Human Papillomavirus - Clinical Tree

Papillomaviruses are species specific and widely distributed among mammals and nonmammalian animal species. Human papillomaviruses (HPVs) are strictly epitheliotropic and cause infections and cancer of the skin and mucous membranes. Clinical conditions include anogenital and oral infections and cancers, as well as recurrent respiratory papillomatosis.

The Virus And Pathogenesis

HPVs are non-enveloped, double-stranded DNA viruses with a small circular genome of approximately 8000 base pairs. HPV genes are classified by their expression, occurring either early or late in the virus replication cycle. The early gene E6 disrupts the antioncogene p53 . E7 disrupts the E2F/pRb complex, leading to activation of E2F, an important cellular transcription factor. Both events lead to abnormal cellular proliferation. E6 and E7 are also associated with activation of numerous other cancer pathways including telomerase to lengthen telomeres, leading to the prolonged life of epithelial cells and blockade of apoptosis. E6 and E7 transcription is regulated by E2 . Interestingly, viral integration, which occurs in >80% of HPV-related cancers, results in E2 loss and the enhanced transcription of E6 and E7 .

HPV infection begins with viral invasion of the epithelial basal cells, particularly in the setting of epithelial disruption due to minor abrasions or inflammation. In the basal and parabasal layers, only the early viral genes are expressed, and viral DNA is replicated in low copy numbers, which likely contributes to evasion of the host immune system. In the more differentiated upper layers of the epithelium, expression of the late genes, L1 and L2, produces capsid antigens that allow the release of fully infectious viral particles with physiologic epithelial desquamation. Inflammatory signals are attenuated because initial HPV infection does not induce cell death, which is a key trigger to activate the immune response.

Extensive study of HPV as a cause of invasive cervical cancer has formed the basis of our understanding of HPV pathogenesis. Cervical cancer originates in the cervical transformation zone, where the proximal single-layered columnar epithelium transitions to the distal stratified squamous epithelium. At this juncture, the physiologic process of squamous metaplasia transforms the columnar cells into squamous cells. Squamous metaplastic activity is thought to be triggered by pubertal hormonal changes and thus is most active during adolescence and young adulthood, when initial HPV infection also commonly occurs. However, the time between initial HPV infection and the development of invasive cancer is several decades in most healthy women. Active viral replication most commonly results in the benign changes of mild basal cell proliferation and perinuclear halos. ^, Benign changes include atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) (equivalent to cervical intraepithelial neoplasia, grade 1 [CIN 1]) ( Table 211.1 ). High-grade squamous intraepithelial lesion (HSIL) (equivalent to CIN 2, 3) is considered a potential precancerous lesion. The changes of aneuploidy, altered chromatin texture, and increased nuclear volume are thought to be related to E6 and E7 expression in the epithelial stem cells. These cells have lost the ability to differentiate and demonstrate mutagenic consequences, including damage of chromosomal integrity, recombination of diverse DNA, and viral integration. Emerging data suggest vaginal microbiome dysbiosis plays an important role. The final mechanisms leading to invasive cancer remain unexplained.

TABLE 211.1

Bethesda Terminology for Cytology and Histology

Squamous Cell Abnormalities
Atypical squamous cells of undetermined significance (ASC-US) ^a
Atypical squamous cells, cannot exclude HSIL (ASC-H) ^b
Low-grade squamous intraepithelial lesion (LSIL) ^a
High-grade squamous intraepithelial lesion (HSIL) ^b
Glandular Cell Abnormalities
Atypical glandular cells (AGC) ^c
Endocervical adenocarcinoma in situ (AIS) ^c
Adenocarcinoma ^d

a Repeat cytology in 12 months.

b Refer to a gynecology specialist for colposcopy.

c Refer to a gynecology specialist for colposcopy including endocervical sampling; consider endometrial sampling depending on clinical history.

d Refer to gynecology specialist.

Immunity

Cell-mediated immunity is critical for HPV control, as evidenced by the increased risk for HPV-related anogenital cancer in individuals with depressed cell-mediated immunity. Likely both genetic and epigenetic factors influence the host immune response. The primary mechanism for HPV persistence is thought to be evasion of both innate and adaptive immune responses. The antibody response to natural HPV infections is relatively low in titer compared with other systemic viral infections and is not universally detected. Antibodies associated with natural infection may not be protective because women with HPV-associated invasive cervical cancer are more likely to have antibodies than women without cancer. In contrast, antibody levels induced by HPV vaccines are 60–100 times higher than those elicited by natural infections.

Epidemiology And Clinical Features

The >200 HPV types are catalogued into the genera α, β, γ, μ, and ν. α Types are further divided according to their natural tropism for cutaneous or mucosal sites. The types associated with cutaneous warts include HPV types 1, 2, 3, and 10. Of the >40 mucosal α types found in the anogenital or oral tracts, several are termed high risk (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) based on their association with cancers. Notably, HPV-16 and HPV-18 are responsible for about 70% of cervical cancers. HPV-16 plays a greater role in other HPV-associated cancers, being associated with >90% of HPV-associated anal, head, and neck cancers. HPV-18 is more commonly associated with adenocarcinoma of the cervix than squamous. High-risk types also are associated with 50% of vulvar, vaginal, and penile cancers, although this association is dependent on histologic type.

The more common low-risk anogenital types (types 6, 11, 40, 42, 43, 44, 54, 61, 72, 73, 83) cause benign or low-grade cervical cellular changes and anogenital warts. Anogenital warts are caused most commonly by HPV-6 and HPV-11, and are transmitted predominantly through sexual contact. Additionally, perinatal transmission can occur at birth from an infected mother to her newborn. Although consequent clinical disease in infants is rare, HPV-6 and HPV-11 can cause juvenile-onset recurrent respiratory papillomatosis (JORRP) or anogenital warts in infants and young children. With increasing age, genital warts in children should increase the suspicion for sexual abuse. Non-genital cutaneous warts caused by HPV are likely transmitted through nonsexual skin-to-skin contact. Fomite reservoirs appear to be important, as evidenced by a higher risk for plantar warts in those who expose their bare feet in communal bathrooms and showers.

Anogenital Tract Infections

Initial anogenital tract HPV infections typically occur shortly after the onset of sexual activity. Lifetime risk reaches 80% in sexually active individuals. In developed countries, women aged 15–25 years exhibit the highest prevalence rates of 25%–40%. Prevalence rates decline to approximately 15% in women 30 years and older and plateau at 10% at about age 40 years. The strongest risk factors for infection are new sexual partners and lack of condom use in women of any age. Ninety percent of infections detected by DNA testing resolve spontaneously within 36 months. Thus, infection by high-risk HPVs (hrHPVs) is common in the female anogenital tract and by itself is not concerning. Most young women with HPV demonstrate either no detectable lesion by cytology or only LSIL. LSIL is a benign manifestation of HPV, and studies show that most CIN 1 lesions regress spontaneously.

Recurrent infections with new HPV types, as well as the same types, are common in young women. Whether recurrence of the same type represents repeated new infections or reactivation of latent infection remains controversial. However, the rare persistent infection with a high-risk type is the necessary step for progression to cervical cancer. It is estimated that among women with cervical cancer, 50% of the causal HPV is acquired by age 21 years and 75% by age 30 years. A prevalent HPV infection detected in an older woman likely represents a persistent infection acquired years earlier. In contrast, an incident infection has a low risk of CIN regardless of age. Hence, HPV DNA testing alone or with cytology is recommended for primary screening in women >30 years.

HPV prevalence in the male anogenital tract is estimated at 50% but varies widely from 1% to 73% according to sampling techniques and the number of HPV types and genital areas tested. In contrast to women, prevalence does not vary with age, leading to the hypothesis that HPV DNA detection in males may represent superficial and transient infections that may not induce a protective immune response. This hypothesis is supported by the finding that most men clear the initial HPV type detected within 6 months. Antibody titers are lower in men than women at all ages, despite the higher prevalence of HPV DNA detection in men than women at all ages. It is hypothesized that HPV persistence is essential to the development of penile cancer; however, there are no natural history data because penile cancer is very rare. Information about anal infection has been derived predominantly from studies of men who have sex with men (MSM). Prevalence of anal infection is approximately 60% in HIV-negative persons and approaches 100% in HIV-positive persons. ^, Anal HPV also is common in women, including adolescents. The cumulative 1-year incidence of anal HPV in women was 70% in one study. Clearance of anal HPV appears similar to cervical HPV infections. In a study of heterosexual women, the majority of anal infections cleared by 3 years. HPV 16 was found to clear more slowly than other hrHPVs. Although similar precancerous lesions (i.e., anal intraepithelial neoplasia [AIN], grades 2 and 3) can be detected in the anus and the cervix, the natural history of these lesions appear to be different. Anal cancer is significantly less common than cervical cancer. The few studies in healthy women find that about 4% of women have AIN.

Anogenital Cancers

Cervical cancer is the fourth most common female malignancy worldwide, following breast, colorectal, and lung cancer. In 2018, about 570,000 new cases of cervical cancer were diagnosed worldwide. In the US, the age-adjusted rate of incident cases is 7.5 per 100,000 women per year, based on 2014–2018 cases, and 14,480 new cases are projected for 2021. US rates have decreased significantly since the 1970s because of the availability of routine cervical screening and management of precancerous lesions, but little change has occurred since the early 2000s. Barriers to healthcare remain a contributing factor in these new cases.

The rates for cancers of the vulva and anus are considerably lower than the rates for cervical cancer. In the US, the projected number of new cases for 2021 is 6120 for vulvar cancer and 9090 for anal cancer. The age-adjusted incidence rate for anal cancer is 2.0 per 100,000 men and women per year, based on 2014–2018 cases. Immunosuppression, including HIV infection and certain autoimmune diseases, increases the risk of HPV associated cancers, including anal and cervical cancers. ^, ^, Risk factors for anal cancer in women also include a history of cancers of the cervix, vulva, or vagina, and CIN-3.

Oral Infections and Cancers

The prevalence of oral HPV infection has been reported to be 4%–10%. However, sampling techniques likely are inadequate to detect HPV from the areas around the tonsils and base of the tongue, and the true prevalence might be higher. Overall, men have higher rates of oral HPV than women. While most cases of oral cancers are associated with alcohol and tobacco use, approximately 70% of oropharyngeal cancers (defined as back of the throat, including the base of the tongue and tonsils) are attributed to HPV, based on data from the Centers for Disease Control and Prevention (CDC) from 2012 to 2016. Over the last decade, the rates of HPV-linked oropharyngeal cancer in men has continued to rise, whereas the rates in women have remained relatively stable. In the US, it is estimated that the number of HPV-attributed oropharyngeal cancers in men has been greater than the number of cervical cancers in women (11,300 versus 10,900 cases annually, respectively).

Infection in Immunocompromised Individuals

Individuals who are HIV infected or otherwise immunocompromised experience increased HPV prevalence, persistence, and progression to cancer. Prevalence of cervical HPV infection reaches 80% in women with HIV infection. These individuals also have increased rates of vulvar and anal cancers. Although invasive cervical cancer is an AIDS-defining condition, recent data show decreases in both cervical and anal cancers in persons with HIV thought to be due to access to improved antiretroviral therapy. The rates of these cancers, however, remain higher than the general population’s. ^, Among the nearly 900,000 men and women with HIV infection in 2010, cases of anal cancer were estimated to 97% higher and cervical cancer 50% higher than their expected rates. Other immunocompromised groups, including solid organ and hematopoietic cell transplant recipients and those with autoimmune disease receiving immunosuppressants, also have increased risks for cervical and anal cancers. ^,

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