Ovarian, Fallopian Tube, and Peritoneal Cancer
BS. Nguyen Hong Anh
KEY POINTS
1 The peak age incidence of invasive epithelial ovarian cancer is approximately 60
years. About 30% of ovarian neoplasms in postmenopausal women are malignant,
whereas only about 7% of ovarian epithelial tumors in premenopausal patients are
malignant. The average age at diagnosis of patients with borderline tumors is
approximately 46 years.
2 Ovarian cancer is associated with low parity and infertility. Because parity is
inversely related to the risk of ovarian cancer, having at least one child is protective,
with a risk reduction of 0.3 to 0.4.
3 Oral contraceptive use reduces the risk of epithelial ovarian cancer—women who use
oral contraceptives for 5 or more years reduce their relative risk by 0.5 (i.e., there is
a 50% reduction in the likelihood of development of ovarian cancer).
4 Given the false-positive results for CA-125 and transvaginal ultrasonography,
particularly in premenopausal women and the absence of evidence from randomized
trials that screening with CA-125 and TVUS reduces the mortality of ovarian
cancer, these tests should not be used routinely to screen women for ovarian cancer.
5 Most epithelial ovarian cancers are sporadic, but up to one-quarter of cases may be
associated with germline mutations in predisposing genes and may be hereditary.
Hereditary ovarian cancers, particularly those caused by BRCA1 mutations, occur at
a younger age, typically about 10 years earlier than sporadic ovarian cancers.
6 Most hereditary ovarian cancers result from germline mutations in the BRCA1 and
BRCA2 genes. The mutations are inherited in an autosomal dominant fashion, and
therefore a full pedigree analysis (i.e., maternal and paternal sides of the family
history for breast and ovarian cancer) must be carefully evaluated in all patients with
epithelial ovarian cancer, fallopian tube cancer, and peritoneal cancer. It is important
to note that almost 40% of women with BRCA-associated ovarian cancer do not
have a family history and hence genetic testing should be offered to all women with
ovarian cancer.
7 In unaffected women with a known BRCA1 mutation, the value of prophylactic
salpingo-oophorectomy is well established and is the most effective way to reduce
the risk of these cancers and reduce mortality.
8 The importance of thorough surgical staging cannot be overemphasized, because
subsequent treatment and prognosis will be determined by the stage of the disease.
All patients with suspected ovarian cancer should be evaluated by a gynecologic
oncologist. Patients with advanced-stage ovarian cancer (stage IIIC or IV) should
have clinical evaluation including chest, abdomen and pelvis imaging. Patients
determined to have a poor performance status, a high perioperative risk, or a low
probability of attaining optimal cytoreduction to no visible, or palpable, residual
2543disease, or at least cytoreduction to less than 1 cm of residual disease, should be
considered for neoadjuvant chemotherapy prior to attempt at interval cytoreductive
surgery after two to three cycles of chemotherapy. Patients with advanced ovarian
cancer who are medically fit for major surgery and who potentially have resectable
disease should be offered primary cytoreductive surgery followed by adjuvant
chemotherapy. In the United States, primary cytoreductive surgery is preferred, if
there is a high likelihood of achieving optimal cytoreduction with acceptable
morbidity from surgery. Prior to initiating neoadjuvant chemotherapy, the
pathologic diagnosis of ovarian, fallopian tube, or peritoneal cancer must be made
on biopsy.
9 Combination chemotherapy with carboplatin and paclitaxel (CP) is recommended for
patients with high-risk, low-stage disease. For advanced-stage epithelial ovarian
cancer, the choice of intravenous (IV) versus intraperitoneal (IP) platinum and
taxane chemotherapy with the addition of bevacizumab should be individualized.
10 The ICON8 trial did not confirm the JGOG study that showed that a dose-dense
regimen of weekly paclitaxel and 3-weekly carboplatin was significantly superior to
the standard every 3-week chemotherapy regimen of both drugs. Therefore 3-weekly
regimens remain the standard of care in non-Japanese women.
11 BRCA-associated ovarian cancers have increased sensitivity to platinum
chemotherapy and to poly (ADP-ribose) polymerase (PARP) inhibitors. PARP
inhibitors are approved to treat selected patients with recurrent ovarian cancer and
for maintenance therapy following response to platinum-based chemotherapy in the
recurrent setting. There is good evidence from a number of randomized trials that
maintenance therapy with PARP inhibitors results in a significant increase in the
progression-free survival (PFS), particularly in BRCA mutation carriers (including
tumors with somatic BRCA mutations). PARP inhibitors niraparib and olaparib are
U.S. Food and Drug Administration (FDA) approved for maintenance therapy in
patients with platinum-sensitive disease with a partial or complete response to
platinum-based chemotherapy. PFS is improved with these agents regardless of
BRCA status, although the PFS is significantly longer in patients with BRCA
mutations. Maintenance therapy with rucaparib was reported to be associated with
significant improvement in PFS in patients with platinum-sensitive recurrent ovarian
cancer after response to chemotherapy, with the benefits being greater in women
with somatic or germline BRCA (gBRCA) mutations.
12 In the first two decades of life, almost 70% of ovarian tumors are of germ cell
origin, and one-third of these are malignant. In contrast to the relatively slowgrowing epithelial ovarian tumors, germ cell malignancies grow rapidly.
13 The most common types of malignant germ cell tumors are dysgerminomas,
immature teratomas, and endodermal sinus tumors (EST). Preservation of fertility
should be standard in most patients. The most effective chemotherapy is bleomycin,
etoposide, and cisplatin (BEP).
14 Stromal tumors include adult granulosa cell tumors, which are low-grade
malignancies. They account for 70% of ovarian sex cord–stromal tumors. Granulosa
2544cell tumors are the most common type of malignant ovarian sex cord–stromal
tumors. In premenopausal women, they can be treated conservatively. Adjuvant
chemotherapy is of unproven value.
15 Metastatic tumors to the ovaries are most frequently from the breast and
gastrointestinal tract.
16 Epithelial serous fallopian tube carcinomas and peritoneal cancers are the same as
ovarian cancer and are treated in the same way, with staging and cytoreductive
surgery followed by platinum and taxane chemotherapy. The distinction between
high-grade serous ovarian, fallopian tube, and peritoneum cancers is an anachronism
because as most high-grade serous cancers arise from the fimbriae of the fallopian
tube.
Ovarian cancer is the second most common gynecologic cancer in the United
States but it accounts for the majority of deaths from these cancers. Epithelial
cancers are the most common ovarian/fallopian malignancy, and at initial
diagnosis, over two-thirds of patients have advanced disease. Ovarian cancer
represents a major surgical challenge as the aim is to resect all visible disease.
Optimal therapy includes maximal attempt at surgical cytoreduction to no gross
disease, or at least optimal debulking (to <1 cm of residual disease), followed by
platinum-based combination chemotherapy. It has the highest fatality-to-case ratio
of all the gynecologic malignancies. There are nearly 22,280 new cases annually
in the United States, and 14,240 women can be expected to succumb to their
illness (1). Ovarian cancer is the seventh most common cancer in women in the
United States, accounting for 3% of all malignancies, 6% of deaths from cancer in
women, and almost one-third of invasive malignancies of the female genital
organs. Ovarian cancer is the fifth most common cause of death from malignancy
in women. The lifetime risk of being diagnosed with ovarian cancer is 1% to
1.5% and of dying from ovarian cancer is almost 0.5% (2).
EPITHELIAL OVARIAN CANCER
Developments, based in part on meticulous pathologic assessment of riskreducing salpingo-oophorectomy specimens from BRCA patients, have
completely changed our perception and understanding of “ovarian” cancer.
While previously thought to be derived from the coelomic epithelium on the
surface of the ovary or from ovarian inclusion cysts, it is now apparent that
most serous carcinomas originate from the fallopian tube (3), while other
subtypes (clear cell, endometrioid) are derived from endometriosis. A detailed
classification of the histologic types of epithelial tumors of the ovary is presented
in Table 39-1. Neoplastic transformation can occur when the cells are genetically
2545predisposed to oncogenesis, exposed to an oncogenic agent, or both (4).
Table 39-1 Epithelial Ovarian Tumors
Histologic Type Cellular Type
I. Serous Endosalpingeal
A. Benign
B. Borderline
C. Malignant
II. Mucinous Intestinal, endocervical
A. Benign
B. Borderline
C. Malignant
III. Endometrioid Endometrial
A. Benign
B. Borderline
C. Malignant
IV. Clear-cell Müllerian
A. Benign
B. Borderline
C. Malignant
V. Brenner Transitional
A. Benign
B. Borderline (proliferating)
C. Malignant
VI. Mixed epithelial Mixed
2546A. Benign
B. Borderline
C. Malignant
VII. Undifferentiated May be anaplastic
VIII. Unclassified
From Seroy SF, Scully RE, Sobin LH. International Histological Classification of
Tumours No. 9. Histological Typing of Ovarian Tumors. Geneva, Switzerland: World
Health Organization; 1973, with permission.
Pathology
Invasive Cancer
Seventy-five percent to 80% of epithelial cancers are of the serous histologic
type. Less common types are endometrioid (10%), clear cell (5%), mucinous
(5%), transitional, and undifferentiated carcinomas, with the last two types
representing less than 1% of epithelial lesions (2). Each of the major tumor
types is named on the basis of a histologic pattern that resembles the epithelium in
the lower genital tract (4). For example, serous tumors have an appearance similar
to that of the glandular epithelial lining of the fallopian tube, endometrioid tumors
resemble proliferative endometrium, and clear cell tumors resemble secretory or
gestational endometrium. Mucinous tumors may contain cells that resemble
endocervical glands, but more commonly these cells resemble the gastrointestinal
epithelium. Transitional tumors are so named because of a resemblance to the
epithelium in Walthard rests and bladder urothelium.
There is growing evidence that many, if not most, high-grade serous
carcinomas of the ovary arise from the fimbrial end of the fallopian tube rather
than from the ovary (5,6). Serous epithelial ovarian cancers can be separated
into two distinct groups—type I and type II serous tumors—as they differ
considerably in the cell of origin, molecular pathogenesis, and their biologic
behavior (7). Type I tumors include serous borderline tumors and low-grade
serous carcinoma; they are genetically stable, do not have p53 mutations,
and may have mutations in KRAS or BRAF. In contrast, type II serous
tumors are rapidly growing, highly aggressive neoplasms that may have
precursor lesions in the fimbriae of the fallopian tube; most are advanced
stage at diagnosis (8). The type II tumors are genetically unstable and almost
universally have p53 mutations.
2547Borderline Tumors
An important group of tumors to distinguish are tumors of low malignant
potential, also called the borderline tumors. Borderline tumors tend to remain
confined to the ovary for long periods, they occur predominantly in
premenopausal women, and are associated with a very good prognosis
(2,4,8–13). They are diagnosed most frequently in women between the ages of 30
and 50 years, whereas invasive carcinomas occur more often in women between
the ages of 50 and 70 years (2).
Although uncommon, extraovarian implants may occur with serous
borderline tumors. These implants are characterized as either noninvasive or
invasive (analogous to low-grade serous carcinoma). The latter has a higher
likelihood of progression, in the peritoneal cavity, which can ultimately lead to
intestinal obstruction caused by associated fibrosis and death (2,7).
Classification of Epithelial Ovarian Tumors
Serous Tumors
Serous tumors are so classified because they resemble tubal secretory cells.
Psammoma bodies are frequently found in these neoplasms, and they are made
up of concentric rings of calcification. Several hypotheses pertaining to the origin
and development of psammoma bodies are proposed, including apoptosis of
tumor cells and osteoinductive cytokines produced by macrophages, which result
in calcification that can be extensive (7). In the wall of the mesothelial
invaginations, papillary ingrowths are common, representing the early stages of
development of a papillary serous cystadenoma. There are many variations in the
proliferation of these mesothelial inclusions. Several foci may be lined with
flattened inactive epithelium; in adjacent cavities, papillary excrescences are
present, often resulting from local irritants (2).
FIGURE 39-1 Serous borderline tumor of the ovary. Complex papillary fronds with
hierarchical branching are lined with pseudostratified columnar cells. The epithelium and
the stroma are clearly separated by a basement membrane, indicating no stromal invasion.
Borderline Serous Tumors
Approximately 10% of all ovarian serous tumors fall into the category of a
tumor of low malignant potential or borderline tumor (Fig. 39-1), and 50%
occur before the age of 40 years. The criteria for the diagnosis of serous
borderline tumors are as follows (12):
1. Epithelial hyperplasia in the form of pseudostratification, tufting, cribriform,
and micropapillary architecture
2. Mild nuclear atypia and mild increased mitotic activity
3. Detached cell clusters
4. Absence of destructive stromal invasion (i.e., without tissue destruction)
Serous borderline tumors that are composed of an exuberant micropapillary
architecture are designated as serous borderline tumors with micropapillary
2549features (Fig. 39-2); these tumors are more frequently bilateral, exophytic, and
high stage than the usual serous borderline tumor.
It should be emphasized that up to 40% of serous borderline tumors are
associated with spread beyond the ovary, but high-stage disease does not
necessarily warrant a diagnosis of an invasive carcinoma. The diagnosis of a
serous borderline tumor versus serous carcinoma is based on the histologic
features of the primary tumor (12). Up to 10% of women with ovarian serous
borderline tumors and extraovarian implants may have invasive implants (i.e.,
low-grade serous carcinoma), and these can behave more aggressively (14). The
5-year overall survival for women with invasive implants (low-grade serous
carcinoma) is about 50% if stringent criteria are applied (11,14–16). Most
implants are noninvasive (11,17). In the noninvasive implants, papillary
proliferations of atypical cells involve the peritoneal surface and form smooth
invaginations (11). In contrast, the invasive implants resemble well-differentiated
serous carcinoma and are characterized by atypical cells forming irregular glands
with sharp borders. Implants are usually confined to the abdominal cavity and
may be seen in the pelvis, omentum, and adjacent tissues, including lymph nodes,
but spread outside the abdominal cavity is rare. Death can occur as the result of
intestinal obstruction (17–20).
Borderline serous tumors may harbor foci of stromal microinvasion (19).
Most patients are young and their tumors are International Federation of
Obstetrics and Gynecology (FIGO) stage I. Stromal microinvasion is increased
about ninefold in pregnant women with serous borderline tumors.
The presence of stromal microinvasion is associated with lymphovascular
space invasion in the primary ovarian tumor (and likely represents a form of true
stromal invasion), but it is not associated with an aggressive clinical course, and
patients with this finding should be managed in the same way as patients without
stromal microinvasion.
Serous Carcinomas
In malignant serous tumors, stromal invasion is present (2). The grade of
tumor is important and needs to be documented. In low-grade serous
adenocarcinomas, papillary and glandular structures predominate (Fig. 39-3);
high-grade neoplasms are characterized by solid sheets of cells, nuclear
pleomorphism, and high mitotic activity (Fig. 39-4). Laminated, calcified
psammoma bodies are found in 80% of serous carcinomas. Serous
psammocarcinoma is a rare variant of serous carcinoma characterized by
massive psammoma body formation and low-grade cytologic features. At
least 75% of the epithelial nests are associated with psammoma body formation.
Patients with serous psammocarcinoma have a protracted clinical course and a
2550relatively favorable prognosis; their clinical course more closely resembles that of
high-stage, progressive serous borderline tumor than serous carcinoma.
nonhierarchical branching pattern and are lined by a monomorphous population of cells.
Mucinous Tumors
These cystic ovarian tumors have loculi lined with mucin-secreting epithelium.
The lining epithelial cells contain intracytoplasmic mucin and resemble those of
endocervix, gastric pylorus, or intestine. They represent about 8% to 10% of
epithelial ovarian tumors. They may reach enormous size, filling the entire
abdominal cavity (2).
FIGURE 39-3 Low-grade serous adenocarcinoma of the ovary. Clusters and papillae of
malignant cells are in direct contact with fibrous stroma indicative of stromal invasion.
Borderline Mucinous Tumors
The mucinous tumor of low malignant potential is often difficult to diagnose.
Although it is common to find a rather uniform pattern from section to section in
the serous borderline tumor, this is not true in the mucinous tumors. Welldifferentiated mucinous epithelium may be seen immediately adjacent to a
poorly differentiated focus. It is important to take multiple sections from
many areas in the mucinous tumor to identify the most malignant alteration
(2).
FIGURE 39-4 High-grade serous adenocarcinoma. Papillae lined by sheets of
cytologically malignant cells invade stroma, often with associated necrosis.
FIGURE 39-5 Mucinous adenocarcinoma of the ovary. Irregular glandular spaces are
lined with a layer of tall columnar cells with abundant mucinous cytoplasm, resembling
intestinal epithelium at the left. At the right, there is destructive invasion into the ovarian
stroma.
Mucinous Carcinomas
Bilateral tumors occur in 8% to 10% of cases. The mucinous lesions are confined
to the ovary in 95% to 98% of cases (Fig. 39-5). Because most ovarian mucinous
carcinomas contain enteric-type cells, they cannot be distinguished from
metastatic carcinoma of the gastrointestinal tract on the basis of histology alone.
Primary ovarian neoplasms rarely metastasize to the mucosa of the bowel,
although they commonly involve the serosa, whereas gastrointestinal lesions
frequently involve the ovary by direct extension or lymphatic spread (2).
Pseudomyxoma Peritonei
Pseudomyxoma peritonei is a clinical term used to describe the finding of
abundant mucoid or gelatinous material in the pelvis and abdominal cavity
surrounded by fibrous tissue. It is most commonly secondary to a well-
2554differentiated appendiceal mucinous neoplasm or other gastrointestinal
primary; rarely, mucinous tumors arising in an ovarian mature teratoma are
associated with pseudomyxoma peritonei.
Endometrioid Tumors
Endometrioid lesions constitute 6% to 8% of epithelial tumors. Endometrioid
neoplasia includes all the benign demonstrations of endometriosis. In 1925,
Sampson suggested that certain cases of adenocarcinoma of the ovary probably
arose in areas of endometriosis (20). The adenocarcinomas are similar to those
seen in the uterine corpus. The malignant potential of endometriosis is very low,
although a transition from benign to malignant epithelium may be demonstrated.
Borderline Endometrioid Tumors
The endometrioid tumor of low malignant potential has a wide morphologic
spectrum. Tumors may resemble an endometrial polyp or complex endometrial
hyperplasia with glandular crowding. When there are back-to-back,
architecturally complex glands with no intervening stroma, the tumor is classified
as a well-differentiated endometrioid carcinoma. Some borderline endometrioid
tumors have a prominent fibromatous component. In such cases, the term
adenofibroma is used to describe them (2).
Endometrioid Carcinomas
Endometrioid tumors are characterized by a markedly complex glandular pattern
with all the potential variations of epithelia found in the uterus (Fig. 39-6).
FIGURE 39-6 Endometrioid cancer. Round to tubular glands lined by stratified columnar
cells with a confluent growth pattern.
Multifocal Disease
The endometrioid tumors afford the greatest opportunity to evaluate multifocal
disease. Endometrioid carcinoma of the ovary is associated in 15% to 20% of
the cases with carcinoma of the endometrium. Identification of multifocal
disease is important because patients with disease metastatic from the uterus
to the ovaries have a 30% to 40% 5-year survival, whereas those with
synchronous multifocal disease have a 75% to 80% 5-year survival (21).
When the histologic appearance of endometrial and ovarian tumors is different,
the two tumors most likely represent two separate primary lesions. When they
appear similar, the endometrial tumor can be considered a separate primary tumor
if it is well differentiated and only superficially invasive.
Clear Cell Carcinomas
Several basic histologic patterns are present in the clear cell adenocarcinoma (i.e.,
tubulocystic, papillary, reticular, and solid). The tumors are made up of clear and
2556hobnail cells that project their nuclei into the apical cytoplasm. The clear cells
have abundant clear or vacuolated cytoplasm, hyperchromatic irregular nuclei,
and nucleoli of various sizes (Fig. 39-7). Focal areas of endometriosis are
common and mixed clear cell and endometrioid carcinoma may occur (21).
The clear cell carcinoma seen in the ovary is histologically identical to that seen
in the uterus or vagina of the young patient who has been exposed to
diethylstilbestrol (DES) in utero. Almost invariably high-grade nuclei are
identified. Hence, clear cell carcinomas are not graded.
Transitional (Brenner) Tumors
Borderline Brenner Tumors
Proliferative Brenner tumors were previously subclassified as proliferating tumors
(those tumors that resemble low-grade papillary urothelial carcinoma of the
urinary bladder) and borderline tumors (those tumors that resemble high-grade
papillary urothelial carcinoma), these groups of tumors are now classified as
borderline Brenner tumors (22). Complete surgical removal usually results in
cure.
FIGURE 39-7 Clear cell carcinoma of the ovary. Note the solid variant of clear cell
carcinoma with sheets of cells that have clear cytoplasm (“hobnail” cells).
Malignant Brenner Tumors
These rare tumors are defined as benign or borderline Brenner tumors
coexisting with invasive transitional cell carcinoma.
Transitional Cell Carcinoma
The designation transitional cell carcinoma has been attributed to primary
ovarian carcinoma resembling transitional cell carcinoma of the urinary
bladder without a recognizable Brenner tumor. It is now thought that these are
a variant of high-grade serous carcinoma and do not represent a distinct epithelial
subtype of carcinoma (23,24). Unlike malignant Brenner tumors these tumors are
more frequently diagnosed in an advanced stage and are associated with a
survival rate similar to that of high-grade serous carcinoma (25).
Peritoneal Carcinomas
Peritoneal tumors are histologically indistinguishable from ovarian and
fallopian tube serous tumors. In the case of borderline serous peritoneal
tumors and serous peritoneal carcinomas, the ovaries are normal or minimally
involved, and the tumors affect predominantly the uterosacral ligaments, pelvic
peritoneum, or omentum. The overall prognosis for borderline serous peritoneal
tumors is excellent and comparable to that of ovarian borderline serous tumors
(26–28). In the review of 38 cases of peritoneal borderline serous tumors from the
literature, 32 women had no persistent disease, 4 were well after resection of
recurrence, 1 developed an invasive serous carcinoma, and 1 died from the effects
of the tumor (26).
Carcinomas that appear to be predominantly peritoneal without
appreciable ovarian or fallopian tube enlargement have traditionally been
called peritoneal carcinoma, when tumors spread from the breast,
gastrointestinal tract, and other organs of non-müllerian origin are excluded.
Most are peritoneal serous carcinomas, and have the appearance of a moderately
to poorly differentiated serous ovarian carcinoma. Peritoneal endometrioid
carcinoma also occurs, but is less common; peritoneal clear cell carcinoma is rare.
[15] Peritoneal serous carcinoma should be considered clinically the same as
ovarian and fallopian tube cancers, as all these cancers share a similar
pathogenesis and clinical behavior and treatment. Patients in whom
exploratory surgery is performed, there may be microscopic or small macroscopic
cancer on the surface of the ovary and extensive disease in the upper abdomen,
particularly in the omentum (29).
2558Mesotheliomas
Peritoneal malignant mesotheliomas may be epithelial, sarcomatous, or
biphasic (2,30). Deciduoid peritoneal mesothelioma is an unusual variant that
resembles exuberant, ectopic decidual reaction of the peritoneum. Asbestos
exposure is not correlated with peritoneal mesotheliomas in women. These
lesions typically appear as multiple intraperitoneal (IP) masses, often coating the
entire peritoneum and can develop after hysterectomy and bilateral salpingooophorectomy for benign disease. Malignant mesotheliomas should be
distinguished from benign multicystic peritoneal mesothelioma (multilocular
peritoneal inclusion cyst), and ovarian tumor implants and primary peritoneal
müllerian neoplasms.
FIGURE 39-8 Ovarian cancer incidence: distribution by age. (From Nagy K. The side
effects of managed care on the drug industry. J Natl Cancer Inst 1995;87:1280, with
2559permission.)
Clinical Features
More than 80% of epithelial ovarian cancers are found in postmenopausal women
(Fig. 39-8). The peak incidence of invasive epithelial ovarian cancer is at 56
to 60 years of age (2,3). The age-specific incidence of ovarian epithelial cancer
rises precipitously from 20 to 80 years of age and subsequently declines. These
cancers are relatively uncommon in women younger than age 45. Fewer than 1%
of epithelial ovarian cancers occur before the age of 21 years, two-thirds of
ovarian malignancies in such patients being germ cell tumors (2,31). [1] About
30% of ovarian neoplasms in women are malignant, whereas only about 7%
of ovarian epithelial tumors in premenopausal patients are malignant (2,3).
The average age of patients with borderline tumors is approximately 46
years (2,3,9). Eighty percent to 90% of ovarian cancers, including borderline
forms, occur after the age of 40 years, whereas 30% to 40% of malignancies
occur after the age of 65 years. The chance that a primary epithelial tumor will be
of borderline or invasive malignancy in a patient younger than 40 years is
approximately 1 in 10, but after that age it rises to 1 in 3 (2,3). Less than 1% of
epithelial ovarian cancers occur before the age of 20 years, with two-thirds of
ovarian malignancies in such patients being germ cell tumors (31).
Etiology
[2] Ovarian cancer is associated with low parity and infertility (32). Although
there are a variety of epidemiologic variables correlated with ovarian cancer, such
as talc use, galactose consumption, and tubal ligation, none is as strongly
correlated as prior reproductive history and duration of the reproductive career
(32,33). Early menarche and late menopause increase the risk of ovarian cancer
(33). These factors and the relationship of parity and infertility to the risk of
ovarian cancer led to the hypothesis that suppression of ovulation may be an
important factor.
Prevention
[2] Because parity is inversely related to the risk of ovarian cancer, having at
least one child is protective for the disease, with a risk reduction of 0.3 to 0.4.
Oral contraceptive use reduces the risk of epithelial ovarian cancer [3] (32).
Women who use oral contraceptives for 5 or more years reduce their relative
risk to 0.5 (i.e., there is a 50% reduction in the likelihood of development of
ovarian cancer). Women who had two children and used oral contraceptives for
5 or more years have a relative risk of ovarian cancer as low as 0.3, or a 70%
2560reduction (34). The oral contraceptive pill is the only documented method of
chemoprevention for ovarian cancer, and it should be recommended to
women for this purpose. When counseling patients regarding birth control
options, this important benefit of oral contraceptive use should be
emphasized. This is important for women with a strong family history of
ovarian cancer.
The performance of a prophylactic salpingo-oophorectomy significantly
reduces, but does not totally eliminate, the risk of nonuterine pelvic cancers;
because the entire peritoneum is at risk, peritoneal carcinomas can occur in 2% to
3% of women even after prophylactic bilateral salpingo-oophorectomy (26,29).
A thorough discussion of the risks and benefits of oophorectomy should be
undertaken in premenopausal women who are undergoing a hysterectomy
for benign disease, do not carry germline mutations, and do not have a
family history that suggests that they are at higher than average risk for
ovarian cancer (35). The ovaries may provide protection from cardiovascular
disease and osteoporosis, and long-term mortality may not be decreased by
the performance of prophylactic oophorectomy in women at population risk
of ovarian cancer (36).
Screening
CA-125 is useful for monitoring epithelial ovarian cancer patients during their
chemotherapy; and is elevated in 50% of patients with stage I disease and in 80%
to 90% of patients with advanced serous cancers (37–46). Transvaginal
ultrasonography is useful to characterize the morphology of ovarian tumors
(47,48). However, the value of tumor markers and ultrasonography to screen
for epithelial ovarian cancer is not established by prospective studies (49). [4]
The use of transvaginal ultrasound alone or in combination with CA-125 for
early ovarian cancer detection has not proven effective in average-risk
women to decrease mortality from ovarian cancer, instead there are harms
to this strategy, including false-positive results and more invasive procedures
being performed such as surgery (50). The inability to use these modalities for
screening is discussed in the American College of Obstetricians and
Gynecologists (ACOG) committee opinion (51).
The U.S. Preventative Services Task Force (USPSTF) recommends against
screening asymptomatic women for ovarian cancer with pelvic examination,
pelvic ultrasound, or serum tumor marker measurements (52). The USPSTF
concluded that there is adequate evidence that there is no mortality benefit to
routine screening for ovarian cancer with transvaginal ultrasonography or
single-threshold serum CA-125 testing and that the harms of such screening
are at least moderate. There is no effective strategy for early detection of
2561ovarian cancer that translates to a reduction in ovarian cancer mortality
(52). Ultrasonography, despite being able to detect changes in size and
morphology of the ovaries, has not been shown be effective for ovarian
cancer screening (2,5).
Final results from United Kingdom Collaborative Trial of Ovarian Cancer
Screening (UKCTOCS), which is fully accrued and follow-up is pending,
should provide more information about the relative benefits and harms of an
algorithm-based approach to screening for ovarian cancer. In the UKCTOCS
study, 202,638 healthy average-risk postmenopausal patients in the age range 50
to 74 years were randomized to receive no screening, annual pelvic ultrasound or
multimodal screening using a combination of CA-125 testing (interpreted using
risk of ovarian cancer algorithm [ROCA]) and ultrasound triggered by a ROCA
score signifying increased risk. Multimodal screening with the ROCA was
superior to using fixed CA-125 cut-off values in combination with ultrasound
screening (positive predictive value = 35.1%). Ten women had surgical
intervention because of a false-positive screening result, demonstrating that the
harm related to unnecessary surgical procedures as a consequence of a falsepositive test can occur (50,53). Thus far, follow-up data has not shown a
significant reduction of ovarian cancer mortality with multimodal screening when
compared with no screening (50,54).
The ROCA uses serially measured CA-125 and mathematical modeling to
determine whether an increase in levels should prompt referral for ultrasound and
has a better predictive performance for detecting ovarian cancer than using a fixed
CA-125 value cut-off (55,56–59). The U.S. Food and Drug Administration (FDA)
has warned that early detection tests, including the ROCA test, are unreliable
(60).
Other large prospective randomized trials in the United States and the United
Kingdom sought to address the utility of a multimodality assessment for early
detection of ovarian cancer. In the US-based Prostate, Lung, Colorectal, and
Ovarian (PLOC) Cancer Screening Trial, 78,216 healthy average-risk women
between age 55 and 74 years were randomized to have either annual CA-125
testing for 6 years and transvaginal ultrasound examination for 4 years (tested
group) versus the “usual care” who were patients not offered this testing, many of
these patients did have annual pelvic examinations. There was an ovarian cancer
mortality rate of 3.1 deaths per 10,000 person-years versus 2.6 deaths per 10,000
person-years in the tested group versus usual care group respectively, after a
median follow-up period of 12.4 years. This study also showed that using a
baseline and annual measurement of CA-125 with a cut-off (35 U/mL) in
combination with pelvic ultrasound as a way for early assessment does not
result in decreased ovarian cancer mortality (45,61). Thus far, this large trial
2562showed that screening women at average risk with annual transvaginal
ultrasound provided no mortality benefit when compared with no screening.
In the future, new markers or technologies may improve the specificity of
ovarian cancer screening, but proof of this will require a large, prospective study
(41,42).
Screening in women who have a familial risk may provide a better yield, but
there is no evidence to demonstrate a benefit of screening high-risk women,
even with active investigation (62,63). The findings of two prospective studies of
annual transvaginal ultrasound and CA-125 screening in 888 BRCA1 and BRCA2
mutation carriers in the Netherlands and 279 mutation carriers in the United
Kingdom are not encouraging and suggest a very limited benefit of screening in
high-risk women (62,64). Despite annual gynecologic screening, Hermsen et al.
reported that a high proportion of ovarian cancers in BRCA1 and BRCA2 carriers
were interval cancers and the large majority of all cancers diagnosed were at
advanced stages; similar results were reported by Woodward et al. (62,64).
Women with particular genetic syndromes are at increased risk of ovarian
cancer, for example patients with a BRCA gene mutation or Lynch syndrome
(hereditary nonpolyposis colorectal cancer). These patients should be referred to
genetic counseling to have an evaluation in order to properly quantify their level
of risk and have a discussion about the available risk reduction strategies.
Genetic Risk for Epithelial Ovarian Cancer
The lifetime risk of ovarian carcinoma for women in the United States is about
1.4% (2,4,65). The risk of ovarian cancer is higher than that in the general
population in women with certain family histories (55,62–64,66–71). [5] Most
epithelial ovarian cancer is sporadic, with causes accounting for up to 24%
of invasive epithelial ovarian cancer (14).
Hereditary Ovarian Cancer
BRCA1 and BRCA2
Most hereditary ovarian cancers result from pathogenic mutations in either
the BRCA1 or BRCA2 genes. Many studies have found that at least 15% of
women with high-grade nonmucinous ovarian cancers have germline
mutations in BRCA1/BRCA2 and almost 40% of these women do not have a
family history of breast/ovarian cancer (71). There are other low-to-moderate–
penetrance genes that predispose to ovarian cancer, and this is an area of intense
research interest (65,72,73). Norquist et al. used next-generation sequencing of
constitutional DNA samples from over 1,900 women with ovarian cancer to
identify germline mutations in a panel of 20 genes, including BRCA1 and BRCA2,
2563DNA mismatch repair genes, double-stranded DNA break repair genes such as
CHEK2 and ATM, and the BRCA1-associated complex or the BRCA2/Fanconi
Anemia pathway genes (including BRIP1, BARD1, PALB2, RAD50, RAD51C,
RAD51D among others). About 80% of mutations were in BRCA1 or BRCA2.
Approximately 3% of patients carried mutations in the Fanconi Anemia pathway
genes, while only 0.4% had mutations in mismatch repair genes (74).
[6] The mutations are inherited in an autosomal dominant fashion, and
therefore a full pedigree analysis (i.e., maternal and paternal sides of the
family) is essential when taking a family history. All women with high-grade
invasive ovarian cancers should be offered genetic testing, even if they do not
have a family history of breast/ovarian cancer (75). A very large study that
followed women enrolled in familial cancer registries primarily in the United
Kingdom, Holland, and France provides the most comprehensive data on the risk
of ovarian cancer and breast cancer in BRCA mutation carriers. Women were
recruited into this cohort from 1997 to 2011 and had not undergone risk-reducing
breast or gynecologic surgery; follow-up continued until 2013 (median, 5 years).
A total of 6,036 BRCA1 and 3,820 BRCA2 mutation carriers were followed
(median age at study entry, 38). The cumulative risk for breast cancer by age 80
was 72% in BRCA1 carriers and 69% in BRCA2 carriers. For ovarian cancer, the
cumulative risk was 44% and 17%, respectively. The peak breast cancer incidence
occurred at age 41 to 50 for BRCA1 carriers and age 51 to 60 for BRCA2 carriers.
The incidence of ovarian cancer was 3.6 times higher among BRCA1 than BRCA2
carriers.
[5] Hereditary ovarian cancers occur in women who are approximately 10
years younger than those with nonhereditary tumors (i.e., closer to age 50
compared to age 60 for those with sporadic cancer) (70). A woman with a first- or
second-degree relative who had premenopausal ovarian cancer may have a higher
probability of being a BRCA carrier. Women with BRCA germline mutations
tend to be diagnosed at a younger age than women with sporadic ovarian cancers.
In women with BRCA1 mutations, less than 2% to 3% of carriers develop ovarian
cancer by the age of 40 which increases to 10% to 21% by the age of 50. In
women with BRCA2 mutations, less than 3% of carriers develop ovarian cancer
by the age of 50 and most develop after age 50. Most BRCA ovarian cancers are
high-grade serous carcinomas (Fig. 39-9).
FIGURE 39-9 BRCA1-associated ovarian carcinoma is typically a high-grade serous
adenocarcinoma with numerous mitotic figures and marked nuclear pleomorphism. A brisk
lymphocytic infiltrate with tumor-infiltrating lymphocytes is not uncommon in these
tumors.
Founder Effect
There is a higher carrier rate of BRCA1 and BRCA2 mutations in women of
Ashkenazi Jewish descent, Icelandic women, and many other ethnic groups
(76–81). There are three specific founder mutations carried by the Ashkenazi
population, 185delAG and 5382insC on BRCA1, and 6174delT on BRCA2.
Individuals of Ashkenazi Jewish descent have a 1 in 40, or 2.5%, chance of
having a mutation in BRCA1 or BRCA2, in contrast to a 1 in 500 risk in the
Caucasian population (82). The increased risk is a result of the founder effect, in
which a higher rate of specific mutations occurs in an ethnic group from a defined
geographic area. These founder mutations generated considerable interest,
because they facilitate studies of prevalence and penetrance and can be used to
quantify the degree of homogeneity within a population.
2565Pedigree Analysis
[6] The risk of carrying a germline mutation that predisposes to ovarian
cancer depends on the number of first- or second-degree relatives (or both)
with a history of epithelial ovarian carcinoma or breast cancer (or both) and
on the number of malignancies that occur at an earlier age. The degree of
risk is difficult to determine precisely without performing a full pedigree
analysis. It is important to be aware that 40% of women with BRCA-related
ovarian cancer do not have a family history.
Lynch Syndrome or Hereditary Nonpolyposis Colon Cancer
Lynch syndrome (HNPCC), which includes multiple adenocarcinomas,
involves a combination of colon cancer and endometrial or ovarian cancer
and other malignancies of the gastrointestinal and genitourinary systems
(83). The chief gene mutations that are associated with this syndrome include
MSH2, MLH1, MSH6, and PMS2 or the EPCAM gene. The risk that a woman
who is a member of one of these families will develop epithelial ovarian cancer
depends on the frequency of this disease in first- and second-degree relatives,
although these women appear to have at least three times the relative risk of the
general population. A full pedigree analysis of such families should be performed
by a geneticist to more accurately determine the risk.
Management of Women at High Risk for Ovarian Cancer
The management of an unaffected woman with a germline BRCA (gBRCA)
mutation or a strong family history of epithelial ovarian cancer where a
mutation has not been found must be individualized and depends on her age,
reproductive plans, and the estimated risk. All these women should be seen by
a geneticist in a high-risk clinic. Decisions about management are best made after
careful study and, whenever possible, verification of the histologic diagnosis of
the family members’ ovarian cancer.
The value of testing for BRCA1 and BRCA2 is well established, and there
are guidelines for testing (75,82,84,85). Essentially all women with epithelial
ovarian cancer, excluding mucinous cancers, should be offered testing
irrespective of whether she has a family history of breast/ovarian cancer. The
American Society of Clinical Oncology offered guidelines that emphasize careful
evaluation by geneticists, careful maintenance of medical records, and a genetic
screening clinic with an understanding of how to effectively counsel and manage
these patients. Concerns remain over the use of the information, impact on
insurability, interpretation of the results, and how the information will be used
within a specific family (e.g., to counsel children).
Although there are some conflicting data, the behavior of breast cancers arising
2566in women with germline mutations in BRCA1 or BRCA2 is comparable to the
behavior of sporadic tumors (86,87). Women with breast cancer who carry
these mutations are at a greatly increased risk of ovarian cancer and a
second breast cancer: the lifetime risk of ovarian cancer is 54% for women
who have a BRCA1 mutation and 23% for those with a BRCA2 mutation,
and for the two groups together, there is an 82% lifetime risk of breast
cancer (87).
[4] Despite recommendation by the National Institutes of Health Consensus
Conference on Ovarian Cancer, the value of screening with transvaginal
ultrasonography, CA-125 levels, or other procedures is not established in
women at high risk (88). Bourne and coworkers showed that, using this
approach, tumors can be detected approximately 10 times more often than in the
general population, and they recommend screening in high-risk women, but other
groups have not confirmed these findings, and bilateral salpingo-oophorectomy
remains the most effective way to reduce the risk (89).
Data derived from a multicenter consortium of genetic screening centers
indicate that the use of the oral contraceptive pill is associated with a lower
risk for development of ovarian cancer in women who have a mutation in
either BRCA1 or BRCA2 (90,91). The risk reduction is significant: in women
who take oral contraceptives for 5 or more years, the relative risk of ovarian
cancer is 0.4, or a 60% reduction in the incidence of the disease (92).
Prophylactic Salpingo-oophorectomy in High-Risk Women
[6] The value of prophylactic salpingo-oophorectomy in these patients is well
established (93–99). Women at high risk for ovarian cancer who undergo
prophylactic salpingo-oophorectomy have a risk of harboring occult neoplasia: in
one series of 98 such operations, 3 (3.1%) patients were found to have an ovarian
cancer or early invasive cancer in a fallopian tube (96). [6] The protection
against ovarian cancer is high: the performance of a prophylactic salpingooophorectomy reduced the risk of BRCA-related gynecologic cancer by 96%
(96). In a series of 42 such operations, 4 patients (9.5%) had a malignancy, 1 of
which was noted at surgery and 3 that were microscopic; all were smaller than 5
mm (94). Although the risk of ovarian cancer is significantly diminished, there
remains the small risk of peritoneal carcinoma. In these series, the subsequent
development of peritoneal carcinoma was reported to be 0.8% and 1%,
respectively (78,79). The risk of developing subsequent breast cancer may be
reduced by 50% to 80% in BRCA carriers. However, this has been
challenged by a prospective study. In an analysis stratified by BRCA mutation
status and age at diagnosis, they found that oophorectomy was associated with a
significantly reduced risk of breast cancer in BRCA2 carriers diagnosed at age
2567<50 years (age-adjusted hazard ratio [HR], 0.18; p = 0.007) but not among
BRCA1 carriers diagnosed at <50 years (age-adjusted HR, 0.79; p = 0.51). These
findings warrant further evaluation (100).
The role of hysterectomy is more controversial. Most studies show no
increase in the rate of uterine and cervical tumors, but there are rare reports of an
increase of serous tumors of the endometrium. A large multicenter prospective
cohort study concluded that the overall risk of uterine cancer after a risk-reducing
bilateral salpingo-oophorectomy was not increased; however, the risk of serous
and serous-like uterine cancer was increased in BRCA1-positive women, although
still very low, and the benefit of a hysterectomy remains uncertain (101). Women
on tamoxifen are at higher risk for benign endometrial lesions (e.g., polyps) and
endometrial cancer. It is reasonable to consider the performance of a
prophylactic hysterectomy in conjunction with salpingo-oophorectomy in
women with BRCA mutations who are potentially at increased risk of an
endometrial cancer, but this decision should be individualized. The progressionfree survival (PFS) of women who have a BRCA1 or BRCA2 mutation and
develop ovarian cancer is longer than that for those who do not have a mutation.
In one study, the median PFS for mutation carriers was 60 months compared with
22 months for controls. There was no difference in the overall survival between
BRCA mutation carriers and controls (102). BRCA patients have increased
sensitivity to platinum drugs and to the newer agents, poly(ADP-ribose)
polymerase (PARP) inhibitors. [10] The advent of PARP inhibitors and their
increased use for recurrent disease and maintenance therapy, particularly in
BRCA mutation carriers may translate to an improvement in the PFS and
overall survival for BRCA patients.
Recommendations
Recommendations for the management of women at high risk for ovarian cancer
are based on the ACOG practice bulletin no. 182 and summarized as follows:
1. Genetic counseling is recommended for all women with ovarian/fallopian
tube/peritoneal epithelial cancer and for individuals who have a personal
or family history of breast cancer or ovarian cancer. Genetic testing is
recommended when the results of a detailed risks assessment that is performed
as part of genetic counseling suggest the presence of an inherited cancer
syndrome and when the results of testing are likely to influence medical
management.
2. Women who wish to preserve their reproductive capacity can undergo
screening by transvaginal ultrasonography every 6 months or CA-125
measurement and this may be a reasonable short-term surveillance
2568strategy for women at high risk of ovarian cancer starting at age 30 to 35
years until they decide to pursue definitive risk-reducing bilateral
salpingo-oophorectomy.
3. Oral contraceptives should be recommended to young women before they
embark on an attempt to have a family.
4. Women who do not wish to maintain their fertility or who have completed
their families should be recommended to undergo prophylactic bilateral
salpingo-oophorectomy after the age of 35, but by age 40 years. The risk of
ovarian cancers under the age of 40 is very low but the decision regarding the
age of surgery should be based on the age of onset of ovarian cancers in the
family. Most BRCA2-related ovarian cancers tend to occur after the age of 50,
whereas BRCA1-related cancers occur at an earlier age. Typically, riskreducing salpingo-oophorectomy is recommended at age 35 to 40 years
for BRCA1 carriers with the highest lifetime risk of ovarian cancer,
whereas women with BRCA2 may consider delaying until age 40 to 45
years because of later onset of ovarian cancer. These women should be
counseled that this operation does not offer absolute protection, because
peritoneal carcinomas can occur after bilateral salpingo-oophorectomy
(26,29,87).
5. Women with BRCA mutations or who carry another actionable
deleterious mutation that is predisposing to breast cancer should be
offered risk-reducing bilateral mastectomy. Women with BRCA mutations
or who carry another actionable deleterious mutation that is predisposing to
ovarian cancer should be offered risk-reducing bilateral salpingooophorectomy.
6. For a risk-reducing bilateral salpingo-oophorectomy, all tissue from the
ovaries and fallopian tubes should be removed. Thorough visualization of
the peritoneal surfaces should be done and pelvic washings taken. Complete
serial sectioning of the ovaries and fallopian tubes is necessary with
microscopic examination for occult cancer.
7. For women aged 25 to 29 years with known BRCA mutations,
recommended breast cancer surveillance includes clinical breast
examination every 6 to 12 months and annual radiographic evaluation
(preferably magnetic resonance imaging [MRI], with contrast). For
women aged 30 years and older with known BRCA mutations or other
actionable breast cancer mutations, recommended breast cancer
surveillance includes annual mammography and annual breast MRI with
contrast, often alternating every 6 months.
8. Women with a personal or family history of breast or ovarian cancer but
who do not have a documented mutation in BRCA1 or BRCA2 or other
2569hereditary breast- or ovarian-cancer–associated genes should be managed
based on their family history.
9. Women with a documented Lynch syndrome (HNPCC) should undergo
periodic colonoscopy every 1 to 2 years, starting at age 20 to 25 years or 2
to 5 years before the earliest colon cancer diagnosis in the family,
depending on which is earlier. Endometrial biopsy every 1 to 2 years
starting at age 30 to 35 years, is recommended for women with Lynch
syndrome, prophylactic hysterectomy, and bilateral salpingooophorectomy is a risk-reducing option after the completion of
childbearing. In general, risk-reducing hysterectomy and salpingooophorectomy should be discussed with patients by their early to mid-40s
(103,104).
Symptoms
The majority of women with epithelial ovarian cancer have vague and
nonspecific symptoms (4,105). In the early-stage disease, if the patient is
premenopausal, she may experience irregular menses. If a pelvic mass is
compressing the bladder or rectum, she may report urinary frequency or
constipation (105–107). Occasionally, she may perceive lower abdominal
distention, pressure, or pain, such as dyspareunia. Acute symptoms, such as pain
secondary to rupture or torsion, shortness of breath from a malignant pleural
effusion, or symptoms of a bowel obstruction are possible reasons for
presentation.
In advanced-stage disease, patients have symptoms related to the presence
of ascites, omental metastases, or bowel metastases. The symptoms include
abdominal distention, bloating, constipation, nausea, anorexia, or early satiety.
Premenopausal women may report irregular or heavy menses, whereas vaginal
bleeding may occur in postmenopausal women but this is not a typical
presentation of ovarian cancer unless the ovarian tumors are estrogen producing
(107).
Traditionally, ovarian cancer was considered a “silent killer” that did not
produce symptoms until far advanced. Some patients with ovarian cancers
confined to the ovary are asymptomatic, but the majority will have nonspecific
symptoms that do not necessarily suggest an origin in the ovary (107,108–110). In
one survey of 1,725 women with ovarian cancer, 95% recalled symptoms before
diagnosis, including 89% with stages I and II disease and 97% with stages III and
IV disease (107). Some 70% had abdominal or gastrointestinal symptoms, 58%
pain, 34% urinary symptoms, and 26% pelvic discomfort. At least some of these
symptoms could have reflected pressure on the pelvic viscera from the enlarging
ovary. Goff et al. developed an ovarian cancer symptom index and reported that
2570symptoms associated with ovarian cancer, when present for less than 1 year and
occurring longer than 12 days a month, were pelvic/abdominal pain, urinary
frequency/urgency, increased abdominal size or bloating, and difficulty eating or
feeling full (108). The index had a sensitivity of 56.7% for early ovarian cancer
and 79.5% for advanced-stage disease. This study and others suggest that women
and their obstetrician–gynecologist should maintain an appropriate level of
suspicion for further investigation when potential symptoms and signs of ovarian,
fallopian tube, or peritoneal cancer may be present.
A population-based study from Australia found that there did not appear to be a
significant difference in the duration of symptoms or the nature of symptoms in
patients with early as opposed to advanced-stage ovarian cancer, reinforcing the
concept that they are biologically different entities and arguing against the widely
held misconception that early-stage ovarian cancers are at an early stage because
they were diagnosed earlier than patients with more advanced-stage cancers
(109). For fallopian tube carcinoma, the classic triad of symptoms that have been
reported include clear or blood-tinged vaginal discharge, pelvic pain, and a
finding of a pelvic mass. The vaginal discharge termed hydrops tubae profluens
historically has been considered pathognomonic of fallopian tube cancer;
however, in retrospect, these signs are uncommon.
Signs
The most important sign of epithelial ovarian cancer is the presence of a
pelvic mass on physical examination. A solid, irregular, fixed pelvic mass is
highly suggestive of an ovarian malignancy. If an upper abdominal mass or
ascites is present, the diagnosis of ovarian cancer is almost certain. Because the
patient usually reports abdominal symptoms, she may not have a pelvic
examination, and a tumor may be missed.
In patients who are at least 1 year past menopause, the ovaries should be
atrophic and not palpable. It was proposed that any palpable pelvic mass in these
patients should be considered potentially malignant, a situation that was referred
to as the postmenopausal palpable ovary syndrome (111). This concept was
challenged, because subsequent authors reported that only about 3% of palpable
masses measuring less than 5 cm in postmenopausal women are malignant (63).
Atypical glandular cells on cervical pathology may signal an upper genital tract
malignancy. This finding on a Papanicolaou (Pap) test should prompt further
evaluation for cervical or endometrial carcinoma. If there are no findings to
suggest these cancers, evaluation should continue for other malignancies of the
female genital tract. In a systematic review of approximately 7,000 women with
atypical glandular cells on a Pap test only 5.2% of patients had a malignancy.
Among patients with a malignancy, there were 5.4% ovarian cancers and 1.0%
2571fallopian tube cancers (112).
Women with ovarian cancer can rarely present with signs of a paraneoplastic
syndrome, which may include disseminated intravascular coagulation,
polyneuritis, dermatomyositis, hemolytic anemia, and cerebellar degeneration
(113).
Diagnosis
Ovarian epithelial cancers must be differentiated from benign neoplasms
and functional cysts of the ovaries. A variety of benign conditions of the
reproductive tract, such as pelvic inflammatory disease, endometriosis, and
pedunculated uterine leiomyomas, can simulate ovarian cancer. Nongynecologic
causes of a pelvic tumor, such as an inflammatory (e.g., diverticular) disease or
neoplastic colonic mass, must be excluded (4). A pelvic kidney can simulate
ovarian cancer.
Serum CA-125 levels are useful in distinguishing malignant from benign
pelvic masses (114). For a postmenopausal patient with an adnexal mass and
a very high serum CA-125 level (>200 U/mL), there is a 96% positive
predictive value for malignancy. For premenopausal patients, the specificity
of the test is low because the CA-125 level tends to be elevated in common
benign conditions.
For the premenopausal patient, a period of observation is reasonable,
provided the adnexal mass does not have characteristics that suggest
malignancy (i.e., it is mobile, mostly cystic, unilateral, and of regular
contour). An interval of no more than 2 months is allowed, during which
hormonal suppression with an oral contraceptive may be used. If the lesion is not
neoplastic, it should regress, as measured by pelvic examination and pelvic
ultrasonography. If the mass does not regress or if it increases in size, it must be
presumed to be neoplastic and must be removed surgically.
The size of the lesion is important. If a cystic mass is greater than 8 cm in
diameter, the probability is high that the lesion is neoplastic, unless the patient is
taking clomiphene citrate or other agents to induce ovulation (115–118).
Premenopausal patients whose lesions are clinically suspicious (i.e., large,
predominantly solid, relatively fixed, or irregularly shaped) should undergo
laparoscopy or laparotomy with keen attention to avoid intraoperative
rupture or spillage, as should postmenopausal patients with complex adnexal
masses of any size. Image-guided biopsy is not performed for fear of rupture
and seeding a potential malignancy.
Ultrasonographic signs of malignancy include an adnexal pelvic mass with
areas of complexity, such as irregular borders, multiple echogenic patterns
within the mass, and dense multiple irregular septae. Bilateral tumors are
2572more likely to be malignant, although the individual characteristics of the lesions
are of greater significance. Transvaginal ultrasonography may have a somewhat
better resolution than transabdominal ultrasonography for adnexal neoplasms
(119–122). Doppler color flow imaging may enhance the specificity of
ultrasonography for demonstrating findings consistent with malignancy (123–
125).
In postmenopausal women with unilocular cysts measuring 8 to 10 cm or
less and normal serial CA-125 levels, expectant management is acceptable,
and this approach may decrease the number of surgical interventions (126–128).
The suspicion of ovarian cancer or the diagnosis of an ovarian cancer
requires surgical exploration by a gynecologic oncologist, which may be by
an exploratory laparotomy or a minimally invasive technique such as
laparoscopy or a robotic platform. The preoperative evaluation of the patient
with an adnexal mass is outlined in Figure 10.2 (see Chapter 10, page 201).
Before the planned exploration, the patient should undergo routine hematologic
and biochemical assessments. A preoperative evaluation in a patient undergoing
laparotomy should include a radiograph of the chest. Abdominal and pelvic
computed tomography (CT) or magnetic resonance imaging (MRI) are of limited
value for a patient with a definite pelvic mass (129–131). A CT or MRI should be
performed for patients with ascites and no pelvic mass to look for liver or
pancreatic tumors. The findings only rarely preclude laparotomy (129). The value
of PET scanning is still being evaluated (131–133). If the hepatic enzyme values
are normal, the likelihood of liver disease is low. Liver–spleen scans, bone scans,
and brain scans are unnecessary unless symptoms or signs suggest metastases to
these sites.
The preoperative evaluation should exclude other primary cancers
metastatic to the ovary. A barium enema or colonoscopy is indicated in selected
patients with symptoms and signs suspicious for colon cancer. This study should
be performed for any patient who has evidence of occult blood in the stool or has
signs of lower intestinal obstruction. An upper gastrointestinal radiographic series
or gastroscopy is indicated if there are upper gastrointestinal symptoms such as
nausea, vomiting, or hematemesis (4,134). Bilateral diagnostic mammography is
indicated if there is any breast mass, because breast cancer metastatic to the
ovaries can simulate primary ovarian cancer.
A Pap test can be performed, although its value for the detection of ovarian
cancer is very limited. Patients who have irregular menses or postmenopausal
vaginal bleeding should have endometrial biopsy and endocervical curettage to
exclude the presence of uterine or endocervical cancer metastatic to the ovary.
Differential Diagnosis
2573Ovarian epithelial cancers must be differentiated from benign neoplasms
and functional cysts of the ovaries (126–128). A variety of benign conditions
of the reproductive tract, such as pelvic inflammatory disease, endometriosis,
and pedunculated uterine leiomyomata, can simulate ovarian cancer.
Nongynecologic causes of a pelvic tumor, such as an inflammatory or neoplastic
colonic mass, must be excluded. Gastrointestinal and breast cancers are the most
common nongenital malignancies that metastasize to the ovary (135,136).
Patterns of Spread
Ovarian epithelial cancers spread primarily by exfoliation of cells into the
peritoneal cavity, lymphatic dissemination, and hematogenous spread.
Transcoelomic
The most common and earliest mode of dissemination of ovarian epithelial
cancer is by exfoliation of cells that implant along the surfaces of the
peritoneal cavity. The cells tend to follow the circulatory path of the peritoneal
fluid. The fluid moves with the forces of respiration from the pelvis, up the
paracolic gutters, especially on the right, along the intestinal mesenteries, to the
right hemidiaphragm. Metastases are typically seen on the posterior cul-de-sac,
paracolic gutters, right hemidiaphragm, liver capsule, the peritoneal surfaces of
the intestines and their mesenteries, and the omentum. The disease seldom
invades the intestinal lumen but progressively agglutinates loops of bowel,
leading to a functional intestinal obstruction. This condition is known as
carcinomatous ileus (4).
Lymphatic
Lymphatic dissemination to the pelvic and para-aortic lymph nodes is
common, particularly in advanced-stage disease (137–139). Spread through the
lymphatic channels of the diaphragm and through the retroperitoneal lymph nodes
can lead to dissemination above the diaphragm, especially to the supraclavicular
lymph nodes (137). Burghardt et al. reported that 78% of patients with stage III
disease have metastases to the pelvic lymph nodes (139). In another series, the
rate of para-aortic lymph nodes positive for metastasis was 18% in stage I, 20% in
stage II, 42% in stage III, and 67% in stage IV (137).
Hematogenous
Hematogenous dissemination at the time of diagnosis is uncommon. Spread to
vital organ parenchyma, such as the lungs and liver, occurs in only about 2% to
3% of patients. Most patients with disease above the diaphragm when diagnosed
2574have a right pleural effusion (4). Systemic metastases appear more frequently in
patients who survived for some years. Dauplat et al. reported that distant
metastasis consistent with stage IV disease ultimately occurred in 38% of the
patients whose disease was originally IP (140).
Prognostic Factors
The outcome of treatment can be evaluated in the context of prognostic
factors, which can be grouped into pathologic, biologic, and clinical factors
(141).
Pathologic Factors
The morphology and histologic pattern, including the architecture and grade
of the lesion, are important prognostic variables (4). The histologic type was
not believed to have prognostic significance, but several papers contained
suggestions that clear cell carcinomas are associated with a prognosis worse than
that of other histologic types (141,142).
Histologic grade, as determined either by the pattern of differentiation or by the
extent of cellular anaplasia and the proportion of undifferentiated cells, seems to
be of prognostic significance (143–146). Studies of the reproducibility of grading
ovarian cancers show a high degree of intraobserver and interobserver variation
(147,148). Baak et al. have presented a standard grading system based on the
morphometric analysis, and the system seems to correlate with prognosis,
especially in its ability to distinguish low-grade or borderline patterns from other
tumors (149).
Clinical Factors
In addition to the stage, the extent of residual disease after primary surgery,
the volume of ascites, patient age, and performance status are all
independent prognostic variables (150–159). Among patients with stage I
disease, Dembo et al. showed, in a multivariate analysis, that tumor grade and
dense adherence to the pelvic peritoneum had a significant adverse impact on
prognosis, whereas intraoperative tumor spillage or rupture did not (156). Sjövall
et al. confirmed that ovarian cancers that undergo intraoperative rupture or
spillage do not worsen prognosis, whereas tumors that are ruptured
preoperatively do have a poorer prognosis (157). A multivariate analysis of
these and several other studies was performed by Vergote et al., who found that
for early-stage disease, poor prognostic variables were tumor grade, capsular
penetration, surface excrescences, and malignant ascites, but not iatrogenic
rupture (159).
2575Table 39-2 2013 FIGO Staging for Primary Carcinoma of the Ovary, Fallopian Tube,
or Primary Peritoneal Cancer
Stage I Growth Limited to the Ovaries or Fallopian Tubes
IA Growth limited to one ovary or fallopian; no ascites containing
malignant cells
No tumor on the external surface; capsule intact
IB Growth limited to both ovaries or fallopian tubes; no ascites containing
malignant cells
No tumor on the external surfaces; capsules intact
IC Tumor limited to one or both ovaries or fallopian tubes with any of the
following:
IC1 Surgical spill
IC2 Capsule ruptured before surgery or tumor on ovarian or fallopian tube
surface
IC3 Malignant cells in the ascites or peritoneal washings
Stage II Growth involving one or both ovaries or fallopian tubes with pelvic
extension (below the pelvic brim)
IIA Extension and/or metastases to the uterus and/or fallopian tubes and/or
ovaries
IIB Extension to other pelvic tissues
Stage III Tumor involving one or both ovaries or fallopian tubes or
peritoneal cancer with cytologically or histologically confirmed
spread to the peritoneum outside the pelvis and/or metastasis to the
retroperitoneal lymph nodes
IIIA Positive retroperitoneal lymph nodes and/or microscopic metastasis
beyond pelvis
IIIA1(i) Positive retroperitoneal lymph nodes with metastasis up to 10 mm in
greatest dimension
IIIA1(ii) Positive retroperitoneal lymph nodes with metastasis more than 10 mm
in greatest dimension
2576IIIA2 Microscopic extrapelvic (above the pelvic brim) peritoneal
involvement, with or without positive retroperitoneal lymph nodes
IIIB Macroscopic peritoneal metastasis beyond pelvis up to 2 cm in greatest
dimension, with or without positive retroperitoneal nodes
IIIC Macroscopic peritoneal metastasis beyond pelvis more than 2 cm in
greatest dimension (includes extension of tumor to capsule of liver and
spleen without parenchymal involvement of either organ), with or
without positive retroperitoneal nodes
IV Distant metastasis (excludes peritoneal metastasis)
IVA Pleural effusion is present, there must be positive cytologic test
results
IVB Parenchymal metastases and metastases to extra-abdominal organs
(including lymph nodes and lymph nodes outside the abdominal
cavity)
The histologic characteristics are to be considered in the staging, as are results of cytologic
testing as far as effusions are concerned. It is desirable that a biopsy be performed on
suspicious areas outside the pelvis.
FIGO, International Federation of Obstetrics and Gynecology.
aDense adhesions with histologically proven tumor cells justify upgrading to stage II.
Transmural bowel infiltration or umbilical deposit are stage IVB.
Initial Surgery for Ovarian Cancer
Staging
Ovarian epithelial malignancies are staged according to the FIGO system
listed in Table 39-2 (160). The FIGO staging is based on findings at surgical
exploration. A preoperative evaluation should exclude the presence of
extraperitoneal metastases.
[7] Thorough surgical staging and search for microscopic metastasis should
be performed when there is no visible or palpable disease in the intraabdominal space outside the ovaries and fallopian tubes. Subsequent
treatment may be determined by the stage of the disease. In earlier series in
which patients did not undergo careful surgical staging, the overall 5-year
survival for patients with apparent stage I epithelial ovarian cancer was only
2577about 60% (161). Survival rates of 90% to 100% are reported for patients who
were properly staged and were found to have stage IA or IB disease.
Technique for Surgical Staging
In patients whose preoperative evaluation suggests a probable malignancy, a
vertical abdominal incision is recommended to allow adequate access to the
upper abdomen (4,161). When a malignancy is unexpectedly discovered in a
patient who has a lower transverse incision, the rectus muscles can be either
divided or detached from the symphysis pubis to allow better access to the upper
abdomen. If this is not sufficient, the incision can be extended on one side to
create a “J” incision (4).
The ovarian tumor should be removed intact, if possible, and a frozen
histologic section should be obtained. A thorough surgical staging should be
performed. Staging involves the following steps (4,161):
1. Any free fluid, especially in the pelvic cul-de-sac, should be submitted for
cytologic evaluation.
2. If no free fluid is present, peritoneal washings should be performed by
instilling and recovering 50 to 100 mL of saline from the pelvic cul-de-sac,
each paracolic gutter, and beneath each hemidiaphragm. Obtaining the
specimens from under the diaphragms can be facilitated with the use of a
rubber catheter attached to the end of a bulb syringe.
3. A systematic exploration of all the intra-abdominal surfaces and viscera is
performed, proceeding in a clockwise fashion from the cecum cephalad along
the paracolic gutter and the ascending colon to the right kidney, the liver and
gallbladder, the right hemidiaphragm, the entrance to the lesser sac at the paraaortic area, across the transverse colon to the left hemidiaphragm, down the
left gutter and the descending colon to the rectosigmoid colon. The small
intestine and its mesentery from the Treitz ligament to the cecum should be
inspected.
4. Any suspicious areas or adhesions on the peritoneal surfaces should be
biopsied. If there is no evidence of disease, multiple IP biopsies should be
performed. Tissue from the peritoneum of the pelvic cul-de-sac, both paracolic
gutters, the peritoneum over the bladder, and the intestinal mesenteries should
be taken for biopsy.
5. The diaphragm should be sampled, either by biopsy or by scraping with a
tongue depressor, and a sample obtained for cytologic assessment.
Biopsies of any irregularities on the surface of the diaphragm can be facilitated
by the use of the laparoscope and the associated biopsy instrument.
6. The omentum should be resected from the transverse colon, including
2578from the hepatic and splenic flexure of the colon and separated from its
attachment to the greater curvature of the stomach, including ligation of
the left and right gastroepiploic and short gastric arteries, a procedure
called supracolic omentectomy. The procedure is initiated on the underside of
the greater omentum, where the peritoneum is incised a few millimeters away
from the transverse colon. The branches of the gastroepiploic vessels are
clamped, ligated, and divided, along with all the small branching vessels that
feed the infracolic omentum.
7. The retroperitoneal spaces should be explored to evaluate the pelvic and
para-aortic lymph nodes. The retroperitoneal dissection is performed by
incision of the peritoneum over the psoas muscles. Any enlarged lymph nodes
should be resected and submitted for frozen section. If no metastases are
present, a formal pelvic lymphadenectomy should be performed. The paraaortic area should be palpated and lymph nodes sampled if enlarged or
suspicious.
Results
Metastases in apparent stages I and II epithelial ovarian cancer occur in as
many as 3 in 10 patients whose tumors appear to be confined to the pelvis
but who have occult metastatic disease in the upper abdomen or the
retroperitoneal lymph nodes (138,162–169). In a literature review, occult
metastases in such patients were found in biopsies of the diaphragm in 7.3%,
biopsies of the omentum in 8.6%, the pelvic lymph nodes in 5.9%, the aortic
lymph nodes in 18.1%, and in 26.4% of peritoneal washings (161).
The importance of careful initial surgical staging is emphasized by the findings
of a cooperative national study in which 100 patients with apparent stages I and II
disease were referred for subsequent therapy and underwent additional surgical
staging (162). In this series, 28% of the patients initially believed to have stage I
disease were upstaged and 43% of those believed to have stage II disease had
more advanced lesions. A total of 31% of the patients were upstaged as a
result of additional surgery, and 77% were reclassified as having actual stage
III disease. Histologic grade was a significant predictor of occult metastasis.
Sixteen percent of the patients with grade 1 lesions were upstaged, compared with
34% with grade 2 disease and 46% with grade 3 disease.
Borderline Tumors
The principal treatment of borderline (low malignant potential) ovarian
tumors is surgical resection of the primary tumor. There is no evidence that
either subsequent chemotherapy or radiation therapy improves survival. When a
frozen section determines that the histology is borderline, premenopausal
2579patients who desire preservation of the ovarian function may undergo a
conservative operation, a unilateral oophorectomy (4,170). In a study of
patients who underwent unilateral ovarian cystectomy for apparent stage I
borderline serous tumors, Lim-Tan et al. found that this conservative operation
was safe, with only 8% of the patients developing recurrences 2 to 18 years later,
all with curable disease confined to the ovaries (170). Recurrence was associated
with positive margins of the removed ovarian cyst. Thus, hormonal function and
fertility can be maintained (4,170). For patients who had an oophorectomy or
cystectomy and a borderline tumor is documented later in the permanent
pathology, no additional immediate surgery is necessary.
Stage I
After a comprehensive staging laparotomy, only a minority of women will
have local disease (FIGO stage I). There are over 20,000 women diagnosed
yearly with epithelial ovarian cancer in the United States, and nearly 4,000 of
these have disease confined to the ovaries (65,171). The prognosis for these
patients depends on the clinical–pathologic features. Because of this emphasis on
the importance of surgical staging, the rate of lymph node sampling increased in
the United States, with a study showing that for women with stages I and II
disease, the percentage having lymph nodes sampled increased from 38% to 59%
from 1991 to 1996 (172).
The primary surgical treatment for stage I epithelial ovarian cancer is
surgical, and patients should undergo total abdominal hysterectomy,
bilateral salpingo-oophorectomy, and surgical staging (161,162). In certain
circumstances, a unilateral salpingo-oophorectomy may be performed as a
part of fertility-sparing surgery. Based on the findings at surgery and the
pathologic evaluation, patients with stage I ovarian cancer can be grouped into
low-risk and high-risk categories (Table 39-3).
Table 39-3 Prognostic Variables in Early-Stage Epithelial Ovarian Cancer
Low Risk High Risk
Low grade High grade
Intact capsule Tumor growth through capsule
No surface excrescences Surface excrescences
No ascites Ascites
Negative peritoneal cytologic findings Malignant cells in fluid
2580Unruptured or intraoperative rupture Preoperative rupture
No dense adherence Dense adherence
Diploid tumor Aneuploid tumor
From Berek JS, Friedlander ML, Hacker NF. Epithelial ovarian, fallopian tube, and
peritoneal cancer. In: Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 6th
ed. Philadelphia, PA: Wolters Kluwer; 2015:483.
Stage I Low Risk
Fertility Preservation in Early-Stage Ovarian Cancer
For patients who underwent a thorough staging laparotomy and who have
no evidence of spread beyond the ovary, abdominal hysterectomy and
bilateral salpingo-oophorectomy are appropriate therapy. The uterus and
the contralateral ovary can be preserved in women with stage IA, grade 1 to
2 disease who desire to preserve fertility. The women undergoing disease
surveillance should be monitored carefully with routine periodic pelvic
examinations and determinations of serum CA-125 levels. The other ovary and
the uterus are removed at the completion of childbearing.
Guthrie et al. studied the outcome of 656 patients with early-stage epithelial
ovarian cancer (169). No untreated patients who had stage IA, grade 1 cancer died
of their disease; thus, adjuvant radiation and chemotherapy are unnecessary. The
Gynecologic Oncology Group (GOG) carried out a prospective, randomized trial
of observation versus melphalan for patients with stages IA and IB, grade 1 or 2
disease (142). Five-year survival for each group was 94% and 96%, respectively,
confirming that no further treatment is needed for such patients.
Stage I High Risk
Patients who have more poorly differentiated disease or who have malignant
cells either in ascites fluid or in peritoneal washings, must undergo complete
surgical staging (4). Most patients require chemotherapy.
Advanced-Stage Ovarian Cancer
The management of all patients with advanced-stage disease is approached in
a similar manner, with modifications made in response to the overall status
and general health of the patient and the extent of residual disease present at
the time treatment is initiated. A treatment scheme is outlined in Figure 39-
10. Most patients subsequently receive combination chemotherapy for an
empiric number of cycles.
2581Cytoreductive Surgery for Advanced-Stage Disease
If the patient is medically stable, she should undergo cytoreductive surgery
to remove as much of the tumor and its metastases as possible (173–200). The
operation to remove the primary tumor and the associated metastatic disease
is referred to as debulking or cytoreductive surgery. The operation typically
includes the performance of a total abdominal hysterectomy and bilateral
salpingo-oophorectomy, along with a complete omentectomy and resection of any
metastatic lesions from the peritoneal surfaces or from the intestines. The pelvic
tumor often directly involves the rectosigmoid colon, the terminal ileum, and the
cecum (Fig. 39-11). In a minority of patients, most or all of the disease is
confined to the pelvic viscera and the omentum, so that removal of these organs
will result in extirpation of all gross tumor, a situation that is associated with a
reasonable chance of prolonged PFS.
The paradigm of routine lymphadenectomy in patients with advanced ovarian
cancer and clinically and radiographically negative nodes has been challenged
with the reporting of the Lymphadenectomy in Ovarian Neoplasms (LION) study.
This was a prospective randomized trial of 647 patients with stage IIB to IV
ovarian cancer with macroscopic complete resection and preoperative and
intraoperative clinically negative lymph nodes randomized intraoperatively to
systematic pelvic and para-aortic lymphadenectomy versus no lymphadenectomy.
This trial showed that systematic pelvic and para-aortic lymphadenectomy in
patients with advanced ovarian cancer with intra-abdominal complete resection
and clinically negative lymph nodes does not provide a PFS or overall survival
benefit, despite the detection and removal of subclinical lymph nodal metastases
in approximately 56% of patients. The authors suggest that routine
lymphadenectomy should be omitted in these patients to reduce postoperative
morbidity and mortality (201).
The removal of bulky tumor masses may reduce the volume of ascites
present. Often, ascites will disappear after removal of the primary tumor and a
large omental “cake.” Removal of the omental cake may alleviate the nausea and
early satiety that many patients experience. Removal of intestinal metastases may
restore adequate intestinal function and improve the overall nutritional status of
the patient, thereby facilitating the patient’s ability to tolerate subsequent
chemotherapy.
A large, bulky tumor may contain areas that are poorly vascularized, and
these areas will be exposed to suboptimal concentrations of
chemotherapeutic agents. Similarly, these areas are poorly oxygenated, so that
radiation therapy, which requires adequate oxygenation to achieve maximal cell
kill, will be less effective. Surgical removal of these bulky tumors may eliminate
areas that could be relatively resistant to radiation and chemotherapeutic
2582treatment.
Larger tumor masses tend to be composed of a higher proportion of cells that
are either nondividing or in the “resting” phase (i.e., G0 cells, which are
essentially resistant to the therapy). A low growth fraction is characteristic of
bulky tumor masses, and cytoreductive surgery can result in smaller residual
masses with a relatively higher growth fraction.
Goals of Cytoreductive Surgery
The principal goal of cytoreductive surgery is removal of all of the primary
cancer and, if possible, all metastatic disease. If resection of all metastases is
not feasible, the goal is to reduce the tumor burden by resection of all individual
tumors to an optimal status (<1 cm of any single implant of residual disease).
Patients whose disease is completely resected to no macroscopic (microscopic
only) residual disease have the best overall survival (Fig. 39-12) (178).
Approximately 30% to 40% of patients in this category will be free of disease
at 5 years.
FIGURE 39-10 Treatment scheme for patients with advanced-stage ovarian cancer. *In
selected cases of stage IIIC/IV disease, neoadjuvant chemotherapy may be given, and then
an interval cytoreductive surgery is performed after three cycles. +Chemotherapy depends
on whether platinum-sensitive or platinum-resistant. (Modified from Berek JS,
Friedlander ML, Hacker NF. Epithelial ovarian, fallopian tube, and peritoneal cancer. In:
Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 6th ed. Philadelphia, PA:
Wolters Kluwer; 2015:485.)
The resectability of the metastatic tumor is usually determined by the
location of the disease. Optimal cytoreduction is difficult to achieve in the
presence of extensive disease on the diaphragm, in the parenchyma of the liver,
along the base of the small bowel mesentery, in the lesser omentum, or in the
porta hepatis. [7] Neoadjuvant chemotherapy is an option for patients with
advanced ovarian/fallopian tube or peritoneal cancer who are determined to
have a low likelihood of optimal cytoreduction or in women determined to
have a high perioperative risk (202).
In two published large randomized control trials, neoadjuvant chemotherapy
was noninferior to upfront cytoreduction (203,204). There was no significant
difference between the PFS or overall survival between the two groups. In one
trial, the EORTC 55971, outcomes were found to vary by the stage of disease and
tumor size. In particular, patients with stage IV disease and more extensive
tumors greater than 45 mm had a better survival with neoadjuvant chemotherapy;
however, patients with stage IIIC cancer and metastatic lesions less than 45 mm
had a better survival with primary cytoreductive surgery (205). All randomized
clinical trials have shown lower perioperative morbidity with neoadjuvant
chemotherapy compared to primary cytoreductive surgery (202).
FIGURE 39-11 Extensive ovarian carcinoma involving the bladder, rectosigmoid, and
ileocecal area. (Redrawn from Heintz APM, Berek JS. Cytoreductive surgery for ovarian
carcinoma. In: Piver MS, ed. Ovarian Malignancies. Edinburgh, UK: Churchill
Livingstone; 1987:134, with permission.)
FIGURE 39-12 Survival of patients with stage IIIC epithelial ovarian cancer based on the
maximal size of residual tumor after exploratory laparotomy and tumor resection. (From
Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. Twenty-sixth
annual report of the results of treatment of gynaecological cancer. Int J Gynecol Oncol
2006;95(suppl 1): S161–S192, with permission.)
Exploration
The supine position on the operating table may be sufficient for surgical
exploration of most patients. For patients with extensive pelvic disease and for
whom a low resection of the colon may be necessary, the low lithotomy position
should be used. Debulking operations should be performed through a vertical
incision to gain adequate access to the upper abdomen and to the pelvis.
After the peritoneal cavity is opened, ascites fluid, if present, should be
evacuated. In some centers, fluid is submitted for in vitro research studies, such
as molecular analyses. In cases of massive ascites, careful attention must be given
to hemodynamic monitoring, especially for patients with borderline
cardiovascular function.
The peritoneal cavity and retroperitoneum are thoroughly inspected and
palpated to assess the extent of the primary tumor and the metastatic
2587disease. All abdominal viscera must be palpated to exclude the possibility that the
ovarian disease is metastatic, particularly from the stomach, colon, or pancreas. If
optimal cytoreduction is not considered achievable, extensive bowel and urologic
resections are not indicated, except to overcome a bowel obstruction. Removal of
the primary tumor and omental cake is usually feasible and desirable.
Pelvic Tumor Resection
The essential principle of pelvic tumor removal is the retroperitoneal
approach. To accomplish this, the retroperitoneum is entered laterally, along the
surface of the psoas muscles, which avoids the iliac vessels and the ureters. If the
uterus is present, the procedure is initiated by bilateral division of the round
ligaments. The peritoneal incision is extended cephalad, lateral to the ovarian
vessels within the infundibulopelvic ligament, and caudally toward the bladder.
With careful dissection, the retroperitoneal space is explored, and the ureter and
pelvic vessels are identified. The pararectal and paravesical spaces are identified
and developed, as described in Chapter 38.
The peritoneum overlying the bladder is dissected to connect the peritoneal
incisions anteriorly. The vesicouterine plane is identified, and with careful sharp
dissection the bladder is mobilized from the anterior surface of the cervix. The
ovarian vessels are isolated, doubly ligated, and divided.
Hysterectomy is performed. The ureters must be carefully displayed to avoid
injury. During this procedure, the uterine vessels can be identified. Ligation of the
uterine vessels and the remainder of the tissues within the cardinal ligaments
completes the hysterectomy and resection of the contiguous tumor.
Because epithelial ovarian cancers tend not to invade the lumina of the
colon or bladder, it is usually feasible to resect pelvic tumors without having
to resect portions of the lower colon or the urinary tract (183,184). Resection
of a small portion of the bladder may be required and, if so, a cystotomy should
be performed to assist in resection of the disease (184).
Intestinal Resection
Resection of focal areas of disease involving the small or large intestine
should be performed if that would permit the removal of all or most of the
abdominal metastases and leave the patient with optimal cytoreduction at the
end of surgery. Apart from the rectosigmoid colon, the most frequent sites of
intestinal metastasis are the terminal ileum, the cecum, and the transverse colon.
Resection of one or more of these segments of bowel may be necessary
(183,185).
If the disease surrounds the rectosigmoid colon and its mesentery, that portion
of the colon may have to be removed in order to clear the pelvic disease (Fig. 39-
258813) (183). After the pararectal space is identified, the proximal site of colonic
involvement is identified, the colon and its mesentery are divided, and the
rectosigmoid is removed along with the uterus en bloc. A reanastomosis of the
colon is performed.
Omentectomy
Advanced epithelial ovarian cancer often completely replaces the omentum,
forming an “omental cake.” This disease may be adherent to the parietal
peritoneum of the anterior abdominal wall, making entry into the abdominal
cavity difficult. After freeing the omentum from any adhesions to the parietal
peritoneum, adherent loops of the small intestine are freed by sharp dissection.
The omentum is lifted and pulled gently in the cranial direction, exposing the
attachment of the infracolic omentum to the transverse colon. The peritoneum is
incised to open the appropriate plane, which is developed by sharp dissection
along the serosa of the transverse colon. Small vessels are ligated with hemoclips,
suture, or a vessel-sealing device. The omentum is separated from the greater
curvature of the stomach by ligation of the right and left gastroepiploic arteries
and ligation of the short gastric arteries (Fig. 39-14).
The disease in the gastrocolic ligament can extend to the hilus of the spleen
and splenic flexure of the colon on the left and to the capsule of the liver and
the hepatic flexure of the colon on the right. Usually, the disease does not
invade the parenchyma of the liver or spleen, and a plane can be found between
the tumor and these organs. It will occasionally be necessary to perform
splenectomy to remove all the omental disease (186).
Resection of Other Metastases
Other large masses of tumor located on the parietal peritoneum should be
removed, particularly if they are isolated masses and their removal will
permit optimal cytoreduction. Resection of extensive disease from the surfaces
of the diaphragm is neither practical nor feasible, although solitary metastases
may be resected, the diaphragm sutured, and a chest tube placed for a few days if
needed (186,187). The use of the Cavitron Ultrasonic Surgical Aspirator (CUSA)
and the argon beam coagulator may facilitate resection of small tumor nodules,
especially those on flat surfaces (188,189).
Feasibility and Outcome
There was no randomized prospective study performed to define the value of
primary cytoreductive surgery, but all retrospective studies indicate that the
diameter of the largest residual tumor nodule before the initiation of
chemotherapy is significantly related to the PFS in patients with advanced ovarian
2589cancer (190). The quality of life may be significantly enhanced by the removal of
bulky tumor masses from the pelvis and upper abdomen (191).
An analysis of the retrospective data indicates that, when performed by
gynecologic oncologists, successful operations are feasible in 70% to 90% of
patients (181,182). Major morbidity is approximately 5% and operative mortality
is 1% (185,192,193). Intestinal resection in these patients does not appear to
increase the overall morbidity caused by the operation (185).
FIGURE 39-13 The resection of the pelvic tumor may include removal of the uterus,
2590tubes, and ovaries, as well as portions of the lower intestinal tract. The arrows represent
the plane of resection. (Modified from Berek JS, Friedlander ML, Hacker NF. Epithelial
ovarian, fallopian tube, and peritoneal cancer. In: Berek JS, Hacker NF. Berek & Hacker’s
Gynecologic Oncology. 6th ed. Philadelphia, PA: Wolters Kluwer; 2015:490.)
FIGURE 39-14 Separation of the omentum from stomach and transverse colon. Arrow, the
direction of the initial surgical approach. (From Heintz APM, Berek JS. Cytoreductive
surgery for ovarian carcinoma. In: Piver MS, ed. Ovarian Malignancies. Edinburgh, UK:
Churchill Livingstone; 1987:134, with permission.)
In a meta-analysis of 81 studies of women who underwent cytoreductive
surgery for advanced ovarian cancer, Bristow et al. documented that the
extent of debulking correlated with incremental benefits in survival (i.e., the
greater the percentage of tumor reduction, the longer the survival). Each
10% increase in cytoreduction equaled a 5.5% increase in median survival
(190). Women whose cytoreduction was greater than 75% of their tumor
burden had a median survival of 33.9 months compared with 22.7 months for
women whose tumors were cytoreduced less than 75% (p <0.001). The
performance of a pelvic and para-aortic lymphadenectomy in patients with stage
III disease does not prolong survival, based on the results of a large prospective,
2591randomized trial (194).
A prospective randomized study of “interval” cytoreductive surgery was
carried out by the European Organization for the Research and Treatment
of Cancer (EORTC). Interval surgery was performed after three cycles of
platinum-combination chemotherapy in patients whose primary attempt at
cytoreduction was suboptimal. The initial surgery for most of these patients was
not an aggressive attempt to debulk their tumors. Patients in the surgical arm of
the study demonstrated a survival benefit when compared with those who did not
undergo interval debulking (195). The risk of mortality was reduced by more than
40% in the group that was randomized to the debulking arm of the study. Based
on these data, the performance of a debulking operation as early as possible in the
course of the patient’s treatment should be considered the standard of care (191).
A prospective phase III study of interval cytoreductive surgery was
conducted by the GOG; the patients entered on the trial had a maximal
attempt at tumor resection at their initial surgery (196). The randomized
findings showed no difference between the patients who had an additional attempt
at debulking after three cycles of chemotherapy compared with those who did not.
The median survival of the 216 women who underwent interval cytoreduction
was 32 months compared with 33 months for the 209 women who did not
undergo surgical cytoreduction.
There is evidence that the survival of women with advanced ovarian cancer is
improved when the surgeon is specifically trained to perform cytoreductive
surgery and when there is centralization of care (197–200). Whenever feasible,
patients with advanced ovarian malignancy should be referred to a
subspecialty unit for primary surgery, and every effort should be made to
attain as complete a cytoreduction as possible.
Chemotherapy
Stage I Epithelial Ovarian Cancer
Early Stage, Low Risk
Guthrie et al. studied the outcome of 656 patients with early-stage epithelial
ovarian cancer (169). Patients who had stage IA, grade 1 cancer and did not
receive radiation or chemotherapy did not die of their disease; indicating that
adjuvant therapy is unnecessary. The GOG carried out a prospective, randomized
trial of observation versus melphalan for patients with stages IA and IB, grades 1
and 2 disease (142). Five-year survival for each group was 94% and 96%,
respectively, confirming that adjuvant treatment did not improve survival.
Therefore, no adjuvant chemotherapy is recommended for these patients.
2592Early Stage, High Risk
In patients whose disease is high risk (e.g., high-grade serous or in whom
there are malignant cells either in ascites fluid or in peritoneal washings),
additional therapy is indicated. Chemotherapy is recommended for these
patients to reduce recurrence risk (206–219).
Two large parallel randomized phase III clinical trials were conducted on
women with early-stage disease more than 20 years ago and reported in 2003: the
International Collaborative Ovarian Neoplasm Trial 1 (ICON1) and the
Adjuvant Chemotherapy Trial in Ovarian Neoplasia (ACTION) (220,221).
In the ICON1 trial, 477 patients from 84 centers in Europe were entered.
Patients of all stages were eligible for the trial if, in the opinion of the
investigator, it was unclear whether adjuvant therapy would be of benefit. Most
patients were considered to have stages I and IIA disease, but optimal surgical
staging was not required, and it is likely that a significant number of these
women had stage III disease. Adjuvant platinum-based chemotherapy was given
to 241 patients, and no adjuvant chemotherapy was given to 236 patients. The 5-
year survival was 73% in the group who received adjuvant chemotherapy
compared with 62% in the control group (HR, 0.65; p = 0.01) (221).
In the ACTION trial, 440 patients from 40 European centers were
randomized; 224 patients received adjuvant platinum-based chemotherapy, and
224 patients did not (220). Patients with stages I and II, grades 2 and 3 were
eligible. Only about one-third of the total group was optimally staged (151
patients). In the observation arm, optimal staging was associated with a
better survival (HR, 2.31; p = 0.03), and in the suboptimally staged patients,
adjuvant chemotherapy was associated with an improvement in survival
(HR, 1.78; p = 0.009). In the ACTION trial, the initial trial results suggested
that the benefit from adjuvant chemotherapy was limited to the patients with
suboptimal staging. However, a long-term follow-up of the randomized trial
after a median of 10.1 years showed that the overall survival after optimal
staging was improved even among those who received adjuvant
chemotherapy (HR of death, 1.89; p = 0.05) (222).
When the data from the two trials were combined and analyzed, a total of 465
patients were randomized to receive platinum-based adjuvant chemotherapy and
460 to observation until disease progression (223). After a median follow-up of
more than 4 years, the overall survival was 82% in the chemotherapy arm and
74% in the observation arm (HR, 0.67; p = 0.001). Recurrence-free survival was
better in the chemotherapy arm: 76% versus 65% (HR, 0.64; p = 0.001). The
results of this analysis must be interpreted with caution, because most of the
patients did not undergo thorough surgical staging, but the findings suggest that
platinum-based chemotherapy should be given to patients who were not
2593optimally staged. It is generally accepted that high-risk early-stage ovarian
cancer patients, including stage I, grade 3 endometrioid, stage IC, serous and
carcinosarcoma, benefit from adjuvant chemotherapy just as advanced-stage
ovarian cancer patients do. There remains uncertainty about the impact of
chemotherapy in women with stage I clear cancers as these cancers are less
chemosensitive than high-grade serous cancers.
A randomized phase III trial of three versus six cycles of adjuvant carboplatin
and paclitaxel (CP) in 457 patients with early-stage epithelial ovarian carcinoma
was conducted by the GOG (224). An unexpectedly large number of patients (126
patients, 29%) had incomplete or inadequately documented surgical staging in
this study. The recurrence rate for six cycles was 24% lower (HR, 0.76;
confidence interval [CI], 0.5–1.13; p = 0.18) versus three cycles, but this was not
statistically significant. The estimates of probability of recurrence at 5 years were
20.1% for six cycles and 25.4% for three cycles (225). An exploratory analysis of
high-risk early-stage epithelial ovarian cancer patients from this trial reported by
Chan et al., suggested that six cycles rather than three cycles may decrease risk of
recurrence, particularly in patients with serous ovarian tumors (226).
The recommendations for therapy follow:
Patients with high-grade, high-risk stage I epithelial ovarian cancer
should be offered adjuvant chemotherapy depending on the patient’s
overall health and medical comorbidities.
Treatment with CP chemotherapy for three to six cycles is used in
these patients, whereas single-agent carboplatin may be preferable for
older women and patients with other medical comorbidities.
Advanced-Stage Epithelial Ovarian Cancer
Systemic multiagent chemotherapy is the standard treatment for metastatic
epithelial ovarian cancer (227–251). After the introduction of cisplatin in the
latter half of the 1970s, platinum-based combination chemotherapy became the
most frequently used treatment regimen in the United States. The secondgeneration platinum analogue, carboplatin, was developed to have less
toxicity than its parent compound, cisplatin (238). Fewer gastrointestinal side
effects, especially nausea and vomiting, were observed than with cisplatin, and
there was less nephrotoxicity, neurotoxicity, and ototoxicity. Carboplatin is
associated with a higher degree of myelosuppression (240). The dose of
carboplatin is calculated by using the area under the curve (AUC) and the
glomerular filtration rate (GFR) according to the Calvert formula (241). The
target AUC is 5 to 6 for previously untreated patients with ovarian cancer.
A major advance in the treatment of advanced-stage disease was the
2594incorporation of paclitaxel into the chemotherapeutic regimens in the late
1990s (224,227–230). Based on two studies (228,229), paclitaxel is included in
the primary treatment of all women with advanced-stage epithelial ovarian
cancer, unless there are contraindications to paclitaxel, such as preexisting
peripheral neuropathy.
Carboplatin and Paclitaxel
A series of randomized, prospective clinical trials with paclitaxel-containing
arms defined CP as the standard treatment protocol in advanced epithelial
ovarian cancer, although there are data to support IP chemotherapy in
selected patients (228,229,235,236). [8] Two randomized, prospective clinical
studies compared the combination of paclitaxel and carboplatin to paclitaxel and
cisplatin (235,236). In both studies, the efficacy and survivals were similar, but
the toxicity was more acceptable with the carboplatin-containing regimen (Fig.
39-15) (237).
Carboplatin and Docetaxel
Docetaxel has a different toxicity profile from paclitaxel. The SCOT-ROC
(Scottish Gynaecological Cancer Trials Group) study randomly assigned 1,077
women with stages IC to IV epithelial ovarian cancer to carboplatin with either
paclitaxel or docetaxel (244). The efficacy of docetaxel appeared to be similar
to paclitaxel: The median PFS was 15.1 months versus 15.4 months, and the
docetaxel group had fewer neurologic effects, arthralgias, myalgias, and
extremity weakness than the paclitaxel group. The docetaxel plus carboplatin
regimen was associated with significantly more myelosuppression and its
consequences (i.e., serious infections and prolonged grade 3 to 4 neutropenia).
Docetaxel is not widely used, but is an option in patients who have had a
significant allergic reaction to paclitaxel or who develop early sensory
neuropathy.
Five-Arm Trial
An Intergroup, international trial—GOG 182/Southwest Oncology Group
(SWOG) 182/ICON5—compared the standard combination of CP with these
drugs in combination with gemcitabine, topotecan, or liposomal doxorubicin in
sequential doublets or triplets (245). The study showed that the addition of any
these three drugs to the standard chemotherapy with CP did not improve the PFS
or overall survival.
Intraperitoneal Chemotherapy
A randomized, prospective GOG study (Protocol 104) of IP cisplatin versus
2595intravenous (IV) cisplatin (100 mg/m2), each given with 750 mg/m2
cyclophosphamide, was performed jointly by the SWOG and the GOG in patients
with minimal residual disease (246). [8] The IP cisplatin arm had a somewhat
longer overall median survival than the IV arm, 49 months versus 41 months
(p = 0.03). In the patients with minimal residual disease (<0.5 cm maximal
residual), paradoxically, there was no difference between the two treatments, 51
months versus 46 months (p = 0.08).
In a follow-up GOG study (Protocol 114), the dose-intense arm was initiated
by giving a moderately high dose of carboplatin (dose AUC = 9) for two
induction cycles, followed by IP cisplatin 100 mg/m2 and IV paclitaxel 135
mg/m2 over 24 hours, versus IV cisplatin 75 mg/m2 and IV paclitaxel 135 mg/m2
(247). The dose-intense arm results were slightly better—the disease progressionfree median survival was 27.6 months compared with 22.5 months for the control
arm (p = 0.02). There was no difference in overall survival (52.9 months vs. 47.6
months, p = 0.056). Based on this study, it was unclear whether dose
intensification with IP cisplatin has a sustained long-term impact on the survival
of these patients.
A third randomized prospective GOG study (Protocol 172) compared IP
cisplatin and paclitaxel versus IV cisplatin and paclitaxel (248). The combination
of cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 given IV every 3 weeks was
compared with paclitaxel 135 mg/m2 IV day 1, followed by cisplatin 100 mg/m2
IP day 2, and paclitaxel 60 mg/m2 IP day 8 every 3 weeks, each given for six
cycles. Although 83% of the patients randomized to IV chemotherapy
completed all six cycles of therapy, only 42% of those treated with IP
chemotherapy completed the six cycles, principally because of catheterrelated complications. For patients in either group who could not complete
the therapy because of cisplatin-related toxicity, the chemotherapy was
switched to IV carboplatin. Comparing the IV and IP arms, the median duration
of the PFS was 18.3 and 23.8 months, respectively (p = 0.05). [8] The median
duration of the overall survival in the IV-therapy and IP-therapy groups was
49.7 and 65.6 months, respectively (p = 0.03) (248). The quality of life was
significantly worse in the IP-therapy group before cycle four and 3 to 6
weeks after treatment but not 1 year after treatment. A summary of the IPcatheter–related issues in this trial was presented (249).
7FIGURE 39-15 Survival of patients with stage III epithelial ovarian cancer treated with
carboplatin and paclitaxel versus cisplatin and paclitaxel: a Gynecologic Oncology Group
study. A: Survival by treatment. B: Survival by treatment group (micro vs. macro). (From
Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel
compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian
cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2003;21:3194–3200, with
permission.)
In GOG 252, 1,560 patients with stage II to IV epithelial ovarian, fallopian
tube, or peritoneal carcinoma were randomized to receive six cycles of
chemotherapy. There were three treatment arms: Arm 1, IV carboplatin AUC
6/IV weekly paclitaxel at 80 mg/m2; Arm 2, IP carboplatin AUC 6/IV weekly
paclitaxel at 80 mg/m2; Arm 3, IV paclitaxel at 135 mg/m2 on day 1/IP cisplatin
at 75 mg/m2 on day 2/IP paclitaxel 60 mg/m2 on day 8. Each arm received IV
bevacizumab at 15 mg/kg with cycles 2 through 6 of chemotherapy and then
single-agent bevacizumab for cycles 7 through 22. The trial results showed a
median PFS of 27 to 29 months in patients with optimal stage II to III disease
treated with regimens consisting of different combinations of IV and IP cisplatin,
carboplatin, and paclitaxel, in combination with bevacizumab. An analysis
limited to patients with optimal stage III tumors and no gross residual disease
found a median PFS of 31 to 34 months. By comparison, the GOG 172 trial
comparing IP and IV chemotherapy regimens in ovarian cancer had a median PFS
of 23.8 months with IP cisplatin (vs. 18.3 months with IV) with an improvement
in OS in favor of IP (252). Differences in the cisplatin arm from the GOG 172
study include a dose reduction from 100 to 75 mg and a shorter infusion time
from 24 to 3 hours. If IP is used, it would be appropriate to follow the GOG 172
protocol rather than the modified protocol with a lower dose of cisplatin.
Investigators at the Mayo Clinic reported in 2009 at the SGO that only 20% of the
105 patients they treated in the clinic could complete 3 or more cycles of the 172
protocol because of toxicity. However, the GOG 172 study did find a significant
survival advantage for IP therapy and there is still support for IP chemotherapy in
some centers.
[8] Based on these randomized trials, the IP route of administration for
carboplatin or cisplatin and paclitaxel chemotherapy in the primary
treatment of optimally resected stage III ovarian cancer is an acceptable
therapeutic alternative to IV chemotherapy with CP (250). IP chemotherapy
is best suited to patients who have optimally resected tumors, a good
performance status, and are in overall good health. Because IP
chemotherapy is more cumbersome and has a higher morbidity than IV
2598therapy, this technique of drug delivery should be individualized after
thorough discussion with the patient.
Dose-Dense Intravenous Chemotherapy
The Japanese GOG randomized 637 patients with ovarian cancer to receive
carboplatin AUC 6 and paclitaxel 180 mg/m2 every 3 weeks, or the same dose of
carboplatin and 80 mg/m2 paclitaxel every week for at least six cycles (251). The
median PFS was 28 months in the dose-dense arm and 17 months in the control
group, and the median overall survival was 100.5 months for those patients
receiving dose-dense therapy, versus 62 months for the every-3-weeks arm. They
reported relatively little difference in toxicity between the two arms and that
grade 3 to 4 neurotoxicity in particular was very low. In the 417 patients who had
stage III disease, about half had less than 1 cm maximum residual disease, similar
to the patients in GOG 172. Women with at least 1 cm of residual disease
following cytoreductive surgery appeared to benefit the most from dose-dense
therapy compared to every 3 weeks therapy. In this analysis, the median PFS was
17.6 months versus 12 months and the median overall survival was 51 months
versus 33 months, respectively. There is good evidence that weekly paclitaxel is
more effective than paclitaxel every 3 weeks in breast cancer and the
Japanese GOG study suggests that the same may apply to ovarian cancer.
Other studies have led to questioning this treatment approach in the United States.
In GOG 262, patients with stage II to IV epithelial ovarian cancer were randomly
assigned to CP every 3 weeks versus dose-dense chemotherapy (carboplatin
every 3 weeks and weekly paclitaxel). Bevacizumab administration was optional
in both arms and 84% of the patients were treated with bevacizumab. Sixty-three
percent had gross residual disease, 24% had microscopic residual disease, and in
13% the amount of residual disease was not noted.
At a median follow-up of 28 months, no difference in PFS was found between
the two groups. The subset analysis suggested a difference based on whether or
not bevacizumab was received. In patients who did not receive bevacizumab,
dose-dense treatment prolonged PFS versus the every 3-week chemotherapy
(median of 14 months vs. 10 months). Among patients treated with chemotherapy
and bevacizumab, there was no significant difference among the every 3-week
chemotherapy versus dose-dense patients (median of 15 months in both arms)
(253).
The Multicenter Italian Trial in Ovarian Cancer (MITO-7), compared every 3-
week CP to a modified dose-dense regimen where CP were delivered on a weekly
schedule (carboplatin AUC 2 and paclitaxel 60 mg/m2 on days 1, 8, 15 every 3
weeks) in stage 1C to IV epithelial ovarian cancer.
2599In this study, there was a similar PFS between the two regimens with the
weekly regimen having better quality-of-life scores. Severe myelosuppression and
neuropathy were less common in the weekly regimen (254).
[9] More convincing evidence that the dose-dense therapy may be not
superior to every 3-week chemotherapy of the JCOG study can be found in
the results from the ICON8 trial. In this trial, 1,566 predominantly European
patients were randomized to receive one of three regimens: Arm 1, carboplatin
AUC 5/6 and paclitaxel 175 mg/m2 every 3 weeks; Arm 2, carboplatin AUC 5/6
every 3 weeks and paclitaxel 80 mg/m2 weekly; Arm 3, carboplatin AUC 2 and
paclitaxel 80 mg/m2 weekly. All patients had received neoadjuvant chemotherapy
with planned interval debulking or received chemotherapy after initial primary
cytoreductive surgery. There was no benefit found for the dose-dense
regimens. The PFS was 24.4 months with every 3-week dosing, compared to
24.9 and 25.3 months in arms 2 and 3, respectively (255).
Neoadjuvant Chemotherapy
[7] Neoadjuvant chemotherapy may be considered for patients with
advanced ovarian/fallopian tube/peritoneal carcinoma who are thought to
have a low likelihood of upfront optimal cytoreduction or in women
determined to have a high perioperative risk based on a poor performance
status. A series performed by Schwartz et al. suggested that these patients treated
with neoadjuvant or cytoreductive chemotherapy had survival that was
comparable to those patients treated in the same institution with debulking
surgery followed by conventional chemotherapy (256). It is accepted that two or
three cycles of chemotherapy before cytoreductive surgery may be helpful in
patients with massive ascites and large pleural effusions. The chemotherapy may
decrease the effusions, improve the patient’s performance status, and decrease
postoperative morbidity, particularly chest morbidity (257,258).
The EORTC completed a large randomized trial in 718 patients with
advanced ovarian cancer comparing initial surgery followed by six cycles of
CP with three cycles of neoadjuvant chemotherapy followed by surgical
debulking and another three cycles of chemotherapy. The study found that the
PFS was identical in both arms (12 months) and the overall survival (30 months)
was the same in both arms (203). The morbidity of surgery was significantly less
in patients receiving neoadjuvant chemotherapy, suggesting that in selected
patients with very advanced (stages IIIC and IV) ovarian cancer and on
average had a poor performance status, two to three cycles of neoadjuvant
chemotherapy prior to surgical debulking is a reasonable option. There have
been other studies in support of neoadjuvant chemotherapy as an option for
2600advanced ovarian/ fallopian tube/peritoneal carcinoma including the CHORUS
trial. This phase III randomized, noninferiority, controlled trial was done across
87 hospitals in New Zealand and the United Kingdom and enrolled patients with
suspected stage III or IV cancer. Patients were randomly assigned to either
primary surgery followed by six cycles of chemotherapy versus three cycles of
primary chemotherapy followed by surgery, then three additional cycles of
completion chemotherapy. Patients could receive CP or another carboplatin
combination regimen or single-agent carboplatin. There was no difference in the
median overall survival comparing primary surgery to the primary chemotherapy
group. The CHORUS trial also concluded that in women with very advanced
stage III or IV ovarian cancer and a poor performance status, survival with
primary chemotherapy is noninferior to primary surgery (204).
Chemotherapy and Bevacizumab
Inhibition of angiogenesis with drugs such as bevacizumab demonstrated
activity and benefit in women with recurrent ovarian cancer. There is
evidence in other tumor types such as breast cancer and colon cancer that the
addition of bevacizumab to chemotherapy increases response rates, PFS, and
survival in some studies (259–261). Two large randomized trials (GOG 218 and
ICON7) investigating the impact of the addition of bevacizumab to standard CP
in patients with advanced ovarian cancer were carried out to address this question
(262,263). GOG 218 was a phase III three-arm randomized double-blind placebocontrolled trial. Patients in arm one received six cycles of CP and placebo starting
with the second cycle and continuing for 16 additional cycles after the completion
of chemotherapy. Patients in arm two received six cycles of chemotherapy with
bevacizumab starting with cycle two and administered with chemotherapy
followed by 16 cycles of placebo, and in arm three patients received bevacizumab
starting with cycle two of chemotherapy and then received 16 additional cycles
after the completion of chemotherapy. This study was designed to investigate the
benefit of bevacizumab in combination with chemotherapy and as a maintenance
therapy. The bevacizumab was administered at a dose of 15 mg/kg, starting with
the second cycle of chemotherapy, to decrease the risk of gastrointestinal
perforation, which is a rare complication of this agent. The GOG 218 reported a
modest improvement of 3.8 months in the PFS in patients randomized to receive
bevacizumab in combination with CP every 3 weeks and then as a maintenance
therapy every 3 weeks for an additional 16 cycles for a total of 15 months’
treatment (262). The toxicity of bevacizumab was acceptable and the risk of
bowel perforation low (below 2%). The study did not find any improvement in
the overall survival with bevacizumab in either arm receiving the drug. An
unplanned subgroup analysis demonstrated that treatment with bevacizumab
2601improved the PFS and overall survival particularly in patients with ascites but not
in other patients. The ICON7 study is similar to the GOG study, although it was a
two-arm study of CP plus or minus bevacizumab 7.5 mg/kg administered every 3
weeks with chemotherapy for six cycles and then as maintenance therapy for 12
additional cycles. The ICON7 results reported a longer median PFS at 42 months
of follow-up for the arm including bevacizumab compared to the standard therapy
arm (24 months vs. 22 months). There was no difference in the overall survival
noted (263). In an exploratory analysis of a predefined subgroup of patients with
poor prognosis/ high-risk disease, a significant difference in the overall survival
was noted between women who received bevacizumab plus chemotherapy and
those who received chemotherapy alone (restricted mean survival time, 34.5
months [95% CI, 32.0–37.0] with standard chemotherapy vs. 39.3 months [37.0–
41.7] with bevacizumab; log-rank p = 0.03). In non–high-risk patients, the
restricted mean survival time did not differ significantly between the two
treatment groups (49.7 months [95% CI, 48.3–51.1] in the standard chemotherapy
group vs. 48.4 months [47.0–49.9] in the bevacizumab group; p = 0.20) (264).
The results of these studies support a potential role of bevacizumab in
combination with chemotherapy in selected patients with advanced ovarian
cancer. However, the cost of bevacizumab is very high and the improvement
in PFS is short and no survival improvement was seen.
Chemotherapeutic Recommendation in Advanced Epithelial Ovarian Cancer
For the treatment of advanced-stage epithelial ovarian cancer, the following
treatment regimens should be considered (Table 39-4):
Combination chemotherapy or IV CP every 3 weeks or IP carboplatin
or cisplatin and paclitaxel are the treatments of choice for patients with
advanced disease. The advantages and disadvantages of the IV versus
IP routes of administration of these drugs should be discussed with the
patient.
The recommended doses and schedule for IV chemotherapy are
carboplatin (starting dose AUC = 5 to 6), and paclitaxel (175 mg/m2),
every 3 weeks for six cycles. Alternatively, the dose-dense regimen of
carboplatin AUC 6 every 3 weeks for six cycles and weekly paclitaxel 80
mg/m2 could be used, but is not superior to the 3-weekly regimen in
non-Japanese women (251). There are no good data to show any
benefit for treatment beyond six cycles but the number of cycles may
need to be individualized based on time to response and toxicity.
Ideally the CA-125 should have normalized by the end of
chemotherapy.
2602The recommended doses and schedule for IP chemotherapy are
paclitaxel 135 mg/m2 IV on day 1, followed by carboplatin AUC 5 or
cisplatin 75 to 100 mg/m2 IP on day 2, followed by paclitaxel 60 mg/m2
IP on day 8, every 3 weeks for six cycles, as tolerated.
Bevacizumab 7.5 to 15 mg/kg can be added to any of these IV or IP
chemotherapy regimens.
In patients who cannot tolerate combination chemotherapy, singleagent, IV-administered carboplatin (AUC 5 to 6) can be given.
In patients who have a hypersensitivity to paclitaxel or carboplatin, an
alternative active drug can be substituted (e.g., docetaxel, nanoparticle
paclitaxel, cisplatin). In the case of carboplatin hypersensitivity,
desensitization could be attempted.
Table 39-4 Combination Chemotherapy for Advanced Epithelial Ovarian Cancer:
Recommended Regimens
The treatment of all patients with advanced-stage disease is approached in
2603a similar manner, with modifications based on the overall status and general
health of the patient and the extent of residual disease present at the time
treatment is initiated.
Maintenance Therapy Following Response to First-Line Chemotherapy
Almost 80% of women with advanced-stage disease who respond to first-line
chemotherapy will relapse. There have been several trials conducted to determine
if there is a benefit of maintenance therapy in these patients immediately
following their primary treatment in an effort to decrease the relapse rate.
Paclitaxel
In a study conducted by the GOG and SWOG, 277 women with advanced ovarian
cancer who had a complete clinical remission to first-line chemotherapy were
randomized to receive 3 or 12 cycles of additional single-agent paclitaxel (175 or
135 mg/m2 every 28 days) (265). Patients were excluded if they developed grade
2 or 3 neurotoxicity during their initial chemotherapy. Because of cumulative
toxicity, the mean number of actual cycles of paclitaxel received by the group
assigned to receive 12 cycles was 9. The treatment-related grade 2 to 3
neuropathy was more common with longer treatment, 24% versus 14% of
patients, respectively. The study closed after a median follow-up of only 8.5
months, and an interim analysis showed a significant 7-month prolongation in the
median PFS (28 months vs. 21 months) with 9 months versus 3 months of
consolidation paclitaxel. There was no difference in the median overall survival
and this study has not changed practice. It is improbable that a survival benefit
will appear with longer follow-up, because patients assigned to three cycles were
given the option of receiving an additional nine courses of paclitaxel after the
study was discontinued (266). Another placebo-controlled, randomized trial using
two formulations of paclitaxel was conducted by the GOG. A total of 1,157
patients with stage III to IV ovarian/fallopian tube/peritoneal cancer who
achieved a clinical complete response after first-line treatment were randomized
to surveillance, paclitaxel infusion every 28 days for 12 cycles, or CT-2103
(paclitaxel poliglumex) on the same schedule. After a median follow-up of 71
months, the median overall survival was not different between the groups. There
was a small extension in the PFS with maintenance therapy compared to
surveillance (267).
Topotecan
Four additional treatment courses of topotecan were administered to patients
following six cycles of CP in two randomized trials, one conducted in Italy and
the other in Germany (268,269). In the larger trial conducted in Germany, 1,059
2604evaluable patients were randomly assigned to six cycles of paclitaxel (175 mg/m2
over 3 hours) and carboplatin (AUC 5) with (537 patients) or without (522
patients) four additional cycles of topotecan (1.25 mg/m2 IV days 1 to 5 every 3
weeks) (269). In the Italian trial, 273 women were randomly assigned to receive
four additional cycles (137 patients) of topotecan at a dose of 1 mg/m2 on days 1
to 5 every 3 weeks or no further chemotherapy (136 patients) (268). No
significant differences in either the PFS or overall survival in patients who
received four to six cycles of consolidation topotecan.
Cisplatin
In a randomized clinical trial of IP cisplatin for consolidation versus observation,
there was no difference in survival between the treatment arms (270). A metaanalysis concluded that maintenance chemotherapy was associated with increased
toxicity but no significant improvement in the PFS or overall survival (271).
Biologic Therapies
Adding the monoclonal antibody (MonAb) bevacizumab to first-line CP
chemotherapy followed by maintenance bevacizumab for a year was
associated with a modest improvement in the PFS (262,263).
There are a number of trials that addressed the role of oral angiogenesis
inhibitors as maintenance therapy after completion of first-line therapy in women
with advanced ovarian cancer. Pazopanib is an oral tyrosine kinase inhibitor of
vascular endothelial growth factor receptors, platelet-derived growth factor
receptors, and c-KIT. In the randomized double-blinded placebo-controlled phase
III AGO-OVAR16/VEG110655 trial, maintenance pazopanib for up to 2 years
after completion of first-line chemotherapy in women with advanced epithelial
ovarian cancer improved the PFS over placebo (HR, 0.77; 95% CI, 0.64–0.91; P
= 0.0021; median PFS 17.9 with PZ vs. 12.3 months with placebo) (272).
However, there was a higher incidence of grade 3 and 4 adverse events in the
pazopanib arm, which led to dose reductions in 58% of patients and early
discontinuation caused by adverse events (AE) in 33% of patients. In view of the
toxicity, the pharmaceutical company who sponsored the trial decided not to
submit for regulatory approval. Nintedanib is a triple angiokinase inhibitor of
VEGF, fibroblast growth factor, and platelet-derived growth factor. AGO-OVAR
12 randomized 1,366 patients 2:1 to maintenance nintedanib or placebo as
maintenance therapy following first-line chemotherapy. The median PFS in
nintedanib was 17.2 months vs. 16.6 months in placebo arm and this is not a
reasonable therapeutic option (273).
Studies investigating MonAbs directed toward CA-125 (OvaRex) and toward
the HMFG (human milk fat globulin) tumor–associated antigens were conducted
2605(274–276). In a randomized, placebo-controlled trial of IV oregovomab (anti-CA-
125 MonAb) as maintenance therapy, Berek et al. reported that oregovomab did
not demonstrate a survival advantage as a maintenance therapy (275). A
randomized trial of an IP-administered yttrium-labeled anti-mucin (HMFG)
MonAb versus placebo was not associated with an improved overall survival after
a negative second-look laparoscopy (276).
Treatment Assessment
Many patients who undergo optimal cytoreductive surgery and subsequent
chemotherapy for epithelial ovarian cancer have no evidence of disease at the
completion of treatment. Tumor markers and radiologic assessments are too
insensitive to exclude the presence of subclinical disease. Historically, a secondlook surgery was performed to evaluate these patients, but that was
abandoned, as there was no evidence of a meaningful benefit to patients
(161,277–286).
Tumor Markers
CA-125 is a surface glycoprotein associated with müllerian epithelial tissues, and
is elevated in about 80% of patients with epithelial ovarian cancers, particularly
those with nonmucinous tumors (287–289). The CA-125 level frequently falls
below the normal range after the initial surgical resection and one or two cycles of
chemotherapy. Carcinoembryonic antigen (CEA) levels may be elevated in
patients with ovarian cancer, but the test is too nonspecific and insensitive to be
used in the management of these patients, apart from patients with a mucinous
cancer of the ovary who may have an elevated CEA and CA19-9 (42).
Levels of CA-125 were correlated with findings at second-look operations.
Elevated levels predicted the presence of residual disease, but levels within the
normal range are an insensitive determinant of the absence of disease. In a
prospective study, the predictive value of a positive test was 100%; if the level of
CA-125 was elevated (>35 U/mL), the disease was always detectable in patients
at the second-look procedure (287). The predictive value of a negative test was
only 56%; if the level was less than 35 U/mL, disease was present in 44% of the
patients at the time of the second-look surgery. A literature review suggests that
an elevated CA-125 level predicts persistent disease at second-look surgery in
97% of the cases, but the CA-125 level is not sensitive enough to exclude
subclinical disease in many patients (288).
Serum CA-125 levels can be used during chemotherapy to follow those
patients whose levels were elevated at initial diagnosis and at the initiation of
therapy (287). The fall in the CA-125 correlates with response. Those patients
with persistently elevated levels after three cycles of treatment almost certainly
2606will still have persistent disease. The majority of patients will have a CA-125 in
the normal range following surgery and first-line chemotherapy and are typically
followed with CA-125 levels every 3 to 4 months. There are well-accepted
Gynecologic Oncology Intergroup (GCIG) criteria for CA-125 progression.
Patients with an elevated CA-125 pretreatment and in the normal range following
the completion of treatment must have a CA-125 greater than, or equal to, two
times the upper normal limit on two occasions at least 1 week apart to be
classified as having CA-125 progression (289).
Radiologic Assessment
CT can be used to assess the response in patients with measurable lesions at
the start of therapy. In patients who have no or minimal residual disease
following cytoreductive surgery, the value of these tests is limited, but they
may be useful in follow-up, especially to document the site of recurrence in
patients with CA-125 progression. Ascites can be readily detected, but other
diseases can be missed on a CT scan in patients with recurrent disease (290). A
CT scan and fine-needle aspiration (FNA) cytology, if appropriate, can diagnose
persistent or recurrent disease, but the false-negative rate of a CT scan is about
45% (291). MRI can be used as an alternative to CT in patients with allergies to
the contrast medium (131,133). PET/CT has high diagnostic accuracy in patients
with recurrent ovarian cancer. The reported sensitivity, specificity, and accuracy
range from 86% to 96%, 93% to 100%, and 85% to 100%, respectively (292).
Second-Line Therapy
Secondary Cytoreductive Surgery
Secondary cytoreduction is defined as an attempt at cytoreductive surgery in
patients with recurrent ovarian cancer. This is usually considered in patients
with platinum-sensitive recurrent ovarian cancer with localized recurrence or
limited number of sites of recurrence when it is considered possible to resect all
disease (293–296). Patients with progressive disease on chemotherapy (platinum
refractory) or with platinum-resistant ovarian cancer are not suitable candidates
for secondary cytoreduction. Although there are no hard and fast rules, secondary
debulking should be restricted to patients who have a disease-free interval of at
least 12, but preferably 24 months or those in whom it is expected that all
macroscopic disease can be resected, regardless of the disease-free interval (293–
301). The role of secondary debulking surgery has been addressed in the
DESKTOP III trial. This study included patients with a PFS OF >6 months after
first-line chemotherapy and who were considered to be good candidates for
surgery based on a positive AGO Study Group score, defined as an ECOG
performance status score of 0, ascites of 500 mL or less, and complete resection at
2607initial surgery. The PFS results have been presented at ASCO 2017 and DuBois
reported that the median PFS in 204 women who met these criteria and were
randomized to undergo surgery followed by chemotherapy was 19.6 months,
compared with 14 months in 203 women who were randomized to receive
only second-line chemotherapy. The primary endpoint of the study is overall
survival which will be available in a few years (302).
Chemotherapy for Recurrent Ovarian Cancer
The majority of women who relapse will be offered more chemotherapy with the
likelihood of benefit related to the initial response and the duration of response.
The goals of treatment include improving control of disease-related
symptoms, maintaining or improving the quality of life, delaying the time to
progression, and possibly prolonging survival, particularly in women with
platinum-sensitive recurrences. Many active chemotherapy agents (platinum,
paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and
etoposide) and targeted agents (bevacizumab) and PARP inhibitors are available,
and the choice of treatment is based on many factors including the likelihood of
benefit, potential toxicity, and patient convenience.
Women who relapse later than 6 months after primary chemotherapy are
classified as platinum-sensitive and usually receive further platinum-based
chemotherapy with response rates ranging from 27% to 65% and a median
survival of 12 to 24 months (303–307). Patients who relapse within 6 months
of completing first-line chemotherapy are classified as platinum-resistant and
have a median survival of 6 to 9 months and a 10% to 30% likelihood of
responding to chemotherapy. Patients who progress while on treatment are
classified as having platinum-refractory disease. Objective response rates to
chemotherapy in patients with platinum-refractory ovarian cancer are low—less
than 20% (308).
The potential adverse effects associated with chemotherapy in trials in
women with recurrent ovarian cancer are well documented and should not
be underestimated. The three most commonly used drugs are paclitaxel,
topotecan, and liposomal doxorubicin (309–335). The reported adverse effects
associated with paclitaxel include alopecia in 62% to 100%, neurotoxicity (any
grade) in 5% to 42% of patients, and grade 3 to 4 leukopenia in 4% to 24% of
patients. Topotecan is associated with significantly greater myelosuppression than
liposomal doxorubicin or paclitaxel and is observed in 49% to 76% of patients.
Liposomal doxorubicin is associated with palmar-plantar erythrodysesthesia
(PPE) of any grade in over 50% of patients and is severe in 23% particularly in
patients treated at higher doses such 50 mg/m2. Severe stomatitis is reported in up
to 10% of patients (309–312).
2608Platinum-Sensitive Disease
The use of combination platinum plus paclitaxel chemotherapy versus a singleagent platinum was tested in two multinational randomized phase III trials and a
randomized phase II study (336,337). In a report of the ICON4 and AGO-OVAR-
2.2 (AGO Studiengruppe Ovarialkarzinom) trials, 802 women with platinumsensitive ovarian cancer, who relapsed after being treatment free for at least 6 to
12 months were randomized to platinum-based chemotherapy (72% carboplatin
or cisplatin alone; 17% CAP; 4% carboplatin plus cisplatin; and 3% cisplatin
plus doxorubicin) or paclitaxel plus platinum-based chemotherapy (80%
paclitaxel plus carboplatin; 10% paclitaxel plus cisplatin; 5% paclitaxel plus
both carboplatin and cisplatin; and 4% paclitaxel alone) (336). The AGOOVAR-2.2 trial did not accrue its planned number of patients. In both trials, a
significant proportion of the patients did not receive paclitaxel as part of
their initial chemotherapeutic regimen. Combining the trials for analysis,
there was a significant survival advantage for the paclitaxel-containing
therapy (HR, 0.82) with a median follow-up of 42 months. The absolute 2-year
survival advantage was 7% (57% vs. 50%), and there was a 5-month
improvement in median survival (29 months vs. 24 months). The PFS was
better with the paclitaxel regimen (HR, 0.76); there was a 10% difference in 1-
year PFS (50% vs. 40%) and a 3-month prolongation in the median PFS (13
months vs. 10 months). The toxicities were comparable, except for a significantly
higher incidence of neurologic toxicity and alopecia in the paclitaxel group, while
myelosuppression was significantly greater with the non-paclitaxel–containing
regimens. These data support the slight advantage of a second-line regimen
containing both paclitaxel and a platinum agent compared with platinumbased therapy alone. There were two randomized trials comparing
carboplatin alone to carboplatin and gemcitabine or liposomal doxorubicin
(338,339). There was a higher response rate with the combination therapy and a
longer PFS, but the studies were not powered to look at the overall survival. In
the GCIG study comparing carboplatin and gemcitabine with carboplatin alone,
the response rate was 47.2% for the combination and 30.9% for carboplatin, with
the PFS being 8.6 months and 5.8 months, respectively (338). A large GCIG
study (CALYPSO) compared carboplatin and liposomal doxorubicin (CD)
with CP in 976 patients (340). The PFS for the CD arm was statistically
superior to the CP arm with a median PFS of 11.3 months versus 9.4 months,
respectively. There was no statistically significant difference in the overall
survival between the treatment groups. Median survival was 33 months versus
30.7 months for CP versus CD. The CD arm was better tolerated with less
severe toxicities, and this combination is now widely used (340).
Carboplatin, gemcitabine, and bevacizumab have been shown in a phase III
2609randomized control trial to be superior to carboplatin and gemcitabine alone
for platinum-sensitive recurrent epithelial ovarian cancer. In the OCEANS
study, 484 with platinum-sensitive disease were randomly assigned to carboplatin
(AUC 4 on day 1) and gemcitabine 1,000 mg/m2 on days 1 and 8 with or without
bevacizumab (15 mg/kg on day 1) with every 21-day cycles. Bevacizumab could
be given concurrently with chemotherapy for a maximum of 10 cycles followed
by bevacizumab alone until progression of disease or toxicity.
The addition of bevacizumab to carboplatin and gemcitabine resulted in an
improvement in the PFS (12 months vs. 8 months; HR, 0.48; 95% CI, 0.39–0.61);
however, there was no overall survival difference between the two arms.
Treatment with bevacizumab was associated with higher rates of serious
hypertension (17% vs. <1%), proteinuria grade 3 or higher (9% vs. 1%) and
noncentral nervous system bleeding (6% vs. 1%) (341,342).
In GOG 213, patients with platinum-sensitive recurrent epithelial ovarian
cancer were assigned randomly to secondary cytoreduction versus no secondary
cytoreduction and separately to chemotherapy (CP) with or without bevacizumab.
Patients treated with bevacizumab received the drug with chemotherapy and
afterward it was continued as a single agent until disease progression.
Compared with chemotherapy alone, the addition of bevacizumab resulted in
an improvement in the PFS (13.8 months vs. 10.4 months, respectively; HR, 0.61;
95% CI, 0.51–0.72). There was an improvement of the overall survival of 5
months with chemotherapy and bevacizumab versus chemotherapy alone; median
overall survival (42.6 months vs. 37.3 months, respectively; HR, 0.84; 95% CI,
0.69–1.01) (343). These studies show that maintenance with bevacizumab can
improve the PFS and may improve the overall survival in a subset of
patients.
PARP Inhibitors
PARP inhibitors, including niraparib and olaparib, have been approved by
FDA for maintenance therapy in patients with platinum-sensitive disease
following a partial or complete response to platinum-based chemotherapy.
The PFS is improved with these agents regardless of the BRCA status,
although the patients with BRCA germline/somatic mutations have a greater
benefit than patients without mutations.
Niraparib
Niraparib has been approved by the U.S. FDA for maintenance therapy in
patients with platinum-sensitive disease following a partial or complete
response to platinum-based chemotherapy for both germline BRCA1 and
BRCA2 carriers and nongermline carriers.
2610In the NOVA study, a phase III trial, 553 patients with platinum-sensitive
recurrent ovarian cancer were assigned randomly after completion of
platinum-based chemotherapy in a 2:1 ratio to niraparib maintenance or
placebo. Patients were stratified based on the presence or absence of a gBRCA
mutation. The patients in the non-gBRCA mutation cohort were further classified
by whether or not homologous recombination deficiency (HRD) was observed.
Niraparib compared to placebo increased the PFS in all groups of patients. In the
gBRCA group, the PFS was 21 months versus 5.5 months (HR, 0.27; 95% CI,
0.17–0.41) in contrast to the non-gBRCA group, where the PFS was 9.3
months versus 3.9 months (HR, 0.45; 95% CI, 0.34–0.61). This study also
attempted to identify the subset of patients with tumors with HRD and reported
that in the HRD-positive group of non-gBRCA patients, the PFS was 12.9 months
versus 3.8 months (HR, 0.38; 95% CI, 0.24–0.59). An exploratory analysis of
HRD-negative patients demonstrated an improvement in the median PFS in favor
of niraparib (6.9 months vs. 3.8 months; HR, 0.58; 95% CI, 0.08–0.90) (344).
Olaparib
Olaparib is FDA approved for the treatment of patients with gBRCAmutated recurrent ovarian cancer who have received three or more prior
lines of chemotherapy.
There are data in support of maintenance olaparib in women with
platinum-sensitive recurrent high-grade serous ovarian cancer from Study
19. This was a randomized phase II controlled trial of approximately 300 women
with platinum-sensitive recurrent high-grade ovarian cancer who had achieved a
response to their most recent treatment regardless of their BRCA status. The
patients were randomly assigned to olaparib 400 mg twice daily or placebo.
Compared with placebo, olaparib was shown to improve the PFS (8 months vs. 5
months; HR for progression or death, 0.35; 95% CI, 0.25–0.49) (345). A separate
analysis of Study 19 evaluated outcomes for gBRCA patients and showed that the
clinical benefit was greatest for these patients. The PFS was (11 months vs. 4
months; HR, 0.18; 95% CI, 0.10–0.31) for olaparib versus placebo, respectively
(346,347).
A randomized, double-blind, placebo-controlled, phase 3 trial was of
maintenance olaparib after first-line combination chemotherapy known as the
SOLO1 study was conducted in 15 countries (348). Of the 391 patients who
underwent randomization, 260 were assigned to receive olaparib and 131 to
receive placebo. A total of 388 patients had a germline BRCA1 or BRCA2
mutation, and 2 patients had a somatic BRCA1 or BRCA2 mutation. After a
median follow-up of 41 months, the risk of disease progression or death was 70%
lower with olaparib than with placebo (at 3 years, 60% vs. 27%, HR = 0.30; 95%
2611CI, 0.23 to 0.41; p <0.0001). Adverse events were consistent with the known
toxic effects of olaparib. The use of maintenance therapy with olaparib
provided a substantial benefit in progression-free survival among women
with newly diagnosed advanced ovarian cancer and a BRCA1 or BRCA2
mutations, and they had a 70% lower risk of disease progression or death
with olaparib than with placebo.
These results were confirmed in the much larger SOLO2 trial, which included
295 patients with gBRCA mutations and platinum-sensitive recurrent ovarian
cancer who had responded to platinum-based chemotherapy. They were randomly
assigned to receive olaparib (n = 196) or placebo (n = 99). The median PFS was
significantly longer with olaparib (19.1 months [95% CI, 16.3–25.7]) than with
placebo (5.5 months [5.2–5.8]; HR, 0.30; 95% CI, 0.22–0.41]; p <0.0001).
Rucaparib
Rucaparib is approved for treatment of BRCA-mutation–associated
advanced ovarian cancer after completion of treatment with two or more
chemotherapy regimens regardless of whether patients are platinumsensitive or resistant.
Ariel 3 included patients with platinum-sensitive, high-grade serous or
endometrioid ovarian, fallopian tube, or peritoneal carcinoma, who had received
at least two prior platinum-based chemotherapy regimens, complete or partial
response to their last platinum-based regimen, and a CA-125 concentration of less
than the upper limit of normal. They were randomized 2:1 to receive oral
rucaparib 600 mg twice daily or placebo. The median PFS in patients with a
BRCA-mutant carcinoma was 16.6 months (95% CI, 13.4–22.9; 130 [35%]
patients) in the rucaparib group versus 5.4 months (3.4–6.7; 66 [35%] patients) in
the placebo group (HR, 0.23 [95% CI, 0.16–0.34]; p <0.0001). Similar to the
NOVA trial, the investigators analyzed all tumors for HRD using a different
method. In patients with an HRD carcinoma (236 [63%] vs. 118 [62%]), the PFS
was 13.6 months (10.9–16.2) versus 5.4 months (5.1–5.6; 0.32 [0.24–0.42]; p
<0.0001).
In a phase II trial of 204 patients with recurrent platinum-sensitive, high-grade
ovarian cancer treated with rucaparib, patients with BRCA mutations and high
loss of heterozygosity (LOH) had a longer PFS compared to patients with low
LOH. Patients were divided into three groups for the study; those with germline
or somatic BRCA mutations, those who were BRCA-wild type but LOH high,
and those who were BRCA-wild type and LOH low. The PFS was longer for
patients with BRCA mutations (12.8 months; HR, 0.27; 95% CI, 0.16–0.44)
and/or LOH high (5.7 months; HR, 0.62; 95% CI, 0.42–0.90) subgroups
compared to those with LOH low (5.2 months) (349).
2612Other PARP Inhibitors
There are a number of other PARP inhibitors under investigation. Veliparib is
another PARP inhibitor with encouraging results in a phase II trial of 50 women
with BRCA mutations who were treated with veliparib monotherapy at a dose of
400 mg twice daily. There was a 26% overall response rate for platinum-sensitive
and resistant patients and a 35% response rate among those with platinumsensitive disease (350). Veliparib is being investigated in GOG-3005 in
combination with chemotherapy in the frontline and maintenance setting.
Platinum-Resistant and Refractory Disease
Patients with platinum-refractory and resistant ovarian cancer are often
treated with chemotherapy and may have a number of lines of therapy
depending on the response and performance status. In platinum-refractory
patients (i.e., those progressing on treatment), response rates to second-line
chemotherapy are less than 10% and the median survival is short, around 3
to 5 months (304–308). The management of women who are platinumresistant (i.e., progressing within 6 months of completion of chemotherapy) is
difficult and “non–cross-resistant agents” are selected, but there does not
appear to be one best treatment. Single-agent therapy is typically used because
combination regimens are associated with more toxicity without any apparent
additional benefit. High response rates of 48% to 64% were reported with dosedense weekly carboplatin (AUC 2) plus paclitaxel (80 mg/m2), and this deserves
more study (351). There are a variety of potentially active drugs: paclitaxel,
docetaxel, topotecan, liposomal doxorubicin, gemcitabine, oral etoposide,
tamoxifen, and bevacizumab are the most frequently used. Other agents include
vinorelbine and newer drugs such as trabectedin.
Chemotherapy plus bevacizumab leads to improved responses in platinumresistant disease. In the Aurelia study, 361 patients with platinum-resistant,
bevacizumab naïve ovarian cancer (progression less than or equal to 6 months
after 4 or more platinum-based cycles) were randomly assigned to treatment with
chemotherapy with or without bevacizumab at 15 mg/kg every 3 weeks. No more
than two prior lines were allowed.
Chemotherapy options included the investigator’s choice of paclitaxel 80
mg/m2 on days 1, 8, 15, and 22 every 4 weeks, or topotecan 4 mg/m2 on days 1,
8, 15 every 4 weeks or 1.25 mg/m2 on days 1 through 5 every 3 weeks, or Doxil
40 mg/m2 on day 1 every 4 weeks. Patients who received chemotherapy alone
were allowed to crossover at time of disease progression to single-agent
bevacizumab. The median follow-up was 13.5 months and compared to
chemotherapy alone, the addition of chemotherapy to bevacizumab resulted in a
2613reduction in the risk of disease progression. Median duration of response was 6.7
months versus 3.4 months (HR, 0.48; 95% CI, 0.38–0.60) in favor of
bevacizumab and chemotherapy. There was no statistical improvement in overall
survival. A planned subset analysis was performed and showed among those
patients who received paclitaxel, the median PFS with or without bevacizumab
was longer, 10 months versus 4 months, respectively; HR, 0.46; 95% CI, 0.30–
0.71 (352).
The results of a study comparing topotecan with liposomal doxorubicin
demonstrate the low response rates and poor prognosis among women with
platinum-resistant ovarian cancer (309). There were two randomized trials
comparing liposomal doxorubicin with either topotecan or paclitaxel. In a study
of 237 women who relapsed after receiving one platinum-containing regimen,
117 of whom (49.4%) had platinum-refractory disease, liposomal doxorubicin 50
mg/m2 over 1 hour every 4 weeks was compared with topotecan 1.5 mg/m2/day
for 5 days every 3 weeks (309). The two treatments had a similar overall
response rate (20% vs. 17%), time to progression (22 weeks vs. 20 weeks), and
median overall survival (66 weeks vs. 56 weeks). The myelotoxicity was
significantly lower in the liposomal doxorubicin–treated patients than with those
receiving topotecan. In a second study comparing liposomal doxorubicin with
single-agent paclitaxel in 214 platinum-treated patients who had not received
prior taxanes, the overall response rates for liposomal doxorubicin and paclitaxel
were 18% versus 22%, respectively, and median survival durations were 46 and
56 weeks, respectively, and these were not significantly different (310). In
practice, most patients are treated with a starting dose of 40 mg/m2 of liposomal
doxorubicin every 4 weeks, because of the toxicity associated with the higher
dose and the need to dose reduce when 50 mg/m2 is used. In a subset analysis of
platinum-resistant patients, the median time to progression ranged from 9.1 to
13.6 weeks for topotecan and liposomal doxorubicin, respectively. The median
survival (p = 0.455) was 35.6 weeks for pegylated liposomal doxorubicin and
41.3 weeks for topotecan. Objective response rates were recorded in 6.5% of
patients who received topotecan and in 12.3% of those who received pegylated
liposomal doxorubicin (p = 0.118). It is not known whether the treatmentimproved symptom control or quality of life because this was not specifically
addressed.
In another randomized trial of 195 patients with platinum-resistant ovarian
cancer, patients were randomized to receive either liposomal doxorubicin (PLD)
or gemcitabine (353). In the gemcitabine and PLD groups, the median PFS was
3.6 months versus 3.1 months; the median overall survival was 12.7 months
versus 13.5 months; the overall response rate was 6.1% versus 8.3%; and in the
2614subset of patients with measurable disease, the overall response rate was 9.2%
versus 11.7%, respectively. None of the efficacy end points showed a statistically
significant difference between treatment groups. The PLD group experienced
significantly more hand–foot syndrome and mucositis; the gemcitabine group
experienced significantly more constipation, nausea or vomiting, fatigue, and
neutropenia.
Taxanes
Single-agent paclitaxel shows objective responses in 20% to 30% in phase II
trials of women with platinum-resistant ovarian cancer (313–318). The main
toxicities are fatigue and peripheral neuropathy. Weekly paclitaxel appears to be
more active than 3-weekly administration in patients with platinum-resistant
ovarian cancer. In a study of 53 women with platinum-resistant ovarian cancer,
weekly paclitaxel (80 mg/m2 over 1 hour) had an objective response of 25% in
patients with measurable disease, and 27% of patients without measurable disease
had a 75% decline in serum CA-125 levels (313).
Docetaxel has some activity in these patients (354–356). The GOG studied 60
women with platinum-resistant ovarian or primary peritoneal cancer (356).
Although there was a 22% objective response rate, the median response duration
was only 2.5 months, and therapy was complicated by severe neutropenia in
three-quarters of the patients.
Topotecan
Topotecan is a relatively active second-line treatment for patients with platinumsensitive and platinum-resistant disease (321–335). In a study of 139 women
receiving topotecan 1.5 mg/m2 daily for 5 days, response rates were 19% and
13% in patients with platinum-sensitive and platinum-resistant disease,
respectively (331). The predominant toxicity of topotecan is hematologic,
especially neutropenia. With the 5-day dosing schedule, approximately 70% to
80% of patients have severe neutropenia, and 25% have febrile neutropenia with
or without infection. In some studies, regimens of 5 days produce better response
rates than regimens of shorter duration, but in others, reducing the dose to 1.0
mg/m2 per day for 3 days is associated with similar response rates but lower
toxicity (324,334). In a study of 31 patients, one-half of whom were platinum
refractory, topotecan 2 mg/m2 per day for 3 days every 21 days had a 32%
response rate (329). Continuous infusion topotecan (0.4 mg/m2 per day for 14 to
21 days) had a 27% to 35% objective response rate in platinum-refractory patients
(328). Weekly topotecan administered at a dose of 4 mg/m2 per week for 3
weeks with a week off every month produced a response rate similar to the 5-
2615day regimen with considerably less toxicity, and this dose schedule is
commonly used in the recurrent setting (334).
Oral topotecan, not available in the United States, results in similar response
rates with less hematologic toxicity (330). The IV and oral formulations of
topotecan were compared in a randomized trial of 266 women as a third-line
regimen after an initial platinum-based regimen (335). Compared with IV
topotecan (1.5 mg/m2 daily for 5 days every 3 weeks), oral topotecan (2.3 mg/m2
per day for 5 days every 3 weeks) produced a similar response rate (13% vs.
20%), less severe myelosuppression, and only a slightly shorter median survival
(51 weeks vs. 58 weeks).
Liposomal Doxorubicin
Liposomal doxorubicin (Doxil in the United States and Caelyx in Europe) has
activity in platinum- and taxane-refractory disease (309–312,339). One of the
most important side effects of liposomal doxorubicin is the hand–foot
syndrome, also known as palmar-plantar erythrodysesthesia or acral
erythema, which occurs in 20% of patients who receive 50 mg/m2 every 4
weeks (310). Most oncologists administer 40 mg/m2 and escalate only if there are
no side effects. Liposomal doxorubicin has a low rate of alopecia. In a study of 89
patients with platinum-refractory disease, including 82 paclitaxel-resistant
patients, liposomal doxorubicin (50 mg/m2 every 3 weeks) produced a response
in 17% (1 complete and 14 partial responses) (312). In another study, an objective
response of 26% was reported, although there were no responses in women who
progressed during first-line therapy (309).
Gemcitabine
Gemcitabine is associated with response rates of 20% to 50%, with 15% to 30%
in patients who are platinum-resistant (357–361). The principal toxicity is
myelosuppression.
Oral Etoposide
The most common toxicities with oral etoposide are myelosuppression and
gastrointestinal issues: grade 4 neutropenia is observed in about one-fourth of
patients, and 10% to 15% have severe nausea and vomiting (362,363). A study of
oral etoposide given for a prolonged treatment (50 mg/m2 daily for 21 days every
4 weeks) had a 27% response rate in 41 women with platinum-resistant disease, 3
of whom had durable complete responses (363). In 25 patients with platinum and
taxane-resistant disease, 8 objective responses (32%) were reported.
Hormonal Therapy
2616Tamoxifen is associated with CA-125 response rates of 15% to 20% in small
studies of patients with recurrent ovarian cancer (364–370). The efficacy of
tamoxifen was analyzed in a Cochrane review which included 623 women with
recurrent epithelial ovarian cancer across several studies. Overall, 10% achieved
an objective response, although the range within individual studies was 0% to
56%. The duration of response is short-lived for patients with high-grade ovarian
cancer (366). Aromatase inhibitors (e.g., letrozole, anastrozole, and exemestane),
which have activity in metastatic breast cancer, are being studied in relapsed
ovarian cancer (371). One of the principal advantages of this class of agents is its
very low toxicity (372).
Bevacizumab
Bevacizumab was the first targeted drug to show significant single-agent
activity in ovarian cancer. It is a humanized MonAb that targets angiogenesis by
binding to VEGF-A, thereby blocking the interaction of VEGF with its receptor.
There are a number of phase II studies reported using bevacizumab in patients
with platinum-sensitive and platinum-resistant ovarian cancer with response rates
ranging from 16% to 22% in platinum-sensitive and refractory patients (373). Up
to 40% of patients had stabilization of disease for at least 6 months. A study of
low-dose metronomic chemotherapy with 50 mg of cyclophosphamide daily and
bevacizumab 10 mg/kg IV every 2 weeks showed significant activity in a study of
70 patients with recurrent ovarian cancer (374). The primary end point was PFS at
6 months. The probability of being alive and progression free at 6 months was
56%. A partial response was achieved in 17 patients (24%). The median time to
progression and survival were 7.2 and 16.9 months, respectively. The use of
bevacizumab brings potential toxicity. The side effects of bevacizumab are well
recognized and include hypertension, fatigue, proteinuria, gastrointestinal
perforation or fistula, and uncommonly, vascular thrombosis and central nervous
system ischemia, pulmonary hypertension, and bleeding and wound-healing
complications. The most common side effects are hypertension that is grade 3 in
7% of patients but is manageable in most patients. The most concerning side
effect is bowel perforation and the study by Cannistra et al. was stopped after
recruiting 44 patients because of an 11% incidence of perforation of the bowel
(375). The bowel perforation complication could be minimized by carefully
screening patients. Simpkins et al. limited bevacizumab treatment to patients
without clinical symptoms of bowel obstruction or evidence of rectosigmoid
involvement on pelvic examination or bowel involvement on CT scan (376).
Their study included 25 patients with platinum-resistant ovarian cancer who were
heavily pretreated, and they observed a response rate of 28% without any bowel
perforations or other grade 3 or 4 toxicities. This highlights the importance of
2617patient selection.
Radiation Therapy
Whole-abdominal radiation therapy was given as a treatment for recurrent
or persistent disease but is associated with high morbidity and is not used.
The principal problem with this approach is the development of acute and chronic
intestinal morbidity. As many as 30% of patients receiving this treatment develop
intestinal obstruction, which necessitated exploratory surgery with potential
morbidity (377).
Intestinal Obstruction
Patients with epithelial ovarian cancer often develop intestinal obstruction, either
at the time of initial diagnosis or in association with recurrent disease (378–393).
Obstruction may be related to a mechanical blockage or to carcinomatous ileus.
The intestinal blockage can be corrected in most patients with obstruction at
initial diagnosis. The decision to perform an exploratory procedure to ease
intestinal obstruction in patients with recurrent disease is more difficult. For
patients whose life expectancy is very short (e.g., less than 2 months), surgical
relief of the obstruction is not indicated (378–383). In those patients with a
longer projected lifespan, features predicting a reasonable likelihood of
correcting the obstruction include young age, good nutritional status, and the
absence of rapidly accumulating ascites (379).
For most patients with recurrent ovarian cancer and intestinal obstruction,
particularly small bowel obstruction, initial management should include proper
radiographic documentation of the obstruction, hydration, correction of any
electrolyte disturbances, parenteral alimentation, and intestinal intubation. For
some patients, the obstruction may be alleviated by this conservative approach. A
preoperative upper gastrointestinal radiographic series and a barium enema will
define possible sites of obstruction.
If exploratory surgery is deemed appropriate, the type of operation to be
performed will depend on the site and the number of obstructions. Multiple sites
of obstruction are not uncommon in patients with recurrent epithelial
ovarian cancer. More than one-half of the patients have small bowel obstruction,
one-third have colonic obstruction, and one-sixth have both (380–384). If the
obstruction is principally contained in one area of the bowel (e.g., the terminal
ileum), this area can be either resected or bypassed, depending on what is easier
to accomplish safely. Intestinal bypass is less morbid than resection, and in
patients with progressive cancer, the survival time after these two operations is
the same (385–390).
If multiple obstructions are present, resection of several segments of intestine is
2618usually not indicated, and intestinal bypass and/or colostomy should be
performed. A gastrostomy may be useful in this circumstance, and this can
usually be placed percutaneously (389,392).
Surgery for bowel obstruction in patients with ovarian cancer carries an
operative mortality of about 10% and a major complication rate of about
30% (378–390). The need for multiple reanastomoses and poor nutrition
increases the morbidity, which consists primarily of sepsis and enterocutaneous
fistulae. The median survival ranges from 3 to 12 months, although about 20% of
these patients survive longer than 12 months (390–393).
Survival
The prognosis for patients with epithelial ovarian cancer is related to several
clinical variables. Survival analyses based on prognostic variables are presented
(4,65,151–155,160). Including patients at all stages, patients younger than 50
years of age have a 5-year survival rate of about 40%, compared with about 15%
for patients older than 50 years.
The 5-year survival rate for carefully and properly staged patients with
stage I disease is as high as 94%, for stage II is 73%, for stage III or IV 28%
(65). The 5-year survival rate for stage IIIA is 41%, for stage IIIB about
25%, for stage IIIC 23%, and for stage IV disease 11% (Fig. 39-16). An
analysis of the National Cancer Institute’s Surveillance, Epidemiology, and
End Results (SEER) database reveals a trend toward improved survival for
ovarian cancer in the United States. In this cohort, the survival for stage I
was 93%, for stage II 70%, for stage III 37%, and for stage IV 25% (394).
Survival of patients with borderline tumors is excellent, with stage I lesions
having a 98% 15-year survival (160). When all stages of borderline tumors are
included, the 5-year survival rate is about 86% to 90%.
Patients with stage III disease with microscopic residual disease at the start of
treatment have a 5-year survival rate of about 40% to 75%, compared with about
30% to 40% for those with optimal disease, and only 5% for those with
suboptimal disease (154,155,178). Patients whose Karnofsky index (KI) is low
(<70) have a significantly shorter survival than those with a KI greater than 70
(160).
2619NONEPITHELIAL OVARIAN CANCERS
Compared with epithelial ovarian cancers, other malignant tumors of the ovary
are uncommon. Nonepithelial malignancies of the ovary account for about
10% of all ovarian cancers (2,3,395). Nonepithelial ovarian cancers include
malignancies of germ cell origin, sex cord–stromal cell origin, metastatic
carcinomas to the ovary, and a variety of extremely rare ovarian cancers (e.g.,
sarcomas). Although there are similarities in the presentation, evaluation, and
management of these patients, the tumors have unique qualities that require a
special approach (2,395–398).
FIGURE 39-16 Survival of patients with epithelial ovarian cancer by substage. (Adapted
from Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. In Twentysixth annual report of the results of treatment of gynaecological cancer. Int J Gynecol
Oncol. 2006;95(suppl 1): S161–S192.)
Germ Cell Malignancies
Germ cell tumors are derived from the primordial germ cells of the ovary.
2620Their incidence is about one-tenth the incidence of malignant germ cell tumors of
the testis, so most of the advances in the management of these tumors are
extrapolations from experience with the corresponding testicular tumors.
Although malignant germ cell tumors can arise in extragonadal sites such as the
mediastinum and the retroperitoneum, most germ cell tumors arise in the gonad
from undifferentiated germ cells. The variation in the site of these cancers is
explained by the embryonic migration of the germ cells from the caudal part of
the yolk sac to the dorsal mesentery before their incorporation into the sex cords
of the developing gonads (2,4,395).
Table 39-5 Histologic Typing of Ovarian Germ Cell Tumors
1. Primitive germ cell
tumors
A. Dysgerminoma
B. Yolk sac tumor
C. Embryonal
carcinoma
D. Polyembryoma
E. Nongestational
choriocarcinoma
F. Mixed germ cell
tumor
3. Monodermal teratoma and somatic-type tumors
associated with dermoid cysts
A. Thyroid tumor
1. Struma ovarii
a. Benign
b. Malignant
B. Carcinoid
C. Neuroectodermal tumor
D. arcinoma
E. Melanocytic
F. Sarcoma
G. Sebaceous tumor
H. Pituitary-type tumor
2. Biphasic or triphasic I. Others
teratoma
A. Immature teratoma
B. Mature teratoma
1. Solid
2. Cystic
a. Dermoid cyst
b. Fetiform
teratoma
(homunculus)
Adapted from Kurman RJ, Carcangui ML, Herrington CS, et al., eds. World Health
Organization Classification of Tumours of Female Reproductive Organs. Lyon: IARC
Press; 2014.
Classification
A histologic classification of ovarian germ cell tumors is presented in Table 39-5
(4,395). Both α-fetoprotein (AFP) and human chorionic gonadotropin (hCG)
2621are secreted by some germ cell malignancies and can be clinically useful in
the diagnosis of a pelvic mass and monitoring patients after surgery.
Placental alkaline phosphatase (PLAP) and lactate dehydrogenase (LDH) are
elevated to 95% of dysgerminomas, and serial measurements of LDH may be
useful for monitoring the disease. A classification of germ cell tumors is based
on the histologic and immunocytochemical feature which include AFP and β-hCG
(Fig. 39-17) (399).
and their secreted marker substances. (From Berek JS, Friedlander ML, Hacker NF.
Germ cell and nonepithelial ovarian cancer. In: Berek JS, Hacker NF. Berek & Hacker’s
Gynecologic Oncology. 6th ed. Philadelphia, PA: Wolters Kluwer; 2015:532.)
2622In this scheme, embryonal carcinoma (a cancer composed of
undifferentiated cells) synthesizes both hCG and AFP, and this lesion is the
progenitor of several other germ cell tumors (399–401). More differentiated germ
cell tumors, such as the endodermal sinus tumor, which secretes AFP, and the
choriocarcinoma, which secretes hCG, are derived from the extraembryonic
tissues; the immature teratomas derived from the embryonic cells have lost the
ability to secrete these substances. Pure germinomas do not secrete these markers.
Epidemiology
Although 20% to 25% of all benign and malignant ovarian neoplasms are of
germ cell origin, only about 3% of these tumors are malignant (2,4). Germ
cell malignancies account for fewer than 5% of all ovarian cancers in Western
countries. Germ cell malignancies represent up to 15% of ovarian cancers in
Asian and African American societies, where epithelial ovarian cancers are much
less common.
[11] In the first two decades of life, almost 70% of ovarian tumors are of
germ cell origin, and one-third of these are malignant (2,4,395). Germ cell
cancers are seen in the third decade, but thereafter they become quite rare.
Clinical Features
Symptoms
[11] In contrast to the slower-growing epithelial ovarian tumors, germ cell
malignancies grow rapidly and commonly present with acute/subacute pelvic
pain related to capsular distention, hemorrhage, or necrosis. The rapidly
enlarging pelvic mass may produce pressure symptoms on the bladder or rectum,
and menstrual irregularities may occur in menarcheal patients. Some young
patients misinterpret the early symptoms of a neoplasm as those of pregnancy,
which can lead to a delay in the diagnosis. Acute symptoms associated with
torsion or rupture of the adnexa can develop. These symptoms may be confused
with acute appendicitis. In more advanced cases, ascites may develop, and the
patient can have abdominal distention (389).
Signs
For a patient with a palpable adnexal mass, the evaluation can proceed as
outlined. Some patients with germ cell tumors will be premenarcheal and may
require examination under anesthesia. If the lesions are principally solid or a
combination of solid and cystic, as might be noted on an ultrasonographic
evaluation, a neoplasm is probable and a malignancy is possible (see Fig. 9.8
and Chapter 9). During the remainder of the physical examination, effort should
be directed to searching for signs of ascites, pleural effusion, and organomegaly.
2623Diagnosis
Adnexal masses measuring 2 cm or larger in premenarcheal girls or 8 cm or
larger in other premenopausal patients will usually require surgical
exploration. For young patients, blood tests should include serum hCG and AFP
and LDH. A CT scan of the chest is important because germ cell tumors can
metastasize to the lungs or mediastinum. A karyotype should be obtained
preoperatively for all premenarcheal girls, particularly those with
dysgerminomas, because they may arise in dysgenetic gonads (396,402). A
preoperative CT scan or MRI may document the presence and extent of
retroperitoneal lymphadenopathy or liver metastases; however, because these
patients require surgical exploration, preoperative imaging may not impact initial
surgical management. If postmenarcheal patients have predominantly cystic
lesions up to 8 cm in diameter, they may be observed or given oral contraceptives
for two menstrual cycles, which may reduce new ovarian cyst formation (403).
Dysgerminoma
[12] Dysgerminoma is the most common malignant germ cell tumor,
accounting for about 30% to 40% of all ovarian cancers of germ cell origin
(2,4,399). The tumors represent only 1% to 3% of all ovarian cancers, but they
represent as many as 5% to 10% of ovarian cancers in patients younger than 20
years. Seventy-five percent of dysgerminomas occur between the ages of 10 and
30 years, 5% occur before the age of 10 years, but they rarely occur after 50 years
of age (2,4,389). Because these malignancies occur in young women, 20% to 30%
of ovarian malignancies associated with pregnancy are dysgerminomas.
Germinomas are found in both sexes and may arise in gonadal or
extragonadal sites. The latter includes the midline structures from the pineal
gland to the mediastinum and the retroperitoneum. Histologically, they represent
abnormal proliferations of the basic germ cell. In the ovary, the germ cells are
encapsulated at birth (the primordial follicle), and the unencapsulated or free cells
die. If either of the latter processes fails, it is possible that the germ cell could free
itself of its normal control and multiply indiscriminately.
The size of dysgerminomas varies widely, but they are usually 5 to 15 cm in
diameter (2,4). The capsule is slightly bosselated, and the consistency of the cut
surface is fleshy and pale tan to gray-brown in color (Fig. 39-18).
FIGURE 39-18 Dysgerminoma of the ovary. Note that the lesion is principally solid with
some cystic areas and necrosis.
The histologic characteristics of the dysgerminoma are very distinctive.
The large round, ovoid, or polygonal cells have abundant, clear, very-pale–
staining cytoplasm, large and irregular nuclei, and prominent nucleoli (Fig.
39-19). Mitotic figures are seen in varying numbers, although they are usually
numerous. Another characteristic feature is the arrangement of the elements in
lobules and nests separated by fibrous septa, which are often extensively
infiltrated with lymphocytes, plasma cells, and granulomas with epithelioid cells
and multinucleated giant cells. When necrosis is extensive, the lesion may be
confused with tuberculosis. Dysgerminomas may contain syncytiotrophoblastic
giant cells and may be associated with precocious puberty or virilization. The
2625presence of these cells does not seem to alter prognosis (2,4). The presence of
calcifications should prompt a search for a possible underlying gonadoblastoma.
Because the dysgerminoma is a germ cell tumor and parthenogenesis
(stimulation of the basic germ cell to atypical division) is the accepted genesis for
the more immature teratomas, it is logical that these two tumors may coexist.
Choriocarcinoma, endodermal sinus tumor, and other extraembryonal lesions may
be associated with the dysgerminoma.
FIGURE 39-19 Dysgerminoma of the ovary. Primitive germ cells are divided into clusters
and lobules by fibrous septa rich in lymphocytes.
Approximately 5% of dysgerminomas are discovered in phenotypic
women with abnormal gonads (2,402,404). This malignancy can be associated
with patients who have pure gonadal dysgenesis (46,XY, bilateral streak gonads),
mixed gonadal dysgenesis (45,X/46,XY, unilateral streak gonad, contralateral
testis), and the androgen insensitivity syndrome (46,XY, testicular feminization).
For premenarcheal patients with a pelvic mass, the karyotype should be
2626determined (see Chapter 34).
For most patients with gonadal dysgenesis, dysgerminomas arise in
gonadoblastomas, which are benign ovarian tumors that are composed of germ
cells and sex cord stroma. If gonadoblastomas are left in situ in patients with
gonadal dysgenesis, more than 50% will develop into ovarian malignancies (404).
About 65% of dysgerminomas are stage I (i.e., confined to one or both
ovaries) at diagnosis (2,4,405–409). About 85% to 90% of stage I tumors are
confined to one ovary; 10% to 15% are bilateral. Dysgerminoma is the only
germ cell malignancy that has this significant rate of bilaterality. Other germ
cell tumors are rarely bilateral.
For patients whose contralateral ovary is preserved, disease can develop in 5%
to 10% of the retained gonads over the next 2 years (2). This figure includes those
not given additional therapy and patients with gonadal dysgenesis.
In the 25% of patients who are diagnosed initially with metastatic disease,
the tumor commonly spreads via the lymphatic system. It can spread
hematogenously or by direct extension through the capsule of the ovary with
exfoliation and dissemination of cells throughout the peritoneal surfaces.
Metastases to the contralateral ovary may be present when there is no other
evidence of spread. An uncommon site of metastatic disease is bone; when
metastasis to this site occurs, the lesions are principally in the lower vertebrae.
Metastases to the lungs, liver, and brain are often in patients with longstanding or
recurrent disease. Metastasis to the mediastinum and supraclavicular lymph nodes
is usually a late manifestation of disease (405,406).
Treatment
The treatment of patients with early dysgerminoma is primarily surgical,
including resection of the primary lesion and proper surgical staging.
Chemotherapy is administered to patients with metastatic disease. [12]
Because the disease principally affects girls and young women, special
consideration must be given to the preservation of fertility whenever
possible. An algorithm for the management of ovarian dysgerminoma is
presented in Figure 39-20.
Surgery
The minimal surgical operation for ovarian dysgerminoma is a unilateral
oophorectomy (407). If there is a desire to preserve fertility, as there almost
always is, the contralateral ovary, fallopian tube, and uterus should be left in
situ, even in the presence of metastatic disease, because of the sensitivity of
the tumor to chemotherapy. If fertility need not be preserved, it may be
appropriate to perform a total abdominal hysterectomy and bilateral salpingo-
2627oophorectomy for patients with advanced disease (409). For patients whose
karyotype analysis reveals a Y chromosome, both ovaries should be removed,
although the uterus may be left in situ for possible future embryo transfer (404).
Whereas cytoreductive surgery is of unproved value, bulky disease that can be
readily resected (e.g., an omental cake) should be removed during the initial
operation.
FIGURE 39-20 Management of dysgerminoma of the ovary. BEP, bleomycin, etoposide,
and cisplatin; CT, computed tomogram. (From Berek JS, Friedlander ML, Hacker NF.
2629Germ cell and nonepithelial ovarian cancer. In: Berek JS, Hacker NF. Berek & Hacker’s
Gynecologic Oncology. 6th ed. Philadelphia, PA: Wolters Kluwer; 2015:536.)
In patients in whom the neoplasm appears on inspection to be confined to
the ovary, a careful staging operation should be undertaken to determine the
presence of any occult metastatic disease. All peritoneal surfaces should be
inspected and palpated, and any suspicious lesions should be sampled for biopsy.
Unilateral pelvic lymphadenectomy and careful palpation and biopsy of enlarged
para-aortic nodes are particularly important parts of the staging. These tumors
may metastasize to the para-aortic nodes around the renal vessels. Dysgerminoma
is the only germ cell tumor that tends to be bilateral, excisional biopsy of any
suspicious masses is desirable (407–409). If a small contralateral tumor is found,
it may be possible to resect it and preserve some normal ovary.
Many patients with a dysgerminoma will have a tumor that is apparently
confined to one ovary and will be referred after unilateral salpingooophorectomy without surgical staging. Recommended options depend on
the pathologic findings, the results of imaging and tumor markers (BHCG
and LDH), the age of the patient and whether she desires fertility
preservation.
The options include (i) completion of surgical staging as stage 1
dysgerminomas do not require adjuvant chemotherapy, (ii) close surveillance
with pelvic and abdominal CT scans and tumor markers, or (iii) adjuvant
chemotherapy if capsular rupture or more advanced stage. Tumor markers
(LDH, AFP, and β-hCG) should be monitored in case occult mixed germ cell
elements are present.
Radiation Therapy
Dysgerminomas are very sensitive to radiation therapy, and doses of 2,500 to
3,500 cGy may be curative, even for gross metastatic disease. Loss of fertility is a
problem with radiation therapy, and radiation is rarely used as first-line treatment.
Chemotherapy
There is very good evidence to demonstrate the effectiveness of platinumbased chemotherapy, which is regarded as the treatment of choice (409–420).
The obvious advantage is the preservation of fertility (421).
[12] The most frequently used chemotherapeutic regimen for germ cell
tumors is BEP (bleomycin, etoposide, and cisplatin), EP (etoposide and
cisplatin), or EC (etoposide and carboplatin) (Table 39-6) (409–426).
Table 39-6 Combination Chemotherapy for Germ Cell Tumors of the Ovary
2630Regimen and Drugs Dose and Schedulea
BEP
Bleomycin 30,000 IU on days 1, 8, and 15 every 3 wks
Etoposide 100 mg/m2/day × 5 days every 3 wks
Cisplatin 20 mg/m2/day × 5 days, or 100 mg/m2/day × 1 day every 3
wks
VBP
Vinblastine 0.15 mg/kg days 1 and 2 every 3 wks
Bleomycin 15 units/m2/wk × 5; then on day 1 of course 4
Cisplatin 100 mg/m2 on day 1 every 3 wks
VAC
Vincristine 1–1.5 mg/m2 on day 1 every 4 wks
Actinomycin D 0.5 mg/day × 5 days every 4 wks
Cyclophosphamide 150 mg/m2/day × 5 days every 4 wks
aAll doses given intravenously.
The GOG studied three cycles of the EC regimen, consisting of etoposide (120
mg/m2 IV on days 1, 2, and 3 every 4 weeks) and carboplatin (400 mg/m2 IV on
day 1 every 4 weeks) for patients with completely resected ovarian
dysgerminoma, stage IB, IC, II, or III (417). The results showed a sustained
disease-free remission rate of 100%. This study was carried out many years ago
when carboplatin dose was based on surface area, but it is now based on AUC.
For patients with advanced, incompletely resected germ cell tumors, the GOG
studied cisplatin-based chemotherapy in two consecutive protocols (410,411). In
the first study, patients received four cycles of vinblastine (12 mg/m2 every 3
weeks), bleomycin (20 units/m2 IV every week for 12 weeks), and cisplatin (20
mg/m2 per day IV for 5 days every 3 weeks). Patients with persistent or
progressive disease at second-look laparotomy were treated with six cycles of
VAC (vincristine, actinomycin D, and cyclophosphamide). In the second trial,
patients received three cycles of BEP initially, followed by consolidation with
2631VAC, which was later discontinued in patients with dysgerminomas (411). The
VAC consolidation after BEP is no longer used. A total of 20 evaluable patients
with stages III and IV dysgerminoma were treated in these two protocols, and 19
were alive and free of disease after 6 to 68 months (median = 26 months).
Fourteen of these patients had a second-look laparotomy, and all findings were
negative. Another study at MD Anderson Cancer Center used BEP in 14 patients
with residual disease, and all patients were free of disease during long-term
follow-up (414). These results demonstrate that patients with advanced-stage,
incompletely resected dysgerminoma have an excellent prognosis when
treated with EP-based combination chemotherapy. [12] The standard
regimen is three to four cycles of BEP, depending on assigned risk based on
the data from testicular cancers, including advanced-stage seminomas which
are the male equivalent of dysgerminoma (425,429).
Recurrent Disease
About 75% of recurrences occur within the first year after initial treatment,
the most common sites being the peritoneal cavity and the retroperitoneal lymph
nodes (2,388,389). These patients should be treated with chemotherapy. Patients
with recurrent disease who had no therapy other than surgery should be treated
with chemotherapy as described above. If prior chemotherapy with BEP was
given, there are a number of second-line options including TIP (paclitaxel,
ifosfamide, cisplatin) or VIP (vinblastine, ifosfamide, cisplatin) (Table 35-7), and
consideration should be given to the use of high-dose chemotherapy in selected
patients. Patients with recurrent dysgerminomas following BEP should be
managed in specialized centers. Radiation therapy may be an option in very
selected subsets, with the major disadvantage being loss of fertility if pelvic and
abdominal irradiation is required.
Table 39-7 POMB-ACE Chemotherapy for Germ Cell Tumors of the Ovary
POMB
Day
1
Vincristine 1 mg/m2 IV; methotrexate 300 mg/m2 as a 12-hr infusion
Day
2
Bleomycin 15 mg as a 24-hr infusion: folinic acid rescue started at 24 hr
after the start of methotrexate in a dose of 15 mg every 12 hrs for 4 doses
Day
3
Bleomycin infusion 15 mg as a 24-hr infusion
Day Cisplatin 120 mg/m2 as a 12-hr infusion, given with hydration and 3-g
26324 magnesium sulfate supplementation
ACE
Days
1–5
Etoposide (VP16–213) 100 mg/m2 IV, days 1–5
Days
3–5
Actinomycin D 0.5-mg IV, days 3, 4, and 5
Day
5
Cyclophosphamide 500 mg/m2 IV, day 5
OMB
Day
1
Vincristine 1 mg/m2 IV; methotrexate 300 mg/m2 as a 12-hr infusion
Day
2
Bleomycin 15 mg as a 24-hr infusion; folinic acid rescue started at 24 hrs
after the start of methotrexate in a dose of 15 mg every 12 hrs for 4 doses
Day
3
Bleomycin 15 mg as a 24-hr infusion
IV, intravenous.
The sequence of treatment schedules is two courses of POMB followed by ACE. POMB is
then alternated with ACE until patients are in biochemical remission as measured by
human chorionic gonadotropin (hCG) and α-fetoprotein (AFP), placental alkaline
phosphatase (PLAP), and lactate dehydrogenase (LDH). The usual number of courses of
POMB is three to five. Following biochemical remission, patients alternate ACE with
OMB until remission has been maintained for approximately 12 weeks. The interval
between courses of treatment is kept to the minimum (usually 9 to 11 days). If delays are
caused by myelosuppression after courses of ACE, the first 2 days of etoposide are omitted
from subsequent courses of ACE.
From Newlands ES, Southall PJ, Paradinas FJ, et al. Management of ovarian germ cell
tumours. In: Williams CJ, Kaikorian JG, Green MR, et al., eds. Textbook of Uncommon
Cancer. New York: John Wiley & Sons; 1988:47, with permission.
Pregnancy
Because dysgerminomas tend to occur in young patients, they may coexist
with pregnancy. When a stage IA cancer is found, the tumor can be removed
intact and the pregnancy continued. For patients with more advanced disease,
continuation of the pregnancy depends on the gestational age of the fetus.
2633Chemotherapy can be given safely in the second and third trimesters in the same
dosages as given for the nonpregnant patient without apparent detriment to the
fetus (421).
Prognosis
For patients whose initial disease is stage IA (i.e., a unilateral encapsulated
dysgerminoma), unilateral oophorectomy alone results in a 5-year diseasefree survival rate of greater than 95% (408). The features associated with a
higher tendency to recur, include lesions larger than 10 to 15 cm in diameter, age
younger than 20 years, and a microscopic pattern that includes numerous mitoses,
anaplasia, and a medullary pattern (2,399,409–426,430–432).
Immature Teratomas
Immature teratomas contain elements that resemble tissues derived from the
embryo. Immature teratomatous elements may occur in combination with
other germ cell tumors as mixed germ cell tumors. [12] The pure immature
teratoma accounts for fewer than 1% of all ovarian cancers, but it is the
second most common germ cell malignancy and accounts for 10% to 20% of
all ovarian malignancies seen in women younger than 20 years (2). About
50% of pure immature teratomas of the ovary occur in women between the ages
of 10 and 20 years, and they rarely occur in postmenopausal women.
Pathology and Grading
Of fundamental importance in the understanding of the teratoma is
recognition of the maturation of the various elements. If maturation
continues along normal lines, it results in a mature teratoma, and the
prognosis is excellent as these are benign tumors with the rare exception of
other tumors arising from mature elements, such as squamous cell
carcinomas. Conversely, abnormal maturation of these elements can result in
an immature teratoma that has metastatic potential. Teratomas containing
immature elements, although relatively rare, are recognized more often as
pathologists are aware of the importance of differentiating them from mature
teratomas (Fig. 39-21). Among the tumors with embryonal elements, those
containing neural tissues demonstrate the ability to mature.
Semiquantification of immature neuroepithelium correlates with survival in
ovarian immature teratoma and is the basis for grading of these tumors (433–
435). Those with less than one low-power field (X 4) of immature
neuroepithelium on the slide with the greatest amount of such tissue (grade
1) have a survival of at least 95%, whereas greater amounts of immature
neuroepithelium (grades 2 and 3) appear to have a higher risk of recurrence
2634and a lower overall survival (approximately 85%) (435). This may not apply
to immature teratomas of the ovary in children because they have a good outcome
with surgery alone, regardless of the degree of immaturity (436,437). The
significant inter- and intraobserver difficulty with a three-tier system led some
authorities to recommend the two-tier grading system in use, with immature
teratomas categorized as either low grade or high grade (433). Immature ovarian
teratomas may be associated with gliomatosis peritonei, a favorable prognostic
finding if composed of completely mature tissues; molecular analyses suggest that
these glial implants are not tumor derived but rather represent teratoma-induced
metaplasia of pluripotent müllerian stem cells in the peritoneum (438,439).
FIGURE 39-21 Ovarian teratoma. This tumor contains both mature and immature neural
elements with a neural tube-like structure near its center.
Somatic malignant change in benign cystic teratomas was recorded as
occurring in 0.5% to 2% of cases, usually in patients older than 40 years of
age (433). The most common malignancy that develops in the initially benign
2635teratoma is squamous cell carcinoma. Other neoplasms were reported (e.g.,
adenocarcinomas, melanomas, which may arise from the skin or retinal anlage,
and sarcomas, including leiomyosarcomas and mixed mesodermal tumors) (2).
Carcinomas may arise from any of the epithelial elements.
Diagnosis
The preoperative evaluation and differential diagnosis of immature teratomas are
the same as for other germ cell tumors. Some of these tumors will contain
calcifications similar to those of mature teratomas, which can be detected by a
radiograph of the abdomen or by ultrasonography. Rarely they are associated with
the production of steroid hormones and can be accompanied by sexual
pseudoprecocity (395). Tumor markers are negative unless a mixed germ cell
tumor is present. Immature teratoma may contain embryonal hepatic or intestinal
differentiation, and the presence of these elements in a tumor with high AFP
levels. It is possible to have a slightly elevated AFP in a pure IT if they have
evidence of hepatic or intestinal differentiation, but high levels would be
associated with a mixed germ cell tumor.
Treatment
Surgery
In a premenopausal patient, immature teratomas are typically confined to a
single ovary, and therefore unilateral oophorectomy and fertility-sparing
surgical staging should be performed. For a postmenopausal patient, a total
abdominal hysterectomy and bilateral salpingo-oophorectomy may be
performed along with complete staging. Contralateral involvement is rare,
and routine resection or wedge biopsy of the contralateral ovary is
unnecessary (4,434,435). Any lesions on the peritoneal surfaces should be
sampled and submitted for histologic evaluation. The most frequent site of
dissemination is the peritoneum and, much less commonly, the retroperitoneal
lymph nodes. Blood-borne metastases to organ parenchyma, such as the lungs,
liver, or brain, are uncommon. When present, they are usually seen in patients
with late or recurrent disease and most often in tumors that are poorly
differentiated (i.e., grade 3).
It is unclear whether extensive debulking enhances the response to combination
chemotherapy (440–442). These are chemosensitive tumors and the cure depends
on the prompt delivery of chemotherapy. Therefore, any surgical resection that is
potentially morbid and could delay chemotherapy should be resisted.
Chemotherapy
Patients with IA, grade 1 tumors have an excellent prognosis, and no
2636adjuvant therapy is required. For patients whose tumors are stage IA, highgrade, adjuvant chemotherapy has been generally recommended, although
there is evidence to support close surveillance (412–414,430–434).
Chemotherapy is indicated for patients who have ascites, regardless of tumor
grade. The standard approach is BEP (412,413,443–449). The GOG investigated
three cycles of BEP for patients with completely resected stages I, II, and III
ovarian germ cell tumors (412,413,449). Overall, the toxicity was acceptable, and
91 of 93 patients treated were clinically free of disease. The BEP regimen,
which is the standard of care for testicular cancer, is the most appropriate
chemotherapy regimen for nondysgerminomatous germ cells tumors of the
ovary. As these tumors can progress rapidly, treatment should be initiated as soon
as possible after surgery, preferably within 7 to 10 days (450). The combined
BEP regimen is the international standard of care, usually administered for three
cycles in completely resected disease or in the adjuvant setting and four cycles for
macroscopic residual disease.
The switch from VBP to BEP was prompted by the experience in patients
with testicular cancer, in which the replacement of vinblastine with etoposide
was associated with a better therapeutic index (i.e., equivalent efficacy and
lower morbidity), especially less neurologic and gastrointestinal toxicity. The
inclusion of bleomycin is particularly important those patients with
nondysgerminomatous germ cell tumors. In a randomized study of three cycles
of EP with or without bleomycin (EP vs. BEP) in 166 patients with germ cell
tumors of the testes, the BEP regimen had a relapse-free survival rate of 84%
compared with 69% for the EP regimen (p = 0.03) (425). Cisplatin appears to be
superior to carboplatin in the setting of metastatic germ cell tumors. One hundred
ninety-two patients with germ cell tumors of the testes were entered into a study
of four cycles of EP versus four cycles of EC. There were three relapses with the
EP regimen versus seven with the EC regimen, although the overall survival of
the two groups is identical (426). In view of these results, BEP is the preferred
treatment regimen for patients with ovarian germ cell tumors.
It is unclear whether adjuvant chemotherapy is indicated or required for all
patients with resected immature teratomas. Several reports support the successful
management of these patients with surgery alone and close surveillance
(442,451). In the largest series, an Intergroup study from the Pediatric Oncology
Group and the Children’s Cancer Group, 73 children with immature teratoma (44
of ovarian origin) underwent surgery followed by surveillance. With a median
follow-up of 35 months, the overall 3-year event-free survival rates for all patients
and those with ovarian teratomas were 93% and 100%, respectively. Thirteen of
the 44 girls with an immature ovarian teratoma had microscopic foci of yolk sac
tumor in the teratoma; one developed recurrent disease and was successfully
2637treated with cisplatin-based chemotherapy. Eighty-two percent of the tumors were
grade 1 or 2; however, 92% of those with foci of yolk sac tumor were grade 2 or
3.
Second-Look Laparotomy or Laparoscopy
Second-look operation is not justified in patients who received adjuvant
chemotherapy, because chemotherapy in these patients is effective (431,432). In
the absence of any residual disease, there is no indication for second-look
laparotomy or laparoscopy. In patients with radiographic evidence of residual
tumor after surgery and chemotherapy, this may represent residual germ cell
tumor, benign teratoma or more commonly, necrotic tissue in a patient whose
tumor markers have normalized.
Second-look laparotomy or laparoscopy in patients with macroscopic residual
disease at the start of chemotherapy should be considered, as patients with
residual mature teratoma and are at risk of growing teratoma syndrome, an
uncommon complication of immature teratomas (452,453). Cancers can arise at a
later date in residual mature teratoma. It is important to resect or biopsy any
residual mass and exclude persistent disease because further chemotherapy may
be indicated. The principles of surgery are based on the much larger experience of
surgery in males with residual masses following chemotherapy for germ cell
tumors with a component of immature teratoma (454). Mathew et al. reported
their experience of laparotomy in assessing the nature of postchemotherapy
residue in ovarian germ cell tumors. Sixty-eight patients completed combination
chemotherapy with cisplatin regimes, and 35 had radiologic residual masses.
Twenty-nine of these 35 patients underwent laparotomy and 3 patients had viable
tumor, 7 immature teratomas, 3 mature teratoma, and 16 necrosis or fibrosis.
None of the patients with dysgerminoma, embryonal carcinoma, absence of
teratoma element in the primary tumor, and radiologic residual mass of less than 5
cm had viable tumor, whereas all patients with tumors containing the teratoma
component initially had residual tumor, strengthening the case for surgery in
patients with immature teratoma and any residual mass (455,456).
Prognosis
The most important prognostic feature of the immature teratoma is the
grade (2,423). The stage of disease and the extent of tumor at the initiation of
treatment have an impact on the curability of the lesion. Overall, the 5-year
survival rate for patients with all stages of pure immature teratomas is 70% to
80%, and it is 90% to 95% for patients with surgically staged, stage I lesions
(430,433,457).
Endodermal Sinus Tumors
2638[12] Endodermal sinus tumors (EST) are also referred to as yolk sac
carcinomas because they are derived from the primitive yolk sac (2,4). They
are the third most frequent malignant germ cell tumors of the ovary. ESTs
occur in patients with a median age of 16 to 18 years (2,4,458). About one-third
of the patients are premenarcheal at the time of diagnosis. Abdominal or pelvic
pain is the most frequent initial symptom, occurring in about 75% of patients,
whereas an asymptomatic pelvic mass is documented in 10% of patients (396).
Pathology
The gross appearance of an EST is soft grayish-brown. Cystic areas caused by
degeneration or necrosis are present in these rapidly growing lesions. The capsule
is intact in most cases.
The EST is unilateral in 100% of cases; thus, biopsy of the opposite ovary
is contraindicated. The association of such lesions with gonadal dysgenesis must
be appreciated, and chromosomal analysis should be performed preoperatively in
premenarcheal patients (4).
Microscopically, the characteristic feature is the endodermal sinus, or the
Schiller–Duval body (Fig. 39-22). The cystic space is lined with a layer of
flattened or irregular endothelium into which projects a glomerulus-like tuft with
a central vascular core. These structures vary throughout the tumor, and the
reticular, myxoid elements simulate undifferentiated mesoblast. The lining of the
papillary infolding and the cavity is irregular, with an occasional cell containing
clear, glassy cytoplasm, simulating the hobnail appearance of the epithelium in
clear cell tumors. There is a possible association of EST with dysgerminoma in
mixed germ cell tumors (2,4).
FIGURE 39-22 Yolk sac tumor of the ovary. Note the classic Schiller–Duval body with its
central vessel and mantle of endoderm.
Most EST secrete AFP and, rarely, alpha-1 antitrypsin (AAT). AFP can be
demonstrated in the tumor by immunohistochemistry. There is a good correlation
between the extent of disease and the level of AFP, although discordance can
occur. The serum level of these markers, particularly AFP, is useful in monitoring
the patient’s response to treatment (458–462).
Treatment
Surgery
The treatment of the EST consists of surgical exploration, unilateral
salpingo-oophorectomy, and a frozen section for diagnosis. The addition of a
hysterectomy and contralateral salpingo-oophorectomy does not alter the
outcome and is not indicated (460). Any gross metastases should be removed, if
possible, but thorough surgical staging may be omitted because all patients need
2640chemotherapy. At surgery, the tumors tend to be solid and large, ranging in size
from 7 to 28 cm (median, 15 cm) in the GOG series (449). Bilaterality does not
occur, and the other ovary is involved with metastatic disease only when there are
other metastases in the peritoneal cavity. Most patients have early-stage disease:
71%, stage I; 6%, stage II; and 23%, stage III (462).
Chemotherapy
All patients with ESTs are treated with either adjuvant or therapeutic
chemotherapy. Before the routine use of combination chemotherapy for this
disease, the 2-year survival rate was only about 25%. The introduction of the VAC
regimen, improved survival rates to 60% to 70%, indicating the chemosensitivity
of most of these tumors (444,445). With conservative surgery and adjuvant
chemotherapy, fertility can be preserved as with other germ cell tumors.
Cisplatin-containing combination chemotherapy with three to four cycles
of BEP should be used as primary chemotherapy for EST. The GOG
protocols used three to four treatment cycles given every 3 weeks (449,463). The
number of cycles is dependent on prognostic factors including whether there is
bulky residual disease after surgery and the site of metastases.
Rare Germ Cell Tumors of the Ovary
Embryonal Carcinoma
[12] Embryonal carcinoma of the ovary is an extremely rare tumor that is
distinguished from a choriocarcinoma of the ovary by the absence of
syncytiotrophoblastic and cytotrophoblastic cells. The patients are very young;
ages ranged between 4 and 28 years (median, 14 years) in two series (464). Older
patients were reported (465). Embryonal carcinomas may secrete estrogen, with
the patient exhibiting symptoms and signs of precocious pseudopuberty or
irregular bleeding (2). The clinical picture is otherwise similar to that of the EST.
The primary lesions tend to be large, and about two-thirds are confined to one
ovary at the time of diagnosis. These lesions frequently secrete AFP and hCG,
which are useful for following the response to subsequent therapy (461). The
treatment of embryonal carcinomas is the same as for the EST (i.e., a
unilateral oophorectomy followed by combination chemotherapy with BEP)
(413,449).
Choriocarcinoma of the Ovary
Pure nongestational choriocarcinoma of the ovary is an extremely rare tumor.
Histologically, it has the same appearance as gestational choriocarcinoma
metastatic to the ovaries (466). Most patients with this cancer are younger than 20
years. The presence of hCG can be useful in monitoring the patient’s response to
2641treatment. In the presence of high hCG levels, isosexual precocity occurs in
about 50% of patients whose lesions appear before menarche (466,467).
There are only limited reports on the use of chemotherapy for nongestational
choriocarcinomas, but complete responses were reported with the MAC
(methotrexate, actinomycin D, and cyclophosphamide) regimen used in a manner
described for gestational trophoblastic disease (see Chapter 41) (435).
Alternatively, the BEP regimen can be used. The prognosis of ovarian
choriocarcinomas is poor, with most patients having metastases to organ
parenchyma at the time of diagnosis.
Polyembryoma
Polyembryoma of the ovary is another extremely rare tumor, which is composed
of embryoid bodies. This tumor replicates the structures of early embryonic
differentiation (i.e., the three somatic layers: endoderm, mesoderm, and ectoderm)
(2,399). They tend to occur in very young, premenarcheal girls with signs of
pseudopuberty and elevated AFP and hCG levels. The same principles of
management apply (399,468).
Mixed Germ Cell Tumors
Mixed germ cell malignancies of the ovary contain two or more elements of
the lesions described above. In one series, the most common component of a
mixed malignancy was dysgerminoma, which occurred in 80%, followed by EST
in 70%, immature teratoma in 53%, choriocarcinoma in 20%, and embryonal
carcinoma in 16% (468). The most frequent combination is a dysgerminoma
and an EST. The mixed germ cell tumors may secrete either AFP, hCG,
both, or neither of these markers, depending on the components.
These tumors should be managed with BEP combination chemotherapy. The
serum marker, if positive initially, may become negative during chemotherapy,
but this finding may reflect regression of only a particular component of the
mixed lesion.
The most important prognostic features are the size of the primary tumor
and the relative size of its most malignant component (469). For stage IA
tumors smaller than 10 cm, survival is 100%. Tumors composed of less than onethird EST, choriocarcinoma, or grade 3, immature teratoma have an excellent
prognosis, but it is less favorable when these components constitute most of the
mixed lesions.
Late Effects of Treatment of Malignant Germ Cell Tumors of the Ovary
Although there are substantial data regarding late effects of cisplatin-based
therapy in men with testicular cancer, there is much less information available for
2642women with ovarian germ cell tumors. However, it is likely that the late effects
will be similar to men treated with BEP and include renal and gonadal
dysfunction, neurotoxicity, cardiovascular toxicity, and secondary malignancies.
Gonadal Function
An important cause of infertility in patients with ovarian germ cell tumors is
unnecessary bilateral salpingo-oophorectomy and hysterectomy. Although
temporary ovarian dysfunction or failure is common with platinum-based
chemotherapy, most women will resume normal ovarian function, and
childbearing is usually preserved (402,408). In one representative series of 47
patients treated with combination chemotherapy for germ cell malignancies,
91.5% resumed normal menstrual function, and there were 14 healthy live births
and no birth defects (423). Factors such as older age at the initiation of
chemotherapy, greater cumulative drug dose, and longer duration of therapy all
have an adverse effect on future gonadal function.
Secondary Malignancies
An important cause of late morbidity and mortality in patients receiving
chemotherapy for germ cell tumors is the development of secondary tumors.
Etoposide in particular was implicated in the development of treatmentrelated leukemias (470,471).
The chance of developing treatment-related leukemia following etoposide is
dose related. The incidence of leukemia is approximately 0.4% to 0.5%
(representing a 30-fold increased likelihood) in patients receiving a cumulative
etoposide dose of less than 2,000 mg/m2, compared with as much as 5%
(representing a 336-fold increased likelihood) in those receiving more than 2,000
mg/m2 (470). In a typical three- or four-cycle course of BEP, patients receive a
cumulative etoposide dose of 1,500 or 2,000 mg/m2, respectively.
Despite the risk of secondary leukemia, risk–benefit analyses concluded that
etoposide-containing chemotherapy regimens are beneficial in advanced germ cell
tumors; one case of treatment-induced leukemia would be expected for every 20
additionally cured patients who receive BEP as compared with platinum,
vincristine, bleomycin (PVB). The risk–benefit balance for low-risk disease, or for
high-dose etoposide in the recurrence setting, is less clear (471–473).
Surveillance Versus Immediate Adjuvant Chemotherapy in Stage I Germ Cell Tumors
Close surveillance is a well-accepted and standard approach to the
management of young men with apparent stage I testicular germ cell tumors.
There is a large body of evidence to support this approach, and guidelines on
surveillance protocols (474). Although as many as 20% to 30% of patients will
2643relapse, almost all will be cured using second-line chemotherapy with BEP,
and the potential adverse effects of chemotherapy can therefore be avoided in
most patients. Although this is a very common approach to management of young
men with stage I testicular germ cell tumors, it has not been widely adopted in
females with ovarian germ cell tumors in the United States. In the United
Kingdom, all women with stage IA malignant ovarian germ cell tumors are
offered surveillance regardless of histologic subtype. However, prior to making
this recommendation there is close scrutiny of operative findings, central
pathologic review, measurement of tumor markers, and whole-body imaging to
ensure that the staging is correct. Surveillance includes regular clinical review,
physical examination, interval imaging, and tumor marker assessments (hCG,
AFP, and LDH). The frequency of surveillance with tumor marker monitoring is
highest early on, as most relapses occur within 2 years.
The Charing Cross Group initially reported a prospective study of 24
patients with stage IA ovarian germ cell tumors who were also enrolled in a
surveillance program. The group consisted of nine patients (37.5%) with
dysgerminoma, nine (37.5%) with pure immature teratoma, and six (25%) with
EST (with or without immature teratoma). Treatment consisted of surgical
resection without adjuvant chemotherapy, followed by a surveillance program of
clinical, serologic, and radiologic review. A second-look operation was
performed, and all patients, but one, were alive and in remission after a
median follow-up of 6.8 years. The 5-year overall survival was 95%, and the 5-
year disease-free survival was 68%. Eight patients required chemotherapy for
recurrent disease or second primary ovarian germ cell tumor. This included three
patients with grade II immature teratoma, three patients with dysgerminoma, and
two patients with dysgerminoma who developed a contralateral dysgerminoma
4.5 and 5.2 years after their first tumor. All but one, who died of a pulmonary
embolus, were successfully salvaged with chemotherapy. The same group
updated its experience and reported on the safety of the ongoing surveillance
program of all stage IA female germ cell tumors (474). Thirty-seven patients
(median age 26, range 14 to 48 years) with stage I disease were referred to Mount
Vernon and Charing Cross Hospitals between 1981 and 2003. Patients underwent
surgery and staging followed by intense surveillance, which included regular
tumor markers and imaging. The median period of follow-up was 6 years.
Relapse rates for stage IA nondysgerminomatous tumors and
dysgerminomas were 8 of 22 (36%) and 2 of 9 (22%), respectively. In
addition, one patient with mature teratoma and glial implants relapsed. Ten of
these 11 patients (91%) were successfully cured with platinum-based
chemotherapy. Only one patient died from chemoresistant disease. All relapses
occurred within 13 months of initial surgery. The overall disease-specific
2644survival of malignant ovarian germ cell tumors was 94%. If this approach is
considered, then the Charing Cross surveillance protocol should be followed.
Sex Cord–Stromal Tumors
Sex cord–stromal tumors of the ovary account for about 5% to 8% of all
ovarian malignancies (2,4,395,396,475–481). This group of ovarian neoplasms
is derived from the sex cords and the ovarian stroma or mesenchyme. The tumors
usually are composed of various combinations of elements, including the
“female” cells (i.e., granulosa and theca cells) and “male” cells (i.e., Sertoli and
Leydig cells), and morphologically indifferent cells. A classification of this group
of tumors is presented in Table 39-8.
Granulosa–Stromal Cell Tumors
[13] Granulosa cell tumors are the most common type of malignant ovarian
sex cord–stromal tumor and make up 2% to 5% of all ovarian malignancies
Granulosa–stromal cell tumors include granulosa cell tumors, thecomas, and
fibromas. They account for 70% of ovarian sex cord–stromal tumors.
Granulosa cell tumors are considered to be a low-grade malignancy.
The majority of granulosa cell tumors are adult (95%) with juvenile granulosa
cell tumors being much less common (5%). Adult granulosa cell tumors almost
always occur in postmenopausal women while juvenile granulosa cell tumors are
diagnosed in women under 30 years of age and may be seen in prepubertal girls in
5% of cases (478). [13] Granulosa cell tumors are bilateral in only 2% of patients
(482).
Table 39-8 Sex Cord–Stromal and Steroid Cell Tumors
1. Granulosa-stromal cell tumors
A. Granulosa cell tumor
B. Tumors in thecoma–fibroma group
a. Thecoma
b. Fibroma
b. Unclassified
2. Androblastomas; Sertoli–Leydig cell tumors
A. Well differentiated
2645a. Sertoli cell tumor
b. Sertoli–Leydig cell tumor
c. Leydig cell tumor; hilus cell tumor
B. Moderately differentiated
C. Poorly differentiated (sarcomatoid)
D. With heterologous elements
3. Gynandroblastoma
4. Sex cord tumor with annular tubules
5. Sex cord–stromal tumors, unclassified
6. Steroid cell tumors
A. Stromal luteoma
B. Leydig cell tumor
C. Steroid cell tumor, not otherwise classified
Pathology
Granulosa cell tumors range from a few millimeters to 20 cm or more in diameter.
The tumors are rarely bilateral and have a smooth, lobulated surface. The solid
portions of the tumor are granular, frequently trabeculated, and yellow or grayyellow in color. After clear cell carcinoma, the granulosa-theca cell tumor is
probably the most inaccurately diagnosed tumor of the female gonad. Of 477
ovarian tumors from the Emil Novak Ovarian Tumor Registry diagnosed initially
as granulosa-theca cell tumors, almost 15% were reclassified after histologic
review. The FOXL2 gene is mutated in almost all adult granulosa cell tumors. It
plays a role in the development of normal granulosa cells and mutations in this
gene have been found in up to 97% of adult granulomas cell tumors. Molecular
testing for mutations in the FOXL2 gene may help to improve the diagnostic
accuracy among patients with sex cord–stromal tumors (483,484). Tumors
misdiagnosed as granulosa cell tumors included primary or metastatic
carcinomas, teratoid tumors, and poorly differentiated mesothelial tumors (475).
A Norwegian study found that almost 30% of adult granulosa cell tumors had
been misdiagnosed after reviewing the pathology and testing for FOXL2
mutations, which raises questions about the reliability of historical series.
2646Juvenile granulosa cell tumors, so named because of their tendency to occur in
younger patients, feature rounder, more hyperchromatic nuclei, and may contain
numerous mitotic figures. The presence of large, irregular follicle spaces is an
additional distinguishing feature of the juvenile granulosa cell tumor.
The classic adult granulosa cell is round or ovoid with scant cytoplasm. The
nucleus contains compact, finely granular chromatin and is either euchromatic or
hypochromatic (4). Better-differentiated granulosa cell tumors may have a variety
of patterns including macrofollicular, microfollicular, trabecular, solid-trabecular,
and insular while less-differentiated tumors have a more diffuse pattern described
as sarcomatoid. “Coffee bean” grooved nuclei are characteristic; mitotic figures
may be present, but numerous mitotic figures should prompt consideration for
poorly differentiated or undifferentiated carcinoma. In the most common
variety, the adult granulosa cells show a tendency to arrange themselves in
small clusters or rosettes around a central cavity, so there is a resemblance to
primordial follicles (i.e., Call–Exner bodies) (Fig. 39-23). The stroma is similar
to the theca and may be luteinized. In children and adolescents, the granulosa cell
tumors are often cystic, contain luteinized cells, and can be associated with
precocious puberty. The adult granulosa cell tumor tends to occur in older women
and the juvenile tumor in children and young women, with the diagnosis not
being based on age of presentation, but on histology. Adult granulosa cell tumors,
but not juvenile granulose cell tumors, harbor a somatic mutation in the FOXL2
gene (483).
FIGURE 39-23 Granulosa cell tumor of the ovary. Note the classic Call–Exner bodies
with a minimal stromal component in this tumor of folliculoid pattern (arrow points to an
example).
Diagnosis
About 70% of granulosa cell tumors secrete estrogen or androgens.
Inhibin is secreted by some adult granulosa cell tumors and is a useful
marker for the disease (485–489). Inhibin is a peptide hormone that is produced
by granulosa cells and plays a role in regulation of FSH secretion. Inhibin exists
in two different isoforms: inhibin A and inhibin B. Although some
laboratories only perform testing for inhibin A, serum levels of inhibin B are
more frequently elevated (490).
Inhibin levels can be used to monitor patients during follow-up or to assess
response to treatment. The lead-time between inhibin levels rising and
documented recurrence is about 12 months.
An elevated serum inhibin level in a premenopausal woman presenting with
2648amenorrhea and infertility is suggestive of a granulosa cell tumor (491). Seventyfive percent of women with AGCT’s also have an elevated anti-müllerian
hormone preoperatively and AMH has a >90% sensitivity in detecting recurrence.
Juvenile Granulosa Cell Tumors
Juvenile granulosa cell tumors of the ovary are rare and constitute less than
5% of ovarian tumors in childhood and adolescence (492). Most juvenile
granulosa cell tumors are clinically benign; only about 10% recur and when they
do, it is generally within 5 years of the initial diagnosis. Of the rare prepubertal
juvenile GCTs, 75% are associated with sexual pseudoprecocity because of
the estrogen secretion (477).
About 90% are diagnosed in stage I, and they have a favorable prognosis. The
juvenile subtype behaves less aggressively than the adult type. Only about 10% of
juvenile granulosa cell tumors are malignant and late relapse is unusual.
Advanced-stage tumors can be treated with platinum-based combination
chemotherapy (e.g., BEP) (493,494).
Adult Granulosa Cell Tumors
Low-grade endometrial cancer occurs in association with adult granulosa
cell tumors in at least 5% of cases, and 25% to 50% are associated with
endometrial hyperplasia (2,466,475–478,483). Most reproductive-age patients
have menstrual irregularities or secondary amenorrhea, and, frequently, cystic
hyperplasia of the endometrium. Abnormal uterine bleeding is often the initial
symptom for postmenopausal women. The estrogen secretion in these patients can
be sufficient to stimulate the development of endometrial cancer.
The other symptoms and signs of granulosa cell tumors are nonspecific and the
same as most ovarian malignancies. Ascites is present in about 10% of cases, and,
rarely, a pleural effusion is present (475–478). Granulosa tumors tend to be
hemorrhagic; occasionally, they rupture and produce a hemoperitoneum.
Adult granulosa cell tumors are stage I at diagnosis in 90% of patients and
are associated with a very good prognosis, but may recur 5 to 30 years after
initial diagnosis (477). The tumors may spread hematogenously, and metastases
can develop in the lungs, liver, and brain years after initial diagnosis. Malignant
thecomas are extremely rare, and their signs and symptoms, management, and
outcome are similar to those of the granulosa cell tumors (475).
Treatment
The treatment of granulosa cell tumors depends on the age of the patient and the
extent of disease. For most patients, surgery alone is sufficient primary therapy;
radiation and chemotherapy are reserved for the treatment of recurrent or
2649metastatic disease (478–481,483,485–487,492,495–497).
Surgery
Because granulosa cell tumors are bilateral in only about 2% of patients, a
unilateral salpingo-oophorectomy is appropriate therapy for stage IA tumors in
children or in women of reproductive age (476). At the time of laparotomy or
laparoscopy, if a granulosa cell tumor is identified by frozen section, a staging
operation is performed, including an assessment of the contralateral ovary. If the
opposite ovary appears enlarged, it should be sampled for biopsy. For
perimenopausal and postmenopausal women for whom ovarian preservation is
not important, a hysterectomy and bilateral salpingo-oophorectomy should be
performed. For premenopausal patients in whom the uterus is left in situ, an
endometrial biopsy should be performed because of the possibility of a
coexistent adenocarcinoma of the endometrium (478).
Radiation Therapy
There is no evidence to support the use of adjuvant radiation therapy for
granulosa cell tumors, although pelvic irradiation may help to palliate isolated
pelvic recurrences (478,495).
Chemotherapy
[13] There is no evidence that adjuvant chemotherapy will prevent
recurrence of disease and improve prognosis (497–500). Patients with
metastatic disease at initial presentation or with recurrent disease may benefit
from chemotherapy. Although the data are inconclusive, BEP or CP are the most
commonly used regimens in selected patients with stage III or IV tumors or
recurrent disease (493). In a GOG study, 37% (14 of 30) patients treated with
BEP had a negative second-look laparotomy, and these patients had a median
time to progression of 24.4 months (494). The GOG is performing a randomized
phase II trial comparing BEP with the combination of paclitaxel and carboplatin
for patients with newly diagnosed and chemo-naïve recurrent/metastatic sex cord–
stromal tumors of the ovary. Taxanes and bevacizumab are active in AGCT’s.
The Alienor trial has recently completed recruitment and randomized patients
with recurrent/metastatic sex cord–stromal tumors to either paclitaxel alone or in
combination with bevacizumab and the results are eagerly awaited. Granulosa cell
tumors are potentially hormonally responsive, with about 30% of granulosa
tumors expressing estrogen receptors and almost 100% expressing progesterone
receptors. Hormonal agents such as progestins or luteinizing hormone–releasing
hormone agonists or aromatase inhibitors have been used to treat these patients
(501–505). There are case reports of durable response to aromatase inhibitors in
patients with metastatic granulosa cell tumors who received multiple prior
2650treatment (503). Small clinical series and case reports indicated that luteinizing
hormone– releasing hormone agonists had a 50% response rate in 13 patients,
while 4 of 5 patients in the literature responded to a progestational agent. Two
case series reported durable responses in a total of 6 patients receiving aromatase
inhibitors among those who progressed on or were intolerant of chemotherapy
(502–505). There are fewer than 100 patients reported in the literature who have
received hormonal therapies and typically these have been individual case reports
or small retrospective series that are subject to bias. The role of hormonal therapy
remains uncertain.
Adult granulosa cell tumors have a prolonged natural history and a
tendency toward late relapse, reflecting their low-grade biology. Ten-year
survival rates of about 90% are reported, with 20-year survival rates dropping to
75% (476–478,491,493). Most histologic types have the same prognosis, but
patients with the more poorly differentiated diffuse or sarcomatoid type tend to do
worse (475).
The DNA ploidy of the tumors is correlated with survival. Holland et al.
reported DNA aneuploidy in 13 of 37 patients (35%) with primary adult
granulosa cell tumors (498). The presence of residual disease is the most
important predictor of PFS, but DNA ploidy is an independent prognostic factor.
Patients with residual-negative DNA diploid tumors had a 10-year PFS of
96%.
Sertoli–Leydig Tumors
Sertoli–Leydig tumors occur most frequently in the third and fourth decades
of life; 75% of these tumors are seen in women younger than 40 years. These
neoplasms are extremely rare and account for less than 0.2% of ovarian cancers
(2,506,507). Sertoli–Leydig cell tumors are most frequently low-grade
malignancies; a poorly differentiated variety may behave more aggressively (Fig.
39-24) (506–508).
The tumors typically produce androgens, and clinical virilization is noted
in 70% to 85% of patients (508). Signs of virilization include oligomenorrhea
followed by amenorrhea, breast atrophy, acne, hirsutism, clitoromegaly,
deepening of the voice, and a receding hairline. Measurement of plasma
androgens may reveal elevated testosterone and androstenedione, with normal or
slightly elevated dehydroepiandrosterone sulfate (2,509). Rarely, the Sertoli–
Leydig tumor is associated with manifestations of estrogenization (i.e., isosexual
precocity, irregular or postmenopausal bleeding). Sertoli–Leydig tumors are
associated with somatic mutations in the DICER1 gene (510).
FIGURE 39-24 Sertoli–Leydig cell tumor of the ovary. Note the aggregates of
eosinophilic Leydig cells in the stroma adjacent to Sertoli cell tubules.
Treatment
Because these low-grade lesions are rarely bilateral (<1%), the usual
treatment is unilateral salpingo-oophorectomy and evaluation of the
contralateral ovary for patients who are in their reproductive years (4,478).
For older patients, hysterectomy and bilateral salpingo-oophorectomy are
appropriate (506,507).
There are insufficient data to document the utility of radiation or chemotherapy
for patients with persistent disease, but some responses in patients with
measurable disease were reported with pelvic irradiation and the VAC
chemotherapy regimen (4,511–515).
Prognosis
The 5-year survival rate is 70% to 90%, and recurrences thereafter are
uncommon (4,509,511–515). Most fatalities occur in the presence of poorly
differentiated tumors.
2652Uncommon Ovarian Cancers
There are several varieties of malignant ovarian tumors that together constitute
only 0.1% of ovarian malignancies (2). Two of these lesions are the lipoid (or
lipid) cell tumors and the primary ovarian sarcomas.
Steroid Cell Tumors
Steroid cell tumors account for less than 1% of ovarian neoplasms (2). Most are
associated with virilization and, occasionally, with obesity, hypertension, and
glucose intolerance, reflecting corticosteroid secretion. Rare cases of estrogen
secretion and isosexual precocity have been reported.
Most of these tumors have benign or low-grade behavior, but about 20%,
most of which are initially larger than 8 cm in diameter, may metastasize.
Metastases are usually in the peritoneal cavity but can occur at distant sites,
including the liver. The primary treatment is surgical removal of the ovary. There
are no data regarding the effectiveness of radiation or chemotherapy for this
disease.
Sarcomas
Carcinosarcomas (malignant mixed mesodermal tumors) of the ovary are
uncommon. Clinical, morphologic, and molecular data suggest that they are
monoclonal and that both epithelial and mesenchymal components are derived
from a single uncommitted, totipotent cell which, after transformation, has
proliferated toward separate differentiation lineages. Carcinosarcomas are thought
to result from epithelial–mesenchymal transition (EMT) characterized by
epithelial plasticity with transdifferentiation toward a mesenchymal cell type.
Most tumors are heterologous, and 80% occur in postmenopausal women. The
signs and symptoms are similar to those of most ovarian malignancies. These
tumors are biologically aggressive, and most patients have evidence of metastases
at presentation. They are treated either with CP or ifosfamide and cisplatin, or
anthracycline-based combination regimens, but in general have a poor prognosis.
Small Cell Carcinoma, Hypercalcemic Type
This rare tumor occurs at an average age of 24 years (range 2 to 46 years)
(516). The tumors are typically unilateral. Approximately two-thirds of the
tumors are accompanied by paraendocrine hypercalcemia. This tumor
accounts for one-half of all of the cases of hypercalcemia associated with ovarian
tumors. About 50% of the tumors have spread beyond the ovaries when they are
diagnosed (516). Small cell carcinoma, hypercalcemic type is characterized by
germline or somatic mutations in SMARCA4. Germline and somatic SMARCA4
mutations characterize small cell carcinoma of the ovary, hypercalcemic type.
2653Similar mutations have been described in rhabdoid tumors and it has been
proposed that small cell ovarian cancers should be considered to be ovarian
rhabdoid tumors and treated as such (517,518).
Immunohistochemical stains are helpful to differentiate this tumor from a
lymphoma, leukemia, or sarcoma.
The management of these malignancies consists of surgery followed by
platinum-based chemotherapy, radiation therapy, or both. It has been
suggested that these patients may benefit from aggressive combination
chemotherapy regimens that have been used in rhabdoid tumors at other
sites. In addition to the primary treatment of the disease, control of the
hypercalcemia may require aggressive hydration, loop diuretics, and the use of
bisphosphonates or calcitonin. The prognosis tends to be poor, with most patients
dying within 2 years of diagnosis, in spite of treatment.
METASTATIC TUMORS
[14] About 5% to 6% of ovarian tumors are metastatic from other organs,
most frequently from the female genital tract, the breast, or the
gastrointestinal tract (519–533). The metastases may occur from direct
extension of another pelvic neoplasm, by hematogenous or lymphatic spread, or
by transcoelomic dissemination, with surface implantation of tumors that spread
in the peritoneal cavity.
Gynecologic
Nonovarian cancers of the genital tract can spread by direct extension or
metastasize to the ovaries. Tubal carcinoma involves the ovaries secondarily
in 13% of cases, usually by direct extension (2,4). Under some circumstances, it
is difficult to know whether the tumor originated in the tube or the ovary, when
both are involved. Cervical cancer spreads to the ovary only in rare cases (<1%),
and most of these are of an advanced clinical stage or are adenocarcinomas.
Adenocarcinoma of the endometrium can spread and implant directly onto the
surface of the ovaries in about 5% of cases, but two synchronous primary tumors
probably occur with greater frequency (532). In these cases, an endometrioid
carcinoma of the ovary is usually associated with the adenocarcinoma of the
endometrium.
FIGURE 39-25 Metastatic carcinoma in the ovary. Note the linear, single-cell pattern
found in this metastatic breast carcinoma.
Nongynecologic
The frequency of metastatic breast carcinoma to the ovaries varies according
to the method of determination, but the phenomenon is common (Fig. 39-25).
In the autopsy data of women who died of metastatic breast cancer, the
ovaries were involved in 24% of cases, and 80% of the involvement was
bilateral (519–524). Similarly, when ovaries are removed to palliate advanced
breast cancer, about 20% to 30% of the cases reveal ovarian involvement, 60% of
those bilaterally. The involvement of ovaries in early-stage breast cancer seems to
be considerably lower, but precise figures are not available. In almost all cases,
ovarian involvement is occult or a pelvic mass is discovered after other metastatic
disease becomes apparent.
FIGURE 39-26 Krukenberg tumor of the ovary metastatic from a gastric carcinoma.
Malignant cells have discrete vacuoles that push nuclei eccentrically, giving a signet-ring
appearance. Mucicarmine stain demonstrates the cytoplasmic vacuoles to be mucin.
Krukenberg Tumor
Krukenberg tumors are characterized by mucin-filled signet ring cells and
make up 30% to 40% of metastatic cancers to the ovaries (Fig. 39-26)
(525,526,534). The primary tumor is frequently located in the stomach and less
commonly in the colon, appendix (the so-called goblet cell carcinoid), breast, or
biliary tract. Rarely, the cervix or the bladder may be the primary site.
Krukenberg tumors can account for about 2% of ovarian cancers, and they are
usually bilateral. They are associated with a very poor prognosis and most
patients die of their disease within 1 year. In some cases, a primary tumor is never
found.
Other Gastrointestinal Tumors
2656In other cases of metastasis from the gastrointestinal tract to the ovary, the
tumor does not have the classic histologic appearance of a Krukenberg
tumor; most of these are from the colon and, less commonly, the
pancreatobiliary tract, appendix, and small intestine (Fig. 39-27). As many as
1% to 2% of women with intestinal carcinomas will develop metastases to
the ovaries during the course of their disease (521). Before exploration for an
adnexal tumor in a woman older than 40 years, a barium enema or colonoscopy is
recommended to exclude a primary gastrointestinal carcinoma with metastases to
the ovaries, if there are any gastrointestinal symptoms. Metastatic colon cancer
can mimic a mucinous cystadenocarcinoma of the ovary histologically, and the
histologic distinction between the two can be difficult (520,521,526–530).
Tumors that arise in the appendix may be associated with ovarian metastasis and
can be confused with primary ovarian mucinous cancer. Pseudomyxoma peritonei
almost always is associated with an appendiceal primary and the appendix should
always be resected at surgery and carefully examined pathologically (526,530).
Melanoma
Rare cases of malignant melanoma metastatic to the ovaries have been
reported (533). In these circumstances, the melanomas are usually widely
disseminated. Removal would be warranted for palliation of abdominal or pelvic
pain, bleeding, or torsion. Malignant melanoma can arise, rarely, in a mature
cystic teratoma (535).
Carcinoid Tumors
Metastatic carcinoid tumors represent fewer than 2% of metastatic lesions to
the ovaries (536). Only about 2% of patients with primary carcinoids have
evidence of ovarian metastasis, and only 40% of them have the carcinoid
syndrome at the discovery of the metastatic carcinoid. In perimenopausal and
postmenopausal women explored for an intestinal carcinoid, it is reasonable to
remove the ovaries to prevent subsequent ovarian metastasis. The discovery of an
ovarian carcinoid should prompt a careful search for a primary intestinal lesion
(537).
FIGURE 39-27 Metastatic colorectal carcinoma in the ovary often has areas of necrotic
debris (so-called dirty necrosis) adjacent to partial gland structures showing a cribriform
pattern.
FIGURE 37-28 Carcinoma of the fallopian tube. This is a high-grade serous carcinoma
that has invaded the lamina propria of the tubal mucosa. Most primary fallopian tube
carcinomas arise in the distal (fimbria) portion of the fallopian tube.
Lymphoma and Leukemia
Lymphomas and leukemia can involve the ovary. When they do, the
involvement is usually bilateral (538–540). About 5% of patients with Hodgkin
lymphoma will have lymphomatous involvement of the ovaries, but this
involvement typically occurs with advanced-stage disease. With Burkitt
lymphoma, ovarian involvement is very common. Other types of lymphoma
involve the ovaries less frequently, and leukemic infiltration of the ovaries is
uncommon (540). Sometimes the ovaries can be the only apparent sites of
involvement of the abdominal or pelvic viscera with a lymphoma; if this
circumstance is found, a careful surgical exploration may be necessary.
Intraoperatively, a hematologist–oncologist should be consulted to determine the
need for these procedures if frozen section of a solid ovarian mass reveals a
lymphoma. Most lymphomas no longer require extensive surgical staging; biopsy
of enlarged lymph nodes should be performed. In some cases of Hodgkin
2659lymphoma, a more extensive evaluation may be necessary. Treatment involves
that of the lymphoma or leukemia. Removal of a large ovarian mass may improve
patient comfort and facilitate a response to subsequent radiation or chemotherapy
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