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- 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.
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 cancers are relatively rare tumours. However, their incidence is increasing, particularly among men who have sex with other men, due to widespread infection by human papillomavirus.
- The annual incidence in the UK is about 1.5 in 100,000.
- Lymph node involvement is seen in 30-40% of patients at diagnosis but systemic spread is uncommon with distant extrapelvic metastases seen in 5-8% at the time of diagnosis.
- Human papillomavirus (HPV): Squamous cell carcinoma of the anus is strongly associated with human papillomavirus (HPV) infection which represents the causative agent in 80-85% of patients (usually from HPV16 or HPV18 subtypes in Europe) as is its precursor lesion anal intraepithelial neoplasia (AIN).
- 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.
- Women with a history of cervical cancer or cervical intraepithelial neoplasia (CIN) are also known to have a greater risk for anal cancer.
- Other important risk factors include immune suppression in transplant recipients, and cigarette smoking.
- Premalignant changes (AIN) occur.
- Although randomised controlled trials evaluating screening and treatment outcomes are lacking, experts support routine screening for AIN in high-risk populations.
- AIN can be treated using topical therapies such as imiquimod, 5-flurouracil, and trichloroacetic acid, as well as ablative therapies such as electrocautery and laser therapy. Reductions in AIN and anal cancer rates have been shown in studies where high-risk populations were vaccinated against the oncogenic strains of HPV.
- 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.
- Anal cancer guidelines state that a careful clinical examination, including a digital rectal examination (DRE), an anoscopic examination with biopsy, and palpation of inguinal nodes, is recommended for the assessment of T stage.
- 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.
With a typical natural history of slow growth and a low rate of distant metastases, anal cancer is usually amenable to locoregional treatment.
Local excision can be considered for small well-differentiated carcinomas of the anal margin. Combined modality chemotherapy, using 5-fluorouracil (5-FU) and mitomycin C, and radiotherapy is recommended as first-line treatment for all other cases, with salvage surgery reserved for those who fail on this regimen. The standard chemotherapy for metastatic anal cancer is with 5-FU and cisplatin.
- 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 pre-treatment 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.
- 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 Care 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.
- Five-year survival has changed little in a period of two decades. In the USA, the overall five-year survival rates for 1994-2000 were 60% for men and 78% for women. In Europe, five-year survival varied between 66% (Central Europe) and 44% (Eastern Europe).
- 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)
Ghosn M, Kourie HR, Abdayem P, et al; Anal cancer treatment: current status and future perspectives. World J Gastroenterol. 2015 Feb 2821(8):2294-302. doi: 10.3748/wjg.v21.i8.2294.
Gami B, Kubba F, Ziprin P; Human papilloma virus and squamous cell carcinoma of the anus. Clin Med Insights Oncol. 2014 Sep 178:113-9. doi: 10.4137/CMO.S13241. eCollection 2014.
Anal Cancer; National Cancer Institute (US)
Roberts JR, Siekas LL, Kaz AM; Anal intraepithelial neoplasia: A review of diagnosis and management. World J Gastrointest Oncol. 2017 Feb 159(2):50-61. doi: 10.4251/wjgo.v9.i2.50.
Medford RJ, Salit IE; Anal cancer and intraepithelial neoplasia: epidemiology, screening and prevention of a sexually transmitted disease. CMAJ. 2015 Feb 3187(2):111-5. doi: 10.1503/cmaj.140476. Epub 2014 Dec 15.
Granata V, Fusco R, Reginelli A, et al; Radiological assessment of anal cancer: an overview and update. Infect Agent Cancer. 2016 Oct 1211:52. doi: 10.1186/s13027-016-0100-y. eCollection 2016.
Management of Squamous Cell Cancer of the Anal Canal: Guideline Recommendations; Cancer Care Ontario, March 2009