Cancer of the ovary

Definition
Ovarian cancer is a heterogeneous group of malignancies that arises from the var
ious cell types that compose the organ.
Epithelial
Nearly 90% of ovarian malignancies are classified as epithelial ovarian carcinom
as. These cancers arise from the germinal epithelium lining the ovary. Epithelia
l ovarian cancer can be further subdivided into several histologic cell types: s
erous, mucinous, endometrioid, clear cell, transitional, and undifferentiated ca
rcinomas. The risk of epithelial ovarian cancer increases with age and is found
predominantly in postmenopausal women. Epithelial tumors of low malignant potent
ial (borderline ovarian carcinoma) are a histologic variant that is less aggress
ive than their invasive epithelial counterparts, are found in younger women, and
are often confined to the ovary at diagnosis.
Germ Cell
Germ cell tumors account for approximately 5% of all ovarian cancers and recapit
ulate the developing embryo or placental structures. Histologic subtypes include
dysgerminoma (most common), endodermal sinus tumor, immature teratoma, chorioca
rcinoma, and embryonal carcinoma. Germ cell ovarian cancer can occur in women of
any age, but approximately 80% of these are diagnosed in women younger than 30
years.
Sex Cord Stromal
Sex cord stromal tumors, which account for approximately 5% of all ovarian cancers
, develop in the connective tissue and supporting ovarian stroma. These tumors a
re generally less aggressive and often produce steroid hormones, including estro
gen, progesterone, and testosterone. Some patients with hormone-producing tumors
present with signs and symptoms of steroid excess, such as vaginal bleeding or
hyperandrogenism.
Prevalence
According to the American Cancer Society, there were more than 23,000 new cases
of ovarian cancer and 14,000 deaths from the disease in the United States in 200
1. It is estimated that a woman has a 1% to 2% lifetime risk for developing ovar
ian cancer. Ovarian carcinoma is the fifth most frequent cause of cancer death i
n women, and one half of all cases occur in women older than 65 years.
Pathophysiology
The cause of ovarian cancer is poorly understood; however, risk factors and mode
of spread have been well described.
Risk Factors
The most significant risk factor for ovarian cancer is a positive family history
. When two or more first-degree relatives have or have had ovarian cancer, a wom
an's lifetime risk for developing this cancer is 7%. If a heritable cancer syndr
ome is identified, this lifetime risk can increase 17- to 50-fold. Three dominan
tly inherited mutations are known to be associated with the development of appro
ximately 10% of all ovarian carcinomas: breast-ovarian cancer syndrome, which is
associated with mutations in BRCA-1 and BRCA-2 genes; site-specific ovarian car
cinoma; and hereditary nonpolyposis colorectal cancer (Lynch syndrome II), which
is associated with mutations in mismatch repair genes. Advanced age is also ass
ociated with increased risk, whereas high parity, oral contraceptive use, tubal
ligation, and hysterectomy decrease one's risk.
Mode of Spread
Ovarian cancer usually spreads via cellular shedding into the peritoneal cavity
followed by implantation on the peritoneal surface. Local invasion of the bowel
and bladder is common in advanced cases. Tumor cells also may block diaphragmati
c lymphatics. The resulting impairment of lymphatic drainage of the peritoneum i
s believed to play a role in development of ascites in ovarian cancer. Transdiap
hragmatic spread and seeding of the pleura with pleural effusion are also common
in advanced cases.
Signs and Symptoms
Unfortunately, most patients with epithelial ovarian cancer experience few or no
symptoms until the disease has widely metastatasized. Manifesting symptoms usua
lly relate to an increasing intra-abdominal tumor burden and ascites and are oft
en vague, mimicking other more common diseases. Symptoms include fatigue; bloati
ng or a feeling of fullness; abdominal swelling or pain; early satiety; vague bu
t persistent gastrointestinal complaints, such as gas, nausea, and indigestion;
frequency or urgency of urination; change in bowel habits; unexplained weight lo
ss or gain; shortness of breath; and obstructive symptoms, such as nausea, vomit
ing, and constipation or obstipation.
On the other hand, borderline, germ cell, and sex cord stromal tumors are often co
nfined to the ovary at the time of diagnosis. They may be quite large at present
ation, and associated symptoms may be related to their large size. These masses
are occasionally detected during the screening pelvic examination. More commonly
, patients feel the mass themselves or present with symptoms of acute abdomen du
e to torsion of the adnexa or rupture of the tumor.
Diagnosis
A complete physical examination is the first step in the diagnosis of ovarian ca
ncer. Although pelvic examination is notoriously inefficient at detecting presym
ptomatic early ovarian cancer, a pelvic mass can often be palpated on examinatio
n in symptomatic patients. The finding of a unilateral or bilateral nonmobile (f
ixed) mass is characteristic of epithelial ovarian carcinoma. Cul-de-sac masses
may also be palpated with rectovaginal examination. Impingement of the rectum an
d compromise of lumen diameter can also be appreciated on this examination. Abdo
minal distention due to ascites is another common finding. The distended abdomen
is dull to percussion and an omental cake may be palpated in the upper abdomen.
Further diagnostic workup is necessary to establish extent of disease and exclu
de other causes of an adnexal mass, carcinomatosis, or ascites.
Imaging Studies
Transvaginal ultrasound uses higher-frequency sound waves to image the ovaries,
allowing improved morphologic characterization. The addition of color flow Doppl
er can further characterize the mass. A vascular mass with low resistive indices
supports a diagnosis of malignancy. Chest x-ray might indicate pleural effusion
, which is common in patients with ovarian carcinomatosis. CT scans of the abdom
en and pelvis with intravenous and oral contrast characterize tumor burden and a
ssist in evaluating other causes of adnexal mass, carcinomatosis, or ascites. Ot
her studies may be performed based on a patient's risk factors and symptoms at p
resentation. These include sigmoidoscopy, colonoscopy, or barium enema; upper ga
strointestinal endoscopy; and intravenous pyelogram.
Serum Tumor Markers
Serum tumor markers can assist in preoperative evaluation; however, their limita
tions must be understood so they are not misinterpreted or obtained inappropriat
ely. Serum testing is essential to monitoring treatment response for ovarian can
cer, but its usefulness as a diagnostic tool is hindered by poor sensitivity and
specificity. CA 125 is a high-molecular-weight glycoprotein that is expressed b
y more than 80% of nonmucinous epithelial ovarian cancers. Although elevated in
most women with advanced ovarian cancer, only 50% of patients with early-stage d
isease have an elevated CA 125, and mucinous epithelial ovarian cancers express
this antigen poorly. Furthermore, an elevated CA 125 is not specific for ovarian
cancer. Many nongynecologic and benign gynecologic conditions also are associat
ed with elevations in this serum antigen.
If nonepithelial ovarian cancer is suspected, other tumor markers may be useful
to assist in diagnosis. Alpha fetoprotein, human chorionic gonadotropin, and lac
tic dehydrogenase may be expressed by germ cell malignancies. If metastatic colo
n or pancreatic carcinoma is suspected, serum carcinoembryonic antigen and CA 19
-9 might also be elevated. Limitations in the sensitivity and specificity of the
se tests must be understood so they can be interpreted appropriately for each pa
tient.
Paracentesis
Malignant ascites is common in patients with metastatic epithelial ovarian carci
noma. However, ascites due to other conditions such as congestive heart failure
and cirrhosis must be ruled out by careful history and, if necessary, diagnostic
testing.
Although paracentesis may be performed for cytologic examination, diagnostic par
acentesis is not necessary for most patients if they have already been deemed ap
propriate for exploratory surgery and operative management. Furthermore, a negat
ive cytology from preoperative paracentesis does not exclude the possibility of
malignancy, and differentiating the site of tumor origin is rarely possible on c
ytologic examination. Large-volume therapeutic paracentesis, however, may be use
ful for palliation of symptoms of abdominal distention and associated respirator
y compromise due to diaphragmatic elevation.
Consultation
If a reasonably high probability for ovarian malignancy exists, consultation wit
h a gynecologic oncologist is essential to ensure appropriate preoperative couns
eling and preparation, operative management, and postoperative care.
Treatment
Ovarian cancer is initially managed with exploratory laparotomy to confirm the d
iagnosis and determine the extent of disease (surgical staging) and for tumor cy
toreduction.
Histologic Identification
The availability of reliable intraoperative frozen section is essential for opti
mal surgical decision making and management. For example, fertility-sparing surg
ery may be an option in select ovarian malignancies, such as germ cell tumors. I
n addition, although tumor debulking appears to have survival benefit in patient
s with ovarian malignancies, carcinomatosis related to an extraovarian primary t
umor does not necessarily benefit from such measures.
Surgical Staging
Accurate staging determines both treatment and prognosis. Inadequate surgical st
aging is a common problem in patients with presumed early-stage disease when the
operating surgeon does not perform the necessary procedures for adequate stagin
g. Therefore, it is imperative that the operating surgeon is familiar with stagi
ng criteria and has the surgical skills necessary to perform all the necessary s
teps of the staging procedure. FIGO staging criteria are described in Table 3.
Table 3: FIGO Staging for Ovarian Cancer
Stage Definition
I Growth limited to the ovaries
II Growth involves one or both ovaries with pelvic extension
III Tumor with peritoneal implants outside the pelvis, or positive retroperi
toneal or inguinal nodes, or both
IV Tumor involves one or both ovaries with distant metastasis
FIGO, International Federation of Gynecology and Obstetrics.
Cytoreduction
Metastatic implants of ovarian cancer typically involve the peritoneal surfaces
and are often amenable to resection along with the primary tumor mass. Although
not documented by any randomized clinical trial, optimal tumor cytoreduction (de
fined as removal of the primary tumor and all gross metastatic implants to less
than 1 cm residual in largest diameter) is believed to improve chemotherapy resp
onse and disease-free survival.3 To achieve these goals, surgical techniques suc
h as en bloc hysterectomy with resection of the rectosigmoid, small bowel, total
omentum, spleen, and possibly more may be necessary.
Aggressive resection of tumor does not appear to have any clinical advantage unl
ess all metastatic implants also can be optimally reduced. The operating surgeon
must exercise judgment as to whether optimal tumor reduction is possible and ca
n be safely achieved without incurring significant complications that would dela
y chemotherapy.
Adjuvant Treatment
Most, but not all, ovarian cancer patients require adjuvant chemotherapy after s
urgery. The importance of adequate surgical staging is evident when making decis
ions regarding adjuvant therapy in stage I disease. Most chemotherapy can be giv
en on an outpatient basis, although some regimens are given over a period of sev
eral days, requiring hospitalization.
For epithelial ovarian cancer, platinum-based therapy-either cisplatin or carbop
latin-in combination with paclitaxel has demonstrated the highest activity of al
l agents studied.4 These agents are generally given intravenously every 3 weeks
for a total of six courses. One study, however, suggests that continuation of si
ngle-agent paclitaxel for 12 courses is associated with an improved disease-free
survival. Although its impact on overall survival is uncertain, these findings
have the potential to significantly affect recommended adjuvant therapy for this
disease.