37 results on '"Papathomas TG"'
Search Results
2. Adrenocortical neoplasia: evolving concepts in tumorigenesis with an emphasis on adrenal cortical carcinoma variants.
- Author
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de Krijger RR, Papathomas TG, de Krijger, Ronald R, and Papathomas, Thomas G
- Abstract
Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a poor prognosis. According to WHO classification 2004, ACC variants include oncocytic ACCs, myxoid ACCs and ACCs with sarcomatous areas. Herein, we provide a comprehensive review of these rare subtypes of adrenocortical malignancy and emphasize their clinicopathological features with the aim of elucidating aspects of diagnostic categorization, differential diagnostics and biological behavior. The issue of current terminology, applied to biphasic tumors with pleomorphic, sarcomatous or sarcomatoid elements arising in adrenal cortex, is also discussed. We additionally present emerging evidence concerning the adrenal cortical tumorigenesis and the putative adenoma-carcinoma sequence as well. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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3. SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity
- Author
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Casey, RT, Ascher, DB, Rattenberry, E, Izatt, L, Andrews, KA, Simpson, HL, Challis, B, Park, S-M, Bulusu, VR, Lalloo, F, Pires, DEV, West, H, Clark, GR, Smith, PS, Whitworth, J, Papathomas, TG, Taniere, P, Savisaar, R, Hurst, LD, Woodward, ER, and Maher, ER
- Subjects
variant ,pathogenesis ,SDHA ,3. Good health - Abstract
Purpose To evaluate the role of germline SDHA mutation analysis by (1) comprehensive literature review, (2) description of novel germline SDHA mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA. Patients and methods A systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of SDHA missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 “control missense variants” were predicted by the mCSM computational platform. These structural predictions were correlated with the results of tumor studies and other bioinformatic predictions. Results Literature review revealed reports of 17 different germline SDHA variants in 47 affected individuals from 45 kindreds. A further 10 different variants in 15 previously unreported cases (seven novel variants in eight patients) were added from our UK series. In silico structural prediction studies of 11 candidate missense germline mutations suggested that most (63.7%) would destabilize the SDHA protomer, and that most (78.1%) rare SDHA missense variants present in a control data set (ESP6500) were also associated with impaired protein stability. Conclusion The clinical spectrum of SDHA-associated neoplasia differs from that of germline mutations in other SDH-subunits. The interpretation of the significance of novel SDHA missense substitutions is challenging. We recommend that multiple investigations (e.g. tumor studies, metabolomic profiling) should be performed to aid classification of rare missense variants before genetic testing results are used to influence clinical management.
4. Data set for the reporting of pheochromocytoma and paraganglioma: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting.
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Thompson LDR, Gill AJ, Asa SL, Clifton-Bligh RJ, de Krijger RR, Kimura N, Komminoth P, Lack EE, Lenders JWM, Lloyd RV, Papathomas TG, Sadow PM, and Tischler AS
- Subjects
- Humans, Paraganglioma pathology, Adrenal Gland Neoplasms pathology, Carcinoma pathology, Pathology, Clinical standards, Pheochromocytoma pathology, Research Design standards
- Abstract
Background and Objectives: The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each anatomic site, to be used throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to improved patient management and enhanced epidemiological research., Methods: Pheochromocytoma and paraganglioma are uncommon and are frequently overlooked in registry data sets. Malignant criteria have previously been defined only when there was metastatic disease., Results: With recent recognition of a significant inheritance association and the development of risk stratification tools, this data set was created in order to obtain more meaningful outcomes and management data, using similar criteria across the global pathology community. Issues related to key core and non-core elements, especially clinical hormonal status, familial history, tumor focality, proliferative fraction, adverse or risk stratification features, and ancillary techniques, are discussed in the context of daily application to these types of specimens., Conclusions: The ICCR data set, developed by an international panel of endocrine organ specialists, establishes a pathology-standardized reporting guide for pheochromocytoma and paraganglioma., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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5. What Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas?
- Author
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Papathomas TG, Suurd DPD, Pacak K, Tischler AS, Vriens MR, Lam AK, and de Krijger RR
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- Genetic Predisposition to Disease, Genomics, Genotype, Humans, Adrenal Gland Neoplasms genetics, Adrenal Gland Neoplasms pathology, Paraganglioma genetics, Paraganglioma pathology, Pheochromocytoma genetics, Pheochromocytoma pathology
- Abstract
Recent advances in molecular genetics and genomics have led to increased understanding of the aetiopathogenesis of pheochromocytomas and paragangliomas (PPGLs). Thus, pan-genomic studies now provide a comprehensive integrated genomic analysis of PPGLs into distinct molecularly defined subtypes concordant with tumour genotypes. In addition, new embryological discoveries have refined the concept of how normal paraganglia develop, potentially establishing a developmental basis for genotype-phenotype correlations for PPGLs. The challenge for modern pathology is to translate these scientific discoveries into routine practice, which will be based largely on histopathology for the foreseeable future. Here, we review recent progress concerning the cell of origin and molecular pathogenesis of PPGLs, including pathogenetic mechanisms, genetic susceptibility and molecular classification. The current roles and tools of pathologists are considered from a histopathological perspective, including differential diagnoses, genotype-phenotype correlations and the use of immunohistochemistry in identifying hereditary predisposition and validating genetic variants of unknown significance. Current and potential molecular prognosticators are also presented with the hope that predictive molecular biomarkers will be integrated into risk stratification scoring systems to assess the metastatic potential of these intriguing neoplasms and identify potential drug targets.
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- 2021
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6. Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study.
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Bancos I, Taylor AE, Chortis V, Sitch AJ, Jenkinson C, Davidge-Pitts CJ, Lang K, Tsagarakis S, Macech M, Riester A, Deutschbein T, Pupovac ID, Kienitz T, Prete A, Papathomas TG, Gilligan LC, Bancos C, Reimondo G, Haissaguerre M, Marina L, Grytaas MA, Sajwani A, Langton K, Ivison HE, Shackleton CHL, Erickson D, Asia M, Palimeri S, Kondracka A, Spyroglou A, Ronchi CL, Simunov B, Delivanis DA, Sutcliffe RP, Tsirou I, Bednarczuk T, Reincke M, Burger-Stritt S, Feelders RA, Canu L, Haak HR, Eisenhofer G, Dennedy MC, Ueland GA, Ivovic M, Tabarin A, Terzolo M, Quinkler M, Kastelan D, Fassnacht M, Beuschlein F, Ambroziak U, Vassiliadi DA, O'Reilly MW, Young WF Jr, Biehl M, Deeks JJ, and Arlt W
- Subjects
- Adrenal Gland Neoplasms diagnosis, Adult, Aged, Diagnosis, Differential, Europe epidemiology, Female, Follow-Up Studies, Humans, Incidental Findings, Male, Middle Aged, Prospective Studies, Adrenal Gland Neoplasms epidemiology, Adrenal Gland Neoplasms urine, Metabolomics methods, Steroids urine
- Abstract
Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC., Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU., Findings: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0)., Interpretation: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours., Funding: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
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7. New and Emerging Biomarkers in Endocrine Pathology.
- Author
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Papathomas TG and Nosé V
- Subjects
- Humans, Biomarkers, Tumor, Endocrinology trends, Pathology trends
- Abstract
Significant advances in genomics and molecular genetics in recent years have reshaped the practice of endocrine pathology. Pan-genomic studies, including the pioneering ones on papillary thyroid carcinoma, phaeochromocytoma/paraganglioma, and adrenal cortical carcinoma from the Cancer Genome Atlas (TCGA) project, provided a comprehensive integrated genomic analysis of endocrine tumors into distinct molecularly defined subtypes. Better understanding of the molecular landscape and more accurate definition of biological behavior has been accordingly achieved. Nevertheless, how any of these advances are translated into routine practice still remains a challenge in the era of precision medicine. The challenge for modern pathology is to keep up the pace with scientific discoveries by integrating novel concepts in tumor classification, molecular genetics, prognostication, and theranostics. As an example, pathology plays a role in the identification of hereditary disease, while it offers the tools for complementing molecular genetics, for example, validation of variants of unknown significance deriving from targeted sequencing or whole exome/genome sequencing approach. Immunohistochemistry has arisen as a cost-effective strategy in the evaluation either of somatic mutations in tumors and/or germline mutations in patients with familial cancer syndromes. Herein, a comprehensive review focusing on novel and emerging biomarkers is presented in order pathologists and other endocrine-related specialists to remain updated and become aware of potential pitfalls and limitations in the field of endocrine pathology.
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- 2019
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8. Novel methods in adrenal research: a metabolomics approach.
- Author
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Papathomas TG, Sun N, Chortis V, Taylor AE, Arlt W, Richter S, Eisenhofer G, Ruiz-Babot G, Guasti L, and Walch AK
- Subjects
- Adrenal Glands cytology, Animals, Chromatography, Liquid, Humans, Mass Spectrometry, Adrenal Glands metabolism, Metabolomics
- Abstract
Metabolic alterations have implications in a spectrum of tissue functions and disease. Aided by novel molecular biological and computational tools, our understanding of physiological and pathological processes underpinning endocrine and endocrine-related disease has significantly expanded over the last decade. Herein, we focus on novel metabolomics-related methodologies in adrenal research: in situ metabolomics by mass spectrometry imaging, steroid metabolomics by gas and liquid chromatography-mass spectrometry, energy pathway metabologenomics by liquid chromatography-mass spectrometry-based metabolomics of Krebs cycle intermediates, and cellular reprogramming to generate functional steroidogenic cells and hence to modulate the steroid metabolome. All four techniques to assess and/or modulate the metabolome in biological systems provide tremendous opportunities to manage neoplastic and non-neoplastic disease of the adrenal glands in the era of precision medicine. In this context, we discuss emerging clinical applications and/or promising metabolic-driven research towards diagnostic, prognostic, predictive and therapeutic biomarkers in tumours arising from the adrenal gland and extra-adrenal paraganglia as well as modern approaches to delineate and reprogram adrenal metabolism.
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- 2019
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9. Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas.
- Author
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Evenepoel L, van Nederveen FH, Oudijk L, Papathomas TG, Restuccia DF, Belt EJT, de Herder WW, Feelders RA, Franssen GJH, Hamoir M, Maiter D, Ghayee HK, Shay JW, Perren A, Timmers HJLM, van Eeden S, Vroonen L, Aydin S, Robledo M, Vikkula M, de Krijger RR, Dinjens WNM, Persu A, and Korpershoek E
- Subjects
- Adrenal Gland Neoplasms genetics, Adrenal Gland Neoplasms metabolism, Biomarkers, Tumor genetics, Contactins genetics, Gene Expression Profiling, Humans, Paraganglioma genetics, Paraganglioma metabolism, Pheochromocytoma genetics, Pheochromocytoma metabolism, Prognosis, RNA, Messenger genetics, Adrenal Gland Neoplasms diagnosis, Biomarkers, Tumor metabolism, Contactins metabolism, Paraganglioma diagnosis, Pheochromocytoma diagnosis, RNA, Messenger metabolism
- Abstract
Context: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, usually benign, tumors. Currently, the only reliable criterion of malignancy is the presence of metastases., Objective: The aim of this study was to identify genes associated with malignancy in PPGLs., Design: Transcriptomic profiling was performed on 40 benign and 11 malignant PPGLs. Genes showing a significantly different expression between benign and malignant PPGLs with a ratio ≥4 were confirmed and tested in an independent series by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed for the validated genes on 109 benign and 32 malignant PPGLs. Functional assays were performed with hPheo1 cells., Setting: This study was conducted at the Department of Pathology of the Erasmus MC University Medical Center Rotterdam Human Molecular Genetics laboratory of the de Duve Institute, University of Louvain., Patients: PPGL samples from 179 patients, diagnosed between 1972 and 2015, were included., Main Outcome Measures: Associations between gene expression and malignancy were tested using supervised clustering approaches., Results: Ten differentially expressed genes were selected based on messenger RNA (mRNA) expression array data. Contactin 4 (CNTN4) was overexpressed in malignant vs benign tumors [4.62-fold; false discovery rate (FDR), 0.001]. Overexpression at the mRNA level was confirmed using qRT-PCR (2.90-fold, P = 0.02; validation set: 4.26-fold, P = 0.005). Consistent findings were obtained in The Cancer Genome Atlas cohort (2.7-fold; FDR, 0.02). CNTN4 protein was more frequently expressed in malignant than in benign PPGLs by immunohistochemistry (58% vs 17%; P = 0.002). Survival after 7 days of culture under starvation conditions was significantly enhanced in hPheo1 cells transfected with CNTN4 complementary DNA., Conclusion: CNTN4 expression is consistently associated with malignant behavior in PPGLs., (Copyright © 2017 Endocrine Society)
- Published
- 2018
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10. SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity.
- Author
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Casey RT, Ascher DB, Rattenberry E, Izatt L, Andrews KA, Simpson HL, Challis B, Park SM, Bulusu VR, Lalloo F, Pires DEV, West H, Clark GR, Smith PS, Whitworth J, Papathomas TG, Taniere P, Savisaar R, Hurst LD, Woodward ER, and Maher ER
- Abstract
Purpose: To evaluate the role of germline SDHA mutation analysis by (1) comprehensive literature review, (2) description of novel germline SDHA mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA., Patients and Methods: A systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of SDHA missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 "control missense variants" were predicted by the mCSM computational platform. These structural predictions were correlated with the results of tumor studies and other bioinformatic predictions., Results: Literature review revealed reports of 17 different germline SDHA variants in 47 affected individuals from 45 kindreds. A further 10 different variants in 15 previously unreported cases (seven novel variants in eight patients) were added from our UK series. In silico structural prediction studies of 11 candidate missense germline mutations suggested that most (63.7%) would destabilize the SDHA protomer, and that most (78.1%) rare SDHA missense variants present in a control data set (ESP6500) were also associated with impaired protein stability., Conclusion: The clinical spectrum of SDHA -associated neoplasia differs from that of germline mutations in other SDH-subunits. The interpretation of the significance of novel SDHA missense substitutions is challenging. We recommend that multiple investigations (e.g. tumor studies, metabolomic profiling) should be performed to aid classification of rare missense variants before genetic testing results are used to influence clinical management.
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- 2017
- Full Text
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11. Sarcomatoid adrenocortical carcinoma: a comprehensive pathological, immunohistochemical, and targeted next-generation sequencing analysis.
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Papathomas TG, Duregon E, Korpershoek E, Restuccia DF, van Marion R, Cappellesso R, Sturm N, Rossi G, Coli A, Zucchini N, Stoop H, Oosterhuis W, Ventura L, Volante M, Fassina A, Dinjens WN, Papotti M, and de Krijger RR
- Subjects
- Adrenal Cortex Neoplasms chemistry, Adrenal Cortex Neoplasms genetics, Adrenal Cortex Neoplasms pathology, Adrenocortical Carcinoma chemistry, Adrenocortical Carcinoma genetics, Adrenocortical Carcinoma pathology, Adult, Aged, Biopsy, Carcinosarcoma chemistry, Carcinosarcoma genetics, Carcinosarcoma pathology, DNA Mutational Analysis, Epithelial Cells chemistry, Epithelial Cells pathology, Epithelial-Mesenchymal Transition, Europe, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Mutation, Neoplastic Stem Cells chemistry, Neoplastic Stem Cells pathology, Transcription Factors analysis, Transcription Factors genetics, Wnt Signaling Pathway, Young Adult, Adrenal Cortex Neoplasms diagnosis, Adrenocortical Carcinoma diagnosis, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Carcinosarcoma diagnosis, High-Throughput Nucleotide Sequencing, Immunohistochemistry
- Abstract
Adrenocortical carcinomas (ACCs) with sarcomatous areas represent an extremely rare type of highly aggressive malignancy of unknown molecular pathogenesis. The current study was planned to gain insight into its molecular genetics using a targeted next-generation sequencing approach and to explore the status of epithelial-mesenchymal transition (EMT)-associated markers (E-/P-/N-cadherins, MMP-2/-9 and caveolin-1), downstream transcriptional regulators of EMT-related signaling pathways (ZEB-1/-2, Slug), stem cell factors (Oct3/4, LIN28, SOX2, SO17, NANOG, CD133, nestin), and markers of adrenocortical origin/tumorigenesis (SF-1, β-catenin, p53) in phenotypically diverse tumor components of 6 cases. Thirteen pathogenic variants of ACC-associated TP53 and CTNNB1 genes were detected in epithelial and/or nonepithelial components in 4 out of 6 tumors. Three cases had identical mutations in distinct components, 1 of which contained TP53/CTNNB1 in 3 out of 5 components, whereas 1 harbored a single TP53 mutation only in the nonepithelial component. By immunohistochemistry, SF-1 and E-/P-/N-cadherins were found positive only in the epithelial component of all cases, whereas the nonepithelial components were mainly enriched for nestin, ZEB-1, and MMP-2/-9. β-Catenin demonstrated an aberrant nuclear localization in the sarcomatoid component of 5 cases, whereas p53 was strongly positive in nonepithelial constituent in 4 of 6 cases. In summary, we have shown that Wnt/β-catenin signaling pathway dysregulation and mutational inactivation of TP53 are common genetic events in sarcomatoid ACCs, a subset of which being monoclonal in origin. These tumors are enriched for EMT-related markers and stem cell factors, potentially conferring a poor prognosis, which might be exploited as novel therapeutic targets., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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12. Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas.
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Creemers SG, van Koetsveld PM, van Kemenade FJ, Papathomas TG, Franssen GJ, Dogan F, Eekhoff EM, van der Valk P, de Herder WW, Janssen JA, Feelders RA, and Hofland LJ
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- Adolescent, Adrenal Cortex Neoplasms diagnosis, Adrenocortical Adenoma diagnosis, Adrenocortical Carcinoma diagnosis, Adult, Aged, Antimetabolites, Antineoplastic pharmacology, Azacitidine analogs & derivatives, Azacitidine pharmacology, Cell Line, Tumor, Child, DNA Methylation, Decitabine, Female, Humans, Male, Middle Aged, RNA, Messenger metabolism, Regulatory Sequences, Nucleic Acid, Young Adult, Adrenal Cortex Neoplasms genetics, Adrenocortical Adenoma genetics, Adrenocortical Carcinoma genetics, Insulin-Like Growth Factor II genetics
- Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients., (© 2016 Society for Endocrinology.)
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- 2016
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13. An International Ki67 Reproducibility Study in Adrenal Cortical Carcinoma.
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Papathomas TG, Pucci E, Giordano TJ, Lu H, Duregon E, Volante M, Papotti M, Lloyd RV, Tischler AS, van Nederveen FH, Nose V, Erickson L, Mete O, Asa SL, Turchini J, Gill AJ, Matias-Guiu X, Skordilis K, Stephenson TJ, Tissier F, Feelders RA, Smid M, Nigg A, Korpershoek E, van der Spek PJ, Dinjens WN, Stubbs AP, and de Krijger RR
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Humans, Image Interpretation, Computer-Assisted, Male, Middle Aged, Observer Variation, Reproducibility of Results, Tissue Array Analysis, User-Computer Interface, Young Adult, Adrenal Cortex Neoplasms pathology, Adrenocortical Carcinoma pathology, Biomarkers, Tumor analysis, Ki-67 Antigen analysis, Pathology, Clinical standards
- Abstract
Despite the established role of Ki67 labeling index in prognostic stratification of adrenocortical carcinomas and its recent integration into treatment flow charts, the reproducibility of the assessment method has not been determined. The aim of this study was to investigate interobserver variability among endocrine pathologists using a web-based virtual microscopy approach. Ki67-stained slides of 76 adrenocortical carcinomas were analyzed independently by 14 observers, each according to their method of preference including eyeballing, formal manual counting, and digital image analysis. The interobserver variation was statistically significant (P<0.001) in the absence of any correlation between the various methods. Subsequently, 61 static images were distributed among 15 observers who were instructed to follow a category-based scoring approach. Low levels of interobserver (F=6.99; Fcrit=1.70; P<0.001) as well as intraobserver concordance (n=11; Cohen κ ranging from -0.057 to 0.361) were detected. To improve harmonization of Ki67 analysis, we tested the utility of an open-source Galaxy virtual machine application, namely Automated Selection of Hotspots, in 61 virtual slides. The software-provided Ki67 values were validated by digital image analysis in identical images, displaying a strong correlation of 0.96 (P<0.0001) and dividing the cases into 3 classes (cutoffs of 0%-15%-30% and/or 0%-10%-20%) with significantly different overall survivals (P<0.05). We conclude that current practices in Ki67 scoring assessment vary greatly, and interobserver variation sets particular limitations to its clinical utility, especially around clinically relevant cutoff values. Novel digital microscopy-enabled methods could provide critical aid in reducing variation, increasing reproducibility, and improving reliability in the clinical setting.
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- 2016
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14. Complex MAX Rearrangement in a Family With Malignant Pheochromocytoma, Renal Oncocytoma, and Erythrocytosis.
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Korpershoek E, Koffy D, Eussen BH, Oudijk L, Papathomas TG, van Nederveen FH, Belt EJ, Franssen GJ, Restuccia DF, Krol NM, van der Luijt RB, Feelders RA, Oldenburg RA, van Ijcken WF, de Klein A, de Herder WW, de Krijger RR, and Dinjens WN
- Subjects
- Adenoma, Oxyphilic complications, Adenoma, Oxyphilic metabolism, Adrenal Gland Neoplasms complications, Adrenal Gland Neoplasms metabolism, Adult, Chromosomes, Human, Pair 14 genetics, Exome, Fucosyltransferases genetics, Fucosyltransferases metabolism, Gene Rearrangement, Germ-Line Mutation, Humans, Lymphatic Metastasis, Male, Middle Aged, Pedigree, Pheochromocytoma complications, Pheochromocytoma metabolism, Polycythemia complications, Polycythemia metabolism, Polymorphism, Single Nucleotide genetics, Uniparental Disomy, Adenoma, Oxyphilic genetics, Adrenal Gland Neoplasms genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Pheochromocytoma genetics, Polycythemia genetics
- Abstract
Context: Familial pheochromocytoma (PCC) has been associated with germline mutations in 16 genes. Here we investigated three siblings presenting with bilateral pheochromocytomas. In addition, the index patient also exhibited renal oncocytoma and erythrocytosis, whereas the second sibling presented with a lymph node metastasis., Design: First, single-nucleotide polymorphism array and exome sequencing were performed on germline and PCC-derived DNA to identify genomic alterations in the index patient. Second, alterations were confirmed and validated by Sanger sequencing, analyzed by (multiplexed) PCR to determine the loss of the wild-type allele, and investigated by immunohistochemistry in the tumors of the three siblings., Results: The index patient's germline DNA revealed a large complex genomic alteration encompassing the intragenic and promoter regions of Myc-associated factor X (MAX) and alpha-(1,6)-fucosyltransferase (FUT8). In all three siblings the MAX alteration was confirmed, and the loss of the wild-type MAX and FUT8 alleles was demonstrated in all tumors. Uniparental disomy of chromosome 14q, previously demonstrated as a hallmark for MAX-related PCC, was shown in the index patient's PCC by single-nucleotide polymorphism array. Loss of MAX and FUT8 protein expression was demonstrated by immunohistochemistry in the tumors from the three siblings., Conclusions: Our results indicate that large genomic deletions of MAX should be considered in familial and bilateral PCC with prior negative testing for gene mutations. In addition, our results confirm that MAX is a tumor suppressor gene for renal oncocytomas.
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- 2016
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15. Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum.
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Niemeijer ND, Papathomas TG, Korpershoek E, de Krijger RR, Oudijk L, Morreau H, Bayley JP, Hes FJ, Jansen JC, Dinjens WN, and Corssmit EP
- Subjects
- Adult, Aged, DNA Mutational Analysis, Female, Humans, Loss of Heterozygosity, Male, Middle Aged, Mutation, Neuroendocrine Tumors pathology, Pancreatic Neoplasms pathology, Pedigree, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology, Retrospective Studies, Neuroendocrine Tumors genetics, Pancreatic Neoplasms genetics, Succinate Dehydrogenase genetics
- Abstract
Context: Mutations in genes encoding the subunits of succinate dehydrogenase (SDH) can lead to pheochromocytoma/paraganglioma formation. However, SDH mutations have also been linked to nonparaganglionic tumors., Objective: The objective was to investigate which nonparaganglionic tumors belong to the SDH-associated tumor spectrum., Design: This was a retrospective cohort study., Setting: The setting was a tertiary referral center., Patients: Patients included all consecutive SDHA/SDHB/SDHC and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center who were affected by non-pheochromocytoma/paraganglioma solid tumors., Main Outcome Measures: Main outcome measures were SDHA/SDHB immunohistochemistry, mutation analysis, and loss of heterozygosity analysis of the involved SDH-encoding genes., Results: Twenty-five of 35 tumors (from 26 patients) showed positive staining on SDHB and SDHA immunohistochemistry. Eight tumors showed negative staining for SDHB and positive staining for SDHA: a pancreatic neuroendocrine tumor, a macroprolactinoma, two gastric gastrointestinal stromal tumors, an abdominal ganglioneuroma, and three renal cell carcinomas. With the exception of the abdominal ganglioneuroma, loss of heterozygosity was detected in all tumors. A prolactinoma in a patient with a germline SDHA mutation was the only tumor immunonegative for both SDHA and SDHB. Sanger sequencing of this tumor revealed a somatic mutation (p.D38V) as a likely second hit leading to biallelic inactivation of SDHA. One tumor (breast cancer) showed heterogeneous SDHB staining, positive SDHA staining, and retention of heterozygosity., Conclusions: This study strengthens the etiological association of SDH genes with pituitary neoplasia, renal tumorigenesis, and gastric gastrointestinal stromal tumors. Furthermore, our results indicate that pancreatic neuroendocrine tumor also falls within the SDH-related tumor spectrum.
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- 2015
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16. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations.
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Evenepoel L, Papathomas TG, Krol N, Korpershoek E, de Krijger RR, Persu A, and Dinjens WN
- Subjects
- Animals, Humans, Germ-Line Mutation, Neoplasms enzymology, Neoplasms genetics, Succinate Dehydrogenase genetics
- Abstract
The tricarboxylic acid, or Krebs, cycle is central to the cellular metabolism of sugars, lipids, and amino acids; it fuels the mitochondrial respiratory chain for energy generation. In the past decade, mutations in the Krebs-cycle enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase have been documented to be causally involved in carcinogenesis. This review is focused on the relationship between SDH mutations and the carcinogenic phenotype. The succinate dehydrogenase complex catalyzes the oxidation of succinate to fumarate; mutations in its subunits SDHA, SDHB, SDHC, and SDHD, and in the assembly factor SDHAF2, result in syndromes with distinct tumor types, including pheochromocytoma/paraganglioma, gastrointestinal stromal tumor, and, less often, renal-cell carcinoma and pituitary adenoma. In this study we collected all previously reported SDH mutations with the aim of defining their nature and tumor spectrum. In addition, genotype-phenotype correlations as well as mechanisms of biallelic inactivation were analyzed in the SDH-deficient setting. Finally, we performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor to predict the functional impact of nonsynonymous mutations. The prediction of the latter was further compared with available SDHA and/or SDHB immunohistochemistry data.
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- 2015
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17. Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations.
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Oudijk L, Neuhofer CM, Lichtenauer UD, Papathomas TG, Korpershoek E, Stoop H, Oosterhuis JW, Smid M, Restuccia DF, Robledo M, de Cubas AA, Mannelli M, Gimenez-Roqueplo AP, Dinjens WN, Beuschlein F, and de Krijger RR
- Subjects
- Adult, Aged, Biomarkers, Tumor analysis, Europe, Female, Humans, Immunohistochemistry, Male, Microarray Analysis, Middle Aged, Receptors, Nerve Growth Factor genetics, Adrenal Gland Neoplasms genetics, Adrenal Gland Neoplasms metabolism, Biomarkers, Tumor metabolism, Mutation genetics, Paraganglioma genetics, Paraganglioma metabolism, Pheochromocytoma genetics, Pheochromocytoma metabolism, Stem Cells metabolism, Succinate Dehydrogenase genetics
- Abstract
Objective: Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs., Design: We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers., Results: SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in <10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease., Conclusion: Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy., (© 2015 European Society of Endocrinology.)
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- 2015
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18. SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).
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Papathomas TG, Oudijk L, Persu A, Gill AJ, van Nederveen F, Tischler AS, Tissier F, Volante M, Matias-Guiu X, Smid M, Favier J, Rapizzi E, Libe R, Currás-Freixes M, Aydin S, Huynh T, Lichtenauer U, van Berkel A, Canu L, Domingues R, Clifton-Bligh RJ, Bialas M, Vikkula M, Baretton G, Papotti M, Nesi G, Badoual C, Pacak K, Eisenhofer G, Timmers HJ, Beuschlein F, Bertherat J, Mannelli M, Robledo M, Gimenez-Roqueplo AP, Dinjens WN, Korpershoek E, and de Krijger RR
- Subjects
- Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Electron Transport Complex II genetics, Humans, Microscopy methods, Mutation, Observer Variation, Succinate Dehydrogenase genetics, Telepathology methods, Adrenal Gland Neoplasms genetics, Electron Transport Complex II analysis, Immunohistochemistry standards, Paraganglioma genetics, Pheochromocytoma genetics, Succinate Dehydrogenase analysis
- Abstract
Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB κ=0.7338; SDHA κ=0.6707) or a three-tiered classification approach (SDHB κ=0.6543; SDHA κ=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (~90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (~16%) VHL-mutated, as well as 1 of 21 (~5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable.
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- 2015
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19. Automated Selection of Hotspots (ASH): enhanced automated segmentation and adaptive step finding for Ki67 hotspot detection in adrenal cortical cancer.
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Lu H, Papathomas TG, van Zessen D, Palli I, de Krijger RR, van der Spek PJ, Dinjens WN, and Stubbs AP
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- Adrenal Cortex Neoplasms pathology, Adrenocortical Carcinoma pathology, Algorithms, Automation, Laboratory, Cell Proliferation, Humans, Predictive Value of Tests, Reproducibility of Results, Workflow, Adrenal Cortex Neoplasms chemistry, Adrenocortical Carcinoma chemistry, Image Interpretation, Computer-Assisted methods, Immunohistochemistry, Ki-67 Antigen analysis
- Abstract
Background: In prognosis and therapeutics of adrenal cortical carcinoma (ACC), the selection of the most active areas in proliferative rate (hotspots) within a slide and objective quantification of immunohistochemical Ki67 Labelling Index (LI) are of critical importance. In addition to intratumoral heterogeneity in proliferative rate i.e. levels of Ki67 expression within a given ACC, lack of uniformity and reproducibility in the method of quantification of Ki67 LI may confound an accurate assessment of Ki67 LI., Results: We have implemented an open source toolset, Automated Selection of Hotspots (ASH), for automated hotspot detection and quantification of Ki67 LI. ASH utilizes NanoZoomer Digital Pathology Image (NDPI) splitter to convert the specific NDPI format digital slide scanned from the Hamamatsu instrument into a conventional tiff or jpeg format image for automated segmentation and adaptive step finding hotspots detection algorithm. Quantitative hotspot ranking is provided by the functionality from the open source application ImmunoRatio as part of the ASH protocol. The output is a ranked set of hotspots with concomitant quantitative values based on whole slide ranking., Conclusion: We have implemented an open source automated detection quantitative ranking of hotspots to support histopathologists in selecting the 'hottest' hotspot areas in adrenocortical carcinoma. To provide wider community easy access to ASH we implemented a Galaxy virtual machine (VM) of ASH which is available from http://bioinformatics.erasmusmc.nl/wiki/Automated_Selection_of_Hotspots ., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_216.
- Published
- 2014
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20. Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia.
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Papathomas TG, Oudijk L, Zwarthoff EC, Post E, Duijkers FA, van Noesel MM, Hofland LJ, Pollard PJ, Maher ER, Restuccia DF, Feelders RA, Franssen GJ, Timmers HJ, Sleijfer S, de Herder WW, de Krijger RR, Dinjens WN, and Korpershoek E
- Subjects
- Adult, Cell Line, Tumor, Female, Head and Neck Neoplasms genetics, Humans, Male, Middle Aged, Mutation, Neuroblastoma genetics, Pheochromocytoma genetics, Adrenal Cortex Neoplasms genetics, Adrenocortical Carcinoma genetics, Paraganglioma genetics, Promoter Regions, Genetic genetics, Telomerase genetics
- Abstract
Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors., (© 2014 Society for Endocrinology.)
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- 2014
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21. Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis.
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Papathomas TG, Gaal J, Corssmit EP, Oudijk L, Korpershoek E, Heimdal K, Bayley JP, Morreau H, van Dooren M, Papaspyrou K, Schreiner T, Hansen T, Andresen PA, Restuccia DF, van Kessel I, van Leenders GJ, Kros JM, Looijenga LH, Hofland LJ, Mann W, van Nederveen FH, Mete O, Asa SL, de Krijger RR, and Dinjens WN
- Subjects
- Adenoma metabolism, Adenoma pathology, Adult, Carcinoma genetics, Carcinoma metabolism, Carcinoma pathology, Carcinoma, Papillary genetics, Carcinoma, Papillary metabolism, Carcinoma, Papillary pathology, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, Exons, Female, Gene Deletion, Germ-Line Mutation, Humans, Loss of Heterozygosity, Male, Middle Aged, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Pituitary Neoplasms metabolism, Pituitary Neoplasms pathology, Succinate Dehydrogenase metabolism, Thyroid Cancer, Papillary, Thyroid Neoplasms metabolism, Thyroid Neoplasms pathology, Adenoma genetics, Carcinoma, Renal Cell genetics, Mutation, Pituitary Neoplasms genetics, Succinate Dehydrogenase genetics, Thyroid Neoplasms genetics
- Abstract
Objective: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated., Design and Methods: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC., Results: Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression., Conclusions: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.
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- 2013
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22. Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments.
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Papathomas TG, de Krijger RR, and Tischler AS
- Subjects
- Humans, Paraganglioma diagnosis, Paraganglioma genetics
- Abstract
Recent developments in molecular genetics have expanded the spectrum of disorders associated with pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGLs) and have increased the roles of pathologists in helping to guide patient care. At least 30% of these tumors are now known to be hereditary, and germline mutations of at least 10 genes are known to cause the tumors to develop. Genotype-phenotype correlations have been identified, including differences in tumor distribution, catecholamine production, and risk of metastasis, and types of tumors not previously associated with PCC/PGL are now considered in the spectrum of hereditary disease. Important new findings are that mutations of succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 (collectively "SDHx") are responsible for a large percentage of hereditary PCC/PGL and that SDHB mutations are strongly correlated with extra-adrenal tumor location, metastasis, and poor prognosis. Further, gastrointestinal stromal tumors and renal tumors are now associated with SDHx mutations. A PCC or PGL caused by any of the hereditary susceptibility genes can present as a solitary, apparently sporadic, tumor, and substantial numbers of patients presenting with apparently sporadic tumors harbor occult germline mutations of susceptibility genes. Current roles of pathologists are differential diagnosis of primary tumors and metastases, identification of clues to occult hereditary disease, and triaging of patients for optimal genetic testing by immunohistochemical staining of tumor tissue for the loss of SDHB and SDHA protein. Diagnostic pitfalls are posed by morphological variants of PCC/PGL, unusual anatomic sites of occurrence, and coexisting neuroendocrine tumors of other types in some hereditary syndromes. These pitfalls can be avoided by judicious use of appropriate immunohistochemical stains. Aside from loss of staining for SDHB, criteria for predicting risk of metastasis are still controversial, and "malignancy" is diagnosed only after metastases have occurred. All PCCs/PGLs are considered to pose some risk of metastasis, and long-term follow-up is advised., (© 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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23. EBV-positive diffuse large B-cell lymphoma of the elderly.
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Ok CY, Papathomas TG, Medeiros LJ, and Young KH
- Subjects
- Aged, Humans, Immunophenotyping, Lymphoma, Large B-Cell, Diffuse epidemiology, Lymphoma, Large B-Cell, Diffuse genetics, MicroRNAs genetics, MicroRNAs metabolism, Models, Biological, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections virology, Herpesvirus 4, Human physiology, Lymphoma, Large B-Cell, Diffuse complications, Lymphoma, Large B-Cell, Diffuse virology
- Abstract
Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly, initially described in 2003, is a provisional entity in the 2008 World Health Organization classification system and is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in patients >50 years of age and in whom there is no known immunodeficiency or history of lymphoma. These tumors are more common in Asia but also occur in North America and Europe at a low frequency. These neoplasms exhibit a morphologic continuum, from polymorphous to monomorphous, but morphologic features do not correlate with prognosis as all patients have a clinically aggressive course. Most EBV-positive DLBCL of the elderly patients have an activated B-cell immunophenotype and are characterized by prominent nuclear factor-κB activation. Cytogenetic complexity is usually low. In this review, we comprehensively delineate the data emerging from analyses of EBV latency program, microRNA-mediated EBV viral oncogenesis, functional genomics of EBV and its biology, and differential diagnosis challenge for EBV-positive DLBCL of the elderly. It is hoped that the improved understanding of these tumors will lead to the development of novel therapeutic approaches, enhance the effectiveness of clinical trials, and improve prognosis.
- Published
- 2013
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24. Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications.
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Papathomas TG, Venizelos I, Dunphy CH, Said JW, Wang ML, Campo E, Swerdlow SH, Chan JC, Bueso-Ramos CE, Weisenburger DD, Medeiros LJ, and Young KH
- Subjects
- Diagnosis, Differential, Female, Humans, Immunophenotyping, Male, Composite Lymphoma pathology, Lymphoma, Mantle-Cell pathology
- Abstract
Composite lymphoma is a rare circumstance in which 2 or more distinct types of lymphoma occur in a single anatomical location. Although composite lymphoma has been increasingly identified with the advent of molecular genetic techniques, this topic has only rarely been a specific focus of the medical scientific literature. In this review, we focus on mantle cell lymphoma occurring as a major pathologic component of composite lymphoma and emphasize the clinicopathologic features of these tumors and associated biologic implications. To date, 26 cases of composite lymphoma including a component of mantle cell lymphoma have been previously published. Issues of clonal relatedness between the individual lymphoma components and emerging biologic implications as well as potential diagnostic pitfalls are evaluated., (Copyright © 2012 Elsevier Inc. All rights reserved.)
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- 2012
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25. Proximal-type epithelioid sarcoma of the uterine corpus.
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Venizelos I, Anagnostou E, Papathomas TG, Arsos G, and Mentzel T
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Diagnosis, Differential, Female, Humans, Hysterectomy, Immunohistochemistry, Middle Aged, Sarcoma metabolism, Sarcoma therapy, Uterine Neoplasms metabolism, Uterine Neoplasms therapy, Sarcoma pathology, Uterine Neoplasms pathology
- Published
- 2011
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26. Orbital involvement in Castleman disease.
- Author
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Venizelos I, Papathomas TG, Papathanasiou M, Cheva A, Garypidou V, and Coupland S
- Subjects
- Aged, Axilla, HIV Seronegativity, Herpesviridae Infections complications, Herpesvirus 8, Human physiology, Humans, Immunophenotyping, Male, Plasma Cells pathology, Tomography, X-Ray Computed, Castleman Disease diagnosis, Lymph Nodes pathology, Orbital Diseases diagnosis
- Abstract
Castleman disease is a quite uncommon lymphoproliferative disorder usually occurring in the lymph nodes. Rarely, Castleman disease develops in an extranodal anatomic location. We report on the first biopsy-proven case of multicentric plasma cell type of Castleman disease involving the orbital areas in a human herpes virus 8 (HHV-8)-unassociated/ human immunodeficiency virus (HIV)-seronegative 70-year-old man suffering from Parkinson disease. The diagnosis was established on the basis of morphologic, immunophenotypic, and molecular findings of a lymph node and orbital soft tissue biopsy. We additionally provide a review of all previously published cases of Castleman disease with an orbital involvement, discussing the distinctive characteristics and potential associations with regard to their counterparts at other sites. Although Castleman disease involving the orbit is an exceptionally rare occurrence that may present initially with ocular signs and symptoms, this should be included in the complete differential diagnosis of orbital mass lesion.
- Published
- 2010
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27. Visceral leishmaniasis in a rheumatoid arthritis patient treated with methotrexate.
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Venizelos I, Tatsiou Z, Papathomas TG, and Orazi A
- Subjects
- Aged, Amphotericin B therapeutic use, Animals, Antiprotozoal Agents therapeutic use, Antirheumatic Agents therapeutic use, Female, Humans, Leishmania isolation & purification, Leishmaniasis, Visceral drug therapy, Leishmaniasis, Visceral pathology, Splenectomy, Treatment Outcome, Arthritis, Rheumatoid complications, Arthritis, Rheumatoid drug therapy, Leishmaniasis, Visceral diagnosis, Methotrexate therapeutic use
- Abstract
Visceral leishmaniasis (VL) is a relatively rare occurrence in rheumatoid arthritis (RA) patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists, corticosteroids and methotrexate, or methotrexate alone. A review of the literature revealed that only one case of VL in an RA patient treated with methotrexate has been previously published. We describe an additional case, that of a 65-year-old female with RA being treated with methotrexate, who presented with fever, abdominal discomfort, splenomegaly and pancytopenia. A diagnosis of VL was ultimately established, after a splenectomy was performed. Because RA is characterized by immune cell dysfunction and dysregulation, which potentially predisposes patients to infection, it is unclear whether this serious opportunistic infection can be solely attributable to the methotrexate, an immunosuppressive medication that also increases the risk of infection.
- Published
- 2009
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28. Novel therapeutics in metastatic bladder cancer.
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Lekas A, Papathomas TG, Papatsoris AG, Deliveliotis C, and Lazaris AC
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- Animals, Antineoplastic Agents therapeutic use, Humans, Neoplasm Metastasis drug therapy, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology, Platinum Compounds therapeutic use, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms pathology
- Abstract
Background: Albeit transitional cell carcinoma of the urinary bladder is a chemosensitive neoplasm, metastatic disease is related with poor prognosis and short-term survival data., Objective: Cisplatin-based combination chemotherapy is recognised as the golden standard therapy for patients with inoperable locally advanced or metastatic bladder cancer. However, owing to treatment-related toxicities and short-response durations, novel treatment options or agents, with both enhanced efficacy and tolerability, have been sought., Methods: Reviewing the current status and addressing the future of novel anticancer therapeutics in metastatic urinary bladder cancer., Results/conclusion: Non-platinum, single agents, such as gemcitabine and taxanes, as well as multidrug regimens in doublet or triplet chemotherapeutic combinations are regarded as promising alternatives. Dose intensification of conventional regimens, dose-dense sequential administration of new agents, the use of molecular markers for predicting chemosensitivity and the integration of biologically targeted agents to enhance chemotherapeutic efficacy are promising approaches.
- Published
- 2008
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29. Inflammatory pseudotumor associated with Mycobacterium tuberculosis infection.
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Androulaki A, Papathomas TG, Liapis G, Papaconstantinou I, Gazouli M, Goutas N, Bramis K, Papalambros A, Lazaris AC, and Papalambros E
- Subjects
- Adult, Humans, Kidney diagnostic imaging, Kidney pathology, Kidney Diseases microbiology, Kidney Diseases pathology, Male, Mycobacterium tuberculosis classification, Mycobacterium tuberculosis genetics, Polymerase Chain Reaction methods, Tomography, X-Ray Computed, Granuloma, Plasma Cell microbiology, Granuloma, Plasma Cell pathology, Mycobacterium tuberculosis isolation & purification, Tuberculosis, Renal microbiology, Tuberculosis, Renal pathology
- Abstract
Background: Inflammatory pseudotumor is a relatively rare entity; originally identified in the lung, it has been described in multiple extrapulmonary anatomic locations., Case Report: We report on the unusual case of an inflammatory pseudotumor associated with Mycobacterium tuberculosis infection, which was initially mistaken for a renal malignancy both in clinical and radiological settings. We additionally present three brief reviews concerning: (1) infectious agents postulated to induce morphological changes of an inflammatory pseudotumor; (2) mycobacterial pseudotumors; and (3) distinction from inflammatory myofibroblastic tumors of the renal pelvis., Conclusions: The present case highlights the diagnostic importance of PCR-based detection of mycobacterial DNA in granulomatous tissue responses. It is of crucial importance that clinicians are aware of this unusual manifestation of mycobacterial infection to ensure that pertinent laboratory evaluation is employed and appropriate treatment is administered in order to avoid potential clinical implications.
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- 2008
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30. Altered expression of adhesion molecules in inflammatory cervical smears.
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Politi EN, Lazaris AC, Kehriotis M, Papathomas TG, Nikolakopoulou E, and Koutselini H
- Subjects
- Adult, Aged, Bacteroides Infections metabolism, Bacteroides Infections physiopathology, Candidiasis metabolism, Candidiasis physiopathology, Chlamydia Infections metabolism, Chlamydia Infections physiopathology, Female, Humans, Immunohistochemistry, Inflammation metabolism, Middle Aged, Trichomonas Vaginitis metabolism, Trichomonas Vaginitis physiopathology, Uterine Cervicitis physiopathology, Vaginal Smears, Cadherins biosynthesis, Uterine Cervicitis metabolism, beta Catenin biosynthesis
- Abstract
Objective: The aim of the present study was to evaluate the expression of pan-cadherin and beta-catenin in cervical smears with various types of infectious agents., Patients and Methods: Cervical smears obtained from 53 women, aged 21-65 years, with a diagnosis of specific inflammation were examined in our study. Eighteen subjects were infected by Candida albicans, 18 by Gardnerella vaginalis, nine by Bacteroides spp. and eight by Chlamydia trachomatis. All infectious agents found in the smears were at the same time confirmed by the microbiological laboratory methods. We performed a biotin-streptavidin-peroxidase immunocytochemical method using anti-beta-catenin (Clone 12F7) and anti-pan-cadherin (pan, polyclonal) antibodies., Results: Aberrant expression of pan-cadherin was found in the cytoplasmic membrane of glandular, metaplastic, superficial and intermediate squamous cells in all types of infections. With regard to beta-catenin, this was expressed in majority (90%) of glandular and metaplastic cells in all types of infections and in a small proportion (15%) of superficial and intermediate squamous cells in infections caused by C. albicans and G. vaginalis., Conclusion: Our data show that infectious agents may cause alterations in the expression and distribution of these adhesive molecules, which can be recognized in cervical smears. Additional studies in larger sets of patients should help clarify this issue further.
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- 2008
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31. Pseudosarcomatous myofibroblastic lesion of the urinary bladder: a rare entity posing a diagnostic challenge and therapeutic dilemma.
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Lekas A, Parasi A, Papathomas TG, Papatsoris AG, Mennonna MR, Chrisofos M, Deliveliotis C, and Lazaris AC
- Abstract
Background: Pseudosarcomatous myofibroblastic lesions of the urinary bladder are relatively rare entities of an uncertain pathogenesis and benign indolent nature., Case Presentation: We present an extremely rare case of an ALK-1-positive pseudosarcomatous myofibroblastic lesion of the urinary bladder, which was initially misinterpreted as a low-grade leiomyosarcoma of myxoid subtype on histologic examination owing to prominent atypia, high mitotic activity, abnormal mitotic figures and infiltration of the bladder wall. Although the histologic features were suggestive of a sarcoma, the correct diagnosis was finally established and radical surgical treatment was subsequently avoided. The patient is currently free of disease without any evidence of tumor recurrence or metastasis at 3 years post-operatively., Conclusion: The key differentiating point rests in distinguishing the aforementioned mass forming lesion from the myxoid subtype of low-grade leiomyosarcoma in order to avoid unnecessary radical therapy.
- Published
- 2008
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32. Adrenaline attenuates the acute lung injury after intratracheal lipopolysaccharide instillation: an experimental study.
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Philippakis GE, Lazaris AC, Papathomas TG, Zissis C, Agrogiannis G, Thomopoulou G, Nonni A, Xiromeritis K, Nikolopoulou-Stamati P, Bramis J, Patsouris E, Perrea D, and Bellenis I
- Subjects
- Acute Disease, Animals, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes pathology, Cell Count, Disease Models, Animal, Drug Antagonism, Drug Therapy, Combination, Intercellular Adhesion Molecule-1 metabolism, Intubation, Intratracheal, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear pathology, Macrophages, Alveolar drug effects, Macrophages, Alveolar metabolism, Macrophages, Alveolar pathology, Male, Pneumonia metabolism, Pneumonia pathology, Rats, Up-Regulation drug effects, Bronchodilator Agents pharmacology, Epinephrine pharmacology, Lipopolysaccharides pharmacology, Pneumonia drug therapy
- Abstract
Endotoxin is a major cause of endotoxinemia, sepsis, and pneumonia due to gram-negative bacteria. Experimental endotoxin administration via the tracheal route has been extensively used to study the biological and pathophysiologic pathways of inflammation. In particular, experimental endotoxin instillation in the respiratory tree has allowed an extended research with regard to the local response of the lungs to the pathogenic stimulus. This study aims (a) to define early events in the inflammatory cascade and (b) to evaluate the efficacy of adrenaline to ameliorate the acute pulmonary inflammation in vivo after administration of intratracheal lipopolysaccharide (LPS) in an in vivo animal model. Two groups of animals were used for that purpose, a control group (single LPS administration) and a study group (subcutaneous adrenaline infusion following LPS administration). We found that mononuclear recruitment, along with an increased population of CD4+ T lymphocytes, is an early event during the course of LPS-challenged inflammation. In the study group, we determined that adrenaline mediated the lung inflammation in a statistically significant degree. By the use of immunohistochemistry, we identified (1) an increased population of CD4+ T lymphocytes in the inflammatory infiltrate, further endorsing the hypothesis that T-helper lymphocytes, along with macrophages, secrete cytokines which amplify the inflammatory response, and (2) an upregulation of ICAM-1 expression, suggesting an important role in the early pathogenesis of LPS-induced acute lung injury. Our study establishes that systemic adrenaline administration after LPS instillation may ameliorate the inflammatory lung response in vivo.
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- 2008
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33. Potential role of apoptosis and apoptotic regulatory proteins in colorectal neoplasia: correlations with clinico-pathological parameters and survival.
- Author
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Tzouvala M, Lazaris AC, Papatheodoridis GV, Kouvidou C, Papathomas TG, Kavantzas N, Elemenoglou I, Karamanolis DG, and Agapitos E
- Subjects
- Adenoma pathology, Adult, Aged, Colorectal Neoplasms pathology, Female, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Immunophenotyping, In Situ Nick-End Labeling, Male, Middle Aged, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins c-mdm2 metabolism, Adenoma metabolism, Apoptosis physiology, Colorectal Neoplasms metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
An imbalance between apoptotic and proliferative processes is believed to underlie colorectal neoplasia. We evaluated the expression of bcl-2, p53, mdm2 proteins, and apoptosis in colorectal neoplasms, as well as their correlation with clinico-pathological parameters, using image analysis. Biopsies from 46 colorectal cancers, 121 adenomas, and 25 controls were studied using monoclonal antibodies against p53, bcl-2, mdm2 and the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) method for apoptosis. P53 and bcl2 protein expression was higher in adenomas >or=1 cm (P < 0.03) and tubulovillous-villous adenomas (P < 0.03), and correlated with dysplasia (P < 0.03). In Cox regression analysis, Dukes' stage was the most significant independent prognostic indicator of a worse survival (P < 0.019), whereas when stage was eliminated, bcl-2 expression was also a powerful predictor for bad prognosis (P = 0.02). In conclusion, both bcl-2 and p53 immunohistochemical profiles may be useful adjuncts in detecting adenomas with a malignant potential, whereas bcl-2 could be used in combination with Dukes' stage as a predictor of prognosis in colorectal cancer.
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- 2008
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34. Topoisomerase I protein expression in primary colorectal cancer and recurrences after 5-FU-based adjuvant chemotherapy.
- Author
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Gouveris P, Lazaris AC, Papathomas TG, Nonni A, Kyriakou V, Delladetsima J, Patsouris ES, and Tsavaris N
- Subjects
- Age Factors, Chemotherapy, Adjuvant, Female, Humans, Immunohistochemistry, Male, Middle Aged, Recurrence, Sex Factors, Colorectal Neoplasms drug therapy, Colorectal Neoplasms enzymology, DNA Topoisomerases, Type I metabolism, Fluorouracil therapeutic use
- Abstract
Purpose: Our aim was to investigate whether chemotherapy with 5-FU induces an alteration in the levels of topoisomerase I (topo I) in colorectal neoplastic tissues, Methods: Twenty-five colorectal cancer patients were included in our study; these had undergone surgical resection of the primary tumor, received post-operatively 5-FU-based adjuvant chemotherapy and then suffered from recurrences. In a standard three-step immunohistochemical procedure, a monoclonal antibody to topo I was applied in both specimens from each patient (one from the primary location and a second one from the recurrence). Statistical analysis was subsequently performed., Results: Malignant cells from the recurrences displayed a statistical significant increase, concerning the levels of topoisomerase I, by comparison with the primary tumors (P=0.01). The increase in topo I levels did not demonstrate significant correlations with Duke's stage (Fisher's Exact Test P value=0.496), differentiation grade (P value=0.661), localization (P value=0.072), patient sex (P value=0.434), nor with relapse free interval (P value=0.493). There was a statistically significant relationship between the age of patients and increase in topo I levels (P=0.011)., Conclusions: Topo I expression may be part of the malignant cells' phenotype in recurrent colorectal carcinomas, suggesting a potential role for Topo I in the acquisition of a metastatic phenotype. The increase of topo I immunohistochemical status is likely to be attributed to 5-FU and given the fact that high levels of topo I correlate with sensitivity to camptothecin, advanced colorectal cancer patients seem to benefit from topo I targeted anticancer drug therapy.
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- 2007
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35. Population-based study of human papillomavirus infection and cervical neoplasia in Athens, Greece.
- Author
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Kroupis C, Thomopoulou G, Papathomas TG, Vourlidis N, and Lazaris AC
- Subjects
- Adolescent, Adult, Aged, Female, Greece epidemiology, Humans, Middle Aged, Papillomaviridae genetics, Papillomaviridae isolation & purification, Papillomavirus Infections virology, Population Surveillance, Precancerous Conditions epidemiology, Precancerous Conditions pathology, Uterine Cervical Neoplasms epidemiology, Uterine Cervical Neoplasms pathology, Vaginal Smears, Papillomaviridae classification, Papillomavirus Infections complications, Precancerous Conditions virology, Uterine Cervical Neoplasms virology
- Abstract
The aim of our study is to describe the prevalence of the different HPV types in women with pre-neoplastic lesions of the cervix in Greece. Cervical scrapes from 841 women were obtained for both cytological evaluation and analysis for the presence of HPV DNA. PCR was performed on specimens from these 841 women. The Pap test results were normal or showed benign cellular changes in 45.8% of the women, atypical squamous cells of undetermined significance (ASCUS) in 23.2%, low-grade squamous intra-epithelial lesion (LSIL) in 27.9% and high-grade squamous intra-epithelial lesion (HSIL) in 3.1%. HPV DNA was demonstrated in 23.6% of cytologically normal women. We detected HPV in 60% of the total samples. Of these, HPV-16 was the most common HPV DNA detected. Interestingly, HPV-58 was inversely correlated with positive cytological findings. A clear pattern of decreasing prevalence of HPV with age was also observed. Our results indicate that HPV infections, especially those with HPV-16, represent a significant public health concern in Greece.
- Published
- 2007
- Full Text
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36. Metastatic low-grade endometrial stromal sarcoma of clitoris: report of a case.
- Author
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Androulaki A, Papathomas TG, Alexandrou P, and Lazaris AC
- Subjects
- Female, Humans, Middle Aged, Sarcoma, Endometrial Stromal pathology, Clitoris pathology, Endometrial Neoplasms pathology, Sarcoma, Endometrial Stromal secondary, Vulvar Neoplasms secondary
- Abstract
Low-grade endometrial stromal sarcoma (ESS) is an uncommon neoplasm, which has a highly recurrent nature. A review of the literature revealed that only one case of low-grade ESS, arising within the vulva from a focus of endometriosis, has been previously published. We describe an additional case of low-grade ESS arising within the vulva and to the best of our knowledge the first report of low-grade ESS metastasized to clitoris. A 46-year-old woman was admitted to our hospital due to a heavy uterine bleeding. A physical examination revealed a lesion in clitoris, which exhibited a densely cellular mesenchymal neoplasm on microscopy. On the basis of the pathologic features alone, a differential diagnosis of a low-grade ESS and cellular leiomyoma was considered. Seven months later, the patient presented again with excessive uterine bleeding and a total hysterectomy was performed. A tumor of white-tan, whorled appearance was found. Its features were suggestive of low-grade ESS. Taking into account the possible extrauterine location of an ESS and reviewing the first case, a diagnosis of rare low-grade ESS metastasized to clitoris was made.
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- 2007
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37. Cytokeratin-7, cytokeratin-19, and c-Kit: Immunoreaction during the evolution stages of primary biliary cirrhosis.
- Author
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Chatzipantelis P, Lazaris AC, Kafiri G, Papadimitriou K, Papathomas TG, Nonni A, and Patsouris ES
- Abstract
Aims: The quantitative and qualitative expression of CK-7, CK-19, and c-Kit markers in various cell types were evaluated during the four stages of primary biliary cirrhosis., Methods: A total of 53 specimens were examined. Thirteen specimens were identified as Ludwig's stage 1, 23 as stage 2, 14 as stage 3, and 2 as stage 4. Immunohistochemical stains were performed for CK-7, CK-19, c-Kit and subsequently graded. The cell types expressing the markers were qualitatively analysed., Results: In normal liver, biliary epithelial cells expressed CK-7, CK-19, whereas the Canals of Hering (CoH) were stained with c-Kit and partly CK-19, contrary to hepatocytes. The aforementioned expression patterns were detected in pathologic samples of PBC, with qualitative and quantitative differences though. CK-7 grading was found to correspond with Ludwig's staging, in contrast to CK-19. c-Kit was absent in the early stages and focally present in the advanced stages. All biliary-type, intermediate cells and hepatocytes were CK-7 positive, particularly in samples with cholestasis, whereas CK-19 was only found in biliary-type and intermediate cells. c-Kit was expressed in CoH which appeared as clusters and strings of cuboidal cells in advanced stages., Conclusions: CK-7 can be regarded as a histological marker of progression in PBC; CK-19 cannot be assessed as a safe marker in the development of the disease. The absence of c-Kit in the early stages of PBC is related to the destruction of the CoH. CK-7 hepatocyte expression in the advanced stages is likely to be related to damaged hepatocytes' metaplastic potential.
- Published
- 2006
- Full Text
- View/download PDF
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