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Item Gleason Grade 4 Prostate Adenocarcinoma Patterns: An Inter-observer Agreement Study among Genitourinary Pathologists(Wiley, 2016-09) Kweldam, Charlotte F.; Nieboer, Daan; Algaba, Ferran; Amin, Mahul B.; Berney, Dan M.; Billis, Athanase; Bostwick, David G.; Bubendorf, Lukas; Cheng, Liang; Compérat, Eva; Delahunt, Brett; Egevad, Lars; Evans, Andrew J.; Hansel, Donna E.; Humphrey, Peter A.; Kristiansen, Glen; van der Kwast, Theodorus H.; Magi-Galluzzi, Cristina; Montironi, Rodolfo; Netto, George J.; Samaratunga, Hemamali; Srigley, John R.; Tan, Puay H.; Varma, Murali; Zhou, Ming; van Leenders, Geert J. L. H.; Department of Pathology and Laboratory Medicine, IU School of MedicineAims To assess the interobserver reproducibility of individual Gleason grade 4 growth patterns. Methods and results Twenty-three genitourinary pathologists participated in the evaluation of 60 selected high-magnification photographs. The selection included 10 cases of Gleason grade 3, 40 of Gleason grade 4 (10 per growth pattern), and 10 of Gleason grade 5. Participants were asked to select a single predominant Gleason grade per case (3, 4, or 5), and to indicate the predominant Gleason grade 4 growth pattern, if present. ‘Consensus’ was defined as at least 80% agreement, and ‘favoured’ as 60–80% agreement. Consensus on Gleason grading was reached in 47 of 60 (78%) cases, 35 of which were assigned to grade 4. In the 13 non-consensus cases, ill-formed (6/13, 46%) and fused (7/13, 54%) patterns were involved in the disagreement. Among the 20 cases where at least one pathologist assigned the ill-formed growth pattern, none (0%, 0/20) reached consensus. Consensus for fused, cribriform and glomeruloid glands was reached in 2%, 23% and 38% of cases, respectively. In nine of 35 (26%) consensus Gleason grade 4 cases, participants disagreed on the growth pattern. Six of these were characterized by large epithelial proliferations with delicate intervening fibrovascular cores, which were alternatively given the designation fused or cribriform growth pattern (‘complex fused’). Conclusions Consensus on Gleason grade 4 growth pattern was predominantly reached on cribriform and glomeruloid patterns, but rarely on ill-formed and fused glands. The complex fused glands seem to constitute a borderline pattern of unknown prognostic significance on which a consensus could not be reached.Item Handling and reporting of orchidectomy specimens with testicular cancer: areas of consensus and variation among 25 experts and 225 European pathologists(Wiley, 2015-09) Berney, Daniel M.; Algaba, Ferran; Amin, Mahul; Delahunt, Brett; Compérat, Eva; Epstein, Jonathan I.; Humphrey, Peter; Idrees, Mohammed; Lopez-Beltran, Antonio; Magi-Galluzzi, Cristina; Mikuz, Gregor; Montironi, Rodolfo; Oliva, Esther; Srigley, John; Reuter, Victor E.; Trpkov, Kiril; Ulbright, Thomas M.; Varma, Murali; Verrill, Clare; Young, Robert H.; Zhou, Ming; Egevad, Lars; Department of Pathology and Laboratory Medicine, IU School of MedicineThe handling and reporting of testicular tumours is difficult due to their rarity. METHODS AND RESULTS: A survey developed by the European Network of Uro-Pathology (ENUP) and sent to its members and experts to assess the evaluation of testicular germ cell tumours. Twenty-five experts and 225 ENUP members replied. Areas of disagreement included immaturity in teratomas, reported by 32% of experts but 68% of ENUP. Although the presence of rete testis invasion was reported widely, the distinction between pagetoid and stromal invasion was made by 96% of experts but only 63% of ENUP. Immunohistochemistry was used in more than 50% of cases by 68% of ENUP and 12% of experts. Staging revealed the greatest areas of disagreement. Invasion of the tunica vaginalis without vascular invasion was interpreted as T1 by 52% of experts and 67% of ENUP, but T2 by the remainder. Tumour invading the hilar adipose tissue adjacent to the epididymis without vascular invasion was interpreted as T1: 40% of experts, 43% of ENUP; T2: 36% of experts, 30% of ENUP; and T3: 24% of experts, 27% of ENUP. CONCLUSIONS: There is remarkable consensus in many areas of testicular pathology. Significant areas of disagreement included staging and reporting of histological types, both of which have the potential to impact on therapyItem Molecular pathology of urogenital tumors : Recommendations from the 2019 International Society of Urological Pathology (ISUP) Consensus Conference(SpringerLink, 2021-05) Hommerding, Oliver; Allory, Yves; Argani, Pedram; Bismar, Tarek A.; Bubendorf, Lukas; Canete-Portillo, Sofía; Chaux, Alcides; Chen, Ying-Bei; Cheng, Liang; Cubilla, Antonio L.; Egevad, Lars; Gill, Anthony J.; Grignon, David J.; Hartmann, Arndt; Hes, Ondrej; Idrees, Muhammad T.; Kao, Chia-Sui; Knowles, Margaret A.; Looijenga, Leendert H.J.; Lotan, Tamara L.; Pritchard, Colin C.; Rubin, Mark A.; Tomlins, Scott A.; Van der Kwast, Theodorus H.; Velazquez, Elsa F.; Warrick, Joshua I.; Williamson, Sean R.; Kristiansen, Glen; Pathology and Laboratory Medicine, School of MedicineComprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.Item Prostate cancer grading, time to go back to the future(Wiley, 2021-02) Egevad, Lars; Delahunt, Brett; Bostwick, David G.; Cheng, Liang; Evans, Andrew J.; Gianduzzo, Troy; Graefen, Markus; Hugosson, Jonas; Kench, James G.; Leite, Katia R.M.; Oxley, Jon; Sauter, Guido; Srigley, John R.; Stattin, Pär; Tsuzuki, Toyonori; Yaxley, John; Samaratunga, Hemamali; Pathology and Laboratory Medicine, School of MedicineItem Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: III: Molecular Pathology of Kidney Cancer(Wolters Kluwer, 2020-07) Williamson, Sean R.; Gill, Anthony J.; Argani, Pedram; Chen, Ying-Bei; Egevad, Lars; Kristiansen, Glen; Grignon, David J.; Hes, Ondrej; Pathology and Laboratory Medicine, School of MedicineRenal cell carcinoma (RCC) subtypes are increasingly being discerned via their molecular underpinnings. Frequently this can be correlated to histologic and immunohistochemical surrogates, such that only simple targeted molecular assays, or none at all, are needed for diagnostic confirmation. In clear cell RCC, VHL mutation and 3p loss are well known; however, other genes with emerging important roles include SETD2, BAP1, and PBRM1, among others. Papillary RCC type 2 is now known to include likely several different molecular entities, such as fumarate hydratase (FH) deficient RCC. In MIT family translocation RCC, an increasing number of gene fusions are now described. Some TFE3 fusion partners, such as NONO, GRIPAP1, RBMX, and RBM10 may show a deceptive FISH result due to the proximity of the genes on the same chromosome. FH and succinate dehydrogenase (SDH) deficient RCC have implications for patient counseling due to heritable syndromes and the aggressiveness of FH-deficient RCC. Immunohistochemistry is increasingly available and helpful for recognizing both. Emerging tumor types with strong evidence for distinct diagnostic entities include eosinophilic solid and cystic RCC and TFEB / VEGFA / 6p21 amplified RCC. Other emerging entities that are less clearly understood include TCEB1 mutated RCC, RCC with ALK rearrangement, renal neoplasms with mutations of TSC2 or MTOR, and RCC with fibromuscular stroma. In metastatic RCC, the role of molecular studies is not entirely defined at present, although there may be an increasing role for genomic analysis related to specific therapy pathways, such as for tyrosine kinase or MTOR inhibitors.Item Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: IV: Current and Future Utilization of Molecular-Genetic Tests for Testicular Germ Cell Tumors(Wolters Kluwer, 2020-03-20) Looijenga, Leendert H. J.; Van der Kwast, Theodorus H.; Grignon, David; Egevad, Lars; Kristiansen, Glen; Kao, Chia-Sui; Idrees, Muhammad T.; Pathology and Laboratory Medicine, School of MedicineThe International Society of Urological Pathology (ISUP) organized a Consultation Conference in March 2019 dealing with applications of molecular pathology in Urogenital Pathology, including testicular tumors (with a focus on germ cell tumors [GCTs]), preceded by a survey among its members to get insight into current practices in testicular germ cell tumor (TGCT) diagnostics and adoption of the ISUP immunohistochemical guidelines published in 2014. On the basis of the premeeting survey, the most commonly used immunomarker panel includes OCT3/4, placental alkaline phosphate, D2-40, SALL4, CD117, and CD30 for GCTs and the documentation of germ cell neoplasia in situ (GCNIS). Molecular testing, specifically 12p copy gain, is informative to distinguish non-GCNIS versus GCNIS related GCTs, and establishing germ cell origin of tumors both in the context of primary and metastatic lesions. Other molecular methodologies currently available but not widely utilized for TGCTs include genome-wide and targeted approaches for specific genetic anomalies, P53 mutations, genomic MDM2 amplification, and detection of the p53 inactivating miR-371a-3p. The latter also holds promise as a serum marker for malignant TGCTs. This manuscript provides an update on the classification of TGCTs, and describes the current and future role of molecular-genetic testing. The following recommendations are made: (1) Presence of GCNIS should be documented in all cases along with extent of spermatogenesis; (2) Immunohistochemical staining is optional in the following scenarios: identification of GCNIS, distinguishing embryonal carcinoma from seminoma, confirming presence of yolk sac tumor and/or choriocarcinoma, and differentiating spermatocytic tumor from potential mimics; (3) Detection of gain of the short arm of chromosome 12 is diagnostic to differentiate between non-GCNIS versus GCNIS related GCTs and supportive to the germ cell origin of both primary and metastatic tumors.Item Utility of Pathology Imagebase for Standardization of Prostate Cancer Grading(Wiley, 2018-07) Egevad, Lars; Delahunt, Brett; Berney, Dan M.; Bostwick, David G.; Cheville, John; Comperat, Eva; Evans, Andrew J.; Fine, Samson W.; Grignon, David J.; Humphrey, Peter A.; Hörnblad, Jonas; Iczkowski, Kenneth A.; Kench, James G.; Kristiansen, Glen; Leite, Katia R.M.; Magi-Galluzzi, Cristina; McKenney, Jesse; Oxley, Jon; Pan, Chin-Chen; Samaratunga, Hemamali; Srigley, John R.; Takahashi, Hiroyuki; True, Lawrence D.; Tsuzuki, Toyonori; van der Kwast, Theo; Varma, Murali; Zhou, Ming; Clements, Mark; Pathology and Laboratory Medicine, School of MedicineAims: Despite efforts to standardise grading of prostate cancer, even among experts there is still a considerable variation in grading practices. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading. Methods and results: The International Society of Urological Pathology (ISUP) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology reviewed independently microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval = 0.62-0.72) and consensus was reached in 50 cases. The interobserver weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score (GS) 3 + 3 = 6 (ISUP grade 1), while higher grades and particularly GS 4 + 3 = 7 (ISUP grade 3) showed considerable disagreement. Once a two-thirds majority was reached, images were moved automatically into a public database available for all ISUP members at www.isupweb.org. Non-members are able to access a limited number of cases. Conclusions: It is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease interobserver variability. It will also help to identify instances where definitions of grades need to be clarified.