PRAME sets its eyes on the road to fame

By Jason B. Lee, MD, FAAD
May 10, 2023
Vol. 5, No. 19

In 1980, the discovery of S100 protein expression in cultured metastatic melanoma cell lines (1) stirred excitement in the pathology community for its potential role as a diagnostic marker for melanoma. The excitement was short-lived once it was found that it was expressed in both benign and malignant melanocytic neoplasms and a variety of other cells and neoplasms. (2) Subsequently, more specific markers for melanocytes have emerged (e.g. Melan-A/Mart-1 and SOX10) that have diminished the role of S100 in evaluating melanocytic neoplasms. The expression of S100 (along with SOX10), however, still plays a critical role today in establishing the diagnosis of desmoplastic melanoma. Similar to S100, the newer melanocytic markers do not differentiate benign from malignant melanocytic neoplasms. They are primarily used for determining the melanocytic nature of the lesion and better visualization of the architecture.

In 1997, another discovery of a protein, again, from cultured metastatic melanoma cell lines (3) excited the pathology community, but this time, the enthusiasm has been sustained. Preferentially expressed antigen in melanoma (PRAME), in contrast to other melanocytic markers, is differentially expressed in melanocytic nevi and melanomas. Overexpression of PRAME is observed in melanomas and a variety of other cancers including breast, lung, kidney, ovary, and leukemias. (4) Because of the robust differential expression in nevi and melanomas, PRAME is utilized in several gene expression profiling tests for the prognostication of uveal melanomas (Decision Dx-UM), diagnosis of melanomas (myPath Melanoma), and guidance on the decision to biopsy (DermTech).

With the availability of PRAME immunohistochemistry (IHC), pathologists have been very busy in the last 5 years evaluating its potential diagnostic role in melanoma. Thus far, the majority of PRAME IHC studies have reported good to excellent agreement with the gold standard (histologic diagnosis) with the exception of desmoplastic melanoma. Multiple studies have reported high sensitivity and specificity of PRAME IHC in a variety of settings that include margin assessment for melanoma in situ, difficult-to-diagnose lesions including spitzoid neoplasms, and determining hyperplasia or neoplasia of solitary melanocytes. (5-7) In one of the largest iterations of the PRAME IHC studies evaluating over 400 melanocytic lesions, the sensitivity in detecting melanoma ranged from 83% to 94% depending on the subtype of melanoma. (8) Slightly lower sensitivity was observed in difficult-to-diagnose melanocytic lesions and, for desmoplastic melanoma, significantly lower sensitivity was observed ranging from 20% to 35%. (6,8,9) For spindle and desmoplastic melanomas, S100 and SOX10 still remain the IHC stains of choice for their diagnosis.

Among the PRAME IHC studies, the diagnostic accuracy study by O’Connor and coworkers stands out for being STARD-compliant. (10) Before reading this article, I was unaware of STARD, an acronym that stands for Standards for Reporting Diagnostic Accuracy. STARD strives to improve the quality of reporting of diagnostic accuracy studies by setting a rigorous standard and reporting structure that comprise a checklist of 30 essential items to be included. (11) STARD-compliant studies are more consistent and transparent in their methodology, which enables the readers to easily assess the potential bias and generalizability. Most diagnostic accuracy studies report overly optimistic estimates of accuracy that are not reproducible due to design deficiencies and methodologies that are not fully transparent. (12) Diagnostic accuracy studies in pathology journals only report about half the STARD checklist items, a deficiency that prevents the accurate assessment of bias, applicability, and generalizability. (13)

In the study by O’Connor and coworkers, the sensitivity of PRAME was 67% while the specificity was 97% for the diagnosis of melanoma. The sensitivity was on the lower end of the range but fell within the reported ranges. The study was a retrospective cross-sectional that included cases in which the PRAME IHC was ordered based on the suspicion of melanoma by the original pathologist, an inclusion criterion that better reflects real-world practice according to the authors. A total of 143 consecutive melanocytic neoplasms (101 nevi and 42 melanomas) that met the inclusion criteria were included in the study. Each lesion received a score between 0 to 4 depending on the percentage of cells staining for PRAME: <25% (0/1+) favoring nevus, 26%-75% (2/3+) non-contributory, and >75% (4+) favoring melanoma. While the results confirm the trend of PRAME expression being predictive of melanoma, 15 of the 101 nevi received an indeterminate score and 3 cases received a melanoma score. Of the 42 melanomas, 5 received a nevus score and 10 received an indeterminate score. The authors conclude that PRAME IHC is an effective diagnostic test for melanoma and recommend grading the percentage of melanocytes that stain for PRAME. As noted by the authors, the limitations of the study include small sample size from a single academic institution and the exclusion of difficult-to-diagnose cases. Moreover, the grading of the PRAME IHC results and staining intensity (not mentioned in this study) adds a layer of subjectivity to a test that may be otherwise viewed as an objective one. Such subjective grading is predictive of affecting reproducibility.

With encouraging results thus far, pathologists are rapidly incorporating this readily available, cost-effective, and fast turnaround test into their daily practice. Straightforward nevi and melanomas should not require PRAME IHC, adding only unnecessary cost if indiscriminately utilized. The true value of PRAME IHC should be judged on its performance on the rarer difficult-to-diagnose lesions where a pathologist needs an additional confirmatory test. Currently, PRAME IHC is undergoing the validation stage of the test where its performance is evaluated on all types of melanocytic neoplasms. Multiple studies have been performed but under different conditions and heterogeneous methodologies that limit the applicability and generalizability of the test. Further multicenter large studies, ideally prospective ones with clinical outcome, that are homogeneous in methodology are needed to assess accurately the role of PRAME IHC in the diagnosis of melanoma. O’Connor and coworkers have reminded us to demand diagnostic accuracy studies that are transparent and rigorous in their methodology and reporting, that is, STARD-compliant studies that are easy to assess for potential bias, applicability, and generalizability.

Point to Remember: The immunohistochemical study PRAME is increasing utilized in the diagnosis of challenging melanocytic lesions.

Our editor’s viewpoint

Warren R. Heymann, MD, FAAD

We are all searching for the holy grail in the diagnosis of melanoma. As Dr. Lee eloquently discussed, there is ongoing excitement about the use of PRAME for these lesions. As more is learned about appropriate use, enthusiasm may become tempered. According to Dr. Philip LeBoit, while PRAME is an acronym for “preferentially expressed antigen in melanoma” it can also  mean “probably right, also makes errors.” In the near future, we will have a better grasp on how to use PRAME to fullest advantage. Like any immunohistochemical stain, it must be used in the context of clinical-pathologic correlation. 

1. Gaynor R, Irie R, Morton D, Herschman HR. S100 protein is present in cultured human malignant melanomas. Nature. 1980;286(5771):400-401. doi:10.1038/286400a0

2. Kahn HJ, Baumal R, Marks A. The value of immunohistochemical studies using antibody to S100 protein in dermatopathology. Int J Dermatol. 1984;23(1):38-44. doi:10.1111/j.1365-4362.1984.tb05661.x

3. Ikeda H, Lethé B, Lehmann F, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity. 1997;6(2):199-208. doi:10.1016/s1074-7613(00)80426-4

4. Xu Y, Zou R, Wang J, Wang ZW, Zhu X. The role of the cancer testis antigen PRAME in tumorigenesis and immunotherapy in human cancer. Cell Prolif. 2020;53(3):e12770. doi:10.1111/cpr.12770

5. Raghavan SS, Wang JY, Kwok S, Rieger KE, Novoa RA, Brown RA. PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features. J CutanPathol. 2020;47(12):1123-1131. doi:10.1111/cup.13818

6. Alomari AK, Tharp AW, Umphress B, Kowal RP. The utility of PRAME immunohistochemistry in the evaluation of challenging melanocytic tumors. J CutanPathol. 2021;48(9):1115-1123. doi:10.1111/cup.14000. 

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