BACKGROUND: The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear.
METHODS: We reviewed clinical data from 93 patients with advanced nccRCC who received first-line systemic therapy including IO combination therapy and tyrosine kinase inhibitor (TKI) monotherapy at our affiliated institutions. Patients were divided based on the period when the treatment was implemented as the standard of care into the IO and TKI eras. Survival and tumor response outcomes were compared between the IO and TKI eras.
RESULTS: Of the 93 patients, 50 (54%) and 43 (46%) were categorized as IO era and TKI era groups, respectively. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the IO era than in the TKI era (median PFS: 8.97 vs. 4.96 months, p = 0.0152; median OS: 38.4 vs. 13.5 months, p = 0.0001). After the adjustment using other covariates, the treatment era was an independent factor for PFS (hazard ratio: 0.59, p = 0.0235) and OS (hazard ratio: 0.27, p < 0.0001). Objective response and disease control rates was not significantly different between the treatment eras (26% vs. 16.3%, p = 0.268; 62% vs. 62.8%, p = 0.594).
CONCLUSIONS: The implementation of IO therapy was significantly associated with longer survival in the nccRCC population. Further studies are needed to establish a more effective treatment strategy in this population using multiple regimens of IO combination therapy.

OBJECTIVE: To assess the computed tomography (CT) findings of papillary renal neoplasm with reverse polarity (PRNRP) and develop a radiomics-based model to distinguish PRNRPs from papillary renal cell carcinomas (PRCCs).
METHODS: We analyzed 31 PRNRPs and 68 PRCCs using preoperative kidney CT. We evaluated CT features that could discriminate PRNRPs from PRCCs. A radiomics signature was constructed using features selected through a least absolute shrinkage and selection operator algorithm. A radiomics-based model incorporating a radiomics signature and subjective CT parameters using multivariate logistic regression was developed. The diagnostic performance of the CT parameters, radiomics model, and their combination was evaluated using the area under the curve (AUC).
RESULTS: Most of PRNRPs had a round shape (93.5%), well-defined margin (100%), and persistent enhancement (77.4%). Compared with PRCC, PRNRPs exhibited distinct CT features including small size (16.7 vs. 37.7 mm, P < 0.001), heterogeneity (64.5 vs. 32.4%, P = 0.004), enhancing dot sign (16.1 vs. 1.5%, P = 0.001), and high attenuation in pre-contrast CT (44.2 vs. 35.5 HU, P = 0.003). Multivariate analysis revealed smaller mass size (odds ratio [OR]: 0.9; 95% confidence interval [CI] 0.9-1.0, P = 0.013), heterogeneity (OR: 8.8; 95% CI 1.9-41.4, P = 0.006), and higher attenuation in pre-contrast CT (OR: 1.1; 95% CI 1.0-1.2, P = 0.011) as significant independent factors for identifying PRNRPs. The diagnostic performance of the combination model was excellent (AUC: 0.923).
CONCLUSIONS: Smaller tumor size, heterogeneity, and higher attenuation in pre-contrast CT were more closely associated with PRNRPs than with PRCCs. Though the retrospective design, small sample size, and single-center data of this study may affect the generalizability of the findings, combining subjective CT features with a radiomics model is beneficial for distinguishing PRNRPs from PRCCs.

BACKGROUND: Cases of severe inflammatory renal disease and renal cell carcinoma (RCC) that occur simultaneously in the same kidney have been occasionally reported. However, extrarenal RCC that does not originate from the native kidney has rarely been reported. To our knowledge, this is the first reported case of RCC developing in the ipsilateral retroperitoneal space after a simple nephrectomy (SN) for inflammatory renal disease.
METHODS: A 63-year-old woman was referred to our hospital following the incidental discovery of a left retroperitoneal mass without specific symptoms. Her medical history revealed a left SN 27 years ago due to a renal abscess. Magnetic resonance imaging of the abdomen revealed three oval masses in the left retroperitoneum. The masses were successfully excised, and subsequent pathology confirmed papillary RCC. After surgery, the patient remained disease-free for 11 years without adjuvant therapy.
CONCLUSIONS: Clinicians should be vigilant of RCC in patients with retroperitoneal masses, especially after SN for inflammatory renal disease.

Historically, papillary renal cell carcinoma (PRCC) was divided into two types, type 1 and type 2, based solely on morphology. However, it is apparent that PRCC is far more complex and represents a histological, clinical, and molecular spectrum. There has been a significant evolution in our understanding of PRCC, highlighted by the recognition of new and molecularly defined entities that were previously included in PRCC type 2. This contemporary review addresses the evolving concepts regarding the PRCC, including why it is no longer needed to subtype PRCC, the current molecular landscape, prognostic parameters, and PRCC variants, including biphasic PRCC, papillary renal neoplasm with reverse polarity, and Warthin-like PRCC. Pathologists should also be aware of the potential mimickers of both low-grade and high-grade PRCCs as well as some new and emerging entities that may show papillary growth that should be excluded in the diagnostic workup. The evolving knowledge of PRCC biomarkers, morphologic patterns, and PRCC variants could also have important implications for clinical management. Lastly, the heterogeneity within the PRCC spectrum needs to be further studied, aiming to better stratify PRCC for appropriate clinical management and systemic therapy.

[This corrects the article DOI: 10.3389/fgene.2022.970900.].

OBJECTIVE: To evaluate the effectiveness of cryoablation compared to partial nephrectomy in patients with stage IA papillary and chromophobe renal cell carcinoma (pRCC; chRCC).
METHODS: The 2004-2016 National Cancer Database was queried for adult patients with stage IA pRCC or chRCC treated with cryoablation or partial nephrectomy. Patients receiving systemic therapy or radiotherapy, as well as those with bilateral RCC or prior malignant disease were excluded. Overall survival (OS) was assessed using Kaplan-Meier plots and Cox proportional hazard regression models. Nearest neighbor propensity matching (1:1 cryoablation:partial nephrectomy, stratified for pRCC and chRCC) was used to account for potential confounders.
RESULTS: A total of 11122 stage IA renal cell carcinoma patients were included (pRCC 8030; chRCC 3092). Cryoablation was performed in 607 (5.5%) patients, and partial nephrectomy in 10515 (94.5%) patients. A higher likelihood of cryoablation treatment was observed in older patients with non-private healthcare insurance, as well as in those with smaller diameter low-grade pRCC treated at non-academic centers in specific US geographic regions. After propensity score matching to account for confounders, there was no statistically significant difference in OS comparing cryoablation vs partial nephrectomy in patients with pRCC (HR = 1.3, 95% CI: 0.96-1.75, p = 0.09) and those with chRCC (HR = 1.38, 95% CI: 0.67-2.82, p = 0.38).
CONCLUSIONS: After accounting for confounders, cryoablation, and partial nephrectomy demonstrated comparable OS in patients with stage IA papillary and chromophobe RCC. Cryoablation is a reasonable treatment alternative to partial nephrectomy for these histological RCC subtypes when radiologically suspected or diagnosed after biopsy.
UNASSIGNED: Cryoablation might be considered as an upfront treatment alternative to partial nephrectomy in patients with papillary and chromophobe stage IA renal cell carcinoma, as both treatment approaches yield comparable oncological outcomes.
CONCLUSIONS: The utilization of cryoablation for stage IA papillary and chromophobe RCC increases. In the National Cancer Database, we found specific patterns of use of cryoablation. Cryoablation and partial nephrectomy demonstrate comparable outcomes after accounting for confounders.

BACKGROUND: Because of to the removal of subclassification of papillary renal cell carcinoma (pRCC), the survival prognostification of localized pRCC after surgical treatment became inadequate. Sarcopenia was widely evaluated and proved to be a predictive factor for prognosis in RCC patients. Therefore, we comprehensively investigated the survival prediction of the body composition parameters for localized pRCC.
METHODS: Patients pathologically diagnosed with pRCC between February 2012 and February 2022 in our center were enrolled. The body composition parameters, including skeletal muscle index (SMI), subcutaneous adipose tissue (SAT), and perirenal adipose tissue (PRAT), were measured by the images of preoperative computed tomography (CT). The primary outcome was set as progression-free survival (PFS), and the cutoff values of body composition parameters were calculated by using the Youden from receiver operating characteristic curve (ROC) curves. Univariate and multivariate Cox proportional regression analyses were performed to explore independent risk factors for survival prediction. Then, significant factors were used to construct a prognostic nomogram. The performance of the nomogram was evaluated by Harrell\'s C-index, calibration curves and time-dependent ROC curves.
RESULTS: A total of 105 patients were enrolled for analysis. With a median follow-up time of 30.48 months, 25 (23.81%) patients experienced cancer progression. The percentage of sarcopenia was 74.29%. Univariate Cox analysis identified that gender, PRAT, SAT, skeletal muscle (SM), sarcopenia, surgical technique, and tumor diameter were associated with progression. Further multivariate analysis showed that sarcopenia (hazard ratio [HR] 0.15, 95% confidence interval [CI] 0.03-0.66), SAT (HR 6.36, 95% CI 2.39-16.93), PRAT (HR 4.66, 95% CI 1.77-12.27), tumor diameter (HR 0.35, 95% CI 0.14-0.86), and surgical technique (HR 2.85, 95% CI 1.06-7.64) were independent risk factors for cancer progression. Then, a prognostic nomogram based on independent risk factors was constructed and the C-index for progression prediction was 0.831 (95% CI 0.761-0.901), representing a reasonable discrimination, the calibration curves, and the time-dependent ROC curves verified the good performance of the nomogram.
CONCLUSIONS: A prognostic nomogram, including sarcopenia, SAT, PRAT, tumor diameter, and surgical technique, was constructed to calculate the probability of progression for localized pRCC patients and needs further external validation for clinical use in the future.

OBJECTIVE: Papillary renal cell carcinoma (PRCC), the second most common kidney cancer, is morphologically, genetically, and molecularly heterogeneous with diverse clinical manifestations. Genetic variations of PRCC and their association with survival are not yet well-understood. This study aimed to identify and validate survival-specific genes in PRCC and explore their clinical utility.
METHODS: Using machine learning, 293 patients from the Cancer Genome Atlas-Kidney Renal Papillary Cell Carcinoma (TCGA-KIRP) database were analyzed to derive genes associated with survival. To validate these genes, DNAs were extracted from the tissues of 60 Korean PRCC patients. Next generation sequencing was conducted using a customized PRCC gene panel of 202 genes, including 171 survival-specific genes. Kaplan-Meier and Log-rank tests were used for survival analysis. Fisher\'s exact test was performed to assess the clinical utility of variant genes.
RESULTS: A total of 40 survival-specific genes were identified in the TCGA-KIRP database through machine learning and statistical analysis. Of them, 10 (BAP1, BRAF, CFDP1, EGFR, ITM2B, JAK1, NODAL, PCSK2, SPATA13, and SYT5) were validated in the Korean-KIRP database. Among these survival gene signatures, three genes (BAP1, PCSK2, and SPATA13) showed survival specificity in both overall survival (OS) (p = 0.00004, p = 1.38 × 10-7, and p = 0.026, respectively) and disease-free survival (DFS) (p = 0.00002, p = 1.21 × 10-7, and p = 0.036, respectively). Notably, the PCSK2 mutation demonstrated survival specificity uniquely in both the TCGA-KIRP (OS: p = 0.010 and DFS: p = 0.301) and Korean-KIRP (OS: p = 1.38 × 10-7 and DFS: p = 1.21 × 10-7) databases.
CONCLUSIONS: We discovered and verified genes specific for the survival of PRCC patients in the TCGA-KIRP and Korean-KIRP databases. The survival gene signature, including PCSK2 commonly obtained from the 40 gene signature of TCGA and the 10 gene signature of the Korean database, is expected to provide insight into predicting the survival of PRCC patients and developing new treatment.

Clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC) are the two most frequently encountered subtypes of renal cell carcinoma (RCC). Rarely, these two entities are identified intermingled within the same mass and have been labeled either collision tumors juxtaposed by random chance or composite tumors that have arisen from a common tumorigenic precursor cell. Regarding this distinction, authors have commonly relied upon macroscopic, histologic, and clinicopathologic findings, which may be prone to subjectivity. Objective molecular evidence has been lacking. We present a renal tumor showing a mixed CCRCC and PRCC with corroborating histologic, immunophenotypic, chromosomal microarray analysis (CMA), and next-generation sequencing (NGS) analysis for the respective tumor components, including classic findings of chromosome 3p loss and VHL mutation within the CCRCC component and gain of chromosomes 7 and 17 within the PRCC component. Of novel interest, CMA revealed a shared loss of chromosome 21q in both components with no other identifiable shared or overlapping mutations. This report adds unique evidence supporting the possibility of a true composite renal cell carcinoma composed of two commonly recognized subtypes. This finding may help to inform early molecular pathogenetic mechanism of RCC tumorigenesis.

BACKGROUND: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets.
METHODS: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to estimate the prevalence of PD-L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD-1, PD-L2, and LAG-3) and their association with PD-L1. We also assessed angiogenic markers and their association with PD-L1.
RESULTS: Overall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were \"double-positive\", as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01).
CONCLUSIONS: These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.