| Objective: To investigate the histological types and clinicopathological features of renal cell carcinoma in end-stage renal disease(ESRD-RCC),and investigate the expression levels of Tuberin,Rheb and p27 in different types of ESRD-RCC and their relationship with clinicopathological features.To analyze the mechanism of acquired cystic disease-associated renal cell carcinoma(ACD-RCC),and provide an important basis for pathological diagnosis,prognosis assessment and treatment of patients.Method: From 2012 to 2022,46 cases of ESRD-RCC were clearly diagnosed at the Affiliated Hospital of Qingdao University,971 Hospital of PLA Navy and Yantai Yuhuangding Hospital were collected,and their relevant clinical information and pathological data were summarized and analyzed.The expression of Tuberin,Rheb and p27 in the above cases were detected by immunohistochemical staining using En Vision method,and to analyze the expression differences between different tissue types and the correlation of protein expression of the three genes.Next-generation sequencing(NGS)was performed on 11 cases of ESRD-RCC to analyze the results of gene variants.Results: 1.Among 46 patients with ESRD-RCC,38 were male and 8 were female,mean age 52.2 years and median age 50 years(25-78 years),maximum tumor diameter ranging from 0.6 cm to 11 cm(mean 4.0 cm,median 3.5 cm),and multifocal in 3 cases.Among the 46 ESRD-RCC cases,the histological type was clear cell renal cell carcinoma(CCRCC)(32/46,69.6%),followed by ACD-RCC(10/46,21.7%).ACD-RCC is a unique histologic subtype of ESRD-RCC.9 of the 10 ACD-RCC cases were treated with dialysis,and 1 case was not treated with dialysis or transplantation.The tumor was grayish-red or grayish-yellow in section,scattered cystic cavities of varying sizes were seen around it.Microscopically,the tumor cells were sieve-like,cyst-like,or glandular vesicle-like in arrangement,with abundant eosinophilic tumor cell cytoplasm and obvious nucleoli.There were 5 cases of WHO/ISUP nuclear grade 2 and 5 cases of grade 3.In 6 cases,calcium oxalate crystals were seen in the interstitium,and 7 cases were accompanied by different degrees of hemorrhage and necrosis.The surrounding renal tissue was highly atrophic,and multiple cystic cavities of varying sizes were seen,some of which were lined with single or multiple layers of epithelial cells with eosinophilic or translucent cytoplasm and obvious nuclei.The majority of immunohistochemistry expressed CD10(8/10)and P504S(9/10),while CK7(3/10)and CA IX(3/10)were not expressed or focally positive.46 ESRD-RCC cases were followed up for 3-128 months,of which 10 cases developed metastasis(21.7%,10/46)and 7 cases died(15.2%,7/46).2.The medium-high expression rates of Tuberin in paraneoplastic tissue,ACD-RCC,CCRCC,and papillary renal cell carcinoma(PRCC)were 89.1%(41/46),90.0%(9/10),53.1%(17/32),and 50.0%(2/4),respectively.The differences in Tuberin expression between non-ACD-RCC(including CCRCC and PRCC)and paraneoplastic tissue and ACD-RCC groups were statistically significant(all P < 0.05);while the differences in expression between paraneoplastic tissue and ACD-RCC were not statistically significant(P > 0.05).3.The medium-high expression rates of Rheb in paraneoplastic tissue,ACD-RCC,CCRCC,and PRCC were 17.4%(8/46),70.0%(7/10),65.6%(21/32),and 75.0%(3/4),respectively.The differences in Rheb expression between paraneoplastic tissues and ACDRCC and non-ACD-RCC were statistically significant(all P <0.05);while the difference in expression between ACD-RCC and non-ACD-RCC was not statistically significant(P >0.05).4.The medium-high expression rates of p27 in paraneoplastic tissue,ACD-RCC,CCRCC,and PRCC were 91.3%(42/46),20.0%(2/10),53.1%(17/32),and 25.0%(1/4),respectively.The expression of p27 was significantly lower in ACD-RCC and non-ACDRCC compared with paracancerous tissues,and the difference was statistically significant(all P < 0.05);while the difference in expression in ACD-RCC and non-ACD-RCC was not statistically significant(P > 0.05).5.Correlation analysis of the expression of Tuberin with Rheb and p27 in each group of ESRD-RCC,ACD-RCC and non-ACD-RCC suggested that the expression of Tuberin did not correlated with Rheb and p27(all P > 0.05).6.The relationship between the expression of Tuberin,Rheb and p27 and the clinicopathological features of ESRD-RCC: Rheb expression was higher in women and ESRD-RCC patients with a maximum tumor diameter of >5 cm,and low expression of Tuberin and p27 often suggested a higher nuclear grade of tumor WHO/ISUP grading(all P < 0.05).The expression levels of Tuberin,Rheb and p27 were not statistically significant in relation to age,side,history of uremia,underlying disease,treatment regimen,whether on dialysis,metastasis and TNM stage(all P > 0.05).7.Univariate analysis showed that patient age,metastasis,WHO/ISUP grading and TNM stage were influential factors in the prognosis of ESRD-RCC patients(all P < 0.05).Multifactorial Cox regression analysis showed that age >50 years and WHO/ISUP grading3-4 were independent risk factors affecting the prognosis of patients with ESRD-RCC(all P < 0.05).8.8 cases of ACD-RCC were detected to contain 42 mutations,including FGFR2,KEAP1,VEGFA,SMARCA4,WT1,NFE2L2,ARID1 A,TP53,KIT,MLH3,EMSY,POLE,SBDS,TERT,PTK2,HGF,BRCA2,GRM8,KDR,IFNGR1,GRM3,SETD2,TNFSF11,MAP3K1,FLCN,EXT1,PDK1,EPHA5,SRC,MTOR,RPTOR,PMS1,ARID1 B,ATM,FGFR1,NTRK3,PIK3 CA,CEP57.It is often associated with the PI3KATK-MTOR signaling pathway,activation of tumor suppressor genes,DNA repair,and mismatch repair.It is worth noting that gene mutations associated with the PI3K-ATKMTOR pathway are the most common.Germline mutations in SBDS exon 2 c.184A>T(p.K62*)were detected in 1 case,FLCN gene mutation in 2 cases,ARID1 A gene mutation in 2 cases,GLRA1-FGFR2 fusion gene in 1 case,MTOR gene mutation in 1 case,and TSC2 gene mutation was not detected in any of the 8 cases.Mutations in the VHL gene were detected in two of the three CCRCC cases,and a germline mutation in PRF1 exon 3c.1228C>T(p.R410W)was detected in 1 case.Conclusion:1.ESRD-RCC is rare,with a significantly higher incidence in men than in women,and age is mostly ≤50 years.The tumor volume is usually small(≤5 cm),and the histological types include CCRCC,ACD-RCC and PRCC,among which ACD-RCC has a higher WHO/ISUP grade and more severe hemorrhage and necrosis.2.Tuberin was differentially expressed in different histological types of ESRD-RCC,where it was high expressed in ACD-RCC and low expressed in non-ACD-RCC.p27 protein was down-regulated or absent in ESRD-RCC,the down-regulation of Tuberin and p27 protein were correlated with the malignancy of the tumor.Rheb expression was significantly higher in ESRD-RCC than in paraneoplastic tissues,and the high expression of Rheb affected the tumor progression.3.>50 years old and high nuclear grade(WHO/ISUP grade 3-4)were independent risk factors affecting the prognosis of ESRD-RCC patients.4.The results of second-generation sequencing indicate that the pathogenesis of ACDRCC is complex and there are often mutations in multiple genes,especially multiple gene variants such as FLCN,ARID1 A,FGFR2,PIK3 CA associated with m TOR pathway activation may play important roles in the development of ACD-RCC.The discovery of the GLRA1-FGFR2 fusion gene and mutations in MTOR and RPTOR genes provides a new theoretical basis for targeted therapy and immunotherapy of this tumor. |
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