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The anal canal is lined from its proximal to distal extent by columnar, transitional, and non-keratinized squamous epithelium, which merges at the anal verge with the keratinized perianal skin. Tumors arising from the mucosa of the anal canal are relatively rare, comprising only 1–2% of all cancers of the anus and large intestine. Squamous cancers make up the majority of anal cancers. Anal cancer is increased among people practicing receptive anal intercourse and those with a history of anorectal warts. In over 80% of cases, HPV may be detected, suggesting that this virus is a major causal factor. In a large controlled trial, HPV vaccination of healthy men (16 to 26 years old) who have sex with men decreased the incidence of anal intraepithelial neoplasia by 50%. Women with anal cancer are at increased risk for cervical cancer (which may be due to a field effect of oncogenic HPV infection) and require gynecologic screening and monitoring. Anal cancer is increased in HIV-infected individuals, possibly due to interaction with HPV. HPV vaccine is recommended for boys and girls starting at age 11 or 12, for females aged 13 through 26 years, and in men who have sex with men up to age 26 who have not been previously vaccinated.

Bleeding, pain, and local tumor are the most common symptoms. The lesion is often confused with hemorrhoids or other common anal disorders. These tumors tend to become annular, invade the sphincter, and spread upward via the lymphatics into the perirectal mesenteric lymphatic nodes. CT or MRI scans of the abdomen and pelvis are required to identify regional lymphadenopathy or metastatic disease at diagnosis. PET imaging may be used in conjunction.

Treatment depends on the tumor location and histologic stage. Well-differentiated and small (less than 2 cm) superficial lesions of the perianal skin may be treated with wide local excision. Adenocarcinoma of the anal canal is treated in similar fashion to rectal cancer (see above), commonly by abdominoperineal resection with neoadjuvant chemoradiotherapy and adjuvant chemotherapy. The more common squamous cell cancer of the anal canal and large perianal tumors invading the sphincter or rectum are treated with combined-modality therapy that includes external radiation with simultaneous chemotherapy (5-fluorouracil plus mitomycin). Local control is achieved in approximately 80% of patients. Radical surgery (abdominoperineal resection) is reserved for patients who fail chemotherapy and radiation therapy. Following completion of chemoradiation therapy, tumors may continue to regress for up to 26 weeks. Surveillance includes DRE, anoscopy, and inguinal lymph node palpation every 3–6 months for 5 years as well as CT scans of the chest, abdomen, and pelvis annually for 3 years. Metastatic disease is generally treated with 5-fluorouracil in combination with cisplatin. Checkpoint inhibitor therapy with either nivolumab or pembrolizumab has been shown in small studies to result in disease control in up to 46% of patients with chemotherapy-refractory, metastatic, or unresectable disease. The 5-year survival rate is 81% for localized tumors and approximately 30% for metastatic (stage ...

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