Publications by authors named "George J Netto"

281 Publications

The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.

Eur Urol 2022 Jul 16. Epub 2022 Jul 16.

Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.

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 urogenital tumours follows a hierarchical classification and lists tumours by site, category, family, and type. The section "essential and desirable diagnostic criteria" included in the WHO fifth edition represents morphologic diagnostic criteria, combined with immunohistochemistry and relevant molecular tests. The global introduction of massive parallel sequencing will result in a diagnostic shift from morphology to molecular analyses. Therefore, a molecular-driven renal tumour classification has been introduced, taking recent discoveries in renal tumour genomics into account. Such novel molecularly defined epithelial renal tumours include SMARCB1-deficient medullary renal cell carcinoma (RCC), TFEB-altered RCC, Alk-rearranged RCC, and ELOC-mutated RCC. Eosinophilic solid and cystic RCC is a novel morphologically defined RCC entity. The diverse morphologic patterns of penile squamous cell carcinomas are grouped as human papillomavirus (HPV) associated and HPV independent, and there is an attempt to simplify the morphologic classification. A new chapter with tumours of the scrotum has been introduced. The main nomenclature of testicular tumours is retained, including the use of the term "germ cell neoplasia in situ" (GCNIS) for the preneoplastic lesion of most germ cell tumours and division from those not derived from GCNIS. Nomenclature changes include replacement of the term "primitive neuroectodermal tumour" by "embryonic neuroectodermal tumour" to separate these tumours clearly from Ewing sarcoma. The term "carcinoid" has been changed to "neuroendocrine tumour", with most examples in the testis now classified as "prepubertal type testicular neuroendocrine tumour".
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http://dx.doi.org/10.1016/j.eururo.2022.06.016DOI Listing
July 2022

ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors.

JCI Insight 2022 07 19. Epub 2022 Jul 19.

Department of Urology, The University of Alabama at Birmingham, Birmingham, United States of America.

Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient derived xenografts, we show that ARID1A-mutant tumors are more sensitive to EZH2 inhibition than ARID1A-wild type tumors. Mechanistic studies reveal that: 1) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via novel upregulation of a non-canonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling, and: 2) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show for the first time that PIK3IP1 inhibits PI3K signaling by inducing proteasomal degradation of PIK3R3. Further, ARID1A deficient bladder cancer is sensitive to combination therapies with EZH2 and PI3K inhibitors, in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K, and reveal mechanistic insights into the role of non-canonical PI3K constituents in bladder cancer biology.
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http://dx.doi.org/10.1172/jci.insight.155899DOI Listing
July 2022

WHO Classification of Tumours fifth edition: evolving issues in the classification, diagnosis, and prognostication of prostate cancer.

Histopathology 2022 Jun 27. Epub 2022 Jun 27.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

The fifth 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 the assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: (1) recognition that prostatic intraepithelial neoplasia (PIN)-like carcinoma is not synonymous with a pattern of ductal carcinoma, but better classified as a subtype of acinar adenocarcinoma; (2) a specific section on treatment-related neuroendocrine prostatic carcinoma in view of the tight correlation between androgen deprivation therapy and the development of prostatic carcinoma with neuroendocrine morphology, and the emerging data on lineage plasticity; (3) a terminology change of basal cell carcinoma to "adenoid cystic (basal cell) cell carcinoma" given the presence of an underlying MYB::NFIB gene fusion in many cases; (4) discussion of the current issues in the grading of acinar adenocarcinoma and the prognostic significance of cribriform growth patterns; and (5) more detailed coverage of intraductal carcinoma of prostate (IDC-P) reflecting our increased knowledge of this entity, while recommending the descriptive term atypical intraductal proliferation (AIP) for lesions falling short of IDC-P but containing more atypia than typically seen in high-grade prostatic intraepithelial neoplasia (HGPIN). Lesions previously regarded as cribriform patterns of HGPIN are now included in the AIP category. This review discusses these developments, summarising the existing literature, as well as the emerging morphological and molecular data that underpins the classification and prognostication of prostatic carcinoma.
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http://dx.doi.org/10.1111/his.14711DOI Listing
June 2022

WHO 2022 landscape of papillary and chromophobe renal cell carcinoma.

Histopathology 2022 May 21. Epub 2022 May 21.

Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland.

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 classification, differential diagnosis, and emerging entities. The WHO 2022 classification eliminated the type 1/2 papillary renal cell carcinoma (pRCC) subcategorization, given the recognition of frequent mixed tumour phenotypes and the existence of entities with a different molecular background within the type 2 pRCC category. Additionally, emerging entities such as biphasic squamoid alveolar RCC, biphasic hyalinising psammomatous RCC, papillary renal neoplasm with reverse polarity, and Warthin-like pRCC are included as part of the pRCC spectrum, while additional morphological and molecular data are being gathered. In addition to oncocytomas and chromophobe renal cell carcinoma (chRCC), a category of 'other oncocytic tumours' with oncocytoma/chRCC-like features has been introduced, including emerging entities, most with TSC/mTOR pathway alterations (eosinophilic vacuolated tumour and so-called 'low-grade' oncocytic tumour), deserving additional research. Eosinophilic solid and cystic RCC was accepted as a new and independent tumour entity. Finally, a highly reproducible and clinically relevant universal grading system for chRCC is still missing and is another niche of ongoing investigation. This review discusses these developments and highlights emerging morphological and molecular data relevant for the classification of renal cell carcinoma.
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http://dx.doi.org/10.1111/his.14700DOI Listing
May 2022

An introduction to the WHO 5th edition 2022 classification of testicular tumours.

Histopathology 2022 May 3. Epub 2022 May 3.

Memorial Sloan-Kettering Cancer Center, Pathology, New York, NY, USA.

The 5th edition of the World Health Organisation Blue Book was published recently and includes a comprehensive update on testicular tumours. This builds upon the work of the 4th edition, retaining its structure and main nomenclature, including the use of the term 'germ cell neoplasia in situ' (GCNIS) for the pre-invasive lesion of most germ cell tumours and division from those not derived from GCNIS. While there have been important developments in understanding the molecular underpinnings of testicular cancer, this updated classification paradigm and approach remains rooted in morphology. Nomenclature changes include replacement of the term 'primitive neuroectodermal tumour' by 'embryonic neuroectodermal tumour' based on the non-specificity of the former term and to separate these tumours clearly from Ewing sarcoma. Seminoma is placed in a germinoma family of tumours emphasising relation to those tumours at other sites. Criteria for the diagnosis of 'teratoma with somatic transformation' have been modified to not include variable field size assessments. The word 'carcinoid' has been changed to 'neuroendocrine tumour', with most examples in the testis now classified as 'prepubertal type testicular neuroendocrine tumour'. For sex cord-stromal tumours, the use of mitotic counts per high-power field has been changed to per mm2 for malignancy assessments, and the new entities, 'signet ring stromal tumour' and 'myoid gonadal stromal tumour', are defined. Well-differentiated papillary mesothelial tumour has now been defined as tumour type with a favourable prognosis. Sertoliform cystadenoma has been removed as an entity from testicular adnexal tumours and placed with Sertoli cell tumours.
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http://dx.doi.org/10.1111/his.14675DOI Listing
May 2022

Spindle Cell Sarcoma of the Uterus Harboring Fusion Gene and Mimicking Endometrial Stromal Sarcoma.

Int J Surg Pathol 2022 Apr 28:10668969221098081. Epub 2022 Apr 28.

O'Neal Comprehensive Cancer Center, 189178The University of Alabama at Birmingham, Birmingham, AL, USA.

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 endometrial stromal sarcoma, smooth muscle tumor, or uterine perivascular epithelioid cell tumor (PEComa). Histologically, sarcomas typically show spindle cell proliferation with hyperchromatic nuclei and a generalized cytologic uniformity, arranged in short fascicles and exhibiting alternating zones of hypo- and hypercellularity. Among the previously reported cases, molecular analysis revealed the fusion as the most commonly detected fusion gene, whereas the fusion gene has been reported in only a single case that involved kidney. Herein we report the first case of uterine sarcoma harboring the fusion gene that was initially misclassified as low-grade endometrial stromal sarcoma, demonstrating its clinicopathologic features, and highlighting the essential role of molecular pathology to arrive at the accurate diagnosis that may alter disease classification and inform therapy.
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http://dx.doi.org/10.1177/10668969221098081DOI Listing
April 2022

Meta-analysis of the robustness of COVID-19 diagnostic kit performance during the early pandemic.

BMJ Open 2022 04 21;12(4):e053912. Epub 2022 Apr 21.

Pathology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA

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 of COVID-19 in the early phase of the pandemic. All relevant articles, published up to 31 May 2020, in PubMed, BioRiXv, MedRiXv and Google Scholar, were included. We evaluated the qualitative (9749 patients) and quantitative (10 355 patients) performance of RT-PCR and serologic diagnostic tests for real-world samples, and assessed the concordance (5538 patients) between test performance in meta-analyses. Synthesis of results was done using random effects modelling and bias was evaluated according to QUADAS-2 guidelines.

Results: The RT-PCR tests exhibited heterogeneity in the primers and reagents used. Of 1957 positive RT-PCR COVID-19 participants, 1585 had positive serum antibody (IgM±IgG) tests (sensitivity 0.81, 95% CI 0.66 to 0.90). While 3509 of 3581 participants RT-PCR negative for COVID-19 were found negative by serology testing (specificity 0.98, 95% CI 0.94 to 0.99). The chemiluminescent immunoassay exhibited the highest sensitivity, followed by ELISA and lateral flow immunoassays. Serology tests had higher sensitivity and specificity for laboratory approval than for real-world reporting data.

Discussion: The robustness of the assays/platforms is influenced by variability in sampling and reagents. Serological testing complements and may minimise false negative RT-PCR results. Lack of standardised assay protocols in the early phase of pandemic might have contributed to the spread of COVID-19.
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http://dx.doi.org/10.1136/bmjopen-2021-053912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023849PMC
April 2022

High-fat diet promotes prostate cancer growth through histamine signaling.

Int J Cancer 2022 Aug 26;151(4):623-636. Epub 2022 Apr 26.

Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan.

Western high-fat diets (HFD) are regarded as a major risk factor for prostate cancer (PCa). Using prostate-specific Pten-knockout mice as a PCa model, we previously reported that HFD promoted inflammatory PCa growth. The composition of the gut microbiota changes under the influence of diet exert various effects on the host through immunological mechanisms. Herein, we investigated the etiology of HFD-induced inflammatory cancer growth and the involvement of the gut microbiome. The expression of Hdc, the gene responsible for histamine biosynthesis, and histamine levels were upregulated in large prostate tumors of HFD-fed mice, and the number of mast cells increased around the tumor foci. Administration of fexofenadine, a histamine H1 receptor antagonist, suppressed tumor growth in HFD-fed mice by reducing the number of myeloid-derived suppressor cells and suppressing IL6/STAT3 signaling. HFD intake induced gut dysbiosis, resulting in the elevation of serum lipopolysaccharide (LPS) levels. Intraperitoneal injection of LPS increased Hdc expression in PCa. Inhibition of LPS/Toll-like receptor 4 signaling suppressed HFD-induced tumor growth. The number of mast cells increased around the cancer foci in total prostatectomy specimens of severely obese patients. In conclusion, HFD promotes PCa growth through histamine signaling via mast cells. Dietary high-fat induced gut dysbiosis might be involved in the inflammatory cancer growth.
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http://dx.doi.org/10.1002/ijc.34028DOI Listing
August 2022

UALCAN: An update to the integrated cancer data analysis platform.

Neoplasia 2022 03 22;25:18-27. Epub 2022 Jan 22.

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA; Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Cancer genomic, transcriptomic, and proteomic profiling has generated extensive data that necessitate the development of tools for its analysis and dissemination. We developed UALCAN to provide a portal for easy exploring, analyzing, and visualizing these data, allowing users to integrate the data to better understand the gene, proteins, and pathways perturbed in cancer and make discoveries. UALCAN web portal enables analyzing and delivering cancer transcriptome, proteomics, and patient survival data to the cancer research community. With data obtained from The Cancer Genome Atlas (TCGA) project, UALCAN has enabled users to evaluate protein-coding gene expression and its impact on patient survival across 33 types of cancers. The web portal has been used extensively since its release and received immense popularity, underlined by its usage from cancer researchers in more than 100 countries. The present manuscript highlights the task we have undertaken and updates that we have made to UALCAN since its release in 2017. Extensive user feedback motivated us to expand the resource by including data on a) microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and promoter DNA methylation from TCGA and b) mass spectrometry-based proteomics from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). UALCAN provides easy access to pre-computed, tumor subgroup-based gene/protein expression, promoter DNA methylation status, and Kaplan-Meier survival analyses. It also provides new visualization features to comprehend and integrate observations and aids in generating hypotheses for testing. UALCAN is accessible at http://ualcan.path.uab.edu.
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http://dx.doi.org/10.1016/j.neo.2022.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788199PMC
March 2022

GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms.

J Pathol 2022 06 29;257(2):158-171. Epub 2022 Mar 29.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). 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 tRCCs and TSC1/2-associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR-Cas9 genome editing as well as in a mouse model of Tsc2 inactivation-driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n = 87), papillary RCC (papRCC, n = 53), chromophobe RCC (chRCC, n = 34), oncocytoma (n = 4), TFE3- or TFEB-driven tRCC (n = 56), eosinophilic solid and cystic RCC (ESC, n = 6), eosinophilic vacuolated tumor (EVT, n = 4), and low-grade oncocytic tumor (LOT, n = 3), as well as AML (n = 29) and perivascular epithelioid cell tumors (PEComas, n = 8). In cell lines, GPNMB was upregulated following TSC2 loss in a MiT/TFE- and mTORC1-dependent fashion. Renal tumors in Tsc2 A/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (p < 0.0001), papRCC (p < 0.0001), and chRCC (p < 0.0001). GPNMB expression in TSC1/2/MTOR alteration-associated renal tumors (including ESC, LOT, AML, and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and TSC1/2/MTOR alteration-associated renal tumors is highly overlapping, likely due to the increased activity of TFE3/TFEB in both, revealing an important caveat regarding the use of TFE3/TFEB-transcriptional targets as diagnostic markers. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9310781PMC
June 2022

BCG invokes superior STING-mediated innate immune response over radiotherapy in a carcinogen murine model of urothelial cancer.

J Pathol 2022 02 10;256(2):223-234. Epub 2021 Dec 10.

Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Radiation and bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response; however, comparison of STING pathway molecules and the immune landscape following treatment in urothelial carcinoma has not been performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15 Gy dose of radiation or three intravesical instillations of BCG (1 × 10  CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using the NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle-invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle-invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation. © 2021 The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8738146PMC
February 2022

Vascular architectural patterns in clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma.

Virchows Arch 2021 Dec 5;479(6):1187-1196. Epub 2021 Oct 5.

Department of Pathology, University of Alabama at Birmingham, NP 3545A, 1802 6th Avenue South, Birmingham, AL, 35249-7331, USA.

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 (ccpRCC). Thirty-four RCC (17 CCRCC and 17 ccpRCC) were included in the study. CD34 was used to evaluate vascular architectural patterns by microscopic estimation in all cases. CD34, ERG, and Bioquant Osteo 2019 Imaging Analysis Software were used to evaluate MVD and ECD in 17 CCRCC and 15 ccpRCC. Mean MVD was 526.63 in CCRCC vs. 426.18 in ccpRCC (p = 0.16); mean ECD was 937.50 in CCRCC vs. 1060.21 in ccpRCC (p = 0.25). CD34 highlighted four distinct vascular architectural patterns: pseudoacinar, Golgi-like, lacunae, and scattered. Lacunae and pseudoacinar was the most frequent combination in CCRCC; lacunae and Golgi-like was the predominant combination among ccpRCC. Pseudoacinar was most extensive in CCRCC and least in ccpRCC; Golgi-like was predominant in ccpRCC and uncommon in CCRCC. The extent of pseudoacinar and Golgi-like vascular architectural patterns was significantly different between CCRCC and ccpRCC (p < 0.05). Pathologists acquainted with these different vascular architectural patterns may utilize them as an additional tool in the distinction of CCRCC from ccpRCC.
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http://dx.doi.org/10.1007/s00428-021-03214-2DOI Listing
December 2021

Androgen Receptor Signaling Induces Cisplatin Resistance via Down-Regulating GULP1 Expression in Bladder Cancer.

Int J Mol Sci 2021 Sep 17;22(18). Epub 2021 Sep 17.

Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.

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 GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in bladder cancer cells and then assessed the functional role of GULP1 in cisplatin sensitivity. Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression. Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive bladder cancers from patients who had subsequently undergone neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression ( = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to cisplatin treatment.
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http://dx.doi.org/10.3390/ijms221810030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466436PMC
September 2021

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

Am J Cancer Res 2021 15;11(8):3990-4001. Epub 2021 Aug 15.

Department of Pathology, Tufts Medical Center Boston, MA, USA.

Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414383PMC
August 2021

Programmed cell death-ligand 1 expression in different molecular subtypes of upper tract urothelial carcinoma.

Int J Urol 2022 Jan 13;29(1):89-90. Epub 2021 Sep 13.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

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http://dx.doi.org/10.1111/iju.14689DOI Listing
January 2022

Testicular Germ-Cell Tumors with Spermatic Cord Involvement: A Retrospective International Multi-Institutional Experience.

Mod Pathol 2022 02 9;35(2):249-255. Epub 2021 Sep 9.

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.

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 and 13 (28%) seminomatous testicular germ cell tumors were collected from 15 institutions in America, Europe, and Asia. Testicular tumor size ranged from 1.3 to 18.0 cm (mean: 6.1). Cases were classified as discontinuous involvement of spermatic cord soft tissue (n = 26), continuous cord involvement (n = 17), or cord lymphovascular invasion (n = 3). The mean follow-up was 39 months. Clinical stage for discontinuous involvement of spermatic cord soft-tissue patients was I (local disease) in 2/24 (8%), II (regional disease) in 6/24 (25%), and III (distant disease) in 16/24 (67%) cases; 16 (67%) patients presented with distant metastasis. Clinical stage for continuous cord involvement patients was I in 9/17 (53%), II in 4/17 (23%), and III in 4/17 (23%); 4 (23%) patients presented with distant metastasis. Disease progression was seen in 4 patients with discontinuous involvement of spermatic cord soft tissue and 5 with continuous cord-involvement (p = 0.699). When comparing discontinuous and continuous cord involvement, a significant difference was found in cord margin status (p = 0.044), spermatic cord tumor size (p = 0.016), lymph-node involvement (p = 0.037), distant metastasis (p = 0.010), individual clinical stage (p = 0.003), and nonadvanced vs. advanced disease (p = 0.003) at presentation. In multivariate analysis, after adjusting for age, histology, testicular tumor size, percent of embryonal carcinoma, lymphovascular invasion, and cord margin status, discontinuous involvement of spermatic cord soft tissue was significantly associated (p = 0.011) with advanced clinical stage at presentation. Our findings support the designation of metastatic disease for discontinuous involvement of spermatic cord soft tissue, as introduced by the 8th edition of the AJCC staging.
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http://dx.doi.org/10.1038/s41379-021-00912-9DOI Listing
February 2022

Clinical Application of Promoter Mutations in Urothelial Carcinoma.

Front Oncol 2021 29;11:705440. Epub 2021 Jul 29.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.

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 detected in UC, and drive telomerase activity. Recent studies have demonstrated a strong association between promoter mutation and tumorigenesis of UC. Also, promoter mutation has great potential for diagnosis, as well as prognosis in UC treatment, and this is also applicable for the liquid biopsy techniques. In this review, we discuss the progress in these areas and highlight the challenges, clinical potential, and future direction for developing UC treatment methods.
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http://dx.doi.org/10.3389/fonc.2021.705440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358429PMC
July 2021

Molecular Pathology of Urothelial Carcinoma.

Surg Pathol Clin 2021 Sep;14(3):403-414

Department of Pathology, University of Alabama at Birmingham, University of Alabama at Birmingham School of Medicine, WP Building, Suite P230, 619 19th Street South, Birmingham, AL 35249-7331, USA. Electronic address:

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 histomorphologic and clinical features. This review provides an update on the recent advances in the molecular characterization and novel molecular taxonomy of urothelial carcinoma and variant histologies.
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http://dx.doi.org/10.1016/j.path.2021.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175507PMC
September 2021

Diagnostic utility of one-stop fusion gene panel to detect TFE3/TFEB gene rearrangement and amplification in renal cell carcinomas.

Mod Pathol 2021 11 19;34(11):2055-2063. Epub 2021 Jun 19.

Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.

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 FusionPlex assay for detection of MiT-RCC with TFE3 or TFEB translocations and TFEB amplifications. RNA was extracted from 49 RCC FFPE tissue samples with known TFE3/TFEB status (26 TFE3 FISH positive, 12 TFEB FISH positive, 4 TFEB amplified (1 case both split and amplified), and 8 FISH negative) using the Covaris extraction kit. Target enriched cDNA libraries were prepared using the Archer FusionPlex kit and sequenced on the Illumina NextSeq 550. We demonstrate that the age of the specimen, quality of RNA, and sequencing metrics are important for fusion detection. Fusions were identified in 20 of 21 cases less than 2 years old, and TFE3/TFEB rearrangements were detected in all cases with Fusion QC ≥ 100. The assay identified intrachromosomal inversions in two cases (TFE3-RBM10 and NONO-TFE3), usually difficult to identify by FISH assays. TFEB mRNA expression and the TFEB/TFE3 mRNA expression ratio were significantly higher in RCCs with TFEB fusion and TFEB gene amplification compared to tumors without TFEB fusion or amplification. A cutoff TFEB/TFE3 ratio of 0.5 resulted in 97.3% concordance to FISH results with no false negatives. Our study demonstrates that the FusionPlex assay successfully identifies TFE3 and TFEB fusions including intrachromosomal inversions. Age of the specimen and certain sequencing metrics are important for successful fusion detection. Furthermore, mRNA expression levels may be used for predicting cases harboring TFEB amplification, thereby streamlining testing. This assay enables accurate molecular detection of multiple subtypes of MiT-RCCs in a convenient workflow.
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http://dx.doi.org/10.1038/s41379-021-00858-yDOI Listing
November 2021

The Genitourinary Pathology Society Update on Classification of Variant Histologies, T1 Substaging, Molecular Taxonomy, and Immunotherapy and PD-L1 Testing Implications of Urothelial Cancers.

Adv Anat Pathol 2021 07;28(4):196-208

Department of Pathology, West German Cancer Center/University Hospital Essen, University of Duisburg-Essen, Duisburg.

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, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.
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http://dx.doi.org/10.1097/PAP.0000000000000309DOI Listing
July 2021

Impact of PD-L1 and PD-1 Expression on the Prognostic Significance of CD8 Tumor-Infiltrating Lymphocytes in Non-Small Cell Lung Cancer.

Front Immunol 2021 26;12:680973. Epub 2021 May 26.

Pathology Unit, IRCCS Sacro Cuore Don Calabria, Negrar di Valpolicella, Italy.

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 (TILs) in a cohort of consecutive patients with primary resected non-small cell lung cancer (NSCLC). Tissue microarrays (TMA) were built using one representative formalin fixed paraffin embedded block for every case, with 5 cores for each block. TMA sections were stained with PD-L1 (clone SP263), PD-1 (clone NAT105) and CD8 (clone SP57). Number of CD8 cells per mm were automatically counted; median, 25 and 75 percentiles of CD8 cells were used as threshold for statistical clinical outcome analysis and evaluated in patients subgroups defined by expression of PD-L1 and PD-1 within tumors. We found an overall strong prognostic value of CD8 cells in our cohort of 314 resected NSCLC, especially in PD-L1 negative tumors lacking PD-1 TILs, and demonstrated that in PD-L1 positive tumors a higher density of CD8 lymphocytes is necessary to improve the prognosis. Our data strengthen the concept of the importance of the assessment and quantification of the immune contexture in cancer and, similarly to what has been carried on in colorectal cancer, promote the efforts for the establishment of an Immunoscore for NSCLC for prognostic and possibly predictive purposes.
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http://dx.doi.org/10.3389/fimmu.2021.680973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187779PMC
October 2021

Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling.

Cancer Res 2021 08 26;81(15):4014-4026. Epub 2021 May 26.

Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan.

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including and , inhibited prostate cancer cell proliferation, and reduced prostate expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 . Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-4090DOI Listing
August 2021

TSC loss is a clonal event in eosinophilic solid and cystic renal cell carcinoma: a multiregional tumor sampling study.

Mod Pathol 2022 03 14;35(3):376-385. Epub 2021 May 14.

Department of Diagnostics and Public Health, University of Verona, Verona, Italy.

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 important role for such tumors. However, only indirect evidence of the clonal origin of TSC mutation has been gathered so far. Therefore, in this paper we aimed to perform multi-regional tumor sampling molecular analysis in four ESC RCC cases that had been completely embedded, three sporadic and one occurring in a patient with tuberous sclerosis complex (TSC). Histologically, the 4 cases showed cystic and solid architecture and cells with abundant eosinophilic cytoplasm with cytoplasmic stippling and round to oval nuclei. Immunohistochemistry showed at least focal expression of cytokeratin 20 in all tissue samples and negative cytokeratin 7, as well as diffuse positivity for S100A1 and at least focal expression of cathepsin K in three out of four cases. The sporadic cases showed the same somatic TSC1 mutations in all tissue samples analyzed, while the TSC-associated case showed the same TSC1 alteration in both normal tissue and all tumor samples analyzed, proving the germline nature of the alteration. In conclusion, our data demonstrate that clonal TSC loss is a key event in ESC RCC and support considering ESC RCC as an entity given its distinct morphologic, immunophenotypical and molecular characteristics.
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http://dx.doi.org/10.1038/s41379-021-00816-8DOI Listing
March 2022

Telomerase reverse transcriptase promoter mutation in tumorigenesis of bladder cancer: Evolutionary trajectory by algorithmic inference from cross-sectional data.

Int J Urol 2021 07 15;28(7):774-776. Epub 2021 Apr 15.

Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

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http://dx.doi.org/10.1111/iju.14574DOI Listing
July 2021

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

Mod Pathol 2021 07 4;34(7):1392-1424. Epub 2021 Mar 4.

Department of Pathology MD Anderson Cancer Center, Houston, TX, USA.

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.
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http://dx.doi.org/10.1038/s41379-021-00779-wDOI Listing
July 2021

Identification of BXDC2 as a Key Downstream Effector of the Androgen Receptor in Modulating Cisplatin Sensitivity in Bladder Cancer.

Cancers (Basel) 2021 Feb 26;13(5). Epub 2021 Feb 26.

Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.

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-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone ( = 0.083) or together with AR negativity ( = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.
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http://dx.doi.org/10.3390/cancers13050975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956795PMC
February 2021

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 06 1;34(6):1167-1184. Epub 2021 Feb 1.

Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

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).
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http://dx.doi.org/10.1038/s41379-021-00737-6DOI Listing
June 2021

Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey.

J Clin Pathol 2021 May 29;74(5):291-299. Epub 2021 Jan 29.

Pathology, University Hospital Center of Martinique, Fort-de-France, Martinique.

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 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 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.
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http://dx.doi.org/10.1136/jclinpath-2020-207372DOI Listing
May 2021
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