Carcinoma of the anus is a rare malignancy that usually is diagnosed at an advanced stage, in spite of being easily visible and accessible. Its treatment has evolved from being mainly surgical to one consisting of chemotherapy (with fluorouracil and mitomycin) and radiation (megavoltage linear accelerator therapy delivering between 40 to 50 Gy). Local surgical excision is most often performed for either carcinoma in situ or microinvasive lesions of the anal margin. Radical resection is indicated for patients with residual disease following chemoradiation or for recurrent disease.

Carcinoma of the anus accounts for 1.5% of digestive system cancers _[1]; when only cancers of the anorectum are considered, it represents about 5% of malignancies (range: 1% to 6%) _{[2, 3]}. It has been estimated that 3400 patients were diagnosed with anal carcinoma in the year 2000 _{[1, 4]}. Anal tumors tend to be most common in the sixth and seventh decades of life and are considered to have a slight female preponderance, although some series have shown a marked preponderance in females (five female patients for every male patient diagnosed) _{[2, 3]}.

The anal region consists of the anal canal and the anal verge (or margin). Considerable confusion exists in defining the anal canal. We recommend using the definition found in the 1987 edition of the International Union Against Cancer staging system _[5], the 1987 edition of the Manual for Staging of Cancer of the American Joint Committee on Cancer _[6], and the criteria of the World Health Organization _[7]. These define the anal canal as extending from the anorectal ring to the anal verge. Using this definition, about 85% of the cancers of the anus originate in the anal canal _{[1, 3]}.

The histologic features of the anal canal and anal margin differ, reflected by the various types of anal cancer found and their management. The skin of the anal margin has a typical dermal structure except it contains an excess of sweat glands and hair. The lining of the anal canal (especially above the dentate line) contains cells that vary in morphology, including transitional cells resembling urinary tract epithelium, and a mixture of cuboidal, columnar, and squamous cells. Tumors of the anal margin can be squamous cell cancer, basal cell cancer, Bowen’s disease, or Paget’s disease. Cancers of the anal canal are described as squamous cell carcinoma, adenocarcinoma, cloacogenic carcinoma, basaloid carcinoma, melanoma, leiomyosarcoma, and carcinoid tumors. Cloacogenic, basaloid, and transitional tumors are considered variants of squamous cell carcinoma, which comprises more than 80% of anal canal tumors _{[2, 3]}.

The clinical presentation of cancer of the anus is nonspecific and includes bleeding (more than 50% of patients) _[3], pruritus, discharge, pain, an anal mass, and history of anal warts. A history of incontinence, change of bowel habits, pelvic pain, or rectovaginal fistula indicate an advanced lesion. Examination reveals a mass, generally ulcerated with indurated margins. The mean size of the tumor at diagnosis is about 3 cm to 4 cm _[3]. Generally, tumors of the anal canal involve only part of the circumference, whereas tumors of the margin tend to be circumferential _[3]. The diagnosis of the lesions is made by biopsy, which is best done with the patient under caudal or spinal anesthesia. The depth of the malignancy (especially for anal canal tumors) is assessed by endorectal ultrasound, which also assesses the involvement of the mesorectal lymph nodes _[2]. The site of lymph node involvement depends on the location of the tumor. Above the dentate line, lymph flow is to the pararectal and paravertebral nodes. Below the dentate line, drainage is through the inguinal and femoral nodes. The incidence of clinically positive nodes is 10% to 20% _{[2, 3]}, and may be 30% to 60% for T3 or larger lesions _[2]; 25% of lymph node metastases from T3 or larger lesions may be may be bilateral _{[2, 3]}.

A number of genetic and environmental factors are implicated in causing anal cancer. Genetic factors include recurrent deletions in chromosome 11 (11q22) or the short arm of chromosome 3 (3p22) _{[2, 3]}. Environmental factors include smoking, sexual orientation (especially an increasing number of sexual partners, male homosexuality, and anoreceptive intercourse), viral warts in the anogenital area (involving human papilloma virus type 16 and 18), and the presence of immunodeficiency states, irrespective of sexual practice _{[1, 2, 3]}. A history of cervical cancer in women has a strong association with anal cancer, which may be due to the common causal factor of human papilloma virus infection _[1]. Other causative factors include prior perianal irradiation for pruritus and the presence of chronic fistulae (especially those due to inflammatory conditions such as Crohn’s disease).

Prognosis depends on the histologic grade of the tumor, its size, and the extent of involvement. The most widely used classification is the one jointly proposed by the Union Internacional Contra la Cancrum and the American Joint Commission on Cancer _[3].

Management of squamous or transitional cell carcinoma of the anus has changed from being purely surgical to mainly consisting of chemoradiation, with surgery being performed for salvage (residual or recurrent tumor). Historically, abdominoperineal resection with an extensive perineal phase was the surgical option of choice, which produced a 5-year survival rate ranging from 30% to 70% _[8]. Naturally, this results in the patient requiring a permanent colostomy. Adenocarcinoma, which comprises 10% of anal cancers _{[2, 3]} and is considered analogous to rectal adenocarcinoma, is still treated primarily with abdominoperineal resection. An additional indication for abdominoperineal resection is residual disease after chemoradiation or for recurrent disease. Local resection is restricted to patients with anal margin cancers that are considered microinvasive or carcinoma in situ, such as Bowen’s disease or Paget’s disease.

Chemoradiation is the standard therapy for the majority of invasive squamous cell carcinomas of the anus. This protocol was introduced by Nigro et al. in 1974 _[9]. Certain modifications have been introduced, especially in radiation dosage. Patients are given a continuous infusion of 5-fluorouracil for 4 days (1000 mg/m2 every 24 hours), with mitomycin given on day 1 (10 to 15 mg/m2 intravenous infusion) _{[10, 11, 12]}. On day 28 after initiation of treatment, 5-fluorouracil is repeated for another 4-day cycle; mitomycin is not repeated. Fluorouracil is considered a radiosensitizer. Mitomycin does not cause sensitization to radiation and has only moderate antitumor activity against squamous cell cancer. It is associated with toxicity to the kidneys, lungs, and bone marrow. However, the use of mitomycin is associated with less likelihood of locoregional recurrence and higher disease-free survival rates. Recently, cisplatin has been recommended as an alternative (in a dose of 25 mg/m2/d for 4 days) to mitomycin because it has been shown to be more effective in other squamous cell cancers _{[1, 13]}.

Radiation therapy on its own can eradicate the tumor locally and is curative in 70% to 90% of small lesions _[14]. However, the probability of cure is reduced if lymph nodes are involved or if the primary lesion is larger than 5 cm _{[1, 14]}. The dose of radiation has prognostic importance, with doses of 40 to 50 Gy producing control of 91% of T2 tumors _[15]. The radiation field includes the primary lesion, the true pelvis, and the inguinal lymphatics. The 5-year survival rate with combined chemoradiation is 60% to 80% _{[3, 4]}; sphincter function is preserved in 80% _[3]. Following completion of chemoradiation, re-examination and possible biopsy is performed at least 2 months later to check for residual disease.

 

Eric J. Szilagy, MD and Asim Farid, MD, FRCS(Edin)
Current Treatment Options in Gastroenterology 2001, 4:275-279
Current Medicine Group LLC ISSN 1092-8472

BIBLIOGRAPHY
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An excellent review of incidence, causes, and current management of anal cancer.
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A comprehensive study and discussion of anal cancer.
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A long-term review comparing surgery with chemoradiation, which advocates aggressive surgery for patients with recurrent or residual disease.
5. International Union Against Cancer: TNM Classification of Malignant Tumors. Edited by Hermanek P, Sobin LH. New York: Springer-Verlag; 1987.</sub>

6. American Joint Committee on Cancer.: Manual for Staging of Cancer. Philadelphia: J B Lippincott; 1987.

7. Morson BC: International Histological Classification of Tumors, No 15. Geneva: World Health Organization; 1976.

8. Nigro ND: Multidisciplinary management of carcinoma of the anus. World J Surg 1987, 11:446-451.
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10. Stafford SL: Combined radiation and chemotherapy for carcinoma of the anal canal. Oncology 1998, 12:373-381.

11. Cleator S, et al.: Treatment of HIV associated invasive anal cancer with combined chemoradiation. Eur J Cancer 2000, 36:754-758.

12. Zelnick R: Results of abdominoperineal resection for failures after combination chemotherapy and radiation therapy for anal canal cancers. Dis Colon Rectum 1992, 35:574-578.

13. Doci R, et al.: Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients. J Clin Oncol 1996, 14:3121-3125.

14. Martenson JA: External radiation therapy without chemotherapy in the management of anal cancer. Cancer 1993, 71:1736-1740.

15. Mendenhall WM: Squamous cell cancer of the anal margin. Oncology 1996, 10:1843-1848.