In a comprehensive TCGA case series examining renal cell carcinoma, researchers identified the TFE3/Xp11 translocation in 1.2% of RCC cases (8). Describing the specific clinical manifestations of MiT/TFE tRCC can be challenging, with the key diagnostic criteria often stemming from its distinctive pathological features. The three patients examined in this study all presented with MiT/TFE tRCC displaying a distinct histological appearance, featuring polygonal-shaped tumor cells with hyaline eosinophilic cytoplasm. Immunohistochemical analysis ( Table 1 ) revealed that all cases were positive for PAX8 and CK pan, while most were negative for vimentin and cytokeratin 7 (CK7). Additionally, CD10 and methylacyl-CoA racemase (P504S) were both expressed. Case 2 patients exhibited a partial immune response to the melanocyte marker HMB45. Previous studies have suggested that this expression may be attributed to the role of MitF as a melanocyte lineage-specific transcription factor (9). Notably, immunohistochemistry results for this young female patient indicated the presence of both Ksp-cadherin and CD34. While literature reports suggest that MiT/TFE tRCC rarely displays Ksp-cadherin, a marker commonly used in diagnosing chromophobe RCC, the co-expression of these markers in this case may imply a more aggressive biological behavior akin to chromophobe RCC (10). Studies have found that Xp11.2 translocation RCC is a highly vascularized solid RCC characterized by extensive microangiogenesis and lymphangiogenesis. CD34 is identified as the most appropriate vascular marker for microvessel count in Xp11.2 translocation RCC and is linked to prognosis (11). Immunohistochemistry can distinguish MiT/TFE tRCC from other types of renal cancer. While most clear cell RCCs typically show diffuse expression of epithelial markers (cytokeratin and EMA), MiT/TFE tRCC usually displays negative or weakly positive results. The relatively low expression of cytokeratin and vimentin aids in distinguishing MiT/TFE tRCC from tRCC (12). Research has demonstrated that the TFE3 FISH assay serves as a valuable supplementary tool in confirming the diagnosis of MiT/TFE tRCC (13). It is particularly beneficial for cases of MiT/TFE tRCC that present with negative or equivocal pathological or clinical characteristics, as these can be further evaluated through the TFE3 FISH assay (14). The patient in Case 3 underwent FISH testing using TFE3 dual-color probe counting, which detected red and green separation signals. A total of 100 tumor cells were detected, clearly showing TFE3-related translocation. Unfortunately, due to the poor preservation of archived tissue, Cases 1 and 2 could not undergo FISH testing for verification. However, all cases exhibited typical morphological characteristics of TFE3 tRCC and diffuse nuclear positivity for TFE3, consistent with WHO classification diagnostic criteria. The lack of further FISH validation in these cases represents a limitation. The cases we have reported also highlight the importance of conducting prospective FISH validation in clinical practice when immunohistochemistry suggests Mit family translocation renal cell carcinoma, in order to establish precise molecular-level correlations.

Clinical behavior in adults with MiT/TFE tRCC can vary significantly, with studies indicating that advanced TNM stage due to pT status is closely linked to poorer progression-free survival (PFS) and overall survival (OS) (15). The article discusses three patients, two of whom are young with disease-free survival (DFS) of 1 month and 10 months, respectively, all of whom developed liver metastases. It is evident from the patient characteristics ( Table 2 ) that the TNM stage of these two patients is more advanced compared to the first patient, indicating a more aggressive clinical behavior. Notably, one male patient had the highest postoperative pathological stage among the three, potentially contributing to the rapid development of multiple liver metastases. Genomic changes play a significant role in the increased invasiveness of translocation renal cell carcinoma. Sun et al. conducted gene enrichment analysis, revealing potential epigenetic dysregulation in this disease (16). The genetic testing of the patient in case 2 showed a reduction in the copy number of CDKN2A and an increase in the copy number of the MYCN gene. In previous studies involving gene-level copy number analysis, the sole recurrent focal alteration identified in translocation renal cell carcinoma was the homozygous deletion of the CDKN2A/2B locus (9p21.3), occurring in 19.2% of cases (17). Specifically, a clinical study highlighted that reduced somatic copy number of the CDKN2A gene was linked to larger tumors, higher tumor stage, presence of tumor necrosis and microvascular invasion, and could independently predict prognosis (18, 19). The MYCN gene is a disease-causing gene that promotes cell proliferation and apoptosis (20). MYCN gene mutations are predominantly found in neurogenic cancers and are infrequently observed in renal cell carcinoma. Research has indicated that the silencing of MYCN can promote cell migration, while the presence of MYCN and CDKN2A correlates with tumor stage, metastasis, and overall survival in renal cell carcinoma (21). Furthermore, investigations suggest that copy number variations may precede somatic mutations in TFE3-tRCC, potentially influencing the aggressive nature and prognosis of this subtype (22). The disease-free survival (DFS) of case 2 in this study was only 1 month, and liver lesions progressed again 2 months later. We attribute this to their unique genetic mutation. However, due to the limited number of cases in this study, a large-scale comprehensive genomic analysis could not be conducted. The relationship between somatic copy number alterations (SCNA) and survival outcomes requires further investigation to better understand the significant heterogeneity of TFE3-tRCC.

Appropriate treatment strategies for MiT/TFE tRCC are currently unclear. Surgery is the preferred treatment for patients with localized tumors, including those with positive regional lymph nodes (3). The three patients discussed in this article were all in the localized stage at diagnosis and underwent radical nephrectomy. For patients with distant metastases, some retrospective studies and single case reports have shown responses to treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) and mTOR inhibitors. However, outcomes from different series vary, with studies suggesting that multimodal treatment may help extend survival in patients with advanced disease (23, 24). The introduction of combination therapies using immune checkpoint inhibitors, along with a deeper understanding of the molecular characteristics of RCC, has sparked interest in utilizing immunotherapy for this rare disease. A study revealed promising results with the ICIs/VEGFR-TKI combination in MiT/TFE tRCC patients (25). In this article, all three patients received a combination of Axitinib and Toripalimab, leading to disease stabilization in 2 patients after 4 treatment courses. Previous research has also highlighted the advantages of Axitinib, a second-generation VEGF-targeting drug. The median PFS for initial treatment was 9.4 months, while subsequent first-line treatment yielded a median PFS of 7.4 months. The group receiving ICI/VEGFR-TKI demonstrated significantly longer median PFS and median OS compared to other VEGFR-TKI groups (25). These findings suggest that combining targeted therapy with immunotherapy could become a standard approach for treating metastatic MiT/TFE tRCC in the future.