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.

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. 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.

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.

Histologic Features

The lesions of scabies are occasionally biopsied when clinical diagnosis cannot be confirmed. The female mite 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.

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.

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.

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. Although most cases of VVC (up to 90%) are caused by Candida albicans , the incidence of VVC caused by non- albicans species (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. Recognition of these non- albicans species is important because they can be more resistant to the traditionally used azole antimycotics.

VVC is uncommon before menarche, with a rapidly increasing incidence late in the second decade, peaking in the third and fourth decades. 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. For a smaller percentage of women (~5%–10%), the condition will become chronic, with multiple relapses over several years. 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.

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. 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, with the proportion rising to 30% in pregnancy. 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 ).

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

Diagnostic Criteria

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 ”).

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.

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. The various other species of Candida cannot be differentiated by light microscopy.

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 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 antifungal agents are the mainstay of therapy, and numerous preparations are available.

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. 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.

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.

Diagnostic Criteria

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, 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.

Treatment

Topical antifungal agents of the imidazole or allylamine family are generally used for the treatment of tinea cruris. At times, systemic administration of antifungals is needed for patients unable to use topical treatments consistently or those with extensive or recalcitrant infection.

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. It is thought that BV results from the presence of a multispecies vaginal biofilm in which G. vaginalis is the predominant species. 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.

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. 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), as well as preterm births, and pelvic inflammatory disease. 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.

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. These have been slightly modified according to subsequent work by Eschenbach et al. to improve the accuracy of these criteria :

• 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.

• 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.

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. 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%.

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 women ; 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), with good sensitivity (up to 95%) and specificity (up to 99%) using clinical criteria as the diagnostic standard. 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.

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 ).

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%), and the absence of BV on a Pap smear does not necessarily rule out disease.

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.

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. 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.

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. The hair shaft is frequently in the center of the pustule ( Fig. 4.7A ). The most common pathogen associated with folliculitis 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.

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

Diagnostic Criteria

Treatment

Topical antibiotics can be administered to accelerate the healing process of superficial follicultis. Oral antibiotics are generally used in the treatment of deep folliculitis.

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 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), or use DNA hybridization probes (e.g., AFFIRM VP III), with good sensitivity and specificity.

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.

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).

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 ).

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

Differential Diagnosis

The clinical differential diagnosis of trichomoniasis includes candidiasis, bacterial vaginosis, desquamative inflammatory vaginitis, gonococcal infections, pelvic inflammatory disease, and urethritis.

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. There are four main subtypes of molluscum contagiosum—MCV-I, -II, -III, and -IV —identified by restriction fragment length polymorphisms of their genomes. MCV-1 is the most common subtype in immunocompetent patients, and MCV-2 has been reported to be more common in HIV-infected patients. 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. 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. 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.

Clinical Examination

The clinical appearance of MC is diagnostic in most cases. The characteristic lesion is a discrete, dome-shaped, flesh-colored 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.

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.

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 (Henderson-Patterson or molluscum bodies) become visible several layers above the basement membrane and, as the cells mature, the eosinophilic or cyanophilic oval viral inclusions (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.

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) .

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. 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. Curettage, cryotherapy, and topical agents are commonly used options for the treatment of MC.

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. HSV-1 has been increasing in cases of genital herpes, especially among young women and men who have sex with men (MSM). In the primary infection, there is no difference in clinical presentation between HSV-1 and HSV-2.

An increased prevalence is seen in the black, non-Hispanic population. Genital herpes infection is also associated with an increased number of lifetime sex partners and the presence of other STIs. 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. HSV-2 genital infections, particularly recent ones, have been associated with an increased risk for HIV-1 infection in multiple studies.

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. 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.

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. 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. Extragenital complications have been reported in a minority of patients with primary herpes infection, including distant skin lesions, aseptic meningitis, and urinary retention syndromes.

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 ). 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 ).

Primary herpes simplex virus infection of the vulva, with a broader distribution of mucosal ulceration and edema.

(Courtesy Mark Pearlman.)

Herpetic ulcers with yellow-white bases.

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. 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. 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)

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%, 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 enzyme-linked 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.

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 ).

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

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.

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. 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.

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) .

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 extensive erosive candidiasis, along with other disorders ( Box 4.2 ).

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

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.

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.

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. In the United States, gonorrhea is the second most common STI, with 333,004 cases reported in 2013, 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. 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.

Risk factors for gonorrhea include young age, multiple or recent sex partners, low socioeconomic status, history of previous gonorrhea, and minority ethnicity. Co-infection with Chlamydia is common. In some studies, gonorrhea has also been shown to be associated with HIV transmission and acquisition and was postulated to increase HIV viral production via activation of HIV-infected CD4 cells and an alteration of the CD8 cellular response.

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). Untreated gonorrhea can progress to pelvic inflammatory disease, perihepatitis, chronic pelvic pain, and infertility.

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.

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 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.

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. Chancres are painless unless traumatized or superinfected. Vulvar lesions also have a tendency to become superinfected, resulting in more painful chancres. 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 scarring, 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.

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.)

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. 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. It has been estimated that up to 7% of syphilis cases seen in HIV patients may meet certain criteria, including the following: (1) strongly positive rapid plasma reagin (RPR) titer; (2) severe Jarisch-Herxheimer reaction (acute febrile illness within the first 24 hours of initial treatment); (3) characteristic gross and microscopic morphology; and (4) rapid resolution of the lesions with antibiotics. These cutaneous lesions are often preceded by prodromal fever, arthralgia, and/or myalgia of variable intensty.

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. 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). 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. 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.

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.

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.

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. Gummas are nodules that sometimes ulcerate and have a soft consistency due to central necrosis.

Ancillary Tests

Testing for syphilis consists of the following modalities, with serologic tests being the mainstay for diagnosis.

Histologic Features

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 ). 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 cell endarteritis is seen more frequently (see Fig. 4.19C and D ). Spirochetes can be visualized with Warthin-Starry or immunohistochemical stains ( Fig. 4.20 ).

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