Chameleon TFE3-translocation RCC and How Gene Partners Can Change Morphology: Accurate Diagnosis Using Contemporary Modalities

Abstract

Translocation renal cell carcinoma (tRCC) with TFE3 gene rearrangements has been born as a distinct entity 20 years ago. These relatively rare tumors were notable among other RCC subtypes because of their disproportionally high incidence among children and young adults. Initial reports were focused on describing unifying morphologic criteria and typical clinical presentation. Follow-up studies of ancillary immunohistochemical and hybridization techniques provided additional diagnostic tools allowing recognition of tRCC tumors in practice. However, a growing body of literature also expanded the clinicomorphologic spectrum of tRCCs, to include a significant morphologic overlap with other RCC variants thus blurring the diagnostic clarity of this entity. More recent molecular studies utilizing next-generation sequencing technology accelerated recognition of numerous novel gene partners fusing at different breakpoints with the TFE3 gene. Accumulating data indicates that morphologic and clinical heterogeneity of tRCC could be explained by fusion subtypes, and knowledge of TFE3 partnering genes may be important in predicting tumor behavior. Herein we provided a comprehensive analysis of ∼400 tRCC cases with known TFE3 fusion partners, estimated their relative incidence and summarized clinicomorphologic features associated with most common fusion subtypes. Our data was based on an extensive literature review and had a special focus on comparing immunohistochemistry, fluorescent in situ hybridization and contemporary molecular studies for the accurate diagnosis of tRCC.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas

“…TRCC is a biologically heterogenous disease depending on fusion partners, which may have different impact on response to ICT combinations. 25 Data regarding the specific fusion partners were not available in our report; therefore, we were unable to assess their effect on outcomes. While we await the prospective data from AREN1721, our study suggests that ICT + VEGF TT regimens may yield higher clinical activity than dual ICT in adult patients with metastatic tRCC.…”

Minimally invasive cytologic evaluation leading to the diagnosis of TFE3‐rearranged renal cell carcinoma: A case report

“…Although strong nuclear staining for TFE3 immunohistochemistry was initially reported as being highly sensitive and specific for TFE3-rearrangments, 13 subsequent studies have found its performance to be less reliable, leading to false-positive, false-negative, and equivocal results. 14,15 TFE3 immunoreactivity can be seen in other entities such as clear cell RCC and ALK-rearranged RCC. 10 Additionally, the sensitivity and specificity may vary depending on fixation time and use of different antigen retrieval methods or antibody clones.…”

TFE3 Rearrangement and Expression in Renal Cell Carcinoma

“…87,88 However, cathepsin K is most useful in PRCC:: TFE3 and TFEB rearranged tumors, as most translocation RCC with other forms of gene rearrangements do not express this antigen. 50,51,88 In labs with limited resources, KRT7 and CA9 IHC may be extremely useful to distinguish TFE3 RCC from clear cell RCC (KRT7-/CA9 + ), clear cell papillary RCC (KRT7 + /CA9 + cup-shaped staining), papillary RCC (KRT7 + /CA9-) and chromophobe RCC (KRT7 + /CA9-) 14,86,89 in the differential diagnosis RCC with clear cell features, along with under-expression of pancytokeratins.…”

“…In a recent review article, immunoprofile of nearly 400 TFE3 RCC cases were reviewed; most commonly expressed biomarkers were PAX8 (100%), TFE3 (95%), CD10 (89%), and racemase (82%); whereas KRT7 (10%), CA9 (3%), melan-A (17%), and HMB45 (19%) were usually negative. 86 They were repeatedly documented to have diminished staining with epithelial markers such as cytokeratins (ie cytokeratin AE1/AE3) and epithelial membrane antigen (EMA) but exceptions do exist. 14,85 Cathepsin K staining is highly specific for MiT translocation RCC.…”