Cancer risk after hospital discharge diagnosis of benign ovarian cysts and endometriosis.

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1 Cacer risk after hospital discharge diagosis of beig ovaria cysts ad edometriosis. Borgfeldt, Christer; Adolf, Ellika Published i: Acta Obstetricia et Gyecologica Scadiavica DOI: /j x 2004 Lik to publicatio Citatio for published versio (APA): Borgfeldt, C., & Adolf, E. (2004). Cacer risk after hospital discharge diagosis of beig ovaria cysts ad edometriosis. Acta Obstetricia et Gyecologica Scadiavica, 83(4), DOI: /j x Geeral rights Copyright ad moral rights for the publicatios made accessible i the public portal are retaied by the authors ad/or other copyright owers ad it is a coditio of accessig publicatios that users recogise ad abide by the legal requiremets associated with these rights. Users may dowload ad prit oe copy of ay publicatio from the public portal for the purpose of private study or research. You may ot further distribute the material or use it for ay profit-makig activity or commercial gai You may freely distribute the URL idetifyig the publicatio i the public portal Take dow policy If you believe that this documet breaches copyright please cotact us providig details, ad we will remove access to the work immediately ad ivestigate your claim. L UNDUNI VERS I TY PO Box L ud

2 Acta Obstet Gyecol Scad 2004: 83: Copyright # Acta Obstet Gyecol Scad 2004 Prited i Demark. All rights reserved Acta Obstetricia et Gyecologica Scadiavica ORIGINAL ARTICLE Cacer risk after hospital discharge diagosis of beig ovaria cysts ad edometriosis CHRISTER BORGFELDT 1 AND ELLIKA ANDOLF 2 From the 1 Departmet of Obstetrics ad Gyecology, Uiversity Hospital, Lud, ad the 2 Divisio of Obstetrics ad Gyecology, Karoliska Istitutet, Daderyd Hospital, Stockholm, Swede Acta Obstet Gyecol Scad 2004; 83: # Acta Obstet Gyecol Scad Backgroud. The aim was to evaluate whether patiets with beig ovaria cysts, fuctioal ovaria cysts, or edometriosis have a icreased risk of developig gyecologic cacer. Methods. The Swedish Hospital Discharge Register was used to idetify a cohort of wome discharged from hospital with the diagoses of ovaria cyst ( ¼ ), fuctioal ovaria cyst ( ¼ ), or edometriosis ( ¼ ). To each case, three cotrols were matched. The Natioal Swedish Cacer Register matched all icidet cacers diagosed amog cases ad cotrols. From the Fertility Register, the date of birth of childre bor to the cases ad cotrols were obtaied. Results. Wome with edometriosis had a icreased risk for ovaria cacer (OR 1.34; 95% CI ), but o associatio was foud betwee ovaria cysts or fuctioal cysts ad ovaria maligacy, icludig all ages. Youg wome (15 29 years old) discharged from hospital for ovaria cysts ad fuctioal cysts showed a icreased risk of developig ovaria cacer later i life (OR 2.2; 95% CI ad OR 1.8; 95% CI ), as well as wome with ovaria cysts who had udergoe ovaria cyst resectio or uilateral oophorectomy (OR 8.8; 95% CI ). The risk of developig ovaria cacer was iversely related to parity. Mea age at diagosis was sigificatly lower i all three study groups. Coclusio. I this study wome with edometriosis ad youg wome who had udergoe surgery with removal of a ovaria cyst had a icreased risk of developig ovaria cacer. Key words: epidemiology; ovaria cacer; ovaria eoplasm Submitted 28 Jauary, 2003 Accepted 5 May, 2003 Ovaria cacer is the sixth most frequet cacer amog Swedish wome ad the fourth leadig cause of death i cacer amog wome aged years (1). As a result of uspecific ad mostly mild symptoms, two-thirds of the patiets are already i a advaced stage of the disease (FigO stages III ad IV) at the time of diagosis, facig a poor progosis (2). The life-time risk for ovaria cacer i Swedish wome is 1.5%, which is comparable to that of the rest of the Wester idustrial world. Thus, oe woma out of 70 will develop the disease (3). The life-time risk rages from 0.6% i wome without a family history of ovaria cacer, at least three term pregacies, ad a miimum of 4 years of oral cotraceptive use, to 3.4% i ulliparous wome ot havig used oral cotraceptives. Eve though the majority of ovaria cacers are sporadic, the greatest risk factor is a family history of the disease (4). The sigificace of beig ovaria cysts ad their relatio to ovaria cacer is uclear. Primary ovaria cacer is supposed to arise from the

3 396 C. Borgfeldt ad E. Adolf mesothelial surface cells of the ovary or its iclusio cysts. It has bee show that a higher rate of surgery for ovaria cysts is ot associated with a earlier diagosis of ovaria cacer (5,6). Furthermore, abormal morphological chages have bee foud i macroscopically ormal ovaries i asymptomatic wome udergoig surgery for hereditary reasos (7). O the other had, weak epidemiological data suggest a maligat potetial i certai beig ovaria tumors (8). Edometriosis ad edometriomas have bee foud to be associated with a icreased risk of developig ovaria cacer (9). Also, dysplasia ad trasitio from beig to maligat epithelium have bee foud i ovaria cystadeocarciomas (10 12), idicatig that ovaria cysts may be precursors of ovaria cacer. Aother questio is whether wome havig had a beig or fuctioal cyst have a altered risk of developig ovaria cacer. The aim of this case cotrol study was to evaluate whether patiets with beig ovaria cysts, fuctioal ovaria cysts, or edometriosis have a icreased risk of developig gyecologic cacer, especially ovaria cacer. Materials ad methods Data from The Swedish Hospital Discharge Registry (The Natioal Board of Health ad Welfare) were used to idetify a cohort of wome bor i Swede before All were discharged from hospital durig the period with the diagoses of ovaria cyst, fuctioal ovaria cyst, or edometriosis. The uique persoal idetificatio umber, assiged to each residet i Swede, was used. The Swedish Hospital Discharge Registry started i At that time it covered 60% of the Swedish populatio, i %, ad i %. Sice 1987, all patiets discharged from hospitals i Swede are icluded. The register cotais iformatio about surgical procedures ad up to eight discharge diagoses, coded accordig to the Iteratioal Classificatio of Diseases (ICD ad ICD ). The diagostic codes used i the preset study were ovaria cyst, icludig beig or ukow ovaria tumor ( beig tumor i ovary; uspecified cyst i ovary; , ukow ovaria tumor), fuctioal ovaria cyst/corpus luteum (615.2 ad ), ad edometriosis (625.3 ad ). To each case three cotrols, with the same date of birth, were matched usig the Swedish Populatio Register, Statistics Swede, which icludes all persos livig i Swede. Codes from The Swedish Hospital Discharge Registry for surgical procedures ad dates of operatios were liked to the cases ad cotrols. Data from the Natioal Swedish Cacer Register, fouded i 1958, matched all icidet cacers diagosed amog cases ad cotrols up to December 31, The Cacer Registry has coded maligat eoplasms accordig to the ICD-7 classificatio durig the etire period of the study. The Fertility Register, also kept by Statistics Swede, cotais iformatio o all childre bor to Swedish wome. From the Fertility Registry, the dates of birth of childre bor to the cases ad cotrols were obtaied. Wome havig chaged their persoal idetificatio umber were excluded ( ¼ 122). The cases were the give a file umber ad the cotrols a correspodig cotrol umber i order to uidetify the database. This database was used i the statistical aalyses. I order to avoid misclassificatio of beig cysts or udiagosed maligacy at the time of hospital discharge, 1 year was allowed to elapse before ay diagosis of maligacy was accepted i the studied populatio. For statistical aalysis the Matel-Haeszel procedure was applied for the determiatio of odds ratio (OR) ad the 95% cofidece itervals (CI) after stratificatios as specified (13). Results Risk of developig gyecologic cacer There was o chage i the risk of developig ovaria cacer havig had a ovaria cyst or fuctioal ovaria cyst, while wome with edometriosis had a icreased risk for ovaria maligacy (Table I). It was ot possible to determie precisely the ovaria status o the basis of the operatio code for hysterectomy. Therefore, wome who had udergoe hysterectomy with or without oophorectomy were excluded, but there were oly mior chages i the results after the exclusio of these wome. No chage i breast cacer risk was foud. A decreased risk of developig edometrial cacer was foud i wome with ovaria cysts ad edometriosis. Wome with edometriosis also had a decreased risk for cervical cacer. Wome with edometriosis showed a eve more proouced risk of developig ovaria cacer more tha 10 years after diagosis (OR 1.46, 95% CI ). There was o chage i total cacer risk (all types of ivasive maligacies) after havig had a ovaria cyst, OR 0.99 (95% CI ) or a fuctioal ovaria cyst, OR 0.90 (95% CI ), whereas wome with edometriosis had a icreased overall risk for maligacy, OR 1.15 (95% CI ). Risk of developig ovaria cacer related to previous ovaria surgery Whe aalyzig wome havig udergoe ovaria cyst resectio ad/or uilateral oophorectomy separately, the risk for subsequet ovaria cacer was almost ie-fold higher, OR 8.8 (95% CI ), as opposed to those who were ot treated surgically, OR 0.48 (95% CI ). Amog wome who later developed ovaria cacer ( ¼ 367), ie wome had bee registered with the surgical code for bilateral oophorectomy at least 1 year before the cacer diagosis (cases ¼ 2 ad cotrols ¼ 7). This may be because of misclassificatio (usig code for bilateral istead of the code for uilateral oophorectomy) or the

4 Ovaria cysts ad risk of ovaria cacer 397 Table I. Odds ratio for gyecologic cacers i wome with hospital discharge diagoses, ovaria cyst, fuctioal cyst or edometriosis Ovaria cyst Fuctioal cyst Edometriosis Cacer type OR 95% CI Case Cotrol OR 95% CI Case Cotrol OR 95% CI Case Cotrol Ovary * Breast Edometrium * * Cervix * No cacer *95% cofidece itervals excluded 1.0 Oly cacer diagoses more tha 1 year sice the primary hospital discharge diagoses are icluded. Wome with surgery as bilateral oophorectomy ad hysterectomy with or without bilateral oophorectomy are excluded. Stratificatio is performed for wome s age ad the umber of childre bor by the wome before ad after the primary hospital discharge diagosis. fact that the ovaria cacer had started as a peritoeal cacer. Risk of developig ovaria cacer i relatio to age of previous ovaria cyst The yougest age group (10 29 years old) with a ovaria cyst or a fuctioal cyst, treated or ot treated, showed a icreased risk of developig ovaria cacer (Table II). A decreased risk for ovaria cacer was observed i wome aged older tha 50 years discharged from hospitals with the diagosis of ovaria cyst. Youg wome with edometriosis showed a eve higher icreased risk of developig ovaria cacer compared with the total age group. Risk of developig ovaria cacer i relatio to umber of childre There was almost o differece i risk figures accordig to the umber of childre bor after the diagosis, whereas the umber of childre before diagosis of ovaria cyst, fuctioal cyst or edometriosis was of importace (Table III). The ovaria cacer risk was sigificatly icreased i ulliparous with fuctioal cysts or edometriosis. I wome with a ovaria cyst diagosis, the cacer risk also decreased with parity. The overall tedecy was decreasig ovaria cacer risk with icreasig umber of childre bor i all three studied groups. Mea age at ovaria cacer diagosis The mea age for ovaria cacer was sigificatly lower i the wome discharged from hospital for ovaria cyst (47.6 years, SEM 1.27; ¼ 80) vs. the cotrol group (54.1 years, SEM 0.56; ¼ 287) (p < 0.001); for the wome discharged from hospital for fuctioal cyst (40.7 years, SEM 1.70; ¼ 31) vs. the cotrol group (49.1 years, SEM 1.12; ¼ 72) (p < 0.02); ad also for the wome discharged from hospital with edometriosis (49.0 years, SEM 0.91; ¼ 90) vs. the cotrol group (51.6 years, SEM 0.60; ¼ 183) (p < 0.001). Eve whe the yougest wome below 30, respectively, 35 years of age with ovaria cacer were excluded i the calculatios, the mea age for ovaria cacer was sigificatly lower i the wome treated for ovaria cysts, fuctioal cysts or edometriosis as compared with their respective cotrol group (p < 0.05 for all six comparisos). Table II. Odds ratio for ovaria cacer diagosis related to woma s age more tha 1 year sice the woma s first hospital discharge with diagoses of ovaria cyst, fuctioal cyst, ad edometriosis Ovaria cyst Fuctioal cyst Edometriosis Age (years) OR CI 95% OR CI 95% OR CI 95% * * * þ * *95% cofidece itervals excluded 1.0 : strata missig cases or cotrols. Wome with surgery as bilateral oophorectomy ad hysterectomy with or without bilateral oophorectomy are excluded. Stratificatio is performed for the umber of childre bor by the wome before ad after the primary hospital discharge diagosis.

5 398 C. Borgfeldt ad E. Adolf Table III. Odds ratio for ovaria cacer diagosis from the first hospital discharge diagoses of ovaria cyst, fuctioal cyst, or edometriosis related to the umber of childre give birth to before ad after diagosis Number of childre Ovaria cyst Fuctioal ovaria cyst Edometriosis before diagosis after diagosis OR CI 95% OR CI 95% OR CI 95% * * * * * * *95% cofidece itervals excluded 1.0. Oly cacer diagoses more tha 1 year sice the primary hospital discharge diagoses are icluded. Gyecologic surgical procedures are ot cosidered. Discussio I this case cotrol study we foud o associatio i the total material betwee the hospital discharge diagosis of a ovaria or fuctioal cyst ad later developmet of ovaria cacer. However, there was a sigificatly icreased risk for ovaria cacer i youg wome discharged from hospital for a ovaria or fuctioal ovaria cyst, especially if they were childless. Edometriosis was associated with a overall icreased risk of developig cacer (all types of ivasive maligacies icluded). Youg age ad ulliparity icreased the risk. Wome with uilateral oophorectomy or ovaria cyst resectio showed a icreased ovaria cacer risk later as compared with those with ovaria cysts i whom o surgery was performed. I additio, the mea ages at diagosis of ovaria cacer were sigificatly lower i the cases as compared with the cotrol groups. There are several limitatios to these data. Primarily, oe may speculate over the geeralizatio of results o patiets hospitalized for ovaria cysts/beig tumors, fuctioal cysts, or edometriosis. Wome hospitalized for a adexal lesio probably had persistig ad/or symptomatic adexal lesios. Also, there may by a icreased risk for dysplasia i a log-stadig cystic lesio especially if epithelial cells icrease i umber by mitosis as the cyst grows. Further, i wome without histopathological verificatio, fuctioal cysts might have bee misclassified as ovaria cysts ad vice versa. Whe the reliability of the registers was tested, the Swedish Hospital Discharge Registry was foud to have a misclassificatio rate of 7% (14). The reliability of the surgical codes was foud to be good (15). Oe percet of the codes are missig ad 5% are erroeous. As for the Natioal Swedish Cacer Registry, approximately 98% of the diagoses are beig morphologically verified (3). The missig cacer diagoses are very few whe compared with the Natioal Death Certificate Register i Swede (3). A quality study of the Fertility Register has also bee performed lately showig good accuracy (persoal commuicatio, Statistics Swede). The discrepacy betwee the Fertility Register ad the Swedish Populatio Register was 5 8% i the 1930s ad 1940s, 2 4% i the 1950s ad 1960s, ad less tha 1% sice Nevertheless, the missig codes ad the errors i the registers should be proportioal i the case ad cotrol groups, miimizig the importace of the errors. The observatio that ulliparity icreases the risk of ovaria cacer is i accordace with earlier reports, where multiparas have a 40 60% risk reductio (16 19). Ifertile wome, usuccessfully treated with hormoes have a higher risk of developig ovaria cacer, especially after logterm use (20,21). However, wome successfully treated did ot have a icreased risk (20). The possible reaso for this icreased risk was ovaria dysfuctio ad ot the hormoal treatmet. I additio, aother iterestig hypothesis has bee proposed to explai the reduced risk of ovaria cacer i parous wome: amely that pregacy hormoes or other immuological chages durig pregacy may clear the ovaries from cells that have udergoe maligat trasformatio (18). As for edometriosis, our results are i accordace with a earlier report based o discharge diagoses where cases were compared with the stadardized icidece ratio of ovaria cacer but parity was ot cosidered (9). Other reports have also suggested a histological trasformatio of beig edometriosis to early epithelial ovaria cacer (22,23). There are several theories cocerig the developmet of edometriosis. Oe theory is that edometriosis arises from metaplasia of the coelomic epithelium, aother that edometrial cells regurgitate through the fallopia tubes at mestruatio ad implat o pelvic structures. Deficiecy i the

6 Ovaria cysts ad risk of ovaria cacer 399 immuological system has also bee cosidered to cotribute to the developmet of edometriosis. Local iflammatory respose at the edometriotic implatatios iitiates proteolytic systems which are ivolved i carciogeesis (24). Chroic iflammatio ad/or a deficiet immuological respose to edometriosis may cotribute to the icreased risk of developig ovaria cacer i patiets sufferig from edometriosis (25). I the preset study, wome with ovaria cyst resectio or uilateral oophorectomy for beig causes had a highly icreased risk of later developig ovaria cacer. This may be because of premaligat dysplasia i the cotra-lateral ovary or misclassified borderlie tumors which may have had urecogized peritoeal implats. Histo-pathological chages have bee foud i macroscopically ormal ovaries i wome operated o because of a strog family history (7,26). I ovaria cacer stage Ia, microscopic chages are foud i up to 7% of the cotra-lateral ovary (27), which may idicate that ovaria cacer is a multifocal disease. This emphasizes the importace of a thorough examiatio of the whole abdomial cavity, both at laparoscopic ad ope surgery, for ovaria cysts ad also peritoeal washig ad biopsies of the peritoeum. Whether beig macroscopic chages, except edometriosis, precede ovaria cacer is uclear. Our fidig may idicate that this is the case. Several studies have bee performed to verify whether a iclusio cyst i the other ovary is more commo i ovaria cacer patiets, but studies are icoclusive (5,7,26,28,29). Aother explaatio may be that the surgical trauma itself starts the process toward dysplasia ad maligacy, as the removal of a cyst traumatizes the ovaria-surface epithelium. The healig process etails icreased cell divisio activity ad iflammatio with activatio of proteolytic ezymes similar to those i cacer ivasio ad metastases (24,25). I additio, iflammatory cytokies activatig itric oxide have show to cause DNA damage ad ihibit DNA repair proteis (30). Thus after ovaria surgery, as well as i edometriosis, a iflammatory respose may be the key to carciogeesis. Cases were sigificatly youger whe receivig the diagosis of ovaria cacer as compared with wome i the cotrol groups. I families with a hereditary risk for ovaria cacer, the media age at diagosis is sigificatly lower tha the media age of wome without a history of familiar ovaria cacer (31). However, oly approximately 5 10% of all ovaria cacer is cosidered to be caused by iherited mutatios, which is why the differeces i mea age at ovaria cacer diagosis ca ot be fully explaied by hereditary factors. I the preset study wome with edometriosis had a decreased risk of developig edometrial ad cervical cacer. Treatmet of edometriosis ofte icludes sythetic progesti, goadotropireleasig hormoe aalogs, or combied oral cotraceptives kow to reduce the risk of edometrial hyperplasia ad cacer (32,33). The reduced risk of cervical cacer may be the result of itesified screeig ad treatmet of premaligat lesios of the cervix i the group of wome with edometriosis, as they may have cotacted their gyecologist more frequetly. I coclusio, this hospital registry study idicates a icreased risk for ovaria cacer i wome sufferig from edometriosis ad youg wome treated for ovaria cysts, especially if the cyst is removed. This latter associatio ecourages expectat moitorig i youg wome with asymptomatic cysts if maligacy is ot suspected. The tetative biological explaatios such as the iflammatory respose after surgery or edometriosis-mediatig carciogeesis eeds to be prove. Ackowledgmet The statistical assistace of Professor Begt Källé is gratefully ackowledged. We also wish to ackowledge Mats Talbäck at the Natioal Board of Health ad Welfare ad Åke Jalo at Statistics Swede for helpig us to match the data registers. Fiacial support was from the Sigrid Simossos ad Agi Olssos Foudatio. Refereces 1. The Natioal Board Health Welfare Cetre for Epidemiology. Causes of death 1997: Official Statistics of Swede Health ad Diseases: Stockholm, Swede: 2000; 3: Pecorelli S, Beedet J, Beller U, Creasma W, Heitz A, Pettersso F. FIGO Aual Report o the Results of Treatmet i Gyaecological Cacer. FIGO Aual Report o the Results of Treatmet i Gyaecological Cacer. Oxford, Eglad: Isis Medical Media Ltd, 2001; 6: The Natioal Board Health Welfare Cetre for Epidemiology. Cacer icidece i Swede 1998: Official Statistics of Swede Health ad Diseases: Stockholm, Swede: 2000; 4: Hartge P, Whittemore AS, Ityre J, McGowa L, Cramer D. Rates ad risks of ovaria cacer i subgroups of white wome i the Uited States. The Collaborative Ovaria Cacer Group. Obstet Gyecol 1994; 84: Westhoff C, Clark CJ. Beig ovaria cysts i Eglad ad Wales ad i the Uited States. Br J Obstet Gyaecol 1992; 99: Crayford TJ, Campbell S, Boure TH, Rawso HJ, Collis WP. Beig ovaria cysts ad ovaria cacer: a cohort study with implicatios for screeig. Lacet 2000; 355:

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