TERT Promoter Mutational Analysis as an Ancillary Diagnostic Tool for Diagnostically Challenging Melanocytic Neoplasms

Abstract

Telomerase reverse transcriptase promoter mutations (TPMs) have been shown to be common in melanoma and uncommon in benign nevi. To assess the use of TPMs as an ancillary diagnostic tool, we report the concordance of the TPM status with the final diagnosis in clinical cases with distinct differential diagnostic scenarios: dysplastic nevus versus melanoma, atypical Spitz nevus versus melanoma, atypical deep penetrating nevus (DPN) versus melanoma, and atypical blue nevus versus malignant blue nevus. In a control cohort, we found a positive TPM in 51/70 (73%) of the total melanomas with the highest frequency in vertical growth phase melanoma cases. Conversely, only 2/35 (6%) dysplastic nevi in our control cases were TPM-positive and b were severely atypical dysplastic nevi. Our clinical cohort of 257 cases had a positive TPM in 24% of cases diagnosed as melanoma and in 1% of cases with a benign diagnosis. The overall concordance of the TPM status with the final diagnosis was 86%. The TPM status had the greatest concordance (95%) with the final diagnosis in the atypical DPN versus melanoma group, with the rest of the groups ranging between 50% and 88%. Overall, our results suggest that TPMs are most useful in the differential diagnosis of atypical DPN versus melanoma. It also has some value in the differential diagnosis of atypical Spitz tumor versus melanoma and dysplastic nevus versus melanoma, whereas in our cohort, it did not contribute meaningfully to differentiating malignant blue nevus and atypical blue nevus.

Characterization of PRAME immunohistochemistry reveals lower expression in pediatric melanoma compared to adult melanoma

“…Melanomas arising from congenital nevi may be an exception to this rule. In a recent case report and a recently published study, it was shown in the differentiation of benign proliferating nodules and melanomas arising from congenital nevi that the latter express an increased amount of PRAME (Boutko et al., 2023; Gill et al., 2021). Our data also support this hypothesis.…”

“…Studies suggest that the use of PRAME in the setting of spitzoid tumors is of limited value (Raghavan, Wang, et al., 2020). In contrast, a recent publication found a possible role of PRAME in the differentiation of benign proliferating nodules of melanomas at the base of congenital giant nevi (Boutko et al., 2023).…”

A clinical and biologic review of congenital melanocytic nevi

“…H3K27 trimethylation (H3K27me3), a well-known epigenetic gene silencer that can inhibit transcription, has been observed to have decreased expression in melanomas arising from CMN but is retained or only mildly reduced in PNs. 42 43,44 They found that anti-PRAME was diffusely positive within the melanoma while negative within PNs most of the time. Of note, the three technologies mentioned above should only be regarded as supplementary tools to other assessments rather than definitive tests of malignancy as they are not entirely specific.…”

“…and Boutko et al. successfully applied the preferentially expressed antigen in melanoma (PRAME) as a helpful diagnostic tool in rendering a diagnosis in atypical melanocytic proliferations 43,44 . They found that anti‐PRAME was diffusely positive within the melanoma while negative within PNs most of the time.…”