Etiology

The papillomaviruses are small (55-nm), DNA-containing viruses that are ubiquitous in nature, infecting most mammalian and many nonmammalian animal species. Strains are almost always species-specific. More than 100 different types of HPVs have been identified through comparison of sequence homologies. The different HPV types typically cause disease in specific anatomic sites; >30 HPV types have been identified from genital tract specimens.

Epidemiology

HPV infections of the skin are common, and most individuals are probably infected with one or more HPV types at some time. There are no animal reservoirs for HPV; all transmission is presumably person-to-person. There is little evidence to suggest that HPV is transmitted by fomites. Common warts, including palmar and plantar warts, are frequently seen in children and adolescents, in whom they infect the hands and feet, common areas of frequent minor trauma.

Human papillomavirus is the most prevalent viral sexually transmitted infection in the USA. Up to 70% of sexually active women eventually acquire HPV through sexual transmission; most have their first infection within 3 yr of beginning sexual intercourse. The greatest risk for HPV in sexually active adolescents is exposure to new non–condom-using sexual partners, underscoring the ease of transmission of this virus through sexual contact. As with many other genital pathogens, perinatal transmission to newborns also occurs, but infections appear transient. Detection of HPV in older preadolescent children is rare. If lesions are detected in a child >3 yr of age, the possibility of sexual abuse should be raised.

The most common manifestation of HPV is latent infection, defined by the detection of HPV DNA in the absence of any detectable HPV-associated lesion. Approximately 20% of sexually active adolescents have detectable HPV at any given time and have normal cytologic findings and no detectable lesions. External genital warts are much less common, occurring in <1% of adolescents. The most common clinically detected lesion in adolescent women is the cervical lesion termed low-grade squamous intraepithelial lesion (LSIL) (Table 258-1). This lesion appears to occur in 25-30% of adolescents infected with HPV. LSILs are considered benign cellular changes associated with HPV infection. As with HPV DNA detection, most LSILs regress spontaneously in young women and do not require any intervention or therapy. Less commonly, HPV can induce more severe cellular changes, termed high-grade squamous intraepithelial lesions (HSILs) (Chapter 547).

Table 258-1 BETHESDA SYSTEM FOR REPORTING CERVICAL/VAGINAL CYTOLOGY

Although HSILs are considered precancerous lesions, they rarely progress to invasive cancer. HSILs occur in approximately 0.4-3% of sexually active women, whereas invasive cervical cancer occurs in 8 cases/100,000 adult women. In true virginal populations, including children who are not sexually abused, rates of both clinical disease and HPV detection are very low to zero. In the USA, there are approximately 12,000 new cases and 3,700 deaths from cervical cancer each year. Worldwide, cervical cancer is the 2nd most common cause of cancer deaths among women.

Some infants may acquire papillomaviruses during passage through an infected birth canal, leading to recurrent respiratory papillomatosis. Cases also have been reported after cesarean section. The maximum incubation period for emergence of clinically apparent lesions (genital warts or laryngeal papillomas) after perinatally acquired infection is unknown but appears to be 6 mo (Chapter 382.2).

Genital warts appearing in later childhood may result from sexual abuse with HPV transmission during the abusive contact. Genital warts may represent a sexually transmitted infection even in some very young children. Their presence is cause to suspect that possibility. A child with genital warts should therefore be provided with a complete evaluation for evidence of possible abuse (Chapter 37.1), including the presence of other sexually transmitted infections (Chapter 114). Presence of genital warts in a child does not confirm sexual abuse, because perinatally transmitted genital warts may go undetected until the child is older. Typing for specific genital HPV types in children is not helpful in diagnosis or to confirm sexual abuse status, because the same genital types occur in both perinatal transmission and abuse. Nonetheless, the type detected in the infant is not always the same as the mother’s type, suggesting other sources of HPV acquisition.

Pathogenesis

Initial HPV infection of the cervix is thought to begin by viral invasion of the basal cells of the epithelium, a process that is enhanced by disruption of the epithelium caused by trauma or inflammation. It is thought that the virus initially remains relatively dormant because virus is present without any evidence of clinical disease. The life cycle of HPV depends on the differentiation program of keratinocytes. The pattern of HPV transcription varies throughout the epithelial layer as well as through different stages of disease (LSIL, HSIL, invasive cancer). Understanding of HPV transcription enhances understanding of its ability to behave as an oncovirus. Early region proteins, E6 and E7, function as trans-activating factors that regulate cellular transformation. Complex interactions between E6- and E7-transcribed proteins and host proteins result in the perturbation of normal processes that regulate cellular DNA synthesis. The perturbations caused by E6 and E7 are primarily disruption of the anti-oncoproteins p53 and retinoblastoma protein (Rb), respectively, contributing to the development of anogenital cancers. Disruption of these proteins results in continued cell proliferation, even under the circumstances of DNA damage, which leads to basal cell proliferation, chromosomal abnormalities, and aneuploidy, hallmarks of SIL development.

Evidence of productive viral infection occurs in benign lesions such as external genital warts and LSILs, with the abundant expression of viral capsid proteins in the superficial keratinocytes. The appearance of the HPV-associated koilocyte is due to the expression of E4, a structural protein that causes collapse of the cytoskeleton. Low level expression of E6 and E7 proteins results in cell proliferation seen in the basal cell layer of LSILs. LSILs are a manifestation of active viral replication and protein expression. However, as the lesions advance in grade, expression of those products important in the process of cell transformation, such as E6 and E7, now predominate, rather than structural proteins, resulting in the chromosomal abnormalities and aneuploidy characteristic of the higher-grade lesions.

Cutaneous lesions (common and genital warts) are not associated with malignant HPV types and do not have any malignant potential except in the rare skin disorder epidermodysplasia verruciformis. Genital lesions caused by HPV may be broadly grouped into those with little to no malignant potential (low risk) and those with greater malignant potential (high risk). Low-risk HPV types, 6 and 11, are most commonly found in genital warts and are rarely if ever found isolated in malignant lesions. High-risk HPV types, specifically types 16 and 18, which cause about 70% of cervical cancer, are commonly found in SILs and invasive anogenital cancers. Other HPV types found in invasive cancers but at much lower frequencies include types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. HPV 16 is also most commonly found in women without lesions, making the connection with cancer confusing. Lesions may also be infected simultaneously with multiple HPV types. Almost all latent infections with low-risk types spontaneously resolve over time. Genital and common warts in general resolve without therapy but may take years to do so. Although 85-90% of high-risk type infections resolve as well, they are more likely than low-risk types to persist. This observation seems to be particularly true for HPV 16, which has a slower rate of regression than some of the other high-risk types. Persistent high-risk–type infections are associated with increased risk for development of HSILs and invasive cancer. LSILs have similar regression patterns as latent infection in young women: 92-95% of LSILs in young women spontaneously regress within 3 yr. Although HSILs are less likely to regress than latent infections or LSILs, progression to invasive cancer is still rare, with only 5-15% showing progression.

Most infants with recognized genital warts are infected with the low-risk types. In contrast, children with a history of sexual abuse have a clinical picture more like that of adult genital warts, consisting of mixed low- and high-risk types. There are rare reports of HPV-associated genital malignancies occurring in preadolescent children and adolescents. On the other hand, HSILs do occur in sexually active adolescents. There is also a concern that younger age of sexual debut has contributed to the increase in invasive cervical cancer seen in women <50 yr of age in the USA. HPV is considered necessary but not sufficient for the development of invasive cancers. Other risk factors for which there is relatively strong suggestive evidence of association include smoking, prolonged oral contraceptive use, Chlamydia trachomatis and herpes simplex virus infections, and greater parity.

Clinical Manifestations

The clinical findings in HPV infection depend on the site of epithelial infection.

Skin Lesions

The typical HPV-induced lesions of the skin are proliferative, papular, and hyperkeratotic. Common warts are raised circinate lesions with a keratinized surface (Fig. 258-1). Plantar and palmar warts are practically flat. Multiple warts are common and may create a mosaic pattern. Flat warts appear as small (1-5 mm), flat, flesh-colored papules.

Figure 258-1 Common warts of the left hand and the chest wall.

(From Meneghini CL, Bonifaz E: An atlas of pediatric dermatology, Chicago, 1986, Year Book Medical Publishers, p 45.)

Genital Warts

Genital warts may be found throughout the perineum around the anus, vagina, and urethra, as well as in the cervical, intravaginal, and intra-anal areas (Fig. 258-2). Intra-anal warts occur predominantly in patients who have had receptive anal intercourse, in contrast with perianal warts, which may occur in men and women without a history of anal sex. Although rare, lesions caused by genital genotypes can also be found on other mucosal surfaces, such as conjunctivae, gingiva, and nasal mucosa. They may be single or multiple lesions and are frequently found in multiple anatomic sites. External genital warts can be flat, dome-shaped, keratotic, pedunculated, and cauliflower-shaped and may occur singly, in clusters, or as plaques. On mucosal epithelium, the lesions are softer. Depending on the size and anatomic location, lesions may be pruritic and painful, may cause burning with urination, may be friable and bleed, or may become superinfected. Adolescents are frequently disturbed by the development of genital lesions. Other rarer lesions caused by HPV of the external genital area include Bowen disease, bowenoid papulosis, squamous cell carcinomas, Buschke-Löwenstein tumors, and vulvar intraepithelial neoplasias (VINs).

Figure 258-2 Common warts of the hand in a mother and perianal condylomata acuminata in her son.

(From Meneghini CL, Bonifaz E: An atlas of pediatric dermatology, Chicago, 1986, Year Book Medical Publishers, p 44.)

Squamous intraepithelial lesions detected with cytology are usually invisible to the naked eye and require the aid of colposcopic magnification and acetic acid. With aid, the lesions appear white and show evidence of neovascularity. SILs can occur on the cervix, vagina, vulva, and intra-anus. Invasive cancers tend to be more exophytic, with aberrant-appearing vasculature. These lesions are rarely found in non–sexually active individuals.

Diagnosis

The diagnosis of external genital warts and common warts may be reliably determined by visual inspection of a lesion by an experienced observer and does not require additional tests for confirmation. A biopsy should be considered if the diagnosis is uncertain, the lesions do not respond to therapy, or the lesions worsen during therapy.

Screening for cervical cancer begins with cytology, which is either performed by Papanicolaou (Pap) smear or liquid-based cytology. Screening guidelines, which were updated in 2009 by the American Society for Colposcopy and Cervical Pathology (ASCCP) and American College of Obstetrics and Gynecology, recommend to start screening at age 21 yr. Screening earlier is more likely to result in unnecessary referrals for colposcopy, because most lesions in this group are likely to be LSILs and therefore to regress. Annual cytology is recommended until at least 3 normal cytology results are obtained. After this, the recommended frequency interval varies between 1-3 yr. The recommended terminology used for cytologic evaluation is based on the Bethesda system (see Table 258-1). Terminology used for histology is based on the World Health Organization recommendation using cervical intraepithelial neoplasia (CIN) 1, 2, and 3 (see Table 258-1). Although the purpose of screening is to identify CIN 3+ lesions, the majority of these lesions are found in women who were referred for atypical squamous cells of undetermined significance (ASCUS) or LSILs on cytology. On the other hand, few CIN 3 or cancers exist in adolescent populations. Cytologic evaluation of cervical cells is a screening test and not confirmatory. New guidelines often take years before their uptake. If cytology is obtained in an adolescent, the 2006 ASCCP guidelines for management of abnormal cytology and histology should be followed. For adolescents, ASCUS and LSIL are treated the same. The current recommendation for adolescents with ASCUS or LSIL is to repeat cytology every 12 mo for up to 24 mo. For persistent ASCUS or LSILs at 2 yr or 24 mo of follow-up, referral for colposcopy is recommended. Adolescents with HSIL at any visit should be referred for colposcopy and biopsy. In adult women, HSIL can be treated without histologic confirmation. However, this approach should be avoided in adolescents because HSIL is often misdiagnosed in this group.

In adult women older than 21 yr, high-risk HPV testing can be used to assist in ASCUS triage. The latter recommendation was based on the observations that adult women with ASCUS and a positive HPV test result for high-risk types are more likely to have CIN 2/3 than women with a negative HPV test result. HPV testing in adolescents, whether used for ASCUS triage or follow-up, is not recommended because of the high prevalence of HPV. If HPV testing is performed inadvertently, it is recommended to ignore the HPV test result. Once the LSIL is confirmed by histology (i.e., CIN 1), treatment of CIN 1 is not recommended; women can be followed with cytology at 12-mo intervals. An adolescent in whom histology confirms CIN 2/3 or CIN 2 can be followed by colposcopy and cytology at 6-mo intervals if the patient is compliant. If CIN 2/3 continues to persistent at 2 yr of follow-up, treatment is recommended. CIN 3 in adolescents is recommended to be treated as in adults. These guidelines and updates can be found at www.asccp.org.

Very sensitive tests for the presence of HPV DNA, RNA, and proteins are becoming generally available, although they are not required for the diagnosis of external genital warts or related conditions. There are no indications for HPV DNA testing in adolescents or children.

Differential Diagnosis

A number of other conditions should be considered, including condyloma latum, seborrheic keratoses, dysplastic and benign nevi, molluscum contagiosum, pearly penile papules, and neoplasms. Condyloma latum is due to secondary syphilis and can be diagnosed with dark-field microscopy and standard serologic tests for syphilis. Seborrheic keratoses are common, localized, hyperpigmented lesions that are rarely associated with malignancy. Molluscum contagiosum is caused by a poxvirus, is highly infectious, and is often umbilicated. Pearly penile papules occur at the penile corona and are normal variants that require no treatment.

Treatment

Most common (plantar, palmar, skin) warts eventually resolve spontaneously (Chapter 659). Symptomatic lesions should be removed. Removal includes a variety of self-applied therapies, including salicylic acid preparations and provider-applied therapies (cryotherapy, laser therapy, electrosurgery). Genital warts in children and adolescents are benign and usually remit, but only over an extended period. It is recommended that genital lesions be treated if the patient or the parent requests therapy. As for common warts, treatment is categorized into self-applied and provider-applied. No one therapy has been shown to be more efficacious than any other. Provider-applied therapies include surgical treatments (electrosurgery, surgical excision, laser surgery) and office-based treatment (cryotherapy with liquid nitrogen or a cryoprobe, podophyllin resin 10-25%, and bi- or tri-chloroacetic acid). Office-based treatments are usually applied once a week for 3-6 wk. Podophyllin resins have lost favor to other methods because of the variability in preparations. Intralesional interferon is no more effective than other therapies and is associated with significant adverse effects; this therapy is reserved for treatment of recalcitrant cases.

Many therapies are painful, and children should not undergo painful genital treatments unless adequate pain control is provided. Parents and patients should not be expected to apply painful therapies themselves. In adolescents and adults, recommended patient-applied treatment regimens for external genital warts include topical podofilox, imiquimod, and sinecatechins. Podofilox 0.5% solution (using a cotton swab) or gel (using a finger) is applied to visible warts in a cycle of applications twice a day for 3 days followed by 4 days of no therapy, repeated for up to a total of 4 cycles. Imiquimod 5% cream is applied at bedtime, 3 times a week, every other day, for up to 16 wk; the treated area should be washed with mild soap and water 6-10 hr after treatment. Sinecatechins is a topical product approved by the U.S. Food and Drug Administration (FDA) for external genital wart treatment that can be used 3 times daily for up to 16 wk. None of the patient-applied therapies are approved for use during pregnancy, and podophyllin resin is contraindicated in pregnancy. For any of the nonsurgical treatments, prescription is contraindicated in a patient with any history of hypersensitivity to any product constituents.

If HPV exposure as a result of sexual abuse is suspected or known, the clinician should ensure that the child’s safety has been achieved and is maintained.

When indicated, the most common treatments for CIN 2/3 are ablative treatments, including cryotherapy and loop electrosurgical excisional procedure. Because laser therapy is expensive and requires anesthesia, its use has fallen from favor in relatively straightforward cases. Once confirmed by histology with CIN 1, LSILs can be observed indefinitely. Decision to treat a persistent CIN 1 rests between the provider and patient. Risks of treatment, including premature delivery in a pregnant patient, should be discussed prior to any treatment decision.

Complications

The presence of HPV lesions in the genital area may be a cause of profound embarrassment to a child or parent. Complications of therapy are uncommon; chronic pain (vulvodynia) or hypoesthesia may occur at the treatment site. Lesions may heal with hypopigmentation or hyperpigmentation and less commonly with depressed or hypertrophic scars. Surgical therapies can lead to infection and scarring. Premature delivery and low birthweight in future pregnancies are complications of excisional therapy for CIN.

It is estimated that 5-15% of untreated CIN 3 lesions will progress to cervical cancer. Most cancer is prevented by early detection and treatment of these lesions. Despite screening, cervical cancer develops rapidly in a few adolescents and young women. The reason for the rapid development of cancer in these rare cases remains unknown, but host genetic defects are likely underlying causes. Respiratory papillomas rarely become malignant, unless they have been treated with irradiation. Vulvar condylomas rarely become cancerous. HPV-associated cancers of the vagina, vulva, anus, penis, and oral cavity are much rarer than cervical tumors, and therefore screening for them is not currently recommended. However, these tumors are more common in women with cervical cancer; hence, it is recommended to screen women with cervical cancer for these tumors with visual inspection.

Prognosis

With all forms of therapy, genital warts commonly recur, and approximately half of children and adolescents require a 2nd or 3rd treatment. Recurrence is also evident in patients with respiratory papillomatosis. Patients and parents should be warned of this likelihood. Combination therapy for genital warts (imiquimod and podofilox) does not improve response and may increase complications. Prognosis of cervical disease is better, with 85-90% cure rates after a single treatment with loop electrosurgical excision procedure (LEEP). Cryotherapy has a slight less cure rate. Recalcitrant disease should prompt an evaluation and is common in immunocompromised individuals, specifically men and women infected with HIV.

Prevention

The only means of preventing HPV infection is to avoid direct contact with lesions. Condoms may reduce the risk for HPV transmission; condoms also prevent other sexually transmitted infections, which are risk factors associated with SIL development. In addition, condoms appear to hasten the regression of LSILs in women. Avoiding smoking cigarettes is important in preventing cervical cancer. Prolonged oral contraceptive use and parity have been shown to be risks for cervical cancer. However, the mechanisms associated with these factors have not been identified, and consequently no change in counseling is recommended.

HPV vaccines show efficacy against type-specific persistence and development of type-specific disease. A quadrivalent HPV vaccine containing types 6, 11, 16, and 18 was licensed in the USA 2006, and a bivalent HPV vaccine containing types 16 and 18 in 2009. The efficacy of these vaccines is mediated by the development of neutralizing antibodies. Vaccination is recommended routinely for all girls at 11-12 yr of age and is administered intramuscularly in the deltoid region in a 3-dose series at 0, 1, 2, and 6 mo. It is important that vaccination take place in children before they become sexually active, because the rate of HPV acquisition is high shortly after the onset of sexual activity. Vaccine can be given to girls as young as 9 yr of age, and a catch-up vaccination is recommended in girls 13-26 yr. Individuals who are already infected with 1 or more vaccine-related HPV types prior to vaccination are protected from clinical disease caused by the remaining vaccine HPV types. However, the vaccines are not therapeutic. The quadrivalent vaccine is also licensed to be administered in a 3-dose series to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts and developing anal dysplasia and cancer.