Genitourinary Infectious Disease Pathology

Hidradenitis Suppurativa

Hidradenitis suppurativa (also known as acne inversa or apocrine acne) is caused by bacterial infection of the apocrine glands, usually in the axilla, but it can also involve apocrine glands in the perineum and vulvar region. Some studies have suggested that coagulase-negative staphylococci are the most common cause, but others have found the microbiologic flora to be variable.

Fournier Gangrene

Fournier gangrene is a necrotizing subcutaneous infection of the genital and anorectal regions caused by a mixture of aerobic and anaerobic enteric organisms. Risk factors include genitourinary trauma, periurethritis, diabetes, immunosuppression, poor nutritional status, septic injection into the penile vein, and, rarely, trans -retinoic acid treatment for hematologic malignancies. A rapidly developing cellulitis, fasciitis, myositis, and systemic toxicity may result; however, the external physical findings may not be prominent and may be out of proportion to the severity of the infection. A localized vasculitis results from a Schwartzman-like reaction. The Schwartzman reaction is the inflammatory process brought about by injection of endotoxin, which on first injection results only in mild inflammation but on second injection results in a thrombohemorrhagic lesion, similar to that seen in Fournier gangrene. The mortality rate ranges from 10% to 30%. Treatment is typically with débridement and broad-spectrum antibiotics, as necrotizing fasciitis in other locations.

Pseudomonal Cellulitis (Ecthyma Gangrenosum)

Pseudomonal sepsis may be complicated by a cellulitis known as ecthyma gangrenosum, which starts with an erythematous or purpuric cutaneous macule that may rapidly develop into a bulla, which sometimes ulcerates. This is caused by a bacterial vasculitis that may eventually result in cutaneous infarction. Penile ecthyma gangrenosum has been reported in patients with a history of drug abuse and neutropenia.

Mycobacterial Disease

Genital tuberculosis can result from sexual contact with individuals who have active oral or genital tuberculosis. Mycobacterium tuberculosis is the most common organism, but infections due to Mycobacterium celatum have also been reported. Clinically, subacute or chronic, painful ulcers with or without lymphadenopathy may be present, and the lesions may even mimic tumors grossly, notably in scrotal lesions. Lupus vulgaris, which is the most frequent form of reinfection tuberculosis, can affect the penis. Confluent papules may coalesce into plaques; when viewed by diascopy, these plaques have an “apple-jelly” deposit representing cellular infiltrates. Involvement of the glans may occur. Bacillus Calmette-Guérin (BCG) balanitis after instillation for bladder carcinoma has rarely been reported.

Syphilis

The spirochetal organism, Treponema pallidum , is the causative agent of syphilis. The anogenital area may be affected by primary, secondary, tertiary, or congenital lesions of syphilis. Three weeks after initial exposure, a primary syphilitic chancre occurs at the site of inoculation, usually the inner prepuce, coronal sulcus, penile shaft, vulvovaginal area, or anus.

The painless, buttonlike papule ulcerates centrally, and adjacent “kissing” lesions may also be present. Histologically, there is a prominent lymphoplasmacytic infiltrate in an edematous ulcer bed with prominent capillary proliferation containing swollen endothelial cells. Spirochetes may be identified with the use of Warthin-Starry or Steiner stains or immunohistochemically. Smears can be analyzed by darkfield examination or by immunofluorescence with antitreponemal antibodies. Secondary syphilis occurs if the primary lesion is left untreated and the spirochete spreads systemically. It typically forms 3 to 6 weeks after the chancre but may arise up to 6 months after healing of the primary lesion. Clinically, large, red to pale, moist, flat-topped or verruciform papules may develop in the anogenital region (condyloma lata). In 80% of patients, there is a diffuse, nonpruritic, papulosquamous eruption. In dark-skinned patients, annular polycyclic lesions may occur. Microscopically, many spirochetes are present, explaining the highly contagious nature of secondary syphilis. Pseudoepitheliomatous hyperplasia may be prominent. The composition of the inflammatory cells is similar to that of the primary lesion; in addition, a neutrophilic infiltrate may be present.

Tertiary syphilis targets bones, the central nervous system, the cardiovascular system, and skin with ulcerative and nodular lesions. In tertiary syphilis, the classic lesion is a gumma, a type of granuloma with a focus of necrobiosis surrounded by multinucleated giant cells, histiocytes, plasma cells, lymphocytes, and fibroblasts. Obliterative endarteritis may be present. A nodular presentation consists of tuberculoid granulomas with a mixed inflammatory cell reaction including plasma cells. Treponemes cannot usually be detected with silver stains, but polymerase chain reaction (PCR) may be useful.

Chancroid

Haemophilus ducreyi is the gram-negative, facultative anaerobic bacterium that causes chancroid. It is uncommon in the United States but is a common cause of genital ulcers in Africa. Chancroid is transmitted by sexual contact during the active phase of lesions, which in untreated patients lasts approximately 6 weeks. A papule or pustule appears at the exposure site after approximately 1 week. This usually develops into a painful ulcer or ulcers with a gray-yellow exudate and sharp, undermined, ragged erythematous borders. Many lesions can arise in the location of the original lesion through autoinoculation, and lesions may merge with serpiginous borders. After 1 to 2 weeks, adenopathy with suppuration (buboes) occurs in approximately 25% to 50% of untreated patients, sometimes leading to inguinal abscesses and draining sinuses. Microscopically, microvascular and endothelial proliferation with overlying surface ulceration and necrotic debris is typically seen. Vessels may be thrombosed. There is often a dense lymphoplasmacytic infiltrate. Special culture medium is required for isolation. Chancroid is treated with antibiotics. Large lymph nodes may need to be drained.

Lymphogranuloma Venereum

Chlamydia trachomatis , an obligate intracellular parasite, particularly serovars L1, L2, and L3, cause lymphogranuloma venereum; the organisms spread through sexual transmission, travel through lymphatic channels, and multiply within draining lymph nodes of the genital and anorectal region. Serotypes D to K are associated with sexually transmitted oculogenital disease.

In the primary stage, eroded papules or groups of small herpetiform ulcers form at the inoculation site (coronal sulcus, frenulum, prepuce, shaft, glans, scrotum, or vulva). Urethritis with a mucopurulent discharge may be present. In the secondary stage, occurring several weeks later, inguinal lymphadenitis and formation of buboes (enlarged lymph nodes, from the Greek boubôn , “groin”) occur, often with concurrent cordlike lymphangitis of the dorsal penis and suppurative inguinal bubo formation. The so-called groove sign may be present, which results from a cleft formed by the inguinal (Poupart) ligament between enlarged involved femoral and inguinal lymph nodes. Proctocolitis may occur.

A third stage comprises various sequelae from inflammation and includes fistula formation, fibrosis, and scarring. This may be complicated by sinuses and tracts between the skin and urethra and deforming scars of the penis. In the anogenital syndrome, proctocolitis and hyperplasia of the perirectal lymph nodes may occur, and fistulas and rectal strictures may form. Obstruction of chronic lymphedema may lead to elephantiasis.

Histologically the ulcers of lymphogranuloma venereum consist of a chronic inflammatory process with scattered giant cells, plasma cells, lymphocytes, necrosis, and granulation tissue. Nonnecrotizing granulomas composed of epithelioid histiocytes may be present. Fibrosis and, eventually, prominent scarring occur as the process becomes more chronic. Pseudoepitheliomatous hyperplasia may be present. Lymph nodes show accumulation of neutrophils, often with prominent necrosis, particularly in the early stages of the infection. Plasma cell infiltration and lymphocytic hyperplasia follow. Eventually, what are referred to as stellate abscesses form; these are suppurative foci that have coalesced and are surrounded by epithelioid cells and multinucleated giant cells.

Culture of the lesions is the best method to identify the organisms in oculogenital chlamydial infections. The obligate intracellular organisms can typically be identified in vacuoles of vacuolated macrophages. The organisms stain faintly blue with hematoxylin and eosin (H&E), are gram-negative, and can be identified with Warthin-Starry stain. Electron microscopy, immunohistochemistry, and PCR for the 16S ribosomal DNA of the organisms are sometimes needed for a definitive diagnosis. Serology may be useful in confirming the diagnosis.

Granuloma Inguinale (Donovanosis)

Klebsiella granulomatis (formerly called Calymmatobacterium granulomatis ), a gram-negative bacillus, leads to donovanosis, a sexually transmitted genital ulcer disease. It is rare in the United States and occurs primarily in the southern states. Clinically, well-defined, single or multiple, painless ulcers with beefy and red granulation tissue at the base and elevated, rolled, serpiginous, or hyperplastic borders form the primary lesion. The ulcer may heal with prominent fibrosis. Lymphedema with eventual elephantiasis of the penis and scrotum can result in chronic disease. Subcutaneous nodules (pseudobuboes) can simulate lymph node involvement. Lesions may be nodular, hypertrophic, cicatricial, and ulcerovegetative. Microscopically, there is prominent granulation-type tissue with an inflammatory infiltrate including plasma cells, neutrophils, and histiocytes that contain 0.6- to 2-µm Donovan bodies, which are encapsulated rods with bipolar granules ( Fig. 16.1 ). Pseudoepitheliomatous hyperplasia may be prominent. The gram-negative coccoid to bacillary bacteria may be difficult to identify, requiring Wright/Giemsa, toluidine blue, or Warthin-Starry stains. Cytologic identification of Donovan bodies in granuloma inguinale (see Fig. 16.1 ) can be accomplished with Papanicolaou-stained smears. Ultrastructural studies have identified the organism in greater detail, demonstrating it in the phagosomes of macrophages. Squamous cell carcinomas of the vulva secondary to granuloma inguinale have been reported.

Dermatophytosis

Dermatophytosis (tinea) is a superficial fungal infection of keratinized tissues caused by species such as Trichophyton , Epidermophyton , and Microsporum . Tinea cruris is an infection of the inguinal area. An infection of the genital area can result from a transfer by hand from a dermatophytosis of the feet (tinea pedis).

Pityriasis Versicolor (Tinea Versicolor)

Although pityriasis versicolor is usually located on the upper trunk or upper arms, this superficial fungal infection, caused by the lipophilic yeast of the genus Malassezia , can cause hypopigmented or hyperpigmented, white to red-brown, macular eruptions in genital areas, notably on the penile shaft. Scales show pale yellow fluorescence with a Wood lamp. Pityriasis versicolor is usually considered to be noncontagious. The organism to which this disorder is usually attributed is Malassezia globosa , which was formerly classified as Malassezia furfur .

Candidiasis

The normal flora of the intertriginous skin, prepuce, and perineal area includes Candida albicans . Candidal balanoposthitis is the most common fungal infection of the penis. Obesity and uncontrolled diabetes mellitus are predisposing factors, as are other immunocompromised states. The infection can be sexually transmitted. More than 75% of women experience at least one symptomatic episode of vulvovaginal candidiasis. Small pustules may be present. Microscopically, there is epidermal thickening and spongiosis with dermal chronic inflammation. Yeast and pseudohyphae are present on the surface, together with degenerated squamous cells and neutrophils.

Molluscum Contagiosum

Molluscum contagiosum is caused by a large poxvirus (molluscum contagiosum virus), which is a double-stranded, brick-shaped DNA virus. It manifests as solitary or multiple, 2- to 8-mm, dome-shaped, pearly, centrally umbilicated papules that may cluster, become more keratotic with trauma, and simulate condyloma acuminata. The lesion may express a white caseous material (caseum). Transmission is via fomites or sexual contact. Children often have a primary inoculation in the anogenital region, and autoinoculation may lead to additional lesions. Microscopically ( Fig. 16.2 ), a lobular epidermal acanthosis is present and causes an inverted pattern of epidermal hyperplasia. Intracytoplasmic eosinophilic inclusions, referred to as Henderson-Paterson bodies, can be identified in the stratum spinosum and granulosum. The lesions usually regress spontaneously within 1 year, although scarring may occur. Approximately 60% of individuals with skin lesions have antibodies to the virus, but this fraction is less among patients with acquired immunodeficiency syndrome (AIDS), who, along with other immunocompromised patients, may have numerous lesions, some of which may manifest as tumor-like lesions. Ultrastructurally, large, brick-shaped viral particles can be seen.

Herpetic Infections

Herpes simplex virus type 2 (HSV-2), a double-stranded linear DNA virus, is the most common organism that leads to sexually transmitted genital herpes; however, HSV-1 has been shown to cause almost half of genital herpes cases in developing countries. The incubation period is approximately 5 days, and the virus is harbored for life in sensory ganglia. Vesicles consisting of clear lesions with an erythematous base form the primary lesions, which may rupture and leave behind erosions. The primary lesion may be accompanied by lymphadenopathy, but the lymphadenopathy usually subsides and does not recur. Histologically the lesions start with epidermal cell peripheral nuclear chromatin clumping, ballooning degeneration, and homogeneous ground-glass changes with eosinophilic nuclear inclusions. Cytoplasmic vacuolization may also be present. Eventually, affected cells swell, losing their attachment to and separating from adjacent cells (a process referred to as secondary acantholysis). Cellular cytoplasm becomes homogeneous and intensely eosinophilic, and multinucleated cells (Tzanck cells) may be present. The basal layer of the epidermis may be destroyed, leading to the formation of a subepidermal vesicle. Reticular degeneration, a process whereby the epidermal cells undergo progressive hydropic swelling and cytoplasmic clearing with peripheral cytoplasmic strands remaining, can occur. Eventually, these break, and further vesicle formation occurs. Vesicles may contain neutrophils, and accompanying vasculitis may be present. Late lesions are often ulcerated, with ghosts of acantholytic, multinucleate epithelial cells. Primary infection and viral excretion last approximately 3 weeks. Extragenital lesions occur in approximately 20% of cases, and aseptic meningitis in approximately 10%.

Recurrences are less severe. Burning and tingling may manifest 1 to 2 days before a recurrence. Vesicles are limited in number and heal in approximately 10 days, and virus is shed for only a few days. The glans, prepuce, and shaft are the primary sites of involvement; however, the scrotum may be involved. Perianal lesions may also be present, particularly in men who have sex with men. Chronic HSV disease manifests as painful ulcers with rolled borders. Chronic persistent herpes lesions may suggest and help define the presence of AIDS if they last for longer than 1 month, and they may also occur in other immunosuppressed states (e.g., history of transplantation, chemotherapy, hematologic disorders). The herpes varicella-zoster virus (VZV) may infect the anogenital area in a dermatomal distribution through involvement of the third and fourth sacral sensory nerves.

Immunohistochemical stains may be useful in distinguishing HSV from VZV in biopsy specimens. Monoclonal antibodies to the VZV envelope protein gp1 are sensitive and specific in distinguishing between HSV and VZV. Cultures and molecular probes for viral antigens can also be useful. Viral antigen can be detected in inflamed nerve twigs. Electron microscopy may reveal the 90- to 130-nm viral particles.

Human Papillomavirus

Human papillomavirus (HPV) is a member of the Papovaviridae family, which consists of circular, double-stranded DNA viruses. HPV is involved in a number of pathologic lesions, from the benign end of the spectrum, the common wart (verruca vulgaris) ( Fig. 16.3 ), to frankly malignant squamous cell carcinoma. More than 100 genotypes are known. Relationships between different HPV types and particular lesions have been recognized ( Table 16.2 ).

HPV was first recognized to have oncogenic potential in patients with epidermodysplasia verruciformis. This is an autosomal recessive condition, associated with a gene locus on chromosome 17, that leads to decreased defenses against several HPV subtypes (HPV-2, 3, 5, 10, and 8), resulting in exophytic lesions on the trunk and upper extremities which appear in the first decade of life. These lesions may undergo malignant transformation into squamous cell carcinoma during young adulthood. Unlike common warts caused by HPV, epidermodysplasia verruciformis lesions are not transmissible to healthy individuals. Lesions resembling epidermodysplasia verruciformis are sometimes seen in organ transplant recipients.

Condyloma acuminatum is one of the most common sexually transmitted diseases. In males, the frenulum, corona, glans, shaft, and scrotum are affected. Multiple lesions may become confluent, forming a cobblestone appearance. Microscopically, condyloma acuminatum typically has some degree of epidermal hyperplasia or hyperkeratosis, acanthosis, parakeratosis, and numerous koilocytes which cytologically are characterized by perinuclear clearing and wrinkled or crenated (“raisinoid”) nuclei ( Fig. 16.4 ). Condyloma acuminatum is usually caused by HPV types 6 and 11, and there is little risk of squamous cell carcinoma from infection with these HPV types. HPV types 16 and 18 are the high-risk types, leading to anogenital squamous intraepithelial lesions and squamous cell carcinomas (e.g., penile squamous cell carcinoma, cervical carcinoma; Fig. 16.5 ). HPV 16 and 18 account for more than 70% of all malignancies in the anogenital region and are present in more than 98% of cases of high-grade dysplasia and squamous cell carcinoma of the cervix. After treatment, latent HPV in perilesional skin may lead to recurrent lesions.

Generic intraepithelial neoplasia terminology has been defined by consensus recommendations in the Lower Anogenital Squamous Terminology (LAST) Project, which was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. In this terminology, “-IN” can be used to refer to intraepithelial neoplasia of particular sites. Thus for particular sites the following designations are used: anus = AIN; perianus = PAIN; penis = PeIN; cervix = CIN; and vagina = VaIN; and, for example, the corresponding designation of -IN3 of each of these sites would be AIN 3, PAIN 3, PeIN 3, CIN 3, and VaIN 3, respectively. In this system, low-grade dysplasia is referred to as grade 1, which is also termed low-grade squamous intraepithelial lesion (LSIL); and grade 2 or 3 is considered to precancerous or high-grade dysplasia, which is also termed a high-grade squamous intraepithelial lesion (HSIL). Thus a three-tiered system formerly used (“-IN1” through “-IN3”) was converted to a two-tiered system (LSIL and HSIL) by the LAST Project.

Immunohistochemistry for p16 can be used as a surrogate marker of HPV infection and can be used in the assessment of dysplasia. So-called “block” p16 positivity, consisting of strong diffuse p16 staining, is considered indicative of an HSIL. If the H&E morphologic differential diagnosis is between negative for dysplasia and low-grade dysplasia (an intraepithelial lesion grade 1 [-IN1]), then p16 should not be used because -IN1 lesions can be p16-negative. Although p16 can be an aid for the diagnosis of HSIL, p16 positivity in and of itself does not define -IN. Ki67 staining has been used in conjunction with p16 staining, and some studies have shown an increased specificity and sensitivity for dysplasia when these stains are used together. Studies have indicated that Ki67 positivity increases with increasing dysplasia.

Bowenoid papulosis due to HPV (mostly type 16) manifests on the anogenital skin as multiple small (2 to 3 mm), pearly papules. Histologically, it resembles squamous cell carcinoma in situ (also known as Bowen disease). Bowenoid papulosis rarely results in invasive carcinoma and often spontaneously regresses. It can usually be distinguished clinically from Bowen disease (also known as erythroplasia of Queyrat).

Verrucous carcinoma (giant condyloma of Buschke and Lowenstein) is sometimes associated with HPV. It is a slow-growing, well-differentiated variant of squamous cell carcinoma with an exophytic papillary appearance, typically 1 to 3 cm in diameter, that arises in the skin (usually the genital skin), oral cavity, larynx, and esophagus. It is defined by a broad base between the tumor and the underlying stroma with minimal atypia and mitoses at the base, although focal stromal invasion may be observed; dense chronic inflammation may also be present at this interface. Microscopically, verrucous carcinoma is hyperkeratotic and acanthotic, with orthokeratosis (the presence of keratohyaline granules), parakeratosis, and papillomatosis. Papillae may have fibrovascular cores, and papillae may also have a central keratin plug with peripherally located tumor cells. Occasional vacuolated (nonkoilocytotic) clear cells may be present. Verrucous carcinoma has been associated with HPV-6, 11, 16, and 18, although koilocytosis is not present. Verrucous carcinoma is sometimes distinguished from giant condyloma by the absence of koilocytic change, and it has been suggested that the term “warty (condylomatous) squamous cell carcinoma” should be used for exophytic warty tumors of the penis and similar lesions that occur on the vulva and are related to HPV-16. These warty carcinomas are described as having more prominent, long, condylomatous papillae and fibrovascular cores with rounded, irregular, jagged bases, and more obvious koilocytotic atypia. Penile warty carcinoma appears to have a better prognosis than typical squamous cell carcinoma.

Both in situ hybridization and immunohistochemistry are available for the detection of HPV in formalin-fixed tissue. In situ hybridization, which is typically considered to be more sensitive, has largely replaced immunohistochemistry for this purpose (except for specific diagnostic purposes in the cervix, discussed later). Immunohistochemistry detects only productive and not latent infections, and it cannot be used to determine the type of virus present, whereas other molecular techniques are useful for some of these purposes.

Schistosomiasis

Schistosoma mansoni is a fluke that can colonize pelvic veins. Adult organisms within abdominopelvic veins can involve surrounding visceral or cutaneous tissue with a granulomatous reaction. Eggs are typically conducted to the bladder lumen and are excreted during micturition. Sinuses, fistulas, and masses may be present. Ulcers and papillary nodules may simulate condyloma acuminata.

Scabies and Lice

Scabies (caused by the mite Sarcoptes scabiei ) can form tunnels under the stratum corneum of the penis, scrotum, buttock, and waist. Immunocompromised patients may have crusted lesions (known as Norwegian scabies). Lice may also infect the genital region.