Burghardt's Primary Care Colposcopy E-Book

Olaf Reich

• Herausgeber: Thieme
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 219

Veröffentlichungsjahr: 2016

Beschreibung

Compact, visually instructive, practice-oriented guide to colposcopy – revised and updated edition

Like the successful first edition, the great strength of this completely revised and updated second edition of Burghardt's Primary Care Colposcopy is its oversized, high-quality color colposcopic photographs. Novice and experienced examining practitioners will appreciate the utility of these diagnostic quality images in making confident assessments regarding the appearance of the cervix as seen in colposcopy. All requisite information for the successful implementation of this standard gynecologic procedure - histopathologic processes, fundamentals of colposcopic technique and examination, equipment, terminology, documentation, and standard guidelines - is encompassed in this concise and practical textbook and atlas.

Augmentations and highlights of the second revised and updated edition:

• More than 350 oversized, high-quality color colposcopic photographs and technical illustrations - 20% of which are new to the second edition
• Updated information on the central role of the human papillomavirus (HPV) in cervical cancer and the development of preventative HPV vaccines
• Essential new chapters on colposcopy of the vulva, vagina, and perianal region and the common etiology of lesions at these sites
• Cohesive concept, organization and presentation - produced and authored by a working team of three experts with decades of experience in gynecology and histopathology
• Current international guidelines and updated nomenclature formulated by the International Federation for Cervical Pathology and Colposcopy (IFCPC) with the International Society for the Study of Vulvar Disease (ISSVD) and the 2014 WHO Classification of Tumors of Female Reproductive Organs

Primary care practitioners, nurse practitioners, residents/fellows-in-training in gynecologic oncology progr

Leseprobe

Burghardt's Primary Care Colposcopy

Textbook and Atlas

Olaf Reich, MD

Associate Professor of GynecologyAssociate Professor of PatholgyDepartment of Obstetrics and GynecologyMedical University of GrazGraz, Austria

Frank Girardi, MD

Professor EmeritusDepartment of Obstetrics and GynecologyMedical University of GrazGraz, Austria

Karl Tamussino, MD, FACS

ProfessorDepartment of Obstetrics and GynecologyMedical University of GrazGraz, Austria

Hellmuth Pickel, MD

Professor EmeritusDepartment of Obstetrics and GynecologyMedical University of GrazGraz, Austria

369 illustrations

ThiemeStuttgart · New York · Delhi · Rio de Janerio

Library of Congress Cataloging-in-Publication Data is available from the publisher

This book represents selections from Girardi F., Reich O., Tamussino K., Pickel H. Burghardt's Colposcopy and Cervical Pathology, newly edited, published and copyrighted by Georg Thieme Verlag, Stuttgart, Germany 2015.

© 2017 by Georg Thieme Verlag KG

Thieme Publishers StuttgartRüdigerstrasse 14, 70469 Stuttgart, Germany+49 [0]711 8931 421, [email protected]

Thieme Publishers New York333 Seventh Avenue, New York, NY 10001 USA+1 800 782 3488, [email protected]

Thieme Publishers DelhiA-12, Second Floor, Sector-2, Noida-201301Uttar Pradesh, India+91 120 45 566 00, [email protected]

Thieme Publishers Rio, Thieme Publicações Ltda.Edifício Rodolpho de Paoli, 25o andarAv. Nilo Peçanha, 50 - Sala 2508Rio de Janeiro 20020-906 Brasil+55 21 3172 2297 / [phone]

Cover design: Thieme Publishing GroupTypesetting by DiTech Process Solutions, India

Printed in Germany by CPI Books GmbH

5 4 3 2 1

ISBN 978-3-13-130722-4

Also available as an e-book:eISBN 978-3-13-162712-4

Important Note: Medicine is an ever-changing science undergoing continual development. Research and clinical experience are continually expanding our knowledge, in particular our knowledge of proper treatment and drug therapy. Insofar as this book mentions any dosage or application, readers may rest assured that the authors, editors, and publishers have made every effort to ensure that such references are in accordance with the state of knowledge at the time of production of the book.

Nevertheless, this does not involve, imply, or express any guarantee or responsibility on the part of the publishers with respect of any dosage instructions and forms of application stated in the book. Every user is requested to examine carefully the manufacturer's leaflets accompanying each drug and to check, if necessary in consultation with a physician or specialist, whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in the present book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Every dosage schedule or every form of application used is entirely at the user's risk and responsibility. The authors and publishers request every user to report to the publishers any discrepancies or inaccuracies noticed.

Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names, even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without a designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain.

This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation, without the publisher's consent, is illegal and liable to prosecution. This applies in particular to photostat or mechanical reproduction, copying, or duplication of any kind, translating, preparation of microfilms, and electronic data processing and storage.

Contents

Preface

1Human Papillomaviruses and Cervical Cancer

1.1Etiology of Cervical Cancer

1.2Natural History of Cervical Cancer

1.3Morphogenesis of Cervical Cancer

1.4HPV Vaccines

2Role of Colposcopy

2.1Routine Colposcopy

2.2Colposcopy to Evaluate an Abnormal Pap Smear

2.3Colposcopy to Evaluate Patients Positive for HPV or Other Biomarkers

2.4Colposcopy to Evaluate Abnormal Cytologic Findings during Pregnancy

2.5Colposcopy to Evaluate Lesions before Treatment

2.6Colposcopy in Screen-and-Treat Approaches in Resource-Poor Settings

3The Colposcope and the Colposcopic Examination

3.1Colposcopic Instruments

3.2Biopsy Instruments

3.3The Colposcopic Examination

3.4Therapeutic Implications of Abnormal Colposcopic Findings

4Teaching and Training Colposcopy

4.1Colposcopy Training in Europe

4.2European Diploma in Colposcopy

5Colposcopic Terminology

6Colposcopic Findings

6.1Normal Colposcopic Appearances

6.2Abnormal Colposcopic Findings

6.3Miscellaneous Colposcopic Findings

6.4Assessment of Colposcopic Findings

6.5Criteria for Differential Diagnosis

6.6Combinations of Abnormalities

7Colposcopy in Pregnancy

7.1Effects of Pregnancy on Colposcopic Findings

7.2Benign Changes in Pregnancy

7.3Suspicious Changes

7.4The Puerperium

7.5Biopsy during Pregnancy

8Colposcopy of the Vulva

8.1Histology of the Vulva

8.2Diagnostic Methods for Evaluating Vulvar Lesions

8.3Vulvar Carcinogenesis

8.4Preinvasive (Intraepithelial) Lesions

8.5Nonneoplastic Conditions

9Colposcopy of the Vagina

9.1Histology

9.2Vaginal Carcinogenesis

9.3Squamous Intraepithelial Lesions

9.4Diagnostic Methods for SIL

9.5Histologic Terminology and Classification

9.6Histomorphology of Vaginal SIL

9.7Management of SIL

9.8Vaginal Melanoma

10Colposcopy of the Perianal Region

10.1Anatomy and Histology

10.2Anal Carcinogenesis

10.3Anal Intraepithelial Neoplasia

10.4Diagnostic methods for AIN

10.5Histologic Terminology and Classification

10.6Management of AIN

Index

Preface

Colposcopy is a widely used technique to visually examine the lower genital tract with exposure, a light source, and magnification. The number of textbooks on colposcopy testifies to the rapid development of the technique over the last 20 years. The first edition of the full version of this book was published in German in 1984. Since then revised editions of the full version, now called Burghardt's Colposcopy and Cervical Pathology in honor of Erich Burghardt who passed away in 2006, have appeared in Spanish, Japanese, French, Italian, and English. The present edition of the compact edition is user-oriented resource for general practitioners, nurses, and other nonspecialists. Accordingly, we have left out detailed histologic pictures and descriptions while keeping the colposcopic images that are the backbone of the book. So-called “extended colposcopy” (i.e., with the acetic acid and the iodine test) is given ample coverage. Like its predecessors, this book intends to explain both the fundamentals of colposcopic technique and how colposcopy can help one appreciate the dynamic processes at the cervix and lower genital tract that we have to understand to prevent invasive cervical cancer and neoplasias of the vulva, vagina, and anus.

We thank Dr. Charles Redman (Stoke on Trent) and Dr. Esther Moss (Leicester) for their contribution to the chapter Teaching Colposcopy.

We would like to thank Thieme Verlag for their longstanding support of this project. And, of course, we thank our wives—Christine, Ursula, Caroline, and Ulrike—for their support.

Olaf Reich,Frank Girardi,Karl Tamussino,Hellmuth Pickel

Chapter 1

Human Papillomaviruses and Cervical Cancer

1.1 Etiology of Cervical Cancer

1.2 Natural History of Cervical Cancer

1.3 Morphogenesis of Cervical Cancer

1.4 HPV Vaccines

1 Human Papillomaviruses and Cervical Cancer

During much of the 20th century, cervical cancer was a scourge. In large parts of the world, this remains the case, the disease often striking women younger than 40 years. In 1908, Friedrich Schauta in Vienna ended his monograph on radical vaginal hysterectomy for cervical cancer on the note that “the early detection of uterine cancer is the greatest challenge facing future generations of academic teachers and practicing physicians.” In the same year, Howard Kelly in Baltimore wrote that “the only avenue open with certainty to progress today lies in the direction of discovering our cases of cancer at an earlier stage in the disease.” Physicians battling this disease appreciated the importance of early detection, but did not know how to get there.

1.1 Etiology of Cervical Cancer

Papillomaviruses are a large and diverse group of small DNA viruses that infect epithelial tissues, and have evolved over millions of years. As parasites, they use species-specific animals and humans for replication. About 120 types of cutaneous or mucosal human papillomavirus (HPV) have been described in humans.

HPVs have a simple structure and are built of only a few proteins. The small circular genomes are organized into a set of six early genes (E6, E7, E1, E2, E4, and E5), which are involved in viral gene expression and replication control, and two late genes (L1 and L2), which encode the major capsid proteins. In cervical carcinogenesis, two of the early genes (E6 and E7) can transform cervical epithelium.

In 1976, Harald zur Hausen found the DNA of HPVs in cervical cancers and genital warts. In 1983, investigators in zur Hausen's laboratory established HPV 16 as the leading candidate in the etiology of preinvasive and invasive cervical neoplasia. HPV types are widely classified into low-risk and high-risk groups according to their ability to promote malignant transformation. HPV types 16, 18, 31, 33, and others are now classified as high-risk types. In contrast, HPV 6, 11, 40, 42, and others are rarely found in cervical cancer and are considered low-risk types.

All cervical epithelia are vulnerable to HPV infection. The development of cervical cancer and its precursor lesions requires persisting infection with high-risk HPV (HR-HPV). HPV 16 infection results in predominantly squamous neoplasia, whereas HPV 18 and 45 have a greater tendency to induce glandular neoplasia. HPV 16 and 18 cause about 70% of cervical cancers. Together with HPV 31 and 45, and cofactors (e.g., smoking, immunodeficiency, number of sexual partners), they are the prime risk factors for cervical cancer.

Worldwide, about 300 million women are infected with HPVs. The majority of genital HPV infections remain asymptomatic, and the majority of infections resolve spontaneously. Genital HPV infection is transmitted almost exclusively through sexual and genital skin-to-skin contact. Most women acquire cervical HPV infection within a few years of initiating sexual intercourse. Coinfection with more than one HPV genotype is common, especially in young women. Most HPV infections clear as a result of cell-mediated immune response. About 90% of women with HPV infection become HPV-negative within 2 years. The peak rate of HPV infection is seen in women younger than 25 years, with a decline that plateaus around 30 to 35 years. In some countries, there is a slight increase in women over 50 years.

1.2 Natural History of Cervical Cancer

HPVs infect epithelial basal cells (reserve cells), which are responsible for regeneration of the epithelium (Fig. 1.1). Subcolumnar reserve cells enable metaplasia from columnar to squamous epithelium.

HPV infection probably occurs when minor trauma (e.g., sexual intercourse) exposes the basal cells (reserve cells) of the cervical mucosa to the virus. Expression of viral genes in individual infected basal cells leads to lateral extension of the initially HPV-infected cell clone (Fig. 1.2a,b).

The time from HPV infection to the development of high-grade squamous intraepithelial lesions (HSIL) varies widely. Generally, persisting infection with HPV 16, 18, or 45 entails a 20 to 30% risk for cervical intraepithelial neoplasia grade III (CIN 3, HSIL) over the next 5 years. However, some high-grade lesions, particularly with HPV 16 infection, develop quickly (i.e., 1 or 2 years after infection). Women with multiple HR-HPV infections are at increased risk.

Fig. 1.1 Individual reserve cells in the basal layer of the columnar epithelium. The nuclei stain darkly for p63.

Fig.1.2 (a) HPV entry model: uptake of HPV into the basal cells is mediated by endocytosis. Upon release from the particle, the circular viral genome is transported to the nucleus, where it resides as an extrachromosomal molecule. (b) Schematic description of the three distinct phases of HPV infection at the cervix. Minor lacerations of the epithelium permits contact of HPV with the cervical reserve (basal) cells. In the latent phase, the HPV genome releases viral copies in low numbers and without significant viral gene expression. In some instances, low levels of viral gene expression occur and result in viral replication (permissive phase). The late gene products permit packaging of the replicated viral genomes, and newly produced HPVs are released at the surface of the cervix. Morphologic effects include low-grade squamous intraepithelial lesions (LSIL). Transforming infections cause HSIL and adenocarcinoma in situ (AIS).

Cervical cancer is an occasional and late manifestation of infection with HR-HPV. The latency from initial HPV infection to invasive cancer is in the range of 8 years and more. HSIL correlates with a greater risk of progression to invasion than low-grade squamous intraepithelial lesions (LSIL). Spontaneous regression can occur in about 57, 43, and 32% of cases of CIN 1, CIN 2, and CIN 3 lesions, respectively, and persistence in 32, 35, and 56%. Only about 1% of CIN 1 lesions and 5% of CIN 2 lesions but more than 12% of CIN 3 lesions progress to invasive cervical cancer. In one study, untreated CIN 3 had a 30% probability of becoming invasive over a 30-year period.

1.2.1 Phases of HPV Infection

HPV infections go through three phases of viral gene expression: the latent phase, the permissive (productive) phase, and the transforming phase. After intraepithelial neoplastic transformation, some HSIL and adenocarcinoma in situ (AIS) will progress to invasive cervical cancer (Fig. 1.2).

Latent Phase

Latent infection does not produce infectious particles, remains clinically inapparent, and triggers no histopathologic changes. Most HPV infections probably end this way, without initiation of major viral gene expression.

Permissive (Productive) Phase

Permissive (productive) infection shows no signs of cellular transformation and can be caused by either low-risk or high-risk HPV types. It frequently results in characteristic morphologic changes of the infected cervical squamous epithelium (koilocytosis) (Fig. 1.3). This corresponds to condylomas or CIN 1 in histologic specimens or LSIL in cytologic specimens. Probably about 90% of productive infections become undetectable within 1 to 2 years, corresponding to spontaneous resolution of LSIL.

Fig. 1.3 (a, b) Permissive (productive) HPV infection with viral replication. (a) Staining for L1 shows HPV capsid protein (red) in superficial layers of the infected epithelium. (b) In situ hybridization shows newly produced HPVs (blue). (This image is provided courtesy of S. Syrjänen.)

Transforming Phase

Transforming infections are almost always associated with HR-HPV types. Transforming infections cause high-grade lesions. These lesions are referred to as CIN 2/3 in histology and HSIL in cytologic specimens (Fig. 1.4). For cancer to develop, HPV has to evade immune detection over a prolonged period for genetic abnormalities to accumulate. Not all HSIL or AIS will progress to invasive cancer.

1.3 Morphogenesis of Cervical Cancer

Squamous cell cervical cancer can develop in metaplastic squamous epithelium (inside the transformation zone) or in the original squamous epithelium.

1.3.1 Morphogenesis of Squamous Cell Carcinoma in Metaplastic Epithelium

Squamous cell carcinoma inside the transformation zone develops via SIL in fields of squamous epithelium of metaplastic origin. Metaplasia begins with the appearance of a row of subcolumnar reserve cells in a well-defined field (Figs. 1.5a–c and 1.6a–d). Later, immature metaplastic squamous epithelium can become mature (Fig. 1.7). Different fields of (immature and mature) metaplastic squamous epithelium can arise on the same cervix, simultaneously or at different times. If present, HPV infection usually does not affect the entire metaplastic epithelium. In permissive (productive) infections, virus replication is also limited to sharply defined fields (Fig. 1.8).

HSIL can appear at the very beginning of the metaplastic process without LSIL. Atypical cells arise simultaneously from the base of whole fields of metaplastic epithelium, not from single cells in an initial focus (Fig. 1.9a,b).

Fig. 1.4 (a, b) HSIL with diffuse overexpression of p16INK4a in all cells of the proliferating compartment at the surface (a) and in a cervical crypt (b). In the transforming phase of HPV infection, the early viral genes E6 and E7 are strongly expressed and p16INK4a is upregulated and overexpressed.

Squamous metaplasia and SIL frequently coexist in separate fields on the same cervix. Adjacent fields are separated by sharp borders. When caused by different HPV types, the appearance of SIL can differ from field to field, but the borders are also sharp (Fig. 1.10). In these cases, the entire lesion is a mosaic of independent primary lesions. SIL remains within its original boundaries and does not enlarge by active surface spread. It grows, enlarges, and spreads by recruiting or apposing new fields of varying appearance.

The synchronous or metachronous development of SIL in various epithelial fields and its confluence play a central role in understanding the pathogenesis of cervical cancer because the likelihood of invasion increases with the surface area of a lesion, which is directly related to the total size. Invasion proceeds unifocally or multifocally from the base of larger lesions, with a small nest of cells penetrating the stroma, so-called early stromal invasion.

1.3.2 Morphogenesis of Squamous Cell Carcinoma in Original Squamous Epithelium

A small percentage of SILs develop in original squamous epithelium of the cervix, outside the TZ. This is not due to active spread of SIL toward the vagina across the original SCJ. SIL outside the TZ develops separately and arises by proliferation of the basal and parabasal layers of the original squamous epithelium.

1.3.3 Morphogenesis of Adenocarcinoma

Adenocarcinoma of the cervix develops via AIS, which is defined as noninvading but highly atypical columnar epithelium. There are no low-grade glandular lesions corresponding to LSIL. AISs most frequently arise at the TZ in fields, often in association with HSIL. As in SIL, the transition between the atypical and normal columnar epithelium is abrupt (Figs. 1.11 and 1.12). Both the surface and the crypts can be involved by AIS. As in SIL, invasion of AIS proceeds from the base of the transformed epithelium, with a small nest of cells penetrating the stroma.

Fig. 1.5 (a–c) Rows of subcolumnar reserve cells as an early feature of squamous metaplasia of columnar epithelium (a, b). Note the well-defined fields and the beginning proliferation of subcolumnar reserve cells (c) (staining for cytokeratin 17).

1.4 HPV Vaccines

The identification of HPVs as the causative agent of cervical cancer soon prompted research into the development of vaccines. Prophylactic vaccines were based on virus-like particles (VLPs) produced by expressing L1, the major capsid protein of HPV, using recombinant DNA technology. The VLPs preserve and resemble the structure of the native virus and induce antibodies cross-reactive with infectious virus particles. Antibodies reach high serum titers and reach the vaginal fluid by transudation.

Two vaccines, one quadrivalent and one bivalent, were developed and entered into clinical trials in 2001 and 2004, respectively. The FUTURE studies evaluated the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with HPV types 6, 11, 16, and 18. Initially, a total of 5,455 women aged 16 to 24 years received the vaccine or a placebo and were evaluated for the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia (VIN/VAIN), or cancer and the incidence of CIN, AIS, or cancer associated with HPV type 6, 11, 16, or 18. In the primary analysis at 3 years of a per-protocol susceptible population of women who had no virologic evidence of HPV infection at baseline, vaccine efficacy for each of the coprimary end points was 100%, showing that the vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women. At 42 months’ follow-up in the per-protocol susceptible population, the efficacy of the vaccine against lesions related to the HPV types in the vaccine was 96% for CIN 1, 100% for both VIN 1 and VAIN 1, and 99% for condylomata. In the FUTURE II study, a total of 12,167 women were randomized and evaluated for CIN 2/3, AIS, or cervical cancer related to HPV 16/18. After 3 years’ follow-up, vaccine efficacy for the prevention of the primary composite end point in the per-protocol susceptible population was 99%.

The PApilloma TRIal against Cancer In young Adults (PATRICIA) included over 18,000 healthy women aged 15 to 25 years with no more than six lifetime sexual partners, irrespective of baseline HPV DNA status. Women were randomly assigned to receive a bivalent HPV 16/18 vaccine or a control hepatitis A vaccine. The primary end point was vaccine efficacy against CIN 2+ associated with HPV 16/18 in women who were seronegative at baseline. After a mean follow-up of 35 months, vaccine efficacy against CIN 2+ associated with HPV 16/18 was 93% in the primary analysis and 98% in an analysis of probable causality to HPV type in lesions with multiple oncogenic types. In the end-of-study analysis, vaccine efficacy was 93% against all CIN 3+ and 100% against CIN 3+ associated with HPV 16/18.

Fig. 1.6 (a–d) Immature metaplastic squamous epithelium at the surface and the crypts. The structure already suggests squamous epithelium, but columnar cells are still present (a, b: staining for cytokeratin 17). Note the proliferation of p63-positive subcolumnar reserve cells (c: staining for p63). (d) Sharp border between newly formed metaplastic squamous epithelium on the right and adjacent mature squamous epithelium on the left (d: staining for p63).

The quadrivalent vaccine (Gardasil, Merck & Co.) and the bivalent vaccine (Cervarix, GlaxoSmithKline Biologicals) were approved by the Food and Drug Administration in the United States in 2006 and 2009, respectively. HPV vaccines have been incorporated into vaccination programs and recommendations in many countries, including developing countries, where cervical cancer is a much larger public health problem. In 2015, results of a trial of a 9-valent vaccine (Gardasil 9, Merck & Co.) were published and this vaccine is becoming available worldwide.

Fig. 1.7 Sharp border between mature metaplastic squamous epithelium on the left and normal squamous epithelium on the right hematoxylin and eosin.

The primary target population for HPV vaccination is adolescent girls before sexual debut. There is also substantial vaccine efficacy in a population approximating a general population of sexually active women, suggesting that catch-up vaccination will also provide benefit. Furthermore, women after surgical therapy of HPV-associated lesions (e.g., conization) after vaccination can continue to benefit from reduction in the risk of development of recurrent lesions. Both vaccines are generally less effective in immunocompromised individuals. Neither of the prophylactic vaccines has shown therapeutic activity.

PATRICIA and FUTURE were landmark studies. In 2007, Australia became one of the first countries to implement a nationally funded program for vaccination of girls and young women with the quadrivalent vaccine. An audit of national surveillance data through 2011 showed large declines in the proportions of young women diagnosed with genital warts in the vaccination period. Genital warts in heterosexual men also declined, probably as a result of herd immunity. These results indicate that HPV vaccines are highly effective outside the trial setting and strongly support their widespread implementation.

Fig. 1.8 Field of a permissive (productive) HPV infection of the squamous epithelium. Note the sharp border between the epithelium with viral replication on the left and the epithelium without HPV replication on the right (in situ hybridization). (This image is provided courtesy of S. Syrjänen.)

Fig. 1.9 High-grade squamous intraepithelial lesion at the beginning of the metaplastic process.(a) Atypical cells arise simultaneously from the base of a whole field of columnar epithelium, not from single cells in an initial focus. (b) Two small fields of severe dysplastic squamous epithelium that are still covered by columnar cells. There is no active spread of the epithelium beyond the borders of the fields (hematoxylin and eosin).

Fig. 1.10 (a–c) Different fields of SIL separated by sharp borders. (a) Border between squamous epithelium with permissive (productive) HPV infection (left) and slightly dysplastic squamous epithelium (LSIL) (right). (b) Border between two fields of HSIL. The borders are indicated by arrows (hematoxylin and eosin). (c) HSIL next to a typical condyloma with tall stromal papillae and marked koilocytosis.

Fig. 1.11 Adenocarcinoma in situ. As in SIL, the border between atypical and normal columnar epithelium is abrupt (hematoxylin and eosin).

Fig. 1.12 Adenocarcinoma in situ near the squamocolumnar junction, positive for HPV 18. The squamous epithelium is negative. Tyramine amplified in situ hybridization. (This image is provided courtesy of S. Syrjänen.)

Further Reading

Ali H, Donovan B, Wand H, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. BMJ 2013;346:f2032

Dürst M, Gissmann L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci U S A 1983;80:3812–3815

FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–1927

Garland SM, Hernandez-Avila M, Wheeler CM, et al. Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356: 1928–1943

Joura EA, Garland SM, Paavonen J, et al. FUTURE I and II Study Group. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ 2012;344:e1401

Joura EA, Giuliano AR, Iversen OE, et al. Broad Spectrum HPV Vaccine Study. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med 2015;372(8):711–723

Lehtinen M, Paavonen J, Wheeler CM, et al. HPV PATRICIA Study Group. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012;13:89–99

Paavonen J, Naud P, Salmerón J, et al. HPV PATRICIA Study Group. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009;374:301–314

Reich O, Regauer S. Thin HSIL of the cervix: detecting a variant of high-grade squamous intraepithelial lesions with a p16INK4a antibody. Int J Gynecol Pathol 2016 (in press)

Ronco G, Dillner J, Elfström KM, et al. International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014;383(9916):524–532

Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet 2007;370:890–907

Schiffman M, Solomon D. Clinical practice. Cervical-cancer screening with human papillomavirus and cytologic cotesting. N Engl J Med 2013;369:2324–2331

zur Hausen H. Condylomata acuminata and human genital cancer. Cancer Res 1976;36 (2, pt 2):794

Chapter 2

Role of Colposcopy

2.1 Routine Colposcopy

2.2 Colposcopy to Evaluate an Abnormal Pap Smear

2.3 Colposcopy to Evaluate Patients Positive for HPV