TFE3 rearrangements characterize histogenetically, topographically, and biologically diverse neoplasms. Besides being a universal defining feature in alveolar soft part sarcoma (ASPS) and clear cell stromal tumor of the lung, TFE3 fusions have been reported in subsets of renal cell carcinoma, perivascular epithelioid cell tumor (PEComa), epithelioid hemangioendothelioma and ossifying fibromyxoid tumors. TFE3 -related neoplasms are rare in the head and neck and may pose diagnostic challenges. We herein describe 22 TFE3 fusion neoplasms affecting 11 males and 11 females aged 4 to 79 years (median, 25) and involving different head and neck sites: sinonasal cavities (n = 8), tongue (n = 4), oral cavity/oropharynx (n = 3), salivary glands (n = 2), orbit (n = 2), and soft tissue or unspecified sites (n = 3). Based on morphology and myomelanocytic immunophenotype, 10 tumors qualified as ASPS, 7 as PEComas (3 melanotic; all sinonasal), and 5 showed intermediate (indeterminate) histology overlapping with ASPS and PEComa. Immunohistochemistry for TFE3 was homogeneously strongly positive in all cases. Targeted RNA sequencing/FISH testing confirmed TFE3 fusions in 14 of 16 successfully tested cases (88%). ASPSCR1 was the most frequent fusion partner in ASPS (4 of 5 cases); one ASPS had a rare VCP::TFE3 fusion. The 6 successfully tested PEComas had known fusion partners as reported in renal cell carcinoma and PEComas ( NONO, PRCC, SFPQ , and PSPC1 ). The indeterminate tumors harbored ASPSCR1::TFE3 (n = 2) and U2AF2::TFE3 (n = 1) fusions, respectively. This large series devoted to TFE3-positive head and neck tumors illustrates the recently proposed morphologic overlap in the spectrum of TFE3 -associated mesenchymal neoplasms. While all PEComas were sinonasal, ASPS was never sinonasal and occurred in diverse head and neck sites with a predilection for the tongue. The indeterminate (PEComa-like) category is molecularly more akin to ASPS but shows different age, sex, and anatomic distribution compared with classic ASPS. We report VCP as a novel fusion partner in ASPS and PSPC1 as a novel TFE3 fusion partner in PEComa (detected in one PEComa). Future studies should shed light on the most appropriate terminological subtyping of these highly overlapping tumors.

Biopticka Laboratory Lts Pilsen Czech Republic

Department of Pathology and Laboratory Medicine Aga Khan University Hospital Karachi Pakistan

Department of Pathology Faculty of Medicine in Pilsen Charles University Prague

Department of Pathology The University of Texas Southwestern Medical Center Dallas TX

DERMPATH München Munich Germany

HistoCenter Khartoum Sudan

Institute of Pathology University Hospital Erlangen Germany

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

Zobrazit více v PubMed

Christopherson WM, Foote FW Jr, Stewart FW. Alveolar soft-part sarcomas; structurally characteristic tumors of uncertain histogenesis. Cancer. 1952;5:100–111.

Sciot R, Dal, Cin P, et al. Alveolar soft-part sarcoma: evidence for its myogenic origin and for the involvement of 17q25. Histopathology. 1993;23:439–444.

Ladanyi M, Lui MY, Antonescu CR, et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 2001;20:48–57.

Sharain RF, Gown AM, Greipp PT, et al. Immunohistochemistry for TFE3 lacks specificity and sensitivity in the diagnosis of TFE3-rearranged neoplasms: a comparative, 2-laboratory study. Hum Pathol. 2019;87:65–74.

Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001;159:179–192.

Argani P, Aulmann S, Karanjawala Z, et al. Melanotic Xp11 translocation renal cancers: a distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma. Am J Surg Pathol. 2009;33:609–619.

Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer. 2013;52:775–784.

Suurmeijer AJH, Song W, Sung YS, et al. Novel recurrent PHF1-TFE3 fusions in ossifying fibromyxoid tumors. Genes Chromosomes Cancer. 2019;58:643–649.

Agaimy A, Stoehr R, Michal M, et al. Recurrent YAP1-TFE3 gene fusions in clear cell stromal tumor of the lung. Am J Surg Pathol. 2021;45:1541–1549.

Argani P, Wobker SE, Gross JM, et al. PEComa-like neoplasms characterized by ASPSCR1-TFE3 fusion: another face of TFE3-related mesenchymal neoplasia. Am J Surg Pathol. 2022;46:1153–1159.

Simmons WB, Haggerty HS, Ngan B, et al. Alveolar soft part sarcoma of the head and neck. A disease of children and young adults. Int J Pediatr Otorhinolaryngol. 1989;17:139–153.

Argyris PP, Reed RC, Manivel JC, et al. Oral alveolar soft part sarcoma in childhood and adolescence: report of two cases and review of literature. Head Neck Pathol. 2013;7:40–49.

Wang HW, Qin XJ, Yang WJ, et al. Alveolar soft part sarcoma of the oral and maxillofacial region: clinical analysis in a series of 18 patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;119:396–401.

Hei Y, Kang L, Yang X, et al. Orbital alveolar soft part sarcoma: a report of 8 cases and review of the literature. Oncol Lett. 2018;15:304–314.

Banerjee SS, Eyden B, Trenholm PW, et al. Monotypic angiomyolipoma of the nasal cavity: a heretofore undescribed occurrence. Int J Surg Pathol. 2001;9:309–315.

Kuroda N, Goda M, Kazakov DV, et al. Perivascular epithelioid cell tumor of the nasal cavity with TFE3 expression. Pathol Int. 2009;59:769–770.

Saluja K, Thomas J, Zhang S, et al. Malignant perivascular epithelioid cell tumor of the oropharynx with strong TFE3 expression mimicking alveolar soft part sarcoma: a case report and review of the literature. Hum Pathol. 2018;76:149–155.

Robinson JT, Thorvaldsdóttir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–26.

Argani P, Zhong M, Reuter VE, et al. TFE3-fusion variant analysis defines specific clinicopathologic associations among Xp11 translocation cancers. Am J Surg Pathol. 2016;40:723–737.

Tretiakova MS. Chameleon TFE3-translocation RCC and how gene partners can change morphology: accurate diagnosis using contemporary modalities. Adv Anat Pathol. 2022;29:131–140.

Dickson BC, Chung CT, Hurlbut DJ, et al. Genetic diversity in alveolar soft part sarcoma: a subset contain variant fusion genes, highlighting broader molecular kinship with other MiT family tumors. Genes Chromosomes Cancer. 2020;59:23–29.

Zhu G, Benayed R, Ho C, et al. Diagnosis of known sarcoma fusions and novel fusion partners by targeted RNA sequencing with identification of a recurrent ACTB-FOSB fusion in pseudomyogenic hemangioendothelioma. Mod Pathol. 2019;32:609–620.

Ge Y, Lin X, Zhang Q, et al. Xp11.2 translocation renal cell carcinoma with TFE3 rearrangement: distinct morphological features and prognosis with different fusion partners. Front Oncol. 2021;11:784993.

Kuentz MA, Blons H, Gimenez-Roqueplo AP, et al. A novel VCP::TFE3 gene fusion resulting from t(X;9)(p11.23;p13.3) chromosome translocation in TFE3 rearranged renal cancer cell carcinoma. Genes Chromosomes Cancer. 2023;62:361–366.

Pozner A, Li L, Verma SP, et al. ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97. Nat Commun. 2024;15:1165.

Wang XT, Xia QY, Ni H, et al. Xp11 neoplasm with melanocytic differentiation of the prostate harbouring the novel NONO-TFE3 gene fusion: report of a unique case expanding the gene fusion spectrum. Histopathology. 2016;69:450–458.

McGregor SM, Alikhan MB, John RA, et al. Melanotic PEComa of the sinonasal mucosa With NONO-TFE3 fusion: an elusive mimic of sinonasal melanoma. Am J Surg Pathol. 2017;41:717–722.

Shah AA, Wang S, Shires C, et al. Sinonasal melanotic PEComa with NONO::TFE3 fusion: a case report and letter to the editor. Am J Surg Pathol. 2024;48:634–636.

Gao Y, Chen G, Chow C, et al. Ocular PEComas are frequently melanotic and TFE3-translocated: report of two cases including the first description of PRCC-TFE3 fusion in PEComa. Virchows Arch. 2021;478:1025–1031.

Knott GJ, Bond CS, Fox AH. The DBHS proteins SFPQ, NONO, and PSPC1: a multipurpose molecular scaffold. Nucleic Acids Res. 2016;44:3989–4004.

Argani P, Gross JM, Baraban E, et al. TFE3-rearranged PEComa/PEComa-like neoplasms: report of 25 new cases expanding the clinicopathologic spectrum and highlighting its association with prior exposure to chemotherapy. Am J Surg Pathol. 2024;48:777–789.

Harada S, Caliò A, Janowski KM, et al. Diagnostic utility of one-stop fusion gene panel to detect TFE3/TFEB gene rearrangement and amplification in renal cell carcinomas. Mod Pathol. 2024;;48:777–789.