Human Papillomaviruses

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. Viral DNA is divided into an early region, which encodes proteins associated with viral replication and transcription, and a late region, which encodes capsid proteins necessary for virion assembly. These structural proteins are also the immunodominant antigens leading to type-specific immune responses. More than 100 different types of HPVs have been identified through the comparison of sequence homologies. The different HPV types typically cause disease in specific anatomic sites; more than 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 times. There are no animal reservoirs for HPV; all transmission is presumably from 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 and typically infect the hands and feet, common areas of frequent minor trauma.

Human papillomavirus is also the most prevalent viral sexually transmitted infection in the United States. Up to 80% of sexually active women will acquire HPV through sexual transmission; most have their first infection within 3 yr of beginning sexual intercourse. Thus, HPV disproportionately affects youth, with 75% of new infections occurring in 15- to 24-yr-olds. The greatest risk for HPV in sexually active adolescents is exposure to new sexual partners, but HPV can still be acquired even with a history of one partner, underscoring the ease of transmission of this virus through sexual contact. It is estimated that after 11 acts of sexual intercourse, 100% of all HPV types infecting an individual will be transmitted to the other sexual partner. Couple studies show that there is high concordance in the genital area as well as between the hand and the genital area in the other partner. Whether the DNA detected in the hand is capable of transmitting infectious particles is unknown. Unlike other sexually transmitted infections, female-to-male transmission appears greater than male-to-female transmission. This may be because males in general have superficial transient infections or deposition. In turn, males do not develop an adequate immune response, so reinfections are quite common. The prevalence of HPV in women decreases with time, suggesting immune protection, whereas in men, the prevalence of HPV remains high across all ages.

As with many other genital pathogens, perinatal transmission to newborns can occur. Transmission from caregiver to child during the early childhood years has also been documented. However, both perinatal and early childhood infections appear transient. It remains unclear whether these HPV DNA detections are simply a deposition of caregiver DNA or a true infection. Detection of HPV DNA in older preadolescent children is rare. HPV DNA detection in nonsexually active adolescents has been reported, but a history of sexual activity in adolescents is not always disclosed and is therefore difficult to confirm. While caregivers can spread HPV to young children, if lesions are detected in a child older than 3 yr of age, the possibility of sexual transmission should be raised.

In adolescents, HPV DNA is most commonly detected without evidence of any lesion. Some of these detections are thought to be the result of partner deposition and hence do not represent a true infection. In older women, detection of HPV DNA is more commonly associated with a lesion. This is because the HPV DNA detected in older women reflects those HPV infections that became established persistent infections. Persistence is now the known necessary prerequisite for the development of significant precancerous lesions and cervical cancer.

Approximately 15–20% of sexually active adolescents have detectable HPV at any given time and have normal cytologic findings. The most common clinically detected lesion in adolescent women is the cervical lesion termed low-grade squamous intraepithelial lesion (LSIL) ( Table 293.1 ). LSILs can be found in 25–30% of adolescents infected with HPV. External genital warts are much less common, occurring in < 1% of adolescents, but approximately 10% of individuals will develop genital warts in their lifetime. LSIL is a cytologic and histologic term to reflect the benign changes caused by an active viral infection and is likely present in most, if not all, women with HPV infection. The majority of women, however, have very minute or subtle lesions not easily detected by cytology. 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) (see Chapter 568 ).

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 per 100,000 adult women. In true virginal populations, including children who are not sexually abused, rates of clinical disease are close to zero. In the United States, there are approximately 12,000 new cases and 3,700 deaths from cervical cancer each year. Worldwide, cervical cancer is the second most common cause of cancer deaths among women. HPV is also associated with a range of other anogenital cancers, including an estimated 4,600 cases of anal cancer and 11,100 cases of oropharyngeal cancers in men and women each year.

Some infants may acquire papillomaviruses during passage through an infected birth canal, leading to recurrent juvenile laryngeal papillomatosis (also referred to as respiratory papillomatosis ). Cases also have been reported after cesarean section. The incubation period for emergence of clinically apparent lesions (genital warts or laryngeal papillomas) after perinatally acquired infection is unknown but is estimated to be around 3-6 mo (see Chapter 417.2 ). It may be that infections can also occur during hygienic care from an infected parent.

Genital warts may represent a sexually transmitted infection even in some very young children. As such, genital warts appearing in childhood should raise suspicion for possible sexual abuse with HPV transmission during the abusive contact. A child with genital warts should therefore be provided with a complete evaluation for evidence of possible abuse (see Chapter 16.1 ), including the presence of other sexually transmitted infections (see Chapter 146 ). However, the 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.

Pathogenesis

Initial HPV infection of the cervix or other anogenital surfaces 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 transactivating 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-oncoprotein 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 squamous intraepithelial lesion (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 a result of 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. In HSILs, expression of E6 and E7 predominates throughout the epithelium, with little expression of the structural proteins L1 and L2. This results in the chromosomal abnormalities and aneuploidy characteristic of the higher-grade lesions. The critical events that lead to cancer have not been verified; however, several mechanisms are thought to be critical, including viral integration into the host chromosome and activation of telomerase to lengthen chromosomes and avoid physiologic cell senescence. Over 150 HPV types have been documented and are classified by extent of their DNA homology into 5 genera, with the different types having different life-cycle and disease characteristics. The predominant group is α HPV types, which are associated with cutaneous and mucosal anogenital infections and cancers. β, γ, µ, and ν cause predominantly benign cutaneous lesions but can be difficult to manage in severely immunocompromised individuals. Β types are commonly detected on the skin without any apparent lesions but are associated with the development of skin cancers in those with epidermodysplasia verruciformis or other forms of immunodeficiencies. Genital lesions caused by the α HPV types 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 found isolated in malignant lesions. High-risk HPV types are those types that are associated with anogenital cancers, specifically cervical cancer. HPV 16 and 18 are thought to be more oncogenic than other HPV types because they comprise 70% of cervical cancers, whereas each of the other 12 high-risk types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 73) contributes less than 1–9%. HPV 16 appears to be even more important in anal and HPV-associated oropharyngeal cancers, comprising close to 90% of these cancers. HPV 16 is also commonly found in women without lesions or in those with LSILs, making the connection with cancer confusing. Genital warts and SIL are commonly associated with the detection of multiple HPV types, including a combination of low- and high-risk HPV types. Data show that it is likely that a single lesion arises from a single HPV type. Detection of multiple HPV types reflects the presence of cervical and anal coexisting lesions. Almost all (95%) incident low-risk and high-risk HPV DNA detections, with or without detectable SIL, will spontaneously resolve within 1-3 yr. Although HPV 16 has a slower rate of regression than some of the other high-risk types, the majority of incident HPV 16 detections also will resolve. Data suggest that clearance of an HPV type results in natural immune protection against reinfection with that same type. Redetections of the same type are not common and when found are often associated with a history of a new sexual partner, suggesting that these are not reactivated infections but are due to new exposures. These redetections rarely result in high-grade disease. Persistent high-risk–type infections are associated with increased risk for development of HSILs and invasive cancer. Progression of HSIL to invasive cancer is still rare, with only 5–15% showing progression. Approximately 50% of HPV 16–associated HSILs and 80% of non–HPV 16 HSILs will spontaneously regress in young women. Genital and common warts in general also resolve without therapy but may take years to do so. Genital warts in only extremely rare conditions can become malignant.

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, precancerous HSILs do occur in sexually active adolescents. There is a concern that younger age of sexual debut has contributed to the increase in invasive cervical cancers seen in women younger than 50 yr of age in the United States, specifically cervical adenocarcinomas. Persistent HPV infections are 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 cigarettes, prolonged oral contraceptive use, greater parity, and Chlamydia trachomatis and herpes simplex virus infections.

Clinical Manifestations

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