Browsing by Author "Hes, Ondrej"

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    Diagnostic Criteria for Oncocytic Renal Neoplasms: A Survey of Urologic Pathologists
    (Elsevier, 2017-05) Williamson, Sean R.; Gadde, Ramya; Trpkov, Kiril; Hirsch, Michelle S.; Srigley, John R.; Reuter, Victor E.; Cheng, Liang; Kunju, L. Priya; Barod, Ravi; Rogers, Craig G.; Delahunt, Brett; Hes, Ondrej; Eble, John N.; Zhou, Ming; McKenney, Jesse K.; Martignoni, Guido; Fleming, Stewart; Grignon, David J.; Moch, Holger; Gupta, Nilesh S.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Renal oncocytoma and chromophobe renal cell carcinoma have been long recognized as distinct tumors; however, it remains unknown if uniform diagnostic criteria are used to distinguish these tumor types in practice. A survey was distributed to urologic pathologists regarding oncocytic tumors. Responses were received from 17 of 26 invitees. Histologically, more than 1 mitotic figure was regarded as most worrisome (n = 10) or incompatible (n = 6) with oncocytoma diagnosis. Interpretation of focal nuclear wrinkling, focal perinuclear clearing, and multinucleation depended on extent and did not necessarily exclude oncocytoma if minor. Staining techniques most commonly used included the following: cytokeratin 7 (94%), KIT (71%), vimentin (65%), colloidal iron (59%), CD10 (53%), and AMACR (41%). Rare cytokeratin 7–positive cells (≤5%) were regarded as most supportive of oncocytoma, although an extent excluding oncocytoma was not universal. Multiple chromosomal losses were most strongly supportive for chromophobe renal cell carcinoma diagnosis (65%). Less certainty was reported for chromosomal gain or a single loss. For tumors with mixed or inconclusive features, many participants use an intermediate diagnostic category (82%) that does not label the tumor as unequivocally benign or malignant, typically “oncocytic neoplasm” or “tumor” with comment. The term “hybrid tumor” was used variably in several scenarios. A slight majority (65%) report outright diagnosis of oncocytoma in needle biopsies. The morphologic, immunohistochemical, and genetic characteristics that define oncocytic renal tumors remain incompletely understood. Further studies correlating genetics, behavior, and histology are needed to define which tumors truly warrant classification as carcinomas for patient counseling and follow-up strategies.
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    Distinct clinicopathological features in metanephric adenoma harboring BRAF mutation
    (Impact Journals, 2016-07-08) Caliò, Anna; Eble, John N.; Hes, Ondrej; Martignoni, Guido; Harari, Saul E.; Williamson, Sean R.; Brunelli, Matteo; Osunkoya, Adeboye O.; Wang, Lisha; Comperat, Eva; Lopez-Beltran, Antonio; Wang, Mingsheng; Zhang, Shaobo; Curless, Kendra L.; Post, Kristin M.; Chang, Hsim-Yee; Luchini, Claudio; Baldrige, Lee Ann; MacLennan, Gregory T.; Montironi, Rodolfo; Grignon, David J.; Cheng, Liang; Pathology and Laboratory Medicine, School of Medicine
    BRAF mutation recently has been reported in metanephric adenoma. We sought to determine the clinical and morphologic features of BRAF-mutated metanephric adenoma and to correlate BRAF mutation with BRAF V600E immunohistochemical staining results. A series of 48 metanephric adenomas and 15 epithelial-predominant nephroblastomas were analyzed for the occurrence of BRAF mutation (BRAF V600E/V600E complex, BRAF V600D, BRAF V600K and BRAF V600R) using the BRAF RGQ PCR kit (Qiagen). Immunohistochemistry was performed using monoclonal mouse antibodies against p16INK4 and VE1 (Spring Bioscience), recognizing the BRAF V600E mutant protein. Forty-one of 48 cases (85%) showed BRAF V600E mutation; none of the other BRAF variants was detected. Of 41 BRAF-mutated metanephric adenomas, 33 showed positive VE1 immunostaining (sensitivity 80%, specificity 100%); in all cases we detected p16INK4 expression regardless of BRAF mutation status. All epithelial-predominant nephroblastomas were BRAF-wild-type and none expressed VE1. The following features were associated with BRAF V600E mutation: older patients (p=0.01), female predominance (p=0.005) and the presence of a predominantly acinar architecture (p=0.003). In summary, BRAF-mutated metanephric adenomas were associated with older age, female predominance, and the presence of a predominant acinar component. A subset (20%) of BRAF-mutated metanephric adenomas was not detected by VE1 immunostaining.
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    Gene Fusion Characterization of Rare Aggressive Prostate Cancer Variants ‐ Adenosquamous Carcinoma, Pleomorphic Giant Cell Carcinoma, and Sarcomatoid Carcinoma: An Analysis of 19 Cases
    (Wiley, 2020) Alhamar, Mohamed; Vladislav, I. Tudor; Smith, Steven C.; Gao, Yuan; Cheng, Liang; Favazza, Laura A.; Alani, Ali M.; Ittmann, Michael M.; Riddle, Nicole D.; Whitely, Lisa J.; Gupta, Nilesh S.; Carskadon, Shannon; Gomez-Gelvez, Juan C.; Chitale, Dhananjay A.; Palanisamy, Nallasivam; Hes, Ondrej; Trpkov, Kiril; Williamson, Sean R.; Pathology and Laboratory Medicine, School of Medicine
    Aims We evaluated the molecular underpinnings of rare aggressive prostate cancer variants adenosquamous, pleomorphic giant cell, and sarcomatoid carcinomas. Methods and Results We retrieved 19 tumors with one or more variant(s) and performed ERG immunohistochemistry, a next‐generation sequencing assay targeting recurrent gene fusions, and fluorescence in situ hybridization (FISH) for ERG and BRAF. Divergent differentiation included: sarcomatoid (n=10), adenosquamous (n=7), and pleomorphic giant cell carcinoma (n=7). Five patients had more than one variant. Four had variants only in metastases. ERG rearrangement was detected in 9 (47%, 7 via sequencing, showing TMPRSS2‐ERG and one GRHL2‐ERG fusion, and 2 via FISH, showing rearrangement via deletion). Of these, ERG immunohistochemistry was positive in the adenocarcinoma for 8/9 (89%) but only 5/9 (56%, typically decreased) in the variant. One patient had false‐positive ERG immunohistochemistry in the sarcomatoid component despite negative FISH. Two (11%) harbored BRAF fusions (FAM131A‐BRAF and SND1‐BRAF). Conclusions ERG gene fusions are present in these rare prostate cancer variants with a close frequency to conventional prostate cancer (9/19, 47%). ERG immunohistochemistry usually detects rearrangement in the adenocarcinoma but is less sensitive for the variant histology with weak to negative staining. Adenosquamous and sarcomatoid variants particularly can occur together. Molecular assessment may be an additional tool in select cases to confirm prostatic origin of unusual tumors. The presence of 2 BRAF gene rearrangements suggests that this gene fusion may be enriched in this setting, as RAF kinase fusions have been previously reported in 1‐2% of prostate cancers.
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    Low-grade Oncocytic Tumor of Kidney (CD117 Negative, Cytokeratin 7 Positive): A Distinct Entity?
    (Wiley, 2019) Trpkov, Kiril; Williamson, Sean R.; Gao, Yuan; Martinek, Petr; Cheng, Liang; Sangoi, Ankur R.; Yilmaz, Asli; Wang, Cheng; Fraile, Pilar San Miguel; Montiel, Delia M. Perez; Bulimbasić, Stela; Rogala, Joanna; Hes, Ondrej; Pathology and Laboratory Medicine, School of Medicine
    Aim To describe a group of distinct low‐grade oncocytic renal tumors that demonstrate CD117 negative/Cytokeratin (CK) 7 positive immunoprofile. Methods and results We identified 28 such tumors from 4 large renal tumor archives. We performed immunohistochemistry for: CK7, CD117, PAX8, CD10, AMACR, e‐cadherin, CK20, CA9, AE1/AE3, vimentin, BerEP4, MOC31, CK5/6, p63, HMB45, melan A, CD15 and FH. In 14 cases we performed array CGH; in 9 cases with successful result. Median patient age was 66 years (range 49‐78 years) with a male‐to‐female ratio of 1:1.8. Median tumor size was 3 cm (range 1.1‐13.5 cm). All were single tumors, solid and tan‐brown, without a syndromic association. On microscopy, all cases showed solid and compact nested growth. There were frequent areas of edematous stroma with loosely arranged cells. The tumor cells had oncocytic cytoplasm with uniformly round to oval nuclei, but without significant irregularities, and showed only focal perinuclear halos. Negative CD117 and positive CK7 reactivity were present in all cases (in 2 cases there was focal and very weak CD117 reactivity). Uniform reactivity was found for: PAX8, AE1/AE3, e‐cadherin, BerEP4 and MOC31. Negative stains included: CA9, CK20, vimentin, CK5/6, p63, HMB45, Melan A and CD15. CD10 and AMACR were either negative or focally positive; FH was retained. On array CGH, there were frequent deletions at 19p13.3 (7/9), 1p36.33 (5/9) and 19q13.11 (4/9); disomic status was found in 2/9 cases. On follow‐up (mean 31.8 months, range 1‐118), all patients were alive with no disease progression. Conclusion Low‐grade oncocytic tumors that are CD117 negative/CK7positive demonstrate consistent and readily recognizable morphology, immunoprofile, and indolent behavior.
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    Molecular pathology of urogenital tumors : Recommendations from the 2019 International Society of Urological Pathology (ISUP) Consensus Conference
    (SpringerLink, 2021-05) Hommerding, Oliver; Allory, Yves; Argani, Pedram; Bismar, Tarek A.; Bubendorf, Lukas; Canete-Portillo, Sofía; Chaux, Alcides; Chen, Ying-Bei; Cheng, Liang; Cubilla, Antonio L.; Egevad, Lars; Gill, Anthony J.; Grignon, David J.; Hartmann, Arndt; Hes, Ondrej; Idrees, Muhammad T.; Kao, Chia-Sui; Knowles, Margaret A.; Looijenga, Leendert H.J.; Lotan, Tamara L.; Pritchard, Colin C.; Rubin, Mark A.; Tomlins, Scott A.; Van der Kwast, Theodorus H.; Velazquez, Elsa F.; Warrick, Joshua I.; Williamson, Sean R.; Kristiansen, Glen; Pathology and Laboratory Medicine, School of Medicine
    Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.
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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.
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    Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: III: Molecular Pathology of Kidney Cancer
    (Wolters Kluwer, 2020-07) Williamson, Sean R.; Gill, Anthony J.; Argani, Pedram; Chen, Ying-Bei; Egevad, Lars; Kristiansen, Glen; Grignon, David J.; Hes, Ondrej; Pathology and Laboratory Medicine, School of Medicine
    Renal cell carcinoma (RCC) subtypes are increasingly being discerned via their molecular underpinnings. Frequently this can be correlated to histologic and immunohistochemical surrogates, such that only simple targeted molecular assays, or none at all, are needed for diagnostic confirmation. In clear cell RCC, VHL mutation and 3p loss are well known; however, other genes with emerging important roles include SETD2, BAP1, and PBRM1, among others. Papillary RCC type 2 is now known to include likely several different molecular entities, such as fumarate hydratase (FH) deficient RCC. In MIT family translocation RCC, an increasing number of gene fusions are now described. Some TFE3 fusion partners, such as NONO, GRIPAP1, RBMX, and RBM10 may show a deceptive FISH result due to the proximity of the genes on the same chromosome. FH and succinate dehydrogenase (SDH) deficient RCC have implications for patient counseling due to heritable syndromes and the aggressiveness of FH-deficient RCC. Immunohistochemistry is increasingly available and helpful for recognizing both. Emerging tumor types with strong evidence for distinct diagnostic entities include eosinophilic solid and cystic RCC and TFEB / VEGFA / 6p21 amplified RCC. Other emerging entities that are less clearly understood include TCEB1 mutated RCC, RCC with ALK rearrangement, renal neoplasms with mutations of TSC2 or MTOR, and RCC with fibromuscular stroma. In metastatic RCC, the role of molecular studies is not entirely defined at present, although there may be an increasing role for genomic analysis related to specific therapy pathways, such as for tyrosine kinase or MTOR inhibitors.