Extracted from: The 21st Century Handbook of Clinical Ovarian Cancer

Krishnansu S Tewari, Bradley J Monk

Concise Reference: Understanding and Diagnosing Ovarian Cancer

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Concise Reference:Understanding andDiagnosing Ovarian CancerExtracted from The 21st Century Handbook of Clinical Ovarian Cancer

4 Krishnansu S Tewari, MDDivision of Gynecologic OncologyUniversity of CaliforniaIrvine, CA

4 Bradley J Monk, MDSt Joseph‘s Hospital and Medical CenterPhoenix, AZ

Published by Springer Healthcare Ltd, 236 Gray’s Inn Road, London, WC1X 8HB, UK.

www.springerhealthcare.com

© 2014 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: 978-1-910315-20-0

Extracted from The 21st Century Handbook of Clinical Ovarian Cancer

ISBN 978-319-08065-9

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.

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CONTENTS

CHAPTER ONE INTRODUCTION TO OVARIAN CANCER 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

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CHAPTER ONE

INTRODUCTION TO OVARIAN CANCER

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.© SH

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INTRODUCTION TO OVARIAN CANCER INTRODUCTION TO OVARIAN CANCERCHAPTER ONE CHAPTER ONE

Table 1.1

World Health Organization histologic classification of ovarian tumors.

Adapted from © World Health

Organization. All rights reserved. SEAP [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 steroid-producing 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

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INTRODUCTION TO OVARIAN CANCERINTRODUCTION TO OVARIAN CANCER CHAPTER ONECHAPTER ONE

Figure 1.1

The main subtypes of epithelial ovarian cancer.

Reproduced with permission from

© Hindawi Publishing Corporation, 2014.

All Rights Reserved. Karst and Drapkin.[6]

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.

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

Serous Endometrioid Mucinous Clear cell

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INTRODUCTION TO OVARIAN CANCERINTRODUCTION TO OVARIAN CANCER CHAPTER ONECHAPTER ONE

Table 1.2

The International Federation of Gynecology and Obstetrics

revised staging system for epithelial ovarian cancer

(continues over).

Table 1.2

The International Federation of Gynecology and Obstetrics revised staging system for epithelial ovarian cancer (continued).

*Old STAGE IIC has been eliminated.

IP, intraperitoneal. Adapted from

© International Federation of Gynecology

and Obstetrics, Elsevier Ireland Ltd, 2014.

All rights reserved. Prat.[9]

In the uncommon event that a seemingly isolated pelvic mass suspicious for ovarian carcinoma is discovered, it is the obligation of the surgeon to remove it ensuring it remains intact, and if intraoperative rapid mandatory frozen section analysis is positive for carcinoma then surgical staging is imperative. Up to 30% of ‘clinical’ stage I ovarian carcinomas will be upstaged based on comprehensive surgical staging, which includes total abdominal hysterectomy, bilateral salpingoophorectomy, total omentectomy, bilateral pelvic and para-aortic lymphadenectomy, peritoneal biopsies, and four-quadrant pelvic washings. Interestingly, many cases of upstaging are due to occult para-aortic lymph node metastases identified by the pathologist after surgical staging.

FIGO staging

FIGO issued a revised staging system for epithelial ovarian cancer, which took effect on January 1, 2014 (Table 1.2).[7] As is the case with endometrial and vulvar cancers, ovarian carcinoma is surgically staged. As there are no reliable early symptoms and because no validated screening tests are available for the general population, most women with epithelial ovarian cancer present with advanced stage disease, usually FIGO stage IIIC (ie, abdominal spread with lesions >2 cm in maximal diameter). The case is usually even more discouraging as the metastatic deposits are occasionally very large and adherent to multiple organs and structures throughout the abdomen and pelvis, including the pelvic sidewall and peritoneum cul-de-sac, the rectosigmoid colon, bladder serosa, abdominal wall peritoneum, small bowel, extra-pelvic colon, spleen, and subdiaphragmatic peritoneum. The omentum is usually extensively involved, so at laparotomy the presentation may at first appear hopeless. Penetrating tumor involving the bladder, diaphragm musculature, and liver parenchyma as well as involvement of the tail of the spleen and porta hepatis may also be encountered. Primary cytoreductive surgery should be carried out if preoperative imaging and physical examination suggests there is a high probability of complete resection (ie, R0 or no gross residual).

STAGE I: Tumor confined to ovaries

Old New

IA Tumor limited to one ovary, capsule intact, no tumor on surface, negative washings/ascites

IA Tumor limited to one ovary, capsule intact, no tumor on surface, negative washings

IB Tumor involves both ovaries otherwise like 1A IB Tumor involves both ovaries otherwise like 1A

IC Tumor involves one or both ovaries with any of the following: capsule rupture, tumor on surface, positive washings/ascites

IC Tumor limited to one or both ovaries

IC1 Surgical spill

IC2 Capsule rupture before surgery or tumor on ovarian surface

IC3 Malignant cells in the ascites or peritoneal washings

STAGE II: Tumor involves one or both ovaries with pelvic extension (below the pelvic brim) or primary peritoneal cancer

Old New

IIA Extension and/or implant on uterus and/or fallopian tubes

IIA Extension and/or implant on uterus and/or fallopian tubes

IIB Extension to other pelvic IP tissues IIB Extension to other pelvic IP tissues

IIC IIA or IIB with positive washings/ ascites*

STAGE III: Tumor involves one or both ovaries with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes

Old New

IIIA Microscopic metastasis beyond the pelvis IIIA Positive peritoneal lymph nodes and/or microscopic metastasis beyond the pelvis

IIIA1 Positive retroperitoneal lymph nodes only

IIIA1(i) Metastasis ≤10 mm

IIIA1(ii) Metastasis >10 mm

IIIA2 Microscopic, extrapelvic (above the brim) peritoneal involvement ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen

IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤2 cm in greatest dimension

IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤2 cm ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen

IIIC Macroscopic, extrapelvic, peritoneal metastasis >2 cm in greatest dimension and/or regional lymph node metastasis

IIIC Macroscopic, extrapelvic, peritoneal metastasis >2 cm ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen

STAGE IV: Distant metastasis excluding peritoneal metastasis

Old New

IV Distant metastasis excluding peritoneal metastasis. Includes hepatic parenchymal metastasis

IVA Pleural effusion with positive cytology

IVB Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)

Other major recommendations are as follows:

■ Histologic type including grading should be designated at staging ■ Primary site (ovary, fallopian tube, or peritoneum) should be designated where possible ■ Tumors that may otherwise qualify for stage I but involved with dense adhesions justify

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INTRODUCTION TO OVARIAN CANCERINTRODUCTION TO OVARIAN CANCER CHAPTER ONECHAPTER ONE

Figure 1.2

The treatment paradigm for patients with epithelial

ovarian cancer.

Chemo, chemotherapy.

with localized disease (FIGO stage I) for which the five-year relative survival rate approaches 92.3%.[10] Among the 18% of patients with regional spread of the disease to adjacent pelvic organs (FIGO stage II), five-year relative survival is 71.7%. For 61% of patients, the disease has spread to distant organs in the abdomen and/or lymph nodes (FIGO stage III) and the five-year relative survival rate is only 27.4%.[9]

Investigators at the Centers for Disease Control and Prevention have reported on mortality trends from ovarian cancer from 2000 to 2009, noting that deaths due to this disease have decreased significantly by 1.5% per year among women overall and among non-Hispanic Caucasian women. Mortality rates among Hispanic women were found to have decreased significantly by 1.1% per year.[11] The mortality rates remained stable among African American, American Indian/Alaskan Native, and Asian/Pacific Islander women.[10]

Historic treatment paradigm – a model in evolution

Patients with epithelial ovarian cancer often present with a constellation of symptoms

consistent with advanced disease. This typically includes ascites with abdominal

bloating and pressure, a pelvic mass or palpable omental disease, possibly difficulty

with urination and bowel movements, and occasionally shortness of breath. At this

point, most patients undergo radiographic imaging most commonly with pelvic

ultrasonography and/or computerized tomography (CT) imaging. The patient then

has definitive cytoreductive surgery followed by six to eight cycles of intravenous (IV)

platinum- and taxane-based combination chemotherapy (Figure 1.2). In some cases

where malnutrition is significant or the metastatic disease process appears unresectable

based on review of radiographic imaging, patients may be treated with neoadjuvant

chemotherapy followed by interval cytoreduction and postoperative chemotherapy.

Although up to 75% of patients can be placed into remission through cytoreductive

surgery and IV platinum- and taxane-based chemotherapy, the majority of patients will

relapse with 10-year disease-free survivorship being below 20%.

Prognosis

According to the Ovarian Cancer National Alliance, overall mortality rates due to ovarian cancer have not improved in 40 years since the ‘War on Cancer’ was declared (ie, 1971). Recently published data from the Surveillance Epidemiology and End Results (SEER) Program of the National Cancer Institute indicates that only 15% of women are diagnosed

Diagnosis Evaluation/Surveillance

Progression Evaluation Progression Death

Surgery/Staging Cure

Supportive care

Chemo #1Symptoms Chemo #2 Chemo #3+/- Maintenance

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References

INTRODUCTION TO OVARIAN CANCERCHAPTER ONE

1. American Cancer Society. Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Last accessed July 29, 2014.

2. Eisenhauer EL, Salani R, Copeland LJ. Epithelial ovarian cancer, In: Clinical Gynecologic Oncology. 8th edn. DiSaia PJ, Creasman WT, eds. Philadelphia, PA: Elsevier Saunders; 2012:285-238.

3. Howlader N, Noone AM, Krapcho M, et al. eds. SEER Cancer Statistics Review, 1975-2011. Bethesda, MD: National Cancer Institute; 2012. seer.cancer.gov/csr/1975_2011/. Last accessed July 29, 2014.

4. Scully R, Sobin L. Histological Typing of Ovarian Tumours. Volume 9. New York, NY: Springer Berlin; 1999.

5. World Health Organization histological classification 2013. www.seap.es/documents/228448/528821/01_Prat.pdf. Last accessed July 29, 2014.

6. Karst AM, Drapkin R. Ovarian cancer pathogenesis: a model in evolution. J Oncol. 2010;2010:932371.

7. Johnson PA, Giles JR. The hen as a model of ovarian cancer. Nat Rev Cancer. 2013;13:432-436.

8. Herrinton LJ, Stanford JL, Schwartz SM, Weiss NS. Ovarian cancer incidence among Asian migrants to the United States and their descendants. J Natl Cancer Inst. 1994;86:1336-1339.

9. Prat J. FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014;124:1-5.

10. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Statistics Review 1975-2011. seer.cancer.gov/csr/1975_2011/browse_csr.php?sectionSEL=21&pageSEL=sect_21_table.08.html. Last accessed July 29, 2014.

11. Edwards BK, Noone AM, Mariotto AB, et al. Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer. 2014;120:1290-1314.

Prevention of ovarian carcinoma

Oral contraceptive pills

Use of oral contraceptive pills (OCPs) has been associated with a significant reduction in the risk of

ovarian cancer. Specifically, after one year of use, the risk has been shown to decrease by 10–12%, and

by approximately 50% after five years of use. The Cancer and Steroid Hormone (CASH) study researchers

reported that the reduction in ovarian cancer risk was the same irrespective of the type or amount of

estrogen or progestin in the OCP.[1] Follow-up analysis of CASH data have indicated that formulations with

high levels of progestin are associated with a lower risk of ovarian cancer compared with formulations with

low progestin concentrations.[2] The Steroid Hormones and Reproductions (SHARE) study was noteworthy

for finding no difference in ovarian cancer risk between androgenic and nonandrogenic pills.[2] Women

harboring genetic mutations that predispose them to the development of breast and ovarian cancer

(ie, the breast cancer susceptibility gene 1 and 2 [BRCA1 and BRCA2] mutation carriers) also seem to

benefit from a reduction in risk of ovarian cancer through the use of OCP.[3]

SCREENING AND PREVENTION OF OVARIAN CANCER

CHAPTER TWO

Risk-reducing bilateral salpingoophorectomy

Risk-reducing bilateral salpingoophorectomy (rrBSO) should be considered for women at the highest risk of epithelial ovarian and fallopian tubal cancer.[4–6] Among patients with BRCA1 gene mutations, the lifetime risk of ovarian cancer is approximately 40%, and in those with BRCA2 gene mutations the lifetime risk is approximately 20%.[7] Finally, women with a strong family history of either ovarian or breast cancer who have not undergone genetic testing may carry a deleterious mutation and can be presumed to be at higher-than-average risk. For this reason they should also be considered candidates for © SH

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SCREENING AND PREVENTION OF OVARIAN CANCERSCREENING AND PREVENTION OF OVARIAN CANCERCHAPTER TWO CHAPTER TWO

cancers and 20 invasive pelvic cancers, involving exclusively the ovary, fallopian tube, or inner peritoneal lining of the body. Of these pelvic cancers only 12 were detected microscopically but all 20 of the cancers were serous carcinomas. Overall, the prevalence of serous pelvic cancers in these asymptomatic women with BRCA mutations was 3.2% as compared with 0.5% among those patients who did not have a BRCA mutation but had strong family history of breast or ovarian cancer. Interestingly, 515 patients had their uterus removed at the time of removal of the ovaries and six endometrial cancers were also found.[8,9] It is not clear whether these cases of endometrial cancer were sporadic or related to BRCA deficiency, but typically endometrial cancers present with bleeding.

Screening for ovarian carcinoma

There are no validated tools that can be used to screen for ovarian cancer in the general population. Neither serum testing for CA-125 alone or in combination with transvaginal pelvic ultrasonography has convincingly succeeded in diagnosing early stage ovarian cancer or decreasing mortality from the disease.

Cancer antigen 125

CA-125 was discovered in 1981 by Bast et al.[10] Although it is the only US Food and Drug Administration (FDA)-approved biomarker for ovarian cancer detection, it is only expressed in approximately 75% of cases, and in particular in the subtype of ovarian cancer called serous carcinoma. It is not expressed by mucinous and other ovarian carcinomas. Additional shortcomings of CA-125 include a lack of sensitivity for detecting early stage ovarian cancer and the potential presence of this protein at abnormally high levels in many different benign (ie, non-cancerous) gynecologic and non-gynecologic conditions.[10] For these reasons, CA-125 is not a suitable screening test for ovarian cancer in the general population of women and the search for more sensitive and informative biomarkers continues. Accepted uses of CA-125 include: (1) helping to determine whether a pelvic mass is malignant; (2) assisting in determining whether a cancer of unknown primary origin has arisen from the ovary; (3) monitoring response of ovarian cancer to systemic chemotherapy; (4) carrying out surveillance of patients treated for ovarian cancer who are in remission; and (5) screening for ovarian cancer in high-risk populations (ie, patients with a strong family history or BRCA mutation carriers).

rrBSO. An additional benefit among BRCA mutation carriers is that rrBSO will reduce the risk of breast cancer by 30–75%. In most situations, rrBSO is typically deferred until women have completed childbearing.

It has been estimated that approximately 15% of patients with Lynch syndrome are at risk for ovarian cancer. These patients also have a lifetime risk of 60% for developing endometrial cancer and therefore risk-reducing surgery includes hysterectomy. The risk of breast cancer in Lynch syndrome is controversial.[4–6]

The finding of occult fallopian tubal cancers in women who have undergone rrBSO suggests that some presumed ovarian cancers can initiate in the fallopian tubes. Due to microscopic rests of residual ovary, occult pre-existing carcinomatosis at the time of prophylactic surgery, and/or multifocal origin of peritoneal tissue, after rrBSO, the risk of developing serous carcinoma of the peritoneum has been reported to be in the range of 1.7–4.3%.[4–6]

The technique of rrBSO and pathologic processing should include:

1. Bilateral salpingoophorectomy with removal of the entire fallopian tube

2. Cytologic examination of peritoneal washings

3. Random peritoneal and omental biopsies along with a biopsy of any suspicious lesion

4. Serial sectioning of the entire fallopian tube and ovaries at 2 mm intervals and microscopic examination of all sections

Gynecologic Oncology Group protocol 0199: risk-reducing bilateral salpingoophorectomy component

Gynecologic Oncology Group (GOG) protocol 0199 is a non- randomized trial that enrolled women at a high risk of developing ovarian cancer (ie, BRCA mutation carriers or strong family history of ovarian cancer).[8,9] It has been designed to compare rrBSO at enrollment with serial transvaginal ultrasonography and cancer antigen 125 (CA-125) screening (Risk of Ovarian Cancer Algorithm [ROCA]). All enrolled patients had a baseline CA-125 and a transvaginal ultrasound performed, and then chose to have either rrBSO or continue to be screened at 3-month intervals with the ROCA evaluation. Pathologic review of the 966 prophylactic surgical specimens revealed four pre-invasive tubal © SH

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Figure 2.1

The Risk of Ovarian Cancer Algorithm (ROCA) showing the relative length of time for early ovarian cancer to become clinically detectable.

Adapted from © American Association for

Cancer Research, 2002. All rights reserved.

McIntosh et al.[15]

SCREENING AND PREVENTION OF OVARIAN CANCERSCREENING AND PREVENTION OF OVARIAN CANCERCHAPTER TWO CHAPTER TWO

Development of the Risk of Ovarian Cancer Algorithm

In a strategy to improve the sensitivity of CA-125 in detecting ovarian cancer, the ROCA was designed (Figure 2.1).[14] The basic concept is to use the CA-125 level of a woman as the yardstick (or baseline level) against which any fluctuations or changes in the CA-125 over time can be measured. Risk estimates or a ROCA score of developing ovarian cancer can then be provided by inputting these CA-125 changes into a mathematical model that includes the age of the woman. Although CA-125 can be abnormally elevated in non-cancerous conditions, the hypothesis is that CA-125 levels should steadily increase over time in a woman who is ultimately going to develop ovarian cancer, whereas the CA-125 levels would be expected to remain typically stable or even decrease in those with non-cancerous conditions (eg, endometriosis). Theoretically then, by monitoring the ROCA score carefully the disease may be intercepted before it starts to spread, leading to higher cure rates. Several important ROCA studies are ongoing.

United States Risk of Ovarian Cancer Algorithm study (general population)

The ROCA study in the United States is being performed by the National Cancer Institute’s Cancer Genetics Network, the Early Detection Research Network, and the Ovarian Specialized Program on Research Excellence. In this single arm, prospective, multicenter screening study, 4051 women (50–74 years) with no significant family

Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

The objective of the ovarian component of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was to estimate whether screening reduces mortality from ovarian cancer in healthy women between the ages of 55–74 years who still have their ovaries.[11] A total of 34,261 women were enrolled onto this trial and were randomly assigned to either no screening interventions or to yearly transvaginal ultrasounds plus CA-125. Eighty-nine patients were diagnosed with ovarian cancer in this study, of which 60 (ie, 67%) were detected through screening with ultrasound plus CA-125. However, 72% of the screen-detected cases were late stage ovarian cancers (ie, stage III and IV). For each case of ovarian cancer discovered, 20 women underwent surgery, meaning that 19 patients underwent surgery for benign conditions for every one case of ovarian cancer diagnosed. These results were initially reported in 2009.[10]

Two important updates from the PLCO study have been published. In 2011, Buys et al compared the mortality rates due to ovarian cancer between the women who did not undergo screening and those who did.[12] In this analysis, the investigators reported that the death rates from ovarian cancer did not significantly differ between the two groups. This means that although more ovarian cancers were found in women assigned to the group that received yearly ultrasounds plus CA-125, because most of these screen-detected cases were advanced stage cases, the screening did not result in a significantly diminished death rate from ovarian cancer. Screening resulted in over 3000 false positive results and a total of 1080 surgeries, the great majority of which were for benign conditions as discussed earlier.[12] Additionally, 15% of patients who underwent surgery suffered serious surgical complications. Clearly, a more sensitive screening tool is needed that can detect ovarian cancer in its earliest stages and which is better able to discriminate between benign and cancerous conditions.

In 2012, Moore et al studied blood samples taken from patients on the PLCO trial and reported that approximately 62% of the 65 patients who had CA-125 data available in blood samples collected less than a year before their ovarian cancer diagnosis had an elevated CA-125 level. These scientists probed these same blood samples for seven other promising biomarkers but even when combined with CA-125, this panel of markers was not found to be more sensitive than CA-125 alone in detecting ovarian cancer.[13]

Leve

l of m

arke

r in

seru

m

Time

EndometriosisNo active issuesEarly ovarian cancer

Clinical detection

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United Kingdom Risk of Ovarian Cancer Algorithm study (high-risk population)

The United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS) has had two phases. In phase I, Rosenthal et al showed that annual transvaginal ultrasound and CA-125 screening in women at high risk of ovarian and fallopian tube cancer lacked sensitivity for early stage disease but may result in improved optimal debulking rates when patients were taken to surgery.[18] It was thought that more frequent screening might provide greater benefits, so a phase II program was launched.[18] Among the modifications in the phase II program were screening every 4 months, implementation of a web-based system notifying physicians when additional testing and/or referral was required, and incorporation of the ROCA scores. Eligibility criteria included >10% lifetime risk of ovarian cancer, age >35 years, and declined rrBSO. For 5 years, 4531 women at high risk of ovarian and fallopian tube cancer were recruited and screened at 42 UK centers. The median age was 45.5 years. CA-125 tests were analyzed every 4 months through ROCA; transvaginal sonography (TVS) was analyzed annually.

Roesenthal et al reported that data from more frequent than annual screening constitute further evidence of a beneficial effect on success of debulking surgery, which may translate into improved survival. Sixteen incident cases of ovarian cancer were detected, of which eight (50%) were stage I or II. The calculated sensitivity ranged from 75–100%, with specificity of 96.1% and positive predictive value (PPV) of 13%.[19] Interestingly, four of the 16 patients with ovarian cancer had normal pelvic ultrasonography and were identified based on an abnormal ROCA. The investigator suggested that potentially avoidable delays in physician referral were reduced by using the internet notification system. This was possibly because the trial did not mandate serial sectioning of the fallopian tubes and ovaries among those patients who ultimately underwent rrBSO (n=653). There was a low rate of occult carcinoma in this high-risk population (n=4; 0.6%).[19]

history of breast or ovarian cancer underwent an annual CA-125 blood test. Based on the ROCA result, women were triaged to the next annual CA-125 test (low risk), to repeat the CA-125 test in 3 months (intermediate risk), or to a transvaginal ultrasound study with referral to a gynecologic oncologist (high risk). Based on the results of the clinical findings and ultrasound result, the gynecologic oncologist then made the decision whether or not to proceed with surgery.[16]

The average annual rate of placement of study participants into the intermediate risk group was 5.8%, while the annual rate of referral for transvaginal ultrasonography and consultation with a gynecologic oncologist was 0.9%.[16] Ten women underwent surgery, with four invasive ovarian cancers (one with stage IA disease, two with stage IC disease, and one with stage IIB disease), two ovarian tumors of low malignant potential (both stage IA), one stage I endometrial cancer, and three benign ovarian tumors, providing a positive predictive value of 40% (95% confidence interval [CI] 12.2, 73.8) for detecting invasive ovarian cancer. The specificity was 99.9% (95% CI 99.7, 100.0).[16] All four women with invasive ovarian cancer were enrolled in the study for at least 3 years with low-risk annual CA-125 test values prior to rising CA-125 levels.

United Kingdom Risk of Ovarian Cancer Algorithm Study (general population)

These results are very consistent with another ROCA study being performed in the United Kingdom (the UK Collaborate Trial of Ovarian Cancer Screening).[17] In this second study, over 200,000 postmenopausal women (ages 50–74 years) have been randomly assigned to one of three arms: (1) no screening; (2) annual CA-125 blood tests with ROCA followed by transvaginal ultrasound if the ROCA is worrisome; and (3) screening with transvaginal ultrasound only on a yearly basis. In this study, the ROCA led to the detection of 16 ovarian or fallopian tube cancers in the early stages (ie, stage I–II).[17]

Risk of Ovarian Cancer Algorithm studies are consistent

The United States and United Kingdom ROCA studies are consistent with one another. The specificity for both studies is 99.8%. In addition, the positive predictive value of the United States study of 37.5% is also identical to the positive predictive value of 37.5% reported for the United Kingdom study.[16,17] These studies make it clear that ROCA can detect ovarian cancers at an early stage in the general population; however, survival data are not yet mature enough to allow us to determine whether ROCA can reduce the mortality rates from ovarian cancer. © SH

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SCREENING AND PREVENTION OF OVARIAN CANCERCHAPTER TWO

The adnexal mass

Although most patients with epithelial ovarian cancer will present with International Federation of

Gynecology and Obstetrics (FIGO) stage III or IV disease, occasionally, a woman with a pelvic mass in

the absence of ascites, carcinomatosis, and pleural effusion or other clinical and radiologic findings of

advanced disease will be ultimately diagnosed with an early stage ovarian carcinoma (Figure 3.1). The

evaluation of a seemingly isolated adnexal mass must take into consideration the following:

1. Patient age

2. Symptoms

3. Family history of breast/

ovarian/Lynch syndrome

4. Physical examination

findings (eg, fixed, firm,

nodular versus mobile,

soft, smooth)

5. Serum markers (eg, cancer

antigen 125 [CA-125])

6. Findings on imaging

studies

CLINICAL PRESENTATION AND DIAGNOSTICS

CHAPTER THREE

1. Centers for Disease Control and Prevention and the National Institute of Child Health and Human Development. The reduction in risk of ovarian cancer associated with oral-contraceptive use. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med. 1987;316:650-655.

2. Schildkraut JM, Calingaert B, Marchbanks PA, Moorman PG, Rodriguez GC. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst. 2002;94:32-38.

3. Greer JB, Modugno F, Allen GO, Ness RB. Androgenic progestins in oral contraceptives and the risk of epithelial ovarian cancer. Obstet Gynecol. 2005;105:731-740.

4. Berek JS, Chalas E, Edelson M, et al. Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer. Obstet Gynecol. 2010;116:733-743.

5. Kurman RJ, Shih Ie-Ming. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34:433-443.

6. Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA. 2006;296:185-192.

7. Welsch PL, King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet. 2001;10:705-713.

8. Green MH, Piedmonte M, Alberts D, et al. A prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer: design and baseline characteristics: a Gynecologic Oncology Group study. Cancer Epidemiol Biomarkers Prev. 2008;17:594-604.

9. Mai PL, Sherman ME, Piedmonte M, et al. Pathologic findings at risk-reducing salpingo-oophorectomy among women at increased ovarian cancer risk: results from GOG-199. J Clin Oncol. 2012;30 (abstr 1519).

10. Bast RC Jr, Klug TL, St John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med. 1983;309:883-887.

11. Cramer DW, Bast RC Jr, Berg CD, et al. Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prev Res (Phila). 2011;4:365-374.

12. Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305:2295-2303.

13. Moore LE, Pfeiffer RM, Zhang Z, et al. Proteomic biomarkers in combination with CA 125 for detection of epithelial ovarian cancer using prediagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cancer. 2012;118:91-100.

14. Partridge E, Kreimer AR, Greenlee RT, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol. 2009;113:775-782.

15. McIntosh MW et al. Generating longitudinal screening algorithms using novel biomarkers for disease. Cancer Epidemiol Biomarkers Prev. 2002;11:159-166.

16. Lu KH, Skates S, Hernandez MA, et al. A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value. Cancer. 2013;119: 3454-3461.

17. Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009;10:327-340.

18. Rosenthal AN, Fraser L, Manchanda R, et al. Results of annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight the need for strict adherence to screening schedule. J Clin Oncol. 2013;31:49-57.

19. Rosenthal N, Fraser L, Philpott S, et al. Final results of 4-monthly screening in the UK Familial Ovarian Cancer Screening Study (UKFOCSS Phase 2). J Clin Oncol. 2013;31(suppl;abstr 5507).

The differential diagnosis of an adnexal mass includes conditions involving adjacent structures. Hydrosalpinx, and paratubal cyst are examples of cystic masses arising from the fallopian tube, while ectopic pregnancy and tubal neoplasms are examples of solid masses; tubo-ovarian abscesses can have both solid and cystic components. An intrauterine pregnancy in a bicornuate uterus may present as a cystic adnexal mass due to the fluid filled amniotic sac, while a pedunculated uterine myoma may present as a solid mass in the adnexa. A distended sigmoid colon gives the appearance of a cystic mass, while diverticulitis or a primary colon cancer may be mistaken for a solid ovarian tumor. Finally, distended bladder or a hydropic pelvic kidney can take on the features of a cystic adnexal mass.© SH

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Figure 3.1

Surgeons removing a left ovarian mass from a patient.

CLINICAL PRESENTATION AND DIAGNOSTICS CLINICAL PRESENTATION AND DIAGNOSTICSCHAPTER THREE CHAPTER THREE

follicles. In this condition, the ovaries may be two to five times the normal size with a thickened capsule. Polycystic ovarian syndrome may be associated with infertility and insulin-resistant diabetes mellitus.

Among the benign mixed cystic and solid ovarian neoplasms are the serous cystadenoma, the mucinous cystadenoma, and the dermoid cyst (benign cystic teratoma). Benign solid tumors of the ovary include the Brenner tumor, struma ovarii, and the fibroma. Meigs’ syndrome is characterized by ascites, hydrothorax, and an ovarian tumor (most commonly a fibroma).

Transvaginal ultrasonography is a powerful tool that allows one to determine whether an adnexal mass is solid or cystic, simple or complex, and if complex, is the complexity due to septations, excrescences, or solid components? Transvaginal ultrasonography can accurately measure the mass in two dimensions and if the mass is large enough to compress the ipsilateral ureter, hydronephrosis and/or hydroureter may also observed. Ultrasonography can also determine if there is ascites present in the pelvis. Computerized tomography (CT) imaging and/or magnetic resonance imaging (MRI) can also be used to evaluate a pelvic mass but is not always necessary, especially if the symptomatology of a patient warrants urgent operative intervention. However, many clinicians routinely order CT or MRI when there is a moderate to high suspicion for malignancy in order to look for signs of omental caking/carcinomatosis. A paracentesis performed under ultrasound or CT guidance can palliate significant bloating and cytologic analysis of the fluid may establish a diagnosis of malignant ascites. False negative cytology in the setting of ovarian cancer may result from laboratory protocol in preparing the cell blocks.

Conditions raising the concern of possible malignancy include:

1. Bilateral adnexal masses

2. Complex masses, especially those with solid components, thick septations, and/or mural nodules

3. Premenopausal patients with complex masses that persist or grow following a period of observation

4. Postmenopausal patients with simple masses >5 cm or complex masses of any size

5. Masses associated with elevated tumor markers

6. Symptomatic masses

If the mass is indeed arising from the ovary itself, benign and malignant conditions of the ovary must also be considered in the differential diagnosis. Among the most common benign ovarian masses are functional cysts (eg, corpus luteum, follicular, and theca-lutein). Endometriotic cysts, although benign, may be the source of significant pelvic pain, and even infertility. Polycystic ovaries contain multiple follicle cysts with hyperplasia and luteinization of the theca interna surrounding the cysts and atretic © SH

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Figure 3.2

Interpreting the results of the OVA1 triage test.

CA-125, cancer antigen 125.

CLINICAL PRESENTATION AND DIAGNOSTICSCLINICAL PRESENTATION AND DIAGNOSTICSCHAPTER THREE CHAPTER THREE

Important attributes of this blood test include its ability to identify different types of ovarian cancer (ie, not only serous cancer); it performs well in the detection of both early and advanced stage ovarian cancers and may identify non-ovarian cancers as well as provide a composite score that can be interpreted depending on the menopausal status of the patient on a scale of 1–10 – an abnormal score for a premenopausal woman is >5 while an abnormal score for postmenopausal woman is >4.4 (Figure 3.2). This blood test should only be used for the triage of a patient with a pelvic mass that needs to undergo surgery and it is not to be used as a screening test.[2,3]

Triage of the adnexal mass

American College of Obstetricians and Gynecologists/Society of Gynecologic Oncology guidelines

To assist in the evaluation of a complex pelvic mass, in 2002 the American College of Obstetricians and Gynecologists joined with the Society of Gynecologic Oncologists (ACOG; later renamed to as Society of Gynecologic Oncology [SGO]) to prepare guidelines to help the general practitioner direct referral when necessary to a gynecologic oncologist.[1] Gynecologists are advised to perform a pelvic examination and imaging as appropriate for the symptoms with which the patient presents or the physical examination findings. For premenopausal women with a suspicious pelvic mass, referral to a gynecologic oncologist should be made as a result of at least one of the following: CA-125 level >200 U/ mL, ascites, abdominal or distant metastases, or one or more first-degree relatives with breast or ovarian cancer. For postmenopausal women with a concerning pelvic mass, consultation should be considered for any CA-125 elevation, ascites, nodularity or limited mobility, evidence of metastasis, or a first-degree relative with breast or ovarian cancer.

OVA1

As discussed in Chapter 2, CA-125 testing is an imperfect tool, with high false positive rates, especially among premenopausal patients. Nonmalignant conditions where the CA-125 can be elevated are classified as gynecologic (eg, acute pelvic inflammatory disease, endometriosis, menstruation, uterine myomas, and adenomyosis) or non-gynecologic conditions (eg, active hepatitis, acute pancreatitis, cirrhosis, colitis, congestive heart failure, diverticulitis, and nonmalignant ascites).

OVA1 is the first blood test approved by the US Food and Drug Administration (FDA) for assisting with the triage of an adnexal mass. It is a multivariate index assay that evaluates the following five biomarkers:[2,3]

1. CA-125 (typically increased in high-grade serous ovarian cancers)

2. Apolipoprotein A1 (decreased in ovarian tumors)

3. Beta-2 microglobulin (increased in ovarian tumors)

4. Transferrin (decreased in ovarian tumors)

5. Pre-albumin (decreased in ovarian tumors)

Low probability of malignancy <5.0

High probability of malignancy ≥5.0Premenopausal

Low probability of malignancy <4.4

High probability of malignancy ≥4.4Postmenopausal

β2Microglobulin

The body's immune response

CA-125 II

Released by tumor cells

Cholesterol

transport

ApolipoproteinA1

Hormone and

vitamin transport

Transthyretin

Iron transport

Transferrin

The OVA1 test has been shown to outperform CA-125 testing and clinical assessment of a pelvic mass performed by a gynecologist. In a study of over 500 women with a pelvic mass, Ueland et al reported that the combination of this blood test plus physician assessment correctly identified cancers missed by physician assessment alone and also detected 76% of cancers missed by CA-125 testing alone.[4] Next, Bristow et al conducted a prospective, multi-institutional trial designed to validate the effectiveness of the OVA1 in identifying ovarian malignancy compared with clinical assessment and CA-125 testing © SH

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CLINICAL PRESENTATION AND DIAGNOSTICSCLINICAL PRESENTATION AND DIAGNOSTICSCHAPTER THREE CHAPTER THREE

In addition to abdominal bloating resulting from malignant ascites, many women with ovarian carcinoma will experience significant gastrointestinal disturbance and may present with signs and symptoms of partial small bowel obstruction. Others may present with unexplained or unintended weight loss due to decreased oral intake as a result of intra-abdominal pressure on the stomach and intestinal tract, and obstructive symptoms making it hard to keep meals down. Loss of appetite is common in these cases. Finally, some patients will present with shortness of breath due to a malignant pleural effusion, while others may have the diagnosis of carcinoma made simultaneously with the occurrence of a thromboembolic event. The eminent German physician Rudolf Virchow (1821–1902) proposed the triad of hypercoagulability, stasis or turbulence of blood flow, and endothelial injury – all of which are associated with malignancy – to elucidate the etiology of pulmonary embolism.

The decision to explore a patient with carcinomatosis likely to have arisen from the adnexae, can only be made by a gynecologic oncologist. A methodical assessment of the preoperative nutritional and performance status of the patient is imperative. Preoperative serum albumin and pre-albumin should be obtained, along with a complete blood count with differential, comprehensive metabolic panel, coagulation panel, liver function tests, blood type and screen for antibodies, a CA-125 test, and urinalysis with culture. A multidisciplinary collaboration is incumbent throughout preoperative medical optimization with the gynecologic oncologist working directly with the patient’s general practitioner and other subspecialist physicians as needed (eg, cardiologist). Personalized review of all films with the radiologist is mandatory. The presence of multiple parenchymal liver metastases, extensive suprarenal adenopathy, porta hepatis disease, bony metastases, pulmonary masses, and any other extra-abdominal metastases are relative contraindications to primary cytoreduction (see Chapter 4 in The 21st Century Handbook of Clinical Ovarian Cancer for more information). Such patients should be treated with neoadjuvant chemotherapy followed by interval cytoreduction if there is radiologic, biochemical and/or physical evidence of objective response. Once a decision to proceed with surgery has been made, however, it is necessary to first correct malnutrition, anemia, coagulopathy, and electrolyte aberrations. In addition, urinary tract infection should be treated if present. Preoperative thoracentesis to address a pleural effusion and an inferior vena cava (IVC) filter placement for any patients that present with thrombosis may also be required.

among women undergoing surgery for an adnexal mass. In this 494-patient study, the study team reported that the test demonstrated higher sensitivity (95.7%) and negative predictive value (98.1%) compared with clinical impression and CA-125 testing.[5]

Human epidermis protein 4

Human epididymis protein 4 (HE4) is the product of the WFDC2 (HE4) gene and is overexpressed in patients with ovarian carcinoma. Marinaccio et al investigated the ability of HE4 to predict survival in 35 women with ovarian cancer (stage III, n=28; stage 4, n=7).[6] All patients with a HE4 >400 pM died within 2 years of diagnosis, while those with a reduced HE4 at both baseline and 3 months had the best overall survival (OS).

Risk of Ovarian Malignancy Algorithm: CA-125 + HE4

The Risk of Ovarian Malignancy Algorithm (ROMA) test (ie, CA-125 plus HE4) makes use of two serum biomarkers to detect ovarian cancer (CA-125 and HE4). This diagnostic test should not be confused with ROCA discussed previously in the context of screening. In a prospective study in 472 patients with a pelvic mass, Moore et al reported that 383 women were diagnosed with benign disease and 89 women were found to have cancer.[7–9] This diagnostic calculator had a sensitivity of 93.8% in detecting ovarian cancer. ROMA (CA-125 plus HE4) was FDA approved in 2011, and like OVA1, it should be used for the preoperative triage of a woman with a pelvic mass and not for ovarian cancer screening. There have been no head-to-head comparisons between the two tests and therefore it is not known which is superior.

Presentation and evaluation of advanced disease

The most common presenting symptoms of ovarian cancer in decreasing order of frequency are abdominal swelling, abdominal pain, dyspepsia, urinary frequency, and weight change. Unfortunately, the presence of any of these symptoms often is indicative of advanced disease. Although there is no reliable constellation of symptoms indicative of early disease, patient advocacy efforts urge women to “listen for the whisper”. Certainly, a high index of suspicion on the part of the physician can sometimes lead to early intervention in any woman between the ages of 40 and 70 with persistent gastrointestinal symptoms. The problem of course is that most nonspecific abdominal and pelvic complaints are not malignant and it is not cost effective to order CT scans on every woman with a presumptive diagnosis of irritable bowel syndrome. © SH

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Figure 3.3

Typical peritoneal distribution of primary ovarian cancer.

Reproduced with permission from

© Nature Publishing Group, 2013.

All rights reserved. Coleman et al.[10]

CLINICAL PRESENTATION AND DIAGNOSTICSCLINICAL PRESENTATION AND DIAGNOSTICSCHAPTER THREE CHAPTER THREE

1. American College of Obstetricians and Gynecologists. ACOG Committee Opinion: Number 280, December 2002. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet Gynecol. 2002;100:1413-1416.

2. Zhu CS, Pinsky PF, Cramer DW, et al. A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer. Cancer Prev Res (Phila). 2011;4:375-383.

3. Miller RW, Smith A, DeSimone COP, et al. Performance of the American College of Obstetricians and Gynecolgists’ ovarian tumor referral guidelines with a multivariate index assay. Obstet Gynecol. 2011;117:1-9.

4. Ueland FR, Desimone CP, Seamon LG, et al. Effectiveness of a multivariate index assayin the preoperative assessment of ovarian tumors. Obstet Gynecol. 2011;117:1289-1297.

5. Bristow RE, Smith A, Zhang Z, et al. Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay. Gynecol Oncol. 2013;128:252-259.

6. Hellström I, Raycraft J, Hayden-Ledbetter M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63:3695-3700.

7. Moore RG, Brown AK, Miller C, et al. The use of multiple novel serum biomarkers for the detection of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2008;108;402-408.

8. Moore RG, McMeekin DC, Brown AK, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2009;112:40-46.

9. Moore RG, Miller C, Disilvestro P, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. 2011;118:280-288.

10. Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol. 2013;10:211-224.

When the clinical picture is unclear, combined positron emission tomography (PET)/CT or even diagnostic laparoscopy may be used to determine whether it is possible to surgically resect all gross disease with a minimal of perioperative morbidity. Due to the risks of inadvertent trocar injury to the bowel and tumor seeding along the port track, laparoscopy should be avoided in the setting of widespread carcinomatosis (Figure 3.3) and large volume malignant ascites. Occasionally intra-abdominal tuberculosis or pseudomyxoma peritonei from a ruptured appendiceal neoplasm will enter into the differential diagnosis.

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