Contributed by Tanner Freeman MD, PhD, John M. Skaugen, MDCASE RESOLUTION
The tumor was diagnosed as undifferentiated melanoma.
Molecular testing demonstrated the tumor to be positive for BRAF p.V600E mutation as well as TERT promoter C228T mutation, TP53 p.M246R mutation and CDKN2A p.Q50* mutation with tumor mutational burden of 24.6 Mutations/Mb (91.1 percentile). There was no copy number alterations identified and the tumor was microsatellite stable. The tumor was diagnosed as undifferentiated melanoma.
Melanoma is a malignant tumor arising from melanocytes. Though melanoma represents less than 5% of all cutaneous malignancies, melanoma accounts for the vast majority deaths associated with skin cancer making timely diagnosis important. Melanoma has been called "the great mimicker" for it can present histologically similar to many other tumors. Typically melanoma does express immunohistochemical markers (S100, Sox10 MelanA /MART1, HMB45, etc.).
However, in this case, the tumor did not express these markers. Undifferentiated melanoma is defined as primary or metastatic melanoma that lacks the morphologic and immunologic features of melanoma. This means that this entity is impossible to diagnose by conventional immunohistochemical methods. Melanoma also has well described driver mutations: BRAF, NRAS, NF1 and KIT. Melanomas also often demonstrate mutations in TERT CDKN2A, PTEN, TP53. These cases may get misdiagnosed as undifferentiated pleomorphic sarcomas meaning it is important when there is history of melanoma or an odd presentation, as in this case to consider molecular testing of these lesions. In this case, a driver BRAF V600E mutation was identified which permitted the diagnosis of undifferentiated melanoma as well as providing a therapeutic target for the patient.
Molecular testing is performed on specimens to aid in diagnosis, provide insight into prognosis and/or identify therapeutic targets. The method of molecular testing may be influenced by the tumor cellularity, amount of tissue present or known melanoma history that was previously tested for molecular alteration. Sanger sequencing works by random incorporation of chain-terminating dideoxynucleotides to identify alterations from a reference genome. Sanger sequencing has the advantage of being faster and more cost effective for detecting single or small number of mutations; however, the sensitivity of Sanger sequencing is 15-20% tumor cellularity within the provided sample. Next generation sequencing is a massively parallel or deep sequencing provides multiple reads over targeted regions of the genome. Next generation sequencing affords greater sensitivity and for a larger number of genes to be examined for alterations. However, next generation sequencing is often more expensive and slower than Sanger sequencing. In this case, next generation sequencing was utilized as the initial diagnosis did not point to a specific panel of genes that should be interrogated.
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Contributed by Tanner Freeman MD, PhD, John M. Skaugen, MD
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