Moderators: Dr. John Eble and Dr. Brett Delahunt
Section 4 -
Translocation Carcinomas of the Kidney
The Johns Hopkins Hospital
Xp11.2 Translocation Renal Carcinomas
Renal cell carcinomas (RCC) with chromosome translocations involving Xp11.2 and resulting
gene fusions involving the TFE3 transcription factor gene are newly
recognized entities in the 2004 WHO Renal Tumor Classification. These neoplasms tend to affect younger
patients. One distinctive subtype bears a t(X;17)(p11;q25), which results in the identical ASPL-TFE3 gene fusion as was initially identified in alveolar soft part sarcoma
(ASPS). Other subtypes are listed in Table 1. The ASPL-TFE3 RCC
characteristically present at advanced stage and virtually all neoplasms (even small ones) have presented
with lymph node metastases at diagnosis, despite the often small size of the primary. While the ASPL-TFE3 RCC usually present at advanced stage, their clinical course has been
indolent in some cases, though other patients have done poorly. Some Xp11-translocation RCC have
recurred 20 or 30 years after initial diagnosis. Approximately 10-15% of Xp11-translocation
RCC have arisen in patients previously treated with chemotherapy, including a unique case in which a
child with a prior ASPL-TFE3 RCC developed a PRCC-TFE3 RCC in the opposite kidney.
Xp11.2 translocation RCC closely resemble conventional (clear cell) renal carcinomas on
gross examination, usually being tan-yellow, and often necrotic and hemorrhagic. A papillary carcinoma
comprised of clear cells is the most distinctive histopathologic appearance, since this combination is
uncommon in other defined types of renal carcinomas. However, the Xp11.2-translocation RCC often have
nested architecture, and often contain cells with granular eosinophilic cytoplasm. The histologies of
Xp11-translocation RCC associated with different TFE3 gene fusions differ.
The ASPL-TFE3 renal carcinomas feature cells with voluminous, clear to
eosinophilic cytoplasm, discrete cell borders, vesicular nuclear chromatin and prominent nucleoli. In
contrast, the PRCC-TFE3 renal carcinomas typically have less abundant
cytoplasm, fewer psammoma bodies, fewer hyaline nodules, and a more nested, compact architecture
Renal carcinomas with Xp11.2-associated translocations characteristically underexpress
epithelial immunohistochemical markers such as cytokeratin and epithelial membrane antigen. Only
approximately one half of cases will be positive with these markers, and the labelling is often focal.
Vimentin immunoreactivity is also often focal compared to the adjacent blood vessels; this also differs
from conventional RCC which are diffusely positive. Rare Xp11.2-translocation carcinomas, specifically
ones with variant gene fusions such as PSF-TFE3 and CLTC-TFE3, have labelled for melanocytic markers HMB45 and Melan A.
The most distinctive immunohistochemical feature of these neoplasms is nuclear labelling for TFE3
protein using an antibody to the C-terminal portion of TFE3, which is retained in the gene fusions.
Nuclear labelling for TFE3 is a common feature of all Xp11.2-translocation RCC and ASPS but does not
occur in clear cell or papillary RCC. Since native TFE3 is known to be ubiquitously expressed but is not
detectable in normal tissues by immunohistochemistry, we suspect that the different TFE3 gene fusions consistently lead to overexpression of the fusion protein
relative to native TFE3, such that the protein becomes detectable by this assay.
t(6;11)(p21;q12) Renal Carcinomas
Another distinctive type of RCC bears a t(6;11)(p21;q12). The distinctive clinicopathologic features
of these neoplasms were not described until 2001. Of the 12 cases with clinical history
available, the median age has been 18 years (range: 6-53 years). One patient has developed metastases
and died in the limited follow-up. On microscopic examination, these neoplasms usually feature nests and
tubules of polygonal epithelioid cells, separated by thin capillaries. Some cases have had papillary
formations. The majority of the tumor cells have abundant clear to granular eosinophilic cytoplasm,
well-defined cell borders and round nuclei with small nucleoli. However, a second population of smaller
epithelioid cells is also characteristic, typically (but not always) clustered around nodules of hyaline
basement membrane material within larger acini. The cases examined have generally been negative for
cytokeratins by immunohistochemistry, but all have labelled at least focally for HMB45 and Melan A.
The t(6;11)(p21;q12) has been shown to result in a fusion of the intronless, untranslated Alpha gene with TFEB, a gene belonging to the same
transcription factor family as TFE3. The consequence of the Alpha-TFEB fusion is dysregulated expression of the normal full-length TFEB
protein. Along these lines, we have found that the t(6;11) RCC (also known as Alpha-TFEB RCC) demonstrate specific nuclear labelling for TFEB protein by IHC
while other neoplasms and normal tissues do not. Hence, nuclear labelling for TFEB is a sensitive and
specific diagnostic marker for this neoplasm with a TFEB gene fusion, just
as nuclear labelling for TFE3 is a sensitive and specific marker for neoplasms bearing TFE3 gene fusions. While the t(6;11) RCC features a distinctive dimorphic
cytology and labels for melanocytic markers immunohistochemically, it shares clinical, morphologic,
immunohistochemical and molecular features with the Xp11 translocation RCC, such that we propose to group
both of them under the broader category of "MiTF/TFE translocation renal cell carcinomas". The
recognition of these carcinomas as distinct from usual RCC, a distinction facilitated by the application
of immunohistochemistry for TFE3 and TFEB, will be critical in defining their clinical behavior and,
consequently, the appropriate management of these patients.
Table 1: MiTF/TFE Translocation Neoplasms
|Gene Fusion ||Chromosome Translocation ||Age (years) ||Tumor|
|ASPL-TFE3 ||der(17)t(X;17)(p11.2;q25) ||5-40 ||ASPS|
|ASPL-TFE3 ||t(X;17)(p11.2;q25) ||2-68 ||RCC|
|PRCC-TFE3 ||t(X;1)(p11.2;q21) ||2-70 ||RCC|
|PSF-TFE3 ||t(X;1)(p11.2;p34) ||5-68 ||RCC|
|NoNo-TFE3 ||inv(X)(p11;q12) ||39 ||RCC|
|CLTC-TFE3 ||t(X;17)(p11.2;q23) ||14 ||RCC|
|Alpha-TFEB ||t(6 ;11)(p21;q12) ||6-53 ||RCC|
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