Familial Atypical Multiple Mole Melanoma Syndrome

Familial atypical multiple mole melanoma syndrome is an autosomal dominant predisposition to melanoma, most often caused by germline CDKN2A variants, and carries an added risk of pancreatic cancer. Carriers of CDKN2A variants have lifetime risks of melanoma that depend strongly on sun exposure and region.

Pathophysiology. CDKN2A encodes p16INK4A and p14ARF, which restrain the cell cycle through CDK4 and p53. Loss of function allows melanocytes to proliferate. CDK4 variants cause a similar picture.

Melanoma often arises at a younger age and as multiple primaries. Pancreatic cancer risk is raised in CDKN2A carriers, and varies by variant.

Penetrance is higher in high ultraviolet environments, so prevention is central.

• Many melanocytic naevi, often atypical (dysplastic), with large and irregular lesions
• Multiple primary melanomas
• Early onset melanoma (often under 40 years)
• Family history of melanoma and pancreatic cancer
• Pancreatic adenocarcinoma, which is usually silent until advanced
• Other cancers in some families: nervous system tumours, breast cancer

• Clinical suspicion: at least 2 or 3 melanomas in first- or second degree relatives, multiple primary melanomas in one person, or melanoma with pancreatic cancer in the family.
• Genetic testing of CDKN2A and CDK4 with deletion and duplication analysis.
• Total body skin examination with dermoscopy and total body photography.
• Biopsy of changing lesions, with full thickness excisional biopsy.
• Pancreatic assessment for carriers: MRI or MRCP, and endoscopic ultrasound.

Differential diagnosis.

• Sporadic dysplastic naevus syndrome
• BAP1 tumour predisposition syndrome
• Xeroderma pigmentosum
• Other genes of melanoma predisposition (MITF, POT1)
• Congenital melanocytic naevus syndrome
• Familial pancreatic cancer of other cause

• Sun protection: sun protection factor 50 or more, protective clothing and hats, avoidance of sunbeds and tanning, and shade at peak ultraviolet hours. Check vitamin D and replace if low.
• Skin surveillance: total body skin examination with dermoscopy every 6 months, with photographic comparison, and monthly self-examination. Start from about 10 to 12 years in CDKN2A carriers.
• Excision of suspicious lesions rather than observation of changing naevi.
• Pancreatic surveillance in CDKN2A carriers: yearly MRI or MRCP, or endoscopic ultrasound, from about 40 years (or 10 years before the youngest affected relative), in a specialist programme.
• Melanoma management: wide local excision with margins by thickness: 1 cm for up to 1 mm, 1 to 2 cm for 1.01 to 2 mm, and 2 cm for over 2 mm. Sentinel node biopsy for thickness of 0.8 mm or more, or with ulceration.
• Adjuvant systemic therapy for high risk resected disease: pembrolizumab 200 mg intravenously every 3 weeks (or 400 mg every 6 weeks) or nivolumab 480 mg every 4 weeks for up to 1 year. For BRAF V600 mutation, dabrafenib 150 mg twice daily with trametinib 2 mg once daily for 12 months.
• Smoking cessation, since smoking raises the risk of pancreatic cancer in carriers.
• Genetic counselling: 50% chance of the variant for each child.

Special groups.

• Children and adolescents: sun behaviour, regular examination, and counselling at the time of testing.

Monitoring. Skin every 6 months, pancreatic imaging yearly, and review of family history.

Referral and escalation. Refer to dermatology, clinical genetics and a pancreatic surveillance service. Urgent for a changing, bleeding or new pigmented lesion, or new jaundice, back pain or weight loss.