MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights

Abstract

MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC.

Keywords: MITF; TFE3; TFEB; translocation renal cell carcinomas.

Figure 1

Morphological and immunohistochemical features of TFE3-tRCC. Captions: (A–C): Morphology and features. (A/B) Papillary architecture; C: eosinophilic cells with prominent nucleoli (HES staining, magnification (A) ×50, (B) ×200, (C) ×200); (D–F): immunohistochemical features. (D): TFE3 positivity of the majority of nuclei; (E): p504 cytoplasmic positivity for some cells; (F): CAIX positivity in hypoxic territory (TFE3/p504/CAIX IHC, respectively, magnification ×200); tRCC: translocation renal cell carcinoma; HES: hematoxylin–eosin–safran.

Figure 2

Morphological and immunohistochemical features of TFEB-tRCC mimicking clear cell RCC. (A–C): Morphology and features. (A,B): Massive architecture; (B,C): mixed eosinophilic and clarified cells (HES staining, magnification (A) ×12.5, (B,C) ×200); (D–F): immunohistochemical features. (D): PAX8 positivity; (E): CAIX negativity; (F): AE1–AE3 positivity for some cells; (G): TFE3 nuclei positivity for some cells; (H): HMB45 cytoplasmic positivity for few cells; (I): Melan-A cytoplasmic positivity for few cells (D): PAX8, (E): CAIX, (F): AE1-AE3, (G): TFE3, (H): HMB45, (I): Melan-A IHC, respectively, magnification ×200); tRCC: translocation renal cell carcinoma; HES: hematoxylin–eosin–safran.

Figure 3

Proposed algorithm of pathologic analyses to identify tRCC; MITF: microphthalmia-associated transcription factor; RCC: translocation renal cell carcinoma; FISH: fluorescence in situ hybridization.