Multiple primary malignancies and prolonged survival in a patient with widespread metastatic cutaneous melanoma

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We report a possibly unique patient who developed four different primary malignancies, in the absence of any detectable germline genetic abnormality or a family history of malignancy. The patient has also survived for more than 15 years after local treatments (without immunotherapy) of cutaneous melanoma metastatic to her orbit, brain, skeleton and peritoneum. A 68-year-old White British woman was referred to the Orbital Service at Moorfields Eye Hospital with a 4-month history of right proptosis and true binocular diplopia, this being 41 months after having a 0.8-mm superficial spreading malignant melanoma of her left ankle treated with wide local resection. She underwent resection of a left frontal lobe metastasis a year before orbital presentation. Computed tomographic scan showed a well-defined Supero-temporal soft-tissue mass in the right retrobulbar fat (Fig. 1a and b). The patient underwent anterior orbitotomy through an upper eyelid skin-crease incision, with macroscopic excision of the mass, and histological examination showed infiltrative melanoma compatible with metastasis from her previous skin malignancy (Fig. 2). She underwent external beam radiotherapy (30 Gy in five fractions over 2 weeks) to the right retrobulbar tissues.
Three months after the orbitotomy (44 months after the primary skin tumour), the patient was found to have a right femoral bony metastasis, which responded well to local radiotherapy and insertion of an intramedullary femoral nail. At 57 months after the primary skin lesion, the patient underwent resection of multiple retroperitoneal deposits of metastatic melanoma. There has been no further recurrence of metastatic cutaneous melanoma at 17 years following removal of the primary tumour (14 years after orbital presentation) (Fig. 1c and d).
The patient also had a melanoma of soft parts resected from her left thigh musculature at the age of 35 years. At age 48, she underwent left lumpectomy, radiotherapy and axillary nodal clearance for breast adenocarcinoma. The patient more recently has developed – at age 80 – squamous cell carcinoma of her scalp, this being treated with wide local excision; the tumour was remote from any area of previous periocular radiotherapy.
There is no family history of malignancy, even on interrogation of an extended family pedigree.
This study received ethics approval from Moorfields Eye Hospital Biobank ethics board (15/SW/0104). Written, informed consent was obtained from the family for participation in research and from the patient to publish her clinical history, imaging and genetic results.
DNA was extracted from the orbital tumour by standard methods and analysed for point mutations in common driver genes for cutaneous melanoma (BRAF, NRAS, KRAS) and ocular melanoma (GNAQ, GNA11); primer sequences and PCR conditions are available upon request. Sequencing of NRAS exon 3 showed a heterozygous point mutation (c.A182G; p.Q61R) (Fig. 1e). Sequencing of orbital tumour DNA was also performed for genes related to melanoma prognosis (SF3B1 and EIF1AX), with no somatic mutations being found. MLPA analysis for copy number variation indicated disomy of chromosome 3, with gain of chromosome 6p.
Genomic DNA extracted from peripheral blood under standard conditions was analysed by next-generation sequencing [Hereditary Cancer Syndromes, Comprehensive Diagnostics (ID 93.00); MGZ, Munich, Germany] – this being a multigene diagnostic panel testing for mutations in 94 genes that have been associated with familial-cancer or multiple-cancer syndromes. No germline mutations were shown for this patient.
Our patient is enigmatic on two counts: first, she has survived a perhaps unparalleled period of more than 15 years with cutaneous melanoma metastatic to the orbit, bone, peritoneum and brain. Second, she has had four different primary malignancies, these being cutaneous melanoma, melanoma of soft parts, breast adenocarcinoma and cutaneous squamous cell carcinoma.

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