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80% of anal cancers are squamous cell carcinomas (SCCs). Other tumour types include melanoma, lymphoma and adenocarcinoma. Tumour behaviour depends on its anatomical site of the primary cancer.
The anal canal extends from the anorectal junction to the anal margin. The dentate line marks the junction between squamous and mucosal epithelium in the anal canal. Immediately above the dentate line there is a zone of transitional epithelium. Below the dentate line, the canal is lined by non-keratinising squamous epithelium, which merges with the perianal skin. The anal margin is the pigmented skin immediately surrounding the anal orifice.
The lymphatic drainage varies in different parts of the canal. Proximally drainage is to perirectal nodes along the inferior mesenteric artery. Lymph from immediately above the dentate line drains to internal pudendal nodes, and to the internal iliac system. Infra-dentate and perianal skin drains to the inguinal, femoral and external iliac nodes.
- Anal cancer is an uncommon malignancy, accounting for only about 4% of all cancers of the lower alimentary tract.
- The annual incidence is about 1 in 100,000. The incidence is higher in women and is increasing.
- Anal margin tumours: are usually well differentiated. They are more common in men and have a good prognosis.
- Anal canal tumours: are usually poorly differentiated. They are more common in women and have a worse prognosis.
- Systemic spread of anal cancer occurs in fewer than 10% of cases. The most common sites of spread are to the liver and lungs.
- Human papillomavirus (HPV) is an important aetiological factor and 50% of tumours contain viral DNA. Anal intercourse and a high lifetime number of sexual partners increase the risk of HPV infection.
- Anal carcinoma is more common in men who have sex with men.
- It is increased in HIV infection and in patients taking immunosuppressive drugs for HIV infection. It is twice as common in HIV-positive as it is in HIV-negative men who have sex with men.
- Other important risk factors include immune suppression in transplant recipients and cigarette smoking.
- Previous malignancy (gynaecological, lymphoma or leukaemia) or subsequent malignancy (eg lung, bladder, vulva, vagina or breast) is more likely in patients with anal cancer.
- Presentation includes perianal pain and bleeding, a palpable lesion and faecal incontinence.
- Neglected tumours in women can cause a rectovaginal fistula.
- Tumours near the anal margin spread to the inguinal lymph nodes; those higher in the anal canal spread to the pelvic lymph nodes.
- Suspicious lesions should always be biopsied.
- Rectal examination under anaesthesia and biopsy are the most useful staging investigations.
- Imaging modalities used for staging include CT, MRI, endo-anal ultrasound and positron emission tomography (PET).
- Patients should be tested for relevant infections, including HIV, and other possible malignancies.
The following is a staging system for anal canal cancer that has been described by the American Joint Committee on Cancer and the International Union Against Cancer. Tumours of the anal margin (below the anal verge and involving the perianal hair-bearing skin) are classified with skin tumours.
- Primary tumour (T):
- TX: primary tumour cannot be assessed.
- T0: no evidence of primary tumour.
- Tis: carcinoma in situ.
- T1: tumour 2 cm or less in greatest dimension.
- T2: tumour more than 2 cm but not more than 5 cm in greatest dimension.
- T3: tumour more than 5 cm in greatest dimension.
- T4: tumour of any size that invades adjacent organ(s) - for example, vagina, urethra, bladder (direct invasion of the rectal wall, perirectal skin, subcutaneous tissue, or the sphincter muscle(s) - is not classified as T4).
- Regional lymph nodes (N):
- NX: regional lymph nodes cannot be assessed.
- N0: no regional lymph node metastasis.
- N1: metastasis in perirectal lymph node(s).
- N2: metastasis in unilateral internal iliac and/or inguinal lymph node(s).
- N3: metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes.
- Distant metastasis (M):
- MX: distant metastasis cannot be assessed.
- M0: no distant metastasis.
- M1: distant metastasis.
- Stage 0: Tis, N0, M0.
- Stage I: T1, N0, M0.
- Stage II: T2, N0, M0; T3, N0, M0.
- Stage IIIA: T1, N1, M0; T2, N1, M0; T3, N1, M0; T4, N0, M0.
- Stage IIIB: T4, N1, M0; any T, N2, M0; any T, N3, M0.
- Stage IV: any T, any N, M1.
Local excision can be considered for small well-differentiated carcinomas of the anal margin. Combined modality chemotherapy and radiotherapy using 5-fluorouracil and mitomycin C is recommended as first-line treatment for all other cases, with salvage surgery reserved for those who fail on this regimen.
- For all stages of localised SCC of the anal canal, concurrent chemotherapy and radiotherapy are recommended over radiotherapy alone to improve local control and decrease colostomy rates.
- The optimal chemotherapy combination for SCC of the anal canal is 5-fluorouracil plus mitomycin C given concurrently with radiation treatment.
- The addition of chemotherapy allows lower radiation doses to be used and effects are therefore less toxic. Combination chemoradiotherapy is considered the treatment of choice for adenocarcinoma as well as SCC.
- Radiotherapy is given to the tumour and inguinal nodes.
- Radiation therapy alone may lead to a five-year survival rate in excess of 70%, although high doses may be required and cause necrosis or fibrosis.
- Chemotherapy concurrent with lower-dose radiation therapy has a five-year survival rate in excess of 70% with low levels of acute and chronic morbidity, and few patients requiring surgery for toxic effects (such as anal stenosis or anal necrosis).
- Radiation with continuous infusion of fluorouracil plus cisplatin is also under evaluation. However, the role of cisplatin in anal cancer is not currently clear.
- Metastatic disease is less responsive to combined chemotherapy and radiation treatment.
- HIV patients: patients with pretreatment CD4 counts of less than 200 cells/mm3 may have increased acute and late toxic effects and doses of radiation and chemotherapy drugs may need to be modified.[11, 12]
- Surgery is required for:
- Tumours that fail to respond to radiotherapy.
- Large tumours causing gastrointestinal obstruction.
- Small anal margin tumours without sphincter involvement.
- Standard salvage therapy for patients with residual disease following chemoradiotherapy has been abdominoperineal resection. Alternatively, patients may be treated with additional salvage chemoradiotherapy in the form of fluorouracil, cisplatin, and a radiation boost to potentially avoid permanent colostomy.
- Patients with anal cancer may require radical inguinal lymphadenectomy. The National Institute for Health and Clinical Excellence (NICE) does not currently recommend endoscopic radical inguinal lymphadenectomy because of inadequate evidence of safety and efficacy.
- Complications of radiation therapy include anal ulcers, anal stenosis and necrosis.
- The overall five-year survival rate in the USA was 62% in the 1980s and has changed little in a period of two decades. The reported five-year survival rate following surgery is 40-70%.
- The three major prognostic factors are site (anal margin tumours are better differentiated and have a better prognosis than anal canal tumours), size and lymph node status.
- A cut-off of 4-5 cm has been proposed as the size that distinguishes good and poor prognosis.
- The level of tumour regression (>80%) after primary chemoradiation may be predictive of colostomy-free survival and disease-free survival.
- Radiation therapy, given as external-beam or brachytherapy, has a cure rate of 70-90% in selected patients. The cure rate is about 50% for those with tumours larger than 5 cm or if lymph nodes are involved.
Further reading and references
Anal cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis treatment and follow-up; European Society for Medical Oncology and others (July 2014)
Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2010)
Poggi MM, Suh WW, Saltz L, et al; ACR Appropriateness Criteria on treatment of anal cancer. J Am Coll Radiol. 2007 Jul4(7):448-56.
Sobhani I, Walker F, Roudot-Thoraval F, et al; Anal carcinoma: incidence and effect of cumulative infections. AIDS. 2004 Jul 2318(11):1561-9.
Esiashvili N, Landry J, Matthews RH; Carcinoma of the anus: strategies in management. Oncologist. 20027(3):188-99.
Belkacemi Y, Berger C, Poortmans P, et al; Management of primary anal canal adenocarcinoma: a large retrospective study from the Rare Cancer Network. Int J Radiat Oncol Biol Phys. 2003 Aug 156(5):1274-83.
Das P, Crane CH, Ajani JA; Current treatment for localized anal carcinoma. Curr Opin Oncol. 2007 Jul19(4):396-400.
Cummings BJ; Current management of anal canal cancer. Semin Oncol. 2005 Dec32(6 Suppl 9):S123-8.
Kauh J, Koshy M, Gunthel C, et al; Management of anal cancer in the HIV-positive population. Oncology (Williston Park). 2005 Nov19(12):1634-8
Salama JK, Mell LK, Schomas DA, et al; Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal J Clin Oncol. 2007 Oct 1025(29):4581-6.
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