Pathology of Translocation Carcinoma

Translocation carcinoma is a renal cell carcinoma (RCC) subtype that harbors a translocation involving a member of the microphthalmia transcription factor gene family. These translocations most commonly involve the TFE3 gene on locus Xp11.2 and less commonly involve the TFEB gene on locus 6p21.

There have been approximately 160 reported cases of Xp11.2 translocation-associated renal cell carcinoma (RCC); this subtype occurs predominantly in children and young adults. The mean age in published cases is approximately 25 years; the median age is 20 years. ^{[1, 2]} This subtype now represents a significant proportion of RCC cases in pediatric patients, although widely divergent incidences have been reported in studies (20–83%). ^{[3, 4, 5, 6, 7, 8]}

In addition, Xp11.2 translocation-associated carcinoma is now being increasingly reported in patients over age 40 years. ^[9] There is a predilection for female patients (in published series, the female-to-male ratio is approximately 2:1) and for African American patients. ^{[1, 2, 10]}

Transcription factor EB (TFEB) RCC is much rarer, with only 12 reported cases in the literature; therefore, less is known about its epidemiology. The mean age in reported cases is 25 years; the median age is 19 years. ^{[1, 2]} There is no evidence for either gender or racial predilection.

Translocation-associated renal cell carcinomas (RCCs) arise from the proximal tubule epithelium, similar to conventional clear cell and papillary RCCs. ^[1]

The tumor typically arises within the cortex of the renal parenchyma. ^{[1, 2, 3, 10]}

Patients with translocation-associated renal cell carcinoma (RCC) present with symptoms typical of RCC, such as flank/abdominal pain, hematuria, renal masses found incidentally on imaging, or nonspecific constitutional symptoms such as weight loss and anemia. ^{[1, 2, 3, 4]}

A significant proportion (17-25%) of patients with Xp11.2 translocation-associated RCCs and at least 1 patient with t(6;11) translocation-associated RCC had a history of chemotherapy. ^{[1, 2, 4, 11]} In rare instances, Xp11.2 translocation-associated RCC is associated with another condition, such as sickle cell hemoglobinopathy trait, hemihypertrophy of the face, Saethre-Chotzen syndrome, cryptorchidism, or coccygeal teratoma. ^{[1, 3, 4, 7, 8]}

Translocation-associated renal cell carcinoma (RCC) usually grossly resembles a conventional clear cell RCC; lesions are typically cortical or subcapsular, well circumscribed, and tan-yellow, with variegated, focally necrotic, and hemorrhagic cut surfaces. (See the image below.) ^{[1, 2, 3, 12]}

Xp11.2 translocation-associated renal cell carcinomas are generally cortical or subcapsular, well-circumscribed lesions with yellow-tan, variegated cut surfaces. Image courtesy of University of Michigan.

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In Xp11.2 translocation-associated renal cell carcinoma (RCC), cells typically have voluminous cytoplasm, which can range from eosinophilic and granular to clear. Cells may also exhibit bulging cell borders—a trait that has been referred to as "soap bubble" morphology. Within any tumor, nuclear size may vary, but uniformly, these tumors are of a high Fuhrman nuclear grade.

The hallmark of these tumors is architectural heterogeneity; within a given tumor, cells may be variably arranged in broad sheets, nests, trabeculae, true papillae, or pseudopapillae (see the first 3 images below). Another characteristic architectural feature found in many of these tumors is a pseudoalveolar pattern in which cells are arranged in alveolae with central cellular discohesion (see the fourth image below). Psammoma bodies and scattered xanthoma cells have been described in some tumors.

Xp11.2 translocation-associated renal cell carcinomas (RCCs) have heterogeneous morphology; at least focally, tumor cells often have abundant clear cytoplasm, mimicking clear cell RCC. Image courtesy of University of Michigan.

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Xp11.2 translocation-associated renal cell carcinomas (RCCs) may have well-developed papillae, mimicking papillary RCCs. Image courtesy of University of Michigan.

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In Xp11.2 translocation-associated renal cell carcinoma, tumor cells with abundant eosinophilic cytoplasm and high nuclear grade are often arranged in large nests with a delicate, intervening vascular stroma. Image courtesy of University of Michigan.

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The nests of tumor cells in Xp11.2 translocation-associated renal cell carcinomas may become centrally discohesive, giving rise to a pseudoalveolar growth pattern. Image courtesy of University of Michigan.

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Because of the architectural variation in these tumors, they often mimic, at least focally, the appearance of other RCC subtypes, such as clear cell RCC and papillary RCC. ^{[2, 3, 10, 13, 14, 12]} Heterogeneous architectural features, in which some foci within a single tumor resemble clear cell RCC and other foci resemble papillary RCC, as well as classically described features of translocation-associated RCC, such as high-grade cells with abundant clear to granular cytoplasm, prominent cell borders, and prominent psammoma bodies, are clues to the correct diagnosis.

Occasionally, a tumor will completely mimic a clear cell or papillary RCC, and the only clue to the diagnosis will be the patient's young age. Papillary and clear cell types each express cytokeratin and are negative for transcription factor E3 (TFE3). ^{[3, 15]}

Another interesting tumor that may potentially be confused with translocation-associated RCC is the clear cell papillary RCC. These tumors were originally described in end-stage kidneys but may also be seen in other settings. They typically occur in older patients. Most importantly, these lesions present as low-grade and low-stage tumors. Clear cell papillary RCC is strongly positive for cytokeratin 7 and negative for alpha-methylacyl-CoA racemase (AMACR) and TFE3.

Transcription factor EB (TFEB) RCC is characterized by polygonal cells that have abundant clear to eosinophilic cytoplasm with Fuhrman nuclear grade 3 nuclei arranged in nests with a delicate, intervening vascular network. Cell borders are typically prominent. A characteristic feature seen in most tumors is a second distinct population of cells that are smaller and epithelioid and that are clustered around hyaline basement membrane (see the image below). These tumors typically have low mitotic activity and are without necrosis. In a few cases, abortive papillae or psammoma bodies have also been described. ^{[2, 10, 16]}

Transcription factor EB (TFEB) renal cell carcinoma is characterized by polygonal cells that have abundant clear to eosinophilic cytoplasm and high nuclear grade arranged in nests with a delicate, intervening vascular network. A characteristic feature is a second distinct population of smaller, epithelioid cells clustered around hyaline basement membrane. Image courtesy of Dr. Pedram Argani, Johns Hopkins University, and Dr. Ming Zhou, Cleveland Clinic.

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The majority of Xp11.2 tumors are either negative or only focally positive for epithelial markers such as cytokeratin cocktail, cytokeratin CAM5.2, cytokeratin 7, and epithelial membrane antigen. These tumors are also generally positive for the renal cell carcinoma (RCC) immunostain. ^{[1, 2, 3, 10, 13, 14]} Rare carcinomas have been reported to be positive for Melan A and HMB45, as these tumors are considered part of the family of microphthalmia transcription factors. ^[2]

An immunostain for aberrant nuclear overexpression of the TFE3 gene product has been developed. Although early studies reported a specificity and sensitivity of 97.5% and 99.6%, respectively, later studies reported a slightly lower sensitivity (82-87.5%). ^{[1, 17]} This variation in sensitivity is likely due in part to differing antibody incubation times. Generally, strong nuclear expression is considered characteristic of translocation-associated RCC (see the image below); weak nuclear expression may represent full-length transcription factor E3 (TFE3) protein rather than a chimeric fusion protein resulting from translocation. ^[18]

Xp11.2 translocation-associated renal cell carcinomas typically exhibit strong nuclear positivity for the transcription factor E3 (TFE3) protein. Image courtesy of University of Michigan.

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A study by Kim et al suggested that break-apart fluorescence in situ hybridization (FISH) assay testing can serve as a complementary modality in confirming the diagnosis of Xp11.2 RCC. ^[19]

Transcription factor EB (TFEB) RCCs are characteristically negative for cytokeratins but are positive, at least focally, for HMB45 and Melan A. Focal positivity for CD10 has also been reported. Tumors are negative for microphthalmia-associated transcription factor (MiTF) and RCC. Nuclear overexpression of the TFEB gene product is thought to be a relatively sensitive and specific surrogate for t(6;11), similar to TFE3 immunostaining in Xp11.2 RCC. ^[2]

It has been shown that translocation-association carcinomas of the MiTF/TFE family also immunologically express cathepsin-K, which may be useful as a surrogate marker for these tumors. ^[20]

Translocation carcinomas most commonly harbor either t(X;17)(p11.2;q25), which leads to a fusion of the transcription factor gene TFE3 with the ASPL gene; t(X;1)(p11.2;p34), which leads to the fusion of the TFE3 gene with the PSF gene; or t(X;1)(p11.2;q21), which leads to a fusion of the TFE3 gene with the PRCC gene.

Other, less commonly described translocations in these renal cell carcinomas (RCCs) include inv (X)(p11;q12), which leads to a fusion of the TFE3 gene to the NonO (p54nrb) gene, and t(X;17)(p11.2;q23), which leads to the fusion of the TFE gene to the CLTC gene. ^{[2, 10, 21, 22]}

Transcription factor EB (TFEB) RCCs are characterized by a translocation between the alpha gene at 11q12 and the first intron of the TFEB transcription factor gene at 6p21. ^{[2, 16]}

TFE3 and TFEB, along with TFEC and MiTF, are members of the microphthalmia-associated transcription factor (MiTF) family, which have homologous deoxyribonucleic acid (DNA) binding sequences. MiTF is probably the best characterized member of this family; it is known to play an important role in melanocyte, mast cell, and eye development. Deregulation of this gene is also thought to be crucial in the development of melanocytic tumors. Although the exact pathogenesis underlying translocation-associated RCC is not known, it has been speculated that loss of downstream target gene expression and loss of cell cycle regulation play key roles. ^{[2, 22]}

A genome-wide study defined the incidence of translocation renal cell carcinoma (TRCC) within a clear-cell RCC-directed project and expanded the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin-remodeling genes. ^[23]

The American Joint Committee on Cancer (AJCC) TNM staging system is applied to translocation-associated RCCs. ^[24] In general, Xp11.2 renal cell carcinoma (RCC) presents at a higher stage than does conventional RCC.

A study summarizing 75 cases in the literature found that 65% of patients with non–translocation-associated RCC presented with low-stage tumors (stage I and II), whereas 65% of patients with Xp11.2 translocation-associated RCC presented with high-stage tumors (stage III and IV). ^[5] Other research found that 48-49% of patients with Xp11.2 RCCs presented with higher-stage disease (pT3 or pT4). ^[1]

In our experience, 66% of patients with Xp11.2 RCC present at an advanced stage. ^[3] The reported percentage of patients with Xp11.2-associated RCCs presenting with regional lymph node involvement or metastases is also high but is widely variable (24.8-85%). ^{[1, 3, 4, 5]} Patients with tumors bearing t(X;17)(p11.2;q35) are even more likely to present with lymph node involvement (reported frequency, 50%). ^[1] Common metastatic sites for these tumors include lung, liver, and brain. ^{[1, 3, 5]}

Although the stages for all of the reported cases of t(6;11)-associated RCCs are not known, the majority of patients have presented with disease of relatively low TNM stage (pT1 or pT2). ^{[1, 11, 25]}

There is controversy regarding the prognosis of patients with Xp11.2 renal cell carcinoma (RCC). Although some early series and smaller series reported a relatively indolent course, later series reported a relatively poor prognosis for these patients. ^{[1, 3, 6, 7, 8, 13, 14]} In our experience, with a median follow-up time of 2.8 years, approximately one half of patients ultimately die of disease. ^[3]

There is some evidence that although patients with these tumors are likely to present with tumors at higher stages, the presence of lymph node metastases alone in the absence of hematogenous spread does not necessarily portend a worse prognosis, at least in the short term. Patients who develop hematogenous metastases, however, seem to have a dismal prognosis. ^[5] Complicating these data is the fact that there have been several case reports of recurrences of Xp11.2 translocation-associated RCC occurring as long as 20-30 years after initial resection. ^{[26, 27]}

Although there is limited follow-up for the reported cases of t(6;11) translocation-associated RCC, in the majority of cases, there has been no evidence of disease following resection. At least 2 patients with t(6;11) RCC, however, died with multiple metastases relatively soon after resection. ^{[1, 2]}