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The Role of Pathology in Evaluation of Reproductive, Developmental, and Juvenile Toxicity

1 Introduction Developmental and reproductive toxicity (DART) studies represent an important component of the toxicology programs supporting both the development of novel therapeutics and the evaluation of environmental, agricultural, and industrial chemicals. Reproductive toxicity generally refers to adverse effects on fertility and sexual function in adult males and females, while developmental toxicity refers to effects on the viability, structure, growth, or function of a developing embryo,…

Morphologic Manifestations of Toxic Cell Injury

1 Introduction 1.1 Importance of Morphologic Assessment in Toxicologic Pathology Microscopic morphologic assessment is a major component of experimental toxicity studies using laboratory animal models. To realize the full value of these studies, toxicologic pathologists should accurately classify all adverse findings and provide a cogent interpretation including a plausible pathogenesis (see Nomenclature and Diagnostic Resources in Anatomic Toxicologic Pathology , Vol 1, Chap 25 ). Cell…

Principles of Pharmacodynamics and Toxicodynamics

1 Introduction: Definition of Pharmacodynamics and Toxicodynamics In simple terms, pharmacodynamics (PD) and toxicodynamics (TD) describe the relationship between exposure (concentration at the site-of-action) of the drug, toxicant, or toxin (xenobiotic) and the extent of resulting effect on the body over a time course ( ). PD and TD can be evaluated through in vitro, ex vivo, or in vivo studies and endpoints can range from the molecular to…

Biotherapeutics ADME and PK/PD Principles

1 Introduction Large molecules therapeutics, also referred to as biologics or biotherapeutics, are proteins designed to modulate their target(s) pharmacology to achieve therapeutic effect. The key advantage that biotherapeutics offer is their high target specificity, which makes them ideal modalities for targeted therapy. In contrast to small molecules, large molecule therapeutics cannot penetrate cell membranes and therefore must exert their intended effect through extracellular binding in…

ADME Principles in Small Molecule Drug Discovery and Development: An Industrial Perspective

Acknowledgments The following individuals have provided valuable insights to this book chapter: Trent Abraham, Kenneth Cassidy, Gemma Dickinson, Timothy Jones, Bridget Morse, Everett Perkins, Maria Posada, John Vahle, and Lian Zhou. 1 Introduction As new medicines are being developed to treat patients, it is important to fully characterize the properties of the new molecular entity (NME) to ensure adequate safety and efficacy. As part of the…

Biochemical and Molecular Basis of Toxicity

1 Introduction This chapter provides an overview of the fundamental principles of toxic mechanisms of injury. It is focused on biochemical, cellular, and molecular mechanisms that contribute to toxicity. Additionally, xenobiotic disposition, representing the integrated action of absorption, distribution, biotransformation, and elimination, plays a central role in the development of toxicity and is often a major determinant of the dose–response relationship for toxicity and the potential for…

Toxicologic Pathology: An Introduction

1 An Overview of Toxicologic Pathology Citizens of industrialized societies generally have enjoyed a rising standard of living since the dawn of the Industrial Age in Great Britain during the mid-18th century and in other countries thereafter. This time of widespread economic and social improvements greatly enhanced both individual and communal health, longevity, and productivity. Substantial declines in life-threatening infections and malnutrition reflect not only better…

Cytology in the Practice of Gynecologic Pathology

Introduction Cytologic examination is an integral part of gynecologic pathology. Many of the specimens presenting to the gynecologic surgical pathology service originate as the result of abnormal cytology examinations. Moreover, in many practices, the review of concurrent cytology and surgical pathology material is performed routinely for diagnostic and quality assurance purposes. Lastly, cytologic sampling of the peritoneal cavity is complimentary to pathologic evaluation in patient staging.…

Immunohistochemistry and Molecular Diagnostics in the Differential Diagnosis of Female Genital Tract Pathology

In the last decades, immunohistochemistry (IHC) has seen a marked expansion in application to the diagnosis and prognosis of lesions of the female genital tract. In this chapter, I concentrate on the diagnostic utility of IHC markers in gynecologic pathology as markers of prognostic and predictive significance have been discussed in previous chapters. The uses of immunohistochemistry are covered at the various sites within the female…

Gestational Trophoblastic Lesions

Gestational trophoblastic disease encompasses a diverse group of trophoblastic proliferations that can be divided primarily into molar and nonmolar lesions. Molar lesions derive from villous trophoblast and include partial (PHM), complete (CHM), and invasive hydatidiform moles. Nonmolar lesions include placental-site nodule (PSN), epithelioid trophoblastic tumor (ETT), placental-site trophoblastic tumor (PSTT), and choriocarcinoma. They can be nonneoplastic (PSN) or neoplastic (ETT, PSTT and choriocarcinoma) and encompass proliferations…

Diseases of the Peritoneum

Diseases affecting the peritoneum are diverse, ranging from reactive to neoplastic, the latter being either benign, borderline, or malignant processes. Among malignant tumors, many are of secondary (metastatic) origin; much less commonly, they are primary Müllerian or mesothelial in nature. Entities covered in detail in this chapter include endometriosis, primary peritoneal carcinoma, mesothelioma, pseudomyxoma peritonei, and a small group of unusual tumors such as desmoplastic small…

Metastatic and Miscellaneous Primary Neoplasms of the Ovary

Metastatic Tumors Involving the Ovary Metastases account for approximately 8% of malignant ovarian neoplasms in women undergoing surgery for an adnexal mass in the United States. Metastases derived from nongynecologic sites are 11 times more common than those originating from the female genital tract, with adenocarcinomas of gastrointestinal tract being most frequent. Ovarian metastases are not infrequently encountered in women with disseminated cancer, and when a…

Germ Cell Neoplasms of the Ovary

Germ cell tumors comprise approximately 30% of all primary ovarian neoplasms. The vast majority are mature teratomas representing >90% of neoplasms in this category. Others, called collectively “primitive germ cell tumors,” are rare in Western countries but account for up to 20% of ovarian malignancies in Japan; they also have a strong predilection for young women in the first three decades of life. Although more frequent…

Sex Cord-Stromal Tumors of the Ovary

This category includes a diverse group of neoplasms believed to derive from the hormone-producing ovarian cortical stroma. Based on their predominant cell population and appearance, the World Health Organization (WHO) classification divides them into two main categories: (1) pure lesions, which are in turn divided into pure stromal tumors (with a mesenchymal appearance suggestive of derivation from gonadal stroma; e.g., fibroma, thecoma, and Leydig cell tumor)…

Epithelial Neoplasms of the Ovary

Epithelial tumors, the most common neoplasms of the ovary, encompass five distinct subtypes. Differentiation into these epithelial cell types is under the control of the same genes that determine different epithelial lineages in the female reproductive tract during embryonic development (e.g., mucinous epithelium in the endocervix, endometrioid epithelium in the endometrium, and serous or tubal epithelium in the fallopian tube). Ovarian epithelial tumors are further subclassified…

Nonneoplastic Lesions of the Ovary

The ovary is a solid organ composed of (1) surface epithelium , an extension of the pelvic peritoneum; (2) the cortex , composed of cellular stroma, follicular units (comprised of a central oocyte surrounded by granulosa and theca cells), corpora lutea, and corpora albicantia; and (3) the medulla , composed of large vessels that merge in to the ovarian hilum , which is the point of…

Diseases of the Fallopian Tube and Broad Ligament

Nonneoplastic Lesions of the Fallopian Tube The fallopian tubes comprise the most upper portion of the Müllerian tract bilaterally. They are attached proximally to the uterus (intramural portion), whereas the isthmus and the ampulla extend outside of the uterus and are covered by peritoneum (serosa). In routine histologic preparations, the wall of the fallopian tube is seen as a hollow tubal structure with a lumen, mucosa,…

Mesenchymal and Miscellaneous Lesions of the Uterus

The spectrum of uterine lesions of mesenchymal and mixed mesenchymal-epithelial type has expanded in recent years, largely due to the cumulative experience reported in larger case series, as well as the identification of recurrent gene fusions and other molecular alterations. In routine practice, the approach to most mesenchymal neoplasms encountered in the uterus starts with a judicious morphologic approach, which in many cases suffices for the…

Endometrial Glandular Neoplasia

The spectrum of Endometrial Glandular Neoplasia is wide and includes different types of etiologically, morphologically, and/or molecularly distinct entities. In this chapter, the rationale for the new classification of precursors of endometrial carcinoma and the main types of endometrial carcinoma are discussed. Common problems in the differential diagnosis, and the role of immunohistochemistry and molecular categorization of endometrial carcinoma, are also covered. Premalignant Glandular Neoplasia Endometrioid…

Nonneoplastic Lesions of the Endometrium

Introduction The conditions presented in this chapter represent a wide spectrum of physiologic and pathologic endometrial changes. Their proper identification is important to exclude malignancy and provide correlation with the clinical context. A list of simplified evidence and consensus-based terminology for the most important benign endometrial pathology findings is shown in Table 9.1 . TABLE 9.1 Benign Endometrial Disorders a Nondiagnostic sample (no endometrial tissue present)…