Browsing by Author "Gordetsky, Jennifer B."

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    Clinicopathologic and molecular spectrum of testicular sex cord-stromal tumors not amenable to specific histopathologic subclassification
    (Elsevier, 2022-12) Siegmund , Stephanie E.; Sholl , Lynette M.; Tsai , Harrison K.; Yang, Yiying; Vasudevaraja, Varshini; Tran, Ivy; Snuderl, Matija; Fletcher, Christopher D. M.; Cornejo, Kristine M.; Idrees, Muhammad T.; Al-Obaidy, Khaleel I.; Collins , Katrina; Gordetsky, Jennifer B.; Wobker, Sara E.; Hirsch, Michelle S.; Trpkov , Kiril; Yilmaz , Asli; Anderson, William J.; Quiroga-Garza, Gabriela; Magi-Galluzzi, Cristina; Canete-Portillo, Sofia; Acosta , Andres M.; Pathology and Laboratory Medicine, School of Medicine
    A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4 cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data.
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    Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment
    (Elsevier, 2022) Jiang, Yu; Meyers, Travis J.; Emeka, Adaeze A.; Folgosa Cooley, Lauren; Cooper, Phillip R.; Lancki, Nicola; Helenowski, Irene; Kachuri, Linda; Lin, Daniel W.; Stanford, Janet L.; Newcomb, Lisa F.; Kolb, Suzanne; Finelli, Antonio; Fleshner, Neil E.; Komisarenko, Maria; Eastham, James A.; Ehdaie, Behfar; Benfante, Nicole; Logothetis, Christopher J.; Gregg, Justin R.; Perez, Cherie A.; Garza, Sergio; Kim, Jeri; Marks, Leonard S.; Delfin, Merdie; Barsa, Danielle; Vesprini, Danny; Klotz, Laurence H.; Loblaw, Andrew; Mamedov, Alexandre; Goldenberg, S. Larry; Higano, Celestia S.; Spillane, Maria; Wu, Eugenia; Carter, H. Ballentine; Pavlovich, Christian P.; Mamawala, Mufaddal; Landis, Tricia; Carroll, Peter R.; Chan, June M.; Cooperberg, Matthew R.; Cowan, Janet E.; Morgan, Todd M.; Siddiqui, Javed; Martin, Rabia; Klein, Eric A.; Brittain, Karen; Gotwald, Paige; Barocas, Daniel A.; Dallmer, Jeremiah R.; Gordetsky, Jennifer B.; Steele, Pam; Kundu, Shilajit D.; Stockdale, Jazmine; Roobol, Monique J.; Venderbos, Lionne D.F.; Sanda, Martin G.; Arnold, Rebecca; Patil, Dattatraya; Evans, Christopher P.; Dall’Era, Marc A.; Vij, Anjali; Costello, Anthony J.; Chow, Ken; Corcoran, Niall M.; Rais-Bahrami, Soroush; Phares, Courtney; Scherr, Douglas S.; Flynn, Thomas; Karnes, R. Jeffrey; Koch, Michael; Dhondt, Courtney Rose; Nelson, Joel B.; McBride, Dawn; Cookson, Michael S.; Stratton, Kelly L.; Farriester, Stephen; Hemken, Erin; Stadler, Walter M.; Pera, Tuula; Banionyte, Deimante; Bianco, Fernando J., Jr.; Lopez, Isabel H.; Loeb, Stacy; Taneja, Samir S.; Byrne, Nataliya; Amling, Christopher L.; Martinez, Ann; Boileau, Luc; Gaylis, Franklin D.; Petkewicz, Jacqueline; Kirwen, Nicholas; Helfand, Brian T.; Xu, Jianfeng; Scholtens, Denise M.; Catalona, William J.; Witte, John S.; Urology, School of Medicine
    Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for PC, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9 × 10−7 and GAB2, p = 2.0 × 10−6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% confidence interval [CI] = 0.94–1.36); whereas decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04–1.50). These results suggest that germline genetics may help inform and individualize the decision of AS—or the intensity of monitoring on AS—versus treatment for the initial management of patients with low-risk PC.
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    New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia
    (Elsevier, 2021) Trpkov, Kiril; Hes, Ondrej; Williamson, Sean R.; Adeniran, Adebowale J.; Agaimy, Abbas; Alaghehbandan, Reza; Amin, Mahul B.; Argani, Pedram; Chen, Ying-Bei; Cheng, Liang; Epstein, Jonathan I.; Cheville, John C.; Comperat, Eva; Werneck da Cunha, Isabela; Gordetsky, Jennifer B.; Gupta, Sounak; He, Huiying; Hirsch, Michelle S.; Humphrey, Peter A.; Kapur, Payal; Kojima, Fumiyoshi; Lopez, Jose I.; Maclean, Fiona; Magi-Galluzzi, Cristina; McKenney, Jesse K.; Mehra, Rohit; Menon, Santosh; Netto, George J.; Przybycin, Christopher G.; Rao, Priya; Rao, Qiu; Reuter, Victor E.; Saleeb, Rola M.; Shah, Rajal B.; Smith, Steven C.; Tickoo, Satish; Tretiakova, Maria S.; True, Lawrence; Verkarre, Virginie; Wobker, Sara E.; Zhou, Ming; Gill, Anthony J.; Pathology and Laboratory Medicine, School of Medicine
    The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.