George J Netto

George J Netto
Johns Hopkins Medicine | JHUSOM · Department of Pathology

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550
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Publications

Publications (550)
Article
The fifth edition of the WHO blue book on urologic tumors, specifically in the bladder chapter, represents a refinement and update in the classification of bladder tumors building on the aggregate major changes made in previous editions. Progress in the molecular underpinnings of urothelial tumors, particularly with promising stratifiers for more p...
Article
The 2022 World Health Organization (WHO) classification of the urinary and male genital tumors was recently published by the International Agency for Research on Cancer. This fifth edition of the WHO “Blue Book” offers a comprehensive update on the terminology, epidemiology, pathogenesis, histopathology, diagnostic molecular pathology, and prognost...
Article
The fifth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO “Blue Book”), published in 2022, contains significant revisions. This review summarises the most relevant changes for renal, penile, and testicular tumours. In keeping with other volumes in the fifth edition series, the WHO classification of urogenita...
Article
Full-text available
Different programmed cell death-ligand 1 (PD-L1) assays and scoring algorithms are being used in the evaluation of PD-L1 expression for the selection of patients for immunotherapy in specific settings of advanced urothelial carcinoma (UC). In this paper, we sought to investigate three approved assays (Ventana SP142 and SP263, and Dako 22C3) in UC w...
Article
The 5th edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of prostatic carcinoma as well as incorporating advancements in assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: 1) recognition that PIN...
Article
The 5th edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems contains relevant revisions and introduces a group of molecularly defined renal tumour subtypes. Herein we present the World Health Organization (WHO) 2022 perspectives on papillary and chromophobe renal cell carcinoma with emphasis on their evolving classi...
Article
MEIS1::NCOA1/2 sarcomas are a newly recognized group of exceedingly rare low-grade spindle cell sarcomas that often involve the genitourinary and gynecologic tracts. Due to its deceptively low-grade morphology and the non-specific immunoprofile, these neoplasms may pose a diagnostic challenge by histologically mimicking other entities such as endom...
Article
Full-text available
Background: Accurate detection of SARS-CoV-2 is necessary to mitigate the COVID-19 pandemic. However, the test reagents and assay platforms are varied and may not be sufficiently robust to diagnose COVID-19. Methods: We reviewed 85 studies (21 530 patients), published from five regions of the world, to highlight issues involved in the diagnosis...
Article
Full-text available
GPNMB (Glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for MiT translocation renal cell carcinomas (tRCC). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCC and...
Article
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Renal cell carcinomas (RCC) are well-vascularized tumors. Although clear cell RCC (CCRCC) show a characteristic vascular network, some cases show overlapping features with other RCC. We aimed to evaluate vascular architectural patterns, microvessel density (MVD), and endothelial cell density (ECD) in CCRCC compared to clear cell papillary RCC (ccpR...
Chapter
Penile cancer is rare in the United States, but highly prevalent in South America, Africa, and some regions of Asia. Most patients present in their fifties to seventies with a mean age of 58 years. Several risk factors have been identified and include HPV infection, phimosis, cigarette smoking, and lichen sclerosus. Most penile carcinomas are squam...
Article
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The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been implicated. Our DNA microarray analysis in control vs. AR knockdown bladder cancer lines identified G...
Article
Urothelial carcinoma is characterized by the presence of a wide spectrum of histopathologic features and molecular alterations that contribute to its morphologic and genomic heterogeneity. It typically harbors high rates of somatic mutations with considerable genomic and transcriptional complexity and heterogeneity that is reflective of its varied...
Article
The 8th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual designates discontinuous involvement of spermatic cord soft tissue by testicular germ cell tumors as a metastatic deposit. We conducted a retrospective international multi-institutional study to validate the current recommendations. Thirty-three (72%) nonseminomatous an...
Article
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 interobserv...
Article
Full-text available
Urothelial carcinoma (UC) is a common urological malignancy with a high rate of disease recurrence. Telomerase activity, a hallmark of cancer characterized by overcoming the replicative senescence, is upregulated in over 90% of patients with UC. Somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) are frequently detec...
Article
The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer...
Article
MiT family translocation renal cell carcinoma (MiT-RCC) harbors translocations involving the TFE3 or TFEB genes. RCC with TFEB amplification is also identified and is associated with a more aggressive clinical course. Accurate diagnosis of MiT-RCC is crucial for patient management. In this study, we evaluated the performance of the Archer FusionPle...
Article
Full-text available
The immune infiltrate within tumors has proved to be very powerful in the prognostic stratification of patients and much attention is also being paid towards its predictive value. In this work we therefore aimed at clarifying the significance and impact of PD-L1 and PD-1 expression on the prognostic value of CD8 ⁺ tumor infiltrating lymphocytes (TI...
Article
Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer (PCa). Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a PCa model to investigate whether there is a gut microbiota-mediated connection between animal...
Article
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Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a pote...
Article
Eosinophilic, solid and cystic (ESC) renal cell carcinoma (RCC) is characterized by a solid and cystic architecture with cells showing abundant eosinophilic cytoplasm with hobnail arrangement and a cytokeratin 7-negative/cytokeratin 20-positive immunophenotype. Recent studies have suggested that bi-allelic events affecting TSC genes might play an i...
Article
Full-text available
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) rem...
Article
Full-text available
Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-p...
Article
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 g...
Article
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...
Preprint
Background Accurate detection of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is necessary to mitigate the coronavirus disease-19 (COVID-19) pandemic. However, the test reagents and assay platforms are varied and may not be sufficiently robust to diagnose COVID-19. Methods We reviewed 85 studies (21,530 patients), published from fi...
Preprint
Full-text available
Metastatic urothelial carcinoma of the bladder is generally incurable by current systemic therapy. Molecular characterization of bladder cancer (BLCa) has revealed multiple candidate driver genes for BLCa tumorigenesis. Epigenetic/chromatin modifiers have been shown to be frequently mutated in BLCa, with ARID1A mutations highly prevalent in nearly...
Article
The spectrum of neuroendocrine (NE) tumors in the genitourinary tract ranges from the aggressive large and small cell carcinomas to the often benign paraganglioma and well differentiated neuroendocrine tumor (WD-NET). At least 15 pure lower urinary tract (LUT) WD-NETs have been described. Due to the rarity of WD-NET in LUT and the limited number of...
Article
Full-text available
Angiomyolipomas (AMLs) are triphasic tumors (smooth muscle, vascular and adipocytic components) with myomelanocytic differentiation, arising most commonly in the kidneys, which can show predominant epithelioid morphology and fat-predominant or fat-poor variants. Fat-predominant AMLs can show areas of hypercellularity and lipoblast-like cells, and t...
Article
Renal cell carcinomas with t(6;11) chromosome translocation has been classically characterized by the rearrangement of the TFEB gene, located on chromosome 6, and MALAT1 gene, located on chromosome 11. Recently, a few other genes have been described as fusion partners in TFEB rearranged renal cell carcinomas. Although most of TFEB rearranged renal...
Article
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...
Article
Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF2 target genes, consequently inducing cell proliferation and other phenotypic changes in cancer cells. Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm. In urotheli...
Conference Paper
Introduction and Objective: The androgen receptor (AR) and estrogen receptor-β (ERβ) pathways have been implicated in urothelial tumor outgrowth, as well as chemoresistance, for which underlying mechanisms are poorly understood. Therefore, the present study aims to identify downstream effectors of AR and ERβ signals and further investigate their ro...
Article
Background: Standard of care for patients with muscle-invasive bladder cancer (MIBC) includes neoadjuvant cisplatin-based chemotherapy (NAC) followed by consolidative therapy with either chemoradiation or radical cystectomy (RC). Some patients experience robust pathologic responses to NAC, and these have been reported to associate with somatic muta...
Article
Full-text available
Enfortumab vedotin is a novel antibody–drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohist...
Article
Full-text available
Vulvar squamous cell carcinoma accounts for 5% of cancers of the female genital tract. Current guidelines recommend wide local excision with negative surgical margins as the standard treatment. However, the extent of the tumor-free resection margin after wide local excision is still controversial in many cases. Drugs targeting immune checkpoints su...
Article
Full-text available
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, an...
Article
Full-text available
Adipocytokines such as leptin and adiponectin have functions in metabolism as well as the development and progression of various types of malignancies. However, little is known about their role in bladder cancer. In this study, we investigated whether leptin, adiponectin, and their receptors have an impact on bladder cancer outgrowth and the mechan...
Article
Full-text available
Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity...
Article
Full-text available
Recent studies showed the clinical utility of next-generation sequencing of urinary cell-free DNA (cfDNA) from patients with urothelial bladder cancer (UBC). In this study, we aimed to develop urinary cfDNA analysis by droplet digital PCR (ddPCR) as a high-throughput and rapid assay for UBC detection and prognosis. We analyzed urinary cfDNA of 202...
Article
Full-text available
Urine cytology is an essential element of the diagnostic work up of hematuria. A significant proportion of cases continue to be placed in the “atypical” or “suspicious” categories of the Paris system for urine cytology, posing difficulty in patient management. We report on the performance of our recently described urine-based assay “UroSEEK” in cas...
Article
Androgen receptor (AR) and estrogen receptor-β (ERβ) have been implicated in urothelial tumor outgrowth as promoters, while underlying mechanisms remain poorly understood. Our transcription factor profiling previously performed identified FOXO1 as a potential downstream target of AR in bladder cancer cells. We here investigated the functional role...
Chapter
Neoplasms of the prostate and bladder are among the most common solid tumors. Recent genomic advances have contributed to our understanding of the key driver genetic alterations in these malignancies offering new opportunities for targeted therapy. Novel molecular classifications have been suggested.
Article
Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with...
Article
Full-text available
Cancer cells utilize vitamin folate to fulfill their excessive demand for nucleotides and amino acids. Dihydrofolate reductase (DHFR), an enzyme involved in folate metabolism converts dihydrofolate into tetrahydrofolate, which is required for the de novo synthesis of purines, and certain amino acids. DHFR inhibitors are used as a chemotherapeutic a...
Article
Full-text available
The Cancer Genome Atlas project introduced genomic taxonomy of basal and luminal molecular subtypes in muscle invasive bladder cancer. Fewer studies have addressed the molecular classification in non-muscle invasive bladder cancer (NMIBC). Our aim is to assess the applicability of the proposed phenotypic classification for NMIBC. Three TMAs were co...
Article
Aims: Among renal cell carcinoma (RCC) the tumour immune microenvironment has been best characterised in clear cell RCC. In this study we investigated the expression of several immune markers, including PD-L1, FoxP3 and CD8 in primary and metastatic papillary RCC. Methods and results: Three tissue microarrays were constructed from 78 cases with...
Preprint
Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Disease incidence and survival rates vary based on aggressiveness and treatment options. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. For a minority (~20%) of patients, T-cell checkpoin...
Article
Background: Recent microarray and sequencing studies of prostate cancer showed multiple molecular alterations during cancer progression. It is critical to evaluate these molecular changes to identify new biomarkers and targets. We performed analysis of glycine-N-acyltransferase like 1 (GLYATL1) expression in various stages of prostate cancer in th...
Conference Paper
Introduction: Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1L) is a mitochondrial enzyme involved in the folate cycle by catalyzing the reaction of formyl-tetrahydrofolate to format and tetrahydrofolate (THF). THF is crucial for de novo purine and thymidylate synthesis and is also involved in the regeneration of methionine. Cancer cells rely on...
Article
Different studies have evaluated the comparability of various immunohistochemical assays for PD-L1 expression evaluation, with contrasting results. Besides the important issues related to analytic performance and comparability of validated assays, not all platforms are available in all laboratories; moreover, standardized assays are very expensive,...