21 results on '"Chen, Ying-Bei"'
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2. Morphologic and Immunohistochemical Assessment of CDH1 Loss of Function Alterations in Prostatic Adenocarcinoma
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Gupta, Sounak, Fine, Samson W., Chang, Jason, Tickoo, Satish K., Chen, Ying-Bei, Al-Ahmadie, Hikmat A., Sirintrapun, Sahussapont J., Abida, Wassim, Ladanyi, Marc, Reuter, Victor E., and Gopalan, Anuradha
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- 2020
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3. TFEB Expression Profiling in Renal Cell Carcinomas: Clinicopathologic Correlations
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Gupta, Sounak, Argani, Pedram, Jungbluth, Achim A., Chen, Ying-Bei, Tickoo, Satish K., Fine, Samson W., Gopalan, Anuradha, Al-Ahmadie, Hikmat A., Sirintrapun, Sahussapont J., Sanchez, Alejandro, Hakimi, Abraham Ari, Mcfarlane, Tiffany, Salazar, Paulo A., Williamson, Sean R., Skala, Stephanie L., Mehra, Rohit, Hes, Ondrej, Antonescu, Cristina R., Ladanyi, Marc, Arcila, Maria E., and Reuter, Victor E.
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- 2019
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4. PD-L1 Expression in Urothelial Carcinoma With Predominant or Pure Variant Histology: Concordance Among 3 Commonly Used and Commercially Available Antibodies
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Reis, Henning, Serrette, Rene, Posada, Jennifer, Lu, Vincent, Chen, Ying-bei, Gopalan, Anuradha, Fine, Samson W., Tickoo, Satish K., Sirintrapun, Sahussapont J., Iyer, Gopa, Funt, Samuel A., Teo, Min Yuen, Rosenberg, Jonathan E., Bajorin, Dean F., Dalbagni, Guido, Bochner, Bernard H., Solit, David B., Reuter, Victor E., and Al-Ahmadie, Hikmat A.
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- 2019
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5. VSTM2A Overexpression is a Sensitive and Specific Biomarker for Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) of the Kidney
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Wang, Lisha, Zhang, Yuping, Chen, Ying-Bei, Skala, Stephanie L., Al-Ahmadie, Hikmat A., Wang, Xiaoming, Cao, Xuhong, Veeneman, Brendan A., Chen, Jin, Cieślik, Marcin, Qiao, Yuanyuan, Su, Fengyun, Vats, Pankaj, Siddiqui, Javed, Xiao, Hong, Sadimin, Evita T., Epstein, Jonathan I., Zhou, Ming, Sangoi, Ankur R., Trpkov, Kiril, Osunkoya, Adeboye O., Giannico, Giovanna A., McKenney, Jesse K., Argani, Pedram, Tickoo, Satish K., Reuter, Victor E., Chinnaiyan, Arul M., Dhanasekaran, Saravana M., and Mehra, Rohit
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- 2018
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6. In Organ-confined Prostate Cancer, Tumor Quantitation Not Found to Aid in Prediction of Biochemical Recurrence
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Ito, Yujiro, Vertosick, Emily A., Sjoberg, Daniel D., Vickers, Andrew J., Al-Ahmadie, Hikmat A., Chen, Ying-Bei, Gopalan, Anuradha, Sirintrapun, Sahussapont J., Tickoo, Satish K., Eastham, James A., Scardino, Peter T., Reuter, Victor E., and Fine, Samson W.
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- 2019
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7. Somatic Mutations of TSC2 or MTOR Characterize a Morphologically Distinct Subset of Sporadic Renal Cell Carcinoma With Eosinophilic and Vacuolated Cytoplasm
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Chen, Ying-Bei, Mirsadraei, Leili, Jayakumaran, Gowtham, Al-Ahmadie, Hikmat A., Fine, Samson W., Gopalan, Anuradha, Sirintrapun, S. Joseph, Tickoo, Satish K., and Reuter, Victor E.
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- 2019
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8. Challenges in Pathologic Staging of Renal Cell Carcinoma: A Study of Interobserver Variability Among Urologic Pathologists
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Williamson, Sean R., Rao, Priya, Hes, Ondrej, Epstein, Jonathan I., Smith, Steven C., Picken, Maria M., Zhou, Ming, Tretiakova, Maria S., Tickoo, Satish K., Chen, Ying-Bei, Reuter, Victor E., Fleming, Stewart, Maclean, Fiona M., Gupta, Nilesh S., Kuroda, Naoto, Delahunt, Brett, Mehra, Rohit, Przybycin, Christopher G., Cheng, Liang, Eble, John N., Grignon, David J., Moch, Holger, Lopez, Jose I., Kunju, Lakshmi P., Tamboli, Pheroze, Srigley, John R., Amin, Mahul B., Martignoni, Guido, Hirsch, Michelle S., Bonsib, Stephen M., and Trpkov, Kiril
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- 2018
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9. Comedonecrosis Revisited: Strong Association With Intraductal Carcinoma of the Prostate
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Fine, Samson W., Al-Ahmadie, Hikmat A., Chen, Ying-Bei, Gopalan, Anuradha, Tickoo, Satish K., and Reuter, Victor E.
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- 2018
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10. Reappraisal of Morphologic Differences Between Renal Medullary Carcinoma, Collecting Duct Carcinoma, and Fumarate Hydratase–deficient Renal Cell Carcinoma
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Ohe, Chisato, Smith, Steven C., Sirohi, Deepika, Divatia, Mukul, de Peralta-Venturina, Mariza, Paner, Gladell P., Agaimy, Abbas, Amin, Mitual B., Argani, Pedram, Chen, Ying-Bei, Cheng, Liang, Colecchia, Maurizio, Compérat, Eva, Werneck da Cunha, Isabela, Epstein, Jonathan I., Gill, Anthony J., Hes, Ondřej, Hirsch, Michelle S., Jochum, Wolfram, Kunju, Lakshmi P., Maclean, Fiona, Magi-Galluzzi, Cristina, McKenney, Jesse K., Mehra, Rohit, Nesi, Gabriella, Osunkoya, Adeboye O., Picken, Maria M., Rao, Priya, Reuter, Victor E., de Oliveira Salles, Paulo Guilherme, Schultz, Luciana, Tickoo, Satish K., Tomlins, Scott A., Trpkov, Kiril, and Amin, Mahul B.
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- 2018
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11. TFEBExpression Profiling in Renal Cell Carcinomas
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Gupta, Sounak, Argani, Pedram, Jungbluth, Achim A., Chen, Ying-Bei, Tickoo, Satish K., Fine, Samson W., Gopalan, Anuradha, Al-Ahmadie, Hikmat A., Sirintrapun, Sahussapont J., Sanchez, Alejandro, Hakimi, Abraham Ari, Mcfarlane, Tiffany, Salazar, Paulo A., Williamson, Sean R., Skala, Stephanie L., Mehra, Rohit, Hes, Ondrej, Antonescu, Cristina R., Ladanyi, Marc, Arcila, Maria E., and Reuter, Victor E.
- Abstract
TFEBis overexpressed in TFEB-rearranged renal cell carcinomas as well as in renal tumors with amplifications of TFEBat 6p21.1. As recent literature suggests that renal tumors with 6p21.1 amplification behave more aggressively than those with rearrangements of TFEB, we compared relative TFEBgene expression in these tumors. This study included 37 TFEB-altered tumors: 15 6p21.1-amplified and 22 TFEB-rearranged (including 5 cases from The Cancer Genome Atlas data set). TFEBstatus was verified using a combination of fluorescent in situ hybridization (n=27) or comprehensive molecular profiling (n=13) and digital droplet polymerase chain reaction was used to quantify TFEBmRNA expression in 6p21.1-amplified (n=9) and TFEB-rearranged renal tumors (n=19). These results were correlated with TFEB immunohistochemistry. TFEB-altered tumors had higher TFEBexpression when normalized to B2M(mean: 168.9%, n=28), compared with non–TFEB-altered controls (mean: 7%, n=18, P=0.005). Interestingly, TFEBexpression in tumors with rearrangements (mean: 224.7%, n=19) was higher compared with 6p21.1-amplified tumors (mean: 51.2%, n=9; P=0.06). Of note, classic biphasic morphology was only seen in TFEB-rearranged tumors and when present correlated with 6.8-fold higher TFEBexpression (P=0.00004). Our results suggest that 6p21.1 amplified renal tumors show increased TFEBgene expression but not as much as t(6;11) renal tumors. These findings correlate with the less consistent/diffuse expression of downstream markers of TFEBactivation (cathepsin K, melan A, HMB45) seen in the amplified neoplasms. This suggests that the aggressive biological behavior of 6p21.1 amplified renal tumors might be secondary to other genes at the 6p21.1 locus that are co-amplified, such as VEGFAand CCND3, or other genetic alterations.
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- 2019
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12. Somatic Mutations of TSC2or MTORCharacterize a Morphologically Distinct Subset of Sporadic Renal Cell Carcinoma With Eosinophilic and Vacuolated Cytoplasm
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Chen, Ying-Bei, Mirsadraei, Leili, Jayakumaran, Gowtham, Al-Ahmadie, Hikmat A., Fine, Samson W., Gopalan, Anuradha, Sirintrapun, S. Joseph, Tickoo, Satish K., and Reuter, Victor E.
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Supplemental Digital Content is available in the text.The differential diagnosis of renal cell neoplasms with solid or nested architecture and eosinophilic cytoplasm has become increasingly complex. Despite recent advances in classifying a number of entities exhibiting this morphology, some tumors remain in the unclassified category. Here we describe a morphologically distinct group of sporadic renal cell carcinoma (RCC) with predominantly nested architecture, eosinophilic, and remarkably vacuolated cytoplasm retrospectively identified from a cohort of previously unclassified tumors. We examined the clinicopathologic and immunohistochemical features of these tumors and investigated their mutational and copy number alterations using a targeted next-generation sequencing platform. The study included 7 patients with a mean age of 54 years (range: 40 to 68 y) and a male to female ratio of 3:4. All patients presented with a solitary renal mass and had no prior medical or family history raising concern for syndromic conditions. Tumors were well-circumscribed, unencapsulated, and comprised of nests of eosinophilic cells in a hypocellular and often edematous stroma. Tumor cells had round nuclei with prominent nucleoli and granular cytoplasm with striking vacuolization. Thick-walled vessels and calcifications were also frequently present, whereas increased mitotic activity, necrosis, foamy histiocytes or lymphocytic infiltrates were not identified. All cases were positive for PAX8, had retained expression of SDHB and FH, and exhibited a CK7−/CK20− phenotype. While cathepsin-K was positive in 5 cases, none exhibited immunoreactivity to HMB45 or Melan A, or TFE3 immunostaining. Next-generation sequencing identified somatic inactivating mutations of TSC2(3/5 tumors tested) or activating mutations of MTOR(2/5) as the primary molecular alterations, consistent with hyperactive mTOR complex 1 signaling which was further demonstrated by phospho-S6 and phospho-4E-BP1 immunostaining. Copy number analysis revealed a loss of chromosome 1 in both cases with MTORmutation. These tumors represent a novel subset of sporadic RCC characterized by alterations in TSC1-TSC2 complex or the mTOR complex 1 pathway. Recognition of their characteristic morphologic and immunophenotypic features will allow them to be readily identified and separated from the unclassified RCC category.
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- 2019
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13. VSTM2AOverexpression Is a Sensitive and Specific Biomarker for Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) of the Kidney
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Wang, Lisha, Zhang, Yuping, Chen, Ying-Bei, Skala, Stephanie L., Al-Ahmadie, Hikmat A., Wang, Xiaoming, Cao, Xuhong, Veeneman, Brendan A., Chen, Jin, Cieślik, Marcin, Qiao, Yuanyuan, Su, Fengyun, Vats, Pankaj, Siddiqui, Javed, Xiao, Hong, Sadimin, Evita T., Epstein, Jonathan I., Zhou, Ming, Sangoi, Ankur R., Trpkov, Kiril, Osunkoya, Adeboye O., Giannico, Giovanna A., McKenney, Jesse K., Argani, Pedram, Tickoo, Satish K., Reuter, Victor E., Chinnaiyan, Arul M., Dhanasekaran, Saravana M., and Mehra, Rohit
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Supplemental Digital Content is available in the text.Our recent study revealed recurrent chromosomal losses and somatic mutations of genes in the Hippo pathway in mucinous tubular and spindle cell carcinoma (MTSCC). Here, we performed an integrative analysis of 907 renal cell carcinoma (RCC) samples (combined from The Cancer Genome Atlas and in-house studies) and the Knepper data set of microdissected rat nephrons. We identified VSTM2Aand IRX5as novel cancer-specific and lineage-specific biomarkers in MTSCC. We then assessed their expression by RNA in situ hybridization (ISH) in 113 tumors, including 33 MTSCC, 40 type 1 papillary RCC, 8 type 2 papillary RCC, 2 unclassified RCC, 15 clear cell RCC, and 15 chromophobe RCC. Sensitivity and specificity were calculated as the area under the receiver operating characteristics curve (AUC). All MTSCC tumors demonstrated moderate to high expression of VSTM2A(mean ISH score=255). VSTM2Agene expression assessed by RNA sequencing strongly correlated with VSTM2AISH score (r2=0.81, P=0.00016). The majority of non-MTSCC tumors demonstrated negative or low expression of VSTM2A. IRX5, nominated as a lineage-specific biomarker, showed moderate to high expression in MTSCC tumors (mean ISH score=140). IRX5gene expression assessed by RNA sequencing strongly correlated with IRX5ISH score (r2=0.69, P=0.00291). VSTM2A(AUC: 99.2%) demonstrated better diagnostic efficacy than IRX5(AUC: 87.5%), and may thus serve as a potential diagnostic marker to distinguish tumors with overlapping histology. Furthermore, our results suggest MTSCC displays an overlapping phenotypic expression pattern with the loop of Henle region of normal nephrons.
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- 2018
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14. Morphologic and Immunohistochemical Assessment of CDH1Loss of Function Alterations in Prostatic Adenocarcinoma
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Gupta, Sounak, Fine, Samson W., Chang, Jason, Tickoo, Satish K., Chen, Ying-Bei, Al-Ahmadie, Hikmat A., Sirintrapun, Sahussapont J., Abida, Wassim, Ladanyi, Marc, Reuter, Victor E., and Gopalan, Anuradha
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- 2020
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15. Comedonecrosis Revisited
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Fine, Samson W., Al-Ahmadie, Hikmat A., Chen, Ying-Bei, Gopalan, Anuradha, Tickoo, Satish K., and Reuter, Victor E.
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From the advent of the Gleason grading system for prostate cancer, cancer displaying intraluminal necrotic cells and/or karyorrhexis within cribriform/solid architecture, a phenomenon termed “comedonecrosis,” has been assigned pattern 5. Intraductal carcinoma (IDC-P) shows morphologic overlap with high-grade cribriform/solid adenocarcinoma architecturally and cytologically and may also show central necrosis, yet due to the presence of basal cells at the duct periphery is not currently assigned a grade in clinical practice. On the basis of observations from routine clinical cases, we hypothesized that comedonecrosis was more significantly associated with IDC-P than invasive disease. From a large series of mapped radical prostatectomy specimens (n=933), we identified 125 high-grade (≥Gleason score 4+3=7), high-volume tumors with available slides for review. All slides were examined for the presence of unequivocal comedonecrosis. Standard immunohistochemistry for basal cell markers was performed to detect basal cell labeling in these foci. In total, 19 of 125 (15%) cases showed some ducts with comedonecrosis—9 cases with 1 focus and 10 cases with ≥2 foci; in all, a total of 73 foci of true comedonecrosis were evaluated. Immunohistochemical stains revealed labeling for basal cell markers in a basal cell distribution for at least some comedonecrosis foci in 18 of 19 (95%) cases, 12 with IDC-P exclusively and 6 with a mix of IDC-P and invasive carcinoma comedonecrosis foci. These results suggest that comedonecrosis is strongly associated with IDC-P and hence, the routine assignment of pattern 5 to carcinoma exhibiting comedonecrosis should be reconsidered.
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- 2018
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16. Distinct Genomic Copy Number Alterations Distinguish Mucinous Tubular and Spindle Cell Carcinoma of the Kidney From Papillary Renal Cell Carcinoma With Overlapping Histologic Features
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Ren, Qinghu, Wang, Lu, Al-Ahmadie, Hikmat A., Fine, Samson W., Gopalan, Anuradha, Sirintrapun, Sahussapont J., Tickoo, Satish K., Reuter, Victor E., and Chen, Ying-Bei
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Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a rare type of renal cell carcinoma that frequently exhibits histologic and immunophenotypic features overlapping with type 1 papillary renal cell carcinoma (PRCC). To clarify molecular attributes that can be used for this difficult differential diagnosis, we sought to delineate the genome-wide copy number alterations in tumors displaying classic histologic features of MTSCC in comparison to the solid variant of type 1 PRCC and indeterminate cases with overlapping histologic features. The study included 11 histologically typical MTSCC, 9 tumors with overlapping features between MTSCC and PRCC, and 6 cases of solid variant of type 1 PRCC. DNA samples extracted from macrodissected or microdissected tumor areas were analyzed for genome-wide copy number alterations using an SNP-array platform suitable for clinical archival material. All cases in the MTSCC group exhibited multiple chromosomal losses, most frequently involving chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22, while lacking trisomy 7 or 17. In contrast, cases with overlapping morphologic features of MTSCC and PRCC predominantly showed multiple chromosomal gains, most frequently involving chromosomes 7, 16, 17, and 20, similar to the chromosomal alteration pattern that was seen in the solid variant of type 1 PRCC cases. Morphologic comparison of these molecularly characterized tumors identified histologic features that help to distinguish MTSCC from PRCC, but immunohistochemical profiles of these tumors remained overlapping, including a marker for Hippo-Yes-associated protein signaling. Characteristic patterns of genome-wide copy number alterations strongly support MTSCC and PRCC as distinct entities despite their immunohistochemical and certain morphologic overlap, and help define histologic features useful for the classification of questionable cases.
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- 2018
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17. Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci
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Smith, Steven C., Trpkov, Kiril, Chen, Ying-Bei, Mehra, Rohit, Sirohi, Deepika, Ohe, Chisato, Cani, Andi K., Hovelson, Daniel H., Omata, Kei, McHugh, Jonathan B., Jochum, Wolfram, Colecchia, Maurizio, Amin, Mitual, Divatia, Mukul K., Hes, Ondřej, Menon, Santosh, Werneck da Cunha, Isabela, Tripodi, Sergio, Brimo, Fadi, Gill, Anthony J., Osunkoya, Adeboye O., Magi-Galluzzi, Cristina, Sibony, Mathilde, Williamson, Sean R., Nesi, Gabriella, Picken, Maria M., Maclean, Fiona, Agaimy, Abbas, Cheng, Liang, Epstein, Jonathan I., Reuter, Victor E., Tickoo, Satish K., Tomlins, Scott A., and Amin, Mahul B.
- Abstract
Supplemental Digital Content is available in the text.An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase(FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes—including FH—performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC−. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FHmutations, including 5 FH−/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC− cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term “FH-deficient RCC” as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.
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- 2016
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18. Atypical Renal Cysts
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Matoso, Andres, Chen, Ying-Bei, Rao, Vishal, Wang, Lu, Cheng, Liang, and Epstein, Jonathan I.
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There is a lack of standardized nomenclature for renal cysts lined by multiple cell layers or with short papillary projections but without nests of epithelial cells within the stroma. We retrieved 29 cases (15 nephrectomies, 14 partial nephrectomies) from the surgical pathology files of Johns Hopkins Hospital from 1993 to 2014 and performed immunohistochemistry for CK7, alpha-methylacyl-CoA racemase (AMACR), CAIX, and CD10 and fluorescence in situ hybridization for trisomy 7 and 17 and 3p deletion. The mean age at excision was 58 years (range, 29 to 80 y) with 16 men and 13 women. Mean size was 2.9 cm (range, 0.3 to 10 cm). The cysts were grouped by their morphology into (1) clear cell, (2) eosinophilic stratified, and (3) eosinophilic papillary. By immunohistochemistry, 7/9 (78%) of the clear cell cases were diffusely positive for both CK7 and CAIX resembling the pattern seen in clear cell papillary renal cell carcinoma. The majority of eosinophilic stratified (4/6; 67%) and eosinophilic papillary (12/14; 86%) cases were positive for CK7 and had variable staining for AMACR, CD10, or CAIX, suggesting a differentiation more aligned with papillary renal cell carcinoma. The most common molecular alterations detected were trisomy 17 (n=6) and trisomy 7 (n=4). One case showed deletion of chromosome 3p. Clinical follow-up information was available in 23 patients; 20 were alive with no evidence of disease after a median follow-up of 20 months (range, 3 to 120 mo), 1 patient was dead due to metastatic lung cancer, 1 of sepsis, and 1 of unknown reason. Atypical renal cysts present as complex radiologic lesions, as secondary lesions in patients with a renal mass, or in a background of chronic renal disease. These atypical cysts appear heterogenous, and some follow in their morphology and immunoprofile with well-established renal tumors. The presence of 3p deletion and trisomy 7/17 suggests that in some cases they may be precursors of renal cell carcinoma. Longer follow-up with more cases is needed, but on the basis of our data, these lesions should not be diagnosed as carcinoma.
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- 2016
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19. Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome–associated Renal Cancer
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Chen, Ying-Bei, Brannon, A. Rose, Toubaji, Antoun, Dudas, Maria E., Won, Helen H., Al-Ahmadie, Hikmat A., Fine, Samson W., Gopalan, Anuradha, Frizzell, Norma, Voss, Martin H., Russo, Paul, Berger, Michael F., Tickoo, Satish K., and Reuter, Victor E.
- Abstract
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant disorder in which germline mutations of fumarate hydratase(FH) gene confer an increased risk of cutaneous and uterine leiomyomas and renal cancer. HLRCC-associated renal cancer is highly aggressive and frequently presents as a solitary mass. We reviewed the clinicopathologic features of 9 patients with renal tumors presenting as sporadic cases but who were later proven to have FHgermline mutations. Histologically, all tumors showed mixed architectural patterns, with papillary as the dominant pattern in only 3 cases. Besides papillary, tubular, tubulopapillary, solid, and cystic elements, 6 of 9 tumors contained collecting duct carcinoma–like areas with infiltrating tubules, nests, or individual cells surrounded by desmoplastic stroma. Prominent tubulocystic carcinoma–like component and sarcomatoid differentiation were identified. Although all tumors exhibited the proposed hallmark of HLRCC (large eosinophilic nucleolus surrounded by a clear halo), this feature was often not uniformly present throughout the tumor. Prior studies have shown that a high level of fumarate accumulated in HLRCC tumor cells causes aberrant succination of cellular proteins by forming a stable chemical modification, S-(2-succino)-cysteine (2SC), which can be detected by immunohistochemistry. We thus explored the utility of detecting 2SC by immunohistochemistry in the differential diagnosis of HLRCC tumors and other high-grade renal tumors and investigated the correlation between 2SC staining and FHmolecular alterations. All confirmed HLRCC tumors demonstrated diffuse and strong nuclear and cytoplasmic 2SC staining, whereas all clear cell (184184, 100), most high-grade unclassified (9397, 96), and the large majority of “type 2” papillary (3545, 78) renal cell carcinoma cases showed no 2SC immunoreactivity. A subset of papillary (22) and rare unclassified (4) tumors showed patchy or diffuse cytoplasmic staining without nuclear labeling, unlike the pattern seen with confirmed HLRCC tumors. Sequencing revealed no germline or somatic FHalterations in 14 tumors that either exhibited only cytoplasmic 2SC staining (n=5) or were negative for 2SC (n=9), despite their HLRCC-like morphologic features. Our results emphasize the pivotal role of pathologic examination in the diagnosis of HLRCC patients and indicate immunohistochemical detection of 2SC as a useful ancillary tool in the differentiation of HLRCC renal tumors from other high-grade renal cell carcinomas.
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- 2014
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20. Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)
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Udager, Aaron M., Alva, Ajjai, Chen, Ying-Bei, Siddiqui, Javed, Lagstein, Amir, Tickoo, Satish K., Reuter, Victor E., Chinnaiyian, Arul M., and Mehra, Rohit
- Abstract
Rapid (“warm”) autopsies of patients with advanced metastatic cancer provide invaluable insight into the natural history, pathobiology, and morphology of advanced and treatment-resistant tumors. Here, we report a rapid autopsy case of a hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patient with advanced metastatic renal cell carcinoma (RCC)—the first such case described for either a primary renal tumor or HLRCC-related cancer. Mutations in the fumarate hydratase (FH)gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors. Loss of heterozygosity at the wild-type FHgene locus results in profound cellular metabolic derangement, “pseudohypoxic” upregulation of hypoxia-inducible factor 1 (HIF-1)-dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients. The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing. In addition, this patient’s RCC demonstrated extensive sarcomatoid and rhabdoid features—morphologies not previously well described in HLRCC-associated kidney tumors. Here, we report the extent of metastatic dissemination and supplement this unique tumor morphology with mitochondrial enzyme histochemistry and extended immunohistochemical analysis. Tumor cells strongly expressed PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers was negative. We also detail microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules.
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- 2014
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21. Primary Carcinoid Tumors of the Urinary Bladder and Prostatic Urethra
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Chen, Ying-bei and Epstein, Jonathan I.
- Abstract
Primary carcinoid tumors of the urinary bladder are exceedingly rare. Although they have been considered to be potentially malignant neuroendocrine neoplasms, some previously reported cases were associated with a carcinoma component that might have altered the outcome. Only 8 histologically well-documented cases of pure carcinoid tumors of the bladder and 1 of the prostatic urethra have been reported in the literature. In this study, we describe 6 additional primary pure carcinoid tumors arising in the bladder (5 cases) or prostatic urethra (1 case). Patients (4 male, 2 female) ranged in age from 45 to 60 years (average, 55 y) and presented with hematuria (n=5 of 6), obstruction (n=1 of 6), or for concurrent genitourinary disease (n=1 of 6). All 6 cases shared gross and microscopic findings. Cystoscopic examination showed small, smooth surfaced, or polypoid nodules. The 5 cases in the bladder were all located within or near the trigone and bladder neck region. Microscopically, these 6 tumors were subepithelial and confined within the lamina propria, associated with adjacent cystitis cystica et glandularis. The tumors were composed of uniform, cuboidal, or columnar cells with finely stippled chromatin and inconspicuous nucleoli in a prominent pseudoglandular pattern composed of acinar and cribriform structures. The cells had moderate-to-abundant cytoplasm and basally located Paneth cell-like eosinophilic granules. Although occasional atypical cells with prominent nucleoli could be seen, mitotic activity was absent or rare and cases lacked necrosis. Neuroendocrine differentiation was confirmed by immunohistochemistry in all 6 cases. All tumors were completely excised by biopsies. There was no evidence of disease recurrence or progression in all 6 patients, including 3 patients who had clinical follow-up for >4 years. Primary pure carcinoid tumors of the urinary bladder (and prostatic urethra) have distinct pathologic characteristics, with their prominent pseudoglandular features leading to difficulty in diagnosis. They are likely to have a very favorable clinical outcome, and should be distinguished from mixed carcinoid tumors or urothelial carcinomas with neuroendocrine differentiation that show focal carcinoid-like histologic features.
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- 2011
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