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Mahul B. Amin - One of the best experts on this subject based on the ideXlab platform.
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claudin 7 and claudin 8 immunohistochemical markers for the differential diagnosis of chromophobe Renal cell carcinoma and Renal Oncocytoma
Human Pathology, 2009Co-Authors: Adeboye O. Osunkoya, Diane Lawson, Mahul B. Amin, Cynthia Cohen, Maria M. Picken, Andrew N. YoungAbstract:Summary Claudin-7 and claudin-8 code for tight junction proteins expressed in distal nephron epithelium. In a recent oligonucleotide microarray study, we identified claudin-7 and claudin-8 as candidate markers to distinguish chromophobe Renal cell carcinoma from other Renal tumors, including Oncocytoma. Distinction of these lesions can be difficult by light microscopy but is clinically important because chromophobe Renal cell carcinoma has malignant biological potential, whereas Renal Oncocytoma is benign. Claudin-7 and claudin-8 expression was studied by immunohistochemistry in 11 chromophobe Renal cell carcinomas and 17 Oncocytomas using formalin-fixed paraffin-embedded tissue sections of tumor with adjacent nonneoplastic kidney. Steam antigen retrieval was performed before immunohistochemistry. Specificity was verified by negative control reactions without primary antibody and appropriate membranous staining patterns in positive control tissues (colon carcinoma and adjacent nonneoplastic kidney). Claudin-7 protein was expressed in a membranous pattern in 10 of 11 chromophobe Renal cell carcinomas and 4 of 17 Oncocytomas ( P P
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ultrastructural observations on mitochondria and microvesicles in Renal Oncocytoma chromophobe Renal cell carcinoma and eosinophilic variant of conventional clear cell Renal cell carcinoma
The American Journal of Surgical Pathology, 2000Co-Authors: Satish K Tickoo, Mitual Amin, Richard J. Zarbo, Thomas Christopherson, John N Eble, Mahul B. AminAbstract:On light microscopic examination, the morphologically overlapping features of granular eosinophilic cytoplasm in Renal Oncocytoma and the eosinophilic variants of chromophobe Renal cell carcinoma and conventional (clear cell) Renal cell carcinoma may pose difficulties in diagnosis. We investigated the ultrastructure of 5 Renal Oncocytomas, 7 eosinophilic variants of chromophobe Renal cell carcinoma, and 5 eosinophilic variants of conventional (clear cell) Renal cell carcinoma. Special attention was paid to mitochondria and microvesicles and interrelations thereof. The electron microscopic features were correlated with the light microscopic findings. All of the tumors had abundant mitochondria. Although abundant microvesicles were present in all of the chromophobe Renal cell carcinomas, scant numbers of microvesicles were also sometimes present in Renal Oncocytomas (2 of 5) and in the eosinophilic variant of conventional (clear cell) Renal cell carcinoma (1 of 5). The mitochondria in all three types of Renal neoplasms studied differed in morphology, being predominantly uniform and round with predominantly lamellar cristae in Renal Oncocytoma, variable in shape and size with predominantly tubulocystic cristae in chromophobe Renal cell carcinoma, and swollen and pleomorphic with rarefied matrix and attenuated cristae in the eosinophilic variant of conventional (clear cell) Renal cell carcinoma. Variable numbers of mitochondria in all of the chromophobe Renal cell carcinomas had outpouchings of the outer membranes, some of which carried parts of inner membrane within them. These outpouchings closely resembled the nearby cytoplasmic microvesicles, as did the tubulocystic cristae of the mitochondria. Some microvesicles contained homogeneous, electron-dense, finely granular matrix, similar to that seen in mitochondria. In one of seven chromophobe Renal cell carcinomas, microvesicles were present in rough endoplasmic reticulum, and in two others, mitochondria were present within some vesicles. These features strongly suggest a close relationship between the microvesicles and mitochondria. Based on the role of vesicle formation in normal mitochondriogenesis, and some of our observations, we propose that defective mitochondriogenesis may be the source of microvesicles in chromophobe Renal cell carcinomas.
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discriminant nuclear features of Renal Oncocytoma and chromophobe Renal cell carcinoma analysis of their potential utility in the differential diagnosis
American Journal of Clinical Pathology, 1998Co-Authors: Satish K Tickoo, Mahul B. AminAbstract:Chromophobe Renal cell carcinoma and Renal Oncocytoma have overlapping morphologic, histochemical, immunohistochemical, and ultrastructural features; however, their distinction is critical inasmuch as the former neoplasm has a malignant potential and the latter is widely believed to be a benign tumor. In this study, we investigated the potential utility of nuclear features in differential diagnosis. Nuclear contours, nuclear chromatin pattern, binucleation or multinucleation, pleomorphism, and mitotic activity were assessed semiquantitatively in routine H&E-stained sections from 16 cases of chromophobe Renal cell carcinoma and 21 cases of Renal Oncocytoma. All cases of chromophobe Renal cell carcinoma were found to have wrinkled, “raisinoid” nuclei in varying proportions, whereas all Renal Oncocytomas had predominantly round, relatively uniform nuclei. Binucleation or multinucleation was significantly more common in chromophobe Renal cell carcinoma. Nuclear chromatin tended to be coarser in chromophobe Renal cell carcinoma and nucleoli were seen more commonly in Renal Oncocytoma. Of the Renal Oncocytomas, 19% had distinct foci of “degenerative” nuclear atypia with pleomorphism. This type of atypia was absent in chromophobe Renal cell carcinoma. Our study shows that in association with the well-described cytoplasmic and architectural features, nuclear parameters are valuable discriminants between chromophobe Renal cell carcinoma and Renal Oncocytoma. Frequent binucleation and “raisinoid” nuclei with perinuclear halos, resulting in “koilocytoid atypia,” is highly characteristic of chromophobe Renal cell carcinoma.
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Renal Oncocytoma a reappraisal of morphologic features with clinicopathologic findings in 80 cases
The American Journal of Surgical Pathology, 1997Co-Authors: Mahul B. Amin, Satish K Tickoo, Thomas B Crotty, George M FarrowAbstract:Renal Oncocytoma has several features that overlap with other Renal neoplasms with a preponderance of granular cytoplasm, such as chromophobe, granular, and papillary Renal cell carcinomas. Lack of knowledge of this entire spectrum of eosinophilic Renal cell neoplasms has led to several misconceptions in the literature regarding Renal Oncocytoma. These include the "grading of Oncocytomas," "metastatic Oncocytomas," and the impression that Renal Oncocytoma is usually low grade and lacks prominent nucleoli. In order to further characterize the histologic features and embelLish diagnostic criteria, we evaluated 93 tumors from 80 patients. Four tumors were bilateral and two were multifocal. The mean age was 67.2 years (32-89 years), men were more commonly affected (3.1:1), and 82.7% tumors were incidental findings. Grossly, the tumors were mahogany brown, lacked necrosis, and averaged 4.4 cm in size (range 0.6-15 cm). Histologically, Renal Oncocytoma was composed of an exclusive or predominant component of acidophilic cells with three architectural patterns of disposition: (a) The "classic" pattern (57.5%), composed of a characteristic nested or organoid arrangement of cells, each surrounded by a distinct reticulin framework; (b) a "tubulocystic pattern" (6.3%) with numerous closely packed cystically dilated tubular structures; and (c) "mixed pattern" (36.2%), which had both the organoid and tubulocystic patterns. A gross or microscopic scar was noted in 53.8% cases, and histologically a distinctive myxoid and/or hyalinized stroma separated nests of cells. Generally, the nuclei of Renal Oncocytoma were round with uniform nuclear contours. Nearly half of the tumors had prominent nucleoli (42.5% had prominent nucleoli equivalent to Fuhrman's grade III or IV). Pleomorphism was absent in 50% of cases but was conspicuous in 12.5% of cases including foci of bizarre cells. Other atypical features included perinephric fat involvement (11.3%), Renal parenchymal invasion not associated with desmoplasia (10%), and hemorrhage (31.3%). Renal Oncocytoma by definition lacks areas of clear cell carcinoma, significant lesional necrosis, or conspicuous papillary formations. Ancillary features noted included normal-appearing Renal tubules within the lesion (15%), intranuclear holes (20%), psammoma bodies (7.5%), and foam cells (7.5%). 15% of tumors were locally excised, and 85% resulted in radical nephrectomy. Mean follow-up of 7.6 years (range 15-200 months) showed no evidence of recurrence, metastasis, or death due to tumor. In conclusion, Renal Oncocytoma, herein described, is a benign neoplasm and therefore does not merit a nuclear grading scheme. It has unique histologic features including an organoid and tubulocystic architecture, myxoid or hyalinized stroma, and occasionally some atypical findings including nuclear pleomorphism, prominent nucleoli, and adjacent Renal parenchymal and perinephric fat involvement.
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Renal Oncocytoma a reappraisal of morphologic features with clinicopathologic findings in 80 cases
The American Journal of Surgical Pathology, 1997Co-Authors: Mahul B. Amin, Satish K Tickoo, Thomas B Crotty, George M FarrowAbstract:Renal Oncocytoma has several features that overlap with other Renal neoplasms with a preponderance of granular cytoplasm, such as chromophobe, granular, and papillary Renal cell carcinomas. Lack of knowledge of this entire spectrum of eosinophilic Renal cell neoplasms has led to several misconcep
Satish K Tickoo - One of the best experts on this subject based on the ideXlab platform.
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ultrastructural observations on mitochondria and microvesicles in Renal Oncocytoma chromophobe Renal cell carcinoma and eosinophilic variant of conventional clear cell Renal cell carcinoma
The American Journal of Surgical Pathology, 2000Co-Authors: Satish K Tickoo, Mitual Amin, Richard J. Zarbo, Thomas Christopherson, John N Eble, Mahul B. AminAbstract:On light microscopic examination, the morphologically overlapping features of granular eosinophilic cytoplasm in Renal Oncocytoma and the eosinophilic variants of chromophobe Renal cell carcinoma and conventional (clear cell) Renal cell carcinoma may pose difficulties in diagnosis. We investigated the ultrastructure of 5 Renal Oncocytomas, 7 eosinophilic variants of chromophobe Renal cell carcinoma, and 5 eosinophilic variants of conventional (clear cell) Renal cell carcinoma. Special attention was paid to mitochondria and microvesicles and interrelations thereof. The electron microscopic features were correlated with the light microscopic findings. All of the tumors had abundant mitochondria. Although abundant microvesicles were present in all of the chromophobe Renal cell carcinomas, scant numbers of microvesicles were also sometimes present in Renal Oncocytomas (2 of 5) and in the eosinophilic variant of conventional (clear cell) Renal cell carcinoma (1 of 5). The mitochondria in all three types of Renal neoplasms studied differed in morphology, being predominantly uniform and round with predominantly lamellar cristae in Renal Oncocytoma, variable in shape and size with predominantly tubulocystic cristae in chromophobe Renal cell carcinoma, and swollen and pleomorphic with rarefied matrix and attenuated cristae in the eosinophilic variant of conventional (clear cell) Renal cell carcinoma. Variable numbers of mitochondria in all of the chromophobe Renal cell carcinomas had outpouchings of the outer membranes, some of which carried parts of inner membrane within them. These outpouchings closely resembled the nearby cytoplasmic microvesicles, as did the tubulocystic cristae of the mitochondria. Some microvesicles contained homogeneous, electron-dense, finely granular matrix, similar to that seen in mitochondria. In one of seven chromophobe Renal cell carcinomas, microvesicles were present in rough endoplasmic reticulum, and in two others, mitochondria were present within some vesicles. These features strongly suggest a close relationship between the microvesicles and mitochondria. Based on the role of vesicle formation in normal mitochondriogenesis, and some of our observations, we propose that defective mitochondriogenesis may be the source of microvesicles in chromophobe Renal cell carcinomas.
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discriminant nuclear features of Renal Oncocytoma and chromophobe Renal cell carcinoma analysis of their potential utility in the differential diagnosis
American Journal of Clinical Pathology, 1998Co-Authors: Satish K Tickoo, Mahul B. AminAbstract:Chromophobe Renal cell carcinoma and Renal Oncocytoma have overlapping morphologic, histochemical, immunohistochemical, and ultrastructural features; however, their distinction is critical inasmuch as the former neoplasm has a malignant potential and the latter is widely believed to be a benign tumor. In this study, we investigated the potential utility of nuclear features in differential diagnosis. Nuclear contours, nuclear chromatin pattern, binucleation or multinucleation, pleomorphism, and mitotic activity were assessed semiquantitatively in routine H&E-stained sections from 16 cases of chromophobe Renal cell carcinoma and 21 cases of Renal Oncocytoma. All cases of chromophobe Renal cell carcinoma were found to have wrinkled, “raisinoid” nuclei in varying proportions, whereas all Renal Oncocytomas had predominantly round, relatively uniform nuclei. Binucleation or multinucleation was significantly more common in chromophobe Renal cell carcinoma. Nuclear chromatin tended to be coarser in chromophobe Renal cell carcinoma and nucleoli were seen more commonly in Renal Oncocytoma. Of the Renal Oncocytomas, 19% had distinct foci of “degenerative” nuclear atypia with pleomorphism. This type of atypia was absent in chromophobe Renal cell carcinoma. Our study shows that in association with the well-described cytoplasmic and architectural features, nuclear parameters are valuable discriminants between chromophobe Renal cell carcinoma and Renal Oncocytoma. Frequent binucleation and “raisinoid” nuclei with perinuclear halos, resulting in “koilocytoid atypia,” is highly characteristic of chromophobe Renal cell carcinoma.
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Renal Oncocytoma a reappraisal of morphologic features with clinicopathologic findings in 80 cases
The American Journal of Surgical Pathology, 1997Co-Authors: Mahul B. Amin, Satish K Tickoo, Thomas B Crotty, George M FarrowAbstract:Renal Oncocytoma has several features that overlap with other Renal neoplasms with a preponderance of granular cytoplasm, such as chromophobe, granular, and papillary Renal cell carcinomas. Lack of knowledge of this entire spectrum of eosinophilic Renal cell neoplasms has led to several misconceptions in the literature regarding Renal Oncocytoma. These include the "grading of Oncocytomas," "metastatic Oncocytomas," and the impression that Renal Oncocytoma is usually low grade and lacks prominent nucleoli. In order to further characterize the histologic features and embelLish diagnostic criteria, we evaluated 93 tumors from 80 patients. Four tumors were bilateral and two were multifocal. The mean age was 67.2 years (32-89 years), men were more commonly affected (3.1:1), and 82.7% tumors were incidental findings. Grossly, the tumors were mahogany brown, lacked necrosis, and averaged 4.4 cm in size (range 0.6-15 cm). Histologically, Renal Oncocytoma was composed of an exclusive or predominant component of acidophilic cells with three architectural patterns of disposition: (a) The "classic" pattern (57.5%), composed of a characteristic nested or organoid arrangement of cells, each surrounded by a distinct reticulin framework; (b) a "tubulocystic pattern" (6.3%) with numerous closely packed cystically dilated tubular structures; and (c) "mixed pattern" (36.2%), which had both the organoid and tubulocystic patterns. A gross or microscopic scar was noted in 53.8% cases, and histologically a distinctive myxoid and/or hyalinized stroma separated nests of cells. Generally, the nuclei of Renal Oncocytoma were round with uniform nuclear contours. Nearly half of the tumors had prominent nucleoli (42.5% had prominent nucleoli equivalent to Fuhrman's grade III or IV). Pleomorphism was absent in 50% of cases but was conspicuous in 12.5% of cases including foci of bizarre cells. Other atypical features included perinephric fat involvement (11.3%), Renal parenchymal invasion not associated with desmoplasia (10%), and hemorrhage (31.3%). Renal Oncocytoma by definition lacks areas of clear cell carcinoma, significant lesional necrosis, or conspicuous papillary formations. Ancillary features noted included normal-appearing Renal tubules within the lesion (15%), intranuclear holes (20%), psammoma bodies (7.5%), and foam cells (7.5%). 15% of tumors were locally excised, and 85% resulted in radical nephrectomy. Mean follow-up of 7.6 years (range 15-200 months) showed no evidence of recurrence, metastasis, or death due to tumor. In conclusion, Renal Oncocytoma, herein described, is a benign neoplasm and therefore does not merit a nuclear grading scheme. It has unique histologic features including an organoid and tubulocystic architecture, myxoid or hyalinized stroma, and occasionally some atypical findings including nuclear pleomorphism, prominent nucleoli, and adjacent Renal parenchymal and perinephric fat involvement.
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Renal Oncocytoma a reappraisal of morphologic features with clinicopathologic findings in 80 cases
The American Journal of Surgical Pathology, 1997Co-Authors: Mahul B. Amin, Satish K Tickoo, Thomas B Crotty, George M FarrowAbstract:Renal Oncocytoma has several features that overlap with other Renal neoplasms with a preponderance of granular cytoplasm, such as chromophobe, granular, and papillary Renal cell carcinomas. Lack of knowledge of this entire spectrum of eosinophilic Renal cell neoplasms has led to several misconcep
Thomas Schwaab - One of the best experts on this subject based on the ideXlab platform.
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identification and validation of radiographic enhancement for reliable differentiation of cd117 benign Renal Oncocytoma and chromophobe Renal cell carcinoma
Clinical Cancer Research, 2018Co-Authors: Jay Amin, Shervin Badkhshan, Terrance Creighton, Daniel Abbotoy, Christine Murekeyisoni, Thomas Schwaab, Kristopher Attwood, Bo Xu, Craig HendlerAbstract:PURPOSE: The diagnostic differential for CD117/KIT(+) oncocytic Renal tumor biopsies is limited to benign Renal Oncocytoma (RO) vs. chromophobe Renal cell carcinoma (ChRCC), however further differentiation is often challenging and requires surgical resection. We investigated clinical variables that might improve preoperative differentiation of CD117(+) RO vs. ChRCC to avoid the need for benign tumor resection. EXPERIMENTAL DESIGN: 124 nephrectomy patients from a single institute with 133 RO or ChRCC tumors were studied. Patients from 2003-2012 comprised a retrospective cohort to identify clinical/radiographic variables associated with RO versus ChRCC. Prospective validation was performed among consecutive RO/ChRCC tumors resected from 2013-2017. RESULTS: Tumor size and younger age were associated with ChRCC, and multifocality with RO, however the most reliable variable for ChRCC vs. RO differentiation was the tumor:cortex peak early-phase enhancement ratio (PEER) using multiphase computer tomography (CT). Among 54 PEER-evaluable tumors in the retrospective cohort (19 CD117(+), 13 CD117(-), 22 CD117-untested), PEER classified each correctly as RO (PEER >0.50) or ChRCC (PEER <0.50), except four misclassified CD117(-) ChRCC variants. Prospective study of PEER confirmed 100% accuracy of RO/ChRCC classification among 22/22 additional CD117(+) tumors. Prospective inter-observer reproducibility was excellent for PEER scoring (intra-class correlation coefficient, ICC=0.97) and perfect for RO/ChRCC assignment (ICC=1.0). CONCLUSIONS: In the largest clinical comparison of RO vs. ChRCC to our knowledge, we identified and prospectively validated a reproducible radiographic measure that differentiates CD117(+) RO from ChRCC with potentially 100% accuracy. PEER may allow reliable biopsy-based diagnosis of CD117(+) RO, avoiding the need for diagnostic nephrectomy.
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identification and validation of radiographic enhancement for reliable differentiation of cd117 benign Renal Oncocytoma and chromophobe Renal cell carcinoma
Clinical Cancer Research, 2018Co-Authors: Jay Amin, Shervin Badkhshan, Terrance Creighton, Daniel Abbotoy, Christine Murekeyisoni, Thomas Schwaab, Craig Hendler, Kristopher Attwood, Michael PetrozielloAbstract:Purpose: The diagnostic differential for CD117/KIT(+) oncocytic Renal tumor biopsies is limited to benign Renal Oncocytoma versus chromophobe Renal cell carcinoma (ChRCC); however, further differentiation is often challenging and requires surgical resection. We investigated clinical variables that might improve preoperative differentiation of CD117(+) Renal Oncocytoma versus ChRCC to avoid the need for benign tumor resection.Experimental Design: A total of 124 nephrectomy patients from a single institute with 133 Renal Oncocytoma or ChRCC tumors were studied. Patients from 2003 to 2012 comprised a retrospective cohort to identify clinical/radiographic variables associated with Renal Oncocytoma versus ChRCC. Prospective validation was performed among consecutive Renal Oncocytoma/ChRCC tumors resected from 2013 to 2017.Results: Tumor size and younger age were associated with ChRCC, and multifocality with Renal Oncocytoma; however, the most reliable variable for ChRCC versus Renal Oncocytoma differentiation was the tumor:cortex peak early-phase enhancement ratio (PEER) using multiphase CT. Among 54 PEER-evaluable tumors in the retrospective cohort [19 CD117(+), 13 CD117(-), 22 CD117-untested], PEER classified each correctly as Renal Oncocytoma (PEER >0.50) or ChRCC (PEER ≤0.50), except for four misclassified CD117(-) ChRCC variants. Prospective study of PEER confirmed 100% accuracy of Renal Oncocytoma/ChRCC classification among 22/22 additional CD117(+) tumors. Prospective interobserver reproducibility was excellent for PEER scoring (intraclass correlation coefficient, ICC = 0.97) and perfect for Renal Oncocytoma/ChRCC assignment (ICC = 1.0).Conclusions: In the largest clinical comparison of Renal Oncocytoma versus ChRCC to our knowledge, we identified and prospectively validated a reproducible radiographic measure that differentiates CD117(+) Renal Oncocytoma from ChRCC with potentially 100% accuracy. PEER may allow reliable biopsy-based diagnosis of CD117(+) Renal Oncocytoma, avoiding the need for diagnostic nephrectomy. Clin Cancer Res; 24(16); 3898-907. ©2018 AACR.
Yi Xiao - One of the best experts on this subject based on the ideXlab platform.
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decreased mitochondrial dna content drives oxphos dysregulation in chromophobe Renal cell carcinoma
Cancer Research, 2020Co-Authors: Rosanna Clima, Jonas Busch, Ergin Kilic, Yi Xiao, Anja Rabien, Sonia L Villegas, Bernd Timmermann, Marcella AttimonelliAbstract:Chromophobe Renal cell carcinoma (chRCC) and Renal Oncocytoma are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in Renal Oncocytoma, but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multiomic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in Renal Oncocytoma. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and Renal Oncocytoma and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy. Significance: These findings establish potential diagnostic markers to distinguish malignant chRCC from its highly similar but benign counterpart, Renal Oncocytoma.
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Renal Oncocytoma characterized by the defective complex i of the respiratory chain boosts the synthesis of the ros scavenger glutathione
Oncotarget, 2017Co-Authors: Gerrit Kurschner, Rosanna Clima, Qingzhou Zhang, Jonas Busch, Ergin Kilic, Klaus Jung, Yi Xiao, Nikolaus BerndtAbstract:// Gerrit Kurschner 1, 2, * , Qingzhou Zhang 3, * , Rosanna Clima 4, 5 , Yi Xiao 1, 6 , Jonas Felix Busch 7 , Ergin Kilic 8 , Klaus Jung 7, 9 , Nikolaus Berndt 10 , Sascha Bulik 10 , Hermann-Georg Holzhutter 10 , Giuseppe Gasparre 5 , Marcella Attimonelli 4 , Mohan Babu 3 and David Meierhofer 1 1 Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany 2 Technical University of Berlin, Institute of Bioanalytics, Department of Biotechnology, Berlin, Germany 3 University of Regina, Department of Biochemistry, Regina, Canada 4 University of Bari, Department of Biosciences, Biotechnology and Biopharmaceutics, Bari, Italy 5 Department of Medical and Surgical Sciences-DIMEC, Medical Genetics Unit, University of Bologna, Bologna, Italy 6 Freie Universitat Berlin, Fachbereich Biologie, Chemie, Pharmazie, Berlin, Germany 7 University Hospital Charite, Department of Urology, Berlin, Germany 8 University Hospital Charite, Institute of Pathology, Berlin, Germany 9 Berlin Institute for Urologic Research, Berlin, Germany 10 Charite University Medicine Berlin, Institute of Biochemistry Computational Systems Biochemistry Group, Berlin, Germany * These authors have contributed equally to this work Correspondence to: David Meierhofer, email: Meierhof@molgen.mpg.de Mohan Babu, email: mohan.babu@uregina.ca Keywords: Renal Oncocytoma; complex I deficiency; glutathione metabolism; mtDNA mutation Received: July 10, 2017 Accepted: September 21, 2017 Published: November 11, 2017 ABSTRACT Renal Oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared Renal Oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed Renal Oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD + , NADH, NADP, ATP, and ADP were significantly higher in Renal Oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of Renal Oncocytoma. Our findings demonstrate that Renal Oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor.
Ondrej Hes - One of the best experts on this subject based on the ideXlab platform.
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comprehensive review of numerical chromosomal aberrations in chromophobe Renal cell carcinoma including its variant morphologies
Advances in Anatomic Pathology, 2021Co-Authors: Reza Alaghehbandan, Kiril Trpkov, Maria S Tretiakova, Ana Silvia Luis, Joanna Rogala, Ondrej HesAbstract:Chromophobe Renal cell carcinoma (ChRCC) accounts for 5% to 7% of all Renal cell carcinomas. It was thought for many years that ChRCC exhibits a hypodiploid genome. Recent studies using advanced molecular genetics techniques have shown more complex and heterogenous pattern with frequent chromosomal gains. Historically, multiple losses of chromosomes 1, 2, 6, 10, 13, 17, and 21 have been considered a genetic hallmark of ChRCC, both for classic and eosinophilic ChRCC variants. In the last 2 decades, multiple chromosomal gains in ChRCCs have also been documented, depicting a considerably broader genetic spectrum than previously thought. Studies of rare morphologic variants including ChRCC with pigmented microcystic adenomatoid/multicystic growth, ChRCC with neuroendocrine differentiation, ChRCC with papillary architecture, and Renal Oncocytoma-like variants also showed variable chromosomal numerical aberrations, including multiple losses (common), gains (less common), or chromosomal changes overlapping with Renal Oncocytoma. Although not the focus of the review, The Cancer Genome Atlas (TCGA) data in ChRCC show TP53, PTEN, and CDKN2A to be the most mutated genes. Given the complexity of molecular genetic alterations in ChRCC, this review analyzed the existing published data, aiming to present a comprehensive up-to-date survey of the chromosomal abnormalities in classic ChRCC and its variants. The potential role of chromosomal numerical aberrations in the differential diagnostic evaluation may be limited, potentially owing to its high variability.
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International Journal of Surgical Pathology 9(3):215-222, 2001 Small Cell Variant of Renal Oncocytoma- A Rare and Misleading Type of Benign Renal Tumor
2016Co-Authors: Ondrej Hes, Petr Mukensnabl, Zdenek Kinkor, Petr MiculkaAbstract:Here we report 3 cases of Renal Oncocytoma with a dominating small cell component arising in adult women. These 3 cases of small cell variant of Renal Oncocytoma were found among 134 cases of Oncocytomas of the kidney in the routine and consultation files of the authors. TAvo of 3 cases were initially thought to be a malignant tumor by the referring pathologists. In all 3 cases minor areas of the tumors, which were iden-tical to the classical Renal Oncocytomas were found. The small cell areas were arranged in a characteristic organoid pattern different from all the known types of the Renal benign and malignant tumors. We summarize all morphologic, immunohisto-chemical, and ultrastructural features of this unusual Oncocytoma variant with re-gard to its differential diagnosis. Int J Surg Pathol 9(3):215-222, 2001 Key words: Renal Oncocytoma, small cell variant, kidney. Renal Oncocytoma (RO) is a distinctive benign tu-mor comprising approximately 4O/ % of all kidney neoplasms, usually presenting as a unilateral soli-tary tumor with the average size of 5 cm. The oc-currence is higher in men, with the peak incidence in the seventh decade of life [1-3]. In general, RO may show a broad spectrum of appearances, the most common being the alveolar, tubular, or cystic arrangement [4]. The polygonal tumor cells are typ-ically uniform with abundant granular eosinophilic cytoplasm packed with mitochondria to the virtual exclusion of other organelles. Besides the classic on-cocytes, RO may contain oncocytic cells with py-knotic nuclei and small cells with a high nuclear/cy-toplasmic ratio and dense hyperchromatic nucle
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Renal Oncocytoma with and without intravascular extension into the branches of Renal vein have the same morphological immunohistochemical and genetic features
Virchows Archiv, 2008Co-Authors: Ondrej Hes, Delia Perezmontiel, Radek Sima, Guido Martignoni, Matteo Brunelli, Isabella A Cabrero, Michal Michal, Naoto Kuroda, Tomas Vaněcek, Milan HoraAbstract:We attempted to investigate the clinicopathological correlation of Renal Oncocytoma (RO) with Renal vein extension. We identified seven ROs with extension into the branches of Renal vein. The age of seven patients ranged from 61 to 82 years. Five cases were identified; incidentally, two patients had gross hematuria. After surgery, all patients were alive and free of tumors with follow-up of 1 to 5 years (mean=3.6). Oncocytomas measured from 2.2 to 7.5 cm. Renal vein extension was grossly suspected in 5/7 cases and histologically confirmed in all seven cases. Tumor cells were positive for cytokeratins, mitochondrial antigen, epithelial membrane antigen, and parvalbumin; 5/7 tumors were focally positive for cluster of differentiation 117. Ultrastructurally, the cytoplasm was packed by mitochondria. Molecular genetic analysis did not detect abnormal numbers of chromosomes 1, 2, 6, 7, 10, 17, and XY by fluorescence in situ hybridization, loss of heterozygosity on 3p, and mutation of Von Hippel-Lindau gene in all cases. Array comparative genomic hybridization analysis of two cases did not show any major genetic changes. Conclusions are: (1) Renal Oncocytomas may have intravascular extension to the branches of the Renal vein; (2) Renal Oncocytomas with intravascular extension to the branches of the Renal vein have the same morphological, immunohistochemical, and cytogenetic findings as have their counterparts without evidence of intravascular invasion; (3) the absence of metastases suggests an overall benign behavior of this tumor, but this has to be substantiated by further studies with a long-term follow-up; (4) in a Renal tumor with granular cytoplasm showing Renal vein extension, it is necessary to carefully exclude Renal cell carcinomas (RCC) such as chromophobe RCC, oncocytic variant of papillary RCC, and granular variant of clear cell RCC.