Xp11 Translocation Renal Cell Carcinoma Research Articles

Xp11 translocation renal cell carcinoma

Xp11 translocation renal cell carcinoma (RCC) is a group of neoplasms characterised by translocations involving a breakpoint at Xp11.2. The resulting gene fusions involve the TFE3 transcription factor gene and multiple reported genes, including the same one (ASPL) found in the characteristic gene fusion of alveolar soft part sarcoma. Xp11 translocation RCCs likely comprise a significant proportion of paediatric RCCs. While uncommon on a percentage basis in adults, adult cases may outnumber paediatric cases due to the much higher overall incidence of RCC in the adult population. The only known risk factor for its development is prior exposure to chemotherapy. The most distinctive histological pattern is a neoplasm with both clear cells and papillary architecture, often with abundant psammoma bodies. Immunohistochemistry typically reveals minimal reactivity to cytokeratins, epithelial membrane antigen (EMA) or vimentin. The most sensitive and specific immunohistochemical markers for these neoplasms are TFE3 protein and cathepsin-K. Clinical outcome data are still premature at this time. However, children with regional nodal metastases but without haematogenous spread have a favourable short-term prognosis. Adults often present with aggressive tumours with widespread systemic metastases and these patients have a poor clinical outcome. Regardless, the tumour can metastasise decades after its initial presentation, so long-term follow-up is necessary. A recently reported melanotic neoplasm with overt melanin pigment may represent a new subset of TFE3 related cancers.

Dual-color, Break-apart FISH Assay on Paraffin-embedded Tissues as an Adjunct to Diagnosis of Xp11 Translocation Renal Cell Carcinoma and Alveolar Soft Part Sarcoma

Both Xp11.2 translocation renal cell carcinoma (RCC) and alveolar soft part sarcoma (ASPS) are characterized by various translocations disrupting chromosome Xp11.2, which result in gene fusions involving the TFE3 transcription factor gene. Diagnostic tools to detect translocations involving the TFE3 gene on chromosome X would be valuable in the evaluation of these tumors. We developed a dual-color, break-apart fluorescence in situ hybridization (FISH) assay to identify the chromosomal break point in paraffin-embedded tissue. This assay was validated using 4 cases of Xp11.2 RCC [proven by karyotype and/or reverse-transcriptase polymerase chain reaction (RT-PCR)], 2 cases of ASPS (proven by karyotype or RT-PCR), the UOK109 cell line carrying the inv(X) (p11;q12), and several negative controls (both neoplastic and non-neoplastic). This break-apart FISH assay is a relatively quick procedure for detecting Xp11.2 RCC and ASPS translocations and can be applied to archival paraffin-embedded tissue.

Vascular endothelial growth factor (VEGF)-targeted therapy for the treatment of adult metastatic Xp11 translocation renal cell carcinoma.

4606 Background: Adult translocation renal cell carcinoma (RCC), bearing TFE3 gene fusions, is a recently recognized entity for which prognosis and therapy remain poorly understood. The effect of vascular-endothelial growth factor (VEGF)-targeted therapy in this histologic subtype is characterized. Methods: Clinical characteristics and treatment outcomes were evaluated in 15 patients with metastatic RCC with strong TFE-3 nuclear immunostaining who received anti-VEGF therapy at 4 US institutions. Response rate by RECIST and overall survival were documented. Results: Fifteen patients were included in this analysis for which 10, 3, and 2 received sunitinib, sorafenib and monoclonal anti-VEGF antibodies, respectively. The median follow-up was 19.1 months, the median age of patients was 40.8 years (range 18.3-64.8) and the male:female ratio was 3:12. All patients had an initial histologic diagnosis of clear cell (N=8), papillary (n=1) or mixed clear cell/papillary RCC (n=6). Five patients had prior systemic therapy (2 immunotherapy, 1 chemotherapy, 1 vaccine, 1 temsirolimus), 12 patients had prior nephrectomy, 13/15 had lymph node metastases and 6/15 had lung metastases. MSKCC risk groups were favorable, intermediate, poor and missing in 2, 9, 3, and 1 respectively. Four patients had FISH analysis and all demonstrated a translocation involving chromosome Xp11. When treated with VEGF-targeted therapy, 3 patients had a partial response, 7 patients had stable disease and 5 patients had progressive disease. The median tumor shrinkage was by 4.5% (range 48% shrinkage to 67% growth). The median progression-free survival and overall survival of the entire cohort was 7.13 and 14.3 months respectively. Conclusions: Adult-onset translocation-associated mRCC is an aggressive disease that affects a younger population with female predominance. VEGF targeted agents demonstrated efficacy in this small retrospective series. No significant financial relationships to disclose.

Xp11 Translocation Renal Cell Carcinoma

A case of Xp11 translocation renal cell carcinoma (RCC) is reported in a pediatric patient, 5 years postchemotherapy for Wilms tumor. The tumor showed nested architecture with numerous psammomatous calcifications. Cytologically, the cells had voluminous clear cytoplasm with prominent nucleoli. While cytokeratin and epithelial membrane antigen stains were negative, TFE3 immunostain (a sensitive and specific marker for these neoplasms) displayed diffuse nuclear immunoreactivity. The clinical history, morphology, and immunohistochemistry were consistent with an Xp11 translocation RCC. These neoplasms all have translocations involving a breakpoint at Xp11.2, resulting in gene fusions involving the TFE3 transcription factor gene, which maps to this locus. Multiple different genes have been identified as TFE3 fusion partners in these RCC, including the same one (ASPL) found in alveolar soft part sarcoma. Xp11 translocation RCC likely comprises the majority of pediatric RCCs. While uncommon on a percentage basis in adults, adult cases may outnumber pediatric cases due to the much higher overall incidence of RCCs in the adult population. Prior exposure to chemotherapy is a distinct risk factor for its development. The tumor can metastasize decades after its initial presentation, so long-term follow-up is necessary.

A Case of Adult Metastatic Xp11 Translocation Renal Cell Carcinoma Treated Successfully With Sunitinib

Renal cell carcinomas (RCC) associated with Xp11.2 translocations (transcription factor E3 gene fusions) are rare tumors predominantly reported in children. Although only a small number of adult Xp11.2 translocation RCC cases have been described, this is likely due to the possibility of this tumor being unrecognized because of its histologic similarity to either clear cell or papillary subtypes based on hematoxylin and eosin staining. Herein, we describe the first successful case of systemic treatment of metastatic Xp11 RCC with sunitinib, a currently accepted standard of care in metastatic RCC, and attempt to elucidate potential mechanisms behind sunitinib activity in this histologic subtype.

Rapid Development of Metastatic Xp11 Translocation Renal Cell Carcinoma in a Girl Treated for Neuroblastoma

We report the case of a 5-year-old girl with metastatic renal cell carcinoma (RCC) diagnosed 19 months after treatment for neuroblastoma. Immunostaining of the secondary tumor was consistent with Xp11 translocation morphology. This is the second report of this translocation RCC presenting after neuroblastoma and the most rapid onset of RCC reported thus far. The literature regarding secondary RCC after neuroblastoma is reviewed and our case is placed within this historical context. As our understanding of the genetic changes in pediatric tumors advances, the reporting of these rare cases with specific emphasis on genetic testing provides a resource for clinicians and researchers.

An aggressive course of Xp11 translocation renal cell carcinoma in a 28‐year‐old man

Cases of renal cell carcinoma (RCC) associated with Xp11 translocations are rare and are reported predominantly in children. We report a case of a young man who developed an aggressive Xp11 translocation RCC. A 28-year-old man presented with back pain, fever and macroscopic hematuria. Computed tomography of the abdomen showed a heterogeneous mass in the left kidney. Left radical nephrectomy was performed. Hematoxylin-eosin staining revealed nested and papillary architecture, clear and eosinophilic cytoplasm and vesicles with prominent nucleoli. Immunohistochemical evaluation revealed that the tumor cells showed nuclear labeling for TFE3 protein. On the basis of these findings, the case was diagnosed as Xp11 translocation RCC. This tumor massively recurred and led to the patient's death 2 years after the initial diagnosis. The utility of immunohistochemistry using antibodies against TFE3 in RCC occurring in young adults may be necessary for accurate diagnosis.

Adult Xp11 Translocation Renal Cell Carcinoma Diagnosed by Cytogenetics and Immunohistochemistry

To determine the incidence of Xp11 translocation renal cell carcinoma (RCC) in adult patients using cytogenetics and immunohistochemstry. Cytogenetic studies were prospectively done using tumor samples from 443 consecutive adult Japanese patients (ages 15-89 years) who underwent nephrectomy for RCC. TFE3 immunohistochemistry was done for cases in which cytogenetic results were not obtained. Clinicopathologic characteristics of Xp11 translocation RCC were examined. Mitotic cells suitable for cytogenetic analysis were obtained in 244 tumor samples (55%); among these, we identified 4 cases (1.6%) of Xp11 translocation RCC. TFE3 immunohistochemistry identified 3 positive cases (1.5%) among the remaining 199 cases. The median age of the 7 patients was 41 years (range, 15-59 years), and 15% of RCC patients (4 of 26) who were younger than ages 45 years had this type of RCC. Of the four Xp11 translocation RCC patients whose karyotypes were determined, two had an ASPL-TFE3 gene fusion. Of these 2, 1 had pulmonary metastasis at presentation, and the other developed liver metastasis 12 months after nephrectomy and died of the disease. The remaining two patients had PRCC-TFE3 and PSF-TFE3 gene fusions, respectively. Both had nodal involvement but remained disease free for 3 and 5 years, respectively, after surgical resection of lymph node metastases. Of the 3 immunohistochemically diagnosed patients, 1 had nodal metastases at presentation and died 9 months after surgery. This is the first report to determine the incidence of Xp11 translocation RCC in adult patients. We found that this disease is relatively common in young adults.

XpII.2 Translocation Renal Carcinoma With Placental Metastasis: A Case Report

Renal cell carcinomas with sporadic Xp11.2 translocations are uncommon malignancies in children and young adults associated with several different reciprocal translocations involving the TFE3 gene located on chromosome Xp11.2. Placental metastases are extremely rare, with only a handful of cases reported. This study reports the case of a 20-year-old woman with an Xp11.2 translocation renal carcinoma that metastasized to the placenta. This is the first reported case of a renal cell carcinoma metastatic to the placenta and highlights the aggressive behavior of Xp11 translocation renal cell carcinomas.

Xp11 Translocation Renal Cell Carcinoma in Adults: Expanded Clinical, Pathologic, and Genetic Spectrum

The recently recognized Xp11 translocation renal cell carcinomas (RCCs), all of which bear gene fusions involving the TFE3 transcription factor gene, comprise at least one-third of pediatric RCC. Only rare adult cases have been reported, without detailed pathologic analysis. We identified and analyzed 28 Xp11 translocation RCC in patients over the age of 20 years. All cases were confirmed by TFE3 immunohistochemistry, a sensitive and specific marker of neoplasms with TFE3 gene fusions, which can be applied to archival material. Three cases were also confirmed genetically. Patients ranged from ages 22 to 78 years, with a strong female predominance (F:M=22:6). These cancers tended to present at advanced stage; 14 of 28 presented at stage 4, whereas lymph nodes were involved by metastatic carcinoma in 11 of 13 cases in which they were resected. Previously not described and distinctive clinical presentations included dense tumor calcifications such that the tumor mimicked renal lithiasis, and obstruction of the renal pelvis promoting extensive obscuring xanthogranulomatous pyelonephritis. Previously unreported morphologic variants included tumor giant cells, fascicles of spindle cells, and a biphasic appearance that simulated the RCC characterized by a t(6;11)(p21;q12) chromosome translocation. One case harbored a novel variant translocation, t(X;3)(p11;q23). Five of 6 patients with 1 or more years of follow-up developed hematogenous metastases, with 2 dying within 1 year of diagnosis. Xp11 translocation RCC can occur in adults, and may be aggressive cancers that require morphologic distinction from clear cell and papillary RCC. Although they may be uncommon on a percentage basis, given the vast predominance of RCC in adults compared with children, adult Xp11 translocation RCC may well outnumber their pediatric counterparts.

Xp11 Translocation Renal Cell Carcinoma: Delayed but Massive and Lethal Metastases of a Chemotherapy-Associated Secondary Malignancy

A recently described subtype of renal cell carcinoma (RCC) bearing chromosome translocations involving a breakpoint at Xp11 and resulting in gene fusions involving the TFE3 transcription factor gene often presents in the pediatric population. Herein we describe an Xp11 translocation RCC associated with prior exposure to cytotoxic chemotherapy, which massively recurred and led to the patient's death 17 years later. This case highlights the association of these RCCs with prior chemotherapy exposure, the tendency of these RCCs to recur late, their unusual pattern of metastases, and the utility of TFE3 immunohistochemistry in confirming their diagnosis in archival pathologic specimens.