PRAME as a Diagnostic Marker in Desmoplastic Melanocytic Lesions: Insights and Challenges

To the Editor: We read with interest Machuca-Aguada et al's study, “Unraveling Preferentially Expressed Antigen in Melanoma (PRAME) Expression in Desmoplastic Melanocytic Neoplasms: Illuminating its Diagnostic Significance in Distinguishing Desmoplastic Spitz Nevi”.1 Although Machuca-Aguada et al's findings on PRAME negativity in desmoplastic Spitz nevi provide valuable insights into the immunophenotypic characteristics of these lesions, we believe that the practical utility of PRAME immunohistochemistry in the differential diagnosis of desmoplastic melanoma remains debatable. We analyzed 5 cases of desmoplastic melanoma from our department's archives (Table 1). In all cases, S100 positivity and the absence of additional melanocytic markers were detected. Three cases were classified as pure subtype and 2 as mixed. PRAME antibody was applied. The optimized assay included heat-induced antigen retrieval for 68 minutes using high pH buffer, followed by incubation with mAb EPR20330 (ABCAM, United Kingdom) at a dilution of 1:200 for 120 minutes using the BenchMark ULTRA (Ventana Medical Systems, Inc.) automated stainer platform. Internal controls were sebaceous glands, and the external control was a melanoma case with diffuse PRAME positivity. None of the desmoplastic melanoma cases showed PRAME positivity. Table 1. - Characteristics of 5 Desmoplastic Melanoma Cases Case Sex Localization Subtype Age Tumor Thickness (mm) In situ Component Perineural Invasion S100 Melan-A SOX10 HMB45 PRAME 1 F Face, malar region Pure 62 9 Present Present (+) (−) (+) (−) (−) 2 M Scalp Mixed 67 14 Absent Present (+) (−) (+) (−) (−) 3 M Nose Pure 79 6.8 Present Present (+) (−) (+) (−) (−) 4 F Nose Pure 60 4.5 Present Present (+) (−) (+) (−) (−) 5 M Scalp Mixed 65 12.5 Absent Present (+) (−) (+) (−) (−) We agree with Machuca-Aguada et al that the differential diagnosis of desmoplastic nevus and desmoplastic melanoma may be challenging in some circumstances. Machuca-Aguada et al demonstrated that desmoplastic Spitz nevi tend to be negative for PRAME antibody, suggesting that PRAME positivity in desmoplastic melanoma could be useful in distinguishing between these 2 entities. Nevertheless, the initial study examining PRAME expression in cases of desmoplastic melanoma found that PRAME positivity is limited to the in situ component and the nondesmoplastic invasive components of desmoplastic melanomas.2 This implies that the unremarkable pure desmoplastic melanoma cells, which are the phenotypic hallmark that leads to the aforementioned differential diagnosis, are unlikely to show a reaction to the PRAME antibody. In addition, in the largest series investigating PRAME expression in desmoplastic melanoma, Rawson et al3 stated that the PRAME reaction is almost always present in high-grade desmoplastic melanomas, which do not usually pose a diagnostic dilemma. Desmoplastic Spitz neoplasms with cytological atypia and variable cellularity may present a diagnostic challenge when differentiating from mixed desmoplastic melanoma, where PRAME expression is typically more prevalent. However, in cases with bland-looking spindle cells on a sclerotic background, PRAME offers no value in the differential diagnosis. Furthermore, Machuca-Aguada et al mentioned in their article that mutations in BRAF, NRAS, and telomerase reverse transcriptase (TERT) may serve as diagnostic aids for desmoplastic melanoma. Although a TERT promoter region mutation may be seen in desmoplastic melanoma and may contribute to the diagnosis, it is widely recognized that common oncogenic mutations in the mitogen-activated protein kinase pathway such as BRAF and NRAS are uncommon in desmoplastic melanomas.4 Desmoplastic melanomas that develop on chronically sun-exposed skin are expected to harbor NF1 mutations.5 NF1 mutations and TERT promoter region mutations may aid diagnosis. Nevertheless, although it is not practical in all situations, the best current approach for the diagnosis of desmoplastic melanoma is searching for an in situ component and conducting investigations to reveal peculiar immunophenotypic findings in cases with bland-looking spindle cells on a sclerotic background, accompanied by lymphoid aggregation and neurotropism in chronically sun-exposed skin lesions in elderly adults, in our opinion.