Subependymal giant cell astrocytoma (SEGA) is a World Health Organization Central Nervous System grade 1 tumor, strongly associated with tuberous sclerosis complex (TSC). Recent research indicates that Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB), regulated by microphthalmia (MiT) family transcription factors may also be modulated by loss-of-function mutations in TSC1/2. We evaluated GPNMB as a diagnostic marker of subependymal giant cell astrocytoma (SEGA). A total of 11 patients with SEGA were included in the study. The control group comprised 185 primary central nervous system tumors, including high-grade and low-grade gliomas and glioneuronal/neuronal tumors. Strong and diffuse (≥ 50% of tumor cells) GPNMB expression was present in all SEGAs. In contrast, TTF-1 expression was detected in nine SEGAs, resulting in a sensitivity of 81.8%. Among the control group, 77 cases (41.6%) were negative for GPNMB and 102 (55.1%) cases were scored as > 1% < 50% positive. Only six control tissues (3.2%) showed diffuse and strong GPNMB expression. Among the tumors with strong GPNMB expression, there were three glioblastomas (GBMs) with morphology potentially mimicking SEGA but lacking TSC1, TSC2, or MTOR mutations. Using a cutoff of diffuse (≥ 50%) and strong positivity, GPNMB demonstrated 100% sensitivity (95% confidence interval: 74.1%-100%) and 96.8% specificity (95% confidence interval: 93.1%-98.5%) for diagnosing SEGA.

1st Department of Pathology Faculty of Medicine Masaryk University and St Anne's University Hospital Brno Brno Czech Republic

Bioptical Laboratory Ltd Pilsen Czech Republic

Cytopathos Ltd Bratislava Slovakia

Department of Neurosurgery and Neurooncology 1st Faculty of Medicine Charles University and Military University Hospital Prague Czech Republic

Department of Pathology Center PATOS Regional Hospital Liberec Liberec Czech Republic

Department of Pathology Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Pathology Military University Hospital Prague Czech Republic

Diagnostic Pathology Centre Unilabs Slovakia Ltd Bratislava Slovakia

Onco Team Diagnostic Bucharest Romania

Parker H Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology Atlanta GA USA

School of Biological Sciences Georgia Institute of Technology Atlanta GA USA

Šikl's Department of Pathology Faculty of Medicineand Faculty of Medicine and University Hospital in Pilsen Charles University Alej Svobody 80 Pilsen 323 00 Czech Republic

The Fingerland Department of Pathology Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Kralove Czech Republic

Zobrazit více v PubMed

Lopes MBS, Cotter JA, Rodriguez FJ, et al (2021) Subependymal giant cell astocytoma. In: WHO Classification of Tumours Editorial Board. WHO classification of tumours. Central nervous system tumours, 5th edn. International Agency for Research of Cancer, Lyon, France, pp 100–103.

Goh S, Butler W, Thiele EA (2004) Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 63:1457–1461. https://doi.org/10.1212/01.wnl.0000142039.14522.1a PubMed DOI

Chan JA, Zhang H, Roberts PS et al (2004) Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 63:1236–1242. https://doi.org/10.1093/jnen/63.12.1236 PubMed DOI

Henske EP, Wessner LL, Golden J et al (1997) Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am J Pathol 151:1639–1647 PubMed PMC

Mizuguchi M, Kato M, Yamanouchi H et al (1996) Loss of tuberin from cerebral tissues with tuberous sclerosis and astrocytoma. Ann Neurol 40:941–944. https://doi.org/10.1002/ana.410400621 PubMed DOI

Bongaarts A, Giannikou K, Reinten RJ et al (2017) Subependymal giant cell astrocytomas in tuberous sclerosis complex have consistent TSC1/TSC2 biallelic inactivation, and no BRAF mutations. Oncotarget 8:95516–95529. https://doi.org/10.18632/oncotarget.20764 PubMed DOI PMC

de Ribaupierre S, Dorfmuller G, Bulteau C et al (2007) Subependymal giant-cell astrocytomas in pediatric tuberous sclerosis disease: when should we operate? Neurosurgery 60:83–89. https://doi.org/10.1016/j.pediatrneurol.2013.08.017 PubMed DOI

Franz DN, Belousova E, Sparagana S et al (2014) Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 15:1513–1520. https://doi.org/10.1016/S1470-2045(14)70489-9 PubMed DOI

Bollo RJ, Berliner JL, Fischer I et al (2009) Extraventricular subependymal giant cell tumor in a child with tuberous sclerosis complex. J Neurosurg Pediatr 4:85–90. https://doi.org/10.3171/2009.3.PEDS08225 PubMed DOI

Almubarak AO, Abdullah J, Al Hindi H et al (2020) Infantile atypical subependymal giant cell astrocytoma. Neurosciences (Riyadh) 25:61–64. https://doi.org/10.17712/nsj.2020.1.20190044 PubMed DOI

Tompe AP, Sargar KM, Kazmi SAJ et al (2020) A solitary extraventricular subependymal giant cell astrocytoma in the absence of tuberous sclerosis. Radiol Case Rep 16:180–184. https://doi.org/10.1016/j.radcr.2020.11.004 PubMed DOI PMC

Roth J, Roach ES, Bartels U et al (2013) Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol 49:439–444 PubMed DOI

Telfeian AE, Judkins A, Younkin D et al (2004) Subependymal giant cell astrocytoma with cranial and spinal metastases in a patient with tuberous sclerosis. Case report J Neurosurg 100:498–500. https://doi.org/10.3171/ped.2004.100.5.0498 PubMed DOI

Aguilera D, Flamini R, Mazewski C et al (2014) Response of subependymal giant cell astrocytoma with spinal cord metastasis to everolimus. J Pediatr Hematol Oncol 36:e448–451. https://doi.org/10.1097/MPH.0000000000000005 PubMed DOI PMC

Azam M, Rath S, Khurana R et al (2017) Rare case of subependymal giant cell astrocytoma without clinical features of tuberous sclerosis: case report and literature review. Precis Radiat Oncol 1:108–112. https://doi.org/10.3857/roj.2020.00458 DOI

Piña-Ballantyne SA, Espinosa-Aguilar EJ, Calderón-Garcidueñas AL (2024) The clinicopathological features of the solitary subependymal giant cell astrocytoma: a systematic review. Neurol India 72:708–717. https://doi.org/10.4103/neurol-india.Neurol-India-D-23-00343 PubMed DOI

Cobourn KD, Chesney KM, Mueller K et al (2024) Isolated subependymal giant cell astrocytoma (SEGA) in the absence of clinical tuberous sclerosis: two case reports and literature review. Childs Nerv Syst 40:73–78. https://doi.org/10.1007/s00381-023-06105-w PubMed DOI

Palsgrove DN, Brosnan-Cashman JA, Giannini C et al (2018) Subependymal giant cell astrocytoma-like astrocytoma: a neoplasm with a distinct phenotype and frequent neurofibromatosis type-1-association. Mod Pathol 31:1787–1800. https://doi.org/10.1038/s41379-018-0103-x PubMed DOI PMC

Grajkowska W, Kotulska K, Jurkiewicz E et al (2011) Subependymal giant cell astrocytomas with atypical histological features mimicking malignant gliomas. Folia Neuropathol 49(1):39–46 PubMed

Švajdler M Jr, Deák L, Rychlý B et al (2013) Subependymal giant cell astrocytoma with atypical clinical and pathological features: a diagnostic pitfall. Cesk Patol 49:76–79 PubMed

Suzuki M, Kondo A, Ogino I et al (2021) A case of solitary subependymal giant cell astrocytoma with histopathological anaplasia and TSC2 gene alteration. Childs Nerv Syst 37:1357–1362. https://doi.org/10.1007/s00381-020-04839-5 PubMed DOI

Hirose T, Scheithauer BW, Lopes MB et al (1995) Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron and microscopic study. Acta Neuropathol 90:387–399. https://doi.org/10.1007/BF00315012 PubMed DOI

Lopes MB, Altermatt HJ, Scheithauer BW et al (1996) Immunohistochemical characterization of subependymal giant cell astrocytomas. Acta Neuropathol 91:368–375. https://doi.org/10.1007/s004010050438 PubMed DOI

Buccoliero AM, Franchi A, Castiglione F et al (2009) Subependymal giant cell astrocytoma (SEGA): Is it an astrocytoma? Morphological, immunohistochemical and ultrastructural study. Neuropathology 29:25–30. https://doi.org/10.1111/j.1440-1789.2008.00934.x PubMed DOI

You H, Kim YI, Im SY et al (2005) Immunohistochemical study of central neurocytoma, subependymoma, and subependymal giant cell astrocytoma. J Neurooncol 74:1–8. https://doi.org/10.1007/s11060-004-2354-2 PubMed DOI

Hewer E, Vajtai I (2015) Consistent nuclear expression of thyroid transcription factor 1 in subependymal giant cell astrocytomas suggests lineage-restricted histogenesis. Clin Neuropathol 34:128–131. https://doi.org/10.5414/NP300818 PubMed DOI

Kleinschmidt-DeMasters BK, Lopes MB (2013) Update on hypophysitis and TTF-1 expressing sellar region masses. Brain Pathol 23:495–514. https://doi.org/10.1111/bpa.12068 PubMed DOI PMC

Bielle F, Villa C, Giry M et al (2015) Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis. Am J Surg Pathol 39:948–956. https://doi.org/10.1097/PAS.0000000000000421 PubMed DOI

Hang JF, Hsu CY, Lin SC et al (2017) Thyroid transcription factor-1 distinguishes subependymal giant cell astrocytoma from its mimics and supports its cell origin from the progenitor cells in the medial ganglionic eminence. Mod Pathol 30:318–328. https://doi.org/10.1038/modpathol.2016.205 PubMed DOI

Weterman MA, Ajubi N, van Dinter IM et al (1995) nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int J Cancer 60:73–81. https://doi.org/10.1002/ijc.2910600111 PubMed DOI

Lazaratos AM, Annis MG, Siegel PM (2022) GPNMB: a potent inducer of immunosuppression in cancer. Oncogene 41:4573–4590. https://doi.org/10.1038/s41388-022-02443-2 PubMed DOI

Maric G, Annis MG, Dong Z et al (2015) GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis. Oncogene 34:5494–5504. https://doi.org/10.1038/onc.2015.8 PubMed DOI

Li Y, Yuan S, Liu J et al (2020) CSE1L silence inhibits the growth and metastasis in gastric cancer by repressing GPNMB via positively regulating transcription factor MITF. J Cell Physiol 235:2071–2079. https://doi.org/10.1002/jcp.29107 PubMed DOI

Taya M, Hammes SR (2018) Glycoprotein non-metastatic melanoma protein B (GPNMB) and cancer: A novel potential therapeutic target. Steroids 133:102–107. https://doi.org/10.1016/j.steroids.2017.10.013 PubMed DOI

Kuan CT, Wakiya K, Dowell JM et al (2006) Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin Cancer Res 12:1970–1982. https://doi.org/10.1158/1078-0432.CCR-05-2797 PubMed DOI

Ono Y, Chiba S, Yano H et al (2016) Glycoprotein nonmetastatic melanoma protein B (GPNMB) promotes the progression of brain glioblastoma via Na PubMed DOI

Bao G, Wang N, Li R et al (2016) Glycoprotein non-metastatic melanoma protein B promotes glioma motility and angiogenesis through the Wnt/β-catenin signaling pathway. Exp Biol Med (Maywood) 241:1968–1976. https://doi.org/10.1177/1535370216654224 PubMed DOI

Feng X, Zhang L, Ke S et al (2020) High expression of GPNMB indicates an unfavorable prognosis in glioma: Combination of data from the GEO and CGGA databases and validation in tissue microarray. Oncol Lett 20:2356–2368. https://doi.org/10.3892/ol.2020.11787 PubMed DOI PMC

Baba M, Furuya M, Motoshima T et al (2019) TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. Mol Cancer Res 17:1613–1626. https://doi.org/10.1158/1541-7786.MCR-18-1235 PubMed DOI PMC

Salles DC, Asrani K, Woo J et al (2022) GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms. J Pathol 257:158–171. https://doi.org/10.1002/path.5875 PubMed DOI PMC

Li H, Argani P, Halper-Stromberg E et al (2023) Positive GPNMB immunostaining differentiates renal cell carcinoma with fibromyomatous stroma associated with TSC1/2/MTOR alterations from others. Am J Surg Pathol 47:1267–1273. https://doi.org/10.1097/PAS.0000000000002117 PubMed DOI PMC

Wangsiricharoen S, Ingram DR, Morey RR et al (2024) Glycoprotein nonmetastatic melanoma protein B (GPNMB) immunohistochemistry can be a useful ancillary tool to identify perivascular epithelioid cell tumor. Mod Pathol 37:100426. https://doi.org/10.1016/j.modpat.2024.100426 PubMed DOI

Soukup J, Gerykova L, Rachelkar A et al (2023) Diagnostic utility of immunohistochemical detection of MEOX2, SOX11, INSM1 and EGFR in gliomas. Diagnostics (Basel) 13:2546. https://doi.org/10.3390/diagnostics13152546 PubMed DOI

Panwar V, Singh A, Bhatt M et al (2023) Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther 8:375. https://doi.org/10.1038/s41392-023-01608-z PubMed DOI PMC

Landrum MJ, Lee JM, Benson M et al (2018) ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 46:D1062–D1067. https://doi.org/10.1093/nar/gkx1153 PubMed DOI

Suda M, Shimizu I, Katsuumi G et al (2022) Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Sci Rep 12:6522. https://doi.org/10.1038/s41598-022-10522-3 PubMed DOI PMC

Bianco V, Kratky D (2023) Glycoprotein non-metastatic protein B (GPNMB): The missing link between lysosomes and obesity. Exp Clin Endocrinol Diabetes 131:639–645. https://doi.org/10.1055/a-2192-0101 PubMed DOI PMC

Szulzewsky F, Pelz A, Feng X et al (2015) Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1. PLoS ONE 10:e0116644. https://doi.org/10.1371/journal.pone.0116644 PubMed DOI PMC

Yalcin F, Haneke H, Efe IE et al (2024) Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma. Acta Neuropathol Commun 12:50. https://doi.org/10.1186/s40478-024-01754-7 PubMed DOI PMC

Tyburczy ME, Kotulska K, Pokarowski P et al (2010) Novel proteins regulated by mTOR in subependymal giant cell astrocytomas of patients with tuberous sclerosis complex and new therapeutic implications. Am J Pathol 176:1878–1890. https://doi.org/10.2353/ajpath.2010.090950 PubMed DOI PMC

Pan R, Wang X, Fang R et al (2025) GPNMB expression differentiates subependymal giant cell astrocytoma from other mimickers. Ann Diagn Pathol 75:152442. https://doi.org/10.1016/j.anndiagpath.2025.152442 PubMed DOI

Furuya M, Hong SB, Tanaka R et al (2015) Distinctive expression patterns of glycoprotein non-metastatic B and folliculin in renal tumors in patients with Birt-Hogg-Dubé syndrome. Cancer Sci 106:315–323. https://doi.org/10.1111/cas.12601 PubMed DOI PMC

Lee B, Hwang S, Bae H et al (2024) Diagnostic utility of genetic alterations in distinguishing IDH-wildtype glioblastoma from lower-grade gliomas: Insight from next-generation sequencing analysis of 479 cases. Brain Pathol 34:e13234. https://doi.org/10.1111/bpa.13234 PubMed DOI PMC