{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T01:59:03Z","timestamp":1790387943483,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"abstract":"\n Background<\/jats:title>\n \n GPNMB is a lysosomal transmembrane protein that has emerged as a diagnostic marker for tumours driven by the microphthalmia\u2010associated transcription factor family (\n TFE3<\/jats:italic>\n and\n TFEB<\/jats:italic>\n ) and mTOR pathway activation. Diffuse, moderate\u2010to\u2010strong GPNMB positivity has been proposed as a surrogate marker for both translocation\u2010driven and mTOR pathway\u2010activated neoplasms, including PEComas. This study investigated the diagnostic utility of GPNMB immunohistochemistry in differentiating uterine PEComas from common morphological mimics among uterine mesenchymal tumours.\n <\/jats:p>\n <\/jats:sec>\n \n Materials and methods<\/jats:title>\n \n We analysed a cohort of 115 uterine mesenchymal tumours, which included nine PEComas and a broad panel of differential diagnoses, comprising leiomyosarcoma (LMS,\n n<\/jats:italic>\n \u2009=\u200919), STUMP (\n n<\/jats:italic>\n \u2009=\u200920), leiomyoma (\n n<\/jats:italic>\n \u2009=\u200910), low\u2010grade endometrial stromal sarcoma (LG ESS,\n n<\/jats:italic>\n \u2009=\u200918), high\u2010grade ESS (HG ESS,\n n<\/jats:italic>\n \u2009=\u200913), adenosarcoma (\n n<\/jats:italic>\n \u2009=\u200911), undifferentiated uterine sarcoma (UUS,\n n<\/jats:italic>\n \u2009=\u20095), inflammatory myofibroblastic tumour (IMT,\n n<\/jats:italic>\n \u2009=\u20093) and a collection of rare entities (1 UTROSCT, 3\n KAT6B\/A::KANSL1\u2010<\/jats:italic>\n , 2\n PLAG1\u2010<\/jats:italic>\n and 1\n NTRK\u2010<\/jats:italic>\n rearranged sarcomas). Immunohistochemistry (IHC) for GPNMB was performed, and a case was strictly defined as positive only if it showed diffuse staining (>75% of tumour volume) of moderate to strong intensity.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n All uterine PEComas (9\/9; 100%) showed diffuse moderate to strong GPNMB positivity. However, diagnostically significant expression was also observed in LMS (9\/19; 47%), UUS (2\/5; 40%), IMT (2\/3; 67%) and LG ESS (1\/18; 6%). All other entities lacked diagnostic GPNMB expression, showing negative or only focal (1%\u201375% of tumour cells) or diffuse but weak staining. Low\u2010level GPNMB expression was common, with focal or weak staining present in 65% of non\u2010positive tumours (60\/92), supporting the use of strict scoring criteria.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Although highly sensitive for uterine PEComa, GPNMB lacks sufficient specificity for distinguishing PEComa from its principal uterine mesenchymal mimics, particularly LMS, IMT and UUS. Although strict scoring criteria (moderate\u2010to\u2010strong positivity in >75% of tumour cells) reduce false\u2010positive interpretation, GPNMB should not be used as a standalone discriminatory marker but interpreted in conjunction with morphology and a broader immunohistochemical panel.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/his.70288","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T01:11:24Z","timestamp":1790385084000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunoreactivity of\n GPNMB<\/scp>\n (glycoprotein nonmetastatic melanoma protein B) across the spectrum of uterine mesenchymal tumours"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7511-4840","authenticated-orcid":false,"given":"Josef","family":"Skopal","sequence":"first","affiliation":[{"name":"Department of Pathology, Faculty of Medicine in Plzen, Charles University University Hospital Plzen Plzen Czech Republic"},{"name":"Biopticka Laborator, Ltd Plzen Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8052-4741","authenticated-orcid":false,"given":"Mari\u00e1n","family":"\u0160vajdler","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine in Plzen, Charles University University Hospital Plzen Plzen Czech Republic"},{"name":"Biopticka Laborator, Ltd Plzen Czech Republic"},{"name":"Department of Pathology General University Hospital in Prague Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2561-4717","authenticated-orcid":false,"given":"Nikola","family":"Pt\u00e1kov\u00e1","sequence":"additional","affiliation":[{"name":"Biopticka Laborator, Ltd Plzen Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5241-9723","authenticated-orcid":false,"given":"Tom\u00e1\u0161","family":"Van\u011b\u010dek","sequence":"additional","affiliation":[{"name":"Biopticka Laborator, Ltd Plzen Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4403-7027","authenticated-orcid":false,"given":"Michael","family":"Michal","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine in Plzen, Charles University University Hospital Plzen Plzen Czech Republic"},{"name":"Biopticka Laborator, Ltd Plzen Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina","family":"Gettse","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics, Faculty of Medicine in Plzen, Charles University University Hospital Plzen Plzen Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7632-4069","authenticated-orcid":false,"given":"Ji\u0159\u00ed","family":"Presl","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics, Faculty of Medicine in Plzen, Charles University University Hospital Plzen Plzen Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislav","family":"Kormunda","sequence":"additional","affiliation":[{"name":"Biopticka Laborator, Ltd Plzen Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Novotn\u00fd","sequence":"additional","affiliation":[{"name":"Department of Pathology General University Hospital in Prague Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8940-6124","authenticated-orcid":false,"given":"Pavel","family":"Dundr","sequence":"additional","affiliation":[{"name":"Department of Pathology General University Hospital in Prague Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Michal","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine in Plzen, Charles University University Hospital Plzen Plzen Czech Republic"},{"name":"Biopticka Laborator, Ltd Plzen Czech Republic"},{"name":"Cytopathos, Ltd Bratislava Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3231-6870","authenticated-orcid":false,"given":"Kv\u011btoslava","family":"Michalov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine in Plzen, Charles University University Hospital Plzen Plzen Czech Republic"},{"name":"Biopticka Laborator, Ltd Plzen Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"Female genital tumours. 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Pathol."},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1097\/PAS.0b013e31824a8a37","article-title":"Perivascular epithelioid cell tumors (PEComas) harboring TFE3 gene rearrangements lack the TSC2 alterations characteristic of conventional PEComas: Further evidence for a biological distinction","volume":"36","author":"Malinowska I","year":"2012","journal-title":"Am. J. Surg. Pathol."},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1097\/PAS.0000000000000389","article-title":"Dichotomy of genetic abnormalities in PEComas with therapeutic implications","volume":"39","author":"Agaram NP","year":"2015","journal-title":"Am. J. Surg. Pathol."},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1159\/000510241","article-title":"Characterization of clinical cases of malignant PEComa via comprehensive genomic profiling of DNA and RNA","volume":"98","author":"Akumalla S","year":"2020","journal-title":"Oncology"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1097\/PAS.0000000000002135","article-title":"Melanotic PEComa: A rare but distinctive subtype analyzed in a series of 7 cases","volume":"48","author":"Fouchardiere A","year":"2024","journal-title":"Am. J. Surg. Pathol."},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1097\/PAS.0000000000001024","article-title":"Fibroma\u2010like PEComa: A tuberous sclerosis complex\u2010related lesion","volume":"42","author":"Larque AB","year":"2018","journal-title":"Am. J. Surg. Pathol."},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1177\/10668969251407227","article-title":"Fibroma\u2010like PEComa as an early indicator of tuberous sclerosis complex: Confirmed with strong GPNMB expression and TSC2 germline mutation","volume":"34","author":"Yin X","year":"2026","journal-title":"Int. J. Surg. Pathol."},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.modpat.2024.100426","article-title":"Glycoprotein nonmetastatic melanoma protein B (GPNMB) immunohistochemistry can Be a useful ancillary tool to identify perivascular epithelioid cell tumor","volume":"37","author":"Wangsiricharoen S","year":"2024","journal-title":"Mod. Pathol."},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1097\/PAS.0000000000002117","article-title":"Positive GPNMB immunostaining differentiates renal cell carcinoma with Fibromyomatous stroma associated with TSC1\/2\/MTOR alterations from others","volume":"47","author":"Li H","year":"2023","journal-title":"Am. J. Surg. Pathol."},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/path.5875","article-title":"GPNMB expression identifies TSC1\/2\/mTOR\u2010associated and MiT family translocation\u2010driven renal neoplasms","volume":"257","author":"Salles DC","year":"2022","journal-title":"J. Pathol."},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.humpath.2025.105799","article-title":"Unlocking diagnostic potential: A retrospective analysis of GPNMB immunohistochemistry in nearly 1000 surgical pathology specimens","volume":"159","author":"Li H","year":"2025","journal-title":"Hum. Pathol."},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.humpath.2025.105797","article-title":"Evaluation of 3,606 renal cell tumors for TFE3 rearrangements and TFEB alterations via fluorescence in situ hybridization, next generation sequencing, and GPNMB immunohistochemistry","volume":"159","author":"Whaley RD","year":"2025","journal-title":"Hum. Pathol."},{"key":"e_1_2_10_16_1","article-title":"Glycoprotein nonmetastatic melanoma protein b immunohistochemistry can be a useful ancillary tool to diagnose subependymal giant cell astrocytoma","volume":"27","author":"\u0160vajdler M","year":"2025","journal-title":"Virchows Arch."},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/cas.12601","article-title":"Distinctive expression patterns of glycoprotein non\u2010metastatic B and folliculin in renal tumors in patients with Birt\u2010hogg\u2010Dub\u00e9 syndrome","volume":"106","author":"Furuya M","year":"2015","journal-title":"Cancer Sci."},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1097\/PAS.0000000000002435","article-title":"GPNMB expression identifies FLCN\u2010associated eosinophilic renal tumors with heterogeneous clinicopathologic Spectrum and gene expression profiles","volume":"49","author":"Xia QY","year":"2025","journal-title":"Am. J. Surg. Pathol."},{"issue":"1","key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum MJ","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s00428-018-2349-6","article-title":"Prognostic significance of 1p36 locus deletion in adenoid cystic carcinoma of the salivary glands","volume":"473","author":"\u0160teiner P","year":"2018","journal-title":"Virchows Arch."},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.modpat.2024.100552","article-title":"PLAG1\u2010rearranged uterine sarcomas: A study of 11 cases showing a wide phenotypical Spectrum not limited to myxoid leiomyosarcoma\u2010like morphology","volume":"37","author":"Michal M","year":"2024","journal-title":"Mod. Pathol."},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1097\/PAS.0000000000001915","article-title":"Recurrent KAT6B\/a::KANSL1 fusions characterize a potentially aggressive uterine sarcoma morphologically overlapping with low\u2010grade endometrial stromal sarcoma","volume":"46","author":"Agaimy A","year":"2022","journal-title":"Am. J. Surg. Pathol."},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/his.15505","article-title":"Renal cell carcinoma with fibromyomatous stroma (RCC FMS) and with hemangioblastoma\u2010like areas is part of the RCC FMS spectrum in patients with tuberous sclerosis complex","volume":"87","author":"Baranova K","year":"2025","journal-title":"Histopathology"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0015793","article-title":"Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization","volume":"5","author":"Hong SB","year":"2010","journal-title":"PLoS One"},{"key":"e_1_2_10_25_1","doi-asserted-by":"crossref","DOI":"10.15252\/embj.201798804","article-title":"The complex relationship between TFEB transcription factor phosphorylation and subcellular localization","volume":"37","author":"Puertollano R","year":"2018","journal-title":"EMBO J."},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"3242","DOI":"10.1038\/emboj.2011.257","article-title":"Regulation of TFEB and V\u2010ATPases by mTORC1","volume":"30","author":"Pe\u00f1a\u2010Llopis S","year":"2011","journal-title":"EMBO J."},{"key":"e_1_2_10_27_1","doi-asserted-by":"crossref","first-page":"5584","DOI":"10.1172\/JCI128287","article-title":"mTORC1 feedback to AKT modulates lysosomal biogenesis through MiT\/TFE regulation","volume":"129","author":"Asrani K","year":"2019","journal-title":"J. Clin. Invest."},{"key":"e_1_2_10_28_1","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.3892\/or.2015.4254","article-title":"Aberrant differentiation of Tsc2\u2010deficient teratomas associated with activation of the mTORC1\u2010TFE3 pathway","volume":"34","author":"Kawano H","year":"2015","journal-title":"Oncol. Rep."},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1016\/j.gene.2017.09.044","article-title":"FLCN: The causative gene for Birt\u2010hogg\u2010Dub\u00e9 syndrome","volume":"640","author":"Schmidt LS","year":"2018","journal-title":"Gene"},{"key":"e_1_2_10_30_1","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1111\/his.70026","article-title":"GPNMB immunohistochemistry is a useful ancillary tool for the diagnosis of pulmonary lymphangioleiomyomatosis","volume":"88","author":"Szalai F","year":"2026","journal-title":"Histopathology"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"478","DOI":"10.3390\/jmp5040032","article-title":"Molecular pathogenesis of renal neoplasms in patients with Birt\u2013hogg\u2013Dub\u00e9 syndrome","volume":"5","author":"Nezami BG","year":"2024","journal-title":"J. Mol. Pathol."},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","first-page":"4573","DOI":"10.1038\/s41388-022-02443-2","article-title":"GPNMB: A potent inducer of immunosuppression in cancer","volume":"41","author":"Lazaratos AM","year":"2022","journal-title":"Oncogene"},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.currproblcancer.2021.100794","article-title":"Discovery of targeted expression data for novel antibody\u2010based and chimeric antigen receptor\u2010based therapeutics in soft tissue sarcomas using RNA\u2010sequencing: Clinical implications","volume":"45","author":"Pestana RC","year":"2021","journal-title":"Curr. Probl. Cancer"},{"key":"e_1_2_10_34_1","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1097\/PAI.0000000000001003","article-title":"Using pan\u2010TRK and RET immunohistochemistry for the detection of fusion types of salivary gland secretory carcinoma","volume":"30","author":"Su YJ","year":"2022","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"e_1_2_10_35_1","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/s00428-025-04102-9","article-title":"A practical approach to better identify NTRK 1\u20103 fusion\u2010positive mesenchymal neoplasms by pan\u2010Trk immunohistochemistry","volume":"487","author":"Haberecker M","year":"2025","journal-title":"Virchows Arch."},{"key":"e_1_2_10_36_1","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s00428-026-04466-6","article-title":"Immunohistochemical expression of GPNMB in TFEB\u2010rearranged and TFEB\u2010amplified renal cell carcinomas","volume":"489","author":"Pivovarcikova K","year":"2026","journal-title":"Virchows Arch."},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.humpath.2025.105768","article-title":"TFE3\u2010rearranged ossifying fibromyxoid tumors are uniquely negative for glycoprotein non\u2010metastatic melanoma protein B: A study of 13 TFE3\u2010rearranged mesenchymal tumors","volume":"157","author":"Tekin B","year":"2025","journal-title":"Hum. Pathol."}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.70288","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/his.70288","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.70288","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T01:11:29Z","timestamp":1790385089000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.70288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":36,"alternative-id":["10.1111\/his.70288"],"URL":"https:\/\/doi.org\/10.1111\/his.70288","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"assertion":[{"value":"2026-06-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"his.70288"}}