Xp11 Translocation Renal Cell Carcinoma Research Articles

High Chromosomal Copy Number Alterations in Xp11 Translocation Renal Cell Carcinomas Detected by Array Comparative Genomic Hybridization Are Associated With Aggressive Behavior

High Chromosomal Copy Number Alterations in Xp11 Translocation Renal Cell Carcinomas Detected by Array Comparative Genomic Hybridization Are Associated With Aggressive Behavior

Establishment of an ASPL-TFE3 renal cell carcinoma cell line (S-TFE)

Xp11 translocation renal cell carcinoma is a rare disease diagnosed in children and adolescents in the advanced stage with an aggressive clinical course. Various gene fusions including the transcription factor E3 (TFE3) gene located on chromosome X cause the tumor. We established an Xp11 translocation renal cell carcinoma cell line from a renal tumor in a 18-y-old Japanese female and named it “S-TFE.” The cell line and its xenograft demonstrated definite gene fusion including TFE3. They showed strong nuclear staining for TFE3 in immunohistochemistry, TFE3 gene rearrangement in dual-color, break-apart FISH analysis and ASPL-TFE3 type 1 fusion transcripts detected by RT-PCR and direct DNA sequencing. Although many renal cell carcinoma cell lines have been established and investigated, only a few cell lines are recognized as Xp11.2 translocation carcinoma. S-TFE will be useful to examine the characteristics and drug susceptibility of Xp11 translocation renal cell carcinoma.

Abstract 2980: Integrated transcriptome and methylome sequencing of Xp11 translocation renal cell carcinomas reveal uncoupling of DNA methylation and transcriptional profiles.

Abstract Background: Xp11 translocation renal cell carcinoma (RCC) is a rare subtype of RCC characterized by the fusion of TFE3 gene to multiple partners. Despite its genetic homogeneity, there is considerable heterogeneity in the clinical course of this disease, probably due to epigenetic events that follow the initial translocation. Material and methods: We performed whole-transcriptome next-gen paired end sequencing of 7 Xp11 RCC samples, 10 clear-cell RCC and 19 papillary RCC. In addition, we performed genome-wide analysis of DNA methylation of 9 Xp11 samples by Digital Restriction Enzyme analysis of Methylation (DREAM), based on next-generation sequencing. Results: Using a robust bioinformatics pipelines, we confirmed 6 previously known TFE3 translocation partners, and discovered a novel partner involving the splicing gene LUC7L3 that we validated by RT-PCR. Unsupervised clustering of gene expression profiling revealed genetic homogeneity of Xp11 cases that clustered together, independently from clear-cell and papillary RCC subgroups. Ingenuity analysis confirmed MITF activation. Gene Set Enrichment Analysis (GSEA) showed mTOR pathway activation. In contrast with genetic homogeneity of gene expression, unsupervised clustering analysis of CpG sites located within CpG islands (CGI) revealed: (1) a CpG islands methylator phenotype (CIMP+) subgroup related to patients with metastatic disease (n=3), and (2) a CIMP negative (CIMP-) subgroup related to patients with local disease (n=6). Integrative analysis showed that genes with differentially methylated levels between CIMP+ and CIMP- tumors (SD: +/-20%) and which were down-regulated in CIMP+ subtype as compared to normal kidney, were also down-regulated in CIMP- subgroup . Of note, FZD10 and CCDC8 were found to gain promoter methylation in three cases of Xp11 RCC, but their baseline expression was already low in normal kidney. In contrast, small gain of promoter DNA methylation in cancer samples was associated with gene silencing of putative tumor suppressor genes. Interestingly, GSEA for gene body methylation identified enrichment of MAPK signaling pathway in CIMP+ versus CIMP- cases. Exome-sequencing of 2 out of 3 cases with CIMP+ phenotype identified non-synonymous IDH1 (p.V71I) mutation present in COSMIC database for one case and a frameshift mutation of the chromatin remodeling enzyme INO80D in the second case. Conclusion: Our data reveal uncoupling of DNA methylation and gene expression profiling in Xp11 RCC. Patients with metastatic disease showed higher methylation level, with CIMP+ phenotype possibly related to IDH1 mutation in one case. These results suggest that additional epigenetic alterations following the initial Xp11 translocation may explain the aggressive biology of some Xp11 RCCs. Citation Format: Gabriel G. Malouf, Xiaoping Su, Hui Yao, Christopher G. Wood, Yue Lu, Shoudan Liang, Erika J. Thompson, Denaha J. Doss, Jaroslav Jelinek, Jean-pierre Issa, Nizar M. Tannir. Integrated transcriptome and methylome sequencing of Xp11 translocation renal cell carcinomas reveal uncoupling of DNA methylation and transcriptional profiles. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2980. doi:10.1158/1538-7445.AM2013-2980

297 ESTABLISHMENT OF A RENAL CELL CARCINOMA CELL LINE ASSOCIATED WITH TFE3 GENE FUSIONS

INTRODUCTION AND OBJECTIVES: Xp11.2 translocation renal cell carcinoma is a rare disease diagnosed in children and adolescents in the advanced stage with an aggressive clinical course. It has been recently recognized as a subtype of renal cell carcinoma primarily described in the 2004 World Health Organization classification of renal tumors, and various gene fusions including the transcription factor E3 (TFE3) gene located on chromosome cause the tumor; however, little is known about the tumor characteristics. We report the cytogenetic and biological characteristics of a renal cell carcinoma cell line with TFE3 gene fusion established from a young female with locally advanced renal cell carcinoma. METHODS: Tumor cells were obtained from a renal tumor in a 16-year-old Japanese female. This primary tumor was pathologically diagnosed as renal cell carcinoma with Xp11 translocations. After cultured in vitro, cell suspension was inoculated into the nude mice to establish xenograft. TFE3 immunostaining and other immunohistochemistries were performed. Molecular and cytogenetic methods such as RT-PCR, karyotype analysis and FISH were added. RESULTS: The established cell line and its xenograft showed strong nuclear staining for TFE3 in immunohistochemistry, TFE3 gene rearrangement in dual-color, break-apart FISH analysis, and ASPLTFE3 type 1 fusion transcripts detected by RT-PCR and direct DNA sequencing. Multicolor FISH analysis showed more complicated rearrangements on the chromosome than expected. CONCLUSIONS: Although many renal cell carcinoma cell lines have been established and investigated, only a few cell lines are recognized as Xp11.2 translocation carcinoma. This cell line will be useful to examine the characteristics and drug susceptibility of Xp11 translocation renal cell carcinoma.

337 Clinicopathological characteristics of Xp11 translocation renal cell carcinoma in adults: Diagnosis using FISH analysis in conjunction with TFE3 immunostaining

337 Clinicopathological characteristics of Xp11 translocation renal cell carcinoma in adults: Diagnosis using FISH analysis in conjunction with TFE3 immunostaining

TFE3 FISH assessment in renal cell carcinomas

Aims Xp11 translocation renal cell carcinomas (TRCCs) showing rearrangements of TFE3 are rare, present in TFE3 rearrangements using FISH. Methods FISH was performed using the ZytoLight SPEC TFE3 Dual Colour Break Apart FISH Probe (ZytoVision). Results Case 1 was a 51-year-old female with TFE3 rearrangement present, one intact fused FISH signal, one broken apart signal. Case 2 was a 48-year-old male with TFE3 rearrangement present and the single TFE3 locus demonstrating a positive breakapart FISH signal pattern. Case 3 was a 45-year-old male with no evidence of TFE3 break-apart signal, however an atypical pattern was observed with an additional, intact TFE3 locus. X and Y FISH to exclude underlying sex copy number changes showed a normal male XY pattern. Discussion TFE3 breakapart FISH is useful for identifying TRCC. We also report a case in a male with very suggestive histology, lacking the classic breakapart pattern, instead showing an additional copy of the TFE3 locus. We postulate that this may represent an as yet unrecognised variant FISH pattern.

Diagnosis of Xp11 translocation renal cell carcinomas in adult patients under 50 years: Interest and pitfalls of automated immunohistochemical detection of TFE3 protein

Renal cell carcinomas associated with Xp11.2 translocations form a new and little known entity of the WHO 2004 classification. An immunohistochemical (IHC) test aiming at demonstrating the nuclear expression of the protein TFE3, product of a gene frequently involved in translocation, has been proposed as a diagnostic tool. The aims of this work were to define our evaluation criteria of the immunohistochemical test with the antibody anti-TFE3 and to describe new cases of renal cell carcinomas with TFE3 translocations.Using immunohistochemistry with antibody anti-TFE3, we retrospectively studied 83 renal cell carcinomas diagnosed at Edouard Herriot Hospital and Biomnis Laboratory, Lyon, between 2003 and 2009. The patients were 50 years old or younger. We detail our experience of the IHC test using the anti-body anti-TFE3 and the interpretation criteria. This work has enabled two new cases of renal cell carcinomas associated with TFE3 translocations to be detailed, confirmed by molecular biology.The TFE3 immunohistochemical test is a useful tool that demands strict interpretation criteria. In our experience, more than 80% of nuclei stained with an intensity of ++ to +++ is necessary to suspect the diagnosis of Xp11 translocation renal cell carcinoma.

Adult Xp11 Translocation Associated Renal Cell Carcinoma: Time to Recognize

First recognized as a distinct entity by the World Health Organization in 2004, Xp11 translocation renal cell carcinomas (TRCCs) are a subtype of renal malignancy characterized by translocations involving the splice site Xp11.2.1 de Jong et al2 and Tomlinson et al3 first described Xp11 translocation as a previously unknown finding in the karyotype of 2 atypical renal masses presenting in infant males. A subsequent series of studies using TFE3 immunoassays have shown that Xp11 TRCCs constitute ≤40% of pediatric renal cell carcinoma (RCC) cases.

Translocation renal cell carcinomas in adults: a single-institution experience.

Translocation renal cell carcinoma is a newly recognized subtype of renal cell carcinoma (RCC) with chromosomal translocations involving TFE3 (Xp11.2) or, less frequently, TFEB (6p21). Xp11 translocation RCC was originally described as a pediatric neoplasm representing 20% to 40% of pediatric RCCs, with a much lower frequency in the adult population. TFEB translocation RCC is very rare, with approximately 10 cases reported in the literature. Here, we describe the clinicopathologic features of adult translocation RCC from a single institution. Using tissue microarray, immunohistochemistry, cytogenetic examination, and fluorescence in situ hybridization, we identified 6 (∼5%) cases of TFE3 translocation RCC and 1 (<1%) case of TFEB translocation RCC in 121 consecutive adult RCC cases between 2001 and 2009. Our results suggest that weak TFE3 staining of a significant proportion of RCC cases may be because of expression of the full-length TFE3 protein rather than the chimeric fusion protein resulting from chromosomal translocation.

Renal Cell Carcinoma With Clear Cell and Papillary Features

The diagnosis of primary renal cell carcinomas (RCCs) with both papillary architecture and cells with clear cytoplasm can be diagnostically challenging for practicing pathologists. The 4 main neoplasms in the differential diagnosis are clear cell RCC, papillary RCC, clear cell papillary RCC, and Xp11 translocation RCC. Accurate diagnosis has both prognostic and therapeutic implications. To highlight the helpful cytomorphologic, immunohistochemical, and cytogenetic features of each of these entities to enable reproducible classification. Published peer-reviewed literature was reviewed, accompanied by the authors' personal experiences. Key morphologic clues and a focused immunohistochemical panel, including CK7, α-methylacyl coenzyme A racemase (AMACR), TFE3, cathepsin K, and carbonic anhydrase IX (CAIX), now allow most resected RCCs with papillary architecture and clear cells to be accurately classified. In other cases, cytogenetic and molecular findings can establish the diagnosis. Despite these tools, some RCCs with papillary architecture and clear cells do not fit into any of the described entities and currently remain unclassified.

Translocation renal cell carcinomas: An evolving entity.

472 Background: Translocation renal cell carcinomas (RCCs) are a novel, rare and distinct clinicopathological entity. The term refers to RCCs with overexpression of transcription factor E3 (TFE3) due to translocation involving the Xp11 locus or less commonly with overexpression of transcription factor EB (TFEB) due to a t(6:11) translocation. In children it is estimated that these tumours account for 40% of RCCs but in adults this proportion is estimated to be 1-4%. As these neoplasms are only recently recognised, outcome data are premature. We report 2 cases of translocation RCC in an Irish regional cancer centre and describe clinicopathological characteristics and early outcome. Methods: In our recent practice, 2 renal cell carcinomas were suspected to be translocation tumours based on morphology and immunohistochemical features (RCC+/CK7-/EMA-). Using immunohistochemistry we tested for expression of TFE3 and TFEB. Results: Both tumours were translocation RCCs. The first case was a 74 year old lady who presented with right upper quadrant pain and had a 9cm right renal mass with no metastatic disease on CT imaging. Radical nephrectomy was performed and histology revealed a pT3aN2, Fuhrman grade 4 renal cell carcinoma with papillary architecture and eosinophillic hyaline nodules within many of the papillae. Staining for TFE3 showed focal nuclear positivity consistent with an Xp11 translocation RCC. She remains disease free 6 months post surgery. The second case was a 46 year old man with an incidental finding of a right renal mass on ultrasound abdomen performed after a new diagnosis of haemochromatosis. Staging CT imaging revealed no metastatic disease and he underwent laparoscopic nephrectomy. Histology revealed a pT1aNx, Fuhrman grade 3 renal cell carcinoma with predominantly alveolar architecture and focal papillary and microcystic areas. Staining for TFEB was positive consistent with a t6:11 translocation RCC. He remains disease free 5 months post surgery. Conclusions: We report 2 new cases of this rare subset of RCC. The therapeutic implications for patients with these mutations are as yet unclear. We plan to update with ongoing follow-up and identification of new cases to determine the clinical behaviour of these rare cancers in the Irish setting.

Molecular heterogeneity of TFE3 activation in renal cell carcinomas

Renal cell carcinomas associated with Xp11.2 translocations have recently been identified as a distinct biological entity. The translocation results in the fusion of the transcription factor TFE3 to one of several different fusion partners including PRCC, PSF, NONO, ASPL or CTLC with consecutive overexpression of the chimeric protein. As the true frequency of these neoplasms as well as the biological properties of TFE3 activation in renal cell carcinomas are largely unknown, we have examined TFE3 expression as well as the underlying genetic alterations in a large, hospital-based series of renal cell carcinomas with long-term follow-up information. Out of a total of 876 tumours, TFE3 translocations were detected in five cases (0.6%). Three additional cases were identified in a second series of cases comprising of renal cell carcinomas developing in patients before the age of 50. However, using immunohistochemistry, 9% of all renal cell carcinomas showed some degree of TFE3 reactivity. Interestingly, these cases were associated with high nuclear grade, greater tumour extent and metastatic disease as well as an unfavourable patient outcome on uni- and multivariate analysis. Fluorescence in situ hybridisation (FISH) revealed TFE3 amplifications as an additional, novel mechanism leading to increased TFE3 expression levels. In conclusion, our data show that Xp11 translocation renal cell carcinomas are uncommon tumours accounting for <1% of adult renal cell carcinomas and that the diagnosis of Xp11 translocation renal cell carcinomas needs to be verified using molecular techniques. In turn, TFE3 overexpressing tumours show an aggressive behaviour and Xp11 translocation is only one of several possible underlying genomic alterations.

Editorial Comment

Most patients treated surgically for renal cortical tumors are >40 years old. In some series, larger, symptomatic tumors with regional nodes have been reported to be more likely in younger patients, 1 Sanchez-Ortiz R.F. Rosser C.J. Madsen L.T. et al. Young age is an independent prognostic factor for survival of sporadic renal cell carcinoma. J Urol. 2004; 171: 2160-2165 Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar but this has not been confirmed by others. 2 Gillett M.D. Cheville J.C. Karnes R.J. et al. Comparison of presentation and outcome for patients 18 to 40 and 60 to 70 years old with solid renal masses. J Urol. 2005; 173: 1893-1896 Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar At our center, we reported a surgical series of 89 (5%) of 1720 patients <40 years old and found that these patients were more likely to have chromophobe carcinoma and symptomatic tumors, although the cancer-specific survival was not different than that of the older patients. 3 Thompson R.H. Ordonez M.A. Iasonos A. et al. Renal cell carcinoma in young and old patients-is there a difference?. J Urol. 2008; 180: 1262-1266 Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar These conflicting reports on the prognosis of younger patients likely reflects small institutional experiences and differences in the referral patterns to surgeons or medical oncologists according to the clinical stage (localized or advanced) at presentation. Young Age as Favorable Prognostic Factor for Cancer-specific Survival in Localized Renal Cell CarcinomaUrologyVol. 77Issue 4PreviewTo evaluate the prognostic effect of age in patients with localized renal cell carcinoma (RCC) and investigate the incidence of Xp11 translocation RCC in young patients who developed recurrence. Full-Text PDF

1265 PROGNOSTIC SIGNIFICANCE OF HIGH NUCLEAR GRADE FOR PATIENTS WITH PATHOLOGIC T1A RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Localized1 Apr 20111265 PROGNOSTIC SIGNIFICANCE OF HIGH NUCLEAR GRADE FOR PATIENTS WITH PATHOLOGIC T1A RENAL CELL CARCINOMA Kenjiro Suzuki, Ryuichi Mizuno, Shuji Mikami, Kento Kanao, Hidaka Kono, Eiji Kikuchi, Hirohiko Nagata, Hiroshi Asanuma, Akira Miyajima, Ken Nakagawa, and Mototsugu Oya Kenjiro SuzukiKenjiro Suzuki Tokyo, Japan More articles by this author , Ryuichi MizunoRyuichi Mizuno Tokyo, Japan More articles by this author , Shuji MikamiShuji Mikami Tokyo, Japan More articles by this author , Kento KanaoKento Kanao Tokyo, Japan More articles by this author , Hidaka KonoHidaka Kono Tokyo, Japan More articles by this author , Eiji KikuchiEiji Kikuchi Tokyo, Japan More articles by this author , Hirohiko NagataHirohiko Nagata Tokyo, Japan More articles by this author , Hiroshi AsanumaHiroshi Asanuma Tokyo, Japan More articles by this author , Akira MiyajimaAkira Miyajima Tokyo, Japan More articles by this author , Ken NakagawaKen Nakagawa Tokyo, Japan More articles by this author , and Mototsugu OyaMototsugu Oya Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.950AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although the prognosis of patients with pathologic T1a stage renal cell carcinoma (RCC) is generally good, some of these patients show distant metastasis or local recurrence. We investigated the clinicopathological features for predicting disease progression in pathologic T1a RCC. METHODS From March 1996 to September 2009, 186 nephron-sparing surgery and 132 nephrectomy were performed to treat pathologic T1a RCC at our institution. Of the 318 cases, 135 cases were treated with laparoscopic and 183 were treated with open surgery. Bilateral and multiple cases were excluded from the study. Correlations between clinicopathological parameters and disease progression were statistically analyzed. RESULTS Histologically the 318 cases of primary and solitary pathologic T1a RCC included 272 of clear cell (85.5%), 26 of papillary (8.2%), 11 of chromophobe (3.5%), 4 of ACDK (acquired cystic disease of the kidney) (1.3%), 1 of spindle, and 1 of Xp11 translocation RCC. Other 3 cases were unclassified. We identified 11 progressive cases, of which 9 were metastatic cases, 2 were recurrent cases. One patient died of metastatic disease after 34.7 months from the surgery. Laparoscopic surgery group demonstrated similar rates of recurrence-free survival compared with open surgery group. The nephron sparing surgery group showed similar rates of recurrence-free survival compared with nephrectomy group. Univariate analysis showed that high nuclear grade was a significant risk factor of disease progression (p=0.001), however, no significant correlation was found between tumor size, microvascular invasion, or other pathologic factors and disease progression. Multivariate analysis showed that high nuclear grade was a significant factor to predict disease progression (p=0.007). CONCLUSIONS These results imply that high nuclear grade is possibly one of the most important prognostic factors for predicting disease progression after surgery in pathologic T1a RCC. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e505-e506 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kenjiro Suzuki Tokyo, Japan More articles by this author Ryuichi Mizuno Tokyo, Japan More articles by this author Shuji Mikami Tokyo, Japan More articles by this author Kento Kanao Tokyo, Japan More articles by this author Hidaka Kono Tokyo, Japan More articles by this author Eiji Kikuchi Tokyo, Japan More articles by this author Hirohiko Nagata Tokyo, Japan More articles by this author Hiroshi Asanuma Tokyo, Japan More articles by this author Akira Miyajima Tokyo, Japan More articles by this author Ken Nakagawa Tokyo, Japan More articles by this author Mototsugu Oya Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Young Age as Favorable Prognostic Factor for Cancer-specific Survival in Localized Renal Cell Carcinoma

To evaluate the prognostic effect of age in patients with localized renal cell carcinoma (RCC) and investigate the incidence of Xp11 translocation RCC in young patients who developed recurrence. From 1990 to 2007, 2403 Japanese patients underwent nephrectomy for presumed RCC at 9 institutions. Of those, 1143 patients had localized RCC (Stage pT1-2N0M0). Their clinical data were retrospectively reviewed. In the present study, 131 patients (11%) were considered young (≤45 years at diagnosis). In the young patients with recurrence, the nephrectomy specimens were immunostained with TFE3 to determine the incidence of Xp11 translocation RCC. During the median follow-up of 47 months, 3 cancer deaths (2.2%) occurred among young patients and 51 (5.0%) among older patients. The 5-year cancer-specific survival (CSS) rate was significantly better for the younger patients than for the older patients (P = .049). Multivariate analysis showed that age was significantly associated with CSS, as were the pathologic T stage, tumor grade, and symptoms at diagnosis. The hazard ratio of young age was 0.31 (95% confidence interval 0.077-0.87). The recurrence-free survival curves revealed no difference between these 2 groups. Of the 74 patients with recurrence, the CSS after recurrence was significantly better in the younger patients than in the older patients (P = .0010). Of the 8 young patients with recurrence, 4 had Xp11 translocation RCC, and 3 survived for >5 years after recurrence. Compared with the older patients, the young patients with RCC had similar recurrence-free survival rates but better CSS rates. This might have been because significant numbers of the young patients had Xp11 translocation RCC.

Renal Cell Carcinoma with t(X;17)(p11.2;q25) in a 5-year-old Taiwanese Boy. A Case Report and Review of the Literature

The classification of adult renal cell carcinomas (RCCs) is well established and is mainly based on histopathologic features and genetic abnormalities [1]. In comparison, pediatric RCCs are more difficult to classify. In the past few years, it has become evident that a great majority of pediatric RCCs belong to the newly-recognized family of Xp11 translocation RCCs [2, 3]. These tumors are genetically characterized by different chromosome translocations, resulting in gene fusions between Xp11.2 and TFE3 transcription factor genes [2]. At least 5 genetic variants have been identified, including t(X;1)(p11.2;q21) translocation with PRCC-TFE3 fusion [4], t(X;1)(p11.2; p34) translocation with PSF-TFE3 fusion [5], inv(X)(p11; q12) translocation with NonO (p54)-TFE3 fusion [5], t (X;17)(p11.2;q25) translocation with ASPL-TFE3 fusion [6],and t(X;17)(p11.2;q23) with CLTC-TFE3 fusion [7]. Additionally, a subset of epithelioid RCCs that harbor t (6:11)(p11.2;q12), which fuses the Alpha gene and TFEB transcription factor gene, has been described [8]. A novel translocation of t(X,3)(p11;q23) has recently been reported in a 32-year-old female patient [9]. As TFEB and TFE3 are closely-related members of the microphthamia transcription factor (MiTF) family (a subfamily of basic helix-loop-helix leucine zipper transcription factors), it has been proposed that these tumors are classified as “MiTF/TFE translocation carcinomas” [2]. In the English literature, most case reports and series studies originate from Western countries [3, 6, 9–14], and case reports and series studies of pediatric RCCs in Asia are rare [15, 16]. Recently, Chen et al described a molecularlydocumented Xp11.2 translocated RCC in a 6-year-old Taiwanese boy [17]. Herein, we report a case of an Xp11.2 translocated RCC in a 5-year-old Taiwanese boy. The diagnosis was established based on the histopathologic features, nuclear expression of TFE3 protein, and the presence of the type 1 TFE3-ASPL fusion gene as detected by reverse transcriptase-polymerase chain reaction. A literature review of translocation RCCs is also included.

Immunohistochemical Diagnosis of Renal Neoplasms

Histologic diagnosis of renal neoplasm is usually straightforward by routine light microscopy. However, immunomarkers may be essential in several contexts, including differentiating renal from nonrenal neoplasms, subtyping of renal cell carcinoma (RCC), and diagnosing rare types of renal neoplasms or metastatic RCC in small biopsy specimens. To provide a comprehensive review of the diagnostic utility of immunomarkers for renal neoplasms. This review is based on published literature and personal experience. The following markers may have diagnostic utility in various diagnostic contexts: cytokeratins, vimentin, α-methylacyl coenzyme A racemase, carbonic anhydrase IX, PAX2, PAX8, RCC marker, CD10, E-cadherin, kidney-specific cadherin, parvalbumin, claudin-7, claudin-8, S100A1, CD82, CD117, TFE3, thrombomodulin, uroplakin III, p63, and S100P. Cytokeratins are uniformly expressed by RCC, albeit in a somewhat limited amount in some subtypes, requiring broad-spectrum anti-CK antibodies, including both low- and high-molecular-weight cytokeratins. PAX2 and PAX8 are sensitive and relatively specific markers for renal neoplasm, regardless of subtype. CD10 and RCC marker are sensitive to renal cell neoplasms derived from proximal tubules, including clear cell and papillary RCCs. Kidney-specific cadherin, parvalbumin, claudin-7, and claudin-8 are sensitive markers for renal neoplasms from distal portions of the nephron, including chromophobe RCC and oncocytoma. CK7 and α-methylacyl coenzyme A racemase are sensitive markers for papillary RCC; TFE3 expression is essential in confirming the diagnosis of Xp11 translocation RCC. The potentially difficult differential diagnosis between chromophobe RCC and oncocytoma may be facilitated by S100A1 and CD82. Thrombomodulin, uroplakin III, p63, and S100P are useful markers for urothelial carcinoma. Together with high-molecular-weight cytokeratins, PAX2, and PAX8, they can help differentiate renal pelvic urothelial carcinoma from collecting duct RCC. A sensitive marker for sarcomatoid RCC is still not available. Immunomarkers are most often used for diagnosing metastatic RCC. Compared with primary RCC, expression of the above-mentioned markers is often less frequent and less diffuse in the metastatic setting. Recognizing the variable sensitivity and specificity of these markers, it is important to include at least CD10, RCC marker, PAX2, and PAX8 in the diagnostic panel.

Response to Sorafenib in a Patient with Metastatic Xp11 Translocation Renal Cell Carcinoma

Sorafenib, a multikinase inhibitor of tumour-cell proliferation and angiogenesis, has been shown to have a role in the treatment of metastatic renal cell carcinoma (RCC). Xp11 translocation carcinoma is a rare subtype of RCC. We report an 18-year-old male patient with metastatic Xp11 translocation RCC who was responsive to sorafenib treatment. Six weeks after commencement of treatment with sorafenib, a CT scan of the patient showed increased central necrosis of the kidney mass and para-aortic lymph nodes as well as regression of the lung and pleural masses. The patient had a progression-free survival of 12 months, and overall survival of 15 months. The most severe adverse effects were grade 3 dermatitis and grade 3 anaemia. This case has demonstrated for the first time that sorafenib is active against Xp11 translocation RCC.

Xp11 Translocation Renal Cell Carcinoma (RCC): Extended Immunohistochemical Profile Emphasizing Novel RCC Markers

Xp11 translocation renal cell carcinoma (RCC) harbor various TFE3 gene fusions, and are known to underexpress epithelial immunohistochemical (IHC) markers such as cytokeratin and EMA relative to usual adult type RCC; however, their profile in reference to other IHC markers that are differentially expressed in other subtypes of RCC has not been systematically assessed. Few therapeutic targets have been identified in these aggressive cancers. We created 2 tissue microarrays (TMA) containing five 1.4-mm cores from each of 21 Xp11 translocation RCC (all confirmed by TFE3 IHC, 6 further confirmed by genetics), 7 clear cell RCC (CCRCC), and 6 papillary RCC (PRCC). These TMA were labeled for a panel of IHC markers. In contrast to earlier published data, Xp11 translocation RCC frequently expressed renal transcription factors PAX8 (16/21 cases) and PAX2 (14/21 cases), whereas only 1 of 21 cases focally expressed MiTF and only 5 of 21 overexpressed p21. Although experimental data suggest otherwise, Xp11 translocation RCC did not express WT-1 (0/21 cases). Although 24% of Xp11 translocation RCC expressed HIF-1alpha (like CCRCC), unlike CCRCC CA IX expression was characteristically only focal (mean 6% cell labeling) in Xp11 translocation RCC. Other markers preferentially expressed in CCRCC or PRCC, such as HIG-2, claudin 7, and EpCAM, yielded inconsistent results in Xp11 translocation RCC. Xp11 translocation RCC infrequently expressed Ksp-cadherin (3/21 cases) and c-kit (0/21 cases), markers frequently expressed in chromophobe RCC. Using an H-score that is the product of intensity and percentage labeling, Xp11 translocation RCC expressed higher levels of phosphorylated S6, a measure of mTOR pathway activation (mean H score=88), than did CCRCC (mean H score=54) or PRCC (mean H score=44). In conclusion, in contrast to prior reports, Xp11 translocation RCC usually express PAX2 and PAX8 but do not usually express MiTF. Although they may express HIF-1alpha, they only focally express the downstream target CA IX. They inconsistently express markers associated with other RCC subtypes, further highlighting the lack of specificity of the latter markers. TFE3 and Cathepsin K remain the most sensitive and specific markers of these neoplasms. Elevated expression of phosphorylated S6 in Xp11 translocation RCC suggests the mTOR pathway as an attractive potential therapeutic target for these neoplasms.

Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network

BackgroundXp11 translocation renal cell carcinoma (RCC) is an RCC subtype affecting 15% of RCC patients <45 years. We analyzed the benefit of targeted therapy [vascular endothelial growth factor receptor (VEGFR)-targeted agents and/or mammalian target of rapamycin (mTOR) inhibitors] in these patients. Patients and methodsPatients with Xp11 translocation/TFE3 fusion gene metastatic RCC who had received targeted therapy were identified. Nuclear TFE3 positivity was confirmed by reviewing pathology slides. Responses according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. ResultsOverall, 53 patients were identified; 23 had metastatic disease, and of these 21 had received targeted therapy (median age 34 years). Seven patients achieved an objective response. In first line, median PFS was 8.2 months [95% confidence interval (CI) 2.6–14.7 months] for sunitinib (n = 11) versus 2 months (95% CI 0.8–3.3 months) for cytokines (n = 9) (log-rank P = 0.003). Results for further treatment (second, third, or fourth line) were as follows: all three patients receiving sunitinib had a partial response (median PFS 11 months). Seven of eight patients receiving sorafenib had stable disease (median PFS 6 months). One patient receiving mTOR inhibitors had a partial response and six patients had stable disease. Median OS was 27 months with a 19 months median follow-up. ConclusionIn Xp11 translocation RCC, targeted therapy achieved objective responses and prolonged PFS similar to those reported for clear-cell RCC.