Towards diagnostic criteria for malignant deep penetrating melanocytic tumors using single nucleotide polymorphism array and next-generation sequencing

Ebbelaar, Chiel F; Schrader, Anne M.R.; Dijk, Marijke van; Meijers, Ruud W. J.; Leng, Wendy W.J. de; Bloem, Lourens T.; Jansen, Anne M.L.; Blokx, Willeke A.M.

doi:10.1038/s41379-022-01026-6

Cited by 16 publications

(9 citation statements)

References 21 publications

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“…Moreover, PRAME expression is associated with a 9.0 risk ratio with a 1.4-57.1 95% CI (P = 0.02) in differentiating malignant deep penetrating tumours from benign mimickers. 27 Thus, the authors proposed its incorporation in the criteria for the classification of deep penetrating Almost all studies in our meta-analysis utilised 4+/ 75% PRAME-positive cells as the threshold for PRAME positivity. Rawson et al 17 found the 3+/50% threshold was more accurate in predicting malignancy, as only 35% of melanomas in their cohort showed 4+ staining compared to 64% with at least a 3+ score.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic test accuracy meta‐analysis of PRAME in distinguishing primary cutaneous melanomas from benign melanocytic lesions

Kunc¹,

Żemierowska

Skowronek

et al. 2023

Histopathology

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Diagnostic test accuracy meta-analysis of PRAME in distinguishing primary cutaneous melanomas from benign melanocytic lesions PRAME is a novel immunohistochemical marker that aids the diagnosis of melanocytic lesions. Diffuse PRAME positivity suggests melanoma, whereas benign naevi are negative or only weakly positive. However, the factual diagnostic accuracy of PRAME is not well established. Moreover, some studies have suggested that the threshold of 3+/50% positive cells may be more useful in practice than the most widely used cut-off (4+/75% of positive cells). Hence, we performed a systematic review and diagnostic accuracy meta-analysis to evaluate sensitivity, specificity, likelihood ratios and optimal threshold for PRAME in distinguishing benign melanocytic proliferations from melanomas. Twenty-six studies were enrolled into the meta-analysis. A total of 2915 melanocytic lesions were analysed. The optimal threshold for PRAME positivity was estimated at 3.11, which translates into 3+ in practice. Sensitivity and specificity calculated from SROC at the 3+ threshold were 0.735 (0.631-0.818) and 0.915 (0.834-0.958), respectively, compared to 0.679 (0.559-0.957) and 0.957 (0.908-0.981) at the 4+ cut-off. In subgroup analysis, the spitzoid subgroup was characterised by the lowest sensitivity and diagnostic odds ratio of PRAME. Our findings indicate that PRAME immunohistochemistry may serve as an ancillary marker to support the diagnosis of melanoma. Nevertheless, the accuracy of PRAME may be lower in spitzoid neoplasms. Our meta-analysis suggests that the 3+/50% threshold might be more useful in practice than the 4+/75% cut-off, as it shows higher sensitivity with retained satisfactory specificity.

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Section: Discussionmentioning

confidence: 99%

Diagnostic test accuracy meta‐analysis of PRAME in distinguishing primary cutaneous melanomas from benign melanocytic lesions

Kunc¹,

Żemierowska

Skowronek

et al. 2023

Histopathology

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“…20 biallelic deletions, TERT promoter alterations, and BAP1 alterations in blue nevus-derived tumors, are associated with increasing probability for melanoma. [47][48][49][50] Thus, because of frequent confusion with melanoma, complete removal of these lesions is considered prudent standard practice in line with class II lesions. However, exceptions to these guidelines may be invoked and re-excision considered unnecessary for some neoplasms.…”

Section: Discussionmentioning

confidence: 99%

“…At present, there are no definitive criteria for the distinction of class III or IV lesions from class II. Nonetheless, the progressive increase in number of abnormal features, including increasing age of the patient, tumor diameter greater than 1 cm, asymmetry, ulceration, aberrant nodular or sheet-like growth, severe cytological atypia, necrosis, mitotic rates at least 3 to 6 per mm 2 (depending on patient age), loss of p16 expression, diffuse (ie >75% nuclear, grade 4+) expression of PRAME , Ki67 greater than 10% to 20%, 3 or more genetic alterations or copy number variations (as seen in melanoma), CDKN2A biallelic deletions, TERT promoter alterations, and BAP1 alterations in blue nevus–derived tumors, are associated with increasing probability for melanoma . Thus, because of frequent confusion with melanoma, complete removal of these lesions is considered prudent standard practice in line with class II lesions.…”

Section: Discussionmentioning

confidence: 99%

Revision of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis Classification Schema for Melanocytic Lesions

et al. 2023

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ImportanceA standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose.ObjectiveTo revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health–funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG).Evidence ReviewPracticing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0.FindingsThe new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low–cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma.Conclusions and RelevanceThe implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.

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“…Early studies have determined that PRAME is generally not expressed in DPN, BN, CBN, or Spitz nevi. [18][19][20][21][22] However, Kline et al 18 have recently determined that borderline CBN and DPN demonstrate low PRAME expression. The goal of this study was to characterize the expression of PRAME and LEF1 in DPN and BN and to explore the utility of these markers for the differentiation of DPN, and in particular CDPN, from histologic mimics, including those showing combined features.…”

Section: Introductionmentioning

confidence: 99%

PRAME and LEF1 in Combined Deep Penetrating Nevus and Combined Blue Nevus: Utility and Pitfalls

Vanderbeck¹,

Rothrock²,

Cho³

et al. 2023

The American Journal of Dermatopathology

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Deep penetrating nevi (DPN), particularly those showing combined features, or combined deep penetrating nevi (CDPN), may show histopathological resemblance to blue nevus (BN) and melanoma. Preferentially Expressed Antigen in MElanoma (PRAME) is a marker that helps distinguish melanoma from benign melanocytic lesions. Lymphoid enhancer–binding factor 1 (LEF1) has been proposed to be used in conjunction with β-catenin for diagnosis of DPN. The immunohistochemical expression of PRAME and LEF1 was evaluated in 10 DPN (including 6 CDPN and 2 DPN-like proliferations with atypical features), 16 BN (including combined and cellular BN), and 2 melanomas with features of DPN or BN. PRAME was negative in most DPN (n = 10/10, n = 9/10, one case with discrepancy between readers) and all BN (n = 16/16), while the 2 melanomas included were positive (n = 2/2). All DPN were positive for LEF1 (n = 9/9) while only a subset of BN were positive (n = 6/16, P = 0.0028; n = 5/16, P = 0.001, per both readers). LEF1 seemed to be easier to interpret than β-catenin because of its nuclear pattern of expression. The expression of LEF1 in the regular nevus component of combined BN presents a potential pitfall in practice because it may lead to misinterpretation of LEF1 as positive in the BN component of the lesion. However, a subset (approximately one-third) of combined BN seemed to show true LEF1 expression. Taking into account pitfalls in interpretation, the combinatorial panel of PRAME and LEF1, in addition to conventional histopathological features, may be useful to distinguish CDPN from combined BN and other benign and malignant mimics.

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Towards diagnostic criteria for malignant deep penetrating melanocytic tumors using single nucleotide polymorphism array and next-generation sequencing

Cited by 16 publications

References 21 publications

Diagnostic test accuracy meta‐analysis of PRAME in distinguishing primary cutaneous melanomas from benign melanocytic lesions

Diagnostic test accuracy meta‐analysis of PRAME in distinguishing primary cutaneous melanomas from benign melanocytic lesions

Revision of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis Classification Schema for Melanocytic Lesions

PRAME and LEF1 in Combined Deep Penetrating Nevus and Combined Blue Nevus: Utility and Pitfalls

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