Case 2 -
Renal Cell Carcinoma Associated with Xp11/TFE3 Translocation
Jesse K. McKenney
Stanford University Medical Center
Palo Alto, CA
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A 32 year old woman presented with abdominal pain. Imaging studies revealed lymphadenopathy in the
retroperitoneum and mediastinum and a calcified renal "cyst". A core biopsy of the retroperitoneal
adenopathy was performed as well as a subsequent partial nephrectomy.
Case 2 - Slide 1
Case 2 - Figure 1
Needle core biopsy of retroperitoneal lymph node. Neoplasm with nested architecture and eosinophilic granular cytoplasm
Case 2 - Figure 2
Needle core biopsy of retroperitoneal lymph node. Associated psammomatous calcifications.
Case 2 - Figure 3
Partial nephrectomy. Gross photograph of ossified renal mass.
Case 2 - Figure 4
Partial nephrectomy. Over 95% of the tumor was ossified with no viable neoplastic cells.
Case 2 - Figure 5
Partial nephrectomy. Low power: Small islands of neoplastic cells within the ossified mass.
Case 2 - Figure 6
Partial nephrectomy. Intermediate power: Small islands of neoplastic cells with nested architecture and eosinophilic granular cytoplasm, identical to original lymph node metastases.
Case 2 - Figure 7
Partial nephrectomy. High power: Neoplastic cells with prominent nested architecture and eosinophilic granular cytoplasm.
Renal cell carcinoma associated with Xp11/TFE3 translocation
This patient presented with widely metastatic disease of unknown primary site. She had a remote
history of a simple renal cyst, which was aspirated approximately 7 years prior, and the concomitant
renal lesion was radiographically thought to represent a residual calcified cyst unrelated to her
disseminated disease. The differential diagnosis included mainly alveolar soft part sarcoma, Xp11/TFE3
renal cell carcinoma, and clear cell renal cell carcinoma with granular features. Immunohistochemically,
the tumor expressed strong and diffuse nuclear TFE3, excluding the latter. The presence of associated
calcifications, the nodal metastatic pattern, and the ossified renal mass were thought to support a
diagnosis of Xp11/TFE3 renal cell carcinoma. The partial nephrectomy specimen confirmed the presence of
a morphologically similar renal neoplasm, confirming the diagnosis. (Note: This degree of
calcification/ossification was recently described by Argani et al. in their study of adult Xp11 RCCs).
History of Xp11/TFE3 renal cell carcinoma:
Renal cell carcinoma classification reached its modern state with the publication of the
internationally accepted Heidelberg system in 1997. This system offered a more precise classification by
establishing morphologic criteria to reflect the known distinctive genetic subtypes of RCC: clear cell,
papillary, chromophobe, and collecting duct/medullary. Tumors that did not fit these diagnostic
categories were diagnosed as unclassified. A major advance in this consensus classification system was
the concept that the "granular" subtype was not an acceptable diagnostic category because it represented
a heterogeneous group of different tumors, and not a distinct entity. Since 1997, other novel renal cell
carcinoma subtypes have been added including, among others, multilocular cystic carcinoma, mucinous
tubular and spindle cell carcinoma, tubulocystic carcinoma, Xp11/TFE3 carcinoma, and t(6;11) carcinoma.
Our current knowledge of translocation associated renal cell carcinomas has evolved slowly from
cytogenetic case reports and series of RCC in children and adolescents. Many tumors were initially
described as papillary RCC variants bearing novel translocations involving the X chromosome. The first
series of these Xp11 carcinomas was likely described in 1968 as "tubulopapillary carcinoma of the kidney
in children", well before the translocation was known. In 1996, two groups reported that the X;1
translocation fused PRCC to a transcription factor named TFE3. In 1999, Renshaw et al. published a
series of RCC in children and young adults and described 4 cases of "voluminous type", which they
suggested represented a unique subset of pediatric RCC possibly related to alterations of the X
chromosome and TFE3. The first formal series of Xp11/TFE3 RCC with molecular confirmation were published
by Argani et al. in 2001 (ASPL-TFE3 fusion) and 2002 (PRCC-TFE3 fusion). Since that time, additional
series have been reported, including cases in adults, an expanded morphologic spectrum, and additional
translocation partners. The Xp11/TFE3 subtype was formally accepted as entity by the WHO in 2004.
Although the Xp11/TFE3 associated renal cell carcinomas were described in children and young adults,
they are now also reported in older adults. While they represent a large percentage of RCC in younger
patients, they are thought to be much rarer in adults where clear cell carcinoma is most common.
However, it is likely that the Xp11/TFE3 carcinomas are under recognized in adults because of their
morphologic overlap with more common subtypes (clear cell and papillary) and because cytogenetics is not
routinely performed for all adult renal tumors as is routine in children. Because RCC in the adult
population is far more common than pediatric RCC (approximately 25,000 adult RCC versus 25 pediatric RCC
per year), adult Xp11/TFE3 carcinomas may possibly outnumber pediatric cases.
asdf Morphologic spectrum:
Xp11/TFE3 RCC is classically characterized by neoplastic cells with voluminous clear to granular
eosinophilic cytoplasm and a papillary to nested architecture. Associated psammomatous calcifications
are fairly common. The morphologic spectrum is broad, however, and includes dense tumor
calcification/ossification, tumor giant cells, a biphasic pattern mimicking t(6;11) RCC, and neoplastic
spindled cells. Studies have also reported cystic change.
Xp11/TFE3 RCC has an immunophenotype distinct from other RCC subtypes. Expression of epithelial
markers in the translocation carcinoma is typically absent to focal.
|Antibody ||Xp11/TFE3 ||Clear cell ||Papillary|
|CK AE1/3 ||-/ focal + ||+ ||+|
|CK7 ||- / focal + ||- (+ in cystic areas) ||+|
|EMA ||-/ focal + ||+ ||+|
|CD10 ||+ ||+ ||+|
|RCC ||+ ||+ ||+|
|Vimentin ||-/+ ||+ ||+|
|Racemase ||+ ||- ||+|
|CA IX ||-/+ (40%) ||+ ||+/-|
|PAX-2 ||- in one series ||+ ||+|
|MelanA ||-/ rare + cases ||- ||-|
|HMB-45 ||-/ rare + cases ||- ||-|
|TFE3 ||+ ||- ||-|
A number of translocation partners have been described in the Xp11/TFE3 subtype of RCC, including:
- PRCC (1q21)
- ASPL (17q25)
- PSF (1p34)
- NonO/p54nrb (inv-Xq12)
- CLTC (17q23)
- ? (3q23)
Because of the nested morphology and granular cytoplasm, alveolar soft part sarcoma may enter the
differential diagnosis, especially if a renal mass has not been identified. The presence of psammomatous
calcifications, areas with distinct papillary architecture, and cytokeratin expression (although only
present in a small subset of Xp11/TFE3 RCC) may be helpful in recognizing Xp11/TFE3 RCC. Alveolar soft
part sarcoma contains intracytoplasmic crystals that are highlighted by PAS, which are absent in
Xp11/TFE3 RCC. Strong nuclear TFE3 immunoreactivity would be seen in both tumors and is not
discriminatory. Other immunohistochemical markers of RCC, as listed in the table above, may also be
useful. By molecular analysis, the non-ASPL subtypes of Xp11/TFE3 RCC would be readily distinguishable
from alveolar soft part sarcoma because of a distinct fusion partner. In RCCs with an ASPL fusion
partner, the distinction is more complicated because the translocation breakpoints are cytogenetically
identical to alveolar soft part sarcoma. However, the RCC translocations are balanced, in contrast to
those of alveolar soft part sarcoma, which are typically unbalanced.
Paraganglioma and granular cell tumor may also be considered. Paraganglioma should express endocrine
markers such as synaptophysin and chromogranin, while granular cell tumor shows diffuse reactivity to
S-100 protein; these markers are negative in Xp11/TFE3 RCC. Both paraganglioma and granular cell tumor
are TFE3 negative by immunohistochemistry.
For clinically apparent primary renal neoplasms, the differential diagnosis would include mainly
t(6;11) RCC, clear cell RCC, chromophobe CC, post-neuroblastoma RCC, and papillary RCC. All of these
neoplasms may be morphologically indistinguishable from Xp11/TFE3 RCC; however, by definition, they all
lack a TFE3 rearrangement.
Our knowledge of prognostic factors and clinical behavior in Xp11/TFE3 RCC is somewhat limited. Some
studies suggest that, in children, these carcinomas may be indolent even in the presence of lymph node
metastases. There are, however, reports of cases with aggressive behavior in children. In adults,
Xp11/TFE3 may be an aggressive carcinoma subtype.
The treatment of metastatic RCC has undergone significant changes in the last few years given the
emergence of targeted therapies inhibiting VEGF, multiple tyrosine kinases, and mTOR. There is very
little data on specific treatment options for Xp11/TFE3 RCC because of its rarity and its relatively
recent description. However, a recent study has shown that TFE3 fusions activate MET signaling and
suggests the possibility of MET inhibition as a potential therapeutic modality.
- Wetyerman MAJ, Wilbrink M, and van Kessel AG. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positve papillary renal cell carcinomas. Proc Natl Acad Sci USA 1996;93:15294-15298.
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