Malignant Mesothelioma (eBook)

Copyright Page 5
Preface 6
Contents 8
1: Mineralogy of Asbestos 14
1.1 Introduction and Historical Background 14
1.2 Geologic and Mineralogic Features 15
1.3 Distribution and Physicochemical Properties of Chrysotile 17
1.4 Distribution and Physicochemical Properties of the Amphibole Species 20
1.5 Identification and Characterization of Asbestos 22
References 23
2: Epidemiology of Mesothelioma and Historical Background 25
References 35
3: Imaging of Mesothelioma 38
3.1 Introduction 38
3.2 Patterns of Presentation and Imaging Features 39
3.3 Preoperative Evaluation of MPM 40
3.4 Postoperative Evaluation 47
3.5 Unresectable Disease 47
3.6 Future Directions 49
3.7 Summary 52
References 52
4: Biopsy Techniques for the Diagnosis of Mesothelioma 55
4.1 Introduction 55
4.2 Clinical Presentation 56
4.3 Investigation of Pleural Effusion 56
4.3.1 Cytology 56
4.4 Investigation of Pleural Thickening with No Effusion 57
4.5 Percutaneous Pleural Biopsy Techniques 57
4.5.1 Abrams Needle 57
4.5.2 Radiologically Guided Percutaneous Pleural Biopsy 58
4.5.3 Positron Emission Tomography (PET) CT 59
4.6 Thoracoscopy 59
4.6.1 Local Anaesthetic Thoracoscopy 60
4.6.2 Video-Assisted Thoracoscopic Surgery 61
4.7 Open Biopsy 62
4.8 Prophylactic Radiotherapy 62
References 63
5: Pathohistological Diagnosis and Differential Diagnosis 66
5.1 Introduction 67
5.2 Malignant Mesothelioma of the Pleura 67
5.2.1 Morphology 67
5.2.1.1 Macroscopy and Tumour Spread 67
5.2.1.2 Histological Patterns 68
Epithelioid Mesothelioma 68
Sarcomatoid Mesothelioma 69
Biphasic Mesothelioma 69
Rare Forms of Mesothelioma 69
5.3 Differential Diagnosis of Malignant Mesothelioma and Pleural Metastases 70
5.3.1 Morphological Differences 70
5.3.2 Immunohistochemistry 71
5.3.2.1 Important Markers for Differential Diagnosis 71
Pancytokeratin 71
CK 5/6 71
Calretinin 72
WT-1 72
D2-40 72
TTF-1 73
BerEP4 73
MOC-31 73
BG8 73
Claudin 73
5.3.2.2 Conclusions Immunohistochemistry 73
5.4 Reactive Versus Neoplastic Mesothelial Proliferation 74
5.5 Primary Pleural Tumours Other than Malignant Mesothelioma 75
5.5.1 Peritoneal Mesothelioma 76
5.5.1.1 Pathohistological Diagnosis 76
Macroscopy 76
Microscopy 77
5.5.2 Malignant Mesothelioma of Tunica Vaginalis Testis 78
5.5.3 Well-Differentiated Papillary Mesothelioma 78
5.5.4 Prognosis and Predictive Factors 79
5.5.5 Differential Diagnosis 80
5.5.6 Benign Lesions 80
5.5.6.1 Benign Multicystic Peritoneal Mesothelioma 80
5.5.6.2 Adenomatoid Tumour 80
5.5.7 Malignant Lesions 81
5.5.7.1 Peritoneal Metastases 81
5.5.7.2 Carcinoma of Unknown Primary (CUP) 81
5.5.7.3 Primary Peritoneal Carcinoma 81
5.5.7.4 Primary Peritoneal Borderline Tumour 82
5.5.8 Immunohistochemistry 82
5.6 Primary Peritoneal Carcinoma/Metastases of Serous Ovarian Cancer Versus Malignant Peritoneal Mesothelioma 83
References 84
6: Mesothelioma and Analysis of Tissue Fiber Content 88
6.1 Introduction 89
6.2 Techniques for Analysis of Pulmonary Mineral-Fiber Content 91
6.2.1 Lung Tissue Digests 91
6.3 Methods for Mineral Fiber Analysis 92
6.3.1 Light Microscopy (LM) 92
6.3.2 Electron Microscopy 92
6.3.3 Comparability of Results Generated by Light or Electron Microscopy 93
6.3.4 Reference Population and Background Lung Asbestos Burden 93
6.3.5 Asbestos Bodies and Fiber Counting 93
6.4 Asbestos Lung Tissue Content in Patients with Mesothelioma 94
6.4.1 Light Microscopy 94
6.4.2 Electron Microscopy 95
6.4.3 Asbestos Content and Fiber Dimensions in Pleural Samples 95
6.5 Discussion 96
6.5.1 Asbestos Bodies and Fiber Burden of the Lung 96
6.5.2 Latency Period and Mean Age at Diagnosis of Mesothelioma 97
6.5.3 Clearance and Biopersistence of Asbestos Fibers 97
6.5.4 Carcinogenic Potency of Asbestos Fibers 98
6.5.5 Peritoneal Mesothelioma 98
6.5.6 Asbestos-Associated Mesothelioma and Other Possible Causes of Malignant Mesothelioma 98
6.5.7 Threshold or Cut-off Level 99
6.6 Conclusion 99
References 99
7: Surgical Therapy of Mesothelioma 105
7.1 Introduction 105
7.2 Natural History 106
7.3 Diagnosis 106
7.3.1 Video-Assisted Thoracoscopy 106
7.4 Staging 108
7.4.1 Laparoscopy 108
7.4.2 Mediastinoscopy 109
7.4.3 Thoracoscopy 110
7.4.4 Endoscopic Staging 110
7.5 Palliative Surgery 111
7.5.1 Pleural Drainage 111
7.5.2 Pleurectomy 111
7.6 Cytoreductive Surgery 113
7.6.1 Extrapleural Pneumonectomy (EPP) 113
7.6.1.1 Technique 113
7.6.1.2 Postoperative Care 117
7.6.1.3 Adjuvant Therapy 117
7.6.2 Pleurectomy/Decortication (P/D) 121
7.6.2.1 Technique 121
7.6.2.2 Postoperative Care 123
7.6.2.3 Adjuvant Therapy 123
7.6.3 Intrapleural Therapies 123
7.6.4 Extrapleural Pneumonectomy Versus Pleurectomy/Decortication 127
7.6.5 Does Cytoreductive Surgery Improve Survival? 128
7.7 Summary 129
References 129
8: Chemotherapy and Radiotherapy for Mesothelioma 134
8.1 Introduction 134
8.2 Radiotherapy 135
8.2.1 Radical Radiotherapy 135
8.2.1.1 Radical Radiotherapy as a Single Treatment 135
8.2.1.2 Radical Radiotherapy as Part of a Multimodal Treatment 135
Radiotherapy Following P/D 136
Radical Radiotherapy After EPP 136
Intensity Modulated Radiotherapy (IMRT) 138
8.2.2 Prophylactic Radiotherapy 139
8.3 Systemic Therapies for Malignant Pleural Mesothelioma 140
8.3.1 Systemic Chemotherapy 140
8.3.1.1 First Line Chemotherapy 140
8.3.1.2 Optimal Time to Start the Treatment and Duration of Chemotherapy 142
8.3.1.3 Second-Line Treatment 143
8.3.2 Targeted Therapies 145
8.3.2.1 Epidermal Growth Factor Receptor (EGFR) 145
8.3.2.2 Vascular Endothelial Growth Factor (VEGF) Inhibitors and Other Anti-angiogenic Drugs 146
8.3.2.3 Ribonuclease Inhibitors 147
8.3.2.4 Histone Deacetylase Inhibitors (HDACi) 147
8.3.3 Immunomodulators, Gene Therapy and Cell Therapy 148
8.3.3.1 Immunomodulators 148
8.3.3.2 Gene Therapy 148
8.3.3.3 Cell Therapy 148
8.4 Conclusion 149
References 149
9: Genetics and Molecular Biology of Mesothelioma 155
9.1 Apoptosis as a Tumor Suppressor Mechanism 155
9.2 Key Alterations in the Core Apoptosis Signaling in Mesothelioma 155
9.2.1 Regulation of the Intrinsic (Mitochondrial) Apoptosis Pathway in Mesothelioma 155
9.2.2 Extrinsic Apoptosis Pathway Regulation in Mesothelioma 158
9.2.3 Inhibitors of Apoptosis in Mesothelioma 158
9.3 Tumor Suppressor Loss in Mesothelioma 158
9.3.1 Loss of nf2 Is Frequent in Mesothelioma 158
9.3.2 NF2 Encodes the Tumor Suppressor Merlin 159
9.3.3 PLZF Is a Novel Tumor Suppressor in Mesothelioma 160
9.4 Therapeutic Inhibition of Survival Pathways 160
9.4.1 PI3K/AKT/mTOR Axis in Mesothelioma 160
9.4.2 HGF/cMET Pathway Is Activated in Mesothelioma 160
9.4.3 WNT Pathway Activation in Mesothelioma 161
9.4.4 Estrogen Receptor Beta 162
9.5 Therapeutic Reactivation of Tumor Suppressors 162
9.5.1 Epigenomic Dysregulation in Mesothelioma 162
9.5.2 Targeting the Mesothelioma Epigenome via Inhibition of Histone Deacetylases 163
9.5.3 Targeting the Ubiquitin Proteasome Pathway 164
9.6 Synthetic Lethal Strategies 164
9.7 Summary 165
References 165
10: Early Stages of Mesothelioma, Screening and Biomarkers 174
10.1 Early-Stage Malignant Mesothelioma, Including the Concept of Mesothelioma In Situ and the Distinction from Reactive Me 174
10.2 Biomarkers for Early-Stage Epithelioid Malignant Mesothelioma Versus Reactive Mesothelial Hyperplasia 179
10.2.1 Epithelial Membrane Antigen (EMA) 179
10.2.2 GLUT-1 180
10.2.3 Bcl-2 181
10.2.4 p53 181
10.2.5 X-Linked Inhibitor of Apoptosis Proteins (XIAP) 182
10.2.6 P-Glycoprotein (P-170) 182
10.2.7 Neural Cell Adhesion Molecules (NCAMs): CD56 182
10.3 Screening for Malignant Mesothelioma and Prognostic Biomarkers: Serum Levels of Soluble Mesothelin-Related Proteins ( 183
10.3.1 Introductory Remarks on Screening for Malignant Mesothelioma 183
10.3.2 Radiological Screening for MM 184
10.3.3 Soluble Mesothelin-Related Proteins (SMRPs) 184
10.3.4 Serum Osteopontin (OPN) Levels 186
10.3.5 Megakaryocyte Potentiating Factor (MKPF) 187
10.3.6 CA125 187
10.3.7 Summary 187
10.4 Aquaporins and Malignant Mesothelioma 188
References 190