Adlard, J

Charlton, R

Graham, JL

Merchant, W

Mitra, A

Newton-Bishop, JA

O'Shea, SJ

PubMed

White Rose Research Online

J Cutan Pathol 2015doi: 10.1111/cup.12625John Wiley & Sons. Printed in SingaporeJournal ofCutaneous PathologyLetter to the EditorHistopathology of melanocytic lesionsin a family with an inherited BAP1mutationKeywords: histopathology, melanocytic lesions, melanomaTo the Editor,We read with interest the report by Marusicet al.1 who expanded on the histopathologicalfeatures of melanocytic neoplasms in a familywith an inherited BAP1 mutation.Marusic et al.1 described the presence ofnuclear pseudoinclusions and multinucleatedmelanocytes within five of six nevi from thisfamily. The lesions were mainly intradermal,composed of large epithelioid melanocytes, andshowed loss of BAP1 expression by immunohis-tochemistry.We report similar histopathological findingsin melanocytic lesions excised from mem-bers of an English family in which a germlinepathogenic BAP1 mutation has been identified.The proband was diagnosed with melanoma at26 years of age that was clinically bland and pinkin appearance. This was initially considered tobe a melanocytic lesion of uncertain malignantpotential (MELTUMP) but on further assess-ment, showed significant cytological atypia andlacked maturation and was therefore treated asa melanoma. The Breslow thickness was 2.4 mmand there was no evidence of ulceration. Thispatient later developed a melanoma in situ. Hehad multiple pink, bland nevi one of whichsubsequently changed and this was excisedin view of his significant history. Histopatho-logical examination showed an intradermalmelanocytic neoplasm composed of epithelioidmelanocytes with abundant cytoplasm, some ofwhich contained multinucleated cells (Fig. 1A)and nuclear pseudoinclusions (Fig. 1B).The proband’s maternal grandfather hadoccupational exposure to asbestos and haddied of mesothelioma. His maternal uncle hada history of stage IIA melanoma, which latermetastasized to a regional lymph node. Strikingpleomorphism, multinucleated melanocytes andnuclear pseudoinclusions were readily identifiedin this nodal metastasis.The proband’s maternal aunt, presentedat 44 years of age with a history of a recalci-trant scalp lesion, which had been curettedtwice elsewhere in the belief that this was acyst. The curettings had not been sent forhistopathological assessment. Following a fur-ther recurrence, approximately 18 monthsafter onset, the lesion was partially excised bygeneral surgeons. Histopathology revealed amalignant blue nevus-like melanoma showinga highly cellular melanocytic tumor, at least11 mm in thickness; composed of spindle cellsand some dendritic-like melanocytes. Nuclearpseudoinclusions were noted, although dis-tributed more sparsely within this lesion. To ourknowledge, there is only one other reported caseof a 64-year-old female with a BAP1 germlinemutation who had a malignant blue nevus-likemelanoma of the scalp.2 Our patient was alsofound to have a meningioma on computedtomography (CT) scanning.Following an invitation for screening, theproband’s maternal cousin had a pink lesionexcised, due to a history of change. This was diag-nosed as a spitzoid tumor of uncertain malignantpotential (STUMP). The tumor consisted of alobulated, intradermal nodule composed ofpleomorphic epithelioid melanocytes, flankedby a more diffuse melanocytic lesion withhyperchromatic nuclei (Fig. 2A). Nuclear© 2015 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd. 1This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction inany medium, provided the original work is properly cited.Letter to the EditorFig. 1. A) Histopathological findings (×20) show a predominantly intradermal melanocytic lesion. Multinucleated melanocytescan be clearly seen. B) High-power view (×63) reveals a melanocytic lesion composed of multinucleated melanocytes. Nuclearpseudoinclusions are seen in some melanocytes. This lesion was considered to be a benign melanocytic nevus and resembled nevidescribed in other patients with a BAP1 mutation.Fig. 2. A) Low-power view (×2.5) shows an intradermal melanocytic neoplasm composed of a nodule flanked by a more diffusemelanocytic lesion. B) High-power view (×60) demonstrates remarkable nuclear pseudoinclusions.pseudoinclusions were numerous within thenodular component (Fig. 2B).Atypical spitzoid tumors are known to occur inpatients who have an inherited BAP1 mutation,the histopathology of which is usually quitestriking in stark contrast to the bland clini-cal appearance of these lesions.3 Recognizingthis pattern of clinical and histopathologicalpresentation is key to identifying possible car-riers of a BAP1 mutation, who have a cancersusceptibility syndrome, having a particulardiathesis to cutaneous and uveal melanomas,3meningiomas,4 mesotheliomas5 and renalcell cancers.1 Nuclear pseudoinclusions canbe identified in several melanocytic tumors,including benign melanocytic nevi and evensome melanomas.1 Although non-specific, theyappear to be a prominent feature of melanocyticlesions from patients with a germline BAP1mutation.Sally J. O’Shea, MB BCh BAO BMedSc1Angana Mitra, MB ChB MD2Jennifer L. Graham, BDS3Ruth Charlton, BA PhD4Julian Adlard, MB BS5Will Merchant, MB ChB FRCPathDipRCPath (Dermpath)3Julia A. Newton-Bishop, MB ChB MD FMedSci11Leeds Institute of Cancer and Pathology, Sectionof Epidemiology and Biostatistics,University of Leeds,Leeds, UK.2Dermatology,St. James’s University Hospital,Leeds, UK.3Histopathology,St. James’s University Hospital,Leeds, UK.4Clinical Genetics, Yorkshire Regional DNALaboratory,St. James’s University Hospital,Leeds, UK.5The Yorkshire Regional Genetics Service,Chapel Allerton Hospital,Leeds, UK.e-mail: S.J.O’Shea@leeds.ac.uk2Letter to the EditorReferences1. Marusic Z, Buljan M, Busam KJ. Histo-morphologic spectrum of Bap1 negativemelanocytic neoplasms in a family withBap1-associated cancer susceptibility syn-drome. J Cutan Pathol 2015; 42: 406.2. Yeh I et al. Ambiguous melanocytic tumorswith loss of 3p21. Am J Surg Pathol 2014; 38:1088.3. Wiesner T et al. Germline mutations inBAP1 predispose to melanocytic tumors.Nat Genet 2011; 43: 1018.4. Abdel-Rahman MH et al. Germline BAP1mutation predisposes to uveal melanoma,lung adenocarcinoma, meningioma, andother cancers. J Med Genet 2011; 48: 856.5. Carbone M et al. BAP1 cancer syndrome:malignant mesothelioma, uveal and cuta-neous melanoma, and MBAITs. J TranslMed 2012; 10: 179.3

Histopathology of melanocytic lesions in a family with an inherited BAP1 mutation

Sally J. O'Shea

Angana Mitra

Jennifer L. Graham

Ruth Charlton

Julian Adlard

Will Merchant

Julia A. Newton-Bishop

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Journal of Cutaneous Pathology

https://eprints.whiterose.ac.uk/92472/1/O%27Shea_et_al-2015-Journal_of_Cutaneous_Pathology.pdf

Histopathology of melanocytic lesions in a family with an inherited BAP1 mutation

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