Anal Cancer

Anal or Anal Canal Cancer

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ANAL CANAL CARCINOMA

Epidemiology, etiology, and Risk Factors

In the United States, anal canal carcinoma occurs more frequently in women than men. More than 80% of anal canal tumors occur in individuals > 60 years of age. Recent epidemiologic studies suggest that receptive anal intercourse is strongly related to anal cancer. The incidence rate of anal cancer for single men is reported to be six times that for married men; in people < 35 years old, anal carcinoma is more common in men than women. A history of genital warts has been observed, suggesting that papillomavirus may be an etiologic factor.

Signs and Symptoms

The diagnosis of anal canal carcinoma is usually delayed because the symptoms (bleeding, pain, and sensation of mass) are so often attributed to benign anorectal disorders, such as hemorrhoids or anal fissures.

Diagnosis

Evaluation should include a careful rectal examination, endoscopic examination with description of lesion size, and assessment of whether there is invasion into adjacent organs (vagina, urethra, or bladder). Reexamination under general anesthesia may be necessary. A diagnostic incisional biopsy is required. Pelvic CT is suggested to evaluate pelvic nodes. Although distant metastases are uncommon at diagnosis, a chest x-ray and liver function tests are recommended. Suspicious inguinal nodes discovered on physical examination must be assessed pathologically. The incidence of inguinal nodal metastases at diagnosis varies from 13% to 25%. The presence of perirectal, inguinal, and pelvic lymph node involvement correlates with tumor size and isunusual for tumors < 2 cm in diameter. Formal groin dissection is notadvised; needle aspiration should be performed with limited surgical biopsy if results of aspiration are inconclusive.

Pathology

Squamous cell carcinomas Most anal canal malignancies are squamous cell carcinomas. These have been cllassified as cloacogenic carcinomas, basaloid carcinomas, transitional cell carcinomas, or mucoepidermoid carcinomas. However, there is little difference in the natural history of these various types.
Unusual tumors arising in the anal canal include small-cell carcinomas, anal melanomas, and lymphomas. Small-cell carcinomas of the anal canal are aggressive neoplasms similar in natural history to bronchogenic small-cell carcinomas. If such a histology is identified, the clinician should be alerted to the possibility of early distant metastases, and treatment should include chemotherapeutic regimens used in bronchogenic small-cell carcinomas.

Treatment

Surgery In selected individuals with small superficial tumors, local excision has achieved adequate local control and survival. However, most studies of local excision have been retrospective, with small numbers of patients. Prior to the advent of primary radiotherapy and combined-modality treatment (see below), abdominoperineal resection was considered the conventional treatment for patients with invasive anal canal cancer. Unfortunately, even with radical surgical procedures, local recurrences are frequent.

Radiation therapy Trials of primary external-beam radiotherapy in the treatment of anal canal carcinomas have used doses varying between 4,500 and 7,550 cGy. Local control rates of 60%-90%, with 5-year survival rates of 32%-90%, are similar to those of surgical series when the trials are controlled for tumor size. Interstitial radiation therapy alone has been used primarily in Europe for early-stage lesions. A relatively high radiation dose is delivered to a small volume. This modality carries a high potential for radiation necrosis and fails to incorporate treatment of the inguinal nodes.

Combined-modality treatment Chemoradiation is the preferred treatment for most patients with anal canal cancer. Investigators from Wayne State University pioneered the use of simultaneous pelvic irradiation and chemotherapy in the treatment of patients with anal canal carcinomas, and demonstrated that the majority of such patients could be treated with this combination, obviating the need for an abdominoperineal esection. The original study design used 3,000 cGy over 3 weeks with 5-FU, 1,000 mg/m²/d, as a continuous infusion on days 1-4, and repeated on days 29-32. Mitomycin, 15 mg/m², was administered as an IV bolus on day 1. Four to 6 weeks after the completion of therapy, patients had a deep muscle biopsy of the anal canal scar.

A randomized trial from the Radiation Therapy Oncology Group (RTOG) showed that the use of mitomycin with radiation and 5-FU increased complete tumor regression and improved colostomy-free survival over radiation and 5-FU alone. At 4 years, colostomy-free survival was higher in the mitomycin arm than in the 5-FU-alone arm (71% vs 59%), as was disease-free survival (73% vs 51%) (Flam MS, John M, Pajak T, et al: J Clin Oncol 114:2527-2539, 1998). An updated analysis of this experience demonstrated that 38 (84%) of 45 patients were rendered disease-free after chemotherapy and irradiation. Individuals who had positive biopsies underwent an abdominoperineal resection.

Because of the success of the above experience, other investigators have attempted to implement infusional 5-FU and mitomycin with radiation as definitive therapy. Most studies have used similar schedules of 5-FU and mitomycin, but have used higher doses of pelvic irradiation (4,500-5,700 cGy). Five-year survival rates > 70% have been reported. Several investigators have compared the results of irradiation alone vs irradiation plus chemotherapy. Cummings et all found that, with identical radiation doses and techniques, the local control rate for cancers > 2 cm in size rose from 49% for radiation alone to 85% when 5-FU and mitomycin were combined with irradiation. Papillion and Montbarbon found an increase in local control from 66% to 81% with a combined-modality approach, compared with pelvic irradiation alone. Two recent ran-domized studies have shown improved local control with chemoradiation over radiation.

Chemotherapy

Reports of other chemotherapeutic agents in anal cancer have been relatively anecdotal, with limited phase II studies. Because of the activity of cisplatin (Platinol) in other squamous cell carcinomas, this agent has been employed as a single agent or combined with infusional 5-FU in advanced disease.

from the NCI:

Treatment Option Overview

Abdominoperineal resection leading to permanent colostomy was previously thought to be required for all but small anal cancers below the dentate line, with approximately 70% of patients surviving 5 or more years in single institutions,but such surgery is no longer the treatment of choice.Radiation therapy alone may lead to a 5-year survival rate in excess of 70%, although high doses (6,000 cGy or greater) may yield necrosis or fibrosis.Chemotherapy concurrent with lower-dose radiation therapy has a 5-year survival rate in excess of 70% with low levels of acute and chronic morbidity, and few patients require surgery for dermal or sphincter toxic effects.The optimal dose of radiation with concurrent chemotherapy to optimize local control and minimize sphincter toxic effects is under evaluation but appears to be in the 45 Gy to 60 Gy range.Analysis of an intergroup trial that compared radiation therapy plus fluorouracil/mitomycin with radiation therapy plus fluorouracil alone in patients with anal cancer has shown improved results (lower colostomy rates and higher colostomy-free and disease-free survival) with the addition of mitomycin Radiation with continuous infusion of fluorouracil plus cisplatin is also under evaluation. Standard salvage therapy for those patients with either gross or microscopic residual disease following chemoradiotherapy has been abdominoperineal resection. Alternately, patients may be treated with additional salvage chemoradiotherapy in the form of fluorouracil, cisplatin, and a radiation boost to potentially avoid permanent colostomy.

from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 7th ed.,2002

Anal Cancer

Anal cancers are infrequent, with an incidence rate of 0.9 per 100,000 population per year.Approximately 3400 new cases were diagnosed in the United States in 2000. The incidence has increased 2% to 3% every year in the U.S. since the early 1980s. Anal cancer occurs with equal frequency in men and women. Almost 80% are squamous cell cancers, 16% are adenocarcinomas, and 4% are other types.Adenocarcinomas of the anal canal behave like adenocarcinomas of the rectum and are treated as such. Patients undergo abdominal-perineal resection with pre- or postoperative chemoradiation therapy when the tumor is large or invasive or lymph nodes are positive for tumor.

The nomenclature of squamous cell carcinoma has been confusing in the past. Tumors arising in the distal anal canal are usually keratinizing squamous cell carcinomas. Those arising in the transitional mucosa frequently are nonkeratinizing squamous cell carcinomas. In the past, the two nonkeratinizing subtypes were referred to as transitional-cell and cloacogenic. These two subtypes now are recognized as variants of squamous cell carcinoma that lack terminal differentiation. One type is composed of large cells, and the other is composed of small cells. The behavior of keratinizing and nonkeratinizing squamous cell cancers is similar. Anal bleeding is the most common symptom (45%), followed by the sensation of a mass (30%) or no symptoms (20%). The development of anal cancer has been associated with infection with human papillomavirus.

Anal Margin Cancers

Cancers arising distal to the anal verge (anal margin) are considered skin cancers and treated as such. Small lesions (less than 4 cm2 ) with no fixation to deeper tissues are excised widely. Treated patients are then followed closely for 5 years. If the disease recurs, chemoradiation therapy is started. Invasive squamous cell cancer of the anal margin is treated with chemoradiation therapy.

Anal Canal Cancers

In the past, standard treatment of anal canal cancers was abdominal-perineal resection with a permanent colostomy. In 1974, Nigro and colleagues presented the results of combined radiation and chemotherapy and showed that cure was possible without abdominal-perineal resection. This led to a regimen of external beam radiation with fluorouracil and mitomycin as the treatment of choice, with surgery reserved for residual cancer seen in the scar after treatment. Recently, cisplatin has been substituted for mitomycin in treatment trials, and complete response rates to combination treatment have been seen in 94% of patients. At a follow-up of 37 months, only 14% of patients required a colostomy for residual or recurrent disease. Further studies are underway to confirm these results.

Patients with persistent or recurrent squamous cell carcinoma of the anal canal are treated with an abdominal-perineal resection. About 50% of patients who undergo surgery can be cured. Success has also been reported with an additional boost of radiation therapy combined with cisplatin-based chemotherapy.

Melanoma

Melanoma is as deadly in the anal region as elsewhere. The cure rate is poor with any treatment, and many investigators have questioned the use of abdominal-perineal resection for anal melanoma. Most patients have regional or distant metastasis at presentation. Thin lesions (less than 0.3 mm thick) are treated by wide local excision. The choice of treatment for lesions greater that 0.3 mm thick is debatable; either wide local excision or abdominal-perineal resection is considered, but the prognosis with either approach is poor. Inguinal lymph node dissection is reserved for palliation.

Bowen’s Disease

Anal intraepithelial neoplasia, also known as Bowen’s disease, is a dysplastic condition of the epithelium of the anal canal and perianal skin. It is speculated that this condition can predispose to cancer, and surgical resection of the dysplastic epithelium has been recommended. It is difficult to determine the extent of disease at surgery and thus difficult to achieve complete resection of the abnormal epithelium. It is also speculated that human papillomavirus is a predisposing factor, and the virus will remain in the “normal” tissue that is not excised. Many authorities recommend that for patients with Bowen’s disease (including HIV-positive patients), the best treatment option may be close observation, with regular biopsy of any suspicious areas to exclude invasive malignancy.

Paget’s Disease (Extramammary)

This is a rare intraepithelial mucinous adenocarcinoma appearing as an erythematous, eczematoid plaque. It probably arises from the dermal apocrine sweat glands. The disease is more common in women than men and presents as an intractable itch. Diagnosis is by biopsy, and wide local excision is the treatment if invasion is not found. For invasive cancer, abdominal-perineal resection is the treatment of choice.