MAP2K1-Mutated Melanocytic Neoplasms With a SPARK-Like Morphology

Donati, Michele; Nosek, Daniel; Waldenbäck, Pia; Martínek, Petr; Jonsson, Bengt‐Gunnar; Galgonkova, Petra; Hawawrehova, Marcela; Berouskova, Petra; Kastnerova, Liubov; Persichetti, Paolo; Crescenzi, Anna; Michal, Michal; Kazakov, Dmitry V.

doi:10.1097/dad.0000000000001840

Cited by 17 publications

(23 citation statements)

References 44 publications

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“…are mostly associated with Spitz lesions, whereas mutations are typical for conventional melanocytic lesions. However, there are well-known exceptions such as HRAS mutation in desmoplastic Spitz nevus and MAP2K1 mutations in Spitz lesions [35][36][37] . RAF proto-oncogene serine/threonineprotein kinase encoded by RAF1 functions as an alternative MAPK signaling mechanism as it forms dimers with wild-type BRAF 38 .…”

Section: Discussionmentioning

confidence: 99%

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%

Novel insights into the BAP1-inactivated melanocytic tumor

et al. 2022

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“…This is in part in agreement with previous publications of 2 variants of PRKAR1A-inactivated pure PEMs with such anomalies. 5 MAP2K1 mutations have also been reported in nevi with a SPARK-like morphology 14 and in the genetic background of pure deep penetrating nevus. 15 It should be noted that combined deep penetrating nevus and combined PRKAR1Ainactivated PEM can both occur from the BRAF-mutated genetic background of common nevus.…”

Section: Discussionmentioning

confidence: 99%

Attempting to Solve the Pigmented Epithelioid Melanocytoma (PEM) Conundrum

Fouchardière

Tirode

Castillo³

et al. 2022

American Journal of Surgical Pathology

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Pigmented epithelioid melanocytoma is a rare cutaneous melanocytic proliferation considered high-grade melanocytoma in the 2018 WHO Classification of Skin Tumors. Little has been reported about the associated genetic drivers in addition to BRAF and MAP2K1 mutations or PRKCA gene fusions. Here, we present a series of 21 cases of PRKAR1A-inactivated melanocytic tumors in which we could assess the associated genetic background. We identified 9 different driver genes related to the common, Spitz, blue nevi, and PRKC-fused groups. Nine cases were associated with a canonical BRAF p.V600E mutation, a hallmark of the common nevus group. They occurred mainly in young adults. All were combined (biphenotypic) cases with a variable proportion of compound nevus. The pigmented epithelioid melanocytoma component was made of thin fascicules or isolated epithelioid cells covered by a dense hyperpigmented melanophage background and was predominantly located in the upper dermis. One such case was malignant. Six cases were associated with Spitz-related genetic anomalies ranging from HRAS or MAP2K1 mutations to gene fusions involving MAP3K8, MAP3K3, and RET. They occurred mainly in children and young adults. Morphologically, they showed large confluent junctional nests in a hyperplastic epidermis and a fascicular dermal component of spindled and epithelioid melanocytes with a frequent wedged silhouette. Intravascular invasion was observed in 4/6 cases. Five cases were associated with canonical mutations of the blue nevus group with 4 CYSLTR2 p.L129Q and 1 GNAQ p.Q209L mutations. They were removed mainly in adults and showed a frequent junctional component with epidermal hyperplasia. The dermal component showed dense fascicules of spindled and epithelioid melanocytes predominating over melanophages. One case occurred in a PRKCA-fused tumor in an adolescent with classic morphologic features. These results could potentially shift the concept of PRKAR1A-inactivated melanocytoma, changing from a rather unified model to a more complex one, including genetic subgroup variations with clinical and morphologic specificities. The genetic background of PRKAR1A-inactivated melanocytic tumors should be systematically explored to better understand the extent and clinical behavior of these complex lesions.

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“…From the histopathological point of view, it is important to make a correct differential diagnosis with a form of dysplastic nevus with severe atypia or with a melanoma, and a careful cytological evaluation of the melanocytes present at the dermal epidermal junction is absolutely mandatory to correctly diagnose this entity without an over- or underdiagnosis [ 1 , 14 ]. Recently, in a paper by Donati et al the authors report four melanocytic lesions with a MAP2K1 mutation, all showing similar microscopic appearances, including spitzoid cytology and dysplastic architectural features resembling the so-called SPARK nevus, suggesting that these lesions may represent another distinctive group [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Spitz Nevus with Features of Clark Nevus, So-Called SPARK Nevus: Case Series Presentation with Emphasis on Cytological and Histological Features

et al. 2021

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Background: SPARK nevus represents a little-known and characterized entity, with few case series available in the literature. Methods and results: we present a case series of 12 patients (6 F and 6 M) between January 2005 and December 2020 and conduct a review of the current literature. Ten articles were selected on the basis of the adopted inclusion criteria and the PRISMA guidelines. Conclusions: The definition of histopathological and dermoscopic criteria are important to allow for an agreement to be reached among dermopathologists, and for the development of a consensus on higher case studies. To our knowledge, there are not many case series in the literature, and ours is part of the attempt to increase the knowledge of an entity that remains little-known and characterized.

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MAP2K1-Mutated Melanocytic Neoplasms With a SPARK-Like Morphology

Cited by 17 publications

References 44 publications

Novel insights into the BAP1-inactivated melanocytic tumor

Novel insights into the BAP1-inactivated melanocytic tumor

Attempting to Solve the Pigmented Epithelioid Melanocytoma (PEM) Conundrum

Spitz Nevus with Features of Clark Nevus, So-Called SPARK Nevus: Case Series Presentation with Emphasis on Cytological and Histological Features

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