Papillomavirus

Definition

Human papillomaviruses (HPVs) are a group of small DNA viruses that cause a variety of benign and malignant lesions of the skin and mucous membranes. The most commonly recognized HPV-associated diseases include warts ( Chapter 407 ) at anogenital sites (condyloma acuminatum), other skin surfaces (common wart or verruca vulgaris, as well as flat wart or verruca plana), and the plantar surface of the foot (verruca plantaris). In addition, HPV infection causes squamous intraepithelial lesions, or incipient cancers, of the cervix, also known as cervical intraepithelial neoplasia, and of other anogenital sites. It is considered the etiologic agent of a variety of cancers, especially cervical ( Chapter 184 ), anal ( Chapter 131 ), and oropharyngeal ( Chapter 176 ) cancers.

Epidemiology

HPV infections are primarily transmitted by direct contact of skin or mucous membranes with an infected lesion. Genital HPV infection is typically contracted through sexual intercourse, although nonpenetrative genital contact, oral-genital contact, and manual-genital contact are also possible routes of transmission. In addition, genital HPV infection can be transmitted to the mouth and upper respiratory tract perinatally from infected mothers to newborns. For nongenital HPV infection, personal skin-to-skin contact also plays a primary role, whereas fomite transmission from moist surfaces is an important source of infection for plantar warts. Both genital and nongenital infection can be transmitted to new sites by autoinoculation.

Recent estimates are that 43 million males and females ages 15 to 59 years in the United States are infected with genital HPV, with about 13 million new infections occurring annually, thereby making genital HPV the most common sexually transmitted infection. Acquisition of infection begins shortly after sexual debut, with risk factors related to probable exposure (e.g., younger age at onset of sexual activity, increased number of recent and lifetime partners, and number of partners of the sex partners), susceptibility (e.g., lack of circumcision for men), and absence of effective prevention (e.g., lack of consistent condom use or immunization). Most infections are asymptomatic and clear without treatment; only 10% are estimated to persist longer than 2 years. The incidence and prevalence of genital HPV infection and genital warts have been declining substantially in countries with successful immunization programs. For example, between 2003 and 2018, the prevalence of infection with the four viral types included in the original quadrivalent vaccine declined by over 80% in vaccinated women under age 25 years. Reductions of over 65% have also been seen in unvaccinated women, thereby indicating some element of indirect or herd protection.

Oral HPV infection is usually asymptomatic, but when symptomatic it takes the appearance of warts or papillomas. Its prevalence in U.S. adults is lower than genital infection—approximately 3 to 7% in women and 10 to 12% in men , almost half of which are due to high-risk types. Risk factors for prevalent infection include number of sex partners, age, and smoking. Newly acquired oral oncogenic HPV infections are rare in healthy men, and most infections are cleared within 1 year. As with genital HPV infection, oral HPV infection has declined in the vaccine era, especially among men. Cutaneous HPV infection is most typically recognized as common and plantar warts, especially in children, in whom annual incidence rates of up to 30% have been reported.

All types and manifestations of HPV infection are more common in persons with impaired cell-mediated immunity, such as those infected with human immunodeficiency virus (HIV) or receiving immunosuppressive therapy. HIV-infected persons have higher rates of intra-epithelial neoplasia at various genital and anal sites, as well as higher rates of cervical and anal cancer, although both have declined in the United States in recent years, likely as a result of widespread HIV antiretroviral therapy. Evidence also suggests that genital HPV infection increases susceptibility to HIV infection.

Cervical cancer ( Chapter 184 ) has declined in developed countries since the initiation of cytologic screening programs, although about 14,000 cases and 4300 deaths still occur in the United States annually. Cervical cancer is the fourth most common and lethal cancer in women worldwide, and almost 90% of the 311,000 annual deaths occur in low- and middle-income countries. Considering all anatomic sites, almost 36,000 HPV-associated cancers occur in the United States each year, about 60% among females. Oropharyngeal cancer ( Chapter 176 ) has risen sharply over the past 20 years, particularly among men, and is now the most common HPV-associated cancer in the United States.

Pathobiology

HPV infections cause disease by inducing proliferation of the epithelium of the skin and mucous membranes. In benign lesions, such as warts and condylomas, all epithelial layers are involved, except for the basal layer of replicating keratinocytes. The proliferation of the stratum spinosum is called acanthosis, that of the stratum granulosum parakeratosis, and that of the stratum corneum hyperkeratosis. The overall growth is called papillomatosis because it typically occurs mostly above the tissue surface but is also associated with a deepening of the rete ridges of the basement membrane. It is also accompanied by large cells with a hyperchromatic, shrunken nucleus (or nuclei) surrounded by a halo (called koilocytes) in the stratum acanthosum. For the cytopathologist, koilocytosis is the hallmark of HPV infection.

Epidermodysplasia verruciformis is an uncommon autosomal recessive disease with diffuse warts that result from the mutation of one of two adjacent genes, EVER1/TMC6 and EVER2/TMC8 , each coding for proteins involved in the transcription factor NF-κB that participates in the control of cell-mediated immunity.

For precancerous or cancerous lesions, dyskaryosis is caused by the proliferation of the basal layer cells, which also exhibit abnormal mitoses. This dyskaryosis progresses by replacing the upper layers of the stratified epithelium, thereby causing increasing grades 1 to 3 of intraepithelial neoplasia, according to how many thirds of the epithelium are involved. Full-thickness involvement defines carcinoma in situ. The breach of the basement membrane indicates invasive cancer. The intraepithelial neoplasias (IN) of the cervix, vagina, vulva, penis, and anus also go by the acronyms of CIN, VAIN, VIN, PIN, and AIN, respectively. For the cervix, low-grade squamous intraepithelial lesion (LSIL) is the equivalent of flat condyloma and CIN1, whereas high-grade squamous intraepithelial lesion (HSIL) regroups CIN2 and 3. To parallel these changes, low- and high-grade cervical intraepithelial neoplasia (LCIN and HCIN, respectively) are now terms also used in histology. The higher the cytologic or histologic grade of neoplasia, the higher the intralesional relative prevalence of high-risk HPV types.

At the cellular level, infection begins in the lowest and least differentiated layer of the epithelium, the basal cells, when they are exposed by microtrauma. Transcription and protein expression are highly coordinated with the level of cellular differentiation. In the basal layer, the viral genome becomes established in the nucleus as an episome that replicates in tandem with cellular replication, thus maintaining a stable copy number of viral genomes. As basal cells migrate up and differentiate in the superficial layers of the epithelium, full vegetative viral DNA replication and expression of structural proteins occur, with assembly of infectious virions in the most superficial layer of the epithelium. Virions are released with the sloughing of dead cells during normal cellular turnover.

Persistent infection with various high-risk types of genital HPV is firmly established as the cause of squamous cell carcinoma and adenocarcinoma of the cervix, and HPV 16 in particular plays a causal role in other anogenital and oropharyngeal squamous cell cancers. There are also associations of beta-HPV types with squamous cell cancer of the skin. HPV DNA can be detected in more than 99% of cervical cancer cases, with 70% of cancers caused by the two most common high-risk types, HPV 16 and 18. The pathogenesis of HPV-induced cancer involves viral integration into the host genome with resulting disruption of the E2 transcription regulatory gene and increased expression of E6 and E7 proteins. These proteins have oncogenic activity and affect cell growth by binding with tumor suppressor proteins, E6 with p53 and E7 with the retinoblastoma tumor suppressor protein, thereby disrupting apoptosis and cell cycle regulation.

The oncogenic risk of HPV varies not only by type, with HPV 16 being the most oncogenic, but also according to variants (i.e., sharing between 95 and 98% of DNA homology) within a given type. A high viral load may also contribute to the risk. Although a persistent infection with a high-risk type is “necessary” for the development of cervical cancer, it is not considered “sufficient” because cancer does not develop in the majority of persistently infected women. Possible cofactors include cigarette smoking, prolonged hormonal contraceptive use, multiparity, micronutrient deficiency, immunodeficiency (e.g., HIV infection), and possibly other infections, (i.e., Chlamydia trachomatis and herpes simplex virus type 2). In addition, data supporting a familial risk for cervical cancer point to possible genetic factors, including genes controlling the immune response (e.g., human leukocyte antigens and tumor necrosis factor) and cell cycle (e.g., p53).

The squamous epithelium of the ectocervix and columnar epithelium of the endocervix form a squamo-columnar junction that, from birth through life, recedes towards the endocervix, traveling an area called the transformation zone, where cervical cancers ( Chapter 184 ) arise. Squamo-columnar junctions, but without a transformation zone, also exist in the anus and larynx, and HPV benign or malignant lesions often arise in epithelium that is in close proximity (see Chapter 131 for anal cancer).

The immune response to HPV infection is less robust than for most viral infections. Viral proteins and infectious virions develop in superficial cells with limited contact with the immune system, and there is no cell lysis or viremia to trigger an inflammatory response. In addition, HPV suppresses several components of the immune response, including the interferon pathway and the expression of inflammatory cytokines and the major histocompatibility complex I. Antibody to HPV develops in only an estimated 60% of infected individuals, often as long as 6 to 12 months after infection. In contrast, the dynamics of the immune response are quite different after immunization, with almost 100% seroconversion within several months and antibody levels many-fold higher than those after natural infection. The high prophylactic efficacy of papillomavirus vaccines is due to humoral immunity and the intense production of neutralizing antibodies. Once papillomavirus infection is established, cellular immunity appears to be critical for clearance of infection.