Chapter 77. Diseases and Disorders of the Male Genitalia

The incidence and prevalence of male genital dermatoses are not known with accuracy, but most, like sexually transmitted diseases, are more common and more severe in the uncircumcised; these include psoriasis, seborrheic dermatitis, and lichen planus (LP).1 The global prevalence of circumcision is estimated at 25%–33% and in the United States, 85%.1–5 Religious and cultural practices and medical intervention account for these rates. Circumcision has been adopted as a measure to reduce human immunodeficiency virus (HIV) transmission.6–17 Neonatal circumcision is a topic that evokes controversy, but some benefits are accepted (Table 77-1).1,2,3,10,18–41 Although there is little evidence of significant adverse effects on health and psychosexual function, circumcision can have side effects and complications, especially when performed “ritually.”3,5,17–19,42–47 Although views of circumcision range from prophylaxis to child abuse, the rational stance is that nontherapeutic circumcision of male infants should be left to parental discretion.3,48–50

Etiologic and pathogenetic factors have to be understood in relationship to structure, function, and microecology.3 Obviously the genital area differs between the sexes, but it also provides a good example of regional human variation.

Although the whole organ of the skin is concerned with sexual expression and activity, the penis is the male structure most intimately involved in sexual intercourse. It is also the conduit for urinary excretion. The scrotum is the extracorporeal sack that maintains the testes at the ideal temperature for spermatogenesis. The essential structures of the penis and its important landmarks are illustrated in Figure 77-1.3 As at other sites, topographical and regional anatomic nomenclature is an essential part of the vernacular for a dermatologist. The anatomic position is that of full penile erection.

The perineal area is abundant in eccrine and apocrine (some functionless) sweat glands and holocrine sebaceous glands, usually in association with hair follicles as pilosebaceous units but also occurring as free glands at some sites such as the anal rim or around the coronal sulcus (Tyson glands). Adnexal secretions lubricate the hinge between limb and torso, lubricate hair, lubricate the mucocutaneous junctions to assist in the voiding of excreta, and protect the epithelia from irritation and lubricate the penis for the retraction of the foreskin during sexual activity. The pattern of keratinization differs throughout the male genital tract area, most markedly so at the mucosal junctions, the prepuce and distal penile shaft, and especially the glans in the circumcised individual. The detritus of mucosal turnover combines with adnexal secretions to produce smegma that can accumulate in the preputial sac of the uncircumcised individual, especially if hygiene is poor. There is wide normal variation in the anatomy of the penis (particularly the urethral meatus) and its relationship to the prepuce, which perhaps reflects susceptibility to minor embryologic anomalies; the embryogenesis of the anogenital structures is complex.3 The foreskin is a delicate, busy tissue that is in close contact with urine and exposed to sexual secretions, detergents, and infectious agents, especially opportunistic organisms and those that are sexually transmitted. Of the latter, human papillomavirus (HPV) is the most important known from the point of view of precancerous dermatoses and invasive squamous carcinoma. All these congenital and acquired factors can conspire to produce a dysfunctional foreskin,51 often clinically expressed as male sexual dysfunction in the form of male dyspareunia. The genitals may be a site of predilection or exclusive manifestation of disorders often encountered extragenitally (e.g., vitiligo, psoriasis, and LP), in part due to the Koebner phenomenon.3

The algorithm shown in Box 77-1 emphasizes the need to obtain a complete history, perform an adequate examination, and construct a differential diagnosis. Initiating investigations to exclude sexually transmitted disease or performing a biopsy may be indicated. Occasionally, a trial of treatment may help crystallize a diagnosis.

The responsibility for the elucidation of anogenital symptoms may need to be shared with the genitourinary physician, pediatrician, urologist, or colorectal surgeon.

History

Although classic dermatologic symptoms (itch, rash, lumps or bumps, or ulceration) may be present, the physician must be alert to symptoms of sexually transmitted disease (e.g., discharge, dysuria), urologic disease (e.g., pain, hematuria, dysuria), and male sexual dysfunction. Symptomatic male sexual dysfunction equates with male dyspareunia, that is, painful or difficult sexual intercourse. Many men will not volunteer such information, so specific inquiry should be tactfully made. The components of normal male sexual function are libido, erection, ejaculation, and orgasm.

Cutaneous Lesions

A systematic approach to the penis and prepuce is summarized in the algorithm (see Box 77-1). The foreskin (if present) should be gently retracted, the gluteal and crural folds and the meatal lips parted, and the rectum examined digitally. Site, distribution, and morphology of lesions should be conventionally noted and analyzed. Specific male genital signs include phimosis (nonretractable foreskin; Fig. 77-2), paraphimosis (foreskin fixed in retraction; Fig. 77-3), balanitis (inflammation of the glans penis), posthitis (inflammation of the prepuce), and dorsal perforation of the prepuce (glans and shaft of penis ulcerated through the prepuce, which lies ventrally as an empty sleeve). Phimosis should be regarded as a sinister situation and impedes complete inspection and palpation of the glans and coronal sulcus. The causes of phimosis are listed in Table 77-2. Paraphimosis is rarer and is usually an acute emergency presentation caused by vigorous sexual activity, acute contact urticaria, acute allergic contact dermatitis, and lichen sclerosus (LSc). Chronic paraphimosis is increasingly recognized in India and is due to chronic inflammation and fibrosis of the foreskin in the retracted state. Balanitis and posthitis xerotica (obliterans) can be confusing terms, used to signify the end stage of all chronic cases of balanitis and posthitis (e.g., scarring dermatoses such as LP and cicatricial pemphigoid), but these conditions are usually due to LSc and are therefore considered synonymous by some. Dorsal perforation of the penis is very rare and is caused by gross penile disease such as hidradenitis suppurativa, pyoderma gangrenosum, florid condylomata, chancroid, herpes simplex, idiopathic balanoposthitis, and podophyllin misuse.3,53,54

Related Physical Findings

The algorithm (see Box 77-1) underlines the necessity to examine patients conventionally, systematically, and completely, because important signs will be found at nongenital sites.

The most commonly required special investigational procedures are taking a swab or smear for microbiologic or virologic analysis, obtaining scrapings for fungal microscopic examination and culture, taking scrapings for mite identification, and performing a skin biopsy. Wood's light examination is helpful in the clinical diagnosis of vitiligo, erythrasma, and fungal infections. The investigations pertinent to the diagnosis of sexually transmitted disease are discussed in Section 32 (see Chapters 200, 202, 203, 204 and 205).

A genital skin biopsy is informative under selected clinical conditions. It is important to obtain the right specimen from the right site at the right time (the most floridly inflamed areas may not be the best from which to obtain a specimen and histologically often show nonspecific or zoonoid features) and to provide the pathologist with a differential diagnosis. Examination of biopsy specimens should not be regarded as a substitute for clinical diagnosis. It is safe and helpful to use small amounts of adrenaline—the region is highly vascular. Knowledge of anatomy is crucial: ventrally, the urethra can lie very close to the surface in the coronal sulcus. It is not often necessary to suture a preputial punch biopsy site.3,55

Special Tests

Diagnostic imaging of the penis, scrotum, and perineum by ultrasonography or magnetic resonance can be helpful under some circumstances.56–58 Patch testing is sometimes indicated.3

The principal presenting scenarios are tabulated in Box 77-2.

Pearly Penile Papules (Angiofibromas)

Pearly or pink penile papules,3 which may be found in between 15% and 48% of men, are flesh-colored, smooth, rounded papules (1–3 mm) occurring predominantly around the coronal margin of the glans, rarely on the glans. Often there are rows or rings of the papules. They are commoner in the uncircumcised male and regress with age.59 Ectopic lesions, for example, on the penile shaft, have been reported. They are frequently mistaken for warts or Tyson “ectopic” sebaceous glands (of Tyson) and sometimes cause anxiety in adolescents. The histologic findings are those of angiofibroma, and 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. Reassurance should suffice, but cryotherapy and laser treatment have been used.3

Sebaceous Gland Prominence

Sebaceous gland prominence, Tyson glands, sebaceous hyperplasia, and “ectopic” sebaceous glands (Fordyce condition) are all essentially equivalent, common, normal variants of the skin of the scrotal sac and penile shaft, analogous to the situation on the vermillion of the lips. Nevoid linear lesions on the penile shaft and lesions on the glans have been reported. Reassurance is usually adequate, but patients can be inordinately distressed.3

Melanocytic Nevi

It is possible that nevi on the penis occur more frequently in patients with the atypical nevus syndrome.3 A divided or “kissing” nevus is a lesion with one-half located on the glans and the other half located on the distal penile shaft separated by uninvolved skin across the coronal divide; an analogous nevus affects the eyelids.60 Epithelioid blue nevus of the genitals is very rare.61

Prominent Veins

Prominent veins are common and very occasionally give rise to concern but very rarely cause complications.3

Angiokeratoma

Angiokeratomas are more common in white men and are common on the genitalia (where, confusingly, together with prominent sebaceous glands they have attracted the eponymous epithet of Fordyce spots). Angiokeratomas are blue to purple, smooth, 2–5-mm papules on the scrotum, penile shaft, or glans. They generally appear and multiply during life but occasionally present as singletons. They may bleed after trauma and may be mistaken for a nevus, melanoma, or Kaposi sarcoma. The angiokeratomas of Fabry disease (see Chapter 136) are smaller than common angiokeratomas, presenting as less hyperkeratotic pinhead lesions, and are found more extensively around the lower limb girdle and upper thighs from the navel to the knees. Angiokeratoma circumscriptum very, very rarely may affect the penis (see Chapter 172).

Electrocautery or laser ablation can be offered, but the lesions may recur.

Congenital Abnormalities

The complicated embryogenesis of the anogenital region involving sexual differentiation and pubertal determination of secondary sexual characteristics means that congenital and developmental anomalies are common. Consequent anatomic and functional abnormality may increase the vulnerability of the area to dermatoses (such as LSc) and infections.

Common abnormalities include meatal pit, hypospadias, median raphe cysts, canals and sinuses, and ambiguous genitalia. Rarer anomalies include hypospadias variants, meatal stricture, mucoid or urethral cysts, dermoid cysts, buried penis, urethral atresia, penoscrotal transposition, congenital lymphedema, giant preputial sac, megaprepuce, accessory scrotum, hemangiomas, strawberry nevus, os penis, and true aposthia. These entities may be features of congenital syndromes.3

Venereal Diseases

The clinical manifestations on the male genitals of syphilis, chancroid, lymphogranuloma venereum, granuloma inguinale, gonorrhea, and other venereal diseases as well as their pathogenesis, diagnosis, treatment, and complications are discussed in depth in Chapters 200, 202, 203, 204, and 205). Here it may suffice to remind the physician that any inflammatory, papulonodular, or ulcerative genital presentation requires consideration and exclusion of sexually transmitted diseases.

Pediculosis

(See Chapter 208)

Pediculosis pubis, or lice infestation (“crabs”), can cause severe genital itching with few physical signs unless the hairs are examined assiduously for nits and the base of individual hairs is scrutinized with a hand lens for the crab lice (1–2 mm), which will be tightly adherent to the skin because their mouth parts are embedded in perifollicular blood vessels. Sometimes gray–blue macules (tache bleu, maculae caeruleae) are seen on the affected sites.

Scabies

(See Chapter 208)

Scabies is a cause of intense itching that characteristically keeps patients awake at night. Usually there is a rash of diagnostic distribution and morphology. Some patients with scabies—who may have been infested for a long time, have had it before, have been inadequately treated, or have been adequately treated but develop secondary eczema or nodules—may have itch in the anogenital region only.

Viral Warts

(See Chapter 196)

Clinical Findings

Genital HPV infection can usually be diagnosed with certainty on clinical grounds (Figs. 77-4 and 77-5). Morphology is described in Chapter 196. Clinically inapparent penile warts may present as balanoposthitis.62–64

Differential Diagnosis

Disorders from which viral warts must be differentiated are listed in Box 77-3.

Complications

HPV infection is a risk factor for anogenital cancer, particularly of the cervix and anus. HPV is associated with the clinical expressions of penile carcinoma in situ (PCIS), or Bowen disease of the penis, erythroplasia of Queyrat (EQ), or bowenoid papulosis (BP) and approximately 50% of cases of squamous carcinoma of the penis.65,66 Infection with HIV may alter and worsen the expression and consequences of anogenital HPV infection: high-grade dysplasia associated with high-risk HPV types have been found in the urothelium and genital warts from HIV-positive individuals and the penis cancer risk is increased three- to sixfold (the anal cancer risk may be increased by as much as 100).3,67–75

Treatment

Patients presenting with warts, as well as their sexual partners, should be counseled and screened for HPV, other sexually transmitted diseases including HIV infection, and cervical neoplasia.

HPV infection may be very difficult to treat. Subclinical infection is very common, difficult to detect, and virtually untreatable, so there is divergence between ambitions for treatment and achievability. The principles of management are based on diagnosing and treating relevant lesions that are causing personal genital morbidity or psychosexual stress or long-term risk to the patient or his partner. Reasonable goals include (1) inducing cure or wart-free periods, (2) relieving or improving symptoms such as dyspareunia, (3) ensuring that side effects or complications of the treatment are no worse than the symptoms or risks of the warts, (4) minimizing morbidity and mortality from cervical cancer in female partners, (5) minimizing mortality and morbidity from PCIS and frank cancer in the patient especially those with HIV.62,69,72,73

Treatments are listed in Box 77-4.3,62,69,76,77

Mollusca

(See Chapter 195)

Mollusca may be sexually acquired, as in adult men, but genital lesions caused by autoinoculation are common in children. Classically small, flesh-colored, monomorphic, dome-shaped papules indented by a central dell or umbilicus are seen. Multiple lesions are usually present. Giant and polypoidal lesions may occur in the setting of HIV infection. Inflammation and purulence may be due to infection but are a common phenomenon when individual lesions spontaneously involute. Condylomata lata (secondary syphilis) and LP enter the differential diagnosis of mollusca, as do simple HPV infection and BP. Treatment may not be necessary especially in children. Options are similar to those for viral warts.3,77

Vitiligo

(See Chapter 74)

Vitiligo commonly affects the genitalia in men and may be the only site to be affected. Perianal involvement is also common.3 Other organ-specific autoimmune diseases should be excluded. Vitiligo has been reported after treatment of genital warts with imiquimod.78,79 An important rare differential diagnosis is depigmented extramammary Paget disease (EMPD).80 Phototherapy of vitiligo might lead to squamous cell carcinoma (SCC).81

Seborrheic Dermatitis

(See Chapter 22)

A diagnosis of seborrheic dermatitis is made when a nonspecific psoriasiform or eczematous balanitis or balanoposthitis is found in conjunction with classic symptoms and extragenital manifestations of the diathesis.3

No treatment other than reassurance may be required. However, treatments that diminish the commensal pityrosporum load and reduce irritation and eczematization can be very successfully and safely used long term. These include topical antifungals (such as clioquinol, nystatin, and imidazoles) in the form of ointments, creams, lotions, or shampoos and mixtures of the same agents with mild and moderately potent topical corticosteroids used alongside emollients and soap substitutes. In severe cases, such as with concomitant seborrheic folliculitis or in acquired immunodeficiency syndrome (AIDS), treatment with an oral imidazole might be indicated.

Psoriasis

(See Chapter 18)

Psoriasis is probably the most common dermatosis of the male anogenitalia, either in isolation or in association with frank or mild, subtle extragenital disease.3 The Koebner phenomenon is a likely factor in site predilection. Drugs such as lithium, β blockers, antimalarials, and angiotensin-converting enzyme inhibitors may be responsible for the onset or exacerbation of psoriasis.

In circumcised men, genital psoriasis presents with variably itchy, silvery-scaled, erythematous patches or plaques (Fig. 77-6). On the glans or in the preputial sac of the uncircumcised patient, scale is absent from the patches or plaques because of the mucosal site (Fig. 77-7). The scalp, ears, umbilicus, and face (in sebopsoriasis) may be involved, and there may be variable additional anogenital involvement, especially of the sacrum, buttocks, intergluteal cleft, pubic mound and groin, perianal skin, and, less commonly, the scrotum. Psoriatic balanoposthitis can be part of the spectrum of inverse-pattern psoriasis and may be associated with intertriginous disease of the axillae, intergluteal cleft, gluteal folds, and groin.

Patients with the reactive arthritis syndrome (see Chapter 20) may sometimes have involvement of the penis with circinate balanitis or small, flat pustules. These penile lesions have the same histopathology and ultrastructure as psoriasis. Sometimes this morphology is seen clinically with no background urethritis, gastroenteritis, or arthritis (Fig. 77-8).

Usually the diagnosis of psoriasis is clinical. Soreness might indicate superinfection, especially with Candida. Inordinate itch would make one suspect another dermatosis such as an eczematized dermatitis or tinea. A biopsy may be necessary if there are solitary mucosal lesions in the uncircumcised to exclude Zoon balanitis (ZB), LP, EQ, and Kaposi sarcoma. Bowen disease and EMPD may be misdiagnosed as psoriasis when there are single or several foci on the penile shaft and/or in the groin.

Topical treatment is based on the use of emollients, soap substitutes, corticosteroids combined with antibiotic and antifungal agents, or weak tar solutions. Atrophy is a risk with long-term use of potent topical steroids, and anogenital skin has a heightened tendency to absorb topical agents. Strong crude tar preparations should also therefore be avoided at this site because of the risk of genital cancer. Dithranol application may lead to burning and so is usually avoided in this region. Vitamin D analogues and calcineurin inhibitors seem safe, but with the latter, the prescriber must be certain of the absence of PCIS. Severe anogenital inverse psoriasis can be an indication for systemic treatment. Phototherapy is conventionally contraindicated because of the risk of anogenital cancer. It is possible that chronic anogenital psoriasis and its treatment may create a risk for anogenital squamous cancer.

Lichen Planus

(See Chapter 26)

LP has a particular predilection for the mucosa, which is perhaps partly explained by the Koebner phenomenon. LP can present in, and remain focalized to, the pelvic girdle, the genital area including the groin, and the perianal skin. Alternatively, symptoms and morphology of the classic disease—lilac papules and plaques with white lacy scale—may be present at other sites (Fig. 77-9). However, it may affect the penis (like the mouth, vulva, and anus) in isolation as the cause or consequence of foreskin dysfunction (by “koebnerization”) and so present as dyspareunia and a nonspecific dermatosis.3

The differential diagnosis includes eczema, psoriasis, seborrheic dermatitis, nonspecific balanoposthitis, ZB, LSc, drug eruption, porokeratosis, viral warts, penile precancer, and frank SCC. LP can cause phimosis; the differential diagnosis of phimosis is given in Table 77-2.

Just as extragenital disease, for example, on the palms and soles, may be erosive in rare cases, occasionally an erosive form of genital disease is encountered (Fig. 77-10). A male equivalent of the vulvovaginal syndrome of Hewitt with chronic erosive gingival and genital lesions (genito-gingival syndrome) has been described.82 Bullous penile LP has also been reported.83

Although LP is self-limiting, some patients experience relapses and remissions. Adhesions can form. Postinflammatory hyperpigmentation can persist for months or years.

Chronic mucosal erosive LP is associated with a risk of SCC, although most reports linking the two concern oral LP. SCC may complicate chronic hypertrophic LP of the lower leg but has also occurred in the context of hypertrophic LP of the glans penis.3,84,85

A biopsy is frequently necessary for diagnostic purposes but, more importantly, is performed in following up the rare cases of chronic anogenital disease in which the appearance of ulcero-erosive or verrucous features leads to concern about the development of SCC. The classic histologic findings are discussed in Chapter 114.

Potent or very potent topical corticosteroids usually produce remission. Patients should be warned about postinflammatory hyperpigmentation. Systemic corticosteroids are sometimes indicated for severely symptomatic disease, erosive orogenital involvement, and scarring of the scalp and nails. Topical and systemic cyclosporin has been used. Circumcision may be necessary if there is phimosis and should be seriously considered in cases of refractory disease, especially the erosive form, because the removal of “koebnerizing” influences may allow the LP to remit. The toxicity and the lack of efficacy of systemic therapy in treating this distressingly symptomatic situation are other powerful arguments in favor of circumcision.3,86

Lichen Nitidus

(See Chapter 27)

Lichen nitidus is sometimes held simplistically and controversially to be a micropapular variant of LP. It has an affinity for the penis and can be difficult to diagnose because the signs may be subtle, even when the lesions are widespread. Also, when the lesions are very pruritic, the signs due to excoriation and eczematization may eclipse those due to the lichen nitidus.3

Granuloma Annulare

(See Chapter 44)

Erythematous smooth, ovoid nodules of granuloma affecting the penis have been described. They are perhaps related to trauma and koebnerization, because circumcision can be curative.87

Necrolytic Migratory Erythema

Necrolytic migratory erythema can be focalized to the male genitalia as a sore or painful annular erythematous eruption with a central glassy appearance and serpiginous border surrounded by scaling. It is a characteristic cutaneous manifestation of the glucagonoma syndrome (see Chapter 153).88

Aphthae

The diagnosis of aphthous ulceration of the genitalia requires the exclusion of sexually transmitted diseases and other causes of genital ulceration, especially Behçet disease. This is in contradistinction to oral ulceration, in which a clinical diagnosis is acceptable practice.3 The causes of aphthae are obscure. The histologic findings of idiopathic aphthous ulceration are nonspecific. Aphthae and idiopathic orogenital ulceration are more common and are worse, symptomatically and morphologically, in HIV-infected individuals. In patients with AIDS, biopsy must be performed on all mucocutaneous ulcers and specimens must be cultured; several pathologies may coexist. Treatment of simple aphthae is with topical corticosteroid/antibiotic/anticandidal combinations. In patients with AIDS, thalidomide may be efficacious.

Behçet Disease

(See Chapter 166)

The genital ulcers in men are painful, sometimes very painful, and this distinction may be helpful. They occur anywhere on the anogenitalia, including the scrotum and perianal skin. They are said to be bigger, deeper, fewer, and less recurrent than those in the mouth.

To diagnose Behçet disease according to strict diagnostic criteria, oral ulceration must be present; then patients must also either manifest genital ulceration and ophthalmic involvement or genital ulceration and skin signs (or a positive pathergy test result). In practice, there are many patients who have an incomplete syndrome. Although their disease does not satisfy these rigid diagnostic criteria, “possible” or “probable” Behçet disease is an acceptable label for everyday practical purposes. Essentially, Behçet disease is a systemic vasculitis that may involve many organs, so that protean presentations and complications are possible. Patients with relapsing polychondritis (see Chapter 159) and Behçet disease have been reported, and the term MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome applied.89,90 Histologic findings are usually nonspecific and do not distinguish idiopathic aphthae, although sometimes necrotizing vasculitis can be seen. Topical treatment with corticosteroid/antimicrobial combinations may suffice. Topical interferon α lozenges have been advocated.91 However, some patients will require systemic treatment with colchicine, prednisolone, azathioprine, cyclosporin, thalidomide, infliximab, or etanercept.3,92,93 (See Chapter 166).

Mucous Membrane Pemphigoid

(See Chapter 57)

Mucous membrane (cicatricial) pemphigoid is a rare disease that must be in the differential diagnosis of blistering, erosions, ulcers, transcoronal adhesions, scarring, and phimosis.3,94 These manifestations can occur in isolation, but ophthalmic, oropharyngeal, and cutaneous lesions are more common than genital involvement. Direct immunofluorescence usually yields positive results, but indirect immunofluorescence does not. Topical and oral steroids may be ineffective. Dapsone, sulphamethoxypyridazine, mycophenolate, and biological therapies may be used.

Pyoderma Gangrenosum

(See Chapter 33)

Pyoderma gangrenosum is a rare event but is frequently misdiagnosed or diagnosed late while infections and cancer are pursued diagnostically (Fig. 77-11). It may represent a pathergic reaction after urologic surgery or complicate inflammatory bowel disease or leukemia. Treatment must be aggressive to avoid permanent damage to the urethra and erectile tissues.3

Drug Eruptions

(See Chapter 41)

The penis is a classic site of predilection for fixed drug eruptions.3 Clinically, fixed drug eruption is characterized by the acute eruption of itchy, painful, swollen plaques, sometimes with central blister formation, erosion, and ulceration. Postinflammatory hyperpigmentation can be persistent. On first exposure to the drug the eruption can take 1–2 weeks to appear but subsequently appears just a few hours after administration. Recurrence is at the same site(s) each time the drug is encountered, and rechallenge/provocation can be used as a diagnostic test. For causes, see Chapter 41.

Ulceration due to papaverine can occur when the drug is inadvertently injected subcutaneously for the treatment of erectile impotence.95 Heparin and warfarin have induced skin necrosis of the genitalia.3 All-trans retinoic acid has been reported to induce genital ulceration in patients with hematologic malignancy.96 Foscarnet can create genital ulceration in HIV-infected patients due to the high urinary concentrations of the drug.97 Nicorandil is a newly-appreciated cause of anogenital and peristomal ulceration.

Lisinopril has been associated with genital angioedema.98 The cutaneous side effects of topical steroids are well known: striae, atrophy, erythema, telangiectasia, erosion, and modification of cutaneous, bacterial, viral, and fungal infections occur commonly. Drugs can also cause pruritus and urticaria.

Streptococcal Dermatitis

(See Chapter 176)

Streptococcal dermatitis causing a perianal cellulitis is a recognized syndrome in children, but a similar clinical situation occasionally occurs in adults and might affect the genitalia alone.3 It is much more common in boys, and if the penis is involved, there may be dysuria, erythema, swelling, and balanoposthitis. Group A β-hemolytic streptococci can be isolated, and the lesions may be associated with streptococcal infection of the upper respiratory tract in other members of the family. Treatment is generally with systemic penicillin.

Herpes Zoster (Shingles)

(See Chapter 194)

Sacral herpes zoster is relatively rare but can be associated with severe morbidity due to nocturia, dysuria, acute urinary retention, constipation, and fecal retention.3 When the pain precedes the rash, the differential diagnosis of an acute surgical emergency is evoked. Painful, grouped, crusting, vesicopustular lesions may be found unilaterally on the buttock, in the perineum, on the scrotum and penis, in the groin, and on the upper thigh. Hospitalization, urologic assessment, observation, possibly catheterization and sigmoidoscopy, and possibly assisted fecal extraction are indicated. Treatment should be with intravenous acyclovir.

Tinea

(See Chapter 188)

Tinea of the penis or scrotum is not common, and when it occurs it is usually associated with crural disease. Rarely encountered is tinea that occurs on the glans penis as a seat of itch or pain and produces an erythematous patch or a crop of scaly papules.3 In India, it is associated with penile lesions due to the wearing of a langota, an occlusive T-shaped loincloth.99

Schistosomiasis

(See Chapter 207)

Perineal granulomatous lesions are a rare manifestation of schistosomiasis (infection with Schistosoma haematobium).3,100 Rarely genital skin lesions may lead to the diagnosis. They occur because of ova shed by worms that have entered the perineal vessels from the pelvic venous plexuses. Papules and nodules may be itchy; may be skin-colored, pink, or brown; may be scattered or grouped; and may affect the penis and scrotum. They can spread onto the perineum and around the anus and may develop into soft, warty, vegetating lesions but remain relatively asymptomatic. Ulceration is rare and carcinoma even rarer. Diagnosis is by biopsy (see Chapter 207). Ova may be recovered from urine or stool.

Onchocerciasis

(See Chapter 207)

The dermatologic genital consequences of onchocerciasis are pruritus, “leopard skin” hypopigmentation (on shins and scrotum), nodules (on ileal crests, scrotum, and ribcage), dermatitis, including “lizard skin” lichenification, “hanging groin,” and scrotal enlargement.3 The differential diagnosis of the scrotal enlargement includes bancroftian filariasis. The diagnosis is made by demonstrating microfilariae in skin snips.

Porokeratosis

Genital porokeratosis of Mibelli (see Chapter 52) is rare.3,101 Annular raised (double-rimmed) lesions have been found in the intergluteal cleft, on the scrotum, and on the penis, including the glans. Rarely lesions may be ulcerative. Porokeratosis may be misdiagnosed clinically as psoriasis, Bowen disease, granuloma annulare, or LP but histologic examination of the margin shows the characteristic cornoid lamella. Cryotherapy and topical 5-fluorouracil can be used for treatment.

Kaposi Sarcoma

(See Chapter 128)

Solitary Kaposi sarcoma of the penis was recognized, if rarely, before the HIV epidemic, and cases are still occasionally seen in HIV-negative patients.3 AIDS-related Kaposi sarcoma is usually multicentric and often involves the face, oral mucosa, palate, and penis (20%). A solitary lesion is not unusual. It can present as a dull red patch or plaque on the glans penis or in the preputial sac and can also affect the penile shaft, scrotum, and perianal skin in one of its more classic manifestations—namely, purple, slightly scaly patches or plaques, nodules, and ulcerative lesions. An engorged, “hypervascular” presentation has been described, as has penile lymphedema, acute phimosis, and rectourethral fistulation. Odd morphology should arouse suspicions of mixed pathology.

Lymphoma, Leukemia, Metastases

Ulceration of the penis in chronic lymphocytic leukemia and scrotal ulceration in acute myelogenous leukemia due to leukemic infiltration have been reported.3 Pyoderma gangrenosum, Pseudomonas infection, and Fournier gangrene can be associated with hematologic malignancy. Although the groin is a classic site of involvement in Langerhans cell histiocytosis (see Chapter 147), involvement of the penis is very rare. Metastases to the penis and scrotum occur uncommonly.102 They are usually secondary to cancer of the urogenital tract or gastrointestinal system (e.g., rectum) or complicate other common cancers such as those of the lung. They may present with pain, swelling, priapism, urinary symptoms, or hematuria. A cutaneous nodule or nodules may be seen or infiltration of the deeper penile structures palpated.

Penile Melanosis and Lentiginosis

Several terms have been coined to describe benign pigmented macules of the penis such as penile melanosis, penile melanotic macules, and atypical pigmented penile macules: penile melanosis, vulvovaginal melanosis, and the predominantly oral mucosal hyperpigmentation of Laugier–Hunziker syndrome (see Chapter 75) may be grouped under the umbrella of essential melanotic hyperpigmentation of the mucosa.3,103 Some if not all cases may represent postinflammatory hyperpigmentation from previous disease or insult [e.g., phimosis, balanoposthitis, topical treatment, LSc (Fig. 77-12), LP, circumcision]. It has been suggested that adjacent depigmentation is an essential element of the condition.104 Although penile melanosis is a good term for lesions without lentiginous hyperplasia on histologic examination, there may be increased basal epidermal pigmentation with or without benign lentiginous melanocytic hyperplasia, including ultrastructurally. The possibility of Addison or Nelson syndrome should be entertained, as should the possibility of a lentiginosis syndrome [Peutz–Jeghers, LAMB (lentigines, atrial myxoma, blue nevi), LEOPARD (multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, growth retardation, deafness), or Bannayan–Riley–Ruvalcaba syndrome (see Chapter 75)], although idiopathic lentigines of the penis are recognized.

If lesions are large or enlarging, with irregular edges and multifocal and variegated pigmentary patterns, concern may be raised about atypical melanocytic proliferation and acral lentiginous melanoma.

Despite being benign, penile melanosis can be cosmetically disturbing. Laser treatment may be helpful.

Zoon Balanitis

Etiology and Pathogenesis

The evidence indicates that ZB is a chronic, reactive, principally irritant mucositis that causes, or is due to, a dysfunctional foreskin.3,51 Irritation is induced by retention of urine and squames between two tightly apposed and infrequently and inadequately separated and/or infrequently or inappropriately bathed, commensally hypercolonized, desquamative, secretory epithelial surfaces.

Clinical Findings

An asymptomatic presentation with little or no dyspareunia is classic. Conversely, the signs can be florid. Well-demarcated, glistening, moist, shiny, bright red, or autumn brown patches symmetrically involve the glans and inner prepuce, sparing the keratinized penile shaft or foreskin (Fig. 77-13). Other signs include dark red stippling or “cayenne pepper spots” due to hemosiderin deposition and solitary or multiple lesions of differing sizes (guttate or nummular), characteristically “kissing.” Rarely, erosive and vegetative presentations have been reported, but lesions with asymmetric, atypical, or unusual morphology should be viewed with great suspicion and the organ inspected diligently for other, less florid signs. ZB may be secondary and may thus conceal more subtle evidence of underlying preputial disease such as LSc, precancer, or frank cancer that might have induced the manifest zoonoid changes. Overt cases of other dermatoses such as contact dermatitis, psoriasis, LSc, LP, penis precancer, and penile cancer may appear to have zoonoid changes on clinical and histologic examination (Fig. 77-14). It is possible that some of the clinical and histologic variants that have been reported and the dubious claim that ZB per se is a premalignant condition are a consequence of this phenomenon.105

Laboratory Tests

On histologic examination the epidermis is attenuated with absence of the granular and horny layers, sparse dyskeratosis and spongiosis, and diamond- or lozenge-shaped basal cell keratinocytes. In the dermis there are variably seen a band of plasma cells infiltration, extravasated erythrocytes, hemosiderin, fibrosis, and vascular proliferation.106

Differential Diagnosis

Disorders from which ZB must be differentiated are listed in Box 77-5.

Treatment

Although the condition may be ameliorated by improvement in washing habits and micturition practices and by the intermittent application of mild or potent topical corticosteroids (with or without antibiotics and anticandidals) and topical tacrolimus, ZB usually persists or relapses. Definitive curative treatment is surgical circumcision.3,107,108

Lichen Sclerosus

(See Chapter 65)

Epidemiology

Genital LSc is more common than extragenital disease, but there may very occasionally be involvement in both areas. In adults, anogenital LSc is said to be about ten times more common in women than in men. Perianal disease is very rarely, if ever, encountered in the male. LSc may be much more frequent than is generally supposed in young boys. In boys, persistent primary phimosis or the secondary development of phimosis in a previously retractable foreskin should be viewed with suspicion: some, many, or most of such cases will be due to LSc.3,51,107,109

Etiology and Pathogenesis

The pathogenesis of LSc, particularly the role of autoimmunity, is discussed in Chapter 65. Antiextracellular matrix protein 1 antibodies have been found in the sera of male and female patients with genital LSc.110,111 In male genital LSc, roles seem likely for trauma (as suggested by cases in which the development of LSc was related to injury or surgery112) and contact with urine (as suggested by the association of genital LSc with anatomic abnormality, particularly hypospadias,113 and the striking differences in the pattern of distribution between the sexes) but not for infection (men with genital LSc rarely if ever have sexual partners with LSc3,107). It is likely that chronic exposure of susceptible epithelium to urine due to a dysfunctional naviculomeatal valve accounts for most cases in men.114

Clinical Findings

LSc is discussed in detail in Chapter 65. The symptoms and signs of male genital LSc are summarized in Table 77-3 and partially illustrated in Figs. 77-15 and 77-16. The principal presentation in men is of dyspareunia. The classic genital morphologic manifestations of LSc are of atrophic white patches or plaques or lilac, slightly scaly patches with telangiectasia and sparse purpura, like those of the classic clinical manifestations of extragenital LSc, may be seen. A constrictive lichenoid posthitis is commonly seen associated with a fibrotic preputial band causing “hourglass” “waisting” of the penile shaft.3 Urethral involvement may be more common and extensive than hitherto supposed.115,116

Most cases of LSc can be diagnosed clinically. If there is clinical doubt, then a biopsy should be performed. The histologic findings are discussed in Chapter 65.

Differential Diagnosis

Disorders from which LSc must be differentiated are listed in Box 77-6.

Complications

The urological morbidity due to urethral disease can be severe.116 The psychological consequences of sexual dysfunction for men and their partners are frequently overlooked. SCC of the penis is the most worrying complication of LSc: the published risk is 2%–12.5% and the latent period may be 10–30 years.3,51,117–126 Involvement of the glans with LSc is a significant risk.126 Carcinoma complicating LSc constitutes approximately 25%–50% of all cases of penile cancer.3,107,120,127–130 LSc is histologically associated with differentiated PCIS, basal epithelial atypia and ‘usual’ or verrucous (rarely pseudohyperplastic) SCC.131

Treatment

Treatment of extragenital LSc132 is discussed in Chapter 65. The aims in male genital disease are to minimize or abolish male sexual dysfunction (dyspareunia), urinary dysfunction, and the risk of penis cancer.114 Avoidance of contact with soap and urine are essential. Very potent topical steroids acheive remission in 50%–60% and the majority of the remainder are cured by circumcision.133 Topical steroids are safe but occasionally HPV may be reactivated.134,135 Topical calcineurin inhibitors should not be used.136,137 Some men require sophisticated urethromeatal surgery.116,125,138

Nonspecific Balanoposthitis

Nonspecific balanoposthitis is viewed either as a diagnosis of exclusion or as a descriptive term that indicates the limitations of diagnostic acumen.3,51,107 Sexually transmitted disease, immunosuppression, and diabetes or an identifiable primary dermatosis such as psoriasis, seborrheic dermatitis, ZB, LSc, LP, warts, or carcinoma in situ must be sought. A biopsy is essential. When patients present with symptoms and signs of balanoposthitis, nonspecific histopathologic features are found in approximately 10% of biopsy specimens.139 Genitourinary physicians frequently diagnose candidosis, but dermatologists believe that Candida infection may complicate any inflammatory mucocutaneous dermatosis and is found as a secondary opportunistic phenomenon rather than as a primary cause of disease.3 Phimosis may be the end stage situation including in diabetes.140 Preputial dysfunction is the cause or consequence ofprobably all cases of nonspecific balanoposthitis, and many patients probably have LSc as the underlying morbid state. Treatment141 can be very difficult, and the disease may fail to respond to local hygienic measures, soap substitution, topical steroids, and topical and systemic antibiotics.

The ultimate recourse is circumcision, which is curative in most instances. Histologic examination of the whole prepuce may substantiate the presence of an underlying genital dermatosis such as LSc. However, in a significant number of patients the circumcision histologic findings will be nonspecific, even after review with the pathologist for early signs of LSc and even if there had been either hard or soft signs of an underlying dermatosis such as LSc on clinical evaluation on one or more occasions. These observations imply that such patients have nonspecific preputial dysfunction due to nonspecific irritation, trauma, and secondary candidosis such that a genuine nonspecific balanoposthitis ensues, with the pace of normal preputial repair and regeneration being exceeded by the pace of day-to-day attrition or wear and tear.3,51,107

Dermatologic Nondisease, Dysesthesia, and Chronic Pain Syndromes

Dermatologic nondisease142 should be considered when florid symptomatology is accompanied by a paucity or complete absence of any primary dermatologic signs.143 Patients with symptoms of itching, burning, redness, and pain focalized to the penis or scrotum, in some cases so severe as to prevent the patient from sitting down, are not uncommonly encountered. The chronic urogenital and rectal pain syndromes are described by the terms penodynia, scrotodynia, orchialgia, prostatodynia, coccygodynia, proctalgia fugax, perineal pain, descending perineum syndrome, and vulvodynia.144–147

The red or burning scrotum syndrome has been defined as “persistent redness of the anterior half of the scrotum that may involve the base of the penis . . usually accompanied by a persistent itching or burning sensation and hyperalgesia.”148 Accompanying the erythema there may be telangiectasia. It is a chronic condition that is resistant to treatment and its cause is unknown.143,148

The neuroanatomy of the pelvis is complicated, and the neuropathophysiologic basis of these syndromes is poorly understood. They seem to share features of neurogenic inflammation and neuropathic pain.149 Although their clinical presentations are well recognized by physicians in many specialties, these diagnoses should be arrived at after comprehensive clinical assessment, contemplation of the differential diagnosis, and a process of exclusion based on suitable investigations and response to treatment.150 Localized dermatographism should be sought by stroking the inside of the thigh. Contact urticaria, irritant and contact dermatitis, and scrotal rosacea due to topical steroid application should be considered. Tinea and candidosis must be excluded. Intercurrent herpes simplex or postherpetic neuralgia might mislead. Angiokeratoma corporis diffusum and multiple sclerosis are causes of odd sensory symptoms. Zinc deficiency and migratory necrolytic erythema could be entertained. Penile sensitivity is reduced in diabetic patients, and this may correlate with erectile dysfunction in some of these men.151 The drug chart should be reviewed. Some men with “idiopathic” anogenital pruritus may be found to have lumbosacral radiculopathy if investigations such as plain radiography, nerve conduction studies, computerized tomography, and needle electromyography are performed, and significant improvement may be obtained by paravertebral injections of triamcinolone and lidocaine.152

A diagnosis of a chronic pain syndrome carries the possibility of considerable psychological morbidity. Dysmorphophobia, depression, and psychosis may be present, and attempted or completed suicide is a real risk in such patients.14

Scrotal rosacea (see Chapter 81) should be treated with oral tetracyclines and these (e.g., doxycycline) may be effective in the red scrotum syndrome.153 If anogenital dermatographism and/or urticaria is suspected, oral antihistamines can be prescribed. Prednisolone and antidepressants such as doxepin, amitriptyline, and paroxetine can afford some relief. Neuromodulation by sacral root stimulation might be tried.96 However, treatment is generally problematic and at best only empiric. Invasive and irreversible procedures should be avoided if at all possible. Multidisciplinary management is the ideal.3,107

Penile Acne

Penile acne is an poorly-documented entity occasionally encountered in clinical practice.3 Young men complain of penile spots or boils or blackheads and on examination have comedones, papules, pustules, and inflammatory nodules of the proximal penile shaft. An important differential diagnosis of acneiform disease presenting at any site is chloracne caused by occlusion of the skin with machine oil. Conventional treatment for acne is prescribed in a hierarchical manner: topical keratolytics, antibiotics, and retinoids; oral antibiotics; and isotretinoin (see Chapter 80).

Chronic “Idiopathic” Penile Edema

Chronic idiopathic penile edema is a rare, ill-understood condition.3,154 It is the cause of significant morbidity, sexual dysfunction, and phimosis. Patients present with swelling and intercurrent attacks of cellulitis and lymphangitis of the penis, scrotum, and pelvic girdle. Recurrent sexually transmitted diseases, a chronic dermatosis, and hypoplastic lymphatics are sometimes incriminated. The antistreptolysin-O titer may be elevated, and a biopsy specimen may show granulomatous lymphangitis, and Crohn disease (Fig. 77-17) should be sought even if the patient has no gastrointestinal symptoms. Sarcoidosis should be excluded. Treatment has to be aggressive to prevent intercurrent infection and further lymphatic damage and scarring. Long-term treatment with oral antibiotics such as erythromycin, clarithromycin, clindamycin, trimethoprim, cotrimoxazole, or ciprofloxacin is advocated. Occasionally, a short cause of oral prednisolone is helpful. The goal should be to reduce the preputial edema to allow circumcision.

Spontaneous Scrotal Ulceration

Rare cases of spontaneous scrotal ulceration in young, previously fit men have been described.155 Histologic examination showed nonspecific vasculitis and spontaneous resolution occurred. A related entity may be idiopathic scrotal panniculitis and fat necrosis,156 because trauma, extreme cold, and Fournier gangrene were excluded.

Fournier Gangrene

(See Chapter 179)

Fournier gangrene is a medical and surgical emergency.3 Patients present with systemic upset and painful erythematous swelling of the genital, perianal, or lower abdominal skin and may be in urinary retention. An ominous black spot may appear on the scrotum. There is gross systemic toxicity (peculiarly, sometimes absent in children) and no suppuration. Necrosis of skin and deeper tissues rapidly supervenes and death ensues (the mortality may be higher than 50%) unless diagnosis is prompt and radical management is instituted. In its clinical picture Fournier gangrene overlaps with necrotizing fasciitis and Meleney gangrene. Risk factors are presented in Table 77-4.

The process probably begins with appendageal or urethral infection, and polybacterial infection develops. Most of the organisms isolated from cases prove to be resident urethral or lower gastrointestinal flora, and most patients have mixed infections. What then follows is a necrotizing cellulitis, perhaps exotoxin mediated that affects skin, subcutis, fascia, and muscle—the human counterpart of the local Shwartzman phenomenon. In children, the most commonly isolated pathogens are staphylococci and streptococci. Radiologic studies may show soft tissue gas.

Disorders from which Fournier gangrene must be differentiated are listed in Box 77-7.

If the clinical diagnosis of Fournier gangrene is entertained, then drastic emergency management is required. Surgical and microbiologic expertise, often in an intensive care setting, may be required. Radical surgical débridement of all affected tissue is undertaken and broad systemic antibiotic therapy initiated. If the patient survives, then plastic surgical repair can be performed.157 Hyperbaric oxygen treatment has been advocated, as has high-dose systemic corticosteroid treatment. Children can be treated with more conservative surgery, and the mortality rate is lower.158

In adults, the mortality is around 25% and is highest in disease of anorectal rather than urogenital origin, which likely reflects a less typical presentation and longer delay in diagnosis.3

Nonsyphilitic Spirochetal Ulcerative Balanoposthitis

Nonsyphilitic spirochetal ulcerative balanoposthitis is recognized in the tropics and South Africa and presents as large, serpiginous, foul-smelling ulcers in uncircumcised men, associated in some with nontender inguinal lymphadenopathy.159 Treatment is with penicillin or metronidazole.

Scrotal Calcinosis

Scrotal calcinosis is a relatively common, benign idiopathic disorder presenting as rock-hard smooth white papules or nodules on the scrotum, multiple or solitary.3 Occasionally, the lesions may become secondarily inflamed or infected after trauma. Rarely, a lesion or lesions occur on the penis. The differential diagnosis includes epidermoid cyst. Indeed, it is debatable whether the lesions are indeed idiopathic or whether they arise from epidermoid cysts, eccrine duct milia, eccrine epithelial cysts, dystrophy of the dartos muscle, trauma, or foreign bodies (e.g., thorn or even Onchocerca organisms). Cold, trauma, and the thinness and specialization of scrotal skin are thought to be etiologic factors. Treatment is by surgical excision, but the lesions recur.

Sclerosing Lymphangitis

Nonvenereal sclerosing lymphangitis [there are a confusing number of synonyms: penile venereal edema, Mondor phlebitis, localized penile (venereal) lymphedema, penile lymphocele] is increasingly recognized.3 Patients present with a serpiginous mass in the coronal sulcus, spreading sometimes onto the dorsal penis. The lesion may appear for the first time or become tender and enlarge after prolonged or frequent sexual intercourse. In circumcised men the circumferential scar may be a predisposing factor. It has not been established whether this entity represents a posttraumatic lymphangitis or phlebitis. The problem may resolve spontaneously or surgical excision may be required.

True thrombophlebitis of superficial penile and scrotal veins is analogous to Mondor phlebitis of the chest wall. Herpes simplex virus infection, polyarteritis nodosa, and thromboangiitis obliterans may initiate it. Penile thrombophlebitis has been seen as the initial presentation of a paraneoplastic migratory thrombophlebitis caused by pancreatic cancer.

Verruciform Xanthoma

Verruciform xanthoma is a rare entity that principally involves the mouth. Genitalia are the next most frequently affected area, where it presents as a painless, yellow–brown or red, verrucous, sessile, or papillary plaque.3 Histologically there is hyperkeratosis, focal parakeratosis, and irregular epidermal acanthosis. Rete ridges are lengthened and extend into the dermis, forming areas called dermal papillae and which enclose capillary vessels surrounded by foam cells that are CD68+ but S100−. It is thought that the lesion results from epidermal degeneration and that keratinocyte lipid is taken up by dermal macrophages or fibroblasts to form the foam cells. HPV-6 DNA has been found in one case. SCC may arise within the lesion. Treatment is by surgical excision.

Penile Carcinoma In Situ and Squamous Cell Carcinoma

Epidemiology

SCC of the penis accounts for 0.3%–0.6% of cases and less than 1% of cancer deaths in the United States.3,51,65,107,160 One hundred deaths and 400 cases are seen per year in the United Kingdom.161,162 It is estimated that penile SCC represents 10%–20% of tumors seen in males in the developing world, where neonatal or infantile circumcision is not part of the culture.163 However, in developed countries such as Japan and Denmark where circumcision is not routinely practiced, penile cancer incidence is falling and is approximating that in the United Kingdom and United States.164,165 The epidemiology of PCIS is not well established; it is probably underdiagnosed and underreported.161,166

Etiology and Pathogenesis

(See Chapter 114). The precise causes of the different types of PCIS and SCC of the penis are unknown. Acknowledged risk factors for SCC are presented in Table 77-5.

HPV (high-risk and mixed infections), LSc, and immunoincompetency are the most important considerations.65,66,74,75,107,129,130,167–169

Clinical Findings

EQ manifests as bright red, shiny patches, or plaques of the mucosal sites, the glans, and prepuce of the uncircumcised (Fig. 77-18 and eFig. 77-18.1). Bowen disease of the penis (BDP) is characterized by red, scaly patches and plaques of the keratinized penis (Fig. 77-19 and eFig. 77-19.1). Both affect the older male. BP presents as multiple warty lesions rather than as erythematous patches or red, scaly plaques (Fig. 77-20). BP is pigmented in keratinized sites, and lesions are multiple and more inflamed in mucosal sites; lesions are more polymorphic, more coalescent, less papillomatous, and smoother topped than common genital viral warts. BP is seen in younger, sexually active men. Pseudoepitheliomatous micaceous and keratotic balanitis is probably not a separate entity but a clinical variant of PCIS, probably associated with LSc and conferring a risk of development of invasive SCC.3,65

In SCC irregular nodular and ulcerative morphology is encountered (Fig. 77-21). Clinically, there may be evident background PCIS and/or LSc (or even LP). Inguinal lymphadenopathy may be present, although in penile cancer only 50% of enlarged glands will be found to contain tumor. Verrucous carcinoma, warty carcinoma, Buschke–Lowenstein tumor (BLT), and giant condyloma may be dramatic clinical lesions, often polypoid or cauliflower-like. Although locally deeply invasive, they are well demarcated from surrounding tissue. These terms are often used synonymously to describe rare, low-grade, well-differentiated squamous carcinomas.170–177 The potential for aggressive behavior, mortality risk, and clinical, histologic, and virologic differences may distinguish them. Giant condyloma and BLT are thought likely to have their origin from common genital warts. BLT has also been associated with LSc.178

Differential Diagnosis (Box 77-8)

A biopsy is indicated in most instances.

Histology

The histopathology of mucosal PCIS is generally that of a bowenoid pattern of dysplasia with dysmaturation and atypical cells and increased mitoses at different levels of the epithelium. This is often accompanied by HPV-related cytopathic changes in the upper layers of the epithelium, but there is as yet no formal consensus on clinicopathologic classification and clinical utility. Increasingly encountered are the terms squamous hyperplasia and squamous intraepithelial lesion of squamous, basaloid, or warty type and low or high grade to describe the histologic findings of epithelial lesions associated with penile SCC.179,180 Differentiated PCIS and basal epithelial atypia are associated with LSc and full thickness, undifferentiated bowenoid dysplasia with HPV.131

In SCC, tongues of invasive atypical keratinocytes invade the lamina propria or deeper structures and contain foci of aberrant and ectopic keratinization (squamous pearls). Penile SCC is morphologically and histologically heterogenous.65,128,131,181–186 The frequency of occurrence of different types in 61 U.S. cases was 59% usual (squamous), 15% papillary (not otherwise specified), 10% basaloid, 10% warty (condylomatous), 2% verrucous, and 2% sarcomatoid.181 Usual or verrucous (rarely pseudohyperplastic) SCC are associated with LSc whereas warty, basaloid or mixed types are associated with HPV.131

Suspected verrucous carcinoma demands a deep surgical biopsy. Verrucous carcinoma has different pathologic features from typical squamous carcinoma, showing well differentiated and maturing squamous epithelium with very little atypia or pleomorphism and few mitoses. The diagnosis of verrucous carcinoma in biopsy specimens may be difficult to establish because it relies very much on the depth of invasion of the lesion in relation to surrounding epidermis, and the growth pattern is of a “pushing” margin rather than infiltration. Warty carcinoma, BLT, and giant condyloma differ further in having marked squamous proliferation with HPV-related changes; they are not associated with bowenoid dysplasia but do have more atypia and mitoses than classic verrucous carcinoma.

Prognosis

Quantifying the malignant potential of BDP/EQ/BP/PCIS is not easy. EQ is probably more dangerous than BDP in terms of risk of progression to invasive SCC. BP may remit spontaneously and probably has less malignant potential than EQ or BDP.3,14,16 The prognosis of established, thick, invasive SCC remains poor, but that of early thin disease is much better. HPV status does not correlate with survival.187 In the United States, previously or currently married men present earlier and have increased survival overall; African-Americans present later and do less well.188 In India late presentation is common.189

The histologic type of SCC has a bearing on prognosis: low mortality risk is associated with mixed, papillary, and warty types, intermediate risk with usual and basaloid types and high risk with sarcomatoid cancers.65,181,182,185,186,190,191 The prognosis is also related to the depth of invasion of crucial anatomic landmarks. Features imparting a poor prognosis include perineural invasion and vascular invasion and high histological grade.192

The role of SCC antigen as a biomarker for penile cancer remains speculative.193,194

Treatment

There are several approaches to the treatment of PCIS, summarized in Box 77-9. The guiding principle is to be conservatively ablative.65,107,161 A rational initial step is to recommend circumcision. Patients presenting with these conditions (and their sexual partners) should be counseled and screened for HPV and other sexually transmitted diseases, including HIV infection. Smoking should be discouraged. Follow-up should be long term, and the focus should include the whole perineum, anus, and perianal skin.

For SCC, adequate surgical excision is required. This may need to be radical (i.e., penile amputation), depending on location and extent, but the trend is toward tissue-conserving techniques for functional and cosmetic reasons.107,162 Mohs micrographic surgery and laser procedures have their proponents. Local staging to inform management decisions is achieved by clinical evaluation, histologic analysis, sonography, and magnetic resonance imaging. The histologic grade helps predict proximal histologic extent beyond grossly visible tumor margin. Sentinel node biopsy has been advocated, but the management of ilioinguinal lymphadenopathy is controversial. Established lymphatic or hematogenous dissemination requires individualized multidisciplinary management. Combination chemotherapy has been used for palliation and proposed for adjuvant treatment but is of uncertain value. Brachytherapy or external beam radiotherapy and chemoradiotherapy have their proponents.

Prevention

Chronic disease and dysfunction of the foreskin confer a significant risk of PCIS or frank SCC. The “field changes” due to LSc and HPV create situations of multifocality or multicentricity and a temporal dynamic, contributing to long-term risk even if corrective treatments have been initiated. Feasible measures for penile cancer prophylaxis are treatment of chronic inflammatory conditions such as LSc, LP, and nonspecific balanoposthitis; prevention of phimosis; limitation of psoralen and ultraviolet A treatment; smoking cessation; and prophylaxis for HPV infection.165,195

Melanoma

(See Chapter 124)

Melanoma is a rare neoplasm of the penis, but the prognosis is poor because of late diagnosis and early lymphovascular invasion. It should always enter the differential diagnosis of penile melanosis and lentiginosis as well as genital papules, nodules, and ulcers.3

Extramammary Paget Disease

(See Chapter 121)

EMPD3 presents as an irritating, itchy, burning, red scaly patch or plaque and may be multicentric. It can be found anywhere around the anogenital area, including the glans penis. An “underpants” pattern of erythema has been described in some patients. EMPD is frequently misdiagnosed as an inflammatory dermatosis, such as psoriasis, eczema, or Bowen disease. Subclinical EMPD disease occurs, in which the skin looks normal macroscopically but is involved microscopically. The disease behaves indolently, spreading by local extension and metastasis. The combination of genital and extragenital EMPD is rare but overt, and latent axillary EMPD disease may coexist. Axillary macular lesions that changed shape and color daily have been reported in association with penile and pubic Paget disease. Very rarely, depigmented EMPD disease presents as a pale patch in the genital area, evoking a differential diagnosis of vitiligo, hypopigmented mycosis fungoides, and LSc.80

EMPD has been treated with cryotherapy and topical 5-flurouracil, but wide excisional surgery (e.g., Mohs), with plastic repair if needed, is probably the treatment of choice. Radiotherapy is controversial. Photodynamic therapy is under evaluation. Topical imiquimod holds promise.196