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Michael CW, Rodgers SA. Role of Immunocytochemistry in the Cytological Diagnosis of Mesothelioma. Acta Cytol 2024; 69:26-43. [PMID: 39667351 DOI: 10.1159/000543048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND Mesothelioma is an aggressive malignancy of the serosal surfaces with very poor prognosis. It traditionally manifests in older patients and at an advanced stage which results in minimal improvement in prognosis despite the recent advances in management. Early detection would therefore significantly impact management and potentially improve survival. Mesothelioma frequently presents with recurrent effusions, posing cytology as the initial procedure in the workup. A definitive diagnosis would not only spare the patients additional diagnostic procedures but also potentially afford them an opportunity for early surgical intervention and therapy. SUMMARY In this article, we review the role of immunocytochemistry (ICC) in the workup of mesothelioma. The various ICC markers to confirm or rule out mesothelial lineage are reviewed. In addition, newly introduced molecular surrogates that confirm the malignant nature of the mesothelial cells and support a definitive diagnosis of mesothelioma are discussed. We also briefly discuss the theranostic implications of such markers and potential impact of such recent advances on the cytological diagnosis and reporting of mesothelioma. KEY MESSAGES The cytological diagnosis of mesothelioma no longer requires the extensive expertise in morphological analysis and can be offered based on supporting ICC that confirms the mesothelial lineage and malignant nature of the cells.
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Affiliation(s)
- Claire W Michael
- Department of Pathology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA
| | - Shannon Alexandra Rodgers
- Department of Pathology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA
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Parra-Medina R, Castañeda-González JP, Chaves-Cabezas V, Alzate JP, Chaves JJ. Diagnostic performance of immunohistochemistry markers for malignant pleural mesothelioma diagnosis and subtypes. A systematic review and meta-analysis. Pathol Res Pract 2024; 257:155276. [PMID: 38603842 DOI: 10.1016/j.prp.2024.155276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 03/21/2024] [Accepted: 03/26/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND Malignant pleural mesothelioma (MPM) poses diagnostic challenges due to its resemblance to benign pleural pathologies and different histological subtypes. Several immunohistochemistry markers have been employed to aid in accurate diagnosis. METHODS The present systematic review and meta-analysis aimed to assess the diagnostic performance of various immunohistochemistry markers in malignant pleural mesothelioma diagnosis and its histological subtypes. Following the PRISMA guidelines, we systematically searched the literature for articles on using different immunohistochemical markers in MPM and its histological subtypes. EMBASE, LILACS, MEDLINE, and Virtual Health Library were searched for studies published up to August 2023. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) criteria to assess the quality of the included articles. Meta-analyses were performed to determine prevalence using a random-effects model. RESULTS 103 studies met the inclusion criteria, comprising a diverse range of immunohistochemistry markers. EMA and desmin-loss exhibited high sensitivity (96% and 92%, respectively) in distinguishing malignant pleural mesothelioma from benign pleural pathologies. Specificity was notably high for both BAP1-loss and survivin expression at 100%. Subtype-specific analyses demonstrated that EMA and HEG1 were sensitive markers for epithelioid mesothelioma, while GLUT1 showed high sensitivity for sarcomatoid mesothelioma. In cases comparing epithelioid mesothelioma and lung adenocarcinoma, CAM5.2 and calretinin displayed high sensitivity, while WT1 and BAP1-loss demonstrated exceptional specificity for malignant epithelioid mesothelioma. In the case of sarcomatoid mesothelioma and sarcomatoid lung carcinoma, GATA3 exhibited the most heightened sensitivity, while GATA3 and D2-40 displayed the best specificity for sarcomatoid malignant mesothelioma diagnosis. CONCLUSION Immunohistochemistry markers are essential in accurately diagnosing malignant pleural mesothelioma and its histological subtypes. This systematic review and meta-analysis provide a comprehensive insight into the diagnostic performance of these markers, facilitating their potential clinical utility in the discrimination of malignant pleural mesothelioma from other pleural pathologies and the differentiation of malignant pleural mesothelioma subtypes.
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Affiliation(s)
- Rafael Parra-Medina
- Research Institute, Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá, Colombia; Department of Pathology, Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá, Colombia; Department of Pathology, Instituto Nacional de Cancerología, Bogotá.
| | - Juan Pablo Castañeda-González
- Research Institute, Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá, Colombia; Department of Pathology, Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá, Colombia.
| | - Viviana Chaves-Cabezas
- Department of Pathology, Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá, Colombia.
| | - Juan Pablo Alzate
- Research Institute, Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá, Colombia.
| | - Juan José Chaves
- Department of Medicine, Norwalk Hospital, Yale School of Medicine, Norwalk, CT, United States.
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Ahuja S, Malviya A. Categorisation of serous effusions using the International System for Reporting Serous Fluid Cytopathology and assessment of risk of malignancy with diagnostic accuracy. Cytopathology 2021; 33:176-184. [PMID: 34913541 DOI: 10.1111/cyt.13089] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/24/2021] [Accepted: 12/08/2021] [Indexed: 11/28/2022]
Abstract
CONTEXT The International System for Reporting Serous Fluid Cytopathology (ISRSFC) standardises the reporting of serous effusion cytology under five categories: Non-Diagnostic (ND), Negative for Malignancy (NFM), Atypia of Undetermined Significance (AUS), Suspicious for Malignancy (SFM), and Malignant (M). Very few studies have been conducted so far to confirm the risk of malignancy of the different categories. AIMS The main objectives of our study were to classify serous effusions according to the ISRSFC categories and assess their risk of malignancy (ROM) and performance parameters. MATERIALS AND METHODS All serous effusion samples received from January 2019 to December 2020 were reclassified according to the ISRSFC. Using histopathological diagnosis as the gold standard, ROM and performance parameters were calculated. RESULTS A total of 831 pleural effusion samples were reclassified as follows: ND, 3 (0.4%); NFM, 635 (76.4%); AUS, 65 (7.8%); SFM, 60 (7.2%); and M, 68 (8.2%). For 457 peritoneal effusion samples, the reclassifications were ND, 5 (1.1%); NFM, 368 (80.5%); AUS, 19 (4.2%); SFM, 17 (3.7%); and M, 48 (10.5%). All 12 (100%) pericardial effusions belonged to the NFM category. The ROM for the ND, NFM, AUS, SRM, and M categories was 0%, 2.1%, 33.3%, 94.1%, 100%, respectively, in pleural effusions, and 50%, 4.8%, 22.2%, 83.3%, 100%, respectively, in peritoneal effusions. The ROM was 0% for NFM in pericardial effusions. CONCLUSION The ISRSFC is an excellent system for accurately classifying serous effusions with greater reproducibility of reports and better communication between pathologist and clinician.
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Affiliation(s)
- Sana Ahuja
- Department of Pathology, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttrakhand, India
| | - Avneesh Malviya
- Department of Pathology, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttrakhand, India
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Sugimoto A, Okuno T, Miki Y, Tsujio G, Sera T, Yamamoto Y, Kushiyama S, Nishimura S, Kuroda K, Togano S, Maruo K, Kasashima H, Ohira M, Yashiro M. EMMPRIN in extracellular vesicles from peritoneal mesothelial cells stimulates the invasion activity of diffuse-type gastric cancer cells. Cancer Lett 2021; 521:169-177. [PMID: 34474145 DOI: 10.1016/j.canlet.2021.08.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/16/2021] [Accepted: 08/25/2021] [Indexed: 02/08/2023]
Abstract
Peritoneal metastasis of gastric cancer (GC) results in extremely poor prognoses. The peritoneal cavity is covered by a monolayer of peritoneal mesothelial cells (PMCs). Interactions between GC cells and PMCs might play a pivotal role in peritoneal metastasis. Extracellular vesicles (EVs) correlate with intercellular communication. Although intercellular communication between cancer cells and PMCs might be associated with the peritoneal metastatic process, the role of EVs from PMCs remains unclear. We investigated the effects of EVs from PMCs on GC cells. Three GC cell lines (OCUM-12, NUGC-3, and MKN74) and four mesothelial cell lines were used. The effects of EVs derived from the PMCs on the invasion and migration of GC cells were evaluated by Matrigel invasion assay. Factors contained in the PMC EVs were analyzed; extra-cellular matrix metalloproteinase inducer (EMMPRIN) was detected in the EVs. The effects of an EMMPRIN inhibitor on the invasion-stimulating activity of EVs were examined. The EMMPRIN expressions of 110 GCs were evaluated by immunohistochemistry. PMC EVs significantly promoted the invasion of diffuse-type GC cells, i.e., OCUM-12 and NUGC-3 cells. EMMPRIN in the EVs stimulated the invasion of OCUM-12 and NUGC-3 cells. The invasion-stimulating activity of PMC EVs was inhibited by the EMMPRIN inhibitor. A high EMMPRIN expression in PMCs was significantly associated with worse cancer-specific survival and peritoneal-recurrence-free survival. EMMPRIN in EVs from PMCs might stimulate the malignant progression of diffuse-type GC. EMMPRIN might be a useful prognostic marker of recurrence in GC patients.
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Affiliation(s)
- Atsushi Sugimoto
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tomohisa Okuno
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuichiro Miki
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Gen Tsujio
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tomohiro Sera
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yurie Yamamoto
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shuhei Kushiyama
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Sadaaki Nishimura
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kenji Kuroda
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shingo Togano
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koji Maruo
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Kasashima
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaichi Ohira
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Japan; Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka, Japan; Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Sadiku-Zehri F, Gamulin O, Škrabić M, Qerimi-Krasniqi A, Sedlić F, Šepac A, Brčić L, Vuletić LB, Seiwerth S. Differentiating Between Malignant Mesothelioma and Other Pleural Lesions Using Fourier Transform Infrared Spectroscopy. APPLIED SPECTROSCOPY 2020; 74:808-818. [PMID: 32312091 DOI: 10.1177/0003702820924726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Histopathology, despite being the gold standard as a diagnostic tool, does not always provide a correct diagnosis for different pleural lesions. Although great progress was made in this field, the problem to differentiate between reactive and malignant pleural lesions still stimulates the search for additional diagnostic tools. Our research using vibrational spectroscopy and principal component analysis (PCA) statistical modeling represents a potentially useful tool to approach the problem. The objective method this paper explores is based on the correlation between different types of pleural lesions and their vibrational spectra. Obtained tissue spectra recorded by infrared spectroscopy allowed us to categorize spectra in different groups using a created PCA statistical model. The PCA model was built using tissues of known pathology as the model group. The validation samples were then used to confirm the functionality of our PCA model. Student's t-test was also used for comparing samples in paired groups. The PCA model was able to clearly differentiate the spectra of mesothelioma, metastasis and reactive changes (inflammation), and place them in discrete groups. Thus, we showed that Fourier transform infrared spectroscopy combined with PCA can differentiate pleural lesions with high sensitivity and specificity. This new approach could contribute in objectively differentiating specific pleural lesions, thus helping pathologists to better diagnose difficult pleural samples but also could shed additional light into the biology of malignant pleural mesothelioma.
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Affiliation(s)
- Fatlinda Sadiku-Zehri
- Department of Histology and Embriology, School of Medicine, University of Prishtina, Prishtina, Kosovo
- Institute of Pathology, University Clinical Center of Kosovo, Prishtina, Kosovo
| | - Ozren Gamulin
- Department of Physics and Biophysics, School of Medicine, University of Zagreb, Zagreb, Croatia
- Center of Excellence for Advanced Materials and Sensing Devices, Research Unit New Functional Materials, Zagreb, Croatia
| | - Marko Škrabić
- Department of Physics and Biophysics, School of Medicine, University of Zagreb, Zagreb, Croatia
- Center of Excellence for Advanced Materials and Sensing Devices, Research Unit New Functional Materials, Zagreb, Croatia
| | - Ardita Qerimi-Krasniqi
- Department of Histology and Embriology, School of Medicine, University of Prishtina, Prishtina, Kosovo
- Institute of Pathology, University Clinical Center of Kosovo, Prishtina, Kosovo
| | - Filip Sedlić
- Department of Pathophysiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ana Šepac
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Brčić
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Lovorka Batelja Vuletić
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Clinical Department of Pathology and Cytology, KBC Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Clinical Department of Pathology and Cytology, KBC Zagreb, Zagreb, Croatia
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Zhong SC, Ao XJ, Yu SH. Diagnostic value of GLUT-1 in distinguishing malignant mesothelioma from reactive mesothelial cells: a meta-analysis. Biomarkers 2020; 25:157-163. [PMID: 31916460 DOI: 10.1080/1354750x.2020.1714735] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background: Previous studies have demonstrated the diagnostic value of glucose transporter 1 (GLUT-1) to distinguish malignant mesothelioma (MM) from reactive mesothelial cells (RMC), but the results are inconsistent. The purpose of this meta-analysis is to investigate the diagnostic accuracy of GLUT-1 in distinguishing MM from RMC.Methods: A systematical search was conducted until May 2019 in PubMed, Medline, Embase and the Cochrane Library. The revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2) was used to assess the quality of the eligible studies. The Stata15 and Review Manager5.3 software programmes were used to perform the meta-analysis.Results: A total of 24 studies, including 969 MM patients and 1080 RMC individuals were explored in the meta-analysis. The summary assessments revealed that the pooled sensitivity was 0.73 (95% CI, 0.62-0.81) and the pooled specificity was 0.95 (95% CI, 0.91-0.98). The area under the summary ROC curve (AUC) was 0.93 (95% CI: 0.91-0.95).Conclusions: GLUT-1 is highly accurate to distinguish MM from RMC.
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Affiliation(s)
- Shan-Chuan Zhong
- Department of Pathology and Clinical Laboratory, 96601 Army Hospital of People's Liberation Army, Huangshan, China
| | - Xu-Jun Ao
- Department of Medical Oncology, 96601 Army Hospital of People's Liberation Army, Huangshan, China
| | - Shang-Hai Yu
- Department of Pathology and Clinical Laboratory, 96601 Army Hospital of People's Liberation Army, Huangshan, China
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Allen CJ, Newhook TE, Vreeland TJ, Das P, Minsky BD, Blum M, Song S, Ajani J, Ikoma N, Mansfield PF, Roy‐Chowdhuri S, Badgwell BD. Yield of peritoneal cytology in staging patients with gastric and gastroesophageal cancer. J Surg Oncol 2019; 120:1350-1357. [DOI: 10.1002/jso.25729] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 10/01/2019] [Indexed: 08/30/2023]
Abstract
AbstractBackgroundGuidelines for gastric and gastroesophageal (GE) cancer recommend staging laparoscopy (SL) with peritoneal cytology (PC). However, the reliability of PC is unknown. The primary purpose of this study was to determine the sensitivity of PC.MethodsWe analyzed a prospectively maintained database of patients who underwent SL and PC for gastric and GE cancer. Test sensitivity of PC for detecting peritoneal disease was assessed. Survival analyses were used to examine the implication of PC.ResultsThere were 1186 patients that underwent SL and PC; 282 (24%) were found with carcinomatosis. PC was analyzed in 214 (76%) of these patients and 77 (36%) were found to have no malignant cells. In this setting, PC had a sensitivity of 64% for confirming peritoneal disease. Those with peritoneal disease had a poorer 5‐year overall survival (5.8% vs 37.7%; P < .001). Those with positive PC without carcinomatosis had a similar survival to those with gross disease with and without cytological confirmation (both P > .05).ConclusionsPC has limited sensitivity for detecting peritoneal disease. Positive PC alone carries a similar poor survival as in patients with gross carcinomatosis. Improvements in the identification of microscopic disease in peritoneal washings are needed.
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Affiliation(s)
- Casey J. Allen
- Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston Texas
| | - Timothy E. Newhook
- Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston Texas
| | - Timothy J. Vreeland
- Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston Texas
| | - Prajnan Das
- Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston Texas
| | - Bruce D. Minsky
- Department of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston Texas
| | - Mariela Blum
- Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston Texas
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston Texas
| | - Jaffer Ajani
- Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston Texas
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Silva ECA, Cárcano FM, Bonatelli M, Zaia MG, Morais-Santos F, Baltazar F, Lopes LF, Scapulatempo-Neto C, Pinheiro C. The clinicopathological significance of monocarboxylate transporters in testicular germ cell tumors. Oncotarget 2018; 9:20386-20398. [PMID: 29755659 PMCID: PMC5945514 DOI: 10.18632/oncotarget.24910] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 02/26/2018] [Indexed: 12/14/2022] Open
Abstract
Background Metabolic reprogramming is one of the hallmarks of cancer. The hyperglycolytic phenotype is often associated with the overexpression of metabolism-associated proteins, such as monocarboxylate transporters (MCTs). MCTs are little explored in germ cell tumors (GCTs), thus, the opportunity to understand the relevance of these metabolic markers and their chaperone CD147 in this type of tumor arises. The main aim of this study was to evaluate the expression of MCT1, MCT2, MCT4 and CD147 in testicular GCT samples and the clinicopathological significance of these metabolism related proteins. Results MCT1, MCT4 and CD147 were associated with higher stages, higher M and N stages and histological type, while MCT4 was also associated with higher risk stratification, presence of vascular invasion, and lower overall and event free survival. MCT4 silencing in JEG-3 had no significant effect in cell viability, proliferation and death, as well as extracellular levels of glucose and lactate. However, MCT4-silenced cells showed an increase in migration and invasion. Conclusion The proteins herein studied, with the exception of MCT2, were associated with characteristics of worse prognosis, lower global and event free survival of patients with GCTs. Also, in vitro MCT4 silencing stimulated cell migration and invasion. Materials and Methods Immunohistochemical expression was evaluated on samples from 149 adult patients with testicular GCT, arranged in Tissue Microarrays (TMAs), and associated with the clinicopathological data. Also, MCT4 silencing studies using siRNA were performed in JEG-3 cells.
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Affiliation(s)
- Eduardo C A Silva
- Pathology Department, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Flavio M Cárcano
- Medical Oncology Department, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.,Barretos School of Health Sciences Dr. Paulo Prata - FACISB, Barretos, São Paulo, Brazil
| | - Murilo Bonatelli
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Maurício G Zaia
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Filipa Morais-Santos
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Luiz F Lopes
- Barretos School of Health Sciences Dr. Paulo Prata - FACISB, Barretos, São Paulo, Brazil.,Barretos Children's Cancer Hospital, Barretos, São Paulo, Brazil
| | - Cristovam Scapulatempo-Neto
- Pathology Department, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.,Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Céline Pinheiro
- Barretos School of Health Sciences Dr. Paulo Prata - FACISB, Barretos, São Paulo, Brazil.,Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
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9
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Bruno R, Alì G, Fontanini G. Molecular markers and new diagnostic methods to differentiate malignant from benign mesothelial pleural proliferations: a literature review. J Thorac Dis 2018; 10:S342-S352. [PMID: 29507804 DOI: 10.21037/jtd.2017.10.88] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor associated with asbestos exposure. Histopathological analysis of pleural tissues is the gold standard for diagnosis; however, it can be difficult to differentiate malignant from benign pleural lesions. The purpose of this review is to describe the most important biomarkers and new diagnostic tools suggested for this differential diagnosis. There are many studies concerning the separation between MPM and benign pleural proliferations from both pleural tissues or effusions; most of them are based on the evaluation of one or few biomarkers by immunohistochemistry (IHC) or enzyme-linked immunosorbent assays (ELISAs), whereas others focused on the identification of MPM signatures given by microRNA (miRNA) or gene expression profiles as well as on the combination of molecular data and classification algorithms. None of the reported biomarkers showed adequate diagnostic accuracy, except for p16 [evaluated by fluorescent in situ hybridization (FISH)] and BAP1 (evaluated by IHC), both biomarkers are recommended by the International Mesothelioma Interest Group guidelines for histological and cytological diagnosis. BAP1 and p16 showed a specificity of 100% in discerning malignant from benign lesions because they are exclusively unexpressed or deleted in MPM. However, their sensitivity, even when used together, is not completely sufficient, and absence of their alterations cannot confirm the benign nature of the lesion. Recently, the availability of new techniques and increasing knowledge regarding MPM genetics led to the definition of some molecular panels, including genes or miRNAs specifically deregulated in MPM, that are extremely valuable for differential diagnosis. Moreover, the development of classification algorithms is facilitating the application of molecular data for clinical practice. Data regarding new diagnostic tools and MPM signatures are absolutely promising; however, before their application in clinical practice, a prospective validation is necessary, as these approaches could surely improve the differential diagnosis between malignant and benign pleural lesions.
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Affiliation(s)
- Rossella Bruno
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Greta Alì
- Unit of Pathological Anatomy, Azienda Ospedaliero Universitaria Pisana, AOUP, Pisa, Italy
| | - Gabriella Fontanini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.,Program of Pleuropulmonary Pathology, Azienda Ospedaliero Universitaria Pisana, AOUP, Pisa, Italy
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10
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Abstract
BACKGROUND Peritoneal injury is an important cause of technical failure of long-term peritoneal dialysis (PD). Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term PD with potentially life threatening consequences. CD147 is a glycoprotein with diverse functions including modulation of extracellular matrix via induction of matrix metalloproteinases, cell adhesion, and regulation of immune reactions. We hypothesized that CD 147 plays a role in the peritoneal cavity. METHODS In this retrospective study, we localized CD147 by immunohistochemistry in peritoneal biopsies from uremic patients not on PD (n = 8), on PD without signs of EPS (n = 7), and in biopsies in patients with the diagnosis of EPS (n = 7). Double immunofluorescence was used to co-localize α-smooth-muscle actin (α-SMA) and CD147 in selected biopsies from each group. Expression was scored semi-quantitatively. RESULTS In biopsies from uremic controls, CD147 was prominently expressed in mesothelial cells, focally between fat cells and by some perivascular cells. In patients on PD, a similar distribution was present (although mesothelium was rarely conserved), with some focal accentuation. In EPS, layers of fibroblastic cells were positive for CD147. EPS biopsies demonstrated a significantly higher score in a blinded evaluation, compared to uremic patients. Cells expressing CD147 were α-SMA positive myofibroblasts as demonstrated by double immunofluorescence. Mean CD147 scores did not differ between patients with different transporter status. CONCLUSIONS This is the first study demonstrating CD147 on a major part of fibroblastic cells in EPS. Future studies need to address the role of these cells in this severe complication of long-term PD.
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Rossi ED, Bizzarro T, Granja S, Martini M, Capodimonti S, Luca E, Fadda G, Lombardi CP, Pontecorvi A, Larocca LM, Baltazar F, Schmitt F. The expression of monocarboxylate transporters in thyroid carcinoma can be associated with the morphological features of BRAF V600E mutation. Endocrine 2017; 56:379-387. [PMID: 27484771 DOI: 10.1007/s12020-016-1044-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/29/2016] [Indexed: 10/21/2022]
Abstract
BRAF V600E mutation, usually performed by DNA techniques, is one of the most common diagnostic markers in papillary thyroid carcinoma. Few papers have demonstrated that plump cells (eosinophilic cytoplasms and papillary thyroid carcinoma nuclei) and peculiar sickle-shaped nuclei represent morphological features of BRAF V600E on papillary thyroid carcinomas. These features seem to be linked to glycolytic phenotype whereby monocarboxylate transporters 1-4 are hypothesized to have a dominant role as lactate transporters. We investigated the association between these morphological features and monocarboxylate transporters 1 and 4 in 48 cyto-histological samples diagnosed as "positive for malignancy-favoring papillary thyroid carcinoma". These cases were processed with liquid-based cytology and underwent BRAF V600E mutational analysis (pyrosequencing) on liquid-based cytology and monocarboxylate transporters immunostaining on histology. The expression of monocarboxylate transporter 1, monocarboxylate transporter 4, glucose trasporter-1 and carbonic anhidrase were scored semi-quantitatively with expression from 0 to 3+ (strong positivity). The 33 mutated and 15 wild type cases showed 100 % cyto-histological concordance. The cytological evaluation revealed plump cells and sickle nuclear shape in 100 % mutated cases. Monocarboxylate transporter 1 yielded 76 % positivity in the mutated cases especially in both the plump cells and sickle-shaped nuclei, whereas the wild types showed 13.3 % positive monocarboxylate transporter 1 (p = 0.00013). Monocarboxylate transporter 4 resulted in 100 % positivity in mutated and 40 % in wild types (p < 0.005). Furthermore, 20 % of the wild types showed weak monocarboxylate transporter 1 nuclear expression associated to a less aggressive behavior. The analysis of glucose trasporter-1 and carbonic anhidrase did not highlight any statistical significance (p > 0.05). This is the first report analyzing the association between monocarboxylate transporter expression and the morphological features of BRAF V600E mutated papillary thyroid carcinomas suggesting the possible involvement of lactate in the morphological features.
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Affiliation(s)
- Esther Diana Rossi
- Division of Anatomic Pathology, Catholic University of Sacred Heart-Rome, Milano, Italy.
| | - Tommaso Bizzarro
- Division of Anatomic Pathology, Catholic University of Sacred Heart-Rome, Milano, Italy
| | - Sara Granja
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Maurizio Martini
- Division of Anatomic Pathology, Catholic University of Sacred Heart-Rome, Milano, Italy
| | - Sara Capodimonti
- Division of Anatomic Pathology, Catholic University of Sacred Heart-Rome, Milano, Italy
| | - Emilia Luca
- Division of Anatomic Pathology, Catholic University of Sacred Heart-Rome, Milano, Italy
| | - Guido Fadda
- Division of Anatomic Pathology, Catholic University of Sacred Heart-Rome, Milano, Italy
| | | | | | - Luigi Maria Larocca
- Division of Anatomic Pathology, Catholic University of Sacred Heart-Rome, Milano, Italy
| | - Fatima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Fernando Schmitt
- Medical Faculty/University, Porto, Portugal
- Institute of Pathology/Molecular Immunology of Porto, Porto, Portugal
- Laboratorie National de Sante-Luxembourg, Luxembourg, Luxembourg
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Rossi E, Bizzarro T, Martini M, Longatto-Filho A, Schmitt F, Fagotti A, Scambia G, Zannoni GF. The Role of Liquid Based Cytology and Ancillary Techniques in the Peritoneal Washing Analysis: Our Institutional Experience. PLoS One 2017; 12:e0168625. [PMID: 28099523 PMCID: PMC5242474 DOI: 10.1371/journal.pone.0168625] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/02/2016] [Indexed: 01/04/2023] Open
Abstract
Background The cytological analysis of peritoneal effusions serves as a diagnostic and prognostic aid for either primary or metastatic diseases. Among the different cytological preparations, liquid based cytology (LBC) represents a feasible and reliable method ensuring also the application of ancillary techniques (i.e immunocytochemistry-ICC and molecular testing). Methods We recorded 10348 LBC peritoneal effusions between January 2000 and December 2014. They were classified as non-diagnostic (ND), negative for malignancy-NM, atypical-suspicious for malignancy-SM and positive for malignancy-PM. Results The cytological diagnosis included 218 ND, 9.035 NM, 213 SM and 882 PM. A total of 8048 (7228 NM, 115SM, 705 PM) cases with histological follow-up were included. Our NM included 21 malignant and 7207 benign histological diagnoses. Our 820 SMs+PMs were diagnosed as 107 unknown malignancies (30SM and 77PM), 691 metastatic lesions (81SM and 610PM), 9 lymphomas (2SM and 7PM), 9 mesotheliomas (1SM and 8SM), 4 sarcomas (1SM and 3PM). Primary gynecological cancers contributed with 64% of the cases. We documented 97.4% sensitivity, 99.9% specificity, 98% diagnostic accuracy, 99.7% negative predictive value (NPV) and 99.7% positive predictive value (PPV). Furthermore, the morphological diagnoses were supported by either 173 conclusive ICC results or 50 molecular analyses. Specifically the molecular testing was performed for the EGFR and KRAS mutational analysis based on the previous or contemporary diagnoses of Non Small Cell Lung Cancer (NSCLC) and colon carcinomas. We identified 10 EGFR in NSCCL and 7 KRAS mutations on LBC stored material. Conclusions Peritoneal cytology is an adjunctive tool in the surgical management of tumors mostly gynecological cancers. LBC maximizes the application of ancillary techniques such as ICC and molecular analysis with feasible diagnostic and predictive yields also in controversial cases.
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Affiliation(s)
- Esther Rossi
- Division of Anatomic Pathology and Histology - Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Rome, Italy
- * E-mail:
| | - Tommaso Bizzarro
- Division of Anatomic Pathology and Histology - Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Rome, Italy
| | - Maurizio Martini
- Division of Anatomic Pathology and Histology - Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Rome, Italy
| | - Adhemar Longatto-Filho
- Department of Pathology, University of São Paulo School of Medicine, Sao Paolo, Brazil
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
- ICVS/3B’s Laboratory of Medical Investigation (LIM)- PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Molecular Oncology Research Center, Barretos Cancer Hospital, Pio XII Foundation, Barretos, Brazil
| | - Fernando Schmitt
- Medical Faculty, Porto University, Porto, Portugal
- Laboratorie National de Sante, Luxembourg, Luxembourg
| | - Anna Fagotti
- Gynecological Oncology, Catholic University, Rome, Italy
| | | | - Gian Franco Zannoni
- Division of Anatomic Pathology and Histology - Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Rome, Italy
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Rossi ED, Martini M, Bizzarro T, Schmitt F, Longatto-Filho A, Larocca LM. Somatic mutations in solid tumors: a spectrum at the service of diagnostic armamentarium or an indecipherable puzzle? The morphological eyes looking for BRAF and somatic molecular detections on cyto-histological samples. Oncotarget 2017; 8:3746-3760. [PMID: 27738305 PMCID: PMC5356915 DOI: 10.18632/oncotarget.12564] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 10/03/2016] [Indexed: 12/12/2022] Open
Abstract
This review article deals with the analysis and the detection of the morphological features associated with somatic mutations, mostly BRAFV600E mutation, on both cytological and histological samples of carcinomas. Few authors demonstrated that some architectural and specific cellular findings (i.e. polygonal eosinophilic cells defined as "plump cells" and sickle-shaped nuclei) are able to predict BRAF V600E mutation in both cytological and histological samples of papillary thyroid carcinoma (PTC) as well as in other carcinomas. In the current review article we evaluated the first comprehensive analysis of the morphological prediction of BRAFV600E and other somatic mutations in different malignant lesions with the description of the possible mechanisms beneath these morphologic features. The detection of predictive morphological features, mostly on FNAC, may add helpful information to the stratification of the malignant risk and personalized management of cancers. Additionally, the knowledge of the molecular mechanism of different oncogenic drivers can lead to the organ-specific triaging selection of cases and can provide significant insight for targeted therapies in different malignant lesions.
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Affiliation(s)
- Esther Diana Rossi
- Division of Anatomic Pathology and Histology, Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Rome, Italy
| | - Maurizio Martini
- Division of Anatomic Pathology and Histology, Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Rome, Italy
| | - Tommaso Bizzarro
- Division of Anatomic Pathology and Histology, Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Rome, Italy
| | - Fernando Schmitt
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
- Department of Medicine and Pathology, Laboratoire National de Santé, Luxembourg
| | - Adhemar Longatto-Filho
- Department of Pathology, Laboratory of Medical Investigation, University of São Paulo School of Medicine, Brazil
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Molecular Oncology Research Center, Barretos Cancer Hospital, Pio XII Foundation, Barretos, Brazil
| | - Luigi Maria Larocca
- Division of Anatomic Pathology and Histology, Università Cattolica del Sacro Cuore, “Agostino Gemelli” School of Medicine, Rome, Italy
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Rossi ED, Schmitt F. When Morphology Meets Somatic Mutations: The New Possible Scenario in Thyroid Fine-Needle Aspiration. Acta Cytol 2016; 60:93-6. [PMID: 27288325 DOI: 10.1159/000446796] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 05/04/2016] [Indexed: 12/30/2022]
Abstract
This study points to the analysis of the morphological features suggestive of somatic mutations, mostly the BRAFV600E mutation, on cytological samples of thyroid carcinomas. According to the literature, the application of ancillary techniques on cytology comes in handy as a challenging aid in ruling out a malignant outcome on both conventional and liquid-based cytological preparations. However, the evaluation of somatic mutations, including BRAFV600E, usually performed by DNA techniques, may have some limitations in a worldwide diffusion. In this perspective, few authors emphasized the morphological search for BRAFV600E mutations harbored in papillary thyroid carcinoma (PTC) and characterized by specific architectural and cellular findings (i.e. eosinophilic cells defined as 'plump cells' and sickle-shaped nuclei). Hence, the detection of eosinophilic cytoplasm of mutated PTC cells seems to suggest the possible involvement of the 'Warburg effect' pioneering the ability of cancer cells to convert glucose into lactic acid. The recent yields of immunohistochemical expression of monocarboxylate transporters in mutated PTCs may suggest the accumulation of lactate in these plump cells. Equally importantly, the detection of these morphological findings using fine-needle aspiration cytology may be helpful in triaging thyroid lesions and limiting costs. Additionally, it may lead to the stratification of the malignant risk and personalized management in cases with multifocal lesions.
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Affiliation(s)
- Esther Diana Rossi
- Division of Anatomic Pathology and Histology, Agostino Gemelli School of Medicine, Universitx00E0; Cattolica del Sacro Cuore, Rome, Italy
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BAP1 facilitates diagnostic objectivity, classification, and prognostication in malignant pleural mesothelioma. Hum Pathol 2015; 46:1670-8. [DOI: 10.1016/j.humpath.2015.06.024] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 06/12/2015] [Accepted: 06/17/2015] [Indexed: 12/12/2022]
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BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. Mod Pathol 2015; 28:1043-57. [PMID: 26022455 DOI: 10.1038/modpathol.2015.65] [Citation(s) in RCA: 199] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 04/20/2015] [Accepted: 04/24/2015] [Indexed: 01/18/2023]
Abstract
The distinction between malignant mesothelioma and reactive mesothelial proliferation can be challenging both on histology and cytology. Recently, variants of the BRCA1-associated protein 1 (BAP1) gene resulting in nuclear protein loss were reported in hereditary and sporadic mesothelioma. Using immunohistochemistry, we evaluated the utility of BAP1 expression in the differential diagnosis between mesothelioma and other mesothelial proliferations on a large series of biopsies that included 212 mesotheliomas, 12 benign mesothelial tumors, and 42 reactive mesothelial proliferations. BAP1 stain was also performed in 70 cytological samples (45 mesotheliomas and 25 reactive mesothelial proliferations). BAP1 was expressed in all benign mesothelial tumors, whereas 139/212 (66%) mesotheliomas were BAP1 negative, especially in epithelioid/biphasic compared with sarcomatoid/desmoplastic subtypes (69% vs 15%). BAP1 loss was homogeneous in neoplastic cells except for two epithelioid mesotheliomas showing tumor heterogeneity. By fluorescence in situ hybridization, BAP1 protein loss was paralleled by homozygous deletion of the BAP1 locus in the vast majority of BAP1-negative tumors (31/41, 76%), whereas 9/10 BAP1-positive mesotheliomas were normal. In biopsies interpreted as reactive mesothelial proliferation BAP1 loss was 100% predictive of malignancy, as all 6 cases subsequently developed BAP1-negative mesothelioma, whereas only 3/36 (8%) BAP1-positive cases progressed to mesothelioma. On cytology/cell blocks, benign mesothelial cells were invariably positive for BAP1, whereas 64% of mesotheliomas showed loss of protein; all 6 cases showing BAP1 negativity were associated with histological diagnosis of BAP1-negative mesothelioma. BAP1 stain also showed utility in the differential of mesothelioma from most common pleural and peritoneal mimickers, such as lung and ovary carcinomas, with specificity and sensitivity of 99/70% and 100/70%, respectively. Our results show that BAP1 protein is frequently lost in mesothelioma, especially of epithelioid/biphasic subtype and is commonly associated with homozygous BAP1 deletion. BAP1 immunostain represents an excellent biomarker with an unprecedented specificity (100%) in the distinction between benign and malignant mesothelial proliferations. Finding BAP1 loss in mesothelial cells should prompt to immediately reevaluate the patient; moreover, it might be useful in mapping tumor extent and planning surgical resection.
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17
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Bedrossian CWM. An update on pleuro-pulmonary cytopathology: Part i: Cytological diagnosis of mesothelioma and molecular cytology of lung cancer with an historical perspective. Diagn Cytopathol 2015; 43:513-26. [PMID: 26100968 DOI: 10.1002/dc.23298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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18
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Rossi ED, Bizzarro T, Schmitt F, Longatto-Filho A. The role of liquid-based cytology and ancillary techniques in pleural and pericardic effusions: an institutional experience. Cancer Cytopathol 2015; 123:258-66. [PMID: 25641902 DOI: 10.1002/cncy.21518] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Revised: 12/15/2014] [Accepted: 12/15/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND Fine-needle aspiration cytology (FNAC) of serous membrane effusions may fulfil a challenging role in the diagnostic analysis of both primary and metastatic disease. From this perspective, liquid-based cytology (LBC) represents a feasible and reliable method for empowering the performance of ancillary techniques (ie, immunocytochemistry and molecular testing) with high diagnostic accuracy. METHODS In total, 3171 LBC pleural and pericardic effusions were appraised between January 2000 and December 2013. They were classified as negative for malignancy (NM), suspicious for malignancy (SM), or positive for malignancy (PM). RESULTS The cytologic diagnoses included 2721 NM effusions (2505 pleural and 216 pericardic), 104 SM effusions (93 pleural and 11 pericardic), and 346 PM effusions (321 pleural and 25 pericardic). The malignant pleural series included 76 unknown malignancies (36 SM and 40 PM effusions), 174 metastatic lesions (85 SM and 89 PM effusions), 14 lymphomas (3 SM and 11 PM effusions), 16 mesotheliomas (5 SM and 11 SM effusions), and 3 myelomas (all SM effusions). The malignant pericardic category included 20 unknown malignancies (5 SM and 15 PM effusions), 15 metastatic lesions (1 SM and 14 PM effusions), and 1 lymphoma (1 PM effusion). There were 411 conclusive immunocytochemical analyses and 47 molecular analyses, and the authors documented 88% sensitivity, 100% specificity, 98% diagnostic accuracy, 98% negative predictive value, and 100% positive predictive value for FNAC. CONCLUSIONS FNAC represents a primary diagnostic tool for effusions and a reliable approach with which to determine the correct follow-up. Furthermore, LBC is useful for ancillary techniques, such as immunocytochemistry and molecular analysis, with feasible diagnostic and predictive utility.
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Affiliation(s)
- Esther Diana Rossi
- Division of Anatomic Pathology and Histology, "Agostino Gemelli" School of Medicine, Sacred Heart Catholic University, Rome, Italy
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19
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Chang S, Oh MH, Ji SY, Han J, Kim TJ, Eom M, Kwon KY, Ha SY, Choi YD, Lee CH, Lee Y, Jung SH. Practical utility of insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1, and epithelial membrane antigen for distinguishing malignant mesotheliomas from benign mesothelial proliferations. Pathol Int 2014; 64:607-12. [PMID: 25376377 DOI: 10.1111/pin.12216] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 09/14/2014] [Indexed: 12/31/2022]
Abstract
The differentiation of malignant mesotheliomas and benign mesothelial proliferations is crucial in determining patient care and prognosis. But, this distinction can be extremely difficult, particularly in small biopsies. Recently, insulin-like growth factor II mRNA-binding protein 3 (IMP3) and glucose transporter 1 (GLUT-1) have been reported as specific and sensitive markers in the distinction of mesotheliomas from benign mesothelial proliferations. The purpose of this study is to evaluate the utility of IMP3, GLUT-1, and epithelial membrane antigen (EMA) immunohistochemistry for distinguishing mesotheliomas from benign mesothelial proliferations. Immunoexpression of IMP3, GLUT-1, and EMA was evaluated in 88 malignant mesotheliomas, 35 adenomatoid tumors, and 20 benign lung tissues with reactive mesothelial cells. The sensitivity for IMP3, GLUT-1, and EMA was 37%, 21%, and 41%, respectively. The specificity for IMP3, GLUT-1, and EMA was 100%. When IMP3, GLUT1, and EMA combined, the sensitivity was 66% for IMP3/EMA staining, 53% for GLUT-1/EMA staining, and 45% for IMP3/GLUT-1. Use of IMP3 and EMA together is more helpful to distinguish malignant mesotheliomas from benign mesothelial proliferations than the use of IMP3 or EMA alone.
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Affiliation(s)
- Sunhee Chang
- Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Republic of Korea
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20
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Alves VA, Pinheiro C, Morais-Santos F, Felipe-Silva A, Longatto-Filho A, Baltazar F. Characterization of monocarboxylate transporter activity in hepatocellular carcinoma. World J Gastroenterol 2014; 20:11780-11787. [PMID: 25206282 PMCID: PMC4155368 DOI: 10.3748/wjg.v20.i33.11780] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 03/07/2014] [Accepted: 06/17/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the immunoexpression of hypoxia-related markers in samples from cirrhosis and primary and metastatic hepatocellular carcinoma (HCC).
METHODS: From a total of 5836 autopsies performed at the Pathology Department - University of Sao Paulo School of Medicine Hospital - from 2003 to 2009, 188 presented primary liver tumors. Immunohistochemical reactivity for monocarboxylate transporters (MCTs)-1, 2 and 4, CD147 and glucose transporter-1 (GLUT1) was assessed in necropsies from 80 cases of HCC. Data were stored and analyzed using the IBM SPSS statistical software (version 19, IBM Company, Armonk, NY). All comparisons were examined for statistical significance using Pearson’s χ2 test and Fisher’s exact test (when n < 5). The threshold for significant P values was established as P < 0.05.
RESULTS: Plasma membrane expression of MCT4 and overall expression of GLUT1 showed progressively higher expression from non-neoplastic to primary HCC and to metastases. In contrast, overall expression of MCT2 was progressively decreased from non-neoplastic to primary HCC and to metastases. MCT1 (overall and plasma membrane expression), MCT2 and CD147 plasma membrane expression were associated with absence of cirrhosis, while plasma membrane expression of CD147 was also associated with absence of HBV infection. MCT2 overall expression was associated with lower liver weight, absence of metastasis and absence of abdominal dissemination. Additionally, MCT4 plasma membrane positivity was strongly associated with Ki-67 expression.
CONCLUSION: MCT4 and GLUT1 appear to play a role in HCC progression, while MCT2 is lost during progression and associated with better prognosis.
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Adam P, Schraml C, Sipos B, Fend F. [Mesothelial proliferation in rectal cancer]. DER PATHOLOGE 2014; 35:88-92. [PMID: 24496993 DOI: 10.1007/s00292-013-1880-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
In an epiphrenic lymph node of a 55 years old female patient who underwent surgical resection of a rectal adenocarcinoma epitheloid proliferations with papillary and solid growth pattern were seen additional to a metastasis of the carcinoma. Adjacent vessels contained similar infiltrates. Immunohistochemically a co-expression of pan-keratin, calretinin and WT1 was seen, suggestive for a diagnosis of a metastasis of a malignant mesothelioma. However, radiologic examination yielded no morphologic correlate to this suspicion. Further immunohistochemical work-up showed positivity for desmin, negativity for EMA, GLUT1, p53 and a low ki67-fraction of 2-3 %. Therefore, a final diagnosis of benign mesothelial proliferations disseminated into the lymph node and the adjacent vessels was made.
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Affiliation(s)
- P Adam
- Abteilung Allgemeine Pathologie und Pathologische Anatomie, Institut für Pathologie und Neuropathologie, Eberhard-Karls-Universität Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Deutschland,
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22
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Minato H, Kurose N, Fukushima M, Nojima T, Usuda K, Sagawa M, Sakuma T, Ooi A, Matsumoto I, Oda M, Arano Y, Shimizu J. Comparative immunohistochemical analysis of IMP3, GLUT1, EMA, CD146, and desmin for distinguishing malignant mesothelioma from reactive mesothelial cells. Am J Clin Pathol 2014; 141:85-93. [PMID: 24343741 DOI: 10.1309/ajcp5knl7qtellyi] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
OBJECTIVES To identify useful biomarkers for differentiating between malignant mesothelioma (MM) and reactive mesothelial cells (RMCs). METHODS Formalin-fixed, paraffin-embedded (FFPE) tissues from 34 MM and 40 RMC samples were analyzed using immunohistochemistry, and the findings were compared. RESULTS Positive markers for MM included insulin-like growth factor 2 messenger RNA binding protein 3 (IMP3), glucose transporter 1 (GLUT1), epithelial membrane antigen (EMA), and CD146, which showed sensitivities of 94%, 85%, 79%, and 71% and specificities of 78%, 100%, 88%, and 98%, respectively. In sarcomatoid MM, EMA had significantly lower expression than did IMP3, GLUT1, and CD146 (P < .001). The areas under receiver operating characteristic curves were the highest for IMP3 (0.95), followed by GLUT1 (0.93). When the optimal cutoff points for IMP3 (30%) and GLUT1 (10%) were used, the sensitivity of IMP3 and GLUT1 for MM was 100%, and the specificity of both for MM was 95%. CONCLUSIONS The combination of IMP3 and GLUT1 is most appropriate for distinguishing MM from RMC using FFPE sections.
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Affiliation(s)
- Hiroshi Minato
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Nozomu Kurose
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Mana Fukushima
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Takayuki Nojima
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Katsuo Usuda
- Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Motoyasu Sagawa
- Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Tsutomu Sakuma
- Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Ishikawa, Japan
| | - Akishi Ooi
- Department of Molecular Pathology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Isao Matsumoto
- Department of General and Cardiothoracic Surgery, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Makoto Oda
- Department of General and Cardiothoracic Surgery, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yoshihiko Arano
- Department of Surgery, KKR Hokuriku Hospital, Kanazawa, Ishikawa, Japan
| | - Junzo Shimizu
- Department of Surgery, KKR Hokuriku Hospital, Kanazawa, Ishikawa, Japan
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Paintal A, Raparia K, Zakowski MF, Nayar R. The diagnosis of malignant mesothelioma in effusion cytology. Cancer Cytopathol 2013; 121:703-7. [DOI: 10.1002/cncy.21342] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Revised: 06/28/2013] [Accepted: 07/12/2013] [Indexed: 01/07/2023]
Affiliation(s)
- Ajit Paintal
- Northwestern University; Feinberg School of Medicine; Chicago Illinois
| | - Kirtee Raparia
- Northwestern University; Feinberg School of Medicine; Chicago Illinois
| | - Maureen F. Zakowski
- Memorial Sloan-Kettering Cancer Center; New York New York
- Weill Cornell Medical College; New York New York
| | - Ritu Nayar
- Northwestern University; Feinberg School of Medicine; Chicago Illinois
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Amit-Cohen BC, Rahat MM, Rahat MA. Tumor cell-macrophage interactions increase angiogenesis through secretion of EMMPRIN. Front Physiol 2013; 4:178. [PMID: 23874303 PMCID: PMC3709141 DOI: 10.3389/fphys.2013.00178] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 06/23/2013] [Indexed: 01/11/2023] Open
Abstract
Tumor macrophages are generally considered to be alternatively/M2 activated to induce secretion of pro-angiogenic factors such as VEGF and MMPs. EMMPRIN (CD147, basigin) is overexpressed in many tumor types, and has been shown to induce fibroblasts and endothelial cell expression of MMPs and VEGF. We first show that tumor cell interactions with macrophages resulted in increased expression of EMMPRIN and induction of MMP-9 and VEGF. Human A498 renal carcinoma or MCF-7 breast carcinoma cell lines were co-cultured with the U937 monocytic-like cell line in the presence of TNFα (1 ng/ml). Membranal EMMPRIN expression was increased in the co-cultures (by 3-4-folds, p < 0.01), as was the secretion of MMP-9 and VEGF (by 2-5-folds for both MMP-9 and VEGF, p < 0.01), relative to the single cultures with TNFα. Investigating the regulatory mechanisms, we show that EMMPRIN was post-translationally regulated by miR-146a, as no change was observed in the tumoral expression of EMMPRIN mRNA during co-culture, expression of miR-146a was increased and its neutralization by its antagomir inhibited EMMPRIN expression. The secretion of EMMPRIN was also enhanced (by 2-3-folds, p < 0.05, only in the A498 co-culture) via shedding off of the membranal protein by a serine protease that is yet to be identified, as demonstrated by the use of wide range protease inhibitors. Finally, soluble EMMPRIN enhanced monocytic secretion of MMP-9 and VEGF, as inhibition of its expression levels by neutralizing anti-EMMPRIN or siRNA in the tumor cells lead to subsequent decreased induction of these two pro-angiogenic proteins. These results reveal a mechanism whereby tumor cell-macrophage interactions promote angiogenesis via an EMMPRIN-mediated pathway.
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Affiliation(s)
- Bat-Chen Amit-Cohen
- Immunology Research Unit, Carmel Medical Center and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology Haifa, Israel
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Geyer SJ. CD147 immunohistochemistry discriminates between reactive mesothelial cells and malignant mesothelioma: an expanded analysis of the data. Diagn Cytopathol 2013; 42:734. [PMID: 23584926 DOI: 10.1002/dc.22985] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 02/14/2013] [Indexed: 01/06/2023]
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IMP3 and GLUT-1 Immunohistochemistry for Distinguishing Benign From Malignant Mesothelial Proliferations. Am J Surg Pathol 2013; 37:421-6. [DOI: 10.1097/pas.0b013e31826ab1c0] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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