Springer Healthcare. Understanding and Diagnosing Ovarian Cancer. Concise Reference: Krishnansu S Tewari, Bradley J Monk

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1 Concise Reference: Understanding and Diagnosing Ovarian Cancer Krishnansu S Tewari, Bradley J Monk Extracted from: The 21 st Century Handbook of Clinical Ovarian Cancer

2 Published by Springer Healthcare Ltd, 236 Gray s Inn Road, London, WC1X 8HB, UK Springer Healthcare, a part of Springer Science+Business Media. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the copyright holder. ISBN: Extracted from The 21 st Century Handbook of Clinical Ovarian Cancer ISBN Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publisher nor the authors can be held responsible for errors or for any consequences arising from the use of the information contained herein. Any product mentioned in this publication should be used in accordance with the prescribing information prepared by the manufacturers. No claims or endorsements are made for any drug or compound at present under clinical investigation. Concise Reference: Understanding and Diagnosing Ovarian Cancer Extracted from The 21 st Century Handbook of Clinical Ovarian Cancer 4 Krishnansu S Tewari, MD Division of Gynecologic Oncology University of California Irvine, CA 4 Bradley J Monk, MD St Joseph s Hospital and Medical Center Phoenix, AZ

3 CONTENTS 1 Anatomy 1 Pathology 2 Epidemiology 4 Etiology 5 FIGO staging 6 Historic treatment paradigm a model in evolution 8 Prognosis 8 References 10 CHAPTER TWO SCREENING AND PREVENTION OF OVARIAN CANCER 11 Prevention of ovarian carcinoma 11 Screening for ovarian carcinoma 13 References 18 CHAPTER THREE CLINICAL PRESENTATION AND DIAGNOSTICS 19 The adnexal mass 19 Triage of the adnexal mass 22 Presentation and evaluation of advanced disease 24 References 27

4 Introduction to ovarian cancer Epithelial ovarian cancer is the most lethal of the gynecologic malignancies. After cancer of the lung, breast, colon, and uterus, it is the fifth most common cancer among women in the United States, and the fourth most common cause of cancer death in women. The American Cancer Society and National Cancer Institute estimate that in 2014 there will be approximately 21,980 new cases of ovarian cancer and 14,270 women will die of this disease. The lifetime risk for epithelial ovarian cancer is 1.38%, or one in every 72 women. The risk is even higher among women with familial and known genetic predisposition to this disease. [1 3] Anatomy The disease arises in the adnexae, which consist of the ovaries, fallopian tubes, broad ligament, and embryologic rests within the broad ligament. Unfortunately, because there are no validated screening tests for ovarian cancer that can be used in the general population and due to an absence of early symptoms, most cases of epithelial ovarian cancer do not come to clinical attention with a solitary adnexal mass. Typically, patients present with widespread intraperitoneal (IP) disease inclusive of an adnexal mass, involvement of other pelvic structures, omental and upper abdominal disease, and intra-abdominal ascites. This constellation of findings is described as carcinomatosis. Many patients will also be found to have a malignant pleural effusion at the time of initial presentation. 1

5 Before discussing the epidemiology and risk factors of epithelial ovarian cancer in detail, it is important to recognize that classification of ovarian pathology can be confusing because there is a significant variation in histologic structure and biologic behavior. Although epithelial ovarian cancer constitutes 85% of malignant ovarian pathology, it is important to consider the other main types as their epidemiology and management are distinct. Pathology There are four major stages of histogenesis of the normal ovary. During the first stage, undifferentiated germ cells (primordial germ cells) are segregated and migrate from their sites of origin to settle in the genital ridges comprised of bilateral thickening of coelomic epithelium. The second stage is marked by proliferation of the coelomic epithelium and underlying mesenchyme. In the third stage, the ovary becomes divided into a peripheral cortex and a central medulla. Development of this cortex and involution of the medulla characterizes the fourth stage. Thus, the three main types of ovarian cancer include the epithelial cancers, malignant germ cell tumors that arise from the primordial germ cells or oocytes, and the sex cord stromal tumors, which are derived from the steroidproducing cells responsible for nourishing the germ cells and oocytes. [4] Nonspecific cancers of the ovary also occur in cell types that are not specific to the ovary and include lymphomas (from lymphocytes) and sarcomas (from fibroblasts). Finally, cancers can secondarily involve the ovaries through direct extension and/or hematologic metastases and lymphatic permeation. Among the most common cancers to spread to the ovary are fallopian tubal carcinomas, endometrial carcinoma, cervical carcinoma, appendiceal cancers, breast cancer, and Krukenberg tumors from the stomach and other parts of the gastrointestinal tract. Interestingly, the specific malignant histologic type of ovarian cancer has less prognostic significance than the International Federation of Gynecology and Obstetrics (FIGO) stage, extent of residual disease, and histologic grade. Particularly in the case of epithelial ovarian cancer, histologic grade is an important independent prognostic factor. [4] The World Health Organization (WHO) Histologic Classification of Ovarian Tumors appears in Table 1.1. In descending order of frequency, epithelial ovarian cancers include serous cystadenocarinoma (characterized by psammoma bodies histologically and elevation in serum levels of the cancer antigen 125 [CA-125] clinically), mucinous cystadenocarcinoma (not associated with CA-125 but may elaborate carcinoembryonic 1. Surface epithelial stromal tumors 1.1 Serous tumors: benign, borderline, malignant 1.2 Mucinous tumors, endocervical-like, and intestinal-type: benign, borderline, malignant 1.3 Endometrioid tumors: benign, borderline, malignant, epithelial stromal and stromal 1.4 Clear cell tumors: benign, borderline, malignant 1.5 Transitional cell tumors: Brenner tumor, Brenner tumor of borderline malignancy, malignant Brenner tumor, transitional cell carcinoma (non-brenner type) 1.6 Squamous cell tumors 1.7 Mixed epithelial tumors (specify components): benign, borderline, malignant 1.8 Undifferentiated carcinoma 2. Sex cord stromal tumors 2.1 Granulosa stromal cell tumors: granulosa cell tumors, thecoma fibroma group 2.2 Sertoli stromal cell tumors, androblastomas: well-differentiated, Sertoli Leydig cell tumor poorly differentiated (sarcomatoid), retiform 2.3 Sex cord tumor with annular tubules 2.4 Gynandroblastoma 2.5 Unclassified 2.6 Steroid (lipid) cell tumors: stromal luteoma, Leydig cell tumor, unclassified 3. Gem cell tumors 3.1 Dysgerminoma: variant-with syncytiotrophoblast cells 3.2 Yolk sac tumours (endodermal sinus tumors): polyvesicular vitelline tumor, hepatoid, glandular 3.3 Embryonal carcinoma 3.4 Polyembryoma 3.5 choriocarcinoma 3.6 Teratomas: immature, mature, monodermal, mixed germ cell 4. Gonadoblatoma 5. Germ cell sex cord stromal tumor of non-gonadoblastoma type 6. Tumors of rete ovarii 7. Mesothelial tumors 8. Tumors of uncertain origin and miscellaneous tumors 9. Gestational trophoblastic diseases 10. Soft tissue tumors not specific to ovary 11. Malignant lymphomas, leukemias, and plasmacytomas 12. Unclassified tumors 13. Secondary (metastatic) tumors 14. Tumor-like lesions Table 1.1 World Health Organization histologic classification of ovarian tumors. Adapted from World Health Organization. All rights reserved. SEAP [5]. 2 3

6 Figure 1.1 The main subtypes of epithelial ovarian cancer. Reproduced with permission from Hindawi Publishing Corporation, All Rights Reserved. Karst and Drapkin. [6] antigen [CEA]), endometrioid carcinoma, undifferentiated carcinoma, and clear cell carcinoma (characterized histologically by hobnail cells and coffee bean nuclei; Figure 1.1). Clear cell carcinomas and undifferentiated carcinomas tend to display the most aggressive behavior and are ultimately believed to confer the worst prognosis. It is important to note that there are benign and borderline malignant counterparts of the first three tumor types (eg, serous cystadenoma, mucinous cystadenoma, and endometrioma). Epidemiology The median age at diagnosis of epithelial ovarian cancer is between 60 and 64 years, but more than one-third of cases occur in patients 65 years or younger. [2] Interestingly, elderly women are more likely than younger women to be in advanced stages of ovarian cancer at initial diagnosis. Over the preceding three decades, mortality rates have decreased for women younger than 65 years, whereas rates have increased for women older than 65 years. This change may result from increased use of oral contraceptives (see later discussion) in younger patients and a shifting of the survival curve to the right. Etiology Despite the high incidence and mortality rates, the etiology of this disease is poorly understood. Established risk factors include age and having a family history of the disease, while protective factors include increasing parity, oral contraceptive use, and salpingo-oophorectomy. Lactation, incomplete pregnancies, and hysterectomy and tubal ligation may confer a weak protective effect. Infertility may contribute to ovarian cancer risk among nulliparous women. Much attention has also been focused on the theory of incessant ovulation. In this model, rupture of the surface epithelium with each ovulatory cycle requires epithelial repair and women with higher numbers of ovulatory cycles are theoretically at a higher risk for spontaneous mutations or errors in DNA repair, which may lead to malignant transformation. Although this theory has been supported by some animal models, such as the unilateral ovulator known as the Long Island chicken [7] in which ovarian carcinoma is found to develop only in the ovary that ovulates, the estimated numbers of ovulatory cycles among infertile and nulliparous women does not seem to account for the full measure of ovarian carcinoma observed in the general population. Approximately 10% of women with ovarian cancer carry deleterious mutations in the breast cancer susceptibility gene 1 or gene 2 (BRCA1 or BRCA2), which prevent repair of double-stranded DNA breaks and directly result in the development of this disease. The main etiologic determinants for epithelial ovarian cancer may also include environmental factors, as highly industrial countries have the highest reported incidence of ovarian cancer, which suggests that physical or chemical products used in industry may be causative factors. Although Japan is highly industrialized the rates of ovarian cancer are among the lowest in the world, but it has been noted that the incidence of the disease increases among Japanese immigrants to the United States and in their offspring. These observations [8] support the theory that the causative carcinogens are in the immediate environment (eg, food and personal customs), that may change during the cultural transition. Although some have suggested that the disease may be initiated by a chemical carcinogen through the vagina, uterus, and fallopian tubes, no specific environmental carcinogens or dietary factors have been identified. Similarly, there is no environmental or epidemiologic evidence that incriminate viruses. Serous Endometrioid Mucinous Clear cell 4 5

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