DP08 Next-generation sequencing: the future for malignant melanoma diagnostic precision? A case of a BAP1 mutation

Abstract

Abstract A 48-year-old man presented to the hand surgeons with a 5-year history of a subcutaneous swelling on his right wrist, associated with paraesthesia and pain, initially thought to be a benign ganglion. Excision biopsy of the lesion on histology revealed an encapsulated pleomorphic tumour attached to a nerve, thought to represent a sarcoma. Immunohistochemistry showed a positive reaction to S100, SOX10, calretinin and synaptophysin. Ki67 showed a 20% proliferation index. Multiple pathology opinions were sought, and further testing was performed at a specialist genomic laboratory. Detailed questioning regarding family history of malignancy revealed that the patient’s mother had died from metastatic uveal melanoma, a maternal aunt had died of a brain tumour and his maternal grandmother had lung cancer. Pan-cancer gene panel DNA next-generation sequencing showed a BAP1 mutation with a very high variant allele fraction, suggestive of germline inheritance. Given the clinical history, morphology, immunoprofile and DNA result, a favoured diagnosis of metastatic malignant melanoma with a BAP1 mutation was made. The patient was referred to the specialist skin cancer multidisciplinary team meeting and reviewed by the dermatology team. Full skin check examination revealed two long-standing atypical naevi (> 10 years), one on the left forearm and another on his back, and these were excised urgently. Histology of the back lesion showed a polypoid melanocytic tumour comprising large epithelioid melanocytes with mild-to-moderate nuclear pleomorphism, multinucleated cells and intranuclear inclusions. This was in keeping with a pT4a nodular malignant melanoma with 7-mm Breslow thickness, associated with BAP1-inactivated syndrome. Histology of the left forearm lesion was consistent with a combined BAP1-inactivated melanocytoma, otherwise known as a ‘BAPoma’. An ophthalmology review did not identify a primary uveal melanoma. Staging scans of his chest, abdomen and pelvis and magnetic resonance imaging of his head showed no evidence of metastatic disease. The patient was referred for genetics counselling, wide local excision of the melanoma on his back, for consideration of adjuvant therapy with oncology and long-term follow-up with dermatology. BAP1 tumour predisposition syndrome is a newly recognized cancer syndrome that predisposes the patient to uveal melanoma, malignant mesothelioma, renal cell carcinoma, cutaneous melanomas and a range of other cancers (Masoomian B, Shields JA, Shields CL. Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. J Curr Ophthalmol 2018; 30:102–9). BAP1-related cancers tend to occur earlier in life and are more aggressive. Our case highlights the need for early identification of germline mutations through sequencing to improve outcomes and treatment-related morbidity by early diagnosis in these rare cancer syndromes.