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Cribriform growth pattern is well-established as an adverse pathologic feature in prostate cancer. The literature suggests "large" cribriform glands associate with aggressive behavior; however, published studies use varying definitions for "large". We aimed to identify an outcome-based quantitative cut-off for "large" vs "small" cribriform glands. We conducted an initial training phase using the tissue microarray based Canary retrospective radical prostatectomy cohort. Of 1287 patients analyzed, cribriform growth was observed in 307 (24%). Using Kaplan-Meier estimates of recurrence-free survival curves (RFS) that were stratified by cribriform gland size, we identified 0.25 mm as the optimal cutoff to identify more aggressive disease. In univariable and multivariable Cox proportional hazard analyses, size >0.25 mm was a significant predictor of worse RFS compared to patients with cribriform glands ≤0.25 mm, independent of pre-operative PSA, grade, stage and margin status (p 0.25 mm had a significantly lower RFS relative to patients with cribriform glands ≤0.25 mm (each subset p = 0.004). Furthermore, there was no significant difference in outcomes between patients with cribriform glands ≤ 0.25 mm and patients without cribriform glands. The >0.25 mm cut-off was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort by biochemical recurrence, metastasis-free survival, and disease specific death, even when cases with admixed Gleason pattern 5 carcinoma were excluded. In summary, our findings support reporting cribriform gland size and identify 0.25 mm as an optimal outcome-based quantitative measure for defining "large" cribriform glands. Moreover, cribriform glands >0.25 mm are associated with potential for metastatic disease independent of Gleason pattern 5 adenocarcinoma.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is the first-line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by IHC and RNA sequencing, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacologic ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases, we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a novel SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5 of 52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacologic ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Furthermore, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer.Significance:Anaplastic lymphoma kinase (ALK) is a validated drug target in cancer. Here we delineate the spectrum of ALK alterations in prostate cancer. We show that ALK overexpression is present in advanced prostate cancers, in particular in cases with features of neuroendocrine carcinoma. Furthermore, ALK expression is associated with responses to pharmacologic ALK inhibition. Our study demonstrates that ALK-directed therapies should be considered in selected prostate cancer cases.

Supplementary Figures 1-19, Tables 1-2

Purpose: Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues [LHRHa]).Experimental Design: Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa.Results: In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm3 vs. 0.06 cm3, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported.Conclusions: Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed. Clin Cancer Res; 23(9); 2169–76. ©2016 AACR.

Prostate androgen levels after enza or enza/dut/LHRHa. Tissue androgens from prostatectomy specimens after 6 months of therapy were measured by mass spectroscopy to determine levels of (A) pregnenolone, (B) progesterone, (C) DHEA, (D) AED, (E) testosterone, and (F) DHT. P values were calculated using the nonparametric Mann-Whitney test. Limits of quantification were 0.015 pg/mg for AED, progesterone, and testosterone, 0.03 pg/mg for DHT and pregnenolone, and 0.49 pg/mg for DHEA.

Figure S3. Change in serum androgen levels after enza or enza/dut/LHRHa. Box plots of serum androgens for each cohort at initiation of therapy (day 0) and at prostatectomy (day 180) are depicted for each treatment arm. Levels of (A) pregnenolone, (B) progesterone, (C) DHEA, (D) AED, (E) testosterone, and (F) DHT were measured by mass spectroscopy. P values were calculated using the nonparametric Mann-Whitney test. Limits of quantification were 0.005 ng/mL for AED, progesterone and testosterone, 0.001 ng/mL for DHT and pregnenolone, and 0.15 ng/mL for DHEA.

Figure S4. Correlation of immunohistochemical expression of the glucocorticoid receptor (GR) after enza or enza/dut/LHRHa with residual cancer burden (RCB). A tissue microarray comprising cores of cancer tissue from each patient was analyzed for RCB and nuclear expression of GR expressed as total proportion of GR-positive tumor nuclei in (A) enza-treated and (B) enza/dut/LHRHa-treated patients. P values were calculated using the nonparametric Mann-Whitney test.

Residual cancer burden (RCB) from each patient in the (A) enza and (B) enza/dut/LHRHa arms.

Supplementary Table 2 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Supplementary Figure 5 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Supplementary Figure 1 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Supplementary Figure 2 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Supplementary Table 3 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Supplementary Table 4 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer. [Cancer Res 2007;68(1):132–42]

Supplementary Table 1 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Supplementary Figure 3 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Supplementary Figure 4 from Paxillin Is a Target for Somatic Mutations in Lung Cancer: Implications for Cell Growth and Invasion

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is the first-line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by IHC and RNA sequencing, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacologic ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases, we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a novel SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5 of 52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacologic ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Furthermore, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer. Significance: Anaplastic lymphoma kinase (ALK) is a validated drug target in cancer. Here we delineate the spectrum of ALK alterations in prostate cancer. We show that ALK overexpression is present in advanced prostate cancers, in particular in cases with features of neuroendocrine carcinoma. Furthermore, ALK expression is associated with responses to pharmacologic ALK inhibition. Our study demonstrates that ALK-directed therapies should be considered in selected prostate cancer cases.

Summary Renal cell tumors with oncocytic phenotypes represent a daily challenge, with several novel, emerging, and provisional entities enriching the diagnostic repertoire. Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), low-grade oncocytic tumor (LOT), and eosinophilic vacuolated tumor (EVT) have been recognized as unique entities, although their distinctive nature remains controversial. Although most of these tumors are sporadic, rare reports of similar tumors in tuberous sclerosis complex (TSC) have been published. We describe multifocal, often bilateral, tumors in six patients without personal or family history of syndromic diseases. More than 60 tumors in various combinations were identified in 10 nephrectomies and one biopsy encompassing ESC-RCC (n = 6), LOT (n = 14), EVT (n = 1), clear cell RCC with fibromyomatous stroma (n = 12), clear cell RCC (n = 2), angiomyolipomas (AMLs; n > 20), unclassified renal cell tumors (n = 2), papillary adenomas (n = 4), and renomedullary interstitial cell tumor (n = 1). TSC1 germline pathogenic mutations were confirmed in two patients. A tumor without germline testing in a third patient revealed TSC1 biallelic inactivation. Two additional patients had molecular testing, which excluded common renal mutations and syndromes. We provide the first evidence of co-existence in the same organ and unequivocal relatedness of ESC-RCC, EVT, and LOT. End-stage renal disease was present in three of six patients with precursor lesions to all above tumors within adjacent renal parenchyma. In conclusion, identification of multifocal tumors with TSC-like morphology, especially in association with AMLs, could be the first manifestation of clinically silent TSC guiding clinical recommendations for further genetic testing and/or treatment recommendations.

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.

Ganglioneuromas are rare, benign, well-differentiated neural crest tumors arising in the paravertebral sympathetic chain, and are classically non-secretory and clinically asymptomatic. As the diagnosis of ganglioneuroma is based on histopathology, the clinical presentation prior to surgical excision often mirrors that of pheochromocytoma or adrenal cortical adenoma. We describe a case of an incidentally found right sided calcified adrenal mass with evidence of marked dopamine excess, suspicious for pheochromocytoma in a 70-year-old female. The patient endorsed a 6-month history of intermittent right flank pain and a 2-year history of weight loss and fatigue. She reported mild symptoms of hypomania but denied other symptoms of dopamine excess including agitation, anxiety, nausea, and vomiting. Exam revealed isolated mild hypertension. The imaging features of this mass were concerning for malignancy including the presence of macrocalcification and irregular borders. After preoperative alpha blockade, the patient underwent open right adrenalectomy and the final pathology was consistent with ganglioneuroma rather than pheochromocytoma. Following resection, the dopamine level normalized, confirming the resected right adrenal ganglioneuroma as the source of dopamine excess. This case represents a rare presentation of dopamine-secreting adrenal ganglioneuroma. This illustrates that although rare, ganglioneuroma should be included on the differential diagnosis for functional adrenal tumors.

Solitary fibrous tumors are mesenchymal fibroblastic tumors that were originally described as intrathoracic lesions but have since been found to occur in many other locations. They may rarely occur as paratesticular masses. Here we present a peculiar case of a solitary fibrous tumor arising in the paratesticular region and exhibiting leiomyoma-like morphology. Confirmation of the tumor as a solitary fibrous tumor was achieved by RNA sequencing showing NAB2::STAT6 fusion. Possible explanations for the unusual tumor morphology include entrapment of normal smooth muscle elements and tumor differentiation into smooth muscle type cells.

Over the past 20 years, the number of subtypes of renal epithelial cell neoplasia has grown. This growth has resulted from detailed histological and immunohistochemical characterization of these tumors and their correlation with clinical outcomes. Distinctive molecular phenotypes have validated the unique nature of many of these tumors. This growth of unique renal neoplasms has continued after the 2016 World Health Organization (WHO) Classification of Tumours. A consequence is that both the pathologists who diagnose the tumors and the clinicians who care for these patients are confronted with a bewildering array of renal cell carcinoma variants. Many of these variants have important clinical features, i.e. familial or syndromic associations, genomics alterations that can be targeted with systemic therapy, and benignancy of tumors previously classified as carcinomas. Our goal in the review is to provide a practical guide to help recognize these variants, based on small and distinct sets of histological features and limited numbers of immunohistochemical stains, supplemented, as necessary, with molecular features.

Chromophobe renal cell carcinoma (ChRCC) accounts for 5% to 7% of all renal cell carcinomas. It was thought for many years that ChRCC exhibits a hypodiploid genome. Recent studies using advanced molecular genetics techniques have shown more complex and heterogenous pattern with frequent chromosomal gains. Historically, multiple losses of chromosomes 1, 2, 6, 10, 13, 17, and 21 have been considered a genetic hallmark of ChRCC, both for classic and eosinophilic ChRCC variants. In the last 2 decades, multiple chromosomal gains in ChRCCs have also been documented, depicting a considerably broader genetic spectrum than previously thought. Studies of rare morphologic variants including ChRCC with pigmented microcystic adenomatoid/multicystic growth, ChRCC with neuroendocrine differentiation, ChRCC with papillary architecture, and renal oncocytoma-like variants also showed variable chromosomal numerical aberrations, including multiple losses (common), gains (less common), or chromosomal changes overlapping with renal oncocytoma. Although not the focus of the review, The Cancer Genome Atlas (TCGA) data in ChRCC show TP53, PTEN, and CDKN2A to be the most mutated genes. Given the complexity of molecular genetic alterations in ChRCC, this review analyzed the existing published data, aiming to present a comprehensive up-to-date survey of the chromosomal abnormalities in classic ChRCC and its variants. The potential role of chromosomal numerical aberrations in the differential diagnostic evaluation may be limited, potentially owing to its high variability.

RATIONALE AND OBJECTIVES: To explore a role for multiparametric MRI (mpMRI) as a biomarker of response to neoadjuvant androgen deprivation therapy (ADT) for prostate cancer (PCa). MATERIALS AND METHODS: This prospective study was approved by the institutional review board and was HIPAA compliant. Eight patients with localized PCa had a baseline mpMRI, repeated after 6-months of ADT, followed by prostatectomy. mpMRI indices were extracted from tumor and normal regions of interest (TROI/NROI). Residual cancer burden (RCB) was measured on mpMRI and on the prostatectomy specimen. Paired t-tests compared TROI/NROI mpMRI indices and pre/post-treatment TROI mpMRI indices. Spearman’s rank tested for correlations between MRI/pathology-based RCB, and between pathological RCB and mpMRI indices. RESULTS: At baseline, TROI apparent diffusion coefficient (ADC) was lower and dynamic contrast enhanced (DCE) metrics were higher, compared to NROI (ADC: 806 ± 137 × 10(−6) vs. 1277 ± 213 × 10(−6) mm(2)/sec, p = 0.0005; K(trans): 0.346 ± 0.16 vs. 0.144 ± 0.06 min(−1), p = 0.002; AUC(90): 0.213 ± 0.08 vs. 0.11 ±1 0.03, p = 0.002). Post-treatment, there was no change in TROI ADC, but a decrease in TROI K(trans) (0.346 ± 0.16 to 0.188 ± 0.08 min; p = 0.02) and AUC(90) (0.213 ± 0.08 to 0.13 ± 0.06; p = 0.02). Tumor volume decreased with ADT. There was no difference between mpMRI-based and pathology-based RCB, which positively correlated (⍴ = 0.74–0.81, p < 0.05). Pathology-based RCB positively correlated with post-treatment DCE metrics (⍴ = 0.76–0.70, p< 0.05) and negatively with ADC (⍴ = −0.79, p = 0.03). CONCLUSION: Given the heterogeneity of PCa, an individualized approach to ADT may maximize potential benefit. This pilot study suggests that mpMRI may serve as a biomarker of ADT response and as a surrogate for RCB at prostatectomy.

BACKGROUND: Plasmacytoid urothelial carcinoma is a rare bladder cancer variant with scarce data on outcomes and prognostic factors. OBJECTIVE: We report our institutional experience with this histology to determine response to neoadjuvant chemotherapy, definitive surgery and survival. METHODS: We conducted a retrospective chart review of consecutive patients with plasmacytoid, as well as conventional urothelial carcinoma (for comparison) seen in our institution (2007– 2018). Baseline characteristics, clinicopathologic and treatment data were captured. T-test, chi-squared and log-rank test was used for group comparison. Kaplan Meier method was used for estimation of overall survival and Cox regression for identification of prognostic factors. RESULTS: 64 patients with plasmacytoid and 418 with conventional urothelial histology were identified; 53% of those with plasmacytoid presented with cT3/4 stage and 67% underwent extirpative surgery. Patients with plasmacytoid histology had higher rates of pT3/4 (65% vs. 28%), nodal disease (37% vs. 16%) and positive surgical margins (23% vs. 5%) compared to urothelial group (p

Translocation renal cell carcinoma (tRCC) with TFE3 gene rearrangements has been born as a distinct entity 20 years ago. These relatively rare tumors were notable among other RCC subtypes because of their disproportionally high incidence among children and young adults. Initial reports were focused on describing unifying morphologic criteria and typical clinical presentation. Follow-up studies of ancillary immunohistochemical and hybridization techniques provided additional diagnostic tools allowing recognition of tRCC tumors in practice. However, a growing body of literature also expanded the clinicomorphologic spectrum of tRCCs, to include a significant morphologic overlap with other RCC variants thus blurring the diagnostic clarity of this entity. More recent molecular studies utilizing next-generation sequencing technology accelerated recognition of numerous novel gene partners fusing at different breakpoints with the TFE3 gene. Accumulating data indicates that morphologic and clinical heterogeneity of tRCC could be explained by fusion subtypes, and knowledge of TFE3 partnering genes may be important in predicting tumor behavior. Herein we provided a comprehensive analysis of ∼400 tRCC cases with known TFE3 fusion partners, estimated their relative incidence and summarized clinicomorphologic features associated with most common fusion subtypes. Our data was based on an extensive literature review and had a special focus on comparing immunohistochemistry, fluorescent in situ hybridization and contemporary molecular studies for the accurate diagnosis of tRCC.

Paragangliomas are rare neuroendocrine tumors which originate from embryonic neural crest cells. These tumors may arise from parasympathetic or sympathetic paraganglia, may secrete catecholamines, and can occur in varied anatomic locations, with some locations being less common than others. Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas and pheochromocytomas and have been associated with germline heterozygous mutations in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127. Herein, we report a case of a middle-aged male who was diagnosed with an intrarenal/renal pelvis paraganglioma after presenting in hypertensive crisis with palpitations, headache, and diaphoresis. He was later found to have extensive metastatic disease, as well as genetic testing that showed biallelic inactivation of SDHB and a co-occurring somatic ATRX mutation. Respectively, these germline and somatic mutations have been associated with increased risk of metastatic spread and clinical aggressiveness. Despite multiple surgical resections and various treatment modalities, the patient eventually elected for palliative care measures and died of disease. Together, the findings seen in this patient are unique and serve as an appropriate catalyst for discussing the unusual locations, interesting genetic profiles, and metastatic risk factors that may be associated with paragangliomas.

Background Transcriptional dysregulation drives cancer formation but the underlying mechanisms are still poorly understood. Renal cell carcinoma (RCC) is the most common malignant kidney tumor which canonically activates the hypoxia-inducible transcription factor (HIF) pathway. Despite intensive study, novel therapeutic strategies to target RCC have been difficult to develop. Since the RCC epigenome is relatively understudied, we sought to elucidate key mechanisms underpinning the tumor phenotype and its clinical behavior. Methods We performed genome-wide chromatin accessibility (DNase-seq) and transcriptome profiling (RNA-seq) on paired tumor/normal samples from 3 patients undergoing nephrectomy for removal of RCC. We incorporated publicly available data on HIF binding (ChIP-seq) in a RCC cell line. We performed integrated analyses of these high-resolution, genome-scale datasets together with larger transcriptomic data available through The Cancer Genome Atlas (TCGA). Findings Though HIF transcription factors play a cardinal role in RCC oncogenesis, we found that numerous transcription factors with a RCC-selective expression pattern also demonstrated evidence of HIF binding near their gene body. Examination of chromatin accessibility profiles revealed that some of these transcription factors influenced the tumor's regulatory landscape, notably the stem cell transcription factor POU5F1 (OCT4). Elevated POU5F1 transcript levels were correlated with advanced tumor stage and poorer overall survival in RCC patients. Unexpectedly, we discovered a HIF-pathway-responsive promoter embedded within a endogenous retroviral long terminal repeat (LTR) element at the transcriptional start site of the PSOR1C3 long non-coding RNA gene upstream of POU5F1. RNA transcripts are induced from this promoter and read through PSOR1C3 into POU5F1 producing a novel POU5F1 transcript isoform. Rather than being unique to the POU5F1 locus, we found that HIF binds to several other transcriptionally active LTR elements genome-wide correlating with broad gene expression changes in RCC. Interpretation Integrated transcriptomic and epigenomic analysis of matched tumor and normal tissues from even a small number of primary patient samples revealed remarkably convergent shared regulatory landscapes. Several transcription factors appear to act downstream of HIF including the potent stem cell transcription factor POU5F1. Dysregulated expression of POU5F1 is part of a larger pattern of gene expression changes in RCC that may be induced by HIF-dependent reactivation of dormant promoters embedded within endogenous retroviral LTRs.

Purpose: Tumor androgens in castration-resistant prostate cancer (CRPC) reflect de novo intratumoral synthesis or adrenal androgens. We used C.B.-17 SCID mice in which we observed adrenal CYP17A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo. Experimental Design: We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy (ADX). We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients. Results: Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, androstenedione (AED), and testosterone (T) in castrated mice became undetectable after ADX (all P < 0.05). ADX prolonged median survival (days) in both CRPC models (33 vs. 179; 25 vs. 301) and suppressed tumor steroids versus castration alone (T 0.64 pg/mg vs. 0.03 pg/mg; DHT 2.3 pg/mg vs. 0.23 pg/mg; and T 0.81 pg/mg vs. 0.03 pg/mg, DHT 1.3 pg/mg vs. 0.04 pg/mg; all P ≤ 0.001). A subset of tumors recurred with increased steroid levels, and/or induction of androgen receptor (AR), truncated AR variants, and glucocorticoid receptor (GR). Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and nine expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3, and HSD17B3). Conclusions: Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of ADX-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical ADX than prior studies using abiraterone, suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Proof-of-concept studies with agents capable of achieving true “nonsurgical ADX” are warranted.

Renal mass lesions with a follicular architecture resembling atrophic kidney have been described, but their distinction from thyroid-like follicular carcinoma of the kidney remains controversial. We collected 8 cases of this purported "atrophic kidney"-like lesion to fully describe their clinical and histologic spectrum, their possible etiology, and to discuss their distinction from other renal neoplasms. Eight total cases were identified with patient ages ranging from 9 to 48 years (mean: 29 y; median: 28.5 y). Four patients were female and 4 were male. The tumors were unifocal and size ranged from 1.6 to 4.9 cm (mean: 3.4 cm; median: 3.4 cm). All 8 tumors had a remarkably similar histology. Each was enveloped by a smooth muscle rich capsule and had an overall low power "follicular" architecture. The luminal spaces of the "follicles" (or cysts) contained eosinophilic secretions and the lining epithelium was often flattened and atrophic, but some had more rounded cells with a distinctive hobnail arrangement. Many cysts contained discohesive round cells floating within the eosinophilic material, and some contained small intraluminal tufts with features of markedly atrophic glomeruli. Periodic acid-Schiff stains highlighted basement membrane material extending into these glomerular-like tufts, and some contained small distinct capillaries surrounded by endothelial cells, interspersed mesangial-like cells, and rare surrounding podocyte-like cells, providing additional evidence for glomerulocystic structures. Scattered calcifications were present within cysts (or within cyst walls) in varying numbers and were characterized by 2 types: psammoma body-like or more amorphous deposits. The tissue between cystic glomeruli contained predominantly small atrophic tubular structures, but collagenized stroma and smaller collapsed glomeruli were also present. The 2 tumors from the oldest 2 patients (48 and 39 y) had a more striking degree of stromal hyalinization. Immunohistochemically, the cyst lining cells had a predominant WT-positive/PAX-8 negative/CK7-negative phenotype, while tubules were typically WT-1 negative/PAX-8 positive/CK7-positive. Upon comparison to a control group of 10 kidneys containing incidental non-mass-forming glomerulocystic change, the morphologic features and immunophenotype were identical. To date, no patient has had any recurrence or aggressive clinical behavior based on follow status in 7 of 8 cases (follow-up range: 9 to 168 mo; median: 24 mo; mean: 40 mo). In summary, we describe the clinicopathologic features of 8 unique, benign "atrophic kidney"-like lesions that may simply represent a non-neoplastic form of organizing tubular atrophy and glomerulocystic change, and emphasize their distinction from thyroid-like follicular carcinoma of the kidney.

The severe acute respiratory syndrome coronavirus 2 pandemic has infected millions of individuals in the United States and caused hundreds of thousands of deaths. Direct infection of extrapulmonary tissues has been postulated, and using sensitive techniques, viral RNA has been detected in multiple organs in the body, including the kidney. However, direct infection of tissues outside of the lung has been more challenging to demonstrate. This has been in part due to misinterpretation of electron microscopy studies. In this perspective, we will discuss what is known about coronavirus infection, some of the basic ultrastructural cell biology that has been confused for coronavirus infection of cells, and rigorous criteria that should be used when identifying pathogens by electron microscopy.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy. Materials and methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics. Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/< 5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance. Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians. (C) 2020 Elsevier Inc. All rights reserved.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.

Summary Background MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. Methods We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. Findings Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6–12) than in the sunitinib group (5·6 months, 3–7; hazard ratio for progression or death 0·60, 0·37–0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. Interpretation Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. Funding National Institutes of Health and National Cancer Institute.

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.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).

We present our institutional experience with 46 patients diagnosed with micropapillary bladder carcinoma compared to conventional urothelial carcinoma, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare. We identified comparable pathologic response to neoadjuvant chemotherapy (NAC) across histologic subtypes, while micropapillary bladder carcinoma was not independently associated with worse outcomes, despite presenting with more aggressive features. The role of NAC should be further evaluated with additional studies in this setting. BACKGROUND: Micropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare. PATIENTS AND METHODS: We retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS. RESULTS: Our institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group. CONCLUSION: Pathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a recently described kidney cancer entity with

BackgroundMorphology, clinical behavior, and genomic profiles of renal oncocytoma (RO) and its malignant counterpart chromophobe renal cell carcinoma (ChRCC) are distinctly different. However, there is a substantial group of sporadic oncocytic tumors with peculiar hybrid phenotypes as well as a perplexing degree of morphologic and immunohistochemical overlap between classic RO and ChRCC with eosinophilic cytoplasm. The aim of this study is to provide detailed characterization of these hybrid tumors.DesignThirty eight sporadic oncocytic neoplasms with ambiguous morphology from two institutions were reviewed by 4 pathologists. CKIT positivity was used as a selection criterion. We correlated CK7 and S100A1 immunostaining and detailed morphologic features with cytogenetic profiles. DNA from the FFPE tissues was extracted and analyzed using Cytogenomic Microarray Analysis (CMA) to evaluate copy number alterations and ploidy.ResultsCMA categorized cases into 3 groups: RO (N=21), RO variant (N=7) and ChRCC (N=10). Cytogenetic RO had either no CNA (48%) or loss of chromosome 1p, X or Y (52%). RO-variant had additional chromosomal losses [-9q, –14 (n=2), –13] and chromosomal gains [+1q (n=2), +4, +7 (n=2), +13, +19, +20, and +22]. ChRCC were either hypodiploid with numerous monosomies (40%) or hypotetraploid with multiple relative losses (60%). RO, RO-variant and ChRCC groups differed significantly in tumor architecture (p5% cells (pConclusionsGenomic profile allows classification of oncocytic tumors with ambiguous morphology into RO, RO-variant and ChRCC. Several architectural and cytologic features combined with CK7 expression are significantly associated with cytogenetic RO, RO-variant or ChRCC tumors. Doubled hypodiploidy by whole genome endoduplication is a common phenomenon in eosinophilic ChRCC.Parts of this study were presented in an abstract form at the 104th annual meeting of the United Stated and Canadian Academy of Pathology, Boston, March 21–27, 2015

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update grading recommendations. Data Sources.— Critical review of the literature along with pathology and clinician surveys. Conclusions.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace “tertiary grade pattern” in radical prostatectomy (RP) with “minor tertiary pattern 5 (TP5),” and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) “atypical intraductal proliferation (AIP)” is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

Studies assessing tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC) and clinical outcomes have mixed results. Given fundamental interaction of MHC class I with CD8+ T-cells, we hypothesized that expression of MHC class I associated protein, beta-2-microglobulin (B2M), may be an important immunologic marker in RCC. We sought to understand potential implications of CD8 + TILs and tumor B2M expression on overall survival and response to high-dose interleukin-2 (IL-2) therapy, in a cohort of patients with high-stage (clinical stage III and IV) ccRCC. Four tumor regions from 56 patients with ccRCC were retrospectively assessed immunohistochemically. At a median follow-up time of 33 months, 22 (39%) patients had died of disease, 23 (41%) were alive disease, and 11 (20%) had no evidence of disease. Tumors with high CD8 + TILs had a significantly lower death rate [hazard ratio (HR): 0.33, p = 0.02]. CD8 + TILs correlated with B2M expression (p = 0.007). On multivariable analyses, patients with both high B2M and CD8 + TILs had lower death rate (HR: 0.27, p = 0.03). Within the subgroup treated with IL-2 (n = 27, 48%), tumors with high CD8 + TILs were more likely to respond to IL-2 therapy [coefficient (coef): 1.6, p = 0.05]. On multivariable analyses, tumors with a combination of both high B2M expression and high CD8 + TILs also showed trend to responding to IL-2 therapy (coef: 2.5, p = 0.06). In conclusion, abundant CD8+ TILs and high tumor expression of beta-2-microglobulin were good prognostic indicators associated with longer survival in patients with high-stage ccRCC. Abundant CD8+ TILs may predict response to IL-2 therapy.

PURPOSE The 17-gene Onco type DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort. MATERIALS AND METHODS Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models. RESULTS GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; P = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; P = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade ( P = .48). CONCLUSION In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.