Anal Melanoma

Anal melanoma is a mucosal melanoma arising from melanocytes of the anal canal and distal rectum. It is aggressive, frequently diagnosed late (mistaken for haemorrhoids), and has a high risk of distant spread. Median survival is about 1.5 to 2 years.

It forms under 1% of all melanomas, about 0.2% to 1% of anorectal malignancies, with an incidence of about 0.02 to 0.04 cases in 100,000 people each year. Median age at diagnosis is 65 to 70, with a female predominance (about 2 to 1) and a higher frequency in white patients.

Risk factors are not established. HPV and sun exposure are not clearly linked. Chronic irritation and immunosuppression have been suggested, but most cases are sporadic.

Pathophysiology. Mucosal melanomas differ from cutaneous melanoma. KIT alterations occur in about 15% to 25% (activating mutations, amplification), NRAS in about 10% to 20%, BRAF V600E in under 10%, and SF3B1 mutations in some. The tumour spreads by local invasion, mesorectal and inguinal nodes, and blood borne spread to liver, lung, bone and brain.

Prognosis. Five year survival is about 10% to 20% overall and is similar for wide local excision and abdominoperineal resection. Tumour thickness, ulceration, nodal and distant disease are the main prognostic factors.

• Rectal bleeding (most common), anal pain, a lump, tenesmus, change in bowel habit and pruritus.
• A pigmented lesion in about two thirds, with amelanotic tumours (about 25%) looking like a polyp or haemorrhoid.
• Inguinal lymphadenopathy (about 25% to 30%), faecal incontinence from sphincter invasion.
• Weight loss, hepatomegaly and respiratory symptoms from metastases.

Red flags.

• A pigmented or ulcerated anal lesion, or a persistent "haemorrhoid" that bleeds or enlarges.
• Rapid enlargement with inguinal nodes.
• Neurological symptoms (brain metastases).

• Digital rectal examination, anoscopy and examination under anaesthesia with incisional or excisional biopsy.
• Histology and immunohistochemistry: S100, SOX10, HMB-45 and Melan-A positive, with Breslow type thickness not used for staging. Amelanotic tumours need melanocytic markers to separate them from carcinoma or lymphoma.
• Molecular testing for KIT, NRAS and BRAF (and other fusions) on tumour tissue.
• MRI of the pelvis, endoanal ultrasound, CT of the chest, abdomen and pelvis (or whole body PET-CT), MRI of the brain and serum LDH.
• Inguinal node ultrasound and biopsy when palpable or suspicious. Sentinel node biopsy is not routine.

Differential diagnosis.

• Haemorrhoids, thrombosed external piles and anal fissure
• Anal squamous cell carcinoma and anal adenocarcinoma
• Rectal gastrointestinal stromal tumour and lymphoma
• Pigmented naevus, melanosis and a metastasis from cutaneous melanoma

Management is individualised in a specialist melanoma and colorectal team.

Localised disease.

• Wide local excision with clear margins (about 1 cm where achievable) when it preserves function, since survival is no different from abdominoperineal resection. Abdominoperineal resection is reserved for bulky tumours, invasion of the sphincters that prevents safe excision, and recurrent disease.
• Postoperative radiotherapy (about 30 to 50 Gy) to improve local control after wide local excision or for close or positive margins.
• Adjuvant immunotherapy is considered for resected high risk disease (nodal involvement or thick tumours): nivolumab 480 mg IV over 30 minutes every 4 weeks (or 240 mg every 2 weeks) for up to 12 months after complete resection; maximum 480 mg each 4-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 and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks

Inguinal nodes. Ultrasound directed biopsy of suspicious nodes, with inguinal node dissection for proven involvement.

Metastatic or unresectable disease.

• Combination immunotherapy: nivolumab 360 mg IV every 3 weeks with ipilimumab 1 mg/kg IV every 6 weeks, for up to 24 months or until progression or unacceptable toxicity; maximum nivolumab 360 mg each 3-week dose and ipilimumab 1 mg/kg each 6-week dose; monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis; 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 and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks
• Anti-PD-1 therapy alone for patients not fit for combination therapy: 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
• KIT-mutant tumours after immunotherapy or when it is not suitable: imatinib 400 mg orally once daily with food and a large glass of water, increased to 400 mg twice daily if there is no response after 4 to 8 weeks and the drug is tolerated, for tumours with an activating KIT mutation, until progression or unacceptable toxicity; maximum 800 mg daily; monitoring: FBC, liver tests, creatinine, weight and fluid retention, phosphate, response imaging at 8 to 12 weeks; adjustment: hold for ALT or AST over 5 times the upper limit or bilirubin over 3 times the upper limit until recovery then resume at 300 mg daily, reduce for grade 3 neutropenia, increase the dose by at least 50% with strong CYP3A4 inducers, avoid paracetamol at high doses and monitor INR in patients taking warfarin
• BRAF V600E-mutant tumours: dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily until progression or unacceptable toxicity, for BRAF V600E tumours in adults and in adolescents weighing 51 kg or more (weight banded doses set by a paediatric oncology pharmacist below 51 kg); maximum dabrafenib 300 mg daily and trametinib 2 mg daily; monitoring: left ventricular ejection fraction at baseline, 1 month and then every 2 to 3 months, skin and eye examination, blood pressure, liver tests, glucose, temperature; adjustment: reduce dabrafenib stepwise to 100 mg then 75 mg twice daily and trametinib to 1.5 mg then 1 mg daily, hold both for fever of 38.5 C or more, stop for a fall in ejection fraction of over 10 points to under the lower limit of normal, avoid strong CYP3A4 or CYP2C8 inducers and inhibitors, no renal adjustment for mild to moderate impairment
• Metastasectomy, palliative radiotherapy for bone and brain metastases, and stereotactic radiosurgery for brain disease. Palliative care input is early.

Monitoring. Clinical examination, proctoscopy and imaging (MRI pelvis and CT chest, abdomen and pelvis) every 3 to 4 months for 2 years, then every 6 months to year 5. Brain imaging as indicated. Thyroid, adrenal and glucose monitoring on immunotherapy.

Referral and escalation.

• Urgent referral to a melanoma and colorectal centre for any pigmented or suspicious anal lesion.
• Same day assessment for bleeding, obstruction, or immune related toxicity (diarrhoea, hepatitis, hypophysitis, pneumonitis).

Special groups.

• Older adults: wide local excision, avoidance of stomas where possible and monotherapy immunotherapy.
• Autoimmune disease or transplant recipients: increased risk with immunotherapy, and specialist assessment is needed.
• Pregnancy: individualised care and delay of systemic therapy where possible.