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,

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