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Review: Renal Cell Carcinomas Associated with Microphthalmia Transcription Factors

Key findings

  • A few rare subtypes of renal cell carcinoma (RCC) are associated with the microphthalmia (MiT) family of transcription factors—MITF, TFEB, TFE3 and TFEC—that play important roles in cell growth, differentiation and survival
  • The World Health Organization has recognized Xp11 translocation RCCs, which involve fusions of the TFE3 gene, and t(6;11) RCC, which involves TFEB–MALAT1 fusion
  • This review describes what's known about the epidemiology, clinical features, prognosis and treatment of these two newly described RCC subtypes
  • RCCs associated with the other two MiT family members, MITF and TFEC, are exceptionally rare

There's increasing recognition that renal cell carcinoma (RCC) can be categorized into subtypes that have distinct morphological, immunohistochemical and molecular characteristics. A few rare subtypes are associated with the microphthalmia (MiT) family of transcription factors—MITF, TFEB, TFE3 and TFEC—that play an important role in cell growth, differentiation and survival in several tissue types.

The World Health Organization's 2016 classification of genitourinary tumors included subtypes of RCC that are associated with the MiT transcription factors TFE3 or TFEB. Writing in the Asian Journal of UrologyChin-Lee Wu, MD, PhD, associate pathologist and director of Genitourinary Pathology Services at Massachusetts General Hospital and the Mass General Cancer Center, and colleagues review what clinicians should know about these newly described RCCs.

Xp11 Translocation RCCs

Xp11 translocation RCCs are characterized by several different translocations of chromosome Xp11.2, but all result in fusions of the TFE3 gene. In the three most common of these RCCs, TFE3 is fused to PRCC, ASPSCR1 or SFPQ.

Estimates vary, but Xp11 translocation RCC is thought to account for 20% to 40% of childhood RCC and 1% to 4% of adult RCC. The prevalence in adults may be underestimated because of confusion with more common RCC subtypes. In adults, Xp11 translocation RCC typically presents in the third to fifth decades, and it's one of the few subtypes of RCC that occurs in females more frequently than males, at a ratio of 2.5 to 1.

Clinical Features

The most common clinical features of Xp11 translocation RCC are hematuria, flank pain and abdominal pain. However, as with other forms of RCC, approximately one-third of tumors present as a painless renal mass, often an incidental finding on abdominal imaging.

The only known risk factor for Xp11 translocation RCC is prior exposure to cytotoxic chemotherapy for various cancers or inflammatory conditions (Wilms tumor, Ewing sarcoma, systemic lupus erythematosus, acute leukemia and bone marrow transplant). The interval between chemotherapy and the documented occurrence of Xp11 translocation RCC has ranged from two to 13 years.


In general, Xp11 translocation RCC metastasizes to the lymph nodes, and the prognosis is similar to that of clear-cell RCC and worse than that of papillary RCC. However, because the tumors are relatively rare, outcomes data are scarce and highly variable. Some patients, particularly children, survive decades with indolent disease whereas others die rapidly of progressive disease.

Xp11 translocation RCC has been known to metastasize as late as 30 years after diagnosis, so additional long-term follow-up data are necessary before any firm conclusions can be drawn about prognosis.


Surgery is the treatment of choice for patients with localized Xp11 translocation RCC, including those with positive regional lymph nodes. For patients with hematogenous metastases, current approaches are immunotherapy using cytokines (such as interleukin-2 or interferon-alfa) or multikinase inhibitors. The optimal therapy is unknown, and many patients have a poor prognosis regardless of treatment, so better options are desperately needed.

Characteristics and History of t(6;11)RCCs

t(6;11) RCC is an extremely rare variant, accounting for only 0.02% of all renal carcinomas. The t(6;11) translocation fuses the TFEB gene with MALAT1, resulting in overexpression of TFEB. Only 70 cases of t(6;11) RCC have been documented, most in children and adolescents, but the reported age at presentation ranges from 3 to 77 years. The male-to-female ratio is approximately equal. Patients may present with hematuria, abdominal pain or an abdominal mass, or the tumor may be found incidentally. Similar to Xp11 translocation RCCs, a subset of cases have occurred in patients who have received cytotoxic chemotherapy for other disorders.

There are no well-established prognostic markers or protocols that predict the behavior of t(6;11) RCC. Most patients have presented at stage pT1 or pT2 and have had an indolent clinical course. In pooled data from several case series of adults with t(6,11) RCC, 17% of tumors were aggressive, presenting as larger masses (12 cm vs. 7 cm) in older patients (age 46 vs. 31). In addition, these tumors can metastasize.

The natural history of t(6;11) RCC remains to be established since it's so rare. Extirpative surgery is the sole therapeutic option—there are no proven neoadjuvant or adjuvant therapies. These tumors can recur late, up to eight years after diagnosis, so close follow-up is needed after surgery.

Toward the Future

The other two MiT transcription factors, MITF and TFEB, can also be associated with RCC, but such tumors are thought to be exceedingly rare. Continued use of genomic technologies should yield more information, as well as suggest prognostic factors and therapeutic targets for all MiT transcription factor–associated RCCs.

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