The term anal cancer usually refers to anal squamous cell carcinoma. Previous histopathological terms for squamous cell carcinoma, including cloacogenic, large-cell keratinizing/nonkeratinizing, and basaloid carcinoma, have been removed from the most recent two World Health Organization (WHO) classification schemes. 
Anal squamous cell carcinoma is a distinct disease entity that, like cervical cancer, is primarily linked to human papillomavirus (HPV) infection. In both diseases, HPV-related inflammation leads to dysplasia and progression to cancer.  Interesting differences between those two disease processes, new indications for HPV vaccines, and a marked increase in the diagnosis of anal cancer have brought more attention to this relatively uncommon disease entity.
Anal squamous cell carcinoma develops at the anal squamocolumnar junction and arises from a precancerous lesion called high-grade anal intraepithelial neoplasia (AIN-II, AIN-III). The presence of AIN in high-risk groups, especially HIV-positive patients, is an indication for ongoing surveillance by means of high-resolution anoscopy, close followup, topical medications, or other methods.
Patients with anal cancer often delay seeking medical care. In addition, anal cancer is often misdiagnosed, or the diagnosis is significantly delayed, during which time the patient receives treatment for other benign anorectal disease (eg, hemorrhoids). To avoid diagnostic delay, it is important to refer patients with persistent or unusual anal disease to a specialty surgeon.
Although the anus can be the site of numerous types of cancers—including adenocarcinoma, melanoma, and carcinoid, among others—this article focuses largely on squamous cell carcinoma. The treatment algorithms for those other disease entities tend to follow the algorithms specific to those cancer types, as opposed to the anal location.
Treatment of anal squamous cell carcinoma is with the combination of radiation and chemotherapy, including 5-fluorouracil and mitomycin at the beginning and at the end of a 4- to 6-week radiation regimen. Continued surveillance and re-evaluation is required.
Some T1, N0 anal margin cancers can be surgically excised without the need for further treatment. For more advanced disease, abdominoperineal resection (removal of the anus and placement of a permanent end-colostomy) was once the common treatment. Currently, this approach is limited almost exclusively to selected patients with chemoradiation-refractory or recurrent disease. (See Treatment.)
Anal squamous cell cancer is believed to be directly linked to the presence of a complex inflammatory process most commonly caused by HPV infection (particularly with serotypes 16 and 18) in the histologically unique area of the anal squamocolumnar epithelium. In one Scandinavian study, serotype 16 HPV DNA was detected in 73% of anal cancer specimens, and serotype 16, 18, or both was detected in 84% of specimens. In contrast, no rectal cancer specimens contained HPV DNA. 
Active HPV infection affects approximately 10% of women worldwide. The high-risk HPV serotypes 16 and 18, which are responsible for most high-grade intraepithelial lesions that may progress to cancer, along with the low-risk serotypes 6 and 11, have been targeted in a widely available quadrivalent HPV vaccine. Although a clear link between HPV vaccination and a decrease in cancer of the cervix may not yet be evident, the prevalence of those four serotypes is decreased by approximately 50% in vaccinated teenage girls and young women.  The relationship of HPV vaccination with anal cancer is less well studied.
Anal cancer research has adopted terminology that mirrors the grading of cervical dysplasia (ie, cervical intraepithelial neoplasia grades I, II, and III). Anal intraepithelial neoplasia (AIN) grade I is low-grade dysplasia (LGAIN), while AIN-II and AIN-III are high-grade dysplasia (HGAIN), which is then thought to progress to invasive cancer, as in the cervical model. The grading system takes into account histological attributes that include the following  :
Abnormalities in differentiation and maturation of the squamous layers
The depth of those abnormalities
Nuclear membrane changes
Terms such as Bowen disease and high-grade and low-grade squamous intraepithelial lesion (HSIL, LSIL) are generally less commonly used in the literature or in pathologic diagnoses in favor of AIN terminology.
The rate of progression from AIN to invasive squamous cell cancer and the risk factors for progression have been inadequately studied until fairly recently. Progression of AIN to invasive cancer of the anus has been shown to occur in 10-11% of cases. [6, 7] HIV-positive individuals have higher rates of conversion, even if their HIV disease is under control and despite lack of progression to AIDS.  Clearly, more clinical research is needed to permit a strong statement about rates and risk factors for progression.
Study of the natural history of AIN is complicated by the fact that it requires biopsy, which often results in excision of the tissue in question. A further complication is that pathophysiologically, cancer of the anal margin (perianal skin) may be more closely related to penile and vulvar cancers than to cervical cancer, and the former are much less well studied than the latter. 
In current algorithms, perianal skin, anal transition-zone and anal canal are considered somewhat distinct, however, much clinical data perceives them as one clinical entity: anal cancer. The American Joint Commission on Cancer (AJCC) makes a distinction in the anatomy, calling the region from the apex of the anorectal ring to the blending of the squamous mucosa/perianal skin as the “anal canal.” A distinct anatomic area that may bear anal cancer is the “anal margin”, which radially extends from the end of the anal canal for 5-6 centimeters, depending on the individual’s body habitus and shape. 
The incidence rate of anal cancer has been increasing in the past 20-30 years. In the era of greater compliance with screening protocols and greater compliance with cancer treatment in general, this apparent rise in incidence is worrisome and is attracting the attention of regulatory and professional bodies in the field. While the incidence of cervical cancer is falling by about 2% per year, the incidence of anal cancer has increased at a rate of approximately 2.2% per year during the past decade. 
Surveillance, Epidemiology and End Results (SEER) data also reveal approximately 7000-8000 new anal cancer cases (64% female) and 1000 deaths recorded annually.  The American Cancer Society estimates that about 8080 new cases (5,160 in women and 2,2920 in men) will be diagnosed in 2016.  Anal cancer accounts for only 2.4% of all gastrointestinal malignancies. 
Risk factors for anal cancer include any of the following, with combinations of two or more factors posing particular risk:
Active HPV infection 
Men having sex with men (MSM) 
Immunosuppression, with a correlation with low T-cell counts 
The cervix, vagina, vulva, penis, anus, and oropharynx (head and neck) are sites of HPV infection, with related squamous cell carcinoma. Worldwide, HPV-related cancers account for approximately 4.8% of cancers and 14-15% in less-developed areas such as India and sub-Saharan Africa. HPV infection is a worldwide public health concern that is growing in importance. 
Cancer types other than squamous cell carcinoma are varied and rare, accounting for only a minority of anal cancers—approximately 20%.  The epidemiology of non–squamous cell cancers of the anus (eg, melanoma, adenocarcinoma) tends to correlate more closely to those histological entities at other body sites.
The prognosis for patients with anal cancer, as for most cancers, is determined by the stage of disease at presentation. There appears to be a range in the indolence or aggressiveness of anal cancers, with faster or slower progression from the time of onset of symptoms. The details of these differences are not known at this time.
With anal cancer presentations at all stages, 5-year survival is 65.7%, according to SEER data from 2006 to 2012. Approximately 49% of patients have localized disease at presentation, and 5-year survival in this group is 80%, whereas in those who present with metastatic disease, 5-year survival is 30%.  The need for surgical treatment does tend to correlate with poorer outcomes as it speaks to more locally and regionally advanced disease at presentation.
It is important for patients who are at increased risk for anal cancer to be aware of the anal area and to alert healthcare providers early to the presence of abnormalities there, such as the following:
Other poorly defined symptoms
Patients who may be at increased risk for anal cancer include the following:
Women who have had an abnormal Pap smear, cervical dysplasia, or cervical cancer
Patients who are immunocompromised from disease or medical therapy
Men who have sex with men
For patient education information, see the Anal Cancer Directory.
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