Anal Adenocarcinoma

Anal adenocarcinoma is a malignant glandular tumour arising in the anal canal. It originates from the anal glands and ducts, from chronic anorectal fistulae, or from rectal type glandular mucosa proximal to the dentate line (colorectal type). It differs from anal squamous cell carcinoma in biology, response to therapy and prognosis, and it is treated on the lines of low rectal adenocarcinoma, not with the chemoradiotherapy used for squamous disease.

It forms about 3% to 10% of anal cancers, with an incidence of about 0.1 to 0.2 cases in 100,000 people each year. Median age at diagnosis is 60 to 65, with a slight male predominance for the colorectal type.

Risk factors are long standing Crohn disease with perianal fistulae (the fistula associated type, often mucinous), chronic anorectal fistula or abscess, and ulcerative colitis. Unlike squamous carcinoma, HPV is not a major cause.

Pathophysiology. Colorectal type tumours share molecular alterations with rectal cancer (APC, KRAS, TP53 mutations, and a minority with mismatch repair deficiency). Fistula associated and anal gland tumours are often mucinous, with difficult early detection and spread along the fistula.

Prognosis. Five year survival is about 40% to 60% overall, and is better after chemoradiotherapy and surgery for localised disease than for tumours found late or with positive margins. Nodal involvement (inguinal and mesorectal) and distant metastases are common.

• Rectal bleeding, anal pain, a mass, pruritus and change in bowel habit.
• Discharge, mucus and recurrent perianal sepsis, with a non-healing fistula in Crohn disease.
• Faecal incontinence from sphincter invasion, and inguinal lymphadenopathy.
• Late: weight loss and symptoms of liver or lung metastases.

Red flags.

• A non-healing perianal fistula or ulcer, or a new induration over a long standing fistula.
• Rectal bleeding with a palpable mass.
• Perianal sepsis not responding to drainage.

• Digital rectal examination and proctoscopy, with examination under anaesthesia and deep biopsies (including fistula tract curettage) when the diagnosis is suspected.
• Histology and immunohistochemistry: CK7, CK20 and CDX2 (colorectal type CK20 and CDX2 positive), with squamous markers (p40, p63, CK5/6) negative. Mismatch repair or microsatellite instability testing, and RAS and BRAF testing.
• MRI of the pelvis for local extent (sphincter complex, mesorectal fascia, nodes), CT of the chest, abdomen and pelvis, and PET-CT for nodal or distant disease. Ultrasound or biopsy of enlarged inguinal nodes.
• CEA, FBC, liver tests and creatinine. Colonoscopy to exclude a synchronous colorectal primary, and Crohn disease activity assessment.

Differential diagnosis.

• Anal squamous cell carcinoma and basaloid carcinoma
• Low rectal adenocarcinoma invading the anus
• Perianal Crohn fistula, anal gland abscess and Paget disease of the perianal skin
• Anal melanoma and neuroendocrine tumour

Management is decided by a colorectal multidisciplinary team and follows the approach for locally advanced low rectal cancer.

Localised and locally advanced disease.

• Neoadjuvant chemoradiotherapy to shrink the tumour and treat the nodes, including the inguinal nodes when involved: capecitabine 825 mg/m2 orally twice daily on each radiotherapy day (Monday to Friday) with meals for 5 to 5.5 weeks, given with pelvic radiotherapy of 50.4 Gy in 28 fractions; maximum 1650 mg/m2 daily; monitoring: FBC, creatinine, liver tests, hand foot syndrome, diarrhoea and perianal skin reaction weekly, DPYD genotype before starting; adjustment: reduce by 25% when creatinine clearance is 30 to 50 mL/min and avoid under 30 mL/min, hold for grade 3 toxicity until grade 1 and resume at 75% of the dose, avoid warfarin because of a marked rise in INR
• Abdominoperineal excision of the anorectum 8 to 12 weeks after chemoradiotherapy, with wide perineal excision and often a flap reconstruction, because sphincter preservation is rarely oncologically safe. Local excision is limited to small, early, well differentiated tumours.
• Adjuvant chemotherapy after surgery for higher risk disease: oxaliplatin 85 mg/m2 IV over 2 hours on day 1, levoleucovorin 200 mg/m2 (or leucovorin 400 mg/m2) IV over 2 hours on day 1 and fluorouracil 400 mg/m2 IV bolus on day 1 followed by 2400 mg/m2 by continuous infusion over 46 hours, every 14 days for 12 cycles after resection or until progression in advanced disease; maximum oxaliplatin cumulative 850 mg/m2 because of cumulative neuropathy; monitoring: FBC, creatinine, liver tests, neuropathy and cold sensitivity, mucositis, diarrhoea, DPYD genotype before starting; adjustment: reduce oxaliplatin to 65 mg/m2 for persistent grade 2 neuropathy and stop for grade 3, reduce fluorouracil by 20% after grade 3 mucositis or diarrhoea, use oxaliplatin 65 mg/m2 when creatinine clearance is 30 to 50 mL/min and avoid under 30 mL/min, delay for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L

Inguinal nodes. Included in the radiotherapy field when involved or when risk is high, with inguinal node dissection for persistent disease.

Metastatic disease.

• Chemotherapy for advanced disease: oxaliplatin 85 mg/m2 IV over 2 hours on day 1, levoleucovorin 200 mg/m2 (or leucovorin 400 mg/m2) IV over 2 hours on day 1 and fluorouracil 400 mg/m2 IV bolus on day 1 followed by 2400 mg/m2 by continuous infusion over 46 hours, every 14 days for 12 cycles after resection or until progression in advanced disease; maximum oxaliplatin cumulative 850 mg/m2 because of cumulative neuropathy; monitoring: FBC, creatinine, liver tests, neuropathy and cold sensitivity, mucositis, diarrhoea, DPYD genotype before starting; adjustment: reduce oxaliplatin to 65 mg/m2 for persistent grade 2 neuropathy and stop for grade 3, reduce fluorouracil by 20% after grade 3 mucositis or diarrhoea, use oxaliplatin 65 mg/m2 when creatinine clearance is 30 to 50 mL/min and avoid under 30 mL/min, delay for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L
• Immunotherapy for tumours with mismatch repair deficiency or high microsatellite instability: pembrolizumab 200 mg IV over 30 minutes every 3 weeks (or 400 mg every 6 weeks) for up to 24 months or until progression or unacceptable toxicity; maximum 200 mg each 3-week dose; monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis, infusion reactions; adjustment: no renal or mild hepatic dose adjustment, withhold for grade 2 immune toxicity and give prednisolone 0.5 to 1 mg/kg daily, stop permanently for grade 3 to 4 toxicity (except endocrinopathies controlled on replacement) and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks
• Metastasectomy, ablation or embolisation for limited liver or lung disease.

Fistula associated tumours in Crohn disease. Treatment of active inflammation is optimised with the gastroenterology team, and the surgical plan includes the diseased segment and sepsis control.

Supportive care. Stoma care and counselling, pain control, perineal wound care, pelvic floor and sexual rehabilitation, and nutritional support.

Monitoring. Clinical examination, CEA and MRI or CT every 3 to 6 months for 2 years and then every 6 to 12 months to year 5. Colonoscopy at 1 year and then every 3 to 5 years.

Referral and escalation.

• Urgent referral to a colorectal cancer centre for any anal lesion with induration or a non-healing fistula.
• Same day assessment for perianal sepsis, obstruction or bleeding.

Special groups.

• Crohn disease: joint gastroenterology and surgical decisions about immunosuppression.
• Older or frail patients: dose reduced chemoradiotherapy or radiotherapy alone with palliative aims.
• Pregnancy: individualised care with delay of therapy where possible.