Renal cell carcinomas (RCCs) encompass a spectrum of tumors with unique clinical and histopathological features as well as characteristic cytogenetic aberrations (28
). Cytogenetic analysis has provided a valuable tool in the diagnosis of the various histological subtypes and has elucidated how their distinctive molecular profiles correlate with different morphological patterns. Pediatric renal cell carcinomas, though uncommon, usually show distinctive chromosomal abnormalities most often involving translocations involving TFE3
, members of the MiTF family of transcription factors (12
While Xp11 translocation RCC is typically considered a pediatric malignancy, its frequency in the adult population remains underestimated (14
). Several reasons could explain this occurrence. One possibility lies in the fact the translocation RCCs usually overlap morphologically or mimic other RCCs (primarily clear cell and papillary RCC). In contrast to pediatric neoplasms, fresh tissue collection for cytogenetics and molecular analysis is not routinely performed in adult translocation RCC making further diagnostic testing difficult.
Previous cytogenetic and immunohistochemistry-based studies attempting to estimate the frequency of Xp11 translocation RCC have revealed an incidence of around 1% (14
) and 1.6 % (25
) respectively among all RCCs examined in these series. Taking the aforementioned into consideration along with the fact that RCC is more commonly encountered in the adult population, it is possible that the frequency of Xp11 translocation RCCs in adults may outnumber cases in the pediatric group (31
). Interestingly, our study revealed a frequency close to 5%, likely because routine fresh tissue collection for cytogenetic testing and cryopreservation of tumor samples is a common practice at our institution allowing us to perform in depth ancillary studies including cytogenetic analysis, RT-PCR and FISH. This emphasizes that the combination of histopathology along with molecular studies increases the diagnostic accuracy of these tumors. Our case series is relatively small (121 cases). A more accurate frequency of Xp11 translocation RCC needs to be confirmed by larger and multi-institutional studies. If our results are representative of the general population, there will be approximately 2500 new TFE3
translocation RCC cases each year in US, considering NCI estimates of 58,240 new kidney tumor cases in the US in 2011.
Although prior exposure to chemotherapy remains the only known risk factor for the development of Xp11 translocation RCC (7
), none of the patients in our study had a history of chemotherapy exposure. Female predominance, as described in the literature (11
), was seen in our study. All TFE3
translocation RCC cases were present in females with a mean age of 43, contrasting with the much younger mean age (~15 years less) of all 121 RCC patients examined.
Grossly, Xp11 translocation RCCs are large tumors resembling conventional clear cell RCC with a variegated appearance including tan-yellow areas admixed with hemorrhagic and necrotic tissue foci. The mean tumor size in our series was 12.5 cm, almost double of that reported in other series (11
). This may be due to the fact that our hospital serves a population of predominantly low socioeconomic status in which patients tend to seek medical attention at more advanced stages of disease due to limited access to health care.
As described by Argani and Ladanyi, TFE3
gene fusions translate histologically to a distinct morphological pattern consisting mainly of mixed papillary and nested cells with granular eosinophilic cytoplasm (1
). The majority of our cases were consistent with this histological picture. Intriguingly, we also found some unique histological features that have not been previously described in the literature. These include signet ring-like cells in a microcystic arrangement () with high grade cytologic atypia and non-clear cells laid in solid/syncytial architectural patterns (). Similar morphology of high grade cytologic atypia and non-clear cells have been previously reported in Xp11 RCC (9
). Abundant psammoma bodies and hyaline nodules were not seen in our cases. These tumors did not contain the typical delicate and uniform small vessels common in clear cell RCC or collections of foamy histiocytes common in papillary RCC. Xp11 translocation RCC should also be distinguished from clear cell papillary renal cell carcinoma (23
), a newly described entity. Most clear cell papillary RCCs contain both clear cell and papillary features in a similar style to Xp11 translocation RCCs. A cardinal feature to differentiate these tumors is based on the location of the nuclei towards either the middle or upper pole of the cell (23
). This reverse polarity is a feature not seen in Xp11 translocation RCC.
Xp11 translocation RCCs are known to variably express epithelial immunohistochemical markers and are consistently positive for renal cell carcinoma marker antigens and CD10 (5
). Still, nuclear immunoreactivity to TFE3 protein remains the most sensitive, specific, and distinct immunohistochemical marker for these neoplasms (5
). For a comprehensive immunohistochemical profile of these tumors, please see a recent publication (5
). The TFE3 protein antibody recognizes the C-terminal portion of TFE3. The C-terminal portion is retained in the gene fusion (9
). Its over-expression in TFE3
translocation RCC is believed to be due to the up-regulation of a chimeric TFE3 protein resulting from a swapping to a stronger promoter (9
). In our study, 6 cases expressed moderate to strong nuclear staining while 5 cases exhibited weak TFE3 staining. Further investigation of the latter cases by FISH and/or RT-PCR failed to reveal any evidence of TFE3 rearrangement suggesting that the weak nuclear TFE3 staining may be the result of an up-regulation of the full-length TFE3 protein, translating into a weak expression(3
). This up-regulation is in contrast to the chimeric fusion proteins resulting from Xp11.2 gene rearrangements. These results re-confirm that weak nuclear staining should not be interpreted as true positive staining in these tumors and that TFE3 IHC is a sensitive marker for Xp11 translocation RCC (9
). Additionally, in all six Xp11 translocation RCC cases determined by FISH and/or cytogenetics, RT-PCR showed strong to moderate nuclear TFE3 staining. These findings also showed that with careful evaluation, TFE3 IHC can be a specific marker for these tumors as well (9
The diagnosis of Xp11 translocation RCC requires the integration of clinical information, histopathologic features, TFE3 IHC stain, cytogenetic, and molecular studies. Any of the following scenarios should prompt work up to further investigate the possibility of an Xp11 translocation RCC: young/middle age patient (<45) with metastatic RCC; typical clear cell with papillary histopathological features along with minimal immunohistochemical reactivity to cytokeratins and EMA. TFE3 IHC is a sensitive and relatively specific marker for Xp11 translocation RCC that could be used as a screening method, followed by FISH assay which should be reserved as a helpful ancillary technique in those cases with equivocal TFE3 IHC staining. To date, the diagnosis of Xp11 translocation RCC remains largely as an academic exercise due to the lack of a specific therapy for these neoplasms. However, awareness among pathologist is pivotal in order to arrive to an accurate diagnosis.
Xp11 translocations have been implicated in several tumors other than RCC. Alveolar soft part sarcoma (ASPS) with the ASPL-TFE3
gene fusion is one example (26
). Interestingly, Xp11 translocation RCC with identical gene rearrangements have shown similar histopathological patterns to ASPS (6
). Perivascular epithelioid cell tumors (PEComas) have also shown immunoreactivity for TFE3. Folpe, et al showed TFE3 positivity in 5 of 17 PEComas (21
). Two cases of PEComa with a PSF-TFE3
gene fusion demonstrated by FISH and RT-PCR have also been reported (16
). More recently, Argani reported a subset of lesions currently classified as PEComas which harbor TFE3
gene fusions (3
). He also reported a distinctive type of renal cancer with overlapping features of PEComa, Xp11 translocation carcinoma, and melanoma (4
In the present series we also report on TFEB
t(6;11)(p21;q12) translocation RCC, another rare subtype of RCC. These
carcinomas are characterized by fusion of the intronless Alpha
gene (11q12) with the first intron of the TFEB
transcription factor gene (6p21)(8
translocation RCCs share similar histopathological features with TFE3
translocation RCCs, but at the same time reveal distinct clinicopathologic features (6
). Microscopically, these tumors display a dimorphic pattern composed of large polygonal epithelioid cells with clear to eosinophilic cytoplasm in a nested pattern co-mingled with a population of smaller epitheliod-like cells typically clustered around hyaline nodules (6
). In our case, however, this dimorphic pattern was not present. Instead, the tumor was composed of medium sized polygonal cells with small round nuclei distributed in solid sheets with multiple foci of papillary and tubular architectural patterns, a feature that has been observed in other TFEB
translocation RCCs confirmed by cytogenetic studies (Argani, personal communication). Immunoprofiling on this case revealed the distinctive features of this tumor subtype including entirely absent staining for pan-cytokeratins AE1/3 and kidney tubule marker CD10 and a diffuse strong immunoreacivity with HMB-45. TFEB staining showed moderate to strong nuclear staining which was more prominent at the periphery of the tumor, perhaps due to better antigen preservation from more complete fixation at the periphery of the tissue (6
MITF, an MIT family protein which also includes TFE3, TFEB and TFEC, has also been implicated in various cancers. MiTF
) and somatic mutations (18
) have been reported in human melanoma. Another correlation of MITF with tumorigenesis has been made for clear cell sarcoma (CCS) (20
), a rare sarcoma that expresses melanocytic markers and harbors the EWS–ATF1
chromosomal translocation. The resulting fusion protein occupies the MITF
promoter and induces its expression, mediating CCS survival. CCS cells can not survive in the absence of MITF, although their survival can be rescued by either MITF or the closely related family members TFE3 or TFEB. Reciprocally, UOK109, an Xp11 translocation RCC cells that harbors the NONO-TFE3
translocation, could not survive upon TFE3 knockdown by small interference RNA (siRNA) but were rescued by expression of MITF(20
). These elegant experiments demonstrated functional oncogenic overlap among MITF, TFE3 and TFEB. Based on oncogenic gene fusion–translocation events, dysregulation of MITF-related family members, and genetic evidence of functional redundancy among several of these factors, Fisher et al suggested a re-evaluation of the classification of these tumors (27
). They coined the term “MiT family cancers” which includes a subset of melanoma, TFE3
translocation RCC, alveolar soft part sarcoma (ASPS), and clear cell sarcoma (CCS) (27
This observation is of crucial importance, as recent therapeutic strategies focusing on targeting common molecular pathways that contribute to critical steps in malignant transformation have proven successful. One such example is with the tyrosine kinase inhibitor Imatinib, which targets BCR-ABL and c-KIT and significantly improves the prognosis of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) respectively. Even though MiT family cancers differ in many clinical aspects, these cancers share common or closely related oncogenic factors. It is reasonable to predict that targeted therapies for the MITF family proteins will be effective for all Mit family cancers including TFE3 translocation RCC.
In conclusion, this study reports on the unique clinicopathologic features of adult RTCs using TMA, immunohistochemistry, cytogenetics and FISH. In addition to histological diagnosis, these adjunctive techniques could potentially be used in an algorithmic combination to strengthen diagnostic accuracy and greatly increase the chances of therapeutic success. We found that these tumors are not uncommon in light of a single institution experience. Despite the significant advances and recent progress in the understanding of the molecular basis of translocation-associated renal cell carcinomas, many aspects of these tumors remain to be uncovered.