TFE3 gene rearrangement and protein expression contribute to a poor prognosis of renal cell carcinoma

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Abstract

Background

TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC) is a type of kidney cancer with a low incidence, with no consensus about whether it has a worse prognosis than clear cell renal cell carcinoma (ccRCC). This study attempted to elucidate the impact of TFE3-rearranged RCC by analyzing its clinical features and prognosis.

Methods

Patients treated in Sun Yat-sen Memorial Hospital (SYSMH) who were suspected to be diagnosed with TFE3-rearranged RCC were divided into two groups, TFE3-rearranged RCC and ccRCC with positive TFE3 protein expression on immunohistochemistry [TFE3(+) ccRCC], by dual-color, break-apart fluorescence in situ hybridization (FISH). After balancing the baseline characteristics with TFE3(+) ccRCC using the propensity score matching (PSM) method in a ratio of 2, we selected patients diagnosed with ccRCC with negative TFE3 protein expression on immunohistochemistry [TFE3(−) ccRCC]. The impact of TFE3 gene rearrangement and protein expression on renal cell carcinoma was determined by feature comparison with a nonparametric test and survival analysis with the Kaplan‒Meier method.

Results

Among 37 patients suspected of having TFE3-rearranged RCC, 13 patients were diagnosed with TFE3-rearranged RCC, and 24 patients had TFE3(+) ccRCC. The recurrence and new metastasis of TFE3-rearranged RCC was relatively common, even if the tumor stage was early at the first diagnosis. Through feature comparison and survival analysis, we found that TFE3-rearranged RCC was quite similar to TFE3(+) ccRCC. Compared with TFE3(−) ccRCC, TFE3(+) ccRCC tended to have a larger tumor diameter ( P = 0.011), higher neutrophil/lymphocyte ratio (NLR) ( P = 0.017) and metastatic potential ( P = 0.022), and worse overall survival (OS) ( P = 0.043) and PFS ( P = 0.016). The survival analysis showed that TFE3-rearranged RCC had a worse PFS than ccRCC ( P = 0.002), and TFE3(+) RCC had a worse PFS than TFE3(−) RCC ( P = 0.001). According to the stratification system based on the combination of TFE3 and lymphovascular invasion (LVI), we further found that the prognosis from good to poor was TFE3(−) LVI(−), TFE3(+) LVI(−), TFE3(+) LVI(+) and TFE3(−) LVI(+), with statistically significant differences in both OS ( P = 0.001) and PFS ( P < 0.001). In addition, we also reported two cases with poor prognosis, of which one was TFE3-rearranged RCC and the other was TFE3(+) ccRCC.

Conclusions

This is a novel finding that both FISH confirmed TFE3 gene rearrangement-mediated TFE3-rearranged RCC and IHC confirmed positive TFE3 protein expression [TFE3(+)] contribute to a poor prognosis in RCC, suggesting more active treatment and careful follow-up for TFE3(+) RCC patients. The combination of TFE3 and LVI may be a new risk stratification system for RCC.

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Most cited references 34

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The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs—Part A: Renal, Penile, and Testicular Tumours

Holger Moch, Mahul B Amin, Daniel Berney … (2022)

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Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay.

V Reuter, Marc Ladanyi, Brian Hutchinson … (2003)

We report the aberrantly strong nuclear immunoreactivity for the C-terminal portion of TFE3 protein in tumors characterized by chromosome translocations involving the TFE3 gene at Xp11.2. This group of tumors includes alveolar soft part sarcoma and a specific subset of renal carcinomas that tend to affect young patients. They contain fusion genes that encode chimeric proteins consisting of the N-terminal portion of different translocation partners fused to the C-terminal portion of TFE3. We postulated that expression of these fusion proteins may be dysregulated in these specific tumors and detectable by immunohistochemistry. We performed immunohistochemistry using a polyclonal antibody to the C-terminal portion of TFE3 in 40 formalin-fixed, paraffin-embedded tumors characterized by TFE3 gene fusions, including 19 alveolar soft part sarcoma (of which nine were molecularly confirmed) and 21 renal carcinomas with cytogenetically confirmed characteristic Xp11.2 translocations and/or fusion transcripts involving TFE3 (11 PRCC-TFE3, 7 ASPL-TFE3, 3 PSF-TFE3). We also screened 1476 other tumors of 64 histologic types from 16 sites for TFE3 immunoreactivity using tissue microarrays and evaluated a broad range of normal tissues. Thirty-nine of 40 neoplasms characterized by TFE3 gene fusions (19 of 19 alveolar soft part sarcoma, 20 of 21 renal carcinomas) demonstrated moderate or strong nuclear TFE3 immunoreactivity. In contrast, only 6 of 1476 other neoplasms labeled for TFE3 (sensitivity 97.5%, specificity 99.6%). Nuclear immunoreactivity in normal tissues was extremely rare. We then applied this assay to a set of 11 pediatric renal carcinomas for which only paraffin-embedded tissue was available, to assess if morphologic features could predict TFE3 immunoreactivity. Of the eight cases in which we suspected that a TFE3 gene rearrangement might be present based on morphology, seven scored positive for nuclear TFE3 labeling. Of the three tumors whose morphology did not suggest the presence of a TFE3 gene fusion, none showed nuclear TFE3 labeling. In summary, we find that nuclear immunoreactivity for TFE3 protein by routine immunohistochemistry is a highly sensitive and specific assay for neoplasms bearing TFE3 gene fusions. Furthermore, the finding in our set of test cases (i.e., that morphologic features can be used to predict TFE3 immunoreactivity) further supports the notion that renal carcinomas with TFE3 gene fusions have a distinctive morphology that corresponds to their genetic distinctiveness. Carcinomas associated with TFE3 gene fusions may account for a significant proportion of pediatric renal carcinomas, and this immunohistochemistry assay may help to clarify their true prevalence.

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TFE3 break-apart FISH has a higher sensitivity for Xp11.2 translocation-associated renal cell carcinoma compared with TFE3 or cathepsin K immunohistochemical staining alone: expanding the morphologic spectrum.

Gregory T. MacLennan, Jun Zhou, Qiu Rao … (2013)

Renal cell carcinoma (RCC) associated with Xp11.2 translocation is uncommon, characterized by several different translocations involving the TFE3 gene. We assessed the utility of break-apart fluorescence in situ hybridization (FISH) in establishing the diagnosis for suspected or unclassified cases with negative or equivocal TFE3 immunostaining by analyzing 24 renal cancers with break-apart TFE3 FISH and comparing the molecular findings with the results of TFE3 and cathepsin K immunostaining in the same tumors. Ten tumors were originally diagnosed as Xp11.2 RCC on the basis of positive TFE3 immunostaining, and 14 were originally considered unclassified RCCs with negative or equivocal TFE3 staining, but with a range of features suspicious for Xp11.2 RCC. Seventeen cases showed TFE3 rearrangement associated with Xp11.2 translocation by FISH, including all 13 tumors with moderate or strong TFE3 (n=10) or cathepsin K (n=7) immunoreactivity. FISH-positive cases showed negative or equivocal immunoreactivity for TFE3 or cathepsin K in 7 and 10 tumors, respectively (both=3). None had positive immunohistochemistry but negative FISH. Morphologic features were typical for Xp11.2 RCC in 10/17 tumors. Unusual features included 1 melanotic Xp11.2 renal cancer, 1 tumor with mixed features of Xp11.2 RCC and clear cell RCC, and other tumors mimicking clear cell RCC, multilocular cystic RCC, or high-grade urothelial carcinoma. Morphology mimicking high-grade urothelial carcinoma has not been previously reported in these tumors. Psammoma bodies, hyalinized stroma, and intracellular pigment were preferentially identified in FISH-positive cases compared with FISH-negative cases. Our results support the clinical application of a TFE3 break-apart FISH assay for diagnosis and confirmation of Xp11.2 RCC and further expand the histopathologic spectrum of these neoplasms to include tumors with unusual features. A renal tumor with pathologic or clinical features highly suggestive of translocation-associated RCC but exhibiting negative or equivocal TFE3 immunostaining should be evaluated by TFE3 FISH assay to fully assess this possibility.

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Author and article information

Contributors

Jian Huang

Tianxin Lin

Xu Chen

Journal

Journal ID (nlm-ta): Heliyon

Journal ID (iso-abbrev): Heliyon

Title: Heliyon

Publisher: Elsevier

ISSN (Electronic): 2405-8440

Publication date PMC-release: 06 May 2023

Publication date Collection: May 2023

Publication date (Electronic): 06 May 2023

Volume: 9

Issue: 5

Electronic Location Identifier: e16076

Affiliations

[a ]Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China

[b ]Department of Urology, Minimally Invasive Surgery Center, Guangdong Key Laboratory of Urology, Guangzhou Urology Research Institute, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China

[c ]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China

[d ]Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China

[e ]Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China

Author notes

[∗ ]Corresponding author. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China. chenx457@ 123456mail.sysu.edu.cn

[∗∗ ]Corresponding author. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China. lintx@ 123456mail.sysu.edu.cn

[∗∗∗ ]Corresponding author. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China. huangj8@ 123456mail.sysu.edu.cn

[1]

These authors contributed equally to this work.

Article

Publisher Item ID: S2405-8440(23)03283-8 Publisher ID: e16076

DOI: 10.1016/j.heliyon.2023.e16076

PMC ID: 10196445

SO-VID: 7d9a64bc-e03e-4e00-b95e-6e613ab1aaf1

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 24 January 2023

Date revision received : 30 April 2023

Date accepted : 4 May 2023

TFE3 gene rearrangement and protein expression contribute to a poor prognosis of renal cell carcinoma

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Abstract

Background

Methods

Results

Conclusions

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Karger: Oncology

Most cited references 34

The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs—Part A: Renal, Penile, and Testicular Tumours

Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay.

TFE3 break-apart FISH has a higher sensitivity for Xp11.2 translocation-associated renal cell carcinoma compared with TFE3 or cathepsin K immunohistochemical staining alone: expanding the morphologic spectrum.

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