correlation between alcohol consumption and ovarian cancer
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THE CORRELATION BETWEEN ALCOHOL CONSUMPTION AND
RISK OF EPITHELIAL OVARIAN CANCER
Monica Raharjo
NIM: 030 09 157
Faculty of Medicine, Universitas Trisakti
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Jakarta, 2012
ABSTRACT
Ovarian cancer is the second most gynecologic malignancy in the world, including in
Indonesia. About 90% of all ovarian cancer are epithelial ovarian cancer which can be divided
into different histological subtypes which are serous, mucinous, endometrioid, clear cell,Brenner, and unclassified. The etiology of ovarian cancer is poorly understood but risk factors
include low parity, infertility, and diet. Alcohol consumption is thought to play a role in
ovarian carcinogenesis. Various studies have been done to assess the effect of alcohol
consumption on the risk of epithelial ovarian cancer. The results of these studies are not
consistent one to the other. One study found that alcohol consumption particularly wine has a
protective effect on epithelial ovarian cancer. Another study found that alcohol consumption
has no significant effect on epithelial ovarian cancer. Studies which found that alcohol
consumption of wine increases the risk of epithelial ovarian cancer, especially for serous type,
also exist. Even though there are many proposed hypothesis for the effects of alcohol
consumption on epithelial ovarian cancer, the correlation between alcohol consumption andepithelial ovarian cancer is still unclear. Further studies should be done.
Key Words: epithelial ovarian cancer, alcohol consumption, wine consumption
INTRODUCTION
Ovarian cancer is the second most common gynecologic malignancy in the world which
may lead to fatality.1 Unlike cervical cancer, the etiology of ovarian cancer is poorly
understood and thus prevention of this cancer has been ineffective.2 Alcohol consumption is a
modifiable factor which is thought to play an etiologic role in ovarian cancer. The basis for this
hypothesis is because alcohol consumption causes hormonal changes (higher levels of estrogen,
lower levels of progesterone, and higher levels of androstenedione). Also, high alcohol
consumption has been related to irregular menses, infertility, spontaneous abortion, and, in rats,
ovarian failure.2-3 To date many studies have been done to assess the relationship between
alcohol consumption and ovarian cancer. This literature review seeks to discuss the effect of
alcohol consumption on the risk of epithelial ovarian cancer based on studies which have been
published.
OVARIAN CANCER
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Ovarian malignancy is one of the most challenging gynecologic cancers. The most
common ovarian malignancies are epithelial ovarian cancers. Epithelial ovarian cancer is
usually asymptomatic until they have metastasized and this is the reason why more than two-
third patients of ovarian cancer have advanced disease at diagnosis. Women with epithelial
ovarian cancer have vague and non-specific symptoms. Symptoms include irregular menses if
the patient is premenopausal, urinary frequency or constipation if the pelvic mass compresses
the bladder or rectum, lower abdominal distention, pressure, or pain, and dysparaeunia. In
advanced disease of epithelial ovarian cancer, patients most often have symptoms related to
ascites, omental metastases, or bowel metastases, which include abdominal distention, bloating,
constipation, nausea, anorexia, or early satiety. The peak incidence of epithelial ovarian cancer
is at 56 to 60 years of age.4
Prevalence of Ovarian Cancer
In Indonesia, cancer is the fifth cause of death in which 40% of female malignancies are
gynecological cancers. The prevalence of gynecological cancers in Indonesia cannot be
accurately assessed because Indonesia does not have an established cancer registry. However,
data from a pathology registry operated by the Indonesian Association of Anatomic Pathology
and the Indonesian Cancer Society shows that ovarian cancer is the second most gynecologic
cancer in Indonesia (cervical cancer is the most gynecologic cancer).5 The table below shows
the prevalence of cancer in Indonesia as documented by the pathology registry in 2002:
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Classification of Ovarian Cancer
About 90% of ovarian cancers are derived from tissues that come from the coelomic
epithelium or mesothelium. The table below shows the classification of the histologic and
cellular types of epithelial tumors of the ovary:
Each of the histologic types can be divided into benign, borderline, or malignant tumor.
The diagnosis of borderline tumor or malignant tumor must be based on the histologic feature
of the primary tumor. Borderline tumor is the term used to denote tumor of low malignant
potential and are lesions that tend to remain confined to the ovary for long periods, occur
predominantly in premenopausal women, and are associated with a very good prognosis.
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Borderline tumors are found most frequently in women between 30-50 years of age. The
diagnostic criteria of borderline tumors, as written in Berek and Novaks Gynecology, are as
follows: 1.epithelial hyperplasia in the form of pseudostratification, tufting, cribriform, and
micropapillary architecture, 2.nuclear atypia and increased mitotic activity, 3.detached cell
clusters, and 4.absence of destructive stromal invasion (without tissue destruction). The term
malignant tumor refers to epithelial ovarian cancer. Malignant tumors are often found in
women 50-70 years of age. More than 75% of epithelial cancers are of the serous histologic
type, 20% of the mucinous histologic type, and 2% of the endometrioid histologic type. The
clear cell type, Brenner type, and undifferentiated carcinomas represents only less than 1% of
epithelial cancers. Serous tumors have an appearance similar to the glandular epithelial lining
of the lower genital tract and fallopian tube, mucinous tumors contain cell that resemble the
endocervical glands, and endometrioid tumors contain cell that resemble the endometrium. 4
Serous tumor develops by the invagination of the surface ovarian epithelium. It is
termed serous because it secretes serous fluid, like secretory cells of the fallopian tube.
Psammoma bodies are associated with these invaginations. 10% of all ovarian serous tumors
are classified as borderline tumors. 50% of borderline serous tumors occur before 40 years old
and 10% of borderline serous tumors have extraovarian implants. Implants are divided into
invasive and noninvase implants according to its histologic features. Noninvasive implants
refer to papillary proliferations of atypical cells which involve the peritoneal surface and form
smooth invaginations. Invasive implants refer to proliferation of atypical cells which form
irregular glands with sharp borders resembling well-differentiated serous carcinoma. The
remaining serous tumors are malignant serous carcinomas. The hallmark of malignant serous
tumors is the presence of stromal invasion. Serous carcinomas can be divided into poorly-
differentiated, moderately-differentiated, and well-differentiated carcinomas. Poorly-
differentiated carcinomas are characterized by sheet of cells, nuclear pleomorphism, and high
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mitotic activity, whereas well-differentiated carcinomas are characterized by predominating
papillary and glandular structures. Moderately-differentiated carcinomas are intermediate
between these two lesions. Laminated, calcified psammoma bodies can be found in 80% of
serous carcinoma. A rare variant of serous carcinoma which is serous psammocarcinoma is
characterized by the formation of massive psammoma body and low-grade cytological features.
The clinical course of patients with serous psammocarcinoma resembles patients with
borderline serous tumors with a relatively favorable prognosis.4
Mucinous tumors have a lining of mucin-secreting epithelium in which epithelial cells
contain intracytoplasmic mucin and resemble cells of the endocervix, gastric pylorus, or
intestine. Mucinous tumors may become very enourmous in size and fill the entire abdominal
cavity. Borderline mucinous tumors are difficult to diagnose because of its atypical pattern.
Mucinous serous carcinoma contains intestinal-type cells and is difficult to differentiate from
metastatic carcinoma of the gastrointestinal tract.4
Endometrioid tumors have cells which resemble the endometrium. Borderline
endometrioid tumors have a wide morphologic spectrum which may resemble an endometrial
polyp or complex endometrial hyperplasia with glandular crowding. Well-differentiated
endometrioid carcinoma is characterized by no intervening stroma between glands. 4
Clear cell tumors are made up of clear and hobnail cells that project their nuclei to the
apical cytoplasm. These clear cells have abundant clear or vacuolated cytoplasm,
hyperchromatic irregular nuclei, and nucleoli of various sizes from grade 1 to grade 3.4
Etiology of Ovarian Cancer
The etiology of ovarian cancer is unknown, however it is hypothesized that induction of
ovulation may be an important factor in the neoplastic transformation of ovarian cells. On the
other hand, suppression of ovulation decreases the risk of ovarian cancer. The basis for this
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hypothesis is because: 1.women with low parity are found to be associated with ovarian cancer
while multiple pregnancies offer a protective effect against ovarian cancer, 2.the risk of ovarian
cancer increases with early menarche and late menopause, and 3.oral contraceptive use
decreases the risk of ovarian cancer. Diet has also been suggested as a possible risk factor for
ovarian cancer, including the consumption of alcohol.4, 6
ALCOHOL CONSUMPTION AND OVARIAN CANCER
Alcohol consumption includes the consumption of wine (red wine and white wine),
beer, and liquor.2-3, 6 Studies have been done to find out if there is a correlation between alcohol
consumption and the risk of epithelial ovarian cancer. These studies are primarily done because
of the possible role alcohol consumption has in the development of ovarian cancer.
A case-control study has been done by Webb et al taking place in Australia. Sample of
this study includes 696 Australian women with histologically confirmed epithelial ovarian
cancer and 786 cancer-free control women. All women provided information in a face-to-face
interview including full history of pregnancy, lactation, contraceptive use, and dietary data.
Dietary data was obtained from a self-completed food frequency questionnaire. Frequency of
drinking different types of alcohol is assessed through the questionnaire and used to estimate a
womans average daily intake of alcohol in grams. Relative risk of ovarian cancer was
calculated with different levels of alcohol intake after adjusting for possible confounders which
includes age, level of education, BMI, parity, duration of oral contraceptive use, smoking
history, and caffeine intakes. Results of this study are as follows: 1.consumption of any type of
alcohol was associated with a reduced risk of epithelial ovarian cancer in drinkers compared to
non-drinkers, 2.there is no significant difference between the effect of alcohol on the different
histologic subtypes whether borderline or invasive cancer, 3.wine drinkers had lower risk of
epithelial ovarian cancer, especially for the consumption of red wine. This study found that an
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average consumption of 1 glass/day of red wine was associated with lower risk
of epithelial ovarian cancer than other types of alcohol. The apparent protective effect of wine
on epithelial ovarian cancer, particularly for red wine, may be independent of the alcohol it
contains because wine contains high levels of antioxidants as well as resveratrol, a
phytoestrogen with anticancer properties.3
Another case-control study done by Peterson et al in populations of Massachusetts and
Wisconsin had different results compared to the previous study done in Australia. This study
which comprises 762 women with epithelial ovarian cancer and 6,271 women as controls,
found that beer consumption as young adults 20-30 years of age was associated with a
significant increase in the risk of invasive tumor, particularly serous invasive tumors (wine and
liquor have no significant effects on the risk of epithelial ovarian cancer). Consumption of 1
beer/day was related with a 56% increase in the risk of invasive epithelial ovarian cancer when
compared to no drinking at this age. This study also found that recent alcohol consumption did
not affect risk of epithelial ovarian cancer. In this study, information regarding average alcohol
consumption as young adults (20-30 years of age), recent alcohol consumption (1-5 years
before diagnosis of cancer), frequency, amount, and type of alcohol consumed were obtained
through a 45-min telephone interview.2
Other than case-control studies, cohort studies have also been done to find out whether
alcohol consumption influences epithelial ovarian cancer risk. Chang et al did a baseline
alcohol assessment on 90,371 eligible members of the California Teachers Study cohort in
which participants reported average weekly consumption of beer, wine/champagne, and
cocktail/liquor at ages 18-22 years, ages 30-35 years, and in the year prior to baseline. 227 of
the women in this study were later diagnosed with invasive epithelial ovarian cancer and 26
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diagnosed with borderline epithelial ovarian cancer (excluding non-epithelial ovarian cancer
cases). This study shows that total alcohol consumption did not affect the risk of epithelial
ovarian cancer. Consumption of beer or liquor was not significantly associated with risk of
epithelial ovarian cancer but consumption of wine during the year before baseline was
associated with a statistically significant increase of the risk of epithelial ovarian cancer. After
adjusting for other risk factors of ovarian cancer, women who drank one glass per day of wine
(at least 11.1 grams per day of alcohol from wine) a year prior to baseline were at 57% higher
risk of epithelial ovarian cancer compared to women who did not drink wine. Intake of alcohol
from wine at ages 30-35 years and 18-22 years of age was associated with an insignificant
higher risk of epithelial ovarian cancer. Women who were heavy wine drinkers in all three
periods of time had over four times the risk of epithelial ovarian cancer relative to women who
never drank wine in any time period. The positive association between wine drinking and
epithelial ovarian cancer may be attributable to constituents found in wine other than alcohol. 6
Results of the case-control study done in Australia and of the California Teachers Study
cohort are contradicting. Because of these conflicting results, Kim et al performed a meta-
analysis comparing epithelial ovarian cancer risk between wine drinkers and never drinkers of
10 studies (3 cohort studies and 7 case-control studies including the three studies explained
above). After analyzing epithelial ovarian cancer risk between wine drinkers and never
drinkers, this meta-analysis found that there was no significant difference in epithelial ovarian
cancer risk between wine drinkers and never drinkers. Re-analysis according to the study
design also demonstrated no significant difference in epithelial cancer risk between wine
drinkers and never drinkers. There was also no difference of epithelial ovarian cancer risk
between former drinkers and never drinkers.7
The results of the four studies explained earlier are inconsistent in regards to the
association of alcohol consumption and epithelial ovarian cancer risk, particularly for wine
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consumption. The proposed hypothesis is that alcohol consumption promotes ovarian
carcinogenesis through its effects on steroid hormones, particularly estrogen. Moderate to high
alcohol consumption is associated with higher levels of total and bioavailable estrogen (and
also androgens) resulting in increased cumulative estrogen exposure which increases the risk of
ovarian cancer.2-3, 5-6 Alcohol consumption is also associated with folate deficiencies which
predispose normal epithelial tissues to neoplastic transformation. Other mechanisms by which
alcohol consumption promotes ovarian carcinogenesis includes alteration of gonadotropin
levels, promotion of DNA damage, DNA hypomethylation, inhibition of carcinogen
detoxification and clearance, and increased metastatic potential of tumor cells.2, 7 On the other
hand, alcohol consumption is also hypothesized to have protective effects against ovarian
cancer. Folate deficiency related to alcohol consumption suppresses tumor growth. Alcohol
consumption also suppresses ovulation and gonadotropin levels which are protective against
ovarian cancer.2 Further, resveratrol which is found abundant in wine is protective against
ovarian cancer because of its anti-inflammatory, anti-carcinogenic, cell-cycle-inhibiting, and
anti-oxidant effects.3, 7 The role of these two conflicting hypothesis on the effects of alcohol
consumption on ovarian cancer may explain why results of studies which have been done are
not consistent.
CONCLUSION
It can be concluded that the effect of alcohol consumption on epithelial ovarian cancer
is still unclear. Results of studies which have been done are not consistent. Some studies show
a positive correlation between alcohol consumption and risk of epithelial ovarian cancer, while
another shows a negative correlation between alcohol consumption and risk of epithelial
ovarian cancer. This means that alcohol consumption cannot be established as a risk factor for
epithelial ovarian cancer. Also, protective effect against epithelial ovarian cancer that is
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attributable to alcohol consumption, particularly wine, is not significant and needs further
research. In the mean time, management of ovarian cancer should focus more on early
diagnosis and less on prevention because the etiology of ovarian cancer is still poorly
understood. Further research needs to be done to assess the effects of alcohol consumption on
the risk of ovarian cancer. Research should also be done to explore the etiology of ovarian
cancer.
REFERENCES
1. Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of
the problem. Best Pract Res Clin Obstet Gynaecol 2006; 20: 207-25.
2. Peterson NB, Trentham-Dietz A, Newcomb PA, Chen Z, Hampton JM, Willett WC, et
al. Alcohol consumption and ovarian cancer risk in a population-based case-control
study. Int J Cancer 2006; 119: 2423-7.
3. Webb PM, Purdie DM, Bain CJ, Green AC. Alcohol, wine, and risk of epithelial
ovarian cancer. Cancer Epidemiol Biomarkers Prev 2004; 13: 592-9.
4. Berek JS, Natarajan S. Ovarian and Fallopian Tube Cancer. Berek and Novaks
Gynecology. 14th ed. In: Berek JS; editor. Philadelphia: Lippincott Williams & Wilkins;
2007. p.1457-73.
5. Aziz MF. Gynecological cancer in Indonesia. J Gynecol Oncol 2009; 20: 8-10.
6. Chang ET, Lee VS, Canchola AJ, Dalvi TB, Clarke CA, Reynolds P, et al. Dietary
patterns and risk of ovarian cancer in the California Teachers Study cohort. Nutr Cancer
2008; 60: 285-91.
7. Kim HS, Kim JW, Shouten LJ, Larsson SC, Chung HH, Kim YB, et al. Wine drinkingand epithelial ovarian cancer risk: a meta-analysis. J Gynecol Oncol 2012; 21: 112-118.
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