CONTENTS 1. Embryology of the Lower Female Genital Tract ........................................................... 1 Cervix and Vagina ..................................................................................................... 1 Vulva .......................................................................................................................... 3 2. Anatomy of the Lower Female Genital Tract ............................................................... 7 Cervix ......................................................................................................................... 7 Gross Anatomy ....................................................................................................... 7 Lymphatic Drainage ............................................................................................... 7 Colposcopic Features and Microscopic Anatomy .................................................. 8 Squamous Epithelium ............................................................................................ 8 Endocervical Glandular Epithelium ....................................................................... 10 Transformation Zone .............................................................................................. 11 Vagina ........................................................................................................................ 16 Gross Anatomy ....................................................................................................... 16 Lymphatic Drainage ............................................................................................... 16 Microscopic Anatomy ............................................................................................ 16 Vulva .......................................................................................................................... 17 Gross Anatomy ....................................................................................................... 17 Lymphatic Drainage ............................................................................................... 18 Microscopic Anatomy ............................................................................................ 19 3. Human Papillomavirus: Biology and Clinical Importance .......................................... 23 Classification and Phylogeny .................................................................................... 23 Structure and General Organization of the Papillomavirus Genome .................... 23 Long-Controlling Region (LCR) ............................................................................. 24 Early Genes ............................................................................................................. 24 HPV Oncogenes: E6 and E7 .................................................................................... 25 The Putative Oncogene E5 ..................................................................................... 26 Late Genes .............................................................................................................. 27 In Vitro Models of HPV Infection .......................................................................... 27 HPV Life Cycle: General Aspects ............................................................................ 27 HPV Life Cycle: Productive (Vegetative) Infections ............................................... 28 HPV Life Cycle: Abortive Infections ....................................................................... 28 HPV Life Cycle: Latency ......................................................................................... 28 HPV Epidemiology..................................................................................................... 29 Oncogenic HPV Types Cause Cervical Cancer ....................................................... 29 Acquisition and Prevalence of HPV ....................................................................... 31 HPV Persistence and Progression ........................................................................... 32 xi Tumors of the Cervix, Vagina, and Vulva Progression of HPV Infection to CIN 3 and Cancer ............................................... 35 Epidemiology of Cervical Adenocarcinoma ........................................................... 35 HPV Immunology ...................................................................................................... 36 Evasion of Host Immune System ........................................................................... 36 Host Defenses: Squamous Epithelium .................................................................... 37 Host Defenses: Immunologic Responses ................................................................ 37 Human Leukocyte Antigens ................................................................................... 38 Subversion of Host Immunity ................................................................................ 39 Clinical Applications of HPV Testing ........................................................................ 39 Rationale for Clinical HPV Testing ......................................................................... 39 Clinical HPV Assays ................................................................................................ 39 The ASCUS/LSIL Triage Study (ALTS) ..................................................................... 40 HPV Testing for Management of Atypical Glandular Cells ................................... 45 HPV Testing for Quality Assurance of Cytologic Interpretations .......................... 46 HPV Testing for Primary Screening ........................................................................ 46 HPV Testing for Post-treatment Follow-up ............................................................ 47 HPV Vaccines ............................................................................................................. 48 Rationale for Developing HPV Vaccines ................................................................ 48 Prophylactic Vaccines ............................................................................................. 49 Therapeutic Vaccines .............................................................................................. 50 HPV Vaccine Research ............................................................................................ 51 4. Classification ................................................................................................................ 59 5. Tumors of the Cervix .................................................................................................... 67 Squamous Lesions ...................................................................................................... 67 Squamous Papilloma .............................................................................................. 67 Condyloma Acuminatum ....................................................................................... 67 Squamous Metaplasia ............................................................................................. 68 Transitional Metaplasia .......................................................................................... 73 Squamous Atypia .................................................................................................... 75 Squamous Intraepithelial Lesions .......................................................................... 79 Squamous Cell Carcinoma ..................................................................................... 105 Microinvasive Squamous Cell Carcinoma ............................................................. 105 Invasive Squamous Cell Carcinoma ....................................................................... 111 Verrucous Carcinoma ............................................................................................. 121 Warty (Condylomatous) Carcinoma ...................................................................... 123 Papillary Squamous Cell (Squamotransitional) Carcinoma ................................... 123 Lymphoepithelioma-Like Carcinoma .................................................................... 124 Glandular Lesions ...................................................................................................... 128 Endocervical Polyp ................................................................................................. 128 xii Contents Müllerian Papilloma ............................................................................................... 128 Tunnel Clusters ....................................................................................................... 128 Endocervical Glandular Hyperplasia ...................................................................... 128 Microglandular Hyperplasia ................................................................................... 128 Mesonephric Remnants .......................................................................................... 134 Mesonephric Hyperplasia ....................................................................................... 134 Arias-Stella Reaction ............................................................................................... 134 Endometriosis ......................................................................................................... 136 Tubal, Tuboendometrioid, and Endometrioid Metaplasias