Final Overall Survival Analysis of S1500: A Randomized, Phase II Study Comparing Sunitinib With Cabozantinib, Crizotinib, and Savolitinib in Advanced Papillary Renal Cell Carcinoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mesenchymal-epithelial transition (MET) signaling pathway plays a role in the pathogenesis of selected patients with papillary renal cell carcinoma (PRCC). In the phase II PAPMET trial (ClinicalTrials.gov identifier: NCT02761057), cabozantinib significantly prolonged progression-free survival and improved objective response rate compared with sunitinib in patients with advanced PRCC. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized phase II, open-label trial, 147 patients with advanced PRCC who have received up to one previous therapy (excluding vascular endothelial growth factor-directed agents) were assigned to sunitinib, cabozantinib, crizotinib, or savolitinib. Ultimately, savolitinib and crizotinib arms were closed because of futility. With a median follow-up of 17.5 months, the median OS was 21.5 months (95% CI, 12.0 to 28.1) with cabozantinib and 17.3 months (95% CI, 12.8 to 21.8) with sunitinib (hazard ratio, 0.83; 95% CI, 0.51 to 1.36; P = .46). The OS landmark estimates for cabozantinib and sunitinib were 50% versus 39% at 24 months and 32% versus 28% at 36 months. In conclusion, we observed no significant difference in OS across treatment arms. Although cabozantinib represents a well-supported option for advanced PRCC, the lack of survival benefit underscores the need to develop novel therapies for this disease.

Evaluating Treatment Patterns and the Role of Neoadjuvant Chemotherapy in Plasmacytoid Urothelial Carcinoma: Insights from a Combined National and Institutional Series.

BACKGROUND: Plasmacytoid urothelial carcinoma (PUC) is a rare histologic subtype of urothelial carcinoma of the bladder (BC). Our objective was to characterize treatment patterns and outcomes of PUC in the NCDB and our recent institutional experience. METHODS: The NCDB was queried for localized PUC cases between 2004 and 2020. Patients with PUC from a single institution (Yale School of Medicine) were also incorporated from 2021 onwards to not double-count patients. The primary outcomes were overall survival and treatment trends. RESULTS: A total of 146 patients were included, 123 from NCDB and 23 from Yale. The median overall survival (mOS) was 28 [IQR 7.5, 50.3] months, 23 [IQR 8.4, 46.3] months for the NCDB patients, and 36 [IQR 4.3, 68.1] for the Yale patients. The mOS for patients receiving neoadjuvant chemotherapy (NAC) was 60.0 [28.0, 91.9] vs. 14.8 months [0, 34.3] for patients without NAC, p = 0.038, though the benefit was not preserved in a Cox proportional hazard analysis incorporating the clinical stage, receipt of NAC, and age. The peritoneum was the most common site of metastasis (78.3%), followed by the liver and bones. CONCLUSION: Our findings underscore the formidable challenge posed by PUC, emphasizing its limited response to current therapies. Despite higher pT0 rates with NAC, the OS benefit remains inconclusive, highlighting the need for more effective treatments.

Pathological concordance rate and outcomes by subtype in advanced papillary renal cell carcinoma.

OBJECTIVE: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. METHODS: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression-free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. RESULTS: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. CONCLUSIONS: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. PATIENT SUMMARY: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial.

Epidemiology, treatment and outcomes of primary renal sarcomas in adult patients.

To assess epidemiology, clinical presentation, treatment and overall survival of adult patients with renal sarcomas, the 2004-2016 SEER and NCDB databases were queried for adult patients diagnosed with renal sarcoma, calculating average annual age-adjusted incidence rates (AAIR) and average annual percentage change (AAPC) as well as overall survival (OS). In n = 1279 included renal sarcoma patients, AAIR remained constant over the study period (average 0.53 cases/1million; AAPC = 0.7, p = 0.6). Leiomyosarcoma (AAIR 0.14 cases/1 million) and malignant rhabdoid tumors (0.06 cases/1 million) were most common. Sarcoma histiotypes demonstrated considerable heterogeneity regarding demographic and cancer-related variables. Patients presented with advanced local extent (T3 33.3%; T4 14.2%) or distant metastases (29.1%) and commonly underwent surgical resection (81.6%). Longer OS was independently associated with younger age, female sex, lower comorbidity index, low T stage, negative surgical margins, absence of tumor necrosis or distant metastases and leiomyosarcoma histiotype (multivariable p < 0.05 each). Treatment efficacy varied according to sarcoma histiotype (interaction p < 0.001). Accounting for 0.25% of renal malignancies, renal sarcomas include 43 histiotypes with distinct epidemiology, clinical presentation, outcomes and sensitivity to systemic therapy, thereby reflecting soft-tissue sarcoma behavior. Renal sarcoma treatment patterns follow recommendations by renal cancer guidelines with surgical resection as the cornerstone of therapy.

Analysis of 3D pathology samples using weakly supervised AI.

Human tissue, which is inherently three-dimensional (3D), is traditionally examined through standard-of-care histopathology as limited two-dimensional (2D) cross-sections that can insufficiently represent the tissue due to sampling bias. To holistically characterize histomorphology, 3D imaging modalities have been developed, but clinical translation is hampered by complex manual evaluation and lack of computational platforms to distill clinical insights from large, high-resolution datasets. We present TriPath, a deep-learning platform for processing tissue volumes and efficiently predicting clinical outcomes based on 3D morphological features. Recurrence risk-stratification models were trained on prostate cancer specimens imaged with open-top light-sheet microscopy or microcomputed tomography. By comprehensively capturing 3D morphologies, 3D volume-based prognostication achieves superior performance to traditional 2D slice-based approaches, including clinical/histopathological baselines from six certified genitourinary pathologists. Incorporating greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, further emphasizing the value of capturing larger extents of heterogeneous morphology.

Sarcomatoid and Rhabdoid Renal Cell Carcinoma: Clinical, Pathologic, and Molecular Genetic Features.

Renal cell carcinoma (RCC) with sarcomatoid and rhabdoid morphologies has an aggressive biological behavior and a typically poor prognosis. The current 2022 WHO classification of renal tumors does not include them as distinct histologic entities but rather as transformational changes that may arise in a background of various distinct histologic types of RCC. The sarcomatoid component shows malignant spindle cells that may grow as intersecting fascicles, which is reminiscent of pleomorphic undifferentiated sarcoma. The rhabdoid cells are epithelioid cells with eccentrically located vesicular nuclei with prominent nucleoli and large intracytoplasmic eosinophilic inclusions. Studies have shown that RCCs with sarcomatoid and rhabdoid differentiation have distinctive molecular features. Sarcomatoid RCC harbors shared genomic alterations in carcinomatous and rhabdoid components, but also enrichment of specific genomic alterations in the sarcomatoid element, suggesting molecular pathways for development of sarcomatoid growth from a common clonal ancestor. Rhabdoid differentiation also arises through clonal evolution although less is known of specific genomic alterations in rhabdoid cells. Historically, treatment has lacked efficacy, although recently immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical responses. Reporting of sarcomatoid and rhabdoid features in renal cell carcinoma is required by the College of American Pathologists and the International Collaboration on Cancer Reporting. This manuscript reviews the clinical, pathologic, and molecular features of sarcomatoid RCC and rhabdoid RCC with emphasis on the morphologic features of these tumors, significance of diagnostic recognition, the molecular mechanisms of tumorigenesis and differentiation along sarcomatoid and rhabdoid lines, and advances in treatment, particularly immunotherapy.

Engineering the future of 3D pathology.

In recent years, technological advances in tissue preparation, high-throughput volumetric microscopy, and computational infrastructure have enabled rapid developments in nondestructive 3D pathology, in which high-resolution histologic datasets are obtained from thick tissue specimens, such as whole biopsies, without the need for physical sectioning onto glass slides. While 3D pathology generates massive datasets that are attractive for automated computational analysis, there is also a desire to use 3D pathology to improve the visual assessment of tissue histology. In this perspective, we discuss and provide examples of potential advantages of 3D pathology for the visual assessment of clinical specimens and the challenges of dealing with large 3D datasets (of individual or multiple specimens) that pathologists have not been trained to interpret. We discuss the need for artificial intelligence triaging algorithms and explainable analysis methods to assist pathologists or other domain experts in the interpretation of these novel, often complex, large datasets.

Recent Advances in Genitourinary Tumors Updates From the 5th Edition of the World Health Organization Blue Book Series.

CONTEXT.­: Urinary and Male Genital Tumours is the 8th volume of the World Health Organization Classification of Tumours series, 5th edition. Released in hard copy in September 2022, it presents an update to the classification of male genital and urinary tumors in the molecular age. Building upon previous volumes in this series, significant effort has been made to harmonize terminology across organ systems for biologically similar tumors (eg, neuroendocrine tumors). Genomic terminology has been standardized and genetic syndromes covered more comprehensively. This review presents a concise summary of this volume highlighting new entities, notable modifications relative to the 4th edition, and elements of relevance to routine clinical practice. OBJECTIVE.­: To provide a comprehensive update on the World Health Organization classification of urinary and male genital tumors, highlighting updated diagnostic criteria and terminology. DATA SOURCES.­: The 4th and 5th editions of the World Health Organization Classification of Tumours: Urinary and Male Genital Tumours. CONCLUSIONS.­: The World Health Organization has made several changes in the 5th edition of the update on urinary and male genital tumors that pathologists need to be aware of for up-to-date clinical practice.

An update on computational pathology tools for genitourinary pathology practice: A review paper from the Genitourinary Pathology Society (GUPS).

Machine learning has been leveraged for image analysis applications throughout a multitude of subspecialties. This position paper provides a perspective on the evolutionary trajectory of practical deep learning tools for genitourinary pathology through evaluating the most recent iterations of such algorithmic devices. Deep learning tools for genitourinary pathology demonstrate potential to enhance prognostic and predictive capacity for tumor assessment including grading, staging, and subtype identification, yet limitations in data availability, regulation, and standardization have stymied their implementation.

AMACR Expression is a Potential Diagnostic Marker in Apocrine Lesions of Breast, and is Associated with High Histologic Grade and Lymph Node Metastases in Some Invasive Apocrine Breast Cancers.

BACKGROUND: Carcinoma with apocrine differentiation (AC) is a subtype of breast carcinoma with apocrine features in >90% of the tumor. Molecular studies demonstrate AC has high expression of androgen receptor (AR) mRNA. Pure AC lack estrogen receptor (ER), progesterone receptor (PR), and express AR, with variable human epidermal growth factor 2 (HER2) status. Currently, in triple negative AC, no targetable therapies or specific diagnostic markers exist. MATERIALS AND METHODS: α-Methylacyl CoA racemase (AMACR) expression was investigated as a marker of apocrine differentiation using a single-plex immunoperoxidase stain, and a novel AMACR/p63 dual stain in a subset of cases, across 1) benign apocrine lesions (apocrine metaplasia, adenosis) 2) apocrine DCIS (ADCIS), 3) AC/ invasive ductal carcinoma (IDC) with apocrine features, 4) non-apocrine triple negative breast cancer (TNBC) and 5) IDC, no special type. A sub-set of cases were evaluated by tissue microarray. RESULTS: AMACR expression was increased in both AC and ADCIS, with minimal expression in benign breast tissue, TNBC and IDC, NST cases. In invasive cases, those with positive AMACR (>5% positivity) were significantly associated with higher histologic grade (P = .006), initial N stage (chi squared 0.044), and lack of ER or PR expression (both P < .001), with no correlation with overall survival. Analysis of TCGA breast cancer datasets revealed AMACR expression was significantly higher in molecularly defined apocrine carcinomas relative to basal and luminal subtypes. Moreover, high AMACR expression predicted worse relapse-free and distant-metastasis free survival, among both ER-/PR-/Her2- and ER-/PR-/Her2+ breast cancer cohorts (log-rank P = .081 and .00011, respectively). CONCLUSION: AMACR represents a promising diagnostic and prognostic marker in apocrine breast lesions. Further study is needed to determine the biologic and clinical significance of this protein in AC.

Prediction of Adverse Pathology at Radical Prostatectomy in Grade Group 2 and 3 Prostate Biopsies Using Machine Learning.

PURPOSE: There is ongoing clinical need to improve estimates of disease outcome in prostate cancer. Machine learning (ML) approaches to pathologic diagnosis and prognosis are a promising and increasingly used strategy. In this study, we use an ML algorithm for prediction of adverse outcomes at radical prostatectomy (RP) using whole-slide images (WSIs) of prostate biopsies with Grade Group (GG) 2 or 3 disease. METHODS: We performed a retrospective review of prostate biopsies collected at our institution which had corresponding RP, GG 2 or 3 disease one or more cores, and no biopsies with higher than GG 3 disease. A hematoxylin and eosin-stained core needle biopsy from each site with GG 2 or 3 disease was scanned and used as the sole input for the algorithm. The ML pipeline had three phases: image preprocessing, feature extraction, and adverse outcome prediction. First, patches were extracted from each biopsy scan. Subsequently, the pre-trained Visual Geometry Group-16 convolutional neural network was used for feature extraction. A representative feature vector was then used as input to an Extreme Gradient Boosting classifier for predicting the binary adverse outcome. We subsequently assessed patient clinical risk using CAPRA score for comparison with the ML pipeline results. RESULTS: The data set included 361 WSIs from 107 patients (56 with adverse pathology at RP). The area under the receiver operating characteristic curves for the ML classification were 0.72 (95% CI, 0.62 to 0.81), 0.65 (95% CI, 0.53 to 0.79) and 0.89 (95% CI, 0.79 to 1.00) for the entire cohort, and GG 2 and GG 3 patients, respectively, similar to the performance of the CAPRA clinical risk assessment. CONCLUSION: We provide evidence for the potential of ML algorithms to use WSIs of needle core prostate biopsies to estimate clinically relevant prostate cancer outcomes.

Artificial intelligence for diagnosis and Gleason grading of prostate cancer: the PANDA challenge.

Artificial intelligence (AI) has shown promise for diagnosing prostate cancer in biopsies. However, results have been limited to individual studies, lacking validation in multinational settings. Competitions have been shown to be accelerators for medical imaging innovations, but their impact is hindered by lack of reproducibility and independent validation. With this in mind, we organized the PANDA challenge-the largest histopathology competition to date, joined by 1,290 developers-to catalyze development of reproducible AI algorithms for Gleason grading using 10,616 digitized prostate biopsies. We validated that a diverse set of submitted algorithms reached pathologist-level performance on independent cross-continental cohorts, fully blinded to the algorithm developers. On United States and European external validation sets, the algorithms achieved agreements of 0.862 (quadratically weighted κ, 95% confidence interval (CI), 0.840-0.884) and 0.868 (95% CI, 0.835-0.900) with expert uropathologists. Successful generalization across different patient populations, laboratories and reference standards, achieved by a variety of algorithmic approaches, warrants evaluating AI-based Gleason grading in prospective clinical trials.

Extent of High-Grade Prostatic Adenocarcinoma in Multiparametric Magnetic Resonance Imaging-Targeted Biopsy Enhances Prediction of Pathologic Stage.

CONTEXT.­: Multiparametric magnetic resonance imaging (mpMRI) of prostate with targeted biopsy has enhanced detection of high-grade prostatic adenocarcinoma (HG PCa). However, utility of amount of HG PCa (Gleason pattern 4/5) in mpMRI-targeted biopsies versus standard 12-core biopsies in predicting adverse outcomes on radical prostatectomy (RP) is unknown. OBJECTIVE.­: To examine the utility of amount of HG PCa in mpMRI-targeted biopsies versus standard 12-core biopsies in predicting adverse RP outcomes. DESIGN.­: We performed a retrospective review of prostate biopsies that had corresponding RP, 1 or more mpMRI-targeted biopsy, and Grade Group 2 disease or higher. For the 169 cases identified, total millimeters of carcinoma and HG PCa and longest length HG PCa in a single core were recorded for 12-core biopsies and each set of mpMRI-targeted biopsies. For RP specimens, Gleason grade, extraprostatic extension, seminal vesicle involvement, and lymph node metastasis were recorded. The main outcome studied was prostate-confined disease at RP. A logistic regression model was used to test which pre-RP variables related to this outcome. RESULTS.­: Univariate analysis showed significant associations with adverse RP outcomes in 5 of 8 quantifiable variables; longest millimeter HG PCa in a single 12-core biopsy, highest Grade Group in any core, and total millimeter HG in mpMRI-targeted biopsies showed no statistical association (P = .54, P = .13, and P = .55, respectively). In multivariate analysis, total millimeter carcinoma in all cores, highest Grade Group in any core, and longest millimeter HG PCa in a single mpMRI-targeted core provided additional predictive value (P < .001, P = .004, and P = .03, respectively). CONCLUSIONS.­: Quantitation of HG PCa in mpMRI-targeted biopsies provides additional value over 12-core biopsies alone in predicting nonorgan confined prostate cancer at RP. Linear millimeters of HG PCa in mpMRI-targeted biopsies is a significant parameter associated with higher pathologic stage and could be of value in risk models.

Targeting prostate cancer with Clostridium perfringens enterotoxin functionalized nanoparticles co-encapsulating imaging cargo enhances magnetic resonance imaging specificity.

Magnetic resonance is a key imaging tool for the detection of prostate cancer; however, better tools focusing on cancer specificity are required to distinguish benign from cancerous regions. We found higher expression of claudin-3 (CLDN-3) and -4 (CLDN-4) in higher grade than lower-grade human prostate cancer biopsies (n = 174), leading to the design of functionalized nanoparticles (NPs) with a non-toxic truncated version of the natural ligand Clostridium perfringens enterotoxin (C-CPE) that has a strong binding affinity to Cldn-3 and Cldn-4 receptors. We developed a first-of-its-type, C-CPE-NP-based MRI detection tool in a prostate tumor-bearing mouse model. NPs with an average diameter of 152.9 ±â€¯15.7 nm (RS1) had a 2-fold enhancement of tumor specificity compared to larger (421.2 ±â€¯33.8 nm) NPs (RS4). There was a 1.8-fold (P < 0.01) and 1.6-fold (P < 0.01) upregulation of the tumor-to-liver signal intensities of C-RS1 and C-RS4 (functionalized NPs) compared to controls, respectively. Also, tumor specificity was 3.1-fold higher (P < 0.001) when comparing C-RS1 to C-RS4. This detection tool improved tumor localization of contrast-enhanced MRI, supporting potential clinical applicability.

Diagnosis of "cribriform" prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations.

Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4.

Adverse Histopathologic Characteristics in Small Papillary Renal Cell Carcinomas Have Minimal Impact on Prognosis.

OBJECTIVES: Tumor size has long been used in the management decision-making of patients with renal masses. Active surveillance had recently gained traction in selected patients with tumor size of 4 cm or less. Adverse histopathologic characteristics in papillary renal cell carcinoma (PRCC) have been shown to correlate with worse prognosis. We aimed to study whether such features in small PRCCs provide additional prognostic information. METHODS: Nephrectomies from our institution were collected and reviewed to evaluate for adverse histopathologic features. Clinical follow-up information was collected for all cases. Relationships between the variables were examined by Wilcoxon test and logistic regression. RESULTS: We identified 291 consecutive cases of PRCC. Adverse tumor histopathologic characteristics were significantly related to size. In PRCCs with size greater than 4 cm, there were more cases with high World Health Organization/International Society of Urological Pathology grade and necrosis. Adverse histologic features are less commonly seen in small PRCC and are not associated with lower disease-free survival or disease-specific survival. CONCLUSIONS: Identification of these features in small PRCCs (≤4 cm) through needle core biopsy examination would not provide additional prognostic information in patients for whom active surveillance is considered. Clinical and radiologic follow-up in patients with small renal masses that have a known histologic diagnosis of PRCC should be sufficient.

Doubling of Decipher Biopsy Genomic Score Is Related to Disease Reclassification on Subsequent Surveillance Biopsy but Not Adverse Features on Radical Prostatectomy.

The utility of serial Decipher biopsy scores in a true active surveillance population is still unknown. In a man on active surveillance for low-risk prostate cancer, a doubling of the Decipher biopsy score within genomic low-risk category from first to the second biopsy related to biopsy reclassification to Gleason grade group 4 on the third biopsy. However, the final pathology at radical prostatectomy showed Gleason grade group 2 with an organ-confined disease. This case suggests that the genomic risk category of Decipher biopsy scores during active surveillance may be more informative than either the interval genomic score change or the biopsy Gleason grade group.

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.