HIPPOKRATIA 2007, 11, 2: 63-66 HIPPOKRATIA 2007, 11, 2 63

REVIEW ARTICLE

Epithelial ovarian cancer. Risk factors, screening and the role of

Abstract
Epithelial ovarian cancer is the seventh most frequent cancer in European women. Many theories have been postulated
regarding the pathogenesis of ovarian cancer. Risk factors are not well defined, with the exception of low parity and
oral contraceptive use. Approximately 10% of ovarian cancer are hereditary, with BRCA1 and BRCA2 explaining the
majority (approximately 90%) of hereditary ovarian cancer cases. The lifetime risk varies between 15 and 66%, sug
gesting the existence of modifying genetic or environmental factors. Family history can be used to define women who
are at increased risk of ovarian cancer. Individuals at high risk are those with a first degree relative (mother, father,
sister, brother, daughter or son) affected by cancer. It must be noted that currently available tests do not attain the
aforementioned high level of sensitivity. Evidence suggest that presymptomatic screening by grey scale ultrasound (with
or without Doppler), CA125, pelvic examination, or combinations of these, are not effective in detecting tumors at an
early stage. Women identified as being at high risk of ovarian cancer can be offered prophylactic oophorectomy. The
decision whether or not to proceed to prophylactic oophorectomy is influenced by the fact that most women at increased
risk of ovarian cancer are also at increased risk of breast cancer and there is evidence that oophorectomy reduces breast
cancer in these cases. Hippokratia 2007; 11 (2): 63-66

Key words: prophylactic oophorectomy, CA125, hereditary cancer

Epithelial ovarian cancer is the seventh most fre screening and the value of prophylactic oophorectomy
quent cancer in European women, with 58000 new in high risk women for ovarian cancer.
cases and 38000 deaths only in 1995 1. The incidence
is low under the age of 40 years but increases rapidly Risk factors
after menopause. Reproductive factors
Despite new chemotherapy agents, the prognosis The protective effects of increasing parity and breast
remains fairly poor with a 5-year relative survival of feeding have been clearly established 6. Early age at
30% 2. The survival rate of women with early-stage menarche and late age at menopause increase the risk of
ovarian cancer is significantly higher than in women ovarian cancer only modestly, so that it can be assumed
with advanced-stage disease. Unfortunately, the vast that the length of menstrual life plays no crucial role in
majority of women with ovarian cancer are diagnosed the pathogenesis of the disease7. The risk of sub/infer
with advanced disease. Retrospective studies show tility on the risk of ovarian cancer has been extensively
that women with ovarian cancer present with non- studied. Most studies use attendance at an infertility
specific symptoms including abdominal pain and clinic as a marker for subfertility. The difficulty is the
bloating; changes in bowel habit, urinary and/or pelvic differentiation between the infertility itself and the
symptoms3-5. Cachexia is uncommon and women with treatment given at the clinic that may itself increase the
advanced disease often look surprisingly well. Most risk of ovarian cancer. A pooled analysis of case-control
women with ovarian cancer present with advanced studies, including 5207 cases and 7705 controls, sug
disease. Patients who present with non-specific gastro gested that specific biological causes of infertility, like
intestinal symptoms may be misdiagnosed as suffering endometriosis, rather than fertility drugs increased the
from irritable bowel syndrome. risk of ovarian cancer 8.
Many theories have been postulated regarding the
pathogenesis of ovarian cancer. Risk factors are not Oral contraceptives
well defined, with the exception of parity and oral con Several studies have consistently shown a decreased
traceptive use. Most theories concider the epidemiology risk of sporadic as well as familial ovarian cancer with the
of epithelial ovarian cancer, representing approximately use of oral contraception 9. The risk reduction is already
90% of all ovarian carcinomas. apparent after a few months of use and persists for years
This paper reviews recent studies on risk factors, after discontinuation. Low-dose formulations (<35g
64 DANIILIDIS A

ethinyl oestradiol) also confer a substantial risk reduction the lifetime risk when an individual has more than one af
10
. However, inconsistent results were reported for women fected relative is sparse but this is estimated at 3 to 23%22,
at risk of hereditary ovarian cancer. Although a case- 23
. Two types of ovarian cancer susceptibility genes have
control study in 207 BRCA heterozygotes11 reported a been identified: the breast and ovarian cancer tumour sup
significant 50% risk reduction, a case-control study in Jew pressor genes (BRCA1 and BRCA2) and the mismatch
ish women12 found that oral contraceptives significantly repair genes associated with Hereditary Nonpolyposis
decreased the risk of ovarian cancer only in non-carriers Colorectal Cancer (HNPCC) families24. Mutations in
but not in carriers of a BRCA mutation. the BRCA1 gene are estimated to confer a 30% lifetime
risk of ovarian cancer up to age 60 years and mutations
Oestrogen/hormone replacement therapy in BRCA2 gene are estimated to confer an ovarian risk
Hormone replacement therapy (HRT) has been in of 27% up to age 70 years22, 25. The mismatch repair genes
consistently linked to ovarian cancer. Recently, several confer an increased lifetime risk of ovarian cancer of ap
prospective studies13, 14 consistently found a small increase proximately 9 to 12% in addition to an increased risk of
of the risk, especially for long-term users of oestrogen endometrial cancer26, 27.
replacement therapy. Intermittently rather than con Approximately 10% of ovarian cancer are heredi
tinuously added progestins might further increase the tary, with BRCA1 and BRCA2 explaining the majority
risk15. (approximately 90%) of hereditary ovarian cancer cases.
The lifetime risk varies between 15 and 66%, suggesting
Diet the existence of modifying genetic or environmental
The evidence remains inconsistent; recent studies sug factors28.
gest that food items high in carotene and lycopene might
decrease the risk 16, whereas red meat was associated with Screening for ovarian cancer
an elevated risk 17. However, all positive studies were case- To be suitable for screening, a disease must have
control studies, and a recent prospective study found no a significant prevalence and be a significant cause of
association between the use of vitamins/carotenoids and mortality. There must be a preclinical phase that can be
ovarian cancer18. It might be that (part of) the reported detected, and the disease must be amenable to therapy.
associations in previous studies were caused by the vari The screening test itself must have sufficient specificity,
ous types of bias (especially recall bias) that can occur in sensitivity, and positive predictive value (PPV) to be ef
case-control studies. fective, and it must be cost-effective. In ovarian cancer, if
one assumes a prevalence of 50/ 100000, a test with 99%
Physical activity specificity and 100% sensitivity would yield only 1 in 21
It is hypothesized that recreational physical activ women with a positive screen actually having the disease
ity may reduce the risk of ovarian cancer by decreasing ( i.e. PPV= 4.8%). It must be noted that currently avail
oestrogen levels. However, although this reduced risk was able tests do not attain the aforementioned high level of
found by several studies, others found no or even a mod sensitivity.
est positive association. The most recent study19 with 327 Family history can be used to define women who
cases and 3129 controls, reported a small non-significant, are at increased risk of ovarian cancer 29. Individuals at
decrease in risk only for the highest category of recent high risk are those with a first degree relative (mother,
vigorous activity. father, sister, brother, daughter or son) affected by
cancer within a family that meets one of the following
Use of non-steroidal anti-inflammatory drugs criteria:
Non-steroidal anti-inflammatory drugs increase - two or more individuals with ovarian cancer, who
apoptosis in ovarian cancer cell lines and can inhibit ovu are first degree relatives of each other
lation19. In observational studies, the association between - one individual with ovarian cancer at any age, and
commonly used anti-inflammatory drugs and ovarian one with breast cancer diagnosed under age 50 years, who
cancer remains unclear. A Danish cohort study found are first degree relatives of each other
no evidence of a protective effect of paracetamol20, and - one relative with ovarian cancer at any age, and two
a case-control study conducted in the USA concluded with breast cancer diagnosed under 60 years, who are
that, although non-significant, the observed risk estimates connected by first degree relationships
appeared to be compatible with a small decrease of risk - known carrier of relevant cancer gene mutations
by regular (more than three times a week for a period of - untested first degree relative of a predisposing gene
at least 6 months) aspirin use21. carrier
- an individual with both breast and ovarian cancer
Hereditary ovarian cancer - three or more family members with colon cancer,
In most cases risk estimates are based on a family or two with colon cancer and one with stomach, ovarian,
history. The lifetime risk estimate for individuals who endometrial, urinary tract or small bowel cancer in two
have one first degree relative with ovarian cancer is two generations. One of these carriers must be diagnosed
to five times the population risk22, 23. Evidence regarding under the age of 50 years.
 HIPPOKRATIA 2007, 11, 2 65

Potential screening tests for ovarian cancer include ing may be appropriate for women whose family history
the bimanual pelvic examination, serum CA 125 and suggests hereditary ovarian cancer syndrome, due to very
ultrasound imaging. One systematic review30 and three high risk of cancer in this disorder.
small cohort studies 31-33 suggest that presymptomatic
screening by grey scale ultrasound (with or without Dop Role of prophylactic oophorectomy
pler), CA125, pelvic examination, or combinations of Women identified as being at high risk of ovarian
these, are not effective in detecting tumors at an early cancer can be offered prophylactic oophorectomy. The
stage. The pelvic examination, which can detect a variety decision whether or not to proceed to prophylactic
of gynecological disorders, is of unknown sensitivity in oophorectomy is influenced by the fact that most women
detecting ovarian cancer. Although pelvic examinations at increased risk of ovarian cancer are also at increased
can occasionally detect ovarian cancer, small, early- stage risk of breast cancer and there is evidence that oophorec
ovarian tumors are often not detected by palpation due tomy reduces breast cancer in these cases35.
to the deep anatomic location of the ovary. Thus, ovarian A woman with one first-degree relative with ovarian
cancers detected by pelvic examination are generally cancer has a lifetime risk of ovarian cancer about 5%.
advanced and associated with poor survival. The pelvic This is probably not high enough to warrant prophylactic
examination may also produce false positives when benign oophorectomy as an independent operative procedure
adnexal masses are found. with its attendant risks. The probability of a hereditary
Tumor markers have limited specificity. Mea ovarian cancer syndrome in a family pedigree increases
surement of serum CA 125 is the blood test most widely with the number of affected relatives, with the number
used to detect ovarian cancer. CA 125 is a glycoprotein of affected generations and with young age of onset of
antigen. Approximately 80% of patients with advanced disease. Therefore, prophylactic oophorectomy should
ovarian cancer have elevated concentrations of CA125. be considered in these settings with careful weighing of
A maximum of only 50% of patients with clinically de the risks and potential benefits. Prophylactic oophorec
tectable stage I disease have elevated CA 125 levels. tomy performed in women undergoing abdominal
Elevated concentrations of CA125 are associated with surgery for other indications such as benign uterine
malignant tumors of the pancreas, breast, lung, colon disease is also associated with a significant reduction in
and ovary. Menstruation and benign conditions such the risk of ovarian cancer. However, estrogen replace
as endometriosis, pelvic inflammatory disease, liver ment therapy should be discussed with the patient prior
disease and recent laparotomy can also be associated to the procedure.
with elevated CA125 levels. Despite its poor sensitivity The risk of ovarian cancer in women from families
and specificity, CA 125 is most useful for detecting and with hereditary ovarian cancer syndromes is sufficiently
monitoring non- mucinous epithelial tumours of the high to recommend prophylactic oophorectomy. Two
ovary. Limited data are available on the potential benefit complementary studies in BRCA 1/2 heterozygotes
of screening with serum CA 125 in women at inherited demonstrated that prophylactic oophorectomy can
risk of ovarian cancer. No clear evidence was identified reduce the risk of hereditary ovarian cancer as well as
as to whether screening in high risk groups has an impact breast cancer. In a prospective study of 170 carriers
on mortality from ovarian cancer. Ultrasound imaging with a mean follow up of 2 years34, one woman devel
has also been evaluated as a screening test for ovarian oped peritoneal cancer and three breast cancer in the
cancer. Transvaginal ultrasound (TVS) is currently the salpingo-oophorectomy group of 98 women. Three oc
preferred modality, since it is able to estimate ovarian cult stage I gynaeocological tumours were found at the
size, detect masses as small as 1cm, and distinguish solid time of prophylactic surgery. In the surveillance group
lesions from cysts. Transvaginal color- flow Doppler ul of 72 women, five women developed ovarian or peri
trasound can also identify vascular patterns associated toneal cancer and eight developed breast cancer. The
with tumors. However, specificity of ultrasonography is combined hereditary risk (HR) for ovarian cancer was
not adequate for use as a single screening modality. In 0.25 (95% CI 0.08- 0.74). In a multicentre retrospective
screening studies, the reported sensitivity and specificity study with a mean follow-up of almost 9 years36, 58 out
of transabdominal or transvaginal ultrasound were 50- of 292 carriers opting for surveillance developed ovarian
100% and 76-97% respectively. Studies have shown that cancer. Among 259 women undergoing prophylactic oo
routine ultrasound testing of asymptomatic women has phorectomy, two women developed primary peritoneal
a low yield in detecting ovarian cancer and generates cancer (HR 0.04; 95% CI 0.01- 0.16). In six women a
a large proportion of false-positive results that often stage I ovarian cancer was diagnosed at the time of
require diagnostic laparotomy or laparoscopy34. surgery. Breast cancer was diagnosed in 60 out of 142
There is no evidence to support routine screening with women opting for surveillance compared with 21 out of
any of the available methods in asymptomatic women. 99 women in the oophoretomy group, giving an HR of
Given the risks, inconvenience, and substantial costs of 0.47 (95% CI 0.29- 0.77).
follow-up testing, and the current lack of evidence that The risk-reducing potential of tubal ligation had al
screening reduces morbidity or mortality from ovarian ready been shown in sporadic ovarian cancer. In addition,
cancer, routine screening cannot be recomented. Screen a matched case-control study in 232 BRCA heterozygotes
66 DANIILIDIS A

with ovarian cancer and 232 carriers without the disease37 16. Bosetti C, Negri E, Franchesci S, et al. Diet and ovarian cancer risk:
showed that the adjusted odds ratio of developing ovar a case- control study in Italy. Int J Cancer 2001; 93: 911- 915
17. Fairfield KM, Hankinson SE, Rosner BA, et al. Risk of ova
ian cancer was 0.39 ( P=0.002) after tubal ligation. The
rian carcinoma and consumption of vitamins A, C and E and
biological mechanism is unclear. Hypothesis include specific carotenoids: a prospective analysis. Cancer 2001; 92:
the reduction of ovarian blood supply or a decreased 2318- 2326
retrograde transport of potential carcinogens through 18. Bertone ER, Newcomb PA, Willet WC, et al. Recreational
the fallopian tubes. physical activity and ovarian cancer in a population- based case-
control study. Int J Cancer 2002; 99: 431- 436
19. Rodriquez- Buford C, Barnes MN, Oelschlager DK, et al. Ef
Conclusions fects of non- steroidal anti- inflammatory agents ( NSAIDS) on
Standards of care of ovarian cancer are determined ovarian carcinoma cell lines: preclinical evalution of NSAIDS as
on the basis of all clinical data available for an individual chemopreventive agents. Clin Cancer Res 2002; 8: 202- 209
case and are the subject to change as scientific knowledge 20. Friis S, Nielsen GL, Mellemkjaer L, et al. Cancer risk in persons
and technology advance and patterns of care evolve. The receiving prescriptions for paracetamol: a Danish cohort study.
Int J Cancer 2002; 97: 96- 101
ultimate judgement regarding a particular counseling, 21. Akhmedkhanov A, Toniolo P, Zeleniuch- Jacquotte A, et al.
clinical procedure or treatment plan must be made by Aspirin and epithelial ovarian cancer. Prevent Med 2001; 33:
the doctor, following discussion of the options with 682- 687
the patient, in the light of the diagnostic and treatment 22. Thompson D, Easton DF. Cancer incidence in BRCA 1 mutation
choices available. carriers. J Natl Cancer Inst 2002; 94: 1358- 1365
23. Stratton JF, Pharoah P, Smith SK, Easton D, Ponder BA. A
systematic review and meta- analysis of family history and risk of
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