Epidemiology and clinical manifestations

Genital warts are caused by nonenveloped, double-stranded DNA-containing human papillomaviruses (HPV). The incidence of HPV infection has risen very rapidly in the United Kingdom and somewhat less rapidly in the United States¹. The estimated lifetime incidence of visible genital warts in women is about 4%². The annual incidence of genital warts in the United States, based on private office visit reports, is somewhat less than 1%¹. These data reflect only clinically apparent HPV infections. It is estimated that the prevalence of clinically inapparent external genital infections is about 13% in women of all ages and about 22% in 20-year-old women³. Moreover, the cumulative incidence in young sexually active women over a 2–3-year period is greater than 40%³. Prevalence declines fairly rapidly with age, falling to about 10% by age 35³. These figures are similar to those reported for HPV infection of the cervix⁴. Taken together, these data suggest that HPV is the most common of all sexually transmitted infections.

From a standpoint of clinical morphology there are four major types of genital warts. Keratotic (common-type) warts are similar to those that occur on the hands and are “square” (5–10 mm in diameter and 5–10 mm in height). They have a rough, scaling surface, are skin-colored or slightly brown, and occur on the mons pubis, the upper inner thighs, and other dry regions of the anogenital area (Figure 19.1). Filiform (condylomata acuminata-type) warts are taller (10–20 mm) than they are wide (2–5 mm), are skin-colored or pink, have a “brush-like” filiform tip, and occur in the moist areas of the anogenital area. Flat-topped (papular) warts are wider (5–15 mm) than they are tall (2–5 mm), are smooth-surfaced, and occur anywhere in the anogenital region (Figures 19.2 and 19.3). Their color is highly variable: they may be skin-colored, pink, red, brown, or black (Figure 19.4). This type of wart may enlarge centrifugally or coalesce to form large plaques. Nodular (Buschke–Lowenstein-type) warts are spherical with a cerebriform or mammillated surface. They are skin-colored to pink and are usually smooth-surfaced (Figures 19.5 and 19.6).

Figure 19.1 Some genital warts show a verrucous, firm surface, as seen in this wart.

(Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-5), Churchill Livingstone.)

Figure 19.2 The term “condylomata acuminata” refers to genital warts such as these, which exhibit acuminata morphology.

Figure 19.3 Papular warts in the vestibule and perineal body and spiky, acuminata warts on perianal skin demonstrate the different morphologies of anogenital warts.

(Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-1), Churchill Livingstone.)

Figure 19.4 Hyperpigmented, flat warts, particularly when large, are a morphology especially likely to exhibit changes of intraepithelial neoplasia on biopsy. However, this wart was benign.

Figure 19.5 Very large warts are likely to exhibit neoplastic changes. This wart, in an immunosuppressed patient, showed changes of vulvar intraepithelial neoplasia 3.

Figure 19.6 Large, spherical warts should be biopsied to rule out the presence of verrucous squamous cell carcinoma (Buschke–Lowenstein tumor).

(Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-6), Churchill Livingstone.)

The first two types of warts have no malignant potential and do not require biopsy whereas the latter two types of warts can have malignant potential and thus may require biopsy.

Diagnosis and differential diagnosis

Genital warts can almost always be recognized on a clinical basis but, if there is uncertainty, a biopsy should be performed. Moreover, as indicated above, biopsy is almost mandatory for the flat-topped papular and the nodular types of warts in order to identify any dysplasia that might be present. In times past, acetic acid whitening was used to identify genital HPV infection but, as this was neither a sensitive nor specific test, it is no longer recommended.

Women with vulvar warts have a high likelihood of concomitant cervical HPV infection and, for this reason, visual inspection of the cervix coupled with cytology is required. When warts occur at the anal verge, anoscopy, possibly with cytology, is desirable for immunocompetent patients and is mandatory for those who are immunosuppressed.

The differential diagnoses for genital warts include vestibular papillomatosis, lymphangiectasia, skin tags, and molluscum contagiosum (Table 19.1). All of these are recognizable clinically. Vestibular papillomatosis consists of closely set, uniform-appearing, small, rounded papules occurring in a cobblestone-like pattern. This normal anatomic variant is only found in the vulvar vestibule. Skin tags are pedunculated, soft on palpation, smooth-surfaced, and primarily located on hair-bearing skin. Molluscum contagiosum are skin-colored to white, hemispherical, often umbilicated papules; they are also located primarily on hair-bearing skin.

Table 19.1 Genital Warts (Human Papillomavirus Infection)

Histology and laboratory tests

Biopsy of genital warts reveals characteristic features of koilocytosis (hyperchromatic nuclei with perinuclear vacuolization) and acanthosis (thickening of the epithelium with elongation of the rete ridges). Note that vacuolated cells are a normal finding in the outer portion of mucosal epithelium and that this normal finding is sometimes overread by pathologists as indicative of HPV infection. True koilocytosis extends into the mid and lower portions of the epithelium and is accompanied by dense staining of the nuclei.

Tests to identify specific HPV types are commercially available⁵. Proponents of such testing state that identification of high-risk HPV types gives useful prognostic information. However, these tests are expensive and limited in scope. The Centers for Disease Control (CDC) do not recommend the use of DNA testing to determine the HPV type⁶. HPV cannot be cultured and therefore the only laboratory approach available to identify and type these viruses requires use of primer-specific polymerase chain reaction (PCR) amplification of viral DNA.

Pathogenesis

Genital warts are caused by HPV. These DNA viruses are very small and only contain approximately 8000 base pairs. The DNA is double-stranded and found in the form of a closed circle. HPV DNA is enclosed in an icosahedral protein capsid. Nucleotide sequence is highly variable, resulting in the evolutionary development of more than 100 HPV types. Genital infections are caused by about 30 or 40 of these types. The genital HPV types are divided into two groups of low- and high-risk viruses based on the predilection to cause epithelial cancers. The most important members of the low-risk group are HPV 6 and 11. These two types account for more than 90% of external genital warts¹. The most important members of the high-risk group are HPV 16 and 18. They account for about 70% of cervical carcinomas⁷ and an even higher proportion of vulvar intraepithelial neoplasia. A dozen or more additional HPV types account for the remainder of HPV-related malignancies⁷.

Although DNA for the genital HPV types can be identified by PCR on fingers and inanimate objects such as specula, underwear, and laser plumes, epidemiological studies suggest that almost all genital infections in adults are spread by sexual contact¹. The average incubation period from the time of acquisition to the development of visible warts ranges from several weeks to several months. Not surprisingly, other concomitant sexually transmitted diseases are found in about 15% of patients with genital warts⁸. Studies suggest that condom use might protect against the acquisition of genital warts⁹. The role played by viral load, hormones, smoking, and male circumcision in the acquisition of HPV infection is controversial³.

The situation in children with genital warts is somewhat different. Development as a result of sexual abuse certainly occurs but vertical transmission from an infected vaginal birth canal is quite common, as is horizontal, nonsexual, transmission (Figure 19.7). It is important to recognize that the mode of acquisition in children cannot be determined by the clinical appearance, the anatomic site, or the specific HPV type. A careful and thorough history for the possibility of sexual abuse should always be obtained even though positive evidence for abuse is found in only a minority of such cases¹⁰.

Figure 19.7 Anogenital warts in children raise the possibility of sexual abuse, but young children are more often infected during delivery through a birth canal with human papillomavirus infection or innocuously from a caregiver.

HPV can only infect epithelial cells. The virus enters the epithelium at the basal layer of the epidermis where initial replication occurs. Additional replication occurs in the suprabasal layers and, eventually, intact virions are shed from the surface as differentiated epithelial cells are sloughed into the environment. In benign infections, the HPV DNA remains in an episomal location and does not become incorporated into the host-cell DNA. The mechanism through which HPV infection results in the development of malignancy is discussed in Chapter 23.

Therapy and prognosis

Untreated genital warts tend to resolve with the passage of time. Unfortunately, there are few published data indicating the percentage and rate of resolution. Information regarding the resolution of cervical HPV infections is much better and this information will be used as a surrogate for external genital infection. As demonstrated by the marked fall-off in prevalence rates with age, most untreated cervical HPV infections are transient, with approximately 90% resolving within 2 or 3 years¹¹. Infections with low-risk HPV types appear to be cleared more rapidly than those due to high-risk HPV types^3,11. Clearance is primarily due to the development of immune reactivity. Innate immune response and humoral immunity presumably play some role but it is cell-mediated immune response that is critical to resolution¹¹. Following clearance, reinfection with the same, or a different, type of HPV is possible.

Immunosuppressed individuals, especially those who are human immunodeficiency virus (HIV)-positive, tend to have infections that persist for many years. Women with persistent infections due to high-risk HPV types (mostly HPV 16 and 18) are at increased risk for the development of cervical and vulvar squamous cell carcinoma¹¹.

In terms of treatment, it is pertinent to ask three questions. First, should sexual partners be examined? The answer is probably no. Acquisition of an asymptomatic infection may have occurred years ago and contact tracing just would not be feasible. And, the contact person may have had latent infection, in which case clinical recognition of the infected partner would not be possible. Second, should genital warts be biopsied? The answer is sometimes. Filiform and small nodular warts are unlikely to show dysplasia and need not be biopsied. Larger nodular warts (Buschke–Lowenstein-type) and flat-topped warts of any color have a higher risk of dysplasia and therefore should be sampled. Third, should genital warts be typed? As indicated above, the high cost coupled with the poor sensitivity and specificity of these tests has led the CDC to recommend that typing not be performed⁶.

The CDC discusses the treatment of genital warts in its revised treatment guidelines for sexually transmitted disease⁶. Two statements from this document are worth quoting: “Existing data indicate that currently available therapies for genital warts might reduce, but probably do not eradicate, HPV infectivity. Whether the reduction in HPV viral DNA resulting from treatment impacts future transmission remains unclear” and “No definitive evidence suggests that any of the available treatments are superior to any other and no single treatment is ideal for all patients or all warts”⁶. In addition to the CDC guidelines, there have been two thorough recent reviews of therapy for genital warts.^12,13 Much of what follows is based on the information from these sources.

Epidemiology and clinical manifestations

Most studies suggest that about 80–90% of all molluscum contagiosum virus (MCV) infections occur in children^17,18. However, over the last 30 years there has been an increased incidence in adults, occurring as a result of sexual transmission. The annual incidence of clinically evident molluscum contagiosum is probably around 1–2% in the western world¹⁹. Asymptomatic infection must occur with even greater frequency as antibodies to MCV are found in 6–23% of the normal population^20,21. The proportion of the population with such antibodies rises with age and may reach 40% by mid-adult life²¹. Individuals with depressed cell-mediated immunity (especially untreated patients with HIV/acquired immunodeficiency syndrome (AIDS)) are at greater risk of developing molluscum contagiosum²². There may also be an increased risk of MCV infection in those with atopic dermatitis and those who are applying topical steroids or tacrolimus on a regular basis¹⁸.

The clinical lesions of molluscum contagiosum are smooth-surfaced hemispherical papules averaging 3–10 mm in diameter. These papules are usually skin-colored but they may also be white, pink, or translucent (Figures 19.8 and 19.9). Central umbilication, a highly characteristic feature, is found in about 30–50% of larger lesions but is generally absent in new, small lesions (Figures 19.10 and 19.11). Rarely, giant lesions (up to 2 cm in diameter) develop. Sometimes as a result of trauma, or in the immunologically mediated resolution phase, a molluscum lesion and the perilesional skin become bright red and tender (Figure 19.12). Such lesions simulate furuncles and inflamed cysts.

Figure 19.8 Firm, white, shiny, dome-shaped papules typical for molluscum contagiosum; this is a sexually transmitted disease in adults, but raises no suspicion when occurring on the vulva of children.

(Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-8), Churchill Livingstone.)

Figure 19.9 Mollusca can be white or skin-colored, and mimic pustules and vesicles. The classic central dell can be seen in several lesions on this patient.

(Reproduced from P. J. Lynch and L. Edwards Genital Dermatology (Fig. 9-9), Churchill Livingstone.)

Figure 19.10 This solitary molluscum shows the typical central umbilication.

Figure 19.11 The firm, skin-colored to pink papules of molluscum contagiosum are most commonly located on the labia majora. The largest lesions usually demonstrate the pathognomonic central umbillication but this feature is often lacking in the smaller papules.

Figure 19.12 Molluscum contagiosum on the labia majora.

Generally 10–30 lesions are present at any one time¹⁸

Related posts:

A Systematic Approach to the Dermatoses of Pregnancy The Papular and Pruritic Dermatoses of Pregnancy Atopic Eruption of Pregnancy Vulvar Dermatoses: the Eczematous Diseases Physiologic Skin Changes of Pregnancy of Vulvovaginal Disease

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