Contributed by Mir Alikhan, M.D.

• MiT family translocation associated renal cell carcinoma
• Granular cell tumor (Hum Pathol 2014;45:1039)
• Alveolar soft part sarcoma
• Subset of epithelioid hemangioendotheliomas
• Subset of perivascular endothelial cell tumors (PEComas)
• Some solid pseudopapillary pancreatic neoplasms
• Subset of ovarian sclerosing stromal tumors
  • Subset (~9%) of RCCs lacking TFE3 rearrangements and associated with higher nuclear grade, advanced tumor stage and metastatic disease, as well as an unfavorable outcome (Adv Anat Pathol 2022;29:131, Histopathology 2018;73:758, BJU Int 2011;108:E71)

• TFE3 break apart probes in FISH analysis are most effective at detection of the fusion due to multiple partners of the gene
• Most common partner genes in MiT family translocation associated renal cell carcinoma are PRCC and ASPSCR1 (ASPL) (Am J Surg Pathol 2016;40:723)
  • Melanotic subtype generally harbors the SFPQ-TFE3 fusion and rarely ARID1B-TFE3 (Am J Surg Pathol 2017;41:1576)
• SFPQ and NONO are also common partners in certain cases of PEComas (Am J Surg Pathol 2015;39:1181, Histopathology 2016;69:450, Am J Surg Pathol 2017;41:717)
• Fusion most commonly seen in alveolar soft part sarcoma is ASPSCR1 (ASPL) (Oncogene 2001;20:48)
• Epithelioid hemangioendotheliomas often show WWTR1-CAMTA1 fusions but a subset can also show concomitant YAP1-TFE3 (Oncotarget 2016;7:7480)
• Reverse transcriptase polymerase chain reaction (PCR) studies can be performed for a more sensitive detection of the fusion product
  • More recently, next generation sequencing using mapping based data mining of sequencing reads can also detect fusions (Am J Surg Pathol 2017;41:1576)
  • Some studies have shown RNA sequencing to be an effective method for novel gene fusion detection (Mod Pathol 2018;31:1346)
• While granular cell tumor expresses TFE3 by immunohistochemistry, it does not show TFE3 gene rearrangements by FISH (Hum Pathol 2015;46:1242)

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Translocations involving the TFE3 gene can be found in which of the following neoplasms?

1. Angiosarcoma
2. Clear cell papillary renal cell carcinoma
3. Clear cell sarcoma
4. Melanotic perivascular endothelial cell tumor
5. Solid pseudopapillary pancreatic neoplasm

D. Melanotic perivascular endothelial cell tumor. TFE3 fusions are most closely associated with Xp11 translocation renal cell carcinoma, alveolar soft part sarcoma, melanotic Xp11 renal cell carcinoma, some PEComas and others. Although increased TFE3 expression is seen in some solid pseudopapillary pancreatic neoplasms, these have been negative for the gene fusion.

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Reference: TFE3

Which of the following is a common, effective method for detection of the TFE3 gene fusion?

1. Break apart FISH probe
2. Conventional karyotype analysis
3. Dual color, dual fusion FISH probe
4. Immunohistochemistry
5. RNA sequencing

A. Break apart FISH probe. Due to the multiple translocation partners seen in TFE3 associated neoplasms, a break apart FISH probe is recommended over a dual color, dual fusion FISH probe. Some fusions are cryptic and cannot be detected by conventional karyotype analysis. Immunohistochemistry would detect the overexpression of TFE3 but cannot confirm whether the overexpression is due to the fusion event or other, possibly epigenetic, factors leading to TFE3 overexpression. While RNA sequencing can detect the multiple fusion partners, it is not commonly utilized at this time.

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Reference: TFE3