Infectious Disorders of the Lower Genital Tract

CHAPTER

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Infectious Disorders of the Lower Genital Tract Thing Rinda Soong, Scott R. Granter, Hope K. Haefner, and Alvaro C. Laga Chapter Outline INTRODUCTION COMMON INFECTIONS

OTHER RARE INFECTIONS Periclitoral Abscess

Pediculosis Pubis (Crab Lice)

Schistosomiasis

Scabies

Epstein-Barr Virus

COMMON INFECTIONS NOT TYPICALLY LINKED TO SEXUALLY TRANSMITTED DISEASES Fungal Infections Bacterial Infections

COMMON SEXUALLY TRANSMITTED INFECTIONS

Necrotizing Fasciitis of the Vulva

COMMON AND RARE VULVAR INFECTIONS ASSOCIATED WITH IMMUNE SUPPRESSION Tuberculosis Bacillary Angiomatosis

Trichomoniasis

Chronic Erosive Genital Herpes

Viral Infections

Varicella-Zoster Disease

Bacterial Infections

Extensive Genital Warts in the Immunosuppressed Patient

UNCOMMON SEXUALLY TRANSMITTED DISEASES Syphilis

Disseminated Molluscum Contagiosum Crusted (Norwegian) Scabies

Chancroid Granuloma Inguinale Lymphogranuloma Venereum

Introduction A variety of organisms can infect the female genital tract, accounting for considerable suffering and morbidity (Table 4.1). Some, such as candidal infections, trichomoniasis, and bacterial vaginosis, are extremely common and may cause significant discomfort, but with no serious sequelae. Others, such as gonorrhea and chlamydial infection, are major causes of female infertility. Viruses, principally human papillomavirus (HPV), are involved in the pathogenesis of vulvar, vaginal, and cervical cancers. Many infections are sexually transmitted, including trichomoniasis, gonorrhea, chancroid, granuloma inguinale, lymphogranuloma venereum, syphilis, chlamydia, herpes, and HPV. This chapter focuses on pathogens encountered principally in the lower genital tract—vulva, vagina, and cervix. Those involving the upper genital tract will be described in the discussion of the the fallopian tube (see Chapter 20). Papillomavirus infections (condylomata) are discussed in Chapters 6 and 13. Many of the common infections discussed in this chapter are so-called clinician’s diseases, meaning that the diagnosis and treatment are carried out exclusively by the clinician, and the role of the anatomic pathologist is largely confirmatory. Many disorders, such as candidiasis, bacterial vaginosis, 62

and common sexually transmitted diseases (STDs), do not require the expertise of a diagnostic surgical pathologist. For others, such as clinically unsuspected candidiasis, syphilis, or other rare STDs such as tuberculosis and bacillary angiomatosis, recognition by the pathologist may be key to diagnosis and treatment (see Table 4.1). Biopsy may also be warranted if the clinical presentation is atypical, or the prescribed treatment is not effective. Treatment of these disorders will be summarized, where appropriate. For treatment specifics for STDs, the Centers for Disease Control and Prevention (CDC) has developed an STD treatment guideline.1 In many of the diseases discussed, additional information relevant to the human immunodeficiency virus (HIV)–positive population can be obtained via online courses offered by tertiary institutions.2-4

Common Infections Pediculosis Pubis (Crab Lice) Clinical Background Pediculosis pubis is caused by an ectoparasite, Phthirus pubis, also known as the crab louse. Patients present with pruritus in the pubic area. Transmission is by direct intimate contact. The parasites are 1 to 3 mm long and have three

Infectious Disorders of the Lower Genital Tract

Abstract Infections of the female genital tract are a significant cause of morbidity. Many infections are sexually transmitted, including trichomoniasis, gonorrhea, chancroid, granuloma inguinale, lymphogranuloma venereum, syphilis, chlamydia, herpes, and human papillomavirus (HPV). Many of the common infections discussed in this chapter are diagnosed clinically, sometimes with the aid of laboratory tests such as cultures, and the role of the anatomic pathologist is largely confirmatory. Diseases such as candidiasis,

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bacterial vaginosis, and common sexually transmitted diseases do not require the expertise of a diagnostic surgical pathologist. For others, such as clinically unsuspected candidiasis, syphilis, or other rare sexually transmitted diseases (STDs) such as tuberculosis and bacillary angiomatosis, recognition by the pathologist may be key to diagnosis and treatment. Biopsy may also be warranted if the clinical presentation is atypical or the prescribed treatment is not effective. This chapter discusses common, uncommon, and rare infections of the female lower genital tract.

Keywords genital infection pathology sexually transmitted

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Table 4.1  Infections of the Lower Female Genital Tract Infections

Class of Microbes

Infectious Agent in the Genital Tract

Common Pediculosis pubis (crab lice)

Ectoparasite

Phthirus pubis

Scabies

Ectoparasite

Sarcoptes scabiei var. hominis

Vulvovaginal candidiasis

Fungus

Candida spp. (most common—Candida albicans)

Tinea cruris

Fungus

Dermatophyte

Bacterial vaginosis

Bacteria

Shift in vaginal flora, resulting in decrease in lactobacilli and increase in anaerobes

Folliculitis

Bacteria (most common)

Staphylococcus aureus (most common)

Trichomoniasis

Protozoan

Trichomonas vaginalis

Molluscum contagiosum

Virus

Molluscipoxvirus genus

Herpes simplex virus (HSV)

Virus

HSV-2 (more common) or HSV-1

Gonorrhea

Bacteria

Neisseria gonorrhoeae

Syphilis

Bacteria (spirochete)

Treponema pallidum

Chancroid

Bacteria

Haemophilus ducreyi

Granuloma inguinale

Bacteria

Klebsiella granulomatis

Lymphogranuloma venereum

Bacteria

Chlamydia trachomatis

Schistosomiasis

Helminth (Trematodes)

Schistosoma haematobium (most common at this location)

Epstein-Barr virus (EBV)

Virus

EBV

Periclitoral abscess (less common)

Bacteria

Sexually Transmitted

Rare

Usually Seen in the Immunosuppressed Patient

No specific single agent; often polymicrobial a

Tuberculosis

Bacteria

Mycobacterium tuberculosis (most common)

Bacillary angiomatosis

Bacteria

Bartonella henselae or Bartonella quintana

Necrotizing fasciitis

Bacteria

No specific single agent; often polymicrobial

Chronic herpes simplex virus (HSV)

Virus

HSV-2 or HSV-1

Varicella-zoster virus (VZV)

Virus

VZV

Disseminated molluscum

Virus

Molluscipoxvirus genus

Crusted (Norwegian) scabies

Ectoparasite

Sarcoptes scabiei var. hominis

Extensive genital warts

Virus

Human papillomavirus

a

For example, in a patient with HIV.

pairs of legs.5 They can be seen with the naked eye and appear as brown-gray specks attached to the pubic hair base. They infest hair in the pubic area and occasionally other body areas that contain terminal hairs. The life cycle of the female is 1 to 3 months. The adult female lays eggs (nits) that adhere to hair at the skin-hair junction. A nit may be seen as a small opalescent gray speck connected

to the hairs6 (Fig. 4.1) and hatch in 6 to 10 days. Nymphs then mature to adults within 10 to 14 days. Pediculosis pubis is diagnosed by the identification of live lice or viable nits.5,6 All patients with pediculosis pubis should have a thorough investigation for other STDs because co-infection can occur, and screening for HIV, syphilis, gonorrhea, 63

Diagnostic Gynecologic and Obstetric Pathology Differential Diagnosis The clinical differential diagnosis of pediculosis pubis includes dermatophyte infection, folliculitis, and contact dermatitis. Scabies can cause similar symptoms of pruritus and excoriations in the pubic area. However, mites are not visible with the naked eye, and nits are absent in scabetic infestation. Treatment Treatments are primarily topical. Decontamination of clothing and bedding, with avoidance of sex partners until the infestation is eliminated, are helpful for control.

Scabies

Fig. 4.1.

  Pediculosis pubis (crab lice) attached to hair shafts. (From Sidhu-Malik N, Rein M: Ectoparasitic infections. In Rein M, editor: Atlas of infectious diseases, vol V: sexually transmitted diseases, Philadelphia, 1996, Churchill Livingstone, p 13.3.)

chlamydial infection, herpes, warts, and trichomoniasis should be considered in this patient population.7 Clinical Examination Physical examination reveals visible opalescent nits or live lice and blue macules (maculae caeruleae) at feeding sites. Diagnostic Criteria Clinical Features Patients with pubic lice usually seek medical attention because of pruritus or because they notice lice or nits on their pubic hair. The vulvar lesions can be scraped onto a slide and the contents viewed under a microscope in the clinic. The entire crab louse can be visualized; it contains three pairs of legs. In contrast to the oval shape of head and body lice, the crab louse is almost as wide as it is long, allowing it to grasp pubic hairs with a large diameter.8 Histologic Features In contrast to ticks, lice do not stay attached to their host after feeding and thus are seldom identified on skin biopsies. It is worth noting, however, that the histopathology of P. pubis may be virtually identical to that of the larvae of Amblyomma and Ixodes ticks, according to one case study.9 On hematoxylin and eosin (H&E) preparations, sections of crab lice (and the aforementioned ticks) show a chitinous body with striated muscle, may contain red blood cells, and may have pigmented mouth parts. Therefore, crab louse infestation should be considered when a small arthropod is encountered in a biopsy. Detailed analysis on gross examination may then allow definitive identification.9 64

Clinical Background Scabies is an infection caused by Sarcoptes scabiei var. hominis (itch mite). Its mode of transmission is via skin contact. It can also be transmitted from bed linens or clothing. Scabies in adults is often sexually acquired. However, scabies in children is not usually sexually acquired. The greatest worldwide burden is seen in children.10,11 Sensitization to S. scabiei must occur before pruritus begins. The first time a person is infected with S. scabiei, sensitization takes as long as several weeks to develop. However, pruritus might occur within 24 hours after a subsequent re-infestation.10,11 Hypotheses have been proposed about the delay in onset of symptoms in a primary infestation—one is that the mites secrete immunomodulatory molecules (e.g., complement inhibitors), suppressing the early immune response in the host.10,11 Recent studies have also suggested that the presence of these inhibitors in mite fecal pellets may have a local effect on growth of the skin-associated bacteria,11,12 which in turn contributes to a complex interaction among mites, host, and the local microbiome. Clinical Examination A small burrow is found on the skin during an infection, appearing as wavy gray-brown lines. A predilection has been reported for the soles, wrists, skin folds such as nipples, inframammary folds, waist, and genitalia.10,11 The mite may be visualized in early disease as a tiny dot at the end of the burrow. The predominant symptom of scabies is pruritus, which is generally worse at night, and a maculopapular rash (Fig. 4.2). Excoriations due to scratching are common and often complicate the clinical examination. Diagnosis can be confirmed by scraping the lesion onto a slide and viewing it with a microscope. When scraping, papules or burrows that have not been scratched or disturbed should be selected. Crusted scabies (e.g., Norwegian scabies) is a florid infestation that usually occurs in immunodeficient, debilitated, or malnourished persons (see later, “Common and Rare Vulvar Infections Associated with Immune Suppression”). Diagnostic Criteria Histologic Features The lesions of scabies are occasionally biopsied when clinical diagnosis cannot be confirmed. The female mite

Infectious Disorders of the Lower Genital Tract body is rounded and smaller than 0.5 mm in diameter. A definitive diagnosis requires demonstration of the mite body, which can be performed with a hand lens or histologic preparations from skin scrapings. Microscopic examination of skin usually reveals acanthosis with variable hyperkeratosis and spongiosis, sometimes with exocytosis of eosinophils or neutrophils (Fig. 4.3A). Special stains may be needed to rule out fungal infection. Superficial and deep perivascular nodules of lymphocytes are seen, often admixed with histiocytes and eosinophils. In persistent nodular scabies, the density of the infiltrate and scattered atypical lymphoid cells can create concern for lymphoma. Serial sections can be used to search for a burrow through the stratum corneum and mite body parts, eggs, or fecal deposits (scybala) in the stratum granulosum or spongiosum (see Fig. 4.3B). In the absence of diagnostic organisms, scabies infestation can be suggested to the clinician when this pattern of lymphocytic infiltration is seen in an appropriate clinical setting.

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The crusted variant of scabies (so-called Norwegian scabies) shows exuberant hyperkeratosis with parakeratosis and mites, and their eggs are usually numerous. Differential Diagnosis The diagnosis of scabies can be complicated by atypical clinical manifestations, low mite burdens, and morphologic and clinical overlaps with other skin diseases. The clinical differential diagnosis for scabies includes arthropod bites, atopic or contact dermatitis, psoriasis, lichen planus, impetigo, pediculosis pubis, lichen simplex chronicus, prurigo nodularis, seabather’s eruption, fungal infections, and drug reactions. The presence of scabies mites, eggs, or scybala is key to a definitive pathologic diagnosis; however, searching for these diagnostic elements is often fruitless, even with exhaustive serial sectioning, in which case clinical correlation is needed in the context of pathologic findings. Treatment As discussed previously, treatment is primarily topical. Bedding and clothing should be decontaminated. Both sexual and close personal or household contacts within the preceding month should be examined and treated.6

Common Infections Not Typically Linked to Sexually Transmitted Diseases Fungal Infections

Fig. 4.2.

  Rash associated with scabies (buttock). (From Sidhu-Malik N, Rein M: Ectoparasitic infections. In Rein M, editor: Atlas of infectious diseases, vol V: sexually transmitted diseases, Philadelphia, 1996, Churchill Livingstone, p 13.7.)

A

Vulvovaginal Candidiasis Clinical Background Candida spp. are the most common cause of fungal infection in humans, and vulvovaginal candidiasis (VVC) is the most common form of mucosal candidiasis.13 Although most cases of VVC (up to 90%) are caused by Candida albicans, the incidence of VVC caused by non-albicans species

B Fig. 4.3.

  Scabies. A, Spongiosis and perivascular infiltrates with numerous eosinophils—the hallmarks of a hypersensitivity reaction—are seen. B, A mite buried immediately underneath the stratum corneum may be encountered occasionally, allowing for a definitive diagnosis.

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Diagnostic Gynecologic and Obstetric Pathology (10%–30%) such as Candida glabrata (second most common causative organism), Candida parapsilosis, Candida tropicalis, Candida lipolytica, Saccharomyces cerevisiae, and others, appears to be rising.14-16 Recognition of these non-albicans species is important because they can be more resistant to the traditionally used azole antimycotics.15 VVC is uncommon before menarche, with a rapidly increasing incidence late in the second decade, peaking in the third and fourth decades.16 In North America, three of four women will experience at least one episode of VVC, and 50% of women will experience more than one episode.13 For a smaller percentage of women (~5%–10%), the condition will become chronic, with multiple relapses over several years.17,18 It has been estimated that over 80% of recurrent VVC cases were caused by azole-sensitive C. albicans, suggesting that host factor(s) rather than pathogen resistance contribute to the development of recurrent infections.18 Predisposing factors for VVC include uncontrolled diabetes mellitus, immunosuppressed state, pregnancy, steroid and antibiotic use, oral contraceptive use, use of an intrauterine device, and postmenopausal state.13,18,19 It should be noted that Candida spp. are commensal organisms that can be part of the mucosal normal flora. Their presence is not necessarily indicative of disease but may only be colonization. As many as 20% of women are asymptomatic carriers of candidal species,15 with the proportion rising to 30% in pregnancy.19 Vulvar involvement in the absence of vaginal infection is rare. Clinical Examination The most common symptoms and signs are intense vulvar pruritus, dysuria, erythema, edema, and a nonmalodorous white vaginal discharge with a curdlike appearance (Fig. 4.4A and B).13,16

A

Diagnostic Criteria Ancillary Tests Diagnosis is usually established by assaying the vaginal pH, a potassium hydroxide (KOH) prep, or fungal cultures.13,18,20 In VVC, the vaginal pH is almost always normal, although an elevated pH may suggest mixed infection. A KOH prep and microscopy are helpful but sensitivity can be low and variable (≈40%–70%).18 If microcopy is negative and the vaginal pH is normal, the culture should be obtained. When a clinician obtains a fungal culture, the vulva as well as the vagina should be swabbed. A yeast culture with identification of species is often helpful when treating patients with recurrent vulvovaginitis. Histologic Features Candida infections are usually associated with hyperkeratosis or parakeratosis, epidermal hyperplasia (often psoriasiform), and a suppurative inflammation, with neutrophil infiltration of the squamous epithelium typically forming microabscesses (Fig. 4.5A and B). Candida may be seen with minimal inflammation when there is no mucosal invasion. The pseudohyphal and budding yeast forms of Candida can be highlighted in the epidermis using periodic acid–Schiff (PAS) or silver stains (see Fig. 4.4C). Candida spp. are also positive for Gram stain, which is helpful in distinguishing it from other, albeit rare, reported fungal infections of the lower genital tract (see later, “Other Uncommon Fungal Agents Detected in the Lower Genital Tract”). C. albicans and C. glabrata, the two most common causative species of VVC, can be differentiated histologically because C. glabrata demonstrates yeast forms and lacks pseudohyphal production in the vast majority of cases.21 The various other species of Candida cannot be differentiated by light microscopy.

B Fig. 4.4.  A, Clinical presentation of candidiasis, with white curdlike deposits at the introitus. B, Erythema of the labia minora and majora, with satellitosis from candidiasis.

66

Infectious Disorders of the Lower Genital Tract

A

4

B

C Fig. 4.5.

  A, Biopsy of candidiasis at low power, illustrating acanthosis. B, Superficial microabscess within the surface keratinocytes, containing acute inflammatory cells, should prompt a search for organisms. Note the resemblance to psoriasis. C, Pseudohyphae within the surface keratotic layer.

It is important to note that fungal infections may have been previously treated by antifungals, steroids, or both at the time of biopsy and may affect the histologic features. In particular, steroid use may reduce the neutrophilic infiltrate. In a histologic section or Papanicolaou (Pap) smear, mucosal fungal infections may be associated with reactive changes of squamous epithelium, such as enlarged hyperchromatic nuclei, which can mimic squamous intraepithelial lesions. Differential Diagnosis The histologic differential diagnosis of candidal infection includes eczematous dermatitis, lichen simplex chronicus, intertrigo, and psoriasis (see Chapter 2; Box 4.1). Before making any of these diagnoses, PAS or silver stain should be used to exclude a fungal infection. Lichen simplex chronicus may also be superimposed on a candidal infection as a result of rubbing to relieve the pruritus. It is

BOX 4.1  Noninfectious Differential Diagnosis of Candida Vulvitis Eczematous dermatitis Lichen simplex chronicus Intertrigo

Psoriasis Intraepithelial neoplasia

important to note that fungal superinfection may occur in many other lesions. In cases in which the underlying diagnosis is unclear and might be complicated by superimposed infection, it is wise to advise the clinician to treat the fungal infection and repeat the biopsy if the lesion persists. Treatment It is necessary to consider removal or improvement of predisposing factors in the treatment of candidiasis. Topical 67

Diagnostic Gynecologic and Obstetric Pathology antifungal agents are the mainstay of therapy, and numerous preparations are available. Tinea Cruris Clinical Background Tinea cruris (jock itch) is a dermatophytic infection of the groin and pubic region. It is more common in men than in women and is acquired by contact. It is not often seen on the vulva or around the anus. The prevalence of specific dermatophyte species is dependent on geographic location.22 Trichophyton rubrum, Trichophyton tonsurans, and Trichophyton mentagrophytes are some of the species that cause this condition. Other organisms, including Epidermophyton floccosum and Trichophyton verrucosum, cause an identical clinical condition. A person in an immunocompromised state (e.g., as seen in those with HIV or diabetes or patients who have had a transplant) is associated with risk of infection and dissemination. Disseminated dermatophytosis due to hematogenous spread can cause symptoms in any organ.22 Clinical Examination The signs and symptoms of tinea cruris include itching and erythema in the groin, vulva, inner thighs, anus, and buttocks. The lesions are erythematous, with central clearing and raised borders. The skin may flake, crack, and peel. A burning sensation may be present.11 Diagnostic Criteria Ancillary Tests The diagnosis of tinea cruris is generally confirmed by culture and microscopy of skin scrapings treated with KOH to visualize the hyphae.22,23 Histologic Features The epidermis exhibits spongiosis or a psoriasiform pattern of hyperplasia. A granulomatous dermatitis may accompany folliculitis (Majocchi granuloma). A diagnostic clue is the presence of neutrophils in the cornified cell layer, and fungal elements can be sandwiched between two zones of differing structure within the cornified cell layer—this is sometimes referred to as the sandwich sign. The upper zone of the cornified cell layer has a typical basket weave pattern of orthokeratosis, whereas the lower zone consists of more compact orthokeratosis and parakeratosis. The presence of spores and branching hyphae can be confirmed using PAS or methenamine silver stains, but histologic examination provides no clues regarding the dermatophyte species.22,23 Differential Diagnosis The following conditions should be considered in the clinical differential diagnosis of tinea cruris: acanthosis nigricans, eczematous dermatitis, including contact dermatitis (allergic and irritant), erythrasma folliculitis, psoriasis, candidal infection, and seborrheic dermatitis. Histologically, dermatophytic hyphae are often morphologically indistinguishable from those of Candida, as well as hyalohyphomycosis,21 which can involve any organ in disseminated disease in immunocompromised patients. Correlation with culture is needed for the definitive classification of the infectious agent in these cases. 68

Treatment Topical antifungal agents of the imidazole or allylamine family are generally used for the treatment of tinea cruris.24 At times, systemic administration of antifungals is needed for patients unable to use topical treatments consistently or those with extensive or recalcitrant infection.24 Other Uncommon Fungal Agents Detected in the Lower Genital Tract Other fungal species uncommonly reported involving the lower genital tract (often on Pap smears or in the setting of disseminated disease) include Histoplasma,25 Cryptococcus,26 Aspergillus,27,28 Blastomyces,29 Coccidioides,30,31 and Paracoccidioides spp.32,33 These agents are seen more commonly at other anatomic sites. Contamination of specimens needs to be ruled out for proper evaluation. Table 4.2 shows the distinguishing features of these fungi, which can show morphologic overlaps with Candida spp.

Bacterial Infections Bacterial Vaginosis Clinical Background Various terms have been used to describe bacterial vaginosis (BV), including nonspecific vaginitis, Haemophilus vaginitis, Corynebacterium vaginitis, Gardnerella vaginalis vaginitis, and anaerobic vaginosis. Bacterial vaginosis represents a complex shift in the normal vaginal flora. It is characterized by a reduction in the prevalence and concentration of hydrogen peroxide–producing lactobacilli and an increase in the prevalence and concentration of a number of microbes that have been implicated in the disease process, including Gardnerella vaginalis, Atopobium and Mobiluncus spp., Mycoplasma hominis, anaerobic gram-negative rods belonging to the genera Prevotella, Porphyromonas, and Bacteroides, as well as Peptostreptococcus, Leptotrichia, and Sneathia spp. and BV-associated bacterium 1 (BVAB1) to BVAB3.34,35 It is thought that BV results from the presence of a multispecies vaginal biofilm in which G. vaginalis is the predominant species.36 G. vaginalis has been detected in culture samples from nearly all symptomatic women with BV and in approximately 50% of the vaginal microflora of healthy women.35 It has been estimated that about 20% to 30% of reproductive age women worldwide suffer from BV. Risk factors include the number of lifetime sex partners, early age of sexual debut, regular douching, and being a commercial sex worker.35 Associations of BV with other sexually transmitted diseases and health issues have been reported, (e.g., HIV, herpes simplex virus type 2 [HSV2], chlamydia, gonorrhea),35 as well as preterm births, and pelvic inflammatory disease.37 Although causality and underlying biologic mechanisms have not been established, studies have suggested that BV is a potential risk factor of acquisition of other sexually transmitted infections (STIs), particularly in high-risk women. Clinical Examination The patient presents with a foul, fishy odor, more noticeable following intercourse and during menses. Vaginal discharge is increased. Vulvar itching or irritation may be present.35

Infectious Disorders of the Lower Genital Tract

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Table 4.2  Differential Diagnoses of Fungal Agents in the Female Lower Genital Tract Associated Disease

Infectious Agent in Humans

Fungal Morphology on Pap Smear or Tissue Section

Typical Stains for Differentiationb

Common Candidiasis

Candida spp. (most common: Candida albicans)

Small yeast cells (2–6 µm) intermingled with pseudohyphae

Gram stain (+)

Blastomycosis

Blastomyces dermititidis

Spherical multinucleated yeast cells (8–15 µm), single broad-based budding, thick refractile wall

Gram stain (−), Fontana-Masson stain (−)

Histoplasmosis

Histoplasma capsulatum, Histoplasma duboisii

Oval small yeast cells (2–4 µm), narrow-based budding

Gram stain (−), Fontana-Masson stain (−)

Cryptococcosis

Cryptococcus neoformans, Cryptococcus gattii

Encapsulated spherical to oval yeast cells (5–10 µm), narrow-based budding, polysaccharide capsule

Fontana-Masson stain (+), mucicarmine and Alcian blue (+) in capsule

Aspergillosis

Aspergillus spp. (most common— Aspergillus fumigates)

Septate hyphae (3–6 µm in diameter), dichotomous branching at 45-degree angle, fruiting body (mostly on Pap smears)

Gram stain (−), Fontana-Masson stain (−)

Coccidioidomycosis

Coccidioides immitis, Coccidioides posadasii

Large, thick-walled spherules (100 µm) containing endospores (≤5 µm)

Gram stain (−), Fontana-Masson stain (−)

Paracoccidioidomycosis

Paracoccidioides brasiliensis

Large round yeast cells (4–40 µm), multiple narrow-based budding conidia (ship’s wheel appearance)

Gram stain (−), Fontana-Masson stain (−)

Rarea

a

These fungal agents detected are mostly contaminants or seen in the setting of disseminated disease. Isolated involvement of the lower female genital tract is extremely rare. b Fungal elements are positive for GMS and PAS stains unless otherwise stated. Data from Guarner J, Brandt ME: Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev 24:247–280, 2011.

Diagnostic Criteria Ancillary Tests Several testing schemes have been proposed for making a diagnosis of BV. Amsel et al. have proposed four criteria (Amsel criteria) in making a clinical diagnosis of BV.38 These have been slightly modified according to subsequent work by Eschenbach et al. to improve the accuracy of these criteria39: 1. Thin, gray-white vaginal discharge 2. High vaginal pH (>4.5) A cutoff of 4.7 or higher has been proposed and used to improve accuracy.37,39 3. Positive whiff test There is an accentuated malodorous fishy discharge on adding 10% KOH to a sample of vaginal discharge due to the production of amines (e.g., cadaverine, putrescine, triethylamine) by anaerobic bacteria; their concentrations increase by 100- to 1000-fold with BV. 4. Identification of vaginal epithelial cells (typically >20%) coated with bacteria (clue cells) Because these markers are not consistent in all subjects with BV, criteria have been modified to include only the presence of clinical symptoms, and two of the three laboratory measures are thought to be acceptable for making a diagnosis of BV.34,35,37 A Gram stain scoring system has been proposed by Nugent et al. in which increased densities of Gardnerella, Bacteroides, and Mobiluncus increase the score and density of Lactobacillus decreases the score.40 The Gram stain scoring

system is more sensitive but less specific than the clinical criteria. The overall concordance between the Gram stain score and the Amsel criteria was reported to be about 80% to 90%.37 A culture is not useful for making a diagnosis of BV, which represents a shift in vaginal flora. Cultures in past studies on BV have been shown to be positive for G. vaginalis in almost all women with symptomatic BV and in about 50% of healthy asymptomatic women35; hence, its presence alone cannot be used to diagnose BV. Commercial tests, such as colorimetric molecular diagnostic tests using nucleic acid probes specific for G. vaginalis RNA, can give results within an hour (Affirm VPIII Microbial Identification Test, BD, Franklin Lakes, NJ),41 with good sensitivity (up to 95%) and specificity (up to 99%) using clinical criteria as the diagnostic standard.42 However, results can be variable based on the concentrations of G. vaginalis in the sample. The Pap smear reveals clue cells in women with BV (Fig. 4.6), which are squamous cells coated by a so-called shag rug of coccobacilli. Lactobacilli and white blood cells are absent, and neutrophils are often scarce. The number of clue cells should be more than 20% to increase the specificity of making a cytologic diagnosis of BV.43 It should be noted that although a Pap smear diagnosis of BV has a high specificity (93%–95%), the sensitivity has been critiqued to be low (as low as 40%– 50%),37,44 and the absence of BV on a Pap smear does not necessarily rule out disease. 69

Diagnostic Gynecologic and Obstetric Pathology

A

B

Fig. 4.6.

  Bacterial vaginosis, seen as dense, evenly distributed collections of bacterial rodlike forms in the squamous cells as seen on a wet prep (A) or Papanicolaou stain (clue cells; B).

Differential Diagnosis The clinical differential diagnosis for BV includes candidiasis, cervicitis, chlamydia, gonorrhea, herpes, trichomonas, and desquamative inflammatory vaginitis. These disorders are typically distinguished by appropriate analysis of the discharge and cultures. Treatment Metronidazole and clindamycin are the mainstays of therapy. Antibiotics, however, are not useful for preventing recurrence due to antibiotic resistance and the inability of the antibiotics to fully eradicate the bacteria associated with the vaginal biofilm in BV.36 An alternative approach for treating BV is by modulating the vaginal microbiota by using probiotics. Studies evaluating the efficacy of vaginal lactobacilli suppositories in addition to oral metronidazole for the treatment of BV have shown inconclusive results.36 Bacteriotherapy, using harmless bacteria (e.g., lactobacilli) to displace pathogenic organisms, is considered natural and without any side effects, but data from randomized controlled trials are mixed and have not yet shown definitive support for routine use.36,37,45,46 Folliculitis Clinical Presentation Folliculitis is a common condition on the buttocks and vulva. The hair follicles can become inflamed by physical injury and chemical irritation. The most common form is superficial folliculitis, which manifests as a tender or painless pustule that heals without scarring.47 The hair shaft is frequently in the center of the pustule (Fig. 4.7A). The most common pathogen associated with folliculitis 70

is Staphylococcus aureus, but commensal organisms such as yeast and fungi occasionally appear, particularly in the immunosuppressed patient. These lesions typically resolve spontaneously. Staphylococci will occasionally invade the deeper portion of the follicle, causing swelling, induration, and erythema, with or without a pustule at the skin surface (see Fig. 4.7B). This inflammation of the entire follicle or the deeper portion of the hair follicle (isthmus and below) is called deep folliculitis. Diagnostic Criteria Clinical Examination Visualization of erythema surrounding the hair follicles provides the clinical diagnosis of folliculitis. Histologic Features Folliculitis is characterized by inflammation of the follicle or perifollicular stroma, which may be composed of acute or chronic inflammation. A granulomatous response can be seen with follicular rupture. Differential Diagnosis The clinical differential diagnosis of folliculitis includes acne vulgaris, candidiasis, irritant contact dermatitis, insect bites, keratosis pilaris, milia, miliaria, rosacea, scabies, seabather’s eruption, tinea, and transient acantholytic dermatosis. Fungal folliculitis should be excluded with a PAS stain. Treatment Topical antibiotics can be administered to accelerate the healing process of superficial follicultis.48 Oral antibiotics are generally used in the treatment of deep folliculitis.

Infectious Disorders of the Lower Genital Tract

A

4

B Fig. 4.7.  Clinical picture of folliculitis. A, Punctate perifollicular inflammation following shaving. B, Diffuse induration produced by dermal follicular inflammation.

Common Sexually Transmitted Infections Trichomoniasis Clinical Background Trichomonas vaginalis (TV) is caused by the flagellated protozoan Trichomonas vaginalis. It is a very common STD worldwide, more prevalent than Chlamydia trachomatis, Neisseria gonorrhoeae, and syphilis combined.49,50 The global prevalence has been estimated to be about 8% for women,51 which is possibly an underestimate because these were mostly based on microscopy rather than on the more sensitive nucleic acid amplification tests (NAATs). Rates of TV vary by populations according to their risk profiles. In the United States, a prevalence of 3.1% was reported in reproductive age women in general52 and 8% to 13% in women who went to antenatal or family planning clinics.53 Infections may occur at any age. Risk factors include unprotected sexual activity, new or multiple sex partners, concurrent STIs, or a history of other STIs.49,50 A higher prevalence was also observed among African women, commercial sex workers, and women with bacterial vaginosis.50 Association of TV with other STIs, such as herpes infections, chlamydia, gonorrhea, and syphilis,54 as well as pelvic inflammatory disease and a poor pregnancy outcome (e.g., preterm labor and premature rupture of membranes),55 have been reported. TV has also been suggested in studies to increase the risk of HIV acquisition.50 Clinical Examination About 50% to 80% of women with trichomoniasis are asymptomatic.49,50 Symptoms and signs of trichomoniasis include a purulent, yellow-green, vaginal discharge and

Fig. 4.8.

  Clinical image of trichomonas (strawberry cervix). (From Krieger JN, Rein MF: Trichomoniasis. In Rein M, editor: Atlas of infectious diseases, vol V: sexually transmitted diseases, Philadelphia, 1996, Churchill Livingstone, p. 6.5.)

vaginal discomfort. In a subset of patients with acute infection, the underlying vaginal and cervical mucosa may have a grossly visible fiery red appearance, so-called strawberry cervix (colpitis macularis; Fig. 4.8). The vulva may be erythematous and edematous. Diagnostic Criteria Ancillary Tests The diagnosis of VT is clinically confirmed by a wet mount consisting of microscopy of vaginal secretions. The vaginal pH is alkaline (>4.5) VT in patients. T. vaginalis is a flagellated ovoid protozoan (average length, 10 µm; width, 7 µm), which is motile, with a jerky spinning motion seen 71

Diagnostic Gynecologic and Obstetric Pathology on wet mounts. The sensitivity of wet mounts depends on the inoculum size and can be variable and low. Alternative point of care test kits are available for clinicians’ use with vaginal swabs. They are rapid antigen tests (e.g., OSOM Trichomonas Rapid Test),56 or use DNA hybridization probes (e.g., AFFIRM VP III), with good sensitivity and specificity.57 T. vaginalis can also be detected by commercial NAATs, which detect the organism’s RNA using a polymerase chain reaction (PCR) assay. They are highly sensitive and specific and are accepted as the gold standard for T. vaginalis detection.49,50 Culture is another method for detecting the organism when the wet mount is negative and clinical suspicion remains high. The traditional diamond broth medium or its variant is used. Although culturing is highly sensitive and specific, it generally takes a few days (2–7) to obtain results. An InPouch culture system (BioMed Diagnostics, White City, OR) has been developed, with a quicker turnaround time (≤3 days).58 Histologic Features On histologic section, the findings are nonspecific. The inflammatory reaction is usually limited to the mucosa and immediately subjacent lamina propria. Pap smears done for routine screening can incidentally detect T. vaginalis. The organisms typically present as oval, pear- or kite-shaped, protozoa, with eosinophilic cytoplasmic granules and vesicular nuclei (Fig. 4.9).

Fig. 4.9.

  Pap smear showing two organisms of Trichomonas vaginalis exhibiting a characteristic indistinct ghostly appearance, with an oval nucleus and faint red granules.

72

Differential Diagnosis The clinical differential diagnosis of trichomoniasis includes candidiasis, bacterial vaginosis, desquamative inflammatory vaginitis, gonococcal infections, pelvic inflammatory disease, and urethritis. Treatment Anti-infective agents are used to treat trichomoniasis. Treatment of patients and their sex partners results in relief of symptoms, microbiologic cure, and reduction of transmission.59

Viral Infections Molluscum Contagiosum Clinical Background Molluscum contagiosum (MC) is a viral disease of the skin and, occasionally, the mucosa. It is caused by a DNA poxvirus, molluscum contagiosum virus (MCV), which is the sole member of the Molluscipoxvirus genus.60 There are four main subtypes of molluscum contagiosum—MCV-I, -II, -III, and -IV61-63—identified by restriction fragment length polymorphisms of their genomes.64 MCV-1 is the most common subtype in immunocompetent patients, and MCV-2 has been reported to be more common in HIV-infected patients.64 Direct contact with infected hosts or contaminated fomites is required for transmission. It can affect the genital area and is associated with a variety of other venereal diseases.63,65 As such, it is an STD often seen in sexually active populations. In addition to sexually active adults, the disease is seen predominantly in children and immunodeficient individuals, such as HIV-positive patients, patients on immunosuppressive drugs, and patients with DOCK8 deficiency. It is an autosomal recessive disease affecting the migration of dendritic and specialized T cells in skin, resulting in an increased propensity to develop extensive MCV lesions as well as other bacterial and viral skin infections.63 The incubation time for MCV is variable, and symptoms typically present within a few weeks of inoculation. MCV infection and proliferation usually remains limited to the keratinocytes, and there is little inflammatory infiltration of the epidermis although, when the virus is exposed, a host immune response is launched. The initial absence of an immune response to MCV is thought to be due to the activity of host response evasion genes in the viral genome that block apoptosis and natural killer cell activity.63,64 Clinical Examination The clinical appearance of MC is diagnostic in most cases.60 The characteristic lesion is a discrete, dome-shaped, fleshcolored papule (Fig. 4.10). Some will contain a dimple beneath, which is a core of cheesy material (umbilicated lesion). The size of the papule ranges from 2 to 6 mm. Less commonly, the molluscum lesion will consist of numerous small confluent papules, mimicking herpes simplex virus infection. The lesions are usually painless except when traumatized.

Infectious Disorders of the Lower Genital Tract

4

B

A Fig. 4.10.

  A, Clinical presentation of molluscum contagiosum, with discrete dome-shaped, pink papules. B, A depressed center (umbilicated papule), characteristic of the disease, allows for clinical diagnosis in most cases.

B

A

Fig. 4.11.  A, Low-power photomicrograph of molluscum contagiosum illustrating the cup-shaped architecture. B, Higher power view of cytoplasmic inclusions, which become more distinct as a function of keratinocyte maturation (arrow). Diagnostic Criteria Histologic Features The diagnosis of MC can be confirmed by excision of the lesion or by cytologic inspection of the debris that is expressed from the center of the lesion and visualized on an H&E or Pap stain. The infection produces an epithelial hyperplasia, with formation of a cup-shaped lesion

(Fig. 4.11A). The periphery of the cup contains several layers of basal cells, which mature centrally, shedding keratinous debris into the lumen or cavity that connects to the surface. Diagnostic viral inclusion bodies (HendersonPatterson or molluscum bodies) become visible several layers above the basement membrane and, as the cells mature, the eosinophilic or cyanophilic oval viral inclusions 73

Diagnostic Gynecologic and Obstetric Pathology (molluscum bodies) completely replace the cytoplasm and marginate the nucleus (see Fig. 4.11B). In ruptured lesions, a marked inflammatory response can obscure the diagnostic viral cytopathic changes. In situ hybridization for MC virus DNA has also been performed but is not necessary for diagnosis. Differential Diagnosis The clinical differential diagnosis includes acrochordon, epidermal inclusion cyst, dermatitis herpetiformis, keratoacanthoma, neurofibroma, condyloma, pyogenic granuloma, herpes, basal cell carcinoma, and disseminated cryptococcosis or penicilliosis. In our experience, some difficulty may be encountered in the histologic diagnosis if the inclusions are not in the plane of section or the lesion is markedly inflamed. For this reason, any inverted or cup-shaped lesion that does not contain sufficient atypia to verify condyloma, keratoacanthoma, or other keratoses should be sectioned thoroughly to exclude MC. Treatment MC is a benign self-limited disease but can cause discomfort, scarring with persistent scratching, and, in some schools and daycare centers, exclusion until treatment.66 In addition, the lesions spread and perpetuate by autoinoculation from scratching or trauma, and some cases may persist for 8 to 12 months or longer.63 Curettage, cryotherapy, and topical agents are commonly used options for the treatment of MC. Herpes Simplex Infections Clinical Background Genital herpes is an erosive, and on occasion ulcerative, sexually transmitted disease caused by the double-stranded DNV herpes simplex virus (HSV) type II (more common) and type I. It is the most common erosive/ulcerative disease in developed countries, with approximately 750,000 new cases/year and a prevalence of more than 20 million cases in the United States.67 HSV-1 has been increasing in cases of genital herpes, especially among young women68,69 and men who have sex with men (MSM).70 In the primary infection, there is no difference in clinical presentation between HSV-1 and HSV-2.69 An increased prevalence is seen in the black, non-Hispanic population.71 Genital herpes infection is also associated with an increased number of lifetime sex partners and the presence of other STIs.72 The presence of active symptoms, hormonal contraceptive use, bacterial vaginosis, and vaginal group B streptococcus colonization have been suggested as risk factors for increased HSV-2 infection.73 HSV-2 genital infections, particularly recent ones, have been associated with an increased risk for HIV-1 infection in multiple studies.74-77 In clinically apparent cases, the primary lesion of genital herpes appears approximately 3 days to 2 weeks after exposure. The lesions are highly infective until they begin to crust over during the healing phase after ulceration (usually ≈10 days after their first appearance). However, even asymptomatic individuals may shed virus.67,71 Importantly, many people infected by herpes do not develop clinical features of the disease and are unaware that they have the disease and are infective.67,71 74

In the United States, approximately one out of five adults is serologically positive for HSV-2. More than 50% of individuals who are seropositive do not experience clinically apparent outbreaks, but they still have episodes of viral shedding, transmit the virus, and have a lifelong risk of infecting their sex partners.77 Lesions on the genitals can spread to other sites such as the fingers, buttocks, and oral or labial areas, presumably by direct contact. Recurrence occurs in about 50% of women infected, usually within 8 months of the initial infection. In recurrent infection, the lesions are typically less extensive and resolve in 5 to 7 days, generally with only mild swelling. Recurrent lesions are more commonly due to infection with HSV-2. HSV-2 recurs in 89% of cases, whereas HSV-1 recurs in up to 25% of cases. HSV-2 infections are often multiple and developing approximately three to four times/year. HSV can be associated with life-threatening systemic disease in immunosuppressed individuals. Transmission to the fetus during childbirth or an intrauterine infection can be a source of significant morbidity.78 Extragenital complications have been reported in a minority of patients with primary herpes infection, including distant skin lesions, aseptic meningitis, and urinary retention syndromes.79 Clinical Examination In primary herpes, the vulva is red and swollen, with numerous vesicles, typical of a more generalized infection. They rapidly become pustular, with open tender erosions lasting 2 weeks (Figs. 4.12 and 4.13).78 In addition, a vaginal discharge may sometimes be noted. The symptoms peak by 7 to 10 days following initial presentation and usually resolve without scarring within 3 weeks. Recalcitrant cases of anogenital herpes, particularly in HIV-infected patients, may mimic a neoplasm and are referred to as pseudotumoral herpes (Fig. 4.14).

Fig. 4.12.

  Primary herpes simplex virus infection of the vulva, with a broader distribution of mucosal ulceration and edema. (Courtesy Mark Pearlman.)

Infectious Disorders of the Lower Genital Tract

Fig. 4.13.

 

4

Herpetic ulcers with yellow-white bases.

Fig. 4.15.

  Pap smear showing herpes simplex infection. Viral cytopathic changes are seen, including multinucleated cells with eosinophilic nuclear inclusions with peripheral chromatin margination.

Fig. 4.14.

  Pseudotumoral herpes. Recalcitrant anogenital herpes may mimic a neoplasm and is more commonly seen in immunosuppressed individuals.

Diagnostic Criteria Ancillary Tests Herpes simplex virus can be difficult to confirm. Cell culture and PCR assay are preferred methods for the detection of active infection when a lesion is present.80 Ideally, lesions not more than 3 days old should be selected for culture. Material needed for successful culture is usually located at the base of the lesion, so aggressive scraping of the base is required. The scraping is placed into the medium for culture. Direct fluorescence testing for the HSV antigen in a smear may be a useful adjunct for culture but is not type specific. The sensitivity of culturing, however, declines rapidly as lesions begin to heal, usually within a few days of onset, and is low in recurrent lesions. Nucleic acid amplification tests, such as typed PCR assays for HSV DNA, are more sensitive. They have become increasingly available and are also used for detecting HSV in spinal fluid for the diagnosis of HSV infection of the central nervous system.80-83 Because viral shedding can be intermittent, a negative culture or PCR test result does not necessarily indicate the absence of viral infection. Furthermore, false-negative HSV cultures are also common in patients with recurrent infection or with healing lesions.

Type-specific serologic tests can be used to establish a diagnosis in the following scenarios: 1. Patients with genital symptoms and/or clinical diagnosis of HSV but negative PCR or culture results 2. Asymptomatic patients who present for STI screening (e.g., infected sexual partner)67 Both type-specific and nonspecific antibodies to HSV develop during the first several weeks following infection and persist indefinitely. Because almost all HSV-2 infections are sexually acquired, the detection of a type-specific HSV-2 antibody generally indicates anogenital infection, but the presence of HSV-1 antibody does not distinguish an anogenital from orolabial infection. Accurate type-specific assays for HSV antibodies must be based on the HSV-specific glycoprotein G2 for the diagnosis of infection with HSV-2 and on glycoprotein G1 for the diagnosis of infection with HSV-1. Such assays are preferable to older assays that do not accurately distinguish HSV-1 from HSV-2 antibody. Therefore, the serologic, type-specific immunoglobulin (IgG)-based assays should be specifically requested when serology is performed. The sensitivities of tests for detection of HSV-2 antibody vary from 80% to 98%,80 and the specificities of these assays are greater than 96%. False-positive results can occur, especially in patients with a low likelihood of HSV infection. Therefore, repeat testing or a confirmatory test (e.g., an immunoblot assay if the initial test was an enzymelinked immunosorbent assay [ELISA]) may be indicated in some settings. False-negative serologic testing results can also occur, especially at an early stage of infection. In addition, there is generally a 2-week to 6-month window following HSV exposure before antibody can be detected; hence repeat serologic testing may be needed to confirm recent acquisition.71 HSV infection is characterized by the presence of a ground-glass appearance of nuclei, which are often multinucleated. The nuclear membranes may appear thickened due to peripheral margination of chromatin (Fig. 4.15). 75

Diagnostic Gynecologic and Obstetric Pathology

A

B Fig. 4.16.  A, Low-power view of a herpetic ulcer, characterized by an eosinophilic zone of epithelial necrosis (right). B, Higher power view demonstrates intranuclear inclusions at the edge of the ulcer (arrows).

It should be noted, however, that cytologic detection of cellular changes of HSV infection is insensitive and the interpretation of results is not always correct, both in genital lesions (Tzanck preparation) and cervical Pap smears. According to current guidelines, it should not be exclusively relied on for the diagnosis or exclusion of HSV infection when the interpretation has clinical or therapeutic consequences.80 Histologic Features Lesions initially show vesicles followed by superficial ulceration. The most telling aspect of a herpetic ulcer is the presence of diffuse epithelial necrosis, presenting as an eosinophilic aggregate of dead and degenerating epithelial cells (Fig. 4.16A). Early in the infection, scattered nuclei may have a homogeneous, ground-glass appearance and may be surrounded by a halo. Over time, multinucleated keratinocytes will be apparent, with eosinophilic or basophilic nuclear inclusions, which should be identified in the viable epithelium or at the interface with the ulcer (see Fig. 4.16B). Viral cytopathic effects can also involve hair follicles. An underlying dermal inflammatory component is present, and neutrophils may be seen when the lesion ulcerates.29 Viral inclusions may not be demonstrated in some ulcerated lesions; therefore, it is important to obtain a biopsy from the edge of ulcerative lesions with intact epithelium. Differential Diagnosis Diseases in the clinical differential diagnosis with HSV infection include syphilis, chancroid, Epstein-Barr virus, herpes zoster, HIV, cytomegalovirus infection, Behçet disease, erythema multiforme, aphthous ulcers, and 76

BOX 4.2  Differential Diagnosis of Ulcerative Lesions Infectious Epstein-Barr virus Human immunodeficiency virus Cytomegalovirus Herpes simplex Herpes zoster Syphilis Erosive candidiasis Mycobacterial infection

Chancroid Lymphogranuloma venereum

Not Infectious Behçet disease Excoriation Aphthous (idiopathic) ulcer Erythema multiforme Carcinoma

extensive erosive candidiasis, along with other disorders (Box 4.2). In the absence of diagnostic viral cytopathic inclusions, the histologic features are those of a nonspecific erosion or ulceration. A high index of suspicion is required to recognize early infection. Immunohistochemical stains for HSV-1 and HSV-2 are extremely helpful in establishing the correct diagnosis when unequivocal viral inclusions are not identified on routine light microscopy (Fig. 4.17). When the viral cytopathic effect is equivocal, a panel of HSV, varicella zoster virus (VZV), and cytomegalovirus (CMV) immunostains may be used for distinction because the latter two can also present as ulcerative lesions in the genital tract. Management of Genital Herpes Antiviral therapy, such as acyclovir, valacyclovir, and famciclovir, is the mainstay of treatment. Systemic antiviral drugs partially control the symptoms of herpes episodes

Infectious Disorders of the Lower Genital Tract

4

Bacterial Infections

A

B

Genital Gonorrhea Clinical Background Gonorrhea is caused by the gram-negative diplococcus Neisseria gonorrhoeae. The number of new cases of gonorrhea has been estimated to be 106 million cases globally, with the highest disease rate observed in less developed countries in Africa and the Western Pacific.84 In the United States, gonorrhea is the second most common STI, with 333,004 cases reported in 2013,85 although this is likely an underestimate due to underreporting because a significant proportion of infected women are asymptomatic. The rate of gonorrhea in the United States had previously declined following the implementation of the national gonorrhea control program in the mid-1970s. However, the incidence of gonorrhea has been rising in the past 2 decades. In 2013, the rate of reported gonorrheal infections rose to 106.1/100,000 persons compared to 98.1 cases/100,000 persons in 2009.85 This trend has paralleled the increase in number of men having sex with men who engage in sexual risk behaviors, which has been thought to contribute to the rising incidence of gonorrhea.86,87 Risk factors for gonorrhea include young age, multiple or recent sex partners, low socioeconomic status, history of previous gonorrhea, and minority ethnicity.88-90 Coinfection with Chlamydia is common. In some studies, gonorrhea has also been shown to be associated with HIV transmission and acquisition91,92 and was postulated to increase HIV viral production via activation of HIV-infected CD4 cells and an alteration of the CD8 cellular response.93,94 It is important to screen women at high risk for STIs for gonorrhea because a significant proportion of women with the infection can be asymptomatic (up to 70% in one series).95,96 Untreated gonorrhea can progress to pelvic inflammatory disease, perihepatitis, chronic pelvic pain, and infertility.97 Clinical Examination Symptomatic patients typically present with a mucopurulent discharge or pruritus. The cervix may be friable. Involvement of the Bartholin gland can result in perilabial pain.98

C Fig. 4.17.

  A, Herpetic ulcer. B, At higher power, rare cells at the ulcer– epithelial interface contain the characteristic inclusions. C, Immunostaining highlights a much higher than expected proportion of infected cells.

when used to treat first clinical episodes and recurrent episodes or when used as daily suppressive therapy to reduce the severity, duration, and recurrence of symptoms. It should be noted that latent virus cannot be eradicated by these drugs; hence, the risk of recurrence cannot be affected after the drug is discontinued.80

Ancillary Tests A variety of diagnostic modalities are available, including microbial culture, Gram staining, ELISA, nucleic acid hybridization, and PCR-based testing. In general, NAAT is the first-line test for initial diagnosis. Co-testing for Chlamydia trachomatis should be done because cervicitis caused by N. gonorrhea and C. trachomatis has similar presentations, and co-infection is common. Culturing remains an important diagnostic tool for testing antibiotic susceptibilities when antibiotic resistance is suspected. Differential Diagnosis Conditions to consider in the clinical differential diagnosis of gonorrheal cervicitis include chlamydial cervicitis (although co-infection is common) or urinary tract infection and vaginitis caused by other infectious agents. Treatment Antibiotic therapy is effective in the treatment of gonorrhea. Because there is a high rate of coinfection of N. gonorrhoeae 77

Diagnostic Gynecologic and Obstetric Pathology with C. trachomatis, gonococcal infections are routinely treated with a regimen effective against uncomplicated C. trachomatis genital infection. Some specialists believe that the routine use of dual therapy has resulted in substantial decreases in the prevalence of chlamydial infection.

Uncommon Sexually Transmitted Diseases Syphilis Clinical Background Syphilis is a sexually transmitted infectious disease caused by the spirochete Treponema pallidum. It is a reportable disease in the United States. The incidence of this disease declined precipitously after the introduction of penicillin; however, there has been a recent increase in the number of cases in the United States and other parts of the world.99-103 In the United States, the incidence rate of primary and secondary syphilis has been increasing since 2001, with the annual rate rising from 2.9 to 6.3 cases/100,000 from 2005 to 2014.104 Although the rate increase in the United States was observed in men and women and in all ethnicities, it was estimated that about 90% of new syphilis cases were detected in men, with over 60% affecting MSM.101,104-106 A higher rate was also seen in black men, and an upward trend has also been noted for late and latent syphilis since 2009, with the rate rising from 5.6 to 7.4/100,000 from 2009 to 2014.104 T. pallidum transmission is via contact with infected secretions, such as during sexual intercourse, with almost any tissue. Moreover, T. pallidum can cross the placenta, resulting in fetal and congenital infection. An increase in congenital syphilis has been reported in the United States—23% increase from 2005 to 2008107—reflecting a rising incidence of syphilis in women without adequate screening and the challenge of diagnosis in asymptomatic patients. In some studies, syphilis has been shown to be synergistically associated with HIV infection, with syphilis enhancing the acquisition of HIV by increasing HIV coreceptor expression in the genital tract108 and by HIV reducing the serologic response to syphilis.77,108,109 Co-infection of syphilis and HIV has become more common,102,110 with an increased risk of developing neurosyphilis, which can occur at any stage of the disease.102 If left untreated, infection with syphilis may progress from primary to secondary and latent or tertiary phases. Clinical Presentation Primary Syphilis During the primary phase of infection, the initial manifestation is a chancre at the site of exposure. Approximately one-third of exposures to T. pallidum will result in a chancre, which occurs 10 to 90 days following exposure (Fig. 4.18). Although a single lesion is typical, primary syphilis can occasionally present with multiple lesions.111 Chancres are painless unless traumatized or superinfected. Vulvar lesions also have a tendency to become superinfected, resulting in more painful chancres.78 Lesions during the chancre stage shed numerous treponemal organisms and are highly infectious. Treated lesions resolve in 1 to 2 weeks. The chancre heals in a few weeks, without scar78

Fig. 4.18.  Syphilitic chancre in the perianal region. (From Fiumara NJ: Primary and secondary syphilis. In Rein M, editor: Atlas of infectious diseases, vol V: sexually transmitted diseases, Philadelphia, 1996, Churchill Livingstone, p 9.7.)

ring, even when untreated. Palpable, enlarged, firm lymph nodes are often present. Unilateral inguinal lymph node involvement is most common with vulvar disease. Vulvar involvement tends to produce chancres with edematous induration rather than the firm lesions seen at other sites. In addition, mirror image or so-called kissing chancres can be seen in the vulva as a result of skin-to-skin contact at this site.112 Secondary Syphilis Untreated primary syphilis will evolve to secondary syphilis over weeks to months. Most commonly, this occurs after the initial chancre has resolved, but the lesions of primary and secondary syphilis can be simultaneous. Secondary lesions usually resolve within 2 weeks to 3 months without treatment. Scarring is not a feature. Systemic symptoms include fever, malaise, and arthralgias.112,113 Presentation at this stage is notoriously variable and includes rashes and condyloma lata, which may be overlooked, and severe manifestations that can require hospitalization. Initially, the lesions of secondary syphilis are rich in treponemal organisms, but the number of organisms declines as the lesions resolve. Relapses of untreated secondary syphilis occur with some frequency. Other organ systems may be involved as well. Lues maligna, also termed malignant syphilis or ulceronodular syphilis, has been described in the literature to be a rare, severe, and atypical form of secondary syphilis, with a distinct clinical presentation. It is usually seen in patients with HIV infection and can be its initial manifestation, but cases have also been reported in immunocompetent men and women.114-117 It has been estimated that up to 7% of syphilis cases seen in HIV patients may meet certain criteria,117,118 including the following: (1) strongly positive rapid plasma reagin (RPR) titer; (2) severe JarischHerxheimer reaction (acute febrile illness within the first

Infectious Disorders of the Lower Genital Tract 24 hours of initial treatment); (3) characteristic gross and microscopic morphology; and (4) rapid resolution of the lesions with antibiotics.115 These cutaneous lesions are often preceded by prodromal fever, arthralgia, and/or myalgia of variable intensty.116 Tertiary Syphilis Tertiary syphilis will develop in approximately one-third of patients with untreated syphilis. The remainder results in latency. The clinical presentations of tertiary syphilis are late benign syphilis, cardiovascular syphilis, and neurosyphilis, although neurosyphilis can occur at any stage of the disease.112 Cutaneous granulomatous involvement and gumma formation by tertiary syphilis falls within the late benign syphilis category. Lesions of tertiary syphilis can be quite destructive and heal with scarring. Latent Syphilis Latent disease can occur when the infected individual is seropositive but is asymptomatic. Latent disease is categorized into early (infection occurring within the previous 12 months) and late disease (infection occurred >12 months ago, or at an unknown time point), according to the Centers for Disease Control and Prevention (CDC).119 The early stage can be established in patients who, within the past year, have have seroconverted, had symptoms of primary or secondary syphilis, or had a sexual partner diagnosed with primary, secondary, or early latent syphilis within the past year. Otherwise, patients should be presumed to have late latent syphilis.112,119 The distinction is important because the time since infection has implications for the risk of transmission as well as treatment duration; patients with early latent disease remain infectious, whereas those with syphilis in the late latency stage are thought to be noninfectious.102,120 Clinical Examination Primary Syphilis The chancre develops as a round to oval macule that becomes papular, with a sharply defined edge and central ulceration (see Fig. 4.18). Secondary Syphilis The cutaneous lesions of secondary syphilis include macular, papular, and mixed maculopapular lesions. Distribution is widespread and is often symmetric. Another important manifestation of secondary syphilis is condyloma lata of the vulva, a verrucoid lesion that may be mistaken for condyloma acuminata.78 The lesions of lues maligna, a severe form of syphilis seen more commonly in HIV patients, may present as multiple nodules, pustules, or ulcers, with or without mucosal involvement, associated with multiple, characteristic, well-demarcated round or oval lesions, with lamellar crusting to the edge.114 Tertiary Syphilis The lesions of tertiary syphilis can be granulomatous or result in gummas. Granulomatous lesions can be nodular or plaquelike and are erythematous and often scaly.121 Gummas are nodules that sometimes ulcerate and have a soft consistency due to central necrosis.

4

Diagnostic Criteria Ancillary Tests Testing for syphilis consists of the following modalities, with serologic tests being the mainstay for diagnosis. Darkfield Microscopy This allows for direct visualization of the spirochete in the ulcer exudate. It is not useful when the lesion has healed and scarred but is most helpful for diagnosis during the window after chancre detection and before seroconversion as the IgM antibodies to T. pallidum. This can take 2 to 3 weeks to develop.102,112 Nontreponemal Serologic Tests These include Venereal Disease Research Laboratory (VDRL) and RPR tests. These first-line screening tests can detect antibodies to cardiolipin in blood, which is a nonspecific antigen that cross-reacts with T. pallidum antigens (develop in ≈4–6 weeks) following infection and hence are not useful for diagnosis of early syphilis. False-positive results (1%–2%) have been reported, particularly in patients with autoimmune diseases, but also in those with malaria, lymphoma, cirrhosis, or acute pneumonia.102,120 Alternatively, a high antibody titer may result in a false-negative result due to the prozone effect. Hence, a negative test result in the setting of high clinical suspicion should prompt repeat serologic testing, and a positive RPR or VDRL test should be followed by specific treponemal testing. Treponemal Serologic Tests These include the fluorescent treponemal antibody absorption assay (FTA-ABS) and T. pallidum particle agglutination test (microhemagglutination–T. pallidum [MHA-TP]). These are confirmatory tests that can detect antibodies to T. pallidum with high specificity and a low false-positive rate. However, because testing relies on antibody formation, these tests cannot be used to establish diagnosis in the first few weeks following infection, before antibodies are formed. As with other STDs, patients with syphilis should also be tested for HIV.102 Polymerase Chain Reaction Assays These have been developed and may be useful adjunctive tests for the confirmation of diagnosis in tissue and body fluids and for testing for drug resistance.122,123 Histologic Features Primary Chancre The primary chancre is the initial manifestation of syphilis and is often limited to the vulva. It is characterized by an intense dermal infiltrate of lymphocytes, histiocytes, and neutrophils, with overlying epidermal hyperplasia.121 Plasma cells may not be conspicuous at this time. The epidermal thickening at the edges of the ulcer often becomes pseudoepitheliomatous. Capillaries and small vessels within the lesion often show marked endothelial swelling accompanied by perivascular plasma cells. The histologic findings are not specific, but the diagnosis may be confirmed with a Warthin-Starry stain or immunohistochemistry (the latter being more sensitive and easier to interpret), which typically reveal spirochetes, often in a perivascular distribution. 79

Diagnostic Gynecologic and Obstetric Pathology Secondary Syphilis The histologic features of lesions of secondary syphilis vary, consistent with the myriad clinical presentations associated with this stage. Classic lesions of secondary syphilis show psoriasiform epidermal hyperplasia and a superficial and deep perivascular, and often lichenoid, infiltrate of histiocytes and plasma cells (Fig. 4.19A). Although the discovery of perivascular plasma cells with endothelial swelling and injury (so-called plasma cell endarteritis) is considered a classic finding, this feature is

often not seen in secondary syphilis and is nonspecific (see Fig. 4.19B).113 Neutrophils may be present in earlier lesions but are less frequent as the spirochetes diminish in number. Late lesions often have a granulomatous appearance. Eosinophils may also be readily evident and should not be overtly relied on in excluding syphilis. Genital condyloma lata do not ulcerate and typically show a markedly hyperplastic epidermis with hyperkeratosis. The mixed chronic inflammatory infiltrate in the dermis is rich in perivascular plasma cells and, in this setting, plasma

A

B

C

D

Fig. 4.19.

  A, Secondary syphilis at low power, with pseudoepitheliomatous hyperplasia and intense submucosal inflammatory infiltrate. B, Higher power view demonstrates numerous plasma cells. C and D, Perivascular inflammation (endarteritis) with endothelial hyperplasia is commonly seen in syphilis but is not specific.

80

Infectious Disorders of the Lower Genital Tract

A

4

B Fig. 4.20.  A, Steiner stain illustrates numerous filamentous spirochetes within a vascular wall (arrow) and in the stroma around it. B, When present, spirochetes are readily identifiable with immunohistochemistry, now a preferred method due to its higher sensitivity.

cell endarteritis is seen more frequently (see Fig. 4.19C and D).121 Spirochetes can be visualized with Warthin-Starry or immunohistochemical stains (Fig. 4.20). Tertiary Syphilis The lesions of tertiary syphilis are granulomatous. Plasma cells are present, and organisms can be difficult to demonstrate. Gummas show central areas of necrosis bound by a fibrous lymphohistiocytic infiltrate rich in plasma cells. Closer inspection of the necrotic areas will reveal eosinophilic outlines of dead cells. Differential Diagnosis As mentioned earlier, the biopsy findings in syphilis—other than direct visualization of spirochetes—are not specific; thus, confirmatory serologic testing is required. In all cases, this should be performed to confirm or support the diagnosis. Syphilis can mimic many different forms of dermatitis. Pathologists should be acquainted with the histologic appearances of syphilis and independently think of this diagnosis when encountered. Biopsy is not the diagnostic method of choice (see above), and therefore the clinical information provided to the pathologist at the time of biopsy may be unhelpful and/or potentially misleading, because syphilis may not be included in the differential diagnosis. Zoon or plasma cell vulvitis (plasmacytosis mucosae; see Chapter 2) is a rare cause of a plasma cell–rich infiltrate in the vulva. A spirochete stain is always advised before accepting this diagnosis. In difficult cases, serologic testing is advised. Other conditions to consider in the differential diagnosis of syphilis include herpes (generally painful, but at times the ulcer is painless), staphylococcal or

streptococcal pyoderma, chancroid, granuloma inguinale, lymphogranuloma venereum, scabies, and tinea corporis. Treatment Penicillin remains the main treatment for all forms of syphilis. The preparation(s) used (e.g., benzathine, aqueous procaine, aqueous crystalline), dosage, and length of treatment depend on the stage and clinical manifestations of disease.102,112 Patients should be reexamined clinically and serologically 6 and 12 months following treatment, with attention to persistence in signs or symptoms and increases in test titer that may signify re-infection or treatment failure.102,112

Chancroid Clinical Background Chancroid is caused by Haemophilus ducreyi, a gram-negative bacillus and facultative anaerobe with fastidious culture requirements.124 Chancroid is most common in developing countries, particularly those with tropical and subtropical climates. The low incidence reported in the United States has partly been due to underreporting and lack of testing.125-127 In the United States, chancroid has been diagnosed primarily in heterosexuals, minority populations (African Americans, Hispanics), and female sex workers and their sex partners.128 Males are more often affected than females.124,128 Exposed individuals experience an incubation period of 3 to 5 days (rarely >10 days), with lesions initially appearing as small groups of papules or pustules that ulcerate as a result of rubbing and scratching. 81

Diagnostic Gynecologic and Obstetric Pathology has a proposed case definition for chancroid for reporting purposes and as a guide for presumptive treatment133: • Definite case of chancroid, as confirmed by culture or PCR assay • Probable case of chancroid meeting the following criteria: 1. One or more painful genital ulcers 2. Presentation of ulcers and lymphadenopathy typical for chancroid 3. No evidence of T. pallidum on darkfield examination of ulcer exudate and/or no serologic evidence of syphilis at least 7 days after ulcer onset 4. Negative HSV by PCR assay or culture from the ulcer exudates Ancillary Tests Testing modalities include Gram stain, culture, and PCR testing.

Fig. 4.21.  Chancroid. (From Allen R: Chancroid. In Rein M, editor: Atlas of infectious diseases, vol V: sexually transmitted diseases, Philadelphia, 1996, Churchill Livingstone, p 16.7.)

H. ducreyi infection is often encountered in the setting of HIV and is itself a risk factor for the heterosexual transmission of HIV.128,129 Co-infection with HIV may lead to an atypical presentation of chancroid, including the development of multiple lesions, delayed resolution, and extragenital involvement.130 Clinical Examination The ulcerated lesions are painful, soft, and friable and exhibit ragged edges with a dusky gray base, composed of granulation tissue that bleeds when manipulated. The ulcers often enlarge and have irregular borders, with an erythematous surrounding halo (Fig. 4.21). Several lesions can coalesce to form larger areas of ulceration.128,131 The lesions are not indurated and thus are described as soft chancres. They can also be associated with unilateral or bilateral inguinal lymphadenopathy that develops 1 to 2 weeks following the appearance of genital lesions. The overlying skin is usually erythematous and, if untreated, these suppurative lesions (buboes) can ulcerate and result in sinus tracts that drain a creamy white exudate.132 Buboes are more common in men than in women. Vulvar lesions that are untreated can also result in draining fistulous tracts. The lesions rarely subside without treatment but, when this occurs, scarring is typically present, and recurrence is common at the same site. Extragenital lesions can occur but are believed to be the result of direct cutaneous spread through damaged skin.128 Diagnostic Criteria Clinical Criteria Given the difficulty with the isolation of this organism, the Centers for Disease Control and Prevention (CDC) 82

Gram Staining of Ulcer Exudates This shows gram-negative rods in a chain, classically described as a school of fish or railroad tracks.124 However, the sensitivity of Gram staining has been reported to be poor.134 Culture This provides a definitive way to detect H. ducreyi, but the required special culture media may not be readily available in different laboratories. Sensitivity was estimated to be 75% when compared to PCR.135 Polymerase Chain Reaction This has been developed with good sensitivity (>90%) and specificity (≥99%),135 but testing results are not rapidly available. Moreover, PCR testing for chancroid is not currently US Food and Drug Administration (FDA)– approved in the United States and may need to be done at commercial laboratories that have developed a PCR test and have Clinical Laboratory Improvement Amendments (CLIA) certification.133 Tissue biopsy is not a common means to confirm a diagnosis of chancroid, although biopsies may be obtained to exclude other conditions.124 In endemic areas, this disease is often diagnosed by its characteristic clinical presentation. Histologic Features The lesions have a characteristic zoned configuration. The surface of the ulcer is composed of a neutrophilic infiltrate associated with fibrin and red blood cells. Beneath this layer is a band of granulation tissue (Fig. 4.22). Finally, the deepest layer is composed of a mixed chronic inflammatory infiltrate, including plasma cells, lymphocytes, and histiocytes. Gram stain is not reliable for the demonstration of H. ducreyi organisms because the ulcers tend to be superinfected with skin commensal bacteria.132 Differential Diagnosis The differential diagnosis includes other ulcerative diseases of the vulva, such as herpes and syphilis. Herpes usually presents as crops of small vesicles that may subsequently form erosions and ulcers associated with a mixed inflammatory infiltrate. Chancroid ulcers lack viral cytopathic

Infectious Disorders of the Lower Genital Tract

Fig. 4.22.  Histopathologic features of chancroid are not specific but exhibit ulceration and dense inflammatory infiltrate.

effects. HSV immunohistochemistry can also aid in the differential diagnosis. Syphilis usually presents as a single lesion and is generally not painful at presentation. However, the presence of plasma cells in both conditions should elicit a comprehensive history and clinical and serologic evaluations. In addition, special stains for organisms may sometimes be helpful. Importantly, genital ulcers can be infected with multiple organisms (e.g., chancroid with herpes superinfection). In complex cases, DNA hybridization or PCR-based methods may be helpful in establishing the diagnosis of chancroid.136 Treatment Antibiotic treatment is curative, resolves the clinical symptoms, and prevents transmission to others. If treatment is successful, ulcers usually improve symptomatically within 3 days and objectively within 7 days after therapy. As with other STDs, patients should be tested for syphilis and HIV infection when chancroid is diagnosed, and sex partners should be examined and treated, regardless of whether symptoms of the disease are present, if they had sexual contact with the patient during the 10 days preceding the patient’s onset of symptoms.5 Patients should be retested for syphilis and HIV 3 months after the diagnosis of chancroid if the initial test results were negative. In advanced cases, scarring can result, despite successful therapy.124,128,137

Granuloma Inguinale Clinical Background Granuloma inguinale (GI), also known as donovanosis, is an ulcerative STD caused by the intracellular gramnegative rod Klebsiella granulomatis (formerly Calymmato-

4

Fig. 4.23.

  Granuloma inguinale, presenting as a combination of hypertrophic mucosa with submucosal edema and focal ulceration. (From Hart G: Donovanosis: granuloma inguinale. In Rein M, editor: Atlas of infectious diseases, vol V: sexually transmitted diseases, Philadelphia, 1996, Churchill Livingstone, p 17.8.)

bacterium donovania). This organism was renamed based on comparative genomic studies.138,139 GI is endemic in tropical and subtropical countries, with only sporadic cases or small isolated epidemics occurring in Western countries.140,141 Very rarely, squamous cell carcinoma can arise in association with GI.142 The condition is sometimes more aggressive in pregnant women.142 Without treatment, ulcers in donovanosis may persist for many years, leading to complications such as pseudoelephantiasis of the vulva and stenosis of the urethral, vaginal, and anal orifices.143 Clinical Examination The disease presents as an erythematous papule or small nodule that ulcerates and is typically painless. The incubation period is variable and ranges from weeks to a few months. The lesions expand to form irregular beefy red ulcers that bleed easily on contact (Fig. 4.23). Multiple different clinical presentations and courses have been described, including ulcerative and scarring forms.144 Rarely, a hypertrophic variant characterized by large vegetating masses is encountered.67 Diagnostic Criteria Ancillary Tests The organism has been grown in specialized in vitro media.145-147 However, these specialized media are not readily available from commercial sources, and the organism is difficult to culture. The diagnosis generally requires detection of Donovan bodies on a tissue specimen or biopsy. 83

Diagnostic Gynecologic and Obstetric Pathology

A

B

Fig. 4.24.  A, Low-power view of inflammation in granuloma inguinale exhibits pseudoepitheliomatous hyperplasia and intense submucosal inflammation, corresponding to the clinical presentation (see Fig. 4.19). B, Donovan bodies are discrete cytoplasmic vacuoles containing organisms (arrow), seen here on H&E staining.

There are no FDA-approved molecular tests to detect K. granulomatis DNA to date.141,148 A serologic test using indirect immunofluorescence has been developed, but the sensitivity is low.141 Histologic Features Histologic sections reveal an exuberant inflammatory infiltrate consisting of neutrophils, plasma cells, macrophages, and scattered lymphocytes (Fig. 4.24A). Although the pattern of inflammation is nonspecific, some of the macrophages have conspicuous vacuoles containing rodshaped organisms (Donovan bodies) that can be seen by conventional H&E staining or with Warthin-Starry or Giemsa stain (see Fig. 4.24B).67 Extracellular organisms may also be seen and can be identified in scrapings from the ulcer bed.141 The edges of the ulcer, where biopsies are often obtained, invariably show acanthosis. Pseudoepitheliomatous hyperplasia can also be seen, which in some cases may be difficult to distinguish from squamous cell carcinoma. Differential Diagnosis The differential diagnosis includes lymphogranuloma venereum, syphilis, chancroid, herpesvirus infection, candidiasis, and genital amebiasis. Although it is less common in the United States, it is still important to consider GI and lymphogranuloma venereum (LGV) in the differential diagnosis. The demonstration of Donovan bodies is diagnostic for GI. Darkfield examination and serology will help exclude syphilis. The characteristic ballooning degeneration, nuclear viral inclusions, and multinucleated cells identify herpes. It is also important to remember that other STDs can also coexist with GI. 84

Treatment Treatment with antibiotics generally halts the disease progression of GI, but prolonged therapy may be required to permit granulation and re-epithelialization of the ulcers. Relapses may occur within 18 months, and patients should be followed clinically until signs and symptoms have resolved. Sexual partners who have had contact with the patient within 10 days before the onset of the patient’s symptoms should be examined and offered therapy. It should be noted that patients with HIV infection should be followed closely because they are less likely to respond to treatment than HIV-negative patients.148

Lymphogranuloma Venereum Clinical Background LGV is caused by C. trachomatis serovars L1, L2, or L3. LGV is a rare disease in industrialized countries but is endemic in parts of Africa, Asia, South America, and the Caribbean. However, LGV has been in the spotlight recently because of outbreaks in the United States and Europe. These outbreaks have been regarded as unique because most cases have been caused by the L2 strain and occurred in HIV-positive homosexual men who presented with proctitis.149,150 In addition to HIV, other risk factors include concurrent ulcerative disease, history of sexually transmitted infection, and unprotected sex; proctitis and proctocolitis are the most common clinical manifestations.151 The clinical course can be divided into three stages—the primary stage involves the site of inoculation; a secondary stage involves the regional lymph nodes and sometimes the anorectum; and late sequelae that affect the genitals or rectum comprise the tertiary stage. Women and active

Infectious Disorders of the Lower Genital Tract male homosexuals may have proctocolitis or inflammatory involvement of the perirectal or perianal lymphatic tissues, resulting in fistulas and strictures. If untreated, long-term complications such as deep tissue abscess formation, strictures, fissures, and chronic pain may occur.150 Clinical Examination A self-limited genital ulcer sometimes occurs at the site of inoculation. However, by the time patients seek care, the ulcer usually has disappeared. The disease is also characterized by tender inguinal or femoral lymphadenopathy (commonly unilateral), with a classic groove sign due to the formation of matted lymph nodes along the course of the inguinal ligament.150 Diagnostic Criteria Ancillary Tests The diagnosis of LGV is traditionally made serologically (complement fixation titer > 1 : 64 or microimmunofluorescence titer > 1 : 256).152 However, the interpretation of serologic test results has not been standardized, and these tests have not been validated for clinical proctitis.150,152 Genital lesions, and other specimens such as rectal swabs and lymph node aspirates, can also be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection.154 Histologic Features Skin lesions may show ulceration associated with a mixed chronic and granulomatous inflammation. The biopsy of lymph nodes can reveal a characteristic stellate area of necrotizing inflammation surrounded by granulomatous and chronic inflammation. Acute inflammation with abscess formation is also associated with the stellate granulomatous area. Differential Diagnosis Many conditions are included in the differential diagnosis of LGV, such as incarcerated inguinal hernia, Hodgkin

A

4

disease, herpes, granuloma inguinale, mycobacterial disease, schistosomiasis, chancroid, syphilis, HIV, amebiasis, and Crohn disease. Treatment Fistulas, sinus tracts, and ulcerations may occur if treatment is not initiated. Lymphedema may occur, occasionally resulting in elephantiasis. Antibiotic therapy cures infection and prevents ongoing tissue damage, although a tissue reaction can result in scarring. Buboes may require aspiration through intact skin or incision and drainage to prevent the formation of inguinal and femoral ulcerations. Persons who have had sexual contact with the patient within 60 days before onset of the patient’s symptoms should be examined and tested.153

Other Rare Infections Periclitoral Abscess Clinical Background Periclitoral abscesses are rare. The abscesses can be unilateral or encompass the entire periclitoral area (Fig. 4.25). They have many different causes, and treatment is dependent on the particular cause, which includes infection, entrapped hair, Crohn disease, and complications from female circumcision.155,156 Ectopic breast tissue on the vulva has been seen to mimic a periclitoral abscess.157,157a Diagnostic Criteria Clinical Examination The periclitoral tissues appear inflamed. At times, it may be difficult to distinguish the clitoral tissue from the prepuce. Histologic Features Histopathologic examination reveals nonspecific acute inflammation, with abscess formation and/or granulomatous inflammation, depending on the cause.

B Fig. 4.25.

  A, A large abscess on the left prepuce is seen. B, Abscess in the superior right interlabial sulcus, with a focus of epithelial rupture.

85

Diagnostic Gynecologic and Obstetric Pathology Differential Diagnosis The clinical differential diagnosis includes ectopic breast tissue, inclusion cyst, angiofibroma, clitoromegaly, lipoma, epidermoid cyst, dermoid cyst, and pilonidal sinus involving the clitoris. Treatment For early infections, antibiotics may be successful for adequate treatment. The abscesses can be unilateral or encompass the entire periclitoral area. For persistent or recurrent abscesses, surgery may be required.158,159 When infection is present, the cause of the infection is not always identifiable. Any purulent drainage should be cultured.

Schistosomiasis Clinical Background Schistosomiasis is an infection by trematodes (a class of helminths) that belong to the superfamily Schistosomatoidae.160 There are three major species of schistosomes that are pathogenic to humans. They have distinct endemic geographic distributions and are associated with diseases of specific organ systems: Schistosoma haematobium, mostly in Africa and South America; Schistosoma mansoni, mostly in Africa and the Middle East); and Schistosoma japonicum, mostly in East Asia. The latter two are usually associated with disease of the gastrointestinal tract, whereas S. haematobium is associated with genitourinary disease.160-162 Schistosomiasis affects approximately 200 million people worldwide. It can affect different organ systems. Globally, about 9 to 13 million women are affected by genital lesions caused by schistosomiasis.161-163 It is endemic in Egypt and occurs in most parts of the Middle East. Female genital schistosomiasis is typically not encountered in immunocompetent American women without a significant travel history. Infection occurs after bathing in infected fresh water containing cercariae, which are the infective form of the parasite that is liberated into fresh water by the specific intermediate snail host. They penetrate unbroken skin and migrate as schistosomules through the venous circulation to the liver, where the adult worms mature. Symptoms may not appear until many months, sometimes years, after infection with the helminth.161-163 The vulva is usually affected in younger women. S. haematobium is the most common species involved. The infection can lead to tissue damage and destruction of the hymen or clitoris, incontinence, and vesicovaginal fistulae. Involvement of the labia majora rather than labia minora is more frequently seen because the ova gains easier access via the veins of the labia majora.164 Female genital schistosomiasis has been postulated to increase HIV acquisition.161 Calcified S. haematobium eggs in the genital tissue were found to increase density of HIV receptor CD4 cells, providing more entry cellular points for the virus.165 In addition, patients infected with S. mansoni were noted to have higher levels of HIV coreceptors in their peripheral blood mononuclear cells, suggesting increased susceptibility to HIV infection.166 In addition to HIV, schistosomiasis was also proposed to facilitate infection by other STDs, such as HPV, by facilitating its implantation via erosions and ulcerations of the cervical mucosa167 86

and interfering with viral clearance by downregulating CD8+ cytotoxic T cell and T helper type 1 (Th1) cell cytokine responses.168 Clinical Examination Symptoms and signs of vulvar schistosomiasis are swelling, ulceration (painful or painless), a nodular surface, pruritus, and a hypertrophic clitoris with an eroded granular surface. Papules or verruciform lesions are seen in patients from nonendemic areas. A sandy patch appearance, due to underlying eggs in the mucosa and associated with atypical blood vessels, has been described in the literature to be characteristic for mucosal infection in female genital schistosomiasis.161 Masses or tumors, ulceration and pain, clitoral hypertrophy, and vulvar swelling tend to occur in patients with more chronic infection.163 In general, the presence of lesions that are acetonegative, grainy or homogenous sandy patches, or rubbery tubercles, seen in women residing in or traveling from endemic areas, should raise suspicion for genital schistosomiasis.161 Diagnostic Criteria Ancillary Tests Immunodiagnosis by the detection of antibody or antigens may be used (e.g., ELISA, indirect hemagglutination, radioimmunoassay, Western blot, complement fixation).169 These tests are mostly not species specific. It is important to note that antibody titers do not reflect the parasite burden and do not distinguish prior from active infection. They remain positive despite treatment, making them unreliable for follow-up and disease monitoring. In addition, these tests are not useful for early acute infection because antibodies do not develop until 6 to 12 weeks after initial infection.170 Direct visualization of schistosome eggs is the diagnostic gold standard. Microscopic examination is performed on fresh crushed biopsies or histologic sections of formalinfixed tissue (Fig. 4.26).171,172 S. haematobium eggs are ovoid, average 150 × 50 µm in their largest dimension, and have a delicate terminal spine, as opposed to the pronounced lateral spine of S. mansoni or S. japonicum, which lacks a spine.

Fig. 4.26.

  Vaginal schistosomiasis. The mature organism burrows into the skin and is established within a vessel, into which the eggs are discharged.

Infectious Disorders of the Lower Genital Tract Histologic Features On histologic evaluation, immature schistosome eggs have a basophilic internal structure.173 The vulvar and vaginal polypoid or papillary lesions are composed of an acute, florid, inflammatory reaction to clusters of viable-appearing eggs (Fig. 4.27; see also Fig. 4.26).172 Granulomata and eosinophils are often seen (Fig. 4.28). A noncaseating

4

granulomatous reaction with epithelioid histiocytes and giant cells surrounded by a thin rim of lymphocytes may be seen. PAS stain will highlight the chitin in the shell of the ova. The extent of pathology depends on worm burden and timing of the infection. Eventually, the inflammatory granulomatous reaction results in local tissue destruction and fibrosis, with little cellular infiltrate, entrapping dead calcified eggs.167 Differential Diagnosis Condyloma, typhoid fever, strongyloidosis, trichuriasis, tuberculosis, and carcinoma are diseases considered in the differential diagnosis of schistosomiasis. The key to distinction is the presence of Schistosoma eggs and eosinophilic inflammation in schistosomiasis. Treatment Anthelminthic drugs are used, providing high cure rates for cutaneous and systemic infections caused by all species of Schistosoma. Lesions heal within a few weeks after administration. A follow-up urine or stool examination within 3 months is advised to assess the efficacy of therapy.161,162

Epstein-Barr Virus

Fig. 4.27.  Low-power view of schistosomiasis showing epithelial hyperplasia, marked chronic inflammation, and a few ova in this section.

Clinical Background Epstein-Barr virus (EBV) is a human herpesvirus and a rare cause of genital ulceration.174-182 EBV vulvitis with vulvar ulceration has been known as Lipschütz disease, as it was described in 1913 by Benjamin Lipschütz. Other terms seen in the literature include ulcus vulvae acutum, acute genital ulceration, and reactive nonsexually related acute genital ulcers.182 Generally, these patients are in their teens to early 20s. Genital contact is not a prerequisite for the development of infection. In many of the cases reported, the ulcers occurred in young females before the onset of genital or oral sexual activity. Interestingly, the acutely painful genital ulcers often presented before the onset of any other features of infectious mononucleosis.181 Clinical Examination An acute infection is associated with a sore throat and painful punched-out ulcers (purple-red edges) on the vulva, with lymphadenopathy distant from the site of ulceration and fever. Diagnostic Criteria Ancillary Tests Confirmation of the diagnosis of EBV can be made by serology (the presence of immunoglobulin M [IgM] to the EBV viral capsid antigen) or the detection of EBV DNA by PCR examination of vulvar swabs. A culture of EBV can take more than 4 weeks to become positive. This test is not performed routinely.

Fig. 4.28.  At higher power, schistosome organisms are admixed with marked inflammatory infiltrate. They may also be calcified.

Histologic Features The histopathologic findings are nonspecific. Ulcerated lesions will reveal acute and chronic inflammation, whereas nonulcerated areas associated with the rash clinically show 87

Diagnostic Gynecologic and Obstetric Pathology

A

B Fig. 4.29.

  Necrotizing fasciitis. A, Ulcerative lesion associated with Pseudomonas infection. B, Severe debilitating example of necrotizing fasciitis of the thigh tissue with extension to the vulva.

a mild, superficial, perivascular chronic inflammatory infiltrate. Clinical Differential Diagnosis and Treatment The differential diagnosis includes aphthous ulcers, Behçet disease, HIV, chancroid, herpes, Crohn disease, syphilis, and a drug reaction. In the child or adolescent, once these conditions are excluded, EBV should be considered.70 The infection is not reported to recur, and ulcers normally resolve in 2 weeks. Thus, therapy is supportive.

Necrotizing Fasciitis of the Vulva Clinical Background Necrotizing fasciitis (NF) of the perineum and abdominal wall, along with the vulva in women (also known as Fournier gangrene), is an aggressive, rapidly progressive infection of the subcutis and underlying fascia.181-187 NF of the vulva is usually seen in the setting of diabetes.181,182 Obesity, peripheral vascular disease, hypertension, and immune compromise are also often associated with NF. A history of prior radiation to the site or a local infection is sometimes elicited. NF may develop after skin biopsy, at needle puncture sites in cases of illicit drug use, at sites of traumatic puncture wounds, after episodes of frostbite, in chronic venous leg ulcers, at sites of open bone fractures, and in insect bites, surgical wounds, and skin abscesses. However, in many cases, no association with these factors can be made. Sometimes, there is no history of trauma.181-184 Most cases (80%) of NF are polymicrobial infections, and 20% are caused by a single organism, usually Streptococcus or Staphylococcus. In polymicrobial infections, frequently implicated organisms include group B hemolytic Streptococcus, Enterococcus faecalis, Escherichia coli, Bacteroides and Klebsiella spp., Staphylococcus aureus, and mixed anerobes.188 A high index of suspicion is necessary for the timely diagnosis of this disease. Early radical treatment appears to improve outcome. Mortality has been reported to range from 25% to 75%,181-184,189 but a lower mortality rate of 0% to 40% has been documented.190 NF has been documented following cesarean section. Cases have also been reported following episiotomy and tend to involve the perineum.182 88

Clinical Examination NF can have an insidious onset, with localized erythema, pain, and edema often forming a rapidly advancing front. Marking the border with a pen at presentation and following its advance will assist in demonstrating its rapid progression and may be a helpful diagnostic exercise. Initially, the skin is intact. Over time, the skin will break down with ulceration, expression of a gray to clear exudate, necrosis, and sloughing of the skin (Fig. 4.29). Crepitation can sometimes be demonstrated. Systemic signs and symptoms such as fever, malaise, and confusion are present only late in the disease process.185 Diagnostic Criteria Histologic Features Because early recognition of NF is critical for improving outcome, histologic examination of frozen section material is often used to aid diagnosis and justify prompt radical surgery. The histologic findings are nonspecific, and clinicopathologic correlation is necessary to establish the diagnosis. The histologic findings may vary from area to area. The advancing front may show scant acute inflammation. Sometimes, sheets of bacteria with little or no associated inflammation are present in the subcutaneous tissue (Fig. 4.30A). In such biopsies, Gram staining may assist in diagnosis, particularly with frozen section (see Fig. 4.30B). Other areas may show suppurative inflammation, with abscess formation extending along fascia and subcutaneous septae. In addition, acute inflammation may also spill over to involve fat lobules. Eccrine glands and ducts may show necrosis. Skeletal muscle, when present, may also be involved. Vessels with fibrin thrombi are a common secondary phenomenon. Differential Diagnosis As discussed previously, it is important to remember that there are no pathognomonic features of NF. Certain histologic features are suggestive, but ultimately clinical correlation is required. It is important not to mistake superficial cellulitis or pyoderma gangrenosum for NF. However, knowing that NF extends to involve fascia, in contrast to cellulitis and pyoderma gangrenosum, in which

Infectious Disorders of the Lower Genital Tract

A

4

B Fig. 4.30.  A, Histopathology of necrotizing fasciitis, showing necrosis of skeletal muscle and collagen with acute inflammatory exudate. B, Gram stain depicts many gram-positive cocci.

the epicenter of the disease is dermal, should prevent this potentially catastrophic error.

Table 4.3  Infections Altered by Immunosuppression Infectious Disease

Special Concerns for HIV Population

Chancroid

Large lesions, extragenital lesions, delayed healing, treatment failure

Granuloma inguinale

Persistent ulcers, higher antibiotic requirement

Lymphogranuloma venereum (LGV)

A cluster of LGV among homosexual men in Rotterdam has been reported

Syphilis

Rapid progression, refractory to therapy, atypical serology including false-positive responses to the rapid plasma reagin card test and Venereal Disease Research Laboratory (VDRL) test

Chlamydia

Increased transmission

Gonorrhea

Increased transmission

Bacterial vaginosis

Refractory to treatment, enhances HIV transmission

Trichomoniasis

Proposed cofactor in amplifying HIV transmission

Vulvovaginal candidiasis

Higher vaginal Candida colonization rates, proportional to the level of immunosuppression

Folliculitis (eosinophilic pustular folliculitis)

Occurs in more advanced stages of HIV infection, usually with a CD4 count < 200 cells/mm3

Treatment Early diagnosis and aggressive surgical management are ideal for treating NF. Cases with sepsis and renal failure have a mortality rate as high as 70%. Once the diagnosis of NF is confirmed, treatment should be initiated without delay; it includes antibiotic coverage for aerobic and anaerobic organisms, thorough surgical débridement, and intensive supportive care.188

Common and Rare Vulvar Infections Associated With Immune Suppression Patients may be immunosuppressed for many different reasons, and this population is at risk for infectious diseases, including the more common infections that affect immunocompetent individuals (Table 4.3).110,130,191-199 A classic condition for immunosuppression is found with HIV infection. HIV or HIV-induced immunosuppression may modify the presentation and course of select STDs. The HIV epidemic has altered the field of STDs.196 In particular, multiple concurrent STDs have been found in HIV-positive patients. An increasing recognition of the ways in which STDs influence HIV transmission has underscored the importance of early detection and treatment of all STDs.199-201 Many common conditions are seen in HIV-infected women, including bacterial vaginosis and T. vaginalis.202 HPV infection is also usually detected and is more likely to be persistent in HIV-infected compared with uninfected women.203 The association between HIV infection and vaginal candidiasis is controversial.204-206 A prospective study of cohorts of HIV-infected and uninfected women has shown no difference in the prevalence of vaginal C. albicans colonization unless there was immunosuppression. In this case, the rates of colonization and symptomatic infection tripled.206 The proportion of non-albicans isolates did not differ among groups. In this study, Candida colonization

Data from references 50, 110, 130, 191–195, 199, and 206.

was not associated with antibiotic or oral contraceptive use. In contrast, in a cross-sectional study of patients referred to a vaginitis clinic, HIV was associated with non–C. albicans infection.207 Data from large cross-sectional studies have shown a similar prevalence of T. vaginalis and bacterial vaginosis among the HIV-infected and uninfected participants and no association with the CD4+ cell counts.208-210 Vulvar, vaginal, and anal intraepithelial neoplasia appear to be prevalent among women infected with HIV.211-215 89

Diagnostic Gynecologic and Obstetric Pathology

Tuberculosis Clinical Background Tuberculosis (TB) results from infection with Mycobacterium tuberculosis or Mycobacterium bovis. Although the incidence of tuberculosis has declined greatly over the past century in developed countries, it is not uncommon and still results in considerable morbidity, particularly in the setting of immunosuppression, with HIV-1 infection being the most common risk factor for developing active TB. The most common site of infection is the lung. Involvement of the female genitalia is mostly seen in endemic areas, with the fallopian tube being the most common site of infection, which spread to the endometrium in 60% of the cases in an endemic retrospective study.216 Involvement of the vulva, vagina, and cervix is less common. Most patients with genital TB present with abdominopelvic pain, menstrual irregularity, or infertility in chronic cases. Coexistence with carcinoma in the female genital tract has been documented in rare cases.217,218 Vulvar TB can occur at any age. It presents mainly with ulcers but, in rare cases, it can cause elephantiasis of the vulva as a result of lymphadenitis219 or occurs as a mass mimicking carcinoma.220 Clinical Examination Cutaneous TB is categorized as primary or secondary.221 Primary lesions are due to direct inoculation of mycobacteria. In the unexposed host, small papules develop into painless ulcers that may heal but become indurated with time, a process termed primary inoculation tuberculosis. The lesions are sometimes called tuberculous chancres. In a previously exposed host, inoculation results in TB verrucosa cutis, also called warty TB. In this condition, papules become hyperkeratotic and eventually involute with scarring over a period of years. This form of disease can be seen in patients who have been inoculated with bacillus Calmette-Guérin (BCG) vaccine and then retested for exposure to TB.221 These lesions are quite rare in the vulva, although cases of venereal transmission have been documented.222 Secondary cutaneous TB is more prevalent and shows two forms of disease—lupus vulgaris and scrofuloderma.221 Lupus vulgaris is seen in the setting of pulmonary TB with hematogenous spread and presents as expanding hyperkeratotic papules with an ulcerated center. The lesions persist indefinitely, with slow expansion. In scrofuloderma, skin involvement is by direct extension from underlying infected bone or lymph nodes. Firm, painless, subcutaneous nodules emerge that eventually ulcerate. Ultimately, sinusoidal tracts undermine the skin as the lesion spreads, resulting in scarring. Vulvar involvement appears to be primarily of the lupus vulgaris type.223,224 Diagnostic Criteria Histologic Features The hallmark of involvement by TB is the presence of necrotizing granulomata—collections of epithelioid histiocytes and Langerhans-type giant cells that are associated with an inflammatory cell infiltrate composed of variable numbers of lymphocytes and neutrophils. Central (case90

BOX 4.3  Differential Diagnosis of Granulomatous Vulvitis Syphilis Lymphogranuloma venereum Mycobacteria Fungus Bacillary angiomatosis Folliculitis

Ruptured pilosebaceous unit Ruptured cyst Crohn disease Vulvitis granulomatosa Hydradenitis suppurativa

ation) necrosis is a frequent feature but is not invariable, and other causes of granulomatous inflammation must be considered (Box 4.3). Acid-fast bacilli may be demonstrated using a Ziehl-Neelsen (AFB) stain. PCR-based molecular testing is also available.221-226 Organisms can be difficult to demonstrate, and an extensive search is often required. Pseudoepitheliomatous hyperplasia can be seen at the edge of the tuberculous ulcers. Differential Diagnosis Although vulvar TB is rare, it is sometimes encountered in endemic areas.224 It is important to differentiate vulvar TB from other ulcerative conditions, particularly venereal diseases, because treatments differ widely for these conditions.222 Serologic investigations and special stains can be used to demonstrate the various organisms causing herpes infection, syphilis, or chancroid. The presence of caseating granulomata in inguinal lymph nodes or genital vulvar or mucosal tissue is highly suggestive of TB. Caseating granulomatous inflammation differentiates TB from metastatic Crohn disease, another granulomatous and ulcerating condition of the vulva that is characterized by noncaseating granulomas. Stains for microorganisms, including AFB, PAS, and Gomori methenamine silver (GMS) stains, can be used to facilitate evaluation. Correlation with tissue culture is essential for establishing the diagnosis. The clinical differential diagnosis also includes schis­ tosomiasis, fungal infections, vulvar intraepithelial neo­ plasia, dermatitis herpetiformis, erythema nodosum, lichen planus, lupus erythematosus, pustular psoriasis, pyoderma gangrenosum, squamous cell carcinoma, syphilis, and hidradenitis suppurativa. Treatment Treatment involves the long-term administration of combinations of isoniazid, rifampin, ethambutol, and pyrazinamide, which are the first-line drugs for the treatment of TB.227 Multidrug-resistant strains have been emerging and are a source of great concern.228,229 Although medical therapy is sufficient for early disease in vulvar TB, surgical removal may be needed if there is extensive disease.

Bacillary Angiomatosis Clinical Background Bacillary angiomatosis (BA) is an opportunistic infection that occurs in the setting of immunosuppression and was first recognized in patients with HIV-AIDS.230 The causative organism is Bartonella henselae or Bartonella quintana. Both

Infectious Disorders of the Lower Genital Tract of these bacteria also cause cat scratch disease in immunocompetent hosts, and cases of BA are often associated with recent contact with a cat.231 Rare cases have been documented in immunocompetent individuals.232 Clinical Examination The mucocutaneous lesions present as red papules or nodules with a smooth surface that increase in size. Lesions can be single or numerous and sometimes ulcerate. Deeper subcutaneous lesions may also be seen and tend to be pink or flesh-colored. If not treated with appropriate antibiotics, the disease can become widely disseminated, with significant morbidity and mortality. Vulvar involvement is rare but has been reported.233,234

A

4

Diagnostic Criteria Histologic Features In immunocompetent individuals, cat scratch disease shows that a suppurative granulomatous response is mounted, particularly in draining lymph nodes, resulting in the characteristic necrotizing granulomatous response, often in a stellate configuration. In immunocompromised individuals, this response does not occur; instead, the characteristic vascular proliferation of BA is seen. Capillaries with plump histiocytoid endothelial cells that protrude into the luminal space are seen. In addition, endothelial cells, not associated with vascular lumina, are present in an edematous stroma. Conspicuous neutrophils and karyorrhectic debris are invariably present throughout the lesion (Fig. 4.31A and B). Clusters of bacilli can sometimes

B

C Fig. 4.31.

  A, Bacillary angiomatosis, seen as a mucosal ulcer with underlying inflammation. B, Neutrophils and debris in an edematous background are characteristic features. C, A Warthin-Starry stain highlights clumps of short, thick bacilli.

91

Diagnostic Gynecologic and Obstetric Pathology be seen with H&E stain but are much better visualized using a modified Warthin-Starry or other silver stain (see Fig. 4.31C). Bacillary angiomatosis may involve extracutaneous sites, including the liver, spleen, lymph nodes, gastrointestinal tract, peritoneum, diaphragm, brain, soft tissue, and bone marrow. Involvement of the liver is characterized by so-called peliosis—the presence of cystic, blood-filled cavities distributed randomly throughout the liver parenchyma. Differential Diagnosis Differentiation from Kaposi sarcoma (KS) is important because this condition often occurs in a similar patient population. However, KS is extremely uncommon in women. Although slitlike vessels may be seen in BA, this is a focal finding, when present (Fig. 4.32A and B). The abundant neutrophils and karyorrhexis in an edematous

A

background argue against KS. Nuclear staining for herpesvirus type 8 (HHV-8)–associated proteins can be demonstrated in cases of KS (see Fig. 4.32C). An ulcerated pyogenic granuloma (PG; lobular capillary hemangioma) may also be confused with BA (Fig. 4.33); however, the neutrophilic infiltrate tends to be limited to areas adjacent to the ulcerated surface in PG, whereas it is more diffuse in BA. Furthermore, bacillary angiomatosis generally lacks the well-developed lobular architecture of PG. Using a silver stain to look for organisms will assist in the diagnosis. Angiosarcoma is readily excluded by the lack of marked cytologic atypia and an infiltrative growth pattern. Treatment Antibiotic therapy (e.g., erythromycin) will typically result in significant clinical improvement after 4 to 7 days of

B

C Fig. 4.32.  A, Low-power histology of Kaposi sarcoma, showing prominent vascular proliferation. B, At higher power, numerous vascular spaces are seen. C, Herpesvirus type 8 is strongly positive. 92

Infectious Disorders of the Lower Genital Tract

A

4

B Fig. 4.33.

  A, Lobular capillary hemangioma (LCH) closely resembles granulation tissue at low power, forming a discrete unit fed by a single vessel. B, Uniform vascular network devoid of inflammation seen in LCH.

therapy, with complete resolution within 3 to 4 weeks.235 Patients with extensive skin or mucosal lesions, lytic bone lesions, or visceral disease may require prolonged treatment.236

Chronic Erosive Genital Herpes Clinical Background Herpes and HIV may be found in association with each other,199 which was noticed as early as 1981.237 Chronic HSV-2 ulcers of longer than 1 month’s duration are an AIDS-defining illness in HIV-infected patients.238,239 Several case reports have described HSV-2 presenting as hyperkeratotic verrucous lesions resembling condyloma in severely immunocompromised patients.240-242 Although genital herpes is usually caused by HSV-2, an increasing number of cases are suspected to be caused by HSV-1.68,69 In HIV-infected patients, severe, atypical clinical presentations often occur. Interaction between HIV and HSV may be associated with an increased size and number of lesions, as well as chronic and highly infectious herpetic ulcers.243 These may persist for several months and are likely to occur on a frequent basis.244 The vesicles and ulcers are more painful and heal slower than those experienced by an immunocompetent host.245 Co-infection with other viruses, such as CMV, may occur.246 As CD4 cell counts decrease and immunosuppression worsens, recurrent outbreaks increase in frequency and severity.247-250 Treatment Treatment of the HIV-positive patient is similar to non–HIVinfected patients but may require increased doses of antiviral medications. Suppressive therapy for HSV appears to improve survival significantly in HIV-positive patients. If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected, and a viral isolate should be obtained for sensitivity testing. Management of these patients should be with a specialist, and an alternate therapy should be administered.

Varicella-Zoster Disease Clinical Background Primary varicella or chickenpox is a common childhood infection caused by VZV, an alpha herpesvirus. It is closely related to HSV types 1 and 2. In the United States and Europe, most adults who have HIV infection have previously been infected with VZV or have been vaccinated. In primary VZV infection, the rash appears 10 to 21 days after exposure. VZV may be recurrent and severe, with more than one dermatome involved in the patient infected with HIV. A lengthened course associated with residual postherpetic neuralgia and scarring may occur. The infection can be more severe in this population, and the disease may sometimes be fatal.251 Clinical Examination In primary infection, lesions progress from small erythematous macules to papules and vesicles. These vesicles later ulcerate, dry, and form crusts (Fig. 4.34). Lesions at all stages are characteristic. Secondary infection (herpes zoster or shingles) is an acute vesiculobullous infection caused by reactivation of VZV dormant in the nerve cell bodies or non-neuronal satellite cells of dorsal root or autonomic ganglia, as well as cranial nerves. It often occurs many years after initial infection with VZV (chickenpox). Symptoms include pain or paresthesia, itching, burning, or tingling, with or without headache and fever. There may be long-term postherpetic neuralgia with chronic pain in that dermatome, resulting in long-term vulvar pain, and clitorodynia. This can be very confusing if the primary condition has been missed. Diagnostic Features Histologic Features VZV and HSV cannot be reliably distinguished by routine light microscopy because both have similar nuclear inclusions and degenerative changes (Fig. 4.35A and B). Immunohistochemistry can be used to distinguish these infections (see Fig. 4.35C). The histopathologic features 93

Diagnostic Gynecologic and Obstetric Pathology

Fig. 4.34.

  Varicella-zoster virus involving the anogenital region and buttocks—unilateral dermatomal distribution. There is a mixture of erosions (center right), erythematous papules (center), vesicles, and blisters (left).

A

of secondary infections are similar to those seen with primary herpes infection, although the degree of inflammation is sometimes less profuse. Treatment of Varicella-Zoster Infection in HIV-Infected Patients Higher concentrations of acyclovir are required to inhibit replication of VZV than replication of HSV. Acyclovir is used for disseminated or visceral VZV infection. It is important to monitor renal function. For acyclovir-resistant VZV infection, foscarnet is used.

B

Extensive Genital Warts in the Immunosuppressed Patient Clinical Background Genital HPV infections occur more commonly in immunosuppressed patients when compared with control populations. In the HIV patient, many of the lesions tend to be diffuse and subclinical.211,252 Also, HIV-positive patients tend to be infected with more HPV types than control populations.213,214,253,254 The shedding of HPV and the extent of disease increase as CD4 cell counts decrease.255 HIV-infected patients’ condylomas may be associated with lesions containing higher risk HPVs; these patients require close follow-up and biopsy of any suspicious areas. It is recommended that as part of every gynecologic examination, these women have a thorough inspection of the vulva and perianal region, and any abnormalities other than the classic exophytic condylomata acuminata should undergo colposcopy and biopsy.212,256 Treatment The treatment for vulvar condyloma in the immunosuppressed patient does not differ from that in the normal population. HIV-positive patients may have more extensive disease than HIV-negative patients (Fig. 4.36). Often, they 94

C Fig. 4.35.

  Varicella-zoster virus. A, At low power, there is pronounced submucosal edema and epithelial hyperplasia. B, Inclusions are conspicuous at higher power, similar in appearance to herpes simplex. C, Immunohistochemical staining for zoster will discriminate this from herpes simplex.

have a delayed response to treatment, and more frequent recurrences are noted. Treatment options available to the HIV-infected host do not differ from those available to the immunocompetent host previously discussed. Both surgery and

Infectious Disorders of the Lower Genital Tract

Fig. 4.36.

 

Extensive vulvar condylomata acuminata.

4

Crusted scabies is characterized by a high mite burden and the presence of thickened skin crusts. Recrudescence and re-infestation are frequent.10 An immunocompetent host is estimated to have 10 to 15 live female mites during an infestation, whereas individual crusts in crusted scabies may harbor thousands of mites.10 It has been proposed that the pathogenesis of crusted scabies may be due, in part, to an imbalanced inflammatory response in the dermis of lesional skin. A CD8+predominant T-cell lymphocytic infiltrate, with minimal CD4+ T cells and absence of B cells, was found in one study, despite normal proportions of B- and T-cell lymphocytes (and subsets) in the blood of the same patients, suggesting preferential movement of CD8+ T cells into the dermis. Nonetheless, the pathogenesis of crusted scabies remains poorly understood.283 Clinical Examination

immunomodulatory approaches have been used based on the clinical scenario and clinician preference. The better the HIV control, the more successful the condyloma treatment.257-264

Patients with crusted scabies have pruritus associated with skin lesions containing thick friable plaques that are often associated with fissuring. As the lesions become more crusted, the pruritus decreases. Recurrent episodes can result in considerable depigmentation in the skin.10

Disseminated Molluscum Contagiosum

Differential Diagnosis The differential diagnosis consists of eczema, psoriasis, contact dermatitis, drug reactions, seborrheic dermatitis, Darier disease, and dermatophytosis.

Clinical Presentation Since the late 1970s, the incidence of MC has been increasing, mainly as an STD, and it is particularly rampant as a result of concurrent HIV infection.265,266 In the HIV patient population, MC usually manifests itself when immune function has been dramatically reduced. Several studies have documented that MC infection is a clinical sign of marked HIV progression and very low CD4 cell counts.267 Numerous lesions on a patient who is not yet diagnosed with HIV disease should prompt discussion of an HIV test.137 The presentation of MC in the HIV-positive patient may be quite atypical, so diagnosis often requires a biopsy.268 Treatment MC in HIV-positive patients is notoriously difficult to treat.269 Unlike otherwise healthy hosts, there is no evidence that lesions spontaneously resolve and may require one of a variety of traditional methods, with varied success.260,270-277 Success is ultimately linked to optimal treatment of the underlying HIV infection.

Treatment The CDC recommendation for HIV-infected patients with crusted or papular scabies is “consultation with an expert” because the disease will invariably require a range of topical and oral medications.284,285 No controlled therapeutic studies for crusted scabies have been conducted, and the appropriate treatment remains unclear. Substantial treatment failure might occur with a single topical scabicide or oral ivermectin treatment and requires aggressive therapy.87 Crusted scabies is associated with greater transmissibility than scabies. Substantial treatment failure might occur with a single topical scabicide or with oral ivermectin treatment. Combined treatment with a topical scabicide and oral ivermectin or repeated treatments with ivermectin has been used.284,285

Crusted (Norwegian) Scabies

KEY POINTS

Clinical Background Crusted scabies, also known as Norwegian scabies or scabies crustosa, is a florid infestation that usually occurs in immunodeficient, debilitated, or malnourished patients. Patients at risk for developing crusted scabies include those who are receiving systemic or potent topical glucocorticoids, organ transplant recipients, patients with mental retardation or who are physically incapacitated, HIV-infected or human T lymphotropic virus-1 (HTLV-1)-infected persons, and those with various hematologic malignancies.199,278-280 As the CD4 cell counts decline, more severe and unusual infestations occur.281,282

• The most common vulvovaginal yeast infection is Candida albicans. It generally responds to oral fluconazole. • Fungal stains should be used in any psoriasiform dermatitis, spongiotic dermatitis, or lichen simplex chronicus because fungal infection mimics these conditions. • Bacterial vaginosis has a vaginal pH higher than 4.5, with the wet prep or Pap smear containing clue cells. There is an absence of lactobacilli and white blood cells. A foul-smelling discharge is almost always present. 95

Diagnostic Gynecologic and Obstetric Pathology • Trichomonas has a vaginal pH higher than 4.5, with a wet prep containing numerous white blood cells. A foul-smelling discharge is often present. • In the United States, approximately one of five adults is serologically positive for HSV-2. More than 50% of individuals who are seropositive do not experience clinically apparent outbreaks, but they still have episodes of viral shedding and transmit the virus. • Recurrent herpetic outbreaks occur in 50% of infected women and are significantly higher in those with HSV-2 versus HSV-1 infection. • Syphilis must be excluded in the setting of any unexplained pseudoepitheliomatous hyperplasia, with or without an accompanying ulcer. Plasma cells may be much less conspicuous in primary lesions. • Chancroid is strongly associated with HIV infection in underserved countries. • VZV and HSV cannot be distinguished by routine light microscopy. • Chronic erosive herpes can present as slow-healing ulcers or hyperkeratotic verruciform lesions.

Please see the Appendix for suggested ICD-10 codes.

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