NRAS-mutated melanocytic BAP1-associated intradermal tumor (MBAIT): a case report

Blokx, Willeke A.M.; Rabold, Katrin; Bovenschen, H.J.; Ligtenberg, Marjolijn J. L.; Mensenkamp, Arjen R.; Lijnschoten, Gesina van; Zelst-Stams, Wendy A. G. van; Groenen, Patricia J.T.A.

doi:10.1007/s00428-014-1674-7

Cited by 11 publications

(7 citation statements)

References 20 publications

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“…This model of progression of BIMT from a benign nevus was proposed in the original description 8 and is also supported from a molecular viewpoint, inasmuch as both combined and pure cases in our series and in the previously reported ones 2,5,33 harbored a BRAF V600E mutation in the presence of BAP1 inactivation. Moreover, combined type BIMTs have also been reported in association with an NRAS mutation and RAF1 fusions 3,4,33 , both known to act as a mitogenic driver in melanocytic neoplasms 34 . Fusions involving receptor tyrosine kinases and serine/threonine kinases Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The rationale for such an interpretation is the identification of remnants of a conventional nevus with retained nuclear expression of BAP1 in many cases of BIMT that is otherwise mainly composed of BAP1-negative large epithelioid melanocytes with well-demarcated cytoplasmic borders and copious eosinophilic cytoplasm. From a molecular biological viewpoint, it is characterized by a BRAF mutation (or, rarely, NRAS mutation or RAF1 fusion) considered to represent a mitogenic driver alteration and biallelic inactivation of the BAP1 gene, leading to dysfunction of BAP1 protein [2][3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

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Novel insights into the BAP1-inactivated melanocytic tumor

et al. 2022

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BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel insights into the BAP1-inactivated melanocytic tumor

et al. 2022

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“…Two had BRAF V600E mutations while one had an NRAS mutation. Prior studies have shown that BIMTs are commonly associated with BRAF V600E mutations, but only rare cases have shown NRAS mutations 3,6,7,26–30 . As such, we were unable to identify driver mutations in two cases, but this is likely because of the limited panel of genes in the assay.…”

Section: Discussionmentioning

confidence: 82%

“…Prior studies have shown that BIMTs are commonly associated with BRAF V600E mutations, but only rare cases have shown NRAS mutations. 3,6,7,[26][27][28][29][30] As such, we were unable to identify driver mutations in two cases, but this is likely because of the limited panel of genes in the assay. While criteria such as cytologic atypia, lack of maturity, and positive staining for one or more of the melanoma markers aided in the initial diagnosis of melanoma for these cases, there may be instances in which BIMTs do not present with all of these characteristics to be called a melanoma on morphology or immunohistochemical staining alone.…”

Section: Discussionmentioning

confidence: 96%

Histopathologic and molecular characterization of BAP‐1‐inactivated melanoma

et al. 2022

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Background: BRCA1-associated protein 1 (BAP-1) is a deubiquitylase that functions as a tumor suppressor, regulating multiple cellular processes including cell cycle control, differentiation, cell death, and DNA repair. BAP-1-inactivated melanocytic tumors (BIMTs) have recently been described and are characterized by epithelioid cytomorphology, are often clonal in appearance, and typically do not recur or show malignant transformation on follow-up.Aim: To describe the histopathologic and molecular characterization of five cases of BAP-1-inactivated cutaneous malignant melanomas. Methods:The archives at two separate institutions were retrospectively searched for tumors classified as melanoma with loss of BAP-1 via immunohistochemistry. Five cases were identified. These cases were classified as malignant melanoma based on cytomorphology, immunohistochemistry, and ancillary molecular testing. The clinical demographics were recorded, along with the histomorphologic features of each case.Genomic analysis for all cases was performed via OncoScan. Results:The five reviewed cases consisted of two females and three males ranging from 67 to 74 years in age. Molecular characterization of each case was performed using OncoScan. Microarray assay showed that there was a complete deletion of 3p in all cases, BRAF V600E mutation in two cases, NRAS missense variant in one case, and loss of 9p in three cases. All cases showed malignant copy number alterations.Conclusions: Herein we describe five cases of BAP-1-inactivated melanomas confirmed by histomorphology and immunohistochemistry, all of which show malignant copy number profiles including loss of 3p. In addition, we provide a case of a likely BIMT showing progression to BAP-1-inactivated melanoma on a 16-year follow-up.

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“…While not very common, some cases of Wiesner nevus without BRAF mutation have been reported (around 10% of cases), first in the initial description of the genetic syndrome and later in reports of sporadic cases . The current report of BAP1‐negative and VE1‐negative AST should help to define AST with loss of BAP1 expression further.…”

Section: Discussionmentioning

confidence: 99%

BAP1‐deficient and VE1‐negative atypical Spitz tumor

et al. 2015

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Atypical Spitz tumor with loss of BAP1 or Wiesner nevus is a peculiar variant of intradermal spitzoid melanocytic neoplasm composed of epithelioid melanocytes with a sheet-like growth pattern, abundant infiltrating lymphocytes and rare or absent mitotic activity. This subset of atypical spitzoid tumors is characterized by the BRAF(V600E) mutation and loss of BAP1 expression. Recognition of these lesions is important because they can be a marker for a hereditary BAP1-associated cancer syndrome. We present an unusual case of sporadic Wiesner nevus that had typical histopathologic features and a BAP1 but not a BRAF mutation. The biological significance of Wiesner nevus is controversial, and little is known about prognosis, particularly in atypical cases like this one.

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NRAS-mutated melanocytic BAP1-associated intradermal tumor (MBAIT): a case report

Cited by 11 publications

References 20 publications

Novel insights into the BAP1-inactivated melanocytic tumor

Novel insights into the BAP1-inactivated melanocytic tumor

Histopathologic and molecular characterization of BAP‐1‐inactivated melanoma

BAP1‐deficient and VE1‐negative atypical Spitz tumor

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