Gisela Dallenbach-Hellweg Magnus von Knebel Doeberitz Marcus J.Trunk Color Atlas of Histopathology of the Cervix Uteri

Gisela Dallenbach-Hellweg Magnus von Knebel Doeberitz Marcus J. Trunk

Color Atlas of Histopathology of the Cervix Uteri

Gisela Dallenbach-Hellweg Magnus von Knebel Doeberitz Marcus J. Trunk

Color Atlas of

Histopathology of the Cervix Uteri

Second Edition

With 239 Figures and 4 Tables

Library of Congress Control Number: 2005926890

ISBN-10 3-540-25188-X Springer Berlin Heidelberg New York ISBN-13 978-3-540-25188-0 Springer Berlin Heidelberg New York 1st Edition ISBN-10 3-540-52295-6 Springer Berlin Heidelberg New York

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Editor: Gabriele Schröder, Heidelberg, Germany Desk Editor: Ellen Blasig, Heidelberg, Germany Production: ProEdit GmbH, 69126 Heidelberg, Germany Cover: Frido Steinen-Broo, EStudio Calamar, Spain Typesetting: K. Detzner, 67346 Speyer, Germany Printed on acid-free paper 24/3151 ML 5 4 3 2 1 0 Professor Dr. med.

Gisela Dallenbach-Hellweg Private address:

Ludolf-Krehl-Strasse 57 D-69120 Heidelbeg Tel. +49 -6221-471461

Professor Dr. med.

Magnus von Knebel Doeberitz Institute of Molecular Pathology University of Heidelberg Im Neuenheimer Feld 220 D-69120 Heidelberg

Email: knebel@med.uni-heidelberg.de &

mvkd@aol.com

Dr. med. Marcus J. Trunk Head of Pathology MTM Laboratories AG Im Neuenheimer Feld 583 D-69120 Heidelberg

Email: trunk@mtm-laboratories.com

The new edition of this atlas integrates all significant advances made in the past 15 years in molecular pathology, tumor virology, and genetics of cervical cancer. It emphasizes the importance of these advances in facilitating its pathological diagnosis and in opti- mizing clinical management and prognosis. A new chapter on immunohistochemistry has been added, which includes refined detection methods, e.g., the overexpression of p16

as a molecular marker in the early differential diagnosis of premalignant le- sions. The section on etiology and pathogenesis in human papillomavirus-induced neoplasia has been incorporated to represent new insights into the sequences of cellu- lar and nuclear deregulation at the molecular level. All chapters have been revised to in- clude the newest advances and relevant experiences in how to interpret and manage cervical disease; they are supported by the addition of 35 new microphotographic illus- trations. The tumor nomenclature is adapted to the latest edition of the WHO classifi- cation; the morphology code of the international classification of diseases for oncology (ICD-O) has been added. We have also updated the list of references by adding recent relevant publications.

Again, the staff of Springer-Verlag deserve our thanks for their patience and skill in preparing the manuscript and in reproducing the microphotographs.

Heidelberg, February 2005 Gisela Dallenbach-Hellweg, Magnus von Knebel Doeberitz, and Marcus J. Trunk

Heading2

Preface to the Second Edition

Heading2

Preface to the First Edition

During the past decade our understanding of the histopathology of the cervix uteri has changed greatly. Because of the lifestyles of the modern permissive society, cervical vi- ral infections have become epidemic, resulting in inflammatory and precancerous le- sions that were uncommon but now are seen mainly in the younger age groups with in- creasing frequency. Then too, progress in molecular biology and immunohistochemis- try has enabled us to distinguish subtypes of papilloma viruses, to proceed in under- standing their action within the genome, and to trace the infected metaplastic and neo- plastic-transformed cells to their histogenetic origins. The resultant refined classifica- tion of cervical neoplasias has helped to predict clinical outcome and to choose type of therapy.

This atlas is intended for all pathologists, to aid them in their routine diagnostic work. We hope it explains just how comprehensive, important and complex the histop- athology of the cervix uteri has become during the last few years. It covers all pertinent differential diagnostic aspects and describes in detail how to reach the correct diagno- sis. The atlas is also meant for the clinician, to guide him in his often difficult decision of how to provide optimal care for the frequently young patient, who desires children but is at risk for cancer. In particular, the atlas is designed to foster an improved dia- logue between the pathologist and the clinician.

The microphotographs were selected from our daily diagnostic material, since they show best the technical variations confronting the clinical pathologist in his daily rou- tine, where effects of specimen transport, differences in tissue fixation, and variations in embedding and staining often compound his diagnostic problems. The various shades of haematoxylin-eosin stains shown by our photographs reflect the differences we have experienced with our material as it comes in daily or is received as referral cas- es from clinics and institutes. We have not attempted to eliminate the deficiencies of these specimens, since the pathologist using this atlas is entitled to find realistic photo- graphs rather than idealistic ones. We want him to recognize a lesion irrespective of the quality of fixation or intensity of staining.

We express our gratitude to Prof. Dr. Frederick D. Dallenbach for the subtle English translation. We also extend our thanks to the staff of Springer-Verlag for their patience, generosity, and skill in preparing the manuscript and in reproducing our microphoto- graphs.

We find ourselves in an exciting period of molecular biology, during which rapid de-

velopments in diagnostic techniques and concepts are clarifying relationships between

molecular changes and the pathogenesis of cervical cancer. As is to be expected, some

of our statements will be short-lived, forced aside as new facts and information emerge

to replace them. In contrast, other statements we have made may grow in importance.

May both the controversial issues and those being accepted with ever-increasing favour contribute to make this atlas a source of stimulus to encourage lively discussions and re- warding ideas.

Mannheim and Copenhagen, July 1990 Gisela Dallenbach-Hellweg

and Hemming Poulsen

Preface of the First Edition

VIII

Screening for Cervical Cancer Precursors

to Prevent Invasive Disease . . . . 1

Methods of Obtaining and Preparing Cervical Tissue for Histological Examination . . . . 2

Diagnostic or Therapeutic Procedures   .  .  .  . 2

Colposcopically Directed (Punch) Biopsy   .  .  .  . 2

Cold Knife Conization   .  .  .  . 2

Loop Electrosurgical Excision Procedure   .  .  .  . 4

Endocervical Curettage   .  .  .  . 4

Simple Hysterectomy  .  .  .  . 5

Preparation of the Cervical Specimen   .  .  .  . 5

Immunohistochemistry and In Situ Hybridization . . . . 7

Immunohistochemistry   .  .  .  . 7

Reasons for Use   .  .  .  . 8

Cervical Tumor Cell Differentiation   .  .  .  . 8

Distinction of Squamous, Glandular and Neuroendocrine Lesions   .  .  .  .  . 8

CIN versus Reactive/Atrophic Epithelia   .  .  .  . 9

Adenocarcinoma In Situ versus Mimics  .  .  .  . 10

Endocervical Lesions versus Upper Genital Tract Lesions   .  .  .  . 11

In Situ Hybridization   .  .  .  . 11

Normal Histology, Regeneration, and Repair . . . 13

Normal Ectocervix   .  .  .  . 13

Ascending Repair   .  .  .  . 18

Normal Endocervix  .  .  .  . 20

Descending Repair   .  .  .  . 24

Transformation Zone   .  .  .  . 29

Heading2

Contents

X Contents

Vestigial and Heterotopic Tissues . . . 32

Mesonephric Duct Remnants and Hyperplasia   .  .  .  . 32

Müllerian Duct Remnants and Metaplasia   .  .  .  . 34

Heterotopic Ectodermal and Mesodermal Structures   .  .  .  . 39

Hormonally Induced Changes . . . 42

Effects of Estrogen   .  .  .  . 42

Parakeratosis and Hyperkeratosis of the Ectocervix   .  .  .  . 42

Cystic Hyperplasia of the Endocervix   .  .  .  . 42

Effects of Endogenous Progesterone under Hypersecretion   .  .  .  . 46

Glandular and Cystic Hyperplasia of the Endocervix   .  .  .  . 46

Effects of Exogenous Gestagens   .  .  .  . 49

Glandular (Adenomatous) Hyperplasia of the Endocervix   .  .  .  . 49

Microglandular Hyperplasia of the Endocervix   .  .  .  . 51

Glandular Papillary Ectropium  .  .  .  . 54

Polyps of the Ecto- and Endocervix   .  .  .  . 54

Inflammatory Lesions . . . 57

Nonspecific Ecto- and Endocervicitis   .  .  .  . 57

Specific Inflammations   .  .  .  . 61

Viral Infections   .  .  .  . 61

Bacterial Infections   .  .  .  . 64

Parasitic Infections  .  .  .  . 67

Fungal Infections  .  .  .  . 69

Infections of Unknown Etiology   .  .  .  . 70

Irradiation Changes   .  .  .  . 72

Postoperative Spindle Cell Nodule   .  .  .  . 72

Benign Tumors . . . 74

Epithelial Tumors   .  .  .  . 74

Mesenchymal Tumors   .  .  .  . 78

Mixed Tumors   .  .  .  . 80

XI Contents

Premalignant Lesions . . . 82

Introduction   .  .  .  . 82

Etiology and Pathogenesis   .  .  .  . 83

Histopathology and Immunohistochemistry   .  .  .  . 86

Dysplasia and Carcinoma In Situ (CIN 1–3)   .  .  .  . 86

Squamous Cell Differentiation   .  .  .  . 87

Reserve Cell Differentiation   .  .  .  . 94

Adenocarcinoma In Situ   .  .  .  . 110

Malignant Tumors . . . 117

Epithelial Tumors   .  .  .  . 117

Squamous and Reserve Cell Types   .  .  .  . 117

Microinvasive Carcinoma   .  .  .  . 117

Invasive Carcinoma   .  .  .  . 122

Small Cell Type of Nonkeratinizing Carcinoma   .  .  .  . 123

Large Cell Type of Nonkeratinizing Carcinoma   .  .  .  . 123

Large Cell Keratinizing Carcinoma   .  .  .  . 123

Lymphoepithelioma-like Carcinoma   .  .  .  . 124

Verrucous Carcinoma  .  .  .  . 124

Warty (Condylomatous) Carcinoma   .  .  .  . 125

Papillary Squamous Cell Carcinoma   .  .  .  . 125

Squamo-Transitional Cell Carcinoma   .  .  .  . 136

Glandular Type   .  .  .  . 136

Mucinous Adenocarcinoma   .  .  .  . 137

Endometrioid Adenocarcinoma  .  .  .  . 141

Clear Cell Adenocarcinoma   .  .  .  . 149

Serous Adenocarcinoma  .  .  .  . 149

Mesonephric Adenocarcinoma   .  .  .  . 149

Mixed Type   .  .  .  . 158

Adenosquamous Carcinoma   .  .  .  . 158

Mucoepidermoid Carcinoma   .  .  .  . 160

Adenoid Type   .  .  .  . 162

Adenoid Cystic Carcinoma   .  .  .  . 162

Adenoid Basal Carcinoma   .  .  .  . 162

Neuroendocrine Type   .  .  .  . 165

Neuroectodermal Type  .  .  .  . 166

Mesenchymal Tumors   .  .  .  . 168

Mixed Epithelial and Mesenchymal Tumors   .  .  .  . 170

Carcinosarcoma   .  .  .  . 170

Müllerian Adenosarcoma   .  .  .  . 170

Embryonal Rhabdomyosarcoma   .  .  .  . 170

Wilms Tumor  .  .  .  . 176

XII Contents

Miscellaneous Tumors   .  .  .  . 176

Malignant Lymphomas  .  .  .  . 176

Granulocytic Sarcoma   .  .  .  . 177

Malignant Melanoma   .  .  .  . 177

Endodermal Sinus (Yolk Sac) Tumor   .  .  .  . 178

Secondary Tumors   .  .  .  . 178

References . . . 180

Subject Index . . . 193