Summary
High expression of PRAME (PReferentially expressed Antigen in MElanoma) and p53 (a
proposed marker of desmoplastic melanoma) and low expression of 5-hydroxymethylcytosine
(5-hmC) have each been reported in melanoma. However, their combined diagnostic utility
for distinguishing melanomas, including uncommon variants, from histological mimics
is unknown.
This study sought to determine the utility of PRAME, p53 and 5-hmC immunostains for
diagnosing melanocytic tumours.
A total of 333 cutaneous melanocytic tumours (melanoma n=280, naevi n=53), 20 cutaneous
neurofibromas, and 15 scars were evaluated using multiplex immunofluorescence (n=313)
or single-plex chromogenic immunohistochemical staining (n=55). Immunostaining for
PRAME and 5-hmC were each scored using a previously described semiquantitative scale
0 (absent) to 4+ (diffuse). p53 was scored using a previously described immunoreactive
score (range 0–300).
PRAME expression was significantly higher in melanomas than in naevi (p<0.0001), with
the lowest PRAME expression found in low-grade desmoplastic melanomas compared to
the other melanoma subtypes. In non-desmoplastic melanomas, 38% showed 4+ staining
(>75% positive tumour cells) and 70% showed 3+ or 4+(>50% positive tumour cells).
Conversely, 96% of naevi showed 0, 1+ or 2+ expression. 5-hmC expression was significantly
lower in melanomas than in naevi (p<0.0001). However, acral melanomas were not significantly
associated with loss of 5-hmC expression (p=0.84). Compared with using PRAME in isolation,
combining PRAME and 5-hmC scores increased sensitivity (64%–84%) for detecting melanoma.
With respect to desmoplastic melanoma compared to scar or neurofibroma, strong PRAME
or p53 staining were almost exclusively found in high-grade desmoplastic melanomas;
low-grade desmoplastic melanomas, neurofibromas and scars were negative. 5-hmC was
not useful in distinguishing desmoplastic melanomas from neurofibromas or scars.
Our data support the use of PRAME as a highly specific ancillary investigation in
the diagnosis of melanoma, however PRAME should be considered ‘positive’ if there
is 3+ or 4+ staining (rather than the widely recommended 4+ threshold). 5-hmC, PRAME
and p53 appear to have a limited role in the diagnosis of low-grade desmoplastic melanomas.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to PathologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The influence of clinical information in the histopathologic diagnosis of melanocytic skin neoplasms.PLoS One. 2009; 4: e5375
- Pitfalls and important issues in the pathologic diagnosis of melanocytic tumors.Ochsner J. 2010; 10: 66-74
- New insights into naevoid melanomas: a clinicopathological reassessment.Histopathology. 2017; 71: 943-950
- Naevoid malignant melanoma: a diagnosis of a naevus that you later regret.Acta Derm Venereol. 2017; 97: 745-746
- Molecular profiling of noncoding mutations distinguishes nevoid melanomas from mitotically active nevi in pregnancy.Am J Surg Pathol. 2020; 44: 357-367
- Melanocytic lesions of the face: diagnostic pitfalls.Ann Acad Med Singapore. 2004; 33: 3-14
- The regenerating naevus.Pathology. 2016; 48: 108-112
- Precursors to melanoma and their mimics: nevi of special sites.Mod Pathol. 2006; 19: S4-S20
- Are melanocytic nevi influenced by pregnancy? A dermoscopic evaluation.Dermatol Surg. 2006; 32: 1497-1504
- Genomic and transcriptomic analysis reveals incremental disruption of key signaling pathways during melanoma evolution.Cancer Cell. 2018; 34: 45-55
- The genetic evolution of melanoma from precursor lesions.N Engl J Med. 2015; 373: 1926-1936
- Molecular genomic profiling of melanocytic nevi.J Invest Dermatol. 2019; 139: 1762-1768
- Trajectories of premalignancy during the journey from melanocyte to melanoma.Pathology. 2018; 50: 16-23
- Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool.Dermatol Ther. 2006; 19: 40-49
- Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization.Cancer Res. 1998; 58: 2170-2175
- Fluorescence in situ hybridization (FISH) as an ancillary diagnostic tool in the diagnosis of melanoma.Am J Surg Pathol. 2009; 33: 1146-1156
- Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor.Immunity. 1997; 6: 199-208
- Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.ESMO Open. 2016; 1e000068
- An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi.Cancer. 2017; 123: 617-628
- PRAME expression in melanocytic tumors.Am J Surg Pathol. 2018; 42: 1456-1465
- Analyses of molecular and histopathologic features and expression of PRAME by immunohistochemistry in mucosal melanomas.Mod Pathol. 2019; 32: 1727-1733
- Comparison of immunohistochemistry for PRAME with cytogenetic test results in the evaluation of challenging melanocytic tumors.Am J Surg Pathol. 2020; 44: 893-900
- Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.Cell. 2012; 150: 1135-1146
- Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers.Oncotarget. 2011; 2: 627-637
- Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors.Mod Pathol. 2014; 27: 936-944
- Loss of the epigenetic mark, 5-Hydroxymethylcytosine, correlates with small cell/nevoid subpopulations and assists in microstaging of human melanoma.Oncotarget. 2015; 6: 37995-38004
- Diagnostic utility of 5-hydroxymethylcytosine immunohistochemistry in melanocytic proliferations.J Cutan Pathol. 2015; 42: 807-814
- Distinguishing neurofibroma from desmoplastic melanoma: the value of the CD34 fingerprint.J Cutan Pathol. 2011; 38: 625-630
- Distinguishing neurofibroma from desmoplastic melanoma: the value of p53.Am J Surg Pathol. 2018; 42: 372-375
- Distinct immune cell populations define response to anti-PD-1 monotherapy and anti-PD-1/anti-CTLA-4 combined therapy.Cancer Cell. 2019; 35: 238-255
- PRAME expression in melanocytic proliferations with intermediate histopathologic or spitzoid features.J Cutan Pathol. 2020; 47: 1123-1131
- PRAME expression in 155 cases of metastatic melanoma.J Cutan Pathol. 2021; 48: 479-485
- Malignant peripheral nerve sheath tumors show decreased global DNA methylation.J Neuropathol Exp Neurol. 2018; 77: 958-963
Article info
Publication history
Published online: August 17, 2022
Accepted:
May 18,
2022
Received in revised form:
April 27,
2022
Received:
February 10,
2022
Identification
Copyright
Crown Copyright © 2022 Published by Elsevier B.V. on behalf of Royal College of Pathologists of Australasia. All rights reserved.
