A Comparative Study Between Copy Number Alterations and PRAME Immunohistochemical Pilot Study in Challenging Melanocytic Lesions

Abstract

Introduction: Diagnostic uncertainty for ambiguous lesions that fall on the spectrum between nevi and melanoma remains a significant challenge and can have consequences for patient management.

Methods: This study aimed to compare the diagnostic utility of preferentially expressed antigen in melanoma (PRAME) immunohistochemistry to molecular testing (FISH and SNP array) in 34 diagnostically challenging melanocytic lesions and 9 non-diagnostically challenging melanomas.

Results: We conclude that while PRAME immunohistochemistry demonstrates high specificity (96.2%) in diagnostically challenging melanocytic lesions, its low sensitivity (12.5%) suggests that it should not replace histopathological evaluation in rendering the final diagnosis.

Conclusions: These findings suggest that PRAME may serve as a useful adjunct in the diagnostic workup, particularly due to its high negative predictive value, but should be used in conjunction with other established diagnostic modalities.

Keywords: PRAME; copy number alteration; diagnostically challenging; melanoma; nevus.

Figure 1

A clinically atypical, pigmented lesion from the left upper back of a 66-year-old female patient that shows significant architectural atypia. The junctional component shows confluence of single cells flattening of rete ridges and the dermal melanocytes grow in the form of expansile nests with associated non-brisk lymphocytic host response. The melanocytes show pleomorphism and no signs of maturation with descent ((A), H&E 100×). The melanocytes show no immunoreactivity for PRAME immunohistochemistry ((B), PRAME immunostain 100×). Fluorescence in situ hybridization showed significant gains in 6p25 (red dots) in comparison to centromere 6 (blue dots) and was seen in 32% of the examined melanocytes; the red arrows highlight two cells with gains ((C) fluorescence in situ hybridization 6p25 probe; 1000×).

Figure 2

A non-pigmented melanocytic lesion on the forearm of a 47-year-old female patient with no previous history of melanoma. The melanocytic proliferation predominantly shows intradermal melanocytes ((A), H&E 40×). The nests grow in expansile nests with no signs of maturation ((B), H&E 100×). The melanocytes show marked pleomorphism with scattered large forms and nuclear inclusions; however, the background shows interspersed solar elastosis ((C), H&E 400×). PRAME immunostaining was negative throughout the lesion ((D), PRAME 40×; (E), PRAME 100×; (F) PRAME 400×). SNP array showed loss of one copy of entire chromosome 9 and X. Chromosome 1 q arm shows chromothripsis that consists of 22 copy number gains (3~4 copies) and 17 copy number losses (1 copy). The presence of chromothripsis is concerning for more aggressive biological behavior. The lesion was treated as a pT2a invasive melanoma and showed no residual disease and no evidence of metastatic melanoma in the sentinel lymph node. The patient is alive without disease at 61 months of follow-up.