BAP1-inactivated Spitzoid Naevi

Vilain, Ricardo E.; McCarthy, Stanley W.; Thompson, John F.; Scolyer, Richard A.

doi:10.1097/pas.0000000000000407

Cited by 15 publications

(6 citation statements)

References 10 publications

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“…For example, when a melanocyte of a conventional nevus, which was initiated by a BRAF (or rarely RAS) mutation, acquires an activating CTNNB1 mutation in addition to the mutation which initiated the nevus, a secondary clonal expansion of melanocytes characterized by increased cell size and pigmentation results in a component of deep penetrating nevus (melanocytoma) 52 . Bi-allelic loss of BAP1 in a melanocyte of a conventional nevus results in a secondary proliferation of epithelioid melanocytes with distinctive spitzoid cytomorphology [73][74][75][76] . Similarly, bi-allelic loss of PRKAR1A leads to development of a pigmented epithelioid melanocytoma within a conventional nevus 77 .…”

Section: Discussionmentioning

confidence: 99%

Spitz melanoma is a distinct subset of spitzoid melanoma

et al. 2020

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Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations such a kinase fusions or HRAS mutations. It is unclear what fraction of 'spitzoid melanomas' defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an eight-year period and performed high coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only 9 cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with a MAPK activating mutation and those without. Both Spitz melanoma and spitzoid melanomas in which a MAPK activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK activating mutations. The MAPK activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1 and KIT while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the 'spitzoid melanomas' comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Discussionmentioning

confidence: 99%

Spitz melanoma is a distinct subset of spitzoid melanoma

et al. 2020

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“…Among these are Wiesner's nevus, BAPoma, NEMMP, melanocytic BAP1-mutated atypical intradermal tumor (MBAIT), epithelioid atypical Spitz tumor, Spitz nevus with halo-like reaction, BAP1-negative atypical Spitz tumor, BAP1inactivated spitzoid nevus, spitzoid tumor of uncertain malignant potential (STUMP), and BIMT. [8][9][10][11][12] There remains a lack of consensus on which terminology to use to best reflect the characteristics and course of this cutaneous tumor; there is merit in all the proposed names for this tumor. For example, the descriptive terminology put suggesting that its reference to nevoid melanoma may unduly imply aggressive biological potential of these cutaneous tumors.…”

Section: Terminologymentioning

confidence: 99%

“…In the past decade, cutaneous BIMTs have been referred to with a wide variety of diagnostic terms. Among these are Wiesner's nevus, BAPoma, NEMMP, melanocytic BAP1 ‐mutated atypical intradermal tumor (MBAIT), epithelioid atypical Spitz tumor, Spitz nevus with halo‐like reaction, BAP1‐negative atypical Spitz tumor, BAP1 ‐inactivated spitzoid nevus, spitzoid tumor of uncertain malignant potential (STUMP), and BIMT . There remains a lack of consensus on which terminology to use to best reflect the characteristics and course of this cutaneous tumor; there is merit in all the proposed names for this tumor.…”

Section: Introductionmentioning

confidence: 99%

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

2019

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Although discussed using variable terminology, cutaneous BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumor (BIMT) has been considered a discrete diagnostic entity since 2011. Here, we review the initial genomic studies that identified these distinct melanocytic tumors and the clinical and histopathological features that define these tumors. These epithelioid, predominantly dermal, and melanocytic tumors present as erythematous nodules and histopathologically have features that may overlap with Spitz nevi and nevoid melanoma. There is no sex predilection, and cutaneous BIMTs can appear at any age; however, in most familial (germline mutant) cases patients have multiple cutaneous tumors with a first diagnosis in the second or third decade of life; ocular melanoma and other tumors are increasingly identified in these kindreds with germline BAP1 mutation. These tumors have been described with a myriad of terms including: Wiesner nevus, nevoid melanoma‐like melanocytic proliferation (NEMMP), BAP1 mutant Spitz nevus, BAP1 mutant nevoid melanoma, cutaneous BAPoma, and most recently cutaneous BIMT.

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“…As these lesions lost BAP1 , the term ‘BAP1-inactivated spitzoid naevus’ might be more appropriate. 46 Hopefully, the nomenclature will be clarified in the next edition of the World Health Organization Classification of Skin Tumours.…”

Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy

et al. 2016

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Summary Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas conventional naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion, may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or reduce and alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour genomics and progression will refine the classification of melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

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BAP1-inactivated Spitzoid Naevi

Cited by 15 publications

References 10 publications

Spitz melanoma is a distinct subset of spitzoid melanoma

Spitz melanoma is a distinct subset of spitzoid melanoma

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy

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