Pathology of the Female Reproductive Tract

862 Pages·2014·450.19 MB·English

by  George L. Mutter

PATHOLOGY OF
THE FEMALE
REPRODUCTIVE
TRACT
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PATHOLOGY OF
THE FEMALE
REPRODUCTIVE
TRACT
George L. Mutter MD
Professor of Pathology
Harvard Medical School
Division of Women’s and Perinatal Pathology
Brigham and Women’s Hospital
Boston, MA, USA
Jaime Prat MD, PhD, FRCPath
Professor and Chairman of Pathology
Hospital de la Santa Creu i Sant Pau
Autonomous University of Barcelona
Barcelona, Spain
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First edition 2002
Second edition 2009
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Preface
In this third edition of Pathology of the Female Reproductive risk factors, precursor lesions, patterns of spread, molecular
Tract, the new editorial team seeks to present new concepts events during oncogenesis, response to chemotherapy, and
and findings as a background to furthering patient manage- prognosis. Accordingly, the five main types of ovarian carci-
ment. By so doing, we hope to improve communication noma, accounting for 98% of the total, are presented in
between the pathologist and the clinician, which is essential three separate chapters (Chapters 25−27) emphasizing con-
for optimal patient care. Balancing the broad range of con- ventional histopathology and differential diagnosis, as well
tents has not been an easy task. We have deleted sections as immunohistochemistry and molecular genetic analysis.
deemed no longer relevant, while retaining classic material The increasing demonstration of both intraepithelial
still pertinent for today’s practice. For example, we kept and high-grade serous carcinoma and putative precursor epithe-
even expanded the clinical discussions because pathologists lial lesions in the distal fallopian tube, particularly in women
should be aware of the therapeutic implications of their carrying BRCA1 mutations, are discussed in detail on the
diagnosis, and clinicians should be able to understand the chapters dealing with diseases of the fallopian tube (Chapter
meaning of a pathology report. Only in this way we can 21) and serous tumors of the ovary (Chapter 25). The rela-
promote optimal patient care tive importance of the fallopian tube mucosa compared
The most significant changes made with respect to the with the ovarian surface epithelium (mesothelium) in the
previous edition include the following: genesis of high-grade serous ovarian cancers is still a subject
The diseases of the lower genital tract related to HPV are of debate. Similarly, the increasing evidence that both
comprehensively presented in six separate chapters includ- endometrioid and clear cell carcinomas of the ovary origi-
ing one (Chapter 9) exclusively devoted to the molecular nate from ovarian endometriosis and the role of AT-rich
biology of cervical squamous neoplasia, early detection, and interactive domain 1A gene (ARID1A) mutations in endome-
prophylactic vaccines. Even if it has been unilaterally pro- trioid and clear cell carcinogenesis are presented on Chapter
posed by the Lower Anogenital Tract Squamous Terminol- 27. The diagnostic value of FOXL2 and pluripotency stem
ogy (LAST) group, the unified nomenclature with two-tier cell markers is discussed in the chapters dealing with ovarian
(LSIL and HSIL) system for all HPV-related preinvasive sex cord−stromal and germ cell tumors (Chapters 28 and
squamous lesions of the lower anogenital tract has been 29), respectively.
adhered to throughout. Regarding molecular diagnosis and biomarkers, we have
Endometrial carcinomas and their precursors are pre- been pragmatic in keeping those which have already dem-
sented in two chapters (Chapters 17 and 18). Besides an onstrated added value in clinical practice, or might become
in-depth discussion of prototypic endometrioid and nonen- so in the foreseeable future. Furthermore, the range of
dometrioid (serous) carcinomas which includes clinico- histopathologic variants of the main gynecological and
pathologic features, differential diagnosis and treatment, obstetrical tumors and tumor-like conditions can be quite
the clinical and molecular characteristics of some unique broad. It would be impossible to rigidly consider all mor-
tumor histotypes (such as clear cell carcinomas and carci- phologic variants as separate entities, much less illustrate
nosarcomas that do not fit into either of the two main types) them well. Rather, aggregation by disease mechanism, clini-
are also analyzed. Uterine sarcomas are also presented in cal outcome, and available therapies has guided us through-
two chapters (Chapters 19 and 20) dominated by the clin- out. In this regard, we admit a tendency to ‘lump’ diagnoses
icopathologic features of leiomyosarcomas and endometrial along clinicopathologic lines, rather than ‘splitting’ them
stromal sarcomas respectively. Among the latter tumors, the according to morphologic variations.
prematurely eliminated high-grade endometrial stromal We are strongly aware that, in today’s wired society, the
sarcoma has been resurrected, based upon its distinctive latest information can outdate any published text. Neverthe-
histologic and molecular characteristics. less, the essence of this work is to give the most accurate
Recent advances in epidemiology, molecular genetics and review of what is currently available.
therapy, have confirmed the older 1960s idea that ovarian
epithelial cancer is not one, but many diseases not only George L. Mutter
exhibiting different morphology, but also different genetic Jaime Prat
xxiii
List of Contributors
Jan P.A. Baak MD, PhD Elke A. Jarboe MD
Professor of Pathology, Department of Pathology, Stavanger Assistant Professor, Department of Pathology, University of
University Hospital, Stavanger, Norway Utah Health Sciences Center, Salt Lake City, UT, USA
Sarah Bean MD Rachel Katzenellenbogen MD
Assistant Professor, Department of Pathology, Duke Assistant Professor, Pediatrics, University of Washington;
University Medical Center, Durham, NC, USA Adjunct Assistant Professor, Global Health, University of
Washington, Seattle, WA, USA
Rex C. Bentley MD
Professor of Pathology, Duke University Medical Center, Kyu-Rae Kim MD, PhD
Durham, NC, USA Professor, Department of Pathology, University of Ulsan
College of Medicine, ASAN Medical Center, Seoul, Korea
Joseph W. Carlson MD, PhD
Specialist Physician, Department of Pathology and Anais Malpica MD
Cytology, Karolinska University Hospital, Stockholm, Professor of Pathology and Gynecologic Oncology,
Sweden Department of Pathology, MD Anderson Cancer Center,
The University of Texas, Houston, TX, USA
Jennifer H. Crow MD
Assistant Professor, Department of Pathology, W. Glenn McCluggage MD
Duke University, Durham, NC, USA Professor of Gynecological Pathology, Department of
Pathology, Belfast Health and Social Care Trust, Belfast,
Emanuela D’Angelo MD, PhD Northern Ireland, UK
Associate Professor of Pathology, Autonomous University
of Barcelona, Hospital de la Santa Creu i Sant Pau, Eoghan E. Mooney MB, BCh, BAO
Barcelona, Spain Consultant Histopathologist, Department of Pathology
and Laboratory Medicine, National Maternity Hospital,
Emma M. Doyle MB, MRCOG Dublin, Ireland
Lecturer in Pathology, School of Medicine and Medical
Science, University College Dublin, Dublin, Ireland George L. Mutter MD
Professor of Pathology, Harvard Medical School, Division
Christopher D.M. Fletcher MD, FRCPath of Women’s and Perinatal Pathology, Brigham and
Vice Chair, Anatomic Pathology, Brigham & Women’s Women’s Hospital, Boston, MA, USA
Hospital; Chief of Onco-Pathology, Dana-Farber Cancer
Institute; Professor of Pathology, Harvard Medical Marisa R. Nucci MD
School, Boston, MA, USA Associate Professor of Pathology, Harvard Medical School;
Associate Pathologist, Department of Pathology, Division
C. Simon Herrington MA, MB BS, DPhil, of Women’s and Perinatal Pathology, Brigham and
FRCP, FRCPath Women’s Hospital, Department of Pathology, Boston,
Professor of Pathology, Division of Cancer Research, MA, USA
Medical Research Institute, University of Dundee,
Dundee, UK Esther Oliva MD
Professor of Pathology, Harvard Medical School;
Mai P. Hoang MD Pathologist, Massachusetts General Hospital, Boston,
Associate Professor of Pathology, Department of Pathology, MA, USA
Harvard Medical School, Massachusetts General
Hospital, Boston, MA, USA Jaime Prat MD, PhD, FRCPath
Professor and Chairman, Department of Pathology,
Brooke Howitt MD Hospital de la Santa Creu i Sant Pau, Autonomous
Soft Tissue Pathology Fellow, Department of Pathology, University of Barcelona, Barcelona, Spain
Women’s and Perinatal Division, Brigham and Women’s
Hospital, Boston, MA, USA
xxv
xxvi List of Contributors
Victor G. Prieto MD, PhD Christopher R. Shea MD
Professor of Pathology and Dermatology; Section Chief, Eugene J. Van Scott Professor in Dermatology, The
Dermatopathology, Department of Pathology, University University of Chicago Medicine, Chicago, IL, USA
of Texas; Director of Dermatopathology, Department
of Pathology, MD Anderson Cancer Center, Houston, Bruce R. Smoller MD
TX, USA Executive Vice President, United States and Canadian
Academy of Pathology, Augusta, GA, USA
Bradley J. Quade MD
Associate Professor of Pathology, Harvard Medical School; Cornelia L. Trimble MD
Division of Women’s and Perinatal Pathology, Brigham Associate Professor, Gynecology/Obstetrics, Oncology,
and Women’s Hospital, Boston, MA, USA Pathology, Johns Hopkins University School of Medicine,
Baltimore, MD, USA
Stanley J. Robboy MD
Professor of Pathology; Professor of Obstetrics and Emanuela F. Veras MD
Gynecology, Department of Pathology, Duke University Private Practice, East Georgia Diagnostic Services, Inc.,
Medical Center, Durham, NC, USA Statesboro, GA, USA
Demaretta S. Rush MD Edward J. Wilkinson MD
Assistant Professor, Department of Pathology, Immunology Professor and Vice Chairman, Department of Pathology,
and Laboratory Medicine, University of Florida College Immunology and Laboratory Medicine, University of
of Medicine, Gainesville, FL, USA Florida College of Medicine, Gainesville, FL, USA
M. Angelica Selim MD Thomas C. Wright, Jr. MD
Professor of Pathology and Dermatology; Director of Professor Emeritus and Special Lecturer of Pathology and
Dermatopathology, Department of Pathology, Duke Cell Biology, Columbia University, New York, NY, USA
University Medical Center, Durham, NC, USA
Ruthy Shaco-Levy MD
Senior Gynecological Pathologist, Department of
Pathology, Soroka University Medical Center, Beer-Sheva,
Israel
To Robert E. Scully MD (1921–2012)
Pioneering pathologist, educator, and gentleman
Acknowledgements
This book began with Malcolm Anderson’s 1991 Female that a period of smooth transition to the current editors
Reproductive System in the Symmers Systemic Pathology followed.
Series, becoming a standalone first edition text in 2002 with All of the current authors have taken valuable time from
Stanley Robboy, Malcolm Anderson, and Peter Russell as their professional, and all too often personal, schedules to
editors, and an expanded second edition with additional contribute their expertise. This is a precious gift in an increas-
co-editors (George Mutter, Jaime Prat, Rex Bentley). ingly busy and overcommitted world. We are most grateful to
Although an international project from its inception, these have the opportunity to work with such a world-class team of
editors greatly increased the roster of authors through tar- experts who have enlightened us all in the process. We would
geted recruitment, and created a truly collaborative inter- also like to recognize the contributions of authors from prior
national environment. These works always kept the reader editions, as we have built upon their solid foundation.
in mind: presenting expertly curated content in a cleanly The gracious support of our families and colleagues is what
written and clinically relevant style. made it possible to engage the many distractions and long
Dr. Robboy facilitated the transition to this third edition hours of extra work necessary for this book. We have suc-
as he turned his attention to another phase of a storied ceeded only because of their understanding, and we should
career. He is extraordinarily prescient in anticipating acknowledge that it is them who make it all worthwhile.
how the practice of pathology might best serve our patients Lastly, the staff at Elsevier has been outstanding, espe-
in the context of a complex healthcare system. Soon after cially Michael Houston who originally commissioned this
the second edition of this book was published, he decided book and has now seen it through every edition. A special
he could best implement many of his goals by running thanks to the efforts of Martin Mellor and Lucía Pérez
for the Presidency of the College of American Pathologists, throughout the long editorial process.
a successful endeavor which led to his inauguration in
2011. It was in anticipation of his duties with the CAP, George L. Mutter and Jaime Prat
xxix
1
Embryology
George L. Mutter, Stanley J. Robboy
CHAPTER OUTLINE
Introduction 1 External Influence on the Developing
Gonadal Development 1 Embryonic Genital Tract Ducts 12
Role of Germ Cells 11 The Müllerian Duct after Week 8 14
Müllerian and Wolffian Duct The Müllerian Duct during the Second
Development 11 Trimester 14
The Müllerian Duct to Week 8 11 External Genitalia 15
person’s sense of self (gender identity) and his/her attrac-
INTRODUCTION
tion to others.
Understanding normal development of the embryonic
genital tract gives insight into many disorders encountered GONADAL DEVELOPMENT
in the female. These can range from relatively simple arrests
of development or malformation (described by organ) to Prior to the period when sex determination begins, the
more complex abnormalities of sexual development that indifferent gonad arises from the gonadal ridge that, with
result from dysembryogenesis (see Chapter 2), and, in some the mesonephros, lies longitudinally on the dorsal aspect of
cases, to help understand the origin of some tumors, par- the celomic cavity. At this time, the indifferent gonad is
ticularly sex cord–stromal and germ cell tumors of the ovary. ‘unisex’ or, more properly, ‘bipotential’ due to its ability to
Most early insights have come from understanding human develop into a testis or an ovary depending upon the
mutations. During more recent years, targeted mutations embryo’s genetic makeup.
using mouse models have disclosed key roles for genes that In humans and other mammals, the karyotype ‘XY’ genet-
had not been anticipated previously. Many regulators of ically defines the sex as male, whereas ‘XX’ defines the
gonadal development are receptors, signal transduction ele- female sex. Sex is determined by the presence or absence
ments, transcription factors, extracellular ligands, and even of a signal from the substance initially called the testis deter-
intracellular signaling pathways mediating downstream mining factor and now recognized as the gene called SRY
transcriptional responses. Recently published references1–7 (Sex determining Region Y) in the human and SRY in the
provide extensive reviews and, to some degree, competing mouse. The gene is found on the Y chromosome. Testes are
theories. formed if this gene is expressed by the embryo before the
Most of the female genital tract is of mesodermal origin. urogenital ridge differentiates. Further male development
Germ cells are of endodermal origin. The vulva and the occurs under the influence of hormones secreted later by
epithelial lining of the vagina are ectoderm. The chronol- the testes. Without SRY, the gonads differentiate as ovaries
ogy and sequence of events that underlie the development and the embryo develops as a female. The timely expression
of the female genital tract are summarized in Figures 1.1 of SRY is critical to the development of male sex. In its
and 1.2, and in Table 1.1. Table 1.2 lists specific genes absence, the embryo develops a female phenotype, regard-
involved in the initial steps of sexual development. less of genetic sex. Although for years believed to occur by
In the broadest view, sex determination takes place in default, a gene has been identified in women (R-spondin1,
three sequential steps.8 The first is chromosomal sex deter- RSPO1)9 critical for development of the ovary through sig-
mination, which occurs as a result of fertilization. Gonadal naling pathways.10
sex determination, the second critical event, results when The SRY gene is located in the region just central to the
the potential gonads actually transform into ovaries or testes pseudoautosomal pairing region at the distal end of the
in accord with the available chromosomal information. short arm of the Y chromosome.11 The pseudoautosomal
Third, the secondary sex characteristics develop along pairing region is named for the two limited regions at the
female or male lines as determined by the preponderant distal ends of the short and long arms of the Y chromosome
estrogenic or androgenic hormonal milieu present systemi- where sequence identity with the X chromosome permits
cally. Sexual identity, not to be discussed here, includes a pairing and recombination during male meiosis.12 The
1