A Study On The Relativity Of Clinicopathology,Immunohistochemistry,Molecular Genetics And Prognosis About Renal Cell Carcinomas With TFE3 High Expression

Background and ObjectiveXpll translocation renal cell carcinoma is a rare renal cell carcinoma subtype harboring TFE3 translocation with aberrant high expression of TFE3 protein,which is usually diffusely strong positive staining for TFE3 in tumor nuclei by immunohistochemistry staining.It is the only known type of renal cell carcinoma with high expression of TFE3.Although fluorescence in situ hybridization(FISH)is the "gold standard" for diagnosing Xpll translocation renal cell carcinoma,its price and technology requirement is too high to be widely used.At present,the coincidence rate of TFE3 immunohistochemistry and FISH is quite different(0-83%).A standard immunohistochemistry detection system with high sensitivity and specificity is very important for the correct diagnosis of Xpll translocation renal cell carcinoma.Because Xpll translocation renal cell carcinoma is a rare renal neoplasm with a small number of cases,its clinicopathological features,morphological features,immunohistochemistry profiles,molecular genetics and survival need to be further improved.In addition,the expression of TFE3 in other types of renal cell carcinomas remains unclear,which needs further study.In this study,we retrospectively studied the clinicopathological features,morphological features,immunohistochemistry profiles,molecular genetics and survival of Xp11 translocation renal cell carcinoma,as well as the expression of TFE3 in other types of renal cell carcinomas.Meanwhile,the sensitivity and specificity of Ventana BenchMark XT system were evaluated for TFE3 immunohistochemistry in diagnosis of Xp11 translocation renal cell carcinoma.Methods1)Ventana BenchMark XT system was used to TFE3 immunohistochemistry for 1818 consecutive renal cell carcinomas in order to screen out the renal cell carcinomas with TFE3 high expression.The pathological types(Xpll translocation renal cell carcinoma or other types of renal cell carcinomas with TFE3 high expression)were further clarified by pathological morphology,immunohistochemistry and FISH.2)To compare the clinicopathological features,morphological features,immunohistochemistry profiles and survival of the Xpll translocation renal cell carcinoma and other types of renal cell carcinomas with TFE3 high expression.3)RT-PCR and Sanger sequencing were performed on Xpll translocation renal cell carcinoma to identify the known TFE3 fusion gene partners.If no known TFE3 fusion gene partner was detected,further RNA sequencing was performed to explore unknown TFE3 fusion gene partner.RNA sequencing was used to detect other types of renal cell carcinomas with TFE3 high expression for excluding FISH false negative Xpll translocation renal cell carcinoma.Results1)The 27 cases with TFE3 high expression were screened out from 1818 renal cell carcinomas.Among of them,20 cases were diagnosed as Xpll translocation renal cell carcinoma(1.1%),and 7 cases were diagnosed as clear cell renal cell carcinoma(0.4%).2)Applying TFE3 immunohistochemistry by Ventana BenchMark XT system to diagnose Xpll translocation renal cell carcinoma,the sensitivity was 100%(all 20 cases of Xpll translocation renal cell carcinomas were diffusely strong positive for TFE3),and the specificity was 99.6%(1791 cases were negative for TFE3 in 1798 cases of non-Xpll translocation renal cell carcinomas).3)Among 20 cases of Xpll translocation renal cell carcinomas,one case had nodule-in-nodule like pattern,and another case had cytoplasmic eosinophilic granular bodies.4)The pale to eosinophilic flocullent cytoplasm and psammomatous calcification were only found in Xpll translocation renal cell carcinoma,and the frequency was 50%and 40%respectively,which was significantly different from that of clear cell renal cell carcinoma with TFE3 high expression(p<0.05).5)In 20 cases of Xpll translocation renal cell carcinomas,CA-IX was locally positive in 2 cases(10%),and diffusely strong positive in all 7 cases of clear cell renal cell carcinomas with TFE3 high expression.There are significant differences between them(p<0.001).6)Within three years,all 4 patients of Xpll translocation renal cell carcinomas with pT3a stage showed local recurrence and distant metastasis,and 2 of them died.Tumor necrosis occurred in all 4 cases of Xpll translocation renal cell carcinomas with pT3a stage,but it never occurred in other cases of Xpll translocation renal cell carcinomas with non-pT3a stage.7)The 17 cases of Xpll translocation renal cell carcinomas were detected by RT-PCR and Sanger sequencing.Seven cases were ASPL-TFE3 gene fusion,and 8 cases were SFPQ-TFE3 gene fusion,and 2 cases were CLTC-TFE3 gene fusion.No TFE3-related gene fusion was detected by RNA sequencing in 7 cases of clear cell renal cell carcinomas with TFE3 high expression.8)There was no significant difference in clinicopathological features,morphological features,immunohistochemistry profiles and survivals between the 7 ASPL subtypes and 8 SFPQ subtypes of Xp11 translocation renal cell carcinomas.9)Of the 4 patients of Xpll translocation renal cell carcinomas with recurrence and metastasis,2 patients were SFPQ subtypes,and the other 2 patients were ASPL subtypes and died of tumors within 3 years.Conclusions1)Xpll translocation renal cell carcinoma accounted for 1.1%of renal cell carcinomas in our hospital,and there was a few clear cell renal cell carcinomas with TFE3 high expression(0.4%).2)Ventana BenchMark XT system has high sensitivity and specificity for TFE3 immunohistochemistry in diagnosis of Xp11 translocation renal cell carcinoma.3)For the first time,the nodule-in-nodule like pattern and cytoplasmic eosinophilic granular bodies were found in Xpll translocation renal cell carcinoma.4)The pale to eosinophilic flocullent cytoplasm and psammomatous calcification are not only common but also specific in Xpll translocation renal cell carcinoma,which are of great value in differential diagnosis of clear cell renal cell carcinoma with TFE3 high expression from Xp11 translocation renal cell carcinoma.5)CA-IX is a very good immunohistochemistry marker to distinguish Xpll translocation renal cell carcinoma from clear cell renal cell carcinoma with TFE3 high expression.6)The Xpll translocation renal cell carcinomas with pT3a stage have poor short-term prognosis,and are prone to recurrence,metastasis and even death within 3 years after operation.Tumor necrosis is closely related to pT3a stage which morphological evidence should be carefully sought as long as tumor necrosis is found.7)The ASPL subtype of Xpll translocation renal cell carcinoma may have worse prognosis than other subtypes.