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Purpose: Develop and validate gene expression-based biomarker associated with recurrent disease to facilitate risk stratification of clear cell renal cell carcinoma (ccRCC)., Materials and Methods: We retrospectively identified 110 patients who underwent radical nephrectomy for ccRCC ( discovery cohort). Patients who recurred were matched on the basis of grade/stage to patients without recurrence. Capture whole-transcriptome sequencing was performed on RNA isolated from archival tissue using the Illumina platform. We developed a gene-expression signature to predict recurrence-free survival/disease-free survival (DFS) using a 15-fold lasso and elastic-net regularized linear Cox model. We derived the 31-gene cell cycle progression (mxCCP) score using RNA-seq data for each patient. Kaplan-Meier (KM) curves and multivariable Cox proportional hazard testing were used to validate the independent prognostic impact of the gene-expression signature on DFS, disease-specific survival (DSS), and overall survival (OS) in two validation data sets (combined n = 761)., Results: After quality control, the discovery cohort comprised 50 patients with recurrence and 41 patients without, with a median follow-up of 26 and 36 months, respectively. We developed a 15-gene (15G) signature, which was independently associated with worse DFS and DSS (DFS: hazard ratio [HR], 11.08 [95% CI, 4.9 to 25.1]; DSS: HR, 9.67 [95% CI, 3.4 to 27.7]) in a multivariable model adjusting for clinicopathologic parameters (including stage, size, grade, and necrosis [SSIGN] score and Memorial Sloan Kettering Cancer Center nomogram) and mxCCP score. The 15G signature was also independently associated with worse DFS and DSS in both validation data sets (Validation A [n = 382], DFS: HR, 2.6 [95% CI, 1.6 to 4.3]; DSS: HR, 3 [95% CI, 1.4 to 6.1] and Validation B (n = 379), DFS: HR, 2.1 [95% CI, 1.2 to 3.6]; OS: HR, 3 [95% CI, 1.6 to 5.7]) adjusting for clinicopathologic variables and mxCCP score., Conclusion: We developed and validated a novel 15G prognostic signature to improve risk stratification of patients with ccRCC. Pending further validation, this signature has the potential to facilitate optimal treatment allocation.

Objectives: Fluorescence in situ hybridization (FISH) assays for the detection of chromosomal rearrangements involving TFE3 and TFEB are considered the gold standard for the diagnosis of MiTF family altered renal cell carcinoma (MiTF-RCC). We reviewed 801 clinical TFE3/TFEB FISH assays performed at our tertiary-level institution between 2014 and 2023 on kidney tumors suspicious at the morphologic or biomarker level for MiTF aberrations., Methods: We summarized and analyzed clinical information, TFE3/TFEB FISH results, and available biomarker staining results in a cohort of 453 consecutive kidney tumor cases suspicious for MiTF-RCC., Results: In total, 61 of 434 (14%) kidney tumors were confirmed for TFE3 translocation; 10 of 367 cases (2.7%) were confirmed for TFEB translocation. Since TFEB amplification interpretation was implemented in our service line, 20 of 306 cases (6.5%) were diagnosed with TFEB amplification. Importantly, TFE3 and TFEB rearrangements were never co-detected within the same kidney tumor. Patients with TFEB amplification were significantly older (P < .001) than patients with TFE3 or TFEB translocation. Kidney tumors with TFEB amplification were seen to be at least 3 times as common as those with TFEB translocation., Conclusions: Clinical TFE3/TFEB FISH assays successfully identified and confirmed rare MiTF-RCC with TFE3 and TFEB rearrangements. Although morphologic and biomarker features associated with a kidney tumor may be suggestive of MiTF-RCC, clinical TFE3/TFEB FISH assays are crucial for a confirmation and definitive subclassification of patients with MiTF-RCC., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is an ongoing need to develop prognostic biomarkers to improve the management of clear cell renal cell carcinoma (ccRCC)., Objective: To leverage enriched pathways in ccRCC to improve risk-stratification., Design, Setting, and Participants: We retrospectively identified two complementary discovery cohorts of patients with ccRCC who underwent (1) radical nephrectomy (RNx) with inferior vena cava tumor thrombectomy (patients = 5, samples = 24) and (2) RNx for localized disease and developed recurrence versus no recurrence (n = 36). Patients with localized ccRCC (M0) in The Cancer Genome Atlas (TCGA, n = 386) were used for validation., Outcome Measurements and Statistical Analysis: A differential expression gene (DEG) analysis was performed on targeted RNA next-generation sequencing data from both discovery cohorts. Using TCGA for validation, Kaplan-Meier survival analysis and multivariable Cox proportional hazard testing were utilized to investigate the prognostic impact of DEGs, cell cycle proliferation (CCP), and a novel epithelial-mesenchymal transition (EMT) score on progression-free (PFS) and disease-specific (DSS) survival., Results and Limitations: In the discovery cohorts, we observed overexpression of WT1 and CCP genes in the tumor thrombus versus the primary tumor, as well as in patients with recurrence versus those without recurrence. A hallmark pathway analysis demonstrated enrichment of the EMT- and CCP-related pathways in patients with high WT1 expression in the TCGA (validation) ccRCC cohort. CCP and EMT scores were derived in the validation cohort, which was stratified into four risk groups using Youden Index cut points: CCP low /EMT low , CCP low /EMT high , CCP high /EMT l ow , and CCP high /EMT hig h . The CCP high /EMT hig h risk group was associated with the worst PFS and DSS (both p < 0.001). In a multivariable analysis, CCP high /EMT hig h was independently associated with poor PFS and DSS (hazard ratio = 4.6 and 10.3, respectively; p < 0.001)., Conclusions: We demonstrate the synergistic prognostic impact of EMT in tumors with a high CCP score. Our novel EMT score has the potential to improve risk stratification and provide potential novel therapeutic targets., Patient Summary: Genes involved in epithelial-mesenchymal transition provides important prognostic information for patients with clear cell renal cell carcinoma., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Renal cell carcinoma (RCC) is a heterogeneous group of neoplasms derived from the renal tubular epithelial cells. Chromophobe RCC (chRCC) is the third most common subtype of RCC, accounting for 5% of cases. chRCC may be detected as an incidental finding or less commonly may manifest with clinical symptoms. The mainstay of therapy for chRCC is surgical resection. chRCC has a better prognosis compared with the more common clear cell RCC. At gross pathologic analysis, chRCC is a solid well-defined mass with lobulated borders. Histologic findings vary by subtype but include large pale polygonal cells with abundant transparent cytoplasm, crinkled "raisinoid" nuclei with perinuclear halos, and prominent cell membranes. Pathologic analysis reveals only moderate vascularity. The most common imaging pattern is a predominantly solid renal mass with circumscribed margins and enhancement less than that of the renal cortex. The authors discuss chRCC with emphasis on correlative pathologic findings and illustrate the multimodality imaging appearances of chRCC by using cases from the Radiologic Pathology Archives of the American Institute for Radiologic Pathology. © RSNA, 2021.

Aims: Renal cell carcinomas are relatively rare in children and young adults. While well characterised in adults, the morphological and molecular characterisation of these tumours in young patients is relatively lacking. The objective of this study was to explore the spectrum of renal cell carcinoma (RCC) subtypes in children and young adults and to determine their clinico-pathological, immunohistochemical and molecular characteristics by evaluating a large retrospective cohort of renal cell carcinoma patients age 30 years or younger., Methods and Results: Sixty-eight cases with confirmed diagnosis of renal cell carcinoma at age 30 years or younger were identified at our institution. Clear cell carcinoma accounted for the most common subtype seen in this age group. Translocation renal cell carcinoma and rare familial syndrome subtypes such as succinate dehydrogenase deficient renal cell carcinoma and tuberous sclerosis complex-associated renal cell carcinoma were found relatively more frequently in this cohort. Despite applying the 2016 WHO classification criteria, a high proportion of the tumours in our series remained unclassified., Conclusions: Our results suggest that renal cell carcinoma in children and young adults is a relatively rare disease that shares many histological similarities to renal cell carcinoma occurring in adults and yet demonstrate some unique clinical-pathological differences. Microphthalmia-associated transcription (MiT) family translocation RCC and rare familial syndrome subtypes are relatively more frequent in the paediatric and adolescent age groups than in adults. Clear cell RCC still accounted for the most common subtype seen in this age group. MiT family translocation RCC patients presented with advanced stage disease and had poor clinical outcomes. The large and heterogeneous subgroup of unclassified renal cell carcinoma contains phenotypically distinct tumours with further potential for future subcategories in the renal cell carcinoma classification., (© 2019 John Wiley & Sons Ltd.)

Hereditary renal cell carcinoma syndromes (HRCCS) are characterized by the presence of pathogenic germline variants that predispose patients to renal cell carcinomas as well as additional extra-renal manifestations. The importance of identifying HRCCS patients cannot be overemphasized, as patients and their families can begin surveillance for syndrome-associated manifestations once identified. The present study is a retrospective clinical and morphologic review of 60 hereditary renal tumors from 30 HRCCS patients treated at our institution with either Von Hippel-Lindau disease (VHL), Birt-Hogg-Dubé syndrome (BHD), tuberous sclerosis complex (TSC), hereditary leiomyomatosis and renal cell cancer syndrome, or succinate dehydrogenase (SDH) deficiency syndrome. Hereditary renal cell carcinoma syndromes kidney tumors often demonstrate specific morphologic features, characteristic background changes in renal parenchyma, and extra-renal manifestations, which, when recognized by the pathologist, can trigger genetic testing referral for specific familial cancer syndromes. Our study demonstrates the majority of tumors were consistent with the anticipated clinicopathologic profile of renal tumors found within HRCCS patients, although we found some unique characteristics within this cohort including a case of clear cell papillary renal cell carcinoma within a VHL patient, and a unique renal tumor with tubulopapillary features present in a patient with a germline SDHD mutation. Additionally, although the literature reports the presence of epithelioid angiomyolipoma (AML) as a common occurrence in TSC patients, our cohort of 3 patients with AMLs demonstrated only classic features. The findings we describe facilitate pathologist-based recognition of HRCCS and can prompt genetic evaluation for relevant patients.

Five percent of urothelial carcinoma occurs in the upper urinary tract (UUT), a challenging location to biopsy. We aim to evaluate concordance between biopsy, cytology, and resection specimens in a large upper tract urothelial carcinoma (UTUC) cohort. One hundred seventeen UTUC resections with UUT biopsy and/or cytology specimens from 2000 to 2016 were retrieved; pathologic material was re-reviewed, evaluated for concordance, and correlated with clinical information. Fourteen percent of preoperative biopsies, including 8 from the renal pelvis and 6 from the ureter, lacked neoplastic diagnoses. Seventy-seven percent of diagnostic biopsies included subepithelial tissue; 11% demonstrated reclassification of grade and 30% demonstrated reclassification of invasion status. Twenty-six percent of renal pelvis UTUC and 36% of ureter UTUC were invasive only on resection. Of 18 UTUCs reclassified from noninvasive high-grade papillary urothelial carcinoma to invasive high-grade papillary urothelial carcinoma, 39% had prior radical cystectomy (versus 8% invasive UTUC and 11% noninvasive UTUC with concordant biopsies). Most high-grade UTUC (88%) and some low-grade UTUC (58%) resections had abnormal cytology results. Biopsy-resection pairs with concordant invasion status and pairs with discordant invasion status showed similar rates of recurrence (38% versus 38%) and metastasis (25% versus 27%). Fourteen percent of UUT biopsies lacked diagnostic neoplastic material. Grade concordance between biopsy and resection was high (89%), but 30% of cases showed invasion only on resection. Subepithelial tissue was less commonly present in ureter biopsies, particularly from the midureter or proximal ureter. UTUC in patients with prior cystectomy were more likely to show invasion on resection but not biopsy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is rare and highly aggressive and is believed to arise mostly in the setting of hereditary leiomyomatosis-RCC syndrome with a germline mutation of FH. Because of the aggressiveness of these tumors and a frequent lack of ascertainable family history, these tumors may first present as metastases and be sampled by cytology. The cytologic findings of FH-deficient RCC have not previously been reported., Methods: Cytologic and limited biopsy samples from patients with FH-deficient RCC were reviewed retrospectively., Results: In total, 24 cytologic and limited biopsy samples from 19 patients (6 women and 13 men; age range, 22-69 years) who had FH-deficient RCC and metastasis at presentation were evaluated. These included 21 cytology samples ranging from malignant effusions (n = 7) to metastases (n = 11), to samples of primary kidney tumors (n = 3). The samples exhibited cells, often in clusters and abortive papillae, with voluminous, finely vacuolated cytoplasm and large, pleomorphic nuclei with prominent, viral inclusion-like nucleoli. A distinctive finding of peripheral cytoplasmic clearing frequently was apparent, and intranuclear cytoplasmic pseudoinclusions were less frequent. Of 7 cell block and biopsy samples, several of which represented sampling from the same patient, all demonstrated tissue fragments that had discernable morphologic patterns associated with FH-deficient RCC, including tubulocystic and intracystic papillary growth., Conclusions: Features characteristic and suggestive of FH-deficient RCC may be identified in cytologic and small biopsy samples. Although the current samples were identified retrospectively in well characterized cases of FH-deficient RCC, the authors argue that, with appropriate clinical correlation, these features are sufficiently distinctive to trigger recognition and confirmatory workup., (© 2018 American Cancer Society.)

Purpose of Review: Large-scale genomic profiling has shed new light on the molecular underpinnings of renal cell carcinoma (RCC), spurring a much needed refinement of RCC subclassification based on an integrative assessment of histopathologic features and molecular alterations. At the same time, renal mass biopsies have become increasingly commonplace, necessitating ancillary tools to help guide clinical management. Herein, we briefly review our current understanding of RCC genomics, highlighting areas of possible clinical utility, as well as potential limitations, for renal mass biopsies., Recent Findings: Distinct RCC subtypes harbor characteristic molecular features, including somatic mutations, copy number alterations, and genomic rearrangements. Existing ancillary tools, including fluorescent in-situ hybridization and immunohistochemistry, may be useful for diagnostic subclassification. Recurrent secondary molecular alterations in clear cell RCC (BAP1, SETD2, PBRM1, and TP53) and papillary RCC (CDKN2A) may be associated with poor prognosis; however, intratumoral genomic heterogeneity may limit the clinical utility of these molecular biomarkers in renal mass biopsies., Summary: Recent technological advances have the potential to fundamentally alter the clinical management of RCC by leveraging our increasing understanding of RCC genomics to assess hundreds of molecular biomarkers simultaneously. Additional focused molecular analyses of renal mass biopsy cohorts are needed prior to widespread implementation of molecular biomarker assays.

Renal cell carcinomas with MITF aberrations demonstrate a wide morphologic spectrum, highlighting the need to consider these entities within the differential diagnosis of renal tumors encountered in clinical practice. Herein, we describe our experience with application of clinical fluorescence in situ hybridization (FISH) assays for detection of TFE3 and TFEB gene aberrations from 85 consecutive renal cell carcinoma cases submitted to our genitourinary FISH service. Results from 170 FISH assays performed on these tumors were correlated with available clinicopathologic findings. Ninety-eight percent of renal tumors submitted for FISH evaluation were from adult patients. Thirty-one (37%) tumors were confirmed to demonstrate MITF aberrations (21 TFE3 translocation, 4 TFEB translocation, and 6 TFEB amplification cases). Overall, renal cell carcinomas with MITF aberrations demonstrated morphologic features overlapping with clear cell, papillary, or clear cell papillary renal cell carcinomas. Renal cell carcinomas with MITF aberrations were significantly more likely to demonstrate dual (eosinophilic and clear) cytoplasmic tones (P=0.030), biphasic TFEB translocation renal cell carcinoma-like morphology (P=0.002), psammomatous calcifications (P=0.002), and nuclear pseudoinclusions (P=0.001) than renal cell carcinomas without MITF aberrations. Notably, 7/9 (78%) renal cell carcinomas exhibiting subnuclear clearing and linear nuclear array (6 of which showed high World Health Organization/International Society of Urological Pathology nucleolar grade) demonstrated TFE3 translocation, an association that was statistically significant when compared with renal cell carcinomas without MITF aberrations (P=0.009). In this cohort comprising consecutive cases, TFEB-amplified renal cell carcinomas were more commonly identified than renal cell carcinomas with TFEB translocations, and four (67%) of these previously unreported TFEB-amplified renal cell carcinomas demonstrated oncocytic and papillary features with a high World Health Organization/International Society of Urological Pathology nucleolar grade. In summary, TFE3 and TFEB FISH evaluation aids in identification and accurate classification of renal cell carcinomas with MITF aberrations, including TFEB-amplified renal cell carcinoma, which may demonstrate aggressive behavior.

Molecular and morphologic interrogation has driven a much-needed reexamination of renal cell carcinoma (RCC). Indeed, the recently released 2016 World Health Organization classification now recognizes 12 distinct RCC subtypes, as well as several other emerging/provisional RCC entities. From a clinical perspective, accurate RCC classification may have important implications for patients and their families, including prognostic risk stratification, targeted therapeutics selection, and identification for genetic testing. In this review, we provide a conceptual framework for approaching RCC diagnosis and classification by categorizing RCCs as tumors with clear cytoplasm, papillary architecture, and eosinophilic (oncocytic) cytoplasm. The currently recognized 2016 World Health Organization classification for RCC subtypes is briefly discussed, including new diagnostic entities (clear cell papillary RCC, hereditary leiomyomatosis and RCC-associated RCC, succinate dehydrogenase-deficient RCC, tubulocystic RCC, and acquired cystic disease-associated RCC) and areas of evolving RCC classification, such as transcription elongation factor B subunit 1 (TCEB1)-mutated RCC/RCC with angioleiomyoma-like stroma/RCC with leiomyomatous stroma, RCC associated with anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangement, thyroidlike follicular RCC, and RCC in neuroblastoma survivors. For each RCC subtype, relevant clinical, molecular, gross, and microscopic findings are reviewed, and ancillary studies helpful for its differential diagnosis are presented, providing a practical approach to modern RCC classification.

Translocation-associated renal cell carcinoma (t-RCC) is a relatively uncommon subtype of renal cell carcinoma characterized by recurrent gene rearrangements involving the TFE3 or TFEB loci. TFE3 and TFEB are members of the microphthalmia transcription factor (MiT) family, which regulates differentiation in melanocytes and osteoclasts, and MiT family gene fusions activate unique molecular programs that can be detected immunohistochemically. Although the overall clinical behavior of t-RCC is variable, emerging molecular data suggest the possibility of targeted approaches to advanced disease. Thus, distinguishing t-RCC from its morphologic, immunophenotypic, and molecular mimics may have important clinical implications. The differential diagnosis for t-RCC includes a variety of common renal neoplasms, particularly those demonstrating clear cell and papillary features; in addition, because of immunophenotypic overlap and/or shared molecular abnormalities (ie, TFE3 gene rearrangement), a distinctive set of nonepithelial renal tumors may also warrant consideration. Directed ancillary testing is an essential aspect to the workup of t-RCC cases and may include a panel of immunohistochemical stains, such as PAX8, pancytokeratins, epithelial membrane antigen, carbonic anhydrase IX, HMB-45, and Melan-A. Dual-color, break-apart fluorescent in situ hybridization for TFE3 or TFEB gene rearrangement may be helpful in diagnostically challenging cases or when molecular confirmation is needed.

Metanephric adenoma (MA) is a rare benign renal tumor comprised of a neoplastic proliferation of primitive metanephric tubular cells. A previous study identified BRAF V600E mutations in approximately 90% of MA and found that similar BRAF exon 15 mutations are exceedingly rare in other common renal tumors, including renal cell carcinoma and oncocytoma. A recent follow-up study has validated mutation-specific immunohistochemistry (IHC) for detection of BRAF V600E mutations in a small cohort of MA. Here, we extend these findings to a larger, independent cohort of MA, demonstrating an overall 88% sensitivity and 100% specificity for BRAF V600E IHC. In addition, we report 2 cases of MA with novel BRAF exon 15 mutations, including a V600D missense mutation and a compound V600D and K601L missense mutation. Finally, we evaluate BRAF V600E IHC in a large tissue microarray cohort of common renal tumors and find no significant expression in several renal cell carcinoma subtypes. These data support a role for BRAF V600E IHC in diagnostically challenging cases of MA and expand the spectrum of BRAF exon 15 mutations in this uncommon but unique renal neoplasm.

Renal cell carcinoma (RCC), clear cell type, is a commonly encountered metastatic tumor that can present at unusual anatomic sites many years after the primary tumor resection. Noncutaneous metastasis to the parotid gland is unusual; however, a number of cases of parotid RCC metastasis have been reported. Fine-needle aspiration biopsy (FNAB) is regularly utilized during the evaluation of salivary gland lesions, where it has a high sensitivity, specificity, and accuracy; however, the identification and definitive diagnosis of primary and metastatic clear cell neoplasms is a potential diagnostic pitfall for salivary gland FNAB. Here, we describe a case of RCC, clear cell type, metastatic to the parotid gland that was diagnosed entirely from FNAB cell block material, which is the first such reported case to our knowledge. We review the literature for cases of parotid RCC metastasis and focus on the utility of FNAB for synchronous versus metachronous presentations. Finally, we evaluate the differential diagnosis of clear cell parotid lesions, including ancillary histologic studies, and propose an algorithmic approach to clear cell neoplasms of the salivary gland., (© 2014 Wiley Periodicals, Inc.)

Rapid ("warm") autopsies of patients with advanced metastatic cancer provide invaluable insight into the natural history, pathobiology, and morphology of advanced and treatment-resistant tumors. Here, we report a rapid autopsy case of a hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patient with advanced metastatic renal cell carcinoma (RCC)-the first such case described for either a primary renal tumor or HLRCC-related cancer. Mutations in the fumarate hydratase (FH) gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors. Loss of heterozygosity at the wild-type FH gene locus results in profound cellular metabolic derangement, "pseudohypoxic" upregulation of hypoxia-inducible factor 1α (HIF-1α)-dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients. The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing. In addition, this patient's RCC demonstrated extensive sarcomatoid and rhabdoid features-morphologies not previously well described in HLRCC-associated kidney tumors. Here, we report the extent of metastatic dissemination and supplement this unique tumor morphology with mitochondrial enzyme histochemistry and extended immunohistochemical analysis. Tumor cells strongly expressed PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers was negative. We also detail microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules.