Diseases of the anogenital skin

Histologic features

The anogenital region, as with other mucocutaneous sites, is characterized by a gradual transition from skin to a mucosal surface.

Histologic features

These sites most closely resemble skin from other regions of the body since the epithelium is keratinized and stratified and adnexal structures are represented. The epithelium of the labia majora normally contains occasional lymphocytes, which are found in very small numbers around the superficial dermal vasculature. In the labia majora, sebaceous glands are present in association with hair follicles and both anogenital mammary-like glands are typically present. On the medial aspect of the labia majora, the hair follicles become modified and there is often no hair seen although sebaceous glands are still present ( Fig. 12.2 ). Some may open directly onto the epithelium (Fordyce spots, see below). In the deep dermis, a layer of smooth muscle known as the tunica dartos labialis is seen. The subcutaneous tissue of the labia majora tends to be prominent in women of reproductive age but decreases in amount after the menopause. The labium majus contains a long smooth muscle called the cremaster. The skin of the perianal area shows numerous terminal hairs with sebaceous glands.

Histologic features

The labia minora represent the female equivalent of the penile corpus spongiosum. They are located lateral to the vaginal vestibule, medial to the labia majora, and are covered by stratified, often pigmented, squamous epithelium. In most females, adnexal structures are absent, as is subcutaneous tissue. The stroma is richly vascular and contains abundant erectile tissue and elastic fibers.

The pilosebaceous unit is incomplete, as the sebaceous gland is not usually associated with a hair follicle and opens directly onto the surface. Anogenital mammary-like glands are sparse and subcutaneous fat is not seen.

Histologic features

The epithelium is stratified and keratinized. No adnexal structures are present. The glans clitoris, unlike its male counterpart, does not contain a corpus spongiosum. The frenulum and the prepuce originate from the labia minora and contain abundant sebaceous and mucus-secreting glands.

Histologic features

The epithelium is stratified and nonkeratinized, i.e., it is a mucosa ( Fig. 12.3 ). Both the vagina and the urethra open into the vestibule. Bartholin glands are located deep to the posterior third of the labia majora. They represent the equivalent of Cowper glands or the bulbourethral glands in the male. The ducts of Bartholin and Skene glands and the minor vestibular glands open into the vestibule.

Histologic features

The pattern of keratinization of the epithelium varies throughout the anogenital area, most markedly in the transition from true urothelium to true skin. There is controversy over the definition of ‘mucosa’ but there is no doubt that the penile urethra does possess a true mucosa, whereas the glans of the circumcised male does not; the glans and inner prepuce of the uncircumcised male probably does not display mucosa but the outer prepuce does. There are several epithelial transition zones. The proximal (pre-prostatic and prostatic) urethra is lined by transitional epithelium, the membranous spongy penile urethra by pseudostratified columnar epithelium. The distal penile urethra is lined by stratified or pseudo-stratified squamous epithelium incorporating a single layer of columnar cells at the surface and contains Littre glands, the distal 5–6 mm of penile urethra, which includes the navicular fossa, manifests a 6–10 cell layer of nonkeratinizing squamous epithelium, contains no adnexae, and is continuous with the epithelium of the uncircumcised glans (which may show some thin keratinization, although some accounts state that the glans is not keratinized in the uncircumcised) and inner preputial epithelium; the outer preputial epithelium is identical to skin. Just as there is wide variability in the size and shape of the navicular fossa, the site of the epithelial transition zones and probably the degree of keratinization of the glans and the disposition of adnexa may vary. Presumed multipotential, mucous secreting cells have been described in the perimeatal epithelium, and mucinous metaplasia of glans and foreskin have also been observed. Also, the final transition will depend on the length of the foreskin: it is our experience that male genital lichen sclerosus (LS) has a greater predilection for the male with a longer foreskin (as does penile cancer). The wide spectrum of differentiation of the male urogenital tract is accompanied by changes in the expression of epithelial cytokeratins, but this is relatively unexplored territory. Normal regional histology is illustrated in Figs 12.4–12.9 .

Clinical features

Skin tags (acrochordons) are common in the groins, especially in the obese. They may catch on clothing, bleed, and get infected. Fibrosed hemorrhoids can result in perianal skin tags, but larger, fleshier, more edematous skin tags should arouse the suspicion of Crohn disease: they can predate gastrointestinal disease by several years. These lesions are particularly relevant in young patients with diarrhea, abdominal pain, and/or growth retardation.

Histologic features

The histology of a skin tag at this site is identical to that of those occurring elsewhere. The presence of granulomata in anal skin tags is often a clue to the diagnosis of Crohn disease.

Clinical features

Pearly/pink penile papules may be found in 15–50% of men. They manifest as flesh-colored, smooth, rounded papules (1–3 mm) occurring predominantly around the coronal margin of the glans, and rarely on the glans. Often, there are rows or rings of papules ( Fig. 12.13 ). Ectopic lesions, for example, on the penile shaft, have been reported, including in children. They are frequently mistaken for warts and Tyson or ectopic sebaceous glands. The lesion is analogous to other acral angiofibromas such as adenoma sebaceum, subungual and periungual fibromas, fibrous papule of the nose, acquired acral angiofibroma, and oral fibroma. These lesions may regress with circumcision and old age.

Histologic features

The histology is that of angiofibroma. Human papillomavirus (HPV) DNA is absent.

Clinical features

Vestibular papillomatosis is not due to HPV infection and is a common finding of no significance. It is asymptomatic and is the female equivalent of penile pearly papules. Individual lesions are dome shaped or filiform and arise on a solitary base. They are found on the inner aspect of the labia minora and vestibule ( Fig. 12.14 ).

Histologic features

There is a normal or thickened epidermis overlying a central fibrovascular core.

Clinical features

The sebaceous glands of the inner labia majora, the labia minora, and clitoral prepuce do not usually have an associated hair follicle. The glands open directly onto the surface and may be very prominent and numerous at these sites. The yellow uniform papules (Fordyce spots) are often seen best if the skin is stretched ( Fig. 12.15 ). Sebaceous gland hyperplasia may sometime be associated with pruritus and pain if they enlarge and the contents rupture into the dermis.

In the male, sebaceous gland prominence, Tyson glands, sebaceous hyperplasia, and ectopic sebaceous glands (Fordyce condition) are all virtually synonymous and are common, normal variants of the skin of the scrotal sac and penile shaft (very rarely the glans) but may cause concern to patients, even amounting to dysmorphophobia ( Fig. 12.16 ).

Histologic features

One or more enlarged sebaceous glands, each composed of numerous lobules, surround a central duct that opens directly into the epidermis ( Fig. 12.17 ).

Clinical features

These are non-specific terms. Intertrigo is the name given to any dermatosis occurring in skin folds: any scale is usually rapidly removed by frictional abrasion, and a degree of epithelial loss may result in erosion that renders the site especially susceptible to secondary infection, e.g., with Candida (see below).

Balanitis denotes inflammation of the glans penis, while posthitis is inflammation of the prepuce. Balanoposthitis means inflammation of the glans and prepuce and is regarded as a special form of intertrigo. By definition, therefore, balanoposthitis cannot occur in the circumcised male, but balanitis might.

Pathogenesis and histologic features

Generally, dermatologists feel that balanitis, posthitis, and balanoposthitis are probably more common due to inflammatory and precancerous dermatoses, whereas genitourinary physicians teach that most cases are due to infection, usually with Candida . However, Candida is a ready opportunist so its presence may not always indicate primary infection as the cause of the genital inflammation. Bacteria have increasingly been implicated in the etiology of the disease, particularly Staphylococcus aureus . In cases in which Streptococcus pyogenes is isolated, it has been suggested that the disease may be sexually transmitted by penile–oral intercourse. Diabetes may be an important predisposing factor to Candida and other infective causes or complications of balanoposthitis.

The histologic features are non-specific.

Clinical features

Seborrheic dermatitis is the most common form of eczema affecting anogenital skin, followed by irritant contact eczema. Eczema, particularly seborrheic dermatitis, is more common than many other inflammatory dermatoses in uncircumcised males. Allergic contact eczema is rare at genital sites and occurs more typically in a perianal distribution. Involvement of genital skin with atopic eczema is rare.

In infants, eczematous reactions are often seen in the napkin area. Most of these represent a primary irritant dermatitis. Seborrheic dermatitis and a psoriasiform napkin rash can also occur. Some, but not all, patients with the latter condition develop psoriasis later in life.

Histologic features

The histologic features are identical to those seen in eczema affecting other areas of the skin. Psoriasiform napkin rashes show histologic features that overlap with psoriasis.

Clinical features

Seborrheic dermatitis is a common pattern of eczematous disease associated with an abnormal hypersensitivity to the normal commensal cutaneous yeast, Pityrosporum ovale . It is discussed in detail elsewhere ( Chapter 6 ). In addition to the classical sites, e.g., scalp (pityriasis capitis, dandruff), ears, glabella and brows, nasolabial folds, axillae, chest and back, the groin, and penis can be involved. Indeed, this may be the sole site, leading to the patient presenting, with pruritus and or balanoposthitis, to a dermatologist. Some patients may also have a tendency to psoriasis (‘sebopsoriasis’, ‘seboriasis’). On the scalp, on the face, in the flexures, and at anogenital sites, seborrheic dermatitis and psoriasis may be indistinguishable. Seborrheic dermatitis is very common in HIV infection. Diagnosis is achieved on clinical grounds, and it is not usually necessary to do a biopsy. Pityrosporum spp. will be seen in large numbers.

In females, seborrheic dermatitis may present as non-specific erythema over the outer labia majora, and there may be some scaling and keratin debris seen in the interlabial sulci ( Fig. 12.18 ).

Histology is identical to that of seborrheic dermatitis occurring elsewhere. However, spongiosis can be more prominent.

Clinical features

Infantile gluteal granuloma (papuloerosive dermatitis of Jacquet and Sevestre) is a rare condition that has been described mainly in the newborn and infants in the napkin area. It frequently develops in a background of an irritant napkin rash. A similar condition has been described in incontinent elderly women with lesions developing on the labia majora ( Fig. 12.19 ). Oval or round papulonodular lesions present on the convex areas of the perineum, which are in direct contact with the napkin or incontinence pad. They tend to regress spontaneously over a few weeks and occasionally leave scars.

Pathogenesis and histologic features

The etiology of the process is unclear, but occlusion, Candida infection, and the application of fluorinated corticosteroids have been implicated. The latter, however, does not seem to be of importance in the incontinent elderly patient.

The histology is fairly non-specific and includes superficial ulceration, focal necrosis, and a prominent mixed inflammatory cell infiltrate with granulomata and numerous lymphocytes and plasma cells. Hemorrhage and hemosiderin deposition can sometimes be present.

Differential diagnosis

Crohn disease and infective granulomatous conditions may need to be excluded but the clinical features of these are usually obvious.

Clinical features

The clinical features of lichen simplex chronicus presenting on genital and anal skin are identical to those seen at other sites of the body. The mons pubis or labia majora ( Fig. 12.20 ), scrotum and perianal skin are the most common sites affected. Giant forms (of Pautrier) occur, e.g., on the scrotum, giving a pineapple appearance ( Fig. 12.21 ).

Histologic features

The histologic features are discussed in detail elsewhere, but lichenification is characterized by hyperkeratosis, hypergranulosis, uniform acanthosis, fibrosis of the papillary dermis, and an unremarkable low-grade perivascular infiltrate of mononuclear leukocytes in the superficial dermis. The papillary dermal fibrosis is streaky and perpendicular to the epidermis. Eosinophils are often present, in some cases reflecting an element of irritant contact dermatitis. At mucosal sites hyper- and orthokeratosis creates a cornified layer, resulting in the clinical appearances of white thickened plaques.

Clinical features

Flexural psoriasis is the most common pattern seen in the anogenital region, with extension into the genitocrural folds and natal cleft ( Figs 12.22–12.25 ). There are often difficulties clinically in distinguishing between psoriasis and seborrheic dermatitis. Genital and flexural disease may reflect koebnerization and is relatively common. In the circumcised male, the signs on the glans and distal penile shaft are similar to those of psoriasis at extragenital sites, whereas the appearances in the uncircumcised male are of balanoposthitis similar to flexural psoriasis. In females, well-demarcated plaques generally affect the labia majora with extension on to the mons pubis and perianal skin. Fissuring is common.

Histologic features

Histology is often unhelpful, as the changes can be non-specific. The typical features of psoriasis are rarely evident, and the presence of secondary spongiosis is common and may be misleading.

Clinical features

Reactive arthritis (previously known as Reiter syndrome) is part of the same continuum as psoriasis in genetically predisposed individuals. Reactive arthritis is defined by the triad of arthritis, urethritis, and conjunctivitis. It is precipitated by non-specific urethritis, bacillary or amebic dysentery, and associated with HIV infection and the immunogenotype human leukocyte antigen (HLA) B27. The classical triad may occur together or develop in sequence, and a range of other symptoms may also be present. It has a worldwide distribution. Reactive arthritis most commonly affects men 20–30 years of age; the male/female sex ratio is approximately 10 : 1. The syndrome is characterized by a relapsing course.

The condition may follow an enteric or a urogenital infection. Shigella dysentery was the first associated enteric infection to be recognized and the causative organisms were either Shigella flexneri or Shigella dysenteriae . Salmonella , Yersinia , and Campylobacter have also been reported preceding reactive arthritis.

Sexually transmitted reactive arthritis may occur with a nongonococcal or ‘non-specific’ urethritis. Chlamydia trachomatis is isolated from the genitourinary tract in 40–60% of male cases; isolation is variable, however, and an indirect immunofluorescence test detects chlamydial infection in 90% of patients. Mycoplasma infection and Streptococcus viridans have also been implicated. The condition has also been linked to the acquired immunodeficiency syndrome (AIDS). Rare associations include Cyclospora , Cryptosporidium , intravesical bacillus Calmette–Guérin (BCG) immunotherapy, Gardnerella vaginalis , hepatitis B immunization, and systemic interferon-alpha (IFN-α) treatment.

Reactive arthritis is more likely to occur in predisposed individuals. HLA-B27, which is thought to occur in up to 90% of patients, increases the risk of developing reactive arthritis by 25 times; the disease is also more severe in HLA-B27-positive individuals. HLA-B27 in patients with reactive arthritis correlates with ankylosing spondylitis. Reactive arthritis develops in 20% of HLA-B27-positive individuals after a specific infective episode. An association with HLA-B51 has been reported. Rarely, familial instances have been documented. Therefore, it appears that the disease is triggered in genetically predisposed individuals by an unknown mechanism precipitated by infection.

The genitourinary tract is virtually always involved in the form of urethritis, prostatitis, seminal vesiculitis, and hemorrhagic cystitis. Urethral strictures also sometimes occur and females may develop cervicitis.

Bilateral mucopurulent conjunctivitis is the usual form of eye involvement occurring in up to 35% of patients, but occasionally iritis, iridocyclitis, keratitis, or blindness occurs.

Weight-bearing joints and the larger ones (knees, ankles, feet, and wrists) are involved by the arthritis, often together with sacroiliitis. Radiological changes include osteoporosis, erosions and loss of joint space, with multiple joints usually affected. Periostitis often affects the metatarsals, the phalanges of the feet, and the tarsal bones; occasionally, ankylosis develops in the small bones of the hands and feet. Ankylosing spondylitis, which is an important manifestation, correlates with a high erythrocyte sedimentation rate (ESR).

In the initial stages of the arthritis the clinical picture resembles that of an acute joint infection, settling to subacute involvement. Although the arthritis in reactive arthritis usually recovers completely, chronic manifestations can sometimes occur; it is important to remember that arthritis may be the only symptom in recurrent episodes.

Skin lesions in reactive arthritis may be similar to those of psoriasis. Cutaneous manifestations include hyperkeratotic cobblestone lesions on the palms and soles and occasionally affecting the trunk and extremities ( Fig. 12.26 ). The lesions initially present as erythematous macules; over the course of several days these become hyperkeratotic waxy papules, with an erythematous halo covered by dry hyperkeratotic material. The papules are numerous and eventually coalesce to form thickened horny plaques. Pustular lesions of the palms and soles may also be evident (keratoderma blenorrhagicum) ( Fig. 12.27 ).

Circinate balanitis, presenting as a moist superficial erosion, 2–4 mm across, may affect the glans penis and meatus ( Figs 12.28–12.30 ). Superficial ulceration of the oral mucosa may also occur, together with reddening and a granular appearance of the surrounding mucous membrane.

Stomatitis and nail dystrophy (indistinguishable from that of psoriasis) may be additional features. Weight loss is common. Aortic incompetence is an important late complication, and immunoglobulin A (IgA) nephropathy has been described in a number of patients.

Reactive arthritis is rarely reported in females. Vulvitis has been described in a small number of case reports, and in one case cervical lesions, presenting as white papules, were seen. The vulval lesions are erythematous and may be ulcerative, eroded, or scaly, and often resemble mucocutaneous candidiasis.

Reactive arthritis may resolve spontaneously, but more often it is characterized by chronicity and recurrences. Rarely, it may prove fatal. Causes of death include aortic incompetence, atrioventricular block, terminal cachexia, systemic amyloidosis, and iatrogenic effects.

Histologic features

Essentially, just as the skin lesions of reactive arthritis have psoriasiform morphology ( Fig. 12.31 , they have the same histopathology and ultrastructure as pustular psoriasis.

The epidermis is acanthotic with elongation and hypertrophy of the epidermal ridges and parakeratosis. The suprapapillary plates are thinned and there is infiltration of the epidermis by neutrophils, associated with vacuolation of superficial keratinocytes, together with the formation of spongiform pustules and microabscesses ( Fig. 12.32 ). The inflammation extends into the adjacent underlying dermis, where it is predominantly mononuclear. The histology is essentially identical to that seen in pustular psoriasis. Therefore, close clinicopathological correlation is critical to establish a diagnosis. Occasional biopsies from typical lesions of patients with reactive arthritis may disclose an underlying leukocytoclastic vasculitis.

A small number of patients presenting with skin lesions that histologically showed sterile neutrophilic folliculitis with perifollicular vasculopathy have been documented. The authors suggested that this histologic pattern may be a marker of systemic disease. Associations may include reactive arthritis, inflammatory bowel disease, Behçet disease, hepatitis B infection, scrofuloderma, connective tissue diseases, and hematological dyscrasias. Patients present with systemic symptoms and variable skin lesions including folliculitis, vasculitis, acneiform eruptions, vesiculopustules, and erythema nodosum-like features.

Early joint lesions are characterized by a neutrophil polymorph inflammatory cell infiltrate with little, if any, synovial changes. Older lesions show features suggestive of rheumatoid arthritis, including lymphoid aggregates, a perivascular chronic inflammatory cell infiltrate, and synovial hyperplasia.

Differential diagnosis

Periodic acid–Schiff (PAS) and/or silver stains should always be performed to exclude a fungal infection which can show similar histologic features.

Clinical features

Anogenital lesions may be found in up to 40% of patients with generalized disease. In some, however, the disease is restricted to the lower genital tract and/or the perianal region. LP manifests the Koebner phenomenon which may partly explain the orogenital predilection. Genital LP in children is exceptional. Women with oral LP often have genital disease which may be asymptomatic.

The lesions are typical, violaceous or white patches, or areas of erythema and erosions. Wickham striae (frequently seen in oral involvement), although sometimes visible, are less often found on anogenital skin ( Fig. 12.33 ). The clinical variants of LP affecting the anogenital skin include squamo-papular, erosive, hypertrophic, and hyperpigmented flexural disease ( Figs 12.34–12.41 ). Lichen planopilaris has also been described on the vulva.

The erosive form of LP is more common at anogenital sites and can lead to scarring and distortion of the architecture. The vulval vestibule and vagina and cervix may also be involved, and sometimes the vagina and/or the cervix are affected alone. There is also an unusual variant of erosive LP in women that involves the oral gingivae, vulval vestibule, and vagina, known as the vulvovaginal-gingival syndrome ( Figs 12.42–12.44 ). This can lead to severe vulval and vaginal scarring with vaginal adhesions, constriction bands, and, in some cases, complete stenosis. A male equivalent to the vulvovaginal syndrome of Hewitt with chronic erosive gingival and genital lesions (genito-gingival syndrome) has been described. Patients with genital lesions may have oral, aural, conjunctival, and esophageal involvement.

Perianal disease can cause deep, painful fissuring, and it is often the hypertrophic variant that involves this site.

In the male genital, LP can present as phimosis. Adhesions are seen in the uncircumcised male, both transcoronal and subcoronal.

Anogenital LP carries a small increased risk of malignancy, usually squamous cell carcinoma (SCC) ( Fig. 12.45 ). Hypertrophic LP of the glans penis should be regarded as having potential sinister biological behavior.

Pathogenesis and histologic features

Studies of oral LP have supported an immunological basis with activated T cell to an unidentified antigenic stimulus. The histologic features of anogenital LP are often more difficult to recognize than those of LP presenting on nonmucosal surfaces. The epidermis may be effaced or thickened, and there is a dense, band-like infiltrate hugging the dermal–epidermal junction ( Fig. 12.46 ). Many genital lesions are mucosal and the inflammatory cell infiltrate is often rich in plasma cells, in contrast with lesions of LP at other sites where lymphocytes and histiocytes predominate ( Fig. 12.47 ). The basal layer is often disrupted with some cytological atypia as regeneration takes place. Cytoid bodies may be seen but tend not to be prominent. This is accompanied by parakeratosis. Focal secondary spongiotic changes are not uncommon, particularly in mucosal surfaces. In long-standing disease, the dense, bandlike infiltrate may be replaced by a patchy, scant infiltrate with small foci of lichenoid inflammation. Many cases of male genital LP are misdiagnosed as ZB or LS.

Immunofluorescence studies may show fibrinogen and IgM along the basement membrane zone and, more rarely, IgG or IgA. Cytoid bodies may also be labeled.

Differential diagnosis

The clinical differential diagnosis includes psoriasis, ZB in the male, LS, viral warts, bowenoid papulosis, and porokeratosis. LP is one of the causes of pruritus ani. A biopsy is frequently necessary for diagnostic purposes but is more importantly done in the follow-up of the rare cases of chronic anogenital disease where the development of ulcero-erosive or verrucous features leads to concern about the development of SCC. LP often overlaps with the features of LS, and in some patients the two disorders may coexist. Hyalinization of the papillary dermis or the superficial lamina propria is indicative of the latter condition. In patients suffering from such a chronic overlap syndrome, particular care should be taken to recognize dysplastic areas or SCC. Those patients with predominantly mucosal disease clinically mimic mucous membrane pemphigoid, but immunofluorescence studies are invariably negative. A case of paraneoplastic LP with orogenital involvement and cicatrizing conjunctivitis in association with thymoma has been described.

Sometimes drugs can precipitate a generalized lichenoid eruption. A case of a lichenoid drug eruption confined to the penis due to propranolol has been reported.

Clinical features

This disease has an affinity for the penis. It can be difficult to diagnose because the signs may be subtle even when the lesions are widespread, and when itchy the signs due to excoriation and eczematization may eclipse those due to the lichen nitidus.

Histologic features

Histologically, the appearances are the same as those of lichen nitidus occurring elsewhere.

Clinical features

Typical annular lesions with a raised hyperkeratotic margin (see Chapter 3 ) are classically generalized in distribution but the anogenital skin may be involved. Rarely, the genital skin is affected alone (genital porokeratosis) or, even more rarely, pruritic, occasionally verrucous involvement limited to the perianal and gluteal folds is seen (porokeratosis ptychotropica). The differential diagnosis includes LP and amyloid (and the latter has been reported in porokeratosis ptychotropica). An association with bone marrow transplantation has been described.

The condition is exceptionally rare in females.

Histologic features

The histology is distinctive and the same as porokeratosis at other sites. In porokeratosis ptychotropica, most cases have superimposed changes of lichenification which obscures the cornoid lamella. The latter and oblique sectioning means that the condition may be missed unless there is a high index of suspicion and further sections are performed.

Clinical features

LS is a lymphocyte-mediated dermatosis of unknown etiology. It has a predilection for the anogenital skin in women and genital skin in men. Women are more frequently affected than men (10 : 1), and it is more common in white than nonwhite patients. It almost never affects men circumcised at birth.

There are two peaks of incidence; in females these occur in the prepubertal years and then post-menopause, and in males in prepubertal and young to middle-aged adult males. When the disease arises in childhood it tends to persist, regression being uncommon. In girls, the condition can present at a very early age with hemorrhagic perianal lesions ( Figs 12.48 and 12.49 . Constipation can occur as a complication of the painful fissuring of the anal canal. If there is marked anogenital involvement, the condition may be mistaken for sexual abuse. Perianal disease does not occur in males, but in boys, genital LS is the most common cause of phimosis. Extragenital lesions occur in 11% of women with genital LS. Such involvement occurs on the upper trunk, groins, upper extremities, neck, lower trunk, and lower extremities in decreasing order of frequency, often at sites of friction ( Figs 12.50 and 12.51 ). Involvement of the scalp and face is rare and can be associated with alopecia. An exceptional case with plantar involvement has been documented. It is very rare to see extragenital lesions in the absence of genital lesions. The Koebner phenomenon is frequent and LS has been described in association with scars, at the sites of radiotherapy, and insulin injection and in association with a tattoo. Lesions can also develop or recur in skin or myocutaneous grafts. Oral involvement including lip lesions as an isolated phenomenon or in association with genital lesions has been described. The exact incidence of the latter is unknown, as suspected cases are not often confirmed by histologic examination. LP can coexist with LS, and this may account for some of the oral lesions. Coexistence of LS with morphea has also been documented. A single case of multiple genital and extragenital lesions in a patient receiving imatinib mesylate has been reported. A further case in association with allogeneic stem cell transplantation and another of genital disease developing in scrotal skin used in a case of male-to-female gender reassignment have been documented.

The typical lesions of LS are porcelain-white papules and plaques with a crinkled surface. They can coalesce to form plaques. There are often associated ecchymoses and areas of hyperkeratosis. The latter occurs in relation to the appendage ostia, which are dilated, giving rise to the physical sign of delling. Bullae only rarely occur. Common symptoms in women include pruritus, burning, and dyspareunia, and in men coital and urinary difficulties. Although anogenital LS is intensely pruritic, lichenification is often not conspicuous. Female anogenital involvement is typically symmetrical and bilateral, and is described as having a figure-of-eight (hourglass) distribution when it affects the perianal as well as vulval skin. In men the involvement is ‘tulip-like’ symmetrically affecting the distal penile shaft, glans, and foreskin (not the perianal skin) ( Fig. 12.52 ). On the other hand, the presentation may be with complete phimosis ( Fig. 12.53 ). Lesions on the vulva predominantly affect the inner aspect of the labia majora, the labia minora, the prepuce of the clitoris, the fossa navicularis, and the posterior commissure ( Figs 12.54 and 12.55 ). Penile disease can affect the glans, and distal foreskin, the frenulum, and ventral subcoronal sulcus is a particular target. Inflammation can be lichenoid and Zoonoid. LS is a scarring disorder, and in women there may be marked anatomical changes with resorption of the labia minora, burying of the clitoris, and introital narrowing. The vagina is unaffected. Urethral involvement is very rare. In men there may be complete phimosis, constrictive posthitis due to a sclerotic band (‘waisting’), transcoronal and subcoronal adhesions, erosion, ulceration and destruction or obliteration of the frenulum, effacement of the coronal sulcal architecture and definition (e.g., loss of pearly penile papules), and meatal ‘pin hole’ narrowing. The involvement of the anterior urethra can be serious: 29% of patients undergoing urethroplasty for urethral stricture had pathological evidence of LS.

An important complication of genital LS is the development of dysplasia and SCC. The latter only very exceptionally has been reported in association with extragenital lesions. In the vulva ( Figs 12.56 and 12.57 ), dysplastic foci may appear as hyperkeratotic adherent, gray-white areas, ice pick erosions, or fixed areas of erythema. Such changes must be examined histologically. Less than 4% of patients with vulval LS will develop an SCC. It has recently been shown that an important number of cases diagnosed as LS with progression to SCC actually represent differentiated vulvar intraepithelial neoplasia and not LS. The main reason for the high number of misdiagnosed cases is probably the difficulty in diagnosing differentiated vulval neoplasia on histologic grounds. These patients tend to have a more rapid progression to invasive SCC. In the group of patients with true LS and progression, a number of histologic features are seen which are absent in cases without progression. It has been suggested that these criteria can be used to identify patients at risk. They include parakeratosis, dyskeratosis, hyperplasia, and basal cell atypia. In males, the published risk of SCC complicating LS is between 4% and 8%. When excision specimens of penile SCC are examined, LS has been found in between 32% and 50% of cases. The type of penile SCC associated with LS is not usually associated with HPV. Chronicity, asymmetry, erythema, zoonoid or erythroplasia, erosions, ulcers, and verrucous change must be regarded with a very high index of suspicion and a low threshold for biopsy.

There are reports of atypical melanocytic lesions in association with LS, and careful clinicopathological correlation is needed. Cases of melanoma developing in LS are also reported.

Pathogenesis and histologic features

The etiology of LS is not consensually agreed. It has been suggested that genetic, hormonal, and autoimmune factors may be of importance. Familial cases are well recognized and have been described in both sexes and in identical and nonidentical twins. A recent study found a family history in up to 12% of patients, suggesting that a number of cases have a genetic component. About 21% of patients with LS have an associated autoimmune disease including alopecia areata, vitiligo, hyperthyroidism, hypothyroidism, pernicious anemia, and diabetes mellitus. Patients and first-degree relatives may have circulating autoantibodies including those to thyroid, gastric parietal cell, and smooth muscle in addition to antinuclear factor. A significant association between LS and the presence of class II antigens including HLA-DQ7, -DR7, -DQ8, and -DQ9 (alone or in combination) has been reported. It has also been suggested that HLA-A2 possibly exerts a protective role, as it tends to be absent in patients with extensive extragenital lesions. Also, linkage of HLA-DR4 with -DQ8 is more common in patients with marked structural damage to the anogenital area. Circulating IgG antibodies to the glycoprotein extracellular matrix protein 1 have been found in the sera of men and women with genital LS. In a few otherwise healthy children with vulval LS, IgG autoantibodies against the BP180 antigen have been detected.

Intriguingly, genital LS has been reported in bone marrow transplant recipients and graft-versus-host disease.

Women with genital LS have been found to have a higher incidence of psoriasis (predominantly extragenital) compared with the general population.

LS developing in premenopausal women has been linked to the use of oral contraceptives, particularly those with antiandrogenic properties.

Additional proposed etiological factors include absence of collagenase, an increase in collagen inhibitor enzyme, and decreased elastase activity. Reduced dihydrotestosterone levels have been described in some patients and there is one report documenting the histologic presence of variably acid-fast bacilli. As with morphea and atrophoderma, a causal relationship to Borrelia burgdorferi has been proposed, but this putative connection derives from cases in Europe and not the United States. There is no serological evidence in British men with genital LS for an association with Borrelia . Borrelia has only exceptionally been demonstrated by nested polymerase chain reaction (PCR) in LS. The variable results may be due to techniques used to detect Borrelia , and it has been suggested that focus floating microscopy should be the gold standard for detection. HPV (types 6, 16, and 18) has been reported in 70% of cases of childhood penile LS and in 17.4% of adult cases (types 16, 18, 45) compared with 8.7% of normal males in one study and in 33% of adult cases (types 16, 18, 33, 51) in another. Topical steroid treatment of LS may lead to HPV reactivation. HPV, however, has not been found in other studies of vulval LS. Epstein–Barr virus (EBV) was reported in 26.5% of samples in the same study. However, the epidemiology and clinical tenor of LS is not that of an infectious or sexually transmitted disease.

In males, obesity, anatomical abnormality, and trauma seem to be contributing factors. LS has been specifically related to hypospadias and its repair. It is often found around urostomies and urethrostomies. The presence of histopathological features of LS in a percentage of acrochordons (skin tags) has led to the suggestion that occlusion of flaccid skin is a pathogenic factor. In men, at least, all the evidence points to LS being due to chronic intermittent occluded contact with urine consequent upon contact with urinary microincontinence.

The histologic changes are identical irrespective of the site involved ( Figs 12.58–12.61 ). However, genital lesions, as opposed to those occurring at extragenital sites, often show absence of atrophy, lichen simplex chronicus-like changes, spongiosis, more prevalent vascular ectasia, and dermal eosinophils. Extragenital LS, on the other hand, seems to be associated in a number of cases with elastophagocytosis, a feature not reported in genital LS. Occasionally, pseudoxanthoma elasticum-like fibers may be seen in patients without pseudoxanthoma elasticum. Fully developed lesions of LS show a thinned, effaced epidermis with interface change and a wide band of hyalinization in the upper dermis and a lymphohistiocytic infiltrate below the hyalinized area. Zoonoid inflammation may be prominent. Marked hyperkeratosis, often associated with follicular plugging on hair-bearing skin, is frequently seen. Subepidermal edema is sometimes present and may be sufficient to cause subepithelial vesiculation ( Fig. 12.62 ). Telangiectasia is common and purpura may be an additional feature. Angiokeratoma-like lesions can also develop. A similar phenomenon is that of lymphangiectasia. Early lesions and the periphery of fully developed lesions display lichenoid changes similar to LP (see differential diagnosis ). Some cases may be associated with foci of marked and highly irregular acanthosis, often with a very jagged lower border (so-called squamous cell hyperplasia). Such cases should be carefully scrutinized for evidence of epithelial dysplasia (differentiated intraepithelial neoplasia) or adjacent carcinoma. Differentiated intraepithelial neoplasia is by far the most common type of dysplasia found in SCC associated with LS. Currently, there is no evidence to suggest that oncogenic HPV is associated with LS-related SCC.

The occasional observation of endarteritis in LS led originally to the usage of the term ‘obliterans’. In two cases in boys, a dermal lymphohistiocytic and granulomatous phlebitis was found, and one also had evidence of HPV. An exceptional case of LS with associated eosinophilic spongiosis representing superimposed bullous pemphigoid has been reported.

Ultrastructural studies of LS show fragmentation, reduplication, and formation of gaps in the basal lamina. Langerhans cells appear to pass through these gaps. The mononuclear infiltrate in LS is composed of an admixture of T-helper and suppressor lymphocytes. Expression of p53 by epidermal cells has been reported in LS. The latter is more often seen in cases associated with SCC.

Differential diagnosis

Most cases of genital LS can be diagnosed clinically. LP and the much rarer mucous membrane pemphigoid are in the differential diagnosis. A biopsy should be performed if there is any clinical doubt or if the lesions are atypical, eroded, or verrucous. Anogenital LS, particularly early lesions, may be difficult to distinguish from LP. Changes present in the early stages of LS, and absent in LP, include a psoriasiform lichenoid pattern, exocytosis of lymphocytes affecting the basal cell layer, basement membrane thickening, foci of epidermal atrophy, and loss of papillary dermal elastic fibers. Prominent Zoonoid inflammation may conceal subtler underlying LS. The histologic features may simulate mycosis fungoides.

Clinical features

Zoon plasma cell balanitis (ZB) is a disorder of middle-aged and older uncircumcised males, although an analogous condition has been reported to afflict the vulva, mouth, lips, and epiglottis. Exceptionally, the disease may present in a circumcised male. True ZB is probably rare with many cases of LS being misdiagnosed as ZB. The presentation is classically indolent and asymptomatic. Well-demarcated, glistening, moist, bright red or brown patches involve the glans and visceral prepuce with sparing of the keratinized penile shaft and foreskin ( Fig. 12.63 ). The navicular fossa may be involved. Other signs include dark red stippling – ‘cayenne pepper spots’ – and purpura with hemosiderin deposition, solitary or multiple lesions of differing sizes (guttate or nummular), characteristically symmetrical about the axis of the coronal sulcus, and ‘kissing’. Although vegetative and nodular presentations have been recorded, atypical or unusual morphology should be viewed with great suspicion and biopsied. The clinical differential diagnosis includes LS, erosive LP, psoriasis, seborrheic dermatitis, contact dermatitis, fixed drug eruption, secondary syphilis, histoplasmosis, erythroplasia of Queyrat, and Kaposi sarcoma. A confident clinical diagnosis is not always possible or safe. Therefore, a biopsy is advisable, and the pathologist should actively seek concomitant disease. Overt cases of LS, LP, bowenoid papulosis, and penile cancer often appear to have ZB-like changes both on clinical examination and on histology : the signs of ZB may be secondary to underlying preputial disease. Probably some of the clinical and histologic variants that have been reported, and the idea that ZB might be a premalignant condition, reflect this phenomenon. ZB indicates a dysfunctional foreskin, potentially concealing a more sinister dermatosis.

Pathogenesis and histologic features

Since Zoon's original reports, there have been many accounts in the literature, but the etiology remains uncertain. The evidence suggests that ZB is a chronic, reactive, principally irritant dermatosis brought about by a dysfunctional prepuce. Retention of urine and squames and excessive frictional trauma (ZB is often located on the dorsal aspect of the glans and/or the adjacent prepuce, sites of maximal friction on foreskin retraction) create the irritation. There is no evidence of an infectious cause, and immunohistochemical findings suggest that ZB represents a non-specific polyclonal tissue reaction, consistent with an irritant dermatosis.

Classically, the epidermis shows attenuation with absent granular and horny layers, and diamond- or lozenge-shaped basal cell keratinocytes with sparse dyskeratosis and spongiosis ( Figs 12.64 and 12.65 ). In the dermis, there is a dense band of infiltration with plasma cells of variable density. Other signs include extravasated erythrocytes, hemosiderin, and vascular proliferation. Zoon stressed the presence of the plasma cell infiltrate in this condition, but in practice the plasma cell density can be very variable

Clinical features

Lesions in females are rare and affect the vestibule and the labia minora. Few lesions have been described on the clitoris. The condition probably is not a single entity but a pattern of inflammation that is seen on a mucosal surface in other chronic dermatoses, particularly LP. The lesions are bright red with a varnished appearance, and sometimes there is cayenne pepper-like speckling. There may also be areas of purpura and hemosiderin pigmentation ( Fig. 12.66 ).

Alternative names proposed for these inflammatory changes include chronic vulval purpura and persistent purpuric dermatitis. Similar lesions have been described in the oral cavity and other mucosal surfaces, including the epiglottis, under names such as plasma cell orificial mucositis and atypical gingivostomatitis.

Histologic features

The histology is the same as that described for ZB. In one histologic study, the percentage of plasma cells seen was felt to be the most important parameter in making the diagnosis. However, the site of the biopsy is important as there are increased numbers of plasma cells seen in the vestibule normally, and this should not be misinterpreted. An exceptional case of Zoon vulvitis with prominent mucinous metaplasia has been described.

Clinical features

This is not an entity that is well recognized in the literature, but it is occasionally encountered in clinical practice. Young men complain of spots, boils, or blackheads, and on examination have comedones, papules, pustules, inflammatory nodules, and scars of the proximal penile shaft ( Figs 12.67 and 12.68 ). An important differential diagnosis of acneform disease presenting at any site is chloracne, due to occlusion of the skin with machine oil.

Histologic features

The histology is identical to that of acne at classical sites.

Clinical features

Hidradenitis suppurativa (acne inversa; chronic perianal pyoderma in Japan and Verneuil disease in France) is a chronic inflammatory dermatosis that affects areas rich in apocrine glands. Bridged comedones, folliculitis and furunculosis, deep discharging sinuses, nodules, cysts, and scars may all be present in the groins ( Fig. 12.69 ), the natal cleft and buttocks, and in the axillae and under the breasts. The patient may have conglobate acne. Pili incarnati (ingrowing hairs) and secondary folliculitis is a common problem in the bikini area in women but rarely encountered in men ( Fig. 12.70 ). It is more common in black individuals and affects the axillae preferentially in women and the perineum in men. A urethral cutaneous fistula and phimosis has been reported. It is a cause of dorsal perforation of the penis. Scarring from the disease and its treatment can be extensive ( Fig. 12.71 ). The morbidity of hidradenitis may be appalling, interfering with sitting, sleeping, walking, defecation, and sexual activity. Depression is common.

Hidradenitis suppurativa has been considered to be a form of ‘apocrine acne’. However, the primary pathological process seems to be associated eminently with the hair follicle. The role of endocrine factors is uncertain as is the primary part played by bacteria. Chronicity and tissue destruction lead to the classical physical signs. Disease that has persisted for more than 20 years carries a significant risk of progression to SCC and rarely verrucous carcinoma

Hidradenitis is usually a clinical diagnosis. Swabs should be taken for bacteriological analysis. Rarely, a biopsy may be necessary to exclude carcinoma or Crohn disease. Perineal Crohn disease mimics hidradenitis with its granulomatous inflammation, ulceration, and fistula formation, but it is less painful. Also, the disease is absent from the axillae and it is rare for patients to be free of overt gastrointestinal symptoms. Very florid perianal disease can be seen in myeloma and leukemia in homosexual men and AIDS.

Histologic features

The histology is identical to that of hidradenitis suppurativa occurring elsewhere.

Clinical features

The cause of aphthous ulcers is not known. Aphthous ulceration of the penis and scrotum does occur, but this is not an acceptable diagnosis in the perianal skin or genitalia without overt exclusion of sexually transmitted diseases, and culture is reasonable practice. When aphthae occur on the vulva, the usual site involved are the labia majora and minora. They can occur with or without oral aphthae and may be a reactive phenomenon.

The impression is that aphthae and idiopathic orogenital ulceration are more common in HIV infection and worse, symptomatically and morphologically. Giant lesions may occur. In HIV, all mucocutaneous ulcers must be biopsied and cultured; several pathologies may coexist.

Histologic features

The histology of idiopathic aphthous ulceration is entirely non-specific. The main reason why a biopsy is performed is to rule out other pathologies.

Clinical features

This condition is seen in teenage girls who present with vulval ulceration of sudden onset. Lesions may be solitary or multiple. The initial lesion is a tender purpuric or hemorrhagic papule that rapidly enlarges and ulcerates. The ulcers are deep and painful, and have sharply delineated erythematous margins. There may be an accompanying fever, malaise, and cervical lymphadenopathy. A similar condition does not occur in males.

Pathogenesis and histologic features

The condition is a toxic reaction to a systemic infection. The most commonly associated infection is EBV infection (infectious mononucleosis). Other associated infections have included typhoid and paratyphoid, mycoplasma, mumps, and cytomegalovirus. The microscopic appearance shows non-specific superficial ulceration with granulation tissue, fibrin deposition, and a mixed inflammatory cell infiltrate. It is suggested that a localized lymphocytic arteritis is a common feature The presence of the EBV can be demonstrated by in situ hybridization.

Clinical features

Sclerosing lymphangitis of the penis (Mondor disease) is a rare condition which presents as a serpiginous cordlike thickening of the skin near the coronal sulcus. Rarely, there is involvement of the dorsal aspect of the shaft. There may be some inflammation and local tenderness. The condition is usually self-limiting and resolves spontaneously after a few weeks. Only occasional cases are persistent and may require surgery. There does not appear to be a female equivalent to this disorder, but there has been a report of the disease involving the upper lip and the labium minus.

Pathogenesis and histologic features

The etiology is unknown but vigorous or traumatic sexual activity is an important precipitant. In general, there does not seem to be any relationship to venereal disease although cases have been reported following genital herpes and Chlamydia infection. A case developing after coadministration of tadalafil and fluconazole has been documented.

The histologic features are characterized by a thrombosed vascular channel, thought to be of either lymphatic or venous derivation. Some authors separate sclerosing lymphangitis from Mondor disease based on the involvement of lymphatics in the former and veins in the latter. Focal Masson-like (intravascular papillary endothelial hyperplasia) changes may be seen. Later, in the course of the disease, the thrombus is replaced by fibrous tissue and a few scattered mononuclear inflammatory cells are also seen. The wall of the affected vessel later becomes thickened and sclerotic.

Histologic features

The histologic features are non-specific identical to those seen in lesions elsewhere.

Clinical features

This serious situation has a number of causes and a wide clinical differential diagnoses. Many of the causes are discussed in this and other chapters; for example, decubitus ulcer, the strangulation and tourniquet syndromes and other autoerotic misadventures and causes of artifact (priapism), pyoderma gangrenosum, infections such as herpes simplex, ecthyma gangrenosum and Fournier gangrene, and as a complication of serious illness (e.g., mucormycosis in acute myeloblastic leukemia). Necrosis can be the result of diabetic small vessel and end-stage renal disease and chronic renal failure with secondary hyperparathyroidism and calciphylaxis, and can complicate polycythemia, thrombocytopenia and leukemia, cryoglobulinemia, and vasculitis. Inferior vena caval thrombosis as part of disseminated intravascular coagulation can lead to necrosis and gangrene of the penis. Heparin necrosis is a coagulopathy due to heparin-induced thrombocytopenia. Warfarin necrosis is a state of acquired protein C dysfunction.

Histologic features

The histologic features consist of extensive necrosis of the skin and deeper tissues, and more specific changes may be found depending on the etiology of the process.

Clinical features

Anogenital lesions occur in about 30% of patients with intestinal Crohn disease, either by direct extension of active intestinal disease or occurring at sites distant from any gastrointestinal lesions (so-called ‘metastatic disease’) such as the face and limbs ( Figs 12.72–12.75 ). Skin involvement is more common in patients with colonic disease (up to 80%), and anogenital disease may present years before there is evidence of gastrointestinal disease. Vulval edema can be the only manifestation, and occasionally it is unilateral Crohn disease may involve the penis and scrotum, presenting as penoscrotal lymphedema. More usually, however, the disease is associated with erosions, ulceration, abscesses, skin tags, sinus, and fistula formation. Lesions can exceptionally mimic hidradenitis suppurativa and pyoderma gangrenosum. Deep fissures (‘knife-cut’ sign) along the skin creases are a characteristic feature. Patients of any age with Crohn disease including children may present with anogenital involvement. Oral involvement includes edema, fissuring, and mucosal ‘cobblestoning’. One patient presented with ‘metastatic’ Crohn disease and oral intraepithelial IgA pustulosis.

Crohn disease is not uncommonly associated with pyoderma gangrenosum and erythema nodosum. Other links include leukocytoclastic vasculitis, erythema elevatum diutinum, granulomatous vasculitis, Sweet syndrome, epidermolysis bullosa acquisita, polyarteritis nodosa, pyostomatitis vegetans, vitiligo, psoriasis, erythema multiforme, lichen nitidus, hidradenitis suppurativa, and acne fulminans.

The condition runs a chronic course. Development of Bowen disease in a case of vulvovaginal Crohn disease has been reported. Rarely, SCC may develop in long-standing disease.

Histologic features

The histology may show only edema, dilated lymphatics, or lymphangiectasia. More commonly, there are dermal or rarely subcutaneous noncaseating granulomata mainly of the sarcoidal type ( Fig. 12.76 ). The latter may have a perivascular distribution. Granulomas are usually sparse and may be missed unless multiple sections are examined. The histologic diagnosis can only be made after careful clinicopathological correlation.

Clinical features

This is an unusual variant of leukocytoclastic vasculitis of infants and young children that may present as tenderness, redness, and swelling of the penis and scrotum with the development of more widespread hemorrhagic lesions.

Pathogenesis and histologic features

Streptococci, staphylococci, and adenoviruses have been implicated. The histology shows typical features of a leukocytoclastic vasculitis.

Clinical features

Erythrasma is a superficial infection of the skin at flexural sites, particularly in the inguinal and genitocrural folds ( Fig. 12.77 ). The skin between the toes and natal cleft may also be involved. The affected areas are covered in red-brown scaly plaques with well-demarcated edges. The rash is usually asymptomatic or mildly itchy. The affected areas fluoresce coral pink under Wood light. This feature is due to the presence of porphyrin and may be absent in some cases. Very rare cases present with generalized involvement. The disease may appear concomitantly with a dermatophytosis and this often makes the diagnosis difficult.

Pathogenesis and histologic features

The organism involved is an aerobic, Gram-positive corynebacterium, Corynebacterium minutissimum , which is a normal skin commensal. Overgrowth and dermatitis are encouraged by the damp and warm conditions of a flexural zone. Obesity, friction, diabetes, and immunosuppression are all contributory factors.

The characteristic clinical picture and the presence of fluorescence under Wood light obviate the need for biopsies in most cases. A biopsy shows the presence of rods and filamentous organisms in the stratum corneum ( Figs 12.78 and 12.79 ). Inflammation is minimal.

Clinical features

Trichosporosis due to Trichosporon beigelii is a common form of genitocrural and perianal intertrigo in India. Predominant symptoms are itching and/or burning. Scaly papules can accompany the intertrigo. Coexisting dermatophyte, Candida , trichomycosis, and erythrasma infection may be found. Infection rarely occurs elsewhere, including the scalp.

Histologic features

The infection involves the hairs but not the surrounding skin. Microscopic examination of hair shafts shows white or brown soft nodules of varying size that can easily be removed. The diagnosis is suspected by a KOH preparation to identify variable-sized arthrospores and is confirmed by culture.

Clinical features

Genital warts (condyloma acuminatum) are usually caused by HPV types 6, 11, 16, 18, 30–32, 42–44, and 51–55. HPV-7, usually associated with warts in butchers, can exceptionally be the cause of condylomas. HPV-6 and 11 account for approximately 90% of these lesions. However, more than one HPV type can be isolated from a single lesion. They occur on the glans penis and prepuce or shaft as soft, fleshy (sometimes filiform) plaques and may extend into the meatus ( Figs 12.86 and 12.87 ). On the shaft, they are less exophytic. Vulval lesions may be bulky and macerated, and can extend into the introitus ( Figs 12.88–12.90 ). Lesions may be difficult to detect on clinical examination. Vulval condylomata usually involve the labia minora, interlabial sulcus, or the area around the introitus. Similar fleshy and filiform soft masses may occur perianally and in the anus, more often in males ( Fig. 12.91 ). Genital warts in children always raise the possibility of sexual abuse but can occur with close nonsexual contact. However, nonvenereal viral warts (verruca vulgaris) mainly caused by HPV type 2 can occur in both young girls and less frequently in adult women, so HPV typing can be very important. Young sexually active adults are the most frequently affected (second and third decades), and often in association with other sexually acquired infections.

Rarely, condyloma acuminatum presents in the oral cavity. Condylomata have also been reported in the abdominal pannus fold of a few obese patients.

It is important to recognize that a significant proportion of genital HPV infections are asymptomatic. The female partners of male patients with genital warts have been shown to have an increased risk of cervical HPV infection and intraepithelial neoplasia. Cervical neoplasia associated with preexistent vulval warts has also been related to immunosuppression, at least in some patients. Up to 80% of invasive cervical squamous carcinomas have been shown to contain HPV DNA. Types 16, 18, 31–33, 35, 39, 42, and 51–54 are most commonly associated with cancer of the cervix, vulva, and penis Malignant transformation of genital warts is rare but may be found in association with penile bowenoid papulosis and VIN usual type (undifferentiated). In the most recent classification of VIN, condylomata acuminata are classified as low-grade squamous intraepithelial lesions.

A large, exuberant, and locally destructive variant of condyloma (Buschke-Löwenstein tumor) may rarely be encountered. This is associated with HPV-6, 11, or 16. It is considered by many to be a variant of verrucous carcinoma, a subtype of well-differentiated squamous carcinoma (see below). However, the issue remains controversial and other authors regard it as a distinctive entity. They may show malignant progression if irradiated. The condition has been described in an HIV-positive patient.

Juvenile laryngeal papillomata containing HPV-6 and 11 can be seen in children born to mothers with condylomata acuminata.

Histologic features

Condylomata acuminata are characterized by marked acanthosis with a solid or trabecular pattern and a broad, rounded, exophytic growth ( Figs 12.92 and 12.93 ). There is a sharp, fairly regular, deep margin. The surface of the lesion is hyperkeratotic and parakeratotic. Superficial vacuolated keratinocytes (koilocytes) are characteristic ( Fig. 12.94 ). The vacuolated epithelium is often most marked in the declivities. Care must be taken not to confuse koilocytes with the vacuolated, glycogenated keratinocytes of mucosal epithelia or with artifactually vacuolated keratinocytes. Distinction can be made fairly readily as koilocytes have an enlarged, wrinkled, hyperchromatic nucleus.

Care should be taken in the histologic interpretation of lesions that have previously been treated with podophyllin (although this treatment is seldom used nowadays since the advent of imiquimod). These can display prominent degenerative changes with cytoplasmic vacuolation, nuclear enlargement, and metaphase arrest. The changes, however, tend to be more focal, and abnormal mitotic figures are not seen. Immunohistochemical stains for papillomavirus common antigen have been used to confirm the diagnosis, but this is only positive in about 60% of cases. More recently, broad-spectrum in situ hybridization in paraffin-embedded tissue has become available.

Giant condyloma acuminatum (Buschke-Löwenstein tumor) occurs most frequently on the genitalia, and is larger and more cauliflower-like. It shows some tendency to endophytic growth, but without any suggestion of frank infiltration. It can recur locally. Anal condylomata may develop bowenoid features, and occasionally invasive tumors supervene.

Clinical features

The incidence of syphilis fell dramatically after the introduction of penicillin in the 1940s. In recent years the incidence has been rising annually largely due to the increased number of cases of HIV infection. Drug abuse and high-risk sexual behavior are also contributory factors. The increase in the incidence of syphilis continues, especially in HIV-infected patients with predilection for young homosexual black males.

In the sixteenth century, syphilis carried a high mortality associated with a chronic disfiguring and disabling disease. The disease currently appears less aggressive, even in untreated cases. It is highly infectious, with the risk of transmission from an infected partner estimated at up to 60%. The chance of acquiring the disease depends on the number of exposures, type of sexual practice, and the location and number of the partner's lesions. There is a close relationship between syphilis and HIV infection, and both diseases can be acquired together. It is recognized that diseases such as syphilis that induce genital ulceration increase the risk of acquiring HIV infection.

The causative organism is Treponema pallidum , a spirochete with fastidious growth requirements. Transmission is primarily sexual. An endemic form known as bejel, caused by an identical organism, occurs in children living in conditions of poor hygiene and is transmitted by cutaneous inoculation. Other endemic forms have been associated with shared drinking vessels when some members of the community have oral or labial syphilitic lesions.

The typical initial lesion, a chancre, develops 20–30 days after exposure to the organism at the site of inoculation. This can be anywhere on the anogenital skin, more often on the glans penis (especially the coronal sulcus), the shaft, or prepuce, or on the labia majora or minora ( Figs 12.95–12.99 ). At least 5% of primary chancres arise at extragenital locations, most commonly oral, but virtually every other part of the skin surface may be affected including the tonsils, fingers, eyelids, and nipples ( Figs 12.100 and 12.101 ). Lesions in the vagina or cervix may go undetected. The chancre appears as an indurated, punched-out, painless ulcer. It is usually accompanied by painless lymphadenopathy. This resolves without scarring after 1–5 weeks.

The secondary cutaneous lesions (syphilids) are highly infectious and may mimic virtually any skin disorder. They present 6–8 weeks after the appearance of the chancre. They develop insidiously (in up to 80% of patients), with a roseolar, macular–erythematous rash, on the head, face, and neck followed by a polymorphic papular eruption. The macules measure 5–10 mm in diameter, are not pruritic, and particularly occur on the trunk, abdomen, and limbs, especially the palms and soles ( Figs 12.102–12.107 ). The papular lesions are characteristically coppery red in color and 3–10 mm in diameter. Hypopigmentation of the neck is known as the ‘collar of venus’.

Other manifestations described include condylomata (in intertriginous areas), annular, lichenoid, papulosquamous lesions (psoriasiform), arcuate lesions, corymbose brownish-red papules (Gr. korymbos , clusters of ivy flowers), bullous, erythema multiforme-like follicular and pustular variants on the skin, with erosive ulcers (mucous patches), often of ‘snail track’ type, and the (highly infectious) condylomata lata affecting the mucosae ( Figs 12.108–12.111 ). Keratoderma can also be seen. Large hypertrophic condylomata are known as framboiseform syphilids. Other variants described are acneiform, varioliform, and rarely, necrotic ( Fig. 12.112 ). Lesions tend to be widely disseminated and often symmetrical in distribution. Papular involvement of the scalp may result in nonscarring, patchy alopecia ( Fig. 12.113 ). The alopecia induced by secondary syphilis is known as alopecia syphilitica and has a characteristic, moth-eaten appearance. The beard, eyebrows, and eyelashes may also be affected. Telogen effluvium has also been described.

Rare ‘malignant’ forms of syphilis (lues maligna) present with rapid progression, papulopustular lesions, much ulceration, and rupial lesions (Gr. rhypos , filth; necrotic lesions covered by dirty, lamellated encrustation resembling oyster shells) mainly affecting the face and limbs. Patients can also present with fever, eye involvement, myalgia, lymphadenitis, and hepatosplenomegaly. This form of syphilis has been described in association with HIV infection and is characterized by necrotic and ulcerative lesions. ²⁰

Secondary syphilis manifestations have typically been described as nonpruritic, but this is not always the case. Indeed, in the series of 105 patients with secondary syphilis published by Chapel, 42% complained of pruritus. Resolution may be accompanied by hypo- or hyperpigmentation. Lymphadenopathy, which may be widespread and is painless and rubbery, occurs in 50–85% of patients. The cutaneous manifestations are often accompanied by pyrexia, headache, weight loss, and non-specific muscle and joint aches. Periostitis can rarely occur. Ocular involvement including uveitis and retinitis can occur at any stage of the disease. Untreated lesions of syphilis resolve in 2–10 weeks, but if treated., there may be a self-limited febrile reaction known as the Jarisch–Herxheimer reaction associated with systemic symptoms.

Atypical clinical forms of syphilis have been reported in HIV-positive patients, and multiple genital ulcers may occur in primary syphilis as well as concomitant ulcer with secondary syphilis.

Secondary syphilis is followed by a latent phase, which may precede a change to:

• seronegativity and cure,

• persistent seropositivity without further lesions,

• development of tertiary lesions.

These late lesions involve mainly the cardiovascular (aortic incompetence) and central nervous system (tabes dorsalis and general paresis of the insane), but cutaneous lesions are seen as noduloulcerative lesions and gummata that tend to break down with central necrosis and suppuration. Gummata may occur up to 15 years after the initial infection. They are painless, frequently ulcerated, firm subcutaneous nodules that show a predilection for the scalp, face, chest, and legs ( Fig. 12.114 ). Noduloulcerative late syphilitic lesions present as superficial nodules that extend peripherally and heal centrally to form ulcerated serpiginous plaques. Lesions of tertiary syphilis can be seen in internal organs and may clinically mimic cancer.

Infants born to infected mothers may have widespread lesions reflecting a systemic infection (congenital syphilis). Development of the disease is mainly associated with lack of antenatal screening. These include fibrosis in many organs, with inflammatory changes seen particularly in bones and lungs. Vesicular skin lesions and maldevelopment of teeth and bone are also sometimes evident. Later changes of congenital syphilis are classically frontal bossing, a short maxilla, a high arched palate, chronic interstitial keratitis, notched (Hutchinson) incisors, Mulberry molars, VIII cranial nerve deafness, and saddle nose. Other manifestations include painless hydroarthrosis, perforation of the nasal septum and palate, and cardiovascular and neurological changes, as seen in late-stage adult disease.

Pathogenesis and histologic features

T. pallidum is a slender, coiled organism, 6–16 µm long, capable of an undulating, corkscrew-like motion. The organisms are readily visualized in material from a primary chancre with dark-field illumination, but can also be grown in culture. The usually nonpathogenic spirochetes, which live as commensals around the gingiva, although still termed Treponema , are quite different, not least in that they have a right-handed spiral in contrast to the left-handed spiral of T. pallidum and other pathogenic spirochetes.

T. pallidum produces a nonantigenic mucin coat, which may be protective in early infections. This mucoid element may be increased by a component produced by host inflammatory cells. A hyaluronidase is associated with the surface of T. pallidum and may facilitate dissemination in tissues.

After the first inoculation of the spirochete through mucosa or abraded skin, the organism becomes systemically distributed before the primary chancre develops at the site of inoculation and numerous spirochetes can again be identified.

The chancre is characterized histologically by initial epidermal hyperplasia with an intense lymphohistiocytic and neutrophil infiltrate in the dermis ( Figs 12.115–12.117 ). Plasma cells are present, but may be more numerous in papular and papulosquamous secondary lesions (see below). The overlying epithelium becomes ulcerated, and the adjacent epidermis often shows pseudoepitheliomatous hyperplasia and infiltration by neutrophils. The induration of the primary lesion is due to a large amount of mucoid substance. Vascular endothelial cell swelling is often prominent. The organisms can be demonstrated by dark-field examination of a smear taken from the primary lesion. A silver stain such as Warthin-Starry and particularly immunohistochemistry are also useful in demonstrating the organisms in tissue sections. By electron microscopy, the spirochetes are often found in macrophages, endothelial cells, plasma cells, and in the intercellular space close to small blood vessels. Resolution of the chancre, while appearing to coincide with immunity to further infection and demonstration of antibodies, nevertheless does not impede the widespread dissemination and proliferation of the treponeme. This leads to its recrudescence in the secondary phase, a paradox that is not understood.

Secondary lesions show variable appearances depending to some extent on the clinical morphology ( Figs 12.118–12.124 ). Purely macular lesions are not distinctive and show a rather sparse perivascular lymphohistiocytic infiltrate with few, if any, plasma cells. The epidermis is normal. As the lesions develop a papular morphology, superficial and deep perivascular infiltrates develop, which may also adopt a bandlike distribution. Involvement of the subcutis is rare. Plasma cells become more numerous, and parakeratosis, acanthosis, spongiosis, and exocytosis may be evident. Thick-walled blood vessels with swollen endothelial cells are characteristic. A prominent infiltrate is often present around hair follicles and sweat glands. Early lesions showing perivascular neutrophils and a heavy neutrophilic infiltrate mimicking Sweet syndrome has been reported. Psoriasiform syphilids show parakeratosis and acanthosis with extended (psoriasiform) epidermal ridges. The inflammatory cell infiltrate is both perivascular and superficial, and bandlike in distribution. Spongiform pustulation and neutrophil exocytosis may be evident, and focal cell hydropic degeneration can sometimes be present. Keratinocyte necrosis may occasionally be seen. Leukocytoclastic vasculitis is very rare. A recent study reported the most frequent histologic features to be psoriasiform hyperplasia with slender elongated rete ridges, plasma cells, and endothelial cell swelling.

Erythrocyte extravasation may be a feature of both papular and papulosquamous variants. A granulomatous element has been described in both papular and papulosquamous eruptions, but this is not a constant feature. In addition to a dense dermal infiltrate, large numbers of plasma cells and occasional giant cells are seen in corymbose syphilis. The number of organisms in secondary syphilis varies. Traditionally, they have been identified by the use of silver stains, mainly Warthin-Starry. However, the latter method is time consuming and difficult to interpret. The organisms can also be identified by PCR, and a polyclonal antibody against T. pallidum is available for immunohistochemistry ( Fig. 12.125 ). Both PCR and immunohistochemistry are much more specific than histochemistry in the diagnosis of syphilis. In primary syphilis, the organisms are found both within the epidermis and around blood vessels, whereas in secondary syphilis organisms are mainly found within the epidermis, suggesting that these patterns can be used as an aid in distinction between the two stages of syphilis. The bacteria have also been identified in vivo in the epidermis by the use of reflectance confocal microscopy. In a case of malignant syphilis, a surprisingly very low number of organisms was found in the lesions. Spirochetes have been demonstrated within hair follicles in a case of alopecia syphilitica.

The nodular variants of secondary syphilis may be associated with granulomatous or pseudolymphomatous histology. Some lesions can contain an impressive number of CD30-positive atypical T cells. The granulomata can mimic those of sarcoid and may rarely have a palisaded distribution resembling granuloma annulare. The rupial and condylomatous forms are characterized by marked epidermal hyperplasia, spongiosis, and a neutrophil infiltrate. The dermis contains a very heavy inflammatory cell infiltrate including numerous plasma cells. Vascular changes are marked.

Late secondary lesions are typified by histiocytic granulomata. These are not well circumscribed and do not usually include multinucleated giant cells. They can be distinguished from tuberculosis by the presence of numerous plasma cells peripherally and the swollen endothelia of small blood vessels. A case of late latent syphilis with prominent dermal mucin mimicking a connective tissue disease has been reported.

Gummata are characterized by central necrosis similar to caseation, but with a visible suggestion of residual cell outlines ( Fig. 12.126 ). The necrosis is surrounded by a lymphohistiocytic and plasma cell infiltrate with fibrosis. Spirochetes are very scanty and very difficult to find with the use of silver stains. Endarteritis is often evident.

Noduloulcerative lesions are granulomatous, and typically there is no significant necrosis. Plasma cells are said to be inconspicuous, which may therefore cause considerable diagnostic difficulty.

Clinical features

Granuloma inguinale (donovanosis) occurs in people with poor hygiene in tropical regions, mainly in India, Brazil, the West Indies, China and West Africa; it was formerly seen in southern United States, but is now rare. The disease is still seen in Australia in the Aboriginal population. The organism is of low infectivity and is presumed to be spread by sexual contact, probably through abraded skin. It occurs most often in the third to fifth decades. The incubation period is uncertain and may range from 2 to 3 weeks to several months.

The initial presentation in females is usually of one or more indurated papules or nodules on the inner aspect of the labia, the fourchette, or around the clitoris ( Fig. 12.127 ). In males, the glans, prepuce, coronal sulcus, or shaft is affected ( Fig. 12.128 ). Dorsal perforation of the prepuce can occur as a late complication. The perianal and inguinal regions and the cervix may also be involved. In one case involving the cervix, there was associated malacoplakia. The papules ulcerate irregularly and extend widely if untreated. The base of the ulcer is ‘beefy’, and the margins are undermined and indurated. Spread to contiguous ‘kissing’ areas may sometimes occur. Variants include verrucous, necrotic, and scarring lesions. Primary infection of the lymph nodes does not occur, but painful lymphadenopathy is common due to secondary infection. Rarely, primary extragenital lesions may be seen (mainly mouth or lips but also at unusual sites such as the foot). Exceptionally, presentation as a psoas abscess and as a pelvic mass mimicking ovarian cancer has been described.

Very occasionally, there is a systemic infection with involvement of many organs including the liver, and osteolytic lesions in bone. The latter may particularly relate to a primary cervical lesion. Spinal compression has also been reported. Later complications include strictures of the urethra, vagina, or anus, destruction of the penile shaft with autoamputation, and pseudoelephantiasis. As with other sexually transmitted diseases, patients with granuloma inguinale are often HIV positive and may also have syphilis. Genital SCC is an uncommon but important complication. Infection in children has rarely been reported and occurs as a result of transmission from an infected mother at birth. Rare manifestations of the disease in children include a mass in the neck, otitis media, and mastoiditis.

Pathogenesis and histologic features

Granuloma inguinale is caused by Calymmatobacterium granulomatis (formerly Donovania granulomatis ), an encapsulated short (1–2 µm) Gram-negative rod with characteristic bipolar staining. It is transmitted by sexual contact, but it is of low infectivity. The organism is found in feces, and this may act as a reservoir of infectivity or, in occasional cases, be the source of genital infection. The higher incidence of infection in homosexuals may support this concept.

The lesion is characterized by a very intense inflammatory infiltrate in which plasma cells are predominant ( Fig. 12.129 ). Focal formation of neutrophilic microabscesses is frequent. Pathognomonic macrophages contain cytoplasmic cyst-like vacuoles in which bacteria can be demonstrated by staining with Giemsa or the Warthin-Starry reaction ( Figs 12.130 and 12.131 ). The bacteria can also be seen extracellularly. In most cases there is associated acanthosis, which sometimes amounts to pseudoepitheliomatous hyperplasia. Ulceration is common. A large study has demonstrated frequent transepidermal elimination of organisms. It is likely that this phenomenon may be an important mechanism in the spread of the disease.

Diagnosis is confirmed by the identification of typical organisms (Donovan bodies) on a scraping from an ulcer or in a biopsy stained with Giemsa or Warthin-Starry. PCR has also been used successfully to confirm the diagnosis. Dark-field illumination microscopy should be performed to exclude syphilis. By electron microscopy, the encapsulated microorganisms can be demonstrated within the phagosomes of macrophages.

Clinical features

Chancroid (soft chancre, genital ulcer disease) is very common in some tropical areas of Africa, Southeast Asia, Central America, and the Pacific. Poor hygiene is a feature of communities where the disease is endemic. It is associated with an increased risk of transmission or acquisition of HIV. Genital ulcers including chancroid appear to develop more commonly in HIV-positive women during the first month of antiretroviral therapy. It has also been diagnosed more frequently in Western Europe and North America in association with increased travel, immigration and prostitution. Chancroid was endemic in New York City and southern Florida in the 1980s. It represented 3% of genital ulcers in a sexually transmitted disease clinic in Paris. The disease is acquired almost always by sexual contact and has a short incubation period of 3 days to 2 weeks (median, 7 days). Exceptionally, nonsexually transmitted lower limb chancroid ulcers have been reported in patients from Papua New Guinea and Samoa, in both adults and children. Concurrence with other sexually transmitted disease including gonorrhea can be seen.

The initial lesion is usually a transient vesicular tender papule, which rapidly ulcerates with copious suppuration. The ulcer is sharply circumscribed with an undermined edge and is typically not indurated. These lesions appear much more commonly in the male, usually on the penis ( Fig. 12.132 ). The prepuce, coronal sulcus, frenulum, and glans are the most favored sites. Circumcised males are at lower risk of developing the disease. Lesions in the female are seen on the fourchette, labia majora and minora, and around the clitoris. The perineum and perianal area may also be affected. Multiple ulcers can be present, which have an irregular ragged edge and slough-covered bases. Cervical and vaginal involvement is uncommon. Variants of primary chancroid ulcers include giant and serpiginous forms, follicular, transient, and dwarf lesions; occasionally, a condyloma lata-like presentation may occur.

The ulcers are tender and especially painful when in contact with urine. Lymphadenitis occurs in about 50% of cases approximately 1 week after the genital lesion, and in 50% of these, suppuration (bubo formation) usually follows. Sometimes rupture may occur, resulting in inguinal ulceration. In other cases, the course is variable, some resolving without treatment in a few days while others go on for several weeks, developing phimosis or even gangrene. Systemic infections do not occur.

Pathogenesis and histologic features

Chancroid is caused by Haemophilus ducreyi , a Gram-negative coccobacillus, which grows in chains sometimes arranged in parallel. It is transmitted through minor abrasions during sexual intercourse. The subsequent lesion comprises:

• a superficial zone of neutrophils, red cells, bacteria, and cell debris,

• a middle zone of edematous granulation tissue,

• an underlying infiltrate of histiocytes, lymphocytes, and plasma cells ( Figs 12.133 and 12.134 ).

  
  

The enlarged lymph nodes show central necrosis with a surrounding mixed inflammatory response of neutrophils and macrophages.

Diagnosis is confirmed by isolation of the organism by culture in a blood-enriched medium containing vancomycin at 33°C. The bacterium may be identified by its chain-like growth in scrapings from the margin of the ulcer, but secondary organisms are often present and it is more helpful to identify the organism in an aspirate from a necrotic lymph node. DNA in situ hybridization and PCR for H. ducreyi has been developed. DNA from the organism has been detected by PCR in esophageal lesions of HIV-positive patients.

Clinical features

Lymphogranuloma venereum is endemic in Asia, Africa, and South America and was considered to be rare in developed countries until several outbreaks were reported in a number of European countries and the United States, mainly in homosexuals and in the context of HIV infection. It is less common in women.

The disease evolves in three stages:

• In stage 1 disease, the primary lesion develops 3–30 days after contact and is a small, transient, frequently asymptomatic papulovesicle or ulcer on the penis, scrotum, rectum, vulva (most commonly at the fourchette), vagina, and/or cervix ( Figs 12.135 and 12.136 ). Primary lesions have been described on the fingers and tongue. Rarely, lymphogranuloma venereum has been reported presenting with a psoas abscess. Cat scratch disease may clinically simulate this disease.

  
  

• Stage 2 develops within a few weeks of the primary lesion and consists of enlargement of the inguinal nodes. The pelvic lymph nodes may be enlarged in females. The lymphadenopathy is severe and initially painless and hard; later, the nodes (buboes) soften and discharge viscous pus. The tissue around the nodes becomes involved in the inflammatory process so that they become matted together. Along with lymphadenopathy, the patient may also experience malaise, joint pains, and hepatosplenomegaly. Erythema nodosum, light-sensitive eruptions, and erythema multiforme may complicate this phase and are more common in women.

• Stage 3 disease consists of complications of the early inflammatory changes. Involvement of the deep iliac and perirectal lymph nodes resulting from drainage from a high vaginal, posterior urethral, cervical, or rectal primary lesion may be complicated by a stricture of the rectum 5–10 cm from the anus. This is associated with periproctitis and proctocolitis, which sometimes fistulates. Rectal carcinoma is an occasional late complication. In both sexes, genital lymphedema and even elephantiasis can develop after the lymphadenopathy. This may be a continuing problem and can be associated with secondary cutaneous erosions and ulceration.

Systemic lesions are rare, and include cardiac and pulmonary involvement, keratoconjunctivitis, episcleritis, uveitis, papilledema and retinal hemorrhages, meningitis, hepatitis, and cutaneous manifestations such as erythema nodosum and erythema multiforme.

Pathogenesis and histologic features

Lymphogranuloma venereum is caused by strains L1, L2, and L3 of the bacterium C. trachomatis . The C. trachomatis species is divided into 15 prototypic serovars according to analysis of their outer membrane protein. Only serovars L1 to L3 are associated with lymphogranuloma venereum, with the L2 serovar causing most cases. Chlamydiae are nonmobile, coccoid, obligate intracellular parasites. They depend on their host cells for ATP metabolites and multiply within membrane-bound vacuoles in the host macrophage cytoplasm. They stain faintly blue with hematoxylin and eosin (H&E), Gram-negative with the Brown-Hopps tissue Gram stain, and black with the Warthin-Starry silver impregnation technique. On the rare occasions that the primary lesion is viewed histologically, the base of the ulcer is lined by intensely inflamed fibrous granulation tissue. Plasma cells and microabscesses are present. The lymphadenitis has a characteristic picture of stellate central necrosis with neutrophils and a surrounding palisaded granulomatous reaction with occasional giant cells.

The central necrosis is slowly absorbed and replaced by fibrosis. As a consequence, lymphedema develops distally. The lymphatics are typically inflamed and granulomata may be seen.

The diagnostic standard is now nucleic acid amplification testing. PCR may also be used to confirm the diagnosis.

Clinical features

Schistosoma hematobium and Schistosoma mansoni are both found extensively in Africa. S. mansoni also occurs in the West Indies and in parts of South America. Schistosoma japonicum is present in China, Japan, and Southeast Asia. These trematodes (blood flukes) do not often cause major disease of the skin, but skin lesions do occur at various stages of infestation.

Invasion of the human host by the aquate cercarial stage may be associated with dermatitis (swimmer's itch). This rash is erythematous, pruritic, and urticarial, but eventually resolves to leave a pigmented spot. It is more often encountered with invasion of avian species.

In schistosomiasis (bilharziasis), the mature worms may be associated non-specifically with erythematous itching macules at the time of release of large numbers of eggs. This probably represents a systemic reaction to antigen liberation. A more severe reaction seen particularly with S. japonicum is Katayama disease or Yellow River fever. In addition to erythema, macules, and pruriginous lesions, patients may also have fever, malaise, chills, sweats, arthralgias, headache, lymphadenopathy, hepatosplenomegaly, and peripheral blood eosinophilia.

Specific skin lesions are seen, usually around the genitalia and most often in prepubertal females, when ova are deposited there ( Fig. 12.137 ). They appear as grouped solid papules, which subsequently become warty and vegetative, resembling condyloma acuminatum ( Fig. 12.138 ). The labia majora are often involved initially. Occasionally, progression to SCC occurs. Periurethral granulomata due to schistosomes may be associated with thrombosis and necrosis, sometimes resulting in fistula formation in the perineum (‘watering can perineum’). In late lesions prominent scarring may occur. More rarely, entrapped ova are seen in other areas of skin, but the means of their migration to those sites is not understood. Extragenital lesions of schistosomiasis have been described in the trunk (mainly periumbilical but also in the axilla, back and inframammary area), face, and proximal lower limbs. Facial lesions may be associated with ocular involvement. Extragenital schistosomiasis, also known as extragenital bilharziasis cutanea tarda, is very rare and its recognition is extremely important as it is usually a sentinel as well as a potential external marker of recurrent visceral disease. Interestingly, it has been noted that this type of disease often occurs in preexisting cutaneous pathology such as squamous papilloma, SCC, scarring, and hidradenitis suppurativa.

Pathogenesis and histologic features

Part of the life cycle of schistosomes takes place in water snails. After their release from the snails, the cercaria penetrates the skin of humans and migrate as schistosomes to the portal veins where they mature into adult male and female worms. Adult females then migrate to the mesenteric plexus ( S. mansoni and S. japonicum ) or vesical plexus ( Schistosoma haematobium ). Ova are deposited in the venules, and the clinical and pathological sequelae are a direct consequence of the immunological response to their presence.

Eggs are released into the urine or feces where they hatch, releasing miracidia, which enter the snail host. Involvement of the female genital tract is usually due to S. hematobium and occurs as a consequence of worms being transported via anastomoses between the vesical and uterovaginal venous plexuses.

Histologically, adult worms are occasionally seen within the lumina of dilated deep dermal veins and lymphatics ( Fig. 12.139 ). Viable ova may be present with a recognizable miracidial structure ( Fig. 12.140 ). These are usually located within abscesses containing numerous neutrophils and variable numbers of eosinophils. Poorly formed granulomata with Langhans giant cells are also sometimes a feature. S. hematobium is recognized by its terminal spine ( Fig. 12.141 ). S. mansoni has a lateral spine and S. japonicum has no spine. The dead ova typically calcify and provoke a chronic, frequently granulomatous, inflammatory response. The overlying epidermis is usually acanthotic, sometimes to the point of pseudoepitheliomatous hyperplasia and may occasionally contain intraepidermal ova undergoing transepidermal elimination ( Fig. 12.142 ). Smearing crushed biopsies between two glass slides with 0.5% trypan blue in saline helps to highlight the ova. Adult parasites can sometimes be identified in anogenital and extragenital lesions.

Identification of the type of schistosoma can be made by molecular methods.