected, the disease is membrane-dominant pemphigus vulgaris, in which there is only minor blistering of the skin. When both desmoglein 1 and 3 are detected, blistering is often seen in the oral mucosa and systemic skin (Table 14.3, Fig. 14.23). Differential diagnosis It is necessary to differentiate the disease from dermatitis herpetiformis, bullous pemphigoid, impetigo, burns, bullous drug eruptions, erythema multiforme and Stevens-Johnson syndrome. Treatment Systemic application of steroids is the first-line treatment. According to the severity, 0.5 mg to 1.0 mg prednisolone per 1 kg of body weight per day is administered. The dosage is tapered off to a maintenance dose or until it can be discontinued. Immunosuppressants (mycophenolate mofetil, cyclophosphamide, azathioprine, methotrexate and cyclosporine) may be used. In intractable cases, plasma exchange therapy and megadose gamma-globulin therapy are also performed. Antibiotic

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Fig. 14.24-1 Pemphigus foliaceus. a: Erosion accompanied by scales and erythema on the back.

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application, fluid replacement and nutrition management are conducted supplementarily.

2. Pemphigus vegetans

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Clinical features Pemphigus vegetans is a subtype of pemphigus vulgaris whose onset is marked by the formation of vesicles and erosions that do not re-epithelialize but gradually proliferate and elevate. Lesions are often accompanied by vesicles and pustules. There is a strong odor, and the disorder frequently occurs on areas exposed to friction, such as the axillary fossa, umbilical fossa, and the periphery of the oculonasal and perioral regions. Pemphigus vegetans can be of Neumann type or Hallopeau type. The onset of the Neup q j is marked i k lby blistering, m nand pemphigus-vulgaris-like o r mann type blistered erosions form. Pustules mainly occur in the Hallopeau type, which has a better prognosis. Differential diagnosis Pemphigus vegetans should be differentiated from condyloma latum, condyloma acuminatum, proliferative chronic pyoderma and fungal granuloma.

Clinical images are available in hardcopy only.

Treatment The treatment is the same as for pemphigus vulgaris.

3. Pemphigus foliaceus b

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Fig. 14.24-2 Pemphigus foliaceus. b: Erosion, erythema and pigmentation on the chest. c: Exfoliation and erythema on the face. The blisters are thin and easily ruptured; tense blisters are rarely seen.

Clinical images are available in hardcopy only.

Fig. 14.25 Pemphigus erythematosus. In addition to the skin lesion of the pemphigus foliaceus, facial eruptions resembling the butterfly rash of systemic lupus erythematosus (SLE) are present.

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Outline

Autoantibodies are produced exclusively against desmoglein 1. ● Acantholysis and blistering are seen in the superficial epidermis (in the granular cell layer). ● Fragile blisters, scaling and erosion, accompanied by crusts, occur systemically. Lesions are not produced in the mucosa. ● Examinations and treatments are the same as for pemphigus vulgaris. The steroid dosage is usually less than for pemphigus vulgaris. ●

Clinical features Pemphigus foliaceus most commonly affects the middle-aged and elderly. Extremely fragile flaccid vesicles are produced, some of which dry to become leafy and to exfoliate successively. The face, head, back and chest are most commonly affected. When the disorder progresses and spreads over the whole body, it resembles exfoliative erythroderma (Figs. 14.24-1 and 14.24-2). Unlike pemphigus vulgaris, pemphigus foliaceus does not involve the mucosa. Nikolsky’s sign is positive.

Blistering diseases / B. Autoimmune blistering diseases

Pathology, Laboratory findings Acantholytic blistering is found in and between the epidermal horny cell layer and the epidermal upper layer. Intercellular in vivo IgG deposition is observed by immunofluorescence. Anti-desmoglein 1 antibodies can be detected by ELISA.

Transient acantholytic dermatosis

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This is also called Grover’s disease. Itching papules and blisters with acantholysis occur on the trunk and extremities, subsiding within three months. The pathogenesis is unknown. Autoantibodies against skin are not present.

Treatment Treatment is the same as for pemphigus vulgaris. The oral steroid dosage may be less than that for pemphigus vulgaris. Topical steroids are sufficient in some cases.

4. Pemphigus erythematosus Synonym: Senear-Usher syndrome Clinical features Pemphigus erythematosus is a subtype of pemphigus foliaceus, and it occurs most commonly in the middle-aged and elderly. It frequently affects the seborrheic zones on the head, face, chest and back. Systemic lupus erythematosus (SLE) like erythema or seborrheic dermatitis-like eruptions occur on the face, and pemphigus foliaceus-like intra-epidermal blisters form on the trunk (Fig. 14.25). The mucosa is not involved. Involvement of SLE is seen in some cases.

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Treatment The treatment is the same as for pemphigus foliaceus.

5. Paraneoplastic pemphigus Outline ● The

disease accompanies malignant or benign neoplasm (lymphoproliferative diseases in particular). Severe mucosal lesions with erosion, and various cutaneous lesions, appear. ● Autoantibodies against several epidermal proteins, such as desmogleins and plakin family molecules, are found.

Clinical images are available in hardcopy only.

Clinical features Erosions, ulceration and bloody crusts are widespread on mucous membranes in the oral cavity, pharynx and lips. Pseudomembranous conjunctivitis may lead to blepharosynechia. Various cutaneous lesions occur. It is important to test for IgG autoantibodies and to identify tumors accompanying paraneoplastic pemphigus. Treatment The neoplasms underlying paraneoplastic pemphigus are treated. Treatment is the same as for severe pemphigus vulgaris.

Fig. 14.26 Pemphigus induced by D-penicillamine. Erythema and vesicles are present. When induced by D-penicillamine, the skin lesion tends to persist even after the medication is discontinued.

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6. Drug-induced pemphigus

intraepidermal blister ―― e.g., pemphigus (flaccid bulla)

Drug-induced pemphigus is a catchall for diseases that cause lesions that resemble pemphigoid clinically and immunologically. It has various clinical symptoms and various histological and immunohistological findings (Fig. 14.26). Acantholysis is found in the epidermis of the lesions. In vivo IgA deposition is found in the epidermis of the lesions. Drug-induced pemphigus is most frequently induced by drugs that contain SH residue, such as dpenicillamine.

easily ruptures subepidermal blister ―― e.g., bullous pemphigoid (tense bulla)

Because a subepidermal blister is caused with all layers of the epidermis intact, it does not easily rupture.

Fig. 14.27 Difference between an intradermal blister and a subepidermal blister.

7. Neonatal pemphigus Neonatal pemphigus is seen in newborns of mothers with pemphigus. The mother’s IgG autoantibodies pass into the placenta, affecting the newborn infant’s skin. The clinical symptoms, and histological and immunohistological findings of pemphigus are transiently observed in neonatal pemphigus.

8. Intercellular IgA dermatosis Synonym: IgA pemphigus

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Intercellular IgA dermatosis is a rare disease that causes epidermal intercellular IgA deposition. Vesicles and pustules are Table 14.4 Autoimmune blistering diseases that cause subepidermal blisters. Bullous pemphigoid

Herpes gestationis

Cicatricial Epidermolysis pemphigoid bullosa acquisita

Dermatitis Linear IgA bullous herpetiformis (Duhring) dermatosis (LAD) Middle age

Age of onset

Elderly (youth in some cases)

4-monthpregnant to postpartum women

Adults and elderly

Frequent site

Whole body

Abdomen, buttocks, extremities

Whole body Oral cavity, Intertriginous areas ocular (e.g., elbows, knees,) (especially elbows, knees, buttocks) mucosa

Clinical findings

Tense blisters, edematous erythema, itching

Urticaria-like Blisters, erythema, erosion, itching scarring

Findings of skin Mucosal infiltration

＋

−

＋＋

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Erosion, blisters, scarring ＋

Itching, erythema, urticaria-like wheal −

<10 or 40

Whole body

Erythema, tense blisters, itching ＋

Pathological findings

Eosinophilic infiltration

Autoantigen

BP180, BP230

ImmunoDirect fluorescence findings

Linear Linear deposition of deposition of IgG and C3 in the C3 in BMZ epidermal basement membrane zone (BMZ)

Linear deposition of IgG in BMZ

Granular deposition of IgA in the papillae of upper dermal layer

Linear deposition of IgG (sometimes C3) in BMZ

Detection of antibasement membrane antibody

Detection of autoantibody against type VII collagen (290kDa)

Anti-autoantibody not detected

Detection of antiIgA antibody in BMZ

Oral steroids, immunosuppressant, plasmapheresis

Oral DDS, gluten-free diet

DDS, oral steroids

Indirect (Serum)

Treatment

Oral steroids, immunosuppressant, DDS

Eosinophilic infiltration BP180

Topical and oral steroids

Neutrophilic infiltration, Neutrophilic microabscess infiltration

Type VII collagen BP180, laminin-332

97kD (Degradation products of BP180)

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produced on the trunk and extremities, and they become chronic. Some cases are not clinically differentiable from subcorneal pustular dermatosis.

9. Fogo selvagem, Brazilian pemphigus foliaceus

Clinical images are available in hardcopy only.

Fogo selvagem (Brazilian pemphigus foliaceus) is endemic to Brazil and certain other areas of South America. Autoantibodies recognize desmoglein 1, which is the same as in pemphigus foliaceus. Transmission is thought to involve black flies of the family Simuliidae.

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b. Diseases with subepidermal blistering (pemphigoid group) Clinical images are available in hardcopy only.

Outline

These are autoimmune blistering diseases in which subepidermal blistering occurs as a result of autoantibody action against epidermal basement membranea structural proteins. ● Unlike the flaccid intra-epidermal blisters of pemphigus, these subepidermal blisters are tense and do not rupture easily (Fig. 14.27). ● Bloody blisters and milium may occur together. ● The disease is divided into pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita and other (Table 14.4). ● Immunofluorescence is useful for diagnosis. ● Steroids and DDS (dapsone) are applied. ●

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1. Bullous pemphigoid (BP) Outline ● Autoantibodies

against hemidesmosomes in the epidermal basement membranes are found. ● The major pathogenic antigen is Type XVII collagen (COL17, BP180). The roof of the blister has the full thickness of the epidermis. ● Elderly people account for the majority of cases. ● The disease is characterized by subepidermal blisters a b c that do not rupture easily, itching and enanthema. ● Oral steroids are administered. Clinical features The elderly are more commonly affected by bullous pemphigoid than are young people. Multiple relatively large and severe subepidermal blisters form immediately below the epidermis. Bullous pemphigoid is often accompanied by edematous

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Clinical images are available in hardcopy only.

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Fig. 14.28-1 Bullous pemphigoid. a: Itching, edematous erythema and tense bullae on the extremities. This is a typical skin manifestation of bullous pemphigoid. b: Skin lesions on the chest. c: Affected back. d: Comparatively large erythema.

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erythema (Figs. 14.28-1 and 14.28-2) and is much less invasive to the mucous membranes (about 20% of the mucous membrane is involved) than is pemphigus vulgaris. The general condition of the patient is favorable; however, it may be complicated by malignant tumors in the internal organs.

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Pathogenesis Autoantibodies are produced against hemidesmosome (HD) p q l m proteins, n o r structural Type XVII collagen (COL17, BP180) and BP230 (BPAG1) in the epidermal basement membranes, which leads to blistering. Autoantibodies against the membrane-proximal NC16a domain of BP180 play a major role in pathogenesis.

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MEMO Differential diagnosis between bullous pemphigoid and epidermolysis bullosa acquisita using salt-split-skin analysis Clinical images are available in hardcopy only.

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Differentiating between bullous pemphigoid and epidermolysis bullosa acquisita is often difficult because of the similar clinical courses and immunofluorescence (IF) findings. Normal human split skin processed with 1M NaCl is used for differential diagnosis. When normal human skin is soaked in 1M NaCl for 48 hours at 4 ˚C, the epidermis and dermis separate in the lamina lucida and artificial blistering occurs. The patient’s serum is reacted to skin with this epidermal-dermal separation as for IF: In the case of bullous pemp q the matrix n o r phigoid, the serum reacts to hemidesmosomes on the epidermal side; in the case of epidermolysis bullosa acquisita, the serum reacts to anchoring fibrils on the dermal side. Using this split-skin method, it is possible to distinguish between the diseases by the location of the blisters.

basal cells hemidesmosomes

Clinical images are available in hardcopy only.

1M NaCl

lamina lucida lamina densa anchoring fibril ① normal skin

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serum q of a patient r with bullous pemphigoid

② Epidermis and dermis are separated at the lamina lucida. serum of a patient with epidermolysis bullosa acquisita

Clinical images are available in hardcopy only. ③ Antibodies adhere to the epidermal side.

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Fig. 14.28-2 Bullous pemphigoid. e, f, g: Tense bullae on the trunk. h, i: Tense bullae on the palms, fingers and toes.

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③ Antibodies adhere to the dermal side.

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Pathology, Laboratory findings In bullous pemphigoid, subepidermal blistering is accompanied by eosinophilic infiltration (Fig. 14.29). Linear IgG and C3 deposition in the basement membranes of the lesions is observed by direct immunofluorescence (IF) (Fig. 14.30). Anti-epidermal basement membrane antibodies in the serum of the patients are detected by indirect IF; autoantibodies against Type XVII collagen proteins are identified by ELISA. High IgE values and elevated levels of eosinophils are found in peripheral blood in some cases. Diagnosis Bullous pemphigoid is diagnosed by clinical and pathological features and by IF and ELISA (Table 14.4). In vivo linear IgG deposition on the epithelial basement membranes is seen in all patients with bullous pemphigoid, which is a necessary criterion for diagnosis. Indirect IF using normal human split skin processed with 1M-NaCl is conducted to distinguish this disease from other subepidermal blistering diseases such as epidermolysis bullosa acquisita (MEMO). Treatment Oral steroids (0.5 mg/kg/day) are administered; and then gradually reduced. Combination therapy of immunosuppressants such as cyclophosphamide, DDS, tetracyclines and nicotinic-acid amide is also useful. Dehydration and secondary infections should be carefully avoided, and nutrition management is important for elderly patients. Topical steroid application may be sufficient in cases with mild symptoms. Plasma exchange therapy may also be performed in severe cases.

Fig. 14.29 Histopathology of bullous pemphigoid. A distinct subepidermal blister. Inflammatory cells including eosinophils are seen.

2. Herpes gestationis Clinical features Multiple urticarial erythema appears on the abdomen, buttocks and extremities between the fourth month of pregnancy and immediately following delivery, and vesicles form in the periphery of the erythema. The mucosa is rarely involved. Intense itching is present. Although herpes gestationis disappears 2 to 3 months after delivery in most cases, it becomes more recurrent and aggravated with each successive pregnancy. Pathogenesis It is thought to be a bullous pemphigoid that is specific to pregnant women. Herpes gestationis occurs in 1 in 5,000 to 1 in 10,000 deliveries. Autoantibodies against Type XVII collagen proteins are found in hemidesmosomes. Diagnosis Itching is intense. Herpes gestationis resembles dermatitis

Fig. 14.30 Direct immunofluorescence of the skin of a patient with bullous pemphigoid. Linear deposition of IgG is observed in the epidermal basement membrane.

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herpetiformis; however, it is distinguished by the absence of IgA deposition and the presence of linear C3 deposition (Table 14.4).

Clinical images are available in hardcopy only.

Treatment Topical steroids are mainly applied. In severe cases, oral steroids are administered.

3. Cicatricial pemphigoid Synonym: Benign mucous membrane pemphigoid Fig. 14.31 Cicatricial pemphigoid. Erosion in the eye and scarring occur.

Blistering and erosive lesions occur, mostly in the oral cavity and conjunctiva, leaving scarring (Fig. 14.31). Lesions may occur in the genitalia, perianal region, pharynx, esophagus and nasal mucosa. Prompt treatment is required if there is blepharosynechia or respiratory difficulty. Autoantibodies against Type XVII collagen proteins and laminin 332 are found.

4. Epidermolysis bullosa acquisita Clinical images are available in hardcopy only.

Outline

Autoantibodies against type VII collagen, which is a structural component of anchoring fibrils, are produced. ● Subepidermal blisters form. They leave milium when they heal. ● Differential diagnosis from bullous pemphigoid is clinically difficult. ● Steroids are administered orally. The disease is intractable. ●

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Fig. 14.32-1 Epidermolysis bullosa acquisita. Blistering, erosion and ulceration occur, which may be partially accompanied by scarring.

Clinical features In epidermolysis bullosa acquisita, friction erosions and blisters appear on the knees, elbows, palms and soles. They may leave scarring or progress in a course similar to bullous pemphigoid. Healing often leaves scarring and milium (Figs. 14.32-1 and 14.32-2). Pathogenesis Autoantibodies against type VII collagen, which is a structural component of anchoring fibrils that connect the epidermis and the dermis, are produced. Subepidermal blisters form as a result. Laboratory findings Linear IgG deposition is observed by direct immunofluorescence on the epidermal basement membrane of the lesions. Autoantibodies against type VII collagen of 290kD are found by immunoblot procedure using the patient’s serum. Diagnosis The absence of a hereditary history of blistering formation is

Blistering diseases / B. Autoimmune blistering diseases

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an important aid for diagnosis. The most reliable methods of diagnosing epidermolysis bullosa acquisita are indirect immunofluorescence using 1M-NaCl split skin as a substrate (MEMO), and immunoblot procedure. Differential diagnosis It is essential to differentiate this disease from other blistering diseases such as bullous pemphigoid, pemphigus, porphiria, drug-induced eruptions and amyloidosis. In progressive cases, cutaneous symptoms similar to dystrophic epidermal bullosa (nail deformity, coalescence of fingers and toes) may be present.

Clinical images are available in hardcopy only.

Treatment Epidermolysis bullosa acquisita is resistant to treatment. Oral steroids, immunosuppressants (e.g., cyclosporine) and plasma exchange are administered.

5. Dermatitis herpetiformis (Duhring) Outline ● It

is characterized by extremely intense itching and irritation, chronically recurrent erythema, and vesicles. The vesicles tend to form circular patterns. ● HLA-B8, DR3 and DQ2 are involved. The disease is rarely seen in ethnic Japanese. It is common in Caucasians. ● Granular IgA deposition is found in the dermal papillary. ● Gluten-induced enteropathy develops as a complication in many cases. ● Oral DDS is effective. Clinical features Extremely intense itching is present. Erythema and urticarial wheals occur, with vesicles produced in a ring-shaped pattern at the periphery (Fig. 14.33). The severe itching causes the patient to scratch, resulting in crusts, including bloody crusts. The eruptions heal with abnormal pigmentation or depigmentation. Eruptions appear symmetrically on the entire body, especially on the elbows, knees and buttocks. However, the palms, soles and mucosa are hardly affected. Gluten-induced enteropathy is found in more than 90% of cases. As in celiac disease, in which there is hypersensitivity to gluten, atrophic changes in jejunal villi are found in dermatitis herpetiformis. Pathogenesis In recent years, it has been discovered that patients with this disease have IgA antibodies against tissue transglutaminase in the serum. The granular IgA deposition in the skin is an immunocomplex.

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Fig. 14.32-2 Epidermolysis bullosa acquisita.

Clinical images are available in hardcopy only.

Fig. 14.33 Dermatitis herpetiformis (Duhring). Eczema and blisters accompanied by intense itching are present.

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Pathology Subepidermal blistering is present. Micro-abscesses are caused in dermal papillary by neutrophilic infiltration.

Clinical images are available in hardcopy only.

Laboratory findings Granular IgA deposition is observed by direct immunofluorescence (IF) in the dermal papillary. Anti-cutaneous autoantibodies are not seen in the patient’s serum by IF. The patient’s serum does not contain IgA-class anti-transglutaminase antibodies. Involvement of HLA-B8 in dermatitis herpetiformis has been found. There are elevated levels of eosinophils in the peripheral blood. Diagnosis Dermatitis herpetiformis is diagnosed by the clinical features, such as rashes, intense itching, subepidermal blistering, and granular IgA deposition in the papillary dermis. The symptoms are reduced remarkably by DDS; this fact has diagnostic significance. Dermatitis herpetiformis is rare in ethnic Japanese.

Fig. 14.34 Linear IgA bullous dermatosis.

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Differential diagnosis Dermatitis herpetiformis should be distinguished from linear IgA bullous dermatosis, bullous pemphigoid, herpes gestationis and erythema multiforme. Treatment Sulfa drugs such as DDS are effective. A gluten-free diet and antihistamines are also useful.

6. Linear IgA bullous dermatosis (LAD) Clinical features Linear IgA bullous dermatosis (LAD) is divided into childhood LAD, whose symptoms appear in children under age 10, and adult LAD, which occurs in adults age 40 or older. Multiple erythema and tense blisters accompanied by intense itching occur over the entire body, as in dermatitis herpetiformis (Fig. 14.34). Lesions may occur in the mucous membranes. The lesions tend to aggregate on the genitalia and inner regions of the thighs in childhood LAD and heal spontaneously in some cases. Pathogenesis, Epidemiology LAD is caused by linear IgA deposition on the epidermal basement membrane; the deposition pattern differs from that in granular dermatitis herpetiformis. In Japan, most cases of IgA deposition on the epidermal basement membrane are LAD; dermatitis herpetiformis is rare. Pathology Subepidermal blistering is found. Neutrophilic infiltration is

Pustular diseases / 1. Palmoplantar pustulosis (PPP)

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seen. Linear IgA deposition is found in the epidermal basement membranes. C3 may also deposit in some cases. Laboratory findings, Diagnosis Linear IgA deposition on the epidermal basement membranes can be identified by direct immunofluorescence (IF). Anti-epidermal basement membrane IgA autoantibodies may be detected in the patient’s serum by indirect IF. Differential diagnosis LAD should be differentiated from dermatitis herpetiformis. In LAD, ① there is a histopathological finding of linear patterns of in vivo IgA deposition, ② there are anti-basement membrane IgA auto-antibodies in serum in some cases, ③ there is no involvement of HLA-B8, DR3, or DQ2, ④ there is involvement of the mucosa, and ⑤ there is no sensitivity to gluten. Treatment DDS is effective, as are oral steroids.

Pustular diseases 14 1. Palmoplantar pustulosis (PPP) Synonym: Pustulosis palmaris et pustulosis Outline ● Multiple

sterile pustules form symmetrically on the palms and soles of the middle-aged and elderly, becoming chronic. ● Smoking, bacterial infection (tonsillitis), dental caries and dental metal allergy are associated with occurrence of PPP. ● Sternocostoclavicular ossification and pain may develop as complications. ● Topical steroid application, smoking cessation and tonsillectomy are the main treatments. Clinical features Multiple vesicles occur on the thenar and antithenar regions of the palms and arches of feet, and these become pustular. Erythema develops at the periphery of the lesions and fuses into plaques (Fig. 14.35). Itching may be present. Punctate depressions and thickening occur frequently in the nails. Pustules recur in 2- to 4week cycles and progress chronically. They may appear on the knees, lower extremities and scalp. In 10% of palmoplantar pustulosis (PPP) cases, sternocostoclavicular ossification accompanied by chest pain develops as a complication.

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Clinical images are available in hardcopy only.

Pathogenesis PPP patients are mainly female and tend to have smoked at least a pack a day for more than 20 years. If focal infections (e.g., tonsillitis, dental caries) are found and treated, PPP may improve. Cases induced by bacterial allergic reaction and metal allergy have been reported. It is hypothesized that PPP is a localized type of pustular psoriasis. Pathology Sterile pustules in the epidermis contain neutrophils and degenerated epidermal cells. Mild cellular infiltration into the dermis is seen.

Clinical images are available in hardcopy only.

Laboratory findings To detect focal infections such as tonsillitis and dental caries, the white blood cell count, antistreptolysin O, CRP and sedimentation rate are examined by peripheral blood tests. In some cases, skin lesions are aggravated by a tonsil provocation test. For confirmation of dental metal allergy in the mouth, metal patch tests are conducted. Tests for detection of arthropathy and ossification (sternocostoclavicular) are also conducted. Differential diagnosis The disease should be distinguished from tinea manus, pustular psoriasis, contact dermatitis, pompholyx and Reiter disease.

14 Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 14.35 Palmoplantar pustulosis (PPP). Multiple pustules aggregate on the hands and feet.

Treatment In most long-term smokers, the disorder disappears with cessation of smoking. Focal infectious diseases, if any, are treated. Prevention of tonsillitis and otological and dental treatments are important. Oral antibiotics are useful. Tonsillectomy may be performed. For skin lesions, topical steroids are the first line of treatment; additionally, vitamin D3 ointment and PUVA therapy are applied. Methotrexate, colchicin and etretinate are administered orally in severe cases.

2. Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) Clinical features Subcorneal pustular dermatosis occurs infrequently but most commonly in women over age 40. Erythema and pustules appear in a ring-shaped or serpigenous pattern on the trunk and on sites exposed to friction. Pustules quickly dry, leaving crusts and scales (frilly scales) (Fig. 14.36). Itching or systemic symptoms are not present, and the mucosa is not involved. The disease becomes chronic with recurrent aggravation and remission. Pathogenesis, Pathology, Differential diagnosis The etiology of subcorneal pustular dermatosis is unknown in

Pustular diseases / 3. Eosinophilic pustular folliculitis

many cases. In some cases, IgA myeloma or ulcerative colitis exists as a complication. Sterile pustules mainly containing neutrophils are found histopathologically under the horny cell layer. Spongiform pustules, seen in pustular psoriasis, are not found. Subcorneal pustular dermatosis is distinguished from intracellular IgA dermatosis by immunofluorescence. IgA class autoantibodies are not detected immunohistologically in the epidermal intercellular space.

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Clinical images are available in hardcopy only.

Treatment DDS and oral steroids are effective. Etretinate (a vitamin A derivative), and PUVA are effective in some cases.

3. Eosinophilic pustular folliculitis Synonyms: Ofuji’s disease, Eosinophilic pustular dermatosis Outline

Clinical images are available in hardcopy only.

● Itching

papules and pustules are produced. They aggregate, mainly in hair follicles. ● Male adults are the most commonly affected. Progress is chronic, with recurrences and remissions. The etiology is unknown. ● Multiple eosinophils are contained in the pustules. ● The disease may accompany HIV infection. ● Indomethacin is effective as a treatment. Clinical features, Pathogenesis Eosinophilic pustular folliculitis occurs most frequently in men in their 20s or 30s. Sterile, follicular and itching papules or small pustules occur and aggregate to form erythematous plaques that spread centrifugally (Fig. 14.37). The face, upper body and extensor surface of the upper arms are the most severely affected regions; in some cases, however, the eruptions can occur in the hands and soles, where hair follicles do not exist. They leave abnormal pigmentation when they heal. Eosinophilic pustular folliculitis recurs with remissions. The disease may accompany a hematologic disorders or HIV infection. Most cases have been reported from Japan. The cause is unknown. Pathology, Laboratory findings, Differential diagnosis, Treatment Eosinophils are found in large quantities in pustular components. Eosinophilic infiltration into the hair follicles and hair apparatuses results in destruction of hair follicles. Elevated levels of eosinophils are seen in the peripheral blood. Eosinophilic pustular folliculitis needs to be differentiated from tinea, candidiasis, folliculitis, acne, rosacea and contact dermatitis. When it occurs on the hands and soles, differentiation from pustulosis palmaris et plantaris is difficult. Indomethacin is very effective.

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Fig. 14.36 Subcorneal pustular dermatosis.

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4. Acute generalized pustular bacterid The appearance of acute sterile pustules on the trunk and extremities is followed by upper respiratory infection. Since the pathogenetic mechanisms have not been clarified, there is a controversy over whether acute generalized pustular bacterid is an independent clinical entity. Clinical images are available in hardcopy only.

5. Infantile acropustulosis The extremities of infants are affected. Infantile acropustulosis is a recurrent pustular disease that causes multiple sterile pustules and vesicles with intense pustular psoriasis. Refer to Chapter 15 for pustular psoriasis.

Fig. 14.37 Eosinophilic pustular folliculitis. Follicular papules and pustules aggregate, accompanied by itching.

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15

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Disorders of Abnormal Keratinization

The mechanisms of keratinization have been clarified in recent years. The genes responsible for many hereditary disorders of abnormal keratinization have been identified, but the pathogenesis of some disorders remain unknown. It is expected that these will be elucidated in the near future. s disease) Disorders of abnormal keratinization are classified as hereditary keratoses (e.g., ichthyosis, Darier’ and acquired diseases. The acquired diseases are subclassified as inflammatory diseases, whose main symptom is inflammation accompanied by itching (e.g., psoriasis, lichen planus), and non-inflammatory keratoses (e.g., clavus, callus). This chapter discusses typical disorders of keratinization, based on that classification.

A. Hereditary keratoses Table 15.1 Classification of ichthyosis.

a. Ichthyosis

Congenital ichthyosis Ichthyosis vulgaris

Ichthyosis is the clinical condition in which the whole body skin dries and becomes coarse, resulting in scaling. It is caused by abnormality in keratinization and exfoliation of the horny cell layer. The skin is covered with what appear to be fish-like scales. Patients with ichthyosis have a congenital abnormality in keratinization and scaling, and most cases are classified as hereditary keratoses. However, some may appear later in life as acquired conditions; these cases often accompany malignant tumors. Ichthyosis is classified by clinical features, inheritance pattern, and affected sites into more than ten subtypes (Table 15.1). This section introduces typical types of ichthyosis.

X-linked ichthyosis Bullous congenital ichthyosiform erythroderma (BCIE) Nonbullous congenital ichthyosiform erythroderma (NBCIE) Lamellar ichthyosis Harlequin ichthyosis Ichthyosis accompanied by internal organ lesion (Ichthyosis syndrome) Sjögren-Larsson syndrome Netherton syndrome KID syndrome Dorfman-Chanarin syndrome

1. Ichthyosis vulgaris

Refsum syndrome Rud syndrome Conradi syndrome

Outline ● It

is caused by mutation in the gene coding for filaggrin, a key protein involved in skin barrier function. This is the mildest form of ichthyosis. The main symptoms are dryness and scaling of the skin. ● The onset is early childhood. Dryness, and scaling of the skin are present, mostly on the extensor surfaces of extremities and trunk. It subsides during summer. ● It is the common inherited disorder of keratinization. ● Inheritance is semidominant. ● Symptomatic therapies including application of moisturizer are the main treatments. Clinical features The onset is early childhood. It is progressive until the patients reach about the age of 10, the symptoms subsiding in adolescence 229

Acquired ichthyosis Acquired ichthyosis

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in most cases. The skin dries, appearing pityroid and lamellar. The extensor surfaces of the legs and the back region are the most commonly affected; the flexure of joints in the extremities, axillary fossae genitals and thoraco-abdominal region are unaffected (Fig. 15.1). Subjective symptoms and itching are rarely observed. The symptoms subside during the summer and aggravate during the winter, when the skin tends to dry. Filaggrin mutation is a major predisposing factor for atopic dermatitis, and atopic disorders are strongly associated with ichthyosis vulgaris.

Clinical images are available in hardcopy only.

Pathogenesis The causative gene has recently been identified as the filaggrin gene (FLG). As a result of a decrease in the production of filaggrin, which moisturizes the epidermis, there is abnormal exfoliation of horny cells and dryness and scaling of the skin (Chapter 1). Ichthyosis vulgaris is semidominantly inherited (homozygous patients have more severe symptoms than heterozygous patients) and often runs in families. Pathology There is thickening of the horny cell layer and reduction or loss of keratohyaline granules and granular cell layer because of loss or reduction of filaggrins. Clinical images are available in hardcopy only.

Laboratory findings, Diagnosis Ichthyosis vulgaris is diagnosed by the clinical and pathological features, family history and filaggrin gene mutation.

15

Fig. 15.1 Ichthyosis vulgaris. The skin dries, and pityriasis-like lamellar exfoliation occurs.

Differential diagnosis In other hereditary ichthyoses, the onset is the time of birth, and the flexures of the joints in the extremities are often involved (Table 15.2). Acquired ichthyosis can be differentiated from ichthyosis vulgaris by the age of onset, the clinical course, and the presence of malignant tumor in the case of the former.

Table 15.2 Comparison between types of ichthyosis. Bullous congenital ichthyosiform erythroderma (BCIE) Rare Uncommon Common Frequency AD XR Inheritance pattern SD (semidominant) At birth or early after birth At birth or early after Babyhood, infancy Age of onset birth Whole body Site Extremities, trunk (back > Abdomen > back, Skin abdomen), intertriginous intertriginous sites, symptom sites, extensor surface > extensor surface = flexor surface flexor surface Form Fine scales Large, dark brown scales Severe hyperkeratosis Ichthyosis vulgaris

Pathology Causative gene

Hyperkeratosis, thinned granular cell layer Filaggrin (FLG)

X-linked ichthyosis

Degeneration of Hyperkeratosis, almost normal granular cell layer granular cell layer Keratin 1 or Steroid sulfatase keratin 10

Nonbullous congenital ichthyosiform erythroderma (NBCIE), lamellar ichthyosis Rare AR At birth

Very rare AR At birth

Whole body

Whole body

Flushing, fine or dark brown (NBCIE) large scales (lamellar ichthyosis)

Markedly thick hyperkeratosis, deep fissures, ectropion Severe hyperkeratosis ABCA12

Hyperkeratosis (with or without parakeratosis) Transglutaminase 1 in some cases

Harlequin ichthyosis

(AD: autosomal dominantly inherited, AR: autosomal recessively inherited, XR: x-linked recessively inherited, SD: semidominantly inherited).

A. Hereditary keratoses

231

Treatment, Prognosis Treatments are symptomatic. Moisturizer, urea ointments, salicylic acid petrolatum, and vitamin D3 ointments are applied. The symptoms subside after adolescence.

2. X-linked ichthyosis Outline ● It

is caused by loss or marked reduction of steroid sulfatase, resulting in delayed exfoliation of the horny cell layer. It is X-linked recessively inherited. ● The symptoms are severer than those of ichthyosis vulgaris. Eruptions also appear on the flexures of joints. Clinical features X-linked ichthyosis manifests shortly after birth and does not improve with age. The cutaneous symptoms are severe; the scales are large and dark brown (Fig. 15.2). The whole body of newborns may be encased in a translucent covering (collodion baby). Not only the extensor surfaces but also the flexures of extremities are affected. The abdomen is most severely affected. Corneal opacification may occur as a complication. As with ichthyosis vulgaris, X-linked ichthyosis aggravates during the winter and subsides during the summer. Pathogenesis It is caused by mutation in the steroid sulfatase gene on Xchromosome. Steroid sulfatase is the enzyme that breaks down cholesterol sulfate, a substance which promotes intercellular adhesion in the horny cell layer. The lack of steroid sulfatase causes accumulation of cholesterol sulfate, leading to delayed exfoliation of horny cells and hyperkeratosis (Chapter 1). Xlinked ichthyosis is recessively inherited and occurs in males.

Clinical images are available in hardcopy only.

Fig. 15.2 X-linked ichthyosis. Relatively large scales are present. The symptoms are severer than those of ichthyosis vulgaris.

Clinical images are available in hardcopy only.

Pathology, Laboratory findings Thickening of the horny cell layer, and normal or mildly thickened granular and suprabasal cell layers are present. Follicular keratinization is rarely found. Absence or marked reduction of steroid sulfatase is observed in the horny cell layer, peripheral leukocytes, and fibroblasts. Estriol in the urine decreases in the mothers (carriers) of children with X-linked ichthyosis. Differential diagnosis, Treatment Ichthyosis vulgaris is differentiated from X-linked ichthyosis by the decrease of steroid sulfatase in the case of the latter. The treatments are symptomatic and the same as those for ichthyosis vulgaris.

Fig. 15.3-1 Bullous congenital ichthyosiform erythroderma. Skin lesions accompanied by flushing and thick keratinization occur on the whole body surface.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

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Fig. 15.3-2 Bullous congenital ichthyosiform erythroderma. Flushing appears on the whole body. Severe, dark keratinization with a dirty appearance occurs on the hands and feet (often in cases of mutation in the keratin 10 gene).

3. Bullous congenital ichthyosiform erythroderma (BCIE)

Fig. 15.4 Histopathology of bullous congenital ichthyosiform erythroderma. Granular degeneration occurs in the epidermis.

Clinical features Patients with bullous congenital ichthyosiform erythroderma (BCIE) are sometimes born as collodion babies. Diffuse flushing and blistering recur for several weeks after birth. Scales gradually thicken, leading to severe keratinization in later childhood (Figs. 15.3-1 and 15.3-2). The thickly keratinized plaques are accompanied by flush and a characteristic odor. The whole body including the flexures of joints and extremities appear erythrodermatic and dark rose in color. The prognosis is good. Pathogenesis The cytoskeleton (intermediate filament) of suprabasal cells is

A. Hereditary keratoses

composed of keratin 1 and keratin 10. Because of mutation in the keratin 1 or keratin 10 gene, abnormal keratin fiber formation, cytoskeleton distortion, and epidermal blistering occur, leading to secondary thickening of the horny cell layer (Fig. 1.14). BCIE is autosomal dominantly inherited. Pathology The horny and suprabasal cell layers thicken, keratin fibers aggregate, and there are vacuolated cells containing large keratohyaline granules in the granular and suprabasal cell layers (granular degeneration, Fig. 15.4). Differential diagnosis, Treatment Blistering is marked, particularly in newborns. It is necessary to differentiate BCIE from epidermolysis bullosa, incontinentia pigmenti and impetigo contagiosa by the pathological findings. The treatments are oral retinoid and application of moisturizer.

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Clinical images are available in hardcopy only.

Fig. 15.5 Ichthyosis bullosa of Siemens. The clinical symptoms are milder than those of bullous congenital ichthyosiform erythroderma. Flushing and hyperkeratosis are present.

4. Ichthyosis bullosa of Siemens It is caused by mutation in the keratin 2e gene. The clinical features are similar to those of the mild type of bullous congenital ichthyosiform erythroderma; nonetheless, erythroderma is not present in ichthyosis bullosa of Siemens (Fig. 15.5). Localized granular degeneration is histopathologically seen in part of the uppermost prickle layer and granular layer where keratin 2e is expressed in the epidermal granular layer.

Clinical images are available in hardcopy only.

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5. Nonbullous congenital ichthyosiform erythroderma (NBCIE) Clinical features Most of the patients are born as collodion babies. Two to three days after birth, the collodion covering exfoliates, leaving the whole body surface with diffuse flushing and scaling (Figs. 15.61 and 15.6-2). The affected sites include the flexures of joints. Ectropion of eyelids may also occur. There are minor changes in the symptoms with season. NBCIE progresses until the age of 10, at which point it stops and subsides. The clinical manifestations range from mild to severe. Pathogenesis It is autosomal recessively inherited. The pathogeneses are various. Six or more genes are thought to be associated with occurrence of NBCIE. A certain mutation in the ABCA12 gene, the causative gene for harlequin ichthyosis, also causes NBCIE. The transglutaminase 1 gene, the causative gene for lamellar ichthyosis, can also cause NBCIE. Complete absence of transglutaminase 1 activity causes typical lamellar ichthyosis; severe reduction in such activity leads to NBCIE. The mechanism of

Clinical images are available in hardcopy only.

Fig. 15.6-1 Nonbullous congenital ichthyosiform erythroderma. Erosive flushing and fine scales are seen on the whole body. Blistering does not occur.

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Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 15.6-2 Nonbullous congenital ichthyosiform erythroderma. loricrin involucrin cellular membrane cornified cell envelope

magnification

magnification

keratin pattern cellular membrane lamellar granule keratohyaline granule nucleus

Cornified cell envelopes cover the horny cell membrane in the horny cell layer. They play an important role in increasing the strength of the horny cell layer against physical and chemical stimuli.

Fig. 15.7 Cornified cell envelope.

A. Hereditary keratoses

235

NBCIE is known to be a marked decrease in physical and functional strength of keratin (Figs. 15.7 and 1.16). Treatment Oral retinoid (a vitamin A derivative) is effective. The skin should be kept clean to prevent secondary infection.

Clinical images are available in hardcopy only.

6. Lamellar ichthyosis In approximately half of all cases of lamellar ichthyosis, the cause is an absence of transglutaminase 1; however, its activity is normal in some cases. Transglutaminase 1 is a calcium-dependent enzyme that is necessary for the formation of cornified cell envelopes in keratinocytes. The pathogeneses of lamellar ichthyosis are various. The scales in lamellar ichthyosis are clinically rough and large in most cases, dark brown, and plate-like or lamellar; these characteristics distinguish the scales from those in nonbullous congenital ichthyosiform erythroderma (NBCIE) (Fig. 15.8).

7. Harlequin ichthyosis Synonym: Harlequin fetus The patient is covered with an extremely thick stratum corneum at birth. Cracks in the skin, ectropion of eyelids, protrusion of lips, and difficulty of opening the mouth are so severe that most patients die within 2 weeks after birth (Fig. 15.9). In 2005, a Japanese dermatologist identified ABCA12 as the causative gene. ABCA12 is a lipid transporter in the lamellar granule, and the lack of ABCA12 leads to marked reduction of lipid content in the horny layer. There is abnormality of the lamellar granules in harlequin ichthyosis. It is autosomal recessively inherited, and DNA-based prenatal diagnosis is clinically applied.

Clinical images are available in hardcopy only.

Fig. 15.8 Lamellar ichthyosis. Large, dark brown scales are characteristic of lamellar ichthyosis.

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Clinical images are available in hardcopy only.

8. Ichthyosis syndrome Ichthyosis syndrome is a general term for congenital ichthyosis accompanied by involvement of certain organs. Most of the cutaneous symptoms resemble those of nonbullous congenital ichthyosiform erythroderma (NBCIE). The most frequently occurring types of ichthyosis syndrome are listed in Table 15.3. ①Sjögren-Larsson syndrome It is autosomal recessively inherited. The main characteristics are congenital ichthyosiform erythroderma, spasmodic acroparalysis, and mild to moderate mental retardation (Fig. 15.12). There is abnormality in the gene that codes for fatty aldehyde dehydrogenase (FALDH/ALD). The condition is caused by absence of FALDH.

Clinical images are available in hardcopy only.

Fig. 15.9 Harlequin ichthyosis. There is marked hyperkeratosis on the whole body surface. Ectropion of the eyelids results in reddening over the eyes. Normal eyeballs are present underneath.

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Table 15.3 Major ichthyosis syndromes. Disease

Inheritance pattern

Eruptions

Other symptoms

Sjögren-Larsson syndrome Netherton syndrome KID syndrome Dorfman-Chanarin syndrome Refsum syndrome

AR AR AD AR

Nonbullous congenital ichthyosiform erythroderma Atopic dermatitis-like eruption, bamboo hair Spiny hyperkeratosis in the extremities and face Nonbullous congenital ichthyosiform erythroderma

AR

Lamellar ichthyosis-like skin

Rud syndrome

AR

Nonbullous congenital ichthyosiform erythroderma

AD or AR

Nonbullous congenital ichthyosiform erythroderma

Mental retardation, spastic quadriplegia Atopic diathesis Hearing impairment, keratitis Lipid droplets in leukocytes, hepatic steatosis, cataract, neurologic manifestation Retinitis pigmentosa, polyneuropathy, cerebellar ataxia, inner-ear deafness Seizure, mental retardation, low height, gonadal hypofunction Skeletal defects, cataract, punctate shadow at bone ends, quadriplegia

Conradi syndrome

(AR: autosomal recessively inherited, AD: autosomal dominantly inherited).

Clinical images are available in hardcopy only.

a

b

c

d

e

Clinical images are available in hardcopy only.

f

g

h

i

j

k

Clinical images are available in hardcopy only.

l

m

n

o

p

q

15 Fig. 15.12 Sjögren-Larsson syndrome. Nonbullous congenital ichthyosiform erythroderma-like eruptions occur. Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

h

Fig. 15.10 Netherton syndrome. a: It is accompanied by atopic dermatitis-like eruptions and nonbullous congenital ichthyosiform erythroderma-like eruptions. b: The scalp hair becomes knotted and easily breaks at the knots, resulting in short hair (bamboo hair).

Fig. 15.11 KID syndrome. Prickle keratotic macules on the scalp.

②Netherton syndrome Autosomal recessively inherited, it is caused by a mutation in the SPINK5 gene, which codes for serine protease inhibitor. The eruptions resemble atopic dermatitis or nonbullous congenital ichthyosiform erythroderma (Fig. 15.10). Scalp hair becomes p q j i k easily l broken m (bamboo n o r knotted, short and hair). ③Keratitis, ichthyosis and deafness (KID) syndrome It is autosomal dominantly inherited. The main symptoms are keratitis, ichthyosis and deafness. Papillomatous or prickle keratotic lesions occur mainly on the face and extremities (Fig. 15.11). ④Dorfman-Chanarin syndrome It is an autosomal recessively inherited metabolic disorder of neutral lipids, caused by mutation in the CGI-58 gene, which codes for an enzyme that regulates metabolism of phospholipids. Triacylglycerol accumulates in the cytoplasma of various cells to form lipid droplets. The disorder may be accompanied by ichthyosis, liver disorder, hearing loss, mental retardation, cataract and nystagmus (Figs. 15.13 and 15.14). ⑤Refsum syndrome It is autosomal recessively inherited. In addition to lamellarichthyosis-like eruptions, there is night blindness caused by

r

A. Hereditary keratoses

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 15.13 Dorfman-Chanarin syndrome.

retinitis pigmentosa. Cerebellar ataxia, multiple neuritis polyneuritis, and sensorineural deafness are present. Levels of phytanic acid in the blood increase from congenital metabolic disorder. ⑥Rud syndrome It is known to be autosomal recessively inherited; boys are more commonly affected than girls, and most cases are sporadic. Congenital ichthyosiform erytheoderma-like skin manifestations, epilepsy, mental retardation, gonadal hypofunction and short stature may occur as complications. ⑦Conradi syndrome (Conradi-Hünermann-Happle syndrome) The symptoms of nonbullous congenital ichthyosiform erythroderma, abnormal formation of bones, cataract, and paralysis in all extremities occur. Conradi syndrome is X-linked dominantly inherited. Males die prenatally. The cause is mutation in the emopamil binding protein (EBP) gene at Xp11.22-p11.23.

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Fig. 15.14 Histopathology of Dorfman-Chanarin syndrome.

b. Palmoplantar keratoderma Definition, Classification Palmoplantar keratoderma is a generic term for diseases that hereditarily cause hyperkeratosis in the palms and soles. It is subclassified by clinical features and patterns of inheritance (Figs. 15.15-1 and 15.15-2; Table 15.4). Genetic mutation is identified in some cases. Further clarification is necessary for exact classification of palmoplantar keratoderma. The main types of palmoplantar keratoderma are shown below. Treatment There is no effective treatment for any types. Oral retinoid (a vitamin A derivative) and topical application of petrolatum salicylate or moisturizer are the main treatments.

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1. Thost-Unna palmoplantar keratoderma Thost-Unna palmoplantar keratoderma is autosomal dominantly inherited. Localized diffuse lesions with a red halo form on the palms and soles of infants. Thickening of the horny cell layer and epidermis is seen. In recent years, cases with mutation in the keratin 1 gene have been reported. The palms and soles of patients with Thost-Unna palmoplantar are usually hyperhidrotic.

Clinical images are available in hardcopy only.

2. Vörner palmoplantar keratoderma It is autosomal dominantly inherited. Differentiation from Thost-Unna palmoplantar keratoderma can be made by histopathological detection of granular degeneration; such differentiation is impossible from clinical findings. Mutation in the keratin 9 gene is found in half of all patients with Vörner palmoplantar keratoderma. Clinical images are available in hardcopy only.

3. Mal de Meleda Synonym: Meleda disease This autosomal recessively inherited disease is often seen in offspring of consanguineous marriages. It hardly ever occurs in Asians. Hyperkeratosis accompanied by flush appears immediately after birth. Keratinization progresses and extends as the patient ages. In many cases, not only are the palms and soles affected, but so are the dorsal hands and feet, arms and legs. It is progressive until the patients become elderly. Mental retardation may occur.

15 Clinical images are available in hardcopy only.

4. Dominant Meleda palmoplantar keratoderma Fig. 15.15-1 Palmoplantar keratoderma. Keratinization of varying severity is present on the hands. It is often difficult to determine the subtype only by clinical findings.

Relatively mild reddening and keratinization affect the dorsal hands and feet.

Table 15.4 Major types of palmoplantar keratoderma. Disease

Inheritance pattern

Age of onset

Eruptions

Other symptoms

Thost-Unna keratoderma

AD

Babyhood, infancy

Vörner keratoderma Mal de Meleda

AD AR

Babyhood, infancy Babyhood

Hyperhidrosis on the palms and soles Granular degeneration (histologically) Mental retardation

Dominant Mal de Meleda keratoderma Keratosis palmoplantaris transgrediens Nagashima Keratosis palmoplantaris linearis/striata Punctate palmoplantar keratoderma

AD

Infancy, early childhood Babyhood, infancy

Diffuse keratotic eruption with a red-halo in the periphery localized on the palms and soles Thost-Unna keratoderma-like eruption Hyperkeratosis accompanied by flushing, spreading to the dorsum of hands and feet with age Resembles eruption in Mal de Meleda; however, keratosis and flushing are milder Mild keratosis on the dorsum of hands and feet

Infancy, early childhood Early childhood to elderly

Linear, band-like, or round hyperkeratosis on the palms and soles Multiple, firm, punctate keratotic papules on the palms and soles

AR AD AD

(AR: autosomal recessively inherited, AD: autosomal dominantly inherited).

May be accompanied by nail deformity resulted from malnutrition

A. Hereditary keratoses

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 15.15-2 Palmoplantar keratoderma.

5. Keratosis palmoplantaris transgrediens Nagashima The symptoms are relatively mild, similar to those of Mal de Meleda. Keratinization is mild. It is autosomal recessively inherited. The pathogenesis has not been identified.

15 Clinical images are available in hardcopy only.

6. Keratosis palmoplantaris linearis/striata It is autosomal dominantly inherited. Linear, band-like or round hyperkeratosis is present in the palms and soles. Mutations in the desmoglein 1 and desmoplakin genes are found in some families.

7. Punctate palmoplantar keratoderma It is autosomal dominant inherited. Punctuate keratinization is seen in the palms and soles.

Fig. 15.16 Keratosis palmoplantaris mutilans (Vohwinkel).

8. Keratosis palmoplantaris mutilans (Vohwinkel) Keratosis occurs in the palms and soles, which leads to strangulation obstruction in fingers and toes (Fig. 15.16). Star-shaped keratinized plaques develop on the dorsal surfaces of the hands and feet and on the kneecaps. Mutation in the loricrin gene has been reported.

Clinical images are available in hardcopy only.

9. Papillon-Lefévre syndrome Flush and hyperkeratosis occur on the palms, soles, the dorsal surfaces of hands and feet, and the extremities. The syndrome is

Fig. 15.17-1 Papillon-Lefévre syndrome. Flushing and the hyperkeratosis are present.

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characterized by periodontal disease (Figs. 15.17-1 and 15.17-2). It is autosomal recessively inherited. Clinical images are available in hardcopy only.

10. Richner-Hanhart syndrome The three major characteristics are painful palmoplantar keratosis, photophobia, and mental retardation. It is autosomal recessively inherited. The pathogenesis is a reduced activity of tyrosine aminotransferase.

Fig. 15.17-2 Papillon-Lefévre syndrome.

11. Náxos disease Keratosis, cardiac myopathy of the right ventricle, cardiac enlargement, and palmoplantar keratosis are present. Cases with mutation in the plakoglobin gene have been reported. Clinical images are available in hardcopy only.

c. Other hereditary keratoses 1. Darier’s disease Synonym: Keratosis follicularis a

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papules of 2 mm to 5 mm in diameter appear, mainly on seborrheic and intertriginous areas. The condition is aggravated by perspiration in summer. ● The pathogenesis is genetic mutation in SERCA2, the calcium pump of keratinocytes. It is autosomal dominantly inherited. ● The characteristic pathological findings are acantholysis, lacunae, corps ronds, and grains.

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Fig. 15.18-1 Darier’s disease. a, b: Dark brown, keratotic papules on the whole body. c: Verrucous keratinization on the palm.

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Clinical features Darier’s disease first occurs in infancy and continues through adolescence. Multiple dark brown keratotic papules of 2 mm to 5 mm in diameter covered by thick crusts occur in the seborrheic and intertriginous areas such as the neck, axillary fossae, sternal region, inframammary region, abdomen and groin (Figs. 15.18-1 and 15.18-2). The papules may be moist and give off a bad odor. On the perspiratory intertriginous areas, papules coalesce and condyloma-like proliferation occurs. The following occur: keratosis in the palms and soles, verrucous keratosis in the dorsal surfaces of hands and feet, punctuate depression in the palms, enanthema, deformity of nails, and sometimes nervous symptoms such as mental retardation and epilepsy. Bacterial or viral infection (e.g., Kaposi’s varicelliform eruption) may occur secondarily.

Clinical images are available in hardcopy only.

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Pathogenesis p q k l m n o r Darier’s disease is caused by mutation in the ATP2A2 gene, which codes for the SERCA2 calcium pump. That pump controls the calcium concentration in the cytoplasm of keratinocytes. j

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Since calcium regulates intercellular adhesion and differentiation of keratinocytes, the genetic mutation promotes keratinization and abnormal formation of desmosomes and keratin fiber complex, leading to abnormal dyskeratosis and acantholysis. Pathology Darier’s disease is characterized by dyskeratosis. Therefore, corps ronds (large round cells with a basophilic pyknotic nucleus and bright cytoplasm) and grains (long, thin cells that resemble parakeratotic cells and stain dark) are found in the granular layer. b There is acantholysis, its accompanying lacunae aformation, andc villi formation in which dermal papillae extend upwards into the lacunae (Fig. 15.19).

Clinical images are available in hardcopy only.

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Fig. 15.18-2 Darier’s disease. d: Changes of nail plates.

Differential diagnosis Darier’s disease should be differentiated from acanthosis nigricans, Hailey-Hailey disease and seborrheic dermatitis. Treatment The symptoms are improved temporarily by oral retinoid. Urea ointments are also useful. Secondary infections and sun exposure should be avoided.

2. Erythrokeratodermia Localized keratotic lesions accompanied by flush may be produced in infancy; erythrokeratodermia is the generic term for these clinical conditions. There are various clinical features and causative genes (Fig. 15.20). The following are the major types of erythrokeratodermia. ①Progressive symmetric erythrokeratodermia It is autosomal dominantly inherited. In some cases, mutation in the gene coding for loricrin has been identified. Localized, sharply circumscribed flushing and keratotic lesions are present. The extremities are most commonly affected. It often appears symmetrically. The lesions extend with time. The main treatment is oral retinoid. ②Erythrokeratodermia variabilis It is autosomal dominantly inherited. In some cases, mutation in the gene coding for connexin has been identified. Localized, sharply circumscribed flushing and keratotic lesions appear in infants under 1 year old. The lesions occur symmetrically on the face, trunk and extremities, and tend to extend and coalesce. They disappear in several days to several weeks, recurring on different sites. Scaling is marked and gives the skin an unwashed appearance, but there are no subjective symptoms. The main treatment is oral retinoid.

15 Fig. 15.19 Histopathology of Darier’s disease. There are dyskeratotic cells, acantholysis, fissures and villi in the epidermis.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Skin fragility syndrome→See Chapter 14. Fig. 15.20 Erythrokeratodermia variabilis. Sharply demarcated keratotic erythema.

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B. Acquired keratoses a. Inflammatory keratoses 1. Psoriasis (Fig. 15.21) Clinical images are available in hardcopy only.

Outline ● It

Fig. 15.21 Psoriasis vulgaris on the back.

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most frequently occurs in young and middle-aged men and women. Erythema and papules are accompanied by thick silvery-white scales. Inflammation in the epidermis and accelerated turnover of epidermal cells are found. ● It is classified by clinical features into five types: psoriasis vulgaris, guttate psoriasis, pustular psoriasis, psoriatic erythroderma and psoriatic arthritis. ● Auspitz phenomenon and Köbner phenomenon are the characteristic features. ● The pathological findings are thickening of the epidermis, hyperkeratosis associated with parakeratosis, vasodilation in the papillary dermis, and neutrophilic infiltration directly under the horny cell layer (Munro’s microabscess). ● The main treatments are topical vitamin D3 ointments, topical steroids, PUVA therapies and narrow-band UVB. Immunosuppressants (methotrexate and cyclosporin) and retinoids are also useful, and biological therapies are also used for severe cases. Classification Psoriasis occurs in 1% to 2% of Caucasians and about 0.1% of ethnic Japanese. Men outnumber women by 2 to 1. Psoriasis is classified by symptoms into five types: psoriasis vulgaris (mainly keratotic erythema accompanied by scaling), guttate psoriasis (scattered small lesions with a diameter of 1 cm or less), pustular psoriasis (mainly pustular eruptions), psoriatic erythroderma and psoriatic arthritis (Table 15.5). Some cases change from one type to another. Psoriasis vulgaris accounts for an overwhelming majority of all cases. Clinical features The onset of psoriasis is mostly in adolescence through middle age. Remissions and exacerbations recur through life. Some cases have complete remission. Each type is described below. Pathogenesis The essential pathogenesis is unknown. The turnover from basal cell to horny cell to exfoliation, which normally takes 28 days, takes only 4 to 7 days, because of enhanced proliferation of epidermal cells. Psoriasis is strongly familial, especially in

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Table 15.5 Types and findings of psoriasis. Clinical findings

Pathological findings

Psoriasis vulgaris

Red papules become sharply demarcated erythema that is accompanied by silver-white scales. Scratching generates silvery-opaque scale. Auspitz phenomenon, Köbner phenomenon

Munro’s microabscess, club-shaped epidermal rete ridges, capillary vasodilation

Guttate psoriasis

The same severity of psoriasis vulgaris. The size of erythema is about 1 cm in diameter.

Munro’s microabscess, club-shaped epidermal rete ridges, capillary vasodilation

Pustular psoriasis

Sterile pustules on erythema, fever, Kogoj’s spongiform pustules malaise

Diffuse flushing, fine scales on the Psoriatic erythroderma whole body Psoriatic arthritis

Fig. 15.22 Histopathology of psoriasis. There is hyperkeratosis and club-shaped extension of the epidermis (regular acanthosis).

Seronegative arthritis accompanied Munro’s microabscess, by psoriasis, in DIP joints and club-shaped epidermal vertebra rete ridges, capillary vasodilation

Caucasians. For this reason, multiple genes are certainly involved. When one identical twin has psoriasis, the other is reported to have a 65% chance of also having the disorder. HLACw6 is associated with the occurrence. Recent study suggests that dysfunction of T cells is the primary event and that dyskeratosis of the epidermis occurs secondarily. Additional inductive factors include irritants, injury, sunlight, infection (hemolytic streptococcus, in particular), and drugs (e.g., lithium, βblockers, calcium antagonists). Pathology Inflammation occurs, most severely in the upper epidermal layer (Fig. 15.22). As the epidermal turnover is abnormally enhanced, epidermal cells forming the horny layer retain their nuclei (parakeratosis). Hyperkeratosis is present. Munro’s microabscesses caused by infiltration of neutrophils are found directly below the horny cell layer. Because epidermal cells move to the horny cell layer before they produce keratohyaline granules, the granular layer thins and disappears, resulting in thickening of the suprabasal cell layer. Because the epidermal rete ridges become club-shaped and extend toward the dermis, the dermis protrudes directly below the horny cell layer in some areas. In pustular psoriasis, multiple neutrophils infiltrate into the upper suprabasal cell layer, and epidermal cells are destroyed to form spongiosis called Kogoj’s spongiform pustule (Fig. 15.23). Laboratory findings Köbner phenomenon and Auspitz phenomenon are present. Inflammatory findings such as elevated erythrocyte sedimentation rate, leukocytosis and hyperproteinemia may be caused in pustular psoriasis and psoriatic erythroderma. In psoriatic arthritis, rheumatoid factors are usually negative.

Fig. 15.23 Histopathology of pustular psoriasis (Kogoj’s spongiform pustule). The dermis projects to the bottom of the horny cell layer. Sterile abscess (Munro’s microabscess) caused by neutrophils is seen directly beneath the horny cell layer.

Clinical images are available in hardcopy only.

Fig. 15.24-1 Psoriasis vulgaris.

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Diagnosis Psoriasis is diagnosed by the characteristic clinical findings; however, a biopsy may be conducted for differential diagnosis. In pustular psoriasis, pustules are sterile. Diseases to be differentiated from psoriasis See Table 15.6.

Clinical images are available in hardcopy only.

Treatment The main treatments are topical active forms of vitamin D3 ointments and steroids, PUVA therapies, and narrowband UVB therapies. In severe cases, retinoids or immunosuppressants (e.g., methotrexate, cyclosporine A) are orally administered. Oral steroids tend not to be used because they may induce pustular psoriasis. The combination of tar with UV light (Goeckerman regimen) is no longer widely used due to its oncogenicity. Biological therapy has come to be used. Types of psoriasis

1) Psoriasis vulgaris

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Clinical images are available in hardcopy only.

Fig. 15.24-2 Psoriasis vulgaris. Sharply demarcated, thick, silver-gray scales adhere to the surface of the erythematous plaques.

Rose pink papules appear and extend to coalesce gradually into sharply circumscribed erythematous plaques with thick silvery scales on the surface (Figs. 15.24-1 to 15.24-4). The eruptions are usually asymptomatic; however, itching is present in some cases. Areas that are subjected to external stimulation, such as the elbows, patellae, scalp and buttocks are most commonly involved. The disorder may also occur in the intertriginous areas of obese people.

2) Guttate psoriasis Multiple keratotic erythema of up to 1 cm in diameter occurs on the trunk and proximal sides of the extremities with a relatively acute course (Figs. 15.25-1 and 15.25-2). Individual eruptions are the same as those of psoriasis vulgaris. It is often seen in children. Streptococcal infection or drugs can be the causative factors.

MEMO

Laboratory findings on psoriasis: Waxfragment phenomenon, Auspitz phenomenon When psoriatic eruptions are scraped with a fingernail, white scales that resemble wax flakes are seen. With the peeling off of the scales, petechia is easily caused; this is called Auspitz phenomenon. It is caused by the intrusion of dermal papillae directly into the horny cell layer. Stimulation such as injury may induce eruptions at normal sites of skin in patients with psoriasis (Köbner phenomenon).

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Waxy silvergray flakes and lamellar scales occur.

Petechia is caused by reduction in the granular layer and telangiectasia (Auspitz phenomenon).

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Table 15.6 Differential diagnosis of psoriasis. Differential points

Disease Seborrheic dermatitis

The clinical findings resemble those of psoriasis, but the affected sites are relatively localized at seborrheic areas.

Chronic eczema

Various, localized skin lesions including erythema, scales, papules, and blisters. Intense itching. The lesions are less clearly margined than in psoriasis.

Parapsoriasis

Pigmentation and atrophy are often present. Histopathological differentiation may be necessary.

Pityriasis rosea Psoriasis-like lesion appears after manifestation of the first eruption, and disappears in 1 or 2 months. (Gibert) Mycosis fungoides

Clinical findings may resemble those of psoriasis. Histopathological infiltration of atypical lymphocytes to the epidermis (Pautrier's microabscess).

Syphilitic psoriasis

Psoriasis-like eruptions on the palms and soles. Historytaking and serologic test for syphilis are important.

Drug eruption

History-taking on drugs and tolerance test are conducted.

Ankylosing spondylitis

Psoriasis-like eruption in some cases; differentiation from psoriatic arthritis is important.

Clinical images are available in hardcopy only.

3) Pustular psoriasis Pustules are the main clinical feature. The disorder is subdivided into a generalized type and a localized type (Table 15.7). In the generalized type, fever, systemic fatigue and bodily chills accompany erythema on which multiple sterile pustules occur and coalesce. The pustules rupture spontaneously to form erosions. Exudative fluid may cause hypoproteinemia, leading to marked systemic aggravation in some cases. It may occur in the course of psoriasis vulgaris, or it may develop suddenly without any history of psoriasis (Fig. 15.26).

Clinical images are available in hardcopy only.

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4) Psoriatic erythroderma Psoriatic skin lesions appear all over the body and become erythroderma. Proteins are consumed in large amounts in the lesions. The horny cell layer forms incompletely, bringing hypoproteinemia, dehydration and electrolyte abnormality.

Clinical images are available in hardcopy only.

5) Psoriatic arthritis Arthritis symptoms may accompany psoriasis. The majority of cases are the peripheral type, which affects distal interphalangeal (DIP) joints. There is a type in which vertebra and sacroilitis are involved. Arthritis proceeds without psoriatic skin lesions in many cases. There is association with the HLA-Cw6 gene.

Fig. 15.24-3 Psoriasis vulgaris on the arm and buttocks.

2. Pityriasis rubra pilaris Clinical features Follicular inflammatory papules of 2 mm to 3 mm in diameter

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 15.24-4 Psoriasis vulgaris on the extremities and nails.

Clinical images are available in hardcopy only.

Fig. 15.25-1 Guttate psoriasis on the trunk. Multiple keratotic erythema of 1 cm in diameter occur.

occur on the fingers, extensor surfaces of the extremities, and upper abdomen. The papules are flushed and have a white keratotic acuminate plug (keratotic plug) in the center (Fig. 15.27). When produced on the elbows and back of the knees, these eruptions coalesce to present sharply circumscribed orange psoriatic plaques to which scales are attached. Multiple white keratotic papules also occur with a coarse, grater-like appearance. Highly diffuse keratosis is seen on the palms and soles. It is usually asymptomatic. There are cases in which the eruptions may spread and become erythroderma, and cases with reduced dark adaptation resulting from lack of vitamin A. Pathogenesis, Epidemiology The etiology is unknown. There are peaks of occurrence at infancy and in the fifth decade of life; pityriasis rubra pilaris is divided into a juvenile type and an adult type. Most of the juvenile

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Table 15.7 Classification of pustular psoriasis. Clinical findings

Classification

Pustules are localized around the plaques of psoriasis vulgaris.

Localized Localized type pustular psoriasis Pustular psoriasis Palmoplantar with generalized pustulosis (PPP) skin lesion

Generalized Generalized type pustular psoriasis (GPP)

Pustules are localized bilaterally on the thenar and arch of the foot.

Acrodermatitis continua of Hallopeau

Often occurs secondarily after an external injury. Pustules and nail deformity occur on the tips of fingers or toes on one side of the body.

Acute generalized pustular psoriasis (von Zumbusch psoriasis)

Psoriasis vulgaris progresses to be accompanied by systemic symptoms. Poor prognosis.

Clinical images are available in hardcopy only.

Fig. 15.25-2 Guttate psoriasis on the buttocks.

Subacute, circular The systemic symptoms pustular psoriasis are milder than those of von Zumbusch psoriasis. Impetigo herpetiformis

Pustules are generalized during the middle and last stages of pregnancy.

cases are familial and autosomal dominantly inherited. A subtype caused by HIV has been reported in recent years. Pathology The follicles are dilated and filled with keratin. The peripheral epidermis is thickened and there is parakeratosis in some parts. Complete keratinization alternates with incomplete keratinization. Polymorphonuclear cells do not infiltrate into the epidermis, which is useful for differentiation from psoriasis. Vasodilation and lymphocytic infiltrate are observed in the upper dermis. Differential diagnosis Pityriasis rubra pilaris should be differentiated from psoriasis, cutaneous T-cell lymphoma, seborrheic dermatitis, drug eruption, ichthyosis and contralateral progressive erythrokeratoderma. Treatment, Prognosis Both types heal spontaneously, within a year in the juvenile type and within 2 to 3 years in the adult type. The symptomatic therapies are application of urea ointments, salicylic acid petrolatum ointments, and active forms of vitamin D3 ointments. Oral retinoid is also useful.

3. Parapsoriasis en plaque It is a generic term for diseases that produce multiple psoriasislike keratotic erythema. The pathogenesis is unknown, but it is thought to be different from that of psoriasis. Some large-plaque

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 15.26 Pustular psoriasis. The main skin lesions are sterile pustules.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

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Fig. 15.27 Pityriasis rubra pilaris. There are follicular papules, diffuse keratinization on the hands and soles, and orange psoriatic plaques.

parapsoriasis may be prodromes of mycosis fungoides. However, there are many cases in which small-plaque and large-plaque parapsoriasis occur at the same time.

1) Small-plaque parapsoriasis MEMO Parapsoriasis The definition, concept and diagnostic name for parapsoriasis have not been clarified. In the 1970s, it became widely accepted that large-plaque parapsoriasis and small-plaque parapsoriasis are two distinct disorders. In recent years, large-plaque parapsoriasis has come to be regarded as the early patch stage of mycosis fungoides. Pityriasis lichenoides is known to be a parapsoriatic disease, and it is classified into pityriasis lichenoides chronica (PLC; formerly called guttate parapsoriasis) and pityriasis lichenoides et varioliformis acuta (PLEVA; also called Mucha-Habermann disease).

Monomorphic round to oval erythematous plaques of 2 to 5 cm in diameter appear mainly on the trunk. Lesions are asymptomatic, and histopathologically findings are non-specific. Emollients and UVB are helpful.

2) Large-plaque parapsoriasis Large erythematous or yellowish atrophic plaques occur on the trunk and extremities. The lesions persist for many years, and gradually increase in number and affected area. They occur most frequently in middle-aged and elderly men (Fig. 15.28). Subjective symptoms such as itching are not present. The eruptions are

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usually more than 5 cm in diameter and accompanied by poikiloderma. Some but not all patients may develop mycosis fungoides (Fig. 22.35). Careful check up of the disease course is necessary. PUVA therapy is effective.

4. Pityriasis lichenoides This disorder is difficult to classify. This entity is sometimes regarded as cutaneous vasuculitis, rather than as a keratotic disorder. Pityriasis lichenoides tends to be limited to the trunk, thighs and upper arms. It rarely occurs on the face, palms or soles. The eruption progresses slowly over the course of many years. Adult men are most commonly affected. Erythema or rose pink papules of several millimeters to 1 cm in diameter, to which white scales are attached, appear. The eruptions are continuously produced, and a distinguishing characteristic of the disorder is the presence of new eruptions together with older ones (Figs. 15.29-1 and 15.29-2). It is asymptomatic. It heals with pigmentation or depigmentation. Pityriasis lichenoides is divided into two main forms, Pityriasis lichenoides chronica (PLC) and Pityriasis lichenoides et varioliformis acuta (PLEVA), but intermediate forms or patients with both forms are often seen. ① Pityriasis lichenoides chronica (PLC) Synonym: guttate parapsoriasis This is a chronic form. This individual eruption is a rose pink plaque. Young adults are usually affected.

Clinical images are available in hardcopy only.

Fig. 15.28 Large-plaque parapsoriasis. Relatively sharply demarcated slight erythema is present.

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Table 15.8 Classification and features of parapsoriasis. Parapsoriasis en plaque and pityriasis lichenoides Clinical findings Pathological findings Large-plaque parapsoriasis Small-plaque parapsoriasis

Pityroid scales and erythema appear. Itching is not present. Lymphocytic infiltration in the dermo-dermal junctions The eruption is 5 cm or more in diameter, accompanied by atrophy, and may be a precursor of mycosis fungoides in some cases. The eruption is less than 5 cm in diameter. Clinical images are available in hardcopy only.

Pityriasis lichenoides (guttate parapsoriasis) Clinical findings

Fine white scales, erythema of 1 cm or less in diameter, polymorphic skin lesion with old and new eruptions Lymphocytic infiltration to the epidermis

Pathological findings Pityriasis lichenoides The main symptom is erythematous plaque. chronica (PLC) (previous guttate parapsoriasis) Pityriasis lichenoides The main symptoms are severe inflammatory et varioliformis acuta symptoms and ulceration. (PLEVA)

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Fig. 15.29-1 Pityriasis lichenoides chronica. Old eruptions are rarely seen simultaneously with new ones on the lesion. Ulceration does not occur.

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② Pityriasis lichenoides et varioliformis acuta (PLEVA) Synonym: Mucha-Habermann disease This is more acute form and less common. Intense acute inflammatory symptoms are present. Multiple papules are accompanied by ulceration. Some patients with lymphomatoid papulois show similar clinical appearance to PLEVA (Figs. 15.30 and 15.31).

Fig. 15.29-2 Pityriasis lichenoides chronica.

5. Lichen planus Outline

Flat-topped, elevated, grayish-blue to purplish-rose plaques form on the flexures of the extremities and in the oral cavity. It progresses slowly. ● It is often induced by drugs. However, the cause is heterogeneous. ● Köbner phenomenon is positive. Delicate white lines known as Wickham striae are seen on the surface. ● Vacuolar degeneration is pathologically found. Band-like infiltration of lymphocytes occurs in the superficial dermis. ● Use of the causative drug is discontinued. Steroid ointments and tacrolimus ointments are useful. ●

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Fig. 15.30 Pityriasis lichenoides et varioliformis acuta. There are intense acute inflammatory symptoms, and old and new eruptions are present. These are accompanied by diffuse ulcers.

Fig. 15.31 Histopathology of pityriasis lichenoides et varioliformis acuta.

Clinical features Lichen planus occurs in male and female adults. Polygonal or map-like, grayish-blue to purplish-red papules or flatly elevated, purplish-red erythema of coin size or smaller appear, often with central concavity. The erythema surface is either characteristically glossy, or it has thick whitish scales attached. The eruptions may coalesce to form plaques (Figs. 15.32-1 and 15.32-2). The flexures of the extremities, and the trunk and genitalia are the most frequently affected sites, with itching in some cases. In the oral mucosa, irregularly shaped infiltrative leukoderma, Wickham striae, or erosive plaques are found. Intense pain may be present in such cases. Deformity and thinning of nails are seen in about 10% of all cases (Fig. 15.33). Pathogenesis Lichen planus is induced by drugs in many cases. When the cause is not identified, the disorder is classified as idiopathic. Inflammation caused by CD4+T cells in the dermo-epidermal junctions leads to dyskeratosis accompanied by impairment of basal keratinocytes, resulting in formation of flatly elevated purplish-rose erythema or papules. It may be caused by drugs (antihypertensive agents such as thiazide, cerebral excitometabolic agents, antitubercular agents) or by chemicals (photographic developing solution, dental metals). Association with hepatitis C and bone marrow transplantation (MEMO) has been suggested.

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Pathology The pathological findings are hyperkeratosis that is not accompanied by parakeratosis, and thickening of the granular layer, serrated extension of epidermal rete ridges, Vacuolar degeneration of the basal layer, and band-like lymphocytic infiltration in the papillae and lower papillary layer (Fig. 15.34). Dyskeratotic keratinocytes that have undergone vacuolar degeneration are called Civatte bodies.

Clinical images are available in hardcopy only.

Laboratory findings, Diagnosis Köbner phenomenon is present (i.e., rubbing normal skin or exposing it to UVB produces lichen planus eruptions). Delicate white lines known as Wickham striae typically cross the slightly scaly surface and form a network on the coalesced plaques. Lichen planus is easily diagnosed by the clinical and pathological findings. History-taking on drugs and dental treatments is conducted to determine whether lichen planus is induced by drugs or dental metal. A drug-induced test may be performed when a drug

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Fig. 15.32-2 Clinical features of lichen planus. b, c: Lichen planus annularis. It is important to differentiate this from porokeratosis. Erythema at the periphery of the lesion is characteristic of lichen planus. d: Lichen planus pigmentosus. e: A typical case of lichen planus on the lower leg. f: It is necessary to differentiate this from lichen sclerosus et atrophicus. g: Multiple lichen planus on the foreskin and glans penis. h, i: Affected lips. j: Linear, white lichen planus near the molar teeth in the buccal mucous membrane. k: Typical lichen planus on the wrist.

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Fig. 15.33 Nail deformities in lichen planus. Atrophic changes to the nails.

is suspected of being the cause. It takes several days to induce an eruption. Treatment Lichen planus progresses chronically but responds to treatment in most cases. The causative drug or other agent is determined and its use is discontinued. It takes several weeks or druginduced eruptions to disappear after such discontinuation of use. Steroid ointments (ODT) and anti-histamines are applied. Tacrolimus ointments are effective against lichen planus in the mucous membranes.

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Fig. 15.34 Histopathology of lichen planus. Hyperkeratosis and hypergranulosis without parakeratosis are characteristic of the disorder. Sawtoothed acanthosis, band-like lymphatic infiltration in the upper dermal layer, and vacuolar degeneration in the basal layer are also seen.

Graft-versus-host-disease MEMO (GVHD) after bone marrow transplantation and lichen planus Lichen planus often occurs as a symptom of chronic GVHD after bone marrow transplantation (100 days after transplantation). GVHD results from destruction of host tissue caused by immunologic response of T cells. The same mechanism is thought to be associated with lichen planus.

Clinical features, Pathogenesis Eruptions arrange in linear arrays or along cleavage lines, most frequently on the extremities (Fig. 15.35). The condition is asymptomatic. Lichen striatus begins as several solitary, polygonal to round, sometimes scaly, light pink to dark rose papules of 2 mm to 4 mm in diameter. The papules tend to coalesce and become 1- to 2-cm-wide, linear or band-like, light pink to dark red eruptions. The etiology is unknown. Differential diagnosis Lichen striatus should be differentiated from inflammatory linear epidermal nevus, incontinentia pigmenti (second-stage), linear warts and lichen planus. Treatment, Prognosis Topical steroids are the main treatment. Lichen striatus heals spontaneously in most cases, particularly in infants.

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7. Lichen nitidus Clinical features, Pathogenesis Small papules of uniform size, with a smooth flat glossy surface and a diameter of 1 mm to 2 mm occur. They can be scattered or aggregated (Fig. 15.36). The eruptions do not coalesce or cause erythema; they are normal skin color to yellowish white. Subjective symptoms such as itching are not present. Lichen nitidus most commonly occurs in the genitalia and extremities of young men, especially the glans penis and penis shaft. Köbner phenomenon is observed in about 50% of all cases.

Clinical images are available in hardcopy only.

Pathology Directly under the epidermal rete ridges that slightly extend from small papules, there are epithelioid cells, lymphocytes, and a small spherical infiltrative nest consisting of Langerhans giant cells. Vacuolar degeneration is seen. Prognosis Lichen nitidus progresses slowly in cycle of several months. Most cases heal spontaneously.

Clinical images are available in hardcopy only.

8. Pityriasis rosea (Gibert) Outline

It is transitory, inflammatory keratotic erythema of unknown etiology. It most commonly occurs in young men. ● Oval eruptions scatter mainly on the trunk, presenting as erythematous plaques with peripheral collarettes of scales. The long axes of eruptions run parallel to the cleavage lines. ● The first eruption is called a herald patch. ● It heals spontaneously in 1 to 3 months. Topical steroids are the first-line treatment.

15 Fig. 15.35 Lichen striatus.

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Clinical features Pityriasis rosea occurs frequently in men and women from the ages of about 10 to 40, especially in spring and autumn. Two thirds of all cases begin as an eruption called a herald patch (Fig. 15.37). An oval erythematous scaling plaque with a diameter of 2 cm to 5 cm occurs on the trunk. The light pink plaque is accompanied by scaling at the rim and slightly yellowish central discoloration (collarette of the herald patch). Seven to ten days after onset, multiple oval erythema of 1 cm to 2 cm in diameter with peripheral scaling occur suddenly. These eruptions vary in size, and the long axes run along the Langer cleavage lines of the skin; a Christmas-tree appearance is seen on the back. The eruptions spread from the trunk to distal areas; however, the palms, soles,

Clinical images are available in hardcopy only.

Fig. 15.36 Lichen nitidus. Small, scattered, mulitple papules of a few millimeters in diameter and normal skin color or yellowish white.

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and head (sun-exposed areas) are not involved. There are no severe systemic symptoms, except mild itching sometimes. The condition usually heals naturally in 1 to 3 months and does not recur. Pathogenesis The cause is unknown. In recent years, association with viral infections including HHV-6 and HHV-7 has been pointed out. Pityriasis rosea may occur as a drug eruption.

Clinical images are available in hardcopy only.

Pathology Thickening of the epidermis, spongiosis, parakeratosis, and intraepidermal filtration of mononuclear cells are found. These findings are similar to those of eczema and are nonspecific. Differential diagnosis a

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Treatment Topical steroids and oral histamines are the main treatments. Petrolatum, UVB and anti-inflammatory analgesics are also useful. Since these drugs may induce eruptions, history-taking is p q j i k l m n o r important.

15 9. Acquired ichthyosis Clinical images are available in hardcopy only.

Outline ● It

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Fig. 15.37 Pityriasis rosea (Gibert). a: The eruptions are distributed in a Christmastree pattern. b: Pityriasis caused by pityriasis rosea (Gibert). c: The first rash, called a herald patch. Table 15.9 Diseases that are differentiated from pityriasis rosea. Disease

Differential points

Flushing does not occur. Malasezia furfur is detected. Seborrheic areas such as the head and face are most commonly involved. Fewer scales are present. Roseola Eruptions also appear on the syphilitica palms and soles. Serologic test for syphilis is positive. Silver-gray scales are present. Psoriasis Auspitz phenomenon and Köbner phenomenon are positive. Drug eruption History-taking on drugs Pityriasis versicolor Seborrheic dermatitis

occurs secondarily to a malignant disorder (e.g., lymphoma), sarcoidosis or drug eruption. ● The skin clinical features similar to that of hereditary p q j k l m n o r ichthyosis; however, both the extensor surfaces and flexures of joints are affected.

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Clinical features Various symptoms of ichthyosis are present. Both the extensor surfaces and flexures of the extremities are affected (Fig. 15.38). Pathogenesis Patients have the primary diseases listed below. The symptoms of ichthyosis appear thereafter. ( i ) malignant tumor (e.g., malignant lymphoma (Hodgkin’s disease in particular), leukemia, carcinoma, Kaposi’s sarcoma). ( ii ) systemic disease (e.g., sarcoidosis, hypothyroidism, Hansen’s disease, tuberculosis, systemic lupus erythematosus) (iii) drug eruption (e.g., from nicotinic acid) Pathology The pathology of acquired ichthyosis is similar to that of ichthyosis vulgaris. Laboratory findings, Diagnosis Acquired ichthyosis cannot be distinguished from ichthyosis vulgaris only by cutaneous symptoms and histopathology. The clinical course and detection of a malignant tumor are important for diagnosis.

Clinical images are available in hardcopy only.

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15 Fig. 15.39 Clavus.

Clinical features, Pathogenesis Clavus, commonly called a “corn,” is localized thickening of the horny cell layer, usually caused by mechanical stimulation (Fig. 15.39). It tends to occur in the feet from the friction of shoes. The center of the thickened horny cell layer sinks deep into the dermis (core), resembling the eye of a chicken or fish. Tenderness is present (Fig. 15.40).

horny cell layer epidermis dermis

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Fig. 15.40 Diagram of clavus and callus.

Differential diagnosis Clavus is distinguished from plantar warts, which are caused by human papilloma virus and tend to occur multiply. Plantar warts also occur in areas that are not subjected to friction, and minor bleeding may be seen; differentiation between planter warts and clavus is easy by scraping the horny cell layer with a razor blade. In clavus, pressure causes pain (tenderness). In plantar wart, pinching causes pain. Treatment Friction should be avoided. Cushioned footpads are helpful. The horny cell layer is removed, and salicylic acid is applied.

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Fig. 15.38 Acquired ichthyosis a: Accompanying Hodgkin’s disease. b: Accompanying mycosis fungoides.

b. Noninflammatory keratoses 1. Clavus

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2. Callus Synonym: Tylosis

Clinical images are available in hardcopy only.

Fig. 15.41 Callus, tylosis.

Clinical features, Pathogenesis Callus (tylosis) is also caused by friction. Sites that are repeatedly subjected to mechanical stimulation, including pressure and friction, and bony sites are involved. The most common site in Japan is between the second and third distal phalanxes (from pen-holding) and the dorsal region of the ankles (from sitting on the floor). The horny cell layer is even in thickness, and there is almost no tenderness (Figs. 15.40 and 15.41). Treatment The treatments are the same as those for clavus.

3. Lichen pilaris Synonym: Keratosis pilaris

15

Clinical images are available in hardcopy only.

Fig. 15.42 Lichen pilaris.

Clinical images are available in hardcopy only.

Fig. 15.43 Erythromelanosis follicularis faciei on the face of a teenage female. Erythematous plaques caused by follicular keratotic papules are observed on the preauricular area and cheek.

Clinical features, Pathogenesis, Pathology Multiple follicular keratotic papules of 1 mm to 3 mm in diameter and normal or light pink in color occur on the extensor surfaces of the upper arms and thighs (Fig. 15.42). Lichen pilaris occurs most commonly in adolescent females. In most cases, the onset is in early childhood, and the clinical features become distinct in adolescence. The papules have a coarse surface and no tendency to coalesce or enlarge. The condition is usually asymptomatic. Pathologically, the hair follicles are dilated and filled with keratin plugs and there is pili torti. Lichen pilaris tends to be hereditary and is assumed to be autosomal dominantly inherited. There are cases associated with ichthyosis vulgaris. Treatment, Prognosis Lichen pilaris occurs with high frequency; however, it heals naturally after adolescence. The symptomatic therapy is topical application of moisturizer or keratolytic agents such as salicylic acid petrolatum.

4. Erythromelanosis follicularis faciei (Kitamura) Erythematous plaques occur symmetrically on the preauricular region and cheeks. Follicular keratotic papules form on the erythematous plaques (Fig. 15.43). Lichen pilaris often occurs on other sites as a complication. It is frequently seen in young men and women. It is thought to be a facial type of lichen pilaris. Moisturizer is applied topically.

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5. Lichen spinulosus In this type of lichen pilaris, follicular papules with pricklelike projections aggregate. The disorder is mostly seen in infants, on the neck.

6. Acanthosis nigricans (AN) Outline ● Plaques

with coarse dark-brown surface occur on the neck and axillary fossae. ● It is divided into three types: malignant AN, accompanying a malignant tumor (stomach cancer in particular); benign AN, accompanying endocrinopathy; and pseudoAN, accompanying obesity. ● The pathological findings are papillomatosis, thickening of the horny cell layer, and pigmentation. Thickening of the epidermis (acanthosis) does not usually occur.

Clinical images are available in hardcopy only.

Clinical features Dark brown papillary elevations with a coarse surface occur on the neck, axillary fossae, umbilical fossa and groin. They have a velvety or rough-textured appearance (Fig. 15.44). Malignant AN tends to have severe symptoms, and often itching is present. In pseudo-AN, pigmentation and coarse surface are found in intertriginous areas.

15 Clinical images are available in hardcopy only.

Pathogenesis The cause is unknown. Some cases are induced by a malignant tumor. Pathology The main symptoms are papillomatosis, hyperkeratosis and hyper-pigmentation. Despite the name, thickening of the epidermis is not present in most cases. Diagnosis Diagnosis of acanthosis nigricans can be confirmed by the clinical features. An eruption precedes or coincides with an internal organ cancer, stomach cancer in particular, in more than 70% of cases of malignant acanthosis nigricans; diagnosis of acanthosis nigricans may lead to early discovery of a cancer. Treatment In malignant acanthosis nigricans, the malignant tumors are detected and treated. Eruptions subside with treatment. In benign AN, endocrine abnormality is investigated and treated. Weight loss is advisable for patients with pseudo-AN.

Clinical images are available in hardcopy only.

Fig. 15.44 Acanthosis nigricans.

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7. Confluent and reticulated papillomatosis Grayish pigmented macules and keratotic papules occur on the trunk (intermammary region and upper abdomen, in particular), and coalesce to form a network of plaques (Fig. 15.45). The disorder occurs most frequently in men and women from adolescence to adulthood. It progresses slowly and is asymptomatic. Differentiation from pityriasis versicolor is important. Treatment is application of topical keratolytic agents, such as salicylic acid petrolatum, and oral administration of mimocycline and retinoids.

Clinical images are available in hardcopy only.

8. Bazex syndrome

Fig. 15.45 Confluent and reticulated papillomatosis.

Several months after psoriatic erythematous keratotic lesions appear symmetrically on the extremities, nasal apex and auricle, a malignant tumor becomes apparent. The syndrome occurs most commonly in men over age 40. The main malignant tumors caused by Bazex syndrome are squamous cell carcinomas in the upper gastrointestinal tract, upper respiratory tract and liver. The keratotic lesions aggravate according to the progression of the malignant tumor.

9. Keratosis follicularis squamosa (Dohi)

Clinical images are available in hardcopy only.

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10. Pityriasis circinata (Toyama) This is an acquired dyskeratosis in which round, sharply circumscribed lesions occur on the hips, abdomen and buttocks. Scaling, crêpe-surfaced, brown to grayish-white plaques form.

11. Hyperkeratosis lenticularis perstans Synonym: Flegel’s disease

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It occurs in middle-aged men and women, most frequently on the extremities, especially on the dorsal surfaces of feet and hands. Prickle-like, flatly elevated papules with red to dark brown keratotic scales of 1 mm to 5 mm in diameter are attached. p q j i k l m n o r They appear symmetrically.

Fig. 15.46 Keratosis follicularis squamosa (Dohi). a: Clinical features. b: Histopathological features.

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16

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Disorders of Skin Color

Human skin color is mainly determined by melanin pigments, carotene and hemoglobin. Of these, melanins contribute the most. Racial differences in skin color result from differences in the kinds and amounts of melanin. Most diseases of abnormal pigmentation are caused by elevated or reduced melanin content; the disorders involving skin color tend to be congenital or to be caused by autoimmune reaction or sun exposure. When carotene, a precursor of vitamin A, is taken into the body, it accumulates in the horny cell layer and subcutaneous fat layer, resulting in yellowish skin color (carotinoid pigmentation). This chapter also discusses dermal deposition of extrinsic substances caused by tattooing or injury. Although abnormalities of the blood vessels and hemoglobin may also cause changes in skin color, they are not included here.

A. Diseases of depigmentation Table 16.1 Major types of oculocutaneous albinism (OCA).

1. Oculocutaneous albinism (OCA)

OCA type 1 Tyrosine-related

Synonym: Congenital albinism Outline

There is congenital abnormality in melanin synthesis (Fig. 1.18). Pigment in skin, hair and eyes is reduced or absent from birth. ● All types are autosomal recessive. ● Patients tend to be prone to skin cancer, from high photosensitivity to sunlight. ● Sunscreen is essential. ●

Classification Oculocutaneous albinism (OCA) is classified by the causative genes into OCA1, OCA2, OCA3 and OCA4 (Table 16.1). It is also seen as a symptom of hereditary diseases including Hermansky-Pudlak syndrome and Chédiak-Higashi syndrome. Pathology Melanocytes are normal in number and size; however, immature melanosomes (stage I, II and III) are observed by electron microscopy (Fig. 16.1). In Chédiak-Higashi syndrome, giant lysosomes are detected in the skin, leukocytes and other organs. Diagnosis, Examinations The maturity of melanosomes in melanocytes should be observed by electron microscopy. In the severest OCA1 cases, there are only immature melanosomes that lack melanin deposition (stage I or II). In OCA in which some pigment production remains, stage III melanosomes are seen and there may also be a few stage IV melanosomes. Prenatal diagnosis may be conducted 259

1A Complete lack of synthesis of tyrosinase (formerly tyrosinasenegative type) 1B Dysfunction of tyrosinase synthesis (formerly yellow mutant type) 1mp Minimal-pigment albinism 1ts Temperature-sensitive OCA type 2 P protein-related type (formerly tyrosinase-positive type) OCA type 3 TRP-1 related OCA type 4 MATP-gene type HPS type Hermansky-Pudlak syndrome CHS type Chédiak-Higashi syndrome

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for the severest OCA1A cases. Identification of the affected gene is necessary for determination of subtype. Mel

Treatment Use of sunscreen is essential from birth, in order to protect the skin from UV-related cancer and skin aging. The eyes are protected by tinted contact lenses or sunglasses. Types of oculocutaneous albinism (OCA)

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Fig. 16.1 Electron microscopic image of a melanocyte (Mel) from a healthy person (a) and from a patient with oculocutaneous albinism (b). a: In a melanocyte from a healthy person, the cytoplasm contains large amounts of mature, blackish, stage IV melanosomes (arrows). The melanocytes transport melanosomes to neighboring keratinocytes. b: In oculocutaneous albinism, most melanosomes are immature, not progressing beyond stage II. Mature melanosomes are not seen in the cytoplasm.

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This is caused by tyrosinase gene mutation. OCA1 is classified into subtypes including OCA1A, in which tyrosinase activity is completely lost from such mutation (this type used to be classified as tyrosinase negative OCA), and OCA1B, in which some tyrosinase activity remains. All OCA1 subtypes are autosomal recessively inherited. When melanin is not synthesized, as is the case in OCA1A, the skin appears white to pink, and the hair is white from birth (Fig. 16.2). The skin is easily sunburned, and sun-exposed areas of the body are easily injured by UVR and are prone to malignant p carcinoma, q j tumor (e.g., basal cell cell i k l carcinoma, m nsquamous o r malignant melanoma). The iris and choroid membrane are blue, and the ocular fundus is pink; the eyes appear blue when lit edgeon, and pink when lit head-on (pink-eye). Patients have a characteristic facial expression of squinting and looking out of the corner of the eyes, from photophobia and impaired eyesight that cannot be corrected. Horizontal nystagmus may be present. When melanin is scant but present, pigment may gradually appear in hair and skin as the patient grows, although it is impossible to distinguish these cases from OCA1A at birth.

2) OCA2

Clinical images are available in hardcopy only.

OCA2 is caused by mutation in the P protein gene on chromosome 15. It is autosomal recessive. In mice, the P protein works to convey tyrosine to melanosomes; however, the functions of human P protein have not been clarified. Pigment may be largely or completely absent at birth; it is impossible to distinguish OCA2 from OCA1 only by the clinical symptoms. In OCA2 the eye color is bluish gray and the hair is pale yellow to blonde; both come to contain more pigment as the patient ages.

3) OCA3

Fig. 16.2 Oculocutaneous albinism (OCA1A) in a girl. The hair will be white throughout her lifetime, from lack of melanin production.

OCA3 is caused by genetic mutation in TRP-1 (tyrosinaserelated protein 1), which controls melanin synthesis. It tends to occur in patients of African descent. The skin color is reddish brown, and the hair is light reddish brown to red. Eye symptoms do not usually occur.

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4) OCA4 OCA4 is caused by abnormality in the membrane-associated transporter protein (MATP). OCA4 is mainly seen in patients of African or Japanese ancestry. In Japan, it occurs with the secondmost frequency, after OCA1. Pigment is present in the skin in small amounts. The hair is light yellow in many cases; however, there are some cases in which the hair is brown (Fig. 16.3). The eyes are blue, gray or reddish brown. Nystagmus is found in about half of all cases.

Clinical images are available in hardcopy only.

5) Hermansky-Pudlak syndrome (HPS) Some causative genes that are thought to be associated with intracellular protein transport have been identified in HermanskyPudlak syndrome (HPS). HPS is classified by the causative genes into four subtypes: HPS1, HPS2, HPS3 and HPS4. It is autosomal recessive. Pigment appears in the skin and hair to some extent (Fig. 16.4). Pulmonary fibrosis or granulomatous colitis may occur as a complication by deposition of ceroid-lipofuscin. There is a hemorrhagic tendency in HPS, which manifests as susceptibility to bruising and nasal or gingival hemorrhaging.

Fig. 16.3 Oculocutaneous albinism (OCA4). This patient had white hair at birth; however, pigmentation gradually appeared in the hair with age. Her hair is now blonde.

6) Chédiak-Higashi syndrome (CHS) Abnormality of the LYST gene on chromosome 1 (1q42) disturbs the normal function of microtubules. It is autosomal recessive. The main symptoms are partial albinism from melanocyte trafficking failure and photosensitive disorder. The hair is red and the skin color is cream, although sun-exposed areas such as the face sunburn to a dark red. Neutrophilic immune compromise often leads to bacterial infection. Histopathologically, giant lysosome granules (peroxidase-positive) are found in the peripheral leukocytes. During exacerbation, lymphatic and histiocytic infiltrate is found in the systemic organs, and acute symptoms of pancytopenia occur. Symptomatic therapies are performed for infection. Bone marrow transplantation may also be conducted. The prognosis is poor; most patients with CHS die young in the so-called “accelerated phase,” which is a lymphoproliferation into various organs resulting in hemophagocytosis, infection and bleeding.

2. Vitiligo vulgaris

16 Clinical images are available in hardcopy only.

Fig. 16.4 Hermansky-Pudlak syndrome (HPS). This patient had blond hair and a fair complexion; however, more pigment gradually appeared as she grew. There was hemorrhagic tendency in this case. Symptoms such as pulmonary fibrosis and intestinal catarrhs often appear after the patient reaches a certain age.

Outline ● Because

melanocytes are reduced or lost, hypopigmented patches (leukoderma) occur. ● Autoimmunity against melanocytes or melanin is thought to cause vitiligo vulgaris; however, the pathogenesis is unknown.

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Classification Vitiligo vulgaris is classified into focal, segmental, generalized and universal types. Vitiligo vulgaris in which leukoderma distribution is not associated with cutaneous innervation is called generalized vitiligo vulgaris. When unilateral leukoderma runs parallel to cutaneous nerves, it is called segmental vitiligo vulgaris.

Clinical images are available in hardcopy only.

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Clinical features, Epidemiology Vitiligo vulgaris often occurs in men and women about age 20. The incidence has been calculated as between 1% and 2% of the population. Familial cases account for 1% to 2% of all cases. Sharply circumscribed complete leukoderma occurs. There is a slight increase in pigmentation at the periphery of the eruptions. The lesions are irregular in shape and size, and they often coalesce (Figs 16.5-1 and 16.5-2). Gray hair is seen around the leukoderma. It is asymptomatic. Generalized vitiligo vulgaris occurs most frequently on areas prone toj mechanical stimulation, areas p q andr i k l m such n as theo seborrheic the extremities, lumbar region, abdomen, intertriginous areas, face and neck. Segmental vitiligo vulgaris occurs unilaterally on certain innervated areas. Young people are most commonly affected. Pernicious anemia, hyperthyroidism, and autoimmune diseases such as Addison’s disease may develop as complications. Pathogenesis The cause has not been identified. Autoimmunity against melanocytes and melanins and abnormal peripheral nerve function are thought to be involved.

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Pathology In the early stages, there is melanocyte degeneration with reduced or lost dopa response and lymphocytic and histiocytic infiltration into in the dermal upper layer. In the final stages, melanocytes are lost and melanin granules are absent in the basal layer. Differential diagnosis The disease should be differentiated from piebaldism, nevus depigmentosus, senile leukoderma, Vogt-Koyanagi-Harada disease, melanoleukoderma, pityriasis versicolor and Hansen’s disease.

Clinical images are available in hardcopy only.

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Fig. 16.5-1 Vitiligo vulgaris on various sites. a: Chest. b: Back. c: Lips. d: Sharply demarcated depigmented macules occur on the dorsum of the hands.

Treatment p q l n o r Topical andmoral PUVA therapies and topical steroids are the first-line treatments. Leukoderma on the face and fingers can be concealed by special cosmetics to alleviate psychological distress. Steroids and sedatives are given in small doses, and k

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surgical intervention (Fig. 16.6) and narrowband UVB exposure are also conducted.

3. Piebaldism Clinical images are available in hardcopy only.

Synonym: Partial albinism Definition Piebaldism is characterized by localized leukoderma with leukotrichia on the forehead and frontal region of the head. Few b c whited melanocytes are found around the areas of aleukoderma and hair; albinism develops locally. A congenital, autosomal dominant disease, it occurs with a frequency of 1 in 200,000.

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Fig. 16.5-2 Vitiligo vulgaris on various sites. e: On the forehead.

Clinical features Triangular or diamond-shaped leukotrichia and leukoderma are seen on the forehead and frontal region of the head (white forelock) at the time of birth. These do not enlarge or shrink with age. Contralateral geographic vitiligo occurs on the extremities and trunk. Small pigmented patches often occur within the leukoderma. Pathogenesis, Pathology Piebaldism is caused by abnormality in the c-kit gene. In fetal development, melanoblasts migrate from the neural crest to the epidermis to anchor and differentiate into melanocytes. The c-kit gene on chromosome 4 (4q12) encodes a receptor that is associated with the migration and anchoring of melanoblasts. Because piebaldism is autosomal dominant, abnormality occurs in half of each receptor, leaving an area on which melanoblasts do not anchor, and resulting in leukoderma. Histopathologically, melanocytes are lacking at the sites with leukotrichia and leukoderma.

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Diagnosis, Treatment Diagnosis is made by history-taking of autosomal dominant expression, and white forelock and small pigmented patches on leukoderma. Waadenburg-Klein syndrome, whose symptoms are similar to those of piebaldism, is accompanied by facial displasia and deaf-mutism. Skin graft and cultured pigmented cell transplantation have been reported to be effective.

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Fig. 16.6 Suction blister treatment of vitiligo vulgaris. a: Vacuum aspiration is applied on normal skin to artificially produce a suction blister. b: Vacuum aspiration is applied on skin with vitiligo vulgaris to produce a suction blister. The covering of the vitiligo vulgaris blister is removed and replaced with the covering of the normal skin blister.

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4. Sutton nevus Synonym: Halo nevus Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 16.7 Sutton nevus. Sharply demarcated leukoderma appears around the nevus cells.

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Definition, Pathogenesis, Clinical features Sutton nevus has nevocellular nevus (lentigo) in the center, surrounded by oval leukoderma (Fig. 16.7). It tends to occur in children and young men and women, on the trunk, face and neck. Autoimmunization occurs against melanin at the center of the lentigo, and immunoreaction occurs against melanin at the periphery of the lentigo; this is thought to be the mechanism of Sutton nevus. Leukoderma may also be produced at the periphery of a malignant melanoma, angioma, blue nevus, soft fibroma, and seborrheic keratosis; it is called Sutton’s phenomenon. Pathology Degenerated or destroyed nevus cells and melanocytes, with dense lymphocytic and macrophagic infiltration, are found at the periphery. Treatment The treatments for vitiligo vulgaris are applied. The central nevus may be removed. It may heal spontaneously. Prognosis Leukoderma enlarges centrifugally. At the same time, the central nevus discolors, flattens and eventually disappears. As the nevus disappears, the leukoderma heals spontaneously. Excision of the central nevus induces spontaneous healing and prevents vitiligo vulgaris, a complication.

5. Vogt-Koyanagi-Harada disease Outline ● Vogt-Koyanagi-Harada

disease is caused by autoimmunization against melanocytes. ● Uveitis, leukoderma, leukotrichia and alopecia occur. ● The treatments for the skin lesions are oral and local steroids and PUVA therapies. Clinical features Vogt-Koyanagi-Harada disease progresses rapidly, and the main symptom is eye lesion. Cutaneous lesions appear during recovery after remission of inflammation (about 2 months after onset) (Fig. 16.8). Melanocytes are destroyed, leading to irregular-shaped diffuse cutaneous leukoderma, symmetrically around the eyes in particular. The eyebrows, eyelashes and hair become white from pigment loss. Alopecia may be present. There are three stages: prodromal, eye disease and recovery. In the prodromal stage, there are persistent headaches, slight fever,

A. Diseases of depigmentation

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dizziness, and pain in the eyes for 5 to 7 days. In the eye disease stage, acute bilateral uveitis develops. Sensorineural deafness and disequilibrium frequently occur. These symptoms persist for 1 to 2 months and then gradually subside. The main symptoms of the recovery stage are those of the prodrome stage and eye disease stage. Loss of uveal melanocytes results in light red color of the entire fundus oculi. Pathogenesis Vogt-Koyanagi-Harada disease is thought to be caused by allergy or viral infection. It should be grouped with autoimmune diseases because of the autoimmune reaction against melanocytes. HLA-DR4 is highly associated with the occurrence of Vogt-Koyanagi-Harada disease.

Clinical images are available in hardcopy only.

Diagnosis, Differential diagnosis Diagnosis is made by the characteristic clinical features. Treatment The main treatment is systemic steroids. Steroid pulse therapies (1,000 mg methylprednisolone administered intravenously for 3 consecutive days) and immunosuppressants (e.g., cyclosporine) are also used for eye involvement. Steroids and PUVA therapies are applied to the cutaneous lesions.

Fig. 16.8 Vogt-Koyanagi-Harada disease. Irregularly shaped leukoderma is sporadically seen.

6. Senile leukoderma Sharply circumscribed, round or irregular-shaped leukoderma of 4 mm to 10 mm in diameter appear diffusely on the trunk and extremities of men and women in their 30s, increasing in number with age. Senile leukoderma is essentially identified with idiopathic guttate hypomelanosis. Pathological findings show a reduction in the number of activated melanocytes and melanosomes and dysfunction in melanocytes and melanosomes from melanocytic senescence.

16 Clinical images are available in hardcopy only.

7. Nevus depigmentosus Nevus depigmentosus is a common nevoid abnormality present in about 1 in 125 neonates. Because of the congenital melanocytic dysfunction in skin, incomplete hypopigmented patches are seen at birth or shortly thereafter (Fig. 16.9). The patches vary in shape and distribution from solitary and irregular to multiple and band-like. Size, distribution and number of nevus depigmentosus patches remain the same over the course of a lifetime.

8. Leukoderma pseudosyphiliticum Leukoderma pseudosyphiliticum most commonly occurs on the lumbar regions and buttocks of men in their 20s and 30s

Clinical images are available in hardcopy only.

Fig. 16.9 Nevus depigmentosus.

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whose skin is naturally dark, in Asians in particular. Multiple, sharply circumscribed, incomplete hypopigmented patches of 1 cm to 2 cm in diameter occur, often coalescing to become reticular. It is asymptomatic. The reticular leukoderma resembles syphilitic leukoderma; nevertheless, the two can be differentiated: Syphilitic leukoderma tends to occur on exposed sites, and the standard serologic test for syphilis is positive.

B. Disorders of hyperpigmentation 1. Ephelides

Clinical images are available in hardcopy only.

16 Clinical images are available in hardcopy only.

Fig. 16.10 Ephelides.

Clinical features Multiple round smooth-surfaced brown patches about 3 mm in diameter occur on the sun-exposed areas of the face, neck and forearms (Fig. 16.10). Ephelides darkens with sun exposure (especially exposure to UVR) in summer and tends to fade in winter. It worsens with age and is most remarkable at puberty; it lightens thereafter. Pathogenesis, Pathology Ephelides tends to run in families; it is thought to be autosomal dominant. However, it can be autosomal recessive in severe cases. Melanocytes are activated by hereditary factors, and melanosomes markedly increase in the basal keratinocytes. Melanocytes in patients with ephelides have well-developed dendritic spines and enhanced functions; however, the number of melanocytes does not change. Diagnosis, Treatment Differentiation from lentigo, Peutz-Jeghers syndrome, xeroderma pigmentosum, and progeria is necessary. Sunscreen is useful for blocking UVR.

2. Melasma Synonym: Chloasma Clinical features Melasma tends to occur in women in their 30s or older. It is rare in men. Sharply demarcated light brown patches occur on the face (forehead, cheeks, and around the mouth, in particular), usually symmetrically. Melasma patches are irregular in size and shape. The disorder is aggravated by UVR in summer, and it subsides in winter (Fig. 16.11). Pregnancy may trigger the onset (chloasma gravidarum).

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B. Disorders of hyperpigmentation

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Pathogenesis Abnormalities in sex hormones and adrenocortical hormones that activate melanocytes are known to cause melasma. Diagnosis, Differential diagnosis Riehl’s melanosis should be distinguished from melasma. Unlike Riehl’s melanosis, melasma is asymptomatic and is not preceded by dermatitis-like symptoms. Histologically, there is an increase in the content of melanin throughout the epidermis and an increase in the number of epidermal melanocytes. Differentiation from nevus of Ota is also important; the periphery of the eyes is affected by nevus of Ota but not by melasma.

Clinical images are available in hardcopy only.

Treatment The causal factors, such as artificial sex hormones, are discontinued. Chloasma gravidarum occurs during pregnancy and subsides several months after delivery. Protection from UVR is useful. Today topical hydroquinone and tretinoin are used for bleaching treatment.

3. Riehl’s melanosis A diffuse, vaguely circumscribed grayish-purplish-brown network of pigment deposition appears, most commonly on the face of middle-aged women. Riehl’s melanosis may be accompanied by follicular keratotic papules. In most cases, inflammatory symptoms such as flush and itching precede pigmentation. The cause is recurrent contact dermatitis on the face. The antigens in most cases are cosmetic products containing tar pigment. Most of such products are no longer produced, because of restrictions on components used in cosmetics. Histopathologically, macrophages that have phagocytosed melanosomes are observed in the dermal upper layer.

Clinical images are available in hardcopy only.

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4. Friction melanosis Synonym: Towel melanosis Definition, Clinical features Prolonged and vigorous use of nylon towels or brushes may stimulate the skin mechanically, resulting in pigmentation. Friction melanosis occurs frequently in persons in their 20s and 30s. A network pattern or diffuse brown pigmentation is seen in the skin above the clavicular region, neck, ribs and vertebral region (Fig. 16.12). Subjective symptoms such as itching are not present. Pathogenesis, Pathology Melanosomes sink into the dermis from mechanical stimulation and inflammation. As a result of histological pigmentary incontinence, increase of melanophages in the upper dermis leads

Clinical images are available in hardcopy only.

Fig. 16.11 Melasma, Chloasma. Brown spots on the cheeks.

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to friction melanosis. Histopathologically, multiple migrant melanosomes and melanophages are seen. Amyloid deposition is found in some cases. Clinical images are available in hardcopy only.

Treatment The skin color gradually returns to normal by discontinuation of the mechanical irritation, such as discontinuation of vigorous rubbing with nylon towels.

5. Dyschromatosis symmetrica hereditaria

Clinical images are available in hardcopy only.

16 Fig. 16.12 Friction melanosis. Diffuse, reticular, brown pigmentation occurs on the trunk, particularly on the back. The eruptions are blackish papules of several millimeters in diameter. Histopathologically, amyloid deposition is observed.

Definition, Pathogenesis, Clinical features Multiple brown patches and hypopigmented patches of 3 mm to 8 mm in diameter occur on the extremities, including the dorsa of hands and feet, coalescing into reticular forms (Fig. 16.13). Generally, the more distally the pigmentation occurs, the severer are the symptoms. The patches are flat and smooth. The onset is age 6 or younger in most cases. It is autosomal dominant, which runs in families, and is caused by mutation in the RNA-specific adenosine deaminase gene (DSRAD). It progresses with age, until adulthood. It most commonly occurs in Asians. Diagnosis Dyschromatosis symmetrica hereditaria can be diagnosed by the characteristic cutaneous features and familial incidence. It should be differentiated from acropigmentatio reticularis (Kitamura), a similar autosomal dominant disease with reticular pigmentation in the distal extremities. Acropigmentatio reticularis is distinguished by the fact that the pigmented patches are concave and there are no hypopigmented patches. Treatment Special concealing cosmetics are useful. Dermabrasion may be conducted for pigmented patches.

6. Senile lentigo Synonym: Solar lentigo Clinical images are available in hardcopy only.

Fig. 16.13 Dyschromatosis symmetrica hereditaria. Multiple brownish macules of 2 mm to 10 mm in diameter occur on the dorsum of hands. They coalesce to present a reticular pattern. Depigmentation is also seen.

Definition, Clinical features Senile lentigo appears in almost all men and women middleaged and older. Round brown patches of various sizes occur on sun-exposed areas of the face, dorsa of hands, and extensor surfaces of the arms. The patches are relatively clearly circumscribed. Mild scaling may be present (Fig. 16.14). Treatment Alexandrite lasers and cryotherapies are conducted.

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7. Addison’s disease Secretion of ACTH and MSH from the anterior lobe of the hypophysis is enhanced by reduced secretion of adrenocortical hormones, and this causes pigmentation by stimulating melanocytes. Pigmentation is seen on the entire body. The face, genitalia, axillary fossae and umbilical region are most severely affected. The pigmentation is also found on areas that normally contain less pigmentation than skin, such as the tongue, gingiva and oral mucosa; this is helpful for diagnosis.

Clinical images are available in hardcopy only.

8. Pigmentatio petaloides actinica Multiple, sharply circumscribed, brown, petal-shaped or spiny patches of several millimeters to 1 cm in diameter occur on the shoulders and upper back (Fig. 16.15). Multiple patches often occur in persons with light complexion, 1 to 3 months after intense sunburn such as from a beach outing.

Clinical images are available in hardcopy only.

9. Erythema dyschromicum perstans Synonym: Ashy dermatosis Multiple, small erythematous lesions occur on the trunk and extremities of non-Caucasians, and these soon turn into grayishwhite to grayish-blue patches of 1 cm to 3 cm in diameter. Erythematous elevation is seen at the periphery in many cases (Fig. 16.16). Itching may be present; however, it is asymptomatic in most cases and develops slowly. Drug eruption or lichen planus resembling erythema dyschromicum perstans may appear.

Fig. 16.14 Senile lentigo. Sharply demarcated brown patches appear. They may partially elevate and progress to seborrheic keratosis in some cases.

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Clinical images are available in hardcopy only.

Fig. 16.15 Pigmentatio petaloides actinica This skin lesion occurred after PUVA therapy for vitiligo vulgaris (center of photo).

Clinical images are available in hardcopy only.

Fig. 16.16 Erythema dyschromicum perstans, ashy dermatosis. Grayish-blue patches and erythematous eruptions are seen around the patches.

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C. Diseases caused by extrinsic deposition 1. Carotenemia Synonym: Aurantiasis cutis

Clinical images are available in hardcopy only.

Fig. 16.17 Carotenemia.

Definition, Pathogenesis, Clinical features Carotene concentration increases in the blood, resulting in carotene deposition in the epidermal horny cell layer and subcutaneous fat tissues. This yellows the skin (Fig. 16.17). The coloration is marked in the palms and soles, whose horny cell layer is thick. The color may appear in the face (e.g., forehead, ala nasi, nasolabial groove); however, it does not occur in the sclera or other mucous membranes, and it rarely becomes generalized. It is asymptomatic. Coloration tends to appear when the carotene concentration in the blood reaches 0.5 mg/dl. Carotenemia is caused by high intake of carotene-containing foods (citrus fruits, pumpkins, carrots, spinach, seaweeds, corn, egg yolks, butter), by liver dysfunction (carotene concentration in the blood increases when carotene fails to be metabolized into vitamin A), or by hyperlipidemia (carotene concentration tends to increase by hyperlipidemia because of its liposolublility). Diagnosis, Treatment Jaundice is differentiated from aurantiasis cutis by yellowed sclera, itching and bilirubin level. Aurantiasis cutis heals spontaneously when intake of the causative food is restricted.

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2. Argyria Clinical images are available in hardcopy only.

Fig. 16.18-1 Tattoo. Pigments of various colors have been injected.

Definition, Pathogenesis, Clinical features Argyria results from deposition of silver in the skin. This occurs from the use of silver medical supplies (silver needles, sutures, dental fillings) or prolonged intake of silver-containing foods. Cases caused by silver-containing health food products in Europe and the United States have been reported. Silver compounds deposit in collagen in the sweat glands, seborrheic glands, connective tissues and basal keratinocytes, giving the skin a bluish-gray hue. The condition tends to occur in exposed areas such as the face, neck and forearms. Diagnosis, Treatment, Prognosis Fine brown granular masses are found histopathologically. Silver can be observed by X-ray microprobe analysis. There is no effective treatment for argyria, except to refrain from intake of silver. Systemic complications of argyria include pulmonary fibrosis, pneumonitis, hepatotoxicity and myopathy.

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3. Tattoos Tattoos are images or text artificially created in the skin by injection of pigment or ink (Figs. 16.18-1 and 16.18-2). Pigmented granules tend to remain in the dermal upper layer; however, some are phagocytosed by macrophages and carried in the lymph flow to deposit in the lymph nodes. Allergic reaction against the injected pigment or photosensitivity may occur as complications. Laser therapies are useful in removing tattoos of certain colors. Clinical images are available in hardcopy only.

Fig. 16.18-2 Tattooed skin.

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Chapter

17

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Metabolic Disorders

Congenital or acquired abnormality in biosynthesis and metabolic pathways can cause qualitative and quantitative abnormalities in bodily substances. Diseases caused by such abnormalities are called “metabolic disorders.” Metabolic abnormalities in amyloids, mucins, lipids, nucleic acids, porphyrins, vitamins and electrolytes, for example, cause various diseases.

A. Amyloidoses Table 17.1 Classification of cutaneous amyloidoses. Localized cutaneous amyloidoses Primary localized cutaneous amyloidosis Lichen amyloidosis Macular amyloidosis Nodular localized cutaneous amyloidosis Poikiloderma-like cutaneous amyloidosis Anosacral cutaneous amyloidosis Secondary localized cutaneous amyloidosis Systemic amyloidoses AL amyloidosis

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AA amyloidosis Familial systemic amyloidosis Hemodialysis-related amyloidosis

Outline ● These

disorders are caused by deposition or accumulation of amorphous glycoproteins, called amyloids, in the tissue or intercellular spaces. ● Amyloids consist of various precursor substances whose compositions differ according to the type of disease. ● Localized cutaneous amyloidosis occurs only in the skin; systemic amyloidosis affects systemic internal organs (Table 17.1). Classification, Pathogenesis Amyloids deposit and accumulate in the tissue and intercellular spaces, inducing dysfunction in the whole body or specific organs. Amyloids are glycoproteins that have a fibrous structure. They are not seen in normal metabolism. They consist of various precursors, such as immunoglobulin L-chains, abnormal prealbumin, and serum proteins. In each disease, the amyloids have a different composition. Cutaneous amyloidoses are classified as shown in Table 17.1. Pathology, Laboratory findings Amyloids stain light red with PAS and orange-red with Congo red, and appear green to fluorescent yellow in polarizing microscopy. Localized cutaneous amyloidosis does not readily stain with Congo red; methyl violet (purple), thioflavine (fluorescent yellow), and dylon staining (reddish brown) are used instead (Fig. 17.1). Detection of Bence Jones proteins in the urine and detection of M proteins by electrophoresis of the serum has diagnostic value for systemic amyloidosis.

Fig. 17.1 Histopathology of amyloidosis. Amyloids stain reddish brown in dylon staining.

Treatment, Prognosis Topical steroids are effective against localized cutaneous amyloidosis, which has a good prognosis. Systemic amyloidosis accompanied by myeloma has a poor prognosis. Most patients die from renal dysfunction or heart failure within several years after onset. 272

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a. Localized cutaneous amyloidoses 1. Lichen amyloidosis Lichen amyloidosis frequently occurs on the extensor surfaces of the lower legs, and on the forearms and back. Multiple, flatsurfaced, smooth, light-brown papules appear and may aggregate (Fig. 17.2). Intense itching is present in most cases. Histopathologically, the horny cell layer and epidermis thicken diffusely, melanin granules increase in the basal layer, and amyloid accumulates in the dermal papillae. Topical steroids and oral histamines are effective.

Clinical images are available in hardcopy only.

2. Macular amyloidosis Punctuate or reticular pigmentation occurs, most commonly on the scapular region and back of middle-aged women. Chronic rubbing of the skin with nylon towels causes ripple pigmentation (friction melanosis; Chapter 16). Amyloids may deposit in the skin. Friction melanosis is thought to be strongly associated with macular amyloidosis.

3. Nodular localized cutaneous amyloidosis

Clinical images are available in hardcopy only.

Synonym: Amyloidosis cutis nodularis atrophicans It most frequently occurs in women middle-aged and older. Tan nodules appear on the lower abdomen. Atrophy of the dermis occurs. Diffuse amyloid deposition is found directly below the epidermis and fat tissue (Fig. 17.3).

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4. Poikiloderma-like cutaneous amyloidosis Amyloid deposition is found in skin with poikiloderma.

5. Anosacral cutaneous amyloidosis

Clinical images are available in hardcopy only.

This occurs in the anus and sacral region of the elderly. It is clinically characterized by pigmentation accompanied by hyperkeratosis. Amyloid deposition is seen pathologically.

6. Secondary localized cutaneous amyloidosis Deposition of amyloids is observed histologically in the dermal papilla in association with various skin disorders. Lesions including those of seborrheic keratosis, actinic keratosis, basal cell carcinoma, Bowen’s disease, cylindroma, calcified epithelioma, nevus sebaceus, verruca vulgaris, malignant lentigo, mycosis fungoides, psoriasis, discoid lupus erythematosus, lichen simplex chronicus, and solar dermatitis occur.

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Fig. 17.2 Lichen amyloidosis. Multiple, light brown papules appear and aggregate, accompanied by intense itching.

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b. Systemic amyloidoses 1. AL amyloidosis

Fig. 17.3 Histopathology of nodular localized cutaneous amyloidosis. Abundant amyloid deposition (arrows) is observed in the upper dermal layer.

Clinical images are available in hardcopy only.

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AL amyloidosis occurs frequently in men and women in their 60s. The cause is known to be plasma cell dyscrasia (such as multiple myeloma), in which abnormal immunoglobulin-related amyloid light chain (AL) was produced. Shiny yellowish-white papules occur, most frequently in the eyelids and often accompanied by purpura. Amyloid deposition is found among the collagen fibers in the epidermis and outer membranes of the blood vessels at the sites around the eruptions. Such deposition is also seen in the systemic organs, such as the gastrointestinal tract, cardiac muscles and skeletal muscles, where it causes various symptoms (Fig 17.4a). Lesions develop in the oral cavity and laryngeal mucosa, resulting in macroglossia and hoarseness. Generalized scleroderma-like stiffness in the fingers and nail deformity are present (Figs. 17.4b and 17.4c). Bence Jones proteins are excreted in the urine in some cases (a finding of myeloma). Treatments are mainly made for plasma cell dyscrasia. It has a poor prognosis as a result of the complication of cardiac insufficiency; most patients die within 2 years after onset. h 2.

AAi amyloidosis j k

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The precursor protein of AA amyloidosis is serum amyloid A (AA) protein. The disorder is caused secondarily by a chronic inflammatory disease or an infectious disease, such as rheumatoid arthritis, tuberculosis or leprosy. Skin lesions rarely form.

17 Clinical images are available in hardcopy only.

3. Familial systemic amyloidosis a

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This disorder is autosomal dominantly inherited. Amyloid deposition organs, including pstomach q andr jin various i k l m n the nerves, o heart, causes dysfunction.

4. Hemodialysis-related amyloidosis Synonym: b 2-microglobulin amyloidosis

Clinical images are available in hardcopy only.

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Fig. 17.4 AL amyloidosis. a: Macroglossia. The tongue is markedly firm and swollen from amyloid deposition. b: Amyloid deposition in the fingers results in hardening of the skin that resembles systemic scleroderma. c: Nail deformity is caused by amyloid deposition in the nail matrix and nail beds.

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This occurs in those who have a prolonged hemodialysis. b 2microglobulin, which is not readily removed by hemodialysis, deposits as amyloids. The intercarpal synovial membranes, p q j k l m n otract and joints, heart, blood vessels, digestive kidneys areraffected. Erythema, papules, purpura and subcutaneous nodules are the main cutaneous symptoms.

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B. Mucinoses Definition, Pathogenesis Mucinosis is a general term for diseases in which acid mucopolysaccharide (mucin) deposits in the skin. The mucin, produced by fibroblasts, consists of complex of mucopolysaccharides (glycosaminoglycans) and proteins. The main types of glycosaminoglycan are hyaluronic acid (hyaluronan), dermatan sulfate, chondroitin sulfate and keratan sulfate. The mucin stains positive with Alcian blue and colloidal iron, and metachromatic with toluidine blue. Abnormal deposition of mucin among collagen fibers results in swelling and separation of those fibers and the edematous skin. Mucin deposition is often induced by collagen disease, thyroid dysfunction or tumor; however, the precise mechanism is unknown. Mucinosis is classified by the location of deposition and clinical features (Table 17.2).

Table 17.2 Classification of major cutaneous mucinoses. Generalized mucinoses Scleredema Diffuse myxedema Pretibial myxedema Lichen myxedematosus Reticular erythematous mucinoses Localized mucinoses Follicular mucinosis Cutaneous focal mucinosis

1. Scleredema Synonym: Scleredema adultorum Stiffness occurs in the skin, especially of the face, neck, shoulders, upper back, and in some cases the upper extremities and trunk (Fig. 17.5). The distal portions of the extremities are not involved. The induration is non-pitting and hard. It is asymptomatic at the early stages; however, mild mobility impairment appears gradually. Scleredema is often induced by acute infectious disease. The epidermis of the lesions thickens. Hyaluronic acid and dermatan sulfate deposit among the dermal collagen fibers (Fig. 17.6). Differentiation from diabetic scleredema (described later) is important; when scleredema is suspected, diabetes should be tested for. Scleredema heals spontaneously in several months to several years.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

2. Diffuse myxedema It is mucoid edema (myxedema) on the entire body skin, which often occurs when there is decreased thyroid activity. The skin is cold, dry and white. When pinched, the skin is soft and no marks are left (non-pitting edema). The disorder is characterized by the facial features: the entire face is swollen, the nose widens, and macroglossia and lip swelling are present. The scalp hair and the hairs in the lateral one-third of each eyebrow become thin and fragile.

3. Pretibial myxedema The frontal tibiae and the dorsa of feet are most commonly

Fig. 17.5 Scleredema. Marked hardening of the skin on the neck and upper back.

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involved. Light pink to brownish plaques, subcutaneous induration, and nodules occur. Dilated follicles and hirsutism are present. The etiology is unknown. It occurs in 1% to 10 % of all hyperthyroid cases. Ophthalmopathy is seen in almost all patients.

4. Lichen myxedematosus Synonyms: Scleromyxedema, Papular mucinosis Soft, yellowish papules aggregate and coalesce on the axillary fossae, dorsal hands and fingers, and extensor surfaces of forearms, presenting an orange-peel-like appearance. Hyalunic acid deposition is present in the lesions. Endocrine function is usually normal. Myeloma, diabetes, and liver dysfunction may occur.

Fig. 17.6 Histopathology of scleredema.

5. Reticular erythematous mucinosis Reticular erythema occurs on sun-exposed areas of the trunk (Fig. 17.7). It is characterized by glycosaminoglycan deposition in the dermal upper layer.

Clinical images are available in hardcopy only.

6. Follicular mucinosis Fig. 17.7 Reticular erythematous mucinosis.

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Papules of normal skin color to rose pink aggregate, coalescing mainly on the scalp and face and becoming elevated plaques (Fig. 17.8). Alopecia often accompanies this. Pathologically, edema and mucin deposition are seen in the outer root sheaths and sebaceous glands. Vacuolization of follicles and lymphatic infiltration also occur. Follicular mucinosis may occur primarily or secondarily. Mycosis fungoides may develop as complications.

Clinical images are available in hardcopy only.

Fig. 17.8 Follicular mucinosis. The skin lesion is accompanied by relatively sharply demarcated, reddish infiltration of 3 cm to 4 cm in diameter, and alopecia.

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C. Xanthomas Definition Lipid-laden foamy histiocytes aggregate on the skin or mucous membranes to form yellowish lesions. This condition usually accompanies a systemic abnormality of lipid metabolism; however, lipid abnormality is not found in all cases. Xanthoma is divided by clinical features into several subtypes described below. Pathology Xanthoma presents histologically as aggregation of foam cells in the dermis (Fig. 17.9). Touton giant cells may be found. Treatment Hyperlipemia should be treated first. Eruptive xanthoma may disappear when the triglyceride level falls. However, cases with nodules do not readily respond to oral drugs.

Fig. 17.9 Histopathology of xanthoma. Foamy histiocytes that have phagocytosed fat droplets are observed in the dermis.

1. Tuberous xanthoma Embossed, firm, pinkish-yellow tumors of 5 mm to several centimeters in diameter occur, mostly on the extensor surfaces of the elbows and knees and on the joints of the hands and feet (Fig. 17.10). The condition accompanies hyperlipoproteinemia (type IIa, type III, type V).

Clinical images are available in hardcopy only.

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2. Tendon xanthoma This is a type of tuberous xanthoma. The Achilles tendons and the tendons of hands, legs and knees become tumorous. It accompanies hyperlipoproteinemia (type IIa).

3. Plane xanthoma Almost flat or slightly elevated, yellowish lesions occur. They may be accompanied by hyperlipoproteinemia (Fig. 17.11).

Fig. 17.10 Tuberous xanthoma on the metacarpophalangeal joints and proximal interpharangeal joints. Redness is seen in some of the affected sites.

4. Xanthelasma palpebrarum The inner canthus of the upper eyelids becomes flatly elevated. This disorder often accompanies hypercholesterolemia (type IIa, type III). About half of all cases are not accompanied by hyperlipoproteinemia (Fig. 17.12).

Clinical images are available in hardcopy only.

5. Eruptive xanthoma Multiple, small, yellowish papules of 5 mm in diameter or smaller occur on the entire body. Eruptive xanthoma accompanies hypertriglyceridemia (Fig. 17.13).

Fig. 17.11 Plane xanthoma that occurred secondarily after chronic lymphedema on the upper arm. There are vaguely demarcated yellow plaques.

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Clinical images are available in hardcopy only. Clinical images are available in hardcopy only.

Fig. 17.12 Xanthelasma palpebrarum. Flatly elevated yellow plaques occur on the inner canthus of the upper and lower eyelids, accompanied by mild infiltration.

Fig. 17.13 Eruptive xanthoma.

D. Electrolytic disorders 1. Acrodermatitis enteropathica Synonym: Zinc deficiency syndrome Outline Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 17.14 Acrodermatitis enteropathica.

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● This

is a zinc deficiency whose main symptoms are dermatitis, alopecia and diarrhea. ● The main types are a congenital type (autosomal recessively inherited) and an acquired type that is caused by administration of parenteral central venous nutrition or excision of the digestive tract. ● Erythema and erosion form on the distal portions of the extremities, and on the genitalia and orifices (the periphery of the eyes and mouth, nares, and auditory meatus), presenting clinical features similar to psoriasis, seborrheic dermatitis and cutaneous candidiasis. Clinical features Dermatitis tends to occur on sites that have mechanical pressure, such as the distal portions of the extremities, the genitalia, and the facial orifices (the periphery of the eyes and mouth, nares, and auditory meatus; Fig. 17.14). Acrodermatitis enteropathica begins with papules, small blisters, or erythema accompanied by pustules, and progresses to erosion and crusts. Annular scaling is clinically observed, resembling psoriasis, impetigo, seborrheic dermatitis and cutaneous candidiasis. Nail deformity and perionychia occur. Alopecia occurs in almost all cases, appearing on the occipital and temporal region of the head first and then spreading to the entire scalp and eyebrows. Diarrhea and vomiting recur. Pathogenesis The congenital type of acrodermatitis enteropathica is autosomal recessively inherited. It is caused by a mutation in the

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D. Electrolytic disorders

SLC39A4 gene on chromosome 8. SLC39A4 is a specific protein for transporting zinc and iron. Acquired zinc deficiency is caused mainly by prolonged parenteral central venous nutrition, excision of the digestive tract, or severe diarrhea or vomiting. It may be induced by the anti-rheumatoid drug oral penicillamine, or by deficiency of zinc in breast milk.

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Clinical images are available in hardcopy only.

Laboratory findings, Diagnosis Zinc levels are low in patients. In normal people, zinc levels are 60 to 130 mg/dl in serum, and 300 to 600 mg/day in urine. The alkaline phosphatase level in the blood is also low, because of the low zinc level. Differential diagnosis The eruptions resemble psoriasis, impetigo, seborrheic dermatitis and cutaneous candidiasis. Acrodermatitis enteropathica is a rare metabolic disease; however, dermatitis, diarrhea, and alopecia may also occur in congenital biotin metabolic disorder and essential fatty acid deficiency. Clinical images are available in hardcopy only.

Treatment Sufficient supply of zinc is essential.

2. Hemochromatosis Synonym: Bronze diabetes Outline

Excessive accumulation of iron in the body leads to organ failure from deposition of hemosiderin (an ironbinding protein) in various organs. It is caused hereditarily or by anemia, liver dysfunction, excessive intake of iron preparations, or excessive transfusions. ● Diffuse, brownish-blue-gray pigmentation occurs on sunexposed areas and genitalia. Diabetes may occur as a complication. Abnormality is not seen in the central nervous system. ● Iron and increased ferritin are found in the serum by a blood test. ● Phlebotomy and iron chelator administration are the main treatments. ●

Clinical features Diffuse, brownish-blue-gray pigmentation occurs in the skin as a result of marked deposition of hemosiderin, ferritin or melanin (Fig. 17.15). The sun-exposed areas of the body such as the face, dorsal hands, extensor surfaces of forearms, and genitalia are most severely affected. Atrophy and dryness are present. The axillary and pubic hair may become sparse. The symptoms progress gradually. Liver dysfunction almost always accompanies the cutaneous

Fig. 17.15 Hemochromatosis.

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symptoms. Impaired hepatic function and hepatomegaly are found. Atrophy and dryness of the skin are present. Without proper treatment, liver cirrhosis may progress to hepatocellular carcinoma.

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Fig. 17.16 Histopathology of hemochromatosis. a: Melanin deposition is observed in the epidermal basal keratinocytes. b: There is iron deposition in the dermis (the portions stained blue).

Classification Hemochromatosis is divided into genetic hemochromatosis p q j (autosomal recessively and hemochromatoh i k inherited) l m secondary n o sis (from excessive intake of iron). Pathogenesis In genetic hemochromatosis there is overabsorption of iron from the intestinal tract and of iron metabolic dysfunction in the endothelial system. Secondary hemochromatosis may be caused by ① anemia accompanied by q j i k ineffective l merythropoiesis n o (e.g.,p sideroblastic r anemia, hemolytic anemia), ② liver disease (e.g., alcoholic cirrhosis), ③ excessive oral intake of iron (e.g., high intake of red wine, excessive intake of iron preparations), or ④ blood transfusion in large volumes. Pathology Hyperpigmentation of the skin is caused by increased dermal melanin and dermal hemosiderin within macrophages, seen as melanophages and siderophages. Iron deposits in the deep dermis. Dermal atrophy and pigmentation are present. Marked iron deposition can be found at the periphery of the sebaceous glands (Fig. 17.16).

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Laboratory findings, Diagnosis Serum iron, transferrin saturation and serum ferritin values increase from iron excess. UIBC is decreased. A liver biopsy is conducted for differential diagnosis. Treatment An iron chelator (deferoxamine) is administered. Symptomatic therapies are performed for organ failure. Alcohol intake is restricted.

3. Menkes disease Synonym: Menkes kinky-hair disease Outline ● This

disease is an X-linked recessive disorder of copper metabolism. ● It is characterized by kinky hair and reduced skin pigmentation. Clinical features Congenital lack of a copper-dependent enzyme that is essential

r

E. Vitamin deficiencies

for synthesis of melanin and keratin leads to reduced skin pigmentation. Hair is whitish and fragile (kinky hair). Babies with Menkes disease are born underweight and demonstrate convulsions and other neurological symptoms shortly after birth. Psychomotor retardation, muscular hypotonia, poor sucking, low body temperature, abnormality in the blood vessels in the whole body, and osteoporosis are present. Without proper treatment, most patients die before age 3. Pathogenesis Mutation in the gene that codes for copper-transporting ATPase (ATP7A) causes malabsorption of copper in the intestinal tract, resulting in copper insufficiency in the body. This leads to various symptoms. It is an X-linked recessive disorder; boys are most commonly affected.

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Clinical images are available in hardcopy only.

Fig. 17.17 Calcinosis cutis on the extensor surface of an infant’s forearm. Multiple papules of several millimeters in diameter are caused by calcium deposition. Some rupture and coalesce, discharging their contents.

Treatment Parenteral copper salt is effective in mild cases. The gene responsible for Menkes disease has been identified; this may be useful for gene therapies. Clinical images are available in hardcopy only.

4. Calcinosis cutis Calcinosis cutis is a condition in which calcium deposits in large amounts to form firm, yellow to white papules or nodules. When the deposition is in the stomach, kidneys, lungs muscles, or is in/under the skin and hypercalcemia is present, the cause is parathyroid tumor, excessive intake of vitamin D, or bone destruction caused by a tumor. Calcinosis cutis may appear as a symptom in systemic sclerosis and dermatomyositis, even in cases with normal serum calcium level (Fig. 17.17). There are also idiopathic cases: e.g. scrotal carcinosis cutis (Fig. 17.18).

Fig. 17.18 Calcinosis cutis on the scrotum.

E. Vitamin deficiencies 1. Pellagra Outline ● It

is caused by lack of B vitamins, especially niacin. main symptoms are dermatitis, diarrhea and dementia. ● It most frequently occurs in recipients of isoniazid (INH), and in alcoholics and those who have had a gastrectomy or who have poor eating habits. ● Supplementation of niacin is the main treatment. ● The

Clinical features Symptoms of pellagra are characterized by the “3D’s”:

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Clinical images are available in hardcopy only.

Fig. 17.19 Pellagra caused by poor diet. Blackish-brown pigmentation is present.

Clinical images are available in hardcopy only.

dermatitis, diarrhea and dementia; however, there now tend to be few cases with all three symptoms together. The cutaneous symptoms are burning sensation and itchy photosensitive dermatosis. Sunburn-like eruptions appear on sun-exposed areas of the body, which develop into red-brown erythema, blistering and erosion. The skin coarsens. Sharply circumscribed, dark-brown pigmentation and atrophy are present (Fig. 17.19). Eruptions on the frontal neck region (the so-called V-neck zone) are called Casal’s necklace. Angular chelitis at the early stages and typhuslike intense diarrhea are characteristic gastrointestinal symptoms. Stomatitis, esophagitis, and nausea and vomiting occur. Psychoneurotic symptoms including depression, epileptic seizure, dementia, and peripheral neuropathy may occur. Pathogenesis Pellagra is caused by niacin deficiency. Although the mechanism of eruptions is unknown, it is associated with cellular deficiency of niacin that results from an inadequate dietary supply of niacin. Laboratory findings, Diagnosis The amount of N1-methyl nicotinamide, a metabolic product of niacin, quantitated in the urine for 24 hours is low. Pellagra should be carefully differentiated from other photosensitive dermatoses. Treatment, Prognosis Administration of nicotinic-acid amide, dietary improvement, and avoidance of exposure to light are useful.

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2. Biotin deficiency

Clinical images are available in hardcopy only.

Biotin deficiency is caused by a lack of this water-soluble vitamin, which is associated with biosynthesis of fatty acids (Fig. 17.20). Cutaneous symptoms that resemble zinc deficiency syndrome occur, and alopecia and exfoliative dermatitis-like lesions are produced at sites that come into contact with diapers and in the intertriginous areas. Ichthyosis and erythroderma appear on the whole body in severe cases. Anemia accompanied by atrophy in the lingual papillae, loss of appetite, fatigue, and muscular pain are present.

3. Vitamin C deficiency Clinical images are available in hardcopy only.

Fig. 17.20 Biotin deficiency.

Synonym: Scurvy Vitamin C (ascorbic acid) is essential for hydroxyproline production, which in turn is necessary for collagen synthesis. Deficiency leads to fragility of the blood vessels and the peripheral supporting structures, resulting in easy bleeding, follicular keratosis, purpura and bleeding in the gums. There may be systemic

F. Porphyrias

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symptoms, such as fatigue and bone fracture. However, these are promptly improved by vitamin C supplementation.

F. Porphyrias Outline ● Porphyria

is a general term for diseases caused by deposition of intermediate products such as porphyrins in the liver or skin, as a result of congenital or acquired impairment of an enzyme essential for heme synthesis. ● It is divided into hepatogenous porphyrias and myelogenous ones. ● The main cutaneous symptom is photosensitivity accompanied by blistering. Classification, Pathogenesis Porphyrin is a general term for molecules that have a porphyrin ring, which is an intermediate metabolite synthesized in the process of heme biosynthesis from glycine and succinyl-CoA. This biosynthesis occurs in various cells, particularly in the liver and bone marrow. Metabolic enzymes such as P450 occur as

glycine + succinyl CoA ALA synthase

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d -aminolevulinic acid (ALA) ALA dehydrase porphobilinogen (PBG) PBG deaminase

deficient in congenital erythropoietic porphyria (CEP) uroporphyrinogen III synthase uroporphyrin III

coproporphyrin III

deficient in acute intermittent porphyria (AIP)

hydroxymethyl bilane uroporphyrinogen I synthase

uroporphyrinogen III

uroporphyrin I uroporphyrinogen I deficient in deficient in uroporphyrinogen III porphyria uroporphyrinogen I porphyria cutanea decarboxylase cutanea tarda decarboxylase tarda (PCT) (PCT) coproporphyrinogen I coproporphyrin I coproporphyrinogen III coporphyrinogen oxidase protoporphyrinogen IX protoporphyrinogen oxidase protoporphyrin IX Fe2＋

ferrochelatase

deficient in variegate porphyria (VP)

deficient in erythropoietic protoporphyria (EPP)

heme

Fig. 17.21 Metabolic pathway of porphyrin and functional enzymes (arrows).

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Table 17.3 Major types of porphyria. Porphyria

Photosensitivity

Erythropoietic Congenital erythropoietic porphyria porphyrias (CEP)

+

Erythropoietic protoporphyria (EPP)

+

Hepatic porphyrias

Porphyrin accumulates in... Urine, feces, erythrocytes

Enzyme deficiency Uroporphyrinogen III synthase

Feces, erythrocytes Ferrochelatase

Inheritance pattern AR AD

Acute intermittent porphyria (AIP)

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Porphobilinogen deaminase AD

Variegate porphyria (VP)

+

Urine, feces

Protoporphyrinogen oxidase AD

Porphyria cutanea tarda (PTC)

+

Urine, feces

Uroporphyrinogen decarboxylase

AD in familial PCT

hemeproteins in the liver and are synthesized into the heme of hemoglobin. That is, there are hepatogenous porphyrias and erythropoietic (myelogenous) porphyrias. These are subclassified by the affected enzyme (Fig. 17.21). The major subtypes are shown in Table 17.3. Porphyrins induce cutaneous and neurological symptoms. They become activated by light energy, which produces reactive oxygen that causes cytotoxicity and results in the cutaneous symptoms of photosensitive diseases. d -aminolevulinic acid (d ALA) passes through the blood-brain barrier and acts neurotoxically.

1. Congenital erythropoietic porphyria (CEP)

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Clinical features Congenital erythropoietic porphyria (CEP) appears shortly after birth, first as photosensitivity (blistering, pustule formation, ulceration) and later as scarring. Wine-colored urine and purplish-black feces result from excretion of intermediate products. The intermediate products deposit in erythrocytes, teeth and bones. They fluoresce red under Wood’s lamp. Hemolytic anemia causes splenomegaly. Pathogenesis Large amounts of uroporphyrin I and coproporphyrin I are produced in the hematopoietic tissue as a result of congenital absence of uroporphyrinogen III synthase (Fig. 17.21). Uroporphyrin I and coproporphyin I deposit in the skin and hemoglobin, where they absorb light energy and destroy cellular membranes. CEP is a rare, autosomal recessively inherited disease.

2. Erythropoietic protoporphyria (EPP) Clinical features Mild photosensitivity, heat sensation, pain, flash, edema or urticaria manifests in children age 10 or younger. Moderate hemolytic anemia occurs. Protoporphyrin deposited in the liver is crystallized and excreted in the bile; mild liver dysfunction and gallstones are present.

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F. Porphyrias

Pathogenesis Erythropoietic protoporphyria (EPP) is caused by congenital abnormality in the ferrochelatase (FECH) gene, the last gene in the heme synthesis pathway. Protoporphyrin IX is not transformed into heme and deposits in the body, particularly in the erythron of the bone marrow, causing EPP (Fig. 17.21). Protoporphyrin increases in the serum, bile and feces. EPP is the second most frequent porphyria subtype after PCT (described later). It is autosomal dominantly inherited.

Clinical images are available in hardcopy only.

Diagnosis, Treatment Differential diagnosis of EPP can be made by photosensitivity in adolescents and increased protoporphyrin in the blood and feces. Administration of b-carotene and the protection from radiation afforded by tanning are effective treatments.

3. Acute intermittent porphyria (AIP)

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Acute intermittent porphyria (AIP) is induced by drugs, sex hormones and stress, for example, and the symptoms appear acutely. It is autosomal dominantly inherited and most frequently occurs in women of adolescent age or older. Reduced activity of porphobilinogen deaminase (PBGD) leads to deposition of d -ALA and porphobilinogen, precursors of porphyrins. Cutaneous symptoms are not seen; however, neurological symptoms, peripheral nervous symptoms and abdominal symptoms are present.

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Clinical images are available in hardcopy only.

4. Variegate porphyria (VP) Variegate porphyria (VP) is autosomal dominantly inherited hepatic porphyria caused by abnormality in protoporphyrinogen oxidase. It is clinically similar to PCT (described later), and thea symptoms are less severe than those of hereditary coproporphyria.

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5. Porphyria cutanea tarda (PCT) Clinical features Blistering is caused by injury and sun exposure on the face and dorsal hands during the spring and summer. It resolves with moderate scarring, atrophy and pigmentation; the course recurs (Fig. 17.22). Reddening of urine from excretion of uroporphyrin, abdominal symptoms resembling those of AIP, hypertrichosis of the face, and liver dysfunction may occur. Pathogenesis a b Uroporphrinogen decarboxylase activity decreases. Intermediate products such as uroporphyrin deposit in the liver and skin (Fig. 17.21). The condition is induced by chronic alcohol consumption, hepatitis, hepatocellular carcinoma, hemodialysis, or drugs such as estrogen, hexachlorobenzene, iron preparations or

Clinical images are available in hardcopy only.

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Fig. 17.22 Porphyria cutanea tarda (PCT) on various sites. a: Face. b: Dorsum of hands. c: Forearm. Blistering, mild scarring, atrophy and pigmentation occurred at all these sites. The symptoms recurred when the sites were exposed to the sun.

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sulfonylurea drugs. Familial cases have been reported; these are autosomal dominantly inherited. Men in their middle ages and older and those who have habitually drunk alcohol for a long period of time are most commonly affected. Pathology Subcutaneous blistering is found. Endothelial cells are injured. PAS-positive substances are detected in the peripheral blood vessels. Laboratory findings Red fluorescence of porphyrins is observed by liver biopsy. There are elevated levels of uroporphyrins in the urine. Treatment Abstinence from alcohol consumption, shading from light, phlebotomy (300 ml to 500 ml of blood drawn over the course of 2 to 3 weeks), administration of an iron chelating agent, liver support therapy, and oral sodium hydrogen carbonate are effective.

G. Skin manifestations associated with diabetes Various cutaneous lesions are induced by diabetes.

1. Diabetic gangrene

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Gangrene occurs on the toes, soles, and fingers. It is associated with underlying diseases such as microangiopathy and arterial sclerosis. External factors such as injury, burn or secondary infection induce ulceration. Sharply circumscribed necrotic foci occur secondarily to ulceration, and these become intractable (Fig. 17.23). Circulatory stimulants, antibiotics, and surgical treatments including débridement, ablation and revascularization are conducted in combination with treatments for diabetes. Arteriosclerosis obliterans in the main artery is surgically treated.

2. Diabetic scleredema Scleredema occurs in the nuchal region (Fig. 17.24). Although it is clinically similar to scleredema adultorum, acute infection does not occur in diabetic scleredema as a prodrome nor is there spontaneous healing.

3. Diabetic xanthoma Eruptive xanthoma occurs commonly on the extensor surfaces of the extremities and buttocks. When hyperlipemia is resolved by diabetic treatment such as administration of insulin, xanthoma also subsides.

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G. Skin manifestations associated with diabetes

4. Necrobiosis lipoidica The frontal tibiae of women age 40 or older are most commonly affected. Irregularly shaped, vaguely circumscribed, atrophic, and yellow to tan plaques of 5 cm to 10 cm in diameter occur. The periphery is purplish-brown, accompanied by telangiectasia (Fig. 17.25). Histological findings are similar to those for granuloma annulare. It may also occur on the thighs and hands.

Clinical images are available in hardcopy only.

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5. Diabetic bulla Tense bullae like those seen in burns are produced by minor trauma. Microangiopathy is thought to be the cause of diabetic bulla. Because the reduced sensory perception of diabetic patients tends to make them less sensitive to high temperatures, differentiation from second-degree burn is necessary. a

6. Dupuytren contracture

Clinical images are available in hardcopy only.

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Painful subcutaneous core-like induration occurs on the palms and soles. As it progresses, flexion contracture occurs in the fingers and toes. It often accompanies diabetes.

7. Pretibial pigmented patches Atrophic brown patches are caused by microvessel abnormality in the frontal areas of the lower extremities.

Clinical images are available in hardcopy only.

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8. Disseminated granuloma annulare Aggregated, solid, light-pink papules or infiltrating erythema occurs (Chapter 18). Glucose intolerance is frequently seen. a

9. Eczema, Pruritus

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The seborrheic and intertriginous areas are the most commonly affected areas. If diabetes is not treated appropriately, the dermatitis recurs, and photosensitivity and purpura occur as complications. Sebum reduction, xeroderma and pruritus are also present. Topical steroids tend to induce mycotic infection.

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Can necrobiosis lipoidica occur without diabetes?

b MEMO

Necrobiosis lipoidica used to be understood as a skin lesion caused by diabetes, hence the name “diabetic necrobiosis lipoidica.” However, some cases without diabetes have recently been described. Even so, reports have found a close association between the two. This textbook includes it in the diabetes section.

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Fig. 17.23 Diabetic gangrene. a: Ulceration occurring secondarily after tinea pedis. b, c: Ulceration resulting from shoe sores. d: Progressed diabetic gangrene in a foot. The aponeurosis is exposed by the deep ulcer.

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10. Opportunistic infection Cutaneous infectious diseases, including various opportunistic infections, occur. These include folliculitis, subcutaneous abscess, cellulitis, perionychia, necrotizing fasciitis, erythrasma, non-Clostridium gas gangrene, mycosis and viral infections. Clinical images are available in hardcopy only.

Fig. 17.24 Diabetic scleredema in the nucha. This is a markedly firm, large, plate-like plaque.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 17.25 Necrobiosis lipoidica. Sharply demarcated, irregularly shaped, atrophic plate-like plaques on the tibial anterior regions.

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H. Other metabolic disorders 1. Fabry’s disease Synonym: Angiokeratoma corporis diffusum (Fabry)

Cer − Glc − Gal − Gal a-galactosidase A Cer − Glc − Gal

This is an X-linked recessive lysosomal storage disorder. The pathogenesis is absence or marked reduction of a-galactosidase activity caused by genetic mutation (Figs. 17.26 and 17.27). Trihexosylceramide fails to be degraded because of a lack of this enzyme, resulting in deposition in the blood vessels, causing dysfunction (Fig. 17.28). Multiple angiokeratoma, small papules of 2 mm to 3 mm in diameter accompanied by telangiectasia, occur, mostly on the abdominal and lumbar regions (“bathing trunk” distribution). Renal failure, cerebrovascular disorder, heart failure and breathing difficulty occur, with most patients dying at about age 40. Clinical features of Fabry’s disease differ greatly from case to case. Enzyme replacement therapies have been attempted in recent years.

Cer − Glc

Cer ceramide

Fig. 17.26 Mechanism of Fabry’s disease. Trihexosylceramide (Cer-Glc-Gal-Gal) deposits in the kidneys and vascular tissue from lack of atrihexosylceramide activation.

2. Kanzaki disease Synonym: Angiokeratoma corporis diffusum (Kanzaki)

Clinical images are available in hardcopy only.

This is a lysosomal storage disorder. Enzyme deficiency results from mutation in the N-acetyl-a-d-galactosaminidase gene on chromosome 22. This disorder of glycoprotein metabolism is autosomal recessively inherited. The cutaneous symptoms resemble those of Fabry’s disease: Small multiple angiokeratomas occur on the whole body, particularly on the lumbar region (Fig. 17.29). Oligohidrosis, sensory nerve failure, and hearing impairment are present. The prognosis is good.

3. Gouty tophus Multiple nodules of 5 mm to 30 mm in diameter occur on the auriculae, finger and toe joints, elbows, knees and Achilles tendons. The skin becomes tense and thin, with yellowish-white tone in subcutaneous areas. When the skin is broken, a chalk-like substance containing uric acid crystals is excreted. Gouty tophus heals with scarring after ulceration. Gout is caused by hyperuricemia; uric acid is hyperproduced and/or underexcreted. Acute gouty arthritis tends to present as intense pain in the great toe that gradually spreads to the other joints. Joint swelling and tenderness are present. Peripheral areas swell and become dark red, and these changes are accompanied by burning sensation, fever, leukocytosis, and elevated erythrocyte sedimentation rate.

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Clinical images are available in hardcopy only.

Fig. 17.27 Fabry’s disease in a male in his 20s. Multiple red papules of 2 mm to 3 mm in diameter are present on the face and trunk, accompanied by telangiectasia (angiokeratoma).

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Fig. 17.28 Electron microscopic view of the dermis in Fabry’s disease. a: Low-power magnification. Arrows indicate the following: A. Vascular endothelial cell. B. Macrophage. C. Neurocyte. b: High-power magnification. Trihexosylceramide is p den-q observed asl black deposition k m n with high o electron sity in various cytoplasms.

4. Lipoid proteinosis Synonym: Hyalinosis cutis et mucosae

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Hyaline-like substances deposit in cutaneous membranes to form wart-like nodules and papules on the eyelids and eyelash regions, and white nodules in the oral cavity. Nodules in the glottis cause hoarseness. Cases caused by autosomal recessively inherited mutation in the extracellular matrix protein 1 (ECM1) gene on chromosome 1q21 have been reported in recent years.

Clinical images are available in hardcopy only.

5. Phenylketonuria

Clinical images are available in hardcopy only.

Fig. 17.29 Kanzaki disease in a female in her 40s. Multiple angiokeratoma of 2 mm to 3 mm in diameter occurred on the chest and abdominal region. It is impossible to differentiate Kanzaki disease from Fabry’s disease only by the clinical features of the eruptions.

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This autosomal recessively inherited disorder is caused by mutation of the phenylalanine hydroxylase (PAH) gene, which codes for an enzyme that metabolizes phenylalanine into tyrosine. Reduced skin pigmentation, brownish hair color, and mental developmental delay result from the atic dysfunction. In Japan, Guthrie newborn mass screening is conducted for phenylketonuria. The incidence is 1 in 60,000 to 1 in 80,000. Maintaining a phenylalanine-restricted diet until about age 3 prevents cerebral disorder. The skin and hair color returns to normal by dietary supplementation of tyrosine.

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Chapter

18

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Disorders of the Dermis and Subcutaneous Fat

The dermis and subcutaneous tissue hold and support the epidermis. If the tissue is injured, the entire structure of the skin may be greatly affected, even though the surface of the skin itself might show only minor changes. This chapter discusses diseases that predominantly affect the dermis and subcutaneous tissue.

Disorders of the dermis

A. Cutaneous atrophy 1. Striae Synonyms: Striae distensae, Striae atrophicae Outline ● Slightly

concave, linear cutaneous atrophy follows the lines of cleavage (skin tension lines). ● The thighs and lower abdomen are most commonly affected. ● Oral steroids may be the inductive factor. Striae occur when skin undergoes rapid growth or stretching, especially in pregnancy (striae gravidarum) and adolescence.

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Clinical features Striae are slightly concave, several millimeters wide, and 10 cm or more long. They run roughly parallel each other. The color is rose pink in the early stages, becoming grayish white later on (Fig. 18.1). The long axis of the striae follows the lines of cleavage (skin tension lines) in most cases. The buttocks, lumbar region, thighs and popliteal fossae are often involved. Striae gravidarum is seen in more than 90% of all pregnancies. It occurs on the abdomen, breasts and groin from the 6 month of pregnancy to after delivery. Adolescent striae occur in the buttocks, lateral thighs, back and breasts. Pathogenesis Glucocorticoid inhibits fibroblast activity (collagen production), leading to reduction of connective tissue. Wound healing is impaired. If skin in this condition is subjected to external pressure or excessive extension, the connective tissue is destroyed, resulting in striae and atrophy in the skin. Striae tend to occur when glucocorticoid levels are elevated, such as in conditions that require oral administration of steroids, Cushing syndrome, severe infection and diabetes. It may occur in those who are preg291

Clinical images are available in hardcopy only.

18 Fig. 18.1 Striae atrophicae (“stretch marks”).

Fig. 18.2 Solar elastosis. The epidermis is atrophic. The elastic fibers and collagen fibers in the upper dermis tear in a club shape.

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nant or obese, or those in adolescence. Pathology Striae (distensae) are basically scars. Clinical images are available in hardcopy only.

Treatment, Prognosis No specific treatment is necessary. The disorder subsides with age; nonetheless, it is irreversible and does not disappear completely.

2. Solar elastosis Synonyms: Actinic elastosis, Senile skin atrophy Clinical images are available in hardcopy only.

Outline ● It

is dermal degeneration caused by excessive exposure to sunlight. ● This is an aging change and atrophy of the skin. ● Cutis rhomboidalis nuchae, a specific subtype of this condition, is deep rhombus striae that occur in the nuchal region.

Clinical images are available in hardcopy only.

18 Fig. 18.3 White fibrous papulosis of the neck. Small, multiple, white papules of 2 mm to 4 mm in diameter appear on the neck.

Clinical features The onset of solar elastosis is in the fourth decade of life. The skin becomes thin and yellowish, and degeneration of dermal elastic fibers is observed histologically. The skin slackens on the whole body. Large folds of skin form on the face, neck and joints. Because of the functional reduction of sweat glands and seborrheic glands, the whole body skin becomes dry and rough, leading to scaling, a characteristically atopic gloss, and brownish color. Solar elastosis is remarkable on sun-exposed areas. Outdoor workers show marked changes caused by solar elastosis. Deep cleavages are seen, particularly in the nuchal region (cutis rhomboidalis nuchae). Pathology Atrophy and thinning of the dermis occur. Reduction of collagen fibers is marked (Fig. 18.2). The elastic fibers are ruptured, and solar elastosis is observed by Elastica-Van Gieson method. The sweat glands and seborrheic glands decrease in size and number, and subcutaneous fat tissue decreases.

3. White fibrous papulosis of the neck (Shimizu) Fig. 18.4 Histopathology of white fibrous papulosis of the neck. Fibrosis in the upper dermis (arrows).

Clinical features Small round or oval papules 2 mm to 4 mm in diameter and white to light yellow occur on the neck region of the elderly (Fig. 18.3). Sharply circumscribed eruptions occur on follicular and

Disorders of the dermis / A. Cutaneous atrophy

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non-follicular sites. They do not coalesce. Thickening of the collagen fibers is histopathologically observed in the upper dermal layer (Fig. 18.4). The pathogenesis is age-related dermal degeneration. Epidemiology White fibrous papulosis of the neck may occur in any race.

4. Lichen sclerosus et atrophicus (LSA) Clinical features White, flat-topped papules of 2 mm to 3 mm in diameter appear and aggregate, forming firm white plaques. Later, the plaques shrink and take on a crepe-like appearance (Fig. 18.5). Inflammation may occur, accompanied by itching and pain. Lichen sclerosus et atrophicus (LSA) is a chronic disorder with a predilection for the anogenital lesion and trunk of middle-aged and elderly women. In postmenopausal women, when the vulva is involved the condition may be accompanied by atrophy in the labia majora and clitoris (kraurosis vulvae). LSA in the male genitalia is called kraurosis penis or balanitis xerotica obliterans. Atrophy may result in urethral stricture in male patients.

Clinical images are available in hardcopy only.

Fig. 18.5 Lichen sclerosus et atrophicus (LSA) on the labia majora (white) of an elderly woman. The lesion has partially progressed to squamous cell carcinoma (elevated red).

Pathogenesis The pathogenesis is unknown; however, hereditary factors, endocrine abnormality or immunological mechanisms may be involved. Autoantibodies against extracellular matrix 1 (ECM1) have been found in the patient’s serum. Pathology Hyperkeratosis epidermal atrophy and vacuolar degeneration are present. In the dermal upper layer, collagen fibers are homogeneous and edematous, leading to reduction of cellular components. As it progresses, band-like lymphatic infiltration is seen in the dermis. There is keratin proliferation and the formation of follicular keratin plugs in some cases (Fig. 18.6).

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Prognosis LSA progresses slowly and tends to be intractable; however, it may resolve spontaneously. When the genitalia are affected, it progresses to squamous cell carcinoma in several percent of all cases, after a long course. Topical steroids and tacrolimus ointment are applied. Fig. 18.6 Histopathology of lichen sclerosus et atrophicus (LSA). Hyperkeratosis, loss of epidermal rete ridges, homogenization of collagen fibers in the upper dermis, edema, and lymphocytic infiltration occur.

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5. Werner’s syndrome Synonym: Adult progeria Outline ● It

typifies diseases of premature aging. Aging occurs in systemic tissue at adolescence. ● It is caused by mutation in RecQ DNA helicase gene, RECQL2. It is autosomal recessively inherited.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

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Fig. 18.7 Werner’s syndrome. a: Thin and sparse scalp hair. b: Ulcer on the foot.

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Clinical features Premature aging begins in systemic organs around adolescence. Subcutaneous fat and muscle markedly atrophy and adhere to the subcutaneous layer. Scleroderma-like articular contracture and atrophic hardening of the skin occur. The nose p q j h i thin and k froml atrophy, m giving n the face o a bird-like becomes pointy appearance. Keratinization and ulceration on the soles, pigmentation on the whole body, telangiectasia, and subcutaneous calcinosis occur. Gray hair and alopecia often accompany these symptoms (Fig. 18.7). In organs other than the skin, osteoporosis, arterial sclerosis, cataracts, insulin-resistant diabetes and gonadal hypofunction are caused by premature aging. Highpitched voice and loss of hircus and pubes are present. i

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Pathogenesis Werner’s syndrome is caused by mutation in RECQL2 encoding the DNA helicase on chromosome 8. The product of the RECQL2 gene is thought to repair genes that are damaged during DNA replication. The mechanism of premature aging is unknown; nonetheless, it is thought that chromosomal instability is increased by incapacitation of the repairing gene, resulting in the onset of Werner’s syndrome. Differential diagnosis Differential diagnosis from other premature aging syndromes (progeria and acrogeria), scleroderma, and Rothmund-Thomson syndrome must be made.

Clinical images are available in hardcopy only.

Prognosis Most patients are short-lived, with an average age of 46 years, as a result of myocardial infarction, cerebral apoplexy and aggravated diabetes. The incidence of malignancy is high.

6. Rothmund-Thomson syndrome

Fig. 18.8-1 Rothmund-Thomson syndrome. Reticular erythema on the cheek.

It is autosomal recessive. The cause is genetic mutation. One of the causative genes is RECQL4 encoding the DNA helicase, on chromosome 8. In infancy and childhood, the skin atrophies, reticular or diffuse erythema occurs on the face, and juvenile cataract appears (Figs. 18.8-1 and 18.8-2). Photosensitivity is present in one third of cases. In adulthood, head and body hair

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Disorders of the dermis / B. Dysplasia

becomes sparse, and keratinization occurs on sun-exposed areas. There is impaired development of nails. Internal malignant tumor accompanies roughly 30% of cases; tibial osteosarcoma and multicentric osteosarcoma have been reported. The prognosis is good in the absence of malignancy. Like Werner’s syndrome, Rothmund-Thomson syndrome may be categorized as a type of progeria.

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Clinical images are available in hardcopy only.

7. Progeria Synonym: Hutchinson-Gilford syndrome This is a premature aging syndrome. Abnormality in the lamin A gene has been reported. The main symptoms are growth impairment, evidenced by short stature, low body weight and skin atrophy. Patients are characterized by bird-like facial features. Basic treatments for progeria have not been found; symptomatic therapies including administration of growth hormones and a high-calorie diet are performed.

Clinical images are available in hardcopy only.

8. Acrogeria Synonym: Gottron’s syndrome Onset is thought to have a genetic contribution; however, the details are unknown. Skin atrophy and loss of subcutaneous fat are observed in the fingers, toes, nasal apex and auriculae. Acrogeria is a premature aging syndrome. It occurs most commonly in women. Atrophy, shortening and thickening of the nail plates occur. There are no systemic symptoms, and the prognosis is good; there are no basic treatments for acrogeria.

Fig. 18.8-2 Rothmund-Thomson syndrome. Thin and sparse body hair. Reticular, diffuse erythema on the buttocks.

B. Dysplasia 1. Congenital ectodermal dysplasia This term is a catchall for congenital diseases of the hair, teeth, nails and sweat glands that cause abnormal formation of ectodermal tissue. It is classified into more than 100 subtypes according to the combinations of dysplastic components. Mutation in p63 has been found and reported. The main diseases caused by congenital ectodermal dysplasia are listed below.

1) Anhidrotic (hypohidrotic) ectodermal dysplasia The main symptoms are thinning of hair, anhidrosis and abnormality in dental formation (Fig. 18.9). It is autosomal recessively inherited or X-linked, and is caused by mutation in the ectodysplasin anhidrotic receptor gene (EDAR) or the ectodysplasin-A

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gene (EDA), respectively. The whole body skin is thin and dry from the absence or marked reduction of sweat gland complex. The patient is prone to heatstroke. Decreased lacrimation and dryness of the oral and nasal membranes lead to conjunctivitis, stomatitis, purulent rhinitis and hoarseness. It is possible for patients to have a normal life as long as they avoid living environments with high temperatures.

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Fig. 18.9 Anhidrotic (hypohidrotic) ectodermal dysplasia. a: Thin and sparse scalp hair. b: Dental dysplasia.

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Deformity of nail plates, thinning of hair, and palmoplantar keratoderma are the three major symptoms. However, 30% of cases demonstrate only deformity of nail plates. Linear patterns form in the nail plates, which thicken and suffer from growth retardation. It is an autosomal dominant disease caused by mutation of the GJB6 gene, which codes for connexin 30 (Chapter 1). The prognosis is good.

Clinical images are available in hardcopy only.

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k l m 2. Cutis verticis gyrata

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Hyperplasia of the scalp results in skin folds at the top of the head. It occurs most commonly in boys. The folds are 1 cm to 2 cm wide, highly elastic and mobile. Normal hair growth is present in the groove portions, but not in the elevated portions (Fig. 18.10). Cutis verticis gyrata is classified into a primary form and a secondary form that accompanies nevoid abnormalities (e.g., nevus-cell nevus, connective tissue nevus) or systemic diseases (e.g., acromegaly). Plastic surgical repair may be conducted. Pachydermoperiostosis (MIM, 167100) is a hereditary disease in which cutis verticis gyrata can be seen with clubbed fingers, osteohypertrophy and brawny skin change. It is autosomal dominant.

3. Chondrodermatitis nodularis chronica helicis Painful keratotic nodules of 1 cm in diameter occur in the helices, particularly their upper parts (Fig. 18.11). These nodules result from chronic inflammatory reaction against collagen fibers that are degenerated by extrinsic stimulation such as of sunlight, injury or the cold. They occur most frequently in men of middle age and older. This disorder should be differentiated from seborrheic keratosis, basal cell carcinoma and squamous cell carcinoma. The main treatments are topical and local injection of steroids and surgical excision.

Fig. 18.10 Cutis verticis gyrata.

Clinical images are available in hardcopy only.

Fig. 18.11 Chondrodermatitis nodularis chronica helices. A painful nodule.

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C. Perforating dermatosis Elastosis perforans serpiginosa Clinical features Small, bilaterally symmetrical, reddish-brown keratotic papules with an atrophic and umbilicated center are produced in linear or circular arrangement on the neck region, extremities and upper trunk, giving the skin a serpentine appearance (Fig. 18.12). Köbner phenomenon tends to be positive. Pathogenesis Transepidermal elimination results from elimination of degenerated elastic fibers in the upper dermal layer through the epidermis. It may appear idiopathically in young men. In up to a third of cases, there is an associated systemic condition or connective tissue disorder. It tends to accompany abnormality of the dermis, such as Marfan syndrome, Ehlers-Danlos syndrome, pseudoxanthoma elasticum or dysosteogenesis. It may be caused by prolonged intake of D-penicillamine. Pathology Degenerated elastic fibers accumulate in the dermal upper layer, on which the epidermis proliferates to enwrap the abnormal fibers into the dermis. Thickening of the epidermis and foreign-body granuloma in the dermis occur.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 18.12 Elastosis perforans serpiginosa in a patient with Wilson disease who was taking D-penicillamine.

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D. Granulomatous disorders 1. Sarcoidosis Outline ● It

is a systemic granuloma of unknown pathogenesis. ● The skin symptoms are granulomatous lesion (cutaneous sarcoidosis) and inflammatory reactive lesion (e.g., erythema nodosum). ● Extracutaneous lesions such as those of bilateral hilar lymphadenopathy (BHL) and uveitis occur. ● Angiotensin converting enzyme (ACE) activity is elevated, and hypercalcemia is present. ● Topical and oral steroids are the first-line treatments.

What is perforating dermatosis?

MEMO

Perforating dermatosis is a general term for skin lesions resulting from epidermal excretion of decomposed skin components. Diseases that cause perforating dermatosis are elastosis perforans serpiginosa (elastic fibers are excreted), Kyrle’s disease (keratin fibers are excreted), perforating folliculitis (follicular components are excreted), and reactive perforating collagenosis (collagen fibers are excreted). These diseases tend to occur in patients with chronic renal failure. Epidermal excretion of decomposed skin components may be seen in some cases of granuloma annulare.

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Pathogenesis It is unknown. Clinical images are available in hardcopy only.

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Fig. 18.13-1 Sarcoidosis. a, b: Nodular sarcoidosis. c, d: Plaque sarcoidosis.

Sarcoidosis and erythema MEMO nodosum Erythema nodosum may occur as a result of reactive inflammation of fat tissue in patients with sarcoidosis. Or sarcoidal granuloma may form in subcutaneous tissue, usually on the extensor surfaces of the extremities. This cutaneous sarcoidosis is also called “erythema nodosum-like eruption.” There is no clinical difference between erythema nodosum and erythema nodosum-like cutaneous sarcoidosis.

Cutaneous symptoms Skin lesions are seen in 20% to 35% of cases of systemic sarcoidosis. Somej cases demonstrate only skin lesions. The p cuta-q h i k l m n o neous symptoms of sarcoidosis vary widely depending on the location and severity of the infiltration of epithelioid cell granuloma (Figs. 18.13-1 and 18.13-2). The disease tends to be asymptomatic and is often classified into nodular, plaque, diffuse, infiltrative and subcutaneous types. More than one type of cutaneous symptom may be seen in one patient. Nodular sarcoidosis: This is the most frequent type. The face, particularly around the nose, and the extremities and the center of p q i trunkj are most k commonly l maffected. n Multiple, o r the slightly elevated infiltrative erythema range in color from light pink to dark red and in diameter from 3 mm to 30 mm. There may be scaling. Small papules are often produced in the lower legs. Plaque sarcoidosis: Relatively large, flat-topped infiltrative plaques with an elevated rim and an atrophic center occur, most frequently on the face (forehead, cheeks and nose in particular). Diffuse infiltrative sarcoidosis: Dark red, diffuse, infiltrative plaques occur symmetrically, mainly on the nose, cheeks, fingers and toes. It is asymptomatic. Areas that are prone to frostbite are frequently involved (lupus pernio). Subcutaneous sarcoidosis: It most commonly appears in the extremities, as palpable, elastic, subcutaneous induration of 1 cm to several centimeters in diameter. p occurq on areas j k infiltrative l m n r that Scarring sarcoidosis: Itotends to are prone to injury, such as knees and elbows. Epithelioid cell granuloma occurs on a preexisting scar that was caused by injury, for example. This is specific to sarcoidosis and has diagnostic value. Other cutaneous sarcoidoses: ① Erythema nodosum-like eruptions resemble erythema nodosum, except that epithelioid cell granuloma is found histopathologically. They heal spontaneously in many cases. ② Lichenoid sarcoidosis is multiple, asymptomatic small papules on the trunk and extremities. p q k Otherl typesmof sarcoidosis n o are ichthyosis-like r eruptions, and ulcerative, leukodermal, verrucous, psoriatic and erythematous types. Besides the granulomatous lesions (cutaneous sarcoidoses) listed above, erythema nodosum may also occur as a nonspecific eruption (MEMO). Systemic symptoms Subjective symptoms are rarely present. Although various organs may be involved, the bilateral hilar lymph node (BHL), lungs (e.g., pulmonary fibrosis) and eyes (uveitis) are most frequently affected. Pulmonary lesion: This is the most frequent sarcoidosis lesion.

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Patients with chronic sarcoidosis are characterized by bilateral hilar lymphadenopathy (BHL). Subjective symptoms are rarely present. Emphysema and pulmonary heart disease may occur in the final stages. Eye lesion: Uveitis and iridocyclitis occur. Cardiac lesion: The condition is known as cardiac sarcoidosis. Heart block, arrhythmia and Adams-Stokes syndrome may cause unexpected death. Bone lesion: Sausage-like swelling of occurs in the finger joints.d a b c Bone cysts are observed by osteal X-ray. Neural lesion: The central nervous system and the peripheral nervous system are affected. Paralysis occurs in the facial nerve, glossopharyngeal nerve and vagus nerve. Additionally, Sjögren syndrome may occur. When facial nerve paralysis, uveitis and parotid bubo are caused, it is called Heerfordt syndrome. Pathology Noncaseating epithelioid cell granuloma is characteristically observed (Fig. 18.14). Slight lymphocytic filtration is seen at the periphery of granulomas (naked granuloma). There are inclusion bodies such as Schaumann bodies and a asteroid b bodies c in the d giante cells of granuloma, but these are not specific for sarcoidosis and they may occur in other granulomation reactions. The Schaumann bodies have a basophilic round lamellar structure that is positive for alkaline phosphatase and calcium deposition. The asteroid bodies have a radiated, acicular structure with a central core. In addition to granulomatous lesion, foreign substances such as silica are found in scarring infiltration.

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Laboratory findings Sarcoidosis is diagnosed mainly from clinical and

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Fig. 18.14 Histopathology of sarcoidosis. Noncaseating granuloma is characteristically observed.

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Fig. 18.13-2 Sarcoidosis. e, f: Diffuse infiltrative sarcoidosis (lupus pernio). g, h: Scarring infiltrative sarcoidosis.

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histopathological findings. Tuberculin test is negative and levels of angiotensin-converting enzyme (ACE) and calcium are elevated. Accumulation of 67Ga is observed by 67Ga scintigraphy. BHL revealed by chest X-ray or CT scan has diagnostic value. Clinical images are available in hardcopy only.

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Treatment Oral steroids are effective; however, they are not usually necessary in the early stages because sarcoidosis tends to heal spontaneously and has a good prognosis. Oral steroids are used when sarcoidosis is progressive and extensive pulmonary lesions p j h causing i k l such m as breathing n o difficulty, are clinical symptoms orq when lesions occur in the heart, eyes or nervous system. Topical steroids are applied for cutaneous lesions.

2. Granuloma annulare (GA) Outline

Clinical images are available in hardcopy only.

● It

is a doughnut-shaped eruption with an elevated rim. there is the formation of a palisading granuloma. ● When GA generalizes to the whole body, diabetes mellitus may be involved. ● Histopathologically,

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Granuloma annulare (GA) is classified by the clinical features into four subtypes: localized, generalized, perforating and subcutaneous (Figs. 18.15-1 and 18.15-2; MEMO). Clinical features, Pathology Small, firm, doughnut-shaped nodules with a concave center appear and spread centrifugally. Firm, small papules 2 mm to

18 Clinical images are available in hardcopy only.

Granuloma annulare classified by clinical features b

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Fig. 18.15-1 Granuloma annulare. a, b: Localized granuloma annulare. c: Generalized granuloma annulare.

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1) Localized granuloma annulare It occurs most commonly in young women and p tends to be localized to k hands l and m n o half of casesq heal spontar the dorsal finger joints. About neously within 2 years after onset. 2) Generalized granuloma annulare Small contralateral or dispersed granuloma annulare occurs multiply, most frequently on the trunk and distal extremities of middle-aged women. In about half of cases, the disease is associated with diabetes mellitus. When generalized granuloma annulare is suspected, examination for diabetes mellitus is highly recommended. 3) Perforating granuloma annulare It is a papule with a centralized concavity that may ulcerate and crust. Dermal excretion of degenerated collagen fibers occurs. It often arises secondarily after localized granuloma annulare. 4) Subcutaneous granuloma annulare A palpable, subcutaneous nodule of normal skin color, it commonly occurs in early childhood. Bony sites that tend to be subject to pressure, such as the elbows, are easily affected.

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4 mm in diameter form in circular arrangement. The papules are normal skin color to light pink and are asymptomatic. Histopathologically, degenerated collagen fibers at the center are radially surrounded by histiocytes, lymphocytes and giant cells (palisading granuloma) (Fig. 18.16). Acid mucopolysaccharides deposit in the lesion in the central area of incomplete necrosis. Pathogenesis The mechanism of GA has not been fully clarified. Impaired peripheral circulation, diabetes, insect bites, UV radiation and injury may induce GA. a b c

Clinical images are available in hardcopy only.

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Treatment GA tends to heal spontaneously. After a skin biopsy, the biopsy lesion often disappears. As local therapies, topical steroids, PUVA therapy and cryotherapy are conducted. If diabetes mellitus is involved, it is treated.

3. Annular elastolytic giant cell granuloma (AEGCG) a

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Synonyms: Actinic granuloma, Elastophagic giant cell granuloma

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Fig. 18.15-2 Granuloma annulare. d: Perforating granuloma annulare. e: Granuloma annulare in a diabetic patient.

A granulomatous lesion whose main components are elastic fiber-phagocytosing giant cells occurs, most frequently in middle-aged women. A large, circular erythematous eruption with an elevated rim and central depigmentation occurs on exposed areas, such as the face, neck region and extremities (Fig. 18.17). It may resemble annular erythema. The lesion heals spontaneously in many cases. AEGCG is widely known as a subtype of GA. It often accompanies diabetes mellitus.

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4. Cheilitis granulomatosa Synonym: Melkersson-Rosenthal syndrome Clinical features Men and women in their 20s are most frequently affected. When all three main symptoms are present together – swelling of the lips, fissured tongue (scrotal tongue, lingua plicata) and facial nerve palsy – it is called Melkersson-Rosenthal syndrome. Swelling of lips: Swelling occurs suddenly in the lips (particularly the upper lip) as the earliest symptom in most cases of cheilitis granulomatosa. The buccal mucosa may also be involved. Although subjective symptoms such as pain are not present, the swelling persists for several hours to several days. It recurs, leading to rubber-like stiffness. Lingua plicata: Swelling occurs in the tongue at the same time as the lips are affected. The folds in the surface of the tongue become marked.

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Fig. 18.16 Histopathology of granuloma annulare. Collagen fiber degeneration and the mucin deposition are observed at the center (★). Palisading epithelioid cell granuloma forms at the periphery.

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Facial paralysis: At the same time or earlier than swelling of the cheeks, peripheral facial paralysis suddenly occurs on one cheek. Recurrences and remissions are repeated. Other symptoms: Migraine, autonomic failure and mental deterioration may occur. Clinical images are available in hardcopy only.

Fig. 18.17 Annular elastolytic giant cell granuloma.

Pathogenesis, Pathology The cause is unknown; however, dental metal allergy and sarcoidosis reaction are suspected. Lymphatic edema in the dermis, and lymphoid and histiocytic infiltration are pathologically found in the early stages. As it progresses, inflammatory granulomatous lesions consisting of lymphocytes, epithelioid cells and Langhans giant cells occur. Treatment Oral antihistamines and oral or locally injected steroids are useful as symptomatic therapies.

E. Hereditary connective tissue disease 1. Ehlers-Danlos syndrome (EDS) Outline ● It

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is a congenital disease of the connective tissue. In most cases, it is autosomal dominant. ● Hyperextensible skin, fragility of the skin and blood vessels, and excessive mobility of joints are the main symptoms. Clinical features Ehlers-Danlos syndrome (EDS) is a common inherited disorder; the incidence is on the order of 1:5000 of the population. The skin is soft and stretches excessively, despite appearing normal; when stretched and released, the skin immediately returns to its former appearance. The skin is easily torn by extrinsic force or injury. Because injuries do not heal promptly, parchment-like scars form. At the terminal stages, the skin hangs saclike from the body. In areas subjected to strong extrinsic forces, such as the heels, subcutaneous fat enters the torn connective tissue and develops into lump tumors. The joints of the digits, elbows and knees hyperextend, exceeding 180 degrees of bending in the direction opposite the flexure direction. They become valgus (Fig. 18.18). Deformity and dislocation of the joints often occur. Congenital dislocation of the hip joints and gait disorder are present. Bleeding under the skin and in the ocular fundus, cardiac anomaly and valvular involvement, aneurysm, lens deviation and severe myopic astigmatism occur in the later stages of life, from fragility of the blood vessels.

Disorders of the dermis / E. Hereditary connective tissue disease

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Table 18.1 Types of Ehlers-Danlos syndrome (EDS). Traditional

Newly established Classical

Causative molecule

Inheritance pattern

Gravis (EDS type I)

Type V collagen

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Mitis (EDS type II)

Type V collagen

AD AD

Hypermobility

EDS type III

Vascular

Arterial-ecchymotic (EDS type IV)

Type III collagen

AD

Kyphoscioliosis

Ocular-Scoliotic (EDS type VI)

Procollagen lysine hydroxylase

AR

Arthrochalasia

Arthrochalasis multiplex congenita (EDS type VII A, VII B) Type I collagen

Dermatosparaxis

Human dermatosparaxis (EDS type VII C)

Other

X-linked EDS (EDS type V)

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Periodontitis (EDS type VIII)

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ADAMTS2

Progeroid EDS

XGPT1

Tenascin X

Tenascin X

AD AR

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AD: autosomal dominant, AR: autosomal recessive, XR: X-linked recessive (Adapted from: Beighton P, et al. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31-37).

Pathogenesis The causative genes vary according to disease type. Abnormality is found in collagen types I, III and V; the genetic mutations have been identified. EDS is classified by the clinical features, pattern of inheritance, causative gene and biochemical abnormality into more than ten subtypes (Table 18.1). The patterns of inheritance are various; however, EDS is autosomal dominant in many cases.

Clinical images are available in hardcopy only.

Laboratory findings, Diagnosis The skin fibroblasts are cultured for detection of collagen abnormality. Genetic mutation is identified.

18 Treatment There are no ultimate treatments for EDS, only symptomatic therapies. Pregnancy and delivery of the patients with EDS may cause uterine rupture or massive bleeding.

2. Marfan syndrome Outline

is a congenital disease of the connective tissue. Skeletal abnormality, eye symptoms and cardiovascular impairment are the main symptoms. ● It is autosomal dominant, caused by mutation in the fibrillin-1 gene. ● Striae occur in the chest as a cutaneous symptom. Abnormal elastic fibers are eliminated from the epidermis. ● The major symptoms are arachnodactyly, skeletal deformity of the chest, annuloaortic ectasia and lens deviation.

Clinical images are available in hardcopy only.

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Fig. 18.18 Ehlers-Danlos syndrome. Overextension of the skin occurs.

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Clinical features Striae distens appear in the chest and thighs. Abnormal elastic fibers produced in the patient’s upper dermal layer are eliminated (elastosis perforans serpiginosa, described previously) in some cases. When this phenomenon occurs, small, keratotic, reddishbrown papules appear in a serpentine or circular pattern with an atrophic center. The patients are abnormally tall, with a markedly elongated lower body relative to the upper body. The extremities and digits are thin and long (arachnodactyly). Deformities occur in the chest (funnel chest or pigeon breast) and spine, and hypertension and dislocation of the joints occur. Mitral valve prolapse often occurs, as a result of reduced elasticity of the cardiovascular system. Incompetence of the aortal valve and dissecting aortic aneurysm are easily caused by annulo-aortic ectasia. Death may result. Since Marfan syndrome is caused by abnormality in the fibrillin-1 gene, deviation occurs in the crystalline lens, because the zonules of Zinn, which support that lens, are composed of fibrillin. Severe myopia may be caused by elongation of the eyeball in the anteroposterior direction. Pathogenesis Marfan syndrome is caused by mutation in the fibrillin-1 gene on chromosome 15. Fibrillin-1, a protein component of the extracellular matrix, is essential to elastic fiber synthesis. The condition is autosomal dominant; however, it is caused by sporadic mutation in about 30% of cases. Diagnosis, Differential diagnosis, Treatment Marfan syndrome can be diagnosed easily by the clinical features. Genetic examination is necessary for differential diagnosis.

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3. Pseudoxanthoma elasticum (PXE) Outline

It is a hereditary disease caused by mutation in the ABCC6 gene. This gene encodes the multidrug-resistant protein MRP6. Abnormality occurs in the elastic fibers. ● Yellow or orange papules aggregate on the neck region and flexor surfaces of joints. Dermal laxity progresses with age. It is asymptomatic. ● Eye symptoms and vasoconstriction occur. ●

Clinical images are available in hardcopy only.

Fig. 18.19 Pseudoxanthoma elasticum. The skin of the axillary fossae becomes soft and saggy, resembling orange peel.

Clinical features Slightly yellowish papules aggregate and form reticular plaques with an orange-peel-like appearance, most frequently on the lateral region of the neck, axillary fossae and flexor surfaces of joints. The skin is soft and saggy. Skin wrinkling becomes marked with age (Fig. 18.19). It is asymptomatic. Visual impairment or blindness results from formation of

Disorders of subcutaneous fat / A. Panniculitis

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angioid streaks caused by degeneration of the Bruch’s membrane, which exists between the retina and choroids and contains abundant elastic fibers. It is at this point that many patients with pseudoxanthoma elasticum (PXE) first see a doctor. Fibrosis and calcinosis occur in the aortic tunica media, leading to constriction of the blood vessels and bleeding. This results in high blood pressure in renal arteries, claudication in the lower legs, cardiac attack, cardiac infarction, coldness of the limbs and gastrointestinal bleeding. Women outnumber men by two to one, but male cases tend to be more severe. Pathogenesis Mutation in ABCC6 on chromosome 16, a member of the ATP binding cassette (ABC), has been associated with the occurrence of PXE. This gene encodes multidrug-resistant protein MRP6. Although both dominant and recessive inheritance patterns are known, recent studies support the leading theory that PXE is autosomal recessive. Pathology Swelling and disruption occur in the elastic fibers in the middle-dermal to deeper-dermal layers, accompanied by calcium deposition and changes in the vascular walls (Fig. 18.20). Treatment, Prognosis The prognosis is good, as long as the cardiovascular symptoms are not severe. Eye symptoms should be treated.

Fig. 18.20 Histopathology of pseudoxanthoma elasticum (von Kossa stain). Calcium deposition stains brownish-black with Kossa.

Disorders of subcutaneous fat 18

A. Panniculitis Inflammatory lesions of the subcutaneous fat can be classified into three distinct categories. ① Septal panniculitis ② Lobular panniculitis ③ Panniculitis associated with vasculitis

1. Erythema nodosum (EN) Outline ● Red

nodules accompanied by tenderness occur, most commonly on the extensor surfaces of the lower extremities. They do not ulcerate. ● It is an inflammatory reaction whose inductive factors include upper respiratory infection, drug eruption, Behçet’s disease and sarcoidosis. ● Inflammation is histopathologically found in the subcuta-

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neous fat tissue septum. should be differentiated from erythema induratum. ● Conservative therapies such as bed rest and cooling are the first-line treatments. When induced by an infection, antibiotics are administered. NSAIDs and potassium iodide are also useful. Steroids may be used for severe cases. ● It

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

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Fig. 18.21 Erythema nodosum (EN). Multiple erythema accompanied by severe tenderness on the extensor of the lower legs.

Clinical features Adult women are most commonly affected. After a precursor of upper respiratory infection, a few symmetrical, vaguely margined, light pink erythema occur, sometimes accompanied by a fever. There is arthralgia. The erythema occur predominantly on the extensor surfaces of the lower legs (Fig. 18.21). The erythemata vary in size from 1 cm to 10 cm. The eruptions are slightly elevated indurations that are accompanied by heat sensation. Tenderness and spontaneous pain are present. Ulceration does not occur. In progressive cases, the same type of eruptions may develop on the arms and hands. The eruptions change color from dark red to yellow to blue in 2 to 4 weeks, and heal without scarring. Pathogenesis Erythema nodosum (EN) is induced by infectious allergy to bacteria, fungi or viruses. It often appears secondarily after upper respiratory or enteric infection caused by hemolytic streptococcus. Hansen’s disease, tuberculosis, toxoplasmosis and chlamydiosis may also cause EN. When the cause is infectious disease, the condition is called acute EN, because it progresses rapidly and resolves in several weeks. Drugs such as sulfa drugs and oral contraceptives can also be causes. Additionally, EN may accompany Behçet’s disease, ulcerative colitis, Crohn’s disease, sarcoidosis or leukemia. However, it may occur sporadically without any underlying diseases. Pathology In the early stages of EN, lymphoid cells and neutrophils infiltrate the dermis and subcutaneous fat tissue (fatty septum in particular); the condition is septal panniculitis. There are no findings of vasculitis or degeneration of fat cells. Granulomas that contain giant cells develop in the later stages. Diagnosis Clinical features of tenderness, histopathological findings and precursory infectious disease are diagnostic. EN often occurs as a symptom of various diseases (Table 18.2); the primary disease should be identified. Differential diagnosis It is differentiated from erythema induratum, cellulitis, thrombophlebitis, Weber-Christian disease, lupus erythematous profundus and polyarteritis nodosa.

Disorders of subcutaneous fat / A. Panniculitis

Treatment Bed rest is required. The lower extremities are kept cool and elevated. In cases with intense inflammation, oral NSAIDs, potassium iodide and steroids are administered. Any primary diseases are treated. If bacterial infection is identified, antibiotics are used. Prognosis When induced by drugs or infection, EN does not recur as long as it is appropriately treated. When the cause is any of the chronic underlying diseases listed above or is unknown, there may be recurrence.

Table 18.2 Primary diseases that cause erythema nodosum (EN). Disease

Findings and check points

Allergy caused by bacterial, fungal or viral infection

Symptoms of various infectious diseases

Behçet’s disease

Findings of other diseases (oral aphtha, uveitis, genital ulcers), needle reaction test positivity

Tuberculosis

Tuberculin skin test positive, tuberculous granuloma in tissue, nodules by chest X-ray

Sarcoidosis

Bilateral hilar lymphadenopathy (BHL) by chest X-ray, uveitis, high concentration in serum of Ca2+/ACE/lysozyme, negative tuberculin skin test

Drug eruption

History-taking and investigation of oral drugs is needed.

Ulcerative colitis, Crohn’s disease

Occult blood in stool, gastrointestinal endoscopy

2. Erythema induratum Synonyms: Erythema induratum Bazin, Nodular vasculitis Outline ● Painless

subcutaneous nodules occur most frequently on the lower legs of women. The primary disease is lobular cellulitis. ● It is clinically similar to EN; however, acute inflammatory findings are not present. The nodules are firm and often accompanied by ulceration with scarring. ● When tubercle bacillus allergy (tuberculid) is identified, therapy for tuberculosis should be given.

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Myelodysplastic Atypical hemocytes in bone syndrome marrow and peripheral blood, chromosomal abnormality Leprosy

Histological findings, lepromin test positive, neurological findings

Clinical features Symmetrical, diffuse, elevated, dark red infiltrative erythema and subcutaneous induration occur on both the extensor and flexor surfaces of the lower legs of middle-aged and elderly adults (Fig. 18.22). Women are more commonly affected than men. The induration disappears in 1 to 2 months; however, it may ulcerate or coalesce to become plate-like, and scarring may be present. The skin lesion may occur singly or multiply. When multiple, eruptions from each stage are present at the same time. Nodular vasculitis is a subtype of erythema induratum.

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Clinical images are available in hardcopy only.

Pathogenesis Erythema induratum used to be regarded as tuberculid, i.e., an allergic reaction to tubercle bacilli or to metabolites of such bacilli. Nevertheless, there were cases in which tuberculosis did not present, and steroids were effective as a treatment. Therefore, erythema induratum has come to be thought of as lobular panniculitis that occurs with circulatory failure as the underlying disease. Even so, the tubercle bacillus was recently reported to have been detected by PCR assay of skin biopsy in about 80% of cases. In recent years, the theory of tubercle bacillus allergy as the causative factor has reemerged.

Fig. 18.22 Erythema induratum. Ulceration and erythema accompanied by induration occurred.

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Disorders of the Dermis and Subcutaneous Fat

Pathology Necrosis of fat lobular tissue and granuloma are accompanied by giant cells and epithelioid cellular infiltration. In typical cases caused by tuberculosis, there are tuberculoid granulomas with caseous necrotic centers surrounded by epithelioid cells, Langerhans giant cells and lymphocytes. Vasculitis of subcutaneous fat tissue (most frequently in veins) is present (Fig. 18.23). Diagnosis, Examination Tuberculin skin test and chest X-ray are conducted to determine whether there is a tubercle bacillus allergy. Tubercle bacillus DNA is identified by PCR assay of biopsy tissue.

Fig. 18.23 Histopathology of erythema induratum.

Differential diagnosis The disorder should be differentiated from EN, thrombophlebitis migrans, cutaneous polyarteritis nodosa and other vasculitis, and ulceration in the lower extremities. EN is differentiated by its tenderness, its acute, intense inflammatory reaction, and lesions that do not rupture spontaneously and whose main pathological component is fat tissue septum. Treatment Therapy for tuberculosis should be given. Tubercular lesions subside with treatment in a few months in most cases. Erythma induratum that is not caused by tuberculosis is intractable and progresses slowly. Bed rest for the lower extremities and prevention of stasis are effective. NSAIDs are administered orally. Steroids are used in severe cases.

3. Weber-Christian disease

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Synonyms: Systemic nodular panniculitis, Relapsing febrile nonsuppurative nodular panniculitis

Weber-Christian disease MEMO as a distinct disorder Weber-Christian disease may display almost the same clinical course and pathology as the panniculitis (lupus profundus) that accompanies collagen diseases. Some studies have questioned whether Weber-Christian disease is a distinct disorder. While cases of WeberChristian disease with poor prognosis have been reported, it is likely that those cases are actually misdiagnosed subcutaneous panniculitis-like T-cell lymphoma (SPTCL).

Weber-Christian disease is subcutaneous inflammation with unknown cause. Internationally, recent theories have described Weber-Christian disease as a subtype of EN or T-cell lymphoma rather than as an independent disease. Weber-Christian disease was defined in the past as a rare disorder with recurrent subcutaneous nodules and plaques, typically or extremities and buttocks, and commonly associated with fever. Young and middle-aged women are most commonly affected. After systemic symptoms such as fever, fatigue and arthralgia, there are multiple, painful, subcutaneous nodules or splenial induration of 1 cm to several centimeters in diameter. The eruptions most frequently occur in the extremities and trunk. They are light pink and edematous at the beginning, gradually becoming dark purplish-red and stiff, with high elasticity. The eruptions chronically recur to cause concavities and pigmentation in the sites. Systemic symptoms are characterized by the markedly high fever. Myocarditis and pericarditis are caused by inflammation of

Disorders of subcutaneous fat / A. Panniculitis

pericardial fat tissue. There is also anemia, neurological symptoms from meningitis, and liver enlargement from hyperlipemia resulting from fat tissue degradation. Degeneration and necrosis occur in the lobular fat tissue. As time passes, foamy and other histiocytes are found in the neutrophilic infiltration, giving the appearance of lipid granuloma. The foamy histiocytes become fibrotic. Blood test shows elevated erythrocyte sedimentation rate, leucopenia and abnormality in the coagulation-fibrinolytic system. Primary diseases and compounding factors, if found, are treated or removed. As symptomatic therapies, systemic steroids and immunosuppressants are administered.

Panniculitis caused by absence of enzyme

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MEMO

a1-antitrypsin deficiency, a1-antichymotrypsin deficiency: These are rare diseases. Enhanced decomposition and Weber-Christian-diseaselike panniculitis may be caused by decrease of proteolytic enzyme inhibiting substances. Enzymic panniculitis: Increase of lipase and amylase in serum may lead to panniculitis in patients with pancreatitis. Pancreatitis is an important underlying disease in patients with panniculitis.

4. Poststeroid panniculitis It occurs a few days after large doses of steroids are reduced or stopped. Multiple subcutaneous nodules 5 mm to 50 mm in diameter suddenly occur on the whole body. They are sometimes accompanied by tenderness, spontaneous pain and itching. They are normal skin color or light pink. The pathological findings are necrosis and degradation of the fat tissue, fat cells and foreignbody giant cells. They subside spontaneously; however, readministration of steroids may be necessary in severe cases.

5. Cold panniculitis Subcutaneous nodules accompanied by erythema occur on skin (mainly the cheeks and extremities) that is exposed to the cold, such as ice and cold air. Newborns and infants are most commonly affected. The skin lesion heals spontaneously in a few days to a few weeks.

6. Traumatic panniculitis It is an inflammatory reaction caused by damage to fat cells after injury. A painful erythematous plaque or nodule accompanied by palpable infiltration forms, most frequently in the breasts or lower legs of obese women.

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B. Lipodystrophy Fat tissue is markedly reduced or lost. It is classified by whether the atrophy primarily occurs systemically or locally, and whether the causative agent is congenital or acquired. Atrophy is often accompanied by dysbolism and internal organ failure.

1. Generalized lipodystrophy 1) Congenital generalized dystrophy Several genes are involved in the occurrence of this rare autosomal recessive disease. With absent or reduced fat in the whole body from the time of birth or early infancy, muscles appear sharply defined. Hyperlipemia, hyperinsulinemia, enlargement of internal organs and insulin-resistant diabetes occur as complications.

2) Acquired generalized lipodystrophy It manifests several days to several weeks after infectious precursors such as measles and varicella. Fat disappears in several months to several years, sometimes in several weeks. Girls are more commonly affected than boys. The cause is thought to be autoimmune abnormality.

2. Localized lipodystrophy

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It is divided into congenital and acquired. Fatty atrophy occurs locally in the body. Atrophy occurs locally in fat tissue after panniculitis or in sites subjected to external stimulation. It may occur at the injection site of insulin, steroids, iron preparations or vaccines (post-injectional panniculitis). Panniculitis accompanying a collagen disease often causes lipodystrophy, such as in lupus erythematosus profundus, dermatomyositis, and scleroderma.

3. HIV-associated lipodystrophy A lipodystrophy can be seen in patients with acquired immunodeficiency syndrome (AIDS). There are some variants. The most common type can develop following the use of protease inhibitor therapy. This type is characterized by the presence of peripheral lipoatrophy and central adiposity.

4. Lipodystrophia centrifugalis abdominalis infantilis It is localized lipodystrophy produced most frequently on the groin or axillary fossae of infants. The etiology is unknown; however, genetic involvement is suspected because there are

Disorders of subcutaneous fat / C. Localized atrophy of fat tissue caused by various injurious stimuli

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familial cases. This is a rare disease, and most patients are Asians. Girls outnumber boys by 1.5 to 1. Painless erythema becomes sharply circumscribed and concave, with a swollen lymph node at the periphery. Within 7 years after onset, the depression stops expanding. It subsides in the two thirds of all cases.

C. Localized atrophy of fat tissue caused by various injurious stimuli Subcutaneous fat necrosis of the newborn Several days to 1 month after birth, plate-like subcutaneous indurations of various sizes occur on the buttocks and thighs, where fat is distributed. This is known to be a localized hypoxic condition in tissue. It may be accompanied by hypercalcemia. The induration heals spontaneously without scarring in 1 to 2 months.

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Disorders of the Skin Appendages

This chapter discusses disorders of the skin appendages: sweat glands, sebaceous glands, hair follicles and nails. When these are affected by intrinsic or extrinsic factors, cosmetic appearance and the ability to regulate the body temperature are affected. The diseases whose main lesions occur in the skin appendages are introduced in this chapter (see Chapter 1 for the functions of skin appendages).

A. Disorders of the sweat glands 1. Miliaria Synonym: Sweat retention syndrome Outline ● Commonly

called heat rash, it is caused by obstruction to the eccrine sweat ducts. ● Skin care is the main treatment. Clinical features, Classification Miliaria is classified by the location of the obstructed sweat ducts into miliaria crystallina, miliaria rubra and miliaria profunda (Fig. 19.1). ① Miliaria crystallina The sweat ducts are obstructed in or directly under the horny cell layer, producing superficial transparent vesicles. Flushing is

19 sweat accumulation at the level of horny cell layer

occlusion of sweat duct

occlusion of sweat duct

intraepidermal sweat accumulation

miliaria crystallina

miliaria rubra

Fig. 19.1 Classification of miliaria, and obstructed portion of the sweat duct.

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intradermal sweat accumulation

miliaria profunda

A. Disorders of the sweat glands

not present. The vesicles soon dry and become thin, white scales. They heal in one to several days without itching or inflammation. They commonly occur on the face of infants; however, they may appear accompanying fever in adults. ② Miliaria rubra It frequently occurs in an environment with high temperature and humidity, or in infants, the obese and persons with hidrosis (Fig. 19.2). Inflammation occurs from obstruction of the sweat ducts in the granular cell layer region, and rose pink papules of 1 mm to 2 mm in diameter are produced. It is accompanied by flushing and itching. The trunk, extensor surfaces of the extremities, neck region and axillary fossae are most commonly affected. It often becomes eczematous (miliaria eczematosa) or pustular (miliaria pustulosa). ③ Miliaria profunda The sweat ducts are destroyed at the dermo-epidermal junction. Flat-surfaced, white papules without itching occur secondarily after miliaria rubra. Pathogenesis The pathogenesis of miliaria is poorly understood. It is thought that the sweat ducts are obstructed by eccrine perspiration, affecting the sweat flow. Retained sweat leaks into the peripheral tissue of the sweat ducts, causing eruptions. Miliaria is easily caused when hyperhidrosis is present from physical exercise in a hot, humid environment. It tends to occur in those who have a febrile disease or who wear dressings, casts, medical tape, or clothing that does not breathe. Treatment High temperature and humidity should be avoided. Careful washing of the body is necessary. When the eruptions are eczematous, the treatments are the same as those for eczema. Secondary infections should be carefully avoided.

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Clinical images are available in hardcopy only.

Fig. 19.2 Miliaria rubra after fever.

Clinical images are available in hardcopy only.

Fig. 19.3 Pompholyx. Multiple vesicles on the palm.

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2. Pompholyx Synonym: Dyshidrosis Pompholyx is a form of eczema of the palms and soles in which edema fluid accumulates to form visible vesicles or bullae. Small blisters 1 mm to 5 mm in diameter occur multiply on the palms and soles. The contents of the blister disappear in a few days, resulting in scaling (Fig. 19.3). The blisters may become eczematous and itchy in some cases; the condition is called dyshidrotic eczema (Fig. 19.4). Previously, pompholyx was thought to be a phenomenon caused by sweat retention, because it most frequently occurs during the summer, and hidrosis accompanies many cases. Nevertheless, the pathology is subcutaneous blistering accompanied by epidermal spongiosis, which is not always associated with sweat

Clinical images are available in hardcopy only.

Fig. 19.4 Dyshidrotic eczema.

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ducts or sweat glands. Further, the blister contents differ from those of sweat. Any exacerbating factors such as allergenic drugs should be removed. Antiperspirant and keratolytic agents are used. Steroids are applied topically on eczematous lesions.

3. Bromhidrosis Synonym: Osmidrosis Definition, Classification, Clinical features Bromhidrosis (osmidrosis) is a general term for abnormal body odor arising from sweat glands. Eccrine bromhidrosis and apocrine bromhidrosis are the main types. ① Eccrine bromhidrosis Eccrine sweat may have a distinct odor, from intake of drugs and foods such as garlic and spices. Bromhidrosis in feet is caused by the bacterial action on keratin softened by sweat. ② Apocrine bromhidrosis Osmidrosis axillae, commonly called body odor, is the wellknown type. Bromhidrosis of the genitalia is also caused by apocrine sweat. The sweat itself is odorless; however, fatty acids are decomposed by superficial bacteria, resulting in the odor. The apocrine glands begin to develop at puberty. Perspiration increases with mental excitement and physical exercise.

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Treatment The skin should be kept clean to reduce bacterial flora and apocrine sweat of the axilla. Application of antiperspirants, deodorants or antibiotics, and shaving are effective. Systemic antibiotics are most helpful. Laser, surgical or electrolysis depilation may be performed as permanent cure. Reduction of eccrine sweating using aluminum chloride may help decreases the local bacterial flora, but will not reduce apocrine sweat production. However, many patients who complain of offensive odor do not actually have the odor; the complaints may represent paranoia and phobia (osmidrophobia).

4. Fox-Fordyce disease Synonym: Apocrine miliaria Definition Chronic, itchy papules occur, mainly on areas distributed with apocrine sweat glands, such as the axillae and the pubic area. Clinical features The disease is uncommon and most of the reported cases have occurred in young or middle-aged women. Follicular, solid, normal skin color or rose pink papules 2 mm to 3 mm in diameter aggregate on the axillary fossae, areola of nipples, and genitalia.

A. Disorders of the sweat glands

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They are accompanied by intense itching. Pathogenesis When the sweat ducts of apocrine sweat glands are obstructed, apocrine sweat exudes into the epidermis. The pathogenesis of sweat gland obstruction is unknown; however, there is possible involvement of hormones. Treatment The treatment of Fox-Fordyce disease is difficult. Laser therapy and topical application or local injection of steroids are the first-line treatments. Clindamycin solution and tretinoin cream are occasionally effective. Prognosis It is chronic and intractable.

5. Hyperhidrosis Synonym: Hyperidorosis Hyperhidrosis, caused by enhanced perspiration from the eccrine glands, is classified into the subtypes described below. ① Generalized hyperhidrosis This occurs physiologically in hot, humid environments, during exercise, or from sympathetic hypertonia. It also occurs in patients with hyperthyroidism, diabetes, hypoglycemia, dumping syndrome, gout, neurologic disease, spinal cord injury, malignancies (especially, in Hodgkin’s disease), or other primary disease, or it may be induced by drugs (e.g., antipyretics, anticholinesterase agents), pregnancy or obesity. ② Localized hyperhidrosis This occurs in the palms, soles, axillary fossae, face and elsewhere. Most cases are from emotional perspiration. The condition is associated with constitutional factors and mental stress. Iontophoresis using tap water is effective as a treatment in some cases. Hyperhidrosis palmaris et plantaris may accompany atopic condition or palmoplantar keratosis. Hemihyperhidrosis is seen in patients with partial paralysis or Parkinson’s disease. The hyperhidrosis occurs on one side of the body from impairment of the peripheral nerves on that side.

Cause of anhidrosis

Disease producing that cause

Congenital absence of sweat gland function

Hypohidrotic ectodermal dysplaisia

Metabolic disorder

Hypothyroidism, dehydration, thermic fever, Fabry’s disease

Neurological Disorder of the hypothalamus and spinal cord, alcoholic neuritis, lepdisorder rosy, diabetic neuropathy

6. Anhidrosis Synonym: Hypohidrosis This is a condition with scant or absent perspiration. The skin is dry and coarse. Scaling and mild itching occur, and fever may be produced by exercise because of lack of perspiration. Diseases suspected of causing anhidrosis are shown in Table 19.1.

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Table 19.1 Diseases thought to cause anhidrosis.

Obstruction of sweat pores and ducts

Ichthyosis, seborrheic dermatitis, atopic dermatitis, erythroderma, psoriasis

Atrophy or damage of sweat glands

Scleroderma, systemic sclerosis, Sjögren syndrome, systemic lupus erythematosus, solar elastosis, and the like

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B. Disorders of sebaceous glands 1. Acne vulgaris Outline ● It

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

most frequently occurs on the face of adolescent men and women. Comedones, folliculitis, papules and pustules are produced. ● Agents and factors such as Propionibacterium acnes, the Demodex folliculorum mite, endocrine secretion and stress are associated with the occurrence. ● Lifestyle guidance and administration of sulfa drugs and antibiotics are effective. Clinical features Multiple follicular inflammatory papules occur, most commonly on the seborrheic areas of the face, precordial region, and back of men and women from the ages of about 10 to 40 (Fig. 19.5). The papules worsen at puberty. The initial eruption, called a comedo, is classified as an open comedo (the follicles are open, also called “blackheads”) or a closed comedo (small yellowishwhite nodules in the skin: “white heads”). Closed comedos often progress to erythematous papules or pustules. Subjective symptoms such as itching are not usually present; however, the comedos become painful as they develop further. Acne vulgaris is characterized by intermingled eruptions of different stages. Pathogenesis The main pathogenesis involves hormonal imbalance, abnormal keratinization and bacterial infection (Fig. 19.6). Along with

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dirt

Clinical images are available in hardcopy only. increase of free fat mechanical stimuli

Fig. 19.5 Acne vulgaris. Multiple, follicular, inflammatory papules occur on oily areas of the face, such as the cheeks and forehead. The hair follicles are obstructed and appear as yellowish-white nodules (closed comedos).

P. acnes

increase of sebum

inflammation comedo

DHT receptors androgen increase, especially in adolescents endogenous factors

Fig. 19.6 Mechanism of acne vulgaris.

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B. Disorders of sebaceous glands

these main factors, hereditary factors, the patient’s age, diet, stress and extrinsic factors such as cosmetics are complicatedly associated with the onset. Acne caused by Demodex folliculorum is called acne demodecica, and it occurs most frequently in women after puberty. Hormonal imbalance: Androgen in the blood increases according to pubertal endocrine changes, and the function of the sebaceous glands is enhanced by adrenogenic dihydrotestosterone (DHT). Accordingly, sebum retention and bacterial proliferation readily occur. Follicular hyperkeratinization: The infundibulum is obstructed by keratin as a result of poor hygiene or hereditary factors. When sebum components are decomposed by bacteria, free fatty acid is produced; stimulated by this phenomenon, the infundibulum induces keratinization. Sebum retention is accelerated by these causative factors to produce an initial comedo. Bacterial infection: Propionibacterium acnes resident in the infundibulum break down triglycerides in the sebum, producing free fatty acids that destroy the hair follicles and lead to inflammation. The bacteria themselves also cause destruction of follicles and inflammation, especially when there is infestation by the Demodex folliculorum mite. Pathology Acne vulgaris is characterized by enlargement of the seba-a ceous glands and follicular keratinization. Cystic dilation occurs in follicles, and destruction of the follicular walls causes inflammatory reaction.

Clinical images are available in hardcopy only.

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Differential diagnosis Acne vulgaris must be differentiated from steroid acne, a side effect of oral or topical steroid use, and from lupus miliaris disseminatus faciei, and verruca plana. Acne-like eruptions are caused by immunosuppressants in the same mechanism as that in steroid acne; these eruptions must also be differentiated from acne vulgaris. Thorough history-taking is important. Treatment a b Lifestyle guidance is primary. Observance of a regular schedule of sleeping and eating, and avoidance of cosmetics (oily creams and foundation, in particular) are helpful. Washing the face and maintaining regular bowel movements are important. Topical application of retinoids (tretinoin or adapalene cream), sulfa drugs, and antibiotic ointments and oral antibiotics such as tetracyclines and roxithromycin are effective. Chemical peeling or extraction of comedos may be useful in some cases. Unless treated appropriately, acne vulgaris heals with scarring, leaving a cosmetic problem.

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Fig. 19.7 Rosacea erythematosa on the tip of the nose. a: A male patient in his 20’s. b: A female patient in her 30s. c. A male patient in his 30s. Telangiectasia is remarkable.

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Disorders of the Skin Appendages

2. Rosacea

Clinical images are available in hardcopy only.

Fig. 19.8 Acne rosacea in a male patient in his 50s. A red skin lesion is present on the nose and cheeks.

Clinical images are available in hardcopy only.

Fig. 19.9 Rhinophyma in a male patient in his 60s. The skin lesion becomes tumor-like and the hair follicles dilate. The skin takes on the appearance of orange peel.

Definition, Pathogenesis Rosacea is a chronic inflammatory disease that causes diffuse reddening and vascular dilation on the face of middle-aged and older men and women. Acne-like papules and pustules may be produced. Clinical features Rosacea is classified by severity into three stages. The first stage (rosacea erythematosa) and second stage (acne rosacea) occur frequently in middle-aged and older women. Progression to the third stage (rhinophyma) is more common in men. In addition to the cutaneous symptoms listed below, eye symptoms (e.g., ketatitis and conjunctivitis) may occur. ① First stage (rosacea erythematosa): Transient reddening appears on the tip of the nose and on the cheeks, glabella and chin. It progresses gradually to become persistent and accompanied by telangiectasia and seborrhea (Fig. 19.7). Cold and warm weather, sunlight and alcohol consumption aggravate it. Subjective symptoms such as itching, hot flashes and irritability are present. ② Second stage (acne rosacea): In addition to the symptoms of the first stage, follicular papules and pustules occur. Seborrhea is intense (Fig. 19.8). The lesions spread to cover the face. ③ Third stage (rhinophyma): The papules aggregate and coalesce to become tumorous. The surface of the nose becomes rough and reddish purple. The skin appears orange-peel-like with open follicles (Fig. 19.9). Rosacea keratitis, conjunctivitis, and blepharitis occur as complications. Pathogenesis Involvement of sunlight, mental stress, intake of alcohol or spicy food, liver dysfunction, and infection by Demodex folliculorum is suspected; however, the pathogenesis is unknown.

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Clinical images are available in hardcopy only.

Treatment, Prognosis Rosacea progresses gradually and tends to be intractable. Spicy foods, excessive sun exposure, and stress should be avoided. Laser irradiation is performed on the telangiectasia. The treatments for acne rosacea are the same as those for acne vulgaris. Topical metrohidazole, imidazoles and tretinoin may bring improvement. Steroid should never be used. Laser therapy, cryotherapy and surgical treatment are conducted for rhinophyma.

3. Rosacea-like dermatitis Fig. 19.10-1 Rosacea-like dermatitis. Eruptions occurred after continuous application of topical steroid for 1 month. Diffuse flushing, exfoliation, itching and burning sensation occurred.

Synonym: Steroid-induced dermatitis Outline ● Prolonged

application of steroids to the faces induces

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B. Disorders of sebaceous glands

rosacea-like erythematous papules, diffuse flushing, and acne. ● Perioral dermatitis is also known to be caused by topical steroid therapy. ● After discontinuation of steroids, the treatments for acne vulgaris are given. Clinical images are available in hardcopy only.

Clinical features Erythema, telangiectasia, papules, pustules, diffuse flushing, and scaling occur on sites where steroids have been applied. These symptoms are accompanied by itching and burning sensation (Figs. 19.10-1 and 19.10-2). Localized rosacea-like dermatitis around the mouth is called perioral dermatitis. Pathogenesis Rosacea-like dermatitis most commonly occurs in middle-aged women. Rosacea-like dermatitis is a typical side effect of topical steroids.

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4. Lupus miliaris disseminatus faciei (LMDF) Synonym: Acne agminata Outline ● Multiple

small papules of 2 mm to 5 mm in diameter the color of normal skin or redder occur on the face, particu-a larly the lower eyelids. They are asymptomatic. ● The histology is epithelioid cell granuloma with central necrosis. ● Tetracyclines are administrated in small doses. Clinical features Lupus miliaris disseminatus faciei (LMDF) occurs in both sexes equally, most patients being in their 20s and 30s. Multiple small papules with central necrosis of 2 mm to 5 mm in diameter the color of normal skin or redder occur symmetrically on the face, especially on the lower eyelids, cheeks and sides of the nose, accompanied by pustules (Figs. 19.11-1 and 19.11-2). The disorder is asymptomatic. Small yellowish-white nodules are observed by diascopy. These heal with concave scarring one to several years after onset. The scars become indistinct in about 1 year. Pathogenesis LMDF is first thought to be a form of tuberculid, but an

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Fig. 19.10-2 Rosacea-like dermatitis as a side effect of topical steroids. a: Eruption at the early stage. b: Eruption that has progressed.

Clinical images are available in hardcopy only.

Fig. 19.11-1 Lupus miliaris disseminatus faciei (LMDF). Small multiple papules of normal skin color or red and 2 mm to 5 mm in diameter occur symmetrically on the face. Some heal with scarring.

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Disorders of the Skin Appendages

association with tuberculosis has been excluded. Tuberculin reaction test is negative in most cases. The mechanism is predominantly thought to be reaction against the hair follicle tissues or their contents. Clinical images are available in hardcopy only.

Pathology A biopsy from a well established lision shows that epithelioid granuloma with central necrosis is present. Differential diagnosis Syringoma, milium, rosacea and acne vulgaris should be differentiated from LMDF. Treatment Tetracyclines are administered in small doses. Topical steroids may be the inductive factor in some cases. After a period of months or up to 2 years, the condition resolves spontaneously.

Clinical images are available in hardcopy only.

5. Xerosis, Asteatosis Fig. 19.11-2 Lupus miliaris disseminatus faciei.

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Dehydration of the horny cell layer and decrease of sebum cutaneum lead to dryness and coarseness of skin, resulting in pityroid scaling. These symptoms tend to aggravate during the winter. Xerosis is often caused by excessive washing and rubbing during bathing. It may be observed as a change in the aging process. It may also be caused by specific climates and environments. It appears as a symptom of nutritional deficiency or atopic dermatitis in some cases. It may progress to pruritus, nummular eczema or asteatotic eczema (Chapter 7).

C. Disorders of the hair 1. Alopecia areata Outline ● Round,

sharply margined hair loss suddenly occurs. regrows spontaneously in several months in most cases. Cases with multiple alopecia areata may progress to alopecia totalis or alopecia universalis. ● Topical steroids and PUVA are applied. ● Hair

Clinical images are available in hardcopy only.

Fig. 19.12-1 Alopecia areata. Sharply demarcated hair loss occurs. In active alopecia areata, the hairs around the lesion easily come out.

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Clinical features Alopecia areata is quite common, affecting up to 1% of the population. Sharply margined hair loss occurs suddenly without prodromes or subjective symptoms (Figs. 19.12-1 and 19.12-2). Alopecia areata is usually a round or oval, single but sometimes multiple, alopecia of 2 cm to 3 cm in diameter. The alopecia patches may coalesce, progressing to complete scalp hair loss (alopecia

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C. Disorders of the hair

totalis) in some cases (Fig. 19.13). Besides occurring in the scalp, alopecia areata may occur in the eyebrows, beard areas and the extremities; cases in which hair on the whole body is affected are called alopecia universalis, which is intractable. In nails, desquamation, coarseness, cloudiness and slight depression occur. Clinical images are available in hardcopy only.

Pathogenesis Hair matrix cells are impaired temporarily for unknown reason. Theories include nutritional failure, heredity and mental stress; however, the pathogenesis is unknown. Some cases are accompanied by autoimmune thyroid deficiency and atopic dermatitis. Autoimmune involvement is suspected. Pathology In the lesion, there is infiltration of CD4+T cells and the appearance of Langerhans cells in the hair follicles at the anagen stage. Expression of MHC class II in hair bulb epitheliocytes, and deposition of C3, IgG and IgM in the hair follicular basement membrane are observed. There is possible involvement of autoimmunity. The affected hair follicles form abnormal atrophic hair that falls out.

Fig. 19.12-2 Alopecia areata. Formation of hairs is observed at the center of the skin lesion.

Diagnosis Alopecia areata is easily diagnosed by the clinical features. The hairs around the lesion easily fall out at the early stages of the lesion. The hairs are characteristically thin and atrophic at the end of the hair root, giving them the appearance of exclamation marks (“exclamation-point hair”). The hairs stop falling out and newly grown hairs are seen during the healing period. Differential diagnosis Trichotillomania and traumatic alopecia are distinguished from alopecia areata. Trichotillomania, which produces short, breakable, hard hair in the lesion, occurs most commonly in children; however, there is no diseased hair in trichotillomania, and the hair around the lesion does not come out easily. In traumatic alopecia, the lesion is not round, and it is caused by extrinsic factors such as scarring. Fibrosis and pigmentation are also found. Alopecia areata also should be distinguished from systemic lupus erythematosus (SLE) and alopecia caused by syphilis.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Treatment Alopecia areata resolves spontaneously in several months, although in some cases it may be intractable or recurrent. It is important to address the patient’s distress about hair loss. Sedatives may be used if necessary. Steroids, immunosuppressants and hair-growth lotionsa are topically applied. In severe cases, PUVA therapy, steroid injection, cryotherapy, and application of squaric acid dibutylester (SADBE) are performed. Steroids and immunosuppressants are administered orally in alopecia totalis or universalis.

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Fig. 19.13 Alopecia totalis. a. Complete alopecia on the head. b. Multiple, small concavities in the nails.

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2. Androgenetic alopecia Synonyms: Male-pattern baldness, Alopecia prematura

Clinical images are available in hardcopy only.

Clinical features Androgenetic alopecia also called male pattern baldness, is hair loss in adolescent and adult men. Androgenetic alopecia is a very common disorder, affecting at least 50% of men by the age of 50. The hairline recedes to form an M shape (with vellus hair at the frontal region of the head) or an O shape (with vellus hair on the top of the head). These patterns may appear separately or simultaneously. The diameter of the vellus hair is smaller than that of normal hair. The density (hairs per unit area), also decreases. It progresses to complete hair loss. Pathogenesis Patients usually have a familial history of baldness. Elevated sensitivity of hair follicles to androgen (dihydrotestosterone, in particular) begins at some point. The anagen period is shortened, hairs at telogen decrease in number, hair follicles contract, and vellus transformation occurs. The thin, sparse vellus hair produced in androgenetic alopecia becomes less densely distributed, eventually progressing to alopecia.

Clinical images are available in hardcopy only.

Treatment Topical minoxidil and anti-androgenetic drugs such as 5a reductase inhibitor fenasteride are effective in some cases. Stimulating the affected site, stimulating the local circulation of the scalp by massaging, and using hair growth lotions containing female hormones are helpful.

3. Congenital alopecia

19 Fig. 19.14 Congenital hypotrichosis in a girl. This patient has thin, sparse hair (oligotrichia). She has never had a haircut, but the hair does not grow beyond this length.

Congenital atrichia, alopecia and oligotrichia are observed in various conditions, including those listed below. ① Atrichia congenita It is autosomal recessive. Hair may be present at birth; however, it falls out between several months after birth and puberty, until no hair remains on the body. Involvement of the hairless (hr) gene has been identified as a cause in some cases of certain subtypes. ② Hypotrichosis congenita Normal hair is present at birth; however, alopecia gradually leads to thin, sparse hair (Fig. 19.14). ③ Arrichia and alopecia associated with hereditary syndrome Arrichia and congenital alopecia are associated with congenital ectodermal defect (aplasia cutis congenita (Fig. 19.15)), dermatothlasia, Werner’s syndrome, poikiloderma congenital and Netherton syndrome. Odontogenesis imperfecta, abnormal nail plates, palmoplantar keratosis and anhidrosis often occur as complications.

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4. Alopecia pityrodes Pityriasis capitis (“dandruff”) occurs in combination with alopecia most frequently in men after puberty. Fine, dispersed, grayish-white scaling occurs constantly on the scalp. The hair is thin and the natural gloss is not present. Itching and reddening of the scalp often occur. The treatments are the same as for seborrheic dermatitis.

Clinical images are available in hardcopy only.

5. Trichotillomania Patients with trichotillomania, who tend to be in their late childhood, have an uncontrollable compulsion to pull out their own hair. The patients may deny this hair-pulling behavior. Vaguely circumscribed, irregular-shaped, incomplete alopecia is present. Both short and broken remaining hairs and newly produced hairs are observed in the same alopecia, which is within reach of the hand, often on the frontal and temporal region of the head on the right side. The patient’s psychological background, personality and domestic environment may trigger trichotillomania; cooperation with a psychiatrist is necessary for treatment.

Fig. 19.15 Aplasia cutis congenita. Hair loss on the top of the head is seen. It is caused by skin loss in the fetus.

6. Scarring alopecia As a result of scarring caused by injury, burn, or discoid lupus erythematosus. The hair follicles are irreversibly destroyed, leading to alopecia. Surgical treatment is necessary.

D. Disorders of nails a. Color change of nail plates 1. Melanonychia Melanonychia may be caused by increased number of nail matrix melanocytes (e.g., from nevocellular nevus, inflammation, melanocytes activated by pressure), fungal infections, malignant melanoma, Behçet’s disease, subungual hemorrhage, Addison’s disease or drugs (e.g., 5-FU, bleomycin, hydroxyurea). When the skin of the nail fold region is also affected, it is called Hutchinson’s sign and has a high likelihood of indicating a malignant melanoma (Fig. 19.16). Approximately 20% of ethinic Japanese and up to 96% of ethnic Africans have pigmented streaks.

2. Yellow nail It is caused by nutritional deficiency or infection of nails, or by aurantiasis cutis, or jaundice. When yellowing of the nails occurs

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in patients with lymphoma and chronic pulmonary disease, it is called yellow nail syndrome, which may be induced by D-penicillamine or tetracyclines. Clinical images are available in hardcopy only.

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3. Green nail This opportunistic infection is caused by Pseudomonas aeruginosa infection and tends to accompany tinea unguium and candida onychomycosis (Fig. 19.17). g e

Fig. 19.16 Melanonychia. a: The nail is partially pigmented. Deformity is seen at the tip. Melanoma is suspected in this case. b: The fingernail of a 25-year-old woman. The symptoms rapidly progressed in the previous 6 months, presenting melanoma in situ histologically.

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Synonym: Leukonychia These white punctate patches may be caused in nails by localized incomplete keratinization from injury (Fig. 19.18). They are harmless. White nail accompanies hypoalbuminemia as in nephrosis and cirrhosis, diabetes, anemia, systemic sclerosis, arsenic poisoning, onychomycosis and onycholysis.

5. Subungual purpura Clinical images are available in hardcopy only.

Punctate or linear purpura results from bleeding caused by injury, Osler’s disease, or subacute endocarditis.

b. Abnormal formation of nail 1. Clubbing Fig. 19.17 Green nail.

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Clinical images are available in hardcopy only.

This disorder is also called clubbed finger or hippocratic nail. The entire nail plate bulges like the glass face of a watch. The distal fingers and toes enlarge in drumstick shape (Fig. 19.19). Clubbing is caused by mucopolysaccharide deposition in the soft tissue of the distal fingers and toes. It occurs in chronic cardiopulmonary diseases (pneumonectasia, lung cancer, bronchiectasis, congenital heart disease), hyperthyrea, ulcerative colitis and Crohn’s disease. It may appear as a symptom of pachydermoperiostosis running in families (Chapter 18).

2. Spoon nail Fig. 19.18 White nail.

Synonym: Koilonychia Spoon nail is associated with iron-deficiency anemia, lichen planus, psoriasis, fungal infection, extrinsic injury and chemical substances. The nail plates become thin, with spoon-like concavity with raised edges. Fingers are more severely affected than toes. It may be seen in otherwise normal infants.

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3. Onycholysis The nail plate detaches from the nail bed at the periungual area. Desquamation occurs, but nails do not fall out. The causes may be injury, nail polish, or inflammation in the periungual skin of the nail plate region caused by detergent, localized diseases including candida onychomycosis, systemic diseases such as hyperthyroidism, peripheral circulatory failure, or drug-induced disease.

Clinical images are available in hardcopy only.

4. Onychomadesis, Nail shedding The nail plate detaches at proximal sites of the nail root, which is the end opposite that in onycholysis desquamation, and the nail exfoliates. It may occur sporadically or be caused by injury, perionychia, psoriasis, lichen planus, syphilis or erythroderma.

Clinical images are available in hardcopy only.

5. Pachyonychia The nail plate thickens, or hyperkeratosis occurs under it. Thickening of the nail is also caused by hindered growth.

6. Longitudinal groove

Clinical images are available in hardcopy only.

Linear grooves run vertically in the nail plate. It is seen as a senile change. It may progress to onychorrhexis, a condition in which nails tend to split longitudinally. Longitudinal grooves are caused by injury, eczema, systemic scleroderma, and anemia. When the nail is thickened and curved, it is called onychogryphosis.

7. Transverse groove Grooves cross in the nail as a result of impaired growth of nail caused by failure in the nail matrix. The width of the grooves shows the period of a disease, and the depth shows the degree of impairment. By measuring the position of the transverse grooves, it is possible to date previous illness. It occurs in infectious diseases including typhus and hemolytic streptococcal infection (scarlet fever), diabetes, severe blood loss, drug-induced diseases, zinc deficiency and cases of periungual injury or infection. Transverse grooves caused by an intrinsic factor are called Beau’s lines.

8. Nail pits Multiple, small, needle-like indentations occur on the nail plate. It is caused by psoriasis and alopecia areata, or it may occur under normal conditions.

Clinical images are available in hardcopy only.

Fig. 19.19 Clubbing. The entire nail plate bulges like the glass face of a watch. The distal fingers enlarge in drumstick shape.

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9. Onychoschisis Fine, scaly, lamellar separation occurs at the tip of the nail, causing fragility. It is most frequently caused by nail polish application; however, it may be induced by systemic diseases such as SLE.

Clinical images are available in hardcopy only.

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g c d e f h i Fig. 19.20 Ingrown nail. a: On the great toe. The sides of the nail grow into the nail fold, causing sharp pain. b: Reactive formation of granulation. c: Part of the nail, including the nail matrix, was removed.

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The sides of the nail grow into the nail fold, leading to p q j swelling, and inflammation with h i reddening k l m n a granuloma-like o appearance. The condition is accompanied by tenderness (Fig. 19.20a). In severe cases, a secondary infection such as paronychia occurs, causing formation of reactive granuloma (Fig. 19.20b). It is commonly caused in the great toes by pressure from wearing shoes or by clipping the toenail too short. When it occurs secondarily after nail deformity caused by fungi of the genus Trichophyton, the primary disease is treated. Avoidance of extrinsic pressure and maintenance of cleanness are the first-line treatments; however, surgery may be necessary for intractable cases (Fig. 19.20c).

Clinical images are available in hardcopy only.

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Nevus and Neurocutaneous Syndrome

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“Nevus” is Latin for “maternal impression” or “birthmark.” It denotes a circumscribed, non-neoplastic skin or mucosal lesion. The term is qualified according to the cell or tissue of origin. Nevi may be caused by hereditary or embryologic factors and may appear at any time in life (Unna, 1894). They progress extremely slowly. Neurocutaneous syndrome includes nevi formed in the skin and nevoid lesions produced in the systemic organs that cause central nervous symptoms. Neurocutaneous syndrome is often categorized as a phacomatosis; however, that term has fallen out of use internationally in recent years. This chapter introduces the most common nevi. Angiomas are described in Chapter 21.

Nevus

A. Melanocytic nevi (Fig. 20.1) a. Nevocellular nevus Synonyms: Pigmented nevus, Nevus pigmentosus Outline ● Nevocellular

nevus is caused by proliferation of nevus cells. A small nevocellular nevus is commonly called a mole. ● A hairy, giant, pigmented nevocellular nevus of 20 cm or more in diameter is called a giant congenital melanocytic nevus. It tends to progress to malignant melanoma. ● Dermoscopic findings are important for diagnosis. ● “Pigmented nevus” may be used as a synonym; however, non pigmented lesions are often seen.

Pathological classification Nevocellular nevus Specific diagnosis

Melanocytic nevus

Dermal melanocytic nevus

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Junctional nevus Intradermal nevus Compound nevus Giant congenital melanocytic nevus Divided nevus Nevus striatus unguis Sutton nevus Spitz nevus Dysplastic nevus Spotted grouped nevus Balloon-cell nevus

Blue nevus Nevus of Ota Nevus of Ito Acquired dermal melanocytosis Mongolian spot

Fig. 20.1 Classification of melanocytic nevi.

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Fig. 20.2-1 Nevocellular nevus.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical features A nevocellular nevus is a flat-surfaced or verrucous macule or tumor that is brown, black, or sometimes normal skin color (Figs. 20.2-1 to 20.2-3). It may be accompanied by terminal hair. Nevocellular nevi are classified by size into three types. Small nevocellular nevus is commonly called mole or lentigo and varies in size from several millimeters to 1 cm in diameter. It is not present at birth but first appears between the ages of 3 and 4 and gradually increases in number and size to peak at puberty. After puberty, the color often fades and the nevus is replaced by fat tissue or fibrotic tissue. When the diameter exceeds 20 cm, the nevus is called a giant congenital melanocytic nevus. Pathogenesis Nevus cells are derived from neural crests and proliferate abnormally, resulting in blackish-brown pigmented macules. Melanocytes and Schwann cells are derived from neural crests; however, nevus cells do not differentiate into either of these (Fig. 20.3). Pathology Nevocellular nevi are classified by location of proliferation into junctional nevus, intradermal nevus and compound nevus (Fig. 20.3).

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 20.2-2 Nevocellular nevus.

Diagnosis, Differential diagnosis Nevocellular nevus should be differentiated from freckles, lentigines, non-melanocytic lesions such as seborrheic keratosis, dermatofibroma, and most importantly early malignant melanoma (Chapter 22). Any pigmented lesion in adults that is growing or changing in any way should be examined carefully. When pigmentation spreads beyond the nail in the nail plate (Hutchinson’s sign), there is a high likelihood that a malignant melanoma is involved. Dermoscopic findings are important for diagnosis. Treatment Even when the dermoscopic findings are benign, follow-up is necessary. Surgical removal is the basic treatment for cases in the palms and soles, which tend to have a high likelihood of malignancy, and in cases with a relatively large congenital nevocellular nevus. Laser therapy may be conducted if there are cosmetic concerns. Excision, ablation or skin grafting may be performed on a giant congenital melanocytic nevus. When it is too large for removal, long-term follow-up may be chosen to observe for any signs of malignant melanoma.

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neural cleft cell ⋮differentiation ⋮

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Fig. 20.3 Origin of nevus cells and histological classification of nevocellular nevi. Clinical images are available in hardcopy only.

Common types of nevocellular nevi

1. Junctional nevus Nevus cells are localized in the dermo-epidermal junction. Junctional nevus is a compound of nevus cells that function similarly to melanocytes and resemble nevus cells morphologically. It is formed by large cubical cells that are able to produce melanin in great quantities. Clinical images are available in hardcopy only.

2. Compound nevus This is a combination of junctional nevus and intradermal nevus. The nevi tend to be small and hyperpigmented.

3. Intradermal nevus

Fig. 20.2-3 Nevocellular nevus.

Nevus cells are localized in relatively deep areas of the dermis (Fig. 20.4). Melanin production is markedly low in cells of intradermal nevus. The cells appear spindled, resembling Schwann cells. Specific types of nevocellular nevi

1. Giant congenital melanocytic nevus Giant congenital melanocytic nevus is seen at birth, sometimes accompanied by black bristles (giant hairy nevus). It may be larger than 20 cm in diameter (Fig. 20.5). In several percent of cases, malignant melanoma may develop, sometimes accompanied by central nervous symptoms (neurocutaneous melatosis, described later). Surgical treatment is difficult.

Fig. 20.4 Histopathology of nevocellular nevus.

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2. Divided nevus

Clinical images are available in hardcopy only.

Divided nevi distribute predominantly on the upper and lower eyelids. With the eye closed, they appear to be a single lesion. The color is blackish-brown. They are found at birth in most cases. When occurring in the penis, it is a pigmented lesion that is separated by the coronal sulcus into the glans and the penis (Fig. 20.6).

3. Melanonychia due to nevocellular nevus Fig. 20.5 Giant congenital melanocytic nevus.

Black lines appear on the nail plate because of the presence of nevus cells in the nail bed (Fig. 20.7). Most cases are benign; however, there is a possibility of malignant melanoma.

4. Sutton nevus Clinical images are available in hardcopy only.

It is nevus pigmentosus that is surrounded by leukodermas (Chapter 16).

5. Spitz nevus Synonyms: Juvenile melanoma, Spindle and epithelioid cell nevus

Fig. 20.6 Divided nevus.

Outline ● This

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Fig. 20.7 Melanonychia due to nevocellular nevus.

Clinical images are available in hardcopy only.

Fig. 20.8 Spitz nevus.

specific subtype of nevocellular nevus frequently occurs in young adults. ● It appears suddenly on the face in most cases and enlarges quickly to about 1 cm in diameter. The periphery may become reddish. ● It may have clinically and histopathologically similar features to malignant melanoma; nevertheless, Spitz nevus is benign and may resolve spontaneously. ● Differential diagnosis from malignant melanoma is essential. Surgical removal is the first-line treatment. Clinical features A small, dome-shaped nodule, usually solitary and ranging in color from light pink to reddish-brown or black and ranging in size from several millimeters to 2 cm occurs, most commonly in children but also in adult men and women. It suddenly appears, mainly on the face but also elsewhere, and enlarges to about 1 cm in diameter (Fig. 20.8). Because it may be accompanied by dark brown pigmentation, Spitz nevus is sometimes difficult to differentiate from malignant melanoma. Spitz nevus is benign and does not enlarge beyond a certain size, nor does infiltration occur. Pathology, Diagnosis Spitz nevus is a compound nevus containing various cells,

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including spindle cells, epithelioid-like cells and multinuclear cells. Dermal edema, telangiectasia, and inflammatory cell infiltration may occur. These findings resemble those of malignant melanoma; differentiation between Spitz nevus and malignant melanoma is often difficult. The basic structural pattern of nevocellular nevi is preserved in Spitz nevus: the lack of cellular atypism in the cells is important in distinguishing Spitz nevus from malignant melanoma. Homogenous nonstructural eosinophilic substances called Kamino bodies are found in the nevus cell nest in 60% of cases (Fig. 20.9). Dermoscopy shows sharply circumscribed pigmented lesions with a characteristic starburst pattern at the periphery.

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Treatment Excision is conducted. Spitz nevus does not aggravate; however, careful differentiation from malignant melanoma is necessary.

6. Dysplastic nevus Synonym: Clark nevus Dysplastic nevus occurs around puberty. A slightly elevated,a flat-topped patch or a pigmented nevus larger than 6 mm in diameter occurs. A light brown or black, sometimes light pink, lesion with roughly margined pigmentation forms. Dysplastic nevus is basically a benign nevocellular nevus. When multiple familial atypical nevi and malignant melanoma occur it is called dysplastic nevus syndrome. Dysplastic nevus syndrome is autosomal dominantly inherited, and it frequently develops into malignant melanoma. Most patients are Caucasians, and there are few Asian cases. Histopathologically, many cases show compound nevi. Atypism is not usually found in the cells. Dermoscopic differentiation from superficial spreading melanoma is necessary.

Fig. 20.9 Histopathology of Spitz nevus. a: Spitz nevus at low magnification. b: Spitz nevus at high magnification. Kamino bodies (arrows) are stained by eosin.

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7. Spotted grouped nevus Small blackish-brown pigmented macules or nodules densely aggregate in brown to light-brown patches. This nevocellular nevus occurs frequently on the trunk and less frequently at other sites.

8. Balloon-cell nevus This nevus consists of balloon cells that contain clear, large cytoplasm. The cells are thought to be degenerated nevus cells. Nevertheless, balloon-cell nevus cannot be distinguished clinically from ordinary nevocellular nevus.

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MEMO Most cases of the pigmentation that is commonly called lentigo are small nevocellular nevus. Lentigo simplex, a dermatological term, is a flat blackish-brown lesion of several millimeters in diameter caused by localized proliferation of epidermal melanocytes in which the nevus cells do not increase in number over time. Lentigo simplex is not usually present at birth, but it may appear around 3 years of age. It accompanies systemic diseases (neurocutaneous syndrome) including Peutz-Jeghers syndrome, Cronkhite-Canada syndrome, and LEOPARD syndrome.

Lentigo

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b. Dermal melanocytic nevus Clinical images are available in hardcopy only.

Fig. 20.10 Blue nevus.

Dermal melanocytes are produced in dermal melanocytic nevus, blue nevus, Mongolian spot and nevus of Ota. The distribution of cells varies according to the disease. Distributions of dermal melanocytes in blue nevus and other melanocytic nevi such as nevus of Ota and Mongolian spot are compared in Fig. 20.12.

1. Blue nevus Outline ●A

flat or slightly elevated blue nodule results from proliferation of melanocytes in the dermis (dermal melanocytes). ● It appears between the time of birth and infancy in most cases. The head, extremities and buttocks are most commonly involved. Clinical features A firm, blue or blackish small nodule of 1 cm or less in diameter appears. It may be flat or tumorous (Fig. 20.10). Blue nevus tends to appear singly and to progress gradually. The head, face, hands, legs, back and buttocks are most commonly affected. Pathogenesis Dermal melanocytes that have the ability to produce melanin and originate from neural crests become tumorous, causing blue nevus. The dermal melanocytes are filled with melanin granules that appear blue to brown on the skin.

Fig. 20.11 Histopathology of blue nevus.

MEMO Dermal melanocytosis is the term used in Japan; dermal melanocytic nevus is the term used internationally.

Dermal melanocytosis

subcutaneous dermis epidermis tissue

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Pathology, Diagnosis There is tumorous proliferation of dermal melanocytes (Fig. 20.11). In nevocellular blue nevus, the dermal Schwann-cell-like cells lacking melanin production are seen. Blue nevus should be

blue nevus

nevus of Ota nevus of Ito

acquired Mongolian spot dermal melanocytosis

Deep dermis to Superficial to Superficial subcutaneous mid-epidermis dermis tissue

Mid to deep dermis

Fig. 20.12 Classification of dermal melanocytic nevi by the distribution of melanocytes.

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differentiated from malignant melanoma: blue nevus is characterized by its double-layered structure, and atypism and irregularity of size are not seen in the cell nuclei. Treatment, Prognosis The entire lesion is usually removed for cosmetic purposes. Careful clinical follow-up is necessary, because blue nevus may become malignant.

Clinical images are available in hardcopy only.

2. Nevus of Ota Synonym: Nevus fuscocaeruleus ophthalmomaxillaris Ota Outline ● Adolescent

Asian women are most commonly affected. A light blue macule appears unilaterally on the skin at the first and second divisions of the trigeminal nerve. Melanosis of bulbar conjunctiva occurs. ● This nevus is caused by proliferation of dermal melanocytes. ● It is not malignant, nor does it heal spontaneously. Laser therapy is effective. Clinical features A light blue nevus occurs unilaterally on the skin over the first and second divisions of the trigeminal nerve (eyelids, zygomatic region, lateral forehead, cheek). The nevus is light blue and punctatedly dispersed with various other colors, including brown, red and dark blue (Figs. 20.13-1 and 20.13-2). It may be bilateral in some cases. Nevus of Ota with pigmentation in the sclera, iris and fundus is called oculodermal melanosis and is found in about half of cases. Pigmentation may also occur in the tympanic membranes, nasal membranes, pharynx and palate. A nevus with the same pigmentation as nevus of Ota but in the acrominon and deltoid region is called nevus of Ito or nevus fuscocaeruleus acromiodeltoideus Ito. It often causes great mental distress and cosmetic concern. Classification Nevus of Ota is classified into an early-onset type, in which pigmentation is present at birth and the color darkens as the patient grows, and a later-onset type, which occurs after puberty. Both types occur most frequently in Asian women and tend not to disappear spontaneously. Pathology Melanocytes are dispersed in the dermis. Pigmentation is present in the epidermal basal cell layer (Fig. 20.12). Treatment Laser therapy is extremely effective.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 20.13-1 Nevus of Ota.

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3. Acquired dermal melanocytosis

Clinical images are available in hardcopy only.

Acquired dermal melanocytosis used to be classified as a subtype of bilateral nevus of Ota; however, the two are now regarded as distinct diseases. Multiple, punctate, grayish-brown pigmentation of 1 mm to 3 mm in diameter occurs on both sides of the forehead and zygomatic region. The bulbar conjunctiva and palate are not involved (Fig. 20.14). Women between adolescence and middle age, particularly those of Japanese and Chinese descent, are most commonly affected. Histologically, there are dermal melanocytes in the upper dermal layer and pigmentation in the epidermal basal cell layer.

4. Mongolian spot

Fig. 20.13-2 Nevus of Ota.

Clinical images are available in hardcopy only.

Clinical features, Differentiation Mongolian spot occurs in the lumbosacral regions and buttocks of newborns. Nearly 100% of Asians, 80% to 90% of Africans (in whom the blue color tends to be invisible), and 1% to 20% of Caucasians are affected. It remains until adulthood in 3% to 4% of all cases. The blue hue intensifies until the age of 2 years and then gradually fades, disappearing by age 10. The Mongolian spot is differentiated from nevus of Ota by its lack of brownish tone. Mongolian spot on sites other than the lumbosacral regions and buttocks is called aberrant or ectopic Mongolian spot (Figs. 20.15-1 and 20.15-2), and the color tends not to fade spontaneously. Pathogenesis Mongolian spot is dermal melanosis in which dermal melanocytes from the embryonic period partially remain.

Fig. 20.14 Acquired dermal melanocytosis.

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Fig. 20.15-1 Aberrant or ectopic Mongolian spot.

Treatment Treatment is not necessary in most cases. Laser therapy may be conducted on large spots or ectopic Mongolian spots by the age of 2 or 3 years (Fig. 20.16).

Nevus / B. Epithelial nevi

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Fig. 20.15-2 Ectopic Mongolian spot. a: Forehead. b: Back. c: Lumbar region.

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Fig. 20.16 Laser treatment of aberrant Mongolian spot. a: Mongolian spot on the shoulder and the right arm (pre-treatment). b: Mongolian spot after one session of alexandrite laser therapy. c: This portion (arrows) has improved significantly by alexandrite laser application.

B. Epithelial nevi 1. Epidermal nevus Clinical features Rough-surfaced, yellow to dark-brown papules or nodules are present at birth or in early childhood. They spread gradually, aggregate and form plaques of various sizes (Fig. 20.17). Although they may be localized, in most cases they are unilateral and arranged systematically along the Blaschko lines (Fig. 1.2). A generalized type spreads on the whole body.

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Although epidermal nevus tends to be asymptomatic, it may be accompanied by itching and eczematous changes. In inflammatory linear verrucous epidermal nevus (ILVEN), multiple, intensely itchy, light pink verrucous papules occur, most commonly on the lower legs of girls. They coalesce, become lichenified and arrange in linear pattern (Fig. 20.18). Central nervous symptoms and skeletal abnormality are seen in rare cases; this is called epidermal nevus syndrome. Pathogenesis Hyperplasia of epidermal keratinocytes results in localized or systematized verrucous nevus that enlarges gradually and becomes distinct.

Clinical images are available in hardcopy only.

Pathology Papilloma-like proliferation occurs in the epidermis. Granular degeneration also occurs in some cases. When ILVEN is accompanied by severer itching than usual, there is also inflammation, thickening of the epidermis, and parakeratosis. Treatment Epidermal nevus can be left untreated, because changes and tumor formation rarely occur. Surgical excision, cryotherapy or laser therapy may be conducted for cosmetic improvement.

Fig. 20.17 Epidermal nevus.

2. Nevus sebaceus Synonym: Organoid nevus Outline ● It

20 Clinical images are available in hardcopy only.

Fig. 20.18 Inflammatory linear verrucous epidermal nevus.

is caused by abnormal proliferation of various cells that originate in the epidermis, dermal appendages and connective tissue. ● It is present at birth. The scalp and face are most commonly affected. Nevus sebaceus on the scalp leads to alopecia. ● Removal is preferable, because malignant tumor such as basal cell carcinoma may develop. Clinical features Nevus sebaceus occurs most frequently on the head and face (Fig. 20.20). The symptoms progress though three stages: first, at birth white to yellowish alopecia-areata-like plaques are present; second, with age the plaques elevate flatly, and gradually become verrucous and brownish; third, at puberty the lesions of the second stage worsen and additional epithelial tumors appear. Epithelial tumors such as dermal appendage tumors (e.g., syringocystadenoma papilliferum, trichoblastoma, outer root sheath tumor) and basal cell carcinomas may occur secondarily.

Nevus / B. Epithelial nevi

normal

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1st stage (at birth) 2nd stage (infancy) 3rd stage (adolescence ∼ )

Clinical images are available in hardcopy only. epithelial tumor

Fig. 20.19 Histopathology of nevus sebaceus classified into three stages. The pathological and clinical features of the sebaceous glands gradually change with age.

Pathology The histology differs for each of the three stages (Fig. 20.21). In the first stage, premature pilosebaceous tissue proliferates. In the second stage, there is maturation of the tissue, papilloma-like proliferation of the epidermis, ectopic proliferation of apocrine glands, and abnormality of dermal connective tissue. In the third stage, the histological changes of the second stage accelerate, with additional epithelial tumorous proliferation (Fig. 20.19). Treatment Surgical excision is conducted when secondary tumor is suspected or there are cosmetic concerns.

Clinical images are available in hardcopy only.

Fig. 20.20 Nevus sebaceous. Nevus sebaceus and hair loss on the scalp.

3. Accessory mamma The primordia of the mammary glands, which exist along the line of the embryonic mammary ridge, normally disappear except for one pair in the chest. Accessory mamma is a condition in which more than one pair of primordia remains, usually on or around the axillary fossae. A brown patch or a palpable nodule of 1 cm to 2 cm in diameter appears on the axillary fossae or the anterior margin in most cases, accompanied by terminal hair. Swelling, pain and galactopoiesis may occur during pregnancy. Breast cancer may occur in rare cases.

Clinical images are available in hardcopy only.

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4. Nevus comedonicus Dilated hair follicles with a black keratin plug aggregate or form a cord-like pattern (Fig. 20.22). They often occur between the time of birth and age 10. The face, neck, precordial region, abdomen and scalp are frequently affected.

5. Hair follicle nevus Dome-shaped or polyp-like papules or nodules of normal skin color are present at birth. The face is most frequently affected. Hair follicles in various stages of differentiation proliferate in all

Fig. 20.21 Nevus sebaceous.

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dermal layers. The disorder may be accompanied by nevus sebaceus.

6. Eccrine nevus Clinical images are available in hardcopy only.

Congenital localized hamartoma occurs in the eccrine sweat glands. A hyperhidrotic nodule and a plaque form. They occur between birth and infancy, most frequently on the extremities. When accompanied by angioma, it is called eccrine angiomatous hamartoma.

Fig. 20.22 Nevus comedonicus.

7. Apocrine nevus Congenital localized hamartoma occurs in the apocrine sweat glands. The apocrine nevus is a papule or a small nodule, often accompanied by nevus sebaceous, which occurs on the scalp or axillary fossae.

C. Mesenchymal-cell nevi 1. Connective tissue nevus Clinical images are available in hardcopy only.

Proliferation of dermal collagen fibers, elastic fibers or mucopolysaccharides results in eruptions of normal skin color that are called connective tissue nevi (Fig. 20.23). They may aggregate in patches.

2. Nevus lipomatosus cutaneous superficialis Ectopic proliferation of fat cells in the dermis results in soft yellow nodules of several centimeters in diameter.

20 Clinical images are available in hardcopy only.

3. Nevus cartilagineus Dome-shaped, cartilage-containing papules of normal skin color appear. Nevus cartilagineus in the ear region, called accessory ear, accompanies embryonic developmental failure of the branchial arch.

Fig. 20.23 Connective tissue nevus.

4. Smooth muscle hamartoma

Clinical images are available in hardcopy only.

This is a hamartoma in the arrector pili (Fig. 20.24). The lumbar and sacral regions are most commonly involved. The onset in most cases is within 6 months after birth. Slightly vaguely margined light brown patches appear. They may be hairy in some cases.

Fig. 20.24 Smooth muscle hamartoma.

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D. Other nevi accompanied by skin pigmentation 1. Nevus spilus Synonym: Speckled and lentiginous nevus Nevus spilus is a sharply margined brown macule that can be of various sizes and shapes (Table 20.1). There is a congenital type and a late-onset type whose onset is infancy or later. A lateonset nevus spilus called Becker’s nevus occurs most commonly on the chest and scapular region of adolescent boys (Section 2, below). Melanocytic nevocellular nevus cells do not proliferate. Enhanced localized melanin pigmentation in the epidermal basal layer is the main finding. When multiple nevus spilus occurs in infancy, there is the possibility of café-au-lait spots of neurofibromatosis type 1 and McCune-Albright syndrome. Laser therapy and concealing cosmetics are useful.

2. Becker’s nevus

Clinical images are available in hardcopy only.

Fig. 20.25 Becker’s nevus.

Synonym: Nevus spilus tardivus This is histopathologically similar to nevus spilus. Irregularly shaped, patchy, light brown pigmentation first appears. It coalesces with newly produced macules at the periphery and enlarges to a diameter of several centimeters to 20 cm (Fig. 20.25). Hypertrichosis is present in about half of all cases. Proliferation of smooth muscle fibers is found in the dermis: Some regard Becker’s nevus as a type of smooth muscle hamartoma. Q-switched laser therapy is more effective on Becker’s nevus than on nevus spilus.

3. Nevus depigmentosus Leukodermas of various sizes appear. They become more distinct several months to 1 year after birth (Chapter 16).

MEMO The term is sometimes used to describe the small, dark patches in the nevus as well as the nevus itself, but in the United States and Europe, those patches are called speckled and lentiginous nevus. Nests of nevus cells are observed in the dark small patches. Café-aulait spots produced in neurofibromatosis type 1 are individually indistinguishable from nevus spilus. The name nevus spilus may be diagnostically ambiguous.

Nevus spilus

Table 20.1 Comparison between congenital nevus spilus and nevus spilus tardivus. Congenital nevus spilus

Nevus spilus tardivus (Becker’s nevus)

Age of onset

Present at birth

Shortly before and after adolescence

Commonly affected sites

Whole body

Shoulders, lumbar area

Complications

Neurofibromatosis in some cases

None

Hypertrichosis

No

Yes, in some cases

Color tone

Light brown to blackish-brown

Darker than that of congenital nevus spilus

Size of eruption

Various

Usually large

Histopathological findings

Elevated levels of melanin in basal keratinocytes

Increased melanin in basal keratinocytes, possibly changes in the epidermis and increased arrector pili muscle

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4. Nevus anemicus A sharply circumscribed white patch occurs, often on the upper chest, when the skin is flushed by bathing or rubbing. Known to be capillary dysfunction (catecholamine sensitivity), it may accompany neurofibromatosis type 1 (NF1) or nodular sclerosis.

Clinical images are available in hardcopy only.

Fig. 20.26 Nevus anemicus.

Neurocutaneous syndrome 1. Neurofibromatosis type 1 (NF1) Synonym: Von Recklinghausen disease Outline ● It

is a neurocutaneous syndrome caused by proliferation of cells that originate from neural crests. Neurofibroma, pigmentation and nervous tumor in multiple organs are the main symptoms. ● It is autosomal dominantly inherited, characterized by multiple pigmentation (café-au-lait spots) at birth and soft tumors (neurofibromas) after infancy. ● Surgical removal and laser therapy are conducted.

Clinical images are available in hardcopy only.

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Fig. 20.27-1 Café-au-lait spot caused by neurofibromatosis type 1 (NF1).

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Clinical features ① Café-au-lait spot This is a flat, oval eruption of the color of coffee with cream or darker brown. It varies in size and appears on the trunk and extremities. A café-au-lait spot with a diameter of about 10 cm is called a large Recklinghausen spot; one with a diameter of 1 cm or less is called a small Recklinghausen spot. Individual eruptions cannot be distinguished from nevus spilus. A café-au-lait spot on the axillary fossae, called axillary freckling, is thought to be a specific symptom of NF1. The pigmentation of the spot is solid (Figs. 20.27-1 and 20.27-2). Café-au-lait spots are present in 70% of all newborns. After infancy, the number of spots does not increase. ② Neurofibroma A neurofibroma is a soft tumor of normal skin color or light brownish-pink of various sizes (Figs. 20.28-1 and 20.28-2). It may be produced on any site of skin. It may be elevated and dome-shaped or papillary, or flat and palpable. Valvular or hanging

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Neurocutaneous syndrome / 1. Neurofibromatosis type 1 (NF1)

neurofibroma is called diffuse plexiform neurofibroma or pachydermatocele (Fig. 20.29). Neurofibroma first appears between childhood and puberty, after which it gradually enlarges and increases in number. It may increase rapidly during pregnancy and after delivery. Nodular plexiform neurofibroma, neurofibroma in the peripheral nerves, is a slightly palpable, spindle-shaped tumor that appears on the skin over the subcutaneous nerves. It may appear in a beaded linear pattern and be accompanied by tenderness or radiating pain. ③ Other skin lesions caused by NF1 Nevus anemicus may occur in some cases with NF1. Small yellow tumors may appear on the face and scalp of infants and disappear spontaneously in several years (juvenile xanthoendothelioma). ④ Other symptoms of NF1 Central nervous symptoms include neurofibroma in the brain and spiral nerves, gliacytic tumor, meningioma, convulsive seizure, and mental retardation or learning impairment. Bone abnormality, including scoliosis, deformity or bone defect in the thorax, occurs in about half of all cases. Ocular symptoms of NF1 are irridic nodules, called Lisch nodules, and orbital neurofibroma in which ophthalmocele may occur. Congenital glaucoma and retinal tumor may occur. Classification Neurofibromatosis (NF) is pathologically classified into 8 types: NF1 through NF8. NF1 is the most common and occurs in 1 in 3,000 births. It is autosomal dominantly inherited, and 60% to 70% of NF1 cases are sporadic and caused by genetic mutation. Occurrence of NF3 through NF8 is extremely rare.

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Clinical images are available in hardcopy only.

Fig. 20.27-2 Café-au-lait spot caused by NF 1. Many small café-au-lait spots are present on the axilla.

Clinical images are available in hardcopy only.

Pathogenesis The gene involved in NF1 is on chromosome 17 (17q11.2). It produces neurofibromin, a tumor suppressor. In NF1, gene mutation in 17q11.2 is thought to increase proliferation of cells (the penetration rate of NF1 is 100%). Pathology Neurofibroma is formed by Schwann cells and intraneural fibroblasts, with thin undulating collagen fibers in the middle (Fig. 20.30). Schwann cells test positive for S-100 protein antibodies. Diagnosis NF1 is easily diagnosed by café-au-lait spots and neurofibroma. Although NF1 in childhood is difficult to diagnose because a few café-au-lait spots are the only symptom, the likelihood of NF1 is high when there are six or more café-au-lait spots (the 6spot criterion) or when there is a Recklinghausen patch on the axillary fossae. The criteria for NF1 established by the National

20

Clinical images are available in hardcopy only.

Fig. 20.28-1 Neurofibroma caused by NF 1.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 20.28-2 Neurofibromatosis type 1 (NF1).

Institutes of Health are shown in Table 20.2. Even areas that are not sun-exposed may be involved in NF1, which distinguishes the condition from freckles. Treatment Symptomatic therapy is the main treatment. Café-au-lait spots are treated by laser therapy and dermabrasion; nevertheless, they tend to recur. Neurofibromas on highly visible areas such as the face or extremities are surgically removed. When a diffuse plexiform neurofibroma is excised, there is a risk of massive perioperative hemorrhage.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

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Prognosis As NF1 is a progressive disease, numerous neurofibromas may occur on the whole body after middle age. The prognosis tends to be good. The central nervous lesion and neurofibroma may worsen and develop a malignant peripheral nerve sheath tumor in rare cases.

2. Neurofibromatosis type 2 (NF2)

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Fig. 20.29 Diffuse plexiform neurofibroma, pachydermatocele. a: Affected breast. b: Side of the body. The lesion has been partially removed by excision and suturing.

Clinical features An elastic, firm, sharply margined subcutaneous neurilemmoma is the main cutaneous symptom. The café-au-lait spots seen with NF1 are not observed. Lesions in the central nervous system, such schwannoma (vestibular arer p tumor), q j as acoustic i k l m n o sheath the main symptoms of neurofibromatosis type 2 (NF2). Hearing impairment and dizziness are present. Paralysis in the extremities and reduced sensory perception are induced by enlargement of the tumor.

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Neurocutaneous syndrome / 3. Tuberous sclerosis

343

Pathogenesis, Epidemiology NF2 is autosomal dominantly inherited. It occurs in 1 in 50,000 to 1 in 100,000 persons. About half of the cases are sporadic. The related gene on chromosome 22 (22q12) codes for a protein called merlin (a moesin-ezrin-radxin-like protein), whose structure is similar to that of cytoskeleton proteins. NF2 is caused by mutation of this gene; however, the mechanism is unknown. Pathology Verocay bodies, which are characteristic to neurilemmoma, are found in NF2. Neurofibromas, which develop in NF1, are not found in NF2. Treatment, Prognosis Total resection of the neurotumor is the basic treatment. Removal may impair hearing. Because tumors enlarge unexpectedly, it is difficult to determine the policy of treatment considering the prognosis for cases with NF2. NF2 has a worse prognosis than NF1.

3. Tuberous sclerosis Synonym: Bourneville-Pringle’s phacomatosis Outline

The main symptoms are multiple facial angiofibroma, intelligence impairment and convulsive seizure. ● It is autosomal dominantly inherited. ● It is characterized by white leaf-shaped macules in infancy and multiple papules (angiofibroma) that occur around the nose after early childhood. Shagreen patch and Koenen’s tumor are also important findings. ●

Clinical features ① Facial angiofibroma Multiple firm papules of normal skin color or light pink and 2 mm to 10 mm in diameter appear symmetrically on the nasolabial sulcus, cheeks, and the area around the nose (Fig. 20.31). The papules occur in about 90% of cases with tuberous sclerosis; the papules and their high specificity are useful for diagnosis of facial angioma. Facial angiofibromas do not appear until the ages of 3 to 4 in most cases, and they become more numerous with age. As the patient grows, the eruptions coalesce to take on a tumorous or plaque-like appearance. Facial angiofibroma used to be called adenoma sebaceum but now is called angiofibroma, because the main pathological condition is degeneration of the blood vessels and connective tissue. ② Shagreen patch Shagreen patch is a special subtype of connective tissue nevus. Shagreen refers to rough, untanned leather. Firm, flatly elevated lesions of about 3 cm in diameter occur mainly on the lumbar

Fig. 20.30 Histopathology of neurofibroma. Table 20.2 Diagnostic criteria of neurofibromatosis type 1 and type 2 (NIH). Neurofibromatosis-1 (NF1) At least 2 of the following 1. Six or more café-au-lait spots of 5 mm or more in diameter (before adolescence) Six or more café-au-lait spots of 15 mm or more in diameter (after adolescence) 2. Two or more neurofibroma, or at least 1 neurofibroma in the peripheral nerves 3. Pigmented macules in the axillary fossae or the groin 4. Neurofibroma in the eye socket 5. Two or more Lisch nodules 6. Bone abnormality 7. Family history of NF1 Neurofibromatosis-2 (NF2) At least 1 of the following 1. Tumors in the acoustic nerves on the both sides observed by CT or MRI 2. Family history of NF2 and the patient has a unilateral acoustic tumor, or at least 2 of the following: neurofibroma, meningioma, glioma, neurilemmoma, juvenile cataract

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

20 Fig. 20.31 Tuberous sclerosis. Angiofibroma on the face.

Clinical images are available in hardcopy only.

Fig. 20.32 Koenen’s tumor.

region and buttocks and coalesce in an arabesque pattern. They often become marked after puberty. Shagreen patch is thought to be a connective-tissue nevus of the sacral region. ③ White leaf-shaped macules White leaf-shaped macules are oblong depigmentations caused by reduced production of melanin, most frequently on the trunk and lower legs. They are seen in about half of all cases with tuberous sclerosis. The onset is usually infancy, and prompt discovery is important. However, they may occur in adults in rare cases. Careful inspection is required for diagnosis. Wood’s lamp is helpful for observation. The white leaf-shaped macules do not become more numerous over time. ④ Koenen’s tumor Angiofibroma appears on the edge or surface of the nail plate (Fig. 20.32). Small spindle-shaped nodules with a diameter of 2 mm to 10 mm and a color range of light pink to brown appear. The nodules are as firm as cartilage. ⑤ Central nervous symptoms Convulsive seizure and intelligence impairment are the main symptoms. Convulsive seizure occurs in about half of all patients with tuberous sclerosis; it subsides within one year after birth. Various symptoms including epilepsia nutans, Lennox-Gastaut syndrome, and tonic-clonic epilepsy are present. Mental retardation may also occur. ⑥ Other symptoms of tuberous fibroma Translucent tumor (astrocytic hamartoma) in the retina and lamellar leukoderma in the iris may occur. Honeycomb lung may be caused in rare cases. Rhabdomyoma may occur in the heart as a complication. Many cases are asymptomatic. Angiomyolipoma and renal failure from hydronephrosis and renal cyst often occur. Pathogenesis The genes responsible for tuberous sclerosis are TSC1 (tuberous sclerosis complex 1) on chromosome 9 (9q34) and TSC2 on chromosome 16 (16p13.3). Both are thought to play a role in tumor suppression. Although tuberous sclerosis is autosomal dominantly inherited, 60% to 70% of all cases are sporadic and there are relatively few familial cases. Laboratory findings Nodule-like calcium deposition on the lateral ventricular walls and basal nuclei and enlargement of the lateral ventricle are found by head CT scan. A nodule-like tumor is observed by MRI in the cerebral cortex. The pathology is that of an anastrocytic hamartoma. Diagnosis Tuberous sclerosis is easily diagnosed by the cutaneous symptoms, which include multiple angiofibroma of the face. Calcium deposition and nodules observed by CT scan and MRI are diagnostic, as is ocular fundus tumor. Electroencephalogram and

Neurocutaneous syndrome / 4. Peutz-Jeghers syndrome

345

renal angiography are also helpful for diagnosis. Treatment, Prognosis Dermabrasion, excision, cryotherapy and laser therapy are conducted on the cutaneous lesions for cosmetic reasons, which nevertheless tend to recur. Drug therapy is useful for convulsive seizure. There is no treatment for the progressive mental retardation. The prognosis depends on the severity of cerebral tumorous lesions and renal leisions.

Clinical images are available in hardcopy only.

4. Peutz-Jeghers syndrome Outline ● Autosomal

dominantly inherited, it is characterized by pigmentation on the lips, oral mucosa and distal extremities, and gastrointestinal polyposis. ● Careful observation is required, because intussusception and cancer may develop as a result of gastrointestinal polyps. ● Laser therapy, dermabrasion and polypectomy are conducted. Clinical features ① Skin pigmentation Flat, asymptomatic, sharply margined, blackish-brown macules of 2 mm to 10 mm in diameter occur symmetrically on the lips, oral mucosa, palms and soles (distal extremities in particular) (Fig. 20.33). The longitudinal axis of the macule runs parallel to the dermatoglyphic lines. Pigmentation is darkest in the crista cutis and lightest in the sulcus cutis. Pigmentation appears between the time of birth and infancy, and tends to increase in number and size with age; it fades in adulthood. ② Gastrointestinal polyposis Gastrointestinal polyposis may occur in any part of the gastrointestinal tract, especially the jejunum. A single lesion or more than ten may be produced. They tend to cause intussusception leading to intense abdominal pain and melena. Most cases of gastrointestinal polyposis are histologically hamartoma; the tissue structure of the lesion is normal and malignant transformation rarely occurs (Table 20.3). Adenoma occurs in about 10% of cases and may become cancerous. Pathogenesis Peutz-Jeghers syndrome is autosomal dominantly inherited; however, about half of all cases occur sporadically. It is caused by mutation in the LKB1 gene on chromosome 19 (19p13.3). The LKB1 gene codes for a serine-threonine kinase whose activity is lost in many patients with Peutz-Jeghers syndrome. The mechanism is unknown.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

20

Fig. 20.33 Peutz-Jeghers syndrome. Pigmentation occurred on the lips and hand.

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Table 20.3 Major cutaneous symptoms accompanying gastrointestinal polyposis. Disease

Inheritance pattern

Sites where polyps likely form

Peutz-Jeghers syndrome

Autosomal dominant Jejunum in many cases

Cronkhite-Canada syndrome

Not inherited

Entire digestive tract

Gardner syndrome Autosomal dominant Large intestine in most cases Turcot syndrome

Fig. 20.34 Incontinentia pigmenti.

Sometimes

Cutaneous symptoms Pigmented macules on the lips, oral mucosa and palms

No

Alopecia, nail plate abnormality, pigmented macules on the dorsum of hands

Yes

Neurofibromatosis, lipoma, dental dysplasia

Sometimes

Autosomal recessive Large intestine

Clinical images are available in hardcopy only.

Canceration of polyp?

Nervous system tumors

Pathology Melanocytes and melanin pigment increase in the epidermal basal layer. There is hyperpigmentation in the crista profunda intermedia, which is the thick portion of the epidermis. The cutaneous lesions do not show malignancy. Differential diagnosis As with Peutz-Jeghers syndrome, Cronkhite-Canada syndrome is characterized by gastrointestinal polyposis and pigmentation (especially on the dorsal hands). However, the onset of Cronkhite-Canada syndrome is at middle age or later and the condition is not inherited. Alopecia and abnormality of nail plate also occur in Cronkhite-Canada syndrome. Treatment, Prognosis Alexandrite laser therapy and dermabrasion are effective in reducing pigmentation when there are cosmetic concerns. Endoscopic or surgical excision is conducted on gastrointestinal polyps.

5. Incontinentia pigmenti (Fig. 20.34) Synonym: Bloch-Sulzberger syndrome

20

Outline

Characteristic pigmentation occurs on the skin. The symptoms are clinically classified into 4 stages. ● Blistering and erythema occur at birth. The disease course begins with papules that progress to pigmentation and disappear. ● It is X-chromosome dominantly inherited; female patients greatly outnumber male patients. ● The prognosis is good. Ocular symptoms and deformity are treated. ●

Clinical images are available in hardcopy only.

Fig. 20.35-1 Incontinentia pigmenti at the inflammatory stage.

Clinical features Incontinentia pigmenti is classified by the clinical features. ① Cutaneous symptoms Inflammatory stage: Vesicles accompanied by erythema appear, most commonly on the trunk (Figs. 21.35-1 and 21.35-2). The

Neurocutaneous syndrome / 5. Incontinentia pigmenti

onset is within a week after birth. They become pustules or erosion, persisting for several weeks to several months before healing gradually. Eruptions resembling alopecia plaques may occur on the scalp. Verrucous and lichenoid stage: After the blisters subside (6 to 12 weeks after birth), multiple hyperkeratotic verrucous papules occur, mainly on the distal extremities. Most cases resolve in several months, but some persist until adulthood (Fig. 20.36). Pigmented stage: Grayish-brown or purplish-brown pigmentation becomes distinct around 6 months after birth at sites where eruptions were. The pigmentation often appears in linear, dropletlike, marbled and reticular patterns (Fig. 20.37). Regression stage: Pigmentation begins to disappear at age 4 or 5. It disappears completely at puberty in most cases. ② Symptoms of incontinentia pigmenti in sites other than skin Ocular symptoms: Ocular symptoms develop in about one third of incontinentia pigmenti cases. Strabismus is the most common such symptom, followed in frequency by cataract, glioma and microphthalmos. There are findings similar to those of retinopathy of prematurity. Central symptoms: Epilepsy and intelligence impairment may be caused in rare cases. Abnormality may occur in teeth (e.g., deficiency, developmental retardation, odontoparallaxis) and bones (e.g., dwarfism, hyperdactylia).

347

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Pathogenesis, Epidemiology Incontinentia pigmenti is caused by mutation in NEMO (NFk B essential modulator), which is mapped on Xq28. It is an Xlinked dominant trait that is usually lethal in males; most male fetuses with the genetic abnormality are not carried to term, which is why more than 95% of all patients are females. More than 700 cases have been reported. About half of all cases occur sporadically. Pathology, Laboratory findings There is eosinophilic infiltration in the intraepidermal blisters of the first stage (Fig. 20.31). Eosinophil levels in the peripheral blood are elevated in 30% of cases. Verrucous papules of the second stage are structurally similar to epidermal nevus. Melanophages are observed in large numbers in the upper dermal layer of pigmentation at the third stage. In the fourth stage, melanophages in the upper layer decrease. Diagnosis, Differential diagnosis It is easy to diagnose incontinentia pigmenti by the characteristic clinical features. The condition is sometimes misdiagnosed as epidermolysis bullosa because of blistering at birth; however, incontinentia pigmenti can be distinguished by its eosinophilic infiltration. Ocular examination is essential, because blindness and amblyopia may occur.

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Fig. 20.35-2 Incontinentia pigmenti at the inflammatory stage. bottom: Eosinophilic infiltration in the epidermis is characteristically seen.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

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Fig. 20.36 Incontinentia pigmenti at the verrucous and lichenoid stage. a: Eruptions on the scalp. Alopecia also occurred. b: Reticular pigmentation. c: Verrucous eruptions accompanied by severe hyperkeratosis, which resembles epidermal nevus.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

20 Fig. 20.37 Incontinentia pigmenti at the pigmented stage. Pigmentation appears in various degrees.

Treatment, Prognosis Complications associated with incontinentia pigmenti and deformities should be promptly treated. As the skin lesion heals spontaneously in many cases, symptomatic therapy may be performed if necessary. The prognosis is good. About half of all male fetuses whose mothers have incontinentia pigmenti do not survive to term. Half of all girls whose mothers have incontinentia pigmenti also have the disease.

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Neurocutaneous syndrome / 6. Sturge-Weber syndrome

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6. Sturge-Weber syndrome Outline ● Hemifacial

hemangioma simplex, choroidal hemangioma and hemangioma of the leptomeninx are the main symptoms. ● The disease is nonhereditary. ● The distribution of facial hemangioma is unilateral on the area over the first division of the trigeminal nerve. ● Glaucoma is caused by hemangioma, leading to buphthalmia. ● Laser therapy, resection of the brain and ocular treatments are conducted. Clinical features Sturge-Weber syndrome is characterized by hemifacial hemangioma simplex, choroidal hemangioma, and hemangioma of the leptomeninx; however, most cases are incomplete, with only hemifacial hemangioma simplex and hemangioma of the leptomeninx. Cutaneous symptoms: Unilateral, or bilateral in rare cases, flat hemangioma simplex is present at birth on the skin over the first or second division of the trigeminal nerve of the face (Fig. 20.38). Central nervous symptoms: Hemangioma of the leptomeninx occurs on the side with semi-facial angioma, especially on the occipital lobe. Contralateral hemiplegia may occur in some cases. Convulsive seizure appears in infancy in about 80% of cases. Atrophy and calcinosis of the cerebral hemisphere and intelligence impairment may also occur. Ocular symptoms: Choroidal angioma may occur on the side with semi-facial angioma, leading to abnormal formation of the anterior chamber of eyes. High fluid pressure is present in the eyes (glaucoma) in early childhood as a result. The cornea is hyperextended by increased fluid pressure of the eyes, and the corneal diameter enlarges accordingly, a condition called buphthalmia. The result is blindness in most cases. Pathogenesis Abnormal development of blood vessels caused by embryonic impairment of the sympathetic nerve is thought to cause SturgeWeber syndrome; however, the details are unknown. It is congenital; nevertheless, it is known to be nonhereditary in general. It occurs in about 1 in 100,000 people. Laboratory findings The double-contoured calcification observed along the cerebral convolution by skull X-ray is called tramline calcification. Head CT scan and MRI are able to find angioma before calcification occurs; this is useful for early diagnosis.

Clinical images are available in hardcopy only.

Fig. 20.38 Sturge-Weber syndrome.

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Treatment Laser therapy is performed on facial hemangioma. When drug therapy is ineffective on convulsive seizure, resection of the brain hemangioma is conducted. For ocular symptoms, early diagnosis and adjustment of ocular pressure are important.

7. Klippel-Trenaunay-Weber syndrome Synonyms: Klippel-Trenaunay syndrome, Klippel-Weber syndrome Outline Clinical images are available in hardcopy only.

Fig. 20.39 Klippel-Trenaunay-Weber syndrome. The right arm, which is affected by hemangioma, is longer than the left arm.

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● Hemangioma

simplex in the extremities and enlargement and extension of the affected limb are observed. ● Spinal curvature is caused by the different length of the extremities, and there is the risk of ulceration and heart failure caused by arteriovenous fistula. ● Symptomatic therapy is the main treatment. Clinical features, Pathogenesis The cause of Klippel-Trenaunay-Weber syndrome is unknown; however, there is fragility of mesodermal tissue in the vascular walls. Cutaneous hemangioma simplex is present at birth in many cases. Usually one arm or leg, but sometimes both arms or legs, is involved. It may spread beyond the extremities (Fig. 20.39). Lymphangioma, congenital venectasia, angiokeratoma and congenital arteriovenous fistula may also occur and become distinct with age. These vascular lesions may cause edema, ulceration and varix secondarily. Klippel-TrenaunayWeber syndrome is also characterized by enlargement and overgrowth of the bone and soft tissue: The extremities may become different in length and the difference becomes more distinct with age. The bone abnormality usually occurs in the leg on the same side of the body as the skin lesion, or rarely, on the opposing side. The different length of the legs results in claudication and compensatory scoliosis. Angioma in internal organs, syndactylism or other dysplasia of fingers and toes, and heart failure (if the arteriovenous fistula is severe) may occur. Abnormality of coagulation may be caused in vascular channels. Severe clotting abnormality called Kasabach-Merritt syndrome may occur in some cases. Diagnosis, Treatment Klippel-Trenaunay-Weber syndrome is easily diagnosed by the characteristic clinical features. Diagnosis can be confirmed by bone radiography and systemic CT scan. Arteriovenous fistula is examined by thermography, blood gas analysis and angiography. Symptomatic therapy is the main treatment. Laser therapy is conducted when the hemangioma simplex raises cosmetic concerns. Ligation or excision is performed on arteriovenous fistulae, because they may cause heart failure. For prevention of

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arthropathy and curvature caused by the different length of the extremities, orthopedic shoes and osteotomy are helpful. Clinical images are available in hardcopy only.

8. Neurocutaneous melanosis Synonym: Mélanoses neurocutanées Clinical features Neurocutaneous melanosis is nonfamilial and occurs in both men and women. Large congenital melanocytic nevus, in most cases a giant hairy pigmented nevus, is present on nearly half the trunk (Figs. 20.40-1 and 20.40-2) or multiple congenital small melanocytic nevi disperse over the whole body. These nevi can be a serious burden cosmetically. Cerebral nervous symptoms such as increased intracranial pressure and secondary hydrocephalia occur. These are accompanied by headache, vomiting, epileptic seizure and intelligence impairment. Malignant melanoma often develops on the site of the body with giant hairy nevus and leptomeninx. a

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Pathogenesis Neurocutaneous melanosis is caused by proliferation of melanoblasts that originate from neural crests in the skin and central nervous system (e.g., leptomeninx). Congenital, extensive or disseminated melanocytic nevi occur. In the brain, perivascular proliferation of melanocytes impairs reabsorption of cerebrospinal fluid, leading to hydrocephalia. Clinical images are available in hardcopy only.

Diagnosis Neurocutaneous melanosis is characterized by giant hairy pigmented nevus and multiple small melanocytic nevi. MRI head scan, lumbar puncture and ventriculography are necessary for diagnosis. Increased levels of proteins and reduced sugar levels are often found in the cerebral fluid. Melanin-containing cells may be detected. a

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Treatment Giant pigmented nevus is removed as completely as possible. The sooner curettage is performed after birth, the better is the result cosmetically (Fig. 20.40-1). Symptomatic therapy such as shunting for hydrocephalia and anti-epilepsy drugs are useful for central nervous symptoms. There is no effective treatment for melanoma of the leptomeninges.

9. LEOPARD syndrome Synonym: Multiple lentigines syndrome The main symptoms are multiple lentigines, café-au-lait spots, systemic symptoms including abnormality in cardiac transmitter function (detected by electrocardiogram), ocular hypertelorism,

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Fig. 20.40-1 Neurocutaneous melanosis. a: On the whole body. b: It is often accompanied by nodules (arrows). c: The affected site (b) was removed.

Origin of the term LEOPARD syndrome

MEMO

LEOPARD is an initialism for the following systemic symptoms: L (multiple lentigines), E (electrocardiographic conduction defects), O (ocular hypertelorism), P (pulmonary stenosis), A (abnormalities of genitalia), R (retardation of growth), D (sensorineural deafness).

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genital abnormality, stunted stature, hearing loss and mental retardation. LEOPARD syndrome is caused by mutation in the PTPN11 gene (protein-tyrosine phosphatase, nonreceptor type 11). It is thought to be autosomal dominantly inherited; nevertheless, many cases occur sporadically. Multiple lentigines are present at birth and gradually increase in number until puberty. They are comparatively small, 5 mm or less in diameter, and appear on the whole body skin. The mucous membranes are not involved. Various skin lesions, including nail malformation and skin hyperelasticity may occur. Among all lesions caused by LEOPARD syndrome, heart lesions affect the prognosis most severely.

Clinical images are available in hardcopy only.

10. Basal cell nevus syndrome Synonym: Nevoid basal cell carcinoma syndrome Multiple basal cell nevi and small depression in the palms and soles occur (Fig. 20.41), accompanied by multiple maxillary cysts, skeletal defects and central nervous symptoms (e.g., calcification of the cerebral dura mater, hydrocephalia, mental retardation). It is autosomal dominantly inherited. The causative gene is PTCH on chromosome 9 (9q22.3). Small multiple brown nodules of 1 mm to 2 mm in diameter are present on the whole body until the age 10. The tissue of the nodules is the same as that of basal cell carcinoma. Infiltrating lesions may form. When basal cell carcinoma is seen in young patients, basal cell nevus syndrome is suspected.

Clinical images are available in hardcopy only.

Fig. 20.40-2 Neurocutaneous melanosis.

11. Von Hippel-Lindau syndrome Clinical images are available in hardcopy only.

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Von Hippel-Lindau syndrome is autosomal dominantly inherited, caused by a mutation in the VHL tumor-suppressor gene on chromosome 3 (3q25). Angioma and café-au-lait spots may appear in rare cases. Multiple tumors occur throughout the body, such as renal cell carcinoma, angioblastoma in the central nerves, retinal hemangioma, pancreatic tumor and pheochromocytoma. h

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Fig. 20.41 Nevoid basal cell carcinoma syndrome. a: Small concavities (pitting) in the palm. b: Multiple basal cell nevi on the eyelid.

This is a comorbid disease of cutaneous hemangioma simplex and nevus pigmentosus. It affects the eyes, skin and central nervous system (Fig. 20.42). Phacomatosis pigmentovascularis, which is known to be nonhereditary, is classified into four types: port-wine stain and linear epidermal nevus (type 1), port-wine stain and dermal melanocytosis (type 2), port-wine stain and nevus spilus (type 3), and port-wine stain, dermal melanocytosis, and nevus spilus (type 4). Type 2 phacomatosis pigmentovascup q j i k o laris accounts for 80%l of allmcases. nAlthough phacomatosis pig-r mentovascularis causes only cutaneous lesions, it is classified as a neurocutaneous syndrome because it is accompanied by SturgeWeber syndrome and Klippel-Trenaunay-Weber syndrome in

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about 20% of cases. Laser therapy and concealing cosmetics are useful.

13. Osler’s disease Synonyms: Hereditary hemorrhagic telangiectasia, OslerRendu-Weber disease Absence of elastic fibers and smooth muscles leads to telangiectasia in the arteriovenous anastomotic region. Osler’s disease is autosomal dominantly inherited. Multiple papules appear on the chest, tongue, lips and palms after puberty. The papules are red at the center and are accompanied by peripheral papillary telangiectasia (Figs. 20.43-1, 20.43-2 and 20.44). Mucosal bleeding, especially recurrent epistaxis, first occurs at the onset; it has diagnostic value. Broken pulmonary arteriovenous fistula may result in hemoptysis, hematothorax, gastrointestinal hemorrhage and hepatic cirrhosis.

Clinical images are available in hardcopy only.

Fig. 20.42 Phacomatosis pigmentovascularis.

14. Blue rubber bleb nevus syndrome Multiple, elastic, rubber-ball-like blue cavernous angiomas occur in the skin and gastrointestinal tract. It is a rare autosomal dominantly inherited disease that occurs between birth and infancy, and the appearance does not change over the course of the patient’s life. The angiomas vary in diameter from 2 mm to 10 cm, or sometimes larger. Gastrointestinal angioma spreads to the oral cavity, tongue and colon, leading to iron-deficiency anemia and intussusception from bleeding. Angiomas may be produced in the liver, brain, lungs, spleen, gallbladder, skeletal muscles or kidneys.

Clinical images are available in hardcopy only.

15. Maffucci syndrome Congenital abnormality of mesoblasts causes angioma in the skin and internal organs, and ossification in the epiphyseal cartilage. Angioma is cavernous in many cases. It may be accompanied by hemangioma simplex and lymphangioma. Condroma and imperfect osteogenesis lead to bone deformity and fracture from impaired ossification of the epiphyseal cartilage.

16. Dyskeratosis congenita Synonym: Zinsser-Cole-Engman syndrome The onset of dyskeratosis congenita is between early childhood and puberty. More men are affected than women. The main symptoms are cutaneous reticulated pigmentation, atrophy and thinning of the nail plate, and oral leucoplakia. The onset is in late childhood. Deformity of the nail plate occurs first, followed by reticular pigmentation on the neck region spreading to the

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Fig. 20.43-1 Osler’s disease.

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trunk and extremities. Leukoderma keratosis-like change appears most frequently on the tongue, buccal mucous membranes and genitalia, and it tends to become malignant. It is accompanied by progressive aplastic anemia, splenomegaly and esophageal blockage. The main treatments are excision for leukoplakia and symptomatic therapy for anemia.

Clinical images are available in hardcopy only.

17. Epidermal nevus syndrome Epidermal nevus syndrome is unilateral epidermal nevus accompanied by central nervous abnormalities such as mental deficiency and epilepsy, nystagmus and strabismus, bone deformity and angioma. Malignant tumor may occur as a complication.

Fig. 20.43-2 Osler’s disease.

18. Cutis marmorata telangiectasia congenita Livedo reticularis appears at the time of birth or shortly thereafter. Telangiectasia usually accompanies it. Deformity occurs in the central nerves, heart, blood vessels, muscles, skeleton and eyes in nearly half of cases. Reticularis disappears with age, and most cases resolve within 2 years after birth. There is no difference in occurrence between sexes and races. Although it usually occurs sporadically, there are rare familial cases.

Fig. 20.44 Histopathology of Osler’s disease.

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Chapter

21

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Benign Skin Tumors

Examination of a skin tumor is for determination not only of malignancy or benignancy but also of the skin component from which the tumor derives. A tumor may originate from epidermal keratinocytes, from cells of appendages such as those in sweat glands, or from neural crest cells or mesenchymal cells including dermal fibroblasts. The epidemiology, pathology and course of tumors vary depending on the origin of the cells. This chapter classifies benign skin tumors into the subtypes below. A: Epidermal tumor F: Neural tumor J: Adipocellular tumor

B: Follicular tumor C: Sebaceous tumor G: Hemangiomas/vascular malformations K: Myogenic tumor L: Osteogenic tumor

D: Sweat gland tumor H: Fibrous tumor M: Hematopoietic tumor

E: Cyst I: Histiocytic tumor

A. Epidermal tumors Epithelial tumors originate mainly from epidermal keratinocytes.

1. Seborrheic keratosis (SK) Synonyms: Senile warts, Senile verruca Outline ●A

benign verrucous tumor occurs, most frequently on the face, head or trunk of men and women middle aged and older. It derives from keratinocytes in the epidermis or infundibular hair follicle. ● Elevated, sharply demarcated, grayish-brown to blackish-brown nodules of 1 cm to 2 cm in diameter occur. ● Cryotherapy, laser therapy and excision are the main treatments. ● When multiple, itchy, SK rapidly occurs on the whole body within 6 months after the onset of SK, it is called Leser-Trélat syndrome. It may be accompanied by internal malignancy. Clinical features Seborrheic keratosis (SK) appears in people in their 20s and is seen in nearly everyone in their 80s or older. Flat-topped papules of 1 cm to 2 cm in diameter, varying in color from brown to blackish brown occur on the face, head and trunk (Figs. 21.1-1 and 21.1-2). The palms and soles are unaffected. The surface of the papules is keratotic and often papillary or granular, resembling clay adhered to the skin. Itching and pain are not usually present. As the synonym “senile warts” suggests, SK occurs as a skin aging change. Senile freckles often elevate to form SK. Pathology There is upward intraepidermal proliferation of basal cells and 355

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Fig. 21.1-1 Seborrheic keratosis (SK). Multiple, flatly elevated, brown or blackishbrown keratotic papules of 1 cm to 2 cm in diameter on the back of an elderly man.

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suprabasal cells (exophytic lesion). The ratio of proliferative cells to normal cells varies. Dysplasia is not present, but melanin pigmentation occurs in each proliferative cell to a varying degree (Fig. 21.2). Pseudohorn cyst formation presents as milia-like cyst by dermoscopy. Clinical images are available in hardcopy only.

Differential diagnosis The disease should be differentiated from actinic keratosis, Bowen’s disease (papular type), basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, follicular tumor, syringoma, flat warts, verruca vulgaris and lentigo simplex.

Clinical images are available in hardcopy only.

Treatment Treatment is not necessary except when there are cosmetic concerns or suspected malignancy. The lesions do not disappear spontaneously but increase in number with age. If necessary, cryotherapy, laser therapy or surgical removal is conducted.

2. Clear cell acanthoma Fig. 21.1-2 Seborrheic keratosis (SK). The skin lesion resembles clay adhered to the skin. The surface of the lesion is keratotic and papillary.

Clear cell acanthoma is usually a solitary, elastic, firm, domeshaped or flatly elevated small tumor whose diameter is up to 2 cm. It may be pedunculated, fungiform or papillomatous. The surface is smooth, granular or velvety. The color is usually rose pink, but it may be brown to blackish brown in some cases. The pathogenesis is unknown. There is a question of whether clear cell acanthoma is a genuine tumorous lesion or a reactive lesion that accompanies inflammation. Histologically, epidermal cells containing clear cytoplasm (clear cells) proliferate.

3. Warty dyskeratoma In warty dyskeratoma there are verrucous or flatly elevated tumors of 1 cm to 2 cm in diameter that tend to keratinize at the center. The condition is largely asymptomatic, although tenderness and pain are present in some cases. Basaloid cells proliferate pathologically toward the dermis directly above which cleavage appears. Warty dyskeratoma clinically resembles Darier’s disease but is a different disease.

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Fig. 21.2 Histopathology of seborrheic keratosis (SK). The epidermis proliferates and elevates above the normal skin surface. Pseudohorn cysts form (arrows).

MEMO Sudden development of numerous seborrheic keratosis lesions, usually, with pruritus, is called Leser-Trélat sign. This sign implies the presence of internal malignancy. Therefore, systemic investigation must be made for such malignancies when dermatologists see this phenomenon.

Leser-Trélat sign

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A. Epidermal tumors

4. Porokeratosis Outline

round, brown keratotic lesions with elevated rims occur on the extremities, trunk and face. ● The disorder is asymptomatic. There is transformation to squamous cell carcinoma in rare cases. ● Characteristic pathological features called cornoid lamella are observed. ● Excision and cryotherapy are the main treatments.

Clinical images are available in hardcopy only.

● Scattered,

Clinical features An elevated keratotic eruption, round or oval in shape, occurs on the extensor surfaces of extremities and on the trunk and face (Fig. 21.3). Atrophy occurs at the center of the lesion, which becomes slightly concave. Porokeratosis begins as a blackishbrown papule, gradually enlarging centrifugally. It is asymptomatic, it progresses slowly, and it does not subside. It maya aggravate and progress to Bowen’s disease or squamous cell carcinoma. Despite the disease name, the eruptions are not associated with the sweat pores. Porokeratosis is divided by morphology into the six subtypes below. Pathologically, the most frequently seen type is disseminated superficial porokeratosis, which occurs on sun-exposed areas of the body. Porokeratosis of Mibelli: This is the classic porokeratosis, in which small multiple eruptions up to 2 cm in diameter occur symmetrically on the extremities and face. a b Linear porokeratosis: The onset is between birth and early infancy. The eruptions are arranged in band-like or linear pattern. Localized porokeratosis: A large, solitary, localized eruption occurs. Disseminated superficial porokeratosis: Multiple, disseminated, small eruptions coalesce. Disseminated superficial actinic porokeratosis: Multiple eruptions occur on sun-exposed areas of the body, particularly the extensor surfaces of extremities in adults. Porokeratosis palmaris et plantaris disseminata: a Small b kera-c totic papules occur multiply on the palms and soles. Pathogenesis Porokeratosis is induced by epidermal clones that cause localized dyskeratosis. It may be triggered by sunlight, external injury or aging. Some cases are autosomal dominant. a b c d Pathology Acanthosis and hyperkeratosis are found at the periphery of porokeratosis. The rim of the lesion is elevated, and there is cornoid lamella, a column of incompletely keratinized cells that stain more brightly than the peripheral horny cell layer. Underneath the cornoid lamella, the granular cell layer is absent (Fig.

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Fig. 21.3 Porokeratosis. a, b: Porokeratosis of Mibelli. The eruption is keratotic, with an elevated rim and a diameter of about 2 cm. c: Disseminated superficial actinic porokeratosis. d, e: Disseminated superficial porokeratosis. The eruptions are 5 mm in diameter and slightly elevated at the edge.

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lesion

normal area

21.4). Thinning of the epidermis accompanied by parakeratosis is present in the concave center of the lesion. Treatment Excision, electrical coagulation, cryotherapy, dermabrasion, and administration of retinoids are the main treatments. Porokeratosis is chronic and intractable.

Fig. 21.4 Histopathology of porokeratosis. The cornoid lamella (arrow) around the lesions can be observed by the naked eye as an elevated rim of the skin lesion.

B. Follicular tumors 1. Trichofolliculoma Small, smooth-surfaced, dome-shaped tumors or papules 5 mm to 10 mm in diameter occur, most commonly in the nasal region and its peripheries (Fig. 21.5). Trichofolliculoma is characterized by small keratotic cavities with several immature woolly hairs at the center. The pathogenesis is unknown. Trichofolliculoma is considered a benign tumor in which the entire follicle – including the inner root sheath, outer root sheath, and dermal hair papilla – differentiates.

Clinical images are available in hardcopy only.

2. Trichoadenoma Fig. 21.5 Trichofolliculoma. There is a small keratotic concavity at the center of the lesion. Many fragile young hairs are present.

21 Hyperplasia, Adenoma, Epithelioma

MEMO

Benign tumors in skin appendages are classified by the degree of cellular differentiation. In order of least abnormal (most differentiated) to most abnormal (least differentiated), they are hyperplasia, adenoma and epithelioma. When the degree of cellular differentiation is lower than that of epithelioma, the tumor becomes a blastoma or malignant tumor. A tumor that has components of all three germ layers (ectoderm, mesoblast, endoblast) is called a teratoma. The diagnostic name epithelioma may also be used for malignant tumors such as basal cell epitheliomas, which are synonymous with basal cell carcinomas.

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A firm, solitary, elastic nodule 1.5 cm or less in diameter appears, most frequently on the face. It is thought to be a tumor whose morphological differentiation falls between that of trichofolliculoma and that of trichoepithelioma. The border between the normal dermis and trichoadenoma is clear. There are multiple keratin-containing cyst(s) and solid masses of cells in the dermis.

3. Solitary trichoepithelioma This is a benign tumor derived from hair germs that differentiate into various hair components, such as hair follicles, outer root sheaths, and hairs. Small, firm but elastic tumors of 2 mm to 5 mm in diameter and normal skin color occur around the nose, eyebrows, upper lip, and chin. It is nonhereditary. Solitary trichoepithelioma histopathologically consists of a small keratincontaining cyst(s) and basaloid cells, and there is proliferation of dermal stroma. It may be difficult to distinguish from basal cell carcinoma; however, in most cases of solitary trichoepithelioma,

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B. Follicular tumors

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there are well-differentiated keratinous cysts and formation, although incomplete, of hair follicles. Foreign body granuloma and calcium deposition may be present.

4. Trichoepithelioma papulosum multiplex Clinical features, Pathogenesis Multiple, dome-shaped, firm papules of several millimeters to 1 cm in diameter and normal skin color occur symmetrically on the midline facial region, scalp, nuchal and neck region, and trunk (Fig. 21.6). The onset is puberty, and the lesions gradually increase in number. Women are slightly more likely to be affected than men. It is autosomal dominant and may be familial. In recent years, abnormality in the cylindromatosis (CYLD1) gene has been identified as the cause. Pathology Trichoepithelioma papulosum multiplex is a tumor mass consisting of basaloid cells that resemble basal cell carcinoma cells. A keratinous cyst forms in the tumor. Differential diagnosis The papules produced on the midline facial region are similar to facial angiofibroma seen in tuberous disease (Chapter 20). In tuberous sclerosis, other symptoms such as leukoderma and shagreen patch are present. Treatment As malignant transformation is not present in trichoepithelioma papulosum multiplex, treatment and follow-up are unnecessary, except when there are cosmetic concerns.

Clinical images are available in hardcopy only.

Fig. 21.6 Trichoepithelioma papulosum multiplex. Multiple, dome-shaped, firm, normal skin color papules of 5 mm in diameter occur on the face.

Clinical images are available in hardcopy only.

5. Desmoplastic trichoepithelioma Circular nodules or plaques of several millimeters to 1 cm in diameter and normal skin color or light yellow occur, most frequently on the cheeks, forehead and nasal region of relatively young adult women. The lesions are characterized by elevated edges and concave centers (Fig. 21.7). Miliary, papular lesions may occur at the periphery of the lesion. Histopathologically, cordlike proliferation of basaloid tumor cells, multiple keratinous cysts and hyalinized collagen fibrils are present. Differentiation from basal cell carcinoma may be difficult.

6. Trichoblastoma A dome-shaped nodule occurs, most frequently on the face or scalp. It consists of fibrous interstitium and tumor cells that resemble follicular germinative cells. It may arise on sebaceous nevi. Differentiation from basal cell carcinoma may be difficult.

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Fig. 21.7 Desmoplastic trichoepithelioma. The skin lesion is 5 mm in diameter, with an elevated-rim and small surrounding circular nodules.

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7. Pilomatricoma Synonyms: Calcifying epithelioma, Pilomatrixoma Clinical images are available in hardcopy only.

Fig. 21.8 Calcifying epithelioma. This is a subcutaneous nodule of 15 mm in diameter. It is accompanied by tenderness and light pink erythema.

Clinical features A firm, intradermal or subcutaneous tumor 3 cm to 4 cm in diameter occurs on the face, neck or upper arms of infants, usually solitarily. The tumor surface is rough and the color is of normal skin or translucent bluish white. It is the firmness of bone (Fig. 21.8). Although it is usually asymptomatic, mild tenderness may be present. Myotonic dystrophy may induce multiple calcifying epithelioma. Malignant formation rarely occurs (pilomatrix carcinoma). Pathogenesis Calcifying epithelioma is a teratoma that originates from the hair follicle bulge. Some cases are caused by genetic abnormality in b-catenin. Pathology A sharply margined, irregularly shaped tumor mass appears in the lower dermal layer or subcutaneous tissue. The mass is not covered by a distinct membrane but is surrounded by fibrous connective tissue (Fig. 21.9). The tumor contains basaloid cells (originating from the hair matrix and staining basophilic) and shadow cells. Shadow cells are enucleated cells that stain eosinophilic. Foreign body granuloma and calcification are seen. Treatment The treatment is surgical removal.

8. Trichilemmoma

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Fig. 21.9 Histopathology of calcifying epithelioma.

A tumor of 3 mm to 8 mm in diameter and normal skin color to light brown occurs, usually solitarily and most commonly on the face. Histopathologically, there are columnar cells arranged in a palisading pattern and a mass of clear cells that resemble outer root sheath cells. Malignant trichilemmoma occurs in rare cases.

9. Proliferating trichilemmal tumor A subcutaneous nodule or tumor 1 cm to 10 cm in diameter occurs, most frequently on the scalp. It is pathologically similar to epidermal cyst and trichilemmal cyst (described later). Erosion and ulceration may be present on the surface. Trichilemmal keratinization is observed histopathologically. Overproliferation of cell components is also seen. Malignant proliferating trichilemmal tumor accompanied by atypism is pathologically differentiated from proliferating trichilemmal tumor.

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C. Sebaceous tumors 1. Sebaceous hyperplasia Synonym: Senile sebaceous hyperplasia Flat, yellowish-white papules or small nodules with a diameter of 3 mm to 8 mm occur on the face (forehead, cheeks, nose), frequently in the elderly (Fig. 21.10). Several eruptions occur in most cases. They are centrally umbilicated and may discharge sebum from the center.

Clinical images are available in hardcopy only.

Fig. 21.10 Sebaceous hyperplasia.

2. Sebaceous adenoma A yellowish nodule or tumor occurs, most frequently on the face or scalp of middle-aged persons. Histopathologically, the tumor differentiates into sebaceous glands that contain a normal sebaceous lobular structure.

3. Sebaceoma

Clinical images are available in hardcopy only.

Synonym: Sebaceous epithelioma This is a dome-shaped or pediculate nodule that occurs on the face or scalp (Fig. 21.11). It may be yellowish. Histopathologically, there is proliferation of tumor cells that resemble basal cells. Some of the tumor cells are anaplastic and some spread to the sebaceous ducts.

Fig. 21.11 Sebaceoma. Dome-shaped yellowish nodule is seen.

21 MEMO Small, multiple, aggregated yellow papules of 1 mm to 2 mm in diameter occur in the lips, buccal membrane, foreskin, or labia majora and minora. They are caused by proliferation of sebaceous glands. The condition is seen in the oral mucosa of about 80% of those middle aged and older. Fordyce’s condition is not related to Fox-Fordyce disease (Chapter 19), a condition of chronic inflammation in the apocrine sweat glands.

Fordyce’s condition

MEMO This is a hereditary disease in which sebaceoma, sebaceous adenoma or sebaceous gland cancers occur multiply, in addition to malignant gastrointestinal tumors such as stomach cancer and colon cancer. Keratoacanthoma may also occur.

Muir-Torre syndrome (also see Chapter 22)

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D. Sweat gland tumors 1. Eccrine hidrocystoma A small, translucent-bluish papule 2 mm to 3 mm in diameter occurs on the face, usually solitarily but sometimes multiply (Fig. 21.12). When there are multiple papules, the number tends to increase in summer and decrease in winter. The skin lesion is thought to be a cystic intradermal channel enlarged by sweat deposition; it is known to be a stagnating cyst that accompanies deformity of the eccrine sweat ducts (Fig. 21.13). Sweat deposition can be identified by puncture with a needle.

Clinical images are available in hardcopy only.

Fig. 21.12 Eccrine hidrocystoma.

2. Syringoma

Fig. 21.13 Histopathology of eccrine hidrocytstoma.

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Pathology Strands of epithelia form luminal structures of various sizes in the upper and middle dermal layers. The strands form cystic luminal structures with a tadpole-like shape. The lumen is com-q p j h i k l m n o posed of double-layered mural cells with peripheral proliferation of connective tissue (Fig. 21.15). Differential diagnosis Differentiation from lupus miliaris disseminatus faciei (LMDF), milium and angiofibroma is easy by histopathological imaging.

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Clinical features Small, multiple, flatly elevated papules with a diameter of 1 mm to 3 mm and normal skin color result from localized proliferation of intradermal sweat ducts. The eyelids are the most commonly affected. The papules may disseminate on the trunk and coalesce (Fig. 21.14). The incidence is higher among women than men, and the disease is seen most often in puberty, when sweat secretion increases. It is asymptomatic and rarely heals spontaneously.

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Fig. 21.14 Syringoma. a: Multiple, small, flatly-elevated papules of 2 mm to 5 mm in diameter on the eyelids. b: Multiple eruptions of syringoma on the axillary fossa. They coalesce into a large plaque.

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3. Eccrine poroma Definition, Clinical features Outer cells of eccrine sweat ducts proliferate in eccrine sweat

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glands. Some of the cells differentiate into sweat duct luminal cells and further into sweat duct excretion cells. A small, domeshaped or pedunculated nodule occurs on any site of the body, particularly on the soles and palms. The nodules are characterized by dark red color and easy bleeding (Fig. 21.16). Pathology There is a proliferating nest of poroid cells in the epidermis and the dermis. Eosinophilic cells form small lumens in the focus (cuticular cells, Fig. 21.17). The tumor cells contain large quantities of glycogen. Treatment Eccrine poroma may become malignant in rare cases (eccrine porocarcinoma). The skin lesion should be surgically removed.

4. Eccrine spiradenoma A firm, solitary, sharply margined, intradermal or subcutaneous nodule 1 cm to 2 cm in diameter occurs on the face, neck, trunk or upper arm. The nodule is normal skin color or bluish. It is accompanied by spontaneous pain and tenderness. Large light cells and small dark cells are pathologically observed to proliferate in a palisading pattern or in clusters, forming a tubular structure.

5. Papillary eccrine adenoma Small solitary nodules of 1 cm to 3 cm in diameter occur on the extremities. Histopathologically, cystic structures of several sizes, and columnar strands of epithelium are found. Papillary eccrine adenoma is thought to be a benign tumor that differentiates into the eccrine sweat ducts; however, it is not known whether it originates from eccrine sweat gland cells or apocrine sweat gland cells.

Fig. 21.15 Histopathology of syringoma. The eruptions contain the tadpole-like or commatail-like tumor cells that are characteristic of syringoma.

Clinical images are available in hardcopy only.

Fig. 21.16 Eccrine poroma. A pedunculated, dark-red nodule is noted.

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6. Nodular hidradenoma This is a solitary intradermal nodule. The tumor cells are

Classification and subtypes of eccrine poroma

MEMO

Hidracanthoma simplex: Tumor cells proliferate within the epidermis. The lower legs are most commonly involved. The surface of the lesion is slightly keratinized. Eccrine poroepithelioma: Tumor cells proliferate in the direction of the dermis. Atypism is slight. Dermal duct tumor: Tumor cells proliferate only in the dermis, without connection to the epidermis. Eccrine porocarcinoma: Eccrine poroma often progresses to eccrine porocarcinoma. High atypism and infiltrative proliferation result in canceration.

Fig. 21.17 Histopathology of eccrine poroma.

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Clinical images are available in hardcopy only.

polygonal cells containing eosinophilic cell bodies. Histopathologically, there are spindle-shaped cells containing long, thin nuclei, and round cells containing round nuclei. Nodular hidradenoma is a benign tumor that differentiates into eccrine sweat glands. There may be malignant formation (malignant nodular hidradenoma) in some cases.

7. Mixed tumor of the skin Synonym: Chondroid syringoma

Clinical images are available in hardcopy only.

Relatively firm intradermal nodules of 3 cm or less in diameter occur, most frequently on the face, head and scalp of young and middle-aged persons (Fig. 21.18). Mobility is present at the bottom of the nodules on the skin surface. There are luminal structures of several sizes in the skin lesion, which are surrounded by single- or double-layered cell walls. Epithelial adenomatous tissue is interspersed with luminal structures and mucus-like or cartilage-like fibrotic stroma. Mixed tumor of the skin is thought to be a benign tumor that differentiates into sweat ducts in the secretory part of the eccrine and apocrine sweat organs. It may be cancerous in rare cases.

Fig. 21.18 Mixed tumor of the skin.

8. Apocrine hidrocystoma

Clinical images are available in hardcopy only.

This is a tumor of the apocrine organs. A small, solitary, dome-shaped nodule with a diameter of several millimeters to 2 cm occurs around the eye or elsewhere on the face, or on the ear or scalp, of persons middle aged or older. The nodule is transparent or bluish. A large cystic structure is found in the dermis. The nodule is composed of single-layered pillar cells that show apocrine secretion, and myoepithelial cells that are located on the outer side of the pillar cells. It is asymptomatic. Excision may be conducted at the patient’s request.

Fig. 21.19 Cylindroma.

9. Cylindroma

21 MEMO Benign tumors that originate from sweat glands in the skin or that differentiate into sweat glands are collectively called hidradenomas. An apocrine hidradenoma divides in the direction of the apocrine glands. An eccrine hidradenoma divides in the direction of the eccrine glands. Hidradenomas are subclassified by the location of the main proliferation into poromas (proliferation is mainly in the epidermal portion of sweat glands), dermal duct tumors (in the dermal sweat duct), and spiradenomas (in the secretory portion). Clear cell poromas, mixed tumors of the skin, cylindromas, hidradenoma papilliferum, and cystadenomas are distinguished by the histological findings of proliferative cells.

Hidradenomas

Multiple dome-shaped or slightly pedunculated tumors of 1 cm to 10 cm in diameter and normal to brown skin color occur, most commonly on the scalp of adolescent boys and girls (Fig. 21.19). When the entire scalp is affected, the head has the appearance of being wrapped by a turban (turban tumor). The condition seldom occurs in ethnic Japanese. Cylindroma may occur solitarily in rare cases. Multiple cylindroma is an autosomal dominant disorder in which abnormality of the cylindromatosis gene (CYLD1 gene) has been identified, and multiple papular trichoepithelioma is seen. Cylindroma is thought to be a tumor of the sweat organs. There may be malignant formation in rare cases (malignant cylindroma).

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10. Hidradenoma papilliferum A small, dome-shaped tumor occurs, often accompanied by erosion and bleeding. It most frequently appears on the female genitalia. The tumor resembles granulation tissue. Pathologically, there is dense papillary proliferation of glandular epithelial cells of apocrine-type secretion. Hidradenoma papilliferum is the typical type of apocrine neoplasm.

Clinical images are available in hardcopy only.

11. Syringocystadenoma papilliferum An erosive rose-pink-surfaced verrucous nodule occurs, most commonly on the scalp or face of infants (Fig. 21.20). It is an apocrine organic hamartoma and often occurs secondarily after sebaceous nevus. Histopathologically, there is a double-layered luminal structure with long cylindrical cells on the inner side, cubical cells on the outer side, and marked plasmacytic interstitial infiltration in the nodule (Fig. 21.21). Basal cell carcinoma occurs secondarily in 10% of cases.

Fig. 21.20 Syriogocystadenoma papilliferum. Verrucous nodule on the nipple. Syringocystadenoma papilliferum on the chest is rare.

12. Tubular apocrine adenoma A nodule of 1 cm to 2 cm in diameter and normal skin color or brown occurs, usually on the scalp. Histopathologically, proliferation of small, multiple cyst-like lumens is seen.

13. Erosive adenomatosis of the nipple A benign tumor occurs in the nipple, often accompanied by erosion and exudation. Differentiation from mammary Paget’s disease and breast cancer is necessary. A dense concave structure and a luminal structure are histopathologically observed. Erosive adenomatosis of the nipple is a benign tumor that differentiates into the apocrine sweat glands. The only treatment is total excision; unless it is complete, there is recurrence. Fig. 21.21 Histopathology of syriogocystadenoma papilliferum.

E. Cysts 1. Epidermal cyst Clinical features A dome-shaped, intradermal or subcutaneous tumor with a diameter of 1 cm to 2 cm (or more than 10 cm in rare cases) occurs, most frequently on the head or neck, upper trunk, or lumbar region (Fig. 21.22). The tumor adheres to the skin surface;

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Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

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Fig. 21.22 Epidermal cyst. a: There is a black opening at the center of the eruption. b: Secondary infection resulted in reddening and swelling at the periphery.

MEMO In Japan, epidermal cysts are also called “atheromas.” Sometimes atheroma refers to a cystic nodule that is similar to an epidermal cyst, such as a trichilemmal cyst, giant comedo or even pilomatricoma.

Atheroma in Japan

however, the sides and bottom of the tumor mass do not firmly adhere to the peripheral tissue. It tends to occur on haired sites. Cysts are elastic but firm, with a surface color of normal skin or light blue and a black punctate opening at the center. They are asymptomatic. When pressed after excision, the cyst exudes a putrid-smelling, white, gruel-like discharge. Most cases clinically diagnosed as “atheroma” are epidermal cyst. Reddening, swelling and tenderness may be caused by secondary infection and rupture p q h the cyst i wallsj (inflammatory k l epidermal m n o of cyst). Pathogenesis The epidermis or infundibulum-derived epithelial components invaginate into the dermis and proliferate to form a cyst that contains keratinous substances. Invagination of the epidermis or epithelial components into dermis that is caused by injury or by infection of HPV-57 or HPV-60 is thought to be associated with epidermal cysts in some cases, in which cases the cysts occur in p q j and soles i palms k l m n o r the (Table 23.1). Pathology The wall of the cyst has the same structure as normal epidermis: basal layer, suprabasal cell layer and granular cell layer (Fig. 21.23). However, instead of the horny cell layer, there are gruel-like, layered keratinous contents. When the keratinous substance is released into the dermis by rupture of the cystic wall, immunological reaction against foreign substance occurs, and a foreign body granuloma containing multiple polynuclear giant cells may be produced. Treatment The cyst and its walls are excised.

2. Milium

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Fig. 21.23 Histopathology of epidermal cyst.

Clinical images are available in hardcopy only.

Fig. 21.24 Milium.

Clinical features A small, firm, white to yellowish-white papule of 1 mm to 2 mm in diameter occurs immediately below the epidermis (Fig. 21.24). White keratinous contents are discharged by incision. Primary milium occurs most frequently on the eyelids, followed by the cheeks, penis and labia. Plaques may form. The histological findings are nearly the same as those of epidermal cyst. Definition, Pathogenesis The pathogenesis of primary milium is thought to be keratotic cyst formation resulting from abnormality of embryonic epithelial buds. Secondary milium occurs after a blistering disease (e.g., dystrophic epidermolysis bullosa, epidermolysis bullosa acquisita), burn scarring or radiodermatitis. The skin appendages and epidermal cells are damaged by these diseases and proliferate in cyst-like shape under the epidermis.

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Treatment A small incision using a scalpel, or a puncture with a hypodermic needle, is conducted to remove the spherical white substance.

3. Dermoid cyst A dome-shaped subcutaneous cyst with a diameter of 1 cm to 4 cm appears, most frequently on the head. It is present at birth. It is often misdiagnosed as an epidermal cyst. Histopathologically, sebaceous glands and sweat glands are found in the cyst walls that are produced by the epidermis.

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4. Trichilemmal cyst The head is affected in about 90% of cases. A trichilemmal cyst pathologically resembles an epidermal cyst. Histopathologia cally, there are epithelial cells that consist of cyst walls, and the epithelial cells on the luminal side of the cyst wall keratinize without forming a granular cell layer (trichilemmal keratinization, Fig. 21.25).

Fig. 21.25 Histopathology of trichilemmal cyst. a: A cyst in the lower dermal layer. b: Trichilemmal keratinization is observed; tumor cells keratinize without formation of a granular cell layer.

5. Steatocystoma multiplex A firm, dome-shaped tumor with a diameter of 1 mm to 5 mm in most cases and a color ranging from that of normal skin to light yellow or light blue occurs, frequently on the axillary fossae, upper chest or upper arm (Fig. 21.26). It is follicle-associated in some cases. Some cases are autosomal dominant; mutation in the keratin 17 gene is associated with the condition. Histopathologically, there are flattened sebaceous glands near or directly attached to the tumor. The cyst wall is composed of intricately multilayered epithelial components.

Clinical images are available in hardcopy only.

Fig. 21.26 Steatocystoma multiplex. Multiple subcutaneous cysts ranging in diameter from 5 mm to 10 mm occurred on the axillary fossa.

6. Eruptive vellus hair cyst

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This is an asymptomatic follicular papule that occurs most frequently on the chest. The cyst is superficial, crusted and umbilicated. It may be accompanied by steatocystoma multiplex. The cyst wall may contain a sebaceous structure.

7. Pilonidal sinus

Clinical images are available in hardcopy only.

Synonyms: Pilonidal cyst, Pilonidal disease Young men whose buttocks, particularly their sacral division, are hairy are most frequently affected. Ingrowth of hair leads to formation of a fistula. The fistula is surrounded by granulomatous tissue or squamous epithelia. Pilonidal sinus may also occur on the occipital division, eyelids, genitalia, axillary fossae, umbilical fossae or interdigital areas. Most cases with interdigital

Fig. 21.27 The opening of a fistula caused by pilonidal sinus on the sacral region.

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involvement occur occupationally, such as in barbers and shearers. The affected site, including the scar tissue, should be completely excised (Fig. 21.27).

8. Branchial cyst

Clinical images are available in hardcopy only.

A branchial cyst is an epidermal-cyst-like cyst that occurs on the preauricular region and neck. As it is caused by branchial debris, mobility is not fully present at the bottom of the cyst. There is a palpable cordlike substance in the cyst. Excision should not be decided quickly. Branchial cysts caused by thyrolingual debris are called thyroglossal duct cysts.

9. Median raphe cyst of the penis A tumor of several millimeters in diameter occurs in the penile raphe of young men (Fig. 21.28). It occurs solitarily at the urethral openings in most cases. The cyst may reach several centimeters in diameter. Its wall is histopathologically composed of single- or several-layered cylindrical epithelia or cubical epithelia that resemble urethral transitional epithelia.

Clinical images are available in hardcopy only.

Fig. 21.28 Median raphe cyst of the penis.

F. Neural tumors 1. Neurofibroma

Clinical images are available in hardcopy only.

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Fig. 21.29 A soft, elevated skin tumor caused by neurofibroma.

A neurofibroma is thought to be a benign tumor that derives from peripheral nerve Schwann cells or from perineurial or endoneurial cells. The tumor is sharply margined, dome-shaped, soft and of normal skin color or light pink (Figs. 21.29 and 21.30). It lacks a covering membrane and contains myxoid stroma. The tumor slowly enlarges (Figs. 21.29 and 21.30). There are almost no symptoms; however, subcutaneous neurofibroma (nodular plexiform neurofibroma) is often accompanied by tenderness. In neurofibromatosis type 1 (NF1), neurofibromas occur multiply on the whole body. In NF5, localized areas, such as on the trunk, may be affected by mosaicism. Nearly all of the subcutaneous tumors caused by NF1 are nervous neurofibromas, and neurilemmomas are not usually found (also see Chapter 20).

2. Neurilemmoma Synonym: Schwannoma

Fig. 21.30 Histopathology of neurofibroma.

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Clinical features A neurilemmoma is a Schwann-cell-derived benign tumor that

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F. Neural tumors

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usually occurs solitarily. However, multiple neurilemmoma is caused by neurofibromatosis type 2 (NF2). An axonal myelin sheath forms. The tumor is palpable, elastic, firm, spherical, and intradermal or subcutaneous. When it softens, palpable pulsation is present. It may appear singly or in beaded pattern. It is accompanied by tenderness, and pain may radiate from the pressured site to the periphery. Malignant transformation occurs in rare cases (malignant neurilemmoma) (Fig. 21.31). Pathology Neurilemmomas are characterized by a biphasic pattern of Antoni A areas and Antoni B areas that is visible by microscopy. Antoni A areas form the cellular component of the lesion and are composed of fairly closely packed spindle cells with tapering, elongated, wavy nuclei. Nuclear palisading is a prominent feature. Antoni B areas are characterized by irregularly scattered spindle or stellate cells set in abundant loose myxoid stroma.

Fig. 21.31 Histopathology of neurilemmoma (schwannoma).

Treatment Excision should be conducted carefully, to avoid injuring the displaced nerves.

3. Traumatic neuroma A traumatic neuroma, also called amputation neuroma, is a tumor that occurs in the peripheral nerve stump. Intense spontaneous pain and tenderness are present. Histopathologically, nerve fibers proliferate in all directions and are surrounded by Schwann cells and fibrotic tissue. Excision may be necessary, depending on the severity of pain. Neuroanastomosis is performed when possible.

Fig. 21.32 Histopathology of a granular-cell tumor.

4. Rudimentary polydactyly A small tumor of 1 cm to 2 cm in diameter is present in a finger, often the thumb, at birth. Histopathologically, natural amputation of embryonic polydactylism is thought to cause outgrowth of nerve fiber bundles and nerve end corpuscles such as Meissner corpuscles and Vater-Pacini corpuscles.

5. Granular-cell tumor A small tumor of 3 cm or less in diameter occurs on the skin and in the genitalia, tongue, lung, esophagus, stomach, intestine, bladder or uterus (Fig. 21.32). The tumor is histopathologically composed of large polygonal cells that contain eosinophilic granules. It is covered by epidermis. It is easily misdiagnosed as squamous cell carcinoma. It is thought to originate from Schwann cells. The cytoplasm contains numerous eosinophilic granules. It is resistant to diastase, PAS positive and S-100 positive. There is malignant transformation in some cases.

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G. Hemangiomas and vascular malformations MEMO Vascular anomalies described in this textbook are categorized on conventional, descriptive terms or histopathologic terms. However, it is a confusing classification, because “hemangioma” simplex is not tumorous but a malformation of normal capillaries. In 1982, Mulliken and Glowacki proposed a novel classification system for vascular anomalies based on cellular features and natural history. Now classification proposed by International Society for the Study of Vascular Anomalies (ISSVA) has been updated and used. According to the classification, cutaneous vascular anomalies described in this textbook could be classified as follows. Note that some syndromes demonstrate various types of hemangiomas and vascular malformations, such as Klippel-TrenaunayWeber syndrome and Maffucci syndrome.

Classification of vascular anomalies is still confusing and changing

Classifications of vascular anomalies. Vascular anomalies Hemangiomas

Representative diseases and associated conditions Congenital

Infantile hemangioma (GLUT1 positive) (Chapter 21) Congenital hemangioma (Chapter 21) Rapidly involuting congenital hemangioma (RICH) Noninvoluting congenital hemangioma (NICH) Kaposiform hemangioendothelioma Tufted angioma (infantile) (Chapter 21)

Acquired

Cherry angioma (Chapter 21) Glomeruloid hemangioma (Chapter 21) POEMS syndrome (Chapter 21) Tufted angioma (acquired) (Chapter 21) Spindle-cell hemangioendothelioma (Chapter 21) Maffucci syndrome (Chapter 20) Hemangiopericytoma (Chapter 21) Pyogenic granuloma (Chapter 21) Intravascular papillary endothelial hyperplasia (Chapter 21) Angiolymphoid hyperplasia with eosinophilia (Chapter 21) Cutis marmorata (Chapter 4) Kaposi's sarcoma (Chapter 22) Angiosarcoma (Chapter 22)

Vascular malformations Capillary

Capillary malformation Sturge-Weber syndrome (Chapter 20) Klippel-Trenaunay-Weber syndrome (Chapter 20) Phakomatosis pigmentovascularis (Chapter 20) Telangiectasia Osler's disease (Chapter 20) Ataxia telangiectasia (Chapter 11) Cutis marmorata telangiectasia congenita (Chapter 20) Spider angioma (Chapter 21)

Venous

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Venous malformation (Chapter 21) Blue rubber bleb nevus syndrome (Chapter 20) Maffucci syndrome (Chapter 20) Venous lake (Chapter 21) Glomuvenous malformation

Old terms Strawberry mark (Chapter 21) Strawberry mark (Chapter 21)

Main cause of Kasabach-Merritt syndrome

Hemangioma simplex, salmon patch

Cavernous hemangioma (Chapter 21)

Glomangioma

Lymphatic

Lymphatic malformation (Chapter 21)

Arterial

Cutaneous arteriovenous malformation (Chapter 21), etc. Lymphangioma

Combined

Capillary-lymphatic malformation (Chapter 21) Other combinations Fast-flow type Slow-flow type Klippel-Trenaunay-Weber syndrome (Chapter 20), etc.

Angiokeratoma

1. Hemangioma simplex Synonyms: Capillary malformations, Port wine stain, Nevus flammeus Clinical features A flat, sharply margined red patch results from capillary

G. Hemangiomas and vascular malformations

telangiectasia in the shallow dermal layer. It is present at birth (Figs. 21.33-1 and 21.33-2). The skin lesion remains through life, deepening in color slightly with age. When the face is involved, it may thicken after puberty and multiple nodular elevations may occur (hypertrophic port wine stain). A light pink patch may be caused on the midline region of the face in a specific type of hemangioma simplex called medial nevus. Hemangioma on the forehead and eyelids, called salmon patch, disappears spontaneously by age 2; hemangioma on the neck, called nevus Unna, does not disappear spontaneously.

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Clinical images are available in hardcopy only.

Complications Hemangioma simplex may occur as a symptom of SturgeWeber syndrome or Klippel-Trenaunay-Weber syndrome. Pathogenesis, Pathology Dilation and increase of capillaries are found in the upper dermal layer (Figs. 21.34 and 21.35). Treatment Dye laser therapy is the first-line treatment. Concealing cosmetics are useful.

  ● Telangiectasia in the superficial dermis.   ● Well-demarcated, flat erythema.   ● No spontaneous regression. Redness and elevation worsen gradually.

● Dilation of capillary vessels.     ● Light-red erythema.   ● Lesions on the forehead and eyelids spontaneously regress by the age of 2. Nuchal lesion does not regress.

Hemangioma simplex

● Proliferation of epithelial cells.     ● Fresh-red nodule/tumor.   ● Regresses with scarring.

Strawberry mark

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

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Salmon patch

● Proliferation of small vessels in   the deep dermis.   ● Soft subcutaneous tumor. Various colors with small erythema on the surface.   ● No spontaneous regression.

Cavernous hemangioma

Fig. 21.34 Classification of hemangiomas.

Fig. 21.33-1 Hemangioma simplex.

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2. Strawberry mark Synonyms: Congenital/infantile hemangiomas. Outline ●A

Clinical images are available in hardcopy only.

Fig. 21.33-2 Hemangioma simplex.

Fig. 21.35 Histopathology of hemangioma simplex. The blood vessels in the dermis are dilated and filled with erythrocytes, which gives the skin surface of the lesion a reddish appearance.

bright red, elevated lesion results from proliferation of premature capillaries. It appears 3 to 4 weeks after birth, enlarging until the age of 6 to 7 months. ● The face and arms are often involved. It heals spontaneously with soft scarring in several years. ● Dye laser irradiation is the main treatment. Follow-up without treatment may be chosen. Clinical features Shortly after birth, telangiectatic erythema occurs on the face or arm, expanding gradually to form an elevated red tumor by the age of 3 to 6 months. A strawberry mark, a soft tumor, is seen in 1% of newborns; it resembles a halved strawberry stuck on the skin (Figs. 21.36-1 and 21.36-2). The color disappears by diascopy. A tumor may develop on the lesion. After its peak, the strawberry mark subsides at the stationary phase, in most cases disappearing with light scarring by later childhood. Pathogenesis, Pathology The primary lesion is proliferation of vascular endothelial cells. The tumor is bright red and composed of the proliferation of premature vessels. Strawberry mark is vascular dysplasia caused by an angioblast mass; it does not differentiate into normal capillary tissue (Fig. 21.34). Treatment Doctors used to take a wait-and-see policy of observation with regard to strawberry mark. However, in recent years, laser therapy

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Clinical images are available in hardcopy only.

Fig. 21.36-1 Strawberry mark.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

G. Hemangiomas and vascular malformations

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 21.36-2 Strawberry mark.

has been performed for cosmetic purposes even at infancy, because scarring may remain after spontaneous healing. The earlier the laser therapy begins, the more effective it is. Systemic administration of steroids may be necessary in cases in which the lesion continues to enlarge 6 months after birth or when eyelid involvement may cause visual disturbance.

3. Cherry angioma

Clinical images are available in hardcopy only.

Fig. 21.37 Cherry angioma.

Synonym: Senile angioma Multiple, punctate, glossy, bright red papules occur on the trunk. The onset is after the second decade of life, and the papules become more numerous with age. The pathogenesis is thought to be reactive vascular proliferation. Localized capillary proliferation is histopathologically found in the lower papillary dermis (Fig. 21.37).

Clinical images are available in hardcopy only.

4. Glomeruloid hemangioma This is vascular proliferation. Hemangioma of 1 cm or less in diameter occurs in about half of patients with POEMS syndrome (MEMO) (Fig. 21.38). There is secretion of vascular proliferation factors and elevated levels of estrogen in the blood. Although glomeruloid hemangioma clinically resembles senile angioma, it appears suddenly on the trunk, extremities, and head

MEMO Synonyms: Crow-Fukase syndrome, Takatsuki disease POEMS is an initialism for polyneuropathy, organomegaly of liver, spleen or lymph nodes, endocrinopathy, monoclonal gammopathy and skin changes. Various skin lesions, such as glomeruloid hemangioma, pigmentation, trichosis, scleroderma, diffuse sclerosis, livedo reticularis and Raynaud’s disease, and clubbed fingers are caused by POEMS syndrome.

Fig. 21.38 Glomeruloid hemangioma.

Clinical images are available in hardcopy only.

POEMS syndrome

Fig. 21.39 Venous lake.

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Clinical images are available in hardcopy only.

and neck region of persons in their second third decade of life. Dome-shaped nodules that are too firm to be displaced by digital pressure and whose color is lighter pink than those in senile angioma appear.

5. Venous lake Fig. 21.40 Vascular spider. There are cobweb-like capillaries at the periphery of a papule-like angiokeratoma.

A small, slightly elevated, dark blue nodule occurs mainly on the face, or lips of the elderly (Fig. 21.39). Histopathologically, the underlying disease is telangiectasia.

6. Spider angioma Synonyms: Nevus araneus, Vascular spider Clinical images are available in hardcopy only.

Fig. 21.41 Angiokeratoma of Mibelli.

Capillaries extending radially from a red papule of several millimeters in diameter give the appearance of a spider spreading its legs (Fig. 21.40). The face, neck, shoulders, chest and upper arms are frequently involved. It is most common in pregnancy or hepatopathy, when estrogen levels are elevated, although it may appear even under normal conditions. The eruptions fade by diascopy. Dye laser therapy and electrocauterization are the main treatments. Spider angioma in children disappears spontaneously.

7. Angiokeratoma Synonym: Capillary-lymphatic malformation Clinical images are available in hardcopy only.

21 Fig. 21.42 Angiokeratoma (angiokeratoma circumscriptum naeviforme).

Fig. 21.43 Histopathology of angiokeratoma. Marked dilation of capillaries in the papillary layer directly under the epidermis.

Angiokeratoma is caused by proliferation of capillaries in the dermal papillae. The epidermis that proliferates around the capillaries becomes hyperkeratotic, leading to verrucous surface (Figs. 21.41, 21.42 and 21.43). Histopathologically, there is capillary telangiectasia immediately below the epidermis. Angiokeratoma is classified into five subtypes. Various factors are associated with the occurrence of angiokeratomas, which are classified into five subtypes. ① Solitary angiokeratoma It results from injury. ② Angiokeratoma of Mibelli Chilblains present as a prodrome. The hands and legs are frequently affected. It is autosomal dominant. ③ Angiokeratoma scroti (Fordyce) It is an angioma that occurs in large numbers. ④ Angiokeratoma circumscriptum naeviforme Verrucous vascular papules arrange themselves linearly on the unilateral extremities and trunk at birth. Crusting is present. ⑤ Angiokeratoma corporis diffusum Small, multiple, papular angiomas occur on the trunk of patients with lysosomal storage diseases such as Fabry’s disease and Kanzaki disease (Chapter 17).

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8. Cavernous hemangioma Synonym: Venous malformation Outline ● Malformed

veins proliferate in the deep dermal layer. soft, subcutaneous tumor of normal skin color or light purplish-pink occurs in early childhood. ● Strawberry mark may occur on the surface of the lesion. ● It is surgically removed. ●A

Clinical features Small, mature, malformed vessels (mainly veins) proliferate in the deep dermal layer (Figs. 21.44 and 21.34). Cavernous hemangioma is present at birth as a large, soft, subcutaneous tumor. The color is in the range of normal skin color to light blue or reddish purple. Small erythemata are dispersed on the surface of the tumor. The surface may have strawberry mark. Bleeding may result from platelet consumption (Kasabach-Merritt syndrome). Tenderness is not present. Cavernous hemangioma does not heal spontaneously.

Clinical images are available in hardcopy only.

Fig. 21.44 Cavernous hemangioma. There is infiltrative hemangioma in the left chest. The blood vessels in the heart are affected.

Complications Cavernous hemangioma is usually solitary. When it occurs multiply, blue rubber-bleb-nevus syndrome and neurocutaneous syndromes such as Maffucci’s syndrome are suspected. Treatment It is surgically removed. Intratumor coagulation (sclerotherapy) may be performed. Radiation therapy is ineffective.

9. Kasabach-Merritt syndrome

Clinical images are available in hardcopy only.

Outline ● Platelet

consumption occurs from large angioma, leading to thrombocytopenia and disseminated intravascular coagulation (DIC). ● Subcutaneous induration appears in the first 3 months of life. It enlarges relatively rapidly to form a giant angioma that is dark red to purple. ● Radiation therapy, oral steroids and treatments for DIC are the main treatments. Clinical features Angioma occurs most frequently on the extremities and the head and neck region. Extremely firm, light pink subcutaneous induration first occurs in the first 3 months of life (Fig. 21.45). It is followed by intratumor bleeding and edematous enlargement, resulting in the formation of a giant, dark purple, tense tumor. Purpura is easily caused by thrombocytopenia. Persistent

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Fig. 21.45 Kasabach-Merritt syndrome. Large hemangioma in the left leg.

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coagulopathy and thrombocytopenia result in DIC. Pathogenesis Intratumor bleeding is caused by rapid enlargement of a large angioma in newborns, leading to platelet consumption. Cutaneous angioma resembles strawberry mark. Premature cutaneous angioma is thought to result in congestion, platelet consumption and coagulation-factor consumption. Histopathologically, most cutaneous angiomas causing Kasabach-Merritt syndrome resemble Kaposi’s sarcoma, which is called kaposiform hemangioendothelioma. Treatment DIC is symptomatically treated. The treatment for KasabachMerritt syndrome is the same as for angioma. Radiation therapy is effective, because the angioma in Kasabach-Merritt syndrome is highly sensitive to radiation. Oral steroids are also useful.

10. Cutaneous arteriovenous malformation Congenital vascular deformity and several embryonic arteriovenous fistulae are the underlying condition. The skin lesion may appear hemangioma-simplex-like or indistinct. It begins to enlarge at a certain point, and swelling accompanied by heat sensation on the surface of the lesion occurs. Pulsation and tremor are present. When the extremities are involved, the lesion enlarges and may cause Klippel-Trenaunay-Weber syndrome.

11. Tufted angioma Synonym: Angioblastoma of Nakagawa It begins as erythema that gradually enlarges to form a flatly elevated, infiltrating plaque. Tufted angioma is a vascular tumor in which immature endothelial cells and peritcytes proliferate. The color ranges from light pink to dark purplish-red. The pathogenesis is unknown.

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12. Spindle-cell hemangioendothelioma Clinical images are available in hardcopy only.

A bluish subcutaneous tumor occurs, most frequently in the distal areas of the extremities in young persons. Histopathologically, it is composed of dilated vascular lumens and portions of proliferated spindle cells. Multiple tumors are caused in localized areas; however, it is benign and does not metastasize.

13. Glomus tumor Fig. 21.46-1 Glomus tumor formed under the nail. Deformity of nail and severe tenderness occurred.

Outline ● It

is a benign tumor that is derived from glomus cells in

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the neuromyoarterial glomus of skin on the distal fingers. firm, dark red to bluish-brown tumor forms in the finger or toe, often under the nail plate. Intense tenderness is present. ● Paroxysmal pain intensifies at night or with exposure to extreme cold. ●A

Clinical features Glomus tumors are either solitary or multiple, with most being solitary. A solitary glomus tumor occurs most frequently under the nail plate of individuals older than age 20. A firm, painful nodule of 1 cm or less in diameter and ranging in color from dark red to purplish red occurs (Figs. 21.46-1 and 21.46-2). Glomus tumors are characterized by extreme pain from pressure or exposure to cold water. In multiple glomus tumors, the tumors are autosomal dominantly inherited and can occur in persons of any age. Asymptomatic, disseminated, soft tumors of normal skin color to blue and about 1 cm in diameter appear on the whole body. They may appear in linear pattern in rare cases.

Clinical images are available in hardcopy only.

Pathogenesis A glomus tumor is a hamartoma caused by proliferation of glomus cells. Pathology Glomus cells surround blood vessels. Pericyte-originated smooth muscle cells proliferate, and the luminal structure is surrounded by single-layered endothelium in the tumor (Fig. 21.47). Glomus cells stain in desmin and myosin. A solitary glomus tumor is covered by a richly enervated membrane. In multiple glomus tumors, vascular lumens extend in a spongiform pattern.

Fig. 21.46-2 Multiple glomus tumors.

Differential diagnosis Multiple glomus tumors are differentiated from cavernous hemangioma and blue rubber-bleb-nevus syndrome. Glomus tumors underneath the nail plate should be differentiated from subungual exostosis.

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Treatment The tumor is excised.

14. Hemangiopericytoma A firm, elastic, relatively sharply margined nodule occurs in the lower leg, the thigh in particular. Histopathologically, round or spindled cells that resemble peritcytes proliferate around the capillary lumens, which are covered by a single-layered endothelium.

Fig. 21.47 Histopathology of glomus tumor.

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15. Lymphangioma Synonym: Lymphatic malformation Outline ● It

Clinical images are available in hardcopy only.

Fig. 21.48 Lymphangioma (lymphangioma cysticum).

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

is a benign lesion caused by lymphangial hyperplasia and dilation resulting from dysplasia of lymph vessels. ● Vesicles of 1 mm to 2 mm in diameter aggregate. Bleeding in the vesicles may result in papules whose color ranges from red to black. ● It is surgically removed. ● Postoperative lymphangioma in the axillary fossae or groin after breast cancer or uterus cancer is called lymphangiectasis (acquired lymphangioma). Classification, Clinical features, Pathology Lymphangiomas are classified into the three types. Lymphangioma circumscriptum: Transparent vesicles of several millimeters in diameter aggregate to form irregularly shaped plaques. The vesicles appear reddish from bleeding. The thickened epidermis may appear verrucous. Histopathologically, lymphangiectasia is found in the dermal papillary layer. Lymphangioma cavernosum: This is a large, deep-seated, subcutaneous tumor. The color ranges from light pink to bluish purple. The tumor pulsates. Lymph fluid is discharged from the tumor by puncture. The tongue, face and genitalia are frequently involved. Histopathologically, irregular lymphagiectasia occurs in the subcutaneous and deep dermal layers. Lymphangioma cysticum: The lateral region of the head is most commonly affected (Fig. 21.47). Lymphangiactasia is histologically observed in the deep dermal layer. Laboratory findings The depth and three-dimensional structure of the tumor are clearly shown by MRI and CT diagnostic imaging.

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Treatment Surgical removal and sclerotherapy are the main treatments.

Clinical images are available in hardcopy only.

16. Pyogenic granuloma Synonym: Telangiectatic granuloma

Fig. 21.49 Soft, pedunculated tumors ranging in color from bright red to dark red caused by pyogenic granuloma.

Clinical features An angioma whose main symptoms are proliferation of capillaries and dilation of vascular lumens is induced by injury. The tumor is soft and pedunculated, ranging in color from bright red to dark red. It is elevated in a dome shape, with a diameter of 5 mm to 20 mm (Fig. 21.49). Bleeding is easily caused by injury, leading to ulceration. The face of children and the trunk and extremities of adults are most commonly involved. The skin

H. Fibrous tumors

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lesion appears suddenly, forms erosion and bleeds. Pyogenic granuloma should be differentiated from amelanotic melanoma. Pathology Pathologically, there is an angioma accompanied by secondary inflammatory granuloma, or there is granuloma that is nonangiomatous in structure. Treatment Excision, cryotherapy and laser therapy are conducted; there may be recurrence in cases of incomplete treatment.

17. Intravascular papillary endothelial hyperplasia The blood vessels proliferate as a result of thrombotic recanalization in the dilated venulae. It is a reactive change of thrombotic vessels often seen in adults. A purplish-red nodule occurs, most frequently in the veins of the palmar surfaces of fingers. Thrombus formation may cause pain.

H. Fibrous tumors 1. Soft fibroma Synonyms: Fibroma pendulans, Acrochordon, Skin tag Clinical images are available in hardcopy only.

Clinical features A soft, dome-shaped or pedunculated tumor with wrinkles on the surface and a color of normal skin or light brown occurs on the neck, axillary fossae or groin (Fig. 21.50). Small, multiple, threadlike tumors 2 mm to 3 mm long on the neck and axillary fossae are called acrochordon. A solitary, relatively large tumor of about 1 cm on the trunk is called soft fibroma. An enlarged soft fibroma hanging from the skin is called a soft fibroma pendulum. Soft fibroma tends to occur in obese persons and women; it is thought to relate to skin aging.

21 Clinical images are available in hardcopy only.

Pathology The primary condition of soft fibroma is proliferation of collagen bundles with few fibroblasts. In soft fibroma, fat cells are contained in tumors in many cases. Treatment The peduncle of the soft fibroma may be excised and the site treated by cryotherapy.

Clinical images are available in hardcopy only.

Fig. 21.50 Soft fibroma.

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2. Dermatofibroma Synonym: Fibrous histiocytoma Outline Clinical images are available in hardcopy only.

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Clinical features, Pathogenesis A dermatofibroma is an intradermal nodule often described as “a button buried in the shallow area of skin.” The skin surface of the nodule is pigmented (Fig. 21.51). Dermatofibroma is solitary in most cases, but it may occur multiply. Tenderness may be present. Connective tissue factors are thought to proliferate reactively against a minor injury and cause dermatofibroma; some dermatologists do not consider it a tumor in the strict sense. Dermatofibroma develops slowly and usually stops changing when it reaches a certain size. In rare cases, a giant dermatofibroma (benign) with a diameter of 5 cm or larger occurs on othe lower p legs.q j i k l m n r

Clinical images are available in hardcopy only.

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It is a firm benign tumor in which fibroblasts or macrophages proliferate in the dermis. It may be caused by external injury, such as an insect sting. ● Elevated brown nodules of several millimeters to 2 cm in diameter are produced, most commonly on the extremities of adults. ●

Fig. 21.51 Dermatofibroma. a: A small nodule caused by dermatofibroma on the lower leg. b: Giant dermatofibroma of 6 cm in diameter on the lower leg.

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Pathology Dermal and subcutaneous proliferation of collagen fibers, fibroblasts and histiocytes occurs (Fig. 21.52). When the main finding is histiocytic proliferation, it is called cellular dermatofibroma, and the tumor is slightly reddish and soft. Dermatofibromas in which fibroblasts and collagen fibers proliferate are called fibrous dermatofibromas. Fibroblasts scatter among collagen fibers. Differential diagnosis When the lesion is firm and blackish or relatively quick-growing, differentiation from malignant melanoma is necessary. Dermatofibrosarcoma protuberans, xanthoma, lentigo and blue nevus are also differentiated from dermatofibroma.

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Treatment Excision is conducted. As dermatofibroma is asymptomatic and there is no malignant transformation, it can be left untreated if it has been differentiated from malignant melanoma.

3. Hypertrophic scar, Keloid Outline Fig. 21.52 Histopathology of dermatofibroma.

A flat, sharply margined, red or brown elevation is caused by proliferation of connective tissue. ● It usually occurs secondarily after external injury or ●

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operation, but it may occur spontaneously in some cases. is itching and tenderness. ● Local injection and ODT of steroids are the main treatments. It is intractable. ● There

Classification An elevated, reddish-brown lesion occurs on preexisting scarring from excessive production of collagen fibers in fibroblasts. A lesion that atrophies spontaneously within a few years after onset is called a hypertrophic scar. However, a lesion with a persistent elevation in which the hyperplastic scar does not disappear is called a scar keloid; it is known to be a pathologic response of skin. Cases in which proliferation expands beyond the edge of the scar are called true keloids; these are highly intractable. Clinical features Hypertrophic scars and keloids are flat or dome-shaped, a sharply demarcated, and elevated. They range in color from bright red to brown (Fig. 21.53). True keloids are characterized by gradual enlargement as they progress. When pinched firmly from the side, they are painful (lateral tenderness). Scar keloids and hypertrophic scars do not enlarge beyond the scar width. Lateral tenderness is not present in scar keloids and hypertrophic scars. Treatment a pres-b Hypertrophic scars and keloids are intractable, although sure dressing, topical ODT of steroids, local injection of steroids, and oral Tranilast are useful at the early stages. For severe cases and when dysfunction is present, these treatments and radiation therapy are performed after surgical removal. Particularly for true keloids, simple excision may double the probability of tumor recurrence versus leaving it untreated.

4. Palmoplantar fibromatosis

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Synonym: Dupuytren’s contracture A superficial fibroma of firm cordlike substance occurs in the aponeuroses of palms and soles. The fingers flex and contract (Dupuytren’s contracture) (Fig. 21.54). Palmoplantar fibromatosis may accompany diabetes mellitus (Chapter 17).

5. Dorsal fibromatosis

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Fig. 21.53 Hypertrophic scar and keloid. a, b, c: Hypertrophic scar and keloid on the trunk. d: Hypertrophic scar and keloid at the former site of a granuloma in the pieced earlobe.

Clinical images are available in hardcopy only.

Synonym: Knuckle pad Multiple keratotic elevations of 1 cm to 2 cm in diameter and ranging in color from normal skin color to brown occur on the joint regions of dorsal fingers and toes.

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Fig. 21.54 Dupuytren’s contracture.

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6. Pearly penile papule Clinical images are available in hardcopy only.

Multiple, systematized, dome-shaped, whitish papules 1 mm to 3 mm in diameter occur on the coronary sulcus of the penis. Pearly penile papules are angiofibromas; they are considered a normal variant, and require no therapy.

7. Acquired digital fibrokeratoma

Clinical images are available in hardcopy only.

A small, dome-shaped or cylindrical, protruding, elastic, firm nodule with a keratinous surface and normal skin color occurs (Fig. 21.55), frequently on the fingers and toes but sometimes on the palms and soles.

8. Fibrous papule of the nose Fig. 21.55 Acquired digital fibrokeratoma.

Clinical images are available in hardcopy only.

A solitary, firm, dome-shaped papule ranging in color from normal skin color to brown or red and with a diameter of 10 mm or less occurs on the face and neck (Fig. 21.56). Angiofibroma is histopathologically observed.

9. Elastofibroma A dome-shaped or flat, discoidal tumor occurs, usually to the side of the subscapular region. There is proliferation of elastic fibers (Fig. 21.57).

Fig. 21.56 Fibrous papule of the nose.

10. Sclerotic fibroma A dome-shaped tumor of 2 cm in diameter occurs. Histopathologically, firm collagen fibers are packed densely in the tumor. Because cellular components are largely absent, sclerotic fibroma appears as be a well-defined tumor in the dermis. Clinical images are available in hardcopy only.

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Fig. 21.57 Elastofibroma.

11. Nodular fasciitis Fibroblasts around the fasciae rapidly proliferate, forming a subcutaneous nodule of 2 cm to 3 cm in diameter (Fig. 21.58). External injury may induce nodular fasciitis. The forearms of persons in their 30s are most frequently affected. The condition is often accompanied by tenderness and spontaneous pain. Pathologically, premature fibroblast-like cells proliferate in irregular patterns, such as bundles or spirals. Nuclear division is seen. Differentiation from sarcoma (fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, myxoid liposarcoma, dermatofibrosarcoma protuberans) is necessary. Nodular fasciitis tends to heal spontaneously.

12. Giant cell tumor of the tendon sheath A painless, intradermal or subcutaneous, firm, multilobular

I. Histiocytic tumors

nodule of several millimeters to 4 cm in diameter occurs, most commonly on the proximal joints of fingers. It is thought to be a tendon-derived or synovial membrane-derived tumor that is characterized by proliferation of histiocyte-like cells. It should be completely removed surgically.

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Clinical images are available in hardcopy only.

13. Desmoid tumor It is a firm, deep-seated tumor of several centimeters to 10 cm in diameter and normal skin color. The muscles of the shoulders, chest wall, thighs and aponeurosis are most frequently involved. It is a benign tumor that histologically consists of differentiated fibroblasts and collagen fibers. It slowly enlarges and infiltrates, and it has a high probability of recurring after it resolves.

Fig. 21.58 Nodular fasciitis.

14. Cutaneous myxoma This is an asymptomatic, soft, nodular benign tumor of up to several centimeters in diameter. Histopathologically, star-shaped or spindled tumor cells appear to float in mucous-membrane-like tissue. Cutaneous myxoma is not a focal mucinosis, but an independent disease.

15. Digital mucous cyst, Ganglion A false cystic lesion containing mucin occurs on the dorsal surface of a finger or toe (Fig. 21.59). It presents a blistered or verrucous appearance. Digital mucous cysts are divided into myxomatous and ganglionic. A myxomatous digital mucous cyst is caused by overproduction of hyaluronic acid by fibroblasts and is essentially focal mucinosis. A ganglionic digital mucous cyst is a joint capsule or tendovaginal hernia. Incomplete removal of the lesion leads to recurrence. Needle aspiration of accumulated mucin is useful.

Fig. 21.59 Histopathology of digital mucous cyst/ganglion.

16. Mucous cyst of the oral mucosa A soft, dome-shaped tumor of 2 mm to 10 mm in diameter occurs, predominantly on the lower lip, or on the buccal mucosa and tongue in rare cases (Fig. 21.60). When incised, the tumor discharges transparent yellowish mucin. The pathogenesis is thought to be rupturing of the salivary excretory duct by a bite, leading to salivary flow and granuloma.

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Clinical images are available in hardcopy only.

17. Pseudocyst of the auricle An intense, pulsating cyst occurs unilaterally in the cartilage of the upper part of the auricle. Inflammatory symptoms including reddening and sharp pain are rarely present. The treatment is local injection of steroids, although the condition is intractable. Fig. 21.60 Mucous cyst of the oral mucosa.

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I. Histiocytic tumors 1. Juvenile xanthogranuloma A flat-topped, yellowish papule or nodule of several millimeters to 1 cm in diameter occurs, most frequently on the face, extremities and trunk (Fig. 21.61). The onset is the time of birth or several months thereafter. It disappears spontaneously by the age of 5 to 6. Serum lipid is not elevated. The condition should be differentiated from neurofibromatosis and Langerhans cell histiocytosis, which may cause similar eruptions. Histopathologically, juvenile xanthogranuloma is a reactive granuloma composed of histiocytes, xanthoma cells and Touton giant cells (Fig. 21.62).

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

2. Verruciform xanthoma A granular-surfaced, pedunculated tumor ranging in color from normal skin color to red and resembling a mulberry occurs, frequently in the genitalia. Histopathologically, there is infiltration of multiple fat-rich foam cells to the dermal papillary and subpapillary layers.

3. Multicentric reticulohistiocytosis

Clinical images are available in hardcopy only.

Firm brown or yellowish papules or nodules occur on the dorsal surfaces of hands and fingers, around the nail plates, and in the elbow regions (Fig. 21.63). They may coalesce and form plaques. Multiple, proliferative, destructive arthritis also occurs. The pathogenesis is thought to be reactive proliferation of phagocytic and activated monocytes or macrophage-derived histiocytes. Infiltration of histiocyte-like cells containing frosted frosted-glass-like eosinophilic cellular cytoplasm is histopathologically observed.

Fig. 21.61 Juvenile xanthogranuloma.

Clinical images are available in hardcopy only.

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Fig. 21.62 Histopathology of juvenile xanthogranuloma. a: Touton giant cells that have phagocytosed fat.

Clinical images are available in hardcopy only.

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Dispersed reddish-brown patches, papules and nodules of 3 mm to 10 mm in diameter occur, most commonly on the face, earlobe, and neck of infants. Intradermal infiltration of mononuclear histiocyte-like cells are found histopathologically. Infiltrating cells are CD68 positive and S-100 protein negative. The skin lesion usually disappears spontaneously; benign cephalic histiocytosis is thought to be a juvenile xanthogranuloma.

Fig. 21.63 Multicentric reticulohistiocytosis. Multiple, firm, yellowish nodules and papules occurred on the dorsum of hand and fingers.

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J. Adipocellular tumor Lipoma Lipoma may appear on any site of the body surface, singly or multiply (Fig. 21.64). It ranges in diameter from 1 cm to 10 cm and usually occurs subcutaneously. The skin lesion is soft, palpable and usually highly mobile. Lipoma is asymptomatic in general; however, pressure on nerves may produce pain. Although the tumor cells resemble normal fat cells, they are characterized by a thin covering of connective tissue. Depending on the mesenchymal tissue elements in the skin lesion, lipoma may be called fibrolipoma, angiolipoma or myolipoma. Lipoblastic cells may also be seen. All these tumors are benign. Malignant transformation is rarely seen. Lipomas extend gradually, and excision may be conducted if necessary.

Clinical images are available in hardcopy only.

Fig. 21.64 Lipoma.

K. Myogenic tumor Leiomyoma Leiomyoma derived from the arrector pili muscle is cutaneous leiomyoma, that from the vascular smooth muscle is angioleiomyoma, and that from the dartos fascia is genital leiomyoma. A solitary or sometimes multiple tumor of 1 cm in diameter occurs, often accompanied by paroxysmal pain (Fig. 21.65). Angioleiomyoma is the most painful of the three types. Scrotal leiomyoma is painless.

Clinical images are available in hardcopy only.

Fig. 21.65 Leiomyoma.

L. Osteogenic tumors

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1. Osteoma cutis Osteoma cutis is ectopic bone formation on the head and on the skin of the extremities. It is divided into primary osteoma cutis, which occurs in newborn and infants; and secondary osteoma cutis. In primary osteoma cutis, multiple papules as firm and large as fine gravel occur, most frequently on the face.

Clinical images are available in hardcopy only.

2. Subungual exostosis A tumor at the distal end of a finger or toe pushes the skin up and appears under the nail plate. It occurs in persons between the

Fig. 21.66-1 Subungual exostosis.

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Clinical images are available in hardcopy only.

ages of 10 and 30 (Figs. 21.66-1 and 21.66-2). The big toes are most frequently involved. Intense pain is present. Subungual exostosis is differentiated from glomus tumor. X-ray is useful. Excision is the main treatment.

Fig. 21.66-2 X-ray of subungual exostosis.

M. Hematopoietic tumors 1. Lymphocytoma cutis Synonyms: Lymphadenosis benigna cutis, Pseudolymphoma Clinical images are available in hardcopy only.

A lymphoid follicle structure forms as the result of an insect sting, external injury, sunlight or Lyme disease, leading to a dark red, dome-shaped tumor 1 cm to 2 cm in diameter, usually on the face (Fig. 21.67). The lesion is elastic and smooth-surfaced. Ulceration does not occur. The lesion appears solitarily in most cases and disappears spontaneously several months after onset. Differentiation from cutaneous B-cell lymphoma is important; follicle formation is the main characteristic of lymphocytoma cutis, and atypism is not found in lymphocytes. Lymphocytoma cutis has a good prognosis, although it progresses to lymphoma in rare cases.

Clinical images are available in hardcopy only.

2. Lymphocytic infiltration of the skin (Jessner)

21 Fig. 21.67 Lymphocytoma cutis.

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An asymptomatic, infiltrative plaque ranging in color from light pink to reddish brown occurs, most frequently on the face. Although it disappears spontaneously, it may recur. Dense lymphocytic infiltration is found in the dermis, especially in the peripheral appendages. Lymphocytic infiltration of the skin is differentiated from discoid lupus erythematosus and lymphoma.

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M. Hematopoietic tumors

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3. Kimura’s disease Kimura’s disease, whose cause is unknown, occurs commonly on the face of pubertal men. Cutaneous lymphoreticular tissue proliferates reactively to cause the disease. Solitary or multiple, flat or dome-shaped, soft, elastic, partially nodular, and subcutaneous or intradermal tumors of 5 cm to 10 cm in diameter appear. The surface of the lesion is brownish, and itching may be present (Fig. 21.68). Subcutaneous lymphatic follicle formation and eosinophilic infiltration are observed histopathologically. Kimura’s disease is characterized by the marked increase of eosinophils in the peripheral blood and bone marrow, and elevated IgE level. It may be accompanied by atopic dermatitis and pruritus. Local steroid injection is effective. Differentiation between Kimura’s disease and angiolymphoid hyperplasia with eosinophilia (ALHE, see the next section) has been controversial.

Clinical images are available in hardcopy only.

4. Angiolymphoid hyperplasia with eosinophilia (ALHE) A firm, bright or dark red nodule of several centimeters in diameter occurs, frequently on the peripheral auriculae, forehead or temporal area (Fig. 21.69). The skin lesion is vascular proliferation of epithelial cells that contain abundant cytoplasm. Dense infiltration of eosinophils and lymphocytes is often found in the peripheral blood vessels. Although angiolymphoid hyperplasia with eosinophilia (ALHE) has some similarities with Kimura’s disease, these two diseases are in different categories. The main treatment for ALHE is local injection of steroids; nevertheless, the disease is intractable. Dye laser therapy is effective in some cases.

Fig. 21.68 Kimura’s disease. An intradermal and subcutaneous nodule and tumor in the auricular region.

5. Mastocytosis Clinical images are available in hardcopy only.

Synonyms: Urticaria pigmentosa, Mastocytoma

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Outline ● Mast

cells proliferate and become tumorous. is caused by rubbing (Darier’s sign). ● It occurs most frequently in infants, healing spontaneously by adulthood. When the onset is in adulthood, the disease is intractable. ● Urticarial attacks may recur in some cases. ● Urticaria

Clinical features The onset of mastocytosis is in the first year after birth, in most cases. The adult type, which is rare, has an onset of puberty or thereafter. In infant mastocytosis, multiple round or spindled brown patches or small nodules of 1 cm or less in diameter occur after recurrent urticaria on the face and trunk. A solitary nodule of several centimeters may occur in rare cases (Table 21.1).

Fig. 21.69 Angiolymphoid hyperplasia with eosinophilia (ALHE). Multiple, firm, itching, dark red nodules up to 1 cm in diameter appear.

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Table 21.1 Classification of mastocytosis (eruption types). Urticaria pigmentosa (Solitary) mastocytoma Diffuse cutaneous mastocytosis Telangiectasia macularis eruptiva perstans

When mechanical stimulation is given to sites with eruptions, histamine is released from the mast cells, leading to the formation of urticaria (Darier’s sign, Figs. 21.70 and 21.71). Urticaria may be caused on the whole body skin by bathing or rubbing with a towel, leading to systemic symptoms such as flushing, nausea, vomiting, diarrhea, stomachache, fever, cardiac palpitation, breathing difficulty and shock (urticarial attacks). In adult mastocytosis, these symptoms first appear at puberty or thereafter, and the eruptions and systemic symptoms tend to be moderate. Darier’s sign is not significantly noticeable. In some cases, extremely itchy diffuse eruptions may occur. There is malignant formation in rare cases. Systemic mastocytosis is accompanied by lymph node enlargement, splenohepatomegaly, osteoporosis and osteosclerosis. Thrombocytopenic bleeding tendency is present. It may become leukemia (mast-cell leukemia). Classification, Pathogenesis Mast cells that become tumorous and proliferate in the skin or in the whole body are stimulated, leading to the release of histamine and heparin, which results in urticaria. Mastocytosis in which localized cutaneous lesions occur is called mastocytoma. When tumorous lesions spread to the bone marrow, gastrointestinal tract or spleen, it is called systemic mastocytosis. The pathogenesis is unknown.

Clinical images are available in hardcopy only.

Pathology There is proliferation of polygonal mast cells of various sizes. In the upper dermal layer, there is abnormal proliferation of polygonal mast cells of various sizes that stain metachromatically in toluidine blue (Fig. 21.72). It is classified by the proliferative pattern into Unna mastocytosis and Róna mastocytosis. In the former, multiple proliferative foci form map-like shapes resembling islands. In the latter, a few dispersed perivascular foci form.

Fig. 21.70 Mastocytosis.

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Fig. 21.71 Mastocytosis. a: Solitary mastocytosis in an infant. b: Darier’s sign: urticaria is artificially caused by mechanical stimulation. c: Mastocytosis with blistering.

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In pigmented areas of the skin lesion, the concentration of melanin increases in the epidermal suprabasal cell layer and basal layer in pigmented areas of the skin lesion. Treatment, Prognosis Any stimulation that may induce release of histamine, such as bathing or rubbing the skin, should be avoided. Treatment for urticarial attacks is that same as for general urticaria (administration of histamine). Infant mastocytosis heals spontaneously in several years to over a dozen years. It does not need treatment, as long as there are few eruptions and no severe attacks. Adult mastocytosis does not heal spontaneously and is intractable.

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Fig. 21.72 Histopathology of mastocytosis (Unna mastocytosis). a: Mast cells of mastocytosis in HE-staining. b: The mast cells stain metachromatically purple – not blue – with toluidine blue (metachromasia).

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Malignant Skin Tumors and Melanomas

Tumors, whether malignant or benign, should be examined to determine the skin component from which they originate. The clinical features, course of progression, and prognosis differ according to the cells from which the tumor derives. Malignant skin tumors may derive from ① epidermal or follicular keratinocytes, ② intradermal mesenchymal cells, ③ skin appendages such as sweat glands, or ④ neural crest cells. Benign tumors described in Chapter 21 may become malignant and have malignant diagnostic names. This chapter introduces malignant tumors that have relatively high incidences.

Malignant skin tumors

A. Epidermal and follicular tumors 1. Basal cell carcinoma (BCC) Synonym: Basal cell epithelioma Outline ● It

is a malignant skin tumor whose incidence is high. is induced by UV and occurs most commonly in the elderly, on the midline of the face. ● Small grayish-black nodules arrange themselves at the edge of the tumor. The center of the tumor may be ulcerative. ● Localized intense infiltration may be present. Metastasis rarely occurs. The prognosis is good. ● Excision is the basic treatment. ● It

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Clinical features Basal cell carcinoma (BCC) occurs most frequently in men and women aged 40 to 60. In all subtypes, there are small, firm, waxy, glossy, blackish-brown nodules at the periphery of the skin lesion (Fig. 22.1). Telangiectasia often occurs in the lesion and at the periphery. The face, especially its midline, is affected in 80% of cases; the most notable exceptions to this are the superficial type and fibroepithelial basal cell carcinoma of Pinkus, which often appear on the trunk. The lesion appears blackish-brown in most cases in Asians; however, it is usually normal skin color in Caucasians. BCC may manifest various subtypes and clinical features. Ulceronodular type: More than 80% of BCCs are of this type. Small, firm, black nodules coalesce, accompanied by epidermal telangiectasia. The center of the lesion often ulcerates (rodent ulcer). Superficial type: A flatly elevated, infiltrative plaque ranging in 390

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Fig. 22.1 Various clinical types of basal cell carcinoma (BCC). a-j: Nodular BCC. k, l: Superficial BCC. m: BCC. Because the BCC was left untreated, it damaged the bone and infiltrated into the brain. n: BCC infiltrated into the eyeball. o: Morphea-form BCC.

color from red to blackish brown gradually expands. Sclerosing type (morphea-form): It is an oval, infiltrative plaque with a slightly concave center. Pinkus type (fibroepithelial basal cell carcinoma of Pinkus): Small, multiple, pedunculated tumors occur, often in the midline of the lumbar and back sacral region. This type is histopathologically diagnosed; it is characterized by deeply expanded strands of tumor cells within fibrous stromata. Pathogenesis BCC results from proliferation of embryonic epithelium (primary epithelial germ cells) that differentiates into various organs. There are hamartomatous factors; however, embryonic epithelium continues to proliferate, destroying normal tissue.

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Fig. 22.2-1 Basal cell carcinoma (BCC) from underlying disease. a: BCC in a patient with xeroderma pigmentosum (group D).

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Sunlight, traumatic injury, radiation and scarring are associated with the occurrence of BCC. It may occur secondarily with an underlying disease, such as xeroderma pigmentosum, basal cell nevus syndrome, chronic radiodermatitis, chronic arsenic poisoning, or nevus sebaceus. In such cases, the young may also be affected, and the skin lesions are multiple (Figs. 22.2-1 and 22.2-2). Clinical images are available in hardcopy only.

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Fig. 22.2-2 Basal cell carcinoma (BCC) from underlying disease. b: On a sebaceous nevus.

Pathology BCC is the proliferation of tumor cells that resemble epidermal basal cells (Fig. 22.3). The cells have a large oval nucleus, a small amount of cytoplasm, and low atypicality. The tumor cells arrange in a palisading pattern (palisading arrangement) at the p around q ther j Connective periphery. proliferate i k l tissuem and mucin n o tumor. BCC is characterized by the presence of spaces between tumor and stroma that result from sectioning (separation artifact). Epidermis-derived and follicle-derived melanocytes are found mingled. The abundance of melanophages in the stroma results in the clinical blackish color. BCCs are histopathologically divided into nodular, adenoid, keratotic, cystic and other types (Fig. 22.4). Differential diagnosis BCC should be differentiated from lentigo, blue nevus, Spitz nevus, seborrheic keratosis, chronic ulcer and chronic granuloma. Dermoscopy is useful in many cases (Chapter 5). The superficial type is further differentiated from psoriasis and Bowen’s disease. The sclerosing type is differentiated from localized scleroderma, discoid lupus erythematosus, granuloma annulare and keloid. Treatment Surgical removal is the basic treatment. As the face is frequently affected, cosmetic surgery may be necessary. Cryotherapy and topical chemotherapy may be chosen.

Fig. 22.3 Histopathology of basal cell carcinoma (BCC).

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Prognosis BCC does not metastasize in general: The prognosis is good. However, it continues proliferating, destroying normal tissue unless excised. Surgical treatment at an early stage is preferable.

adenoid

Fig. 22.4 Clinical and histological features of basal cell carcinoma.

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2. Squamous cell carcinoma (SCC) Synonym: Squamous cell cancer Clinical images are available in hardcopy only.

Outline ● This

cancer is caused by malignant proliferation of epidermal keratinocytes. ● In situ lesions including those of solar keratosis and Bowen’s disease are often caused. Scarring lesions are sometimes accompanied by SCC. ● There is often a preexisting lesion, such as scarring or precancerous lesion. ● A firm nodule occurs, frequently on a sun-exposed area of the body. It often necrotizes and ulcerates, and gives off a foul odor. ● Pathologically, individual cell keratinization and cancer a pearls are seen. The less keratinous are the cells, the more undifferentiated and malignant the cancer is. ● Surgical removal, lymph node dissection, radiation therapy and chemotherapy are the main treatments.

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Clinical features Squamous cell carcinoma (SCC) occurs in the elderly solitarily on sun-exposed areas of the body, such as the face and dorsum of hands. Small papules and nodules appear on preexisting alesions,b gradually extend, and form tumors or intractable ulcers (Figs. 22.5-1 and 22.5-2). They proliferate, taking on a cabbage-like appearance. The skin lesion is often accompanied by keratinous substance and crusts. When the surface of the lesion ulcerates, bacterial secondary infection accompanied by distinct odor occurs. SCC tends to spread to the regional lymph node, which then feels firm when palpated. Pathogenesis a b c SCC frequently occurs on a preexisting chronic epidermal lesion. In addition to the preceding lesions shown in Table 22.1, carcinogenic factors such as exposure to sun (UV), arsenic, tar and irradiation are associated with the onset.

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Table 22.1 Preexisting lesions of squamous cell carcinoma (SCC). Type of disease Scarring

Disease or condition Burn, chronic radiodermatitis, lupus a vulgaris, b chronic c pyoderma, discoid lupus erythematosus

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Precancerous

Bowen’s disease, actinic keratosis, leukoplakia, xeroderma pigmentosum, porokeratosis, lichen sclerosis et atrophicus

Other

Phimosis, congenital poikiloderma, dystrophic epidermolysis bullosa, condyloma acuminatum, lichen planus

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Fig. 22.5-1 Squamous cell carcinoma (SCC). a: Actinic keratosis progressed to SCC. b: SCC on the lower lip. c: SCC on the abdominal region. d: SCC on the buttocks. e: SCC on the dorsum of the hand.

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Malignant Skin Tumors and Melanomas Table 22.2 TNM classification and stage grouping of SCC (UICC, 2002). T classification (primary lesion)

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T0 Tis T1 T2 T3 hT4

Primary lesion is not found. Carcinoma in situ Lesions of 2 cm or less in diameter Lesions of 2 cm to 5 cm in diameter Lesions of 5 cm or more in diameter p Lesions that jinvade tissues deeper than muscle, i k l m skin (e.g., n cartilage, o bone)

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M classification (distant metastasis) M0 Lesions without distant metastasis M1 Lesions with distant metastasis Staging

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Fig. 22.5-2 Squamous cell carcinoma (SCC). a: SCC in the palm where chronic radiodermatitis had occurred. b: SCC in a patient with recessive dystrophic epidermolysis bullosa.

Stage I j i Stage II Stage III Stage IV

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(Sobin LH, et al. TNM classification of malignant tumors. 6th ed. Wiley-Liss; 2002).

Pathology Abnormal keratinocytes that destroy the epidermal basal layer are found within the infiltrative and thickened epidermis (Fig. 22.6). SCC is characterized by individual cell keratinization, disturbance in cellular arrangement, nuclear atypicality, cancer pearls and cellular division. The more undifferentiated and malignant are the cells, the less keratinization may occur.

Fig. 22.6 Histopathology of squamous cell carcinoma (SCC).

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Fig. 22.7 Chemotherapeutic example of squamous cell carcinoma (SCC). The lesion markedly reduced in size after intraarterial injection of cisplatin.

Diagnosis, Differential diagnosis Differential diagnosis is histopathologically made. Lymph node involvement and distant metastasis are examined by image analysis to identify the disease stage (TNM classification, Table 22.2). Keratoacanthoma, actinic keratosis and basal cell carcinoma are differentiated from SCC. Treatment Surgical removal is the first-line treatment. Lesions are excised together with 4 mm to 10 mm of adjoining normal skin. Radical lymph node dissection is conducted in cases with lymph node involvement. However, prophylactic lymph node dissection tends not to be conducted. Combined modality therapies, such as irradiation therapy and chemotherapy (Fig. 22.7), are conducted on progressive cases.

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3. Actinic keratosis Synonyms: Senile keratosis, Solar keratosis Clinical images are available in hardcopy only.

Outline ● UV

exposure induces keratinocytic atypia, particularly in the basal cell layer. The atypical keratinocytes proliferate in the epidermis. It is the early stage of squamous cell carcinoma in situ. ● Asymptomatic, vaguely margined erythema or keratotic lesions accompanied by scaling and crusting occur in the elderly, on sun-exposed sites of the body. ● Horn-like protrusions (cutaneous horns) form in cases with marked keratinization. ● Cryotherapy, excision and topical anti-cancer agents are the main treatments. a

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Table 22. 4 Three histological types of actinic keratosis. Type

Characteristics

Hypertrophic Acanthosis, hyperkeratosis, parakeratosis, atypism of actinic keratosis suprabasal cells, infiltration of inflammatory cells Atrophic actinic keratosis

Atrophy in the basal cell layer of the epidermis

Bowenoid Cellular atypia resembling that of Bowen’s disease actinic keratosis

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Pathology There are three histological types of actinic keratosis (Fig. 22.9, Table 22.4). Malignant changes are localized in the covering epidermis, and follicular and sweat pore regions remain normal. Atypism is found in the lower epidermal basal layer. a b c Diagnosis, Differential diagnosis Skin biopsy is conducted when it is difficult to differentiate actinic keratosis from seborrheic keratosis and senile lentigo.

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Clinical features A light-pink erythematous plaque several millimeters to 1 cm in diameter occurs on a sun-exposed area of the body, such as the face or dorsal hand. The plaque is covered with scales and crusts. The margin of the plaque is often vague. Keratinization is usually intense. Grayish-white keratotic nodules or horn-like protrusions (cutaneous horns) may form (Fig. 22.8). The skin lesion occurs singly or multiply, most frequently in persons over age 60. Nearly all elderly Caucasians are affected. Actinic keratosis occurs in infancy in patients with xeroderma pigmentosum. Pathogenesis a b Epidermal keratinocytes that are damaged by UV proliferate abnormally in the dermis.

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Fig. 22.8 Actinic keratosis. a: Multiple actinic keratosis on the face. b: Erythematous lesion is present. c: Cutaneous horn formed on the preauricular area. d: Actinic keratosis in a patient with xeroderma pigmentosum (group D).

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Treatment The main treatments are surgical removal, cryotherapy and topical application of anticancer agents such as 5-FU and bleomycin. Prognosis Some cases progress to squamous cell carcinoma. Aggravation and enlargement of the peripheral erythema and rapid enlargement of ulcers often indicate progression of actinic keratosis.

4. Bowen’s disease Fig. 22.9 Histopathology of actinic keratosis. Marked atypism is observed, especially in the lower epidermal layer.

Outline ● It

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is a squamous cell carcinoma in situ. Highly atypical cells proliferate in all epidermal layers. ● It presents as a sharply-margined plaque, ranging from reddish brown to blackish brown, with a diameter of 1 cm to 10 cm. ● Multiple lesions may be induced by chronic arsenic poisoning. ● It is pathologically characterized by individual cell keratinization and cell clumping. ● Surgical removal and cryotherapy are the main treatments.

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Clinical features Bowen’s disease occurs solitarily, in the elderly. A round or oval, flatly elevated, relatively sharply edged, infiltrative plaque of several centimeters in diameter, ranging from brown to reddish brown, forms. Underneath the scales and crusts that cover the plaque, red erosion is present (Figs. 22.10-1 and 22.10-2). Small nodules and granuloma may be present.

Fig. 22.10-1 Bowen’s disease

22 MEMO This disease typifies skin diseases caused by chronic arsenic poisoning. The clinical features are diffuse thickening of the horny cell layer and the formation of multiple verrucous keratinized plaques. Multiple Bowen’s disease frequently occurs regardless of whether the area is exposed to the sun. Arsenical keratosis may progress to squamous cell carcinoma, an infiltrative cancer. Basal cell carcinoma may occur as a complication. Chemicals other than arsenic may induce malignant skin tumors, such as keratosis from machine oil or tar, and tar carcinoma from tar.

Arsenical keratosis

Pathology The pathology of Bowen’s disease corresponds to that of squamous cell carcinoma in situ. Hyperkeratosis, parakeratosis, individual cell keratinization and multinuclear dyskeratotic cells are found in the epidermis. These atypical cells proliferate in all the epidermal layers (Fig. 22.11). Pathogenesis The cause of solitary Bowen’s disease is unknown in many cases. UV exposure and human papillomavirus may induce the disease. Multiple Bowen’s disease is highly associated with arsenic intake. Therefore, history-taking on preexisting conditions such as mass arsenic-poisoning or chronic pesticide poisoning and treatments such as arsenic antisyphilitic therapy are important.

Malignant skin tumors / A. Epidermal and follicular tumors

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Fig. 22.10-2 Bowen’s disease.

Diagnosis, Differential diagnosis It is differentiated from chronic eczema, psoriasis, actinic keratosis, extramammary Paget’s disease, and superficial type of basal cell carcinoma. Differential diagnosis is made by skin biopsy. Treatment Surgical removal is the first-line treatment. Application of ointments containing anticancer agents (5-FU and bleomycin) and cryotherapy are also useful. Prognosis Unless treated, the lesion destroys the basement membranes and progresses to squamous cell carcinoma; it may spread to the lymph nodes.

Fig. 22.11 Histopathology of Bowen’s disease. Dyskeratotic cells and clumping cells are present in all epidermal layers.

5. Erythroplasia of Queyrat This is Bowen’s disease on the mucous membranes and at the mucocutaneous junction. Red, characteristically velvety-surfaced plaques appear, mainly on the penis (Fig. 22.12). It may also occur in the female genitalia and oral region. Erythroplasia of Queyrat tends to progress to SCC.

22 6. Leukoplakia Definition A white keratinous plaque occurs in the mucous membranes and at the mucocutaneous junction. Leukoplakia used to be a diagnostic name for precancerous leukodermas; however, the term has come to include leukodermas caused by various diseases. Leukoplakia may be benign or malignant. Clinical features The oral cavity and lips are most frequently involved. The tongue, nipples and genital membranes (glans penis, vagina,

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Fig. 22.12 Erythroplasia of Queyrat.

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perianal region) are affected. Leukoplakia that occurs as a precancerous lesion is slightly infiltrative, smooth-surfaced, keratinous, verrucous, papillary and/or erosive. The epidermis thickens from keratinous proliferation. There is high malignancy when an erythroplasia-like lesion is produced (Fig. 22.13). Men over age 50, especially smokers, are most commonly affected. Pathogenesis When leukoplakia occurs as a precancerous skin lesion, chronic stimulation such as from smoking may induce cellular atypism, leading to leukoplakia of the mucosa. Benign leukoplakia may be caused by lichen planus, discoid lupus erythematosus, syphilis, candidiasis or external injury.

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Fig. 22.13 Leukoplakia.

Pathology In malignant leukoplakia, varying degrees of atypism and dyskeratosis are found in the epidermal cells. Diagnosis Skin biopsy is necessary to determine whether the lesion is malignant or benign. If there is malignancy, treatment should be done accordingly. If benign, investigation should be made for the underlying disease. Treatment When there is the possibility of leukoplakia being precancerous, surgical removal, topical 5-FU application, laser therapy or cryotherapy is conducted. Smoking must be stopped.

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7. Oral florid papillomatosis

Fig. 22.14 Verrucous carcinoma.

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A keratotic or infiltrative plaque varying in shape from papillary to cauliflower-like occurs on the lip or oral mucosa of the elderly. It clinically resembles lip cancer at first sight. The pathogenesis in some cases is thought to be a type of condyloma acuminatum (Chapter 23), with which human papillomavirus is associated. Severe thickening and keratinization of the epidermis are pathologically observed; however, infiltrative proliferation is not present.

8. Verrucous carcinoma This is a squamous cell carcinoma with low-grade malignancy in which elevated keratotic nodules form (Fig. 22.14). Although localized proliferation of the nodules is marked, they rarely metastasize to other organs. Verrucous carcinoma is classified by the affected site into oral mucous verrucous carcinoma, genital verrucous carcinoma and plantar verrucous carcinoma. Surgical removal is the most reliable treatment; the disorder may recur if treated by irradiation or electrosurgery.

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Fig. 22.15-1 Natural history of keratoacanthoma (from onset to spontaneous resolution). a: Onset. It begins as a dome-shaped tumor of 1 cm in diameter. b: The tumor gradually grows. c: It grows further. The center ruptures spontaneously. d: The lesion heals without treatment, with slight scarring.

9. Keratoacanthoma Outline ● It

is a clinically benign tumor that occurs in a hair follicle. Histopathologically, it closely resembles squamous cell carcinoma. ● It appears suddenly and solitarily on the face or dorsal hand, grows rapidly, and forms a dome-shaped, cratered a b c d nodule. ● Most cases heal spontaneously in several months. Total resection including skin biopsy is generally performed. ● It is important to differentiate it from squamous cell carcinoma. Clinical features More than 90% of cases involve the face. Middle-aged and a b c d is soli-e older men are most frequently affected. Keratoacanthoma tary in most cases; however, multiple lesions occur in many cases of young persons, and these lesions usually accompany MuirTorre syndrome. A small papule occurs and rapidly enlarges in several weeks to a diameter of 1 cm to 2 cm, resulting in formation of a domeshaped or hemispheric nodule (Figs. 22.15-1 and 22.15-2). The nodule is elastically soft or firm, centrally umbilicated, cratered and accompanied by a red halo. It ranges in color from normal c enlarges d to ae certainf skin to light pink or dark red.a After bit rapidly size, keratinization occurs at the center of the nodule, to form a large keratin plug. Many cases heal spontaneously in several months, with scarring. Pathogenesis Many years of exposure to sun (UV) or tar, and viral infection or external injury are associated with the occurrence of

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Fig. 22.15-2 Keratoacanthoma. Keratoacanthoma is characterized by domeshaped nodules with a volcano-like center (e-g).

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Malignant Skin Tumors and Melanomas Table 22. 5 Clinical differences between keratoacanthoma and squamous cell carcinoma (SCC). Keratoacanthoma

SCC

Site of onset

Most frequently the face The whole body

Shape of eruption

Volcano-like

Various

Eruption size change

Does not grow larger

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Multiple, or solitary

Solitary in many cases, multiple in some cases

Solitary in most cases

Age of onset

Younger than SCC

Elderly persons

Development of eruption

Proliferates by the week Proliferates by the month

Spontaneous regression?

Yes

Lymph node invasion? No

No Yes

keratoacanthoma. Pathology Hyperkeratosis is found at the center of the tumor, whose periphery is surrounded by proliferating keratinocytes (Fig. 22.16). The keratinocytes are characterized by clear eosinophilic cytoplasm and atypia. Tumor cells tend not to infiltrate the basement membrane, but lymphocytes and neutrophils infiltrate below the tumor. Keratoacanthoma is thought to be well-differentiated squamous cell carcinoma or pseudocarcinoma. Fig. 22.16 Histopathology of keratoacanthoma. There is marked hyperkeratosis at the center of the tumor. Suprabasal cells proliferate to envelope the tumor.

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Differential diagnosis The main distinguishing characteristics of keratoacanthoma are listed in Table 22.5. Skin biopsy is necessary to differentiate keratoacanthoma from squamous cell carcinoma. In squamous cell carcinoma, the border between the edge of the tumor and normal tissue is unclear, and there is asymmetrical morphology and a high tendency of infiltration. Squamous cell carcinoma enlarges far more slowly than keratoacanthoma. Keratoacanthoma is also differentiated from large molluscum contagiosum, in which keratinization does not occur, and from basal cell carcinoma. Treatment For diagnosis, it is necessary to examine the overall structure of the skin lesion. Total resection of the skin lesion is conducted, which is simultaneously a treatment. If pathological diagnosis is made, follow-ups may be given instead of treatment until the condition resolves. Irradiation, topical application or local injection of steroids or bleomycin ointments, and administration of oral etretinate and cryotherapy are useful.

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B. Sebaceous gland tumors Sebaceous carcinoma An orangey nodule occurs, most frequently on the Meibom glands in the palpebra sebaceous glands and less frequently in the skin (Fig. 22.17). Histopathologically, the tumor cell nest contains atypical clear sebaceous cells. In the autosomal dominantly inherited Muir-Torre syndrome, multiple benign or malignant sebaceous tumors occur, often accompanied by visceral malignancies.

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Fig. 22.17 Sebaceous carcinoma in the Meibom gland.

C. Sweat gland tumors 1. Mammary Paget’s disease Outline ● Infiltrative

eczema-like erythema or erosion occurs in the nipples and at their periphery. ● It occurs most commonly in the opening of the lactiferous ducts of middle-aged women. It is a carcinoma in situ that derives from the lactiferous duct epithelia. It corresponds to breast cancer. ● A tumor does not form in most cases. ● It is not itchy, nor does it respond to steroids. Mammary Paget’s disease can be distinguished from eczema by these characteristics. ● The treatments are the same as those for breast cancer. Clinical features A plaque with clearly circumscribed erythema, infiltration and crusts appears on the nipple and areola (Fig. 22.18). The lesion is slightly firm and palpable, and usually unilateral. Middle-aged women are most frequently affected. Bilateral mammary Paget’s disease and mammary Paget’s disease in men are extremely rare. Mammary Paget’s disease accounts for 1% to 4% of all breast cancer cases. The symptoms progress gradually with each year. As they progress, a palpable tumor forms in the breast and metastasizes to a regional lymph node (mainly the axillary lymph node). Pathogenesis Mammary Paget’s disease is thought to originate from cancer in the excretory duct cells of the mammary glands (intraductal carcinoma) or carcinoma from epidermal keratinocytes. Pathology Large, clear Paget’s cells replace wall cells in the ducts and

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Fig. 22.18 Mammary Paget’s disease. Infiltrative erythema is present on the nipple. The treatment for mammary Paget’s disease is generally the same as for breast cancer.

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glands. The Paget’s cells may also proliferate in cavities in the lactiferous ducts and mammary glands. Although the skin lesion does not clinically appear to be severe, Paget’s cells infiltrate lactiferous ducts and mammary glands more extensively than is clinically obvious. With further progression, Paget’s cells infiltrate into the dermis. Immunostaining is positive for CEA. Differential diagnosis Chronic breast eczema, tinea corporis, and basal cell carcinoma should be distinguished from mammary Paget’s disease. Intractable eczematous lesions on the breast that do not respond to topical agents should be suspected of being mammary Paget’s disease. Treatment The treatments are the same as those for breast cancer. Mastectomy and regional lymph node dissection are the basic treatments.

2. Extramammary Paget’s disease Outline ● This

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Fig. 22.19 Extramammary Paget’s disease. a: Sharply demarcated erythematous plaques. b: Mix of hypopigmented macules and erythematous plaques. c: Paget cells present in hypopigmented macules around the anus. d, e: Extramammary Paget’s disease on the labia majora of an elderly woman. f: Extramammary Paget’s disease on the axillary fossa.

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The elderly are affected. Sharply margined eczematous erythema and erosion occur. ● It is thought to be intraepidermal cancer that originates from the apocrine glands. The genitalia, anal region and axillary fossae are most frequently involved. ● It occasionally destroys the basement membranes and progresses to invasive carcinoma. ● Extensive resection and lymph node dissection are necessary, if regional lymph node metastasis may occur.

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Clinical features Extramammary Paget’s disease occurs most commonly in the elderly. A bright red infiltrative plaque resembling mammary Paget’s disease appears (Fig. 22.19), most frequently on the genitalia, less frequently on the perianal region, perineum, axillary fossa or umbilical region. Itching is often present. The lesion gradually spreads, with melanin deposition at the periphery in some cases. Extramammary Paget’s disease occasionally destroys the basement membranes and develops a palpable small tumor in the lesion (Fig. 22.20). Regional lymph node metastasis occurs in advanced cases; the prognosis is poor.

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Fig. 22.20 Invasive extramammary Paget’s disease that had been left untreated for a long period of time. A flat lesion elevated gradually, forming infiltrative nodules. The lesion destroyed the basal membrane and infiltrated in the deep portions of the dermis. Metastasis to the regional lymph node was observed.

Pathogenesis Extramammary Paget’s disease is thought to originate from apocrine sweat gland cells. Pathology Large, bright, scattered or aggregated Paget’s cells are found in the epidermis and sweat ducts (Fig. 22.21). Differential diagnosis Eczema, candidiasis, genital tinea, Bowen’s disease, HaileyHailey disease and pemphigus vegetans are distinguished from extramammary Paget’s disease. Diagnosis can be made by pathological observation of Paget’s cells. Treatment The basic treatment is extensive surgical removal with a 1-to 3-cm margin including the peripheral normal skin.

3. Eccrine porocarcinoma This is a malignant form of eccrine poroma (Chapter 21). A red plaque or nodule, often ulcerative, occurs, most frequently on the lower legs of the elderly (Fig. 22.22). In most cases, eccrine porocarcinoma is clinically observed as a tumor that is mix of eccrine poroma and eccrine porocarcinoma. It often metastasizes.

Fig. 22.21 Histopathology of extramammary Paget’s disease. There are scattered Paget’s cells with large, clear cytoplasm.

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4. Microcystic adnexal carcinoma (MAC) Synonym: Syringoid eccrine carcinoma A firm, discoidal, intradermal nodule 1 cm to 3 cm in diameter occurs, most commonly around the mouth of persons of middle age and older. Some think it to be a sclerosing eccrine porocarcinoma or a cancer derived from a hair follicle or apocrine sweat gland. After extensive resection, the site should be examined pathologically for any remaining lesions because of the high frequency of local recurrence. For this reason, Moh’s microsurgery is also effective. Distant metastasis rarely occurs.

Clinical images are available in hardcopy only.

Fig. 22.22 Eccrine porocarcinoma arising from eccrine poroma. a: Eccrine porocarcinoma (malignant). b: Eccrine poroma (benign).

5. Mucinous carcinoma of the skin A nodule of 2 cm to 3 cm in diameter occurs, frequently on the eccrine secretory part of the face or scalp. The tumor is covered by abundant mucin. The nuclei of tumor cells show slight atypism. Metastatic carcinoma of the skin with mucus production should be distinguished from mucinous carcinoma of the skin.

D. Nervous system tumors Merkel cell carcinoma Outline

Clinical images are available in hardcopy only.

● It

is a skin cancer that originates from Merkel cells of the epidermis. These cells are thought to be tactile receptor cells. ● A highly malignant, domed red tumor forms on the face, head, neck or extremities of the elderly. ● Extensive resection, irradiation and chemotherapy are the main treatments.

Fig. 22.23 Merkel cell carcinoma.

Clinical features A firm, domed nodule varying in color from light pink to purplish red and with a diameter of 1 cm to 3 cm occurs, most frequently on the face of the elderly (Fig. 22.23).

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Pathology Deep-staining small cells arrange densely in a palisading pattern, resembling the tumor cells of small-cell lung cancer (Fig. 22.24). Merkel cell carcinoma is characterized by dense-core granules that resemble Merkel cells (Fig. 22.25). Immunohistochemically, neuron specific enolase (NSE) and cytokeratin 20 are positive in many cases. Fig. 22.24 Histopathology of Merkel cell carcinoma.

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Malignant skin tumors / E. Mesenchymal tumors

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Diagnosis, Differential diagnosis Merkel cell carcinoma is diagnosed by clinical features and histopathological tests. Adnexal malignant tumors, amelanotic malignant melanoma, and lymphoma are differentiated from it. Metastasis of small-cell lung cancer to the skin presents the same symptoms and pathology as Merkel-cell carcinoma. If this carcinoma is suspected, examination for lung cancer should be performed. Treatment, Prognosis Merkel cell carcinoma tends to be highly malignant. At the relatively early stages, there is lymph node involvement or hematogenous metastasis. Because of its recurrent tendency, extensive excision and lymph node dissection are conducted. Radiation therapy and chemotherapy are also useful. Cases with spontaneous healing have been reported.

Fig. 22.25 Electron microscopic image of Merkel cell carcinoma, enlarged image of dense-core granules.

E. Mesenchymal tumors a. Fibrous tissue tumors 1. Dermatofibrosarcoma protuberans (DFSP) Dermatofibrosarcoma protuberans (DFSP) is a malignant tumor that is thought to derive from fibroblasts, myofibroblasts or histiocytes. The trunk of adult men is most commonly involved. It begins as an intradermal or subcutaneous nodule that slowly forms a dome-shaped or fungiform tumor at the local site (Fig. 22.26). The tumor is firm and dark reddish brown, often accompanied by erosion or crusts. A characteristic swirl arrangement of tumor cells and fibers called storiform pattern is histopathologically observed (Fig. 22.27). The tumor cells are usually factor XIIIa negative and CD34 positive. DFSP rarely metastasizes (fewer than 10% of cases); however, extensive resection is necessary because of its high tendency to recur.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

22 2. Malignant fibrous histiocytoma (MFH) This is the most frequently occurring soft-tissue sarcoma. The proximal limb muscles and retroperitoneum of adults are most commonly involved. Skin is rarely affected primarily. A painless, lobulated, multinodular subcutaneous tumor occurs in most cases. Hematoma-like lesions (angiomatoid type) may form. Malignant fibrous histiocytoma (MFH) is histopathologically composed of highly atypical fibroblast-like cells and histiocytelike cells. It displays various pathological features, including peculiarly shaped giant cells and inflammatory cellular infiltration. MFH is classified by pathological findings into several types: storiform-pleomorphic (the highest incidence), myxoid,

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Fig. 22.26 Dermatofibrosarcoma protuberans (DFSP).

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giant-cell, inflammatory and angiomatoid. MFH is highly malignant, and the prognosis tends to be poor.

3. Atypical fibroxanthoma A lesion composed of histiocyte-like cells with low malignant potential forms, most frequently on a sun-exposed area. Some consider it as identical to superficial MFH.

4. Epithelioid sarcoma Fig. 22.27 Histopathology of dermatofibrosarcoma protuberans.

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This is a rare malignant tumor. It occurs most commonly at the ends of the extremities and progresses relatively slowly. It begins as intradermal or subcutaneous nodules that gradually increase in number and size (Fig. 22.28). Epithelial cells with abundant eosinophilic components histopathologically proliferate in sheetlike formation. The center of the nodule is necrotic in many cases. At the early stages, epithelioid sarcoma resembles granuloma annulare and rheumatoid nodule; differential diagnosis can be made by the immunohistochemical finding of keratin-positive cells in epithelioid sarcoma. Extensive resection is the basic treatment. When epithelioid metastasizes, lymph nodes areq p j h i k sarcoma l m n o often involved. The prognosis is poor.

5. Synovial sarcoma Clinical images are available in hardcopy only.

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Fig. 22.28 The course of epithelioid sarcoma. a: It begins as nodules of 1 cm in diameter. b, c: The number of nodules increases gradually. The tumors become infiltrative and enlarged.

A soft, painful tumor occurs, frequently in the large joint of an extremity, particularly in the knee. In rare cases, it occurs subcutaneously or subfascially. Although synovial sarcoma used to be attributed to abnormal production of synovial tissue, that idea has been disproven p q t (X;r j i k in recent l years. m Chromosomal n o translocation 18) (p11.2; q11.2) occurs in the cells of the sarcoma. The tumor grows slowly and metastasizes to the lymph nodes. The prognosis is poor. Extensive resection is essential. j

k l of the m fat n cells o b. Tumors

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Liposarcoma A liposarcoma is a malignant mesenchymal tumor that differentiates into fat cells. It is deep-seated, clearly defined, large and nearly asymptomatic. According to the new WHO classification, the malignant types are the well-differentiated type, myxoid type, round cell type, pleomorphic type, and dedifferentiated type. Well-differentiated liposarcoma has a good prognosis and is also called atypical lipomatous tumor. Extensive resection is the main treatment.

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c. Vascular tumor 1. Angiosarcoma Clinical images are available in hardcopy only.

Synonym: Malignant angioendothelioma Outline ● Vaguely

margined, dark-reddish-violet erythema, bloody blisters and easily bleeding elevated plaques form on the head and face of the elderly. ● It is a malignant tumor caused by proliferation of endothelial cells in the blood vessels and lymph vessels. ● It tends to metastasize to the lungs. The prognosis is extremely poor, with a 5-year survival rate of less than 10%.

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Clinical features Angiosarcoma is induced in some cases by minor external injury. A small black nodule first appears and progressively enlarges to present an edematous dark red plaque (Fig. 22.29).a The plaque easily bleeds and forms erosion and crusts, resulting in exudative ulceration. As it progresses, tumorous nodules appear, metastasizing to the lungs, liver and lymph nodes, leading to hemopneumothorax and death in many cases. Angiosarcoma that occurs at sites with prolonged postoperative lymphedema is called Stewart-Treves syndrome, which usually occurs on the arm with lymphedema after mastectomy.

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Pathology Markedly atypical tumor cells proliferate, forming a luminal structure (Fig. 22.30). Immunostaining is positive for UEA-I lectin and factor VIII related antigen (von Willebrand factor) in many cases. Diagnosis Angiosarcoma can be diagnosed by the characteristic clinical features; however, differential diagnosis is made by skin biopsy. a b As most cases have already progressed at the time of diagnosis, various tests are performed to examine the systemic condition. Because metastasis to other organs, the lungs in particular, influences the prognosis, chest X-ray, CT, MRI and nuclear medicine imaging are conducted. Treatment, Prognosis Local recurrence and hematogenous metastasis often occur in angiosarcoma. In cases at the early stages with good systemic condition and no metastasis, combination therapy of extensive a b resection and irradiation or chemotherapy is conducted. Local orc arterial injection of IL-2 may also be given. The average survival period between the patient’s first consultation and death is about one year. The 5-year survival rate is only 12%.

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Fig. 22.29 Angiosarcoma. a, b: Dark red erythema and an elevated plaque form. c: The lesion partially ulcerates. d: Angiosarcoma on lymphedema.

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2. Kaposi’s sarcoma Outline ● The

lower legs of the elderly and patients with immunodeficiency are most frequently affected. ● It is characterized by endothelial and vascular proliferation. Edema first appears, forming a firm nodule that is accompanied by intense pain and easy bleeding. ● The lymph nodes and internal organs are involved. Patients may die from bleeding of the internal organs. ● HHV-8 is associated with the onset. ● Irradiation therapy and chemotherapy are the main treatments.

Fig. 22.30 Histopathology of angiosarcoma.

Clinical images are available in hardcopy only.

Fig. 22.31 Multiple Kaposi’s sarcoma on a patient with AIDS.

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Fig. 22.32 Histopathology of Kaposi’s sarcoma.

Clinical features Kaposi’s sarcoma occurs on the extremities, particularly on the feet, gradually spreading to the proximal areas. Multiple, purplish-brown patches or angioma-like papules appear in the skin, mucosa and internal organs (Fig. 22.31), rapidly spreading and forming elevated plaques that become firm nodules. The progression begins with a patch stage, followed by a plaque stage and then a nodule stage. The eruptions themselves are largely painless; however, secondary lymphedema causes sharp pain. In progressive cases, infiltration occurs in the lymph nodes, gastrointestinal tract, liver, lungs and bones, causing various symptoms. Classification, Pathogenesis Kaposi’s sarcoma is caused by various factors related to immunodeficiency, race and country of residence. It is divided into four types: classic, African endemic, immunosuppressivetreatment-related, and epidemic HIV-associated. The epidemic HIV-associated type progresses rapidly, whereas the others progress slowly. When human herpes virus type 8 (HHV-8) infection occurs in patients with immunodeficiency – such as those with AIDS or leukemia, or those who have been administered steroids or immunosuppressants – the result in canceration of primitive mesenchymal cells. The mechanism is unknown. Association of HLA-DR5 with Kaposi’s sarcoma has been suggested. Kaposi’s sarcoma occurs in about 5% of patients with AIDS in Japan. Pathology There are three stages. Patch stage: Early lesions show uncharacteristic features. Perivascular and periadnexal proliferation of endothelial cells with little atypia is seen. Plaque stage: There is more extensive angio-proliferation with vascular spaces. Inflammatory lymphocytes and extravascular red cells with siderophages are numerous throughout the dermis.

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Malignant skin tumors / E. Mesenchymal tumors

Nodular stage: Well-defined nodules containing spindle cells with mitosis are seen. Treatment Irradiation therapy and combination chemotherapy are the main treatments. Surgical removal may be conducted on localized lesions. Prognosis Cases in which patients died within 2 to 8 years after onset have been reported. The immediate cause of death is bleeding from the gastrointestinal tract or liver. Kaposi’s sarcoma heals spontaneously in about 2% of cases.

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d. Histiocytic tumors Clinical images are available in hardcopy only.

Langerhans cell histiocytosis (LCH) Synonym: Histiocytosis X Malignant Langerhans cells proliferate in systemic organs such as the skin, liver, spleen, lymph nodes and lungs, and in the bonea marrow. Langerhans-cell histiocytosis (LCH) had been classified by the onset age and clinical features into Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma. In recent years, these types have come to be unified under the name of LCH. The cutaneous symptoms are hemorrhagic papules and eczema-like lesions that frequently appear on the seborrheic areas (Fig. 22.33), and juvenile xanthogranuloma-like eruptions. Histologically, the tumor cells are positive for CD1a and S-100 proteins (Fig. 22.34). Letterer-Siwe disease: It occurs suddenly in infancy, rapidly on the whole body. Hemorrhagic papules appear on the whole body, accompanied by fever, splenohepatomegaly and pulmonary lesion. Seborrheic dermatitis-like lesions occur on the scalp. The prognosis is poor. Hand-Schüller-Christian disease: It occurs most frequently in early childhood. The three main symptoms are pericranial deficiency in osteolytic areas including the skull, ocular proptosis, and diabetes insipidus. Granulomatous and xanthomatous eruptions appear.

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Fig. 22.33 Langerhans cell histiocytosis. a: Multiple, keratotic, erythematous plaques on the trunk. b: Eczema-like plaques on the scalp. Alopecia, pustules and crusts are present.

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Congenital self-healing reticulohistiocytosis MEMO It is also called congenital self-healing Langerhans cell histiocytosis a and Hashimoto-Pitzker disease. Within several weeks after birth, multiple or disseminated, red to brownish papules or nodules 2 mm to 20 mm in diameter occur on the whole body. There is proliferation of Langerhans cells. Langerhans cell histiocytosis may be difficult to differentiate from congenital self-healing reticulohistocytosis; however, in the latter, the eruptions disappear spontaneously in several weeks to 1 year.

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Fig. 22.34 Histopathology of Langerhans cell histiocytosis. a: HE-staining image of Langerhans cells. There is marked infiltrative proliferation of Langerhans cells in the upper dermal layer. b: CD1a chromatic-staining of Langerhans cells. There are CD1apositive infiltrative cells.

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Table 22.6 WHO/EORTC classification of cutaneous lymphomas.

Eosinophilic granuloma: It occurs in late childhood and adulthood. Granulomas form in the bones. The prognosis is good.

Cutaneous T-cell and NK-cell lymphomas

e. Hematopoietic tumors (also refer to e-2 and e-3 on p. 418-9)

Mycosis fungoides (MF) MF variants and subtypes Folliculotropic MF Pagetoid reticulosis Granulomatous slack skin Sézary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous CD30+ lymphoproliferative disorders Primary cutaneous anaplastic large-cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified (PTL) Primary cutaneous aggressive epidermotropic CD8 T-cell lymphoma (provisional) Cutaneous g/d T-cell lymphoma (provisional) Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

e-1. Cutaneous lymphoma Lymphoma is a malignant tumor of the lymphoid linage cells. Primary cutaneous lymphoma, classified as a non-Hodgkin’s disease, is the second most common extranodal lymphoma after those that occur in the gastrointestinal tract or nasopharyngeal region. Ninety percent of cases with cutaneous lymphoma are Tcell derived. Primary cutaneous lymphoma is defined as a lymphoma that presents in the skin with no evidence of extracutaneous disease at the time of diagnosis. There are several systems for classifying cutaneous lymphoma; however, classification has been standardized by the European Organization for Research and Treatment of Cancer (EORTC) and WHO (Table 22.6). Cutaneous lymphoma is first categorized according to the cells from which it derives, clinical features, pathological features and response to treatment. It is then subcategorized according to malignancy and prognosis into indolent, intermediate and aggressive. Histopathological features are important for diagnosis. The origin and monoclonality of the tumor cells and the severity of infiltration can be determined by the surface marker, T-cell receptors (TCR) and immunoglobulin (Ig) using monoclonal antibodies, and gene rearrangement of TCR and Ig.

Cutaneous B-cell lymphomas Primary cutaneous marginal-zone B-cell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other Intravascular large B-cell lymphoma Precursor hematologic neoplasm Precursor hematologic neoplasm CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma) (Willemze R. et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005; 105: 3768-85).

Cutaneous T-cell lymphomas This section broadly defines and classifies cutaneous T-cell lymphomas (Figs. 22.35-1 and 22.35-2). They are classified into the several subtypes listed in Table 22.6.

1. Mycosis fungoides (MF)

22 Outline ● It

Clinical images are available in hardcopy only.

Fig. 22.35-1 Cutaneous T-cell lymphoma. A solitary skin tumor occurred in this case.

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is a T-cell lymphoma that occurs primarily in the skin and presents characteristic cutaneous symptoms. ● It progresses slowly. The three stages are classified morphologically as patch, plaque and tumor. It does not spread to other organs until the final stage. ● Atypical lymphocytic infiltration (Pautrier’s microabscess) in the epidermis is a characteristic histopathological finding. ● PUVA therapy is the first-line treatment. Combination chemotherapy is conducted at the final stage.

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Malignant skin tumors / E. Mesenchymal tumors

Clinical features Mycosis fungoides (MF) follows a course that is divided into three stages, according to the skin clinical features of eruptions (Figs. 22.36-1 and 22.36-2). At the early stage, dermatitis or psoriasis-like eruptions occur and persist for several to ten years (patch or erythematous stage). The skin lesion becomes infiltrative and flatly elevated (plaque stage). Several years later, cutaneous nodules and tumors form, metastasize to lymph nodes, and infiltrate other organs (tumor stage). ① Patch stage (erythematous stage) Multiple erythema of various shapes and sizes, accompanied by moderate scaling, occur on the trunk and extremities. MF at this stage is sometimes clinically indistinguishable from seborrheic dermatitis, psoriasis, and pityriasis rosea (Gibert) and parapsoriasis. It may respond to topical steroids; however, eruptions spread with repeated exacerbation and remission for several to ten years. As the eruptions progress, they are often accompanied by atrophy of skin and pigmentation. The large-plaque type of parapsoriasis en plaque is considered to be the early patch stage of MF (Chapter 15). ② Plaque stage Circular or horseshoe-shaped, flatly elevated, red or reddishbrown eruptions with palpable infiltration appear. They progress to the tumor stage with repeated exacerbation and remission. ③ Tumor stage Dome-shaped, elevated, elastic, dark red tumors occur. The surface is smooth at first; however, they may become partly erosive and ulcerate later on. After the tumor stage, the lesions progress rapidly and infiltrate the lymph nodes and internal organs. They rarely become leukemic. Immunodeficiency and lesions of internal organs lead to death in 1 to 2 years in many cases. Pathology Patch stage: Lymphocytic infiltration occurs in the superficial dermis. As MF progresses, lymphocytic infiltration also occurs ina the epidermis (epidermotropism). Atypical lymphocytes are observed in some cases. Plaque stage: Markedly dense, band-like cellular infiltration occurs in the upper dermal layer. Large atypical cells containing deeply constricted nuclei, called mycosis cells, are found in the infiltrative lymphocytes. Epidermotropism becomes distinct. Multiple honeycomb epidermal lymphocytic infiltration, called Pautrier’s microabscess (Fig. 22.37), is observed. Tumor stage: Epidermotropism is lost. Mycosis cells infiltrate all dermal layers and subcutaneous tissue. Diagnosis, Differential diagnosis a b There are few abnormal findings in blood tests and biochemical tests until MF progresses to the final stages. MF is diagnosed by clinical features and histopathological findings. As characteristic

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Fig. 22.35-2 Cutaneous T-cell lymphoma. Generalized follicular papules occurred in this case (folliculotropic mycosis fungoides).

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Fig. 22.36-1 Mycosis fungoides. a, b, c: Mycosis fungoides at the erythematous stage.

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Fig. 22.36-2 Mycosis fungoides. d, e: Plaque stage. f-j: Tumor stage. Severely infiltrative ulcers form.

Gene rearrangement analysis

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MEMO

Rearrangement of the TCR and immunoglobulin (Ig) genes occurs during lymphocyte differentiation for recognition of non-self, which leads to various antigenic recognitions. In lymphoma, lymphocytes proliferate monoclonally and there is often one rearrangement pattern to the TCR/Ig gene. Thus, southern blotting from skin lesion tissue is useful for differentiating between lymphoma and benign diseases. When the gene encoding TCR/Ig is excised by a restriction enzyme and the tissue is lymphoma (monoclonal), a single band is observed in electrophoresis; in the case of a benign reactive disease (polyclonal), there is no specific band in electrophoresis. These findings are helpful for diagnosing the malignancy of tissues and blood (gene rearrangement analysis, GRA). GRA of the Jg chain and the Cb1 chain of the TCR gene are performed in T-cell lymphoma. A similar analysis is made for diagnosis of Bcell lymphoma, using southern blotting for IgH-JH, a gene that codes for an immunoglobulin fragment.

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findings of MF are difficult to obtain at the early stages, skin biopsies may be conducted repeatedly at certain intervals in suspected cases. Immunohistological tests are conducted on the biopsy specimen: The surface marker of helper T-cells is confirmed in the infiltrating lymphocytes. Monoclonality of T-cell receptor gene rearrangement is identified (MEMO). Dermatitis, psoriasis, parapsoriasis, adult T-cell leukemia, and other types of malignant lymphoma are differentiated from MF. Treatment Phototherapies such as PUVA and narrow-band UVB inhibit the progression of lesions in the patch and plaque stages to some extent. Topical steroids and interferon are also useful. For progressive cases such as MF in the tumor stage, electron beam irradiation and chemotherapy (e.g., CHOP therapy; the treatment is the same as for non-Hodgkin’s disease; Table 22.7) are performed.

2. Sézary syndrome (SS) Outline ●

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It is a T-cell lymphoma that occurs primarily in skin, lymph nodes and peripheral blood.

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Malignant skin tumors / E. Mesenchymal tumors

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Table 22.7 Therapeutic examples of CHOP used in the tumor stage of mycosis fungoides. Drug

Dose

Administration example

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itching is present. The main symptoms are erythroderma, swelling of lymph nodes and the appearance of atypical lymphocytes in the peripheral blood. ● The laboratory findings and treatments are largely the same as those for mycosis fungoides. Clinical features Men over age 50 are most frequently affected by Sézary syndrome (SS). Erythema accompanied by scaling on the whole body surface occurs diffusely, presenting as erythroderma (Fig. 22.38). Intense itching is often present. There is enlargement of lymph nodes and splenohepatomegaly. The systemic symptoms tend to be mild, and fever is not present. As SS progresses, nodular eruptions occur and may infiltrate into the internal organs. Pathology, Laboratory findings Leukocytosis and lymphocyte atypicality are found in the peripheral blood. These atypical lymphocytes, called Sézary cells, have a nucleus with a deep slit as seen in the cells found in tissue with mycosis fungoides, and they contain superficial markers of helper T cells. Band-like or perivascular lymphocytic infiltration including Sézary cells are found in the upper dermal layer of the areas with erythroderma. Pautrier’s microabscess may occur in the epidermis (Fig. 22.36).

Fig. 22.37 Histopathology of mycosis fungoides. Histological image of mycosis fungoides at somewhere between the erythematous and infiltrative stages. Atypical lymphocytes invade the epidermis and form microabscess (Pautrier’s microabscess).

Treatment The treatments are the same as for mycosis fungoides. The prognosis is generally worse than that of mycosis fungoides.

3. Primary cutaneous anaplastic large-cell lymphoma This is a T-cell lymphoma caused by infiltration of CD30-positive lymphocytes. Solitary nodules or papules, tumors that may ulcerate, and infiltrative erythema occur (Fig. 22.39). Pathologically, there is infiltration of atypical cells and histological morphology of undifferentiated large tumor cells resembling that of Hodgkin’s disease. Diagnosis of primary cutaneous anaplastic large-cell lymphoma (ALCL) is confirmed if the tumor cells react to anti-CD30 antibodies (Ki-1 antibodies). When cutaneous lymphomas including mycosis fungoides, Sézary syndrome or

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Fig. 22.38 Sézary syndrome. Flushing accompanied by intense itching occurs on the whole body.

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adult T-cell leukemia/lymphoma are present as a precursor or a current symptom, the condition is not diagnosed as ALCL even if there is infiltration of CD30-positive cells in the skin lesion. The prognosis is generally good. Clinical images are available in hardcopy only.

Fig. 22.39 Primary cutaneous anaplastic large-cell lymphoma.

Clinical images are available in hardcopy only.

Supplement: Lymphomatoid papulosis Lymphomatoid papulosis begins as papules of several millimeters to 1 cm in diameter, usually several to several dozen in number, which are accompanied by scaling and bloody crusts. The center of the papules may be necrotic or crusted. The papules may reach several centimeters in diameter. The eruptions heal spontaneously in 2 to 3 weeks, with moderate scarring and pigmentation (Fig. 22.40). Infiltrative atypical cells are CD30positive. Histopathologically, there is infiltration of polymorphic lymphocytes whose atypical chromatin stains deeply, cellular division, leakage of erythrocytes, and eosinophilic infiltration: These findings seem to suggest malignancy. However, whether lymphomatoid papulosis is a benign disease or a subtype of ALCL is still controversial. Mycosis fungoides or other lymphoma occurs as a complication in fewer than 20% of cases. When it does not heal spontaneously, topical steroids and PUVA therapy are applied.

4. Pagetoid reticulosis (Woringer-Kolopp) Tumor cells are markedly epidermotropic and resemble Paget’s cells. Clinically distinctive parapsoriasis-like or psoriasis-like plaques form. Pagetoid reticulosis is considered to be a specific type of mycosis fungoides.

5. Adult T-cell leukemia/lymphoma (ATLL) Outline Clinical images are available in hardcopy only.

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Fig. 22.40 Lymphomatoid papulosis.

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is a hematopoietic malignancy caused by human T-cell leukemia virus type-1 (HTLV-1). ● Multiple, firm, reddish-brown skin tumors with domeshaped elevation appear. Erythroderma and elevated, scaling plaques form. ● Serum anti-HTLV-1 antibodies are positive. Characteristic “flower cells” are found in the peripheral blood. Clinical features Adult T-cell leukemia/lymphoma (ATLL) is classified by the course into several types, including smoldering, chronic, acute and lymphoma types. Cutaneous lesions may be seen in all variants. Multiple, firm, dome-shaped, reddish-brown tumors ranging in size from several millimeters to 10 cm occur. They may be accompanied by scaling, infiltrative elevated reddish-brown plaques, and erythroderma (Figs. 22.41-1 and 22.41-2). Besides

Malignant skin tumors / E. Mesenchymal tumors

the characteristic eruptions, non-specific eruptions caused by immunodeficiency, various infections such as mycosis and herpes zoster, erythema, urticaria, acquired ichthyosis, palmoplantar keratosis and eczema-like eruptions also appear. There are systemic symptoms such as fever, lymph node enlargement, and splenohepatomegaly. As ATLL progresses, opportunistic infection is caused by fungus or virus resulting from cellular immunodeficiency. The main complications are HTLV-1-associated myelopathy (HAM/TSP), HTLV-1-associated arthropathy (HAAP), and HTLV-1-associated uveitis.

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Epidemiology The incidence varies by region. In Japan, about 1.2 million persons have tested positive for anti-HTLV-1 antibodies, and it is estimated that 500 to 600 of these persons will develop ATLL every year. Worldwide, many patients are from the Caribbean and parts of Africa. The routes of infection may be through sexual activity or blood. Most cases are transmitted materno-fetal by breast milk. In sexual activity, it is transmitted from male to female in semen. The incubation period between transmission and development of ATLL is usually more than 40 years. Most persons who are infected in infancy do not have the symptoms throughout life. Most patients are over age forty. Cases in youths are rare. Pathogenesis HTLV-1, an RNA virus, is known to induce monoclonal proliferation of T cells. HTLV-1 proviral DNA is integrated in the malignant T cells. Laboratory findings, Diagnosis Serum anti-HTLV-1 antibodies are positive. The antibody titer is measured first for diagnosis. For patients whose serum is positive for anti-HTLV-1 antibodies, Southern blot is performed to identify monoclonal integration of HTLV-1 proviral DNA into tumor cells. There is a marked increase of leukocytes and atypical lymphocytes called flower cells in the peripheral blood (Fig. 22.42), increased LDH in the blood from tumor cell destruction, increased serum Ca, and increased soluble IL-2 receptor. ATLL is classified into subtypes according to the severity of these changes (Table 22.8). Treatment, Prognosis Follow-ups are given to patients with chronic and smoldering types of ATLL, to check for any signs of acute transformation. The acute, lymphoma, and acute transformation types are treated with conventional chemotherapy. The prognosis is remarkably poor, most patients dying within 2 years from the initiation of treatment. Pneumocystis carinii pneumonia is treated by preventive administration of trimethoprim-sulfamethoxazole combination.

Clinical images are available in hardcopy only.

Fig. 22.41-1 Adult T-cell leukemia/lymphoma.

22

416

22

Malignant Skin Tumors and Melanomas Table 22.8 Clinical characteristics and types of adult T-cell leukemia/lymphoma. Smoldering Chronic Lymphoma Acute

Clinical images are available in hardcopy only.

Anti-HTLV-1 antibody

＋

＋

＋

＋

Number of lymphocytes (x109/L)

<4

≧ 4a

<4

*

Atypical T-cells

≧ 5%

＋

≦ 1%

＋

Flower cells

Often

Often

None

＋

≦ 1.5N

≦ 2N

*

*

LDH Ca concentration (mg/dl)

Fig. 22.41-2 Adult T-cell leukemia/lymphoma.

<11

<11

*

*

None

*

＋

*

Skin

**

*

*

*

Lungs

**

*

*

*

Liver

None

*

*

*

Spleen

None

*

*

*

Central nervous system

None

None

*

*

Bones

None

None

*

*

Ascites

None

None

*

*

Pleural effusion

None

None

*

*

Digestive tract

None

None

*

*

Lymph node infiltration Tumor lesion

N: Uppermost normal value, *: Unnecessary for diagnosis, **: Necessary for diagnosis of cases in which peripheral atypical T cells account for 5% or less of total leukocytes. a: T lymphocyte density is 3.5x109/L or more. b: When atypical T lymphocytes account for 5% or less of total leukocytes, histological diagnosis is necessary. (Adapted from; Shimoyama M. Diagnostic criteria and classification of clinical subtypes ofadult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol 1991; 79: 428-37).

IV fluid and calcitonin are administered for hypercalcemia.

6. Natural killer (NK)/ T-cell lymphoma

22

Fig. 22.42 Histopathology of adult T-cell leukemia/lymphoma.

In natural killer (NK)/T-cell lymphoma, abnormally increased NK/T-cells damage various normal tissue cells, resulting in the clinical appearance of destruction, such as ulcers. NK cells may be difficult to distinguish from T cells and are sometimes described as NK/T cells. A hydroa vacciniforme-like eruption that is associated with viral infection, chronic active Epstein-Barr (EB) virus infection and hypersensitivity to mosquito bites may progress to NK/T-cell lymphoma several years to several decades after onset. Extranodal nasal T/NK-cell lymphoma (lethal midline granuloma): This is a typical type of extranodal T/NK cell lymphoma. It occurs in the nasopharynx region. The positivity of an NK cell marker (CD56) in the lymphoma cells is typical. There is an association between EB virus and extranodal nasal T/NK-cell lymphoma. It may be misdiagnosed as sinusitis resulting from rhinophonia. Cutaneous symptoms are panniculitis-like lesions that are prone to ulceration (Fig. 22.43), swelling in the eyelids, face and lips, aphtha in the lips, and chilblain-like eruptions. Cases with multiple lesions or infiltration in multiple organs have

Malignant skin tumors / E. Mesenchymal tumors

a poor prognosis. CD4+/CD56+ hematodermic neoplasm (blastic NK cell lymphoma): This is caused by NK precursor cells. It is not associated with the EB virus. The pathogenesis is unknown. A purplish red, infiltrative erythematous plaque or tumor occurs. Lymphoma associated with hydroa vacciniforme: Hydroa vacciniforme used to be attributed to photosensitivity (Chapter 13); the cause is now thought to be proliferation of NK/T cells from EB viral infection. Papules or blisters accompanied by central umbilication and necrosis occur on sun-exposed areas such as the dorsal hands and cheeks. Edema appears on the eyelids, lips and face.

417

Clinical images are available in hardcopy only.

7. Subcutaneous panniculitis-like T-cell lymphoma Panniculitis-like clinical features resemble those of erythema nodosum (Fig. 22.44). The tumor cells derive from cytotoxic T cells. The prognosis is poor. It may worsen rapidly in some cases. Cutaneous B-cell lymphoma Cutaneous B-cell lymphoma that remains localized in the skin at the time of diagnosis is called primary cutaneous B-cell lymphoma (PCBCL). The classification of cutaneous B-cell lymphoma has not been completely clarified; however, terminology adopted from the WHO/EORTC classification is widely used (Table 22.6). The main subtypes of PCBCL are follicle center lymphoma, marginal-zone B-cell lymphoma, and diffuse large Bcell lymphoma. A nodule or tumor appears solitarily, leading to a localized red or purplish-red plaque. Multiple papules, nodules or infiltrating erythema occur in some cases. The eruption rarely ulcerates. Although the skin surface is normal, erosive lymphocytic infiltration occurs in the dermis; the deeper the infiltration, the severer it tends to be (bottom-heavy appearance). B-cell-specific antigens are expressed, and T-cell surface antigens are not detected (Table 22.9). When single B-cells abnormally proliferate, monoclonality of immunoglobulin gene becomes apparent; gene rearrangement analysis (described previously; MEMO) is useful for differential diagnosis. The main treatment is radiation therapy. Chemotherapy and CD20 monoclonal antibodies (rituximab) are administered in cases with multiple lesions.

1. Primary cutaneous marginal zone B-cell lymphoma The trunk and extremities are most frequently affected. The tumor is composed of the cells that form the marginal zone, mature B cells that passed the germinal center, and plasma cells (Fig. 22.45). 5-year survival rate is almost 100%. The main treatments are excision and radiation.

Fig. 22.43 Natural killer/T-cell lymphoma.

Clinical images are available in hardcopy only.

22

Fig. 22.44 Subcutaneous panniculitis-like Tcell lymphoma. Erythema nodosum-like erythema is accompanied by tenderness and panniculitis. Histopathological observation revealed an infiltration of lymphoma cells.

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Malignant Skin Tumors and Melanomas

2. Primary cutaneous follicle center lymphoma The head, neck, and trunk are most frequently involved. There is proliferation of the centrocytes or centroblast-like cells that are normally seen in lymphoid follicles. The prognosis is good; the 5-year survival rate is 95%. The main treatments are excision and radiation (Fig. 22.46).

Clinical images are available in hardcopy only.

3. Primary cutaneous diffuse large B-cell lymphoma It occurs most commonly on the lower legs of elderly people. There is proliferation of centroblasts and/or immunoblasts. The prognosis is rather poor; the 5-year survival rate is 50% to 70%. The first line treatment is chemotherapy (Fig. 22.47).

e-2. Leukemia cutis This specific eruption is caused by infiltration of leukemic tumor cells from blood into the skin. Papules, nodules, tumors and erythroderma are the main cutaneous symptoms (Fig. 22.48). It occurs frequently in adult T-cell leukemia, acute monocytic leukemia, and acute transformation of chronic myelogenous leukemia. Skin lesions that accompany leukemia but are not caused by direct infiltration of tumor cells are called non-specific Fig. 22.45 Primary cutaneous marginal zone B cell lymphoma. Top: Red plaques and nodules are seen on the chest. Middle: Negative for IgG l chain staining. Bottom: IgG k chain stains positively.

22

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 22.46 Primary cutaneous follicle center lymphoma.

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Table 22.9 Differentiation of B cells and cellular surface traits. Mature phase

Tumor

TdT Cellular surface trait

clg

Lymphatic stem B-ALL cell B-ALL B-ALL B-ALL

＋ ＋

CD19 CD19, CD10 CD19, CD10, CD20

Pro B cell

B-ALL

＋

CD19, CD10, CD20

Pre B cell

B-ALL, CLL

＋

CD19, CD20, CD21, IgM

m

HRLR

Immature B cell

CLL

CD19, CD20, CD21, CD35, IgM, IgD,Fc, (CD5)

Ig

HRLR

Mature B cell

ML, PL, HCL

CD19, CD20, (CD21), Fc, (CD10), CD35, IgG, IgA, IgM

Ig

HRLR

Plasma-cell-like ML, MG, B cell HCL

Ig CD19, CD20, CD35, CD38, IgM, Fc, PCA-1, (PC-1)

HRLR

Plasma cell

CD38, PC-1, PCA-1

Ig

HRLR

MM

＋

HO/RLO HRLO HRLR/O HRLR/O HRLR/O

TdT: terminal deoxynucleotidyl transferase, clg: Immunoglobulin class, H: Immunoglobulin heavy chain, L: Immunoglobulin light chain, O: No rearrangement, R: gene rearrangement, Fc: Fc receptor of IgG, B-ALL: B-cell acute lymphocytic leukemia, CLL: Chronic lymphocytic leukemia, PL: Prolymphocytic leukemia, ML: Malignant lymphoma, HCL: Hairy-cell leukemia, MG: Macroglobulinemia, MM: Multiple myeloma. (Hase T, et al. B-cell lymphomas. In: Hori Y, et al., editors. Cutaneous lymphoma atlas. Bunkodo; 1996: 82-5).

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419

Melanoma

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

b

c

d

e

f

g

h

Fig. 22.48 Leukemia cutis.

eruptions, and they may appear as urticaria, erythema multiforme, erythema nodosum, ichthyosis or pigmentation.

e-3. Multiple myeloma Atypical plasma cells proliferate in the bone marrow. As a result of bone and skin involvement, skin nodules appear. Rarely, multiple nodules caused by hematogenous metastasis and extramedullary plasmacytoma occur. Multiple myeloma may be accompanied by cryoglobulinemia. Purpura may be caused by amyloidosis as a cutaneous symptom in some cases.

a

Fig. 22.47 Primary cutaneous diffuse large B-cell lymphoma. a: Bright red nodule of primary cutaneous diffuse large B-cell lymphoma. b: Proliferation of large atypical lymphocytes with distinct nucleoli. Nuclear division is also discernable.

F. Metastatic carcinoma of the skin This is a visceral cancer that metastasizes to the skin hematogenously or lymphogenously. The primary cancer in many cases is in the mammary glands, stomach, lungs, intestines, uterus and ovaries. Metastatic carcinoma of the skin is a terminal symptom of a primary cancer. Multiple, asymptomatic, intradermal or subcutaneous nodules occur in most cases (Figs. 22.49-1 and 22.49-2). The clinical types are as follows. Carcinoma erysipelatodes: Reddening and palpable infiltration suddenly appear, resembling erysipelatodes. Alopecia neoplastica: Tumor cells metastasize to the scalp. Localized alopecia occurs. The primary cancer in most cases is at the terminal stages; the prognosis is poor, and most patients die in several months.

Clinical images are available in hardcopy only.

22 Fig. 22.49-1 Metastatic carcinoma of the skin.

Melanoma Outline ● It

is a malignant tumor of the melanocytes. It is classified into the following melanomas: nodular, superficial spreading, acral lentiginous and lentigo maligna. Lesions of all types are blackish and vaguely margined. ● It tends to metastasize lymphogeneously or hematoge-

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420

22

Malignant Skin Tumors and Melanomas

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 22.49-2 Metastatic carcinoma of the skin.

Hodgkin’s disease, Non-Hodgkin’s disease Malignant lymphomas are classified into Hodgkin’s disease and non-Hodgkin’s disease. In Japan, 90% of malignant lymphomas are non-Hodgkin’s disease. Hodgkin’s disease begins as painless swelling in the lymph nodes and progresses slowly. Specificity is rarely seen in the skin lesion; however, Hodgkin’s disease metastasizes from swollen lymph nodes, causing papules or nodules. Prurigo nodularis and herpes zoster result from decreased resistance against infection. Non-Hodgkin’s disease tends to multiply and may appear first at sites other than lymph nodes (photo). Although there had been many pathological classifications of cutaneous malignant lymphoma, a unified WHO-EORTC classification was proposed recently. See Table 22.6 for non-Hodgkin’s disease of the skin.

MEMO

Clinical images are available in hardcopy only.

Staging notation of Hodgkin’s disease according to the Codtwolds-modified Ann Arbor classification. Stage I

Involvement of a single lymph node region or lymphoid structure (spleen, thymus, Waldeyer’s ring)

Stage II Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is a single site, whereas hilar lymph nodes are considered bilaterally). Stage III Involvement of lymph node regions or structures on both sides of the diaphragm III1: With splenic, hilar, celiac or portal nodes III2: With para-aortic, iliac, mesenteric nodes

22

Stage IV Diffuse or disseminated involvement of one or more extranodal organs or tissue, with or without associated lymph node involvement Designations applicable to any disease stage A: No systemic symptoms B: B symptoms present, one or more: ・ Unexplained weight loss >10% during previous 6 months ・ Unexplained fever (>38 ℃) during the previous months ・ Recurrent drenching night sweats during the previous months X: Bulky disease is present when: ・ A palpable lymph node defined by the largest dimension is >10 cm ・ The maximum width of a mediastinal mass is > one-third of the internal transverse diameter of the thorax at the level of T5/6 interspace on a chest X-ray E: The subscript 'E' is used for documented limited extranodal extension continuous or proximal to the known nodal site. More extensive extranodal disease is designed stage IV CS: Clinical stage PS: Pathological stage (as determined by laparotomy) （Lister TA, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989 ; 7 : 1630-6).

421

Melanoma

nously, and to infiltrate the lungs and bones. detection and surgical removal are essential. Other treatments are largely ineffective.

● Early

Classification Melanoma is classified by clinical features and pathology into nodular, superficial spreading, acral lentiginous, and lentigo maligna (Fig. 22.50, Table 22.10). There are many other types that do not fit these categories, such as an intermediate type and a non-classifiable type. Clinical features The distinguishing clinical features of the four types are listed in Table 22.10. All types of melanoma begin as horizontal proliferation of tumor cells in the epidermis (radial growth phase). At this phase, a dark brown or black patch is clinically observed. After the patch enlarges to a certain size, the tumor cells begin to proliferate vertically (vertical growth phase). The patch partially elevates and forms a black nodule, erosion and ulcer (Figs. 22.51-1 and 22.51-3). When the patch infiltrates beyond the dermis, the risk of metastasis sharply increases. Metastasis is lymphatic in most cases; satellite lesions form around the primary location and metastasize to the regional lymph nodes, resulting in

a. nodular melanoma

b. superficial spreading melanoma

c. acral lentiginous melanoma

d. lentigo maligna melanoma

individual atypical melanocytes alveolar configuration of atypical melanocytes

Fig. 22.50 Classification of melanoma (Clark’s level).

Clinical images are available in hardcopy only.

Table 22.10 Clinical and pathological findings of the 4 major types of melanoma. 1. Nodular melanoma (NM) A dome-shaped nodular lesion occurs, often accompanied by ulceration. The lesion progresses to the vertical growth phase without undergoing the radial growth phase in most cases. Therefore, rapid metastasis may occur. The prognosis is poor. It may occur on any site of the body. Atypical tumor cells proliferate in the vertical direction. Proliferation of tumor cells is almost never seen around the nodules.

a

c

d

e

f

g

h

g

h

i

Clinical images are available in hardcopy only.

2. Superficial spreading melanoma (SSM) Pigmented spots appear. They enlarge over the course of several months to several years. Some of the spots elevate and progress to the vertical growth phase. The epidermis thickens slightly. There are large, clear a melanoma cells that resemble Paget’s cells in all epidermal layers.

b

b

c

d

e

f

3. Acral lentiginous melanoma (ALM) The ends of extremities, fingernails and toenails are most frequently involved. ALM begins with light brown macules that continue to enlarge over the course of several to a dozen years. Nodules appear on the macules. When a nail is affected, a black macule may spread beyond the nail fold (Hutchinson’s sign). There is acanthosis and extension of the epidermal rete ridges. Atypical melanocytes proliferate in the lower epidermal layer. a b 4. Lentigo maligna melanoma (LMM) A blackish-brown spot first appears. It gradually enlarges over the course of decades. Because of the mild progression over a long period of time, the primary black spot is often misdiagnosed as lentigo. The precursor pigmented macule of LMM is called lentigo maligna. Sun-exposed areas of the body such as the face are most frequently involved. The epidermal rete ridges disappear. Atypical melanocytes are scattered in the basement of the atrophied epidermis. Solar elastosis is caused in the upper dermal layer.

22 Clinical images are available in hardcopy only.

c

d

e

f

g

h

i

Fig. 22.51-1 Melanoma. a: Nodular melanoma (NM). b: Superficial spreading melanoma (SSM). c: Acral lentiginous melanoma (ALM).

j

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Malignant Skin Tumors and Melanomas

Clinical images are available in hardcopy only.

c

d

e

f

g

Clinical images are available in hardcopy only.

d b

e c

df

g e

h

i

j

ki

Pathogenesis, Epidemiology Melanoma is caused by malignant melanocytes in normal skin, or it may originate from nevus-cell nevus, blue nevus, lentigo maligna or xeroderma pigmentosum. External injury, excision, sunlight, UV, blisters caused by footwear, clavus removal, scratching, chilblains and burn scarring may also induce melanoma. The incidence and the site of origin depend greatly on environmental factors and on intrinsic factors, including race and inheritp q pr q lj genotype. m k nl m o nis the most o r ed Sun exposure notable environmental factor. The disorder occurs frequently in Caucasians, from a lack of natural protection against UV (i.e., little melanin pigment in the skin), particularly on sun-exposed areas. It rarely occurs in persons of African descent, whose protective capacity is high, and when it does it is most frequent at the ends of the extremities. Asians fall between these two extremes. The global increase in melanoma in recent years is attributed to demographic aging, changes in lifestyle such as clothing, and ozone layer depletion.

m

n

Clinical images are available in hardcopy only.

hf

gi

hj

Clinical images are available in hardcopy only.

f

g

h

i

j

k

l

Clinical images are available in hardcopy only.

g

h

22

Fig. 22.51-2 Melanoma. d-h: Acral lentiginous melanoma (ALM).

i

j

k

l

m

n

Table 22.11 Clinical characteristics of melanoma (ABCDE). Finding Feature

A

Asymmetry

B

Borderline irregularity

C

Color variegation

D

Diameter enlargement (over 6 mm)

E

Elevation of surface

distant metastasis. Melanomas occur not only in skin, but also in the eyeballs, oral cavity and nasal mucosa. Melanocytes continue to produce melanin after they become malignant; the skin lesion in most cases becomes blackish brown. There are five characteristic clinical features of melanoma, whose initials read ABCDE (Table 22.11). In rare cases, melanoma cells lack melanin propmelanoma q k l This m n amelanotic o duction. is called andr has an even worse prognosis.

p

q

p q oDiagnosis

r

o

r

Pathology In all types of melanoma, atypical melanocytes of various sizes proliferate in the epidermis and dermis. Cells often coalesce to form defined tumor nests of various sizes (Fig. 22.52). Each type of melanoma presents a characteristic infiltration pattern of atypical cells (Table 22.10).

Clinical findings of tumors are essential for diagnosis. Whenever a blackish-brown lesion is found, melanoma should be suspected. Dermoscopic findings such as parallel ridge pattern and atypical pigment network are useful for diagnosis. Differential diagnosis Melanoma is differentiated from nevus-cell nevus, Spitz nevus, basal cell carcinoma, pyogenic granuloma, squamous cell carcinoma, verruca, angiosarcoma and subungual hematoma. Treatment Treatments are chosen according to the stage of melanoma. If the tumor is shallower than 2 mm, it should be removed with a 1cm margin. When the tumor is thicker than 2 mm, total resection

423

Melanoma

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

p

q

q

r

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

Clinical images are available in hardcopy only.

Fig. 22.52 Histopathology of melanoma. Atypical melanocytes proliferate in the epidermis and dermis. When the melanomas are clinically blackish, the tumor cells contain large quantities of melanin pigment. g j a b c d e f h i

with 2 cm margin should be conducted. Dissection of the regional lymph node and amputation of fingers, toes or other extremities may be conducted. In recent years, sentinel node biopsy has been frequently conducted to measure the necessary range of surgery. In progressive cases with distant metastasis, surgery is rarely performed; instead, chemotherapy, radiation therapy and immunotherapy are conducted. Interferon may also be used. The patient responds to chemotherapy in fewer than 30% of cases. Prognosis The prognosis is estimated by Breslow thickness (mm), which is the thickness of melanoma cells from the deepest area of the skin to the epidermal granular layer (Table 22.14). Nearly all cases with lesions 1 mm or thinner have a 100% survival rate; the 5-year survival rate in cases with lesions thicker than 4 mm is 50%. TNM classification made by Union Internationale Contra le Cancer (UICC) is shown in Tables 22.14 and 22.15.

k

l

m

n

o

p

Fig. 22.51-3 Melanoma. i: Lentigo maligna melanoma (LMM). j: Metastatic melanoma to the skin. k: Leukoderma in a patient with progressive melanoma.

22

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Malignant Skin Tumors and Melanomas

Table 22.15 Staging classification of melanoma (AJCC/UICC, 2002). Clinical stage

Pathological stage

Table 22.14 TNM classification for melanoma (AJCC/UICC, 2002). T classification (primary tumor) T0 No evidence of primary tumor

0

Tis

N0

M0

0

Tis

N0

M0

Tis Melanoma in situ

IA

T1a

N0

M0

IA

T1a

N0

M0

T1 Tumor thickness ≦ 1.0 mm

IB

T1b

N0

M0

IB

T1b

N0

M0

T2 Melanoma 1.01 mm to 2.0 mm in thickness, with or without ulceration

T2a

N0

M0

T2a

N0

M0

T3 Melanoma 2.01 mm to 4.0 mm in thickness, with or without ulceration

IIA T2b

N0

M0

T2b

N0

M0

T4 Melanoma greater than 4.0 mm in thickness, with or without ulceration

T3a

N0

M0

T3a

N0

M0

IIB T3b

N0

M0

T3b

N0

M0

T4a

N0

M0

T4a

N0

M0

N0 No regional lymph node metastasis

IIC T4b

N0

M0

IIC

T4b

N0

M0

N1 Metastasis to 1 regional lymph node

M0

IIIA

T1a-4a

N1a-2a

M0

N1a Micrometastasis

IIIB

T1a-4a

N1b,2b,2c

M0

N1b Macrometastasis

T1b-4b

N1a,2a,2c

M0

III

Any T N1-3

IIA

IIB

IIIC

IV

Any T Any N M1

IV

T1 through T4 without ulceration (a), with ulceration (b) N classification (regional lymph nodes)

N2 Metastasis to 2 or 3 regional nodes, or intralymphatic regional metastasis without nodal metastasis

T1b-4b

N1b-2b

M0

Any T

N3

M0

N2b Macrometastasis

Any T

Any N

M1

N2c Satellite or in-transit metastasis without regional nodal metastasis

(Adapted from; Balch M, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19 : 3635-48).

N2a Micrometastasis

N3 Metastasis to 4 or more regional lymph nodes, or matted metastatic, or in-transit metastasis or satellites(s) with metastasis to regional node(s) M classification (distant metastasis) M0 No distant metastasis M1a Metastasis in skin, subcutaneous tissues, or distant lymph nodes M1b Metastasis to lung M1c Metastasis to all other visceral sites or distant metastasis to any site associated with an elevated serum LDH (Adapted from; Balch M, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19; 3635-48). The thickness of melanoma is the same as in Breslow’s tumor thickness; it is the vertical length between the granular uppermost layer and the bottom of the tumor. Micrometastasis: Lymph node metastasis is pathologically identified Macrometastasis: Lymph node is clinically palpable. Metastasis is pathologically identified, or infiltration spreads beyond the lymph node membrane. In-transit: Lesion between the primary tumor and regional lymph node Satellite metastasis: Isolated lesion within 2 cm of the primary tumor

22

MEMO When radioactive isotope or pigment such as indigo carmine is injected locally into a malignant tumor, the substance flows in the lymph vessel and temporarily accumulates in the regional lymph node. A lymph node that takes in pigment or radioactive isotope is called a sentinel lymph node (SLN). Early detection for lymph node metastasis of a malignant tumor is possible if the sentinel lymph node is selectively biopsied. When the biopsy is negative, it is possible to avoid highly invasive lymph node dissection, leading to improvement in quality of life. This biopsy is called sentinel lymph biopsy and may be conducted on melanomas.

Sentinel lymph node biopsy

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Chapter

23

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Viral Infections

A virus is a particle of DNA or RNA enclosed by structural proteins. Viruses infect cells and proliferate to cause viral infections. Viral skin diseases are classified by clinical features into three types: ① degeneration of epidermal cells and blistering (e.g., in herpes simplex and herpes zoster), ② tumorous changes in epidermal cells (e.g., in verruca vulgaris), and ③ allergic eruptions on the whole body (e.g., in measles and rubella). The first two types are caused by viral infection in epidermal keratinocytes; the last type is caused by systemic viral infection (viremia). This chapter introduces various viral skin diseases, including HIV infection.

A. Viral infections whose main symptom is blistering 1. Herpes simplex sensory ganglion

Outline ● It

is caused by infection or reactivation of herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2). ● HSV-1 causes herpes labialis, herpes gingivostomatitis and, Kaposi’s varicelliform eruption. ● HSV-2 causes herpes genitalis. In recent years, the number of herpes genitalis cases caused by HSV-1 has been increasing. ● Detection of the viral antigen and Tzanck test are useful for diagnosis. The main treatment is administration of acyclovir. Pathogenesis Herpes simplex is caused by herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2). The oral cavity, eyes and genitalia are affected by HSV-1, whereas the genitalia are mainly involved in HSV-2. The infection pattern of HSV is shown in Fig. 23.1. The virus enters the skin through a minor external injury, or through the oral mucosa, eyes or genitalia. It travels along the sensory nerve axons to reach the trigeminal ganglia or lumbosacral spinal cord ganglia. In 90% of cases, primary infection does not progress beyond latency, however, symptoms may be apparent in infants or in people with immunodeficiency. After the symptoms subside, viral DNA remains in the gangliocytes and becomes reactivated by stress or a common cold. Some viruses may travel along the axons anterogradely to reach the skin and become reactivated. Clinical features The initial latency is between 2 and 10 days. Localized aggregation of small herpetic blisters occurs in primary infection. It 425

① De novo infection; virus invades through mucous membranes, and latent infection occurs in the ganglion. HSV infection de novo herpes gingivostoma genital herpes VZV infection de novo varicella

② Viruses are reactivated by immunosuppression or stress. HSV reactivation labial herpes genital herpes VZV reactivation herpes zoster

Fig. 23.1 Mechanism of infection by HSV and VZV. HSV: Herpes simplex virus. VZV: Varicella zoster virus.

23

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Viral Infections

Clinical images are available in hardcopy only.

a

b

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b

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Fig. 23.2 Herpes simplex. a, b: Vesicles aggregated around the lips (herpes labialis) caused by herpes simplex. c: Affected eyebrow. d: Genital herpes.

may occur on any site of the body, particularly the lips, genitalia and fingers (Fig. 23.2). In severe cases, small blisters spread on the whole body. Recurrent herpes simplex may cause serious mental distress. ① Herpes labialis (cold sore) This is the most common clinical form of herpes simplex seen in adults. Most cases are caused by reactivated HSV-1. It begins with prodromes such as itching and discomfort in the lips and their periphery, including the anterior naris cheeks and orbital region. After a day or two, edematous erythema appears and p q jwith central small blisters umbilication occur and h i k l m n o aggregate, sometimes coalescing to form irregularly shaped blisters. The blisters soon form pustules, erosions and crusts. They heal in about 1 week. ② Herpes gingivostomatitis This type occurs most frequently in initial infection of HSV-1 in infancy. It begins 2 to 10 days after infection, with discomfort, fever and pharyngeal pain. Accompanied by a high fever, multiple painful small blisters and erosions occur in the oral mucosa, tongue and lips. ③ Herpes genitalis (genital herpes) p qHerpesr j i This type k m infection n o recurrently. occurs asl an initial or genitalis is often transmitted through sexual activity and can be regarded as a sexually transmitted disease (STD). Although men and women in adolescence and older are frequently affected, it may also occur in infants in rare cases. It may be transmitted to an infant by the hands of the mother or nurses. The causative virus in most cases is HSV-2; however, the number of cases caused by HSV-1 has been increasing in recent years. In initial infection, small blisters form in the glans penis or foreskin of q women. j adult men, k or inl the labia m or perineal n oregionpof adult r The blisters become severely painful small ulcers. The inguinal lymph node becomes painful and enlarged. The lesions usually disappear spontaneously in 2 to 4 weeks; however, when the sacral nervous root is involved it may leave urinary disturbance. The symptoms of recurrent cases are moderate. ④ Kaposi’s varicelliform eruption HSV-1 infection may spread widely on the face and over the whole body when the local skin is weak or damaged, especially in infants or atopic dermatitis patients. It is described in the next section. ⑤ Herpetic whitlow HSV-2 nin some ther body from a p invades q k HSV-1 l (or m o cases) minor injury in the tip of a finger, leading to aggregated formation of painful blisters and pustules in fingers. The blisters on the fingers are not as fragile as those on other sites of the body. Infants who have a habit of finger-sucking and dentists may be infected. It is recurrent and heals in 2 to 4 weeks. Pathology Repetitive replication of viral DNA leads to ballooning degeneration and reticular degeneration of infected epidermal cells.

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These degenerated epidermal cells are observed as ballooning cells containing intranuclear inclusion bodies by smear staining of the blister contents (Fig. 23.3). Laboratory findings Tzanck test, detection of the virus using monoclonal antibodies, and serological diagnosis are conducted. HSV-infected epidermal cells are easily and quickly observed by Tzanck test. Monoclonal antibody detection is conducted to differentiate between HSV-1, HSV-2 and varicella zoster virus (VZV). Serological diagnosis is made by ELISA. Treatment Antiviral drugs such as acyclovir are given topically, orally or intravenously, depending on the severity of the symptoms.

Fig. 23.3 Histopathology of herpes simplex. There is necrotic degeneration in epidermal cells. The giant cells contain inclusion bodies (ballooning cells).

2. Kaposi’s varicelliform eruption Synonym: Eczema herpeticum Outline ● The

cause in most cases is infection of herpes simplex virus type 1 (HSV-1). The virus infects a skin lesion, leading to severe blistering and erosion on the whole body. ● Infants are frequently affected. It is often induced by HSV reactivation in patients with atopic dermatitis. ● Oral or intravenous administration of antiviral drugs and systemic management are the main treatments. Clinical features Kaposi’s varicelliform eruption occurs most frequently in infants with atopic dermatitis or eczema. In recent years, the number of recurrent cases of Kaposi’s varicelliform eruption in adults with atopic dermatitis has been increasing. Acute high fever and swelling in systemic lymph nodes occur. Multiple blisters appear on eczematous plaques. Slightly larger than those in herpes simplex, the blisters rapidly disseminate. They are surrounded by red halo, coalesce, and form large erosions (Fig. 23.4-1 and 23.4-2). Pustules, bleeding, and secondary bacterial infection occur in many cases. The face and upper body are commonly involved; in breast-fed infants, the lesions often occur on the whole body. The eruptions usually form crusts in 4 to 5 days. Because eruptions occur successively, the course of Kaposi’s varicelliform eruption may be from 10 days to more than 1 month. Pathogenesis Primary viral infection or reactivation affects localized areas of skin with deficient barrier function, such as areas affected by atopic dermatitis, eczema, Darier’s disease or burns. Autoinoculation causes extensive lesions. The causative virus is usually HSV-1 but sometimes HSV-2.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 23.4-1 Kaposi’s varicelliform eruption. The eruptions are rimmed with a vivid red halo. The vesicles coalesce into a large erosion.

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Treatment Antiviral drugs are given orally or intravenously. Clinical images are available in hardcopy only.

Prognosis Kaposi’s varicelliform eruption responds well to treatment. Nevertheless, dehydration and multiple organ failure accompanying high fever may be fatal.

3. Varicella Synonym: Chickenpox Clinical images are available in hardcopy only.

Outline ● It

Fig. 23.4-2 Kaposi’s varicelliform eruption.

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Clinical images are available in hardcopy only.

Fig. 23.5-1 Varicella in an adult.

is commonly known as chickenpox. Infants are most frequently affected. ● It is caused by primary infection of varicellazoster virus (VZV) and is highly infectious. ● A fever emerges concurrently with erythematous papules on the whole body. Eruptions progress in the course of vesicles, pustules and crusts, and healing. New eruptions continue to occur such that preexisting eruptions appear together with new eruptions. ● It heals in 7 to 10 days. ● Symptomatic treatments are helpful. Aspirin is contraindicated. Clinical features After a latency of 2 to 3 weeks, erythematous papules appear on the whole body, accompanied by fever (37 to 38˚C) and systemic fatigue. The eruptions are accompanied by itching. They progress in the order of erythema, papules, blisters, pustules and crusts, over the course of several days. Varicella is characterized by small blisters that resemble insect bites and blisters that form on the scalp. Because the eruptions continue to appear, preexisting eruptions are found together with newly formed ones (Figs. 23.5-1 and 23.5-2). Blistering also occurs in the oral mucosa and palpebral conjunctiva. Varicella heals in 7 to 10 days, without scarring (Fig. 23.6). If the eruptions are scratched or secondarily infected, they heal with moderate scarring. The main complications are pneumonia, encephalitis, unilateral high-frequency deafness (thought to be a symptom of RamsayHunt syndrome), and Reye’s syndrome (cerebritis and fatty liver). Pathogenesis, Epidemiology Varicella is caused by infection of the varicella zoster virus (VZV). This virus enters the upper respiratory tract by droplet infection or contact infection and proliferates in the regional lymph nodes, inducing primary viremia. The virus further proliferates in the liver and spleen, leading to secondary viremia, and reaches the skin, resulting in blistering. Varicella occurs most frequently between weaning and early childhood. Ninety-five

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percent of children aged 9 have the antibodies. The age of initial infection has risen in recent years; varicella in adults is increasing. In adult cases, varicella is often accompanied by encephalitis and pneumonia, and it can easily become severe. Laboratory findings, Diagnosis Tzanck test is useful for early diagnosis. Varicella is characterized by balloon cells, the epidermal cells that are infected by VZV. Clinical images are available in hardcopy only.

Treatment Symptomatic therapies such as oral antihistamines against itching, and topical petrolatum or antibiotic ointments for eruptions are the main treatments for infants. In recent years, oral antiviral drugs have been used increasingly to keep the infection from worsening. Aspirin is contraindicated because of the danger of Reye’s syndrome. Antiviral drugs are administered intravenously to adults, patients with immunodeficiency, and newborns. Prevention Within 72 hours after infection, the onset can be inhibited by varicella vaccine in 60% to 80% of cases. Oral antiviral drugs may reduce the symptomatic severity in patients who have had contact with an affected individual within the previous week. Varicella can be fatal in patients with immunodeficiency; human immunoglobulin containing high anti-VZV antibody titer is used in some cases.

23 Clinical images are available in hardcopy only.

4. Herpes zoster Fig. 23.5-2 Varicella.

Outline ● Latent

VZV in the ganglia reactivate to form band-like

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 23.7-1 Herpes zoster on various sites of the body.

herpetic aggregations of small blisters on certain innervated regions. Pain is present in areas over the involved nerves. It occurs in individuals with history of varicella infection. ● The blisters may disseminate on the whole body in cases with immunodeficiency, such as when there is malignant tumor, regardless of the affected nervous regions. ● The main examinations are Tzanck test, detection of viral antigens, and evaluation of the antibody titer in the blood. There is permanent immunity after the first infection. ● The pain that persists after healing is called post-herpetic neuralgia (PHN). When the ears and the peripheral regions are involved, hearing loss and peripheral facial paralysis may occur (Ramsay-Hunt syndrome). Clinical features Herpes zoster symptoms are divided into cutaneous and nervous. There are several specific types of herpes zoster. ① Mucocutaneous symptoms Multiple herpetic vesicles appear in band-like patterns over certain innervated regions. The skin over the intercostal nerve is most frequently involved, followed in frequency by the trigeminal area of the face (Figs. 23.7-1 and 23.7-2). Prodromes such as neuralgic pain and abnormal paresthesia occur several days before the eruptions manifest. Later, edematous erythema and papules occur and transform into blisters. All these blisters progress in the same course; this differs from varicella, in which preexisting blisters are found concurrently with newly formed ones. The blisters soon rupture and become erosions. They heal after crust formation in 2 to 3 weeks. ② Nervous symptoms Neuralgic pain is often present several days before the onset of eruptions. The pain is severest 7 to 10 days after the eruptions occur. The severity of pain ranges from moderate to intense, causing sensory disturbance, insomnia or paralysis. The pain in most cases subsides with remission of the eruptions. ③ Types of herpes zoster Generalized herpes zoster: In patients who are immunocompromised as a result of steroid or immuno-suppressant intake or a primary disease, small widespread blisters resembling varicella may spread on the whole body 4 to 5 days after manifestation of typical eruptions of herpes zoster. Eye symptoms (Hutchinson’s sign): Complications involving the eyes, such as conjunctivitis and keratitis, may occur in herpes zoster at the first division of the trigeminal area (ophthalmic nerve). Herpes zoster on the nasal dorsum is called Hutchinson’s sign. It often induces eye complications. In rare cases, a severe complication called acute retinal necrosis occurs. Ramsay-Hunt syndrome: The external auditory canal and auricle are involved. Peripheral facial palsy and acoustic nerve impairment are present. The pathogenesis is thought to be

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pressure exerted on the facial nerve by genicular ganglia. In some cases, facial palsy is the only symptom and there is no blistering. Post-herpetic neuralgia (PHN): Neuralgia may persist after the eruptions disappear. The pathogenesis is thought to be irreversible nerve degeneration. It often occurs after the onset of herpes zoster in the elderly and is often accompanied by sharp pain. Antidepressants and nerve block are administered. It may be treated at a pain clinic. Pathogenesis, Epidemiology Herpes zoster is caused by reactivation of latent VZV. During the course of varicella, VZV travels to the sensory nerves to reach the ganglia, whose dorsal-root cells remain latently infected after varicella heals and the anti-VZV antibodies increase. Stress, aging, malignant tumor and immunodeficiency can trigger re-proliferation of VZV (Fig. 23.1). Herpes zoster occurs most frequently in persons between the ages of 10 and 30 and over 50.

Clinical images are available in hardcopy only.

Pathology Ballooning cells are observed by Tzanck test, as in herpes simplex (Fig. 23.8). Diagnosis, Examination Tzanck test, detection of viral antigens, and serological diagnosis are conducted, as in the cases of herpes simplex and varicella. Cases in the elderly or with generalized herpes zoster should be carefully observed, because there is the possibility of malignant tumor immunodeficiency as an underlying disease. Ophthalmologic examination is conducted on any lesions involved in the first division of the trigeminal area. Treatment As a basic treatment, antiviral drugs are administered, orally at the early stages and intravenously in severe cases. The main purpose of treatment is to alleviate the sharp pain in the acute stages to prevent sequelae that may include post-herpetic neuralgia and motor palsy. NSAIDs are used as a symptomatic therapy. The prognosis tends to be good. After first infection, patients obtain permanent immunity due to reactivated cell-mediated immunity.

Clinical images are available in hardcopy only.

Fig. 23.7-2 Herpes zoster on the first division of the trigeminal nerve. Eye symptoms such as conjunctivitis and keratitis occur as complications in some cases.

23

MEMO Variola is caused by infection of the upper respiratory mucosa by the Orthopoxvirus variola virus. Infection is by droplet or contact. This pathogen is so virulent that it used to be fatal in many cases; however, Jenner’s cowpox vaccine made prevention possible. A smallpox eradication program was developed in 1958 by WHO, and no cases of variola have occurred since 1977. In 1980, WHO declared the disease eradicated. The virus is kept at secure institutions in biosafety level 4 labs in the U.S. and Russia.

Variola (Synonym: Smallpox)

Fig. 23.8 Histopathology of herpes zoster.

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5. Hand, foot and mouth disease (HFMD) Outline

An eruption is caused by coxsackievirus A16 or enterovirus 71. Breast-fed infants are most frequently affected. ● Blistering is present in the distal portions of the extremities and oral mucosa. It disappears in 4 to 7 days. Oral enanthema occurs on the buccal mucosa and tongue. Erythema or aphtha-like eruptions may also occur. ● The only treatment that is usually necessary is oral hydration. ●

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Pathogenesis, Epidemiology The main causative viruses are coxsackievirus A16 and enterovirus 71. These proliferate in the intestinal tract and are found in stool and in pharyngeal secretions. The viruses are spread by droplet and oral infection. The infectiousness is so high that widespread outbreaks sometimes occur in hospitals. HFMD occurs most commonly in 1- to 2-year-old breast-fed infants and in summer epidemics.

Clinical images are available in hardcopy only.

b

Clinical features occurs suddenly pafter 2q j mouth h Hand,i foot and k disease l (HFMD) m n o to 5 days of latency. In about half of cases, slight fever is present for 1 or 2 days. Dispersed small blisters with red halos appear on the hands, soles, knee joints and buttocks (Fig. 23.9). The blisters are oval, and their long axis is often parallel to the dermatoglyphic line. Some degree of tenderness, but not itching, may accompany these. The blisters disappear in 4 to 7 days without rupturing. Painful erythema, blisters, or aphtha-like erosions that number from a few to several dozen occur on the buccal mucosa and tongue. They resolve in several days. When caused by enterovirus 71, HFMD may be accompanied by aseptic meningitis.

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Fig. 23.9 Hand, foot and mouth disease. a: Vesicles accompanied by red halo and slight tenderness. b: Eruptions on the knees. c: Vesicles accompanied by sharp pain and aphtha in oral mucosa .

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Treatment No treatment is necessary. Symptomatic therapy is performed only in cases with severe symptoms.

B. Viral infections whose main symptom is verruca 1. Verruca vulgaris Outline ● It ● It

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is caused by human papillomavirus (HPV) infection. occurs most frequently on the fingers, toes, soles and

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dorsal surfaces of hands. It is largely asymptomatic. nitrogen cryotherapy, topical glutaraldehyde application, carbon dioxide gas laser therapy, and electrosurgery are useful. Some cases heal spontaneously.

● Liquid

Pathogenesis Verruca vulgaris is caused by human papillomavirus (HPV), a virus in the Papovaviridae family. The most frequent HPV infection is HPV-2, followed by HPV-4, HPV-7, HPV-26, and HPV27 (Table 23.1). The virus invades the skin from minor external injury and infects the epidermal cells. It replicates simultaneously with differentiation of epidermal cells, leading to maturation of viral particles in the granular cell layer. The viral particles are released concurrently with exfoliation of verruca, causing spreading to other areas. Clinical features Verruca vulgaris occurs most commonly on the hands and feet of infants, after a latency of 3 to 6 months. It begins with small papules. They enlarge, elevating in verrucous shape and becoming several millimeters to several centimeters in diameter (Fig. 23.10). Usually multiple but sometimes solitary eruptions of verruca vulgaris aggregate, coalesce, and may form plaques. It is largely asymptomatic and has specific clinical features. There are some types of verruca vulgaris that are given characteristic clinical diagnostic names according to the clinical features, type of virus and the affected site. ① Plantar wart Verruca vulgaris occurs on the soles. A keratotic lesion forms without distinct elevation. It resembles tylosis and clavus, but can be differentiated from those by scraping. If surface scraping of the keratotic lesion causes petechiae, the diagnosis is plantar wart. ② Myrmecia A small, dome-shaped nodule forms on the soles. It is caused by HPV-1 infection (Fig. 23.11) and may resemble molluscum contagiosum. It is also called deep palmoplantar wart. It has a red, cratered appearance. Tenderness is often present. It is a type of plantar wart.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 23.10 Verruca vulgaris.

Table 23.1 HPV types and clinical symptoms. Type

Symptoms

1

Myrmecia

2,4,7,26-29

Verruca vulgaris

3,10

Flat warts (verruca plana juvenilis)

23 Clinical images are available in hardcopy only.

5,8,9,12,14,15,17,19-26,36,47,50 Epidermodysplasia verruciformis 57,60

Epidermal cyst in the soles

6,11

Condyloma acuminatum

16,18,31, 33-35, 39-41, 51-60

Cervical dysplasia, endocervical cancer

13, 32

Oral focal epithelial hyperplasia

30, 40

Pharyngeal carcinoma

Fig. 23.11 Myrmecia. A dome-shaped nodule accompanied by tenderness occurred. Scraping the nodule revealed that the lesion had invaded the deep intradermal portion.

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Fig. 23.12 Filiform wart.

③ Pigmented wart This is caused by infection of HPV-4 or HPV-65, or of HPV60 in rare cases. It has the clinical features of verruca vulgaris and blackish pigmentation; it is also called a black wart. ④ Punctate wart This is caused by HPV-63 infection. Multiple, punctate, white keratotic lesions of 2 mm to 5 mm in diameter occur on the hands and soles. ⑤ Filiform wart A long, small, thin protrusion of several millimeters in diameter occurs on the face, head region or neck (Fig. 23.12). Pathology There is hyperkeratosis, incomplete keratinization and thickening of the papillary epidermis, accompanied by thickening of the granular cell layer in the epidermis. Cells with vacuolar degeneration and large keratohyaline granules are found in the granular cell layer. These cellular changes, called koilocytosis, are characteristic of HPV infection (Fig. 23.13).

Fig. 23.13 Histopathology of verruca vulgaris.

Treatment The main treatment for verruca vulgaris is liquid nitrogen cryotherapy. Local injection of bleomycin and cauterization by electrical scalpel or carbon dioxide laser are conducted on sites where cryotherapy is not fully effective, including hands and soles. For multiple lesions, coix seed (Coix lacryma-jobi L.) extract may be administered orally. Topical application of glutaraldehyde is useful. Topical vitamin D and oral retinoids have been reported effective for severe cases.

Clinical images are available in hardcopy only.

2. Flat wart Synonym: Verruca plana juvenilis

23 Clinical images are available in hardcopy only.

Clinical features Multiple, slightly elevated, flat papules of 2 mm to 10 mm in diameter occur on the face (forehead and cheeks). These may coalesce or appear in linear pattern from autoinfection (Köbner phenomenon) (Fig. 23.14). The papules are normal skin color or light pink and nearly asymptomatic. They may disappear spontaneously with scaling, which is followed by inflammatory symptoms such as itching and reddening. However, flat wart may persist for several years. Pathogenesis Flat wart is a viral wart that is often caused by HPV-3 or HPV-10.

Fig. 23.14 Flat wart.

Treatment Some cases heal spontaneously. Liquid nitrogen cryotherapy is conducted. Coix seed (Coix lacryma-jobi L.) extract may be administered orally.

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3. Condyloma acuminatum Outline ● Genital

verrucous papules are caused by HPV-6 or HPV11. This is an STD. ● Latency is 2 to 3 months. ● Cryotherapy and laser surgical removal are the main treatments.

Clinical images are available in hardcopy only.

Clinical features The latency of condyloma acuminatum is 2 to 3 months. Multiple verrucous papules of papillary or cauliflower shape occur in the genitalia or perianal region (Fig. 23.15). Keratinization is rarely present. The papules are infiltrative at the surface and may give off foul odor. Condyloma acuminatum may enlarge. Keratinization and ulceration may closely resemble squamous cell carcinoma (Buschke-Lowenstein tumor). Pathogenesis Condyloma acuminatum is caused by HPV-6 or HPV-11. Most cases occur in the sexually active years, transmitted through sexual activity. The virus invades through minor external injury of the genitalia, perianal region, or vaginal introitus, and infects epidermal basal cells, inducing abnormal cellular proliferation. Proliferation of the epidermis results in formation of papillary tumors (warts).

Clinical images are available in hardcopy only.

Fig. 23.15 Condyloma acuminatum. The verrucous papules resemble cauliflower.

Diagnosis, Differential diagnosis Condyloma acuminatum can be diagnosed by the clinical features; however, biopsy may be needed for differential diagnosis, such as from Bowenoid papulosis, a tumor that is often caused by HPV-16 and that histologically resembles Bowen’s disease. Treatment Treatment for condyloma acuminatum is the same as for verruca vulgaris. Liquid nitrogen cryotherapy and surgical removal using electrical scalpel or carbon gas laser are conducted. Local injection of bleomycin is used in intractable cases.

Clinical images are available in hardcopy only.

23 4. Bowenoid papulosis Multiple black papules of 2 to 20 mm in diameter occur on the genitalia of young people (Fig. 23.16). Small papules may coalesce and form plaques. HPV-16 is detected in the lesion. Bowenoid papulosis is histopathologically indistinguishable from Bowen’s disease. It rarely becomes malignant, and it may heal spontaneously. The prognosis is good. Liquid nitrogen cryotherapy and electrical cauterization are the main treatments. Bowenoid papulosis is thought to be an atypical type of condyloma acuminatum.

Fig. 23.16 Bowenoid papulosis. The papules caused by Bowenoid papulosis are blackish in most cases or close to normal skin color in some cases.

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5. Epidermodysplasia verruciformis

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

The main causes are HPV-5, HPV-8, HPV-17 and HPV-20 infection. Susceptibility to the virus is inherited, usually autosomal recessively; however, some cases with autosomal dominant and X-linked dominant patterns have been reported. Congenital cellular immunocompromise against HPV is thought to be associated with the occurrence. Relatively large, flat-wart-like, reddish-brown keratotic patches appear on the dorsal surfaces of the hands and trunk of infants, often coalescing to form plaques or reticular arrangements. Pityriasis-versicolor-like leukoderma and erythema may occur (Fig. 23.17). Multiple cells containing bright and enlarged cytoplasm are histopathologically observed in the upper suprabasal cell layer. The eruptions gradually spread on the whole body surface. Malignant skin tumor (e.g., squamous cell carcinoma, basal cell carcinoma, Bowen’s disease) occurs in about half of adolescent and older patients. There is no specific treatment for epidermodysplasia verruciformis. Sunscreen is used for prevention, because lesions on sun-exposed areas tend to worsen. Oral retinoid administration is effective.

6. Molluscum contagiosum Outline ●A

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Fig. 23.17 Epidermodysplasia verruciformis. Large, flat, verrucous, reddish-brown keratotic macules occur. The eruptions elevate and form tumors in some cases.

wart forms as a result of infection by the molluscum contagiosum virus. ● Infants are most frequently affected. ● Small, multiple, dome-shaped nodules of 2 mm to 10 mm in diameter occur. Autoinfection is caused by wart contents adhering to the epidermis. ● Tweezer excision of the wart is the most effective treatment. ● Multiple molluscum contagiosum may appear on the face of patients with AIDS. Clinical features The latency of molluscum contagiosum is between 14 and 50 days. Small, multiple, flat-surfaced, glossy, centrally concave, dome-shaped nodules of 2 mm to 10 mm in diameter occur (Fig. 23.18). They contain an opaque white gruel-like substance. They are asymptomatic except for mild itching. The trunk and extremities of infants are most frequently affected. When sexually transmitted, the genitalia, lower abdomen, and medial thighs are involved. Pathogenesis, Epidemiology Warts are produced by molluscum contagiosum, a virus in the Poxviridae family. Cells at the center of the skin lesion are distorted or destroyed, giving the appearance of large hyaline bodies (molluscum bodies) that contain large amounts of cytoplasmic

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Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 23.18 Molluscum contagiosum. The small papules are glossy on the surface and umbilicated at the center.

virus material. Molluscum contagiosum is spread by contact infection. The virus enters through a break in the skin or a hair follicle, and proliferates in the suprabasal cell layer of the epidermis. When a wart is scratched, the contents adhere to the epidermis and cause autoinfection. Children with atopic dermatitis are most commonly affected. In recent years, the numbers of infections in healthy children at swimming schools, in adults from STDs, and in patients with immunodeficiency have been increasing. Pathology Molluscum contagiosum is characterized by lobulated, endophytic hyperplasia that produces a circumscribed intracutaneous pseudotumor. The keratinocytes contain very large intracytoplasmic inclusions (molluscum bodies).

Fig. 23.19 Histopathology of molluscum contagiosum.

Diagnosis Molluscum contagiosum is easily diagnosed by the clinical features. In sudden occurrence of multiple molluscum contagiosum in adults, AIDS involvement is highly suspected. Treatment Tweezer excision of the lesions is most effective. Cryo-coagulation therapy and application of 40% silver nitrate are also useful. Molluscum contagiosum heals spontaneously in some cases.

C. Viral infections whose main symptom is erythematous eruptions 1. Measles Outline ● It

is an infectious disease caused by the measles virus. Young children are most frequently affected. It occurs in epidemics with intervals of several years, often during the spring. ● A fever and common-cold-like symptoms occur after an

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Fig. 23.20 Measles.

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Fig. 23.21 The course of measles.

Clinical images are available in hardcopy only.

23 Fig. 23.22 Koplik spots.

incubation period of about 2 weeks. When the fever subsides, white macules called Koplik’s spots appear. Fever recurs and eruptions and catarrhal symptoms and skin lesion appear on the whole body. The fever subsides rapidly in 3 to 4 days with exfoliation of the eruptions. It heals with pigmentation. ● Otitis media, encephalitis, and subacute sclerosing panencephalitis (SSPE) may occur as complications. ● It is diagnosed by the clinical features or serologically. Clinical features The clinical features of measles appear after an incubation period of 10 to 14 days. There are prodromal symptoms such as fever, cough and nasal congestion for about 5 days. Grayish-white papules on the buccal mucosa called Koplik’s spots appears as the prodrome subsides, and then enanthema spreads on the forehead, behind the ears, and on sites on the long axis of the body. It is accompanied by high fever. Measles eruptions are characterized by coalesced pink macules and elevated papules (Figs. 23.20 and 23.21). The course of measles is divided into three stages: first (catarrh or prodrome), second (eruption), and third (recovery). ① First stage (catarrh) A fever of about 38˚C and catarrhal symptoms such as nasal discharge, sneezing, eye discharge and cough persist for 3 to 4 days. The respiratory secretions, lacrimal fluid and saliva at this stage are at their most infectious. On the last 1 to 2 days of the catarrhal symptoms, punctate white macules called Koplik’s spots appear on the buccal mucosa and sometimes on the gums at almost the same time as the fever subsides (Fig. 23.22). ② Second stage (eruption) After the fever subsides, it recurs (diphasic fever), accompanied by eruptions and aggravation of the catarrhal symptoms. It persists for 3 or 4 days. Eruptions first appear behind the ears and cheeks, spreading to the trunk and extremities. Small erythema coalesces and enlarges, forming irregular shapes with a reticular pattern. By this time Koplik’s spots have already disappeared. The measles virus is not found at the lesion; the mechanism is thought to be allergic reaction. Dehydration and various complications often occur from the persistent high fever. ③ Third stage (recovery) The fever subsides in several days. Healing is with exfoliation of eruptions and pigmentation. Complications Complications of measles include otitis, pneumonia, encephalitis, myocarditis and subacute sclerosing panencephalitis (SSPE). In atypical measles, vaccination leads to measles with symptoms different from those of usual measles. Atypical measles in recipients of killed measles vaccine (used from 1963 to 1968 in Japan) and immunocompromised persons have been reported.

C. Viral infections whose main symptom is erythematous eruptions

Pathogenesis The causative viruses are in the family Paramyxoviridae, genus Morbillivirus. Infants in the first three months after birth are not infected by the measles virus because of maternal-to-fetal transfer of passive immunity. Infants between the age of 3 months and early childhood are most commonly affected. The measles virus is highly infectious and invades by droplet infection. It proliferates in the epithelial cells of the nasopharynx, resulting in viremia. Subclinical infection rarely occurs; more than 95% of the infected patients show apparent infection. Affected individuals obtain strong permanent immunity. Diagnosis A decrease of both neutrophils and lymphocytes (leukocytopenia) and an increase of LDH are observed by peripheral blood examination. Serologic assay of antibody responses, viral isolation of respiratory secretions, and PCR are useful for diagnosis. Differential diagnosis It is differentiated from other viral infection including rubella and exanthema subitum, hemolytic streptococcal infection (scarlet fever), drug eruption, erythema multiforme, Kawasaki disease and sepsis (Fig. 23.23). Treatment There is no effective treatment for measles. Bed rest, keeping the body warm, and oral antipyretics and antitussives are recommended as symptomatic therapies. Bacterial complications are treated with antibiotics. Human immuoglobulin may be used in severe cases. Prevention When the route of infection has been defined and no more than 5 days has passed after infection, the onset can be prevented or the symptoms can be mitigated by intramuscular injection of human immunoglobulin. Attenuated live vaccine is used for immunization.

active phase

439

postdisease

Koplik’s spot

pigmentation

disseminated and coalescent erythema and papules

Measles no pigmentation postauricular lymph node swelling

erythema and papules (without coalescence, milder than those of measles) Rubella malar flush perioral pallor strawberry tongue erythema on the chest

exfoliative scales

2. Rubella

23

Outline ● Caused

by the rubella virus, it is commonly known as German measles or “three-day measles.” ● The main symptoms are eruptions, enlarged lymph nodes (the postauricular lymph node, in particular) and fever. ● Eruptions and fever occur concurrently. Papular erythema accompanied by moderate itching on the face spreads to the whole body surface and does not coalesce. Healing is without scaling or pigmentation.

diffuse small erythema

lamellar scales

Streptococcal infection

Fig. 23.23 Differential diagnosis of measles.

440

23

Viral Infections

body temp.(˚C)

● Thrombocytopenic

purpura and arthritis occur as complications. Arthritis is the only symptom in many adult cases. ● Rubella infection in early pregnancy may induce congenital rubella syndrome in fetus. Pregnant women must avoid rubella infection and vaccination.

40 39 38 37

days symptoms

1 2 3 4 5 6 7 8 9 10 11

Clinical features Rubella is commonly known as “three-day measles.” The clinical course is shown in Fig. 23.24. After a latency of 2 to 3 weeks, the systemic lymph nodes enlarge. Enlargement in the postauricular region and cervical lymph node is particularly noticeable and persists for several weeks. In some cases it begins with eruptions and fever without lymph node enlargement. Several days later, papular erythema accompanied by moderate fever and itching spread on the whole body (Fig. 23.25). Unlike measles, the eruptions of rubella are solitary and do not usually coalesce. They disappear without scaling or pigmentation in 3 to 5 days. Petechiae-like enanthema called Forschheimer spots occur in the palate mucosa in about half cases.

papules lymph node swelling

incubation period

2-3 weeks

Fig. 23.24 The course of rubella

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

Complication Encephalitis, meningitis, thrombocytopenic purpura in infancy, and arthritis in adulthood occur as complications. If a woman is infected in or before her 5th month of pregnancy the newborn may also be affected (congenital rubella syndrome, CRS) (Table. 23.2). h

i

j

k

l

m

n

o

p

q

Pathogenesis The rubella virus, an RNA virus in the family Togaviridae, genus Rubivirus, invades the body from the upper respiratory tract by droplet infection or contact infection, proliferates in the regional lymph node, and causes viremia resulting in the onset of rubella. Permanent immunity is obtained after the first infection, although reinfection occurs in rare cases. Most patients are between 5 and 15 years old. Rubella tends to occur in spring and summer epidemics at intervals of 3 to 10 years. Clinical images are available in hardcopy only.

Laboratory findings, Diagnosis Leukocytopenia, thrombocytopenia and atypical lymphocytes are found by peripheral blood test. Increased antibody titer is observed by serological assay. Differential diagnosis can be made by detecting IgG and IgM, which is specific to rubella. Cases with moderate symptoms are diagnosed by the clinical course and epidemic circumstances.

23

Differential diagnosis a

b

c

d

e

f

g

h

Fig. 23.25 Rubella. a: Erythematous papules on the face and upper chest. b: Erythematous papules on the trunk.

p q j i Rubella k l m measles, n o is differentiated from exanthema subitum andr

hemolytic streptococcus infection (scarlet fever) (Fig. 23.23). Most cases are clinically difficult to diagnose, so serological examination is necessary.

r

C. Viral infections whose main symptom is erythematous eruptions

Treatment, Prevention Rubella is treated symptomatically. Vaccination is effective for prevention, but pregnant women must not be immunized with live vaccine.

441

Table 23.2 Symptoms of congenital rubella syndrome. 3 classic symptoms Eye symptoms Cataract Microphthalmia

3. Roseola infantum

Congenital heart disease

Synonym: Exanthema subitum

Patent ductus arteriosus Ventricular septal defect

Outline ● It

is caused by human herpes virus (HHV) types 6 and 7. Breast-fed infants are most commonly affected. ● A high fever occurs suddenly and persists for 3 or 4 days. As the fever subsides, measles-like eruptions appear on the whole body. They do not coalesce, but disappear without pigmentation in 2 to 3 days. ● Febrile convulsions may occur as a complication.

Pulmonic stenosis Sensorineural hearing loss Other symptoms Low birth weight Thrombocytopenia Liver disorder (e.g., hepatitis, splenohepatomegaly) Microencephaly

Clinical features After 2-week latency, an acute high fever of 38˚C to 39˚C occurs and persists for 3 to 4 days. Infected children in most cases appear normal. About when the fever subsides, mild measles-like eruptions occur on the face and trunk. They do not coalesce but disappear in 2 to 3 days without leaving pigmentation (Fig. 23.26). Diarrhea and moderate cough often occur. Seizers may occur during the febrile period in up to 10% of patients. Acute encephalitis and liver dysfunction are complications in rare cases.

Mental impairment

Treatment The entire course is between 4 and 6 days, and the prognosis is good. Most cases of roseola infantum are mild and respond well to antipyretics during the febrile period.

23

40 39 38 37

days symptoms

Diagnosis Roseola infantum can be diagnosed by the characteristic clinical features. In more than half cases, enlargement and reddening occur in the lymph follicles at the base of the uvula. These findings are helpful for diagnosis.

body temp. (˚C)

Pathogenesis The causative viruses are thought to be HHV-6 type B and HHV-7. Although HHV-6 is spread by saliva transfer, newborns are not infected because of maternal passive immunity; infants between the ages of 6 months and 3 years are affected.

1 2 3 4 5 6 7 8 9 10 11

measles-like erythema diarrhea

incubation period

2 weeks

Fig. 23.26 The course of exanthema subitum/roseola infantum.

442

23

Viral Infections

4. Erythema infectiosum Outline Clinical images are available in hardcopy only.

a

b

c

d

e

f

● Eruptions,

g

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

h

Fig. 23.27 Erythema infectiosum. a: Erythema on the cheeks (“slapped cheek”). b: Erythema on the upper arm.

23

commonly known as fifth or “slapped cheek” disease, are caused by human parvovirus B19. ● Flush appears in the cheeks, and papular erythema occurs p q j to present lacy, h on the i extremities, k coalescing l m n o reticulated eruptions that predominate in the extremities. These heal without scaling or pigmentation in about 1 week. ● Infection in pregnancy may lead to fetal hydrops. If patients with hemolytic anemia are infected, acute pure red cell aplasia occurs, resulting in marked anemia, fetal hydrops or death. Clinical features Erythema infectiosum is commonly known as fifth or “slapped cheek” disease. It tends to occur in spring and summer epidemics at intervals of 4 to 6 years. It occurs most frequently in children between 4 and 10 years of age; however, there are also cases in which adults, especially mothers and nurses, are infected by infants and children. Latency is between 2 and 3 weeks. Erythema infectiosum may begin with mild prodromal symptoms. Influenza-like catarrhal symptoms occur in some cases. Erythema that j resembles a hand-slap occurs suddenly on both qcheeks p i k l m n o r and disappears in 1 to 4 days (Fig. 23.27). A day or two after the facial lesion manifests, erythematous lesions of about 1 cm in diameter occur on the extensor surfaces of arms and legs. These coalesce gradually and begin to heal at the center, leaving the characteristic lacy, reticulated pattern. When the trunk is involved, no lacey pattern is present. The eruptions disappear without scaling or pigmentation in about 1 week. When a pregnant woman is infected, prenatal infection occurs in 30% of cases and may cause fatal edema (fetal hydrops) or fatal death. Rapid decrease of erythrocytes (aplastic crisis caused by acute pure red cell aplasia) occurs in cases with hemolytic anemia as an underlying disease, leading to marked anemia. Pathogenesis Erythema infectiosum is caused by droplet infection of human parvovirus B19, which is in the Parvovirus genus of DNA viruses. The virus invades the body by respiratory infection and proliferates within erythroblasts of the bone marrow in 4 to 7 days, resulting in viremia. About 2 weeks after infection, production of antibodies begins. At the same time, eruptions appear; involvement of immunocomplex is suggested. Manifest infection occurs in 70% of infant cases and 30% of adult cases. Laboratory findings Specific IgG and IgM antibodies are examined by serological assay. In adult cases, antinuclear antibodies are sometimes

r

C. Viral infections whose main symptom is erythematous eruptions

443

detected, which may lead to a misdiagnosis of erythema infectiosum as lupus erythermatosus. Treatment No specific antiviral therapy is available. Intense accessory symptoms are treated symptomatically.

5. Gianotti-Crosti disease

Clinical images are available in hardcopy only.

Synonyms: Gianotti disease, Infantile papular acrodermatitis, Papular acrodermatitis of childhood Outline

Liver dysfunction and eruptions are caused by initial infection of hepatitis B virus. It occurs most frequently in infants. ● Papules appear on the legs, ascending to the arms and face. ● There is a risk that the patient may eventually become a hepatitis B carrier. ●

Clinical images are available in hardcopy only.

Clinical features Gianotti-Crosti disease occurs most frequently in infants between the ages of 6 months and 12 years. After a latency 50 to 180 days, multiple, flat, light pink papules of 3 mm to 4 mm in diameter suddenly appear solitarily on the distal portions of the lower legs. They rapidly ascend to the buttocks, upper arms and face in 3 to 4 days (Fig. 23.28). The trunk is almost never involved. The papules are nearly asymptomatic and disappear spontaneously in about 1 month. Enlargement in the superficial lymph node and liver is present, and hepatic symptoms such as elevated liver enzyme occur; nevertheless, jaundice does not occur.

Fig. 23.28 Flat, red erythema caused by Gianotti-Crosti disease.

Pathogenesis Gianotti-Crosti disease is caused by infection of the hepatitis B virus (HBV) in infancy. In most cases there are hepatitis B patients or HBV carriers in the family; the cause is thought to be horizontal transmission. Laboratory findings, Diagnosis Increases in serum AST, ALT, LDH and ALP are observed from hepatic symptoms. HBs antigens are positive. The eruptions disappear in about 1 month, and HBs antigens disappear in several months. Gianotti-Crosti disease is relatively easily diagnosed by the clinical features and enlargement of the lymph nodes and liver. HBs antigens are observed by blood test; if they are negative, there is high possibility of Gianotti-Crosti syndrome (described below). Treatment, Course of disease When HBs antigens persist after the eruptions disappear, the

23

Clinical images are available in hardcopy only.

Fig. 23.29-1 Gianotti-Crosti syndrome.

444

23

Viral Infections

patient may progress to become a carrier. About half of patients under the age of 1 become carriers. Prevention of such progression is of primary importance. Interferon, anti-HBV antibody hyperimmune globulin, and glycyrrhizinate are used.

Gianotti-Crosti syndrome The eruptions caused by Gianotti-Crosti syndrome closely resemble those of Gianotti-Crosti disease; however, the former are accompanied by intense itching and often occur on the trunk (Figs. 23.29-1 and 23.29-2). The main causative viruses are cytomegalovirus, Epstein-Barr virus, and coxsackievirus. HBs antigen is negative. There are no findings of liver dysfunction.

Clinical images are available in hardcopy only.

6. Infectious mononucleosis Outline ● It

is caused by infection of Epstein-Barr virus. It occurs most frequently in puberty. ● The main symptoms are high fever, pharyngeal pain, and swelling in the cervical lymph nodes. Rubella-like and measles-like eruptions and erythema multiforme appear in 30% of cases. ● Symptomatic therapy is the main treatment. Penicillincontaining drugs and aspirin are contraindicated.

Fig. 23.29-2 Gianotti-Crosti syndrome.

Clinical images are available in hardcopy only.

a

23

a

b

c

d

e

f

g

Clinical images are available in hardcopy only.

b

c

d

e

f

g

h

Fig. 23.30-1 Infectious mononucleosis. a: Lesion on the soft palate. b: Lesion on the shoulder and upper arm.

Clinical features The latency of infectious mononucleosis is 1 to 2 months. After prodromes such as headache and generalized fatigue that persist for several days, a high fever (higher than 39˚C) and intense pharyngeal pain occur. Eruptions appear 4 to 10 p daysq j h i k l m n o after the onset in about 30% of cases (Figs. 23.30-1 and 23.30-2). The eruptions may present as rubella-like eruptions, measles-like eruptions, or erythema multiforme. Drugs (penicillin in particular) induce hypersensitive reaction and aggravate the eruptions. Marked swelling is seen in the whole body, particularly in the cervical lymph nodes. There is tenderness but no spontaneous pain. Splenohepatomegaly accompanied by hepatic dysfunction often occurs. The fever subsides in 7 to 10 days, after which symptoms gradually subside. Thrombocytopenia, hemolytic anemia, encephalomeningitis and Guillain-Barre syndrome occur as complications. Pathogenesis, Epidemiology Infectious mononucleosis is caused by infection of EpsteinBarr virus (EBV). Permanent immunity is obtained from the first infection. present in nthe oralo cavity, p and itq easilyr j EBVk is always i l m spreads orally or through inhalation. The virus invades the body, proliferates in the epithelial cells of the pharyngeal mucosa, and travels to the regional lymph node. It immortalizes B cells by

r

445

C. Viral infections whose main symptom is erythematous eruptions

Laboratory findings The leukocyte count approaches 10,000 per microliter, and more than half of it is mononuclear cells, of which 10% are particularly large atypical lymphocytes. These cells are not B cell but CD8+T cells that are activated to exclude infected cells. Increased serum AST, ALT and ALP titers resulting from liver dysfunction and antibodies produced by B cells lead to elevated levels of polyclonal human immunoglobulin. Paul-Bunnel test, which measures an antibody reaction in blood to sheep erythrocytes, used to be helpful for diagnosis. However, because of the more diagnostically valuable measurement of viral antibody titer (Fig. 23.31), it is no longer used. Diagnosis Infectious mononucleosis is diagnosed by the clinical features, which include marked lymph node enlargement, findings of the blood, and serological findings (Table 23.3).

Clinical images are available in hardcopy only.

c

d

e

g

f

h

i

j

Fig. 23.30-2 Infectious mononucleosis. c: Lesion on the trunk.

titers of antibodies (AB)

latently infecting them through CD21 on their surface. The pathogenesis is thought to be reactivation of B cells against the organic immune mechanism, which induces inflammation. In Japan more than 80% of infants experience EBV exposure through mother-to-child infection, but they are subclinical. Conversely, when the first infection occurs in adolescence, apparent infection takes place as infectious mononucleosis. Patients are often infected by the opposite sex; infectious mononucleosis is commonly called kissing disease. In recent years, antibody prevalence has decreased, and the incidence of infectious mononucleosis is increasing. It occurs most frequently in adolescents between the ages of 14 and 18, regardless of the season. a b

640

incubation period

acute phase

recovery phase

onset

anti-VCA-IgG Ab.

160 anti-VCAIgM Ab. 40 anti-EA-IgG Ab.

anti-EBNA-Ab.

10

Fig. 23.31 Changes of antibody titer related to EBV, and staging of infectious mononucleosis. VCA: viral capsid antigen, EA: early antigen, EBNA: EB nuclear antigen. (Adapted from; Ito A, et al., editors. Textbook of internal medicine. 6th ed. Nakayama Shoten; 2002: 1123-5).

Treatment There are no specific treatments for infectious mononucleosis, other than bed rest and symptomatic therapies. Drugs containing aspirin or penicillin are contraindicated: Aspirin may cause Reye’s syndrome and penicillin may induce hypersensitive reaction as severe eruptions. Table 23.3 Diagnostic criteria for infectious mononucleosis. 3 major symptoms

Remittent fever swelling of systemic lymph nodes, elevated atypical lymphocytes in the peripheral blood

Hematological findings

Rate of lymphocytes + monocytes >50% (typically >60%) Rate of atypical lymphocytes >10% (typically >20%)

Liver function findings

Increases in AST, ALT, and LDH Abnormality of TTT and ZTT

Serological findings

EB virus antibody titer rise 1. Anti-VCA IgG antibody 1: >160 2. Anti-VCA IgM antibody 1: >10 or anti-EA-DR IgG antibody 1: >10 3. Anti-EBNA antibody negative in acute phase All criteria (1.-3.) are generally met. In some cases, 3. and either 1. or 2. are met.

Auxiliary findings

Palpebral edema, palate ecchymosis, pharyngitis, fever unresponsive to antimicrobials for 5 days or more (young person), liver pain by tapotement, and splenohepatomegalies

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D. Specific viral infectious diseases Acquired immunodeficiency syndrome (AIDS) Outline

Diagnosis is confirmed when the CD4+T cell count is found to be reduced by HIV and the diagnostic criteria are met. ● The infection routes are sexual activity, blood infection and mother-to-child transmission. ● Opportunistic infections produce various skin eruptions, but they display atypical clinical features and are difficult to diagnose. ● Mucocutaneous symptoms such as Kaposi’s sarcoma, oral candidiasis, molluscum contagiosum and seborrheic dermatitis may be helpful for diagnosis. Generalized herpes zoster, cryptococcus, tinea and drug eruptions often occur. ●

Clinical images are available in hardcopy only.

Fig. 23.32 Candidiasis of the tongue in a patient with HIV.

Cutaneous symptoms of AIDS The symptoms of AIDS are listed below. A decreased CD4+T cell count is associated with AIDS. ① Kaposi’s sarcoma In Japan, homosexual males are most commonly affected. Multicentric nodules ranging from reddish purple to blackish brown occur most frequently. See Chapter 22 for details. ② Mucocutaneous infectious disease Candidiasis occurs in the oral cavity in all cases of AIDS; it has diagnostic value (Fig. 23.32). Herpes simplex and herpes zoster are easily caused and tend to become generalized and severe. Multiple molluscum contagiosum appears on the face. Verruca vulgaris, cryptococcus, tinea and impetigo also occur and become intractable, displaying atypical clinical features in many cases. Viral infection such as in herpes zoster may recur

23

MEMO

Names of HHV Diagnostic name

Common name

Abbreviation

human herpes virus 1

herpes simplex virus type 1

human herpes virus 2

herpes simplex virus type 2

HSV-1 HSV-2

human herpes virus 3

varicella zoster virus

VZV

human herpes virus 4

Epstein-Barr virus

EBV

human herpes virus 5

cytomegalovirus

CMV

human herpes virus 6

human herpes virus type 6

HHV-6

human herpes virus 7

human herpes virus type 7

HHV-7

human herpes virus 8

human herpes virus type 8

HHV-8

D. Specific viral infectious diseases

447

(/ml)

1,000

asymptomatic herpes zoster

CD4 ＋ T cells

500

Kaposi’s sarcoma

HAART therapies should be started.

400

tuberculosis 300 oral candidiasis diarrhea, weight loss

200 Prevention of carinii pneumonia should be started.

esophageal candidiasis

toxoplasmosis

CMV infection

100 Monthly funduscopy is recommended.

carinii phneumonia cryptococcal meningitis

atypical mycobacteriosis malignant lymphoma AIDS encephalopathy

0 1-2 months

Acute phase

several years to decades

Asymptomatic period

1-3 months

ARC

AIDS

Fig. 23.33 Relation between the number of CD4 ＋ T cells in an HIV patient and the course of opportunistic infection. ARC: AIDS-related complex, HAART: highly active antiretroviral therapy. (Adapted from; the Textbook of internal medicine of Hokkaido University).

and aggravate. ③ Other symptoms Seborrheic dermatitis, psoriasis vulgaris and eosinophilic pustular folliculitis often occur. Drug eruptions are induced by drugs that are taken for other diseases, including for pneumocystis carinii pneumonia. Systemic symptoms of AIDS Primary HIV infection progresses to the asymptomatic stage and then to symptomatic HIV infection, resulting in the onset of AIDS (Fig. 23.33). ① Primary HIV infection Three to 6 weeks after infection, fever, fatigue, sore throat, headache, diarrhea, arthralgia or enlarged lymph nodes as well as papular eruptions on the body occur and resolve. ② Asymptomatic stage This stage lasts for 5 to 10 years. The CD4+T cell count gradually decreases. There is AIDS-related complex (ARC), which includes swelling in two or more lymph nodes (persistent generalized lymphadenopathy (PGL)).

23

448

23

Viral Infections

③ Symptomatic HIV infection The lymph nodes and tissues become damaged. The symptoms are non-specific, such as fever, weight loss and persistent diarrhea. Reduced immune response also leads to herpes zoster, oropharyngeal candidiasis, and seborrheic eczema. ④ Progression from HIV to AIDS HIV antigens begin to increase and the CD4+T cell count falls below 200 per microliter. Opportunistic infection, malignant tumor and exhaustion syndrome occur. Epidemiology HIV/AIDS infected patients numbered 40.3 million worldwide at the end of 2005. The main endemic areas are Africa, Asia and the U.S. The disease has been increasing rapidly in Asia. Japan reported 7,338 cases of HIV infection and 3,623 cases of full-blown Table 23. 4 Revised WHO clinical staging of HIV/AIDS for adults and adolescents (2005). Primary HIV infection Asymptomatic Acute retroviral syndrome Clinical stage 1 Asymptomatic Persistent generalized lymphadenopathy (PGL) Clinical stage 2 Moderate unexplained weight loss (<10% of presumed or measured body weight) Recurrent respiratory tract infections (RTIs, sinusitis, bronchitis, otitis media, pharyngitis) Herpes zoster Angular cheilitis Recurrent oral ulcerations Papular pruritic eruptions Seborrhoeic dermatitis Fungal nail infections of fingers Clinical stage 3 Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations

23

Severe weight loss (>10% of presumed or measured body weight) Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever (intermittent or constant for longer than one month) Oral candidiasis Pulmonary tuberculosis (TB) diagnosed in last two years Severe presumed bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, gingivitis or periodontitis

Clinical stage 4 Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations HIV wasting syndrome Pneumocystis pneumonia Recurrent severe or radiological bacterial pneumonia Chronic herpes simplex infection (orolabial, genital or anorectal of more than one month’s duration) Oesophageal candidiasis Extrapulmonary TB Kaposi’s sarcoma Central nervous system (CNS) toxoplasmosis HIV encephalopathy Conditions where confirmatory diagnostic testing is necessary: Extrapulmonary cryptococcosis including meningitis Disseminated non-tuberculous mycobacteria infection Progressive multifocal leukoencephalopathy (PML) Candida of trachea, bronchi or lungs Cryptosporidiosis Isosporiasis Visceral herpes simplex infection Cytomegalovirus (CMV) infection (retinitis or of an organ other than liver, spleen or lymph nodes) Any disseminated mycosis (e.g. histoplasmosis, coccidiomycosis, penicilliosis) Lymphoma (cerebral or B cell non-Hodgkin) Invasive cervical carcinoma Visceral leishmaniasis

Conditions where confirmatory diagnostic testing is necessary Unexplained anaemia (<8 g/dl), and/or neutropenia (<500/mm3) and or thrombocytopenia (<50,000/mm3) for more than one month The UN defines adolescents as persons aged 10-19 years but, in this table, the category of adults and adolescents comprises people aged 15 years and over for surveillance purposes. For the details of each clinical events or conditions, and the staging of HIV/AIDS for infants and children, please refer to: http://www.who.int/hiv/pub/guidelines/clinicalstaging.pdf.

D. Specific viral infectious diseases

AIDS as of January 2006. Although the main infection route in Japan used to be blood products, the number of sexually transmitted patients has been increasing in recent years (UNAIDS: http:// www.unaids.org/en/HIV_data/2006GlobalReport/default.asp). Pathogenesis, Mechanism AIDS is caused by infection of human immunodeficiency virus (HIV), which can be isolated from blood, serum, genital secretions, breast milk, cerebrospinal fluid, urine, saliva and lacrimal fluid. The main infection routes are sexual activity, blood infection (from blood products, transfusion, sharing of needles for drugs, needle-stick accidents), and mother-to-child infection. The cells targeted by HIV are CD4+T cells and macrophages. The virus invades the cells by binding gp120 on the virus to CD4 on the target cells. In recent years, coreceptors besides CD4 have been found to be involved. When HIV invades the cells, proviral DNA is produced by HIV reverse transcriptase and transcribed into lymphocytic DNA, leading to latent infection. Viral particles synthesized from the implanted DNA mature from the action of protease, and they bud (Fig. 23.34).

449

HIV RNA CD4 chemokine receptors

RNA

reverse transcriptase

CD4＋ T cells

RNA/DNA hybrid double-strand DNA

proviral DNA LTR LTR nucleus RNA HIV RNA

ribosome

proteins protease

Fig. 23.34 Life-cycle of human immunodeficiency virus (HIV).

Diagnosis, Examination Anti-HIV antibody screening is conducted by ELISA. Although the test is highly sensitive, it is ineffective for differential diagnosis because there are false positives in patients with autoimmune disease and it takes 6 to 8 weeks after HIV infection for antibodies to be produced (window period). Screenings that show positive must be re-examined by more specific tests, such as Western blot or PCR. The clinical staging of HIV/AIDS proposed by WHO is shown in Table 23.4. Treatment Reverse transcriptase inhibitors such as azidothymidine (AZT) work effectively as anti-HIV drugs. Highly active antiretroviral therapy (HAART) of reverse transcriptase inhibitors and protease inhibitors improve the prognosis significantly. Combination therapy of anti-HIV drugs is helpful.

23

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Bacterial Infections

Cutaneous bacterial infections are caused by resident or transient bacteria in the epidermis and mucosa. These bacteria invade the skin where its barrier function is weaker, such as at hair follicles, sweat glands or sites of minor trauma. The severity of infection tends to depend on the relative balance between the amount and virulence of the bacteria and the defenses of the host. When a cutaneous bacterial infection is suspected, the causative bacteria must be identified by culture and microbial sensitivity test in order to choose the appropriate antibacterial drugs. This chapter introduces four main subtypes of bacterial infections, classified by the clinical features, and the representative diseases of each subtype: ① acute cutaneous infections (acute pyoderma), ② chronic cutaneous infections (chronic pyoderma), ③ systemic infections caused by toxins that are produced by bacteria, and ④ diseases with specific clinical features that are caused by specific bacteria.

A. Acute pyodermas 1. Impetigo Synonym: Impetigo contagiosa Outline Clinical images are available in hardcopy only.

● Bacterial

infection occurs under the horny cell layer, producing toxins that cause blisters and crusts. The infection spreads by autoinoculation. ● Infants are most frequently affected. Impetigo is divided into bullous impetigo, in which blistering is caused by Staphylococcus aureus, and nonbullous impetigo, in which crusts form from group-A b -hemolytic Streptococcus infection. ● Antibiotics and keeping skin clean are the main treatments.

1) Bullous impetigo Clinical images are available in hardcopy only.

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Fig. 24.1-1 Impetigo. Erosions, blisters, pustules and crusts are present.

Clinical features Bullous impetigo occurs most commonly in infants under age 3, during the summer. It often spreads through epidemic outbreaks at daycare centers or nursery schools. It first occurs at a minor trauma, eczema, or atopic dermatitis that is scratched and affected. Bullous impetigo begins as an itching and slightly inflammatory vesicle that enlarges and forms flaccid blisters. The blisters easily break and become erosive, forming new blisters by spreading peripherally or by being dispersed to distant locations (Figs. 24.1-1 and 24.1-2). Bullous impetigo is transmitted by contact with an infected person. Nikolsky’s sign is negative. It tends to heal without scarring; however, it may progress into staphylococcal 450

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scalded-skin syndrome (SSSS, described later). Pathogenesis Staphylococcus aureus proliferate in the horny cell layer, producing exfoliative toxin (ET), which leads to intraepidermal blisters. Differential diagnosis Insect bites, in which blisters are severely inflammatory and contain sterile components, can be distinguished from bullous impetigo. In staphylococcal scalded-skin syndrome, there are the characteristic features of lesions around the eyes and mouth, and positive Nikolsky’s sign; it should be differentiated from bullous impetigo. Cases whose onset is in adulthood should be differentiated from pemphigus foliaceus.

Clinical images are available in hardcopy only.

Treatment The skin should be kept clean. To prevent transmission, patients should not share towels until crusts form. Topical application of antibiotic ointments and oral cefem antibiotics are useful.

2) Nonbullous impetigo Synonym: Streptococcal impetigo Clinical features, Epidemiology A few blisters form. Nonbullous impetigo begins as small erythema, followed by multiple pustules and formation of yellowishbrown crusts. The crusts are thick and firmly adherent; they discharge pus when pressured. Pain and swelling occur in the regional lymph node, often accompanied by pharyngeal pain and fever. Unlike in bullous impetigo, the onset of nonbullous impetigo is acute and is independent of age and season. The prevalence has been increasing among patients with atopic dermatitis.

Clinical images are available in hardcopy only.

Pathogenesis It is mainly caused by subcorneal infection of group-A bhemolytic Streptococcus (Streptococcus pyogenes). Differential diagnosis It is difficult to distinguish nonbullous impetigo from Kaposi’s varicelliform eruption, particularly in children with atopic dermatitis. The two conditions may occur at the same time.

Clinical images are available in hardcopy only.

Treatment Oral antibiotics are the first-line treatment. Urine analysis is conducted in cases with streptococcal nonbullous impetigo, because glomerulonephritis may occur as a complication. To prevent nephritis, administration of oral antibiotics is continued 10 days after remission of the eruptions.

Fig. 24.1-2 Impetigo. Disseminated vesicles and pustules appear on the arm and face.

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2. Erysipelas Outline ● It

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

24

Clinical images are available in hardcopy only.

is most often caused by group-A b-hemolytic streptococcal infection (Streptococcus pyogenes). ● It occurs with sudden fever. The face is most frequently affected. Sharply demarcated edematous erythema rapidly spreads. Intense tenderness and heat sensation are present. ● Because Streptococcus pyogenes is not easily detected by culture, ASO and ASK values are also measured. ● Penicillin antibiotics are the first-line treatment. Clinical features Sharply demarcated edematous erythema accompanied by chills and fever occurs suddenly, frequently on the face and legs. The erythema surface is tense and glossy. There is intense tenderness. The eruptions spread rapidly and centrifugally. Blistering may occur on the edematous erythema (erysipelas bullosa). When the face is involved, first one side is affected and soon the other side is affected (Fig. 24.2). Systemic symptoms such as fever, nausea and vomiting are present. In about 1 week, the eruptions and fever disappear. However, the eruptions may recur repeatedly on previously affected sites; this is called recurrent erysipelas. Pathogenesis Erysipelas is a purulent inflammatory disease that affects primarily the dermis. It is most frequently caused by group-A bhemolytic streptococcus (Streptococcus pyogenes). Streptococcus pyogenes of other groups (group B in newborns), Staphylococcus aureus, and pneumococcus may cause symptoms similar to those of erysipelas. The pathogenesis of recurrent erysipelas is thought to be local lymphatic blockage or inadequate treatment of erysipelas; the details are unknown. Laboratory findings Antistreptolysin O (ASO) and antistreptokinase (ASK) increase as a result of streptococcal infection. Elevated erythrocyte sedimentation rate, leukocytosis (left shift of the nuclei in leukocytes), and CRP positive are observed. The rate of bacterial detection from tissue fragment or aspirated tissue fluid is low. Streptococcal MEMO Erysipeloid is caused by the gram-positive bacillus Erysipelothrix rhusiopathiae. It occurs most frequently in those who handle animals, meat or seafood. The bacilli invade a minor trauma in a hand or finger. After 1- to 4-day incubation, sharply circumscribed, painful, edematous erythema appears. The lesion enlarges centrifugally, and the center tends to heal. Oral penicillin and tetracycline drugs are extremely effective.

Erysipeloid

Fig. 24.2 Erysipelas. Sharply demarcated, edematous erythema on the face. It is accompanied by flush and tenderness.

Treatment Antibiotics such as penicillin drugs and next-generation oral cefem are administered. Treatment is continued for 10 days after remission to avoid recurrence and to prevent the complication of nephritis.

subcutaneous tissue

Differential diagnosis Cellulitis is more deeply seated than erysipelas, (Fig. 24.3), and its erythema edges are less clearly defined. Necrotizing fasciitis can be distinguished from erysipelas by the rapidly progressing necrotic lesions and intense systemic symptoms. Insect bites, thrombophlebitis, Sweet’s disease, herpes zoster, and carcinoma erysipelatodes also must be differentiated from erysipelas.

muscle

bacteria can be detected by PCR.

dermis epidermis

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folliculitis, furuncle, carbuncle erysipelas necrotizing fascitis

cellulitis

gas gangrene

Fig. 24.3 Acute pyoderma classified by the depth of the affected skin.

3. Cellulitis Outline ● This

acute purulent inflammation occurs extensively in the deep dermal layer and subcutaneous tissue (Fig. 24.3). ● Vaguely demarcated erythema, swelling, localized heat sensation, and sharp pain occur suddenly in the face and extremities. ● It may progress to necrotizing fasciitis or septicemia. ● The main treatments are bed rest and parenteral antibiotics. Clinical features The face and extremities, particularly the lower legs, are most frequently involved. Cellulitis begins with ill-demarcated erythema, swelling and localized heat sensation, quickly becoming intense infiltration that is accompanied by tenderness and spontaneous pain (Figs. 24.4-1 and 24.4-2). Although the infiltration is usually absorbed in the skin over time and heals, a pustule may form at the soft center of the lesion. Systemic symptoms such as fever, headache, chills and arthralgia are present. Cellulitis may progress to necrotizing fasciitis or septicemia.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Pathogenesis Most cases of cellulitis are caused by Staphylococcus aureus. Group-A b-hemolytic Streptococcus and Hemophilus influenzae are among the causative species. Bacteria usually invade the skin through a minor trauma, cutaneous ulcer, folliculitis or tinea pedis, causing cellulitis secondarily; however, the entry route may not be identifiable. Localized impairment in venous circulation and lymphatic edema may induce cellulitis. Laboratory findings Elevated erythrocyte sedimentation rate, leukocytosis (left

24

Fig. 24.4-1 Cellulitis. Vaguely demarcated erythema, swelling, local heat, localized flush and tenderness are present.

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shift of the nuclei in leukocytes), and CRP positive are observed. Hepatic enzyme levels increase in some cases. Bacteria are easily detected from the pus in the lesion. Bacterial culture is more difficult to perform in cases without pus discharge. Clinical images are available in hardcopy only.

Differential diagnosis Lesions caused by erysipelas are superficial and the progressive lesions are sharply circumscribed; however, differentiation from cellulitis is difficult. Necrotizing fasciitis is accompanied by purpura, blisters, bloody blisters and severe systemic symptoms. Thrombophlebitis, erythema nodosum, insect bites and herpes zoster should also be differentiated from cellulitis.

Fig. 24.4-2 Cellulitis.

Treatment Systemic administration or intravenous cefem antibiotics and bed rest are the main treatments. Necrotizing fasciitis is suspected when non-localized symptoms present, including high fever, abnormally high leukocyte and CRP levels, and marked systemic symptoms. Clinical images are available in hardcopy only.

4. Folliculitis Synonym: Acne vulgaris Outline ● It

Fig. 24.5 Folliculitis caused by Malassezia furfur (Chapter 25).

is a localized bacterial infection in a single hair follicle. It is a pustule accompanied by erythema. ● Folliculitis that occurs on the face in puberty is called acne vulgaris. ● It may progress to furuncle or carbuncle. ● The main treatments are skin care and topical or oral antibiotics. Clinical features Erythema and pustule occur at the hair follicle (Fig. 24.5). The skin lesion forms crust in several days and heals without scarring in most cases. Superficial folliculitis that causes multiple eruptions on the face especially in puberty is called acne vulgaris (Chapter 19). Deep-seated folliculitis is accompanied by intense inflammatory symptoms and may progress to furuncle or carbuncle in some cases. The deep-seated folliculitis in the barba areas is called sycosis vulgaris.

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Pathogenesis A hair follicle is infected by Staphylococcus aureus or Staphylococcus epidermidis. A minor trauma, obstruction and scratch around a hair follicle, or topical application of steroids may induce the infection. The hair follicle becomes inflamed. Treatment When there are only a few eruptions, folliculitis heals

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spontaneously and can be left untreated. Topical or oral antibiotics are used in cases with multiple eruptions.

5. Furuncle, Carbuncle Clinical images are available in hardcopy only.

Outline ● It

is advanced folliculitis. Pustular plug forms at the center of the skin lesion. There is purulent swelling. ● It is called a furuncle when a single hair follicle is involved, and a carbuncle when the furuncle spreads to multiple hair follicles. When a furuncle occurs over a long period of time or when multiple furuncles occur at the same time, it is called furunculosis. ● Administration of antibiotics, and incision and drainage of pus are the main treatments. Clinical features A small red follicular papule or pustule (folliculitis) appears and is accompanied by induration. Reddening, tenderness, spontaneous pain, and localized heat sensation become marked. The pustule develops a pustular plug. The induration softens and becomes an abscess. Inflammatory symptoms quickly subside when the pus discharges, and in 1 or 2 weeks the furuncle heals leaving a small scar. When a furuncle repeatedly recurs over a long period of time or when multiple furuncles occur, it is called furunculosis. Immunodeficiency from diabetes or malignant tumor underlies many cases of furunculosis. A carbuncle is a further aggravated furuncle whose inflammation spreads to multiple peripheral hair follicles. It is accompanied by sharp pain, fever and systemic fatigue. Areas of stretching, such as the back, thighs and nape of the neck, are often involved. Carbuncles are dome-shaped, reddening or swelling induration with several pustular plugs at the top (Fig. 24.6).

Clinical images are available in hardcopy only.

Fig. 24.6 Furuncle (top) from folliculitis that progressed to form an abscess. A carbuncle (bottom) results from a furuncle that further progresses and aggregates into a large abscess.

Pathogenesis In most cases, Staphylococcus aureus invades a hair follicle and causes follicular inflammation (Fig. 24.7). An underlying

hair

pustular plug

24 inflammation inflammation abscess folliculitis

furuncle

carbuncle

Fig. 24.7 Classification of bacterial infectious diseases of hair follicles.

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condition such as diabetes is present in the most severe cases of furuncle or carbuncle. Diagnosis Painful, pointy red swelling occurs in a hair follicle. Diagnosis can be confirmed when a pustular plug is seen in the center of the eruption. It may be difficult to differentiate infectious epidermal cyst from furuncle or carbuncle. Clinical images are available in hardcopy only.

Differential diagnosis An infectious epidermal cyst is an inflamed cyst that develops abscesses. White gruel-like contents and the cyst wall discharge from the dome-shaped elevation by small incision. Hidradenitis suppurativa occurs, most frequently on sites with apocrine sweat glands, such as axillary fossae. It progresses slowly, and pustular plugs do not form. Treatment Antibiotics effective against Staphylococcus aureus are administered orally, or intravenously in severe cases. Incision and drainage of pus is conducted in cases with palpable pulsation.

Clinical images are available in hardcopy only.

6. Bacterial paronychia Outline Fig. 24.8 Bacterial paronychia. Purulent inflammation occurs in the fingers, toes, nails and their periphery. It is accompanied by severe tenderness.

● It

is purulent inflammation in the fingers and toes from paronychia. ● The widely used term “whitlow” often refers to herpetic whitlow. ● The main symptom is pulsating reddening accompanied by sharp pain. ● Bed rest, administration of antibacterial drugs, and incision and drainage of pus are the main treatments. Clinical features, Classification Intense throbbing pain, swelling, reddening and heat sensation occur in the periungual region and distal portion of the finger (Fig. 24.8). The nail plate may appear green when the infection is caused by Pseudomonas aeruginosa, which produces that pigment. The nail may exfoliate.

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Pathogenesis The main causes of bacterial paronychia are Staphylococcus aureus, Staphylococcus pyogenes, coliform bacilli, and Pseudomonas aeruginosa. Minor trauma and ingrown nails often induce it. Differential diagnosis Mucous cyst, glomus tumor, metastatic cancer, Osler’s node, herpes whitlow and candidal paronychia should be differentiated

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from whitlow. Treatment Cooling the affected site and administering antibiotics that are effective against Staphylococcus aureus and Staphylococcus pyogenes are the main treatments. Incision and drainage of pus are necessary in many cases.

7. Multiple sweat gland abscesses in infants Multiple painful pustules and subcutaneous induration occur on the face, scalp and buttocks of newborns and infants, most frequently in summer. The eruptions mix with miliaria. Miliaria appears first as a precursor in which Staphylococcus aureus infection occurs, resulting in multiple sweat gland abscesses. Eccrine sweat glands are mainly involved. Antibacterials against Streptococcus are administered. The skin should be kept clean for preventive purposes by frequent changing of clothes.

B. Chronic pyodermas Definition, Classification Chronic pyoderma is a general term for chronic purulent diseases in which multiple obliterative lesions of hair follicles are infected by bacteria, leading to prolonged inflammatory reaction or granulomatous inflammation. Many diagnostic names for chronic pyoderma exist; in fact, they all refer to the same disease. The axillary fossae, scalp and buttocks are most commonly involved. Diseases that are typically classified as chronic pyoderma are listed below (Fig. 24.9). Squamous cell carcinoma may originate from these conditions.

Chronic pyoderma

Scalp/face

Perifolliculitis abscedens et suffodiens Dermatitis papillaris capillitii Folliculitis decalvans

Other than head

Hidradenitis suppurativa Pyoderma chronica glutealis Acne conglobata

Entire body (especially in hairy area)

Multiple infected epidermal cysts

Fig. 24.9 Classification of chronic pyoderma.

Clinical images are available in hardcopy only. Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

24 Fig. 24.11 Dermatitis papillaris capillitii. Thickening and scarring plaques on the back of head and neck.

Fig. 24.10 Hidradenitis suppurativa. Subcutaneous nodules of several millimeters in diameter on the axillary fossae rupture spontaneously. The lesion softens and coalesces, leading to formation of scarring plaques.

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Bacterial Infections

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 24.12 Pyodermia chronica glutealis. Large infiltrating plaques accompanied by pustules, papules, fistulas and abscesses spread to the crotch.

Clinical features, Treatment ① Hidradenitis suppurativa This is hidradenitis in the opening of a hair follicle that is contained in the apocrine sweat gland. The follicular opening is blocked by a keratin plug, leading to secretion deposition where Staphylococcus aureus infects (Fig. 24.10). One or several subcutaneous nodules about 5 mm in diameter occur, most frequently on the axillary fossae of women. The nodules soften, rupture, excrete pus, and heal with scarring. Hidradenitis suppurativa often becomes chronic. Other sites with apocrine sweat glands, such as the genitalia, anus and breasts, may also be involved. Administration of antibiotics and incision and drainage of pus are the main treatments. ② Dermatitis papillaris capillitii This is also known as keloidal folliculitis. Folliculitis appears multiply and continuously on the occipital and nuchal region of middle-aged men. Infiltration of the lesion gradually becomes intense, and connective tissue proliferates and forms a keloidal plaque (Fig. 24.11). Abscess formation and secretion of pus may be present in severe cases. Administration of antibacterials is the first-line treatment. Plastic surgery may be necessary. ③ Pyodermia chronica glutealis Middle-aged men are most frequently affected. Acne-like pustules or papules appear on the lumbar region, genitalia, and thighs, gradually coalescing into a large infiltrative plaque. Abscesses with intricately netted fistulae form, and these excrete pus when pressed (Fig. 24.12). There is hidradenitis suppurativa or acne conglobata as an underlying disease in many cases. Systemic administration of antibiotics, incision and drainage of pus, and removal and skin graft are the main treatments.

C. Systemic infections 1. Staphylococcal scalded-skin syndrome (SSSS) Synonym: Staphylococcal toxic epidermal necrolysis (S-TEN) Outline

It is caused by exfoliative toxins of Staphylococcus aureus in the epidermis. ● It occurs most frequently in infants and children up to age 6. A fever and reddening around the mouth or eyes first appear, followed by painful exfoliation, erosion and blistering. ● Nikolsky’s sign is positive. ● Systemic management and care, and administration of antibiotics are the main treatments. ●

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C. Systemic infections

Clinical features Staphylococcal scalded-skin syndrome (SSSS) occurs most frequently in infants and children up to age 6; it is extremely rare in adults. It begins with reddening and blistering around the mouth, nostrils, and periocular area. This is accompanied by systemic symptoms, such as a fever of about 38°C, irritability, and poor appetite. Wrinkles and fissures around the mouth, eye discharge and crust formation result in characteristic facial features. Erythema occurs on the neck, axillary fossae, and groin, and the whole body skin begins to exfoliate as if burned, which leads to erosion (Figs. 24.13-1 and 24.13-2). Skin at normal sites also exfoliates easily by friction (Nikolsky’s sign is positive). Sharp pain is present. The mucous membranes tend not to be affected. Exfoliation in the scalp can occur in rare cases. SSSS begins to heal after exfoliation is accelerated by systemic administration of antibiotics. The entire course of SSSS is 1 to 2 weeks (Fig. 24.14). Pathogenesis SSSS is caused by exfoliative toxin (ET) produced by Staphylococcus aureus. The nasopharynx, conjunctivae, external ears, and navel are most frequently infected. When ET spreads to the whole body by blood circulation, desmoglein 1, a desmosome structural protein, is broken. Pemphigus foliaceus-like acantholytic and intraepidermal blisters form on the upper epidermal layer. Pathology Acantholysis, lacunae and infiltration of polymorphonuclear cells are observed under the horny cell layer and in the granular cell layer.

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Diagnosis SSSS can be diagnosed by the characteristic facial features, burn-like systemic epidermal exfoliation, marked Nikolsky’s sign, and normality of oral mucosa. Differential diagnosis Most cases of toxic epidermal necrolysis (TEN) are induced by drugs. Histopathologically, there is necrosis in all epidermal layers and severe infiltration to the mucous membranes. Infants are rarely affected by TEN. In widely spread multiple bullous impetigo, the characteristic facial features of SSSS do not occur and Nikolsky’s sign is negative. Treatment Hospitalization and systemic care including transfusion and intravenous antibiotics that are effective against Staphylococcus aureus are given. The affected site is sterilized and treated with topical application of ointments that contain antibiotics or petrolatum. SSSS tends to have a good prognosis; however, it may become severe, with sepsis or pneumonia appearing as complica-

Clinical images are available in hardcopy only.

24

Fig. 24.13-1 Staphylococcal scalded-skin syndrome (SSSS). SSSS is characterized by the facial features that include wrinkles around the mouth, eye discharge and crust formation.

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Clinical images are available in hardcopy only.

body temp. (˚C)

tions in infants and in adults with immunodeficiency.

39 38 37

days

1

2

3

4

5

6

7

8

9 10 11

symptoms

periocular/perioral erythema erythema on the neck erythema on the axilla/genital region perioral fissure Milia-like vesicles pityriatic scales

Clinical images are available in hardcopy only.

lamellar scales on extremities disease stages

erythema

most severe period

scale

Fig. 24.14 Clinical course of staphylococcal scalded-skin syndrome (SSSS).

2. Toxic shock syndrome (TSS) Synonym: Staphylococcal toxic shock syndrome (STSS)

Clinical images are available in hardcopy only.

24

TSS is caused by an exotoxin called toxic shock syndrome toxin (TSS toxin-1 or TSST-1), which is produced by infection and proliferation of Staphylococcus aureus. It may occur in burn patients and women who use sanitary tampons. TSS is a systemic toxic disease whose main symptoms are acute fever, decreased blood pressure, scarlet-fever-like erythema, and multiple organ dysfunction (Fig. 24.15). Diffuse erythema, chills, headache, and arthralgia on the whole body are present, leading to systemic fatigue, vomiting and diarrhea. Antibiotics, mainly b-lactum drugs, are useful in large doses, in combination with immunoglobulin preparations.

3. Scarlet fever (Streptococcal infection) Fig. 24.13-2 Staphylococcal scalded-skin syndrome (SSSS). bottom: There is burn-like exfoliation and erosion of the skin of the whole body. Nikolsky phenomenon is positive.

Outline ● It

is erythematous exanthema and enanthema caused by group-A b-hemolytic streptococci (GAS). ● It begins with pharyngeal pain and high fever. It is

C. Systemic infections

characterized by reddening of the tongue (strawberry tongue) and dense erythema on the whole body. ● Eruptions do not appear around the mouth (perioral pallor). ● Increased antistreptolysin O has diagnostic value. Penicillin is administered. Clinical features Scarlet fever most frequently occurs in late childhood. The incubation period is known to be 2 to 3 days. It begins with a sudden fever and pharyngeal pain, soon followed by strawberry tongue. At the early stages, tongue fur which is often referred to as “white strawberry tongue” is seen in many cases. However, the tongue fur resolves in a day or two, leaving the typical strawberry tongue. Eruptions appear 1 to 2 days after onset of streptococcal infection. Patchy, vivid red papules appear on the neck, axillary fossae, and medial thighs, spreading over the whole body. The eruptions may be accompanied by itching and burning. Diffuse erythema appears on the face, except at the peripheries of the mouth and nasal alae (perioral pallor). Hemorrhagic lesions and systemic lymph node enlargement also occur. As the fever subsides on the third or fourth day after onset, the eruptions begin to disappear. After exfoliation, the eruptions heal without postinflammatory pigmentation. Clinical features that characterize scarlet fever are shown in Fig. 24.16.

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Clinical images are available in hardcopy only.

Fig. 24.15 Toxic shock syndrome.

Pathogenesis Eruptions are caused on the whole body by an exotoxin produced by Streptococcus pyogenes. This bacterium first infects the palatal tonsil or skin.

Differential diagnosis Rubella, Kawasaki disease and drug eruptions should be differentiated from streptococcal fever (Fig. 23.23). Treatment, Prognosis Oral penicillin G is the first-line treatment. Although eruptions disappear in 2 to 3 days, administration of penicillin G should be continued for at least 2 weeks because if the medication is stopped early, Streptococcus may proliferate again in the phar-

body temp. (˚C)

Laboratory findings Elevated levels of ASO and ASK, leukocytosis, and left shift of the nuclei in leukocytes are caused by streptococcal infection. Bacteria are detected from the primary infection site, such as the pharynx. The rapid diagnostic test kit is also useful, although the detection sensitivity is relatively low.

40 39 38 37

days

1 2 3 4 5 6 7 8 9 10 11 eruption

symptoms

Complications Post-infectious complications of Streptococcus pyogenes may occur, such as acute glomerulonephritis and rheumatic fever.

nausea strawberry tongue tonsilitis

incubation period of several days

Fig. 24.16 Clinical course of scarlet fever (streptococcal infection).

24

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Toxic-shock-like syndrome (TSLS)

MEMO

Synonym: Severe invasive streptococcal infection The main cause is streptococcal pyogenic exotoxin (SPE), produced by streptococci and so-called “killer bugs.” Swelling in the extremities and fever occur, rapidly progressing to necrotizing fasciitis (described later), multiple organ failure and shock.

MEMO The immunological response between antigen-presenting cells and T cells is usually mediated by a certain antigen. However, recent study has discovered molecules that induce T-cell activation whether or not the antigen is specific to the T-cell receptor. Those molecules are called superantigens. T cells are activated abnormally by superantigen TSST-1 and SPE-C, leading to severe, systemic inflammatory reaction.

Superantigens

ynx, causing complications such as nephritis or rheumatic fever. After termination of medication, periodic examinations such as urine test are necessary to detect bacteria.

4. Necrotizing fasciitis Outline ● It

is an acute bacterial infection in subcutaneous tissue and superficial fascia (Fig. 24.3). The extremities and genitalia of persons middle-aged and older are most frequently affected. ● The main systemic symptoms are reddening and swelling of skin, ulceration, and fever accompanied by intense pain. ● High doses of antibiotics at the early stages and surgical débridement are the main treatments. Multiple organ failure may lead to death. Clinical features The extremities (lower legs in particular), genitalia and abdomen of persons over age 40 are most frequently affected. Necrotizing fasciitis begins with localized reddening and swelling that rapidly progress with marked systemic symptoms. In 1 to 3 days, purpura, blisters, bloody blisters, concave necrosis and ulceration occur (Fig. 24.17). The sensation of touch is reduced according to the progression of the fasciitis. Even when the periphery of the lesion appears normal to the naked eye, the subcutaneous tissue is affected. Necrotizing fasciitis is characterized by intense systemic symptoms such as high fever, severe arthralgia, muscle pain, shock and multiple organ failure. Necrotizing fasciitis of the genitalia is called Fournier’s gangrene. Necrotizing fasciitis frequently occurs as a complication of toxicshock-like syndrome (MEMO). Pathogenesis The main causative bacteria are Streptococcus pyogenes and anaerobes such as Bacterioides fragilis and Peptostreptococcus anaerobius. Streptococcus pyogenes may infect healthy persons, leading to a sudden onset of necrotizing fasciitis. Anaerobic bacteria tend to infect individuals with an underlying disease, such as diabetes. In some cases, a micro-injury or tinea pedis induces necrotizing fasciitis; however, details of the pathogenesis are unknown.

24

Pathology Edema is marked throughout the dermis. Panniculitis, necrosis, blockage of the blood vessels, and infiltration of polymorphonuclear leukocytes occur from the lower dermal layer to the underlying fat tissue and fascia.

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C. Systemic infections

Laboratory findings Leukocytosis, left shift of the nuclei in leukocytes, elevated levels of CRP, liver failure and coagulation abnormality (when DIC is caused) are present. Prior to administration of antibiotics, bacteria are detected from the puncture fluid, necrotizing tissue at débridement, and blood. MRI, CT, and X-ray images are helpful in testing for the depth and size of lesion and for any retention of gas. Diagnosis Prompt diagnosis and initiation of treatment are important. Necrotizing fasciitis is diagnosed by its sudden onset, rapid progression, intense systemic symptoms, purpura, blisters, bloody blisters and the depth of necrosis measured by débridement. Bacterial culture and skin biopsy are conducted for differential diagnosis. Differential diagnosis Some cases are difficult to differentiate from ordinary cellulitis; however, necrotizing fasciitis is characterized by rapid progression of skin lesion, purpura and bloody blisters, and intense systemic symptoms. The spread of inflammation and involvement of fascia can be determined by MRI. Gas gangrene is found in the muscle layer of the lesion. Marked retention of gas is observed by X-ray. The causative bacteria are Clostridium. Treatment, Prognosis Large doses of antibiotics that are effective against the pathogen (e.g., drugs containing penicillin, clindamycin) and sur-a gical débridement in the early stages are essential. Unless treated in the early stages, the prognosis is extremely poor.

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

h

h

i

Clinical images are available in hardcopy only.

b

c

d

e

f

g

5. Gas gangrene Outline ● Most

cases are caused by anaerobic bacteria such as those of the genus Clostridium. Mortality is high. ● Intense systemic symptoms, muscular necrosis and aerogenesis occur. There is crepitation from gas in the tissues. ● Rapid incision and lavage of the lesion, large doses of antibiotics, and hyperbaric oxygen therapy are the main treatments. Clinical features a b Six to 72 hours after injury, gas gangrene begins with a localized sharp pain. Systemic symptoms such as chills and tachycardia occur. The skin becomes dark purple or blackish. Hematoid serous blisters form. Liquefactive necrosis occurs in muscle tissue. The lesion swells with the gas. The affected site releases foul

Clinical images are available in hardcopy only.

24

c

d

e

f

g

h

i

Fig. 24.17 Necrotizing fasciitis. a, b: Generalized purpura, blisters, bloody blisters, necrosis and ulcer progress quickly. c: Surgical débridement was performed on the lesion. The subcutaneous tissues including fascia had been affected.

j

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odor. When the site is pressed, the gas moves, causing crepitation. Bubbles are observed by X-ray. If left untreated, exotoxin circulates through the bloodstream to the entire body, leading to jaundice, DIC or shock, and resulting in death.

Clinical images are available in hardcopy only.

Fig. 24.18 Osler’s node. Painful erythema on the fingers.

Pathogenesis Gas gangrene is most frequently caused by Clostridium perfringens (formerly Clostridium welchii), Clostridium oedematicus, Clostridium septicum and Clostridium histolyticum, but in some cases by non-Clostridium bacteria. The causal bacteria exist in soil and sometimes in the feces of humans and animals, invading the body through a severely crushed and contaminated wound. These bacteria grow in the anaerobic environment and produce an exotoxin containing proteolytic enzymes, which induce hemolysis and shock. Treatment, Prognosis Quick incision, lavage and surgical débridement are important. At the same time, penicillin G or cefem antibiotics are administrated in large doses. Proliferation of anaerobic bacteria can be prevented by opening the lesion. When the bacteria are anaerobic, hyperbaric oxygen therapy is useful. Systemic care is performed for shock, kidney failure and DIC. Amputation of extremities may be necessary in severe cases.

6. Sepsis Sepsis occurs when a localized cutaneous infection such as in abscess, cellulitis or erysipelas aggravates and disseminates in the blood flow. The bacteria themselves or thrombosis caused by bacteria in the blood induces septic vasculitis, resulting in septicemide formation including erythema, purpura, bloody blisters and pustules.

7. Osler’s node This is transient, painful, nodular erythema that often accompanies subacute bacterial endocarditis. Elevated erythema of 5 mm in diameter occurs on the finger pads, thenar and hypothenar eminences (Fig. 24.18). Sharp pain occurs as a precursor, and a brown patch appears and disappears in 1 or 2 days. Osler’s node accompanied by painless erythema or infiltrative purpura is called Janeway lesion. Allergic reaction against the bacteria and vascular blockage are thought to be the causes in all cases. Osler’s node is known to appear in 15% of infectious endocarditis cases.

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D. Other bacterial infections 1. Trichomycosis palmellina It occurs most frequently in young patients with hyperhidrosis and poor hygiene. Bacteria in colloidal suspension, ranging from yellowish brown to white, attach in clusters to axillary or pubic hairs. The hairs appear to be yellowish and swollen. The condition may be accompanied by foul odor. The pathogenesis in most cases is infection caused by Corynebacterium tenuis, which fluoresces as yellow, white, or blue under Wood’s lamp. The treatments are hygiene improvement, antisepsis, shaving of hair, and topical tetracycline.

2. Erythrasma Clinical features Moist intertriginous regions such as the genitocrural region, axillary fossae and interdigital clefts are most commonly involved. Erythrasma presents as sharply margined, red or reddish-brown patches on whose surface thin and fine scales attach. Papules or blisters do not occur. The center of the lesion does not heal, whereby erythrasma can be distinguished from tinea. Erythrasma tends to be asymptomatic, and there may be itching and burning in rare cases. Pathogenesis Erythrasma is caused by infection in the horny cell layer by Corynebacteria called diphteroids. It often occurs in patients with diabetes, obesity or hyperhidrosis. It is thought to be an opportunistic infection. Diagnosis, Examination It is difficult to differentiate erythrasma in the toe clefts from tinea pedis; however, coral-red fluorescence of erythrasma observed under Wood’s lamp is diagnostic. Since erythrasma and tinea pedis are present together in many cases, mycological examination of scales is necessary. Gram-positive short bacilli are observed in the scales of the lesion. Treatment Topical imidazole antifungal agents and oral erythromycin are effective.

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Bacterial Infections

3. Actinomycosis

Clinical images are available in hardcopy only.

Fig. 24.19 Actinomycosis. A small nodule in the lower lip. Actinomyces israelii was detected by excision.

Clinical features, Classification Actinomycosis is classified by the primary site into cervicofacial actinomycosis, thoracic actinomycosis and abdominal actinomycosis. Of these three subtypes, cervicofacial actinomycosis, which is often induced by dental caries and accompanied by skin lesions, accounts for about half of all actinomycosis cases. Thoracic actinomycosis and abdominal actinomycosis are accompanied by a lesion in the internal organs; unless there is a fistula that affects the skin, these two subtypes are not addressed in dermatology. Reddening, swelling and induration occur, forming a dark red subcutaneous nodule (Fig. 24.19). The nodule partly softens and forms an abscess, leading to a fistula from which pus excretes for a long period of time. A chronic suppurative granulomatous lesion is produced. Mild fever and pain are present in most cases. Actinomycosis is nearly asymptomatic; however, there is difficulty opening the mouth when the masticatory muscle is involved. Pathogenesis Actinomyces israelii, a microbe resident in the human oral cavity, tonsillar fossae and dental plaques, invades the body from a minor injury, proliferates and forms a lesion. Once believed to be a fungus, Actinomyces israelii has been found to be a bacterium.

Fig. 24.20 Histopathology of actinomycosis. A cluster of Actinomyces israelii called a granule or Drüse is observed in the microabscess.

Pathology Microabscess forms in parts of fibrotic inflammatory granulomatous tissue. Actinomycosis is characterized by bacterial mass in the microabscess called “sulfur granule”(Fig. 24.20). Differential diagnosis Nocardia infection causes lesions similar to those of actinomycosis. External dental fistula and inflammatory epidermal cyst should be differentiated from actinomycosis. Treatment Penicillin, tetracycline and cefem antibiotics are administered orally.

24 4. External dental fistula As a result of progression of dental caries or alveolar osteitis, a fistula forms from which pus is excreted (Fig. 24.21). Dental treatment is necessary. It may be misdiagnosed as subcutaneous ulcers such as epidermal cyst or actinomycosis.

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5. Nocardiosis Clinical features Skin lesions caused by nocardiosis are divided by morphology into three subtypes: nocardia mycetoma, which progresses in a process very similar to that of actinomycosis; localized cutaneous nocardiosis, in which subcutaneous abscess forms; and cutaneous lymphatic nocardiosis, in which the lesion enlarges on skin over the lymph vessels. This section focuses on nocardia mycetoma. The legs are most frequently involved. Dark red subcutaneous nodules appear after multiple reddening, swelling and induration. The nodules form abscesses where fistulae are produced, excreting pus for a long period of time. Some of the pus may be granular. Opportunistic infectious nocardiosis invades the lung and progresses in a course similar to that of bacterial pneumonia. A skin lesion and a cerebral abscess occur in cases with hematogeneous dissemination. Pathogenesis Nocardiosis is infection by the anaerobic bacteria of the genus Nocardia. In developing countries, Nocardia in the soil causes skin lesions. The bacteria may invade the lung and cause an opportunistic infection and systemic nocardiosis. Nocardia asteroids is the causative species in most cases. Laboratory findings, Diagnosis Pus or sputum smears are examined after Gram staining. Cultures are obtained on Sabouraud glucose medium. Or Nocardia are identified by skin biopsy. Infiltration of Nocardia into bone is investigated by bone X-ray. Drugs for treatment are chosen by measuring MIC.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 24.21 External dental fistula. A fistula in the lower jaw from inflammation of the dental root, which was caused by dental caries.

Treatment The most effective drug for each case is chosen from among sulfate drugs, minocycline, or penicillin. The treatment is continued for several months. For cases in which all drugs are ineffective or bone is involved, surgical removal is performed.

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Chapter

25

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Fungal Diseases

Fungi are eukaryotic microorganisms that have a cellular wall and do not photosynthesize. They parasitize organisms or exist as spores. In superficial mycoses, fungi invade keratinized tissue such as the horny cell layer, hair and nails. In deep fungal infection, fungi tend to parasitize the dermis and deeper layers.

A. Dermatophytoses Table 25.1 Classification of dermatophytes. Trichophyton T. rubrum T. mentagrophytes T. verrucosum T. violaceum T. schoenleinii T. tonsurans T. concentricum T. equinum Microsporum M. canis M. gypseum M. audouinii M. cookei M. equinum M. ferrugineum M. gallinae M. nanum Epidermophyton E. floccosum

Table 25.2 Classification of tinea. Tinea superficialis

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Tinea pedis Tinea unguium Tinea manus Tinea cruris Tinea corpooris Tinea faciei Tinea capitis Tinea incognito Tinea profunda Kerion celsi Sycosis trichophyica Granuloma trichophyticum Trichophytid

Outline ● They

are caused by dermatophytes that parasitize the skin, the horny cell layer in particular. ● They have various common names, depending on the affected site. The main subtypes are tinea pedis (commonly called athlete’s foot; it accounts for more than half of tinea cases), tinea capitis (scald head, which occurs frequently in childhood), tinea corporis (serpigo, which heals in the center to present a ring shape or lesion) and tinea cruris (jock itch, which involves the genitalia). ● The causative dermatophyte is microscopically identified from scales of the lesion or nail using KOH solution. ● The treatments are topical or oral antifungal agents. Classification Fungi called dermatophytes parasitize the horny cell layer, causing dermatophytosis. Dermatophytes are divided into three genera, each with various species (Table 25.1). The most common dermatophytes are Trichophyton rubrum and Trichophyton mentagrophytes. Because dermatophytes feed on keratin, they usually infect the epidermal horny cell layer, nails and hair follicles, causing lesions (tinea superficialis). Dermatophytosis in which dermatophytes proliferate in the dermis and deep dermal layers is called tinea profunda (Table 25.2). The name of the dermatophytosis differs by the location. Laboratory findings, Diagnosis Diagnosis of dermatophytosis is confirmed when dermatophytes or segmental spores of 3 mm to 4 mm in diameter containing septum are found microscopically with KOH solution in a specimen taken from a scale, blister covering, nail or hair (Figs. 25.1 and 25.2). For observation by light microscopy, a specimen is placed on a slide glass with 1 or 2 drops of 20% KOH solution and then covered with glass and heated for a few minutes. Use of DMSO-added KOH solution makes rapid microscopic examination 468

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possible, because heating is unnecessary. Microscopy with KOH solution is always used when dermatophytosis is suspected. Other major tests are ① culture in Sabouraud’s glucose agar for color tone and morphological observation of the colony, ② morphological observation of conidium by slide culture, ③ molecular examination by PCR or in situ hybridization, and ④ regular hematoxilin-eosin stain. Treatment The basic treatment for all sites infected with tinea superficialis except hairy areas is topical application of antifungal agents such as imidazole. For tinea superficialis in hairy areas, intractable tinea, and tinea profunda with cutaneous and subcutaneous symptoms (e.g., hyperkeratotic tinea pedis, tinea unguium, kerion celsi and granuloma trichophyticum), useful treatments are systemic itraconazole and terbinafine hydrochloride. Griseofulvin is no longer commonly used in Japan.

Fig. 25.1 Trichophyton rubrum. Filamentous hyphae (arrows) are microscopically observed in the horny cell layer with the addition of KOH solution.

a. Superficial dermatophytic infections 1. Tinea pedis It is commonly called athlete’s foot. More than half of tinea cases are tinea pedis. Multiple dermatophytes are seen in the scales. The most common causative fungus is Trichophyton rubrum, followed in frequency by Trichophyton mentagrophytes. Tinea pedis is classified by clinical features into three clinical subtypes. Interdigital erosive: This is the most common of the three subtypes. The fourth toe cleft is most commonly affected. It begins with erythema and vesicles on the interdigital region, leading to scaling. The skin lesion is often infiltrative, softening to become whitish, then exfoliating and becoming erosive (Fig. 25.3). Itching is intense. Secondary infection from erosion causes sharp pain or cellulitis. Vesicular scaling: The plantar arch and the base of the toes are most frequently involved. Multiple vesicles occur and dry, leading to scaling. It tends to appear during the rainy season and subside in autumn. Hyperkeratotic: It occurs most frequently on the heels. Hyperkeratosis causes roughness of the skin. Itching is rarely present, but sharp pain results from cracking. This type is resistant to topical agents; oral antifungals are effective.

Fig. 25.2 Histopathology of tinea. Filamentous hyphae (arrows) are observed in the horny cell layer.

Clinical images are available in hardcopy only.

25 2. Tinea unguium

Clinical images are available in hardcopy only.

Synonym: Onychomycosis (referring to nondermatophytic and dermatophytic infections of nail plate) Tinea unguium frequently occurs on the first toe, often secondarily after tinea pedis. Usually, white nail (leukonychia) first

Fig. 25.3 Tinea pedis. bottom: Tinea pedis with secondary infection.

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Fungal Diseases

Fungi and molds

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

MEMO Molds and mushrooms are fungi. Yeasts, which are used for food products and are mononucleated, are also regarded as fungi. A fungus is composed of a long, thin hypha and a spore that is usually spherical and proliferates by germination. Spores parasitize humans by becoming airborne and attaching to the body, where they form hyphae and reproduce sexually or asexually. Spores may be elongated, depending on the environment, resembling hyphae (pseudohyphae). In culture media such as slide culture, hyphae with a characteristic shape (conidiophores) and asexual spores called conidia form. The conidium consists of the macroconidium and the microconidium. Disease-causing fungi may be identified by the features of the hyphae.

appears at the tip of the toenail and gradually spreads to the nail matrix. The nail becomes fragile and pulverizes when cut with clippers (Fig. 25.4). The fungal elements occur mostly in the deeper portions of the nail plate and in the hyperkeratotic nail bed, rather than on the surface of the nail plate. It is often left untreated for a long period because of its asymptomatic nature. Dermatophytes spread in a patient from a tinea unguium skin lesion to a tinea pedis skin lesion, causing autoinfection and intrafamilial infection. It is sometimes difficult to improve with topical agents. Oral antifungal drugs are more effective.

3. Tinea manus Fig. 25.4 Tinea unguium.

The skin lesion may be hyperkeratotic, vesicular or scaling. One hand, rather than both, tends to be involved (Fig. 25.5). The majority of patients have tinea pedis as a complication. Topical antifungal agents are the main treatment.

4. Tinea cruris It is commonly called “jock itch.” The crotch and buttocks of adult men are most frequently affected; the scrotum is rarely involved. The same type of skin lesion as in tinea corporis appears, often symmetrically. Itching is intense. The treatments are topical and oral antifungal agents. Clinical images are available in hardcopy only.

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Fig. 25.5 Tinea manus. The interdigital areas, fingers and fingernails are frequently affected.

5. Tinea corporis Commonly known as serpigo, it appears as small erythematous papules on the trunk and extremities, gradually spreading centrifugally. The papule tends to heal centrally, giving the lesion a ring shape (Fig. 25.6). Although the center of the lesion subsides with mildly abnormal pigmentation, the periphery is elevated, and papules, vesicles and scales form there. Itching is present. As in tinea pedis, the causative dermatophyte in most cases of tinea corporis is Trichophyton rubrum. Tinea corporis is occasionally caused by Microsporum canis, which parasitizes dogs and cats. Tinea corporis caused by Microsporum canis is characterized by

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Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 25.6 Tinea corporis. Erythematous lesions enlarge centrifugally. The center tends to heal and the rim elevates in a banked shape.

intense inflammatory symptoms. Topical and oral antifungal agents are the main treatments.

6. Tinea faciei It is a Trichophyton infection on the face. Unlike in eczema, the plaques have a slightly elevated rim and tend to heal centrally (Fig. 25.7).

Clinical images are available in hardcopy only.

7. Tinea capitis Commonly known as “scald head,” this occurs most frequently in children. Trichophyton infection in hair follicles results in sharply edged alopecia of the scalp. There are dry pityroid scales and short, broken off hairs in the lesion. Subjective symptoms such as pain are not present. Head hair is sparse. Inflammation is absent. Tinea capitis accompanied by itching and black dot formation at the follicles after the hairs break off is called black dot ringworm; it is associated with misuse of topical steroid ointments, and its incidence has been increasing (Fig. 25.8). Oral antifungal drugs are the first-line treatment. The affected site should be kept clean and dry.

Fig. 25.7 Tinea faciei.

25 Clinical images are available in hardcopy only.

8. Tinea incognito The tinea lesion heals centrally; however, if tinea is misdiagnosed as eczema and topical steroids are misused for treatment,

Fig. 25.8 Tinea capitis.

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Clinical images are available in hardcopy only.

the inflammation subsides and the characteristic central healing in the lesion is not distinctly observed. This complicates diagnosis, and such manifestation is called tinea incognito. Tinea incognito presents clinically atypical cutaneous symptoms in such a case (Fig. 25.9).

b. Deep dermatophytic infection Instead of remaining in their usual location of the epidermal horny cell layer or nail plate, fungi of the genus Trichophyton invade the dermis or subcutaneous tissue, causing skin lesions.

1. Kerion (celsi) Clinical images are available in hardcopy only.

Fig. 25.9 Tinea incognito causes different clinical symptoms from typical tinea.

Clinical images are available in hardcopy only.

Kerion is most common on the scalp but can be produced in other sites. Pityriatic scales appear in the scalp, as in tinea capitis. Inflammation soon occurs, leading to erythema, follicular papules, pustules, and flat or dome-shaped abscesses (Fig. 25.10). The lesions are accompanied by sharp pain, mild pulsation and discharge of pus. The hairs in the lesion fall out. There are systemic symptoms such as swelling of the regional lymph node and fever. Most cases are caused by misuse of steroid ointments on tinea capitis of the scalp, and the incidence has been increasing in recent years. The most common causative agent of kerion celsi is Microsporum canis, which infects humans through their pets. Infants are most frequently affected. Histopathologically, Trichophyton infection is found in hairs; inflammatory cellular infiltration occurs in peripheral follicles. However, Trichophyton does not proliferate in the dermis. The main treatment is oral antifungal agents. The incidence of Trichophyton tonsurans has been increasing in recent years (MEMO).

Fig. 25.10 Kerion (celsi).

2. Tinea barbae

Clinical images are available in hardcopy only.

This is equivalent to kerion celsi at sites with barbae (mustache, beard). The upper lip and its periphery are most frequently involved (Fig. 25.11). Reddening and swelling occur in the entire area with barbae. Pus is discharged from the hair follicles. The hairs come out easily when pulled. Most cases are caused by shaving or misuse of steroids. The treatments are the same as for kerion celsi.

Fig. 25.11 Sycosis trichophytica.

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MEMO Group infection of Trichophyton tonsurans occasionally occurs in Japan. The main skin lesions caused by this fungus are kerion celsi, black-dot ringworm, and tinea corporis. There are cases in which annular erythema, characteristic of tinea, is only vaguely seen. Athletes of sports with much physical contact, such as wrestling and judo, are most frequently affected; all team members should receive a medical checkup. Oral antifungal drugs are the first-line treatment, followed by the same treatments as for tinea.

Trichophyton tonsurans

B. Candidiases

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3. Trichophytic granuloma Synonym: Majocchi’s granuloma A nodule appears intradermally, subcutaneously, or in a skin lesion caused by tinea superficialis. Flat infiltrative plaques or tumorous plaques may form (Fig. 25.12). The granuloma may occur locally (localized granuloma trichophyticum) or multiply on the whole body (generalized ganuloma trichophyticum). Localized ganuloma trichophyticum may be associated with misuse or abuse of topical steroids. Oral antifungal drugs are the main treatment. The condition often occurs in immunocompromised individuals such as organ transplantation recipient.

Clinical images are available in hardcopy only.

Fig. 25.12 Granuloma trichophyticum. Infiltrative skin lesion from prolonged use of topical steroids on granuloma trichophyticum. This was misdiagnosed as eczema.

MEMO Trichophytid is thought to be an allergic reaction to fungal components or metabolites. Like tuberculid, this is an “id” lesion, which reflects the intense inflammatory reaction that accompanies tinea infection. Patients with severe tinea are most frequently affected. Erythema, papules and vesicles occur on contralateral sites of the body that are not affected by tinea. Trichophytid often occurs during the exacerbation of kerion celsi or tinea pedis. Fungi of the genus Trichophyton do not exist at sites of eruptions.

Trichophytid

B. Candidiases Table 25.3 The Candida species most frequently cultured from humans.

Outline ● It

is an infection of the skin or mucous membrane caused by yeasts of the genus Candida. ● It is classified by location and clinical features into three subtypes: cutaneous candidiasis (e.g., candida intertrigo, erythema mycoticum infantile, candidal paronychia), mucosal candidiasis (thrush, genital candidiasis), and atypical candidiasis (e.g., chronic mucocutaneous candidiasis). ● It may also occur as an occupational disease in workers whose hands are in frequent contact with water, or as a sexually transmitted disease or an opportunistic infection resulting from immunodeficiency. ● The affected site should be kept clean and dry. The antifungal imidazole is topically applied.

C. albicans C. tropicalis C. guilliermondii C. krusei C. kefyr C. glabrata C. parapsilosis C. lusitaniae C. zeylanoides C. glabrata

Classification, Pathogenesis, Clinical features There are seven to ten virulent species in the genus Candida (Table 25.3). The main causative species is known to be Candi-

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Fungal Diseases

Table 25.4 Classification of candidiasis. Cutaneous candidiasis Candida intertrigo Interdigital candidiasis (Erosio interdigitalis blastomycetica) Candidal paronychia and onychia (Onychia et paronychia blastomycetica) Canidida onychomycosis Mucosal candidiasis

da albicans. Candidiasis cannot be diagnosed only by culturing fungi taken from the skin lesion, because the fungi inhabit the oral cavity, stool and vagina even in healthy individuals. Proliferation of Candida should be confirmed directly by microscopy of scales, leucorrhoea, or nail fragments. Candidiasis can also be an endogenous mycosis or an opportunistic infection. Candidiasis in dermatology is classified by location and clinical features into three main subtypes: cutaneous, mucosal and atypical. These are subdivided into various diseases (Table 25.4).

Oral candidiasis Genital candidiasis Atypical candidiasis Chronic mucocutaneous candidiasis: CMCC Monilial granuloma

Fig. 25.13 Microscopy of Candida in KOH solution. Filamentous pseudohyphae and racemose spores are present.

Diagnosis Racemose spores and pseudohyphae are observed by direct microscopy with KOH solution (Fig. 25.13). For candidal paronychia, a small amount of horny cell layer scraped by scalpel is examined. Tongue fur or leucorrhea is examined for mucosal lesion. When cultured in Sabouraud’s glucose agar at 25˚C, white or cream-colored aggregation of candida forms in 2 to 3 days. Treatment Most cases are improved by bathing, cleansing, topical application of zinc oxide ointment, and keeping the affected site dry. Topical antifungal agents such as imidazole are extremely effective against cutaneous candidiasis. In oral candidiasis, gargling with amphotericin B syrup or oral miconazole gel is useful. Vaginal suppositories containing miconazole are given to treat genital candidiasis in women. Oral antifungal drugs (e.g., itraconazole and fluconazole) and intravenous fluconazole may be necessary in severe cases.

a. Cutaneous candidiasis 1. Candida intertrigo Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

Fig. 25.14 Interdigital candidiasis (erosio interdigitalis blastomycetica). The third interdigital area is most frequently involved.

Sharply margined erythema with scales at the periphery, erosive in some cases, is induced by sweating or poor hygiene in intertriginous regions, such as the genitocrural region, buttocks, neck and nuchal region, and axillary fossae, or in the inframammary region. Mild itching and sharp pain may be present. Diabetes, malignant tumor or immunodeficiency tend to be associated with the occurrence of candida intertrigo. It is necessary to differentiate candida intertrigo from eczema and Paget’s disease. Candida intertrigo in healthy infants under the age of 3 months is called erythema mycoticum infantile or napkin candidiasis. In this disorder, sharply margined erythema covered with thin scales occurs in the genitocrural region, perianal region, buttocks and thighs. The incidence is highest during summer, from increased perspiration. Candida intertrigo should be differentiated from miliaria and diaper dermatitis.

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2. Interdigital candidiasis Synonym: Erosio interdigitalis blastomycetica The third interdigital cleft is most frequently involved. Erythema appears on the interdigital areas and gradually enlarges. The center of the erythema becomes moist, vivid red and erosive, with an infiltrative white rim (Fig. 25.14). It may be accompanied by mild pain or itching.

Clinical images are available in hardcopy only.

3. Periungual candidiasis As with interdigital candidiasis, it occurs often in those whose hands are in water a great deal. Reddening and swelling occur in the periungual region of the fingers (Fig. 25.15). Pus may be discharged from the nail by pressure. Deformity may appear at the nail root. It takes several months to heal and tends to recur.

Clinical images are available in hardcopy only.

4. Candida onychomycosis Candida albicans parasitizes nails, causing hyperkeratosis under the nail plate and deformity and fragmentation of the nail (Fig. 25.16). Since candida onychomycosis cannot be clinically distinguished from tinea unguium, culture is necessary for diagnosis. Hyphae are the main findings obtained by direct microscopy. Itraconazole, fulconazole and terbinafine are administered orally.

5. Candida granuloma

Fig. 25.15 Periungual candidiasis and onychia (onychia et paronychia blastomycetica).

Clinical images are available in hardcopy only.

It occurs in infancy and progresses slowly. The scalp, face and mucous membranes are commonly infected by Candida albicans, leading to multiple horn-like papules. The nail plates cloud and thicken. Multiple hyphae are found in the granuloma.

b. Mucosal candidiasis

Fig. 25.16 Candida onychomycosis. Candida infected the entire nail, causing deformity.

1. Oral candidiasis This is also known as thrush. A white pseudomembrane or white fur attaches to the oral mucosa and tongue, accompanied by inflammatory flush. Burning sensation and gustatory anesthesia are present. Erosive plaques form at the site where the pseudomembrane detaches, causing sharp pain. Newborns and immunocompromised children are most frequently affected. It heals spontaneously in 1 to 2 weeks. An underlying disease such as diabetes or immunodeficiency is often found in adult cases. Oral candidiasis also occurs as an early symptom of AIDS.

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2. Vulvovaginal candidiasis

MEMO Black hairy tongue A hairy change varying in color from black to brown is observed on the surface of the tongue. There may be blackish pigmentation without hair. It is asymptomatic. The color comes from the production of a pigment from abnormal hyperkeratosis of lingual papillae to which bacteria attach. When Candida is found secondarily, the treatment is the same as for oral candidiasis.

Synonym: Genital candidiasis Pregnant women and adult women with diabetes are frequently affected. There is erosive reddening, formation of white fur, and white vaginal discharge. In male cases, reddening and scaling occur on the corona of the glans penis and foreskin. Genital candidiasis may occur as a symptom of a sexually transmitted disease.

3. Chronic mucocutaneous candidiasis (CMCC)

Clinical images are available in hardcopy only.

Various types of candidiasis appear in childhood accompanying underlying disease such as immunodeficiency or endocrine abnormality, and progress slowly. Multiple skin lesions occur. Unlike other candidiases, chronic mucocutaneous candidiasis (CMCC) is characterized by thick crust that may become verrucous. CMCC responds well to treatment; however, recurrence often results when treatment is terminated. It is intractable.

C. Malassezia infections 1. Pityriasis versicolor Synonym: Tinea versicolor Outline

Clinical images are available in hardcopy only.

● It

is a superficial infection caused by Malassezia furfur, a fungal yeast that is resident in more than 90% of adults. ● Light brown patches or hypopigmented macules 1 to 3 cm in diameter appear on the upper trunk of young men and women and may coalesce into larger macules. ● Scales exfoliate in large amounts from the eruption when scraped. ● For diagnosis, detection of hyphae and microscopic examination with KOH solution or Wood’s lamp (yelloworange fluorescence) are important. Clinical images are available in hardcopy only.

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Fig. 25.17 Pityriasis versicolor, tinea versicolor.

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Clinical features Pityriasis versicolor begins as light brown patches or hypopigmented macules of 5 mm to 20 mm in diameter, most frequently on the trunk, but sometimes on the upper arms and neck (Fig. 25.17). They gradually enlarge and coalesce, presenting larger macules. Pityriasis versicolor in which brown patches are produced is called pityriasis versicolor nigra; pityriasis versicolor in which hypopigmented macules occur is called pityriasis versicolor alba. The patches tend to be asymptomatic, although there

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C. Malassezia infections

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may be mild reddening or itching. Epidemiology Malassezia furfur, the causative fungus of pityriasis versicolor, is resident in the seborrheic regions. It has spherical spores and short, thin hyphae. Pityriasis versicolor tends to occur in spring and summer, when perspiration increases. It is found most frequently in young men and women of about age 20. Laboratory findings A mass of thin hyphae and spherical spores is observed by KOH direct microscopy of the scales. It is easily observed when blue ink is added to the KOH solution (Fig. 25.18). Wood’s lamp shows yellow-orange fluorescence and the size of the skin lesion.

Fig. 25.18 Malassezia furfur. Long, thin hyphae and spherical spores are observed in the scales of pityriasis versicolor by direct microscopy with KOH solution.

Diagnosis Diagnosis of pityriasis versicolor is confirmed by clinical features, KOH direct microscopy and fluorescence under Wood’s lamp. Differential diagnosis KOH direct microscopy is necessary for differential diagnosis. Pityriasis versicolor is differentiated from vitiligo vulgaris, pityriasis rosea and leukoderma pseudosyphiliticum.

Clinical images are available in hardcopy only.

Treatment Pityriasis versicolor heals relatively easily with topical imidazole antifungal agents in about two weeks. It is both chronic and recurrent.

2. Pityrosporum folliculitis This is folliculitis caused by fungi of the genus Malassezia. A red follicular papule of 2 mm to 3 mm in diameter occurs (Fig. 25.19), sometimes accompanied by a small pustule. Itching and sharp pain are present. It accompanies pityriasis versicolor or seborrheic dermatitis in some cases.

Fig. 25.19 Pityrosporum folliculitis

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D. Other deep fungal infections 1. Sporotrichosis Outline

schenckii in the soil enters the human body through a minor injury. Farmers and infants are most commonly affected. ● A red papule or a pustule first occurs, forming a firm subcutaneous nodule or ulcer. ● A granuloma containing asteroid bodies is found histopathologically. Sporotrichin test is positive. p q j ● Oral antifungal h i k m ntreatment. o drugs arel the first-line Potassium iodide and thermotherapy are also effective. ● Sporothrix

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

Clinical images are available in hardcopy only.

a

25

g b c d e f h Fig. 25.20 Sporotrichosis. It most frequently occurs in the temperate regions. a: On the face. b: On the lower leg.

Clinical features After a latency of about 3 weeks, a red papule or pustule occurs at the site of bacterial invasion (Fig. 25.20). The eruption gradually enlarges to a firm, infiltrative, subcutaneous nodule up to 4 cm in diameter. The nodule easily ruptures, and chronic ulcer forms at the center. Mild pain may accompany the ulceration; sporotrichosis is otherwise asymptomatic. It is clinically subdivided into fixed, lymphangitic and systemic. The systemic subtype features generalized subcutaneous nodules on the whole body. In fixed sporotrichosis, eruptions appear solitarily and enlarge gradually. The face and upper arms of children are most commonly involved. Lymphangitic sporotrichosis causes multiple skin lesions along the lymph vessels, and most frequently occurs on the area between the dorsal hands and forearms of p q j i k l m n o r adults. Pathogenesis, Epidemiology Sporotrichosis is caused by Sporothrix schenckii, a fungus that lives in soil and is widely distributed in tropical and temperate regions. It occurs most commonly in tropical and temperate regions and in those who often are exposed to the soil, such as farmers, gardeners, and children who play outdoors. Sporothrix schenckii invades the dermis through a minor injury such as a cut, scratch or splinter. Pathology A nonspecific chronic granulomatous lesion is observed by HE staining. Eosin-chromophilic asteroid bodies may be found in the lesion. In PAS staining, PAS-positive spherical spores may be found at sites with abundant cellular infiltration. Laboratory findings, Diagnosis To confirm the diagnosis, crust or exudative fluid is cultured in

r

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479

Sabouraud’s glucose agar. If a mass of Sporothrix schenckii is identified by slide culture, the diagnosis is sporotrichosis. Sporotrichin intradermal test is a specific test for sporotrichosis: 48 hours after intradermal injection of 0.1 ml sporotrichin antigen fluid in the flexor surface of the forearm, the site is examined for nodule formation; a nodule of 10 mm or larger is considered a positive. If a reddish-brown granulomatous lesion or ulcer that does not respond to antibiotics is found, sporotrichosis is suspected. The crust should be cultured for identification. As it is difficult to find spores and asteroid bodies histopathologically, detection of Sporothrix schenckii using an antibody against its fungal components is also conducted. Treatment Sporotrichosis tends not to heal spontaneously, and progresses for several years. It heals in 1 to 3 months with oral potassium iodide, an extremely effective treatment. Oral itraconazole and terbinafine, thermotherapy and surgical removal are useful.

2. Chromoblastomycosis Synonym: Chromomycosis Outline ● It

is a chronic fungal infection of the skin and subcutaneous tissues caused by dematiaceous fungi. Single or multicelled clusters with thick walls (sclerotic or muriform bodies) form in the tissue. ● The skin lesion is exophytic. It develops slowly. Clinical features Chromoblastomycosis most frequently occurs in men and women in adolescence and later. Red papules solitarily occur on sun-exposed areas of the extremities and face. They enlarge centrifugally and form red scaling or elevated plaques. The lesion may heal centrally. It may be patchy, ring-shaped or horseshoe shaped (Fig. 25.21), and slightly exudative. Since abscess formation and rupture rarely occur, the lesion tends to be dry. The surface of the lesion may become verrucous. However, chromoblastomycosis is nearly asymptomatic. It does not heal spontaneously and progresses slowly. Nevertheless, there have been some fatal cases of generalized chromoblastomycosis. Pathogenesis Dematiaceous fungi invade the skin through trauma, such as a puncture from a splinter, and form a granulomatous lesion. Most cases are caused by Fonsecaea pedrosoi, followed in frequency by Phialophora verrucosa and Cladophialophora carrionii (Cladosporium carrionii). These fungi are resident in soil, plants and rotting wood. Chromoblastomycosis has been reported in North, South and Central America, the Caribbean (Cuba, Jamaica,

25 MEMO According to dermatology textbooks in Europe and the U.S., phaeohyphomycosis is defined as “a group of superficial and deep infections caused by fungi that form pigmented hyphae and yeast-like cells in tissue.” The main causative fungal species are Exophiala jeanselmei and Wangiella dermatitidis.

Phaeohyphomycosis

480

25

Fungal Diseases

Clinical images are available in hardcopy only.

Fig. 25.21 Chromomycosis. The surface of the lesion may appear verrucous.

Martinique), India, South Africa, Madagascar, Australia and Northern Europe. Pathology, Diagnosis Large round or polygonal brown cells called sclerotic cells are observed in scales from the lesion by KOH direct microscopy. Histopathologically, a chronic granulomatous lesion forms in the dermis. The spores are found by regular HE staining. Spores that are phagocytosed by multinucleated giant cells are also observed. Treatment When the lesion is small, it is excised with a margin of 5 mm to 10 mm of normal skin. Oral itraconazole, flucytosine (5-FC), and terbinafine, and local injection of amphotericin B are useful. Thermotherapy, in which a warmer or infrared light is applied for a long time, may cure the lesion.

3. Mycetoma

25

Mycetoma, a localized chronic infection, is classified by the causative microorganism as actinomycetoma (caused by Nocardia brasiliensis, Nocardia otitidiscaviarum, Nocardia asteroids and similar microorganisms) or eumycetoma. A small nodule gradually becomes a pustular granuloma, forming a fistula. Mycetoma is characterized by the formation of aggregated causative organisms (grains) in abscesses. Skin, subcutaneous tissues and bones of the feet and hands are severely affected. Grains are discharged by sinus drainage. Granules are observed by microscopy, appearing as a mass of bacteria 1 mm to 10 mm in diameter. Actinomycotic mycetoma is treated with large longterm doses of sulfa drugs or a combination of sulfamethoxazole and trimethoprim (combined ST). For eumycetoma, intravenous

D. Other deep fungal infections

481

amphotericin B and itraconazole or oral terbinafine are used.

4. Cutaneous aspergillosis Clinical features Cutaneous aspergillosis most frequently occurs at moist sites with chronically poor hygiene. Aspergillus fungi invade a hair follicle or minor injury to produce folliculitis, pyoderma, acnelike papules or carbuncle-like lesion. Classification, Pathogenesis The infection is caused by fungi of the genus Aspergillus, which are found in soil. In most cases, they cause a lesion in the lung or external auditory canal as an opportunistic infection; they almost never cause skin lesions. When Aspergillus travels hematogenously from a pulmonary lesion to the skin, a skin lesion occurs (secondary cutaneous aspergillosis). Poor hygiene, prolonged bed rest, cast immobilization or topical steroids may induce direct parasitism on the skin (primary cutaneous aspergillosis). The several species of Aspergillus fungi include Aspergillus fumigatus and Aspergillus flavus.

5. Cutaneous cryptococcosis Clinical features The face, neck and scalp are most commonly involved. Cutaneous cryptococcosis begins with asymptomatic papules and acne-like eruptions and abscess formation. The various skin lesions include ulcers, firm subcutaneous nodules, and cellulitis. Classification, Pathogenesis Cutaneous cryptococcosis is a dermal or subcutaneous infection caused by Cryptococcus neoformans, a fungus that exists in pigeon droppings and soil. The main subtypes are primary cutaneous cryptococcosis and secondary cutaneous cryptococcosis. The former is caused by direct invasion by the fungi into an external injury and may occur in healthy individuals in rare cases. The latter is caused by hematogenous dissemination from pulmonary granulomas. It is highly associated with immunodeficiency and is a symptom of AIDS. Pathology In primary cutaneous cryptococcosis, a granulomatous lesion forms but there are few cryptococcal capsules. In secondary cutaneous cryptococcosis, mild inflammatory reaction occurs, a gelatinous lesion forms, and numerous cryptococcal capsules appear.

25

482

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Fungal Diseases

Laboratory findings, Diagnosis Cutaneous cryptococcosis is diagnosed when microscopic observation shows characteristically thick, capsulated spores in the pus, or by histopathological identification of Cryptococcus neoformans or separation of cutaneous cryptococcosis in culture. When cultured in Sabouraud’s glucose agar, Cryptococcus neoformans forms glossy white colonies whose colour changes to brown. Identification of this fungus has become possible recently by IF or ELISA. Treatment Intravenous amphotericin B in combination with oral fulcytosine (5-FC) is effective. Antifungal drugs containing imidazole are useful. Primary cutaneous cryptococcosis has a good prognosis; systemic cutaneous cryptococcosis tends to have a poor prognosis.

6. Paracoccidiomycosis Synonym: South American blastomycosis

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

25

Clinical images are available in hardcopy only.

This chronic granulomatous fungal infection is caused by Paracoccidiodes brasiliensis. It is characterized by the formation of a lesion in the lung caused by aspiration. The causative fungi disseminate, leading to papules and ulceration on the skin and mucous membranes, and further spread to the lymph nodes (Figs. 25.22-1 and 25.22-2). Histopathologically, the spores germinate in the characteristic shape of the pilot’s wheel of a ship (Fig. 25.23). Itraconazole or amphotericin B is administered. Paracoccidiomycosis has been reported from most South American countries, particularly Brazil.

7. Coccidioidomycosis This disease is endemic to desert areas of the southwestern United States, Mexico, and Central and South America. Coccidioides immitis aspirated into the lung induces a pulmonary lesion and disseminates hematogenously to the skin, causing a papule, most commonly on the medial area of the face such as the nasal region or nasolabial groove, and also on the extremities. It gradually enlarges and becomes a nodule or plaque, resembling a pustule or cellulitis. When spread to the skin or central nervous system, it may be fatal.

8. North American blastomycosis

Fig. 25.22-1 Paracoccidiomycosis. Papules and ulceration occur in the oral cavity and throat.

It occurs in the North American continent and in parts of Africa. A pulmonary lesion occurs and readily spreads to the skin and bone. Verrucous papules, nodules and ulcers form on the face and in the oral mucosa. The causative fungus is Blastomyces dermatitidis. Potassium iodine agents and amphotericin B are

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483

effective.

9. Histoplasmosis It is caused by Histoplasma capsulatum var. capsulatum and occurs in tropical, subtropical and temperate areas of the world, particularly in the Mississippi Valley and Africa. This fungus is thought to inhabit bat-infested caves. It may infect humans by aspiration, forming a skin lesion hematogenously.

Clinical images are available in hardcopy only.

10. Cutaneous zygomycosis (mucormycosis) It is usually caused by fungi of the orders Mucorales (most commonly by Rhizopus arrhizus). Patients with immunodeficiency or severe diabetes are prone to this infection.

Clinical images are available in hardcopy only.

11. Protothecosis cutanea Caused by Prototheca wickerhamii or Prototheca zopfii, it occurs as an opportunistic infection in patients with immunodeficiency.

Clinical images are available in hardcopy only.

Fig. 25.22-2 Paracoccidiomycosis.

Fig. 25.23 Histopathology of paracoccidiomycosis.

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Mycobacterial Infections

26

Mycobacteria, which stain well in the Ziehl-Neelsen, are acid-fast bacteria that causes mycobacterial infection. Of species in the genus Mycobacterium, three are the main pathogens to human skin: Mycobacterium (M.) tuberculosis, the nontuberculous (atypical) M. marinum, and M. leprae. Diseases caused by these mycobacteria are introduced in this chapter.

A. Mycobacterium tuberculosis infections Outline ● Skin

lesions are caused by M. tuberculosis complex. main type is tuberculosis of the skin (true cutaneous tuberculosis), in which M. tuberculosis causes lesions directly in the skin. Tuberculid is allergic skin reaction to M. tuberculosis. ● Tuberculosis of the skin is further classified into subtypes by clinical features and mechanisms (Table 26.1). Most cases of tuberculosis of the skin are secondary infection in those who have a history of extracutaneous tuberculosis. ● The

Clinical images are available in hardcopy only.

a. Tuberculosis of the skin 1. Lupus vulgaris Outline ● This

a

b

c

d

e

f

g

Fig. 26.1-1 Lupus vulgaris. a: A large, firm, infiltrative elevated plaque occurred on the right cheek.

Classification of mycobacterial infections

MEMO

Mycobacteria include tuberculosis bacteria (M. tuberculosis), nontuberculosis (atypical) bacteria, and leprosy bacilli (M. leprae). These are the pathogens of diseases listed below.

26

was once the most common type of tuberculosis of

j h the skin. i k l m It rarely occurs today.

n

o

p

● Reddish-brown

q

papules appear on the face and neck, coalescing into elevated, infiltrative plaques. ● It is caused by M. tuberculosis that disseminates hematogenously or lymphogenously from a focus of

Causative Mycobacteria

Diagnostic name

M. tuberculosis Tuberculosis of the skin Tuberculid

Bacteria

484

Leprosy

Treatment Isoniazid, Rifampicin

＋

＋

Tuberculin reaction (＋)

−

−

Tuberculin Isoniazid, reaction (＋＋) Rifampicin

＋

DNA homology Minocyclin probing thermotherapy, excision, etc.

−

Skin smear test Multidrug therapy, （−∼＋） new quinolones

M. marinum Nontuberculous −∼＋ and other mycobacterial nontuberculous infection mycobacteria M. leprae

Bacterial Examination culture

−∼＋

r

485

A. Mycobacterium tuberculosis infections Table 26.1 Classification of cutaneous tuberculosis (TB). Disease

Mechanism of skin infection

Frequent site

Lesion of Caseous necrosis Tubercle bacillus other organs in pathological in cutaneous (e.g., lungs) tissue tissue

Remarks

Tuberculosis of the skin Differentiate from DLE and sarcoidosis.

1. Lupus vulgaris Exogenous infection / Face endogenous spread

＋／−

＋

＋

2. Scrofuloderma Endogenous spread Neck

＋

＋＋＋

＋＋

Exogenous infection Extremities

＋／−

＋＋

＋

Immune response to M. tuberculosis (mainly extracuta2. Papulonecrotic neous TB) tuberculid

Lower legs

＋／−

＋＋＋

＋／−

Extensor surfaces of the extremities

＋／−

＋

−

Multiple, contralateral eruptions

3. Lichen scrofulosorum

Trunk

＋

−

−

Most frequently occurs after BCG vaccination.

3. Warty TB

Cold abscess Affects those who have a history of tuberculosis.

Tuberculid 1. Erythema induratum

See Chapter 18.

extracutaneous tuberculosis. progresses slowly, and may progress to squamous cell carcinoma in rare cases.

● It

Clinical features A single or several, unilateral, reddish-brown papules first appear on the face, neck or arms, coalescing into erythematous plaques. The surface of the papules exfoliates, and the centers scar. Papules recur on the scarred areas, gradually and repeatedlya enlarging and coalescing. This leads to the formation of large, firm, elevated plaques (Figs. 26.1-1 to 26.1-3). At the periphery are small reddish-yellow or brown nodules. Yellowish-brown papules resembling apple jelly are observed by diascopy. Lupus vulgaris progresses extremely slowly over the course of many years. In addition to preexisting lesions, ulceration and atrophy occur, sometimes leading to squamous cell carcinoma. Lupus vulgaris is classified by clinical course into flat macular, ulcerative, and proliferative hypertrophic. a b Pathogenesis M. tuberculosis is thought to disseminate hematogenously or lymphogenously from a focus of tuberculosis in extracutaneous organs, such as lungs and lymph nodes. In lupus vulgaris, a tubercle forms by hematogenous dissemination at the first infection of tuberculosis reactivates. Pathology A tubercle consisting of epithelioid cells and Langerhans giant cells accompanied by caseous necrosis appears in the dermis. Diagnosis Lupus vulgaris is diagnosed by the clinical features, pathology, and strong positive in tuberculin skin test. Identification of M.

Clinical images are available in hardcopy only.

b

c

d

e

f

g

h

i

i

j

Clinical images are available in hardcopy only.

c

d

e

f

g

h

Fig. 26.1-2 Lupus vulgaris. b, c: Infiltrative plaque on the nose.

MEMO Lupus is a general term for diseases in which erosive, erythematous ulceration occurs on the face. The name is Latin for wolf, and it comes from the facial appearance that was thought to resemble the bites of a wolf. Until the 19th century lupus was most commonly caused by cutaneous tuberculosis. In recent years, the prevalence of lupus vulgaris has drastically decreased. The term lupus now almost always refers to lupus erythematosus (Chapter 12).

Lupus

26

486

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Mycobacterial Infections

tuberculosis is made by PCR or culture. Differential diagnosis Chronic discoid lupus erythematosus, cutaneous sarcoidosis, tertiary syphilis and sporotrichosis should be differentiated from lupus vulgaris.

Clinical images are available in hardcopy only.

c

d

e

f

g

h

i

j

Treatment Lupus vulgaris responds well to antitubercular drugs. Although the prognosis is good, it leaves distinct scarring. k

l

m

n

o

p

q

r

2. Scrofuloderma Outline ● This

is the most common tuberculosis of the skin. The neck and trunk are most frequently involved. ● It begins as painless subcutaneous nodules. It is characterized by fistula formation and pus discharge from cold abscesses. ● It is caused by M. tuberculosis disseminated from extracutaneous tuberculosis throughout to the skin. ● Cordlike scars form in most cases.

Clinical images are available in hardcopy only.

d

e

f

g

h

Fig. 26.1-3 Lupus vulgaris. d: On the face. e: On the back.

i

j

k

Clinical features, Pathogenesis Scrofuloderma, tuberculosis of the skin, is caused by a lesion in the lung, lymph node, bone, muscle or tendon that continuousp q m to the n skin.oA painless lyl spreads light pinkrsubcutaneous nodule called a cold abscess first appears. It softens and forms a fistula in the skin, from which pus discharges. At a previously formed scrofuloderma, ulceration and characteristic cordlike scarring occur. There is slight localized fever and pain for the entire course of the disease. Diagnosis, Treatment Large quantities of M. tuberculosis are seen in the pus and tissue of the lesion. The treatments for scrofuloderma are the same as for lupus vulgaris. Identification of M. tuberculosis is made by PCR or culture.

3. Warty lupus Synonym: Tuberculosis verrucosa cutis

26

Clinical features, Pathology Warty lupus occurs most frequently at the ends of the extremities, dorsal surfaces of joints, and buttocks, after subjection to external stimulation or injury (Fig. 26.2). Several small, asymptomatic, indurated wart-like papules with a slight inflammatory edge coalesce and enlarge, forming erythematous plaques with

A. Mycobacterium tuberculosis infections

verrucous periphery. The lesions enlarge centrifugally and tend to heal in the center. Warty tuberculosis is an infection of the superficial layers of the skin. There is inflammation with histopathological atypism. Ulceration does not occur. Pathogenesis Warty lupus is a tuberculosis of the skin caused by M. tuberculosis. It occurs from inoculation of organisms into the skin of a previously infected patient who usually has a moderate or high degree of immunity. Diagnosis, Differential diagnosis Identification of M. tuberculosis is made by PCR or culture. Strong positive in tuberculin skin test and pathological findings of the skin are diagnostic. Lupus vulgaris, chromomycosis, viral warts and tinea cruris should be differentiated from warty tuberculosis.

487

Clinical images are available in hardcopy only.

Fig. 26.2 Warty tuberculosis, tuberculosis verrucosa cutis. Keratotic erythematous plaque with verrucous periphery enlarges centrifugally. The center of the lesion shows a tendency to heal.

Treatment Warty lupus responds well to antituberculosis drugs.

b. Tuberculid Tuberculid is a disorder that is associated with a focus of internal tuberculosis. The cutaneous symptoms are thought to be immune reactions in the skin resulting from hematogenous dissemination of M. tuberculosis or its antigens from a primary infection. Individuals with strong antituberculous cell-mediated immunity are affected.

1. Papulonecrotic tuberculid This is thought to be vasculitis caused by allergic reaction to M. tuberculosis. It occurs in young people, most frequently on the extensor surfaces of extremities, particularly on the elbows and popliteal fossae. Multiple, contralateral dark red papules with a diameter of 1 cm or less appear and necrotize, forming pustules and ulceration. They heal with scarring. These eruptions occur in succession and progress slowly, presenting new eruptions mixed with old ones. Antituberculosis drugs are useful.

2. Lichen scrofulosorum Lichen scrofulosorum most frequently occurs after the initial infection of M. tuberculosis or BCG vaccination. Scattered or aggregated, red follicular papules of 1 mm to several millimeters in diameter appear on the trunk or extremities. Histopathologically, epithelial cells and Langerhans giant cells are found in the dermis. There is granulomatous formation; nevertheless, necrosis is not present nor is M. tuberculosis detected. Therefore, lichen scrofulosorum is considered tuberculid, an allergic reaction

26

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Mycobacterial Infections

against fungal compounds. Antituberculosis drugs and minocycline are useful. Most cases heal in several months. See Chapter 18 for erythema induratum.

B. Nontuberculous mycobacterial infections Table 26.2 Nontuberculous mycobacterioses in Japan (1969-1996). # of reported cases

(%)

M. marinum

161

64.1

M. fortuitum

26

10.4

M. avium-intracellulare complex

19

7.6

M. chelonae

18

7.2

M. abscessus

11

4.4

M. kansasii

9

3.6

M. grodonae

2

0.8

M. peregrinum

1

0.4

M. scrofulaceum

1

0.4

M. smegmatis

1

0.4

M. ulcerans-like organism

1

0.4

1

0.4

Pathogen

M. vaccae

251

Total

(Adapted from; Nakajima H, et al. Cutaneous mycobacterial infections, clinical aspects and case reports in Japan. Medical Sense; 1998).

Nontuberculous (atypical) mycobacteriosis is a general term for infections caused by nontuberculous mycobacteria other than M. tuberculosis and M. leprae. The term “nontuberculous mycobacteria” has become more commonly used than “atypical mycobacteria” in recent years. There are about 30 nontuberculous mycobacteria that are pathogenic to humans. The main nontuberculous mycobacteriosis and the number of reported cases are shown in Table 26.2.

1. Mycobacterium marinum infection Synonyms: Fish tank granuloma, Swimming pool granuloma Outline ● Aquarium

staff and tropical fish breeders are most commonly affected. ● Contaminated water from a swimming pool or tropical fish tank enters a minor injury, causing infection. Nodules, exfoliation and ulceration occur. ● Tetracyclines and rifampicin are effective. Clinical features Aquarium staff and tropical fish breeders are commonly infected with M. marinum. The onset is after a 2-week incubation period of infection in an external injury. Areas that are subjected to external friction such as the dorsum of fingers and joints are most commonly involved. Skin lesions accompanied by central reddening and crusting progress to nodular plaques. Scaling and verrucous plaques occur later on. The eruptions are solitary in most cases. However, M. marinum may be disseminated by lymph flow or spread systemically in immunodepressed patients. Pathogenesis Among nontuberculous mycobacteria, M. marinum is the most common cause of skin disease. Because M. marinum favors freshwater environments, most cases of infection are caused by water from swimming pools or fish tanks. Pathology There are findings of pustular inflammation and epithelial cell granuloma in M. marinum infection. It is difficult to detect the mycobacteria from a pathologic specimen.

26

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C. Mycobacterium leprae infection

489

Diagnosis, Differential diagnosis M. marinum infection is suspected when skin lesions in patients whose occupation involves fish are examined. Mycobacteria are detected from the pus, biopsy tissue, or cultured fish tank water. Cutaneous mycosis such as sporotrichosis, various forms of cutaneous tuberculoses, and foreign-body granuloma should be differentiated from M. marinum infection. M. marinum is detected by PCR or cultured pus. Treatment M. marinum infection heals in 2 to 3 months with the administration of tetracycline antibiotics or rifampicin. Since M. marinum is active in the temperature range of 25 to 33˚C, local thermotherapy is helpful. Antibiotics and rifampicin are helpful.

Clinical images are available in hardcopy only.

2. Mycobacterium avium intracellular complex Nodules, ulcers and subcutaneous induration occur on areas subjected to pressure. The extremities and buttocks are most commonly involved. Antituberculosis drugs are used in combination with either macrolide or new quinolone drugs for most cases. Surgical removal may be helpful for localized skin lesions.

3. Mycobacterium fortuitum infection, Mycobacterium chelonae infection A cold abscess, fistula, ulcer or nodule occurs (Fig. 26.3). Antituberculosis agents are often ineffective. Incision, drainage of pus, debridement or excision is often conducted.

4. Mycobacterium kansasii infection A verrucous plaque, nodule or ulcer occurs. Antituberculosis drugs, new quinolone drugs and macrolide drugs are useful.

Fig. 26.3 Mycobacterium fortuitum infection on a woman in her 20s. Pulsating nodules and abscesses occurred in a large area of the trunk. Pus was discharged in large amounts by puncture.

C. Mycobacterium leprae infection Leprosy Synonym: Hansen’s disease Outline ● It

is a chronic infection caused by M. leprae. The skin and peripheral nerves are mainly involved. ● It is classified into tuberculoid leprosy (TT), lepromatous leprosy (LL), borderline leprosy, and indeterminate leprosy (IL), according to the cellular immunity against M. leprae. In TT, there are few erythema, papules, and

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26

490

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Mycobacterial Infections

slightly reduced sensory perception. In LL, M. leprae proliferate in the entire body to form lepromas. ● Multidrug therapy including DDS (dapsone) is the main treatment. Pathogenesis, Epidemiology Leprosy is an infection caused by Mycobacterium leprae. The mechanism of infection has not been fully clarified. Because the pathogenicity of M. leprae is extremely low, the natural immune response usually eliminates the infection. The incubation period is usually 3 to 5 years. This makes the disease rare. Leprosy occurs worldwide, with half of the world’s roughly 12 million cases occurring in Asia and Africa. Clinical features, Classification Leprosy is divided by the strength of the host’s cellular immunity against M. leprae into the subtypes listed below (RidleyJopling classification, Table 26.3). The severity of the skin lesions and peripheral nerve symptoms varies by subtype (Fig. 26.4). Tuberculoid leprosy (TT): This type is mildest. It occurs in hosts with strong cellular immunity. Sharply demarcated, localized, patchy erythema or papules appear singly or multiply. Faded patches also appear. Alopecia and reduced sensation and Table 26.3 Ridley-Jopling classification of leprosy. Clinical findings Number and distribution of Clinical features of eruptions eruptions

Peripheral nerve hypertrophy

Pathological findings

Mild

None

Slight, lymphocytic, perivascular infiltration, perineural cellular infiltration

Elevated erythema with dry surface. Reduced Alopecia is present. sensation, paralytic

Irregular and marked in adjacent areas of the eruptions.

Epithelioid cells, giant cells, and ++ ∼ +++ the lymphocyte in the dermis.

Relatively Borderline leprosy that many is close to tuberculoid leprosy (BT)

Smaller eruptions than those of TT. Macular or plate-like. Vaguely demarcated. Satellite eruptions are present.

Paralytic

Multiple and regular in adjacent areas of the eruptions.

Epithelioid cells enclosed by lymphocyte

+ ∼ ++

Multiple Borderline leprosy (BB)

① Elevated, sharply demarcated erythema. ② Vaguely outlined erythema with a delle-like center. Satellite eruptions may be present.

Mild

Multiple, mild

Diffuse epithelioid cells

±∼+

Multiple/ Macular or plate-like erythema, Borderline leprosy that Asymmetrical papules, or nodules. The eruptions distribution are less glossy than those of LL. is close to lepromatous leprosy (BL)

Mild

From the early stages onward.

① Absent of foamy changes; few lymphocytes ② Histiocytes with foamy changes. (Globi are not produced,)

−∼ ±

Lepromatous Multiple/ leprosy (LL) Symmetrical distribution

Mild. Paralytic Systemic. Occurs at late stages. when the course is prolonged.

Collagen layer is present between a leprous granuloma and epidermis. Foamy structure is present in old leproma.

−

Indeterminate A few leprosy (IL) Tuberculoid leprosy (TT)

26

Lepromin test

Sensation abnormality

Disease type

A few

Vaguely demarcated, flat, macular, light pink

Multiple, macular changes from diffuse infiltration to small nodules. Erythema nodosum leprosum is present. The lesion is glossy and accompanied by alopecia.

(Based on; Ridley DS, Jopling WH. Classification of leprosy according to immunity: a five-group system. Int J Leprosy 1966; 54: 255-73).

−∼ +

C. Mycobacterium leprae infection

● Skin lesion Large elevated erythema Dry skin Hair loss ● Sensory loss Always ● Nerve enlargement Localized

Tuberculoid leprosy (TT)

● Skin lesion Macules, nodules, papules Acanthotic Hair loss

491

● Skin lesion Light red erythema Not elevated Vaguely-demarcated

● Sensory loss Mild

● Sensory loss Mild

● Nerve enlargement Diffuse

● Nerve enlargement None

Lepromatous leprosy (LL)

Intermediate leprosy (IL)

Fig. 26.4 Comparison between lepromatous leprosy, tuberculoid leprosy and indeterminate leprosy.

perspiration are found. Lepromatous leprosy (LL): M. leprae proliferates systemically in hosts with cellular immunodeficiency. A leproma, a mass of histiocytes containing large quantities of M. leprae, forms in the peripheral nerves, eyes and lymph nodes. Multiple nodules appear on the skin. As the infection progresses, visual impairment, neuralgia, and deformity of the face and extremities occur (facies leontina). Borderline leprosy (BT, BL and BB): The clinical condition is intermediate in severity between those of TT and LL (Fig. 26.5). The number of patients with borderline leprosy has been increasing in recent years. Intricate clinical features of TT and LL are observed. Indeterminate leprosy (IL): This type easily escapes diagnosis as leprosy. Two or three flat, poorly demarcated, light pink patches appear. Peripheral nerve symptoms are mild or absent. Characteristic findings of leprosy are not found in a skin biopsy. The WHO classification published in 1995 subdivided indeterminate leprosy into multibacillary (MB) and paucibacillary (PB) subtypes according to the results of skin smear examination, cutaneous symptoms and nervous symptoms. Nervous symptoms tend to precede eruptions. During the course of LL and BL, the symptoms rapidly aggravate in some cases (lepra reaction). Multiple, nodular, erythema-like eruptions accompanied by perspiration and arthralgia may occur on the whole body during the leprosy reaction (erythema nodosum leprosum).

Clinical images are available in hardcopy only.

Fig. 26.5 Borderline leprosy.

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Pathology In tuberculoid leprosy (TT), epithelioid granuloma and Langerhans giant cells surrounded by infiltration of multiple lymphocytes are observed. In lepromatous leprosy (LL), lymphocytes are not fully responsive to M. leprae, and there are few inflammatory lymphocytes. M. leprae proliferates in macrophages. Laboratory findings, Diagnosis Leprosy is diagnosed by skin lesions that are accompanied by reduced sensation, thickening of peripheral nerves, and neurological disorders. M. leprae is detected from the tissue fluid or pathological tissue of the lesion by acid-fast stain. Lepromin test (see Chapter 5) may be used for classification of leprosy: It is strongly positive in TT and weakly positive in BB, BL and LL. However, diagnostic value of lepromin test is limited because the test may be false positive under normal conditions. When direct detection of M. leprae is difficult, such as for the TT type, PCR is performed. Serological anti-PGL-1 assay, a peripheral blood test, has diagnostic value. There are elevated levels of human immunoglobulin and biological false positive (BFP) for syphilis in serological reaction. Differential diagnosis Leprosy should be differentiated from tuberculosis, syphilis, cutaneous mycosis, diseases that are accompanied by peripheral nerve impairment including diabetes and syringomyelia, and mycosis fungoides. Treatment Multidrug therapy of DDS, rifampicin and clofazimine is recommended by WHO. The therapy should be continued for 6 months in mild cases and 2 years in severe cases, until the cure is complete. In recent years, new quinolone antibiotics have also been used. NSAIDs are administered when leprosy reaction causes sharp pain.

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Sexually Transmitted Diseases

Diseases whose main transmission route is sexual intercourse or sexual activity are generically called sexually transmitted diseases (STD). Syphilis, chancroid, lymphogranuloma venereum, and gonorrhea, as well as genital herpes, condyloma acuminatum, scabies and pediculosis pubis are the most common STDs. The rapidly increasing number of STD cases has become a serious social issue. This chapter introduces the STDs that are not discussed in other chapters, such as syphilis, chancroid and lymphogranuloma venereum.

1. Syphilis Outline ● The

causative bacterium is the spirochete Treponema pallidum. ● The various mucocutaneous symptoms include ulceration in the genitalia and eruptions on the whole body. ● In primary syphilis (that in the first 3 months after infection), primary lesions in the genitalia, ulcerative hard chancre and regional lymph node enlargement occur. ● In secondary syphilis (that up to 3 years after infection), syphilitic roseola, papular syphilide, condylomata lata and syphilitic alopecia occur. ● Secondary syphilis recurs every several months, with asymptomatic intermissions (latent syphilis). ● In tertiary syphilis (that more than 3 years after infection), syphilis nodosa and gumma occur in the skin. As systemic symptoms, neurological and cardiovascular symptoms occur. ● There is no primary syphilis in congenital syphilis (transplacental infection). ● Diagnosis is made by detection of the pathogenic microbe and serologic test. Penicillin antibiotics are useful for treatment. Classification, Pathogenesis Syphilis is caused by the spirochete Treponema pallidum. The route is contact infection (acquired syphilis) or intrauterine infection (congenital syphilis). Acquired syphilis is caused by sexual activity in most cases; however, it may be transmitted in healthcare workers non-sexually through work. In rare cases, syphilis may be transmitted by transfusion or by mother-to-child transmission from birth canal infection or breast feeding. Clinical features Syphilis is divided into manifest syphilis and asymptomatic syphilis. In manifest syphilis, lesions occur on the skin and mucosa membranes. Asymptomatic syphilis progresses gradually 493

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Primary

Secondary/Latent

Primary syphilis

Tertiary

Secondary syphilis

Tertiary syphilis

3 months

②hard  chancre

Asymptomatic period (

Serological test (+)

①fever, fatigue ②syphilitic  roseola ③papular syhilide ④condylomata lata  (mucous lesion)

↑

③cardiovascular syphilis ④neurosyphilis

Serological (+)

3 months

6 weeks

3 weeks

infection

②gumma

10 years

∼

Serological (-)

①syphilis nodosa

Recurring secondary syphilis and latent syphilis every several months.

3 years

③bubo  indolenta

∼

Incubation (asymptomatic) period ( 3 weeks)

︶ ①primary  lesion

Fig. 27.1 Clinical course of syphilis.

and symptoms are not apparent. The course of syphilis is divided into four stages: primary, secondary, latent and tertiary (Fig. 27.1). Primary syphilis is highly infectious; tertiary syphilis is not. Congenital syphilis has a specific course. Syphilis was thought to occur as manifest syphilis in various degrees in all syphilis-infected individuals; however, the infection remains latent in many cases.

Clinical images are available in hardcopy only.

Fig. 27.2 Primary lesion. A firm, asymptomatic papule with a diameter of 2 cm occurred on the border of the glans penis and foreskin.

1) Primary syphilis After the initial incubation period of 3 weeks, a firm papule of 1 cm to 2 cm in diameter occurs at the site invaded by the spirochete (Fig. 27.2), gradually ulcerating into a hard chancre. Numerous Treponema pallidum organisms are observed on the surface of the hard chancre by microscopy. Several days after the primary chancre, firm painless enlargement of the regional lymph node occurs, which is called bubo indolenta. These asymptomatic changes often go unnoticed by the patients. The eruption heals spontaneously in about 3 weeks, after which is no skin manifestation for 2 to 6 weeks until occurrence of an eruption in secondary syphilis.

2) Secondary syphilis

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The period from the third month (to the third year) after infection is secondary syphilis. The Treponema pallidum organisms that have proliferated in the regional lymph node at primary syphilis disseminate hematogenously to the whole body, leading

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1. Syphilis

to various asymptomatic eruptions. Antibody titer becomes highest at this stage and decreases thereafter. The eruptions recur and disappear repeatedly for several years. Although eruptions first occur symmetrically on the whole body, they gradually become localized asymmetrically. The main symptoms of the secondary syphilis are the following. ① Syphilitic roseola Multiple, asymptomatic, light pink erythema of 5 mm to 20 mm in diameter occur on the whole body surface, markedly on the palms and soles (Fig. 27.3). These are accompanied by slight fever and systemic fatigue. The skin lesion disappears in several days. ② Papular syphilide Two to 3 weeks after the onset of syphilitic roseola, multiple, vivid red papules of 5 mm to 10 mm in diameter appear, most frequently on the trunk (Fig. 27.4), and most severely on the palms and soles. It is asymptomatic. ③ Papulosquamous eruption (Syphilitic psoriasis) Localized psoriasis-like eruptions occur on the palms and soles; they are highly diagnostic for syphilis. ④ Condylomata lata Highly infectious, moist, flatly elevated papules with a dirty appearance appear on the intertriginous areas of the anus, genitalia, axillary fossae and inframammary region (Fig. 27.5). Treponema pallidum organisms are observed in high concentration in the lesions. a ⑤ Pustular syphilide Multiple pustules occur. Papular syphilide may progress to pustular syphilis in some cases. Immunocompromised patients are most likely to be affected. ⑥ Syphilitic leukoderma It is vaguely demarcated, incompletely hypopigmented leukoderma. It occurs in patients who have darkly pigmented skin. ⑦ Syphilitic paronychia This paronychia is associated with syphilis. There are no clinically characteristic findings in syphilitic paronychia. ⑧ Syphilitic alopecia Six months after infection, multiple patches of hair loss of 5 mm to 20 mm in diameter appear and spread gradually on the entire scalp. It should be differentiated from alopecia areata. ⑨ Syphilitic angina A highly infectious mucosal lesion accompanied by tonsillitis occurs in the oral cavity (Fig. 27.6).

Clinical images are available in hardcopy only.

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Clinical images are available in hardcopy only.

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Fig. 27.3 Syphilitic roseola. a: Erythema up to 1 cm in diameter that is slightly infiltrative at the edge, on the palms. b: Closeup of lesion in another case. The erythema is partially infiltrative. Both cases are secondary syphilis.

3) Latent syphilis Untreated secondary syphilis may resolve in 3 to 12 weeks, leaving the patient asymptomatic. Diagnosis can be made by a positive serology test without any clinical evidence of treponemal infection. Latent syphilis is divided into an early latent stage (within 1 year after onset of disease) and a late latent stage (1 year after onset of disease).

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4) Tertiary syphilis

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

In tertiary syphilis, Treponema pallidum is difficult to detect during the period of 3 to 10 years after infection. Multiple, copper-colored nodules of several centimeters in diameter appear on the face at the early stage of tertiary syphilis and heal with scarring in several months (syphilis nodosa). A few subcutaneous nodules occur, soften and rupture, forming ulcers (gumma). These eruptions are rarely seen today, thanks to improved treatments using antibiotics. After 10 years or more of infection, eruptions are no longer seen. However, the heart, blood vessels and central nervous system become involved (metasyphilis). The main symptoms are myocarditis, aortic aneurysm, myelophthisis and general paresis. Syphilis today rarely progresses to this stage.

5) Congenital syphilis Fig. 27.4 Syphilis papulosa. Multiple, bright red papules of 5 mm to 10 mm occur. They are accompanied by infiltration.

Clinical images are available in hardcopy only.

Treponema pallidum passed through the placenta from the mother infects the child. Intrauterine infection in early pregnancy may result in stillbirth or miscarriage. Therefore, congenital syphilis is usually caused by infection after the first trimester, when the placenta is completely formed. The infection is systemic and hematogenous; congenital syphilis begins with secondary syphilis and without primary syphilis. Within 6 months after birth, symptoms of secondary syphilis appear (early congenital syphilis). Symptoms of tertiary syphilis appear after late childhood (late congenital syphilis). In early congenital syphilis, premature facial aging, radial scarring around the mouth called Parrot’s furrow, syphilitic nephritis, and pseudoparalysis from the sharp pain of osteochondritis (Parrot’s pseudoparalysis) are present. In late congenital syphilis, Hutchinson’s triad (dental abnormality, ocular interstitial keratitis, impairment of vestibulocochlear nerve) becomes pronounced. Pathology Swelling and proliferation of the vascular endothelium and perivascular infiltration of plasma cells and lymphocytes are observed by skin biopsy of a syphilitic eruption. Central caseation necrosis of the eruption and granulomatous infiltration are found after second syphilis.

Fig. 27.5 Condylomata lata. Multiple, flatly elevated infiltrative eruptions, these coalesce in some areas.

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Laboratory findings, Diagnosis Treponema pallidum is investigated by microscopy and serologic test. Because Treponema pallidum cannot be cultured, specimens are collected and directly investigated by microscopy from moist lesions such as a hard chancre, condylomata lata, enanthema in the oral cavity, or pustules. Treponema pallidum stains bluish black in parker ink and shines in dark-field examination. Serological test is useful for finding, screening and judging the progression of syphilis. Nevertheless, the test is negative in the

2. Chancroid

4th to 6th week after infection. The main examinations are serologic test for syphilis (STS) using lipid antigen (cardiolipin), treponemal hemagglutination (TPHA) test, and fluorescent treponemal antibody absorption test (FTA-ABS). The STS results show positive at the early stages of infection, and the elevation of antibody titer closely relates to the disease progression. STS is effective for screening and is used as an index of therapeutic performance. However, STS may show false positive in patients with other disorders, such as collagen disease. Called biological false positive (BFP), it is useful for diagnosis of lupus erythematosus and antiphospholipid syndrome. Because of its high specificity, TPHA and FTA-ABS are used to confirm the diagnosis for individuals who show positive by STS screening. STS and TPHA are compared in Table 27.1. The incidence and progression of syphilis are determined by the combination of TPHA and FTA-ABS.

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Clinical images are available in hardcopy only.

Fig. 27.6 Syphilitic angina.

Treatment Penicillin antibiotics are the first-line treatment. Penicillin-resistant strains have not been found so far. In the late stages of syphilis, the same treatments for early syphilis are repeated every 6 months; nonetheless, the disease tends to be intractable at that stage. Macrolide or tetracycline drugs are given to patients with penicillin hypersensitivity. Although administration of antibiotics at the early stage kills Treponema pallidum quickly and effectively, the residue of dead Treponema pallidum may cause toxic reaction; within several hours of drug intake, a fever of about 40˚C occurs and the syphilis eruptions aggravate (Jarisch-Herxheimer reaction). NSAIDs are administered for this phenomenon. Aqueous penicillin administered by large-bore IV is recommended for neurological syphilis, because oral and intramuscular administration of penicillin fail to reach the cerebrospinal fluid in sufficient concentration. For the reason that HIV carriers may fail to respond well to treatment, larger doses of drugs based on the same treatment for neurological syphilis may be necessary for a prolonged period. Reinfection of Treponema pallidum may occur in some cases.

Serologic test for syphilis MEMO (STS) As described in the text, STS is a nontreponemal screening test using cardiolipin. Several tests have been used which are categorized into STS. ・Glass slide test (venereal disease research laboratory (VDRL)) ・Rapid plasma reagin card test (RRR) ・Complement fixation test ・Wassermann test ・Kahn’s test

2. Chancroid Pathogenesis, Epidemiology Chancroid is an infection caused by the Streptobacillus Haemophilus ducreyi and transmitted by sexual activity. This Gram-negative bacillus stains well in Unna-Pappenheim. Chancroid is most common in tropical and subtropical countries. Clinical features Two to three days after infection, a red papule occurs on the coronal sulcus, foreskin, labium or vaginal opening and becomes pustular, leading to ulceration. The ulcer is accompanied by severe pain and a pustular coat in the center. The ulcer is soft to the

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MEMO Sexually transmitted superinfection of HIV and syphilis has been increasing. Syphilis patients who are immunocompromised from HIV infection are prone to severe symptoms of secondary syphilis. Those cases are often difficult to cure by the usual syphilis treatments. The spread of neurologic syphilis in HIV-positive patients has become a serious problem. HIV-positive patients may have atypical clinical findings of syphilis, serological findings and response to treatments.

HIV and syphilis

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Table 27.1 Interpretation of STS and TPHA results, and courses of action. STS TPHA

Interpretation

Course of action

1. Not syphilis −

−

2. Syphilis, immediately after exposure to Treponema (incubation period)

Perform re-examination in several weeks.

1. Syphilis after treatment 2. Syphilis, many years after onset

−

＋

3. Nonspecific inflammatory reaction (e.g. alveolar pyorrhea)

−

1. Early-stage syphilis infection

Make reexamination after a certain period of time; confirm by FTAABS.

2. BFP caused by other disease

Investigate for diseases other than syphilis, such as autoimmune diseases.

1. Syphilis ＋

＋

Laboratory findings, Diagnosis Chancroid is often diagnosed by the clinical features. The Ito reaction test, an intradermal test using Hemophilus ducreyi vaccine, is no longer conducted. Treatment Azithromycin, ceftriaxone and erythromycin are the first-line drugs. Most Haemophilus ducreyi strains are tolerant to tetracycline, amoxicillin and sulfamethoxazole/trimetoprim.

Confirm the results by FTAABS.

Dilute the serum 4. Zone phenomenon (STS and make was false negative reexamination. from high concentration of antigen)

＋

touch. It begins as a single lesion; however, it rapidly spreads to form multiple lesions from autoinoculation. Two to 3 weeks after onset, painful unilateral swelling occurs in the inguinal lymph node in 25% to 60% of all patients with chancroid.

3. Lymphogranuloma venereum Synonym: Lymphogranuloma inguinale Outline ● It

is an infection by bacteria of the genus Chlamydia. is transmitted by sexual activity. One to two weeks after infection, a small papule or vesicle appears in the genitalia. One to two weeks after the onset of the skin lesion, fever and swelling occur in lymph nodes in the groin and thighs. ● It occurs most frequently in tropics. ● It

Pathogenesis Lymphogranuloma venereum is caused by the Chlamydia trachomatis serovars L1-3.

Initiate treatment.

Confirm by FTA2. BFP and nonspecific reaction ABS.

STS: serologic test for syphilis TPHA: Treponema pallidum hemagglutination test FTA-ABS: fluorescent treponemal antibody absorption test BFP: biological false positive (Adapted from; Sugahara T, et al. Treponema pallidum. Nippon Rinsho 1990; S48: 408-12).

Clinical features Lymphogranuloma venereum occurs most frequently in the tropics. Several days after infection, a small herpes simplex-like papule of 1 mm in diameter occurs singly on the genitalia or anus. The skin lesion is asymptomatic and heals unnoticed. About 1 week later, systemic symptoms such as fever and splenohepatomegaly occur. The regional lymph node becomes firm, swollen and ruptures, discharging pus. The inguinal lymph node of men and the anorectal lymph node of women are often involved. In women there may be vulvar lymphatic edema, elephantiasis-like change, or urethral or rectal stenosis (esthiomène). Laboratory findings, Diagnosis, Treatment Antigen test and PCR are conducted. Chlamydia trachomatis is detected from the skin lesion or lymph fluid by microscopy. Frei test, an intradermal test using fluid taken from the patient’s lymph node, is no longer conducted. Skin biopsy must not be performed, because it may lead to fistula formation. Tetracycline and macrolide drugs are administered orally.

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Skin Diseases Caused by Arthropods and Other Noxious Animals

Various cutaneous symptoms, including blistering and contact dermatitis, allergic reaction and secondary infection, are caused by arthropods. Pathogens transmitted by insects or other noxious animals may cause systemic symptoms. Infestation by arthropods or insects may result in cutaneous symptoms, and various pathogens carried by arthropods and other noxious animals can infect humans.

A. Diseases caused by insects and other noxious animals 1. Insect bite Insect bite is a general term for the dermatitis that is caused by the bite or sting of a mosquito, gnat, horsefly, bee or other insect. It is thought to be an allergic reaction to the salivary components that the insect discharges while sucking blood or to the venom of stings. The severity of the clinical symptoms depends largely on the age of the patient and the severity of allergic reaction. Immediately after an insect bite, itching wheals or erythema appears. There are two major clinical types of insect bites: those of immediate hypersensitivity, in which symptoms subside in 1 to 2 hours, and those of delayed hypersensitivity, in which erythema or blistering may occur 1 to 2 days after a bite (Figs. 28.1-1 and 28.1-2). Treatments are topical steroid application for eruptions, and oral antihistamines for itching lesions. A bee sting may cause an anaphylactic reaction.

Clinical images are available in hardcopy only.

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Fig. 28.1-1 Insect bite. a: Itching erythema on the lower leg. b: A tense blister on the lower leg. c: Insect bite on the eyebrow. Severe edema occurred around the lesion.

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Clinical images are available in hardcopy only.

2. Hypersensitivity to mosquito bite After a mosquito bite, an allergic reaction occurs against the protein in the salivary components of the mosquito, sometimes leading to systemic symptoms such as high fever, liver dysfunction and lymph node enlargement, and cutaneous symptomsa including blistering. Later, swelling, induration, necrosis and ulceration occur. During the course of hypersensitivity to mosquito bite, the histopathological symptoms may resemble those of hydroa vacciniforme. Recent study has found the Epstein-Barr virus (EBV) to be associated with hypersensitivity to mosquito bite. Cases have proven the association between chronic EBV infection and NK/T cell lymphoma. a MEMO Flies lay eggs in necrotic tissue. Eggs and maggots are present at the site, requiring curettage.

Myiasis

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Skin Diseases Caused by Arthropods and Other Noxious Animals

3. Caterpillar dermatitis

Clinical images are available in hardcopy only.

The urticating hairs of larval moths and butterflies (caterpillars) including those of the tussock moth, tea tussock moth and browntail moth cause caterpillar dermatitis. The affected site has tingling pain. Punctate, itching erythema is followed by a red wheal (Fig. 28.2) that progresses to vesicles and papules.

4. Dermatitis linearis Fig. 28.1-2 Insect bite. Small, itching papules of about 5 mm in diameter occur, most frequently on the lower legs.

The hemolymph of the beetle Paederus fuscipes Curtis comes into contact with the skin, causing dermatitis linearis (Fig. 28.3). Two to three days after contact, characteristic linear skin lesions, reddening, vesicles, swelling, burning sensation and sharp pain occur.

5. Scabies Outline ● It

Clinical images are available in hardcopy only.

is an infestation caused by the mite Sarcoptes scabiei var. hominis. Multiple papules occur. Intense itching is present, worsening at night. ● The genitalia, trunk and interdigital areas are most frequently involved. It is characterized by “tunnels” (burrows) in the interdigital area. ● It may be transmitted by bedclothes or skin-to-skin contact. It often occurs as a STD or in-hospital epidemic. ● Benzyl benzoate, topical g -benzenehexachloride and oral ivermectin are the main treatments.

Fig. 28.2 Caterpillar dermatitis. Punctate, itching erythema occurs, accompanied by pruritus and blistering in some areas of the lesion.

Clinical images are available in hardcopy only.

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Fig. 28.3 Dermatitis linearis.

Clinical images are available in hardcopy only.

Fig. 28.4-1 Scabies on the scrotum. Scabies is characterized by small multiple nodules.

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Clinical features Small, multiple, light pink papules 2 mm to 5 mm in diameter occur on the trunk, genitalia, thighs, inner arms and interdigital areas (Figs. 28.4-1 and 28.4-2). Small nodules may form in the genitalia and axillary fossae. Both the papules and nodules are accompanied by intense itching that worsens when the skin is warmed, such as at bedtime. Patients with scabies often complain of difficulty of sleeping from itching. Scratching of the skin lesions may lead to formation of eczematous plaques. When the interdigital areas and palms are involved, there may be slightly elevated, grayish-white linear lesions (mite burrows) several millimeters long where female insects lay eggs. Blistering occurs in some cases (Fig. 28.4-2). Pathogenesis Scabies is an infestation in the epidermal horny cell layer by the mite Sarcoptes (S.) scabiei var. hominis. This mite is ovoid and has body dimensions of 0.4×0.3 mm for males and 0.2×0.15 mm for females, with 4 pairs of legs at the adult stage (Fig. 28.5). A mated female forms a mite burrow in the horny cell layer and lays 1 or 2 eggs daily there, dying in 4 to 5 weeks. Eggs incubate for 3 to 5 days. S. scabiei var. hominis inhabits creases of the skin or the hair follicles and grows to adult stage in 14 to 17 days. Scabies infestation is caused by direct skin-to-skin contact or indirect contact through bedclothes or clothing. The incubation period is about 1 month. Scabies often occurs within a family and at hospitals and eldercare homes. Infection may be direct, from sexual transmission. Norwegian (crusted) scabies is caused by a large number of S. scabiei var. hominis in persons with poor nutrition, poor hygiene or immunosuppression. Under such conditions, scabies is highly contagious and may cause severe symptoms including generalized hyperkeratosis and crusts. Diagnosis When disseminated small papules accompanied by intense itching are found on the trunk, mite burrows should be carefully searched for in the interdigital areas. Multiple papules on the genitalia, particularly on the scrotum or labia majora, should be carefully examined. To confirm the diagnosis, a specimen including the horny cell layer is removed from the skin by pinching with tweezers, scraping the skin with a scalpel, pricking with a needle, or exfoliating with adhesive tape for direct identification of the mite body or eggs by light microscopy. Inquiry on symptoms of scabies among the patient’s family members and partners, and history-taking on sexual activity are helpful. Differential diagnosis Insect bite, eczema and urticaria are differentiated from scabies. Mite burrows and the nodules on the genitalia are useful for differentiation.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 28.4-2 Scabies on the hand and foot of an elderly person. Distinct blistering is present.

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Fig. 28.5 Sarcoptes scabiei var. hominis. a: S. scabiei var. hominis has four pairs of legs. b: Eggs of S. scabiei var. hominis.

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Fig. 28.6 Eggs of the louse Phithilus pubis on pubic hair.

Treatment Topical application of ointments containing sulfur, crotamiton and benzyl benzoate is helpful. Previously, g -BHC (benzene hexachloride) was most commonly used in the U.S. and Europe. It is important to apply the ointment to the entire body skin below the neck of all family members and partners, regardless of whether they are symptomatic. In recent years, oral ivermectin has become available for use. It is extremely effective, requiring only one administration a day. Antihistamines may be used, if necessary. Thorough laundering and sun drying of bedclothes is recommended.

6. Pediculosis Definition, Classification Allergic reaction is induced by a louse that parasitizes human skin to suck blood, causing intense itching. Lice are host-specific and spend their entire life on the host. The three main causative lice of pediculosis are Pediculus capitis (head lice, 2 mm to 4 mm long, inhabiting head hair), Pediculus humanus (clothing or body lice, 2 mm to 4 mm long, inhabiting clothing), and Pthirus pubis (pubic or crab lice, 1 mm long, inhabiting pubic hair; Figs. 28.6 and 28.7). It is impossible to distinguish between Pediculus capitis and Pediculus humanus by appearance.

Fig. 28.7 Pediculosis.

Clinical features A louse parasitizes a hair shaft and lays eggs on the hair. The eggs incubate for about 1 week. The lice mature and suck human blood. In most cases, intense itching begins 1 to 2 months after infection. Eruptions do not usually occur.

a

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Clinical images are available in hardcopy only.

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Fig. 28.8-1 A tick bite. a: Shoulder 2 hours after the bite. The legs of the tick are still moving (the patient is Hiroshi Shimizu, the author of this textbook). b: A tick bite on the eyelid.

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Pathogenesis Pediculus capitis infestation may become epidemic among p q j h i l m at schools n schoolchildren during kgroup activities oro daycare centers. Pthirus pubis infestation is caused most frequently by sexual intercourse. The eyebrows are involved in rare cases. Pediculus humanus infestation is epidemic among individuals under environments with poor hygiene, such as in the homeless. Diagnosis, Treatment Itching on the head or genitalia is the main complaint of a p jwhen pediculosis i k l n It is o important patient, is m suspected. toqsearchr for lice and eggs attached to the hair. Phenothrin shampoos and Skin diseases caused by jellyfish, coral and sea anemones

MEMO

An eruption may be caused by the sting of jellyfish, coral or sea anemones in the ocean. Some marine organisms sting humans with the nematocysts on their tentacles or otherwise injure human skin by contact. Systemic symptoms may be severe.

r

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B. Skin diseases transmitted by insects and other animals

powders are helpful treatments. The family members and sexual partners are also treated to avoid “ping-pong” infestation, in which the disease repeatedly rebounds from untreated to treated persons. Clinical images are available in hardcopy only.

7. Tick bite Clinical features a b Tick bite is caused by ixodid (hard) ticks. Because ticks of the family Ixodidae tend not to be felt when crawling on human skin, they are able to attach insidiously to the face, arms or even the trunk or genitals of humans (Figs. 28.8-1 and 28.8-2). The bite tends to be painless. The main symptoms are inflammation around the bite, erythema, edematous swelling, bleeding and blistering. The mouthpart is firmly fixed in the skin while sucking blood; a tick bite is often found when the complaint has been a wart or skin tumor. A tick that has sucked its fill of blood falls naturally from the skin. Borrelia spirochetes may be transmitted by a tick bite, leading to Lyme disease (described later). Pathogenesis Ixodidae are 2 mm to 8 mm long (Fig. 28.9) and tend to inhabit grasslands or woods. They burrow into the skin of humans and animals to suck blood.

c

d

e

f

g

h

i

j

Fig. 28.8 A tick bite. c: A tick on the neck.

Fig. 28.9 An ixodid tick removed from human skin. It is generally 5 mm to 8 mm long.

Treatment If a tick is forcefully pulled while sucking blood, it may tear, leaving the mouthpart in the skin. This can lead to foreign-body granuloma. The whole tick, including the mouthpart, should be removed by either inserting scissors into the bite spot or punching the site out with the tick attached. Oral administration of tetracycline 1 week after removal is advised as a prophylactic against Lyme disease.

B. Skin diseases transmitted by insects and other animals Table 28.1 Classification of Borrelia species.

is an infection caused by the spirochete bacteria Borrelia burgdorferi sensu lato, transmitted by ticks of the family Ixodidae. ● It occurs most frequently in USA, Scandinavia and central Europe, during spring and summer. ● It begins as erythema chronicum migrans (first stage) and progresses to arthritis and cerebral meningitis (second stage) and then to dysfunction of the joints and central

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" "!

B. burgdorferi B. burgdorferi sensu lato B. garinii B. afzelii

Outline ● It

 !

1. Lyme disease Borrelia

Other Borrelia species

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Skin Diseases Caused by Arthropods and Other Noxious Animals

Table 28.2 Stages and symptoms of Lyme disease. Stage First stage Erythema period

Course of disease Up to 1 month

Clinical findings Erythema chronicum migrans, influenza-like symptoms (fever, headache, generalized malaise, arthralgia)

Second stage Several Dissemina- weeks to several tion period months

Lymphocytoma cutis, choriomeningitis, radiculitis, cranial neuritis, Bell’s palsy

Several Third stage Chronic peri- months to several od years

Acrodermatitis chronica atrophicans, chronic arthritis, chronic encephalomeningitis

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Fig. 28.10-1 Erythema chronicum migrans (ECM) at the first stage of Lyme disease. Ring-shaped eruptions that are characterized by a bright red periphery appear after a tick bite.

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nervous system (third stage) is the first-line treatment.

● Tetracycline

Clinical features Lyme disease occurs from Borrelia (B.) burgdorferi (Table 28.1) infection caused by the bite of ixodid ticks. The course follows repeated remissions and recurrences. It is divided into three stages. Besides the typical courses shown in Table 28.2, courses with localized scleroderma, lichen sclerosus et atrophicus, and Bcell lymphoma have been reported. First stage (erythema period): After an incubation of 3 to 40 days, an erythema or papule occurs at the bite in about half of all cases. Ixodid ticks tend to bite the thighs, groin and axillary fossae. The skin lesion enlarges within several days, forming a characteristic ring-shaped lesion (erythema chronicum migrans, ECM) (Figs. 28.10-1 and 28.10-2). The periphery is vivid red and sometimes elevated. There is discoloration at the center. It is asymptomatic and may become as large as 40 cm in diameter. Influenza-like symptoms such as fever, headache and general malaise, and cerebral meningitis-like symptoms are often present. These subside in several weeks. Secondary multiple annular erythema occurs in about 30% of all cases. Second stage (dissemination period): One to three months after infection, B. burgdorferi spread to the whole body and cause various organ symptoms, such as arthritis, peripheral neuritis, meningitis and dysfunctional transmission of cardiac muscle impulse. Multiple erythema chronicum migrans occurs on the whole body. Dome-shaped tumors may appear on the face (pseudolymphoma, also called lymphadenosis benigna cutis; Chapter 21). Third stage (chronic period): Several months to several years after onset, lesions develop in the joints and central nervous system. Acrodermatitis chronica atrophicans, which is characterized by the insidious onset of painless, dull-red nodules or plaques on the extremities leaving central areas atrophy, occurs as a late skin trauma. Asymptomatic, infiltrative, edematous erythema occurs and enlarges. The skin atrophies and becomes so thin that subcutaneous vessels can be seen. Epidemiology Lyme disease was first recognized in 1975 from a study of epidemic infections whose main symptoms were erythema and arthritis, made in Lyme, Connecticut (USA). Lyme disease occurs worldwide, especially in the U.S.A., Scandinavia and central Europe. Pathogenesis Lyme disease is caused by spirochete bacteria B. burgdorferi sensu lato, mainly by B. burgdorferi, a tick-borne spirochete bacterium, most frequently transmitted by the ixodid tick Ixodae ovatus. B. burgdorferi inhabits the midgut of the ticks, which

B. Skin diseases transmitted by insects and other animals

505

burrow into human skin. The bacteria spread hematogenously, causing systemic lesions. Laboratory findings Detection of specific antibody: IgM-specific antibodies are detected at the early stage; IgG-specific antibodies are detected later. The specific antibodies may be false positive in patients with systemic lupus erythematosus or rheumatoid arthritis. Detection of B. burgdorferi sensu lato: The bacteria are isolated from blood, cerebrospinal fluid or skin lesion for culturing. Borrelia proteins can be detected by Western blot, and Borrelia DNA can be identified by nested PCR. Diagnosis, Differential diagnosis Diagnosis can be made by the tick bite and by erythema chronicum migrans (ECM). To confirm the diagnosis, an antibody test is conducted.

Clinical images are available in hardcopy only.

Fig. 28.10-2 Erythema chronicum migrans (ECM).

Treatment Doxycycline, penicillin or cefoxime is orally administered for 20 days. Cefem drugs are used at the second and third stages of the disease because they are transported to the nerves in sufficient concentrations.

2. Leishmaniasis Definition Leishmaniasis is a parasitic infection caused by protozoa of the genus Leishmania. Several species in the genus cause leishmaniasis, and each species tends to occupy a particular zoogeographical zone. Leishmania protozoa are transmitted to humans by bloodsucking sand flies. Human leishmaniasis is usually classified as cutaneous or visceral. Leishmaniasis is endemic in 88 countries, occuring most frequently in Brazil, Iran, Afghanistan and Sudan. Leishmaniasis is classified into three subtypes by Leishmania species. The distribution and clinical features differ for each type. Clinical features, Classification ① Cutaneous leishmaniasis The causative protozoan of cutaneous leishmaniasis is Leishmania tropica, which is predominantly distributed in Africa. The main parasite hosts are dogs and rodents. A painless papule appears at the bite and progresses to an ulcer that is accompanied by induration and enlargement. The skin lesion heals with scarring. The patient obtains permanent immunity. ② Mucocutaneous leishmaniasis The causative protozoan of mucocutaneous leishmaniasis is Leishmania braziliensis, which inhabits South America, is carried by dogs and rodents, and is transmitted to humans by sand

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Skin Diseases Caused by Arthropods and Other Noxious Animals

flies. Tumors and odorous ulcers form. For decades after an infection, secondary ulceration involving the skin, mucosa and bones occurs in the ears, nasal cavity, oral cavity, pharynx and esophagus. ③ Visceral leishmaniasis The causative protozoan of visceral leishmaniasis is Leishmania donobani, which inhibits many countries, particularly India and parts of South America and Africa. It parasitizes human liver, spleen, bone marrow and leukocytes. After an incubation period of several months, remittent fever, anemia and splenohepatomegaly occur. At the terminal stages, black pigmentation appears in the skin of the abdomen, hands and feet. Examination, Treatment History of sandfly bites or exposure to an endemic area is important for diagnosis. The causative protozoan of Leishmaniasis is detected from skin lesions, blood or bone marrow. Amastigotes are observed in Gimza-stained smears from skin lesion by direct microscopy. Leishmanial DNA is found by PCR. Pentostam, a pentavalent antimony drug, is the first-line treatment.

3. Cat scratch disease, Cat scratch fever Infection is caused by Bartonella henselae, a gram-negative bacillus, after a cat scratch or bite. Among cats, the bacillus is transmitted by fleas. After a latency of several days to 2 weeks, a red papule and crust appear at the inoculated site. One to three weeks later, painful swelling accompanied by systemic symptoms including fever and headache occurs in the regional lymph node. It resolves spontaneously in several weeks to several months. In persistent cases, trimethoprim, ciprofloxacin, cefem regimen, tetracycline or macrolide antibiotics are administered orally.

4. Tsutsugamushi disease Synonym: Scrub typhus Outline ● It

is a rickettsial infection caused by the obligate intracellular bacterium Orientia tsutsugamushi and transmitted by the mite Leptotrombidium akamushi. ● It is characterized by high fever and light pink eruptions 2 mm to 5 mm in diameter on the trunk and extremities. ● Careful observation may reveal the bite of the mite Leptotrombidium akamushi. ● Tetracycline and chloramphenicol are effective treatments.

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Clinical features Five to fourteen days after a bite by the mite Leptotrombidium

B. Skin diseases transmitted by insects and other animals

Pathogenesis, Epidemiology Tsutsugamushi disease is a rickettsial infection caused by the obligate intracellular bacterium Orientia tsutsugamushi and transmitted by the mites Leptotrombidium akamushi, Leptotrombidium pallidum, and Leptotrombidium scutellare. These feed on field mice; however, they may attach to humans. Orientia tsutsugamushi in the body of Leptotrombidium akamushi invades the human body. Fewer than 1% of all Leptotrombidium akamushi are thought to carry Orientia tsutsugamushi. Tsutsugamushi disease is not transmitted from human to human. The prevalence of tsutsugamushi disease decreased in the 1960s. Use bans on chloramphenicol initiated in 1976 for its side effects have resulted in increased numbers of cases. There are more than 1,000 new cases annually throughout Japan.

body temp. (˚C)

40 39 38 37

days

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 erythema

symptoms

akamushi, a fever of about 40 ˚C occurs, accompanied by sudden chills and headache (Fig. 28.11). A bite can be found by careful examination of the trunk, genitalia and axillary fossa. The bite presents infiltrative erythema 1 to 2 cm in diameter with black crusts at the center. Two to three days after the onset, light pink eruptions appear on the trunk and extremities, disappearing in 7 to 10 days. There is systemic painful swelling of lymph nodes, conjunctival congestion, pharyngeal reddening, splenohepatomegaly and hallucinations from high fever.

507

incubation period

chills, headache, arthralgia

lymphadenopathy, hepatosplenomegaly, pneumonia, conjunctivitis 10 ∼ 14 days

Fig. 28.11 Clinical course of tsutsugamushi disease.

Diagnosis, Differential diagnosis Leptotrombidium akamushi bites, eruptions, increased levels of anti-Rickettsial IgM antibodies, and detection of rickettsial DNA are diagnostic for tsutsugamushi disease. Other rickettsial diseases such as Rickettsia japonica infection and Rocky Mountain spotted fever should be carefully differentiated from tsutsugamushi disease (Table 28.3). Treatment Tetracycline or chloramphenicol is administered. With appropriate treatment, the mortality is less than 1%. Without proper Table 28.3 Comparisons between tsutsugamushi disease and diseases that resemble it. Tsutsugamushi disease

Japanese spotted fever

Rocky Mountain spotted fever

Rickettsia pathogen

Orientia tsutsugamushi

Rickettsia japonica

Rickettsia rickettsii

Incubation period

10-14 days

2-8 days

3-12 days

Season of common infection

Autumn, winter, spring (new type); April to October summer (classical type)

Early summer

Erythema

Most commonly on the trunk, little subcutaneous bleeding

Extremities tend to be involved.

Most of the body, large ecchymosis

Palms and soles are not involved.

Palms and soles are also involved. Necrosis in the ends of fingers and toes, tip of the nose, and ears

Large (about 10 mm in diameter)

Small (about 5 mm in diameter)

Not found

Swelling in lymph nodes Systemic

Localized

(-)

Treatment

Tetracycline, chloramphenicol

Bite

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Skin Diseases Caused by Arthropods and Other Noxious Animals

treatment, the disease may cause DIC and the mortality is about 30%.

5. Lymphatic filariasis The causative filarial worms of lymphatic filariasis, Wuchereria bancrofti and Brugia malayi, are carried by mosquitoes. These parasitic nematodes invade the human body and inhabit the lymph system, causing inflammation in lymph nodes and lymph vessels and lymphatic obstruction. They lead to lymphatic edema or testicular hydrocele, progressing to elephantiasis. Diethylcarbamazine and ivermectin are administered.

C. Diseases caused by parasitic worms Creeping eruption A cutaneous parasitic larva causes a linear eruption called “creeping eruption” when it moves in the skin (Fig. 28.12). In this textbook two frequent types of creeping eruption are described; cutaneous larva migrans and cutaneous gnathostomiasis. ① Cutaneous larva migrans Ancylostoma braziliense, a larva of hookworms of dogs and other mammals, mainly causes creeping eruption in tropical/subtropical areas such as southeastern United States. A few days after skin contact with contaminated sand or soil, characteristically pruritic linear or serpentine erythema occurs. Feet, buttocks and genitalia are frequently involved. ② Cutaneous gnathostomiasis Cutaneous gnathostomiasis results from ingestion of the thirdstage larvae of the nematode Gnathostoma spinigerum transmitted by eating raw snakes, freshwater fish or frogs. Several weeks to several months after eating a contaminated animal, localized edema and induration occur. The larva continues to move, causing linear eruptions in the trunk and the thighs. Common endemic areas are Southeast Asia (especially Thailand and Japan) and Latin America (mainly Mexico and Ecuador). Other species may cause creeping eruption, such as the larvae of Spinometra mansoni (found in amphibian and poultry meat) and nematodes of the superfamily Spiruroidea (found in softshelled tortoises and squid). Treatment is removal of the parasite. Oral albendazole and ivermectin are effective.

Clinical images are available in hardcopy only.

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Fig. 28.12 Creeping eruption: cutaneous gnathostomiasis caused by linear movement of a parasitic larva in human skin.

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Genodermatoses: Genetic Counseling and Prenatal Diagnosis

Prenatal diagnosis (PND) has become technically possible in cases where there is at high risk of severe genetic disease, thanks to recent advances in molecular biology and diagnostic technology. In dermatology, PND of severe skin diseases can be performed at the request of the parents. However, genetic counseling should be thoroughly and carefully made from the ethical point of view, and patients and their families should be provided with accurate information on the diseases. It is important to remember that the final decision of confirmation of pregnancy should always be left to the client. This chapter compiles genodermatoses and their causative genes and proteins, and introduces the latest advances in PND, genetic counseling and gene therapy.

A. Genodermatoses Outline ● The

term “genodermatoses” tends to refer to monogenic diseases. ● In recent years, the causative genes and proteins have been identified for many genodermatoses. MEMO Updated information of the human genome and genetic diseases

What are genodermatoses? “Genodermatoses” usually refers to diseases caused by monogenic abnormality. This textbook addresses genetic diseases separately in terms of their clinical features: It describes ichthyosis in the chapter on keratinization, epidermolysis bullosa in that on blistering diseases, and oculocutaneous albinism in that on disorders of skin color. The human genome project, which was completed in 2003, mapped and sequenced the 3 billion nucleotides in the human genome to identify all human genes. It has been clarified that the human genome consists of 22,000 genes, which produce about 100,000 proteins. Accordingly, almost all of the genes and proteins that are responsible for monogenic diseases including genodermatoses are being clarified. The major genodermatoses and the causative genes and proteins that have been identified so far are shown in Table 29.1. Nevertheless, the pathogeneses of multifactorial genetic diseases, such as psoriasis vulgaris and atopic dermatitis, have not been fully resolved. These diseases are not usually referred to as genodermatoses. The genes that are associated with the onset of these diseases are called disease-related genes or predisposing factors; their importance to the disease is considerably different from that of monogenic causative genes for genodermatoses.

The pathological conditions of genodermatoses are being clarified every day, and what was once common knowledge is no longer enough in responding to patients and their families. Fortunately, improvements of information technology, including the Internet, have contributed to the spread of up-todate information on the human genome and genetic diseases. This information is now available for free to anyone. ① The National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/) The site provides updated information on the Human Genome Project. ② Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=OMIM/) Six thousand human Mendelian disorders and their characteristics are listed. The latest information and documents on diseases caused by genetic mutation, gene maps and images are available. The diseases are categorized and numbered as a matter of convenience. For example, autosomal dominant inherited diseases are designated by numbers from 100,000, autosomal recessively inherited diseases by numbers from 200,000, X-linked inherited diseases by numbers from 300,000, and mitochondrial inherited diseases by numbers from 500,000. Clinical conditions caused by genetic mutation are compiled separately in clinical synopsis.

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Genodermatoses: Genetic Counseling and Prenatal Diagnosis

Table 29.1 Main genodermatoses and their causative genes and proteins.    





     

    

          

  

      



   

   

     

  



  

 

  

   

  

     

    

 

    

     



 

    

   

 



       

  

    

   



   

   

 

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A. Genodermatoses

511

Table 29.1 Main genodermatoses and their causative genes and proteins (cont.).      

  

 

 



   

   

 

 

  

 



     

   

  

  

 

 

  

 



  

 



     

   

 



      

  

   

 

    

  

              

 



    

  

      

 



 



   

  

 



             

     

    

      

         

 

        

   

   

      



           

 

    

  

    

 

  

 

    

        

 

      

 

      

   

          

    

     

 



               

   

 



     

              

                  

     

 

     

     

      

          

 



 



   

 



    

 



 



     

    

 



   

 

 

         

                   





  

   

   

    

      

       





     

 α    

  

    

                   

                          

      

    

     

    

   

  

       

  

   

 

 

              

      

  

   

        

 

     



        

                

 

   

    

AD: autosomal dominant inheritance, AR: autosomal recessive inheritance, XR: X-linked recessive inheritance, SD: semidominant

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B. Genetic counseling and prenatal diagnosis Outline ● Genetic

counseling is important in dermatological practice. Estimation of genetic risks requires accuracy. ● Prenatal diagnosis (PND) may be chosen for severe genodermatoses. It is essential that PND be based on ethical considerations.

1. Genetic counseling Genetic counseling is the process whereby a patient or family receives advice on the prognosis of a disease, the risk of occurrence, inheritance, prevention and treatment. Such counseling was first introduced in the U.S. and Europe in the 1940s. Because neither carrier diagnosis nor fetal diagnosis was possible at that time, the recipients of the counseling used to have only two choices: terminate the pregnancy, or accept the risks of continuing it. Recent advances in molecular biology, clarification of responsible genes for genodermatoses, and technical improvements have made it possible to perform PND on carriers and fetuses. Accordingly, the process and details of genetic counseling have been greatly changing. For genetic counseling, accurate diagnosis of the disease is essential. Careful family history-taking, physical examinations, and evaluation of inheritance patterns are necessary, and the penetration rate of the disease should be discussed thoroughly each case (Fig. 29.1).

a

b

2. Estimation of genetic risk c

Male

Female

Unaffected

Affected

Carrier

Fig. 29.1 Examples of inheritance patterns. a: Autosomal dominant inheritance (AD). b: Autosomal recessive inheritance (AR). c: Xlinked recessive inheritance (XR).

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Newborns with relatively severe inherited disorders account for approximately 2% of all pregnancies. A pregnancy with 10% or greater risk of severe genetic abnormality is considered highly risky. Estimating genetic risk, i.e., the risk of a fetus being affected by a genetic disease, is one of the most important parts of genetic counseling. Monogenic diseases are caused by abnormality in a single gene and are inherited as Mendel’s law of segregations. Genetic risk can be estimated mathematically as a probability of severe genetic abnormality. Autosomal dominant, recessive and X-linked inheritance are monogenic inheritances. In multifactorial diseases and many cases of congenital or chromosomal abnormality, the risk calculated statistically based on family history is used (empirical genetic risk). However, it is impossible to accurately calculate genetic risk in many cases.

513

B. Genetic counseling and prenatal diagnosis

3. Prenatal diagnosis and its ethics Prenatal diagnosis (PND) and medical genetics have a long history of association and improvement. In the 1970s, diagnosis based on amniotic fluid played a central role in PND. Then diagnosis of metabolic anomaly from cultured cells collected from amniotic fluid became possible. In the 1980s, improvements in ultrasonography made it possible to perform villus sampling and fetal tissue biopsy of skin and other fetal materials for PND. Before PND became common, some patients and parents whose first child had been affected with a genetic disease would choose to terminate the pregnancy. For example, if a child with an autosomal recessive inherited disease was born to healthy parents, it was clear that the parents were carriers of the disease. In this case, the risk of the second child being affected by the same disease would be 25%. Many parents were afraid of those odds, choosing to terminate the pregnancy after long suffering (Fig. 29.2). In cases with a PND that does identify a fetus as being affected by a genetic disease, the parents are likely to terminate the pregnancy. This means PND can influence life-or-death choices. For this reason, the decision of whether PND should be conducted should be carefully justified. It is necessary for the hospital ethics committee to discuss the appropriateness of PND in each case. The final decision regarding the confirmation of pregnancy should be left to the parents. Of the numerous genetic skin diseases, the only ones for which PND is indicated are those severe enough to cause serious morbidity or mortality. Providing accurate and proper PND to clients is an important part of dermatology. The genetic skin diseases for which PND is common include severe subtypes of epidermolysis bullosa and ichthyosis (particularly harlequin ichthyosis).

4. Prenatal diagnosis in practice When the clients are considering whether to terminate a pregnancy, PND must be made by the 21st week of pregnancy so that artificial abortion can be performed as early as possible to reduce the physical and emotional burden on the parents. DNA-based PND is widely used in the early stages of pregnancy, in the 10th to 14th week. PND of genodermatoses used to be conducted by fetal skin biopsy in the 19th week of pregnancy in most cases. When genetic mutation has been identified in a family, PND is now commonly made from fetal DNA, which is possible in the earlier stages of pregnancy. Common techniques for sampling fetal DNA are chorionic villus sampling, which can be performed from the 10th week of pregnancy onward, and amniocentesis, which is possible from the 13th week onward. It is essential to enlist the cooperation of a skilled gynecologist.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

h

staining for type VII collagen

b

stain (+)→normal baby

no stain→patient

Fig. 29.2 Prenatal diagnosis. a: Examples of an autosomal recessive inherited disease (Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (RDEB)). b: It is possible to make prenatal diagnosis of Hallopeau-Siemens RDEB by embryonic skin biopsy in the 19 th week of pregnancy. If type VII collagen is found in the epidermal basement membrane, the embryo is normal.

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

Fig. 29.3-1 Embryonic skin biopsy is available from the 19th week of pregnancy onward. a: The position of the embryo is confirmed by ultrasound scan, and then the skin biopsy site is determined.

h

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Genodermatoses: Genetic Counseling and Prenatal Diagnosis

1) Fetal skin biopsy

Clinical images are available in hardcopy only.

a

b

c

d

e

f

g

h

Fetal skin biopsy is useful when the causative gene of a genodermatosis is unknown or there is an unidentified genetic mutation in the family. The biopsy can be performed from the 19th week of pregnancy onward, when the fetal skin has formed completely. A punch biopsy of fetal skin 1 mm to 2 mm in diameter is removed with biopsy forceps while confirming the position of the fetusj using ultrasound (Figs. 29.3-1 and 29.3-2). p The qpheno-r i k l m n o typic change in fetal skin is examined by electron microscopy and immunohistochemistry.

2) Chorionic villus sampling and amniocentesis

b

c

d

e

f

g

h

i

These tests are conducted when a causative genetic mutation has been identified in a family. In chorionic villus sampling, which can be conducted from the 10 th week of pregnancy onward, fetal placental villi are collected. In amniocentesis, j k m n o 13 th pweek qof pregnancy r which can be l performed from the onward, fetal cells are collected from amniotic fluid. Fetal DNA is extracted from the specimen and investigation is made for genetic mutation (Fig. 29.4). The diagnosis of the fetus is determined by direct sequencing of fetal DNA, restriction enzyme digestion, and allele-specific oligonucleotide hybridization.

5. Prospects in prenatal diagnosis c

d

e

f

g

h

i

j

Fig. 29.3-2 Embryonic skin biopsy is available from the 19 th week of pregnancy onward. b: Skin biopsy. c: Devices used for embryonic skin biopsy. d: Electron microscopy of biopsied embryonic skin (low magnification).

extraction of fetal DNA

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Fig. 29.4 Biopsy of the chorionic villus is performed in about the 10th week of pregnancy.

years, pre-implantation has been pgenetic q diagnosis k In recent l m n o r introduced for genetic diseases such as cystic fibrosis. In such diagnosis, 1 or 2 cells are taken from an in-vitro fertilized egg when it is at the stage of 4 or 8 cells, and investigation is made of the target genetic mutation using nested PCR (polymerase chain reaction). Only fertilized eggs without the mutation are selected for artificial implantation: This can prevent the need for artificial abortion. Problems remain in pre-implantation genetic diagnosis, such as those of ethics, low success rate, procedural safety, physical burden on the mother, and cost. There are few opportunities for clinical application of pre-implantation genetic diagnosis other than for the skin diseases that are reported in skin fragility syndrome and epidermolysis bullosa. It has recently been clarified that fetal cells exist in the blood of women in their 8th to 11th week of pregnancy. Special techniques have made the selection of fetal cells possible. PND has been successfully made in certain diseases by DNA extracted from fetus-derived cells to determine the genetic pattern. It is expected that minimally invasive, accurate and safe PND of genodermatoses will one day be available.

C. New treatments for genodermatoses

515

C. New treatments for genodermatoses Techniques for diagnoses and PND of genodermatoses have significantly improved; however, there are no specifically effective treatments for these conditions. Diseases whose causative genes have been identified are theoretically targets for gene therapies (Figs. 29.5 and 29.6). Such therapies consist of replacement therapy and gene expression inhibition therapy. For example, recessive dystrophic epidermolysis bullosa is caused by genetic mutation in type VII collagen and lack of anchoring fibrils, a structural component of the epidermal basement membrane. For treatment of genodermatoses, transplantation of autologous cultured epidermal or dermal sheets has come into use. However, it has little effectiveness, because the cells of the patients have genetic mutation and are unable to produce normal type VII collagen. Therefore, studies have focused on transplanting the patient’s cultured cells that have been supplied with the normal type VII collagen gene and on applying type VII collagen cDNA directly to the patient’s skin (Fig. 29.5). New techniques are being studied, such as allogenic bone marrow transplantation, in which bone marrow stem cells are differentiated to epidermal stem cells to cure genodermatoses.

patient’s cultured epidermal sheet

Clinical images are available in hardcopy only.

Clinical images are available in hardcopy only.

synthesized type VII collagen

Fig. 29.5 Example of a newly improved treatment method. Synthetic type VII collagen is injected into the skin ulcer of a patient with recessive dystrophic epidermolysis bullosa. In this condition, genetic mutation prevents the patient from producing type VII collagen. Epidermal sheet cultured from the patient’s own skin is grafted over the injected site.

Fig. 29.6 Type XVII collagen knockout mouse, a model animal for epidermolysis bullosa. This mouse can survive and can be used in therapeutic experiments (adapted from; Nishie W, et al. Humanization of autoantigen. Nat Med 2007;13: 378-83).

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Appendix : Dermoscopy Dermoscopy, also known as dermatoscopy, epiluminoscopy and epiluminescent microscopy, is an effective non-invasive diagnostic technique. Dermoscopy improves the accuracy of diagnosis for pigmented skin lesions and has been used increasingly for differential diagnosis of nonpigmented lesions. It allows the in vivo evaluation of colors and microstructures of the epidermis, the dermo-epidermal junction, and the papillary dermis that are not visible to the naked eye. Dermoscopy can be used on lesions to examine the distribution of pigment, the skin surface horney layer, vascular patterns, borders and ulceration. The procedure serves as a valuable aid in diagnosing various skin changes, particularly those of pigmented skin lesions. Dermoscopic patterns are particularly helpful in diagnosing melanomas, moles, freckles, atypical nevi, blue nevi, seborrheic keratoses, basal-cell carcinomas, and hemangiomas. Dermoscopy involves using dermoscope (dermatoscope), a hand-held imaging device with a built-in illuminating system and a high-quality magnifying lens. A dermoscope is a simple and inexpensive direct skin microscope. Examination takes only short time, and the device is able to record images. Magnification at a power of ten works well for diagnosing pigmented skin lesions. Gel is applied to the skin lesion to reduce reflectivity and to increase the transparency of the stratum corneum. Examination can be by contact non-polarized light dermoscopy (NPD), polarized light non-contact dermoscopy (PNCD), or contact polarized light dermoscopy (PCD). These give complementary views of skin lesions. Cross-polarized light is capable of showing the subsurface morphology either with or without direct skin contact. The appendix demonstrates fundamental dermoscopic patterns.

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f Ae range of dermoscopy equipment. a: Delta10 (Heine), b: DermLite (3Gen), c: DermoGenius (Biocam), d: Epilight (Ondeko), e: Derma9500 (Derma Medical), f: f Lumio (3Gen).

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Reticulation A grid of thin brown lines on a diffuse, light brown background, covering most of a melanocytic lesion. The color tone may vary with changes in the biologic behavior of the melanocytic lesion.

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Frequently seen in... All categories of melanocytic lesion

Images are available in hardcopy only

Parallel furrow pattern Bandlike brownish pigmentation on the sulci of skin markings It is seen in acral skin, palms and soles. It reflects the proliferation of melanocytes in the crista profunda limitans of the epidermis.

Images are available in hardcopy only

Frequently seen in... Acral lentiginous nevus (benign)

Images are available in hardcopy only

Images are available in hardcopy only

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Lattice-like pattern Linear pigmentation follows and crosses the sulci of skin markings. It is a variant of the parallel furrow pattern.

Images are available in hardcopy only

Frequently seen in... Acral lentiginous nevus (benign)

Globular pattern Characterized by the presence of numerous, variously sized, round to oval structures in various shades of brown and grayish-black. They distribute regularly or irregularly within the lesion. This pattern reflects aggregations of pigmented melanocytes, melanophages or even clumps of melanin within the cornified layer, the epidermis, the dermo-epidermal junction or the papillary dermis. Frequently seen in... Dysplastic (Clark) nevus, Unna nevus

Images are available in hardcopy only

Images are available in hardcopy only

Images are available in hardcopy only

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Cobblestone pattern Closely aggregated globules resemble cobblestones. It is quite similar to the globular pattern.

Images are available in hardcopy only

Frequently seen in... Unna nevus, Congenital nevus

Images are available in hardcopy only

Images are available in hardcopy only

Parallel-ridge pattern Bands of brownish pigmentation are seen on ridges of skin markings. It occurs in acral skin. The pattern reflects the proliferation of melanocytes in the crista profunda intermedia of the epidermis.

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Frequently seen in... Malignant melanoma in situ

Images are available in hardcopy only

Images are available in hardcopy only

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Multicomponent pattern Three or more distinct dermoscopic structures present in combination. For instance, the pattern may be made up of pigmented networks, clusters of dots/globules, and areas of diffuse hyper- or hypopigmentation.

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Frequently seen in... Malignant melanoma, Basal cell carcinoma, Seborrheic keratosis Images are available in hardcopy only

Fibrillar pattern Fine fibrillar or filamentous pigmentation runs perpendicular to the furrows. It resembles the sweep of a paintbrush. This pattern is seen in all categories of melanocytic lesion, including malignant melanoma in situ and lentiginous nevus on palms and soles. It reflects melanin granules oriented slanting to skin surface in the horny cell layer.

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Frequently seen in... All melanocytic lesions of acral sites Images are available in hardcopy only

Images are available in hardcopy only

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Homogenous blue pigmentation Sharply demarcated, round to oval, blue or blue-gray pigmented areas without a pigmented network or other distinctive local feature. It reflects the abundance of melanin granules in dermal tumor components.

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Frequently seen in... Blue nevus

Images are available in hardcopy only

Images are available in hardcopy only

Blue-whitish veil Gray-blue to bluish-white, diffuse pigmentation overlies a whitish film of ground glass appearance. Bluish areas reflect the abundance of melanin granules in dermal tumor components and whitish areas reflect compact orthokeratosis.

Images are available in hardcopy only

Frequently seen in... Malignant melanoma (invasive), Spitz nevus Images are available in hardcopy only

Images are available in hardcopy only

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Streaks Brownish-black linear structures are observed at the periphery of the lesion. They reflect discrete nests of pigmented junctional nevus.

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Frequently seen in... All categories of melanocytic lesion

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Images are available in hardcopy only

Atypical pigment network A black, brown or gray network of irregular meshes is distributed irregularly throughout the lesion, usually ending abruptly at the periphery.

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Frequently seen in... Malignant melanoma

Images are available in hardcopy only

Images are available in hardcopy only

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Light-brown fingerprint-like structures The light brown, finely meshed pigmentation of the peripheral lesion resembles fingerprints. It reflects basal melanosis of the elongated epidermis.

Images are available in hardcopy only

Frequently seen in... Seborrheic keratosis

Images are available in hardcopy only

Images are available in hardcopy only

Comedo-like openings These sharply circumscribed structures are yellowish-brown or dark brown, and round to oval. They reflect keratin plugs within dilated follicular openings.

Images are available in hardcopy only

Frequently seen in... Seborrheic keratosis, Unna nevus

Images are available in hardcopy only

Images are available in hardcopy only

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Multiple milia-like cysts White or yellowish-white, round bodies of various sizes. They reflect intraepidermal keratin cysts.

Images are available in hardcopy only

Frequently seen in... Seborrheic keratosis

Images are available in hardcopy only

Images are available in hardcopy only

Fissures/ridges (brain-like appearance) Light brown fissures alternate with dark brown ridges, giving the wrinkled appearance of a brain.

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Frequently seen in... Seborrheic keratosis

Images are available in hardcopy only

Images are available in hardcopy only

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Leaf-like areas (structures) These are brown to blue-gray, independent, bulbous extensions around the lesion. When big, they sometimes resemble maple leaves. They reflect aggregation of tumor cells that were distributed throughout the epidermis.

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Frequently seen in... Basal cell carcinoma

Images are available in hardcopy only

Images are available in hardcopy only

Arborizing vessels Telangiectasia with distinct tree-like branching. It reflects dilated vessels of the papillary dermis.

Images are available in hardcopy only

Frequently seen in... Basal cell carcinoma

Images are available in hardcopy only

Images are available in hardcopy only

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Large blue-gray ovoid nests Well-circumscribed, uniform, pigmented, ovoid or elongated areas larger than blue-gray globules. They reflect large tumor nests with melanin granules.

Images are available in hardcopy only

Frequently seen in... Basal cell carcinoma

Images are available in hardcopy only

Images are available in hardcopy only

Spoke-wheel areas Well-circumscribed radial projections. They tend to be more heavily pigmented at the center. When big, they are called leaf-like structures. They reflect tumor nests that are oriented perpendicular to the run of the epidermis.

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Frequently seen in... Basal cell carcinoma

Images are available in hardcopy only

Images are available in hardcopy only

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Red-blue lacunae Sharply demarcated, round to oval areas with reddish, bluish-red or dark-red to black coloration. They reflect dilated vascular spaces and pooling of red blood cells in the upper dermis.

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Frequently seen in... Hemangioma, Angiokeratoma, Subungual and subcorneal hematomas Images are available in hardcopy only

Images are available in hardcopy only

Hairpin vessels Long, visible vascular loops that sometimes twist and bend. The diameter remains constant for the entire length of the vessel. They are often seen in the peripheral zone of the lesion.

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Frequently seen in... Malignant melanoma

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