PURPOSE:To report the clinicopathological features and mid- to long-term oncologic results of Xp11.2 translocation/transcription factor E3 (TFE3) gene fusion renal cell carcinomas (Xp11.2 translocation RCCs) in a single large-volume centrecentre. METHODS:Clinical and follow-up data of 46 patients who were diagnosed with Xp11.2 translocation RCC and underwentunderwent surgical intervention were retrospectively reviewed. RESULT:Forty-six Xp11.2 translocation RCC patients were identified from 4218 renal tumour patients who were underwentunderwent surgery in our centrecentre from Jan. 2014 to Apr. 2020. The incidence of Xp11.2 translocation RCCs in our centre was 1.09%. During a median follow-up period of 30.5 months, 4 patients died of the disease. The total median overall survival and cancer specific survival were 30.0 months and 24.0 months, respectively. The 1-year, 3-year and 5-year OS rates were 97.4%, 88.8%, and 88.8%, respectively. In multivariable analysis, displaying symptoms when diagnosed (p = 0.019), lymph node metastasis (p = 0.002) and distal metastasis (p = 0.020) were identified as risk factors for poor prognosis. CONCLUSION:Xp11.2 translocation RCC is a type of renal cell carcinoma with a relatively low incidence and various prognoses. Early-stage Xp11.2 translocation RCCs have a similar prognosis to most typical RCCs, but late-stage Xp11.2 translocation RCCs can lead to poor oncological outcomes.

OBJECTIVES:To investigate the impact of TFE3 rearrangement, analyzing clinicopathological features that influence renal cell carcinoma (RCC) recurrence, and clarify the role of immunohistochemistry (IHC) staining in diagnosis. METHODS:We screened patients diagnosed of clear cell RCC (ccRCC), fluorescence in situ hybridization (FISH) was performed on all TFE3 positive IHC tumors. Clinicopathological and survival features were collected for analysis. RESULTS:Out of 695 patients treated for renal tumors, 478 (68.7%) were ccRCC and 22 were suspected of TFE3 rearrangement based on IHC. Subsequent testing revealed 8 (1.15%) were positive in the FISH test (TFE3-rearranged-RCC) and 14 (2.01%) tested negative. No significant differences were noted in general characteristics among the three groups, except for age, TFE3-rearranged-RCC were younger than ccRCC (median age, 49 vs. 58 years, p=0.02). TFE3-rearranged-RCC exhibited a significant higher recurrence rate compared to ccRCC (50% vs 18.8%) and multivariate analysis revealed that TFE3 rearrangement, along with tumor size and metastasis, was an independent prognostic factor for recurrence (HR=4.6; 95% CI 1.1-21.2; p=0.05). Survival analysis demonstrated a significant shorter PFS (progression-free survival) for TFE3-rearranged-RCC compared to ccRCC. CONCLUSIONS:TFE3 rearrangement is an independent prognostic factor for recurrence and contributes to a worse PFS, suggesting the necessity of careful follow-up. Diagnosis should be confirmed using FISH due to low specificity of IHC. Further studies are needed to confirm TFE3 IHC staining as a prognostic factor.

To investigate the clinical characteristics, treatments and prognosis of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 tRCC), the epidemiological features and treatment results of 34 cases of Xp11.2 tRCC, which were diagnosed by immunohistochemistry staining of TFE3 and fluorescence in situ hybridization at our center, were retrospectively reviewed. The 34 patients included 21 females and 13 males aged 3 to 64 years (median age: 27 years). Four patients were children or adolescents (<18 years of age), and 26 patients were young or middle-aged adults (18-45 years). Radical nephrectomy was performed on 25 patients. Laparoscopic nephron-sparing surgery was performed on 9 patients who presented with an isolated mass with a small diameter (<7 cm) and well-defined boundary on computed tomography imaging. Postoperative staging showed that 25 cases (73.53%) were at stage I/II, while 9 cases (26.47%) were at stage III/IV. All stage I/II patients received a favorable prognosis with a three-year overall survival rate of 100%, including the patients who underwent laparoscopic nephron-sparing surgery. With the exception of 2 children, the other 7 stage III/IV patients died or developed recurrence with a median follow-up of 29 months. On univariate analysis, maximum diameter, adjuvant treatment, TNM stage, lymph node metastasis, inferior vena cava tumor thrombosis and tumor boundary were identified as statistically significant factors impacting survival (P<0.05). Multivariate analysis indicated that TNM stage and inferior vena cava tumor thrombosis were independent prognostic factors (P<0.05). In conclusion, Xp11.2 tRCC is a rare subtype of renal cell carcinoma that mainly occurs in young females. Nephron-sparing surgery was confirmed effective preliminarily in the treatment of small Xp11.2 tRCCs with clear rims. Advanced TNM stage and inferior vena cava tumor thrombosis were associated with poor prognosis.

OBJECTIVE:This study aims to establish an effective predictive model for predicting Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma (TFE3-RCC) and develop optimal therapeutic strategies. METHODS:Data from 4961 patients diagnosed with renal cell carcinoma at two medical centers in China were retrospectively analyzed. A cohort of 1571 patients from Zhejiang Provincial People's Hospital (Ra cohort) was selected to construct the model. Another cohort of 1124 patients from the Second Affiliated Hospital of Zhejiang Chinese Medical University was used for external validation (the Ha cohort). All patients with TFE3-RCC in both cohorts were included in the Ta cohort for the prognostic analysis. Univariate and multivariate binary logistic regression analyses were performed to identify independent predictors of the predictive nomogram. The apparent performance of the model was validated. Decision curve analysis was also performed to assess the clinical utility of the developed model. Factors associated with progression and prognosis in the Ta cohort were analyzed using the log-rank method, and Cox regression analysis and Kaplan-Meier survival curves were used to describe the effects of factors on prognosis and progression. RESULTS:Univariate and multivariate logistic regression analyses demonstrated that age, sex, BMI, smoking, eosinophils, and LDL were independent predictors of TFE3-RCC. Therefore, a predictive nomogram for TFE3-RCC, which had good discriminatory power (AUC = 0.796), was constructed. External validation (AUC = 0.806) also revealed good predictive ability. The calibration curves displayed good consistency between the predicted and observed incidences of TFE3-RCC. Invasion of regional lymph nodes, tyrosine kinase inhibitors, and surgical methods were independent factors associated with progression. Tyrosine kinase inhibitors are independent prognostic factors. CONCLUSION:This study not only proposed a high-precision clinical prediction model composed of various variables for the early diagnosis of Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma but also optimized therapeutic strategies through prognostic analysis.

TFE3 is accepted as a good marker for the diagnosis of Xp11 translocation renal cell carcinoma. However, the significance of TFE3 in other types of renal cell carcinomas remains unclear. We examined the expression of TFE3 using immunohistochemistry by automated Ventana BenchMark XT system in 1818 consecutive renal cell carcinomas and verified the strong positive cases with TFE3 break-apart fluorescence in situ hybridization and RNA sequencing. Among the 27 renal cell carcinomas with TFE3 strong positive immunostaining, 20 cases were diagnosed as Xp11 translocation renal cell carcinoma, and seven cases were diagnosed as clear cell renal cell carcinoma. We further analyzed the morphology, clinicopathological features, and immunohistochemistry markers (CK7, CD117, CD10, P504s, vimentin, CA-IX, AE1/AE3, EMA, HMB45, Melan-A, and cathepsin K) of them. Pale to eosinophilic flocculent cytoplasm and psammomatous calcification were seen only in Xp11 translocation renal cell carcinomas (P < 0.05). Tumor necrosis occurred in all four cases of Xp11 translocation renal cell carcinomas with pT3a stage, which had local recurrence and distant metastasis (two of them died) within 3 years. The expressions of Vimentin, CA-IX, AE1/AE3, and EMA were significantly different between them (P < 0.05). CA-IX was diffusely strong positive in clear cell renal cell carcinomas but negative or focally mild positive in Xp11 translocation renal cell carcinomas. Our study first demonstrates that a very small minority (0.4%) of clear cell renal cell carcinomas with TFE3 strong positive immunostaining, which points out a potential pitfall in diagnosis of Xp11 translocation renal cell carcinomas by TFE3 immunohistochemistry. CA-IX is a good marker to distinguish clear cell renal cell carcinoma with TFE3 strong positive immunostaining from Xp11 translocation renal cell carcinoma. Tumor necrosis could be a potential factor relevant to pT3a stage, which may be a high-risk factor for the patients with Xp11 translocation renal cell carcinomas.

OBJECTIVE:To explore the clinicopathological features and prognosis of TFE3-rearranged renal cell carcinomas (TFE3-rRCC). METHODS:In this retrospective observational study, the data of patients with TFE3-rRCC admitted to Xijing Hospital from January 2010 to October 2023 were collected, encompassing the general information, pathological diagnosis, immunohistochemistry, and the results of FISH detection. The treatment information and survival data of the patients were recorded during the follow-up. RESULTS:A total of 55 patients with TFE3-rRCC were enrolled, among whom 25 were males and 30 were females. TFE3 FISH assay suggested the disruption of the TFE3 gene. Fifty-four patients underwent surgical resection of kidney lesions, while 1 patient did not. By the end of follow-up in December 2023, 3 patients were lost to follow-up, 28 patients remained alive, and 24 patients had died. Among the 52 patients followed up, 31 developed metastases, involving lymph nodes, liver, bone, lung, peritoneum, pleura, adrenal gland, and brain. The 1-year and 5-year survival rates of the patients were 84.6% and 50.6%, respectively. In this study, there were 31 patients with TFE3-rRCC recurrence or metastasis. Median PFS was 7 and 13 months in the VEGFR-TKI and VEGFR-TKI+ ICI groups, respectively. The median OS was 12 months in the VEGFR-TKI treatment group. The median OS data of VEGFR-TKI+ ICI group has not been reached. The ORR and DCR was 25%, 66.7% in the VEGFR-TKI group. The ORR and DCR was 33.3%, 77.8% in the VEGFR-TKI+ ICI group. CONCLUSION:TFE3-rRCC is a rare subtype of malignant renal tumor. The diagnosis mainly relies on pathological morphology, immunohistochemistry, and the detection of TFE3 gene disruption by FISH. In terms of treatment, surgery is the primary approach, and lymph nodes, liver, and bone are the main metastatic sites. VEGFR-TKI+ICI treatment might be an option of recurrent or metastatic TFE3-rRCC.

BACKGROUND:TFE3 immunohistochemistry (TFE3-IHC) is controversial in the diagnosis of TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC). This study is to investigate the accuracy and sensitivity of IHC and establish a predictive model to diagnose TFE3-rearranged RCC. METHODS:Retrospective analysis was performed by collecting IHC and fluorescence in situ hybridization (FISH) results from 228 patients. IHC results were evaluated using three scoring systems. Scoring system 1 is graded based on nuclear staining intensity, scoring system 2 is graded based on the percentage of stained tumor cell nuclei, and scoring system 3 is graded based on both the nuclear staining intensity and the percentage. We collected patients' IHC results and clinical information. Important variables were screened based on univariate logistic regression analysis. Then, independent risk factors were established through multivariate logistic regression, and a nomogram model was constructed. The model was validated in internal test set and external validation set. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) were generated to assess discriminative ability of the model. RESULTS:The accuracy of IHC based on three scoring systems were 0.829, 0.772, and 0.807, respectively. The model included four factors including age, gender, lymph node metastasis and IHC results. Area under the curve (AUC) values were 0.935 for the training set, 0.934 for the internal test set, 0.933 for all 228 patients, and 0.916 for the external validation set. CONCLUSIONS:TFE3 IHC has high accuracy in the diagnosis of TFE3-rearranged RCC. Clinical information such as age and lymph node metastasis are independent risk factors, which can be used as a supplement to the results of TFE3 IHC. This study confirms the value of IHC in the diagnosis of TFE3-rearranged RCC. The accuracy of the diagnosis can be improved by incorporating IHC with other clinical risk factors.

BACKGROUND:TFE3-rearranged renal cell carcinoma (TFE3-rRCC) harbors gene fusions involving TFE3 with one of many different partner genes. Because of their diverse morphologies, the differential diagnosis is broad and challenging. Publications focusing on the cytomorphology of TFE3-rRCC are sparse. METHODS:Fifteen cytology cases of TFE3-rRCC from 12 patients were retrieved, comprising seven primary kidney cases and eight metastatic cases. RESULTS:Cytology smears showed tumor cells with moderate granular or vacuolated cytoplasm, arranged in diverse patterns, such as three-dimensional clusters, nested/sheeted formations, isolated cells, papillary, and tubular/acinar structures. The tumor cells exhibited enlarged eccentric, round or oval nuclei, possibly situated peripherally, with small to prominent nucleoli and irregular nuclear membranes. Macrophages, hyalinized globules, or necrosis were occasionally seen. Core and cell block histology often showed papillae with surface-oriented nuclei. Tumor cells were also arranged in nested, sheeted, and tubular patterns. Tumor cells were immunoreactive to TFE3 (100%), AMACR (100%), PAX8 (88%), and CD10 (83%) and showed focal staining for CA9 (64%), CK7 (20%), and CD117 (25%). TFE3 rearrangement was confirmed in 13 of 15 cases through fluorescence in situ hybridization or RNA fusion next-generation sequencing testing. Metastasis was observed in nine of 12 patients (80%), with retroperitoneal lymph nodes being the most common site, followed by distant lymph nodes, lung, brain, adrenal gland, and bone. Six patients (50%) underwent nephrectomy alone, two patients (17%) received chemotherapy alone, and four patients (33%) received combined nephrectomy and chemotherapy. CONCLUSIONS:Timely recognition of TFE3-rRCC's distinct cytomorphologic and histomorphologic features is essential for accurate diagnosis and effective treatment.

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 ( = 0.011), higher neutrophil/lymphocyte ratio (NLR) ( = 0.017) and metastatic potential ( = 0.022), and worse overall survival (OS) ( = 0.043) and PFS ( = 0.016). The survival analysis showed that TFE3-rearranged RCC had a worse PFS than ccRCC ( = 0.002), and TFE3(+) RCC had a worse PFS than TFE3(-) RCC ( = 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 ( = 0.001) and PFS ( < 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.

Background:This study aimed to investigate the expression profile of TFE3 in renal cell carcinoma (RCC) and the clinicopathological features as well as prognosis of TFE3-positive RCC. Methods:Tissue sections from 796 patients with RCC were collected for immunohistochemical staining of TFE3. Molecular TFE3 rearrangement tests were also carried out on the TFE3-positive RCCs using fluorescence hybridization and RNA-sequencing assays. Both clinicopathological features and follow-up information were collected for further analysis. Results:The present study showed that 91 patients with RCC (91/796, 11.4%) were TFE3 positive expression but only 31 (31/91, 34.1%) of the patients were diagnosed with Xp11.2 translocation RCC. Further, it was found that the patients with TFE3-positive RCCs were more likely to develop lymph node and distant metastasis at diagnosis as well as presented a significantly higher WHO/ISUP nuclear grade and AJCC stage as compared with patients with TFE3-negative RCCs (<0.01). Results of univariate and multivariate analyses showed that TFE3 positive expression was an independent prognostic factor associated with poor progression-free survival. Further, the findings of survival analysis showed that patients with positive TFE3 expression showed a shorter progression-free survival as compared with the patients with negative expression of TFE3 (<0.001). In addition, results of the survival analysis found that there was no significant difference in progression-free survival between the Xp11.2 translocation RCC and TFE3-positive non-Xp11.2 translocation RCC groups (=0.9607). Conclusion:This study found that nuclear TFE3 expression is not specific to the Xp11.2 translocation RCC. Moreover, the positive TFE3 expression is associated with tumor progression and poor prognosis in patients with RCC irrespective of the presence of TFE3 translocation.