Renal Cell Carcinoma Associated with Xp11.2 Translocation/Transcription Factor E3 (TFE3) Fusion

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Introduction
Renal cell carcinomas (RCC) associated with Xp11.2 translocations (Xp11.2 TRCCs) form a new and little known entity of the WHO 2004 classification . de Jong et al. [1] and Tomlinson et al [2] first described Xp11 translocation as a previously unknown finding in the karyotype of two atypical renal masses presenting in infant males [13].
This review aims to highlight the helpful histologic, immunohistochemical, and cytogenetic features of this entity to enable correct diagnosis.

Incidence and Clinical Presentation
Xp11.2 TRCCs occur primarily, but not exclusively, in children and young adults with a strong female predominance [3][4][5]. It is estimated that approximately one third of pediatric renal carcinomas are TFE3related translocation carcinomas [3]. Recent studies have shown that adult Xp11 TRCC is more common than originally perceived, making up anywhere from 1.6% to 5% of adult RCCs [13].

Gross Features
Macroscopically, Xp11.2 TRCCs are usually solid, tan-yellow, and may display hemorrhage and necrosis. The gross appearance may mimic conventional clear cell RCC. A multilocular cystic gross appearance is uncommon.

Microscopic Features
Microscopically, Xp11.2 TRCCs show papillary and/or nested architecture in a background of prominent capillary vasculature (Figures 1A and 1B) . Areas with a solid growth pattern are rarely observed. The neoplastic cells are voluminous and polygonal, with clear and/or eosinophilic granular cytoplasm ( Figure 1C). The nuclei are vesicular with prominent nucleoli. The stroma is desmoplastic and contains a variable amount of lymphocytes. Psammomatous calcifications and foci of stromal eosinophilic hyaline globules ( Figure 1D) may be numerous and widespread. Satellite tumor nodules, multifocal necrosis and lymphovascular invasion are frequently observed.

Electron Microscopic Features
Ultrastructural examination demonstrates a distinctive combination of alveolar soft part sarcoma (ASPS)-like and conventional clear cell RCC epithelial features: well-formed rhomboid crystals, abundant electron-dense granules, well-formed cell junctions, intracellular glycogen and fat, well-formed glandular lumens with microvilli, and prominent basement membrane [4,19].

Immunohistochemical Features
The most sensitive and specific immunohistochemical markers for these neoplasms bearing TFE3 gene fusion are TFE3 protein and cathepsin-K ( Figure 2)

Differential Diagnosis
On routine hematoxylin-eosin sections, Xp11.2 TRCC requires morphologic distinction from renal neoplasms with clear cell cytology and papillary architecture: conventional clear cell RCC, papillary RCC, and clear cell papillary RCC (CCPRCC) [22]. The formations of true papillae, psammomatous calcifications and hyaline stromal nodules are rare in conventional clear cell RCC [3]. Furthermore, clear cell RCCs are typically negative for both CK 7 and AMACR, although both may be focally positive, especially in higher-grade tumors [22]. Cathepsin-K and TFE3, two markers of Xp11.2 TRCC, are consistently negative [22]. Clear cell RCCs have consistent genetic abnormalities. A deletion on the short arm of chromosome arm (del 3p), where the VHL gene resides, is present in most sporadic and familial tumors.
Xp11.2 TRCCs with prominent eosinophilic cytoplasm might be confused with type 2 papillary RCC [3,22]. Clear cell change and fine cytoplasmic granulations are typically seen in association with hemosiderin deposition and/or necrosis. The cytoplasmic clearing may reflect phagocytic activity of the renal carcinoma cells in these settings. [22]. The immunohistochemical profile of papillary RCC typically shows strong membranous positivity for CK7. Cathepsin-K and TFE3 are both consistently negative. Cytogenetic studies show distinctive abnormalities unique to papillary RCC, including trisomy of chromosomes 7 and 17 along with loss of Y [22].
CCPRCC is a recently characterized, distinctive renal neoplasm, initially described in patients with end-stage renal disease, but is now known to arise in healthy kidneys as well [22,24]. CCPRCC can show a wide range of architectural features, including true papillary structures, branching tubules, and solid nests or ribbons. The neoplastic cells contain clear cytoplasm, small-to-intermediate size round or irregular nuclei, and inconspicuous nucleoli. The nuclei are typically polarized away from the basement membrane, creating a characteristic subnuclear vacuole similar to that seen in secretory endometrium. Pertinent negatives include lack of foamy histiocytes, psammomatous calcifications, or hemosiderin. CCPRCCs show a distinct immunoprofile not seen in conventional renal cell carcinomas [24]. The neoplastic cells are positive for CK7 and vimentin, and negative for RCC and AMACR [24]. Furthermore, no expression of cathepsin-K and TFE3 is observed in CCPRCC [22]. Cytogenetically, CCPRCC lacks typical abnormalities seen in either clear cell RCC or papillary RCC.
In conclusion, the diagnosis of an Xp11.2 TRCC is based on microscopic appearance, TFE3 immunostaining, and genetic analyses. TFE3 is a highly sensitive and specific immunohistochemical marker for screening tumors for the Xp11.2 translocation [15].

Biologic Behavior
Xp11.2 TRCCs occur primarily, but not exclusively, in children and young adults and are believed to be rather indolent, even when diagnosed at advanced stages. In contrast, the tumor tends to be more aggressive in adults with widespread systemic metastases. These patients have a poor clinical outcome [21]. Klatte et al [15] found a strong association between TFE3 expression and regional lymph node metastasis, which is generally accepted as a poor prognostic marker in the setting of metastatic RCC. Furthermore, ASPL-TFE3 gene fusion RCCs are more likely to present at an advanced stage in comparison with other TRCC [17]. The relatively short follow-up periods currently reported and the potential bias inherent in nonconsecutive case series and case reports preclude a definite statement as to the exact biologic behavior of this rare tumor.

Treatment
Because of the small number of TFE3 gene fusion-related renal tumors described in the literature, the impact of current treatment modalities remains to be uncertain [25]. The observed objective response rate and progression-free survival of targeted agents were similar to those reported for clear cell RCCs [26]. VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11.2 TRCCs [26]. Sunitinib appears to be more effective than cytokine. Prospective randomized studies on novel targeted agents are needed to identify the optimal treatment strategy for this specific patient population [25].