Frontiers in Ovarian Cancer Science 1st ed 2017 Edition

by Hidetaka Katabuchi

Frontiers in Ovarian Cancer Science 1st ed 2017 Edition This volume presents the latest advances and the current status of our understanding regarding ovarian cancer addressing both the basic and clinical aspects of the disease

Publisher : Springer

Author : Hidetaka Katabuchi

ISBN : 9789811041594

Year : 2017

Language: en

File Size : 10.92 MB

Category : Used Textbooks

Comprehensive Gynecology and Obstetrics

Hidetaka Katabuchi
Editor

Frontiers in
Ovarian Cancer
Science

Comprehensive Gynecology
and Obstetrics
Series Editor
Ikuo Konishi
National Kyoto Medical Center
Kyoto
Japan
Hidetaka Katabuchi
Department of Obstetrics and Gynecology
Kumamoto University
Kumamoto
Japan

This series presents the current and future perspectives of medical science in
gynecology and obstetrics. The authors fully describe the current understanding of
a disease including clinical features, imaging, pathology, and molecular biology,
and also include the historical aspects and theories for exploring the etiology of the
disease. Also, recent developments in diagnostic strategy, medical treatment,
surgery, radiotherapy, prevention, and better health-care methods are clearly shown.
Thus, each volume in the series focuses on the scientific basis for the pathogenesis
of a disease and provides clinical applications that make it possible to offer
personalized treatment for each patient.Over the past 20 years, physicians have been
working to develop a standard treatment and publish clinical guidelines for a disease
based on epidemiological evidence, mainly through the use of randomized clinical
trials and meta-analyses. Recently, however, comprehensive genomic and genetic
analyses have revealed the differences and variations in biological characteristics
even among patients with the same diagnosis and have been focusing on personalized
therapy. Now all physicians and patients are entering a new world of “precision
medicine” through the use of genomic evidence. We are confident that readers will
greatly benefit from the contents of the series with its purview of the exciting and
promising future of gynecology and obstetrics.
More information about this series at http://www.springer.com/series/13621

Hidetaka Katabuchi
Editor

Frontiers in Ovarian
Cancer Science

Editor
Hidetaka Katabuchi
Department of Obstetrics and Gynecology
Kumamoto University
Kumamoto
Japan

ISSN 2364-1932     ISSN 2364-219X (electronic)
Comprehensive Gynecology and Obstetrics
ISBN 978-981-10-4159-4    ISBN 978-981-10-4160-0 (eBook)
DOI 10.1007/978-981-10-4160-0
Library of Congress Control Number: 2017950491
© Springer Nature Singapore Pte Ltd. 2017
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Preface

The ovaries are not only reproductive organs that hold the ova, which are a source
of life, but also endocrine organs that produce female sex steroid hormones. Diverse
germ cell tumors and sex-cord tumors develop from respective precursor cells.
Although epithelial tumors, which constitute the most common type of ovarian
tumors, have long been thought to arise from the ovarian surface epithelium, a new
theory has emerged indicating that they can arise within the tubal fimbriae in serous
tubal intraepithelial cancer (STIC) as precursor cells. In 2014, the World Health
Organization revised its histological classifications of gynecological tumors for the
first time in 13 years based on these findings, issuing the WHO Classification of
Tumours of Female Reproductive Organs. Rapid advances in molecular biology
have resulted in a new classification of epithelial ovarian cancer into two types
through the addition of precursors and known molecular genetic alterations to the
conventional histological type. A new point of view for the diagnosis and prevention
of epithelial ovarian cancer was introduced when two genes responsible for hereditary breast–ovarian cancer, which accounts for approximately 5–10% of cases of
epithelial ovarian cancer, were identified.
Clinically, over the past 30 years, a markedly increasing trend in cases of epithelial ovarian cancer has been seen in developed Western countries. Epithelial ovarian
cancer is now the eighth most common disease among women worldwide and the
seventh leading cause of death. For cases of epithelial ovarian cancer, half of which
are progressive cancer cases, it is important to implement multimodal therapy with
surgery and chemotherapy. As various international clinical trials on chemotherapy
with platinum agents and taxane are under way, new and innovative treatments such
as neoadjuvant chemotherapy (NAC) are beginning to be clinically applied. In addition to the introduction of molecular-targeted therapy, the current feasibility of
immunotherapy has made it possible to anticipate improvement in the long-term
prognosis. However, as no marked improvement in prognosis for cases of progressive ovarian cancer is expected, the most important clinical issue is the treatment of
recurrent ovarian cancer, with the basis of treatment being the early introduction of
palliative medicine. Moreover, the introduction of the concept of oncofertility is an
important issue for young patients, while treatment strategies for elderly patients,
whose number is increasing with the aging population, must not be neglected.
On this topic, we scientifically studied ovarian cancer and summarized the basic
principles and frontline clinical management in Chap. 17. I take pride in the fact that
v

vi

Preface

all authors are highly renowned in their field worldwide. I sincerely hope that this
book becomes a must-have resource not only for basic scientists and gynecologic
oncologists but also for many doctors, ranging from those in the younger generation
who have just started engaging in research or clinical care to experienced
gynecologists.
Kumamoto, Japan

Hidetaka Katabuchi

Contents

1 Epidemiology and Etiology of Ovarian Cancer����������������������������������������  1
Hiroyuki Nomura, Naomi Iwasa, Tomoko Yoshihama,
Yoshiko Nanki, and Daisuke Aoki
2 Hereditary Ovarian Cancer����������������������������������������������������������������������  15
Masayuki Sekine and Takayuki Enomoto
3 Morphological and Molecular Pathogenesis of Epithelial
Ovarian Tumors ����������������������������������������������������������������������������������������  37
Hironori Tashiro, Yuko Imamura, Takeshi Motohara,
Isao Sakaguchi, and Hidetaka Katabuchi
4 Screening and Prevention of Ovarian Cancer����������������������������������������  57
Hiroshi Kobayashi
5 Pathology of Epithelial Ovarian Tumors ������������������������������������������������  83
Hiroyuki Yanai
6 Pathology of Non-epithelial Ovarian Tumors����������������������������������������� 115
Masaharu Fukunaga
7 Ovarian Cancer Genome and Molecular
Experimental Sciences ������������������������������������������������������������������������������ 143
Noriomi Matsumura and Ikuo Konishi
8 Strategies for the Management of Epithelial Ovarian Cancer�������������� 155
Nozomu Yanaihara and Aikou Okamoto
9 Strategies for the Management of Epithelial Ovarian
Borderline Tumors ������������������������������������������������������������������������������������ 165
Kimio Ushijima
10 Strategies for the Management of Non-­epithelial
Ovarian Tumors ���������������������������������������������������������������������������������������� 173
Satoru Kyo
11 Primary Surgical Treatment of Epithelial Ovarian Cancer������������������ 191
Mikio Mikami

vii

viii

Contents

12 Primary Chemotherapy and Targeted Molecular Therapy
of Epithelial Ovarian Cancer�������������������������������������������������������������������� 207
Satoru Nagase, Tsuyoshi Ohta, and Manabu Seino
13 Immunology and Immunotherapy in Ovarian Cancer�������������������������� 225
Masaki Mandai, Junzo Hamanishi, Kaoru Abiko,
Noriomi Matsumura, Tsukasa Baba, and Ikuo Konishi
14 Treatment of Recurrent Epithelial Ovarian Cancer������������������������������ 243
Shintaro Yanazume and Hiroaki Kobayashi
15 Management of Ovarian Cancer in Adolescents
and Young Adults �������������������������������������������������������������������������������������� 267
Norihito Yoshioka and Nao Suzuki
16 Management of Ovarian Cancer in the Elderly Population������������������ 281
Masanori Kaneuchi and Hideaki Masuzaki
17 Palliative Medicine in the Management of Ovarian Cancer������������������ 305
Masaki Fujimura

1

Epidemiology and Etiology of Ovarian
Cancer
Hiroyuki Nomura, Naomi Iwasa, Tomoko Yoshihama,
Yoshiko Nanki, and Daisuke Aoki

Abstract

The median age of patients diagnosed with ovarian cancer is 63 years in the
United States, and the risk for developing this cancer increases with age. The
age-adjusted incidence rate of ovarian cancer is 11.9 per 100,000 females, which
is relatively low, and it ranks 17th among all cancers. On the other hand, the
mortality from this cancer is relatively high, and the age-adjusted mortality is 7.5
per 100,000 females. Both the annual incidence rate and the mortality have been
declining in recent years, reflecting advances in treatment. From a global viewpoint, the incidence rate is higher in developed countries (especially in Northern
Europe) compared to developing countries.
Although the cause of ovarian cancer is still unknown, several risk factors
related to its development have been identified. The most important factors are
the family history and genetic background, which account for approximately
10% of ovarian cancer. Hereditary breast and ovarian cancer and Lynch syndrome are associated with mutations of certain genes. Other causes of ovarian
cancer that have been suggested include continuous ovulation, excessive gonadotropin stimulation, excessive hormone stimulation, and pelvic inflammation.
Ovarian cancer occurs more frequently among nulliparous women and infertile
women, while it is less frequent among women with a history of oral contraceptive use, pregnancy, or breastfeeding.
Keywords

Ovarian cancer • Incidence rate • Mortality • Risk factor

H. Nomura, M.D., Ph.D. • N. Iwasa, M.D. • T. Yoshihama, M.D. • Y. Nanki, M.D.
D. Aoki, M.D., Ph.D. (*)
Department of Obstetrics and Gynecology, Keio University School of Medicine,
35 Shinanomachi, Shinjuku-ku, Tokyo, Japan
e-mail: [email protected]
© Springer Nature Singapore Pte Ltd. 2017
H. Katabuchi (ed.), Frontiers in Ovarian Cancer Science, Comprehensive
Gynecology and Obstetrics, DOI 10.1007/978-981-10-4160-0_1

1

2

1.1

H. Nomura et al.

Introduction

Ovarian cancer is uncommon and often advanced at the time of diagnosis and has a
poor prognosis. The prevalence of ovarian cancer is influenced by the social background, demographic factors, racial and ethnic factors, and lifestyle factors. The
survival rate of ovarian cancer patients has improved with the development and
standardization of new treatments. It is important to be aware of epidemiological
trends in the diagnosis and treatment of ovarian cancer. This section provides an
outline of the age distribution of ovarian cancer, annual changes of the incidence
rate and mortality, and international comparisons, as well as information about epidemiology and etiology with a focus on risk factors.

1.2

General Epidemiology of Ovarian Cancer

Ovarian cancer includes various tumors that arise from the ovaries, and its histological classification is based on the classification of the World Health Organization
(WHO) [1]. Superficial epithelial/stromal tumors account for approximately 80% of
all ovarian tumors. These tumors contain epithelial and interstitial tissues in various
proportions, and the tumor components are normally derived from the epidermis.
Sex cord-stromal tumors are derived from granulosa cells and Sertoli cells, theca
cells differentiating from the interstitium, or Leydig cells and account for approximately 5% of all ovarian tumors. Germ cell tumors are derived from germ cells or
extraembryonic tissues and comprise approximately 15–20% of all ovarian tumors.
Although ovarian cancer occurs in all age groups, the histological types vary with
age (Table 1.1) [2]. While malignant germ cell tumors are most frequent in young
women aged 20 years or younger, malignant epithelial tumors are frequent in older
women aged 50 years or older.
Some patients with ovarian cancer have a positive family history or genetic background, and the disease is called familial ovarian cancer in a broad sense if a patient
has a relative with ovarian cancer. If a patient has a family history of ovarian cancer
in close relatives or a number of relatives with this cancer, it is called familial or
hereditary ovarian cancer, including hereditary breast and ovarian cancer (HBOC)
and Lynch syndrome. Hereditary ovarian cancer is estimated to account for approximately 10% of all ovarian cancer [3, 4].
Globally, it has been reported that approximately 200,000 women are diagnosed
with ovarian cancer and 125,000 women die of this cancer every year [5, 6].

Table 1.1  Primary ovarian neoplasms related to age (From ref. 2)
Type
Coelomic epithelium
Germ cell
Specialized gonadal stroma
Non-specific mesenchyme

<20 years
29%
59%
8%
4%

20–50 years
71%
14%
5%
10%

>50 years
81%
6%
4%
9%

1  Epidemiology and Etiology of Ovarian Cancer

1.3

3

 urrent Status and Changes of Ovarian Cancer
C
Incidence Rate

The “number of cases (or number of deaths)” is the “number of cases (or deaths) newly
diagnosed during a certain period (usually 1 year) in a target population,” and it is often
expressed as the “incidence rate (mortality).” However, in diseases such as cancer for
which age is considered to be a contributing factor, the age-stratified incidence rate (or
mortality) is important, and therefore the “age-specific incidence rate (or mortality)” is
calculated. When comparing incidence rate (or mortality) between different regions or
periods, it is difficult to perform accurate comparison due to differences in the age distribution of the target populations. To overcome this problem, the “age-adjusted incidence rate (or mortality)” is often calculated, which is the incidence rate (or mortality)
adjusted for the age-specific population of the standard population, in order for the age
composition to be the same as that of the standard population.
The detailed trends of cancer prevalence and mortality are reported by the
Surveillance, Epidemiology, and End Results (SEER) program compiled by the
National Cancer Institute (NCI) in the United States [7]. Although SEER is based
on data from the United States, it can be used as a relatively general reference since
the racial composition of the population is diverse in the United States.
According to the 2009–2013 data, the age-adjusted incidence rate of ovarian
cancer is 11.9 per 100,000 females. According to the 2010–2012 data, the lifetime risk of ovarian cancer for women is 1.3% (approximately 1 out of every 78
females). The population of women in the United States is approximately 160
million (2015 data) [8], and the estimated annual number of patients developing
ovarian cancer in the United States is 22,280 (as of 2016), while it is estimated
that there were a total of 195,767 patients with ovarian cancer in 2013. The cancer causing the highest age-adjusted incidence rate for women is breast cancer,
and the incidence rate is 125.0 per 100,000 females. The incidence rate due to
ovarian cancer is less than one tenth of that caused by breast cancer, and it is
ranked 17th among all cancers affecting women in terms of the estimated annual
number of patients, accounting for only 1.3% of new cancers annually (Table 1.2).
Table 1.2  Estimated new cases and deaths compared to other cancers: ovarian cancer (From ref. 7)
Common types of cancer
  1  Breast cancer (female)
  2  Lung and bronchus cancer
  3  Prostate cancer
  4  Colon and rectum cancer
  5  Bladder cancer
  6  Melanoma of the skin
  7  Non-Hodgkin lymphoma
  8  Thyroid cancer
  9  Kidney and renal pelvis cancer
10 Leukemia

17  Ovarian cancer

Estimated new cases 2016
246,660
224,390
180,890
134,490
76,960
76,380
72,580
64,300
62,700
60,140

22,280

Estimated deaths 2016
40,450
158,080
26,120
49,190
16,390
10,130
20,150
1,980
14,240
24,400

14,240

4

H. Nomura et al.
20
Number per
100,000 females

New cases
15
11.9
10
Deaths
5

7.5

0
1975

1980

1985

1990

1995

2000

2005

2010 2013

Year

1975

1980

1985

1990

1995

2000

2004

2008

5–Year relative
survival

33.7%

38.2%

38.7%

40.4%

42.2%

43.0%

44.3%

46.2%

1975–2013, All races, females. Rates are age-adjusted.

Fig. 1.1  Trends of age-adjusted incidence rate, mortality, and 5-year relative survival rate: ovarian
cancer (From ref. 7)
30
24.2%

25
18.6%

20

15.9%
15
10

8.0%

6.9%
3.8%

5

21.4%
20

<20

14.3%

15
10.4%

10
5

1.3%
0

25.8% 25.0%

25
21.3%

Percent of deaths

Percent of new cases

30

20–34 35–44 45–54 55–64 65–74 75–84
Age

> 84

2009–2013, All races, females.

0

0.1%
<20

0.7%

2.3%

20–34 35–44 45–54 55–64 65–74 75–84
Age

> 84

2009–2013, All races, females.

Fig. 1.2  Percentage of new cases and deaths by age group: ovarian cancer (From ref. 7)

Thus, ovarian cancer is relatively infrequently in proportion to all cancers. The
annual age-adjusted incidence rate of ovarian cancer has been decreasing, as it
was 16.3 per 100,000 females in 1975, 15.4 in 1990, 13.0 in 2005, and 11.9 in
2013 (Fig. 1.1).
The median age of women diagnosed with ovarian cancer is 63 years. As for the
age-specific incidence, 1.3% of women with ovarian cancer are diagnosed at
19 years or younger, 3.8% at 20–34 years, 6.9% at 35–44 years, 18.6% at
45–54 years, 24.2% at 55–64 years, 21.3% at 65–74 years, 15.9% at 75–84 years,
and 8.0% at 85 years or older (Fig. 1.2). Thus, the prevalence of ovarian cancer
increases with age, and it increases rapidly from the age of 45 years. Patients who
are 45 or older comprise 88% of the total number of patients, with a peak at
55–64 years. These points suggest that aging is an important factor in the development of ovarian cancer.
As for racial/ethnic background, the age-adjusted incidence rate per 100,000
females is 12.5 for whites, 9.6 for blacks, 9.3 for Asian/Pacific islanders, 10.4 for
American Indians/Alaskan natives, 10.6 for Hispanics, and 12.0 for non-Hispanics.
Thus, ovarian cancer incidence rate tends to be lower among blacks and Asians,
while it is higher among whites and non-Hispanics (Fig. 1.3).

5

1  Epidemiology and Etiology of Ovarian Cancer
Number of new cases

Number of deaths
Female

Female

All races

11.9

All races

7.5

White

12.5

White

7.8

Black

9.6

Black

6.5

Asian/
Pacific Islander
American Indian/
Alaska Native

Asian/
Pacific Islander
American Indian/
Alaska Native

9.3
10.4

4.5
6.7

Hispanic

10.6

Hispanic

5.5

Non–Hispanic

12.0

Non–Hispanic

7.7
Per 100,000 persons
2009−2013, Age-adjusted.

Per 100,000 persons
2009−2013, Age-adjusted.

Fig. 1.3  Age-adjusted incidence rate and mortality by race/ethnicity: ovarian cancer (From ref. 7)

6%

15%

19%

60%

5-year relative survival rate
Localized (15%)
Confined to
primary site
Regional (19%)
Spread to regional
lymph nodes
Distant (60%)
Cancer has
metastasized
Unknown (6%)
Unstaged

Percent

Percentage of cases by stage

100
90
80
70
60
50
40
30
20
10
0

92.1%
73.1%

28.8%

ed

aliz

Loc

l

iona

Reg

ant

Dist

24.2%

d

tage

Uns

Stage
2006−2012, All Races, Females.

Fig. 1.4  Percentage of cases and 5-year relative survival rate by stage at diagnosis: ovarian cancer
(From ref. 7)

Ovarian cancer is confined to the ovary at diagnosis in 15% of patients, while it has
spread to regional lymph nodes in 19% and has spread or metastasized beyond the
primary site in 60% (the details are unknown in 6%), indicating that more than half of
all patients have advanced disease at diagnosis (Fig. 1.4). In older women, ovarian
cancer is diagnosed at a relatively more advanced stage than in young women.
On the other hand, the trends of cancer prevalence and mortality in Japan are
reported by the Cancer Registry and Statistics in Cancer Information Service,
National Cancer Center, Japan [9], and the annual report of the Committee on
Gynecologic Oncology, Japan Society of Obstetrics and Gynecology (JSOG)
[10]. As of 2012, the age-adjusted incidence rate of ovarian cancer was 8.3 per
100,000 females. That of all sites of female cancer was 265.8 per 100,000
females, and that of breast cancer was 64.3 per 100,000 females, which was the
highest in female cancers. Ovarian cancer is ranked seventh among all sites of

6

H. Nomura et al.

female cancers and accounting for 3.1% of new cancers. In Japan, the annual
age-adjusted incidence rate of ovarian cancer has doubled in these 30 years.
Patients aged 60–69, 50–59, and 40–49 years accounted for 26.9%, 24.6%, and
21.5%, respectively, of all patients whose treatment was initiated in 2013. Women
in their 50s and 60s were predominantly affected by ovarian cancer, same as the
report on SEER. The distribution of surgical stages is as follows: stage I (confined to primary site) accounted for 42.2%, stage II (spread to pelvic cavity)
accounted for 9.8%, stage III (spread to regional lymph nodes and/or peritoneal
cavity) accounted for 28.2%, and stage IV (metastasize to distant organs)
accounted for 8.3% of all patients. Neoadjuvant chemotherapy was administered
to 10.9% of patients.

1.4

 urrent Status and Changes of Ovarian Cancer
C
Mortality

According to SEER [7], the age-adjusted mortality rate of ovarian cancer was 7.5
per 100,000 females in 2009–2013. Based on the 2006–2012 data, the 5-year survival rate of ovarian cancer patients was 46.2%, indicating that more than half of
these patients die within 5 years. In the United States, 14,240 patients are predicted
to die of ovarian cancer in 2016 (Table 1.2). Ovarian cancer accounts for 2.4% of all
cancer deaths, which is high in proportion to the number of patients with this tumor.
When compared to the 5-year survival rate of 89.7% for breast cancer and the
40,450 estimated annual deaths (21.5 per 100,000 females) from this cancer, which
has the highest estimated annual incidence, the higher risk of death from ovarian
cancer becomes obvious. However, the annual age-adjusted mortality due to ovarian
cancer is decreasing, as it was 9.8 per 100,000 females in 1975, 9.3 in 1990, 8.7 in
2004, and 7.5 in 2013. In addition, the 5-year survival rate is increasing, since it was
33.7% in 1975, 40.4% in 1990, and 46.2% in 2008 (Fig. 1.1). This improvement is
thought to be due to advances in operative treatment and to the development and
standardization of novel chemotherapy regimens.
The median age at which patients die of ovarian cancer is 70 years. As for the
age-specific mortality, 0.1% of patients die at 19 years or younger, 0.7% at
20–34 years, 2.3% at 35–44 years, 10.4% at 45–54 years, 21.4% at 55–64 years,
25.8% at 65–74 years, 25.0% at 75–84 years, and 14.3% at 85 years or older
(Fig.  1.2). The ovarian cancer mortality is in proportion to the incidence of this
cancer and thus increases with age to a peak at 55–64 years.
With respect to the influence of racial/ethnic background, the age-adjusted mortality per 100,000 females is 7.8 for whites, 6.5 for blacks, 4.5 for Asian/Pacific
islanders, 6.7 for American Indians/Alaskan natives, 5.5 for Hispanics, and 7.7 for
non-Hispanics. Thus, mortality tends to be lower in Asian/Pacific islanders and
Hispanics compared with the incidence of this cancer (Fig. 1.3).
The 5-year survival rate at the time of diagnosis of ovarian cancer is 92.1% if the
tumor is confined to the ovary, 73.1% if it has spread to regional lymph nodes,
28.8% if it has spread or metastasized beyond the region, and 24.2% when the

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