Uterine Fibroids and Adenomyosis (Comprehensive Gynecology and Obstetrics)

This volume elucidates state-of-the-art findings of uterine fibroids and adenomyosis, incorporating expert basic knowledge. Uterine fibroids and adenomyosis are common uterine tumors in reproductive-age women. However, the pathogenesis of the tumors is still poorly understood, and both genetic and environmental factors may be involved in their generation or development. Recent research on the genomics and molecular biology of uterine fibroids and adenomyosis has facilitated a better understanding of the pathogenesis and pathophysiology of these benign tumors. Renowned experts provide detailed discussions of basic research and clinical aspects of uterine fibroids and adenomyosis in this book, from histopathology and molecular pathogenesis to diagnosis and the latest treatment of uterine fibroids, including pregnancy complications of adenomyosis. A great deal of information and a deep understanding of molecular and genetic biology have led to development of more innovative treatments of these tumors. Thus this book benefits not only oncologists, seasoned gynecologists, and obstetricians, but also molecular biologists and other basic researchers who are involved in the treatment of uterine fibroids. Preface 6 Contents 7 1: Histopathology of Uterine Leiomyoma 8 1.1 Introduction 8 1.2 General Aspects and Clinical Features 9 1.3 Pathological Features 10 1.3.1 Gross Features 10 1.3.2 Microscopic Features 12 1.3.2.1 Cellular Leiomyoma 12 1.3.2.2 Leiomyoma with Bizarre Nuclei 12 1.3.2.3 Mitotically Active Leiomyoma 16 1.3.2.4 Hydropic Leiomyoma 16 1.3.2.5 Apoplectic Leiomyoma 17 1.3.2.6 Lipomatous Leiomyoma (Lipoleiomyoma) 17 1.3.2.7 Epithelioid Leiomyoma 18 1.3.2.8 Myxoid Leiomyoma 18 1.3.2.9 Dissecting (Cotyledonoid) Leiomyoma (“Sternberg Tumor”) 20 1.3.2.10 Diffuse Leiomyomatosis 20 1.3.2.11 Intravenous Leiomyomatosis 20 1.3.2.12 Metastasizing Leiomyoma 23 1.3.3 Differential Diagnosis 24 1.4 Hereditary Leiomyomatosis and Renal Cancer Syndrome (HLRCC) 25 1.5 Extrauterine Leioyomatosis 25 1.6 Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP) 25 1.7 Prognosis and Predictive Factors 26 References 27 2: Genetics and Genomics of Uterine Fibroids 29 2.1 Introduction 30 2.2 Genetic Backgrounds 30 2.3 Clonality 31 2.4 Genome-Wide Association Study 31 2.5 Chromosomal Rearrangements 31 2.6 Syndrome-Associated Fibroids 32 2.7 Genetic Driver Alterations of Uterine Fibroids 33 2.7.1 MED12 Mutations 33 2.7.2 HMGA2 Overexpression 34 2.7.3 Biallelic FH Inactivation 35 2.7.4 Alterations of COL4A5 and COL4A6 35 2.8 Role of MicroRNAs in the Pathogenesis of Uterine Fibroids 36 References 37 3: Molecular Pathogenesis of Uterine Fibroids 42 3.1 Origin of Uterine Fibroid and the Importance of Molecular Pathogenesis 42 3.2 Genetic Features 43 3.2.1 High-Mobility Group AT-Hook 2 and Mediator Complex Subunit 12 43 3.3 Molecular Mechanism of Development of Uterine Fibroid 44 3.3.1 Estrogen 44 3.3.2 Progestogen 46 3.3.3 Hypoxia 47 3.4 Growth Factor 49 3.4.1 Transforming Growth Factor-β 49 3.4.2 Insulin-Like Growth Factor 50 3.4.3 Epidermal Growth Factor 51 3.4.4 Heparin-Binding Epidermal Growth Factor 51 3.4.5 Vascular Endothelial Growth Factor 51 3.4.6 Basic Fibroblast Growth Factor 52 3.4.7 Platelet-Derived Growth Factor 52 3.5 Wnt-β Catenin 53 References 54 4: Stem Cells and Uterine Fibroids 63 4.1 Introduction 64 4.2 Leiomyoma Stem Cells 66 4.3 Paracrine Sex Steroid Action on Leiomyoma Stem Cells 67 4.4 Challenges and Future Directions 68 References 69 5: Epigenetics and Uterine Fibroids 72 5.1 Introduction 73 5.2 Epigenetics 73 5.2.1 DNA Methylation 73 5.2.2 Histone Modifications 74 5.2.3 Noncoding RNAs 74 5.3 Aberrant DNA Methylation in Uterine Fibroids 75 5.3.1 Aberrant Expression of DNA Methyltransferases (DNMTs) 75 5.3.2 Genome-Wide DNA Methylation Profiles of Uterine Fibroids 75 5.3.3 Aberrantly Methylated Genes in Uterine Fibroids 77 5.3.4 Aberrantly Enriched DNA Hypomethylation in X Chromosome in Uterine Fibroids 78 5.3.5 Estrogen Receptor Alpha and Its Target Genes 78 5.4 Noncoding RNAs and Uterine Fibroids 80 5.4.1 Aberrantly Expressed MicroRNAs in Uterine Fibroids 80 5.4.2 Steroid Hormone and MicroRNAs in Uterine Fibroids 83 5.4.3 Chromosomal Abnormality and Deletion of MicroRNAs 83 5.4.4 Racial Differences in MicroRNA Expression in Uterine Fibroids 83 5.4.5 Long Noncoding RNAs and Uterine Fibroids 84 References 85 6: Biomarkers of Uterine Fibroids 89 6.1 Introduction 90 6.2 Pathological Diagnostic Markers of Uterine Leiomyomas 91 6.2.1 Cytogenetic Aberrations in Uterine Leiomyomas 91 6.2.2 Transcriptomes of Uterine Leiomyomas 92 6.2.3 MicroRNA Expression in Uterine Leiomyomas 92 6.2.4 Protein Expression (Proteome) in Uterine Leiomyomas 92 6.2.5 Leiomyoma-Specific Aberrant Genes Identified Using DNA Methylome and Transcriptome 94 6.2.6 Somatic Mutations of the MED12 Gene in Uterine Leiomyomas 94 6.2.7 Other Genomic Alterations in Uterine Leiomyomas 95 6.3 Differential Diagnostic Markers to Differentiate Uterine Leiomyomas and Uterine Leiomyosarcomas 95 6.3.1 Genomic Mutations in Uterine Leiomyosarcomas 96 6.3.2 MicroRNA Expression in Uterine Leiomyomas and Leiomyosarcomas 97 6.3.3 Omics Analysis Using Genomic, Epigenomic, and Transcriptomic Profiling in Uterine Leiomyomas and Leiomyosarcomas 97 6.3.4 Immunohistochemical Staining in Uterine Leiomyomas and Leiomyosarcomas 97 6.3.5 Leiomyoma-Specific Marker Genes Based on DNA Methylation 98 6.4 Concluding Remarks 99 References 102 7: Current Medical Treatments for Uterine Fibroids 105 7.1 Introduction 105 7.2 GnRH Agonist 106 7.3 GnRH Antagonist 107 7.4 Aromatase Inhibitor 107 7.5 Levonorgestrel Intrauterine System 107 7.6 Selective Progesterone Receptor Modulators 108 References 110 8: Diagnostic Imaging for Uterine Fibroids, Adenomyosis, and Uterine Sarcomas 112 8.1 Selection of Imaging Modalities 113 8.2 Uterine Leiomyoma 113 8.2.1 Usual Leiomyoma 113 8.2.2 Variation of Morphological Features 116 8.2.3 Uterine Peristalsis and Leiomyoma 118 8.3 Uterine Sarcomas 119 8.3.1 Leiomyosarcoma 119 8.3.2 Endometrial Stromal Sarcoma (ESS) 119 8.3.3 Differentiation Between Degenerated Leiomyoma and Various Sarcomas 120 8.4 Adenomyosis 122 8.4.1 Imaging Findings of Adenomyosis 122 8.4.2 Pseudolesions 124 8.4.3 Unusual Growth Patterns of Adenomyosis 124 References 125 9: Role of Epithelial-Mesenchymal Transition in Human Adenomyosis: A New Insight into Its Pathogenesis 130 9.1 Introduction 131 9.2 Biological Differences Between Functionalis and Basalis Endometria 133 9.3 Stress Reaction at the Endo-myometrial Interface 133 9.4 Effect of HGF on Basal EECs and E-Cadherin/ N-Cadherin Expression 134 9.5 Expression of HGF, E-Cadherin/N-Cadherin in Functionalis and Basalis Endometria 134 9.6 Tissue Concentration of HGF at the Endo-myometrial Junction 135 9.7 Effect of HGF/Estrogen on Changes in Cell Morphology and Cell Migration 136 9.8 Effect of HGF and E2 on SLUG and SNAIL Expression in Ishikawa Cells 136 9.9 Expression of E-Cadherin and SLUG/SNAIL in Functionalis and Basalis Endometria 137 9.10 Summary and Perspective 137 References 139 10: Adenomyosis and Subfertility 142 10.1 Introduction 142 10.2 The Presence of Adenomyosis Is Associated with Infertility 143 10.3 Adenomyosis Is Also Linked to Perinatal Complication 144 10.4 Possible Mechanisms of Adenomyosis-Related Infertility 145 10.5 Medical and Surgical Treatment for Adenomyosis-­Associated Infertility 146 References 148 11: Surgical Treatments for Adenomyosis 151 11.1 Introduction 152 11.1.1 Surgical Indication of LA 152 11.1.2 Two Types of LA Methods and Criteria for Selection 153 11.2 Surgical Procedure 155 11.2.1 Wedge Resection (WR) 155 11.2.2 Double Flap Method: (DF) 155 11.3 Patient Characteristics 156 11.4 Result 157 11.4.1 Operative Findings and Outcome 157 11.4.2 The Change of Symptoms 157 11.4.3 The Outcome of Second-Look Laparoscopy (SLL) 158 11.4.4 Postoperative Pregnancy Rate and Cumulative Pregnancy Rate 159 11.4.5 Outcome of Pregnancy and Delivery 159 11.5 Discussion 160 References 161 12: Pregnancy Complications in Women with Adenomyosis 163 12.1 Introduction 163 12.2 Adenomyosis and Fetal Loss 164 12.3 Adenomyosis and Preterm Delivery 165 12.4 Adenomyosis and Preeclampsia: Fetal Growth Restriction 167 12.5 Adenomyosis and Uterine Infection 168 12.6 Other Pregnancy Complications 168 12.7 Pretreatment for Adenomyosis and Pregnancy Complications 169 12.8 The Type of Adenomyosis and Pregnancy Complications 170 12.9 Challenges and Future Directions 170 References 171 Front Matter ....Pages i-vii Histopathology of Uterine Leiomyoma (Yoshiki Mikami)....Pages 1-21 Genetics and Genomics of Uterine Fibroids (Hiroshi Ishikawa, Makio Shozu)....Pages 23-35 Molecular Pathogenesis of Uterine Fibroids (Fuminori Kimura, Shunichiro Tsuji, Takashi Murakami)....Pages 37-57 Stem Cells and Uterine Fibroids (Masanori Ono, Tetsuo Maruyama, Hiroshi Fujiwara, Serdar E. Bulun)....Pages 59-67 Epigenetics and Uterine Fibroids (Ryo Maekawa, Norihiro Sugino)....Pages 69-85 Biomarkers of Uterine Fibroids (Shun Sato, Norihiro Sugino)....Pages 87-102 Current Medical Treatments for Uterine Fibroids (Izumi Kusuki, Jo Kitawaki)....Pages 103-109 Diagnostic Imaging for Uterine Fibroids, Adenomyosis, and Uterine Sarcomas (Aki Kido)....Pages 111-128 Role of Epithelial-Mesenchymal Transition in Human Adenomyosis: A New Insight into Its Pathogenesis (Khaleque N. Khan)....Pages 129-140 Adenomyosis and Subfertility (Yasushi Hirota, Yutaka Osuga)....Pages 141-149 Surgical Treatments for Adenomyosis (Mari Kitade, Makoto Jinushi, Shinichiro Ikuma, Keisuke Murakami, Rie Ozaki, Ayako Masuda et al.)....Pages 151-162 Pregnancy Complications in Women with Adenomyosis (Hiroshi Tamura, Norihiro Sugino)....Pages 163-173