HPVs are double-stranded DNA viruses that are host and tissue specific—canine virus infects dogs, bovine virus infects cows, human virus infects humans, and rabbit virus infects rabbits. Greater than 200 HPV serotypes have been identified. These are separated into two large groups based on location: skin versus internal wet-squamous mucosa. Further, subclassification is based on oncogenic potential (low risk vs. high risk) as shown in Table 8.2 [31].

HPV is associated with cancers of the cervix, penis, vulva, vagina, anus, and oropharynx [32]. High-risk HPVs, most notably HPV-16 and 18, are found in the majority of anal cancers [33–36]. HPV 6 and 11 are associated with genital warts [31].

Increased risk for anal neoplasm is seen in patients who are immunosuppressed because of HIV infection, solid organ transplantation, hematologic malignancy, and autoimmune diseases. In 1990, Svenson and coworkers [37] described carcinoma of the anal canal in a 40-year old homosexual man with AIDS. The patient presented with an anal abscess that became a fistula. Histology of the resected fistula showed extensive, poorly differentiated squamous cell carcinoma. In 2000, Frisch et al. [38] reported the incidence of invasive and in situ HPV-associated cancers (cervix, vulva, vagina, anus, and penis) among 309,365 US patients with HIV infection/AIDS. HPV-associated cancers in AIDS patients occurred in statistically significant excess; the relative risk for anal cancer was increased to 6.8 in females and to 37.9 in males.

Chronic immunosuppression from solid organ transplant also is associated with increased incidence of anal cancer [39, 40]. Penn and Starzl reported de novo tumors in 75 survivors of organ transplantation, the incidence being approximately 80 times greater than in the average population in a comparable age range [41]. The authors felt that there was strong evidence for an association between immunosuppression and tumor growth. In 2000, Penn, who was then in charge of the transplant registry at the University of Cincinnati, reported that skin cancers were the most common tumors being 38 % of all de novo malignancies [42]. Anogenital carcinoma was found on the vulva, perineum, scrotum, penis, perianal skin, and the anus. These patients were much younger and had in situ lesions. More than 40 % of these patients had a history of condyloma acuminata secondary to infection with HPV types 16 and 18. There have been many studies that have assessed the de novo cancer incidence in transplant patients, but, unfortunately, when the studies were initiated, the registry developed, and data collected, anal dysplasia and anal cancer were not in the data set although cervical and vulvar cancer may have been assessed.

An association between anal cancer and genital dysplasia/cancer has been recognized since the mid-part of the last century. In 1940, Gabriel reported that 3 of 29 women with anal cancer had associated malignancy of the uterine cervix [43]. Gabriel proposed that this finding was “suggestive of a similar tendency to carcinoma in the epithelium of the cervix uteri and the anal region.” In 1966, Cabrera et al. [44] presented a series of 64 anal carcinomas in the female; 11 had multiple primaries in the anogenital tract. The authors suggested “a more than casual relationship.” In 1989, Scholefield et al. [45] prospectively studied the use of an endoscope in examination of the anal canal for the detection of premalignant lesions. The authors noted that the etiology of anal cancer and its association with a sexually transmissible agent bear strong similarities to the etiology of cervical cancer and that these similarities may reflect the common embryological origins of the anal and endocervical canals noting that “both are derived from the cloacogenic membrane.” In 2003, Evans et al. [46] found that second primary cancers of the anus, vulva, and vagina were significantly increased after a diagnosis of either cervical intraepithelial neoplasia III or invasive cervical cancer. For anal cancer, the standardized incidence rates were 5.9 and 6.3 after a diagnosis of CINIII and cervical cancer, respectively. They concluded that these results supported the hypothesis that cancers of the cervix, anus, vulva, and vagina share common risk factors such as HPV.

Anoreceptive intercourse has been implicated in the pathogenesis of anal cancer. In 1979, Cooper and coworkers [47] described cloacogenic carcinoma of the anorectum in homosexual men. Reasoning (1) that cloacogenic carcinoma arises from the transitional zone epithelium and (2) that transitional zone epithelium is derived from the embryologic cloacogenic membrane as is the uterine cervix and vagina in the female, the authors questioned if there is an etiologic potential of receptive intercourse in the development of cloacogenic carcinoma. In 1989, Holly et al. [48] conducted a study of 126 patients with anal and rectal squamous cell carcinoma and 372 randomly selected control subjects. They found that the relative risk for cancer was elevated for men with a history of homosexual activity (RR = 12.4). In 1987, Daling and coworkers [49] found that in men, history of receptive anal intercourse was associated with the occurrence of anal cancer with a relative risk of 33:1. In 1997, Frisch et al. [35] conducted telephone interviews with women and men in whom invasive or in situ anal cancer was diagnosed. Multivariate analysis revealed statistically significant associations between measures of sexual promiscuity and the risk of anal cancer in both men and women. In women, receptive anal intercourse and venereal infections in the partner were associated with increased risk. Fifteen percent of men with anal cancer reported having homosexual contact.

An association between anal cancer and smoking has been found. In 1999, Frisch et al. [50] compared patients with anal cancer in Denmark and Sweden with two control groups: subjects drawn at random from the central population and patients with adenocarcinoma of the rectum. They found that the risk of anal cancer was high among premenopausal women who smoke tobacco compared with the risk for lifetime nonsmokers. The authors noted that the mucosa of the anal canal and the vagina derive from the cloaca. In a 2004 population-based case-control study of anal cancer, Daling et al. [51] found that current smokers among men and women were at particularly high risk for anal cancer independent of other risk factors. The authors proposed that current smoking likely has a promotional effect at late stages of disease progression.

In 2004, Sobhani et al. [52] studied patients with anal canal condyloma after curing their lesions. They checked for HIV and anal coinfection with syphilis, gonococci, Epstein–Barr virus, cytomegalovirus, herpes simplex, and HPV types and determined the incidence and effect of cumulative infections on anal carcinoma. They found that the risk of invasive carcinoma in HPV-infected patients is increased by HIV and anal coinfection.

Malignant transformation of high-grade anal dysplasia has been reported to be between 3.5 % and 29 % as seen in Table 8.4.

Anal HPV serotyping is done using the digene HC2 High-Risk HPV DNA test, Qiagen™. The HC2 High-Risk HPV DNA test is an in vitro nucleic acid hybridization assay for the qualitative detection of thirteen high-risk types of human papillomavirus (HPV) DNA. The HPV types detected by the assay are the high-risk HPV types 16/18/31/33/35/39/45/51/52/56/58/59/68. The test does not determine the specific HPV type present [59].

Anal cytology is interpreted according to the terminology proposed by the Bethesda system [60]. In 1997, Palefsky et al. [61] examined a total of 2958 anal examinations assessing anal cytology as a screening tool for anal SIL. The authors found that the grade of disease on anal cytology did not always correspond to the histologic grade and concluded that anal cytology should be used in conjunction with histopathologic confirmation. A report by Scholefield et al. in 1998 [62] supported the use of anal cytology for diagnosis and follow-up of at risk individuals. In 2003, Friedlander et al. [63] blindly reviewed anorectal cytology specimens from 51 patients. Of these, 32 patients had anoscopic evaluation and 30 had histologic correlation. A 2005 report by Arain et al. [64] reported the cytomorphological features of 200 consecutive anal smears collected in liquid medium. Findings were correlated with results of surgical biopsies and/or repeat smears. The authors found that anal smears had a high sensitivity (98 %) for anal squamous intraepithelial lesions but a low specificity (50 %) for predicting the severity of the abnormality in a subsequent biopsy. A review of anorectal cytology by Bean and Chhieng in 2009 [65] found that sensitivity and specificity of a single anal–rectal cytology specimen are comparable with that of a single cervical cytology test, but that cytological interpretations do not always correlate with lesion severity.

According to the 2010 Sexually Transmitted Diseases Treatment Guidelines [66], treatment is directed to the macroscopic (i.e., genital warts) or pathologic (i.e., precancerous) lesions caused by infection. As shown in Table 8.5, choice of therapy is based on lesion characteristics, patient preference, cost, convenience, adverse effects, and clinician experience [67].