ANGIOGENESIS, CYCLOOXYGENASE-2 AND MATRIX METALLOPROTEINASES IN MALIGNANT MESOTHELIOMA

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1 ANGIOGENESIS, CYCLOOXYGENASE-2 AND MATRIX METALLOPROTEINASES IN MALIGNANT MESOTHELIOMA A thesis presented for the degree of DOCTOR OF PHILOSOPHY at The University o f Leicester Mr. John G. Edwards M.B. Ch.B. F.R.C.S.(Glasg.) Department o f Oncology University o f Leicester October 2002

2 UMI Number: U All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U Published by ProQuest LLC Copyright in the Dissertation held by the Author. Microform Edition ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml

3 To Katherine, Eleanor and Aoife.

4 DECLARATION This thesis was composed by myself. The work of which it is record was planned and performed entirely by myself except for the specific instances quoted in the Acknowledgements or text, and was carried out between 1998 and All sources of information have been acknowledged and referenced. The tissue samples collected and used for this work were handled as surplus tissue under the terms of the report Human tissue: ethical and legal issues (Nuffield Council on Bioethics, London, 1995) which were the guidelines followed at the commencement of this project. This was with agreement of the chairman of the Local Ethical and Research Committee. Latterly, written patient consent was gained for prospective tissue collection on the hospital operation consent forms. The computerised database was registered according to the Data Protection Act and hardcopy data anonymised to protect patient confidentiality. There are no conflicts of interest regarding the financial support of this project. John G Edwards October 2002

5 Angiogenesis, Cyclooxygenase-2 and Matrix Metalloproteinases in Malignant Mesothelioma Mr. John G Edwards M.B. Ch.B. F.R.C.S.(Glasg.) Malignant Mesothelioma (MM) is a fatal tumour, related to prior asbestos exposure, of increasing incidence. Current treatment modalities may provide symptom palliation but survival benefits remain unclear. Angiogenesis is essential for tumour growth of greater than l-2mm in diameter and is stimulated by hypoxia, which is reflected by tumour necrosis (TN). Angiogenesis can be assessed by the intratumoural microvessel density (MVD). Cyclooxygenase(COX)-2 plays a central role in the upregulation of angiogenic growth factors, such as vascular endothelial growth factor and matrix metalloproteinases (MMPs). Epidermal Growth Factor Receptor (EGFR) is overexpressed in many solid tumours and participates both in COX-2 and MMP upregulation. These factors may be prognostic in solid tumours. A database of MM cases in Leicester from 1987 to 2001 was created. Clinical and pathological prognostic factors were derived. Angiogenesis, TN and EGFR were assessed in 171 MM cases by immunohistochemistry and/or microscopy. COX-2 and MMP expression were analysed prospectively by semi-quantitative Western blotting and gelatin zymography, respectively, in up to 47 snap-frozen samples. TN, COX-2 and MMPs were identified for the first time in MM. MVD, COX-2, and EGFR correlated with TN but not with each other. The prognostic significance of MVD and EGFR were confirmed in the largest series of MM studied. TN, COX-2 and MMP-2 were novel prognostic factors. MVD, TN, EGFR, COX-2 and MMP-2 each contributed both to the CALGB and EORTC prognostic scoring systems in multivariate analyses. In addition to establishing new laboratory methods and the prognostic importance of these factors, this work has identified novel targeted therapies for MM. These include antiangiogenic therapies, such as thalidomide, and COX-2, EGFR and MMP inhibition, all of which are now either under current or future investigation in clinical trials in Leicester and other international centres.

6 ACKNOWLEDGEMENTS I am indebted to Dr Ken O Byrne, as my supervisor for this project, for his support, advice and ever-present guidance. The miracles of modern communication meant his dulcet Irish tones were never far away. I will remain grateful to him for passing onto me much of his enthusiasm, and a little of his knowledge, at the start of my research career. Mr David Waller, Consultant Thoracic Surgeon at the Glenfield General Hospital, introduced me to Dr O Byme and gave me great encouragement at the periphery of the project, helping me develop some of the attributes of a surgical oncologist. This project took place in four different laboratories on three sites in Leicester. Professor Rosemary Walker, Dr Louise Jones and Sheila Dearing welcomed me into the Breast Cancer Research Unit. Dr Giles Cox led my way through the optimisation of immunohistochemical and microvessel counting techniques. Dr Salli Muller and Dr Cathy Richards were always available for expert histopathologial advice. Dr John McLaren, of the Department of Obstetrics and Gynaecology, taught me zymography. Dr Steve Faux, of the Pulmonary Toxicology Section at the MRC Toxicology Laboratories, supervised the COX-2 work with Dr Simon Plummer: I could not have got through the trial by COX-2 Western blot without the support of Paul, Jim, Bill, Babs, and Lynne. Kirsti Hill assisted me with the PGE2 EIA workup. Latterly, as the Thoracic Oncology Research Group flourished under Ken s leadership, Dr Daniel Swinson, Dr Donna Richardson, Dr Catherine Richardson and Allan Andi all helped me along the way. And my thoughts and prayers go to our patients, without whom this would never have happened. Such is the tragedy of mesothelioma that I made, followed and lost many great friends along the way. Their interest in my work has driven and will continue to drive my efforts to increase our understanding of the disease and return to them some hope. Financial support came from many sources: a Glenfield Hospital R&D Grant, the June Hancock Mesothelioma Research Fund, the Sir Samuel Scott of Yews Trust. Professor David Evans et al. listened intently to my plea and awarded me a Leicester Royal Infirmary Research Fellowship, which allowed me to complete the project, worrying no longer about the next round of grant applications. Finally, I owe everything to the support o f my wife, who has survived my absence at work and my absence at home. The never-quite-fulfilled promise of a holiday without my laptop has kept her focused for the last four years.

7 ABBREVIATIONS 3h t ALP ABC APS BCRU bfgf BSA CA CALGB camp CD CEA Cl cm CMHT CMI COX CSF CT CXR DAB dl DNA tritiated-thymidine alkaline phosphatase Streptavidin-biotin complex ammonium persulphate Breast Cancer Research Unit basic fibroblast growth factor bovine serum albumin carbonic anhydrase Cancer and Leukemia Group B cyclic adenosine monophosphate cluster of differentiation antigen carcino-embryonic antigen confidence interval centimetre Centre for Mechanisms of Human Toxicity, University of Leicester cell-mediated immunity cyclooxygenase colony-stimulating factor computed tomography chest X-ray diaminobenzidine tetrachloride decilitre deoxyribonucleic acid

8 d-pas DTPA DTT ECL ECM ECOG EDTA EGF EIA EORTC EPP FDG FFPE FITC FN g GFR GGH GP Gy H&E H20 HA HAB Hb diastase-periodic acid-schiff diethylenetriamine penta-acetic acid Dithiothreitol enhanced chemiluminescence extracellular matrix Eastern Co-operative Oncology Group ethylenediaminetetraacetic acid epidermal growth factor enzyme immunoassay European Organisation for Research and Treatment of Cancer extrapleural pneumonectomy fluorodeoxyglucose formalin-fixed, paraffin-embedded fluoroscein isothiocyanate fibronectin gram growth factor receptor Glenfield General Hospital, Leicester general practitioner Grays haematoxylin and eosin water hyaluronic acid hyaluronidase-alcian blue Haemoglobin

9 HGF/SF HI HIF HMC HR HSV-tk ICRF IFN Ig IGF IGF-IR IL IMIG IMRT IMS IP IRS kda hepatocyte growth factor/scatter factor humoural immunity hypoxia inducible factor human mesothelial cells hazard ratio Herpes simplex virus-thymidine kinase Imperial Cancer Research Fund interferon immunoglobulin insulin-like growth factor insulin-like growth factor-i receptor interleukin International Mesothelioma Interest Group intensity-modulated radiotherapy industrial methylated spirit inflamed pleura insulin receptor substrate kilodaltons 1 litre LAK LDH LPF M ma pg lymphokine activated killer lactate dehydrogenase low power field Molar milliamps microgram

10 pi mg MHC ml MM mm mm MMP MMPI MoAb MRI MT-MMP MVD NFKB NK NGS NRS NSCLC O+G microlitre milligram major histocompatability complex millilitre malignant mesothelioma millimetre millimolar matrix metalloproteinase matrix metalloproteinase inhibitor monoclonal antibody magnetic resonance imaging membrane-type matrix metalloproteinase microvessel density nuclear-factor-kb natural killer normal goat serum normal rabbit serum non-small cell lung cancer Department of Obstetrics and Gynaecology, University of Leicester C degrees centigrade OD 595 P/D PAGE PAI-1 PBS optical density at, e.g., 595nm radical pleurectomy and decortication polyacrylamide gel electrophoresis plasminogen activator inhibitor-1 phosphate buffered saline

11 PD-ECGF PDGF PDT PET PF PG PMSF PolyAb PRL PS Rb RNA RT SD SDS platelet-derived endothelial cell growth factor platelet-derived growth factor photodynamic therapy positron emission tomography platelet factor prostaglandin phenylmethylsulphonyl fluoride polyclonal antibody prolactin performance status retinoblastoma ribonucleic acid room temperature standard deviation sodium dodecyl sulphate SV40 Simian virus 40 Tag tag TBS large-t antigen small-t antigen tris-buffered saline TBST tris-buffered saline with Tween 20 TCR TEMED TGF Th TIMP T-cell receptor N,N,N,N -tetramethylenediamine transforming growth factor T-helper tissue inhibitor of metalloproteinase

12 TN TNF TNM tpa TSP UICC UK UP upa upar USA V VATS VEGF WBC wt tumour necrosis tumour necrosis factor tumour-nodes-metastasis tissue plasminogen inhibitor thrombospondin International Union Against Cancer United Kingdom uniflamed pleura urokinase plasminogen activator urokinase plasminogen activator receptor United States of America volts video assisted thoracoscopic surgery vascular endothelial growth factor white blood cell count wild type ix

13 LIST OF CONTENTS DECLARATION ABSTRACT ACKNOWLEDGEMENTS ABBREVIATIONS LIST OF CONTENTS LIST OF TABLES LIST OF FIGURES i ii iii iv x xvii xx CHAPTER ONE INTRODUCTION BACKGROUND Epidemiology Clinical features Histopathological features CURRENT MANAGEMENT OF MALIGNANT MESOTHELIOMA Staging TNM staging Prognostic factors Surgery Diagnostic and pall iative surgery Radical surgery Chemotherapy Radiotherapy Multimodality therapy MOLECULAR BIOLOGY OF MALIGNANT MESOTHELIOMA Angiogenesis Hypoxia and necrosis Growth factors and growth factor receptors Extracellular matrix proteinases Matrix metalloproteinases MMPs and angiogenesis Fibrinolytic enzymes Hyaluronic acid Cyclooxygenase Angiostatic factors Simian Virus 40, p53 and apoptosis SV p Apoptosis 33 x

14 Immune responses Cytokine response to asbestos inhalation Cell mediated and humoral immunity in MM NOVEL THERAPIES FOR MALIGNANT MESOTHELIOMA Immunotherapy Photodynamic therapy Gene therapy Anti-angiogenesis therapy CONCLUSIONS AIMS OF THE STUDY 44 CHAPTER TWO MATERIALS AND METHODS MATERIALS General chemicals and reagents Primary antibodies Secondary antibodies Standards Kits Buffers PATIENTS Case selection and data collection Data validation METHODS Paraffin-embedded blocks Block selection Processing offormalin-fixed paraffin-embedded blocks Microtomy Snap-frozen tissue blocks Collection Microtomy Acetone fixation Immunohistochemistry Dewaxing of FFPE slides Antigen retrieval - pressure cooking A ntigen retrieval - trypsin digestion Immunohistochemical methods Light Microscopy Assessment o f angiogenesis Assessment o f necrosis A ssessment o f EGFR immunohistochem istry 58 xi

15 Laser scanning confocal microscopy Snap-frozen sample homogenisation Buffers Homogenisation technique Bradford protein assays Standard Brafford assay Bradford microassay Western blotting Gel preparation Sample and standard preparation Electrophoresis Electroblotting Processing of nitrocellulose membrane Enhanced chemiluminescence exposure Western blot densitometry Nitrocellulose stripping and reprobing Enzyme immunoassay Gelatin zymography Gelatin zymogram band densitometry STATISTICAL METHODS Survival analysis Assessment of immunohistochemistry, necrosis scores and angiogenesis Correlations between clinicopathological and prognostic factors REAGENTS General Immunohistochemistry Snap-frozen sample homogenisation Western blotting Gelatinase zymography 73 CHAPTER THREE PROGNOSTIC FACTORS INTRODUCTION AIMS METHODS Data collection Statistical analysis EORTC and CALGB prognostic groups RESULTS Data validation Demographic and diagnostic data 78 xii

16 Survival Prognostic factors - univariate analysis Prognostic factors - multivariate analysis EORTC and CALGB prognostic groups DISCUSSION EORTC and CALGB prognostic groups CONCLUSIONS 84 CHAPTER FOUR ASSESSMENT OF ANGIOGENESIS INTRODUCTION AIMS METHODS Patients Anti-CD34 immunohistochemistry Microvessel quantification Anti-CD31 immunohistochemistry Statistical analysis RESULTS Immunohistochemistry and microvessel quantification Correlations with clinical and pathological factors Survival - univariate analysis Survival - multivariate analysis Inter-and intra-observer variation Assessment of anti-cd31 immunohistochemistry DISCUSSION CONCLUSIONS 98 CHAPTER FIVE TUMOUR NECROSIS INTRODUCTION AIMS METHODS Necrosis assessment Statistical analysis RESULTS Tumour necrosis scores Correlation with clinicopathological factors and angiogenesis Survival Multivariate analysis DISCUSSION CONCLUSIONS 107 xiii

17 CHAPTER SIX EPIDERMAL GROWTH FACTOR RECEPTOR INTRODUCTION AIMS METHODS Immunohistochemistry Interpretation Statistical analysis RESULTS Immunohistochemistry Correlation with clinicopathological and biological factors Survival Multivariate analysis DISCUSSION CONCLUSIONS 117 CHAPTER SEVEN CYCLOOXYGENASE INTRODUCTION AIMS METHODS Immunohistochemistry Western blotting Method Method Method Method Method Method Western blot densitometry Method Method Method Bicyclo-PGE2 enzyme immunoassay Statistical analysis RESULTS Immunohistochemistry Western blotting Method Method Method3 125 xiv

18 Method Method Method Method Method Method Correlation with clinicopathological variables Survival - univariate analysis Survival - multivariate analysis Survival - a -tubulin PGE2 enzyme immunoassay DISCUSSION CONCLUSIONS 135 CHAPTER EIGHT MATRIX METALLOPROTEINASES INTRODUCTION AIMS METHODS Method Experiment Experiment Method Method Method Statistical analysis RESULTS Method Experiment Experiment Correlation with clinicopathological factors Survival Multivariate analysis Method Method Method DISCUSSION CONCLUSIONS 148 CHAPTER NINE CONCLUDING REMARKS 149 XV

19 APPENDIX I PUBLICATIONS 156 APPENDIX II SELECTED PRESENTATIONS 159 REFERENCES 164 xvi

20 LIST OF TABLES The International Mesothelioma Interest Group TNM staging system The Brigham staging system for MM Matrix Metalloproteinase family members Anti-angiogenesis therapies under investigation in MM Case note retrieval fields Snap-frozen samples Streptavidin-ABC immunohistochemistry technique Primary antibodies used for immunohistochemistry and their conditions Immunofluorescence technique Primary antibodies which may be used for microvessel immunohistochemistry EORTC Prognostic Scoring System for Malignant Mesothelioma Type of operation performed Immunohistochemical stains used to aid diagnosis Overall survival rates for the patients in the study Univariate log rank and Cox regression analysis of categorical variables Univariate Cox regression analysis of continuous variables Associations between the type of surgery performed and outcome Cox multivariate regression analysis Prognostic significance of EORTC and CALGB groups Survival of patients in the Leicester series compared to the EORTC series Survival of patients in the Leicester series compared to the CALGB series Comparison of published series with multivariate analyses of prognostic factors Published reports of assessment of MVD in MM Correlations between the MVD and categorical variables 86 90

21 Correlations between the MVD and continuous variables Univariate log rank and Cox regression analysis of angiogenesis Cox multivariate regression analysis Cox multivariate regression analysis with CALGB or EORTC groups Inter- and intra-observer variation Level of agreement between the two observers scoring for TN Correlations between TN and categorical variables Correlations between TN and continuous variables Univariate log rank and Cox regression analysis of TN Cox multivariate regression analysis Cox multivariate regression analysis with CALGB or EORTC groups Distribution EGFR immunostaining Correlations between EGFR and categorical variables Correlations between EGFR and continuous variables Univariate log rank and Cox regression analysis of EGFR Cox multivariate regression analysis Multivariate analysis of EGFR with CALGB or EORTC groups Contingency table of unadjusted versus adjusted COX-2 Contingency table of COX-2 versus COX-2 :Tubulin ratio Correlation between COX-2 expression and categorical variables Correlations of COX-2 expression and continuous variables Correlation between a -Tubulin expression and categorical variables Correlations of a -Tubulin expression and continuous variables Univariate log rank and Cox regression analysis of COX-2 expression Univariate log rank and Cox regression analysis of categorical variables Multivariate analysis of COX-2 with CALGB or EORTC groups

22 Table 7.10 Univariate log rank and Cox regression analysis of a -tubulin expression 129 Table 7.11 Multivariate analysis of a -Tubulin with CALGB or EORTC groups 129 Table 7.12 Multivariate analysis of COX-2 and a -tubulin expression 129 Table 8.1 Zymogram densitometry values in MM and benign pleura 140 Table 8.2 Correlation between MMP-2 and MMP-9 and clinicopathological variables 141 Table 8.3 Correlation between MMP-2 and MMP-9 and biological variables 141 Table 9.1 Biological prognostic factors in MM 154 xix

23 LIST OF FIGURES Contrast-enhanced Magnetic resonance imaging in MM Video-assisted thoracoscopic surgery in MM - assessment and decortication Arachidonic acid and cyclooxygenase pathways Cytokine responses of macrophages and mesothelial cells to asbestos Comparison of Bradford Standard assay and Microassay 60 Flowchart showing the derivation of the CALGB Prognostic Groups Kaplan-Meier plot - weight loss, chest pain, performance status, platelet count Kaplan-Meier plots - cell type Kaplan-Meier plot - surgical procedure performed Kaplan-Meier plot - EORTC prognostic groups Kaplan-Meier plots - CALGB prognostic groups Photomicrograph of stromal anti-cd34 immunostaining Photomicrographs of tumour sections with a high and low MVD Boxplot showing the distributions of MVD by cell type Scatterplot showing the correlation between MVD and platelet count Kaplan-Meier plot - MVD Variation in the MVD obtained between two observers Comparison between anti-cd34 and anti-cd31 immunohistochemistry Grades of TN of haematoxylin and eosin stained tumour sections Correlation between angiogenesis and tumour necrosis Kaplan-Meier plot - presence of TN Kaplan-Meier plot - grades of TN Kaplan-Meier plot - presence of TN, in epithelioid cases only

24 EGFR immunohistochemistry Kaplan-Meier - EGFR expression I ll 112 Cyclooxygenase-2 immunohistochemistry Early western blot photograph Photographic comparison between PG27B and SC-1745 primary antibodies COX-2 and a-tubulin Western blot photographs COX-2 time course collection Western blot Densitometry values - serial dilution study The effects of the blocking peptide on the COX-2 band densitometry Correlation between results using the PB27B and SC-1745 primary antibodies Relationship between unadjusted and adjusted COX-2 densitometry values Relationship between COX-2 and a-tubulin densitometry values Correlation between COX-2 and a -Tubulin Boxplot - COX-2 according to presence of TN Boxplot - a -Tubulin according to cell type Kaplan-Meier plot - COX-2 Kaplan-Meier plots - COX-2 (Oxford antibody vs. Santa-Cruz antibody) Kaplan-Meier plot - a -tubulin Kaplan-Meier plot - COX-2 and/or a-tubulin Gelatin zymogram Boxplots - differences in MMP activity between MM, uninflamed and inflamed pleura Correlation between adjusted and unadjusted MMP values Scatterplot - total MMP-2 vs. survival Kaplan-Meier plot - total MMP-2 Densitometry values - variation between gels run on different occasions Densitometry values - variation within and between gels run simultaneously Densitometry values - serial dilution study Carbonic Anhydrase-IX immunohistochemistry xxi

25 C hapter 1 Introduction Chapter One Introduction i

26 C hapter 1 Introduction 1.1. Background Malignant Mesothelioma (MM) is an aggressive tumour with a poor prognosis. MM most commonly involves the pleura and is usually associated with asbestos exposure. MM responds poorly to conventional modes of therapy, including surgery, chemotherapy and radiotherapy. A number of small-scale trials of these conventional treatments have been published, but no real impact on survival has been made. Given the poor prognosis in MM and other solid tumours, research has focused on the development of new treatment modalities, such as immunotherapy, gene therapy, photodynamic therapy and antiangiogenesis therapy. Developments in our understanding of the molecular biology of MM are expected to continue to lead to novel treatment strategies Epidemiology Until recently, MM was considered to be a rare tumour. In 1960, an association was noted in South Africa between occupational or environmental exposure to asbestos, particularly the crocidolite asbestos fibre, and MM (Wagner 1993). This observation subsequently was confirmed in several other studies. The usual duration of exposure to asbestos may vary from a few months to many years. During that time there is usually a period of intense exposure to asbestos fibres. A history of asbestos exposure is given in about 80% of cases of MM (Aisner 1995). More recently, exposure to Simian Virus 40 (SV40) has also been postulated as an aetiological factor. Contaminated polio and adenovirus vaccines exposed a portion of the population to SV40 between 1955 and 1963 (Carbone et al. 1997a). The role of SV40 in the pathogenesis of MM will be considered further later. Evidence of a genetic susceptibility to MM has been reported (Roushdy-Hammady 2

27 Chapter 1 Introduction et al 2001) amongst Turkish villagers exposed to the carcinogenic zeolite fibre, erionite, which is found in the stone used for house construction there. The incidence of MM in the villages of Karain and Tuzkoy is approximately 50%. MM was associated with houses of death, which did not have a greater amount of erionite but whose residents were closely related. Genetic pedigree analysis has suggested that, in this setting, susceptibility to MM is transmitted genetically, possibly in an autosomal dominant manner reported (Roushdy- Hammady et al 2001). The UK Health and Safety Executive have kept a register of deaths where mesothelioma was mentioned on the death certificate since Annual deaths have risen from 154 in 1968 to 1527 in There is a long latent period between the first exposure to asbestos and onset of symptoms: this is usually greater than twenty years and frequently more than forty years. Taking into account the likely exposure of the population to asbestos, judged historically by the importation and industrial use of asbestos, the incidence of MM is expected to rise well into the next century. It has been estimated that there may be a peak of over 3000 deaths per year at about 2020 (Peto et al 1999). For the cohort of men bom in the UK in the 1940's, MM may account for approximately 1% of all deaths (Peto et al 1995) Clinical Features The most common primary site is the pleura, although MM can also occur in the peritoneum (Corson 1997). MM is characterised by extensive primary growth and invasion into intrathoracic tissues and organs. Eventually the pleura may be replaced with a thick "rind" of tumour, which constricts lung expansion. Symptoms of dyspnoea occur in 80%, cough in 60% and chest pain in 40% of patients. There may be other symptoms such as

28 Chapter 1 Introduction weight loss or an abdominal mass. Respiratory examination reveals reduced breath sounds and a dull percussion note over the area of the tumour. A mass may be palpable in the abdomen or in intercostal spaces. Distant metastasis occurs late in the course of the disease, but haematogenous spread is present in about 50% of patients at the time of death. Nodal metastasis is seen in about 40% of patients who undergo radical surgery in the form of extrapleural pneumonectomy. Death is usually due to the local invasion by the primary tumour. Cytological analysis o f aspirated pleural fluid may suggest a diagnosis of MM, but this alone is rarely diagnostic. Closed (percutaneous) biopsy may be inadequate due to poor tissue sampling, whereas Video Assisted Thoracoscopic Surgery (VATS) not only produces an adequate tissue sample but usually allows a full intrathoracic assessment of the tumour (Sugarbaker et al. 1997) Histopathologcial features There are three main cellular types of MM. Epithelioid cell (epithelial, carcinomatous) MM is the most common, accounting for approximately 50% of cases. Cells may be in tubular, papillary or solid forms. Biphasic (mixed cell) MM consists of sarcomatoid and epithelioid cell elements and is the pattern in a third of cases. Sarcomatoid (sarcomatous) MM, in which the cells may display one or more of a variety of connective tissue phenotypes, accounts for the remainder. Most commonly, sarcomatoid MM consists of spindle-shaped cells, although it may be difficult to distinguish the desmoplastic variant of sarcomatoid MM from florid fibrous proliferations and even osseous differentiation can occur. There is a high proliferation rate, suggested by a high mitotic index, staining for nuclear antigens and the pattern of nucleolar organisation (Attanoos and Gibbs 1997). 4

29 Chapter 1 Introduction The difficulty in distinguishing between MM and its differential diagnoses, in particular adenocarcinoma, may be overcome using histochemistry, immunohistochemistry, electron microscopy, or cytogenetic techniques (Corson 1997; Attanoos and Gibbs 1997). Positivity for histochemical stains such as diastase-periodic acid-schiff (d-pas) is found in approximately 5% of cases of MM, whereas it is positive in 50-60% of adenocarcinomata. Hyaluronidase-alcian blue (HAB) is very specific for adenocarcinoma. The pattern of keratin staining in epithelial MM is diffuse and perinuclear, whereas it is peripheral and membrane bound in adenocarcinoma. Carcino-embryonic antigen (CEA) is positive in only 10% of MM and it is usually weakly so and focal. It is positive in 93% of lung adenocarcinomata and 84% of metastatic adenocarcinomata from other primary tumours. CEA is often used initially to help exclude MM. Similarly, Leu-Ml, B72.3 Sialyl-TN, CD 15 and Ber-EP4 are rarely positive in MM but usually so in adenocarcinoma (Dejmek et al. 1997). The differential expression of cadherins has recently been described. N- Cadherin appears sensitive and specific for mesothelioma, whereas E-Cadherin is so for adenocarcinoma (Peralta Soler et al. 1995). Calretinin positivity has been proposed recently as specific for MM rather than adenocarcinoma (Cury et al. 2000). Electron microscopy may be useful in differentiating epithelial MM and adenocarcinomata, or sarcomatoid MM and sarcomas. For example, the length to diameter ratio of microvilli may aid the identification of epithelial MM (Bums et al. 1985). There are a number of chromosomal deletions which may be present in MM (Fletcher 1995). For example, deletion of the short arms of chromosome 1 or 3, or the long arm of chromosome 22, are common. Deletions of the long arm of chromosome 6 or the short arm of chromosome 9 are less common. These deletions are similar to those found in 5

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