Christopher P. Crum

Cervical Squamous Neoplasia

Abstract This chapter has been extensively revised to address several important issues in the field of cervical neoplasia. These include new information about the origin of cervical squamous neoplasia and its impact on our perceptions of lesion development. This leads in to a discussion of the conundrum of lesion grading, specifically the laboratory management of lesions that fall between cervical intraepithelial neoplasia grade 1 (CIN1) and grade 3 (CIN3). Strategies for managing this problem are offered, and the concept of squamous intraepithelial lesion (SIL) of intermediate (or indeterminate) grade is unveiled. The underpinning of this concept is the absence of any biomarker that can be depended upon to segregate low-grade squamous intraepithelial lesion (LSIL) from high-grade squamous intraepithelial lesion (HSIL) in light of the widespread variations in interpretation between observers and the lack of compelling information to support p16 as either a marker of HSIL or a predictor thereof. Other important topics include new approaches to superficially invasive squamous carcinoma, new management schemes, and the promise of vaccination programs. Finally, the concept of prophylactic ablation of the squamocolumnar junction (SCJ) is addressed as another possible approach to cervical cancer risk reduction in vulnerable populations.

Adenocarcinoma, Carcinosarcoma, and Other Epithelial Tumors of the Endometrium

Abstract This chapter addresses new concepts in the prevention, pathogenesis, diagnosis, and management of endometrial epithelial neoplasia. Superimposed on the traditional two disease system (endometrioid and serous carcinomas) is newly discovered molecular subgroups of tumors that correlate with both improved (POLE mutations) and poor (high copy number variation [CNV]) outcomes. Prevention now focuses on more extensive screening for mismatch repair defects by immunohistochemistry to identify a small percentage of patients with a familial predisposition (Lynch syndrome). In practice, the most common classification issues are (1) the identification of subsets of endometrioid carcinomas that are at higher risk for an adverse outcome, including excluding serous carcinoma and (2) distinguishing clear cell carcinoma from clear cell change. Management issues center on determining the depth of invasion, separating real from artifactual vascular space invasion, interpreting nodal micrometastases, and distinguishing metastatic disease from new primary tumors. Ultimately, the role of radiation merits more scrutiny when balancing quality of life with recurrence risk if survival will not be altered. Chemotherapy beyond hormonal therapy remains an ongoing challenge.

Benign Conditions of the Ovary

Abstract The primary purposes of this chapter are to both acquaint the reader with the myriad of pathologic findings that will be encountered in the benign ovary and provide a detailed description of pathologic conditions, including altered ovarian cortical and follicular biology (polycystic ovary syndrome [PCOS]), endometriosis, infections, and infertility. Potential mimics of neoplasia, such as tangentially sectioned follicles, stromal or hilar cell hyperplasias, and atypias in endometriosis, are also discussed.

Altered Endometrial Differentiation (Metaplasia)

Abstract The endometrium plays host to a variety of alterations in epithelial differentiation, and all of these alterations display a morphologic spectrum from benign changes to those that are malignant. The best way to conceptualize metaplasias is to consider them as alterations of differentiation and visualize them as running parallel to benign processes, endometrial precancers, and cancer. This chapter will focus on a practical approach to the management of such alterations, specifically those changes that merit the most concern.

Epithelial and Mixed Epithelial-Stromal Neoplasms of the Vagina

Abstract This chapter addresses a spectrum of neoplasms that can be found in the vagina, ranging from the more common, the squamous intraepithelial lesions, to the more obscure. Particularly problematic are the adenocarcinomas, which can be primary (originating in endometriosis), metastatic from a range of sites, or emerge in misplaced embryonic remnants (cloacogenic neoplasia). Tumors that can be particularly confusing include vaginal melanomas and spindle cell epitheliomas (mixed tumors).

Sex Cord-Stromal and Miscellaneous Tumors of the Ovary

Abstract Stromal and sex cord–stromal tumors of the ovary represent a varied group of tumors composed of ovarian and/or testicular-type cells that are remarkable for their morphologic diversity. Their ability to exhibit a wide morphologic spectrum in combination with many of them being rarely encountered contributes to diagnostic uncertainty when a tumor from this group is seen in daily practice. This chapter organizes these tumors into groups that the pathologist can readily recognize and provides diagnostic alternatives to minimize the chance of misclassification.

Preinvasive Endometrial Neoplasia

Abstract Hormonal field effects (non–atypical endometrial hyperplasia) must be distinguished from true precancerous lesions (endometrioid intraepithelial neoplasia [EIN]) because of their differing management. This chapter also presents mimics of precancerous lesions and includes special presentations of lesions with altered differentiation (metaplasias).

Female Genital Tract Development and Disorders of Childhood

Abstract Female reproductive tract development is a complex process intricately tied to the patterning of the male (Wolffian) reproductive tract and renal anlage. Development starts from undifferentiated mesoderm known as the genital ridge, with germ cells migrating to this location from the yolk sac. The mullerian duct begins as an invagination of the coelomic epithelium at the top of the genital ridge and elongates by active cell proliferation using the Wolffian duct as a guide. Many genes have been linked to female reproductive tract development, but only a few have been directly implicated by animal knockout models; this is because the simplex female reproductive tract pattern (i.e., one with a single cervix and uterus, with two separate fallopian tubes) is limited to humans and other primates. Most recently, genomic sequencing has identified more genes, mostly transcription factors and extracellular signaling molecules, and mutations in those genes, associated with malformations of the female reproductive tract. The most common congenital abnormality of the human female genital tract occurs when the paired mullerian ducts fail to fuse or the subsequent septum fails to resorb, yielding a spectrum of uterine anomalies, including uterus didelphys and bicornuate uterus. External female genital tract development requires both the absence of a key male determining factor (SRY) and presence of its antagonist (WNT4). Virilization of genetically female fetuses is due to excessive androgens from congenital adrenal hyperplasia or maternal blood.

Evaluation of the Cyclic Endometrium and Benign Endometrial Disorders

Abstract Endometrial sampling is a major component of gynecologic care as practitioners endeavor to identify the causes of abnormal uterine bleeding (AUB), potential explanations for infertility, and abnormalities that might place the patient at greater risk for malignancy. The plethora of patterns that might be encountered during reproductive life and postmenopause can be confusing, and an informed pathologist is critical to optimal care. Fundamental to this task is a thorough understanding of and a systematic approach to non-neoplastic endometrial disorders. This chapter brings together detailed descriptions of the entities encountered when evaluating uterine bleeding and an authoritative clinical perspective. The goal is to provide the reader a road map of benign endometrial disorders from both a pathologic and clinical perspective, and provide the foundation needed to address both benign and neoplastic endometrium.

Squamous Neoplasia of the Vulva

Abstract Vulvar squamous neoplasia clinical management depends on the identification of low-grade squamous intraepithelial lesions (exophytic and flat condyloma), high-grade squamous intraepithelial lesions (classic and differentiated vulvar intraepithelial neoplasias [VINs]), early invasive squamous cell carcinoma, and the different squamous carcinoma morphologies and variants. This chapter provides a comprehensive review of these topics, including the key questions faced by the pathologist during the different stages of the diagnosis process of each of these lesions. Among the updates for this edition, the reader will find (1) new information on the complications of human papillomavirus (HPV) infection in children (genital warts and recurrent respiratory papillomatosis), (2) VIN terminology, gross and frozen section exams pitfalls, and (3) invasive squamous cell carcinoma prevention, clinical/epidemiological background, and outcome. Particularly, this new edition introduces the reader to a recently described category of preinvasive squamous neoplasia named differentiated exophytic vulvar/squamous intraepithelial lesions (DE-VILs or DE-SILs). Although not yet entirely clarified in respect to their pathogenesis and link to squamous carcinoma, these lesions are almost exclusively HPV negative and seen in association with HPV-negative squamous cell and verrucous carcinomas.