510 results on '"Esther Oliva"'
Search Results
2. P1693: PATIENT-REPORTED OUTCOMES IN LYMPHOMA TRIALS: A SYSTEMATIC REVIEW
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Edward Laane, Sam Salek, Esther Oliva, Nicole Skoetz, Mario Csenar, Julia Schroer, Annika Oeser, and Tatyana Ionova
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. PB2672: EXPLORING UNMET NEEDS OF PATIENTS WITH MYELODYSPLASTIC NEOPLASMS AND CAREGIVERS IN A NATIONAL ITALIAN SURVEY
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Elena Crisà, Annamaria Nosari, Daniela Cilloni, Sam Salek, Tatyana Ionova, Matteo Giovanni Della Porta, Maria Teresa Voso, Luca Maurillo, Carlo Finelli, Valeria Santini, Enrico Balleari, Federica Pilo, Giuseppe Palumbo, Alfredo Molteni, Marta Riva, and Esther Oliva
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. PB2670: EQOL-MDS TRIAL: PATIENT-REPORTED OUTCOMES IN PATIENTS WITH LOWER RISK MYELODYSPLASTIC SYNDROMES WITH SEVERE THROMBOCYTOPENIA.
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Esther Oliva, Giuseppe Iannì, Marta Riva, Pasquale Niscola, Valeria Santini, Massimo Breccia, Valentina Gaidano, Antonella Poloni, Andrea Patriarca, Elena Crisà, Isabella Capodanno, Prassede Salutari, Gianluigi Reda, Grazia Sanpaolo, Dario Ferrero, Attilio Guarini, Giovanni Tripepi, Andrea Castelli, Bruno Fattizzo, Germana Beltrami, Monica Bocchia, Alfredo Molteni, Pierre Fenaux, Ulrich Germing, Alessandra Ricco, Giuseppe A. Palumbo, Stefana Impera, Nicola DI Renzo, Francesco Buccisano, Aspasia Stamatoullas, Anna Marina Liberati, Anna Candoni, Ilaria Maria Delfino, Patrizia Cufari, Lorenzo Rizzo, and Roberto Latagliata
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease
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Jessica A Pilsworth, Dawn R Cochrane, Samantha J Neilson, Bahar H Moussavi, Daniel Lai, Aslı D Munzur, Janine Senz, Yi Kan Wang, Sina Zareian, Ali Bashashati, Adele Wong, Jacqueline Keul, Annette Staebler, Hannah S vanMeurs, Hugo M Horlings, Stefan Kommoss, Friedrich Kommoss, Esther Oliva, Anniina EM Färkkilä, Blake Gilks, and David G Huntsman
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adult‐type granulosa cell tumor of the ovary ,FOXL2 ,TERT promoter ,KMT2D ,targeted sequencing ,mutation profiling ,Pathology ,RB1-214 - Abstract
Abstract Adult‐type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord‐stromal tumors and 2–5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one‐third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole‐genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon‐based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle‐related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.
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- 2021
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6. Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary
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Sarah H. Kim, Arnaud Da Cruz Paula, Thais Basili, Higinio Dopeso, Rui Bi, Fresia Pareja, Edaise M. da Silva, Rodrigo Gularte-Mérida, Zhen Sun, Sho Fujisawa, Caitlin G. Smith, Lorenzo Ferrando, Ana Paula Martins Sebastião, Yonina Bykov, Anqi Li, Catarina Silveira, Charles W. Ashley, Anthe Stylianou, Pier Selenica, Wesley R. Samore, Achim A. Jungbluth, Dmitriy Zamarin, Nadeem R. Abu-Rustum, Kristian Helin, Robert A. Soslow, Jorge S. Reis-Filho, Esther Oliva, and Britta Weigelt
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Science - Abstract
Little is known about the genetics of sclerosing stromal tumor of the ovary, a rare type of sex cord-stromal tumor. Here, the authors use sequencing strategies to show that in a cohort of 26 tumor samples 65% carry a FHL2-GLI2 fusion gene and demonstrate in vitro that the fusion gene has oncogenic properties.
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- 2020
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7. Allele Loss and Reduced Expression of CYCLOPS Genes is a Characteristic Feature of Chromophobe Renal Cell Carcinoma
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Riuko Ohashi, Peter Schraml, Aashil Batavia, Silvia Angori, Patrik Simmler, Niels Rupp, Yoichi Ajioka, Esther Oliva, and Holger Moch
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS (CYCLOPS) genes have been recently identified as the most enriched class of copy-number associated gene dependencies in human cancer. These genes are cell essential and render tumor cells highly sensitive to the expression of the remaining copy. Chromophobe renal cell carcinoma (chRCC) is characterized by frequent chromosomal deletions, but the relevance of CYCLOPS genes in this tumor subtype is unclear. We found 39 (31%) of 124 recently published candidate CYCLOPS genes (B. Paolella et al., eLife 2017;6:e23268) located on 7 autosomes that are frequently lost in chRCC. GISTIC and RNA-seq data obtained from the TCGA-KICH database showed that 62% of these CYCLOPS genes had significantly lower expression levels in samples with deletion of the respective gene. As copy number (CN) loss of the CYCLOPS gene SF3B1 (Splicing factor 3B subunit 1) has been recently reported in 71% chRCC, we explored the relevance of SF3B1 CN alteration and SF3B1 expression in a set of chRCC and additional oncocytic renal neoplasms. The frequency of SF3B1 CN loss (65%) was similar to that obtained from the TCGA-KICH database and correlated significantly with both lower SF3B1 mRNA (P
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- 2019
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8. SARS-CoV-2 in Myelodysplastic Syndromes: A Snapshot From Early Italian Experience
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Sandra Mossuto, Enrico Attardi, Francesco Alesiani, Emanuele Angelucci, Enrico Balleari, Massimo Bernardi, Gianni Binotto, Costanza Bosi, Anna Calvisi, Isabella Capodanno, Antonella Carbone, Andrea Castelli, Marco Cerrano, Rosanna Ciancia, Daniela Cilloni, Marino Clavio, Cristina Clissa, Elena Crisà, Monica Crugnola, Matteo G. Della Porta, Nicola Di Renzo, Ambra Di Veroli, Roberto Fattizzo, Carmen Fava, Susanna Fenu, Ida L. Ferrara, Luana Fianchi, Carla Filì, Carlo Finelli, Valentina Giai, Francesco Frattini, Valentina Gaidano, Gianluca Guaragna, Svitlana Gumenyuk, Roberto Latagliata, Stefano Mancini, Emanuela Messa, Alfredo Molteni, Pellegrino Musto, Pasquale Niscola, Esther Oliva, Giuseppe A. Palumbo, Annamaria Pelizzari, Federica Pilo, Antonella Poloni, Marta Riva, Flavia Rivellini, Chiara Sarlo, Mariarita Sciumé, Roberto Secchi, Carmine Selleri, Agostino Tafuri, and Valeria Santini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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9. Proceedings of Patient Reported Outcome Measure’s (PROMs) Conference Oxford 2017: Advances in Patient Reported Outcomes Research
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Galina Velikova, Jose M. Valderas, Caroline Potter, Laurie Batchelder, Christine A’Court, Matthew Baker, Jennifer Bostock, Angela Coulter, Ray Fitzpatrick, Julien Forder, Diane Fox, Louise Geneen, Elizabeth Gibbons, Crispin Jenkinson, Karen Jones, Laura Kelly, Michele Peters, Brendan Mulhern, Alexander Labeit, Donna Rowen, Keith Meadows, Jackie Elliott, John Brazier, Emma Knowles, Anju Keetharuth, Janice Connell, Jill Carlton, Lizzie Taylor Buck, Thomas Ricketts, Michael Barkham, Pushpendra Goswami, Sam Salek, Tatyana Ionova, Esther Oliva, Adele K. Fielding, Marina Karakantza, Saad Al-Ismail, Graham P. Collins, Stewart McConnell, Catherine Langton, Daniel M. Jennings, Roger Else, Jonathan Kell, Helen Ward, Sophie Day, Elizabeth Lumley, Patrick Phillips, Rosie Duncan, Helen Buckley-Woods, Ahmed Aber, Gerogina Jones, Jonathan Michaels, Ian Porter, Jaheeda Gangannagaripalli, Antoinette Davey, Ignacio Ricci-Cabello, Kirstie Haywood, Stine Thestrup Hansen, Jose Valderas, Deb Roberts, Anil Gumber, Bélène Podmore, Andrew Hutchings, Jan van der Meulen, Ajay Aggarwal, Sujith Konan, Andrew Price, William Jackson, Nick Bottomley, Michael Philiips, Toby Knightley-Day, David Beard, Joanne Greenhalgh, Kate Gooding, Chema Valderas, Judy Wright, Sonia Dalkin, David Meads, Nick Black, Carol Fawkes, Robert Froud, Dawn Carnes, Jonathan Cook, Helen Dakin, James Smith, Sujin Kang, The ACHE Study Team, Catrin Griffiths, Ella Guest, Diana Harcourt, Mairead Murphy, Sandra Hollinghurst, Chris Salisbury, Anqi Gao, Agnieszka Lemanska, Tao Chen, David P. Dearnaley, Rajesh Jena, Matthew Sydes, Sara Faithfull, A. E. Ades, Daphne Kounali, Guobing Lu, Ines Rombach, Alastair Gray, Oliver Rivero-Arias, Patricia Holch, Marie Holmes, Zoe Rodgers, Sarah Dickinson, Beverly Clayton, Susan Davidson, Jacqui Routledge, Julia Glennon, Ann M. Henry, Kevin Franks, Roma Maguire, Lisa McCann, Teresa Young, Jo Armes, Jenny Harris, Christine Miaskowski, Grigorios Kotronoulas, Morven Miller, Emma Ream, Elizabeth Patiraki, Alexander Geiger, Geir V. Berg, Adrian Flowerday, Peter Donnan, Paul McCrone, Kathi Apostolidis, Patricia Fox, Eileen Furlong, Nora Kearney, Chris Gibbons, Felix Fischer, Joel Coste, Jose Valderas Martinez, Matthias Rose, Alain Leplege, Sarah Shingler, Natalie Aldhouse, Tamara Al-Zubeidi, Andrew Trigg, Helen Kitchen, Colin Green, Joanna Coast, Sarah Smith, Jolijn Hendriks, Koonal Shah, Juan-Manuel Ramos-Goni, Simone Kreimeier, Mike Herdman, Nancy Devlin, Aureliano Paolo Finch, John E. Brazier, Clara Mukuria, Bernarda Zamora, David Parkin, Yan Feng, Andrew Bateman, Thomas Patton, and Nils Gutacker
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Computer applications to medicine. Medical informatics ,R858-859.7 - Published
- 2017
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10. Single-cell sequencing of neonatal uterus reveals an Misr2+ endometrial progenitor indispensable for fertility
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Hatice Duygu Saatcioglu, Motohiro Kano, Heiko Horn, Lihua Zhang, Wesley Samore, Nicholas Nagykery, Marie-Charlotte Meinsohn, Minsuk Hyun, Rana Suliman, Joy Poulo, Jennifer Hsu, Caitlin Sacha, Dan Wang, Guangping Gao, Kasper Lage, Esther Oliva, Mary E Morris Sabatini, Patricia K Donahoe, and David Pépin
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uterus development ,AMH ,MIS ,infertility ,Mullerian duct ,mesenchyme ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The Mullerian ducts are the anlagen of the female reproductive tract, which regress in the male fetus in response to MIS. This process is driven by subluminal mesenchymal cells expressing Misr2, which trigger the regression of the adjacent Mullerian ductal epithelium. In females, these Misr2+ cells are retained, yet their contribution to the development of the uterus remains unknown. Here, we report that subluminal Misr2+ cells persist postnatally in the uterus of rodents, but recede by week 37 of gestation in humans. Using single-cell RNA sequencing, we demonstrate that ectopic postnatal MIS administration inhibits these cells and prevents the formation of endometrial stroma in rodents, suggesting a progenitor function. Exposure to MIS during the first six days of life, by inhibiting specification of the stroma, dysregulates paracrine signals necessary for uterine development, eventually resulting in apoptosis of the Misr2+ cells, uterine hypoplasia, and complete infertility in the adult female.
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- 2019
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11. Patient-centered research and practice in the era of genomics: a novel approach
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Sam Salek, Esther Oliva, and Tatyana Ionova
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2016
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12. Patients’ needs in hematology: whose perspectives?
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Sam Salek, Tatyana Ionova, and Esther Oliva
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2013
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13. Sex Cord-Stromal Tumors of the Ovary
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Madeleine Sertic, Kyle M. Devins, Esther Oliva, Susanna I. Lee, and Aoife Kilcoyne
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Radiology, Nuclear Medicine and imaging ,General Medicine - Published
- 2023
14. Uterine Endometrial Stromal Tumors With Pure Low-Grade Morphology Harboring YWHAE::NUTM2 Fusions
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Kyle M. Devins, Ayoma D. Attygalle, Sabrina Croce, Katherine Vroobel, Esther Oliva, and W. Glenn McCluggage
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Surgery ,Anatomy ,Pathology and Forensic Medicine - Published
- 2023
15. A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes
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Giulia Maggioni, Matteo Bersanelli, Erica Travaglino, Ana Alfonso Piérola, Annika Kasprzak, Arnan Sangerman Montserrat, Elisabetta Sauta, Claudia Sala, Tommaso Matteuzzi, Manja Meggendorfer, Matteo Gnocchi, Lin-Pierre Zhao, Cristina Astrid Tentori, Kathrin Nachtkamp, Daniele Dall'Olio, Ettore Mosca, Marta Ubezio, Alessia Campagna, Antonio Russo, Giulia Rivoli, Massimo Bernardi, Lorenza Borin, Maria Teresa Voso, Marta Riva, Esther Oliva, Matteo Zampini, Elena Riva, Elena Saba, Saverio D'Amico, Luca Lanino, Benedetta Tinterri, Francesca Re, Marilena Bicchieri, Laura Giordano, Giovanni Angelotti, Pierandrea Morandini, Anne Sophie Kubasch, Francesco Passamonti, Alessandro Rambaldi, Victor Savevski, Armando Santoro, Arjan A. van de Loosdrecht, Alice Brogi, Valeria Santini, Shahram Kordasti, Guillermo Sanz, Francesc Sole, Norbert Gattermann, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Ulrich Germing, Maria Diez-Campelo, Matteo G. Della Porta, Hematology, AII - Cancer immunology, AII - Inflammatory diseases, CCA - Cancer biology and immunology, Maggioni, G, Bersanelli, M, Travaglino, E, Alfonso Piérola, A, Kasprzak, A, Sangerman Montserrat, A, Sauta, E, Sala, C, Matteuzzi, T, Meggendorfer, M, Gnocchi, M, Zhao, L, Astrid Tentori, C, Nachtkamp, K, Dall'Olio, D, Mosca, E, Ubezio, M, Campagna, A, Russo, A, Rivoli, G, Bernardi, M, Borin, L, Teresa Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Saba, E, D'Amico, S, Lanino, L, Tinterri, B, Re, F, Bicchieri, M, Giordano, L, Angelotti, G, Morandini, P, Sophie Kubasch, A, Passamonti, F, Rambaldi, A, Savevski, V, Santoro, A, A van de Loosdrecht, A, Brogi, A, Santini, V, Kordasti, S, Sanz, G, Sole, F, Gattermann, N, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, Germing, U, Diez-Campelo, M, and G Della Porta, M
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Malalties hematològiques ,Hematologic diseases ,Myelodysplastic Syndrome ,Factors sexuals en les malalties ,Sex factors in disease ,sex ,Hematology ,personalized medicine ,Settore MED/15 - Abstract
Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p
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- 2023
16. Uterine Tumors Resembling Ovarian Sex Cord Tumors
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Baris, Boyraz, Jaclyn C, Watkins, Robert H, Young, and Esther, Oliva
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Surgery ,Anatomy ,Pathology and Forensic Medicine - Abstract
Uterine tumors resembling ovarian sex cord tumors (UTROSCTs), first characterized by Drs Clement and Scully in 1976, are rare neoplasms showing clinical, morphologic, and immunohistochemical overlap with a number of other uterine tumors, most being mesenchymal. Criteria for aggressive behavior are not clearly established. We report 75 tumors from patients ranging from 21 to 84 (mean=52.4) years. Seventy-one patients were treated by hysterectomy and 4 by conservative total excision. Thirty-eight tumors were intramyometrial, 34 submucosal, and 3 cervical; they ranged from 0.6 to 20 (mean=4.9) cm and were typically tan-yellow. Sixty-eight neoplasms were well-circumscribed and 7 had infiltrative borders (4 only minimally). In 56 tumors, a smooth muscle component was intimately admixed with the neoplastic cells ("pseudoinfiltration"; extensive in 29). Architectural patterns included cords (n=53), diffuse (n=51), hollow tubules (n=48), nests (n=38), trabeculae (n=37), retiform (n=23), solid tubules (n=21), pseudoangiomatoid (n=11), pseudopapillary (n=4), and whorled (n=2); typically, more than 1 pattern was seen. Tumor cells were epithelioid (n=62), epithelioid and spindled (n=12), or spindled (n=1) and/or rhabdoid (n=20; extensive in 2). Cytologic atypia was absent to mild in 57, moderate in 16, and moderate to severe in 2 tumors. Fifty-seven UTROSCTs had ≤2mitoses/10 high power fields (HPF), 12 had 3 to 5/10 HPF, and 65/10 HPF. Necrosis was present in 3 and lymphovascular invasion in 1. Tumor cells showed a polyphenotypic immunohistochemical profile (with positivity for sex cord, smooth muscle, and epithelial markers), most commonly inhibin (17/33+) and calretinin (22/31+) positive. Five of 58 patients with follow-up (22 to 192; mean=73.2 mo) had recurrences/metastases from 30 to 144 months, and 2 died of disease. Malignant tumors showed3 of the following 5 features compared with benign tumors: size5 cm, at least moderate cytologic atypia, ≥3 mitoses/10 HPF, infiltrative borders, and necrosis. One of the 5 malignant tumors showed an extensive rhabdoid morphology. UTROSCTs are uncommon, show a wide morphologic spectrum, often pose problems in differential diagnosis, and typically have a benign outcome. Rare tumors are associated with late recurrences and a combination of more than 3 of the 5 features listed above predicted aggressive behavior in this series.
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- 2022
17. Embryonal Rhabdomyosarcoma of the Uterine Cervix
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Kyle M, Devins, Robert H, Young, Mariachristina, Ghioni, Eike, Burandt, Jennifer A, Bennett, and Esther, Oliva
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Ribonuclease III ,Adenosarcoma ,Uterine Cervical Neoplasms ,Cervix Uteri ,Prognosis ,Pathology and Forensic Medicine ,DEAD-box RNA Helicases ,Diagnosis, Differential ,Neoplastic Syndromes, Hereditary ,Uterine Neoplasms ,Humans ,Female ,Rhabdomyosarcoma, Embryonal ,Surgery ,Anatomy - Abstract
Embryonal rhabdomyosarcoma of the uterine cervix (cERMS) is rare and frequently associated with DICER1 mutations. We report 94 tumors that arose in patients aged 7 to 59 (median=23) years and presented with vaginal bleeding (52), protruding vaginal mass (17), cervical polyp (8), or expelled tumor fragments per vagina (5). Nine had DICER1 syndrome, 8 of whom had other syndromic manifestations including ovarian Sertoli-Leydig cell tumor (7), multinodular goiter (3), pleuropulmonary blastoma (2), pineoblastoma (1), and osteosarcoma (1). Syndromic patients were younger than nonsyndromic patients (16 vs. 24 y). Tumor size ranged from 2 to 24 (median=4.5) cm. Ninety-two tumors were polypoid, most being grape-like (77 of 92). They were characterized by aggregates of primitive cells, almost always exhibiting a cambium layer, within a variably myxoedematous stroma and were hypocellular (63), moderately cellular (22), or hypercellular (9). Entrapped glands, typically scant, were present in 84 tumors. Primitive hyperchromatic ovoid to spindled cells with minimal cytoplasm predominated but differentiated rhabdomyoblasts with abundant eosinophilic cytoplasm (having cross-striations in 30) were seen in 83 tumors; they were often sparse but predominated in three. Nine tumors showed areas of intersecting fascicles and 4 zones with densely cellular (solid) growth. Cartilage was present in 38. Anaplasia was seen in 15 tumors, as was necrosis. Mitotic activity ranged from 1 to 58/10 high-power fields (median=8). The varied microscopic features resulted in a spectrum of differential diagnostic considerations, mainly typical and cellular forms of fibroepithelial polyps, Mullerian adenosarcoma, and other sarcomas. Follow-up was available for 79 patients ranging from 6 to 492 (median=90) months. Treatment information was available in 62 and included polypectomy in 6 patients (2 also received chemotherapy), limited resection in 26 (14 also received chemotherapy), hysterectomy in 29 (15 with adjuvant chemotherapy), and biopsies only in 1 (with chemotherapy). Staging was possible in 56 tumors; according to the "uterine sarcoma" system (tumor size and extent) they were: stage I (10/56; could not be further subclassified as size not available), IA (22/56), IB (18/56), IIA (2/56), IIB 3/56), IIIC (1/56). According to the "adenosarcoma" system (depth of invasion and extent) they were: stage IA (26/56), IB (14/56), IC (10/56), IIA (2/56), IIB (3/56), IIIC (1/56). Eight patients had local recurrence following incomplete excision (10%). Eleven of 79 patients had extrauterine recurrences (14%) and 9 died of disease (11%). Older age was associated with extrauterine recurrence (median 44 vs. 22; P =0.002) and decreased disease-specific survival (median 44 vs. 22; P =0.02). For patients with tumors initially confined to the cervix, the adenosarcoma staging system was superior to the uterine sarcoma staging system for predicting survival ( P =0.02). Three patients with DICER1 syndrome who underwent fertility-preserving surgery developed a second primary cERMS 7, 7, and 12 years after their primary tumor. All 9 patients with DICER1 syndrome had tumors confined to the cervix and none died of disease. This study highlights the intriguing clinical aspects of cERMS including its long-known tendency to occur in the young but also more recently appreciated association with DICER1 syndrome. Establishing the diagnosis may still be difficult because of the hazard of sampling a neoplasm which in areas may appear remarkably bland and also because of its potential confusion with other neoplasms. This study indicates that this tumor has a good prognosis at this site and in selected cases a conservative surgical approach is a realistic consideration.
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- 2022
18. Clinical correlation of lymphovascular invasion and Silva pattern of invasion in early-stage endocervical adenocarcinoma: proposed binary Silva classification system
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Simona Stolnicu, Lien Hoang, Noorah Almadani, Louise De Brot, Glauco Baiocchi, Graziele Bovolim, Maria Jose Brito, Georgia Karpathiou, Antonio Ieni, Esther Guerra, Takako Kiyokawa, Pavel Dundr, Carlos Parra-Herran, Sofia Lérias, Ana Felix, Andres Roma, Anna Pesci, Esther Oliva, Kay J. Park, Robert A. Soslow, and Nadeem R. Abu-Rustum
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Lymphatic Metastasis ,Carcinoma ,Humans ,Uterine Cervical Neoplasms ,Female ,Adenocarcinoma ,Prognosis ,Neoplasm Staging ,Retrospective Studies ,Pathology and Forensic Medicine - Abstract
Silva invasion pattern can help predict lymph node metastasis risk in endocervical adenocarcinoma. We analysed Silva pattern of invasion and lymphovascular invasion to determine associations with clinical outcomes in stage IA and IB1 endocervical adenocarcinomas. International Federation of Gynecology and Obstetrics (FIGO; 2019 classification) stage IA-IB1 endocervical adenocarcinomas from 15 international institutions were examined for Silva pattern, presence of lymphovascular invasion, and other prognostic parameters. Lymph node metastasis status, local/distant recurrences, and survival data were compared using appropriate statistical tests. Of 399 tumours, 152 (38.1%) were stage IA [IA1, 77 (19.3%); IA2, 75 (18.8%)] and 247 (61.9%) were stage IB1. On multivariate analysis, lymphovascular invasion (p=0.008) and Silva pattern (p0.001) were significant factors when comparing stage IA versus IB1 endocervical adenocarcinomas. Overall survival was significantly associated with lymph node metastasis (p=0.028); recurrence-free survival was significantly associated with lymphovascular invasion (p=0.002) and stage (1B1 versus 1A) (p=0.002). Five and 10 year overall survival and recurrence-free survival rates were similar among Silva pattern A cases and Silva pattern B cases without lymphovascular invasion (p=0.165 and p=0.171, respectively). Silva pattern and lymphovascular invasion are important prognostic factors in stage IA1-IB1 endocervical adenocarcinomas and can supplement 2019 International Federation of Gynecology and Obstetrics staging. Our binary Silva classification system groups patients into low risk (patterns A and B without lymphovascular invasion) and high risk (pattern B with lymphovascular invasion and pattern C) categories.
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- 2022
19. A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study
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Maggioni, G, Bersanelli, M, Travaglino, E, Alfonso Piérola, A, Kasprzak, A, Sangerman Montserrat, A, Sauta, E, Sala, C, Matteuzzi, T, Meggendorfer, M, Gnocchi, M, Zhao, L, Astrid Tentori, C, Nachtkamp, K, Dall'Olio, D, Mosca, E, Ubezio, M, Campagna, A, Russo, A, Rivoli, G, Bernardi, M, Borin, L, Teresa Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Saba, E, D'Amico, S, Lanino, L, Tinterri, B, Re, F, Bicchieri, M, Giordano, L, Angelotti, G, Morandini, P, Sophie Kubasch, A, Passamonti, F, Rambaldi, A, Savevski, V, Santoro, A, A van de Loosdrecht, A, Brogi, A, Santini, V, Kordasti, S, Sanz, G, Sole, F, Gattermann, N, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, Germing, U, Diez-Campelo, M, G Della Porta, M, Giulia Maggioni, Matteo Bersanelli, Erica Travaglino, Ana Alfonso Piérola, Annika Kasprzak, Arnan Sangerman Montserrat, Elisabetta Sauta, Claudia Sala, Tommaso Matteuzzi, Manja Meggendorfer, Matteo Gnocchi, Lin-Pierre Zhao, Cristina Astrid Tentori, Kathrin Nachtkamp, Daniele Dall'Olio, Ettore Mosca, Marta Ubezio, Alessia Campagna, Antonio Russo, Giulia Rivoli, Massimo Bernardi, Lorenza Borin, Maria Teresa Voso, Marta Riva, Esther Oliva, Matteo Zampini, Elena Riva, Elena Saba, Saverio D'Amico, Luca Lanino, Benedetta Tinterri, Francesca Re, Marilena Bicchieri, Laura Giordano, Giovanni Angelotti, Pierandrea Morandini, Anne Sophie Kubasch, Francesco Passamonti, Alessandro Rambaldi, Victor Savevski, Armando Santoro, Arjan A van de Loosdrecht, Alice Brogi, Valeria Santini, Shahram Kordasti, Guillermo Sanz, Francesc Sole, Norbert Gattermann, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Ulrich Germing, Maria Diez-Campelo, Matteo G Della Porta, Maggioni, G, Bersanelli, M, Travaglino, E, Alfonso Piérola, A, Kasprzak, A, Sangerman Montserrat, A, Sauta, E, Sala, C, Matteuzzi, T, Meggendorfer, M, Gnocchi, M, Zhao, L, Astrid Tentori, C, Nachtkamp, K, Dall'Olio, D, Mosca, E, Ubezio, M, Campagna, A, Russo, A, Rivoli, G, Bernardi, M, Borin, L, Teresa Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Saba, E, D'Amico, S, Lanino, L, Tinterri, B, Re, F, Bicchieri, M, Giordano, L, Angelotti, G, Morandini, P, Sophie Kubasch, A, Passamonti, F, Rambaldi, A, Savevski, V, Santoro, A, A van de Loosdrecht, A, Brogi, A, Santini, V, Kordasti, S, Sanz, G, Sole, F, Gattermann, N, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, Germing, U, Diez-Campelo, M, G Della Porta, M, Giulia Maggioni, Matteo Bersanelli, Erica Travaglino, Ana Alfonso Piérola, Annika Kasprzak, Arnan Sangerman Montserrat, Elisabetta Sauta, Claudia Sala, Tommaso Matteuzzi, Manja Meggendorfer, Matteo Gnocchi, Lin-Pierre Zhao, Cristina Astrid Tentori, Kathrin Nachtkamp, Daniele Dall'Olio, Ettore Mosca, Marta Ubezio, Alessia Campagna, Antonio Russo, Giulia Rivoli, Massimo Bernardi, Lorenza Borin, Maria Teresa Voso, Marta Riva, Esther Oliva, Matteo Zampini, Elena Riva, Elena Saba, Saverio D'Amico, Luca Lanino, Benedetta Tinterri, Francesca Re, Marilena Bicchieri, Laura Giordano, Giovanni Angelotti, Pierandrea Morandini, Anne Sophie Kubasch, Francesco Passamonti, Alessandro Rambaldi, Victor Savevski, Armando Santoro, Arjan A van de Loosdrecht, Alice Brogi, Valeria Santini, Shahram Kordasti, Guillermo Sanz, Francesc Sole, Norbert Gattermann, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Ulrich Germing, Maria Diez-Campelo, and Matteo G Della Porta
- Abstract
BACKGROUND: Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. METHODS: In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Düsseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. FINDINGS: The study included 7792 (58·7%) men and 5492 (41·3%) women. 10 906 (82·1%) patients were White, and race was not reported for 2378 (17·9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0·0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0·0062 in the IWG-PM cohort; IDH2 p<0·0001 in EuroMDS vs p=0·042 in IWG-PM; TET2 p=0·031 vs p=0·035; U2AF1 p=0·033 vs p<0·0001) and mutations in two genes were enriched in women (DNMT3A p<0·000
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- 2023
20. Molecular genetic heterogeneity in undifferentiated endometrial carcinomas
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Rosa-Rosa, Juan M, Leskelä, Susanna, Cristóbal-Lana, Eva, Santón, Almudena, López-García, Ma Ángeles, Muñoz, Gloria, Pérez-Mies, Belen, Biscuola, Michele, Prat, Jaime, Esther, Oliva E, Soslow, Robert A, Matias-Guiu, Xavier, and Palacios, Jose
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- 2016
- Full Text
- View/download PDF
21. Supplementary Data from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements
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George Jour, Matija Snuderl, Deborah F. DeLair, Paolo Cotzia, Esther Oliva, Anais Malpica, Pratibha S. Shukla, Lauren E. Schwartz, Kristen M. Thomas, Julieta E. Barroeta, Sarah Chiang, Xiaojun Feng, Rebecca L. Linn, Guomiao Shen, Jonathan Serrano, Varshini Vasudevaraja, Kelsey Zhu, and Theodore Vougiouklakis
- Abstract
Supplementary Data from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements
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- 2023
22. Supplementary Figure from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements
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George Jour, Matija Snuderl, Deborah F. DeLair, Paolo Cotzia, Esther Oliva, Anais Malpica, Pratibha S. Shukla, Lauren E. Schwartz, Kristen M. Thomas, Julieta E. Barroeta, Sarah Chiang, Xiaojun Feng, Rebecca L. Linn, Guomiao Shen, Jonathan Serrano, Varshini Vasudevaraja, Kelsey Zhu, and Theodore Vougiouklakis
- Abstract
Supplementary Figure from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements
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- 2023
23. Data from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements
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George Jour, Matija Snuderl, Deborah F. DeLair, Paolo Cotzia, Esther Oliva, Anais Malpica, Pratibha S. Shukla, Lauren E. Schwartz, Kristen M. Thomas, Julieta E. Barroeta, Sarah Chiang, Xiaojun Feng, Rebecca L. Linn, Guomiao Shen, Jonathan Serrano, Varshini Vasudevaraja, Kelsey Zhu, and Theodore Vougiouklakis
- Abstract
Purpose:Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers.Experimental Design:Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS) panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites.Results:We identified frequent KMT2C-truncating mutations along with other mutated genes implicated in the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, in addition to previously reported hotspot AKT1 and DICER1 mutations. Targeted transcriptome sequencing revealed recurrent TERT rearrangements (13%) involving partners CLPTM1L or DROSHA, and differential gene expression analysis showed FGFR1 upregulation in the TERT non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level, further supporting its diagnostic utility in distinguishing among these tumors.Conclusions:This is the largest comprehensive molecular study of JGCTs, where we further expand our current understanding of JGCT pathogenesis and demonstrate putative oncogenic drivers and TERT rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.
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- 2023
24. Data from Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene
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Scott Goode, Sandra Orsulic, Susan G. Hilsenbeck, Thomas Wheeler, Xiaoyun Shen, Esther Oliva, Jiangyong Miao, Runsheng Wang, and Chad A. Hall
- Abstract
The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ∼50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer. Cancer Res; 70(21); 8517–25. ©2010 AACR.
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- 2023
25. Supplementary Figure Legends 1-2, Methods and Materials from A Role for BRCA1 in Uterine Leiomyosarcoma
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Sandra Orsulic, Gayatry Mohapatra, Beth Y. Karlan, Esther Oliva, Matthew L. Anderson, Cyrus Y. Hedvat, Paul-Joseph Aspuria, Yevgeniya J.M. Ioffe, Xuan Xu, Lei He, Mai Nitta, George Scangas, and Deyin Xing
- Abstract
Supplementary Figure Legends 1-2, Methods and Materials from A Role for BRCA1 in Uterine Leiomyosarcoma
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- 2023
26. Supplementary Figure 1 from A Role for BRCA1 in Uterine Leiomyosarcoma
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Sandra Orsulic, Gayatry Mohapatra, Beth Y. Karlan, Esther Oliva, Matthew L. Anderson, Cyrus Y. Hedvat, Paul-Joseph Aspuria, Yevgeniya J.M. Ioffe, Xuan Xu, Lei He, Mai Nitta, George Scangas, and Deyin Xing
- Abstract
Supplementary Figure 1 from A Role for BRCA1 in Uterine Leiomyosarcoma
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- 2023
27. Supplementary Figure 1 from Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene
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Scott Goode, Sandra Orsulic, Susan G. Hilsenbeck, Thomas Wheeler, Xiaoyun Shen, Esther Oliva, Jiangyong Miao, Runsheng Wang, and Chad A. Hall
- Abstract
Supplementary Figure 1 from Hippo Pathway Effector Yap Is an Ovarian Cancer Oncogene
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- 2023
28. Supplementary Figure 2 from A Role for BRCA1 in Uterine Leiomyosarcoma
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Sandra Orsulic, Gayatry Mohapatra, Beth Y. Karlan, Esther Oliva, Matthew L. Anderson, Cyrus Y. Hedvat, Paul-Joseph Aspuria, Yevgeniya J.M. Ioffe, Xuan Xu, Lei He, Mai Nitta, George Scangas, and Deyin Xing
- Abstract
Supplementary Figure 2 from A Role for BRCA1 in Uterine Leiomyosarcoma
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- 2023
29. Supplementary Tables 1-2 from A Role for BRCA1 in Uterine Leiomyosarcoma
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Sandra Orsulic, Gayatry Mohapatra, Beth Y. Karlan, Esther Oliva, Matthew L. Anderson, Cyrus Y. Hedvat, Paul-Joseph Aspuria, Yevgeniya J.M. Ioffe, Xuan Xu, Lei He, Mai Nitta, George Scangas, and Deyin Xing
- Abstract
Supplementary Tables 1-2 from A Role for BRCA1 in Uterine Leiomyosarcoma
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- 2023
30. Data from A Role for BRCA1 in Uterine Leiomyosarcoma
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Sandra Orsulic, Gayatry Mohapatra, Beth Y. Karlan, Esther Oliva, Matthew L. Anderson, Cyrus Y. Hedvat, Paul-Joseph Aspuria, Yevgeniya J.M. Ioffe, Xuan Xu, Lei He, Mai Nitta, George Scangas, and Deyin Xing
- Abstract
Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies. To elucidate the roles of the p53 and BRCA1 tumor suppressor genes in gynecologic malignancies, we generated mice in which p53 and/or BRCA1 can be conditionally deleted using anti-Müllerian hormone type II receptor (Amhr2)–driven Cre recombinase. We showed that conditional deletion of p53 in mice results in the development of uterine tumors that resemble human ULMS and that concurrent deletion of p53 and BRCA1 significantly accelerates the progression of these tumors. This finding led to our hypothesis that BRCA1 may play a role in human ULMS development. Consistent with this hypothesis, we showed that the BRCA1 protein is absent in 29% of human ULMS and that BRCA1 promoter methylation is the likely mechanism of BRCA1 downregulation. These data indicate that the loss of BRCA1 function may be an important step in the progression of ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS. [Cancer Res 2009;69(21):8231–5]
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- 2023
31. BAP1 and Claudin-4, But Not MTAP, Reliably Distinguish Borderline and Low-grade Serous Ovarian Tumors From Peritoneal Mesothelioma
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Kyle M, Devins, Lawrence, Zukerberg, Jaclyn C, Watkins, Yin Pun, Hung, and Esther, Oliva
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Obstetrics and Gynecology ,Pathology and Forensic Medicine - Abstract
Peritoneal mesothelioma (PM) and serous neoplasms can be difficult to differentiate, particularly in small biopsies. BRCA1-associated protein 1 (BAP1) is expressed in benign tissues, but over 50% of PMs demonstrate complete loss of nuclear expression. Claudin-4, a tight junction protein, is expressed in most epithelial tumors but not in mesotheliomas. Methylthioadenosine phosphorylase (MTAP) is frequently co-deleted with cyclin-dependent kinase inhibitor 2a in mesotheliomas. These markers have proven useful in separating mesothelioma from its mimics, particularly when tumors are pleural based. In the peritoneum, BAP1 loss has been rarely reported in high-grade serous carcinomas, but overall, these markers have been minimally evaluated in ovarian serous borderline tumors and low-grade serous carcinomas. Thus, we assessed the utility of BAP1, claudin-4, and MTAP in the differential diagnosis of PM and low-grade serous neoplasms. Eighteen PM (16 epithelioid, 1 biphasic, and 1 sarcomatous), 24 low-grade serous carcinomas, and 25 serous borderline tumors were stained for BAP1, claudin-4, and MTAP. Loss of BAP1 nuclear expression was observed in 12 (67%) PM (11 epithelioid, 1 biphasic) but was retained in all serous tumors. Claudin-4 was positive in all serous tumors and negative in all PM. Complete loss of cytoplasmic MTAP was noted in 3 (17%) PMs and 1 (4%) serous borderline tumor, while all low-grade serous carcinomas showed retained expression. BAP1 loss reliably distinguishes PM from serous tumors, although it lacks sensitivity. Claudin-4 is a reliable marker to exclude PM. MTAP loss may occur in both PM and serous tumors, and thus is not useful in distinguishing these entities.
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- 2022
32. Uterine PEComas: correlation between melanocytic marker expression and TSC alterations/TFE3 fusions
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Pankhuri Wanjari, Zehra Ordulu, Esther Oliva, Lauren L. Ritterhouse, Jennifer A. Bennett, Andre Pinto, and Cristina R. Antonescu
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Mesenchymal stem cell ,TFE3 ,Pathology and Forensic Medicine ,Targeted therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Smooth Muscle Tumor ,Medicine ,Immunohistochemistry ,DNA mismatch repair ,TSC1 ,business ,ATRX - Abstract
Uterine PEComas often present a diagnostic challenge as they share morphological and immunohistochemical features with smooth muscle tumors. Herein we evaluated a series of 19 uterine PEComas to compare the degree of melanocytic marker expression with their molecular profile. Patients ranged from 32–77 (median 48) years, with six tumors classified as malignant based on the modified gynecologic-specific prognostic algorithm. All patients with malignant PEComas were alive with disease or dead of disease at last follow-up, while all those of uncertain malignant potential were alive and well (median follow-up, 47 months). Seventeen of 19 (89%) PEComas harbored either a TSC1 or TSC2 alteration. One of the two remaining tumors showed a TFE3 rearrangement, but the other lacked alterations in all genes evaluated. All showed at least focal (usually strong) positivity for HMB-45, with 15/19 (79%) having >50% expression, while the tumor lacking TSC or TFE3 alterations was strongly positive in 10% of cells. Melan-A and MiTF were each positive in 15/19 (79%) tumors, but staining extent and intensity were much more variable than HMB-45. Five of six (83%) malignant PEComas also harbored alterations in TP53, ATRX, or RB1, findings not identified in any tumors of uncertain malignant potential. One malignant PEComa was microsatellite-unstable/mismatch repair protein-deficient. In summary, TSC alterations/TFE3 fusions and diffuse (>50%) HMB-45 expression are characteristic of uterine PEComas. In morphologically ambiguous mesenchymal neoplasms with myomelanocytic differentiation, especially those with metastatic or recurrent disease, next-generation sequencing is recommended to evaluate for TSC alterations; as such, patients can be eligible for targeted therapy.
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- 2022
33. Clear Cell Carcinoma (CCC) of the Cervix Is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome
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Simona Stolnicu, Georgia Karpathiou, Esther Guerra, Claudia Mateoiu, Armando Reques, Angel Garcia, Joost Bart, Ana Felix, Daniela Fanni, Joao Gama, David Hardisson, Jennifer A. Bennett, Carlos Parra-Herran, Esther Oliva, Nadeem Abu-Rustum, Robert A. Soslow, Kay J. Park, and Targeted Gynaecologic Oncology (TARGON)
- Subjects
Carcinoma ,Papillomavirus Infections ,Uterine Cervical Neoplasms ,Cervix Uteri ,Alphapapillomavirus ,Prognosis ,Article ,Pathology and Forensic Medicine ,Humans ,Female ,Surgery ,Anatomy ,Papillomaviridae ,Adenocarcinoma, Clear Cell ,Neoplasm Staging ,Retrospective Studies - Abstract
Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.
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- 2022
34. TSC2-mutant uterine sarcomas with JAZF1-SUZ12 fusions demonstrate hybrid features of endometrial stromal sarcoma and PEComa and are responsive to mTOR inhibition
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Rajmohan Murali, Amir Momeni-Boroujeni, Seth M. Cohen, Kay J. Park, Lora H. Ellenson, Matija Snuderl, Edaise M da Silva, Cheng-Han Lee, Ryma Benayed, Nadeem R. Abu-Rustum, Jason A. Konner, Varshini Vasudevaraja, Marc Ladanyi, Sarah Chiang, Achim A. Jungbluth, Jonathan Serrano, Mark A. Dickson, Britta Weigelt, Carol Aghajanian, Robert A. Soslow, Martee L. Hensley, Arnaud Da Cruz Paula, Esther Oliva, and Colin J.R. Stewart
- Subjects
Pathology ,medicine.medical_specialty ,Somatic cell ,Biology ,Article ,Perivascular Epithelioid Cell ,Pathology and Forensic Medicine ,Cohort Studies ,Diagnosis, Differential ,medicine ,Humans ,Epigenetics ,In Situ Hybridization, Fluorescence ,PI3K/AKT/mTOR pathway ,Aged ,Endometrial stromal sarcoma ,Sarcoma ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Mutation ,Uterine Neoplasms ,Female ,Epithelioid cell - Abstract
Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that occasionally shares morphologic and immunohistochemical overlap with low- and high-grade endometrial stromal sarcoma (LGESS and HGESS). In this study, we sought to characterize the clinical, morphologic, genetic, and epigenetic features of five uterine sarcomas that display histologic features of LGESS, HGESS, and PEComa. All tumors demonstrated epithelioid cells often associated with a low-grade spindled component resembling LGESS, with both regions expressing CD10, ER, PR, variable HMB45, and Melan-A immunoreactivity, and strong cathepsin K and pS6 expression. Targeted massively parallel sequencing analysis revealed the presence of somatic TSC2 mutations in all five cases, of which four harbored concurrent or consecutive JAZF1-SUZ12 gene fusions. Unsupervised hierarchical clustering analysis of methylation profiles of TSC2-mutant uterine sarcomas (n = 4), LGESS (n = 10), and HGESS (n = 12) demonstrated two clusters consisting of (1) all LGESS and TSC2-mutant uterine sarcomas and (2) all HGESS. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, calcium, and Rap1 signaling. TSC2-mutant uterine sarcomas were responsive to hormone suppression, and mTOR inhibition demonstrated clinical benefit in four patients with these neoplasms. Our results suggest that these tumors represent histologically distinctive LGESS with TSC2 mutations. TSC2 mutations and JAZF1-SUZ12 fusion may help diagnose these tumors and possibly direct effective treatment.
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- 2022
35. An Unusual Endometrial Stromal Neoplasm With JAZF1-BCORL1 Rearrangement
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Parnian A. Moghaddam, Robert H. Young, Nadia D. Ismiil, Jennifer A. Bennett, and Esther Oliva
- Subjects
Obstetrics and Gynecology ,Pathology and Forensic Medicine - Published
- 2023
36. GLI1 Gene Alterations in Neoplasms of the Genitourinary and Gynecologic Tract
- Author
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Pedram, Argani, Baris, Boyraz, Esther, Oliva, Andres, Matoso, John, Gross, Eddie, Fridman, Lei, Zhang, Brendan C, Dickson, and Cristina R, Antonescu
- Subjects
Adult ,Aged, 80 and over ,Sarcoma, Endometrial Stromal ,Middle Aged ,Glomus Tumor ,Zinc Finger Protein GLI1 ,Article ,Endometrial Neoplasms ,Pathology and Forensic Medicine ,Uterine Neoplasms ,Biomarkers, Tumor ,Humans ,Female ,Surgery ,Gene Fusion ,Anatomy ,Aged - Abstract
We report four neoplasms of the kidney (2 cases) and uterus (2 cases) harboring rearrangements or amplifications of the GLI1 gene, which due to their unusual clinical presentation, morphology and immunoprofile mimicked other neoplasms, causing significant diagnostic challenge. The neoplasms occurred in four female patients ages 33–88 years. Histologically they all demonstrated nodular growth, solid architecture, bland epithelioid to ovoid spindle cells with pale cytoplasm set in a variably myxoid or hyalinized stroma. One uterine tumor also demonstrated a focal round cell pattern, while another demonstrated focal pleomorphism. Unlike most previously reported neoplasms with these genetic abnormalities, the neoplasms in the current series were negative for S100 protein and minimally reactive for actin. All labeled for CD10 and cyclin D1, while two labeled for estrogen receptor and BCOR and one labeled for desmin, raising consideration of endometrial stromal sarcoma, myxoid leiomyosarcoma, metastatic breast carcinoma, and glomus tumor. One renal neoplasm demonstrated a GLI1-FOXO4 gene fusion and the other harbored a GLI1 gene rearrangement (unknown partner). The two uterine neoplasms exhibited GLI1 gene amplifications. GLI1-altered neoplasms (particularly those with GLI1-amplification) show variable morphology and lack a consistent immunophenotype, and thus may trigger diagnostic challenges which can be resolved by molecular testing.
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- 2021
37. Claudin-18 as a Promising Surrogate Marker for Endocervical Gastric-type Carcinoma
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Takako, Kiyokawa, Lien, Hoang, Anna, Pesci, Isabel, Alvarado-Cabrero, Esther, Oliva, Kay J, Park, Robert A, Soslow, and Simona, Stolnicu
- Subjects
Stomach Neoplasms ,Carcinoma ,Claudins ,Biomarkers, Tumor ,Racemases and Epimerases ,Humans ,Uterine Cervical Neoplasms ,Female ,Surgery ,Adenocarcinoma ,Anatomy ,Article ,Pathology and Forensic Medicine - Abstract
HIK1083 and trefoil factor 2 (TFF2) are known to be expressed in gastric-type carcinoma (GAS), but they do not reliably mark all GASs, and focal expression can be missed in biopsy specimens. We aimed to investigate whether claudin-18 and alpha-methylacyl-CoA racemase (AMACR) could be surrogate markers to separate GAS from other types of endocervical adenocarcinoma (ECA) and to compare their usefulness with that of HIK1083 and TFF2. Claudin-18 and AMACR immunohistochemistry was performed, and the results were compared with that of TFF2 and HIK1083, using whole sections of 75 ECAs (22 GASs and 53 non-GASs) and 179 ECAs with tissue microarrays (TMAs). TMAs were built to simulate the assessment of immunohistochemical stains in small biopsies. Any membranous (claudin-18) or cytoplasmic/membranous (AMACR, TFF2, HIK1083) staining of5% of tumor cells was considered positive. Of 75 ECAs with whole sections, claudin-18 was significantly more frequently expressed in GASs (21/22) compared with non-GASs (8/53) (P0.01). In ECAs with TMAs, claudin-18 expression was significantly frequent in GASs (15/23, 65.2%) than in non-GASs (3/152, 2.0%; all usual-type) (P0.01). All claudin-18-positive GASs showed intense staining except 1 case. Claudin-18 shared the same degree of sensitivity and specificity with HIK1083 and TFF2. Three clear cell carcinomas were positive for claudin-18, but none showed intense staining. AMACR was expressed in a subset of ECAs and showed no impact in distinguishing between GAS and other ECAs. Our results suggest that claudin-18 is a promising surrogate marker to separate GAS from other types of ECA, including clear cell carcinoma.
- Published
- 2021
38. Horizontal tumor extent (HZTE) has limited prognostic significance in 2018 FIGO stage I endocervical adenocarcinoma (ECA): a retrospective study of 416 cases
- Author
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Georgia Karpathiou, Esther Guerra Fernandez, Andres A. Roma, Simona Stolnicu, Graziele Bovolim, Anna Pesci, Robert A. Soslow, Louise De Brot, Esther Oliva, Lien Hoang, Pavel Dundr, Ana Félix, Glauco Baiocchi, Maria José Brito, Antonio Ieni, Kay J. Park, Sofia Lerias, Takako Kyiokawa, Nadeem R. Abu-Rustum, Carlos Parra-Herran, and Noorah Almadani
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Uterine Cervical Neoplasms ,Adenocarcinoma ,Hysterectomy ,Article ,Figo staging ,Recurrence free survival ,Internal medicine ,Humans ,Medicine ,Stage (cooking) ,Aged ,Retrospective Studies ,Univariate analysis ,business.industry ,Retrospective cohort study ,General Medicine ,Middle Aged ,Prognosis ,Cervical cancer staging ,Survival Rate ,Endocervical Adenocarcinoma ,Endocervical adenocarcinoma ,FIGO ,Horizontal tumor extent ,Management ,Prognostic significance ,Stage ,Female ,business ,Follow-Up Studies - Abstract
PURPOSE: The 2018 International Federation of Gynecology and Obstetrics (FIGO) update on cervical cancer staging eliminated horizontal tumor extent (HZTE) as a staging parameter in stage IA (microscopic) disease. We aimed to determine whether HZTE correlates with outcomes in early stage ECAs and FIGO should reinstate HZTE as a staging parameter in futures updates. METHODS: We retrospectively analyzed 416 FIGO 2009 stage I ECAs from 17 institutions and re-assigned stage using FIGO 2018. Correlation between HZTE, overall (OS) and recurrence free survival (RFS) was performed using univariable and multivariable analyses. RESULTS: Re-staging 416 cases resulted in 126 (30.3%) IA and 290 (69.7%) IB cases; 85 (67.5%) IA tumors had HZTE ≤7mm, while 41 (32.5%) were >7mm; 32 (11%) IB tumors had HZTE ≤7mm, while 258 (89%) were >7mm (p=0.0001). Four (3.2%) IA (1 IA1, 3 IA2) patients developed recurrence (3 ≤7mm, 1 >7mm) compared to 41 (14.1%) IB patients (p=0.002). Fourteen IB and no IA patients died of disease (8 IB1, 1 ≤7mm). Cox univariate analysis demonstrated that only RFS is significantly influenced by HZTE (p=0.01), while OS and RFS were not influenced by HZTE on multivariate analysis. CONCLUSION: HZTE has limited prognostic value in early stage ECAs and is only associated with RFS on univariate but not multivariate analysis. HZTE does not improve prognostication of patients with stage I ECAs as per 2018 FIGO staging. Consequently, the rationale to remove this variable from FIGO staging is justified for ECAs.
- Published
- 2021
39. Undifferentiated and dedifferentiated neoplasms of the female genital tract
- Author
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Jennifer A. Bennett and Esther Oliva
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Ovary ,Endometrium ,Pathology and Forensic Medicine ,Targeted therapy ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Carcinoma ,Humans ,Undifferentiated Uterine Sarcoma ,business.industry ,Genitalia, Female ,medicine.disease ,Immunohistochemistry ,Radiation therapy ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Differential diagnosis ,business - Abstract
Undifferentiated neoplasms in the female gynecologic tract comprise two main groups-undifferentiated carcinoma, most common in the endometrium and ovary, and undifferentiated uterine sarcoma, although tumors with an undifferentiated appearance may occur in all gynecologic organs. Their differential diagnosis is broad and generous sampling, careful morphological evaluation, judicious use of immunohistochemistry, and in many cases, molecular testing is often essential in the diagnostic work-up. As some of these neoplasms fail to respond to conventional chemotherapy regimens and/or radiation therapy, targeted therapy may be valuable in treating these highly aggressive tumors, thus the importance of precise diagnosis. In this review we discuss the clinicopathological features of undifferentiated carcinoma, dedifferentiated carcinoma, and undifferentiated uterine sarcoma, followed by a comprehensive analysis of morphological mimickers. Finally, we briefly review ovarian and lower genital tract tumors with an undifferentiated histological appearance.
- Published
- 2021
40. Malignant Gonadal Germ Cell Tumors (Other Than Pure Germinoma) in Patients With Disorders of Sex Development
- Author
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Robert H. Young, Esther Oliva, Sheila E. Segura, and Thomas M. Ulbright
- Subjects
Pathology ,medicine.medical_specialty ,Germinoma ,Gonadoblastoma ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,Embryonal carcinoma ,medicine.anatomical_structure ,embryonic structures ,medicine ,Surgery ,Immature teratoma ,Teratoma ,Germ cell tumors ,Spindle cell sarcoma ,Anatomy ,Yolk sac - Abstract
We describe 21 nonpure germinomatous gonadal germ cell tumors (9 with a germinoma component), all but 1 associated with gonadoblastoma, in patients with disorders of sex development who ranged from 7 to 36 years old (average, 20 y). Twenty patients were clinically described as phenotypic females with ambiguous genitalia/virilization and primary amenorrhea. The most common documented peripheral karyotype was 46,XY (10/12; 83%). Fifteen of 16 tumors with available clinicopathologic data were unilateral. They ranged from 7 to 30 cm (mean, 15.5 cm) and were solid and cystic with frequent necrosis and hemorrhage. Gonadoblastoma, in its classic (70%), dissecting (5%), or combined (25%) forms, was identified in all but 1. The malignant germ cell tumors were typically mixed except for 5 pure yolk sac tumors and 1 expansile gonadoblastoma with syncytiotrophoblast cells. When admixed, the most common component was yolk sac tumor (n=10), followed by germinoma (n=9), embryonal carcinoma (n=5), choriocarcinoma (n=4), immature teratoma (n=3), and teratoma (n=2). Typical morphologic patterns of yolk sac neoplasia, including reticular/microcystic, solid (including blastema-like), and endodermal sinus (Schiller-Duval bodies), were seen, as well as glandular (n=10) and hepatoid (n=6) differentiation, with cystically dilated glands and diffuse hepatoid morphology in 3 and 2 tumors, respectively. Two yolk sac tumors showed a sarcomatoid pattern. Somatic-type malignancies (alveolar rhabdomyosarcoma and low-grade spindle cell sarcoma, not otherwise specified) were identified in 1 case each. This is the first large series of germ cell tumors other than typical pure germinoma associated with gonadoblastoma. The high frequency of yolk sac tumor with glandular (especially cystic glandular) and hepatoid morphologies is noteworthy, and their presence should prompt further evaluation for an associated gonadoblastoma and possible disorder of sex development.
- Published
- 2021
41. Embryonal rhabdomyosarcoma of the uterine corpus: a clinicopathological and molecular analysis of 21 cases highlighting a frequent association with DICER1 mutations
- Author
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Leanne de Kock, Esther Oliva, Andre Pinto, Robert H. Young, Zehra Ordulu, Jennifer A. Bennett, W. Glenn McCluggage, William D. Foulkes, Lauren L. Ritterhouse, Koen Van de Vijver, Rajeev Shah, Pankhuri Wanjari, and Eike Burandt
- Subjects
Adult ,Ribonuclease III ,0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Pathology ,medicine.medical_specialty ,Tumor Cell Necrosis ,Pleuropulmonary blastoma ,medicine.disease_cause ,MULLERIAN ADENOSARCOMA ,Pathology and Forensic Medicine ,UTERUS ,DEAD-box RNA Helicases ,03 medical and health sciences ,0302 clinical medicine ,Medicine and Health Sciences ,medicine ,Humans ,Rhabdomyosarcoma, Embryonal ,HETEROLOGOUS ELEMENTS ,WILMS-TUMOR ,Anaplasia ,Aged ,DICER1 Syndrome ,business.industry ,PLEUROPULMONARY BLASTOMA ,PURE ALVEOLAR RHABDOMYOSARCOMA ,Wilms' tumor ,Middle Aged ,medicine.disease ,GENOMIC ANALYSIS ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Uterine Neoplasms ,CHILDHOOD RHABDOMYOSARCOMA ,Female ,Embryonal rhabdomyosarcoma ,KRAS ,medicine.symptom ,PRIMARY OVARIAN RHABDOMYOSARCOMA ,URINARY-BLADDER ,business - Abstract
Herein we evaluated a series of 21 embryonal rhabdomyosarcomas of the uterine corpus (ucERMS), a rare neoplasm, to characterize their morphology, genomics, and behavior. Patients ranged from 27 to 73 (median 52) years and tumors from 4 to 15 (median 9) cm, with extrauterine disease noted in two. Follow-up (median 16 months) was available for 14/21 patients; nine were alive and well, four died of disease, and one died from other causes. Most tumors (16/21) showed predominantly classic morphology, comprised of alternating hyper- and hypocellular areas of primitive small cells and differentiating rhabdomyoblasts in a loose myxoid/edematous stroma. A cambium layer was noted in all; seven had heterologous elements (six with fetal-type cartilage) and eight displayed focal anaplasia. The remaining five neoplasms showed only a minor component (
- Published
- 2021
42. Leiomyoma-like Morphology in Metastatic Uterine Inflammatory Myofibroblastic Tumors
- Author
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Kyle M. Devins, Wesley Samore, G. Petur Nielsen, Vikram Deshpande, and Esther Oliva
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Pathology and Forensic Medicine - Published
- 2023
43. Uterine inflammatory myofibroblastic tumor: First report of a<scp>ROS1</scp>fusion
- Author
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Pankhuri Wanjari, Peng Wang, Jennifer A. Bennett, Lidia Diaz, and Esther Oliva
- Subjects
Adult ,Cancer Research ,Pathology ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,Uterus ,Biology ,Neoplasms, Muscle Tissue ,Exon ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Genetics ,medicine ,ROS1 ,Humans ,Anaplastic Lymphoma Kinase ,RNA-Seq ,Uterine Neoplasm ,Inflammation ,RNA ,Protein-Tyrosine Kinases ,Fibronectins ,Staining ,medicine.anatomical_structure ,Cytoplasm ,Uterine Neoplasms ,Immunohistochemistry ,Female - Abstract
Inflammatory myofibroblastic tumor (IMT) of the uterus is an uncommon mesenchymal neoplasm that frequently harbors ALK rearrangements. In this report, we describe the first uterine IMT with a FN1-ROS1 fusion, which occurred in a 43-year-old woman who presented with menorrhagia. Morphologically, the well-circumscribed 3 cm tumor was comprised of compact and myxoid foci of relatively bland spindle cells admixed with scattered chronic inflammatory cells limited to the myxoid areas. ROS1 showed moderate cytoplasmic granular staining in < 30% of cells in the myxoid foci, while ALK was negative. RNA sequencing detected a FN1-ROS1 rearrangement that fused FN1 exon 37 to ROS1 exon 34. Although non-ALK-rearranged uterine IMTs are exceedingly rare, this example highlights the importance of performing ROS1 immunohistochemistry and/or molecular analysis in ALK-negative uterine neoplasms morphologically compatible with IMT.
- Published
- 2021
44. A Distinctive Adnexal (Usually Paratubal) Neoplasm Often Associated With Peutz-Jeghers Syndrome and Characterized by STK11 Alterations (STK11 Adnexal Tumor) A Report of 22 Cases
- Author
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Brooke E. Howitt, Emily E. Meserve, Loes F. S. Kooreman, Britta Weigelt, Sabrina Croce, Sofia Westbom-Fremer, Mona El-Bahrawy, Gian Franco Zannoni, Pankhuri Wanjari, Eduardo Benzi, Thomas Krausz, Jennifer A. Bennett, Arnaud Da Cruz Paula, Esther Oliva, Lauren L. Ritterhouse, Ninad M Patil, Chaojie Zhen, Robert H. Young, J. Kenneth Schoolmeester, W. Glenn McCluggage, MUMC+: DA Pat Pathologie (9), and RS: GROW - R2 - Basic and Translational Cancer Biology
- Subjects
Adult ,sex cord-like ,RECURRENT KRAS MUTATIONS ,Pathology ,medicine.medical_specialty ,Peutz-Jeghers syndrome ,PROBABLE WOLFFIAN ORIGIN ,Adolescent ,CORD-STROMAL TUMORS ,Peutz–Jeghers syndrome ,Histogenesis ,Protein Serine-Threonine Kinases ,Article ,OVARIAN-TUMORS ,Pathology and Forensic Medicine ,Loss of heterozygosity ,adnexal ,Cytokeratin ,Young Adult ,AMP-Activated Protein Kinase Kinases ,Medicine ,Humans ,Sex Cord-Gonadal Stromal Tumors ,IMMUNOHISTOCHEMISTRY ,Aged ,Ovarian Neoplasms ,PERITONEAL MESOTHELIOMA ,Settore MED/08 - ANATOMIA PATOLOGICA ,business.industry ,STK11 ,1103 Clinical Sciences ,Middle Aged ,medicine.disease ,salivary gland-like ,FALLOPIAN-TUBE ,CARCINOMAS ,Mutation ,Immunohistochemistry ,paratubal ,ANNULAR TUBULES ,Surgery ,Female ,Anatomy ,Calretinin ,DIFFERENTIAL-DIAGNOSIS ,business ,PAX8 ,Epithelioid cell - Abstract
We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 (median 39) years and the tumors from 4.5 to 25.5 (median 11) cm. Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median 9 per 10 high-power fields). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2–40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphological, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.
- Published
- 2021
45. Massively parallel sequencing analysis of 68 gastric-type cervical adenocarcinomas reveals mutations in cell cycle-related genes and potentially targetable mutations
- Author
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Karen L. Talia, Britta Weigelt, Yoshiki Mikami, Esther Oliva, Cathleen Matrai, Pier Selenica, W. Glenn McCluggage, Emanuela Veras, Yaser R. Hussein, Regina G. H. Beets-Tan, Takako Kiyokawa, Barbara Alemar, Kay J. Park, Rajmohan Murali, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, School Office GROW, and Faculteit FHML Centraal
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Somatic cell ,STK11 ,Uterine Cervical Neoplasms ,ENDOCERVICAL GLANDULAR HYPERPLASIA ,Adenocarcinoma ,medicine.disease_cause ,Gastroenterology ,Article ,Cervix ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Immunophenotyping ,CDKN2A ,Internal medicine ,Genetics ,Medicine ,Humans ,Gene ,P53 ,Massive parallel sequencing ,business.industry ,Mucin ,IMMUNOPHENOTYPE ,High-Throughput Nucleotide Sequencing ,UTERINE CERVIX ,INHIBITOR ,Sequence Analysis, DNA ,DNA ,CANCER ,PREVALENCE ,Genes, cdc ,Gastric-type adenocarcinoma ,030104 developmental biology ,COPY NUMBER ,030220 oncology & carcinogenesis ,DISCOVERY ,Mutation ,Female ,KRAS ,business - Abstract
Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n = 68) were subjected to massively parallel sequencing targeting 410-468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n = 21), PAs (n = 178), and IGAs (n = 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53 (41% vs 5%, p
- Published
- 2021
46. Follicular Dendritic Cell Sarcoma of Uterine Corpus: Report of 2 Cases
- Author
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Baris Boyraz, Miriam D. Post, Robert P. Hasserjian, and Esther Oliva
- Subjects
Obstetrics and Gynecology ,Pathology and Forensic Medicine - Abstract
Follicular dendritic cell sarcoma is a rare dendritic/histiocytic tumor of intermediate malignant potential, which often involves extranodal sites, most commonly the gastrointestinal tract and mediastinum with only 5 cases reported in the female genital tract. We present the clinical and pathologic features of 2 such examples arising in the uterine corpus. Both patients (63 and 72-yr old) presented with postmenopausal bleeding and underwent an endometrial biopsy diagnostic of follicular dendritic cell sarcoma that was followed by hysterectomy. The tumors were polypoid, 3.5 and 5.0 cm, and were confined to the endometrium. Microscopically, ovoid to round to spindled tumor cells with pale eosinophilic cytoplasm and vesicular nuclei were arranged predominantly in sheets with an accompanying lymphocyte-rich inflammatory infiltrate. The tumor cells were positive for CD35, CD23, D2-40 in both tumors and additionally positive for CD21 in 1 tumor, all highlighting cell bodies and processes. Patients were alive without evidence of disease at 1 and 4 years with no adjuvant treatment. These cases highlight the importance of entertaining a broad differential diagnosis in lesions with epithelioid and/or spindled morphology involving the uterus.
- Published
- 2022
47. Cervical Adenosquamous Carcinoma: Detailed Analysis of Morphology, Immunohistochemical Profile, and Outcome in 59 Cases
- Author
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Simona Stolnicu, Lynn Hoang, Qin Zhou, Alexia Iasonos, Cristina Terinte, Anna Pesci, Sarit Aviel-Ronen, Takako Kiyokawa, Isabel Alvarado-Cabrero, Esther Oliva, Kay J. Park, and Robert A. Soslow
- Subjects
Adult ,HPV ,glassy cell carcinoma ,Obstetrics and Gynecology ,Uterine Cervical Neoplasms ,invasive stratified mucin-producing carcinomas ,Middle Aged ,Immunohistochemistry ,Article ,Pathology and Forensic Medicine ,Carcinoma, Adenosquamous ,cervical adenosquamous carcinoma ,Biomarkers, Tumor ,Humans ,Female ,Aged - Abstract
Although 2014 World Health Organization criteria require unequivocal glandular and squamous differentiation for a diagnosis of cervical adenosquamous carcinoma, in practice, adenosquamous carcinoma diagnoses are often made in tumors that lack unequivocal squamous and/or glandular differentiation. Considering the ambiguous etiologic, morphological, and clinical features and outcomes associated with adenosquamous carcinomas, we sought to redefine these tumors. We reviewed slides from 59 initially diagnosed adenosquamous carcinomas (including glassy cell carcinoma and related lesions) to confirm an adenosquamous carcinoma diagnosis only in the presence of unequivocal malignant glandular and squamous differentiation. Select cases underwent immunohistochemical profiling as well as human papillomavirus (HPV) testing by in situ hybridization. Of the 59 cases originally classified as adenosquamous carcinomas, 34 retained their adenosquamous carcinoma diagnosis, 9 were reclassified as pure invasive stratified mucin-producing carcinomas, 10 as invasive stratified mucin-producing carcinomas with other components (such as HPV-associated mucinous, usual-type, or adenosquamous carcinomas), and 4 as HPV-associated usual or mucinous adenocarcinomas with benign-appearing squamous metaplasia. Two glassy cell carcinomas were reclassified as poorly differentiated usual-type carcinomas based on morphology and immunophenotype. There were significant immunophenotypic differences between adenosquamous carcinomas and pure invasive stratified mucin-producing carcinomas with regard to HPV (p 0.0001), PAX8 (p = 0.038; more in adenosquamous carcinoma), p40 (p 0.0001; more in adenosquamous carcinoma), p63 (p = 0.0018; more in adenosquamous carcinoma) and MUC6 (p 0.0001; less in adenosquamous carcinoma), HNF-1beta (p = 0.0023), vimentin (p = 0.0003), p53 (p = 0.0004), and CK7 (p = 0.0002) expression. Survival outcomes were similar between all groups. Adenosquamous carcinomas should be diagnosed only in the presence of unequivocal malignant glandular and squamous differentiation. The two putative glassy cell carcinomas studied did not meet our criteria for adenosquamous carcinoma, and categorizing them as such should be reconsidered.
- Published
- 2022
48. Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway
- Author
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Junbing Zhang, Claire M. Simpson, Jacqueline Berner, Harrison B. Chong, Jiafeng Fang, Zehra Ordulu, Tommy Weiss-Sadan, Anthony P. Possemato, Stefan Harry, Mariko Takahashi, Tzu-yi Yang, Marianne Richter, Himani Patel, Abby E. Smith, Alexander D. Carlin, Adriaan F. Hubertus de Groot, Konstantin Wolf, Lei Shi, Ting-Yu Wei, Benedikt R. Dürr, Nicholas J. Chen, Tristan Vornbäumen, Nina O. Wichmann, Mohammed S. Mahamdeh, Venkatesh Pooladanda, Yusuke Matoba, Shaan Kumar, Eugene Kim, Sara Bouberhan, Esther Oliva, Bo R. Rueda, Roy J. Soberman, Nabeel Bardeesy, Brian B. Liau, Michael Lawrence, Matt P. Stokes, Sean A. Beausoleil, and Liron Bar-Peled
- Subjects
General Biochemistry, Genetics and Molecular Biology - Published
- 2023
49. Tumor Typing of Endocervical Adenocarcinoma: Contemporary Review and Recommendations From the International Society of Gynecological Pathologists
- Author
-
Kay J. Park, Takako Kiyokawa, W. Glenn McCluggage, Simona Stolnicu, Robert A. Soslow, and Esther Oliva
- Subjects
0301 basic medicine ,Oncology ,Female circumcision ,medicine.medical_specialty ,Pathology ,Uterine Cervical Neoplasms ,Adenocarcinoma ,Immunophenotyping ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Histologic type ,Humans ,HPV-associated ,Typing ,Human papillomavirus ,Papillomaviridae ,Societies, Medical ,Hpv status ,Cervical cancer ,HPV-independent ,business.industry ,Papillomavirus Infections ,Obstetrics and Gynecology ,Articles ,Classification ,medicine.disease ,Pathologists ,Endocervical Adenocarcinoma ,ISGyP ,030104 developmental biology ,Gynecology ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Types ,Endocervical adenocarcinoma ,Female ,Neoplasm Grading ,Differential diagnosis ,business - Abstract
The incidence of endocervical adenocarcinoma, the second most common cervical cancer in the world, has been on the rise. While most cervical cancers are squamous cell carcinomas and associated with high-risk oncogenic human papillomavirus (HPV), approximately 15% of endocervical adenocarcinomas, which now represent about one quarter of all cervical cancers, are HPV-independent. In this review, we will focus on the shortcomings of historical histologic classification systems of female genital tract tumors as they pertain to endocervical adenocarcinomas, and we will highlight the advantages of the new International Endocervical Adenocarcinoma Criteria and Classification system, which forms the basis for the WHO 2020 classification. We will cover the various histologic types, subtypes, and variants of endocervical adenocarcinoma with regard to morphology, immunophenotype, molecular genetics, HPV status and differential diagnosis, and we will provide International Society of Gynecological Pathologists recommendations for diagnosing these tumors.
- Published
- 2021
50. Endocervical Adenocarcinoma, Gross Examination, and Processing, Including Intraoperative Evaluation: Recommendations From the International Society of Gynecological Pathologists
- Author
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Pedro T. Ramirez, Carlos Parra-Herran, Esther Oliva, Joseph T. Rabban, Anais Malpica, and Gian Franco Zannoni
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Trachelectomy ,Sentinel lymph node ,Uterine Cervical Neoplasms ,Lymph node dissection ,Adenocarcinoma ,Hysterectomy ,Pathology and Forensic Medicine ,Gross examination ,03 medical and health sciences ,0302 clinical medicine ,Monitoring, Intraoperative ,Medicine ,LEEP ,Humans ,Radical Hysterectomy ,Societies, Medical ,Cancer staging ,Cervical cancer ,Evidence-Based Medicine ,Pelvic exenteration ,business.industry ,General surgery ,Obstetrics and Gynecology ,Articles ,medicine.disease ,Pelvic Exenteration ,Specimen processing ,Pathologists ,030104 developmental biology ,Gynecology ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Endocervical adenocarcinoma ,Lymph Node Excision ,Lymphadenectomy ,Female ,Sentinel Lymph Node ,business ,Cone - Abstract
The International Society of Gynecological Pathologists (ISGyP) Endocervical Adenocarcinoma Project aims to provide evidence-based guidance for the pathologic evaluation, classification, and reporting of endocervical adenocarcinoma. This review presents the recommendations pertaining to gross evaluation and intraoperative consultation of specimens obtained from patients in the setting of cervical cancer. The recommendations are the product of review of published peer-reviewed evidence, international guidelines and institutional grossing manuals, as well as deliberation within this working group. The discussion presented herein details the approach to the different specimen types encountered in practice: loop electrosurgical excision procedure, cone, trachelectomy, radical hysterectomy, pelvic exenteration, and lymphadenectomy specimens. Guidelines for intraoperative evaluation of trachelectomy and sentinel lymph node specimens are also addressed. Correlation with ISGyP recommendations on cancer staging, which appear as a separate review in this issue, is also included when appropriate. While conceived in the framework of endocervical adenocarcinoma, most of the discussion and recommendations can also be applied to other cervical malignancies.
- Published
- 2021
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