THE CORRELATION BETWEEN ALCOHOL CONSUMPTION AND RISK OF EPITHELIAL OVARIAN CANCER

Monica Raharjo NIM: 030 09 157

Faculty of Medicine, Universitas Trisakti

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 and epithelial 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 twothird 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 Novak’s 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 poorlydifferentiated, 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 woman’s 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 <1.8 g/day of alcohol was related with a 20% reduction in the risk of epithelial ovarian cancer, and increasing consumption of alcohol (≥25 g/day) was associated with ±50% reduction in risk. Drinking >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 metaanalysis 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,
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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 Novak’s

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 drinking and epithelial ovarian cancer risk: a meta-analysis. J Gynecol Oncol 2012; 21: 112-118.

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