Alpha-methyl CoA racemase (AMACR) reactivity across the spectrum of clear cell renal cell neoplasms.

a-Methylacyl coenzyme A racemase (AMACR) is traditionally considered to be a marker of papillary renal cell carcinoma. However, AMACR expression can be seen in other renal tumors. The aim of this study was to investigate AMACR immunoreactivity within the spectrum of clear cell renal cell neoplasms. Fifty-three clear cell renal epithelial tumors were used in assembling the following four cohorts: low grade (LG) clear cell renal cell carcinoma (CCRCC), high grade (HG) CCRCC, CCRCC with cystic changes, and multilocular cystic renal neoplasm of low malignant potential (MCRNLMP). Representative blocks were stained for AMACR, using two different clones (SP52 and OV-TL12/30). There were at least some AMACR immunoreactivity in 77.8 % and 68.9 % of CCRCCs (using SP52 and OV-TL12/30 clone, respectively). Moderate to strong positivity, or positivity in more than one third of the tumor (even weak in intensity) was detected in 46.7 % of CCRCCs using SP52 and in 48.9 % of CCRCC using OV-TL12/30 clone. The highest AMACR reactivity was observed in HG CCRCC (60 % by SP52 and 66.7 % by OV-TL12/30). Strong and diffuse AMACR positivity was detected in 8.9 % of all CCRCCs. AMACR immunoreactivity in MCRNLMP was 37.5 % (SP52 clone) and 25 % (OV-TL12/30 clone). We demonstrated relatively high expression rate of AMACR in CCRCC, while very variable in intensity and distribution. This finding may have diagnostic implications especially in limited samples (i.e., core biopsies), as AMACR positivity does not exclude the diagnosis of CCRCC.

Concomitant antihypertensive medication and outcome of patients with metastatic castration-resistant prostate cancer receiving enzalutamide or abiraterone acetate.

BACKGROUND: The introduction of novel hormonal therapies represented by enzalutamide (ENZ) and abiraterone acetate (ABI) has reached a great progress in the treatment of metastatic castration-resistant prostate cancer (mCRPC). The majority of mCRPC patients are elderly suffering from chronic co-morbidities requiring use of various concomitant medications. In the present study, we focused on impact of concomitant antihypertensive medication on the outcomes of mCRPC patients treated with ENZ or ABI. METHODS: In total, 300 patients were included and their clinical data were retrospectively analyzed. RESULTS: Angiotensin-converting enzyme inhibitors (ACEIs) represented the only concomitant medication significantly associated with survival. The median radiographic progression-free survival (rPFS) and overall survival (OS) for patients using ACEIs were 15.5 and 32.3 months compared to 10.7 and 24.0 months for those not using ACEIs (p = 0.0053 and p = 0.0238, respectively). Cox multivariable analysis revealed the use of ACEIs a significant predictive factor for both rPFS (HR = 0.704, p = 0.0364) and OS (HR = 0.592, p = 0.0185). CONCLUSION: The findings of this study suggest an association between the concomitant use of ACEIs and longer survival of mCRPC patients receiving ENZ or ABI therapy.

Association of lncRNA and transcriptome intersections with response to targeted therapy in metastatic renal cell carcinoma.

Long non-coding RNAs (lncRNAs) serve an important role in cancer progression and may be used as efficient molecular biomarkers. The present study aimed to identify lncRNAs associated with the response to the receptor tyrosine kinase inhibitor sunitinib and transcriptome profile and clinical features of metastatic renal cell carcinoma (mRCC). The gene expression of 84 cancer-associated lncRNAs in tumor and non-malignant tissue samples of 38 patients with mRCC was evaluated using quantitative PCR. In addition, the coding transcriptome was estimated using RNA sequencing in a subgroup of 20 patients and mRNA-lncRNA intersections were identified. In total, 37 and 13 lncRNAs were down- and upregulated, respectively, in tumor compared with non-malignant adjacent tissue samples. A total of 10 and 4 lncRNAs were up- and downregulated, respectively, in good responders to sunitinib compared with poor responders. High expression of HNF1A-AS1 and IPW lncRNAs was associated with prolonged progression-free survival of patients and a high expression of the TUSC7 lncRNA was associated with poor response and worse survival. Significant associations of dysregulated MEG3 and SNHG16 lncRNAs with expression of protein-coding genes representing various pathways, were identified. Furthermore, a significantly higher expression of CLIP4 gene was observed in good responders. The present study revealed promising candidates for predictive and prognostic biomarkers with further therapeutic potential.

Lynch syndrome-associated upper tract urothelial carcinoma frequently occurs in patients older than 60 years: an opportunity to revisit urology clinical guidelines.

Upper tract urothelial carcinoma (UTUC) is the third most common malignancy associated with Lynch syndrome (LS). The current European urology guidelines recommend screening for LS in patients with UTUC up to the age of 60 years. In this study, we examined a cohort of patients with UTUC for potential association with LS in order to establish the sensitivity of current guidelines in detecting LS. A total of 180 patients with confirmed diagnosis of UTUC were enrolled in the study during a 12-year period (2010-2022). Loss of DNA-mismatch repair proteins (MMRp) expression was identified in 15/180 patients (8.3%). Germline analysis was eventually performed in 8 patients confirming LS in 5 patients (2.8%), including 4 germline mutations in MSH6 and 1 germline mutation in MSH2. LS-related UTUC included 3 females and 2 males, with a mean age of 66.2 years (median 71 years, range 46-75 years). Four of five LS patients (all with MSH6 mutation) were older than 65 years (mean age 71.3, median 72 years). Our findings indicate that LS-associated UTUCs can occur in patients with LS older than 60 years. In contrast to previous studies which used mainly highly pre-selected populations with already diagnosed LS, the most frequent mutation in our cohort involved MSH6 gene. All MSH6 mutation carriers were > 65 years, and UTUC was the first LS manifestation in 2/4 patients. Using current screening guidelines, a significant proportion of patients with LS-associated UTUC may be missed. We suggest universal immunohistochemical MMRp screening for all UTUCs, regardless of age and clinical history.

The 2022 Updated European Association of Urology Guidelines on the Use of Adjuvant Immune Checkpoint Inhibitor Therapy for Renal Cell Carcinoma.

In KEYNOTE-564, adjuvant pembrolizumab, a PD-1 antibody, significantly improved disease-free survival (DFS) in localised clear-cell renal cell carcinoma (ccRCC) with a high risk of relapse. In 2021, the European Association of Urology RCC Guidelines Panel issued a weak recommendation for adjuvant pembrolizumab for high-risk ccRCC as defined by the trial until final overall survival data and results from other trials were available. Meanwhile, the primary DFS endpoints were not met for adjuvant atezolizumab (PD-L1 inhibitor; IMmotion010), adjuvant nivolumab plus ipilimumab (CheckMate 914), or perioperative nivolumab (PROSPER). Owing to heterogeneity, a meta-analysis is not recommended. Pembrolizumab remains the only immune checkpoint inhibitor currently recommended in this setting. Overall survival data are immature and biomarkers to predict outcome are lacking. Uncertainty exists and overtreatment is occurring. Treatment decisions should be made with caution and with the involvement of each patient. PATIENT SUMMARY: New results from three trials of immunotherapy after surgery for kidney cancer to reduce the risk of recurrence showed no improvement with these treatments. These results are in contrast to an earlier study that showed that the antibody pembrolizumab did extend the time before kidney cancer recurrence, even though it is not yet clear if overall survival is longer. Thus, we cautiously recommend pembrolizumab as additional treatment in high-risk kidney cancer after surgery, but patient preference should be carefully considered and the risk of overtreatment should be discussed.

European Association of Urology Guidelines Panel on Renal Cell Carcinoma Update on the New World Health Organization Classification of Kidney Tumours 2022: The Urologist's Point of View.

The fifth edition of the World Health Organization (WHO) classification of urogenital tumours published in 2022 will be implemented in the European Association of Urology guidelines on renal cell carcinoma for 2023. Here we provide an update summarising changes in the new WHO classification of renal tumours from a clinician perspective.

Enzalutamide or Abiraterone Acetate With Prednisone in the Treatment of Metastatic Castration-resistant Prostate Cancer in Real-life Clinical Practice: A Long-term Single Institution Experience.

BACKGROUND/AIM: Enzalutamide (ENZ) and abiraterone acetate with prednisone (AAP) represent novel hormonal therapies used in the treatment of metastatic castration-resistant prostate cancer (mCRPC). The aim of the study was to assess the long-term outcome of mCRPC patients treated with ENZ or AAP in real-life clinical practice. PATIENTS AND METHODS: The outcomes of 337 mCRPC patients treated with ENZ or AAP were retrospectively analysed. RESULTS: Median radiographic progression-free (rPFS) and overall survival (OS) of patients treated in the first line (pre-chemotherapy) was 13.89 (95% CI=12.40-16.80) and 31.02 (95% CI=24.27-37.44) months vs. 10.97 (95% CI=8.97-14.82) and 26.57 (95% CI=15.97-33.92) months for those treated in the second line (post-chemotherapy). We found inferior survival for patients with synchronous metastases, high Gleason score (GS) and visceral metastases. CONCLUSION: The efficacy of both ENZ and AAP in mCRPC patients is herein confirmed. Synchronous metastases, high GS and visceral metastases were identified as significant adverse prognostic factors.

Assessment of Prostate Carcinoma Aggressiveness: Relation to 68Ga-PSMA-11-PET/MRI and Gleason Score.

BACKGROUND/AIM: To test the correlation of 68Ga-PSMA-11 uptake and the expression of PSMA (prostatic specific membrane antigen) with the Gleason score, apparent diffusion coefficient (ADC) and pharmacokinetic parameters obtained from dynamic contrast agent-enhanced MRI/PET. PATIENTS AND METHODS: Forty newly diagnosed, therapy naïve patients with prostatic carcinoma (PC) (mean age of 56.7, range=34-79), who were referred for 68Ga-PSMA-11-PET/MRI for primary staging and had undergone radical prostatectomy (RAPE) were included in this prospective study. Their blood samples were tested for serum levels of prostate-specific antigen (PSA) and proPSA. The patients' prostates were evaluated using whole-mount sections, which helped determine the extent and grade of the tumor; tests were performed to determine immunohistochemical PSMA expression. RESULTS: A correlation between PSMA expression and the accumulation of 68Ga-PSMA-11 was found using the Spearman correlation coefficient (p=0.0011). A stronger correlation was found between Gleason patterns 3 or 4 and PSMA expression (p=0.06). Furthermore, the correlation of Gleason score with the overall 68Ga-PSMA-11 accumulation within the tumor or non-tumor tissue was found to be significant (p=0.0157). A significant relation was found only with the Kep elimination rate constant, which was stronger in Gleason pattern 4 than in Gleason pattern 3. A weaker correlation was found between the accumulation of 68Ga-PSMA-11 and Ktrans in Gleason pattern 4: the most significant relation being between ADCmin and Gleason pattern 3 and 4 (p=0.0074). The total size of the tumor correlated with levels of proPSA (p<0.0001), and its extra prostatic extension correlated with levels of proPSA (p<0.0001). CONCLUSION: 68Ga-PSMA-11 correlates well with the expression of PSMA. Gleason pattern 3 and 4 had a higher correlation with 68Ga-PSMA-11 levels than did Gleason pattern 5. Either no correlation, or a weak correlation, was established with pharmacokinetics.

A Renewal of the TNM Staging System for Patients with Renal Cancer To Comply with Current Decision-making: Proposal from the European Association of Urology Guidelines Panel.

Over the past decade, only minor changes have been introduced in the TNM staging system for renal cancer. Conversely, many milestones and modifications in management of the disease have been achieved, especially for patients with locally advanced and metastatic cancers. The European Association of Urology guidelines panel proposes a new TNM classification scheme for staging of renal cell carcinoma to reflect these breakthrough clinical improvements.

Histologic diversity in chromophobe renal cell carcinoma does not impact survival outcome: A comparative international multi-institutional study.

Predicting the clinical behavior and trajectory of chromophobe renal cell carcinoma (ChRCC) by histologic features has so far proven to be challenging. It is known that ChRCC represents a heterogeneous group of neoplasms demonstrating variable, yet distinctive morphologic and genetic profiles. In this international multi-institutional study, we aimed to assess the impact of histologic diversity in ChRCC (classic/eosinophilic versus rare subtypes) on survival outcome. This is an international multi-institutional matched case-control study including 14 institutions, examining the impact of histologic subtypes of ChRCC on survival outcome. The study group (cases) included 89 rare subtypes of ChRCC. The control group consisted of 70 cases of ChRCC including classic and eosinophilic features, age- and tumor size-matched. Most of the rare subtypes were adenomatoid cystic/pigmented ChRCC (66/89, 74.2%), followed by multicystic ChRCC (10/89, 11.2%), and papillary ChRCC (9/89, 10.1%). In the control group, there were 62 (88.6%) classic and 8 (11.4%) eosinophilic ChRCC. There were no statistically significant differences between the study and control groups for age at diagnosis, gender distribution, tumor size, presence of tumor necrosis, presence of sarcomatoid differentiation, and adverse outcomes. No statistically significant differences were found in clinical outcome between the rare subtypes and classic/eosinophilic groups by tumor size, necrosis, and sarcomatoid differentiation. Further, no statistically significant differences were found in clinical outcome between the two groups, stratified by tumor size, necrosis, and sarcomatoid differentiation. Our findings corroborated previous studies that both sarcomatoid differentiation and tumor necrosis were significantly associated with poor clinical outcome in classic/eosinophilic ChRCC, and this was proven to be true for ChRCC with rare histologic subtypes as well. This study suggests that rare morphologic patterns in ChRCC without other aggressive features play no role in determining the clinical behavior of the tumor.

European Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update.

CONTEXT: The European Association of Urology (EAU) Renal Cell Carcinoma (RCC) Guideline Panel has prepared evidence-based guidelines and recommendations for the management of RCC. OBJECTIVE: To present a summary of the 2022 RCC guideline, which is based on a standardised methodology including systematic reviews (SRs) and provides transparent and reliable evidence for the management of RCC. EVIDENCE ACQUISITION: For the 2022 update, a new literature search was carried out with a cutoff date of May 28, 2021, covering the Medline, EMBASE, and Cochrane databases. The data search focused on randomised controlled trials (RCTs) and retrospective or controlled comparator-arm studies, SRs, and meta-analyses. Evidence synthesis was conducted using modified GRADE criteria as outlined for all the EAU guidelines. EVIDENCE SYNTHESIS: All chapters of the RCC guideline were updated on the basis of a structured literature assessment, and clinical practice recommendations were developed. The majority of the studies included were retrospective with matched or unmatched cohorts and were based on single- or multi-institution data or national registries. The exception was systemic treatment of metastatic RCC, for which there are several large RCTs, resulting in recommendations that are based on higher levels of evidence. CONCLUSIONS: The 2022 RCC guidelines have been updated by a multidisciplinary panel of experts using the highest methodological standards. These guidelines provide the most reliable contemporary evidence base for the management of RCC in 2022. PATIENT SUMMARY: The European Association of Urology panel for guidelines on kidney cancer has thoroughly evaluated the research data available to establish up-to-date international standards for the care of patients with kidney cancer.

A Comprehensive Commentary on the Multilocular Cystic Renal Neoplasm of Low Malignant Potential: A Urologist's Perspective.

Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) is a cystic renal tumor with indolent clinical behavior. In most of cases, it is an incidental finding during the examination of other health issues. The true incidence rate is estimated to be between 1.5% and 4% of all RCCs. These lesions are classified according to the Bosniak classification as Bosniak category III. There is a wide spectrum of diagnostic tools that can be utilized in the identification of this tumor, such as computed tomography (CT), magnetic resonance (MRI) or contrast-enhanced ultrasonography (CEUS). Management choices of these lesions range from conservative approaches, such as clinical follow-up, to surgery. Minimally invasive techniques (i.e., robotic surgery and laparoscopy) are preferred, with an emphasis on nephron sparing surgery, if clinically feasible.

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.

A large-scale assay library for targeted protein quantification in renal cell carcinoma tissues.

Renal cell carcinoma (RCC) represents 2.2% of all cancer incidences; however, prognostic or predictive RCC biomarkers at protein level are largely missing. To support proteomics research of localized and metastatic RCC, we introduce a new library of targeted mass spectrometry assays for accurate protein quantification in malignant and normal kidney tissue. Aliquots of 86 initially localized RCC, 75 metastatic RCC and 17 adjacent non-cancerous fresh frozen tissue lysates were trypsin digested, pooled, and fractionated using hydrophilic chromatography. The fractions were analyzed using LC-MS/MS on QExactive HF-X mass spectrometer in data-dependent acquisition (DDA) mode. A resulting spectral library contains 77,817 peptides representing 7960 protein groups (FDR = 1%). Further, we confirm applicability of this library on four RCC datasets measured in data-independent acquisition (DIA) mode, demonstrating a specific quantification of a substantially increased part of RCC proteome, depending on LC-MS/MS instrumentation. Impact of sample specificity of the library on the results of targeted DIA data extraction was demonstrated by parallel analyses of two datasets by two pan human libraries. The new RCC specific library has potential to contribute to better understanding the RCC development at molecular level, leading to new diagnostic and therapeutic targets.

2021 Updated European Association of Urology Guidelines on the Use of Adjuvant Pembrolizumab for Renal Cell Carcinoma.

Adjuvant treatment of nonmetastatic high-risk renal cell carcinoma is an unmet medical need. In the past, several tyrosine kinase inhibitor trials have failed to demonstrate an improvement of disease-free survival (DFS) in this setting. Only one trial (S-TRAC) provided evidence for improved DFS with sunitinib but without an overall survival (OS) signal. Keynote-564 is the first trial of an immune checkpoint inhibitor that significantly improved DFS with adjuvant pembrolizumab, a programmed death receptor-1 antibody, in clear cell renal cell carcinoma with a high risk of relapse. The intention-to-treat population, which included a group of patients after metastasectomy and no evidence of disease (M1 NED), had a significant DFS benefit. The OS data are not mature as yet. The Renal Cell Carcinoma Guideline Panel issues a weak recommendation for the adjuvant use of pembrolizumab for high-risk clear cell renal carcinoma, as defined by the trial until final OS data are available. However, the trial reilluminates the discussion on when and in whom metastasectomy should be performed. Here, caution is necessary not to perform metastasectomy in patients with poor prognostic features and rapid progressive disease, which must be excluded by a confirmatory scan of disease status prior to planned metastasectomy. PATIENT SUMMARY: New data from the adjuvant immune checkpoint inhibitor trial with pembrolizumab (a programmed death receptor-1 antibody) for the treatment of high-risk clear cell renal cell carcinoma (ccRCC) after surgery showed that the drug prolonged the period of being cancer free significantly, although whether it prolonged survival remained uncertain. Consequently, pembrolizumab is cautiously recommended as additional (ie, adjuvant) treatment in high-risk ccRCC after kidney cancer surgery.

Clear cell renal cell carcinoma with prominent microvascular hyperplasia: Morphologic, immunohistochemical and molecular-genetic analysis of 7 sporadic cases.

Clear cell renal cell carcinoma (CCRCC) is well known for intratumor heterogeneity. An accurate mapping of the tumor is crucial for assessing prognosis, and perhaps this can be linked to potential success/failure of targeted therapies. We assembled a cohort of 7 CCRCCs with prominent vasculature and microvascular hyperplasia (ccRCCPV), resembling those seen in high grade gliomas. A control group of classic CCRCC with no variant morphologies was also included. Both groups were analyzed for clinicopathologic, morphologic, immunohistochemical, and molecular genetic features. No statistically significant differences in mRNA expression of studied genes between the two groups were found. Using NGS panel Trusight Oncology 500 (TSO500), only one clinically significant gene mutation, VHL c.263G > A, p. (Trp88Ter), was found. TMB (Tumor Mutation Burden) and MSI (MicroSatellite Instability) were low, and no copy number variations (CNVs) were detected in the study cohort. Prominent microvascular hyperplasia in CCRCC is a rare phenomenon. From molecular genetic point of view, these tumors do not appear to be different from classic CCRCC. Prognostically, they also demonstrated similar clinical behaviors.

Mutation Profile Variability in the Primary Tumor and Multiple Pulmonary Metastases of Clear Cell Renal Cell Carcinoma. A Review of the Literature and Analysis of Four Metastatic Cases.

(1) Background: There are limited data concerning inter-tumoral and inter-metastatic heterogeneity in clear cell renal cell carcinoma (CCRCC). The aim of our study was to review published data and to examine mutation profile variability in primary and multiple pulmonary metastases (PMs) in our cohort of four patients with metastatic CCRCC. (2) Methods: Four patients were enrolled in this study. The clinical characteristics, types of surgeries, histopathologic results, immunohistochemical and genetic evaluations of corresponding primary tumor and PMs, and follow-up data were recorded. (3) Results: In our series, the most commonly mutated genes were those in the canonically dysregulated VHL pathway, which were detected in both primary tumors and corresponding metastasis. There were genetic profile differences between primary and metastatic tumors, as well as among particular metastases in one patient. (4) Conclusions: CCRCC shows heterogeneity between the primary tumor and its metastasis. Such mutational changes may be responsible for suboptimal treatment outcomes in targeted therapy settings.