Atlas of Uterine Pathology [1st ed.] 978-3-030-17930-4;978-3-030-17931-1

Table of contents :
Front Matter ....Pages i-xii
Normal Histology of the Uterine Corpus (Oluwole Fadare, Andres A. Roma)....Pages 1-22
Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium (Oluwole Fadare, Andres A. Roma)....Pages 23-53
Precancerous and Putative Precursor Lesions of Endometrial Carcinoma (Oluwole Fadare, Andres A. Roma)....Pages 55-77
Epithelial and Mixed Epithelial/Mesenchymal Malignancies of the Uterine Corpus (Oluwole Fadare, Andres A. Roma)....Pages 79-121
Mesenchymal and Miscellaneous Neoplasms of the Uterine Corpus (Oluwole Fadare, Andres A. Roma)....Pages 123-162
Gestational Trophoblastic Tumors of the Uterus (Oluwole Fadare, Andres A. Roma)....Pages 163-172
Functional Disorders, Pregnancy, and Hormone-Related Changes of the Endometrium (Oluwole Fadare, Andres A. Roma)....Pages 173-192
Normal Anatomy of the Uterine Cervix (Oluwole Fadare, Andres A. Roma)....Pages 193-196
Pseudoneoplastic and Benign Diseases of the Cervix (Oluwole Fadare, Andres A. Roma)....Pages 197-212
Precancerous Lesions of the Cervix (Oluwole Fadare, Andres A. Roma)....Pages 213-226
Epithelial and Mixed Epithelial/Mesenchymal Malignancies of the Cervix (Oluwole Fadare, Andres A. Roma)....Pages 227-255
Mesenchymal and Other Miscellaneous Tumors of the Cervix (Oluwole Fadare, Andres A. Roma)....Pages 257-263
Back Matter ....Pages 265-269

Citation preview

Oluwole Fadare Andres A. Roma

Atlas of Uterine Pathology

123

Atlas of Anatomic Pathology Series Editor Liang Cheng Indianapolis, IN, USA

Oluwole Fadare • Andres A. Roma

Atlas of Uterine Pathology

Oluwole Fadare University of California, San Diego La Jolla, CA USA

Andres A. Roma University of California, San Diego La Jolla, CA USA

ISSN 2625-3372     ISSN 2625-3380 (electronic) Atlas of Anatomic Pathology ISBN 978-3-030-17930-4    ISBN 978-3-030-17931-1 (eBook) https://doi.org/10.1007/978-3-030-17931-1 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

I dedicate this book to the memory of my mother, Alhaja Ajoke Iyabo Fadare, RPh (1948–2019), in complete appreciation for everything she embodied and imparted, and in celebration of her cherished legacy. Oluwole Fadare Dedicated to my father and mentors who pushed me to be the best version of myself. Andres A. Roma

Series Preface

One Picture Is Worth Ten Thousand Words — Frederick Barnard, 1927

Remarkable progress has been made in anatomic and surgical pathology during the last 10 years. The ability of surgical pathologists to reach a definite diagnosis is now enhanced by immunohistochemical and molecular techniques. Many new clinically important histopathologic entities and variants have been described using these techniques. Established diagnostic entities are more fully defined for virtually every organ system. The emergence of personalized medicine has also created a paradigm shift in surgical pathology. Both promptness and precision are required of modern pathologists. Newer diagnostic tests in anatomic pathology, however, cannot benefit the patient unless the pathologist recognizes the lesion and requests the necessary special studies. An up-to-date Atlas encompassing the full spectrum of benign and malignant lesions, their variants, and evidence-based diagnostic criteria for each organ system is needed. This Atlas is not intended as a comprehensive source of detailed clinical information concerning the entities shown. Clinical and therapeutic guidelines are served admirably by a large number of excellent textbooks. This Atlas, however, is intended as a “first knowledge base” in the quest for definitive and efficient diagnosis of both usual and unusual diseases. The Atlas of Anatomic Pathology is presented to the reader as a quick reference guide for diagnosis and classification of benign, congenital, inflammatory, nonneoplastic, and neoplastic lesions organized by organ systems. Normal and variations of “normal” histology are illustrated for each organ. The Atlas focuses on visual diagnostic criteria and differential diagnosis. The organization is intended to provide quick access to images and confirmatory tests for each specific organ or site. The Atlas adopts the well-known and widely accepted terminology, nomenclature, classification schemes, and staging algorithms. This book series is intended chiefly for use by pathologists in training and practicing surgical pathologists in their daily practice. It is also a useful resource for medical students, cytotechnologists, pathologist assistants, and other medical professionals with special interest in anatomic pathology. We hope that our trainees, students, and readers at all levels of expertise will learn, understand, and gain insight into the pathophysiology of disease processes through this comprehensive resource. Macroscopic and histological images are aesthetically pleasing in many ways. We hope that the new series will serve as a virtual pathology museum for the edification of our readers. More information about this series at http://www.springer.com/series/10144 Indianapolis, IN, USA

Liang Cheng

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Preface

Every year, diseases of the uterus exert a significant burden to individual patients and, accordingly, to society at large. The prevention, diagnosis, treatment, and posttreatment monitoring for various uterine diseases will ultimately affect most adult women at some point in their lives. Many patients present with symptoms that are ultimately attributed to common uterine diseases such as uterine prolapse, adenomyosis, endometrial polyps, chronic endometritis, or dysfunctional uterine bleeding. Leiomyomas of the uterus remain the most common benign pelvic tumors in women, as well as the most common indication for hysterectomies in the United States. Many countries have large screening programs whose ultimate goal is to minimize the mortality associated with cervical cancers by detecting and eventually treating them at a precancerous phase or at an early stage. These screening programs affect large proportions of the population. Endometrial carcinomas are the most common malignancies of the female genital tract in Western countries and, along with cervical cancers, collectively account for approximately 75,000 new cancer cases diagnosed annually in the United States. Optimal management of the various uterine diseases is clearly one of the more significant functions of medicine as a discipline, and accurate pathologic diagnosis is integral to the entire process. As with most other organs, pathology of the uterus evolves with time: new morphologic variants of classically known entities continue to be recognized; new biomarkers that purport to aid in diagnostic classification of neoplasms are regularly reported even as some older ones are reassessed; molecular profiles that may aid in diagnosis and/or prognosis are now well-­ known for several neoplasms; traditional tumor classification schemes are periodically reassessed to incorporate newly available information and to ensure that they achieve maximal prognostic and predictive stratification of the larger disease groups. Nonetheless, at present time, the practice of uterine surgical pathology is still largely based on the traditional tenets of the discipline, including a detailed assessment of morphologic features of a lesion, supplemented where applicable by its macroscopic and immunophenotypic profiles, and clinical correlation. Our goal for this book is to present the broad morphologic spectrum of the most commonly encountered diseases of the uterine corpus and cervix in an easy-to-use, practically relevant format. Diseases are presented mostly as approximately 1200 images of the various entities. The book emphasizes the morphologic and immunophenotypic features of disease entities, with some additional coverage of normal histology, but is not meant to be a comprehensive treatise on all aspects of uterine surgical pathology. Short clinicopathologic summary descriptions are presented as figure legends for each entity, emphasizing the most salient information a diagnostic pathologist or trainee may wish to know. The image selection focuses on classical appearances as well as less common morphologic variations. Selected images that depict classical immunophenotypes are also presented. The information is broadly consistent with the entities that are recognized in the 2014 classification from the World Health Organization but is also inclusive of developments that have occurred in the subsequent 5 years, as well as the authors’ experiences on and approaches to diagnostic classification. The book is divided into 12 chapters that reflect broad clinicopathologic categorizations and presumed lines of differentiation, with chapters on uterine corpus diseases authored by Dr. Oluwole Fadare and chapters on uterine cervix diseases, as well as gestational trophoblastic ix

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Preface

diseases authored by Dr. Andres Roma. Information about an individual disease entity is best located by referring to the subject index at the end of the book, or by browsing the chapter that is most likely to host that entity. We are confident that this book will prove to be very useful to practitioners and trainees of uterine surgical pathology, as well as to clinicians and investigators interested in the morphology of uterine diseases. La Jolla, CA, USA La Jolla, CA, USA

Oluwole Fadare Andres A. Roma

Contents

1 Normal Histology of the Uterine Corpus �����������������������������������������������������������������   1 1.1 Embryology and Normal Anatomy of the Uterine Corpus ���������������������������������   1 1.2 Uterine Vasculature ���������������������������������������������������������������������������������������������   3 1.3 Inflammatory Cells of the Endometrium�������������������������������������������������������������   4 1.4 Histology of the Premenopausal Endometrium During the Menstrual Cycle���������������������������������������������������������������������������������������������  11 1.5 Normal Endometrium During Perimenopause and After Menopause�����������������  19 1.6 Artifacts of the Endometrial Biopsy �������������������������������������������������������������������  21 References���������������������������������������������������������������������������������������������������������������������  22 2 Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium��������������������������������������������������������������������������������������������������������  23 2.1 Epithelial Metaplasias�����������������������������������������������������������������������������������������  23 2.2 Endometrial Polyps���������������������������������������������������������������������������������������������  37 2.3 Adenomyosis and Adenomyoma�������������������������������������������������������������������������  42 2.4 Chronic Endometritis�������������������������������������������������������������������������������������������  45 2.5 Miscellaneous Endometrial Lesions �������������������������������������������������������������������  50 References���������������������������������������������������������������������������������������������������������������������  53 3 Precancerous and Putative Precursor Lesions of Endometrial Carcinoma ���������  55 3.1 Lesions Associated With Endometrioid Carcinoma �������������������������������������������  55 3.2 Lesions Associated With Serous Carcinoma�������������������������������������������������������  68 3.3 Lesions Associated With Mucinous Carcinoma �������������������������������������������������  72 References���������������������������������������������������������������������������������������������������������������������  76 4 Epithelial and Mixed Epithelial/Mesenchymal Malignancies of the Uterine Corpus�������������������������������������������������������������������������������������������������  79 References��������������������������������������������������������������������������������������������������������������������� 120 5 Mesenchymal and Miscellaneous Neoplasms of the Uterine Corpus��������������������� 123 References��������������������������������������������������������������������������������������������������������������������� 161 6 Gestational Trophoblastic Tumors of the Uterus����������������������������������������������������� 163 6.1 Hydatidiform Moles��������������������������������������������������������������������������������������������� 165 6.2 Malignant Trophoblastic Lesions������������������������������������������������������������������������� 169 References��������������������������������������������������������������������������������������������������������������������� 172 7 Functional Disorders, Pregnancy, and Hormone-Related Changes of the Endometrium��������������������������������������������������������������������������������������������������� 173 References��������������������������������������������������������������������������������������������������������������������� 192 8 Normal Anatomy of the Uterine Cervix������������������������������������������������������������������� 193 References��������������������������������������������������������������������������������������������������������������������� 196 9 Pseudoneoplastic and Benign Diseases of the Cervix ��������������������������������������������� 197 References��������������������������������������������������������������������������������������������������������������������� 212 xi

xii

10 Precancerous Lesions of the Cervix�������������������������������������������������������������������������� 213 10.1 Squamous Preneoplasia������������������������������������������������������������������������������������� 213 10.2 Glandular Preneoplasia ������������������������������������������������������������������������������������� 221 References��������������������������������������������������������������������������������������������������������������������� 226 11 Epithelial and Mixed Epithelial/Mesenchymal Malignancies of the Cervix ��������������������������������������������������������������������������������������������������������������� 227 11.1 Squamous Cell Carcinoma��������������������������������������������������������������������������������� 227 11.2 Adenocarcinoma ����������������������������������������������������������������������������������������������� 232 11.3 Mesonephric Carcinoma ����������������������������������������������������������������������������������� 245 11.4 Neuroendocrine Tumors������������������������������������������������������������������������������������� 246 11.5 Miscellaneous Tumors��������������������������������������������������������������������������������������� 249 11.6 Adenosarcomas ������������������������������������������������������������������������������������������������� 252 11.7 Carcinosarcoma������������������������������������������������������������������������������������������������� 254 References��������������������������������������������������������������������������������������������������������������������� 255 12 Mesenchymal and Other Miscellaneous Tumors of the Cervix ����������������������������� 257 References��������������������������������������������������������������������������������������������������������������������� 263 Index�����������������������������������������������������������������������������������������������������������������������������������  265

Contents

1

Normal Histology of the Uterine Corpus

1.1

 mbryology and Normal Anatomy E of the Uterine Corpus

The uterus is the fusion product of the embryologic paramesonephric (müllerian) ducts. By the second trimester, the endometrial lining is composed of columnar epithelium with surface ciliation, abundant nuclear pseudostratification, and occasional mitotic figures. The epithelium is mostly flat but may show undulations and gland-like invaginations into the underlying mesenchyme, in which a vague layering is often morphologically discernible (Figs. 1.1, 1.2, 1.3, 1.4, and 1.5). The adult, non-gravid uterus is a pear-shaped structure that measures 7–9  cm on average along its long axis (Figs.  1.6 and 1.7). The caudal third of the uterus represents the cervix, and the proximal two thirds is the corpus [1–4]. The portion of the corpus cephalad to a line connecting the two fallopian tube origins is called the fundus. The body—the portion of the uterine corpus caudal to the same line—tapers into a lower uterine segment or uterine isthmus, which in turn is in continuity with the cervix. The uterine body is anteflexed on the cervix and the whole uterus is tipped slightly forward (anteversion). The hollow center of the uterus is a triangular space whose lining is continuous with the fallopian tube mucosa at the bilateral tubal cornu, and with the endocervical mucosa caudally. The endometrial cavity is lined by endometrium (comprising endometrial epithelium, endometrial mesenchyme, and vessels) and is surrounded by a myometrium composed of smooth muscle, vessels, and other mesenchymal elements. The myometrium comprises bundles of woven smooth muscle, which are arranged in two or three somewhat distinct layers, although this layering is not always clearly discernible. The outer portions of the myometrium are in continuity with the outer musculature of the fallopian tube, cervix, and vagina. The uterine musculature has a larger component of collagenous tissue at the level of the internal os and distally.

Fig. 1.1  Uterus at 18 weeks. Note the central epithelium-lined uterine canal surrounded by uterine mesenchyme

Fig. 1.2  Uterus at 22  weeks. The endometrial lining shows surface undulations and gland-like invaginations. Even at term, the endometrial lining is often simple and is devoid of the complex glandular architecture that may be encountered in the adult endometrium

© Springer Nature Switzerland AG 2019 O. Fadare, A. A. Roma, Atlas of Uterine Pathology, Atlas of Anatomic Pathology, https://doi.org/10.1007/978-3-030-17931-1_1

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1  Normal Histology of the Uterine Corpus

a

b

Fig. 1.3 (a, b) Uterus at 18 weeks. Endometrial epithelium shows ciliation and abundant pseudostratification. The surrounding mesenchyme shows vague layering and increased cellularity. Smooth muscle differentiation is demonstrable in the uterine mesenchyme at this stage

Fig. 1.4  Uterine mesenchyme at 23 weeks. A muscular layer is well developed. An outer layer (lower field) and inner layer are discernible. The endometrium epithelium is seen in the upper right field Fig. 1.6  Primary components of the uterus

Fig. 1.5  Myometrium in the second trimester. There is more cellularity than in the adult myometrium, and there is significantly less fascicular arrangement of cells

1.2 Uterine Vasculature

Fig. 1.7  The anterior surface of the uterus (left) can be distinguished from the posterior surface (right) based on the fact that the anterior surface has a larger area that is devoid of peritoneal lining than the

1.2

3

posterior, in its lower component. Additionally, the stump of the round ligament is anteriorly directed

Uterine Vasculature

The immediate arterial supply of the uterus comprises the right and left uterine arteries, which are subsidiaries of the internal iliac arteries [5, 6]. At the level of the uterine isthmus, the uterine artery on each side bifurcates into two branches, whose subsidiaries include the circumferentially arranged arcuate arteries, their myometrium-penetrating branches (radial arteries), basal branches of radial arteries, and ultimately, the spiral arterioles that terminate in the endometrium (Figs.  1.8, 1.9, 1.10, 1.11, and 1.12). Spiral arteries are hormone-sensitive, and their pericytes have been shown to be estrogen- and progesterone-receptor positive. The venous drainage of the uterus is largely comparable.

Fig. 1.8  Uterine arteries. Thick-walled vessels of the outer myometrium include the lateral perforating branches of the uterine artery, from which branch the arcuate artery and then the radial arteries. These arteries not infrequently show atherosclerosis and calcification

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1  Normal Histology of the Uterine Corpus

Fig. 1.9  Uterine arteries. Comparing this specimen to Fig. 1.8 highlights the fact the relative thickness and prominence of myometrial vessels may vary significantly between patients Fig. 1.12  Uterine arteries. Clustered arterioles in the functionalis at high magnification

1.3

Fig. 1.10  Uterine arteries. Arteries at the endometrial basalis and at the myometrial/endometrial interface may also be prominent and notably clustered. These are basal branches of the radial arteries

Fig. 1.11  Uterine arteries. Arterioles may occasionally be clustered in the endometrial functionalis; this is a clinically insignificant variation

Inflammatory Cells of the Endometrium

Leukocytes represent about 10–25% of all endometrial cells, and they vary in number and distribution during the menstrual cycle [7–9] (Figs.  1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, and 1.35). Table 1.1 summarizes the full distribution of inflammatory cells that may be encountered in the endometrium [8, 9]. Scattered lymphoid aggregates are essentially a normal finding, typically present in the stratum basalis (Fig. 1.32). However, the presence of large numbers of lymphocytic aggregates has been associated with chronic endometritis. There is some evidence that in the setting of chronic endometritis, there is a change in the distribution and ratio of lymphocytic subpopulations. Neutrophils are commonly present when the menstrual phase is well developed, typically around day 2 of the cycle [9, 10] (Fig. 1.35). Plasma cells may be associated with breakdown and menstruation, but may be pathologic when seen in significant populations outside of these settings.

1.3 Inflammatory Cells of the Endometrium

5

Table 1.1  Relative distribution of inflammatory cells in the functional endometrium at three specific points of the normal menstrual cycle Cell type Macrophages Eosinophils Neutrophils Mast cells T lymphocytes B lymphocytes NK cells/granulated lymphocytes

Proliferative phase (days 10–12) + – – ++ + +/– –

Secretory phase (days 22–23) ++ – – ++ + +/– +/++

Menstrual phase (days 26–28) +++ ++ +++ ++ + + +++

Percentage of total endometrial cells at menses 6–15% 3–5% 6–15% 3–5% 1–2% – 5–6%

Adapted from Salamonsen and Lathbury [8]; with permission NK Natural killer

Fig. 1.15  The stratum compactum is the sub-surface epithelial zone that has the appearance of comprising mostly confluent predecidualization. The stratum spongiosum is the deeper zone of serrated glands. The stratum compactum/spongiosum layering is seen in the late secretory phase

Fig. 1.13  The endometrium is composed of a functional layer (stratum functionalis) and a basal layer (stratum basalis). The functional layer is generally of greater volume than the basal layer, especially in cycling, premenopausal patients. The functional layer shows significantly greater sensitivity to endogenous and exogenous hormones than the basal layer

Fig. 1.14  The stratum functionalis in the secretory phase can be classified into a superficial compact layer (stratum compactum) and a deep spongy layer (stratum spongiosum), but in the early and mid parts of the secretory phase, as shown here, the stratum compactum is not apparent

Fig. 1.16  The stratum basalis in a patient who has been treated with exogenous progestins. Even in this setting, the stratum basalis frequently shows less hormonal responsiveness than the stratum functionalis. In the second half of gestation, however, or after prolonged treatment with progestins, the stratum basalis may show alterations consistent with hormone responsiveness, including complete stroma precidualization/decidualization

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1  Normal Histology of the Uterine Corpus

a

b Fig. 1.17  Stratum basalis. The stroma typically appears more compact and cellular than the stratum functionalis with which it is associated. The stroma may also be spindled, especially near the myometrial/endometrial interface

Fig. 1.18  Stratum basalis. Clusters of vessels are commonly present, representing the basal branches of the myometrial radial arteries

Fig. 1.19 (a, b) Stratum basalis in a biopsy specimen. The stroma of the stratum basalis fragment is often distinct because of its increased stromal cellularity compared with the stratum functionalis fragments. The glands of the basalis are often simple or branched tubular glands lined with nonsecretory, pseudostratified cells with basophilic chromatin; mitotic figures are rare. The glands in the stratum basalis may show slight dilatation, which is most likely either a secretion retention or an atrophic phenomenon. Another feature that may be seen in the basalis is one or more lymphoid aggregates

1.3 Inflammatory Cells of the Endometrium

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b

Fig. 1.20 (a, b) Stratum basalis in a biopsy specimen. The glands of the stratum basalis may display more dilatation than the glands of the stratum functionalis. This finding should not be mistaken for an anovulatory pattern (disordered proliferative endometrium). The concurrent

a

presence of increased stromal spindling and cellularity are useful morphologic features that support the interpretation that the fragment that displayed such glands represents stratum basalis

b

Fig. 1.21 (a, b) Surface epithelium overlying proliferative pattern endometrium. The surface epithelium is continuous with the underlying glands, but generally shows less cyclic variation. The epithelium is lined by cells that are columnar, variably pseudostratified, and frequently ciliated

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a

b

Fig. 1.22 (a, b) Surface epithelium overlying early secretory pattern endometrium. The surface epithelium shows less secretory change than the underlying glands. This dissonance is more appreciable in the early parts of the secretory phase Fig. 1.23  Surface epithelium overlying mid secretory pattern endometrium. The surface epithelium more closely resembles the underlying glands, with which it is contiguous

a

Fig. 1.24 (a, b) The uterine isthmus (lower uterine segment) shows significantly reduced responsiveness to hormones, compared with the uterine corpus. Accordingly, the functional state of the lower uterine segment endometrium should not be used as an indicator for the func-

b

tional state of the entire endometrium. The glands are typically lined by weakly proliferative columnar glands with prominent ciliation. The stroma is more spindled, more collagenous, and generally less cellular than the endometrial stroma in the upper uterine corpus

1.3 Inflammatory Cells of the Endometrium

9

Fig. 1.25  Endometrial epithelium. Proliferative-type glands are lined by cells with fusiform nuclei, variably dense chromatin, and inconspicuous nucleoli. During the proliferative phase, mitotic figures are easily identifiable in such glands in the stratum functionalis, and the nuclei appear to be pseudostratified Fig. 1.27  Endometrial epithelium. Clear cells (such as the one at the 9 o’clock position) are characterized by round nuclei and clear cytoplasm; they often have a cytoplasm diameter that appears to be significantly wider than adjacent non-clear cells. These cells are significantly less common than ciliated cells, but are almost invariably identified in association with the latter and are thought to be their precursors. Clear cells also show a more specific association with conditions of estrogen excess than ciliated cells

Fig. 1.26  Endometrial epithelium. Proliferative-type glands frequently show ciliation. Ciliated cells are commonly identified in the surface epithelium and underlying endometrial glands, especially towards the cornu and the cervix. Ciliated cells become more prominent in conditions associated with estrogen excess

Fig. 1.28  Endometrial epithelium. Secretory cells vary in appearance depending on the day of the menstrual cycle, as described in detail in subsequent sections

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Fig. 1.29  Endometrial stroma. The endometrial stroma in the proliferative phase comprises round to fusiform cells with scant cytoplasm, dense chromatin, and inconspicuous nucleoli. Mitotic activity is prominent during the proliferative phase

1  Normal Histology of the Uterine Corpus

Fig. 1.30  Endometrial stroma. At various points during the cycle, the endometrial stroma shows prominent interstitial edema, giving the cells a “dispersed” appearance

Fig. 1.31  Endometrial stroma. Later in the menstrual cycle, the endometrial stroma shows increased eosinophilic cytoplasm, poorly defined cell membranes, nuclei with more vesicular chromatin, and variably discernible nucleoli. These changes define stroma “pseudodecidualization” or “predecidualization” [10]. Similar changes associated with pregnancy are termed “decidualization”

a

b

Fig. 1.32 (a, b) Endometrial lymphocytes. Aggregates of lymphocytes are a common (and essentially normal) finding in the endometrium. They are more commonly identified in the stratum basalis than in the stratum functionalis

1.4 Histology of the Premenopausal Endometrium During the Menstrual Cycle

Fig. 1.33  Endometrial foam cells show abundant vacuolated cytoplasm and oval or bean-shaped nuclei. They are associated with conditions of estrogen excess, such as endometrioid carcinomas and hyperplasias, but they are nonspecific and may be seen in other conditions, such as xanthogranulomatous endometritis. Various authors think them to be of either histiocytic origin or stromal origin

11

Fig. 1.35  Neutrophils are commonly present when the menstrual phase is well developed, typically around day 2 of the cycle

1.4

Histology of the Premenopausal Endometrium During the Menstrual Cycle

The menstrual cycle during the reproductive years has traditionally been classified into proliferative (preovulatory/ovarian follicular) and secretory (postovulatory/ovarian luteal) phases, to which menstrual and interval phases may be added [1–5] (Figs.  1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, and 1.58). The proliferative phase accounts for most of the observed interpatient variability in the length of the menstrual cycle. Fig. 1.34  Stromal granulocytes (also known as granular/granulated lymphocytes, K cells, large granular lymphocytes, endometrial granulocytes, or decidual granulated lymphocytes) are present in large populations during the last days of the menstrual cycle. Stromal granulocytes display eosinophilic cytoplasmic granules; small, somewhat lobulated hyperchromatic nuclei; and a CD3−CD56brightCD16− phenotype. This phenotype distinguishes them from the natural killer (NK) cells of the peripheral blood, wherein CD56 expression is dim. These cells should not be mistaken for neutrophils

12

1  Normal Histology of the Uterine Corpus

a

Fig. 1.36  Early proliferative phase (Cycle days 4–7). The early proliferative phase is characterized by short, straight glands devoid of any significant tortuosity

b

Fig. 1.37  Early proliferative phase (Cycle  days 4–7). The stroma is loose and forms a significant component of the sample

Fig. 1.39 (a, b) Mid proliferative phase (Cycle  days 8–10). Glands begin to show early tortuosity, accompanied by stromal edema

Fig. 1.38  Early proliferative phase (Cycle  days 4–7). Glands show nuclear pseudostratification, with round to oval nuclei and dense chromatin. There is brisk mitotic activity in both stroma and glands

Fig. 1.40  Mid proliferative phase (Cycle days 8–10). Glands show nuclear pseudostratification with round to oval nuclei and dense chromatin. The mitotic activity and nuclear characteristics of the proliferative phase glands are generally similar in different points of the proliferative phase

1.4 Histology of the Premenopausal Endometrium During the Menstrual Cycle

a

13

a

b

b

c

Fig. 1.41 (a–c) Late proliferative phase (Cycle days 11–14). Glands are overtly tortuous. Stroma is cellular and dense, although edematous areas may be seen. Glands show nuclear pseudostratification with round to oval nuclei and dense chromatin. Brisk mitotic activity is present in glands and stroma

Fig. 1.42 (a, b) The interval phase pattern is the morphologic correlate to the 48-hour period between ovulation and definitive morphologic evidence of ovulation on day 17. The glands show proliferative-type nuclear features, mitotic figures, and scattered glands with subnuclear vacuolization. This pattern does not allow for a definitive conclusion that ovulation has taken place

14

Fig. 1.43 Early secretory phase: menstrual cycle day 17 (post-­ ovulatory day 3): Tortuous glands lined by columnar cells. Mild pseudostratification is still present, but the uniform subnuclear vacuolization pushes the nuclei to the center of the cell, aligned in a “piano-keys” pattern. Subnuclear cytoplasmic vacuolization is seen in the majority of glands. Mitotic figures are scant. Stroma is loose and edematous. The day 17 pattern is the first unequivocal morphologic evidence that ovulation has taken place

1  Normal Histology of the Uterine Corpus

Fig. 1.45 Early secretory phase: menstrual cycle day 18 (post-­ ovulatory day 4): Tortuous glands lined by columnar cells. Subnuclear cytoplasmic vacuolization is still present, but supranuclear vacuolization is now prominent

a

Fig. 1.44 Early secretory phase: menstrual cycle day 17 (post-­ Fig. 1.46 (a, b) Early secretory phase: menstrual cycle day 18 (post-­ ovulatory day 3). By late day 17, subnuclear cytoplasmic vacuolization ovulatory day 4): Tortuous glands lined by columnar cells. Subnuclear is still prominent, but early supranuclear vacuolization is discernible cytoplasmic vacuolization is still present, but supranuclear vacuolization is now more prominent than subnuclear vacuolization. Mitotic figures are notably scant. Mild pseudostratification may be present. Nuclei are more round than oval. There is stroma edema

1.4 Histology of the Premenopausal Endometrium During the Menstrual Cycle

b

15

a

Fig. 1.46 (continued)

b

Fig. 1.48 (a, b) Mid secretory phase: menstrual cycle day 20 (post-­ ovulatory day 6). Glands are similar to day 19, except with more prominent intraluminal secretions. Glands with intraluminal secretions constitute the majority of glands on day 20 Fig. 1.47  Mid secretory phase: menstrual cycle day 19 (post-ovulatory day 5). Glands no longer show cytoplasmic vacuolization and are predominantly lined by columnar cells with no significant nuclear pseudostratification. Mitotic figures are absent. Scattered glands display intraluminal secretions. Stroma is edematous

Fig. 1.49  Mid secretory phase: menstrual cycle day 21 (post-ovulatory day 7). Glands are irregular and are without serrations. There is increasing stromal edema

16

1  Normal Histology of the Uterine Corpus

a

Fig. 1.50 (a, b) Mid secretory phase:; menstrual cycle day 22 (post-­ ovulatory day 8). Glands are irregular but are devoid of overt serration. There is maximal stromal edema, resulting in stromal cells that appear

a

b

Fig. 1.51 (a, b) Mid secretory phase: menstrual cycle days 23 and 24 (post-ovulatory days 9 and 10). Predecidua surrounds spiral arterioles, which are mostly clustered. The peri-arteriolar predecidualization starts on day 23 and becomes more prominent in day 24. For both days, predecidualization is not diffuse and is absent from the superficial subepithelial zone. Non-predecidualized stroma show edema. Stromal mitotic figures may be seen. Glands are irregular, and may show variable luminal secretions. On day 24, secretory exhaustion begins. (See Fig. 1.56)

b

to be devoid of cytoplasm. Scattered spiral arterioles may be seen, but they are neither prominent nor clustered. The spiral arterioles do not display any peri-arteriolar stromal predecidualization

a

b

Fig. 1.52 (a, b) Mid secretory phase: menstrual cycle day 25 (post-­ ovulatory day 11). Small predecidualized zones are present throughout the stroma, including in the zone below the surface epithelium. Diffuse areas of coalesced predecidualization are absent. Non-predecidualized stroma show some edema. Stromal mitotic figures may be seen. Glands are irregular, and may show variable luminal secretions

1.4 Histology of the Premenopausal Endometrium During the Menstrual Cycle

17

Fig. 1.53  Late secretory phase: menstrual cycle day 26 (post-­ ovulatory 12). Stromal predecidualization is diffuse. There is an abundance of granulated lymphocytes. Glands show secretory exhaustion

a

Fig. 1.54 (a, b) Late secretory phase: menstrual cycle day 27 (post-­ ovulatory day 13). Stromal predecidualization is diffuse. There is an abundance of granulated lymphocytes. Glands show prominent serra-

Fig. 1.55  Late secretory phase: menstrual cycle day 27 (post-­ ovulatory day 13). The compactum spongiosum shows confluent glands. Constituent cells are tall and columnar

b

tion. Focal necrosis of stroma may be seen. The stratification between the compactum and spongiosum layers of the functionalis has become very prominent

18

1  Normal Histology of the Uterine Corpus

a

a

b

b

c

Fig. 1.56 (a–c) Various iterations of glands with secretory exhaustion. These glands are seen on menstrual cycle days 24–27, but become more diffuse after day 26. Secretory exhaustion is variably characterized by tortuous glands with intraluminal serration or sawtooth pattern, “fluffy” luminal borders, some vacuolization, and (to various extents) luminal secretions

Fig. 1.57 (a, b) Menstrual phase endometrium. The first day of clinical menstruation denotes the first day of the menstrual cycle. Key features include marked fragmentation of endometrial glands; glands with secretory exhaustion or a vaguely secretory appearance; absence of any mitotic figures; an abundance of red blood cells, neutrophils, and other inflammatory cells, (including plasma cells and histiocytes); and prominent stromal breakdown. If the biopsy is obtained at the beginning of the menstrual phase or late on day 28, residual predecidua may be prominent; if obtained later in the menstrual phase, fragments of proliferative endometrium may be seen

1.5 Normal Endometrium During Perimenopause and After Menopause

a

b

Fig. 1.58 (a, b) Menstrual phase endometrium. Prominent stromal breakdown is a key feature of menstrual pattern endometrium, and is characterized by nodules of condensed stromal cells with associated

1.5

19

syncytial regenerative cells (the so-called blue balls). The stromal condensates may display apoptotic bodies and scattered plasma cells

 ormal Endometrium During N Perimenopause and After Menopause

In the postmenopausal age group, following a marked reduction in production of ovarian hormones, the endometrium loses its cyclic stimulation and becomes progressively more inactive, to atrophic (Figs. 1.59, 1.60, 1.61, and 1.62).

Fig. 1.59  Weakly proliferative endometrium. “Weakly proliferative endometrium” is a term that is used to describe endometrium with a predominance of non-tortuous glands that are lined by non-stratified or mildly pseudostratified columnar cells but which are devoid of mitotic figures. The lesser pseudostratification, as well as the absence of abundant mitotic figures, distinguishes weakly proliferative endometrium from proliferative-pattern endometrium. Weakly proliferative endometrium does not denote a specific functional state but is better conceptualized as a morphologic pattern. This pattern may be seen in the perimenopausal years, or in postmenopausal years if there is a source of at least low-level estrogenic stimulation (e.g., from endogenous sources such as obesity or from exogenous sources such as hormone replacement therapy)

20

a

b

Fig. 1.60  Endometrium after menopause. (a, b) This atrophic endometrium shows foci with complete glandular absence and only a residual surface epithelium. The endometrium after menopause may range from proliferative to weakly proliferative to inactive or atrophic

Fig. 1.62  Endometrium after menopause. Atrophic endometrium in biopsies or curettages is characterized by detached fragments of atrophic epithelium. The sample is typically of small volume

1  Normal Histology of the Uterine Corpus

a

b

Fig. 1.61 (a, b) Endometrium after menopause. An advanced form of atrophy (called “cystic atrophy”) is characterized by cystic glands that are lined by flat cells with very minimally discernible cytoplasm. Some weakly proliferative endometrium may be concurrently present (b, lower field). Atrophy may also be associated with some stromal fibrosis

1.6 Artifacts of the Endometrial Biopsy

1.6

21

Artifacts of the Endometrial Biopsy

A few artifactual changes also can be seen in endometrial biopsy specimens, some of which may be a result of the biopsy itself (Figs. 1.63, 1.64, and 1.65).

a

b

Fig. 1.63 (a, b) Endometrial biopsy artifact: Telescoping. This effect is brought about by the biopsy itself, which causes an intussusception of the bottom half of the gland, and making it appear as if there is a gland within a larger gland

Fig. 1.64  Endometrial biopsy artifact. In this uncommon artifact of unknown cause, a small cluster of glands appear “pasted” onto each other, with each constituent gland modulating the shape of the other “attached” glands

Fig. 1.65  Endometrial biopsy artifact: Artifactual crowding due to stromal “breaks.” In this artifact, there are areas of stromal “degeneration” that are probably associated with the biopsy itself. The net effect is for stroma to collapse onto each other, giving a false crowded appearance

22

References 1. Heller DS.  The normal endometrium. New  York: Igaku-Shoin Medical; 1994. 2. Zaino RJ.  The logical patterns of the normal endometrial cycle. Interpretation of endometrial biopsies and curettings. In: Silverberg SG, editor. Biopsy interpretation series. Philadelphia: Lippincott-­ Raven; 1996. p. 53–99. 3. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3–25. 4. Murray MJ, Meyer WR, Zaino RJ, Lessey BA, Novotny DB, Ireland K, et  al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril. 2004;81:1333–43.

1  Normal Histology of the Uterine Corpus 5. Robertson WB. Uteroplacental vasculature. J Clin Pathol Suppl (R Coll Pathol). 1976;10:9–17. 6. Ellis H.  Anatomy of the uterus. Anaesth Intensive Care Med. 2011;12:99–101. 7. Wira CR, Fahey JV, Sentman CL, Pioli PA, Shen L.  Innate and adaptive immunity in female genital tract: cellular responses and interactions. Immunol Rev. 2005;206:306–35. 8. Salamonsen LA, Lathbury LJ.  Endometrial leukocytes and menstruation. Hum Reprod Update. 2000;6:16–27. 9. Lee SK, Kim CJ, Kim DJ, Kang JH. Immune cells in the female reproductive tract. Immune Netw. 2015;15:16–26. 10. Deligdisch L.  Hormonal pathology of the endometrium. Mod Pathol. 2000;13:285–94.

2

Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

2.1

Epithelial Metaplasias

Metaplasia of the endometrium represents a change from one epithelial type to another, the latter typically being of a cell type seen elsewhere in the müllerian tract [1–4]. The aforementioned “change” may be conceptualized as a reactive alteration in the cellular cytoplasm and nuclei, although the precise causative factors are not always clear in each individual case [3]. Table  2.1 summarizes the distribution and frequencies of endometrial metaplasias. In 58–82% of cases, a metaplasia of one type is admixed with a metaplasia of another type [1, 2]. Metaplasias may be associated with a variety of neoplastic and non-neoplastic diseases, with benign or malignant neoplasms, with patients of all ages, and with the use of exogenous hormones [1–13] (Figs. 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.30, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, and 2.39).

Table 2.1  Frequency of endometrial metaplasias

Ciliated (tubal) metaplasia Eosinophilic metaplasia Squamous metaplasia and morules Mucinous metaplasia Papillary syncytial metaplasia Hobnail metaplasia Clear cell metaplasia

© Springer Nature Switzerland AG 2019 O. Fadare, A. A. Roma, Atlas of Uterine Pathology, Atlas of Anatomic Pathology, https://doi.org/10.1007/978-3-030-17931-1_2

Hendrickson and Kempson [1] 58%

Toomine et al. [2] 22.3%

48% 34%

36% 70.9%

24% 12%

38.8% “Others”: 11.7%

6% 4%

23

24

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

a

b

c

d

Fig. 2.1 Papillary syncytial metaplasia. (a–d) This retrogressive change is frequently associated with stromal breakdown. It is typically a surface process that may also involve underlying glands, comprising a syncytial mass of cells with poorly defined cell membranes and typi-

cally bland, pyknotic, or degenerated nuclei. When associated with breakdown, the syncytial cells appear to partially envelop the stromal condensates with which they are associated

Fig. 2.2  Papillary syncytial metaplasia with a more overtly papillary appearance

Fig. 2.3  Papillary syncytial metaplasia with pyknotic nuclei. The nuclei are hyperchromatic and irregular. There are no mitotic figures

2.1 Epithelial Metaplasias

Fig. 2.4  Papillary syncytial metaplasia, showing the typical level of pleomorphism. There is only a slight variability in nuclear size and shape

25

Fig. 2.6  Papillary syncytial metaplasia, showing typical infiltration by neutrophils

a

Fig. 2.5  Papillary syncytial metaplasia. Rare cases display nuclear enlargement, but other features identify it as papillary syncytial metaplasia Fig. 2.7 (a, b) Florid papillary syncytial metaplasia. Some cases are overtly florid and may show complicated branching, but it remains a surface process without significant anaplasia or mitotic figures

26

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

b

a

b Fig. 2.7 (continued)

Fig. 2.10 (a, b) A florid iteration of papillary syncytial metaplasia may be associated with infarcted endometrial polyps [12]. The foci may display moderate atypia, which is thought to be a reactive change. Mitotic figures are absent or inconspicuous Fig. 2.8  Papillary syncytial metaplasia: This papillary syncytial metaplasia is in direct morphologic continuity with background endometrial epithelium, highlighting the fact that it is a direct derivative of the epithelium

Fig. 2.11  Papillary syncytial metaplasia shows a very low proliferative index (lower right field) Fig. 2.9  Papillary syncytial metaplasia. Apoptotic bodies may be identified, but mitotic figures are distinctly rare

2.1 Epithelial Metaplasias

27

a

Fig. 2.12  Papillary syncytial metaplasia is diffusely positive for p16 (lower right field)

Fig. 2.13  Papillary syncytial metaplasia shows increased staining for p53 relative to background epithelium, but is still p53-wild type (lower right field)

b

Fig. 2.14 (a, b) Icthyosis uteri. In conventional squamous metaplasia, the endometrial surface is replaced to various extents by mature, squamous, well-differentiated squamous epithelium. When the entire surface of the endometrium is replaced by squamous epithelium, the condition is referred to as icthyosis uteri. Conventional squamous metaplasia has been associated with conditions where there is irritation of the uterine surface, including cervical canal obstruction, foreign bodies, chronic endometritis, or pyometra. Squamous change also has been associated with vitamin A deficiency, embolization of uterine leiomyomata, and hormonal therapy [3]. Conventional squamous metaplasia is immunoreactive for epithelial membrane antigen (EMA), CK5/6, and p63, and is mostly negative for CD10, SATB2, CDX2, estrogen receptor (ER), progesterone receptor (PR), synaptophysin, and chromogranin. β-catenin shows mostly membranous expression without significant nuclear expression [3]. Conventional squamous metaplasia and squamous morular change (also known as “squamous morular metaplasia,” “morular metaplasia.” or “morular change,” seen in Figs. 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.21, and 2.22 below) are two distinct and different processes, although both may coexist in approximately 20% of cases [3]. Both conventional squamous metaplasia and squamous morular change may be associated with endometrial hyperplasias and endometrioid carcinoma

28

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

Fig. 2.15  Morular change describes the presence of squamous morules, which are nodular aggregates of uniform, oval or spindle-shaped cells with bland nuclei and eosinophilic cytoplasm. They are functionally inactive (low proliferative index and lack of estrogen and progesterone receptor expression) and arise directly from endometrial epithelium, eventually abridging the epithelium on both sides of the gland [5, 6]

Fig. 2.16 Squamous morules arise directly from endometrial epithelium

a

b

c

d

Fig. 2.17 (a–d) Squamous morules are frequently associated with benign hyperplasia, atypical hyperplasia/endometrioid intraepithelial neoplasia, and endometrioid adenocarcinoma. When associated with

these entities, they share the same PTEN mutation, suggestive of a shared lineage [6]. Squamous morules are also strongly associated with atypical polypoid adenomyoma

2.1 Epithelial Metaplasias

29

a

b

Fig. 2.19  Isolated squamous morules may occasionally be identified without any cytoarchitectural abnormalities in the associated glands. In one study of 31 cases, follow-up showed 7.4% regression, 16.1% persistence, and 6.5% cancer rates, with an interval to cancer of approximately 98 months [6]

c

Fig. 2.20  Isolated squamous morules. In these cases, the squamous morules themselves are functionally inert and as such are not intrinsically worrisome. The concern is for an occult glandular lesion that may not have been sampled. Our approach in these cases is to get at least one round of levels/recuts into the block; if no lesion emerges, we report the finding with a comment suggesting follow-up sampling. In this case, the focus of glandular crowding (right field) was not apparent on the initial sections, wherein only apparently isolated squamous morules were initially found

Fig. 2.18 (a–c) Squamous morules may display varying degrees of central necrosis. This finding has no clinically significant implications

30

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

a

b

Fig. 2.21 (a, b) Florid squamous morules without any cytoarchitectural abnormalities in the associated glands. The approach for these cases is similar to the approach for isolated squamous morules. The clinical concern for the pathologist is uncertainty regarding whether an

Ki-67

Estrogen receptor

Fig. 2.22  Squamous morular metaplasia is immunoreactive for CDX2, SATB2, and CD10, with mosaic staining for p16, nuclear and cytoplasmic expression of β-catenin, and occasional expression of synaptophy-

underlying clinically significant lesion is being obstructed by the florid squamous morules. If no underlying lesion is identified after recuts into the block, our approach is to report the finding and suggest follow-up sampling

CDX2

Beta-catenin

sin and chromogranin. Morules show no diffuse expression of p63, EMA, CK5/6, ER, or PR [3, 10]

2.1 Epithelial Metaplasias

a

31

a

b

b

Fig. 2.23 (a, b) Hobnail metaplasia can be attributed in most cases to one or more conditions: a recent endometrial curettage, chronic inflammation, Arias-Stella reaction, an intrauterine device, ischemia within a polyp or endometrium, or radiation. It may also be an idiopathic finding. Hobnail metaplasia appears on the surface of the endometrium or constituent glands as a non-stratified layer of cells with high nuclear/ cytoplasmic ratios and hyperchromatic nuclei, whose nuclei protrude into the glandular lumina

Fig. 2.25  Hobnail metaplasia associated with an infarcted polyp

Fig. 2.24 (a, b) Hobnail metaplasia in an isolated fragment in an endometrial curettage. This case highlights the potential for significant hyperchromasia and some nuclear enlargement in hobnail metaplasia. The differential diagnosis is an endometrial serous or clear cell carcinoma. These foci are not mass-forming, lack mitotic activity, and are devoid of the known architectural patterns of those carcinomas

32

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

Fig. 2.26  Reactive active and other reparative changes, including hobnail metaplasia post-curettage

Fig. 2.27  Hobnail change at the superficial part of a myometrium-­ invasive endometrial carcinoma, likely a reaction to the prior curettage

a

b

c

d

Fig. 2.28 (a–d) Ciliated (tubal) metaplasia. The surface epithelium and most endometrial glands are lined by variably pseudostratified ciliated cells with oval to round monomorphic nuclei, eosinophilic cytoplasm, and surface cilia. A second population of cells with clear cytoplasm (clear cells) are thought to be the precursor of ciliated cells.

The term ciliated (tubal) metaplasia should not be applied to the ciliated change of normal endometrium. True ciliated (tubal) metaplasia has a prominently dual cellular population, including the ciliated and clear cells. Extensive tubal metaplasias are highly associated with conditions of estrogen excess but in themselves are not diagnostic of it

2.1 Epithelial Metaplasias

Fig. 2.29  Normal surface epithelium. The normal surface endometrial epithelium and most glands are lined by ciliated cells. The second population of clear cells are less predominant in the absence of true tubal metaplasia

a

Fig. 2.31 (a–d) The spectrum of atypical changes that may be encountered in ciliated (tubal) metaplasia includes nuclear enlargement (b) nuclear pleomorphism (b), and hyperchromasia (a, c, d). These are degenerative changes that show staining patterns for p53 and Ki67 that

33

Fig. 2.30  Ciliated (tubal) metaplasia shows immunoreactivity for p16 [8]. They are also p53-wild type and show a low Ki67 proliferative index

b

are similar to the patterns seen in tubal metaplasia without such changes. These changes do not increase the risk of follow-up hyperplasia or malignancy [7]

34

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

c

d

Fig. 2.31 (continued)

a

Fig. 2.32 (a, b) Focus of hyperplasia with ciliated (tubal) change. Ciliated (tubal) change is not infrequently identified in endometrial hyperplasias or endometrioid carcinomas. When assessing the malignant potential of a given focus with tubal change, the complexity of the

b

glandular architecture is the primary determinant. In essence, the emphasis in diagnostic assessment should be placed entirely on the architecture, and the tubal change should be ignored

2.1 Epithelial Metaplasias

35

a

b

Fig. 2.34  Eosinophilic change may be associated with endometrial hyperplasias and endometrioid carcinomas. In this case, the focus with eosinophilic change (right field) and the focus without (left field) are different areas of the same hyperplasia, and the eosinophilic change is devoid of any intrinsic significance. When assessing the malignant potential of a given focus with eosinophilic change, the glandular architecture is the primary determinant

a

c

Fig. 2.33  Eosinophilic metaplasia, also known as oncocytic metaplasia, describes the phenomenon whereby endometrial glands or surface epithelium are lined by non-ciliated cells with abundant eosinophilic to granular cytoplasm, and round (usually uniform) nuclei (a, b). Variations include nucleolomegaly, nuclear enlargement, hyperchromasia (c), and notably granular cytoplasm. An association with mucinous metaplasia has been postulated

b

Fig. 2.35 (a, b) Mucinous metaplasia is a characterized by a replacement of native glands or surface epithelium by cells with mucin-­ containing cytoplasm. The mucinous change should be discernible at the morphologic level. Mucinous metaplasia most commonly resembles endocervical epithelium but may occasionally display an intestinal mucinous or gastric-type mucinous phenotype. Nuclei are bland and mitotic figures are rare to absent. Mucinous metaplasias may be associated with endometrial polyps, papillary syncytial metaplasias, or otherwise unremarkable endometrium

36

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

a

a

b

b

c

c

Fig. 2.36 (a–c) Mucinous metaplasia may show some focal tufting or minor papillary change. In defining the upper limit of what is allowable for mucinous metaplasia, the key points are simplicity and localization. Mucinous metaplasia do not display complex branching papillae and are limited in extent. The changes illustrated here are within the morphologic spectrum for mucinous metaplasia

Fig. 2.37 (a–c) Clear cell metaplasia. Clear cell change is most commonly associated with pregnancy or exogenous use of progestins, but it occasionally may be present without an identifiable underlying cause. Clear cell metaplasia displays cytoplasmic clarity, with bland nuclear features, and is devoid of mitotic figures. The cells may be columnar in configuration (secretory-like) or round/epithelioid. Unlike the principal differential diagnostic consideration, clear cell carcinoma, clear cell metaplasia is typically a focal finding that lacks cytologic atypia and does not form masses. Clear cell metaplasia is also devoid of the architectural patterns of clear cell carcinoma

2.2 Endometrial Polyps

37

Fig. 2.38  Clear cell change associated with radiation to the pelvis. The changes are diffuse within the endometrium and may be associated with some nuclear atypia. There are no other abnormalities

a

b

Fig. 2.39 (a, b) Synovial-like metaplasia is a recently described endometrial alteration that is associated with the levonorgestrel-releasing intrauterine system [13]. This alteration is thought to be a stromal reaction to the foreign body–associated endometrial surface erosion. Typically a focal finding, synovial-like metaplasia is characterized by a

palisade of cells that are oriented perpendicular to the endometrial surface. Occasional multinucleate cells may be present, but overt granulomatous inflammation is absent. Constituent cells express to varying degrees vimentin and CD68, whereas smooth muscle antibody (SMA), PAX8, cytokeratin, ER, PR, and CD10 expression are largely absent [13]

2.2

[19]. In their meta-­analysis, Lee et al. [20] found the prevalence of premalignancy or malignancy in polyps to be 5.42% in postmenopausal women, compared with 1.7% in reproductive-age women, and the risk of neoplasia was substantially increased in patients with symptomatic bleeding [20]. The pathologic diagnosis of endometrial polyps is typically straightforward when there is a clinical/imaging suspicion and a polypoid fragment with classic features is sampled. Many cases are not clinically suspected, however, but are seen by the pathologist as fragmented pieces with poorly developed morphologic features. Figures 2.40, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.50, 2.51, and 2.52 illustrate both the classic appearance of endometrial polyps and morphologic variations.

Endometrial Polyps

Endometrial polyps are common, being present in up to 23% of biopsies performed for abnormal uterine bleeding [14]. Reslová et al. [15] found that postmenopausal uterine bleeding was a prominent clinical symptom in 44% of postmenopausal women with endometrial polyps, and 82% of premenopausal women reported menstrual disorders; the remaining patients in each group were asymptomatic. In one study of over 1019 cases, Schindler and Schmidt [16] found endometrial polyps to be the most common cause (23.7%) of postmenopausal bleeding. Endometrial polyps is the most frequent endometrial lesion associated with tamoxifen therapy [17, 18], and polyps in this setting tend to be larger and more fibrous than those in controls

38

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

a

Fig. 2.40  Endometrial polyp, showing differences in the cellularity and collagenization of the polyp (central field) compared with the background endometrium (right field). In general, the stroma of endometrial polyps is more collagenized and less cellular than background endometrium

a

b

b

Fig. 2.41  Endometrial polyp. The glands of endometrial polyps may be modestly crowded. The crowded areas do not show cytologic demarcation from the background polyp epithelium, and exist in a polypoid fragment with fibrous stroma and thick-walled vessels, features that help identify it as a polyp. The glands are ectatic and irregularly shaped, and may also be cystic. The lining of these glandular units may be atrophic, weakly proliferative, secretory, or proliferative; most often they are weakly proliferative to atrophic. Overall, we refrain from diagnosing the “simple” iteration of the old diagnostic category “simple hyperplasia without atypia” in polyps. Note the thick-walled vessels at the center of the polyp in (a), shown at higher magnification in (b). These vessels are mostly thick-walled and are diagnostically useful in a sampling specimen

Fig. 2.42 (a, b) Endometrial polyps occasionally show stromal cellularity that is comparable to proliferative-type endometrium. In these cases, stromal mitotic figures may be present

2.2 Endometrial Polyps

39

a

Fig. 2.44  Endometrial polyp. This case highlights the distinct collagenization that may be seen in some polyps

b

Fig. 2.43 (a, b) Endometrial polyp with paucity of glands. Some endometrial polyps display such paucity of glands as to raise the possibility of an endometrial stromal neoplasm. Diagnostically useful features include classic areas of an endometrial polyp (not shown), the presence of thick-walled vessels, the presence of residual glands typically at the surface area or periphery of the polyp, and foci of uniform collagenization

Fig. 2.45  Mixed endometrial/endocervical polyp. Polyps of this kind show both endocervical and endometrial type glands, and are frequently located in the lower uterine segment. They may protrude through the cervical os

40

2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

a

Fig. 2.46 (a, b) Endometrial polyp with myomatous stroma. Some conventional endometrial polyps have distinctive “lobules” of smooth muscle, which may or may not entrap glands. These may be conceptualized as iterations of lesions that some authors classify as “adenomyomatous polyps” or just “adenomyoma” [21], but in endometrial polyp

a

b

with myomatous stroma, most of the polyp is a conventional endometrial polyp. The glands are also devoid of periglandular endometrial stroma. We prefer to classify these cases as endometrial polyps with myomatous stroma

b

Fig. 2.47  Endometrial polyp with myomatous stroma. (a) In some polyps, the myomatous stroma takes on a distinctive perivascular, pseudo-­ rosetted arrangement. (b) Diffuse expression of desmin in constituent cells

2.2 Endometrial Polyps

41

a

a

b

b

Fig. 2.48 (a, b) Endometrial polyp, functional. The lining of glandular units in endometrial polyps may be atrophic, weakly proliferative, secretory, or proliferative; most often they are weakly proliferative to atrophic. When the endometrial glands are secretory, such polyps have been traditionally referred to as “functional,” but the level of secretory maturation in such endometrial polyps may differ from the background, and does not provide any information on the functional state of the background endometrium. Other features of endometrial polyps, including the polypoid configuration, thick-walled vessels, and altered stroma, are diagnostically useful in identifying them as polyps Fig. 2.50  Endometrial polyp associated with tamoxifen use. The pathologic features of these polyps are not distinctive enough to be diagnosable based on their morphologic features alone. Such polyps tend to be larger than controls and to display notably fibrous stroma [18, 19], with no to very scant residual periglandular stromal cells. They have also been described as showing glands that are oriented along the long axis of the polyp, with glandular dilatation and frequent metaplastic changes, but the diagnostic specificity of these features has not been assessed in a large cohort

Fig. 2.49 (a, b) Endometrial polyp with atypical (bizarre) stromal cells. These cells may show hyperchromasia of the “smudged” chromatin variety, nuclear enlargement, and no mitotic figures [22]. The atypical cells may be focal or multifocal, and rarely, may be distributed in a band-like fashion beneath the surface epithelium. Full architectural features of adenosarcoma are absent, including intraglandular stromal papillation, robust and diffuse peri-epithelial stromal condensation, and stromal mitotic figures

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2  Selected Non-neoplastic and Benign Diseases of the Endometrium and Myometrium

a

b

Fig. 2.52  Endometrial polyps may occasionally show confluent zones of infarction, which may be seen as active, hemorrhagic, or prior necrosis (diffuse hyalinization). The residual viable glands within these zones frequently show reactive changes, including hobnail, papillary syncytial, clear cell, and eosinophilic metaplasia, and moderate nuclear atypia [12]. These areas are devoid of significant mitotic figures. This image highlights necrosis in the upper field and glands with papillary syncytial metaplasia in the lower right field

2.3

c

Fig. 2.51 (a–c) Endometrial polyp with some focal features that overlap with müllerian adenosarcoma, including intraglandular polypoid projections or focal phyllodes-like architecture, alterations in the periglandular stromal zones, mild stromal atypia, mildly increased stromal mitoses, and rigid cysts. Unlike müllerian adenosarcoma, these endometrial polyps are small (15 MF/10 HPF are rare, and their long-term outcomes are unclear. Such tumors should be classified as smooth muscle tumor of uncertain malignant potential (STUMP) (Table 5.1)

Fig. 5.12  Leiomyoma with surface ulceration. Leiomyomas with surface ulceration are typically submucosal. The ulcerated foci may display suppurative inflammation and fibrin deposition. The underlying tumor may show surface nonspecific necrosis, hemorrhage, and reactive nuclei with pyknosis

5  Mesenchymal and Miscellaneous Neoplasms of the Uterine Corpus

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Fig. 5.14  Cellular leiomyoma. By definition, a cellular leiomyoma shows significantly more cellularity than the background myometrium (right field), ≤4 MF/10HPF, and no coagulative necrosis. This is an assessment that is best made at low or intermediate magnification

a

c

Fig. 5.15  Highly cellular leiomyoma. Highly cellular leiomyoma (HCL) is otherwise similar to cellular leiomyoma but displays such increased cellularity as to resemble low-grade endometrial stromal tumors (EST). HCLs are well circumscribed (a). Unlike EST, HCLs show thick-walled vessels (a–c), may display subtle spindle cell fascicular patterns (d, e) and cleft-like peripheral spaces (b), are devoid of

b

d

a consistent and diffuse network of small arterioles (although focal small arterioles may be seen [f]), and display a desmin-positive/CD10-­ negative immunophenotype. HCL and EST may show significant immunophenotypic overlap, however. HCLs comprise mostly spindle cells (d), but much like EST, round to fusiform cells may be present (f)

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e

5  Mesenchymal and Miscellaneous Neoplasms of the Uterine Corpus

f

Fig. 5.15 (continued)

a

Fig. 5.16 (a–f) Leiomyoma with bizarre nuclei. Leiomyomas with bizarre nuclei are clinically benign neoplasms that, by definition, show atypical, enlarged, or multinucleated (so-called bizarre) cells with variably prominent nucleoli, no coagulative necrosis, and a mostly low mitotic index. Hyperchromasia and nuclear pseudoinclusions are almost invariably present, at least focally. The bizarre cells may be focal, multifocal, or diffuse. Grossly, most of the tumors are solid masses with white to yellow cut surfaces. Tumoral margins are mostly (but not invariably) well-circumscribed (a). 10% are grossly cystic [8].

b

In one study, mitotic counts ranged from 0 to 7/10 HPF (average 1–2/10 HPF); 63% had