case-control study of borderline ovarian tumors...
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[CANCER RESEARCH 48, 5849-5852, October 15, 1988]
Case-Control Study of Borderline Ovarian Tumors: Reproductive History and
Exposure to Exogenous Female HormonesBernard L. Harlow,1Noel S. Weiss, Gilbert J. Roth, Joseph Chu, and Janet R. Daling
Department of Epidemiology, School of Public Health and Community Medicine [B. L. H., N. S. W., ]. C., J. R. D.J and Department of Pathology, School of MedicineIG. J. R.], University of Washington, Seattle 98195; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center [B. L. H., N. S. W., J. C., J. R. D.J;Laboratory of Pathology of Seattle [G. J. RJ, Seattle, Washington 98104; and Obstetrics and Gynecology Epidemiology Center, Harvard Medical School, Brigham andWomen's Hospital, Boston, Massachusetts 021 IS [B. L. H.]
ABSTRACT
Borderline ovarian tumors possess many of the same morphologicalfeatures as their malignant counterparts, but they do not destructivelyinvade the ovarian stroma, and the women in whom they develop generallyhave a favorable prognosis. Female residents of three urban counties ofwestern Washington diagnosed with serous and mucinous borderlineovarian tumors between 1980 and 1985 (n = 116) were interviewedregarding past reproductive events. A random sample of women from thesame counties (n = 158) was identified through random digit dialing andwere interviewed. The risk of these ovarian tumors among women whohad given birth to 1 or 2 children and to 3 or more children was,respectively, 0.7 and 0.4 that of nulliparous women. There was noconsistent influence of increasing age at first live birth. Adjusting forparity, a history of lactation was associated with a 50% reduction in risk.Among nulliparous women, a further increase in risk was present in thosewho reported a history of infertility. Use of oral contraceptives wasassociated with a 60% reduction in risk. However, the size of theassociation was not dependent on duration, age at first use, or years sincelast usage. In conclusion, borderline tumors appear to have similarepidemiológica!patterns with regard to reproductive events as their moremalignant counterparts.
INTRODUCTION
Ovarian tumors of low malignant potential (borderline ovarian tumors) exhibit mitotic activity, nuclear abnormality, andcellular stratification to a degree intermediate between that ofbenign and malignant tumors of the same histology (1). Incontrast to malignant ovarian tumors, borderline tumors do notdestructively invade the ovarian stroma, and their presence isassociated with a low case-fatality ratio (2). On the basis of theSeattle-Puget Sound population-based cancer registry at thepresent time, the incidence of malignant tumors of the ovary isabout 10 times that of borderline tumors (2). Previous epide-miological investigations have shown that certain features of awomen's reproductive and contraceptive history influence herrisk of developing ovarian cancer (3-20). The purpose of thisstudy was to determine if these same factors play a role in theetiology of borderline tumors as well.
MATERIALS AND METHODS
From the files of the western Washington Cancer Surveillance System, one of 11 population based cancer registries which comprise theSurveillance Epidemiology End Results network of the National CancerInstitute, we identified all white female residents of King, Pierce, andSnohomish counties 20-79 years old who were diagnosed with a serousor mucinous ovarian tumor (ICDO: 8440-8481) from 1980 to 1985.These two histológica! types constitute about 95% of all borderlinetumors (2). Potential cases had ovarian tumors characterized by corn-
Received 3/14/88; revised 6/10/88; accepted 7/20/88.The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1To whom requests for reprints should be addressed, at Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, 221 Longwood
Ave., Boston, MA 02115.
munity pathologists as either borderline per se, or as well differentiated(Grade 1) malignant based on the WHO International Classification ofDiseases for Oncology (21). Of the 178 eligible cases, 9 were known tobe deceased at the time the study began in 1984. The remaining womenwere asked, after permission was obtained from their physician, toparticipate in an in-person interview that covered their medical, reproductive, and sexual histories, and certain measures of life-style. Physicians refused permission to contact 12 cases. We were unable to locate19 cases for an interview, and there were 17 who refused to participate.A completed interview was obtained from 121 women, 68% of thoseeligible.
There is some nonuniformity in the criteria pathologists use codistinguish between borderline and Grade 1 malignant ovarian tumors.In an effort to minimize the impact of this nonuniformity on ourresults, one of us (G. R.) reviewed the pathology slides from 88 of the121 (73%) women who had agreed to participate in the study. Amongthe 66 tumors originally classified as borderline, 62 were confirmed assuch on review; excluded were 2 benign cystadenomas and 2 endome-trioid tumors. Among the 22 ovarian tumors classified as grade 1malignancies, all but one were judged "also to meet the study criteriafor a borderline tumor, and these 21 were included as well. The WHO's
international histological classification for borderline ovarian tumorsserved as the benchmark for this review (21). The basis for this level ofdisagreement very likely stems merely from the differences amongpathologists in classifying ovarian neoplasms that exhibit malignantcytological features but no apparent stromal invasion, rather than anydifferences in their ability to detect stromal invasion itself. Given theresults of the histological review of cases for whom we did have slides,we chose to include in the analysis all 33 cases whose tumors had notbeen reviewed.
We identified controls by means of a one-step process of household
screening and interviewing by using random digit dialing. A detaileddiscussion of this random digit dialing procedure can be found elsewhere (22). In short, we estimated by twelve 5-year age categories andthree counties of residence, the distribution of women with borderlineovarian tumors. A random sample of telephone numbers was chosento identify a sufficient number of controls for each of the 36 age-
residence strata. These telephone numbers were called, and a householdcensus was conducted to identify women 20-79 years of age. Eligiblewomen were sent a letter explaining the study and were asked during asubsequent telephone call to participate in an in-person interview. Thehousehold census was successfully conducted on 91% of the 464 residential telephone numbers. Of the 247 eligible subjects identified, 187in-person interviews were completed (74%). After excluding 17 non-white respondents and 12 white women who had both ovaries removedprior to the assigned reference date, 158 controls were available for theanalysis.
The women with ovarian tumors were asked only about events thatpreceded the diagnosis. For the purpose of comparability, each eligiblecontrol was assigned a "reference" year equivalent to that of the year
of diagnosis of a particular woman with a borderline ovarian tumor.This control group also served as a comparison group for another studyand therefore more controls were assigned a reference year of 1985than were needed for the borderline ovarian tumor case control study.Nevertheless, this was inconsequential since "year of diagnosis" was
not associated with any of the exposures of interest.The evaluation of differences between cases and controls was accom
plished by using stratified analysis (23).
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BORDERLINE OVARIAN TUMORS AND REPRODUCTIVE HISTORY
RESULTS
Cases and controls were similar with respect to demographiccharacteristics (Table 1). There was also no increased riskassociated with the use of cigarettes or the consumption ofalcohol and/or coffee.
Reproductive History. Women with borderline tumors gavebirth to fewer children than did controls (Table 2). The riskamong women who gave birth to 1 or 2 children was 70% thatof nulliparous women; among women who gave birth to 3 ormore children the risk was 40% that of nulliparous women. Asimilar proportion of cases and controls reported a history ofinduced abortion. However, relatively more cases reported ahistory of a prior miscarriage.
There was no consistent trend in risk with increasing age atfirst live birth, adjusting for parity, and use of oral contraceptives (Table 3). However, when we stratified the analysis on useof oral contraceptives, we found a substantial increase in risk
Table 1 Selected characteristics of cases and controls
Table 3 Age at first live birth among cases and controls by use of oralcontraceptives"
CharacteristicsAge
(yr)20-3435-4950-6465-79Reference
yr198019811982198319841985No.
ofcases28393712111422251826%ofcases24.133.631.910.39.512.119.021.615.522.4No.ofcontrols43524320111919202267%ofcontrols27.232.927.212.77.012.012.012.613.942.4Annual
familyincome<$15,000$15.000-30.000>$30,000EducationS12yr>12yrMarital
statusNevermarriedEver
marriedBody
massindex"<20.0020.00-21.9922.00-26.99627.002648395759161001924522122.441.433.649.150.913.886.216.420.744.818.14162556197211372153642025.939.234.838.661.413.386.713.333.540.512.7°
Quetelet's index: weight (kg)/height(m)2.Table
2Live
births'01
or2>2Induced
abortionsr01>1Miscarriages'01>1Pregnancy
outcomes in cases andcontrolsCases(n=
116)32483676125612210Controls(n=158)336857111169108208RR°1.00.70.41.01.20.91.02.23.095%CI0.3,
1.30.2,1.00.5,3.10.2,
3.71.0,5.10.9,
11.2" RR, relative risk.' Adjusted for age (20-39, 40-59, 60-79 years).' Excludes nulligravid women; adjusted for age (20-39, 40-59, 60-79 years)
and gravidity (1, 2, 3, 4, or more pregnancies).
Use of oralcontraceptivesYesYesYesNoNoNoTotalTotalTotalAge
at firstlivebirth(yr)<2020-24>24<2020-24>24<2020-24>24Cases9221062215154425Controls17322917228345437RR*1.0e1.40.71.0e3.04.61.0e1.8"1.5"95%
CI0.5-4.40.2-2.30.9-13.01.0-27.50.8-4.10.6-4.0
°Parous women only.* RR, relative risk; adjusted for parity (1, 2, or S3 live births).c Reference group.d Adjusted for parity (1, 2, or a3 live births) and use of oral contraceptives
(ever used, never used).
Table 4 History of lactation among cases and controls"
Duration oflactation<1
mo orneveralmo1-2mo3-9mo>9
moCases453910209Controls4184243426RR*1.00.50.40.60.395%
CI0.2-0.80.1-0.90.3-1.20.1-0.7
" Restricted to parous women.* RR, relative risk; adjusted for parity (1 or 2, S3 live births), age at diagnosis
(20-39, 40-59, 60-79 years), and use of oral contraceptives (ever used, neverused).
with increasing age at first live birth among nonusers of oralcontraceptives after adjustment for parity (test for linear trend:P =0.021).
Among parous women, those who breast fed for 1 or moremonths had a 50% reduction in risk of borderline ovariantumors, controlling for age, parity, and use of oral contraceptives (Table 4). Controlling for the same variables above, wefound the risk to be little influenced by the total duration ofbreast feeding.
In an attempt to separate the influence of completed pregnancies per se from the ability to conceive and sustain a pregnancy, we examined the association of "infertility" on the
occurrence of borderline tumors. An infertile women was defined as one who tried unsuccessfully to conceive a child for 1year or longer, and whose husband was not known to have anabnormality that was believed to be the explanation for theinfertility. Among the 19 ever-married cases who had neverborne a child, 6 (32%) had tried and failed to conceive, incontrast to only 1 of 14 (7%) nulliparous ever-married controls(relative risk = 6.0, 95% CI = 0.6-57.1).2 In parous women,
there was no such difference. Among women with no history ofinfertility, the increased risk associated with nulliparity wasmodest: 13 of 81 cases (16%) and 13 of 116 controls (11%) hadnever borne a child (relative risk = 1.5, 95% CI = 0.6-3.7).
Oral Contraceptives. A greater proportion of controls thancases reported ever having used oral contraceptives (relativerisk = 0.4, 95% CI = 0.2-0.9). The size of this association wassimilar irrespective of the duration or of the age at which useof oral contraceptives first began (Table 5). Women who lastused oral contraceptives more recently than 5 years were somewhat more strongly protected than women who last used oralcontraceptives earlier in their lives.
A relative risk of less than one associated with the use of oralcontraceptives was present among both parous and nulliparouswomen. This association was strongest in parous women whose
1The abbreviation used is: CI, confidence interval.
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BORDERLINE OVARIAN TUMORS AND REPRODUCTIVE HISTORY
Table 5 History of oral contraceptive use in cases and controls by duration, onset,and recencyafuse"CharacteristicsDuration
of oral contraceptive use (yr)
0£2>2-4>4Age
(in yr) of first useof oral contracep
tivesNeverused<1818-2021-25>25No.
of yr since lastuse of oral contraceptives
NeverusedS5>5No.
of cases(n =92)332011283110151917311843%ofcases35.921.712.030.433.710.916.320.718.533.719.646.7No.
ofcontrols
(n=124)243614502312274320234061%ofcontrols19.428.811.339.518.59.721.833.916.118.532.349.2RR*1.00.40.40.41.00.60.30.20.81.00.30.695%Cl0.1-0.90.1-1.50.2-1.00.1-3.60.1-1.80.1-0.70.3-2.10.1-0.90.3-1.4
" Includes only women younger than 60 years old.* RR, relative risk; adjusted for age (20-39, 40-59 years), and parity (1 or 2,
S3).
Table 6 History of oral contraceptive use in cases and controls by parity and ageat first live birth"
First OC usebefore first First OC use
No OC* use Any OC use child after first child
NulliparouswomenCasesControlsRRParous
womenCasesControlsRR"Age
at firstlivebirthS21yrCasesControlsRR'Age
at firstlivebirth>21yrCasesControlsRR'1051.0e23191.0e8171.0e1521.0e19250.4(0.1-1.5)40750.4
(0.2-0.9)21291.5(0.5-4.8)19460.1
(0.01-0.3)19250.4(0.1-1.5)13370.2
(0.04-0.5)260.7(0.1-5.5)11310.1
(0.01-0.3)27380.7(0.3-1.6)19231.8(0.6-5.7)8150.1(0.01-0.5)" Includes only women younger than 60 years.* OC, oral contraceptive; RR, relative risk.' Reference group.' Adjusted for age at first live birth (<20, 20-24, >24 years).' Adjusted for parity (1 or 2, >2).
first use of oral contraceptives was before the birth of their firstchild (Table 6). There was no greater protection offered towomen with increasing numbers of live births. The reductionin risk associated with use of oral contraceptives was particularly great in (and largely confined to) women who had bornetheir first child after the age of 21.
Menstrua) History. The reported age at menarche was similarin both cases and controls. Menstruation began at age 13 orolder in 56% of the cases and 52% of the controls. On theaverage, cessation of menses occurred slightly later in lifeamong cases than among controls. The Kaplan-Meier estimateof mean age at menopause, among women who had neverundergone a hysterectomy was 51.7 years for cases and 50.5years for controls, a difference that could well have been due tochance (/> =0.51).
Postmenopausal Estrogens. We found no difference in the useof postmenopausal estrogens among cases and controls. Therelative risk associated with such use was 0.9, irrespective ofduration of use.
Gynecological Surgery. Relative to women with an intactuterus, there was no difference in the risk of developing aborderline tumor among women who previously had undergonea hysterectomy without bilateral oopherectomy. The similaritybetween cases and controls was present regardless of age at thetime of hysterectomy, or the interval between hysterectomy anddiagnosis.
A negative association was present between a history of tubailigation and the incidence of borderline tumors. However, thedifference between cases and controls waned as the time sincetubai ligation increased, to the point where no association waspresent among women whose tubai ligation occurred more than12 years prior to diagnosis (or reference date in controls).
DISCUSSION
Comparing our results to those obtained in studies of malignant ovarian tumors is one way to determine whether anyfeatures of a women's reproductive history can explain the
difference in the risk of developing a more or less malignantovarian tumor. In making this comparison we recognize theexistence of some incomparability, since most previous studiesof ovarian cancer include all epithelial tumors, whereas ourswas restricted to the serous and mucinous cell types.
In general, our finding of a negative association with increasing parity is of the same magnitude as that reported in previousstudies both of ovarian cancer (3-6, 11, 12) and the one studythat reported results of borderline tumors separately (20). Ourfinding of a lack of an overall association with increasing ageat first live birth after adjustment for parity is similar to that ofmost prior studies (5, 10, 24, 25). However, our findings dosuggest that without the protection afforded by the use of oralcontraceptives, the risk of developing a borderline tumor increases with increasing age at first live birth.
Seven previous case-control studies examined the risk ofovarian cancer in relation to a history of lactation. Four foundno association (5, 7, 26, 27), one (from Japan) found a strongpositive association (13), and two found a strong negativeassociation (3, 18). While we observed a negative association,the lack of variation in the size of that association with increasing duration of lactation fails to provide support for a causalrelationship.
Five studies examined the influence of a history of infertilityon the risk of ovarian cancer; two found no association (5, 6),two reported a positive association (10, 20), and one found anassociation with some but not all measures of infertility (4). Inour study, we attempted to separate the risk associated withinfertility from that of nulliparity. Our results suggested thatever-married nulliparous women who reported a history ofinfertility were at a substantially greater risk of being diagnosedwith a borderline tumor than ever-married nulliparous womenwith no reported infertility problem. However, a noncausalexplanation for this association might be that the ovarian tumorduring its early, preclinical development, interferes with fertilityin some manner. Since 5 of the 6 women with borderline tumorswho reported a history of infertility were in their 20s or early30s at the time of diagnosis, we cannot rule out this possibleexplanation.
Several case-control studies have reported a nearly two-foldreduction in the incidence of ovarian cancer among women who
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BORDERLINE OVARIAN TUMORS AND REPRODUCTIVE HISTORY
used oral contraceptives (14-20). In most studies this reducedrisk was noted to have been present as early as about 1 yearafter use began, and to have remained fairly uniform withincreasing duration of use. In our study, overall, the risk ofdeveloping a borderline tumor was reduced by the use of oralcontraceptives as well. The rate in users was only about 50%that in nonusers, and the association did not vary greatly byage or duration of use. Our finding of little protection in womenwho First began using oral contraceptive after their first livebirth and in women who gave birth to their first child early inlife supports the theory that oral contraceptives are most protective in women not already protected by a history of a fullterm pregnancy.
A number of studies have reported a reduction in the incidence of ovarian cancer in women who have had either ahysterectomy without bilateral oopherectomy (5, 9, 20, 26) ora tubai ligation (28). Although this association could be causal,it has been suggested that the association could result fromscreening for visible ovarian malignancy at the time of surgery(29). In our study, a similar proportion of cases and controlsunderwent removal of their uteri. On the other hand, we didfind a negative association between borderline tumors and ahistory of tubai ligation. However, since the association waspresent only in the first few years after the operation took place,it seems likely to have arisen only because of the selective"removal" of women with tumors at the time of tubai ligation,
leaving a group that would be expected to have a very low rateof diagnosed ovarian tumors during the ensuing several years.
A limitation of most studies is the omission of potential casesand controls. Our results were based on the responses from67% of women known to have borderline tumors and 74% of acorresponding sample of healthy women from the same population. Thus, the validity of our results depends upon theassumption that either the respondents and nonrespondentswere similar regarding parity, use of exogenous hormones, etc.,or that the magnitude of any respondent-nonrespondent difference was similar for both cases and controls. Since we had noalternate source of "exposure" information, other than that
provided during the interview, we could not assess how goodan assumption this was.
Another potential source of error in this study results frominaccuracy of the information provided to us by the subjects.As indicated above, we did not attempt to corroborate theresponses we obtained with that present in medical records.However, when this has been done for such characteristics aspregnancy history and the use of contraceptive estrogens, a highlevel of agreement has generally been reported (30-32).
In summary, we have found that several of the same characteristics of a woman's reproductive history that have been
consistently shown to predispose her to developing a malignantovarian tumor (e.g., low parity and the use of oral contraceptives) are risk factors for borderline ovarian tumors as well. Wealso found that an increased incidence of borderline tumors wasrelated to a history of infertility and to not having lactated,characteristics that in at least some studies have been associatedwith an increased risk of malignant ovarian neoplasia. Thus, ifthe etiologies of borderline and malignant ovarian tumors differ, the difference probably lies elsewhere than in features of awoman's reproductive history.
ACKNOWLEDGMENTS
The authors wish to thank Dr. Daniel Cramer for his helpful comments and advice on this manuscript.
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1988;48:5849-5852. Cancer Res Bernard L. Harlow, Noel S. Weiss, Gilbert J. Roth, et al. HormonesReproductive History and Exposure to Exogenous Female Case-Control Study of Borderline Ovarian Tumors:
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