Papillary renal neoplasm with reverse polarity: an observational study of histology, immunophenotypes, and molecular variation.

Background: Papillary renal neoplasm with reverse polarity (PRNRP) is a novel entity with unique clinicopathological characteristics, and only a small number of patients with PRNRP have been described. Methods: We retrospectively analyzed the data for nine patients with PRNRP and evaluated differences in the clinical, histomorphological, immunohistochemical, and molecular features; prognosis; and differential diagnosis of PRNRP from other renal tumors with papillary structure. Results: There were six males and three females aged 36 to 74 years (mean: 62.33 years; median: 68 years). All the tumors were solitary and ranged from 1 to 3.7 cm (mean: 2.17 cm; median: 2 cm), with three and six tumors arose in the left and right renal tract, respectively. Pathologically, PRNRP is a small, well-circumscribed neoplasm with predominant papillary formations. The lining epithelium is composed of a monolayer of cuboidal to low-columnar cells with low-grade nuclei arranged against the apical pole of the tumor cells. Edema, mucinous degeneration, and hyaline degeneration are found in the fibrovascular cores. Foamy macrophages, psammoma bodies, hemosiderin deposition, and infiltrative tumor boundaries were present in some patients. Immunohistochemically, all tumors showed diffuse positive staining for GATA3. Sanger sequencing confirmed the presence of KRAS mutation in seven patients. All patients had a good prognosis after surgery and were relapse free. Positive staining for GATA3 and negative staining for vimentin were the most significant markers for differentiating PRNRP from other renal tumors with analogous structure. Conclusions: These findings suggested that PRNRP is a distinctive subtype of renal tumor with specific pathological features and indolent behaviors that should be distinguished from other renal tumors, especially papillary renal cell carcinoma. A monolayer of tumor cells with an inverted nuclear pattern, positive staining for GATA3, and KRAS mutation are essential for pathological diagnosis. Owing to its satisfactory prognosis, the surveillance and follow-up of patients with PRNRP should be additionally formulated.

Whether histologic subtyping affect the oncological outcomes of patients with papillary renal cell carcinoma: evidence from a systematic review and meta-analysis.

BACKGROUND: Whether the histologic subtype (type 1 and type 2) of papillary renal cell carcinoma (pRCC) is a tool to predict the prognosis is of great debate. This study is aimed to evaluate the prognostic significance of histologic subtype in patients with pRCC after surgery through a systematic review and meta-analysis. METHODS: We searched PubMed, the Web of Science, Cochrane library and EMBASE databases to identify studies published until January 20, 2021 according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies were deemed eligible if they compared the overall survival (OS), cancer specific survival (CSS), recurrence-free survival (RFS) or disease-free survival (DFS) between patients with type 1 or type 2 pRCC. And the corresponding hazard ratios (HRs) and 95% conference intervals (CIs) were collected for meta-analysis and further subgroup analysis. RESULTS: Overall 22 studies with a total of 4,494 patients were considered eligible and included for the systematic review and meta-analysis. The pooled results showed that type 2 pRCC was associated with a worse OS (pooled HR 1.61, 95% CI: 1.10-2.36, P=0.02) and CSS (pooled HR 1.59, 95% CI: 1.00-2.51, P=0.05). However, the subgroup analysis yielded the same result as the initial analysis only when the HRs were extracted from univariate analysis. In studies with multivariate analysis, type 2 pRCC was not statistically associated with a worse OS (pooled HR 1.22, 95% CI: 0.97-1.53, P=0.27), CSS (pooled HR 1.16, 95% CI: 0.67-2.00, P=0.60), and DFS (pooled HR 1.33, 95% CI: 0.93-1.91, P=0.12) compared to type 1 pRCC. DISCUSSION: Histologic subtype is not an independent prognostic factor for patients with pRCC, although the result needs to be taken with caution. And studies with retrospective study design, larger sample size and longer follow-up period are required to verify these results.

Prognostic significance of preoperative neutrophil-to-lymphocyte ratio in papillary renal cell carcinoma patients after receiving curative surgery based on a retrospective cohort.

BACKGROUND: Inflammatory response biomarkers have been studied as promising prognostic factors in renal cell carcinoma, but few studies have focused on papillary renal cell carcinoma (PRCC). This study was performed to evaluate the prognostic value of the preoperative neutrophil-to-lymphocyte ratio (NLR) in PRCC patients. METHODS: In total, 122 postoperative PRCC patients selected from 366 non-clear cell renal cell carcinoma patients were enrolled from our institution between 2012 and 2020. The optimal cutoff value of the NLR was assessed by receiver operating characteristic (ROC) curve analysis, and the Kaplan-Meier method and Cox's proportional hazards regression models were performed to analyze the association of the NLR with overall survival (OS). In addition, the potential of tumor-node-metastasis (TNM) stage, the NLR and an NLR-TNM system to predict survival were compared with ROC curves, and clinical usefulness of the predicting models were assessed by decision curve analysis. RESULTS: A threshold value of 2.39 for the NLR for OS analysis was determined by ROC curve analysis. An NLR ≥ 2.39 was associated with a more advanced TNM stage (P < 0.01) and larger tumors (P < 0.05) than a low NLR, as well as pathological subtype II (P < 0.05), and the patients with a high NLR also exhibited significantly worse overall survival outcomes (P < 0.05). The NLR was determined to be a significant independent prognostic indicator by univariable and multivariable analyses (HR = 5.56, P < 0.05). Furthermore, TNM stage and the NLR were integrated, and the area under the curve (AUC) of for the NLR-TNM system was larger than that of for the TNM system when predicting overall survival (0.84 vs 0.73, P = 0.04). Decision curve analysis also demonstrated a better clinical value for the NLR-TNM model to predict the prognosis. CONCLUSION: A high preoperative NLR was associated with poor clinical and pathologic parameters in patients with PRCC; moreover, the NLR was also an independent prognostic factor for the OS of patients with PRCC. The NLR-TNM system, which was a model that integrated the NLR with TNM staging, could improve the ability to predict overall survival.

Clinicopathological and molecular characterisation of papillary renal neoplasm with reverse polarity and its renal papillary adenoma analogue.

AIMS: Papillary renal neoplasm with reverse polarity (PRNRP) is a newly defined entity with distinct histomorphology and recurrent KRAS mutation. It has been estimated to constitute 4% of previously diagnosed papillary renal cell carcinoma (PRCC). Renal papillary adenoma (PA) is suggested to be the precursor of PRCC. This study aimed to investigate the association between PRNRP and PA, particularly the morphologically similar type D PA. METHODS AND RESULTS: Nephrectomy specimens of PRCC and PA from our 10-year pathology archives were retrieved and reviewed. GATA3 immunohistochemistry and RAS/BRAF testing were performed in all cases reclassified as PRNRP and all PAs with sufficient materials. Overall, PRNRP accounted for 9.1% (10 of 110) of PRCC and there was no recurrence/metastasis with a mean follow-up period of 39 months. Three novel morphological features were described, including clear cell change, mast cell infiltration and metaplastic ossification. Nine of the 10 PRNRPs showed diffuse and strong GATA3 expression and KRAS missense mutations at codon 12. One case exhibited moderate GATA3 staining on 80% of the tumour cells and RAS/BRAF wild-type. In a total of 73 PAs, 11 were classified as type D. GATA3 expression was significantly more frequent in type D versus non-type D PAs (100 versus 35%, P < 0.01). KRAS missense mutations were identified in six of eight (75%) of the type D PAs but none of the 18 non-type D PAs. CONCLUSIONS: Type D PA was different from other types of PA and represented an analogue or a small-sized PRNRP for their identical morphology, immunophenotype and molecular signature.

Stemness-associated senescence genes as potential novel risk factors for papillary renal cell carcinoma.

BACKGROUND: Papillary renal cell carcinoma (PRCC) is the 2nd most common type of renal carcinoma; however, there is limited data about PRCC, and strategies for the diagnosis and treatment of PRCC need to be identified. METHODS: In this study, the stemness-associated senescence (SAS) phenotype of PRCC was obtained by a bioinformatics analysis. We acquired the gene expression profiles of patients with PRCC and calculated the PRCC messenger ribonucleic acid stemness index (mRNAsi). We then screened the SAS genes from the GenAge database. A least absolute shrinkage and selection operator-Cox regression was conducted to examine correlations between risk signatures and the abundance of the SAS genes in the PRCC samples. Functional enrichment analyses were then performed via molecular co-expression studies of mRNAsi, and the risk scores of PRCC patients were calculated. RESULTS: We identified the following 8 SAS signatures that were strongly associated with prognosis in PRCC patients: cyclin-dependent kinase 1, heat shock protein family D member 1, platelet-derived growth factor receptor A, cyclin-dependent kinase inhibitor 2B, pyrroline-5-carboxylate reductase 1, sequestosome-1, sirtuin-3, and cyclin-dependent kinase inhibitor 1A. The SAS signatures were significantly associated with the stage and type of PRCC. The calculated risk scores can be used to divide PRCC patients into low- and high-risk groups, and provide guidance in determining treatment plans. CONCLUSIONS: We have developed a reliable prognostic tool to predict the clinical outcomes of PRCC patients. This tool could improve treatment decisions regarding drug therapy, surgery, and conservative options.

Three-gene risk model in papillary renal cell carcinoma: a robust likelihood-based survival analysis.

BACKGROUND: Papillary renal cell carcinoma (PRCC) accounts for 15% of all renal cell carcinomas. The molecular mechanisms of renal papillary cell carcinoma remain unclear, and treatments for advanced disease are limited. RESULT: We built the computing model as follows: Risk score = 1.806 * TPX2 - 0.355 * TXNRD2 - 0.805 * SLC6A20. The 3-year AUC of overall survival was 0.917 in the training set (147 PRCC samples) and 0.760 in the test set (142 PRCC samples). Based on the robust model, M2 macrophages showed positive correlation with risk score, while M1 macrophages were the opposite. PRCC patients with low risk score showed higher tumor mutation burden. TPX2 is a risk factor, and co-expression factors were enriched in cell proliferation and cancer-related pathways. Finally, the proliferation and invasion of PRCC cell line were decreased in the TPX2 reduced group, and the differential expression was identified. TPX2 is a potential risk biomarker which involved in cell proliferation in PRCC. CONCLUSION: We conducted a study to develop a three gene model for predicting prognosis in patients with papillary renal cell carcinoma. Our findings may provide candidate biomarkers for prognosis that have important implications for understanding the therapeutic targets of papillary renal cell carcinoma. METHOD: Gene expression matrix and clinical data were obtained from TCGA (The Cancer Genome Atlas), GSE26574, GSE2048, and GSE7023. Prognostic factors were identified using "survival" and "rbsurv" packages, and a risk score was constructed using Multivariate Cox regression analysis. The co-expression networks of the factors in model were constructed using the "WGCNA" package. The co-expression genes of factors were enriched and displayed the biological process. Based on this robust risk model, immune cells infiltration proportions and tumor mutation burdens were compared between risk groups. Subsequently, using the PRCC cell line, the role of TPX2 was determined by Cell proliferation assay, 5-Ethynyl-20-deoxyuridine assay and Transwell assay.

Nomograms for predicting overall and cancer-specific survival in patients with papillary renal cell carcinoma: a population-based study using SEER database.

BACKGROUND: To establish and validate nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in patients with papillary renal cell carcinoma (pRCC). METHODS: Patients diagnosed with pRCC between 2010 and 2014 in the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively included in this study and divided into training and validation groups randomly. Uni- and multivariate Cox regression analyses were used to identify significant variables related to OS and CSS in the training group. Based on results of multivariate Cox regression analysis, nomograms for 3- and 5-year CSS and OS were established, respectively. Additionally, Kaplan-Meier (KM) survival curves were produced to learn the actual effects of different variables. Finally, the nomograms were evaluated both in the training group and the validation group using the area under the receiver operating characteristic (ROC) curve, the concordance index (C-index) and calibration curves. RESULTS: A total of 4,859 eligible patients were enrolled, with 3,403 categorized into the training group and 1,456 into the validation group. Seven factors [age, T stage, N stage, M stage, use of surgery/lymph node removal (LNR) and insurance status] were significantly related to OS and seven factors (age, T stage, N stage, M stage and use of surgery/chemotherapy/LNR) were significantly associated with CSS. These factors were eventually included in the predictive nomograms. The C-indexes for OS in the training and validation groups were 0.764 and 0.723 respectively, and 0.859 and 0.824 for CSS. The 3- and 5-year AUCs for OS were 0.779 and 0.752 in the training cohort, and 0.749 and 0.722 in the validation cohort. Similarly, 3- and 5-year AUCs for OS were 0.871 and 0.844 in the training cohort, and 0.853 and 0.822 in the validation group. Finally, the calibration curves suggested that the predictive nomograms had a good consistency between the observed and the predicted survival. CONCLUSIONS: It was the first time to develop nomograms to predict the survival outcomes of pRCC patients. The prognostic nomograms were reliable with high accuracy, which might have guiding significance for clinical practice.

Identification of miR-21-5p and miR-210-3p serum levels as biomarkers for patients with papillary renal cell carcinoma: a multicenter analysis.

BACKGROUND: Expression of circulating serum microRNAs has not been studied in a cohort of patients with papillary renal cell carcinoma (pRCC) so far. We hypothesized that miRNA deregulation in malignant tissue is reflected in serum and could be used for non-invasive diagnosis of pRCC as well as differentiation between type 1 and type 2 pRCC. METHODS: We selected 11 differentially regulated miRNAs from the Cancer Genome Atlas (TCGA) pRCC data set as potential serum validation candidates. Serum miRNA expression was determined by qRT-PCR in a total of 34 pRCC type 1, 33 pRCC type 2 and 33 control subjects of three german high-volume medical centers. RESULTS: Heatmap and principal component analysis showed that miRNA expression did not cluster the samples into distinct sample groups and that miRNA levels did not significantly discriminate healthy individuals from patients with pRCC, nor between patients with type 1 and type 2 pRCC. However, miR-21-5p levels were significantly increased in patients with advanced pRCC (>pT3, and/or pN+ and/or pM+) in comparison to localized pRCC. Moreover, adding the expression of miR-210-3p, which was significantly down-regulated in localized pRCC sera in comparison to healthy sera, additionally increased diagnostic accuracy in our study cohort. CONCLUSIONS: In our multicenter cohort, we were not able to identify a single miRNA serum marker for pRCC including its subclasses. However, our study revealed that miR-21-5p levels were elevated in advanced disease (with added diagnostic accuracy via addition of miR-210-3p expression), proposing these two miRs as potential biomarkers in pRCC.

Genome-wide mutation profiling and related risk signature for prognosis of papillary renal cell carcinoma.

BACKGROUND: The papillary renal cell carcinoma (pRCC) is a rare subtype of renal cell carcinoma with limited investigation. Our study aimed to explore a robust signature to predict the prognosis of pRCC from the perspective of mutation profiles. METHODS: In this study, we downloaded the simple nucleotide variation data of 288 pRCC samples from The Cancer Genome Atlas (TCGA) database. "GenVisR" package was utilized to visualize gene mutation profiles in pRCC. The PPI network was conducted based on the STRING database and the modification was performed via Cytoscape software (Version 3.7.1). Top 50 mutant genes were selected and Cox regression method was conducted to identify the hub prognostic mutant signature in pRCC using "survival" package. Mutation Related Signature (MRS) risk score was established by multivariate Cox regression method. Receiver Operating Characteristic (ROC) curve drawn by "timeROC" was conducted to assess the predictive accuracy of overall survival (OS) and Kaplan-Meier analysis was then performed. Relationships between mutants and expression levels were compared by Wilcox rank-sum test. Function enrichment pathway analysis for mutated genes was performed by "org.Hs.eg.db", "clusterProfiler", "ggplot2" and "enrichplot" packages. Gene Set Enrichment Analysis was exploited using the MRS as the phenotypes, which worked based on the JAVA platform. All statistical analyses were achieved by R software (version 3.5.2). P value <0.05 was considered to be significant. RESULTS: The mutation landscape in waterfall plot revealed that a list of 49 genes that were mutated in more than 10 samples, of which 6 genes (TTN, MUC16, KMT2C, MET, OBSCN, LRP2) were mutated in more than 20 samples. Besides, non-synonymous was the most frequent mutation effect, and missense mutation was one of the most common mutation types in mutated genes across 248 samples. The AUC of MRS model consisted of 17 prognostic mutant signatures was 0.907 in 3-year OS prediction. Moreover, pRCC patients with high level of MRS showed the worse survival outcomes compared with that in low-level MRS group (P=0). In addition, correlation analysis indicated that 6 mutated genes (BAP1, OBSCN, NF2, SETD2, PBRM1, DNAH1) were significantly associated with corresponding expression levels. Last, functional enriched pathway analysis showed that these mutant genes were involved in multiple cancer-related crosstalk, including PI3K-AKT signaling pathway, JAK-STAT signaling pathway, extracellular matrix (ECM)-receptor interaction or cell cycle. CONCLUSIONS: In summary, our study was the first attempt to explore the mutation-related signature for predicting survival outcomes of pRCC based on the high-throughput data, which might provide valuable information for further uncovering the molecular pathogenesis in pRCC.

Overexpression of interleukin-20 receptor subunit beta (IL20RB) correlates with cell proliferation, invasion and migration enhancement and poor prognosis in papillary renal cell carcinoma.

Papillary renal cell carcinoma (PRCC) accounts for about 10 percent of all renal cell carcinomas, and the prognosis is poor for people with advanced disease. Interleukin-20 receptor subunit beta (IL20RB) is a single-pass type I membrane protein of the type II cytokine receptor family and is related to the pathogenesis of chronic inflammation and autoimmune diseases, including psoriasis, glaucoma, vitiligo, rheumatoid arthritis, and inflammatory bowel disease. However, little has been reported on IL20RB with respect to cancer, especially in PRCC. Thus, we performed this study to explore its biological characteristics in PRCC. Data from the TCGA database were used to analyze the expression and prognosis of IL20RB. qRT-PCR was used to detect the expression of IL20RB in PRCC cells in vitro. After knockdown of IL20RB with small interfering RNA (siRNA) technology, the proliferation, migration, and invasion of Ketr-3 cells and the expression of related proteins in the epithelial-mesenchymal transition (EMT) pathway were measured with Cell Counting Kit-8 (CCK-8), transwell, and western blot assays. The findings demonstrated that the expression of IL20RB was upregulated in both PRCC tissues and cells and that the high expression of IL20RB led to low overall survival (OS). Furthermore, after knockdown of IL20RB in vitro, the proliferation, migration, and invasion of Ketr-3 cells were reduced, and the expression of related proteins in the EMT pathway declined, suggesting that IL20RB plays a vital role in PRCC through the EMT pathway. These results reveal the biological significance of IL20RB in PRCC and provide new insight for future targeted drugs.

Papillary Renal Cell Carcinomas Rewire Glutathione Metabolism and Are Deficient in Both Anabolic Glucose Synthesis and Oxidative Phosphorylation.

Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7-20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increased de novo synthesis rate of GSH, based on glutamine consumption. Furthermore, profound downregulation of gluconeogenesis and oxidative phosphorylation was observed at the protein level. In contrast, analysis of the The Cancer Genome Atlas (TCGA) papillary RCC cohort revealed no significant change in transcripts encoding oxidative phosphorylation compared to normal kidney tissue, highlighting the importance of proteomic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies.

Clinical characteristics and prognosis of metastatic papillary renal cell carcinoma / 中国肿瘤临床

Objective: To investigate the clinical characteristics, treatment methods, and prognosis of metastatic papillary renal cell car-cinoma (pRCC). Methods: The clinical data of metastatic pRCC patients treated at the Department of Kidney Cancer and Melanoma, Pe-king University Cancer Hospital, were retrospectively analyzed. The prognosis of these patients was stratified through international metastatic renal cell carcinoma database consortium (IMDC) model. Survival and influencing factors were further analyzed using the Kaplan-Meier method and Cox proportional risk regression model. Results: From January 2003 to March 2018, 93 patients (median age, 50.0 years) were diagnosed with metastatic pRCC: 89 (95.7%) typeⅡcases and 4 (4.3%) typeⅠcases. The median follow-up dura-tion was 23.1 months, with 90, 44, and 14 patients having received first-line, second-line, and third-line treatments, respectively. The median overall survival (OS) of the 93 patients was (31.5±5.9) months [95% confidence interval (CI): 19.9-43.1], while the median OS of patients with low-, intermediate-, and high-risk (classified as per the International Metastatic Renal Cell Carcinoma Database Con-sortium [IMDC]) were (100.0±32.8), (38.3±8.2), and (16.4±1.2) months, respectively (high-risk vs. low/intermediate-risk, P<0.001; low-risk vs. intermediate-risk, P=0.015). The median progression free survival (PFS) with first-line treatment was (6.6±0.5) months. And the median PFS of the corresponding three groups stratified by IMDC score were (17.5±5.7), (7.1±2.3), and (5.2±1.5) months, respectively (high-risk vs . low-risk, P=0.002; high-risk vs . intermediate-risk, P=0.01). Conclusions: Metastatic pRCC is noted to have unique biologi-cal characteristics. The IMDC model can be used to predict the efficacy of first-line treatment using tyrosine kinase inhibitors as well as the prognosis of metastatic papillary renal cell carcinoma in such patients.

Identifying biomarkers of papillary renal cell carcinoma associated with pathological stage by weighted gene co-expression network analysis.

Although papillary renal cell carcinoma (PRCC) accounts for 10%-15% of renal cell carcinoma (RCC), no predictive molecular biomarker is currently applicable to guiding disease stage of PRCC patients. The mRNASeq data of PRCC and adjacent normal tissue in The Cancer Genome Atlas was analyzed to identify 1148 differentially expressed genes, on which weighted gene co-expression network analysis was performed. Then 11 co-expressed gene modules were identified. The highest association was found between blue module and pathological stage (r = 0.45) by Pearson's correlation analysis. Functional enrichment analysis revealed that biological processes of blue module focused on nuclear division, cell cycle phase, and spindle (all P < 1e-10). All 40 hub genes in blue module can distinguish localized (pathological stage I, II) from non-localized (pathological stage III, IV) PRCC (P < 0.01). A good molecular biomarker for pathological stage of RCC must be a prognostic gene in clinical practice. Survival analysis was performed to reversely validate if hub genes were associated with pathological stage. Survival analysis unveiled that all hub genes were associated with patient prognosis (P < 0.01).The validation cohort GSE2748 verified that 30 hub genes can differentiate localized from non-localized PRCC (P < 0.01), and 18 hub genes are prognosis-associated (P < 0.01).ROC curve indicated that the 17 hub genes exhibited excellent diagnostic efficiency for localized and non-localized PRCC (AUC > 0.7). These hub genes may serve as a biomarker and help to distinguish different pathological stages for PRCC patients.

Papillary renal cell carcinoma and clear cell renal cell carcinoma: Differentiation of distinct histological types with contrast - enhanced ultrasonography.

PURPOSE: Papillary renal cell carcinoma (pRCC) and clear cell renal cell carcinoma (ccRCC) have different biological behaviours and imaging features. The role of contrast-enhanced ultrasound (CEUS) in differentiating these two carcinoma subtypes has not been comprehensively studied. MATERIALS AND METHODS: Forty-eight patients with 49 pRCC lesions and 153 patients with 156 ccRCC lesions underwent preoperative conventional ultrasound (US) and CEUS. Among them, 91 patients (25 pRCCs and 66 ccRCCs) also underwent preoperative contrast-enhanced computed tomography (CECT) in our hospital. The characteristics of CEUS and CECT images for each patient imaged were analysed by each of two blinded observers. RESULTS: Images for five (5/25, 20%) pRCC patients demonstrated equivocal or no enhancement using CECT, while all lesions were enhanced using CEUS. From CEUS, images of pRCCs, when compared with ccRCC images, demonstrated significantly higher frequencies of slow wash-in (59.2% vs. 5.8%), fast wash-out (87.7% vs. 46.1%), and hypo-enhancement (57.1% vs. 7.1%) patterns, p<0.001, as well as the presence of pseudocapsule (42.9% vs. 23.1%), p=0.007. For lesions with large diameters (> 3 cm), a higher percentage of pRCC images demonstrated homogeneous enhancement compared with ccRCC images. Using the combination of slow wash-in, fast wash-out, and hypoenhancement patterns at peak as criteria to differentiate pRCC from ccRCC, positive and negative predictive value, and sensitivity and specificity were found to be 86.7%, 86.9%, 53.1%, and 97.4%, respectively. CONCLUSIONS: CEUS imaging features of slow-in, fast-out, and hypo-enhancement patterns may be useful for differentiating pRCC and ccRCC. In addition, CEUS may be helpful for diagnosing hypovascular renal lesions that demonstrate equivocal or no enhancement by CECT and, thus, for improving diagnostic confidence.