NMRK2 is an efficient diagnostic indicator for Xp11.2 translocation renal cell carcinoma.

Xp11.2 translocation renal cell carcinomas (tRCC) are a rare and highly malignant type of renal cancer, lacking efficient diagnostic indicators and therapeutic targets. Through the analysis of public databases and our cohort, we identified NMRK2 as a potential diagnostic marker for distinguishing Xp11.2 tRCC from kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) due to its specific upregulation in Xp11.2 tRCC tissues. Mechanistically, we discovered that TFE3 fusion protein binds to the promoter of the NMRK2 gene, leading to its upregulation. Importantly, we established RNA- and protein-based diagnostic methods for identifying Xp11.2 tRCC based on NMRK2 expression levels, and the diagnostic performance of our methods was comparable to a dual-color break-apart fluorescence in situ hybridization assay. Moreover, we successfully identified fresh Xp11.2 tRCC tissues after surgical excision using our diagnostic methods and established an immortalized Xp11.2 tRCC cell line for further research purposes. Functional studies revealed that NMRK2 promotes the progression of Xp11.2 tRCC by upregulating the NAD+/NADH ratio, and supplementation with ß-nicotinamide mononucleotide (NMN) or nicotinamide riboside chloride (NR), effectively rescued the phenotypes induced by the knockdown of NMRK2 in Xp11.2 tRCC. Taken together, these data introduce a new diagnostic indicator capable of accurately distinguishing Xp11.2 tRCC and highlight the possibility of developing novel targeted therapeutics. © 2024 The Pathological Society of Great Britain and Ireland.

A genetic basis for sex differences in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.

Treatment of metastatic TFE3 microphthalmia transcription factor translocation renal cell carcinoma: a case report.

Background: Microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) translocation renal cell carcinoma (RCC) is a rare type of non-clear cell RCC (nccRCC), which is more common in females. Currently, there is no standardized treatment for advanced metastatic microphthalmia translocation RCC (MiT-RCC). The main treatment modalities include surgery, chemotherapy, immunotherapy, anti-vascular endothelial growth factor or vascular endothelial growth factor receptor (VEGFR) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and targeted therapy against the mesenchymal-epithelial transition (MET) factor signaling pathway. Case Description: We present the case of an 8-year-old male patient with hematuria and paroxysmal urinary pain. Based on tumor genetic testing results and targeted drug matching analysis, the patient underwent tumor biopsy, tumor radical surgery with vascular osteotomy, and cervicothoracic lymph node dissection. The patient was then treated with a combination of immunotherapy [sintilimab, a drug directed against programmed cell death receptor-1 (PD-1)] and VEGFR tyrosine kinase inhibitor (TKI) (from pazopanib to sunitinib). Throughout the 10 cycles of conventional chemotherapy (seven courses of sintilimab since the start of the third chemotherapy treatment), the patient's condition remained stable, with no tumor recurrence at the primary site. However, in the later stages, the patient developed a large amount of ascites, and the family requested discontinuation of treatment, ultimately leading to the patient's death. Conclusions: In this case report, we summarize the therapeutic strategy of a young patient with metastatic transcription factor E3 (TFE3) MiT-RCC. For this disease, early immunotherapy and the use of precision-targeted drugs may have a favorable impact on the survival prognosis of the patient but may still be of less benefit in children with advanced multiple metastases. Therefore, further research on tumor driver genes, among other treatment components, is urgently needed to improve precision therapy.

Avelumab plus axitinib for translocation renal cell carcinoma: A case series and literature review.

Introduction: Patients with translocation renal cell carcinoma (tRCC) have a poor prognosis without standardized treatment. Case presentation: The first case was of a 72-year-old woman who underwent robot-assisted partial nephrectomy for a left renal tumor and was pathologically diagnosed with tRCC. Recurrence was observed in the left retroperitoneal soft tissue. After treatment with avelumab-axitinib, continued progression-free survival was confirmed at the 90-week follow-up. The second case was of a 41-year-old woman referred to our hospital and presented with translocation renal cell carcinoma metastasis to a para-aortic lymph node. After treatment with avelumab-axitinib, continued progression-free survival was confirmed at the 43-week follow-up. Conclusion: The outcomes of these cases indicate that avelumab-axitinib therapy has a long-term antitumor effect in some patients with tRCC.

Incidental Detection of TFEB-Amplified Renal Cell Carcinoma by Colocated Gene Amplification of CCND3 (6p21): A Case Report and Review of the Literature.

TFEB-amplified renal cell carcinoma (RCC), which belongs to the MITF family of RCC, is characterized by genomic amplification at the 6p21.1 locus where the TFEB gene is located. The vascular endothelial growth factor A and cyclin D3 genes are also located at this same locus. When tumors lack classic morphologic features, they may be classified as "RCC not otherwise specified (NOS)." However, it is increasingly important to accurately diagnose the RCC subtype to define the patient's individual prognosis and select the subsequent therapeutic modalities, which now include targeted agents. Therefore, knowledge of the diagnostic features of TFEB-altered RCCs, such as t(6;11) RCCs and TFEB-amplified RCCs, is critical for identifying these tumors. Herein, we present an interesting case of TFEB-amplified RCC that was initially diagnosed as RCC NOS on biopsy of a renal tumor in a community practice setting with available molecular findings demonstrating CCND3 amplification. The genetic abnormality was "accidentally" detected due to the amplification of the colocated CCND3 gene at the 6p21 locus of the TFEB gene on a limited genetic sequencing panel. This case highlights the importance of molecular tests in accurately diagnosing RCC and carefully interpreting molecular findings in the context of histomorphologic features.

Renal cell carcinoma in the contralateral kidney with TFE3 gene translocation following chemotherapy for childhood nephroblastoma: A case report and literature review.

Key Clinical Message: Renal cell carcinoma as a secondary malignant neoplasm is relatively rare; however, the possibility of secondary renal cell carcinoma following chemoradiotherapy for childhood nephroblastoma should be considered. Abstract: The occurrence of secondary renal cell carcinoma (RCC) following chemoradiotherapy for nephroblastoma is relatively rare, especially in microphthalmia transcription factor family translocation renal cell carcinoma. A 13-year-old Japanese male was referred to our department for treatment of a right kidney mass. The patient had undergone open left nephrectomy and adjuvant chemotherapy for nephroblastoma, 12 years before. Diagnostic imaging revealed a tumor in the right kidney and a lesion suspected to be metastasis in the left eighth rib. Chromophobe RCC or translocation RCC was suspected from the imaging pattern. TNM classification was cT1aN0M1, and the clinical stage was IV. Partial nephrectomy by robot-assisted surgery for the right renal tumor and resection of the left eighth rib were performed. Pathologically, the renal tumor was diagnosed as translocation RCC, and the rib lesion demonstrated no evidence of malignancy. We are currently undergoing imaging follow-up and the patient has been recurrence-free for 15 months. In this study, we present a rare case of secondary translocation RCC after successful treatment of nephroblastoma.

Multimodality imaging of Xp11.2 translocation/TFE3 gene fusion associated with renal cell carcinoma: a case report.

Background: Xp11.2 translocation/TFE3 gene fusion associated with renal cell carcinoma (Xp11.2 RCC) exhibits unique biological characteristics and is associated with an increased incidence of tumor thrombosis, lymph node metastasis, and advanced disease stages. Multimodality imaging, including US, contrast-enhanced CT, multi-parametric MRI, and 18F-FDG PET/CT plays a crucial role in the preoperative diagnosis and differentiation of renal tumors. Case report: A 15-year-old female presented with lumbar pain worsened, and developed persistent painless hematuria. The CT attenuation values of the scan without contrast, corticomedullary phase, nephrographic phase, and delayed phases were 35 HU, 83 HU, 82 HU, and 75 HU, respectively. The solid component of the mass displayed heterogeneous marked enhancement. Furthermore, MRU indicated that the lesion involved the cortical medulla and infringed on the renal sinus fat. The lesion appeared isosignal in T1WI, slightly low signal in T2WI, and slightly high signal in DWI. The degree of enhancement in the three phases of enhancement scan was lower than that in the renal parenchyma, and hemorrhage and necrosis were observed within the internal part of the lesion. To further clarify the staging, the patient underwent 18F-FDG PET/CT. PET/CT images showed multiple irregular occupancies in the right kidney with unclear borders, showing a heterogeneous increase in 18F-FDG uptake, with SUVmax values ranging from 2.3 to 5.2 in the routine imaging phase (60 min post-injection), compared to SUVmax values ranging from 2.8 to 6.9 in the delayed imaging phase (160 min post-injection). Additionally, multiple enlarged and fused lymph nodes were observed in the medial part of the right kidney and the retroperitoneum, exhibiting a heterogeneous increase in 18F-FDG uptake, with SUVmax values ranging from 4.1 to 8.7 in the routine imaging phase, compared to SUVmax values ranging from 4.4 to 9.1 in the delayed imaging phase. The postoperative pathology, immunohistochemistry, and molecular analysis of histiocytes were consistent with a diagnosis of Xp11.2 RCC. One month after surgery, enhanced-CT examination of the patient revealed lung metastasis, peritoneal metastasis, and multiple lymph node metastases throughout the body, with an overall survival of 16 months. Conclusion: Xp11.2 RCC exhibits unique biological characteristics and is associated with an increased incidence of tumor thrombosis, lymph node metastasis, and advanced disease stages. Long-term follow-up is essential to monitor the likelihood of recurrence and metastasis. 18F-FDG PET/CT examination can comprehensively visualize the lesion's location and extent, providing a basis for clinical tumor staging and aiding in treatment monitoring and follow-up. To address the limitations of FDG, the utilization of specific tracers designed for RCC or tracers that are not excreted via the urinary system would be ideal. Further advancements in molecular imaging technologies and the development of novel tracers hold great promise in advancing the diagnosis and management of RCC, ultimately contributing to better patient outcomes and overall disease management.

MiT family translocation renal cell carcinoma with retroperitoneal metastasis in childhood: a case report.

RCC accounts for only 0.1%-0.3% of all kidney tumors and 2%-6% of malignant kidney tumors in children. Accounting for approximately one-third of the total number of cases in children and adolescents with RCC, Xp11.2 tRCC is the most common subtype of the MiT family translocation renal cell carcinoma, which is a group of rare childhood and adult tumors, characterized by recurrent gene rearrangements of TFE3. Here we report a rare case of a 6-year-old male patient with MiT family translocation renal cell carcinoma (MiTF tRCC) where the patient developed retroperitoneal metastasis. The patient underwent partial nephrectomy (PN), radical nephrectomy (RN), abdominal lymph node resection, and intestinal adhesion lysis. Microscopically, we detected focal and nest clump-shaped clusters of tumor cells whose cytoplasm was bright and clear. Immunohistochemistry (IHC) showed tumor cells diffusely expressed TFE3, and fluorescence in situ hybridization (FISH) demonstrated disruption of the TFE3 locus, confirming the diagnosis of Xp11.2 tRCC, the most common subtype of MiTF tRCC. Eventually, the patient obtained a good therapeutic result. This case can provide a good reference and guidance for pediatric urologists and oncologists to recognize and diagnose rare renal cell carcinoma in children.

Factors associated with survival in paediatric and adolescent renal cell carcinoma: a population-based study.

BACKGROUND: The purpose of this study was to conduct a population-based study to determine the prognosis of renal cell carcinoma (RCC) in children and adolescents. METHODS: Patients with RCC who were registered in the Surveillance, Epidemiology, and End Results (SEER) program between 2000 and 2018 had their demographic and clinical characteristics evaluated retrospectively. The log-rank test was used to compare survival curves. Kaplan-Meier estimates were used to generate survival curves based on various factors. To identify factors associated with overall survival, Cox proportional-hazards regression was used. RESULTS: A total of 251 patients were enrolled in the study. For all patients, the overall survival (OS) rates at 3- and 5- year were 93.5% and 92.0%, respectively. A multivariable study revealed that the following factors were independently associated with overall survival: sex, race, histologic type, SEER stage, AJCC stage, and type of surgery. Cox analysis showed that white patients had the lowest risk of mortality (hazard ratio (HR) 2.58, 95% confidence interval (CI), 1.33-4.99; P = 0.005), compared with black patients. Patients having metastatic disease had significantly higher mortality risk (HR 43, 95% CI, 14.8-125; P < 0.001) than the patients with localized tumour. CONCLUSIONS: Our study emphasizes the importance of race, SEER stage, and surgery in the prognosis of paediatric RCC, providing valuable epidemiological evidence for clinical practice. Economic studies assessing a race/ethnic group specific strategy are also required.

Renal Cell Carcinoma of Variant Histology: Biology and Therapies.

The term variant histology renal cell carcinomas (vhRCCs), also known as non-clear cell RCCs, refers to a diverse group of malignancies with distinct biologic and therapeutic considerations. The management of vhRCC subtypes is often based on extrapolating results from the more common clear cell RCC studies or basket trials that are not specific to each histology. The unique management of each vhRCC subtype necessitates accurate pathologic diagnosis and dedicated research efforts. Herein, we discuss tailored recommendations for each vhRCC histology informed by ongoing research and clinical experience.

Clinical and pathological heterogeneity of four common fusion subtypes in Xp11.2 translocation renal cell carcinoma.

Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a group of rare and highly heterogeneous renal cell carcinoma (RCC). The translocation involving TFE3 and different fusion partners lead to overexpression of the chimeric protein. The purpose of this study is to explore the clinicopathological features of Xp11.2 tRCC with four common fusion subtypes. Methods: We screened out 40 Xp11.2 tRCC patients from January 2007 to August 2021 in our institution. The diagnosis was initially confirmed by TFE3 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assay and their fusion partners were verified by RNA sequencing. Then the 40 cases were divided into two groups (DBHS family and non-DBHS family group) and a clinical comparison among the four common fusion subtypes was performed. Results: Among the 40 cases, 11 cases with SFPQ-TFE3 gene fusion and 7 cases with NONO-TFE3 gene fusion were classified in DBHS group, the remaining cases with ASPL-TFE3 (11 cases) or PRCC-TFE3 (11 cases) gene fusion were classified in non-DBHS group. Lymph node (LN) metastasis (P=0.027) and distant metastasis (P=0.009) were more common seen in non-DBHS family group than DBHS family group and cases in DBHS family group have better progressive-free survival (PFS) (P=0.02). In addition, ASPL-TFE3 fusion was associated with worse outcome (P=0.03) while NONO-TFE3 fusion (P=0.04) predicted a better prognosis. Conclusions: Different fusion partner genes may play a functional role in various morphology, molecular and biological features of Xp11.2 tRCCs. The impact of fusion partners on clinical characteristics of Xp11.2 tRCCs deserves further exploration.

A novel VCP::TFE3 gene fusion resulting from t(X;9)(p11.23;p13.3) chromosome translocation in TFE3 rearranged renal cancer cell carcinoma.

Renal cell carcinoma (RCC) with rearrangement of transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3; TFE3-rearranged RCC) at Xp11.2 is a rare tumor entity but the most frequent among the microphthalmia transcription factor family translocation RCCs. Here, we report the identification of a new VCP::TFE3 fusion gene as the result of a t(X;9)(p11.23;p13.3) translocation identified by whole transcriptome sequencing. No other relevant molecular alteration was identified by whole exome sequencing. This case showed typical morphological features of TFE3-rearranged RCC with positive TFE3 immunostaining and positive TFE3 break-apart fluorescence in situ hybridization. MET was also overexpressed on immunohistochemistry. The patient had metastatic disease and was treated by surgery and five lines of therapy, including 24 months of stable disease on the mesenchymal epithelial transition (MET) inhibitor cabozantinib, with an overall survival of 7 years. In addition to expanding the spectrum of TFE3 rearrangement partners, this report highlights the complexity of these tumors and supports the development of translational programs in renal cancer.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.

"Papillary Adenoma-like" Renal Tumor with TFE3 Gene Rearrangement, A Potential Precursor to or Early Event in the Development of TFE3 Translocation Renal Cell Carcinoma.

MiT family translocation renal cell carcinomas harbor gene fusion involving members of MiT family of transcription factors. Their precursor lesions have not been identified. Herein, we report the first case of small papillary tumors morphologically resembling papillary adenomas but harboring TFE3 gene alteration. The patient was a 23-year old man with multiple small papillary tumors in the right kidney discovered following a gunshot wound injury. These lesions were < 5 mm, well-circumscribed but not encapsulated tubulopapillary proliferation lined with a single layer of cuboidal cells with WHO/ISUP grade 1 or 2 nuclei. The tumor cells were immunoreactive to PAX8, AMACR, high molecular weight cytokeratin, and keratin 7 and negative for CD10, CA9, TTF1, and cathepsin K. Morphologically and immunohistochemically, these lesions were diagnosed as papillary adenomas. TFE3 gene rearrangement was confirmed by fluorescence in-situ hybridization (FISH) using a TFE3 break-apart probe. We term these tumors "papillary adenoma-like" renal tumor with TFE3 gene rearrangement. These tumors are likely a precursor to or represent an early event in the development of TFE3 translocation renal cell carcinomas. An understanding of such tumors to translocation renal cell carcinoma progression can provide insight into the pathogenic mechanism, and ultimately aid the diagnosis and management of translocation renal cell carcinoma.

Current clinical perspective of urological oncology in the adolescent and young adult generation.

Among adolescents and young adults, hematological tumors are the most common malignancies in younger patients; however, solid tumors also increase with advancing age. The pathogenesis of some of these tumors differs from that of tumors which develop in children, or middle-aged and older adults, and special care should be taken in their treatment and management. A treatment plan that takes into consideration future fertility is necessary for testicular tumors, and an educational campaign to encourage early detection is also essential. The treatment of adolescents with advanced testicular tumors should resemble therapeutic approaches for young adults and not a pediatric regimen. Adrenal tumors often develop as part of familiar hereditary syndrome. Therefore, taking the personal and family history is very important, and genetic counseling should be also recommended. In renal tumors, the incidence of translocation renal cell carcinomas is higher. Complete resection is the only promising method for long-term prognosis because of no established treatment for translocation renal cell carcinomas with distant metastasis. Bladder tumors are often detected by symptoms of gross hematuria and are found at a relatively early stage. Along with renal tumors, oncological evaluation including cystoscopy is also considered essential for gross hematuria. Wilms tumors and rhabdomyosarcomas could be managed in accordance with pediatric protocols to improve the treatment outcomes. The dedicated cancer survivorship care for adolescents and young adults could be also indispensable to conquer cancer and maintain a better quality of life.

Mechanism of disordered subcellular localization of TFE3 fusion protein in TFE3 translocation renal cell carcinoma / 现代泌尿外科杂志

【Objective】 To investigate the effects of the loss of exon 1 of TFE3 on nuclear localization of chimeric TFE3 protein in TFE3 translocation renal cell carcinoma (TFE3 tRCC). 【Methods】 The localization of TFE3 protein in TFE3 tRCC and clear cell renal cell carcinoma (ccRCC) were detected with immunochemistry. The exon retention of TFE3 gene in TFE3 tRCC was analyzed in databases and literatures. The plasmids containing TFE3 full-length and different-length of TFE3 exons which were constructed to pCDH-MCS-EGFP-Puro were transfected into HEK293T using Lipo FiterTM. The localization of EGFP protein in HEK293T cells were detected with confocal microscopy. The localization of TFE3 protein and truncated TFE3 protein were detected with Western blotting. The mRNA expression of the downstream genes of TFE3 protein were detected with q-PCR. 【Results】 Strong nuclear signal of TFE3 protein was observed in TFE3 tRCC, whereas TFE3 protein in ccRCC was mainly localized in cytoplasm. The results of fluorescence imaging and Western blotting showed that TFE3 full-length protein was expressed both in nucleus and cytoplasm, and the expression of truncated TFE3 protein was mainly localized in nucleus. The q-PCR analysis demonstrated that the deletion of exon 1 in TFE3 gene led to a higher transcriptional level of targeted genes of TFE3 protein. 【Conclusion】 The loss of exon 1 in TFE3 played a critical role in preventing TFE3 protein from entering the nucleus. In TFE3 tRCC, the loss of exon 1 in TFE3 gene leads to the nuclear localization of TFE3 fusion protein and activation of its downstream target genes. This mechanism promises to uncover the occurrence and development of TFE3 tRCC.

TFE3 and TFEB-rearranged renal cell carcinomas: an immunohistochemical panel to differentiate from common renal cell neoplasms.

TFE3/TFEB-rearranged renal cell carcinomas are characterized by translocations involving TFE3 and TFEB genes. Despite the initial description of typical morphology, their histological spectrum is wide, mimicking common subtypes of renal cell tumors. Thus, the diagnosis is challenging requiring the demonstration of the gene rearrangement, usually by FISH. However, this technique is limited in most laboratories and immunohistochemical TFE3/TFEB analysis is inconsistent. We sought to identify a useful immunohistochemical panel using the most common available markers to recognize those tumors. We performed an immunohistochemical panel comparing 27 TFE3-rearranged and 10 TFEB-rearranged renal cell carcinomas to the most common renal cell tumors (150 clear cell, 100 papillary, 50 chromophobe renal cell carcinomas, 18 clear cell papillary renal cell tumors, and 50 oncocytomas). When dealing with neoplasms characterized by cells with clear cytoplasm, CA9 is a helpful marker to exclude clear cell renal cell carcinoma. GATA3, AMACR, and CK7 are useful to rule out clear cell papillary renal cell tumor. CK7 is negative in TFE3/TFEB-rearranged renal cell carcinoma and positive in papillary renal cell carcinoma, being therefore useful in this setting. Parvalbumin and CK7/S100A1 respectively are of paramount importance when TFE3/TFEB-rearranged renal cell carcinoma resembles oncocytoma and chromophobe renal cell carcinoma. Moreover, in TFEB-rearranged renal cell carcinoma, cathepsin K and melanogenesis markers are constantly positive, whereas TFE3-rearranged renal cell carcinoma stains for cathepsin K in roughly half of the cases, HMB45 in 8% and Melan-A in 22%. In conclusion, since TFE3/TFEB-rearranged renal cell carcinoma may mimic several histotypes, an immunohistochemical panel to differentiate them from common renal cell tumors should include cathepsin K, CA9, CK7, and parvalbumin.

Case Report: Clinical complete response of advanced renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion by treated by camrelizumab and axitinib: A rare case report.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusions is a rare subtype of renal tumor. This entity predominantly occurs in juveniles, but rarely in adults. Xp11.2 translocation RCC (tRCC) patients with lymph node or organ metastasis are associated with poor prognosis, and the strategy remains controversial. Herein, we presented our experience with the diagnosis and treatment of an adult case of Xp11.2 tRCC. In our clinical practice, a 32-year-old male manifested fever and right flank paroxysmal blunt pain, and computed tomography showed an inhomogeneous mass, 6 cm in diameter, in the right kidney. Then right partial nephrectomy (PN) and renal hilar lymph node dissection by laparoscopic surgery were performed. Pathology revealed that the tumor cells were positive for TFE3 immunohistologically and positive for TFE3 break-apart fluorescence in situ hybridization assay. A splice site mutation c.1544-1G>T of protein tyrosine phosphatase receptor delta (PTPRD) was detected by next-generation sequencing and weak PTPRD expression was confirmed in tumor tissues compared to tumor periphery. This patient was diagnosed with stage III RCC and received immune checkpoint inhibitor (camrelizumab) in combination with tyrosine kinase inhibitor (axitinib) treatment for 1 year. He achieved a clinical complete response with no sign of recurrence or metastasis. PTPRD mutation might be a favorable indicator for Xp11.2 tRCC patients managed by PN and followed by the adjuvant therapy of immune checkpoint inhibitor and tyrosine kinase inhibitor.

Efficacy of Cabozantinib in Metastatic MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear. METHODS: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS). RESULTS: Fifty-two patients with metastatic TRCC treated in the participating centers and evaluable for response were included. Median age at metastatic diagnosis was 40 years (IQR 28.5-53). Patients' IMDC risk groups at diagnosis were favorable (9/52), intermediate (35/52), and poor (8/52). Eleven (21.2%) patients received cabozantinib as frontline therapy, 15 (28.8%) at second line, and 26 (50%) at third line and beyond. The proportion of patients who achieved an objective response was 17.3%, including 2 complete responses and 7 partial responses. For 26 (50%) patients, stable disease was the best response. With a median follow-up of 25.1 months (IQR 12.6-39), median PFS was 6.8 months (95%CI 4.6-16.3) and median OS was 18.3 months (95%CI 17.0-30.6). No difference of response was identified according to fusion transcript features. CONCLUSION: This real-world study provides evidence of the activity of cabozantinib in TRCC, with more durable responses than those observed historically with other VEGFR-TKIs or ICIs.

Phenotypical screening on metastatic PRCC-TFE3 fusion translocation renal cell carcinoma organoids reveals potential therapeutic agents

PurposeTranslocation renal cell carcinoma (tRCC) is a subtype that occurs predominantly in children and young individuals. Metastatic tRCC occurring in young patients is more aggressive than that occurring in older patients, and there are still no effective therapies. Organoids can mimic original tissues and be assessed by high-throughput screening (HTS). We aimed to utilize patient-derived organoids and HTS to screen drugs that can be repurposed for metastatic tRCC with PRCC-TFE3 fusion.MethodsTumor tissues were obtained from treatment-naïve metastatic tRCC patients who underwent surgery. Histopathology and fluorescence in situ hybridization (FISH) confirmed the tRCC. Organoids derived from the dissected tissues were cultured and verified by FISH and RNA-seq. HTS was performed to seek promising drugs, and potential mechanisms were explored by RNA-seq and cell-based studies.ResultsWe successfully established a metastatic tRCC organoid with PRCC-TFE3 fusion, a common fusion subtype, and its characteristics were verified by histopathology, FISH, and RNA-seq. An HTS assay was developed, and the robustness was confirmed. A compound library of 1816 drugs was screened. Eventually, axitinib, crizotinib, and JQ-1 were selected for further validation and were found to induce cell cycle arrest and apoptosis. RNA-seq analyses of posttreatment organoids indicated that crizotinib induced significant changes in autophagy-related genes, consistent with the potential pathogenesis of tRCC.ConclusionsWe established and validated organoids derived from tissues dissected from a patient with metastatic tRCC with PRCC-TFE3 fusion and achieved the HTS process for the first time. Crizotinib might be a targeted therapy worthy of exploration in the clinic for metastatic tRCC with PRCC-TFE3 fusion. Such organoid and HTS assays may represent a promising model system in translational research assisting in the development of clinical strategies.