Cancer of the Anal Canal

Anatomy

The anal canal extends cranially from the anorectal ring, where the rectum passes through the puborectalis sling to the anal verge, measuring approximately 3 to 4 cm in length ( Fig. 76.1 ). The anal margin or perianal skin is the hair-bearing skin within a 5-cm radius immediately beyond the anal verge, and neoplasms involving the anal margin have been traditionally managed as skin cancers. The anal verge is the junction of stratified squamous epithelium of the anal canal and the keratinized squamous epithelium of the perianal skin. The anorectal ring, which is palpable on digital rectal examination, is composed of a muscular bundle at the junction of the internal sphincter, the puborectalis muscle, and the external sphincter. The puborectalis muscle is one of the three muscles (the iliococcygeus, pubococcygeus, and puborectalis) which comprise the levator ani muscle or pelvic floor. The mucosa overlying the anorectal ring is a columnar epithelium which extends approximately 1 cm caudally to the dentate line, the histologic transitional zone between the columnar and stratified squamous epithelium. Tumors arising near the dentate line have historically been referred to as cloacogenic or transitional cell tumors and are composed of nonkeratinizing squamous cells; however, such tumors have similar prognoses and are treated in the same fashion as squamous cell cancers of the anal canal. Tumors that develop from mucosa (columnar, transitional, or squamous) are true anal canal cancers, whereas tumors that arise from skin distal to the anal verge are termed perianal skin cancers.

Epidemiology

Squamous cell carcinoma of the anus is relatively rare and comprises only 6% of all large bowel cancers. The Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review of the National Cancer Institute (NCI) estimated that 8580 new cases would be diagnosed in the United States and 1160 deaths would occur from the disease in the United States in 2018. From 2005 to 2009, the median age at diagnosis was 61 years of age. The age-adjusted incidence rate was 18 per 100,000 men and women per year, with a slight female predominance (2.1 per 100,000 women and 1.5 per 100,000 men). There has been a steady increase in the incidence of anal cancer in recent years in both men and women, with an annual percent change of 2.7% per year among males and 2.8% per year among females in the SEER regions from 1992 to 2004. There were some differences in anal cancer incidence by race and ethnicity from 1998 to 2003, with white women demonstrating a significantly higher rate of anal cancer than black women. Conversely, in men, blacks had a higher rate of anal cancer than whites, and Hispanic men had the lowest incidence. Another analysis of the SEER registry between 1973 and 2009 demonstrated that there was a clear inflection point in the incidence of both anal carcinoma in situ and invasive anal cancer cases. Before 1997 the combined incidence of anal carcinoma in situ and anal cancer increased at an annual rate of 2.2%, and after 1997 the combined incidence increased at a rate of 7.2%, likely a result of the increasing rate of human papillomavirus (HPV) infection and an increase in screening. Mortality rates from anal cancer also rose, on average, 3.2% each year from 2004 to 2013. Fortunately, at diagnosis, 48% of patients have localized (stages I/II) disease and only 13% have metastatic disease. The 5-year overall survival (OS) rate for all patients diagnosed between 2006 and 2012 was 66%, with 81% of patients with localized disease surviving 5 years.

Etiology and Biologic Characteristics

Several factors have been implicated in the pathogenesis of anal cancer, including HPV, immunosuppression, and cigarette smoking. The most important risk factor for squamous cell anal cancer is infection with HPV, especially types 16 and 18. These high-risk HPV types act as carcinogens in the development of anogenital cancers. A meta-analysis has suggested that HPV-16 is found more frequently (75%) and HPV-18 less frequently (10%) in anal carcinomas than in cervical carcinomas. Moreover, approximately 80% of anal cancers demonstrated more than one HPV genotype.

As in cervical neoplasia associated with HPV, the viral proteins E6 and E7 mediate oncogenic transformation of the anal squamous epithelia. The viral E6 protein binds to the E6-associated protein (E6 AP) and ubiquinates the protein p53, which in turn leads to the proteosomal degradation of this major cellular transcription factor, leading to loss of the cell cycle arrest and apoptotic mechanisms that allow for deletion of errors in DNA replication. The viral E7 protein binds to the product of the retinoblastoma (Rb) gene, and consequently accelerates the cell cycle, allowing cells to progress from the G ₁ into the S phase of the cell cycle.

As anal lesions progress from condylomata to low-grade dysplasia and then high-grade anal intraepithelial neoplasia (AIN) and invasive cancer, there is an accumulation of mutant p53 expression, emphasizing its role in tumor development. A prior history of anal condylomata has been reported in as many as 50% of homosexual and 30% of heterosexual patients diagnosed with anal carcinoma. The E2 protein allows HPV to escape intracellular detection by facilitating attachment of the HPV DNA to the host chromatin, an effect that allows steady replication of the virus in tandem with epithelial cells. Therefore through concerted actions of the HPV proteins E2, E6, and E7, the anal epithelium accumulates genetic errors leading to proliferation and eventually carcinogenesis.

Immunosuppression, in particular impaired cellular-mediated immunity, is another important risk factor in the development of anal cancer. The impact of suppressed cell-mediated immunity may be related to a reduced host response that would clear the HPV virus and prevent the establishment of a prolonged viral presence. Support for this finding comes from the observation that anal cancer rates are increased in both human immunodeficiency virus (HIV)–positive patients and patients who undergo renal transplantation, in which cell-mediated immunity is suppressed. In one series there was an approximate 100-fold increased risk of developing anogenital cancer in renal transplant patients. In another series, patients receiving chronic steroid therapy for amelioration of autoimmune disorders were also found to be predisposed to HPV-associated anal lesions.

Data from the prospective US Military Natural History Study (1985–2008) suggest that in HIV-infected men the incidence rate of anal cancer has been rising dramatically, even with the introduction of highly active antiretroviral therapy (HAART), reaching 128 per 100,000 men in 2006 to 2008. In addition, the risk of developing anal cancer increased with the duration of HIV infection, with a 12-fold higher rate of anal cancer in men infected with HIV for at least 15 years versus those infected for less than 5 years. Fortunately, the use of HAART appears to delay progression to anal cancer in HIV-positive men who have sex with men (MSM).

Cigarette smoking is also associated with the development of anal cancer, much as it is with cervical cancer. The risk of anal cancer appears to be related to pack-year history of smoking, with more extensive histories associated with a higher risk. The mechanism of smoking-associated tumors is unclear, but smoking may act as a cocarcinogen in the context of HPV infection.