Anal Cancer

DEFINITION AND PATHOGENESISTop

The term “anal cancer” refers to epithelial malignancies that develop around the anus (anal margin caner) or in the anal canal (anal canal cancer). Anal cancers are most commonly squamous cell carcinomas (SCCs). The main cause of anal SCC is human papillomavirus (HPV) infection, specifically serotypes 16 and 18. Risk factors for anal cancers can be grouped into 2 categories:

1) HPV-related risk factors (eg, lifetime number of sexual partners, history of anogenital warts, anoreceptive intercourse, history of cervical, vaginal, or vulvar cancer).

2) Immunosuppression (eg, HIV infection, solid organ transplant recipient).

3) Other important risk factors, including female sex, smoking, and advanced age.

EPIDEMIOLOGYTop

Anal cancer is a relatively rare gastrointestinal (GI) malignancy (~2%). Patients are most commonly aged between 50 and 60 years. Women are more commonly affected than men.

Adenocarcinoma constitutes up to 10% of anal canal cancers, and <1% present as melanoma (often amelanocytic in this localization).

CLINICAL FEATURESTop

Initial symptoms may include burning, itching, and pain in the anus, presence of mucus or fresh blood in stool, and/or palpable hardness around the anus. As the disease progresses, patients may begin to experience pelvic pain and pressure, tenesmus, sphincter dysfunction (gradual loss of the ability to discriminate between feces and gases followed by impaired fecal continence), and obstructive symptoms (eg, constipation, obstipation, narrowed caliber of stool). Up to 20% of patients diagnosed with anal SCC have no prior symptoms.

DIAGNOSISTop

Physical examination is the first step in diagnosis. A thorough anorectal examination with digital rectal examination (DRE) and palpation of the inguinal regions for lymphadenopathy are important in defining the location (ie, anal canal versus anal margin) and extent of disease. Endoscopy-guided biopsy is then required for tissue diagnosis (usually anoscopy, rectoscopy, or sigmoidoscopy). This may be done in the clinic, endoscopy suite, or operating room. A fine-needle aspiration of material from any suspicious inguinal lymph nodes is also required for tissue diagnosis. Women should undergo a concomitant gynecologic examination with cervical cancer screening. The remainder of the staging investigations include colonoscopy, magnetic resonance imaging (MRI) of the pelvis, and computed tomography (CT) of the chest, abdomen, and pelvis or positron emission tomography (PET)/CT. If patients describe symptoms that suggest central nervous system involvement (eg, headache, visual disturbances), a CT scan of the head can be considered as part of staging investigations.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to observational nature of data. Stewart DB, Gaertner WB, Glasgow SC, Herzig DO, Feingold D, Steele SR. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for Anal Squamous Cell Cancers (Revised 2018). Dis Colon Rectum. 2018;61(7):755-774. doi: 10.1097/DCR.0000000000001114. PMID: 29878949. Bhuva NJ, Glynne-Jones R, Sonoda L, Wong WL, Harrison MK. To PET or not to PET? That is the question. Staging in anal cancer. 2012 Aug;23(8):2078-2082. doi: 10.1093/annonc/mdr599. Epub 2012 Jan 31. Osborne MC, Maykel J, Johnson EK, Steele SR. Anal squamous cell carcinoma: An evolution in disease and management. World J Gastroenterol. 2014 Sep 28;20(36):13052-9. doi: 10.3748/wjg.v20.i36.13052. PMID: 25278699; PMCID: PMC4177484.

Staging: Table 1 and Table 2.

TREATMENTTop

Treatment depends on cancer location and stage.

1. Anal canal SCC: A chemoradiotherapy regimen (labelled the Nigro protocol) including high-dose radiotherapy, 5-fluorouracil, and mitomycin C is the standard of care for curative-intent therapy for anal canal SCCs.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Stewart DB, Gaertner WB, Glasgow SC, Herzig DO, Feingold D, Steele SR. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for Anal Squamous Cell Cancers (Revised 2018). Dis Colon Rectum. 2018;61(7):755-774. doi: 10.1097/DCR.0000000000001114. PMID: 29878949. Osborne MC, Maykel J, Johnson EK, Steele SR. Anal squamous cell carcinoma: An evolution in disease and management. World J Gastroenterol. 2014 Sep 28;20(36):13052-9. doi: 10.3748/wjg.v20.i36.13052. PMID: 25278699; PMCID: PMC4177484. Nigro ND, Vaitkevicius VK, Considine B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974 May-Jun;17(3):354-6. doi: 10.1007/BF02586980. PMID: 4830803. UKCCCR Anal Cancer Trial Working Party; UK Coordinating Committee on Cancer Research. Epidermoid anal cancer: results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996 Oct 19;348(9034):1049-54. PMID: 8874455. If patients recur following that protocol or have incomplete disease response, salvage abdominal-perineal resection (APR) is offered. Survival following salvage APR is poor (5-year overall survival in 30% of cases).

2. Anal margin SCC: Early stage (T1-T2) tumors that do not have nodal metastases and do not involve the anal sphincter complex can be treated with a wide local excision with 1-cm margins. More advanced tumors, disease that extends to lymph nodes or other distant organs, or disease that involves unresectable local structures should be treated according to the Nigro protocol.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Stewart DB, Gaertner WB, Glasgow SC, Herzig DO, Feingold D, Steele SR. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for Anal Squamous Cell Cancers (Revised 2018). Dis Colon Rectum. 2018;61(7):755-774. doi: 10.1097/DCR.0000000000001114. PMID: 29878949. Osborne MC, Maykel J, Johnson EK, Steele SR. Anal squamous cell carcinoma: An evolution in disease and management. World J Gastroenterol. 2014 Sep 28;20(36):13052-9. doi: 10.3748/wjg.v20.i36.13052. PMID: 25278699; PMCID: PMC4177484. Nigro ND, Vaitkevicius VK, Considine B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974 May-Jun;17(3):354-6. doi: 10.1007/BF02586980. PMID: 4830803. UKCCCR Anal Cancer Trial Working Party; UK Coordinating Committee on Cancer Research. Epidermoid anal cancer: results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996 Oct 19;348(9034):1049-54. PMID: 8874455.

3. Other histopathologic types (adenocarcinoma and melanoma) require specific treatment strategies, usually guided by a multidisciplinary team.

FOLLOW-UPTop

DRE, endoscopic evaluation (eg, anoscopy, flexible sigmoidoscopy), and imaging should be continued for 5 years following completion of treatment. Physical examination with DRE is recommended every 3 to 6 months, and CT of the chest, abdomen, and pelvis is recommended every year for patients with T3 to T4 or lymph node–positive disease.Evidence 4Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to observational data and pattern of practice. Stewart DB, Gaertner WB, Glasgow SC, Herzig DO, Feingold D, Steele SR. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for Anal Squamous Cell Cancers (Revised 2018). Dis Colon Rectum. 2018;61(7):755-774. doi: 10.1097/DCR.0000000000001114. PMID: 29878949. Osborne MC, Maykel J, Johnson EK, Steele SR. Anal squamous cell carcinoma: An evolution in disease and management. World J Gastroenterol. 2014 Sep 28;20(36):13052-9. doi: 10.3748/wjg.v20.i36.13052. PMID: 25278699; PMCID: PMC4177484. National Comprehensive Cancer Care Network. NCCN clinical practice guidelines in oncology anal carcinoma, version 1.2018. Accessed July 14, 2022. https://www.nccn.org/login?RetVal=1&ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf

SCREENING AND PREVENTIONTop

There are several vaccines against HPV that are recommended by public health guidelines. Bivalent vaccines available in Canada have high efficacy against HPV-16 (eg, Cervarix, GlaxoSmithKline). Available quadrivalent vaccines are highly effective against HPV-16 and HPV-18 (eg, Gardasil, Merck & Co). Screening modalities for precursor squamous intraepithelial lesions include anal Pap smears and high-resolution anoscopy and can be used in high-risk populations. However, detailed screening guidelines are not well established.

PROGNOSISTop

Disease stage at diagnosis is the most important prognostic factor for anal SCC. Five-year overall survival is 80% for patients presenting with local disease (ie, T1-T3N0), 65% for locoregional disease (ie, locally invading adjacent organs, involved lymph nodes), and 35% for distant disease (ie, distant metastases).

TABLESTop