Bleeding symptoms and subsequent risk of gynecological and other cancers

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1 Acta Obstet Gynecol Scand 1998; 77: Copyright C Acta Obstet Gynecol Scand 1998 Printed in Denmark all rights reserved Acta Obstetricia et Gynecologica Scandinavica ISSN ORIGINAL ARTICLE Bleeding symptoms and subsequent risk of gynecological and other cancers MERJA VIIKKI 1, EERO PUKKALA 2 AND MATTI HAKAMA 1,2 From the 1 Tampere School of Public Health, University of Tampere, Tampere and the 2 Finnish Cancer Registry, Helsinki, Finland Acta Obstet Gynecol Scand 1998; 77: C Acta Obstet Gynecol Scand 1998 Background. The purpose of our study was to find out whether bleeding symptoms are predictive factors of subsequent gynecological or urinary cancers among women screened negative. Methods. The data stemmed from the Finnish Mass Screening Registry, and were linked to the National Cancer Registry: 37,596 screening negative women in the nationwide populationbased mass screening program for cervical cancer were classified by their bleeding symptom (bloody discharge, coital bleeding, irregular bleeding, postmenopausal bleeding) at the time of screening ( ) and followed up ( ) in order to assess the subsequent risk of cancer. Results. Bleeding symptoms with prevalence of 5.9% were more likely to be signs of preinvasive than invasive cervical cancer with the exception of coital bleeding, nevertheless relative risk of cervical cancer (SIR 1.1, 95% CI ) was not significantly increased during the total follow-up of maximum 10 years. Women with any bleeding symptom had increased risk of cancer of the corpus uteri (SIR 2.1, 95% CI ), postmenopausal bleeding was the strongest symptom (RR 3.6, 95% CI ). None of the bleeding symptoms increased subsequent risk of ovarian, vaginal or vulvar carcinoma. The risk of kidney cancer was increased (SIR 1.7, 95% CI ). Conclusions. The prevalence of bleeding symptoms was small and relative risks for cancers were low for them to be suitable as predictive factors of cancer neither in clinical practice nor for public health purposes, e.g. in developing selective screening based on this high risk group. Only 34 gynecological cancers during 220,000 person-years in women with bleeding symptoms were attributable to bleeding. Relative risks remained increased only for a short time after screening. Therefore, short term surveillance is important, but due to the fact that relative risks approached unity during the follow-up, reassurance of a woman that she is cancer-free should be emphasized more in the long term after the bleeding symptoms. Key words: bleeding symptoms; cancer risk; screening Submitted 12 August, 1997 Accepted 27 November, 1997 The importance of bleeding symptoms as a sign of cancer has for decades been emphasized both in health education and clinical practice. The experience stems from clinical setting, i.e. simultaneous Abbreviations: CI: confidence interval; Exp: expected; Obs: observed; Pap: Papanicolaou; RR: relative risk; SIR: standardized incidence ratio. occurrence of the symptom and the disease. We wanted to find out whether there is also long term significance of bleeding symptoms, i.e. whether they have predictive value of cancers among women diagnosed cancer-free at the time of recording the symptom. In Finland there is a highly developed health infrastructure which includes linkable Population Register Center, Finnish Cancer Registry and Mass Screening Registry for or-

2 Bleeding symptoms and cancer incidence 565 ganized screening program of cervical cancer. The women screened were classified by their bleeding symptom and followed up in order to assess the subsequent risk of cancer in terms of incidence rates and relative risks. Materials and methods Population-based organized screening for cervical cancer was introduced in Finland in The screening population consists of women aged years. The screening interval is five years. Every woman gets a personal invitation letter to screening, and is also personally informed of the result of the screening. The basic screening test for cervical malignancy is cytological examination of exfoliated cervical cells, the Papanicolaou or Pap smear (1). Every woman who takes part in mass screening for cervical cancer in Finland is recorded in the Mass Screening Registry. The data in the Mass Screening Registry includes self-reported information about possible symptoms and gynecological operations, and the result of Pap smear. In this study we followed cohorts of women registered in the Finnish National Mass Screening Registry with bloody discharge, coital bleeding, irregular bleeding or postmenopausal bleeding at screening in The linkage of data in Mass Screening Registry and the Finnish National Cancer Registry was done with personal identification numbers as the key, and the dates of death or migration to a foreign country were obtained from the files of Statistics Finland. The follow-up was complete. The Finnish Cancer Registry was founded in 1952 and since 1961 it has been obligatory for all physicians under public as well as private administration to report all cases of diagnosed cancer, since 1964 cancer in situ and since 1991 also severe dysplasia in cervix uteri to the national cancer registry. The follow-up of our study cohort members for cancer started at the beginning of the month following the date of mass screening when the symptom was first reported (possibly different dates for each symptom), and ended at death/migration or on December 31st, 1994, whichever occurred first. The number of observed cases and person-years at risk were counted by time since the beginning of follow-up (0, 1 4, 5 9 and 10π completed years), by 5-year age group, and by the calendar period. The expected numbers of cases for total cancer and for specific cancer types were calculated by multiplying the number of person-years in each age group by the corresponding average cancer incidence in the whole Finnish female population during the period of observation. The specific cancer types a priori selected for the analyses included the cancer sites with known or suspected exceptional risk among patients with bleeding symptoms in earlier studies. In addition, other common cancer types were selected in order to give the whole picture of cancer situation among Finnish symptomatic patients. To calculate the standardized incidence ratio (SIR) the observed number of cases was divided by the expected number. The statistical significance was tested by the Mantel-Haenszel c 2, on the presumption that the number of observed cases followed a Poisson distribution. Results The total number of women who were registered with bleeding symptoms in Finnish Mass Screening Registry in was 37,596. Table I shows the number of women and person-years in different symptom categories. The mean length of follow-up of a person was 7.0 years. During the follow-up 753 cancers were observed among women with bleeding symptoms; 197 (26%) of these cancers were gynecological cancers. The prevalence of different bleeding symptoms in 1990 varied from 0.2% to 3.9%. Women with bloody discharge had an elevated risk of gynecological cancers (Table II). The excess was attributable to cancer of corpus uteri (SIR 2.2, CI ). The risk of kidney cancer was increased, too, but the numbers were small and the Table I. Number of women in different age categories at the beginning of follow-up and number of person-years at risk in by symptom category Symptom yrs yrs yrs 60π yrs Total Person-yrs Prevalence %* Bloody discharge 826 5,937 2, ,870 63, Coital bleeding 453 3,096 1, ,632 32, Irregular bleeding 2,191 15,338 5, , , Postmenopausal bleeding , ,421 9, Combined cohort of bleeding symptoms 3,098 20,740 7, , , * Based on all women participated in the mass screening program in Finland in 1990.

3 566 M. Viikki et al. Table II. Observed (Obs) and expected (Exp) numbers of cancer cases and standardized incidence ratios (SIR) with 95% confidence intervals (95% CI) among Finnish women with bloody discharge in mass screening in by primary site Primary site Obs Exp SIR 95% CI Gynecological organs Cervix Preinvasive Invasive Corpus uteri Ovary Vagina, vulva Urinary organs Bladder, ureter, urethra Kidney Other sites Table IV. Observed (Obs) and expected (Exp) numbers of cancer cases and standardized incidence ratios (SIR) with 95% confidence intervals (95% CI) among Finnish women with postmenopausal bleeding in mass screening in by primary site Primary site Obs Exp SIR 95% CI Gynecological organs Cervix Preinvasive Invasive Corpus uteri Ovary Vagina, vulva Urinary organs Bladder, ureter, urethra Kidney Other sites increase in risk was not statistically significant. Coital bleeding was rare and not associated with gynecological cancer (SIR 1.0) nor with cancers of urinary organs (SIR 0.9) or cancers of other primary sites (SIR 1.0). Irregular bleeding was indicative of cancer of corpus uteri (SIR 1.8, ), but there was no excess in risks of other gynecological cancers (Table III). In addition, the risk of kidney cancer was significantly increased (SIR 2.0, CI ). Postmenopausal bleeding (Table IV) was a strong symptom of cancer of corpus uteri; the risk of corpus uteri cancer was 3.6-fold (CI ) compared to the average Finnish female population. Bleeding symptoms in general (bloody discharge, coital bleeding, irregular bleeding or postmenopausal bleeding) were associated with risk of both endometrial and renal cancers (Table V). The risk of other cancers was not increased. The risk Table III. Observed (Obs) and expected (Exp) numbers of cancer cases and standardized incidence ratios (SIR) with 95% confidence intervals (95% CI) among Finnish women with irregular bleeding in mass screening in by primary site Primary site Obs Exp SIR 95% CI Gynecological organs Cervix Preinvasive Invasive Corpus uteri Ovary Vagina, vulva Urinary organs Bladder, ureter, urethra Kidney Other sites of corpus uteri carcinoma was greatest during first five years after registration of bleeding symptoms and that of kidney cancer during the second to fifth year. In addition, there was significant excess of cervical cancer risk during the first year of follow-up. Discussion Current texts state that most women with invasive cervical cancer have abnormal vaginal bleeding (2, 3). Pretorius et al. in 1991 (4) found that 56% of cervical cancer patients presented with abnormal vaginal bleeding, whereas in Pardanani et al. s series ( ) (5) 76% and Truelsen s series ( ) (6) 91% of cervical cancer patients had vaginal bleeding. Gredmark et al. in 1995 (7) found only six histopathologically diagnosed cervical cancers of 457 women presenting with postmenopausal bleeding, whereas Payne et al. (8) described malignant conditions in 30% of women presented with postmenopausal bleeding, and nearly one third were cervical squamous cell carcinomas. Thus, in earlier studies women diagnosed with cancer more often had bleeding symptoms, and the more widely spread the carcinoma was, the more likely it was to bleed. Since then there has been a decrease in importance of bleeding symptoms in clinical practice as a sign of cancer. It partly reflects the effectiveness of cervical cancer screening; the utilization of Pap smear has decreased the incidence and mortality of cervical cancer (9), increased the proportion of stage I cases (10); the screening has also increased the proportion of adenocarcinoma (11) which is known to bleed less than squamous cell carcinoma. Anyhow, the experience that bleeding

4 Bleeding symptoms and cancer incidence 567 Table V. Observed numbers of cancer cases (Obs) and standardized incidence ratios (SIR) with 95% confidence intervals (CI) among Finnish women with any bleeding symptom (combined cohort of bleeding symptoms) in mass screening in by years of follow-up Years of follow-up π Total Primary site Obs SIR CI Obs SIR CI Obs SIR CI Obs SIR CI Gynecological organs Cervix Preinvasive Invasive Corpus uteri Ovary Vagina, vulva Urinary organs Bladder, ureter, urethra Kidney Other sites symptoms are signs of gynecological cancer stems from clinical setting, i.e. simultaneous occurrence of the symptom and the disease. The purpose of our study was to find out whether bleeding symptoms have a predictive value of cancers among cancer-free women, and, thus, can bleeding symptoms be considered as risk indicators for cancers for public health purposes and as a basis for surveillance in clinical practice. In this study we followed-up women registered at the Finnish National Mass Screening Registry in by different bleeding symptoms and estimated the incidence of cancers at different anatomical sites. Ascertainment of personal identification numbers of the cohort as well as follow-up for death were complete for the period of this study. The Finnish cancer registration system is virtually complete (12) and computerized record linkage procedure precise (13), i.e., technical incompleteness is not likely to cause any bias in the results. The thorough validation of self-reported symptoms was not possible due to the fact that the data were routinely collected by the Finnish health care system. However, Finnish women recognize bleeding symptoms as abnormal and to some extent alarming, and are therefore willing to report the nature of symptoms carefully. There is no good reason to assume that self reporting of the symptoms caused any substantial bias in the estimates of relative risks of cancer or of prevalence of the symptom. The potential of intermixing of hematuria and bleeding symptom will be discussed separately for kidney cancer. The prevalence of different bleeding symptoms was 5.3% in Finland in the 1970 s (15). Of all bleeding symptoms coital bleeding was the strongest indicator for incidence of invasive cervical cancer during the subsequent follow-up (RR 15); relative risks for other bleeding symptoms were smaller and other symptoms of bleeding were more likely to be signs of preinvasive cervical cancer (15). We found that bleeding symptoms have not only become more common from the 1960 s ( ) to 1990, but their predictive value as cancer markers has also reduced, i.e. relative risks have decreased: in our study with cases about 20 years later ( ) coital bleeding followed by negative histology had a prevalence of 0.7% but carried only a 3.4-fold risk of invasive cervical cancer compared to nonsymptomatic women (SIR 1.7/0.5). However, some characteristics of symptoms of cervical cancer remained the same: we found that coital bleeding was still the only bleeding symptom more likely to be associated with increased risk of invasive than preinvasive cervical cancer. The decrease in relative risks can be explained by the fact that nowadays bleeding symptoms are more often caused by hormonal replacement therapy and not by cervical cancer. Thus, of all bleeding symptoms, the proportion of classical bleeding symptoms caused by cervical cancer has become smaller. In our study, the risk of cancers of the corpus uteri and kidney was increased during the first five years of follow-up among women with bleeding symptoms. Cervical cancer screening could not have had any impact on the risk of these cancers. There are two explanations for the excess relative risk of corpus uteri cancer subsequent to bleeding symptoms: First atypical

5 568 M. Viikki et al. endometrial hypoplasia from anovulation or from an inadequate progestational phase may result in dysfunctional uterine bleeding. Therefore, bleeding symptoms may indicate etiological exposure during the cancer sequel. Second, bleeding may not be indicative of etiological exposure, but rather a marker of an existing preclinical tumor. The excess in kidney cancer risk may partly be explained by the fact that symptoms are reported by women themselves, not by physicians, so it is possible that the woman has in fact been referring to blood in the urine when reporting bleeding symptoms, or in cases of incontinence has regarded hematuria as gynecological bleeding. It is also possible that gestational steroids may have some effect on the increased risk of kidney cancer. For any case, observed increase in the occurrence of corpus uteri and kidney cancer, especially after 1 5 years of follow-up, suggests that there is a possibility for earlier diagnosis through notice of the symptom as a marker of the cancer. Bleeding symptom is one of the classical warning signs of cancer, a patient with cancer often has a bleeding symptom. However, this does not imply that women diagnosed cancer free with bleeding symptoms were at particularly high risk of cancer or that such symptoms were of public health importance. Bleeding symptoms often occur without being a sign of cancer. In fact, 99% of women with irregular bleeding are healthy for cervical abnormality, and very few (0.2%) have invasive cervical cancer (16). Even less attention has been paid to find out whether the same bleeding symptoms to be sign of gynecological cancer applies for predictive purposes, i.e. in a longitudinal setting given that no cancer was diagnosed at the time of recording the symptom. In our study among 37,596 women with bleeding symptoms only 650 cancers were diagnosed during 7 years follow-up. Furthermore, 172 cancers were at gynecological sites and the excess number of cases due to bleeding symptoms was only 20%. Therefore, only 34 gynecological cancers among 37,596 women with bleeding symptoms in 7 years were attributable for bleeding. Bleeding symptoms were not very common, only 5.9% of the women attending screening for cervical cancer in Finland 1990 were registered with bleeding symptoms. Women with clinical symptoms as high risk group are of importance in cancer control only if the symptom is a strong indicator of cancer (RR high) and the prevalence of the symptom is high, so that most cancer cases in the total population appear in the risk group. Therefore, bleeding symptoms cannot be used either in public health, e.g. in designing selective screening, or as a basis on surveillance in normal clinical practice. Their value remains established in the short term clinical setting: women with bleeding symptoms may have cancer, it may be missed if it is not diagnosed early. The excess in relative risk remained only for a short period of time after screening, indicating the possibility of false negative diagnosis. Therefore, short term surveillance is important. Because relative risks approached unity, the attributable risk was not persistent. Thus, reassurance of a woman that she is free from cancer is more necessary than surveillance for cancer occurrence in the long term after the bleeding symptoms. Acknowledgment Financial support was given by Pirkanmaa Cancer Society. References 1. Papanicolaou GN. A new procedure for staining vaginal smears. Science 1942; 95: Hatch KD. Cervical cancer. In: Berek JS and Hacker NF, eds. Practical gynecologic oncology. Baltimore: Williams and Wilkins, 1989: Morrow CP, Townsend DE. Synopsis of gynecological oncology. 3rd ed. New York: Wiley, 1987: Pretorius R, Semrad M, Watring W, Fotheringham N. Presentation of cervical cancer. Gynecol Oncol 1991; 42: Pardanani NS, Tischler LP, Brown WH, De Feo E. Carcinoma of cervix. N Y State J Med 1975; 75: Truelsen F. Cancer of the uterine cervix. Copenhagen: Rosenkilde and Bagger, Gredmark T, Kvint S, Havel G, Mattson L-Å. Histopathological findings in women with postmenopausal bleeding. Br J Obstet Gynaecol 1995; 102: Payne FL, Wright RC, Fetterman HH. Postmenopausal bleeding. Am J Obstet Gynecol 1959; 77: Hakama M, Chamberlain J, Day NE, Miller AB, Prorok PC. Evaluation of screening programmes for gynaecological cancer. Br J Cancer 1985; 52: Johannesson G, Geirsson G, Day N. The effect of mass screening in Iceland, , on the incidence and mortality of cervical carcinoma. Int J Cancer 1978; 21: Nieminen P, Kallio M, Hakama M. The effect of mass screening on incidence and mortality of squamous and adenocarcinoma of cervix uteri. Obstet Gynecol 1995; 85: Teppo L, Pukkala E, Lehtonen M. Data quality and quality control of a population-based cancer registry. Experience in Finland. Acta Oncol 1994; 33: Pukkala E. Use of record linkage in small-area studies. In: Elliot P, Guzick J, English D, Stern R, eds. Geographical and environmental epidemiology. Oxford: Oxford University Press, 1992: Hakama M. Efficacy of screening for cervical cancer. In: Peto R, zur Hausen H, eds. Banbury Report 21: Viral Etiology of Cervical Cancer. Cold Spring Harbor Laboratory, 1986: Hakama M, Pukkala E. Selective screening for cervical

6 Bleeding symptoms and cancer incidence 569 cancer: Experience of the Finnish mass screening system. Br J Prev Soc Med 1977; 31: Hakama M, Joutsenlahti U, Virtanen A, Räsänen-Virtanen U. Mass screening for cervical cancer in Finland Ann Clin Res 1975; 7: Address for correspondence: Merja Viikki, M.D. Tampere School of Public Health University of Tampere Box 607, FIN Tampere Finland