Conventional Renal Cell Carcinoma Research Articles

Molecular characteristics and markers of advanced clear cell renal cell carcinoma: Pitfalls due to intratumoral heterogeneity and identification of genetic alterations associated with metastasis.

To identify clear cell renal cell carcinoma-related gene mutations potentially associated with aggressive disease, sarcomatoid differentiation or poor prognosis. We carried out genomic analysis of 217 tumor foci from 25 patients with conventional clear cell renal cell carcinoma (14 patients), clear cell renal cell carcinoma with sarcomatoid differentiation (six patients) and non-clear cell renal cell carcinoma (five patients). Each tumor nodule on the tissue block that corresponded to the same focus on the slide was separated from the normal parenchyma and other histologically distinct areas of tumor. The isolated tumor foci were used for subsequent analyses and sequencing. Deoxyribonucleic acid from the formalin-fixed paraffin-embedded tissues was extracted. Multiplex bar-coded polymerase chain reaction amplification was carried out using next-generation sequencing libraries. Overall, 67 protein alterations, including amino acid alterations, frame shifts and splice site mutations in seven genes were identified in the cohort of renal cell carcinoma tumors included in this study. Fewer patients with clear cell renal cell carcinoma with sarcomatoid differentiation had clear cell renal cell carcinoma-related mutations in comparison with patients with conventional clear cell renal cell carcinoma. Additionally, the average number of unique clear cell renal cell carcinoma-related protein alterations per patient was significantly lower in clear cell renal cell carcinoma with sarcomatoid differentiation than in conventional clear cell renal cell carcinoma. Mutations in PBRM1 were identified in a higher proportion of patients with high-grade tumors (World Health Organization/International Society of Urological Pathology grade4) and in the primary tumors of six of 10 (60%) patients with metastatic disease. Although there are pitfalls due to intratumoral heterogeneity and sampling bias, mutations in PBRM1 may be associated with metastasis and aggressive disease in clear cell renal cell carcinoma.

Nephron-Sparing Surgery for Adult Xp11.2 Translocation Renal Cell Carcinoma at Clinical T1 Stage: A Multicenter Study in China

PurposeTo evaluate the oncologic efficacy and feasibility of nephron-sparing surgery (NSS) in adult Xp11.2 translocation renal cell carcinoma (RCC).Patients and MethodsSeventy patients with Xp11.2 translocation RCC and 273 with conventional RCC from five institutions in Nanjing were retrospectively studied. All patients were older than 18 years and were categorized into clinical T1 (cT1) stage using preoperative imaging. Using the preoperative imaging and electronic medical records, anatomical and pathological features were collected and analyzed.ResultsAmong patients with Xp11.2 translocation RCC, 18/36 (50.0%) with cT1a and 12/34 (35.3%) with cT1b tumors underwent NSS. The respective proportions in the conventional RCC group were 121/145 (83.4%) and 93/128 (72.7%). Among cT1a tumors, the Xp11.2 translocation RCCs tended to be adjacent to the collecting system, sinus, and axial renal midline compared with conventional RCCs. Patients with Xp11.2 translocation RCCs who underwent NSS had comparable progression-free survival (PFS) and overall survival to radical nephrectomy (RN) patients (P > 0.05). Among cT1b tumors, surgical margin positivity and pelvicalyceal, vascular, and region lymphatic involvement were more likely to occur in the Xp11.2 translocation RCCs (P < 0.05). Patients with Xp11.2 translocation RCC who underwent RN had a more favorable PFS than those who underwent NSS (P = 0.048). However, multivariate analysis of PFS did not identify surgical method as a risk factor (P = 0.089).ConclusionsAmong adults with Xp11.2 translocation RCC, NSS can be an alternative for patients with cT1a tumor but should be performed with more deliberation in patients with cT1b tumors.

Malignant melanotic Xp11 neoplasms exhibit a clinicopathologic spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification.

The classification of the distinct group of mesenchymal neoplasms, first described as 'Xp11 translocation perivascular epithelioid cell tumor (PEComa)' and for which the term 'melanotic Xp11 neoplasm' or 'Xp11 neoplasm with melanocytic differentiation' has recently been proposed, remains challenging and controversial. We collected 27 melanotic Xp11 neoplasms, the largest series to date, for a comprehensive evaluation. Fourteen of the cases, together with eight alveolar soft part sarcomas (ASPS), nine conventional PEComas and a control group of seven normal tissues were submitted to RNA sequencing. Follow-up available in 22 patients showed 5-year overall survival and 5-year disease-free survival of 47.6 and 35.7%, respectively, which were similar to ASPS and significantly worse than conventional PEComa. Univariate analysis of location (occurring in the kidney versus not kidney), infiltrative growth pattern, nuclear pleomorphism, mitotic activity ≥2/50 high-power fields (HPF), necrosis and lymphovascular invasion were found to be associated with overall survival and/or disease-free survival. Multivariate analysis identified that location was the only factor found to independently correlate with disease-free survival. More importantly, RNA sequencing-based clustering analysis segregated melanotic Xp11 neoplasm and ASPS from other tumors, including conventional PEComa and Xp11 translocation renal cell carcinoma, and formed a compact cluster representative of the largely similar expression signature. Here we clearly define the true biologic nature of melanotic Xp11 neoplasms which are distinctive malignant mesenchymal tumors, rather than simply PEComa variants with occasionally unpredictable behavior. Meanwhile, melanotic Xp11 neoplasm and ASPS more likely represent phenotypic variants of the same entity, which is distinct from conventional PEComa and Xp11 translocation renal cell carcinoma. Based on these important findings, melanotic Xp11 neoplasm might be reclassified into a distinctive entity together with ASPS, independent from PEComa, in future revisions of the current WHO categories of tumors of soft tissue and bone for the improved reclassification. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cytoplasmic Expression of AXL Is Associated With High Risk of Postoperative Relapse of Conventional Renal Cell Carcinoma.

Despite early detection by widespread use of abdominal imaging more than 40% of patients with conventional renal cell carcinoma (RCC) will die due to metastatic disease. Small kinase inhibitors for AXL receptor tyrosine kinase may delay the progression of metastatic cRCC. We analysed AXL expression by immunohistochemistry on tissue multi arrays of 691 conventional RCC without metastasis at the time of nephrectomy. The Kaplan-Meier survival analysis indicated a poor disease-specific survival rates for patients with tumour showing cytoplasmic AXL staining, whereas expression on the cell membrane is associated with excellent disease outcome. Multivariate Cox regression analysis identified cytoplasmic AXL expression as an independent prognostic factor indicating a five-times higher risk of postoperative tumour progression (RR=5.048; 95% CI=2.391-10.657; p<0.001). Detecting cytoplasmic expression of AXL can be used to define a subset of conventional RCC with high risk of progression, thus identifying patients for more aggressive surveillance and adjuvant AXL inhibitor treatment as early as possible.

Frequent KRAS mutations in oncocytic papillary renal neoplasm with inverted nuclei

Papillary renal neoplasm with reverse polarity (PRNRP) is a newly documented rare tumour type. Its molecular pathological features have thus far been very little studied. There were 13 PRNRP cases including 3 The Cancer Genome Atlas (TCGA) cases and our 10 cases in this study. The 3 TCGA cases were found by a combined analysis of GATA3 mRNA expression levels and digital slides from the TCGA papillary renal cell carcinoma project. KRAS codon 12 mutations were identified in the three PRNRPs from TCGA. Of our 10 PRNRP cases, the mutations were also discovered using Sanger sequencing in seven (77.8%) of nine cases with available DNA, where KRAS p.G12V (n=3), p.G12D (n=2), p.G12R (n=1) and p.G12C (n=1) alterations were found. PRNRP shared similar gene expression profiles with renal distal tubules via an interprofile correlation analysis. Gene set enrichment analysis revealed that genes involved in 'KEGG aldosterone regulated sodium reabsorption' or 'hallmark apical surface' were enriched in PRNRP. Moreover, polarised immunostaining patterns for L1CAM and EMA in the distal tubule were maintained in PRNRP. These results imply that the tumour potentially originates from the distal tubule, especially from the cortical collecting duct, and probably retains its cell polarity, except for nuclear inversion. We therefore propose that oncocytic papillary renal neoplasm with inverted nuclei (OPRNIN) is a better name for this tumour type. OPRNIN is a kidney site-specific KRAS mutation neoplasm different from conventional papillary renal cell carcinoma.

Expression of RARRES1 and AGBL2 and progression of conventional renal cell carcinoma

BackgroundApproximately 15% of clinically localised conventional renal cell carcinoma (RCC) will develop metastasis within 5 years of follow-up. The aim of this study was to identify biomarkers predicting the postoperative tumour relapse.MethodsTissue microarrays of conventional RCC from a cohort of 691 patients without metastasis at the time of operation were analysed by immunohistochemistry for the expression of carboxypeptase inhibitor RARRES1 and its substrate carboxypeptidase AGBL2. Univariate and multivariate Cox regression models were addressed to postoperative tumour relapse and the metastasis-free survival time was estimated by Kaplan–Meier analysis.ResultsIn multivariate analysis, the lack of staining or cytoplasmic staining of RARRES1 was a significant risk factor indicating five times higher risk of cancer relapse. Combining its co-expression with AGBL2, we found that RARRES1 cytoplasmic/negative and AGBL2-positive/negative staining is a significant risk factor for tumour progression indicating 11–15 times higher risk of cancer relapse, whereas the membranous RARRES1 expression, especially its co-expression with AGBL2, associated with excellent disease outcome.ConclusionsRARRES1 and AGBL2 expression defines groups of patients at low and high risk of tumour progression and may direct an active surveillance to detect metastasis as early as possible and to apply adjuvant therapy.

Similarities and Differences between Clear Cell Tubulo-Papillary and Conventional Clear Cell Renal Cell Carcinoma: A Comparative Phenotypical and Mutational Analysis

Background: Clear cell tubulo-papillary renal cell carcinoma (cctpRCC) is characterized by clear cell morphology, but differs from conventional clear cell carcinoma (ccRCC) for its indolent clinical behavior and genetic background. The differential diagnosis between the two is based on histology and immunohistochemistry (IHC). Methods: We performed a comparative case-control histological, IHC, and genetic analysis by next generation sequencing (NGS), to point out the differences in 10 cases of cctpRCC, and six controls of ccRCC with low stage and grade. Results: All 16 cases showed the IHC profile with cytokeratin 7, racemase, and carbonic anhydrase IX expected for the histological features of each tumor type. By contrast, the NGS mutation analysis that covered 207 amplicons of 50 oncogenes or tumor suppressor genes provided conflicting results. Among the 10 cctpRCC cases, eight (80%) were wild type for all of the genes in the panel, while two (20%) harbored VHL mutations typical of ccRCC. Three of the six (50%) ccRCC control cases showed expected VHL mutations; two (33%) harbored pathogenic mutations in the p53 or the CKIT genes; and one (16%) was wild type. Conclusion: We can assume that histology and ICH are not sufficient for a definitive diagnosis of cctpRCC or ccRCC. Although with a panel covering 50 genes, we found that 80% of cctpRCC were genetically silent; thus, suggesting an indolent biology of these tumors. The differential diagnosis between ccptRCC and ccRCC for the choice of the best therapeutic strategy likely requires the comprehensive evaluation of histology, IHC, and at least VHL mutations.

Pink renal conundrum

A 62-year-old man underwent a right radical nephrectomy for an incidentally discovered right renal tumour. Macroscopic examination of the specimen demonstrated an 11 cm diameter, well-circumscribed, tan-brown, solid tumour with...

Sarcomatoid Chromophobe Renal Cell Carcinoma with Heterologous Component

Clear cell renal cell carcinoma (RCC) is the most common malignant renal tumor in adults, while chromophobe RCC (CRCC) is the third most common. Any subtypes of RCC can undergo sarcomatoid differentiation, but heterologous differentiation in sarcomatoid area is very rare in RCC. Here a 61-year male is presented with hematuria and palpable mass. Clinicoradiologically, RCC was considered and left radical nephrectomy was performed. A well-circumscribed renal mass located in the upper pole of the left kidney with variegation and extensive areas of bony hard calcification noted, was reported as CRCC with sarcomatoid differentiation containing heterologous component. CRCC subtype has good prognosis but show dismal prognosis when associated with sarcomatous differentiation. We found 11 cases of sarcomatoid CRCC containing heterologous elements reported in indexed English literature. CRCC must be differentiated from Conventional RCC and Oncocytoma. The extensive sampling of the tumor is needed. We report a very rare case of CRCC with sarcomatoid differentiation containing heterologous elements.

M2 Macrophage Marker Chitinase 3-Like 2 (CHI3L2) Associates With Progression of Conventional Renal Cell Carcinoma.

In spite of early detection, appoximately 15% of the small renal cell carcinomas (RCC) will develop metastasis within 5 years follow-up. The aim of this study was to identify new biomarkers to estimate the postoperative relapse of the most common conventional RCC. Tissue multi arrays of conventional RCC without metastasis at the time of operation from a cohort of 634 patients were analysed by immunohistochemistry for expression of the chitinase 3-like protein 2 (CHI3L2). Cancer specific survival of patients was estimated with Kaplan-Meier analysis, univariate and multivariate Cox regression models. Kaplan-Meier analysis estimated a shorter cancer-free survival for patients with CHI3L2 positive tumors. In multivariate analysis, the CHI3L2 positivity associated with a 3.5 times higher risk for tumor relapse (p<0.001). Expression of CHI3L2 in tumor cells of conventional RCC define a group of patients at high risk for postoperative progression.

MicroRNA-15a tissue expression is a prognostic marker for survival in patients with clear cell renal cell carcinoma.

None of the currently investigated molecular markers demonstrated sufficient accuracy in prognostication of the renal cell carcinoma (RCC) oncologic outcomes; thus, none of them has been recommended for the application in the routine clinical practice. The role of miR-15a as a potential prognostic marker for RCC is still not unveiled. The aim of our study was to assess the expression of miR-15a in tumor tissues of the patients with RCC and to evaluate the possibility of its usage as a prognostic molecular biomarker of this disease. The retrospective included 64 adult patients with clear cell RCC (ccRCC) in whom radical or partial nephrectomy was conducted. After deparaffinization of formalin-fixed paraffin-embedded (FFPE) ccRCC specimens, the tissue expression of miR-15a was measured using the reverse transcription and quantitative polymerase chain reaction in the real time. For the reference, the expression of miR-15a was estimated in 15 FFPE tissue specimens of the normal renal parenchyma. Survival analysis involved all cases of non-metastatic RCCs (n = 57). Five-year cancer-specific survival (CSS) was estimated by means of the Kaplan-Meier method and was calculated from the date of surgery to the date of death. Patients with the RCC were characterized by significantly upregulated tumor tissue mean levels of miR-15a compared to the healthy controls: 0.10 ± 2.62 relative units (RU) versus 4.84E - 03 ± 3.11E - 03 RU (p < 0.001). Overexpression of miR-15a was strongly associated with poor histologic prognostic features of ccRCC. Poorly differentiated tumors tend to have more pronounced upregulation of miR-15a compared to highly differentiated lesions: Mean expression values were 4.57 ± 3.19 RU for Fuhrman grade 4 versus 0.02 ± 0.01 RU for Fuhrman grade 1 (p < 0.001). The metastatic involvement of the regional lymphatic nodules (N +) was associated with significantly upregulated miRNA-15a in comparison with N - cases: Mean expression values were 4.92 ± 2.80 RU versus 1.10 ± 2.29 RU, respectively (p < 0.001). In patients with miR-15a expression in RCC tissues ≤ 0.10 RU, mean 5-year CSS was significantly longer compared to patients with expression levels above this threshold: 92.31% (mean duration of survival-59.88 ± 0.12months) versus 54.8% (mean duration of survival-49.74 ± 2.16months), respectively (p < 0.001). The tissue expression of miR-15a could be used as a potential prognostic molecular biomarker for conventional RCC.

Abstract 1783: A combination therapy of atypical protein kinase inhibitor and phosphatidylinositol-3- kinase inhibitor reduces multidrug resistance in renal cell carcinoma (RCC)

Abstract Renal Cell Carcinoma (RCC) is the most common type of kidney cancer (85%) of which 75% of the cases involve conventional clear cell RCC (ccRCC). Choice of treatments recommended for clear cell carcinoma and non-clear cell carcinoma are partial nephroctomy (Stage I), radical nephoroctomy (Stage II and III) and chemotherapy (stage IV). Phosphatidylinositol-3- kinase (PI3K) inhibitors are one of the most prospective candidate in the therapy of ccRCC as the PI3CA gene for p110α (a class of the catalytic sub unit of PI3K) is mutated in most of the cases. Hence, PI3K inhibitors like Alpelisib (BYL 719) can be a treatment. But current therapeutic prospects are limited to the fact that RCC is a chemotherapy-resistant cancer type that acts as a barrier for successful treatment with this inhibitor. In addition, of all the other aPKCs, PKC ί/λ and PKC ζ are reported to be frequently overexpressed in most cancer cells and to have different significant roles in tumor progression and carcinogenesis of different type of cancers. Caki-1 metastatic clear cells were treated with PKC ζ inhibitor [8-hydroxynaphthalene-1,3,6-trisulfonic acid] or ζ-stat, Alpelisib and combination of both ζ-stat and Alpelisib at different doses. The results of WST-1 shows that the combination of ζ-stat (7.5 µM) and Alpelisib (10.0 µM) has the most cytotoxicity compared to the single therapy of Alpelisib. Annexin-V/PI assay also suggested that the combination therapy caused greater percentage of apoptosis and cell death compared to the single therapy of Alpelisib. The efflux proteins, (p-glycoprotein (P-gp) and ATP-binding cassette sub-family G member 2 (ABCG2), are responsible for developing cell resistance in Caki-1 cells had reduced expression in the cells when treated with the combination treatment of Alpelisib and ζ-stat. Therefore, combination therapy of Alpelisib and an aPKC inhibitor for metastatic ccRCC can reduce expression of multi drug resistance (MDR) proteins/efflux transporter P-gp and ABCG2. Hence, this combination may be a possible treatment that might help eradicating MDR of ccRCC. Thus, a combination of Alpelisib and an aPKC inhibitor can be a two pronged approach reducing the cell proliferation and resistance. Citation Format: Khandker Mohammad Khalid. A combination therapy of atypical protein kinase inhibitor and phosphatidylinositol-3- kinase inhibitor reduces multidrug resistance in renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1783.

Abstract 3417: Genomic analyses of clear cell papillary kidney cancers reveal large metabolic alterations and activation of the hypoxia pathway

Abstract Tumors arising from the nephron of the kidney are collectively called renal cell carcinomas (RCCs). Recent high-throughput genomics endeavors, such as the TCGA initiative, have provided a roadmap for a deepened molecular understanding of these tumor types. With the aim to characterize RCCs that do not conform to the most common subtypes of RCC we scrutinized RNA-Seq transcriptomes of kidney tumor samples supplied by the TCGA project. Dimensionality reduction analyses revealed one defined a transcriptional subset of RCCs, which upon re-review of tissue histology could be classified as clear cell papillary RCC (ccpRCC). In line with previous analyses, samples were defined by overexpression of KRT7, CA9, CCND1 and GATA3 and harbored few genomic alterations as well as a limited number of gene mutations; only mTOR was found recurrently mutated. We observed upregulation of the Hypoxia inducible factor (HIF) pathway, possibly caused by VHLinactivation by gene promoter methylation in the majority of ccpRCCs. This may explain the morphological resemblance of ccpRCCs to VHL driven conventional clear cell RCCs. Further, the methylomes of ccpRCCs were distinct from other tumors and transcription factors specific for epithelial cells of the distal nephron were overexpressed, thus suggesting distinct tumor ontogeny of ccpRCCs compared to other renal tumors. Citation Format: David Lindgren, Jonas Sjolund, Helen Nilsson, Borje Ljungberg, Martin Johansson, Hakan Axelson. Genomic analyses of clear cell papillary kidney cancers reveal large metabolic alterations and activation of the hypoxia pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3417.

Re: Axitinib versus Placebo as an Adjuvant Treatment of Renal Cell Carcinoma: Results from the Phase III, Randomized ATLAS Trial.

No AccessJournal of UrologyUrological Survey1 Jul 2019Re: Axitinib versus Placebo as an Adjuvant Treatment of Renal Cell Carcinoma: Results from the Phase III, Randomized ATLAS Trial M. Pilar LagunaMD, PhD M. Pilar LagunaM. Pilar Laguna More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000268AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Re: Axitinib versus Placebo as an Adjuvant Treatment of Renal Cell Carcinoma: Results from the Phase III, Randomized ATLAS Trial." The Journal of Urology, 202(1), pp. 27–28 Suggested Reading : Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol 2005; 174: 466. Link, Google Scholar : Clinical characteristics and outcomes of patients with recurrence 5 years after nephrectomy for localized renal cell carcinoma. J Urol 2011; 185: 433. Link, Google Scholar : An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 2002; 168: 2395. Link, Google Scholar : Independent validation of the 2002 American Joint Committee on Cancer primary tumor classification for renal cell carcinoma using a large, single institution cohort. J Urol 2005; 173: 1889. Link, Google Scholar : A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001; 166: 63. Link, Google Scholar : A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. J Urol 2005; 173: 48. Link, Google Scholar : Validation of an integrated staging system toward improved prognostication of patients with localized renal cell carcinoma in an international population. J Urol 2003; 170: 2221. Link, Google Scholar : Symptoms as well as tumor size provide prognostic information on patients with localized renal tumors. J Urol 2004; 172: 2167. Link, Google Scholar © 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 202Issue 1July 2019Page: 27-28 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information M. Pilar Laguna More articles by this author Expand All Advertisement Loading ...

MDM2 amplification and immunohistochemical expression in sarcomatoid renal cell carcinoma

The sarcomatoid variant of renal cell carcinoma is a highly aggressive tumor with propensity for metastasis and limited therapeutic options. Metastases of sarcomatoid renal cell carcinoma can sometimes be mistaken for a variety of spindle cell sarcomas, particularly at soft tissue sites in the absence of a history of a kidney tumor. Immunoreactivity for markers associated with certain types of soft tissue sarcomas can, therefore, pose a pitfall for diagnosis under such circumstances. We evaluated the immunohistochemical and molecular features of 49 cases of sarcomatoid renal cell carcinoma with special emphasis on the expression of MDM2 by immunohistochemistry and MDM2 amplification by fluorescence in situ hybridization. Of the 49 sarcomatoid renal cell carcinoma cases evaluated by fluorescence in situ hybridization, 5 (10%) were positive for MDM2 gene amplification and 5 (10%) contained polysomy 12. Immunohistochemical nuclear expression for MDM2 was also observed in 30/49 (61%) cases; of these, 15/19 (78%) were metastatic and 15/30 (50%) were primary. MDM2 expression by immunohistochemistry has been previously reported in conventional clear cell renal cell carcinoma; however, occurrence of this phenomenon has not yet been properly assessed in the sarcomatoid variant of renal cell carcinoma. Our study demonstrates that alterations of the MDM2 pathway are relatively frequent in sarcomatoid renal cell carcinoma, and nuclear positivity for MDM2 by immunohistochemistry, as well as MDM2 amplification by fluorescence in situ hybridization may pose a potential pitfall for diagnosis with dedifferentiated liposarcoma at metastatic sites. A panel approach to immunohistochemical testing is recommended for the diagnosis of these lesions. Also, identification of cases of sarcomatoid renal cell carcinomas harboring MDM2 copy number gain or gene amplification may also have potential therapeutic implications.

Dual role of KRT17: development of papillary renal cell tumor and progression of conventional renal cell carcinoma.

Expression of KRT17 has been described in multi-layered epithelia as well as in tumors derived from these cells. In cancers arising from KRT17 negative single layered epithelia neo-expression of KRT17 has been associated with tumor progression. To obtain more insight into the biology of kidney cancers we have investigated KRT17 expression by immunohistochemistry in normal kidney, in papillary preneoplastic lesions and in 151 papillary and 692 conventional renal cell carcinomas placed on tissue microarray. We found a positive staining in ureteric bud and collecting duct cells in foetal kidney, in all papillary preneoplastic lesions and also in 77% of the 151 papillary renal cell tumors indicating a continuos KRT17 expression during tumor development. The neo-expression of KRT17 in conventional renal cell carcinomas, which derives from KRT17 negative proximal tubules showed a significant correlation with postoperative tumor relapse (RR=2.50; 95% CI=1.59-3.94; p<0.001). In conclusion, the continuous expression of KRT17 from emerging fetal kidney tubules and microscopic pre-neoplastic lesions towards papillary renal cell tumors and its neo-expression in aggressive growing conventional renal cell carcinomas reflects the multiple function of KRT17 in kidney cancers with distinct natural history. This should be taken into account in clinical managements and therapy.

Diagnostic utility of GATA3 immunohistochemical expression in urothelial carcinoma.

This study aims to explore the utility of GATA binding protein 3, a zinc finger transcription factor, expression in genitourinary carcinoma, especially urothelial carcinoma. It is a prospective study where 74 consecutive cases of urothelial carcinoma along with 10 cases each of prostatic adenocarcinoma (PC) and conventional clear cell renal cell carcinoma were included between August 2016 and January 2017. All the cases were histopathologically evaluated and immunohistochemically stained for GATA binding protein 3. Only nuclear positivity was considered as positive. Immunoreactivity score for GATA expression was calculated based on the staining intensity as well as percentage. The statistical analysis was done using Statistical Package for Social Sciences Version 15.0 statistical analysis software. P value of <0.05 was considered statistically significance. GATA3 expressions were seen in 77% of the cases of urothelial carcinoma, whereas none of the clear cell renal cell carcinoma and prostatic adenocarcinoma cases was GATA3 positive. GATA3 expression significantly correlated with histological grade and muscle invasion with a weaker or negative expression in high-grade muscle invasive tumor as compared to low-grade and noninvasive neoplasm. Significantly weaker expression of GATA3 was found in cases with severe nuclear pleomorphism, mitosis >10/10 hpf, presence of necrosis, and tumor-infiltrating lymphocytes. No significant change in the status of GATA3 expression was seen in follow-up cases between initial Transurethral resection of bladder tumor (TURBT) and post-recurrence TURBT or radical cystectomy specimens. GATA3 as a sensitive and specific marker for urothelial carcinoma can be effectively used to exclude other genitourinary malignancies, PC, and renal cell carcinoma, at metastatic site. This marker can also be effectively used in predicting the probable grade and invasion in biopsy material with poor morphological characteristics, thereby helping in appropriate management in such cases.

Intranuclear inclusions in conventional clear cell Renal Cell Carcinoma (RCC): A case report and review of the literature

Intranuclear inclusions are important diagnostic features in many benign and malignant neoplasms. It has also been identified in major epithelial subtypes of renal cell carcinomas (RCCs), particularly in the chromophobe RCC. However, the finding in ccRCC has not been well studied. The finding of intranuclear inclusions may cause diagnostic difficulty, particularly in metastatic lesions. Herein, we reported a case of ccRCC with prominent intranuclear inclusions. The tumor also metastasized to local lymph nodes. Furthermore, in contrast to previous publications, we also found that intranuclear inclusions were immunoreactive with anti-PAX8 (paired box8) antibody. The potential diagnostic and clinical implications of intranuclear inclusions in ccRCC need to be addressed.

Imaging biomarkers based on multiphase CT data in differentiation of renal cell carcinoma

Background. Renal-cell carcinoma (RCC) is one of 10 mostly widely spread malignant tumors in the world. Recently scientists focused on investigation of new imaging biomarkers of RCC based on USG, CT, MRI and radionuclide examinations data in order to increase efficiency of current pathology diagnostics. The goal of this study was to evaluate an efficiency of application of the novel biomarkers based on multiphase CT in differential diagnostics of RCC. Materials and methods. In total 120 patients with solid renal tumors >4 cm in greatest dimension in whom nephrectomy followed by pathological analysis were enrolled into this retrospective study: 84 (70,0%) with RCC, 14 (11,67%) with transitional cell carcinoma of renal pelvis and 22 (18,33%) with benign renal tumors. We analyzed and compared pathologic and multiphase CT data. Results. Using of signal intensity with threshold 54,80 HU allowed to differentiate RCC from other renal tumors with sensitivity and specificity accordingly 98,8% and 69,4% (AUC=0,844, 95% CI=0,746–0,942, р<0,001) on excretory CT images. Differentiation of RCC and benign renal tumors using signal intensity with threshold of 61,84 HU demonstrated 79,8% sensitivity and 63,6% specificity (AUC=0,745, 95% CІ=0,599–0,891, р<0,001) on excretory CT images. Differentiation of conventional RCC histologic subtype from non-conventional using signal intensity of nephrographic CT images with threshold 79,39 HU was possible with 71,7% specificity and 54,8% sensitivity (AUC=0,718, 95% CІ=0610–0,826, р=0,001). Identification of papillary and chromophobe subtypes as well as Fuhrman grades of clear-cell RCC was also possible. Conclusions. Application of radiodensity of tumor measured using multiphase CT as diagnostic imaging biomarker of solid RCC is valuable clinical tool for differentiation of current pathology, its histologic subtypes and Fuhrman grades. The drawback of the method is relatively high radiation exposure of the patient.

The significance of apparent diffusion coefficient of MRI in early therapeutic response assessment in patients who undergo systemic treatment of renal cell carcinoma

Existing criteria of the systemic treatment assessment in patients with renal cell carcinoma (RCC) do not allow to completely characterize profound changes in tumor tissues which appear due to target agents action, and to prognosticate degree of early therapeutic response.The objective was to define the role of the apparent diffusion coefficient (ADC) of the diffusion-weighted images (DWI) of MRI in early therapeutic response assessment in patients who undergo systemic therapy of advancer RCC.Material and methods. The study involved 32 patients with advanced RCC – main group, and 30 healthy volunteers - control group. In all patients with RCC as the first line of treatment, pazopanib 800 mg per os was administrated on daily basis. In all patients as a baseline (0-5 days prior to beginning of systemic treatment) and control (1 month after, mean 1,10±0,25 months) examination, contrast enhanced MRI with additionally included into scanning protocol DWI sequence with b-values 0 and 800 s/mm2 was performed.Results. We achieved significant difference in mean ADC values after 1 month of treatment in patients’ subgroups: in patients with partial response (PR) mean ADC value was 1,36±0,16×10-3 mm2/s, in cases with stabile disease (SD) it was 1,57±0,12×10-3 mm2/s and in patients with progressive disease (PD) – 1,77±0,06× mm2/s. In subgroup with PR we observed mean decrease of ADC by ↓19,11±10,64% (95% CI=12,35-25,87); in subgroup with SD mean ADC decrease was ↓7,66±6,72% (95% CI=2,86-12,47); in subgroup with PD conversely ADC increased by ↑1,11±2,46% (95% CI=-0,64-2,67), р&lt;0,001. Conclusion. ADC unlike size of the primary tumor objectively reflects early changes which take place in tumor tissues of the advanced conventional RCC under the influence of the systemic treatment with pazopanib and can be used for the assessment of the early therapeutic response.