Scand J Soc hled 7: 79-85, 1979
Inverse Association Between Risk Factors for Benign and Malignant Breast Lesions Irma Soini and hlatti H a k a m a
Itrv~rsc.crssocirrtiotr bet~t.eetcrisk frrrrors for belrigtl trtrcl t~rnligtrtrtlrbrenst lesiotls. Soini, I. and Hakama, hl. (Detection Center and Laboratories of the Pirkanmaa Cancer Society, and Dept. of Public Health, University of Tampere, Tampere, Finland). Sccct~dJ Soc hled 1979.2 (79-85).
The purpose of the present study was to compare the risk of breast cancer and the risk of benign breast disease using known risk factors for breast cancer. The series was taken during breast cancer screening of women aged 41-60 in an industrial city in Finland. 158 breast lesions were diagnosed, 27 of which were malignant. Women with breast disease and 534 controls were interviewed to obtain epidemiological data. The prevalence of benign lesions decreased after menopause but the prevalence of carcinomas was essentially the same over the age span 41-60. Several risk factors for breast cancer, such a s selected reproductive and hormonal characteristics, were not associated with t h e risk of benign breast disease. Thus it was concluded that benign and malignant breast lesions are not associated in general, and the decrease in the prevalence of benign breast lesions after menopause is more likely to be due to regression than to transition to carcinoma.
It has been proposed that breast c a n c e r is preceded by benign breast disease. T h e estimated risk o f breast c a n c e r a m o n g women with previous benign disease varies from 1.7 t o 4.5 times that of t h e general population (4). I n a prospective study ( 6 ) breast c a n c e r developed in 3.8% o f w o m e n with a median period o f 13.5 years after t h e diagnosis o f benign breast disease. A n excess risk o f breast c a n c e r w a s found t o persist 30-40 years after the diagnosis o f t h e benign breast lesion (18). T h e purpose of the present study w a s t o c o m p a r e the risk o f breast cancer a n d the risk o f benign breast disease using known risk factors f o r breast cancer. T h e most important of these factors are: a n unmarried state, early menarche, late first marriage a n d late first confinement (19, 20). T h e empirical series originates from a mass screening project or-
ganized in Finland (18). T h e incidence o f breast c a n c e r in Finland is 33.9 p e r 10' (29). which is below t h e rates in most western countries. T h e incidence of.benign breast lesions is difficult t o estimate a n d n o reliable d a t a a r e available. hlATERIAL A N D hlETHODS The series in this study was compiled during a breast cancer screening project organized in 1974-75 in Tampere, an industrial city in central Finland. Tampere had a population of 160750 in 1974, and 20644 females were in the age group 41-60. All wornen in this group were personally invited to the screening. The response rate was 83%. These women were screened through a clinical examination by trained nurses. Subjects with an abnormal finding (615) were referred to a physician for further examination. The indications for this further examination were: a lump; retracted nipple; big breast, difficult to palpate; change in the skin.of the breast and the nipple; secretion; intense pain in the breasts and pathologically enlarged axillary lymph nodes. hlammography was performed on these women and a fine-needle biopsy was obtained when needed. All women referred for further examination were interviewed by .nurses to obtain epidemiological data concerning the risk of breast cancer. Eighty-four women with benign and 27 women with malignant breast lesion were diagnosed and histologically confirmed. The histological typing was made according to the classification of the WHO (32). The diagnosis of a benign lesion included benign mammary dysplasias (45 cases of cyst, adenosis, ductectasia, fibrosclerosis) and benign or apparently benign tumours (39 cases of adenorna, papilloma, tibroadenorna). A further 47 benign cases were diagnosed but not histologically confirmed. These cases had in a fine-needle biopsy Papanicolaou class 2 with morphological changes suspicious of benign dysplasia or tumour (36), and also marked dysplastic features at mammography. Women with no referral from clinical examination by nurses and following an abnormal finding were selected as controls, of which 534 attended the interview concerning reproductive, hormonal and other characteristics associated with the risk of breast cancer. The breast of these controls were judged normal solely on the basis of the Sctrrrcl J Soc ,\led 7
Table I. Dirrgrloscs of tlre 1~siorr.s
RESULTS No. of patients
Diagnosis
Benign breast lesion 131 Confirmed by histology 84 Confirmed by mammography and cytology 47 hlalignant breast lesion 17 Normal control 534 Total 691
The age distribution of the women invited to the screening and the screening prevalence rates of the benign and malignant lesions by age are given in Table 11. T h e screening prevalence of benign lesions decreased from 8291 10511 the age range 41-50 to 4291 IOi in the age range 5 1 4 0 years. T h e screening prevalence of carcinomas was essentially the same over the age span 41 to 60.
Rcpro(lrrcti~~e arrd horr~ror~nl chrrrrrcteristics clinical examination. In the epidemiological series (Table I) there are about three times as many controls as cases Relative risks by reproductive and hormonal because some of the women with an abnormal finding at characteristics are resented in Fic. - I. clinical examination and referred for further examination T h e relative risk of breast cancer for single womhad no abnormality at mammography or cytology and were not operated on. Only women originally selected as .en in terms of unit risk for women who had ever controls were accepted in the analysis. Details on the been married was 1.2 in the present series; the organization of the study and the histological classification corresponding estimate for a benign breast lesion of the series are given by Soini & Lauslahti (28). was 1.4. The risk of breast cancer for women enterThe risk of the disease was estimated in terms of the ing their first marriage at the age of 25 years o r older prevalence of benign and malignant lesions at the screening. The effect of a proposed aetiological factor was was 2.6 times greater than for women who married evaluated in terms of relative risk. Relative risk was esti- earlier. mated using the formula for a casecontrol study Women with benign breast lesions showed an inverse relationship. The relative risk with the first marriage at the age of 25 or older was 0.5 compared with those who married earlier. T h e relative risks of where XI,is the number of cases with a selected charac- breast cancer and benign lesions for nulliparous teristic, X,,the number of controls with the same charac- women in terms of unit risk for parous women with teristic, X,, and XZZthe numbers of cases and controls their first birth under 25 years of age were 1.7 and withoutthis characteristic. Confidence intervals for the 0.9, respectively. The total number of.full-term relative risks were estimated using the method proposed births also had an effect o n cancer risk, but only by Gart (9). Three classes of socioeconomic status were based on when women had more than two births ' ( ~ i g .2). the occupation of the woman or her husband and desig- hlultiparity had only a minor effect(RR=O.S) on the nated as low, average, and high, according to the classifi- risk of a benign lesion. Women aged 25 o r over at cation used by Finnish sociologists (23). When the risk of breast cancer and benign diseases the first full-term birth had a lower r i s k ' ( ~ ~ = 0 . 6of) associated with hereditary factors was estimated, the benign breast lesions than women with a n earlier female maternal relatives considered were the mother, first birth. grandmother, sisters and aunts. Paternal female relatives There was an excess of cancer cases in women were not included. reporting one o r more abortions. T h e relative risk The size of the women was taken as the product height abor2.1 compared with (cm)xweight (kg). The size of the breast was evaluated tion. Benign breast lesions had no relation to aborusing the brassikre cup size. A was the smallest and D the largest size. tions. Table 11. Nrrrnber nrrd screerrirtg p r c ~ ~ ~ l e r (/lo5) l c e o f berligri trrrd rrinligrrnrrt lesiorrs artrorrg tlre scrcerrerl poprrlntiorr by nge Age (years)
S r n r ~ dJ Soc Aied 7
No. of women invited
No. of controls
Benign lesions
hlalignant lesions
Number
Number
110'
/lOi
kt.d
Aarital status: Single vs. ever married
no i so lmnebo I malignant lesion
denarche: At 14 yrs. or earlier vs. at older age First marriage: At 25 yrs. or later vs. younger marriage First birth: At 25 yrs. or later vs. at earlier age First birth: N o birth vs. first birth under 25 yrs.
Uumber of births: 3 or more vs. no birth hbortions: 1 or more vs. no abortions
,actation periodlone child: Over 6 months vs. a shorter period Uenstrual cycle: Irregular vs. normal
! Fig. I. Relative risks of benign and malignant breast le-
0.3
0.5
1
2
3
relative risk
$ions distributed by reproductive and hormonal characteristics.
A relationship was found between the duration of actation and cancer risk. An average lactation period per child of more than 6 months was associated with decreased risk of cancer (RR=0.4) relative to women with a shorter lactation period. In benign breast lesions the decrease in risk was slight when the lactation period per child was longer. Women with an irregular menstrual cycle had a smaller risk of breast cancer (RR=0.3) and benign disease (RR=0.5) than women with a normal cycle. No association was found between the age at menarche and the risk of breast cancer or between the age at menarche and the risk of a benign lesion. Women who were given exogenous female hormones for therapy (in these age groups no oral contraceptives were used) for 6 months or more also had a lower risk of cancer (RR=0.4) than women who received no hormonal therapy. No relationship between exogenous female hormones and the risk of benign breast disease was found. 28 controls were oophorectomized, while 2 benign and 2 malignant cases were subjected to oophorectomy.
anamnesis. This risk of breast cancer was not increased for women with anamnestic breast disease (RR=0.2) Socioecononlic strrtits There were more cancer patients (RR=3.3) in the highest socioeconomic class than in the other two classes (Fig. 3). The effect of socioeconomic status was not as strong among women with benign breast diseases as among women with carcinomas. Hcretfity
The cancer patients had no breast cancer patients among their female maternal relatives. Women with benign breast diseases had more relatives with breast cancer than expected (RR=2.5) (Fig. 3).
relative
0 benrgn
1111
l m a l ~ g n a n t
Earlier breast cliseases
Women with acute mastitis in their anamnesis did not have an increased risk of cancer or of other breast diseases. Women who were operated on earlier for a benign breast tumour had 2. l times the risk of benign breast disease of women without this
1-2
3 or
more
2
number of btrlhs
Fig. 2. Estimates of relative risks of benign and malignant breast lesions distributed by number of full-term biths. Sro~rdJ Sor .\led 7
pk-
Socioeconomic status: High vs. average or low
I=-
Relatives with breast cancer vs. not Height x weight: over Size of
10700 vs. 10700 or less
33
2-5
breasts: Large vs. small a5
0.7
I 1
2
3
relative risk
0 benign lesion malignant lesion
Fig. 3 . Estimates of relative risks of benign and malignant
breast lesions distributed by socioeconomic status, fa-
Size
Cancer patients were somewhat smaller than the controls, and patients with benign breast lesions were clearly smaller than the controls (Fig. 3). Women with large breasts had a smaller risk of breast cancer (RR=0.4) and benign disease (RR= 0.7) than women with small breasts (Fig. 3).
DISCUSSION The risk of breast cancer depends on the age of the woman and increases up to the age of menopause, after which there is a IevelIing off for the next few years. Depending on the population, the risk increases, decreases, o r remains unchanged from the age of 50 years upwards. This irregularity around the menopausal age is known as 'Clemesen's hook' (3) and is an indication of two components of the disease possibly with different aetiology (1 1). In Finland the risk of breast cancer continues to rise after menopause (29). In the present study the prevalence of benign breast diseases decreased from the age of 50 upwards. This decrease indicates that either benign lesions become malignant, benign lesions regress in older age groups, or else benign lesions are more difficult to diagnose in older than in younger age groups. The last alternative has least credibility because the breast parenchyma becomes atrophic after menopause and its lesions are thus easier to detect. Because the population screened in this study was partly around the age of menopause, it was considered necessary to repeat the analyses separately for the age groups 41-50 and 51-60. The Scand J Soc .\lei/ 7
rnilial breast cancer anamnesis, and size of woman and breasts.
results were essentially the same for the risk of both benign and malignant lesions. However, the material was too small for detailed analysis by age. It is proposed that atypia of the ductal cells of the female breast is positively correlated with breast cancer (2). Gallager et al. (8) concluded that benign hyperplastic epithelial lesion and carcinoma are causally related, and that epithelial hyperplasia is premalignant in a non-obligate sense. On the other hand, Haagensen (10) proposed that though carcinoma is more common in women with a benign lesion, it does not especially arise from the dysplastic tissue. Women who previously had a breast biopsy because of benign breast disease..were proposed to have a 7-fold risk of a new breast lesion (31). In this series the risk was double. The frequency of benign disease in breast tissue removed at mastectomy for carcinoma varies from 39% to 46% (4, 24). Benign disease without malignancy was confirmed in 53% of autopsied women without breast symptoms during life (7). Consequently benign lesions are very common in the population. However, women with an earlier benign lesion confirmed histologically comprise only a small proportion (1.2%) of breast cancer patients (4). It is known that an increased risk of breast cancer is linked with hormone-associated factors such as early menarche (34), late first confinement (19). abortions (35) and an unmarried state (20). A high risk of breast cancer is also associated with a high standard of living (l7,21,30,35) and d i t h a familial breast cancer anamnesis (15,26). Different opinions exist as to lactation (20, 34), the size of the woman (5, 21) and the size of the breasts (30,33). In this material the mean age at first marriage and
Risk frtctot-s ofboiigrt lit-eotst lc~sioi~s 83
Table 111. Re1rrrh.e risks (RR) ~t'itlr95 % cortfitlcrtce litrtiis ( R R . RH)of bertigtr lesiorrs it1 ilre present strrrfj risks of hrcrrs~ccrrtcer l7rrsrtl oft sclcctrd rc.f~rcrtcesb j rc~prot1rrcti1.e clrarocterisrics trttol relrrti~~c Benign lesion Number
hialignant lesion
Cases Risk factor hlarital status: Single vs. ever married hlenarche: At 14 yrs. or earlier vs. at older age First marriage: At 25 yrs. or later vs. younger mamage First birth: At 25 yrs. or later vs. at an earlier age First birth: No birth vs. first birth under 25 yrs. Number of births: 3 or more vs. no birth Abortions: 1 o r more vs. no abortions
Controls RR
References
2.4
1.2-1.5
18
1.0
1.6
1.3-1.5
27,24
0.3
0.5
0.8
1.7
15
208
0.4
0.6
1.0
1.5
17
121
208
0.6
0.9
1.5
1.7
17
32
171
I21
0.5
0.8
1.4
0.4-0.5
14, 15
101
130
40-1
0.6
0.9
1.5
1.2
27
Exposed
Nonexp.
Exposed
23
108
69
465
0.9
1.4
74
57
303
23 1
0.7
24
85
175
290
38
61
205
32
61
37 30
at first birth was 22.1 and 25.3 years, respectively (27). The mean age at menarche for controls was 14.3 years (27). Among younger cohorts the age at menarche is lower. For the Finnish females born in 1949-59, it was estimated to be 13.2 years (12). Table 111 shows a summary from published reports on the most important reproductive factors associated with the risk of breast cancer. Even though the present series is small, many of these associations were confirmed (socioeconomic status, age at marriage, parity, abortions). A twofold risk was associated with short lactation. The risk was not affected by the size of the woman. The association of breast cancer with the period of lactation was possibly confounded by other hormonal and reproductive characteristics. Hormonal therapy was found to be associated with reduced risk of breast cancer (RR=0.4), which is consistent with the results of no increase in risk (I). Even though socioeconomic status, parity, and abortions were associated with the risk of breast cancer, no such association was found for benign lesions. The relative risks for benign lesions varied between 0.8 and 1.3 and were consistently closer to I as compared with breast cancer. Hormonal therapy was not associated with the risk of benign lesions, either (RR= 1.2). One of the most important high-risk factors for breast cancer, late first marriage and late age at birth of first child (19), was
Nonexp.
RR
inversely associated with benign lesions. Those with marriage or first birth at the age of 25 or younger had a ?-fold risk of benign breast disease as compared with those 25 o r older. There are only a few published reports dealing with the risk factors of benign breast lesions. Exogenous female hormones are likely to be associated with a reduced risk of benign lesions (25). In t\do earlier reports (13, 22) benign breast disease appeared to be unrelated to the age at first birth, whereas low parity was related to the increased risk of benign lesion (13). In the present study the epidemiological dharacteristics of benign and malignant lesions were dissimilar. However, the risk factors should also be related if benign and malignant lesions are causally related (8) or if they are associated without the transition of a benign lesion into breast cancer (10). The results published are markedly influenced by diagnostic difficulties. The prevalence of benign breast disease depends on the diagnostic facilities and diagnostic criteria (4). In the present series the prevalence of benign breast disease was less than 1 %, indicating marked underdiagnosis (7). If diagnostic errors affect the relative risks, thi? effect should decrease the observed inverse relationship rather than cause one. We therefore conclude that benign and malignant lesions of the female breast either are not associated o r else an associated subSccrricl J Soc ,\led 7
g r o u p o f benign lesions is small e n o u g h to remain undetected without detailed morphological o r o t h e r classification o f t h e lesions ( 2 , 14). Consequently t h e d e c r e a s e in t h e prevalence o f benign breast les i o n s after menopause is m o r e likely t o be d u e t o regression than t o transition t o carcinoma. T h e n u m e r o u s results in t h e literature s h o w i n g t h e reverse m a y b e d u e t o methodological artefacts, a s it is likely t h a t w o m e n with breast c a n c e r are m o r e accurately diagnosed f o r earlier benign breast dise a s e , which is v e r y prevalent in a n unselected population.
ACKNOWLEDGEhlENT This study was supported (I. S.) by the Pirkanmaa Cancer Society, Finland
14. IS. 16. 17. 18. 19.
20.
REFERENCES I. Arthes, F. G., Sartuell, P. E. & Lewison, E. F.: The pill, estrogens and the breast. Epidemiologic aspects. Cancer 28: 1391, 1971. 2. Black, hi. hl., Barclay, T. H. C, Cutler, S. J., Hankey, B. F. & Asire, A. J.: Association of atypical characteristics of benign breast lesions with subsequent risk of breast cancer. Cancer 29: 338, 1971. 3. Clemmesen, J.: Carcinoma of the breast. Symposium. Results from statistical research. Br J Radiol 21:583, 1948. 4. Davis, H. H., Simons, hl. & Davis, J . B.: Cystic disease of the breast. Relationship to carcinoma. Cancer 17: 957, 1964. 5. de Waard, F., Baanders-van Halewijn, E. A. & Huizinga, J.: The bimodal aSe distribution of patients with mammary cancer. Cancer 17: 141, 1964. 6. Donnelly, P. P., Baker, K. W., Carney, J. A. & O'FalIon, W. hi.: Benign breast lesions and subsequent breast carcinoma in Rochester, hlinnesota. hlayo Clin Proc 50: 650, 1975. 7. Frantz, V. K., Pickren, J. W., hfelcher, G. W. & Auchincloss, H., Jr: Incidence of chronic cystic disease in so-called "normal breasts". Study based on 225 postmortem examinations. Cancer 4:762, 1951. 8. Gallager, H. S. & hlartin, J. E.: Early phases in the development of breast cancer. Cancer 24: 1170, 1969. 9. Gart, J.: Approximate confidence limits for the relative risk. J R Statist Soc B 24:454, 1962. 10. Haagensen, C. D.: Diseases of the breast, 2nd ed., pp. 168-172. Philadelphia, Saunders, 1972. 11. Hakarna, hi.: The Peculiar age specific incidence curve for cancer of the breast-Clemmesen's hook. Acta Pathol hlicrobiol Scand [A] 75: 370, 1969. 12. Kantero, R-L. 8:\Vidholm, 0.: The age of menarche in Finnish girls in 1969. Acta Obstet Gynecol Scand, Suppl. 14:7, 1971. 13. Kelsey, J. L., Lindfors, K. K. & White, C:: A casecontrol study of the epidemiology of benign breast Scn~tclJ Soc .\let1 7
21. 22. 23. 24. 25.
26. 27. 28. 29.
30.
31. 32.
l use. Int diseases with reference to o c ~ contraceptive J Epidemiol 3:333, 1974. Kern, W. H. & Brooks, R. N.: Atypical epithelial hyperplasia associated with breast cancer and fibrocystic disease. Cancer 24: 668, 1969. Lilienfeld. A. Xl.: The epidemiology of breast cancer. Cancer Res 23: 1503, 1963. Lin, T. hl., Chen, K. P. 8: XIacXlahon. B.: Epidemiologic characteristics of cancer of the breast in Taiivan. Cancer 27: 1497, 1971. L o ~ e C. . R. & XlacXlahon, B.: Breast cancer and reproductive history of women in South Wales. Lancet i: 153, 1970. hlachlahon, B., Cole, P. & Brown, J.: Etiology of human breast cancer: A review. J. Natl Cancer lnst 50:21, 1973. hlachlahon. B., Cole, P., Lin, T. hi., Lone, C. R., hlirra, A. P., Ravnihar, B., Salber, E. J., Valaoras, V. G. & Yuasa, S.: Age at first birth and breast cancer risk. Bull WHO 43: 209, 1970. hlachlahon, B., Lin, T. hi., Lowe, C. R., hlirra, A. P., Ravnihar, B., Salber, E. J., Trichopoulos, D., Valaoras, V. G. & Yuasa, S.: Lactation and cancer of the breast. A summary of an international study. Bull WHO 42: 185, 1970. hlirra, A. P., Cole, P. 8: hlachlahon, B.: Breast cancer in an area of high parity: Sao Paolo, Brazil. Cancer Res 3 1:77, 1971. Ory, H., Cole, P., hlachlahon, B. & Hoover, R.: Oral contraceptives and reduced risk of benign breast diseases. N Engl J hted 294: 419, 1976. Rauhala, U.: Suomalaisen yhteiskunnan sosiaalinen kerrostuneisuus. With English summary. Helsinki WSOY, 1966. Rimsten, A., Stenqvist, B. & Lindgren, A.: Clinical findings in relation to morphology in breast carcinoma. Ann Clin Res 7:89, 1975. Sartaell, P. E., Arthes, F. G. & Tonascia, J. A.: Epidemiology of benign breast lesions: Lack of association with oral contraceptive use. N Engl J hled 228: 55 1, 1973. Shapiro, S., Strax, P., Venet, L. & Fink, R.: The search for risk factors in breast cancer. Am J Public Health 58: 820. 1968. Soini, I.: Risk factors of breast cancer in Finland. Int J Epidemiol 6: 365, 1977. Soini, I. & Lauslahti, K.: Screening for breast cancer in women aged 41-60. Ann Clin Res 8:403, 1976. Teppo, L., Hakama, hl., Hakulinen, T., Lehtonen, hl. & Saxkn, E.: Cancer in Finland 1953-1970. Incidence, mortality, prevalence. Acta Pathol hlicrobiol Scand [A], Suppl. 252: 36, 1975. Valaoras, V. G . , htachlahon, B., Trichopoulos, D. & Polychronopoulou, A.: Lactation and reproductive histories of breast cancer patients in Greater Athens, 1965-67. Int J Cancer 4: 350, 1960. Vessey, hl. P., Doll, R. 8: Sutton, P. hI.: Oral contraceptives and breast neoplasia: A retrospective study. Br hled J iii: 719, 1972. WHO: Histological typing of breast tumours. International histological classification of tumours No. 2. Geneva, 1968.
Risk firctors of D r r i i . ~Bretrst ~~ lesiorls
33. Wynder. E. L.: Identification of women at high risk for breast cancer. Cancer 74: 1235. 1969. 34. Wynder, E. L., Bross, I . J . Rr Hi~iyama.T.: A study of the epidemiology of cancer of the breast. Cancer 13: 559, 1960. 35. Yunsn. S. & hlachlahon. B.: Lactation and reproduclive histories of breast cancer patients in Tokyo, Japan. Bull WHO 42: 195, 1970. 36. Zajicek, J.: Aspintion biopsy cytology of the breast. international Academy of Cytology. Tutorials of Cytology. Chicago, 1973.
85
Adrlrcssfor rcprinls:
Irma Soini, h1.D. Department of Public Iiealth of Tampere Vuolteenkatu I I P . ~ Box . 607 SF-33101T~~~~~~10 Finland
Sccrr~dJ Sor ,\led 7
Inverse Association Between Risk Factors for Benign and Malignant Breast Lesions Irma Soini and hlatti H a k a m a
Itrv~rsc.crssocirrtiotr bet~t.eetcrisk frrrrors for belrigtl trtrcl t~rnligtrtrtlrbrenst lesiotls. Soini, I. and Hakama, hl. (Detection Center and Laboratories of the Pirkanmaa Cancer Society, and Dept. of Public Health, University of Tampere, Tampere, Finland). Sccct~dJ Soc hled 1979.2 (79-85).
The purpose of the present study was to compare the risk of breast cancer and the risk of benign breast disease using known risk factors for breast cancer. The series was taken during breast cancer screening of women aged 41-60 in an industrial city in Finland. 158 breast lesions were diagnosed, 27 of which were malignant. Women with breast disease and 534 controls were interviewed to obtain epidemiological data. The prevalence of benign lesions decreased after menopause but the prevalence of carcinomas was essentially the same over the age span 41-60. Several risk factors for breast cancer, such a s selected reproductive and hormonal characteristics, were not associated with t h e risk of benign breast disease. Thus it was concluded that benign and malignant breast lesions are not associated in general, and the decrease in the prevalence of benign breast lesions after menopause is more likely to be due to regression than to transition to carcinoma.
It has been proposed that breast c a n c e r is preceded by benign breast disease. T h e estimated risk o f breast c a n c e r a m o n g women with previous benign disease varies from 1.7 t o 4.5 times that of t h e general population (4). I n a prospective study ( 6 ) breast c a n c e r developed in 3.8% o f w o m e n with a median period o f 13.5 years after t h e diagnosis o f benign breast disease. A n excess risk o f breast c a n c e r w a s found t o persist 30-40 years after the diagnosis o f t h e benign breast lesion (18). T h e purpose of the present study w a s t o c o m p a r e the risk o f breast cancer a n d the risk o f benign breast disease using known risk factors f o r breast cancer. T h e most important of these factors are: a n unmarried state, early menarche, late first marriage a n d late first confinement (19, 20). T h e empirical series originates from a mass screening project or-
ganized in Finland (18). T h e incidence o f breast c a n c e r in Finland is 33.9 p e r 10' (29). which is below t h e rates in most western countries. T h e incidence of.benign breast lesions is difficult t o estimate a n d n o reliable d a t a a r e available. hlATERIAL A N D hlETHODS The series in this study was compiled during a breast cancer screening project organized in 1974-75 in Tampere, an industrial city in central Finland. Tampere had a population of 160750 in 1974, and 20644 females were in the age group 41-60. All wornen in this group were personally invited to the screening. The response rate was 83%. These women were screened through a clinical examination by trained nurses. Subjects with an abnormal finding (615) were referred to a physician for further examination. The indications for this further examination were: a lump; retracted nipple; big breast, difficult to palpate; change in the skin.of the breast and the nipple; secretion; intense pain in the breasts and pathologically enlarged axillary lymph nodes. hlammography was performed on these women and a fine-needle biopsy was obtained when needed. All women referred for further examination were interviewed by .nurses to obtain epidemiological data concerning the risk of breast cancer. Eighty-four women with benign and 27 women with malignant breast lesion were diagnosed and histologically confirmed. The histological typing was made according to the classification of the WHO (32). The diagnosis of a benign lesion included benign mammary dysplasias (45 cases of cyst, adenosis, ductectasia, fibrosclerosis) and benign or apparently benign tumours (39 cases of adenorna, papilloma, tibroadenorna). A further 47 benign cases were diagnosed but not histologically confirmed. These cases had in a fine-needle biopsy Papanicolaou class 2 with morphological changes suspicious of benign dysplasia or tumour (36), and also marked dysplastic features at mammography. Women with no referral from clinical examination by nurses and following an abnormal finding were selected as controls, of which 534 attended the interview concerning reproductive, hormonal and other characteristics associated with the risk of breast cancer. The breast of these controls were judged normal solely on the basis of the Sctrrrcl J Soc ,\led 7
Table I. Dirrgrloscs of tlre 1~siorr.s
RESULTS No. of patients
Diagnosis
Benign breast lesion 131 Confirmed by histology 84 Confirmed by mammography and cytology 47 hlalignant breast lesion 17 Normal control 534 Total 691
The age distribution of the women invited to the screening and the screening prevalence rates of the benign and malignant lesions by age are given in Table 11. T h e screening prevalence of benign lesions decreased from 8291 10511 the age range 41-50 to 4291 IOi in the age range 5 1 4 0 years. T h e screening prevalence of carcinomas was essentially the same over the age span 41 to 60.
Rcpro(lrrcti~~e arrd horr~ror~nl chrrrrrcteristics clinical examination. In the epidemiological series (Table I) there are about three times as many controls as cases Relative risks by reproductive and hormonal because some of the women with an abnormal finding at characteristics are resented in Fic. - I. clinical examination and referred for further examination T h e relative risk of breast cancer for single womhad no abnormality at mammography or cytology and were not operated on. Only women originally selected as .en in terms of unit risk for women who had ever controls were accepted in the analysis. Details on the been married was 1.2 in the present series; the organization of the study and the histological classification corresponding estimate for a benign breast lesion of the series are given by Soini & Lauslahti (28). was 1.4. The risk of breast cancer for women enterThe risk of the disease was estimated in terms of the ing their first marriage at the age of 25 years o r older prevalence of benign and malignant lesions at the screening. The effect of a proposed aetiological factor was was 2.6 times greater than for women who married evaluated in terms of relative risk. Relative risk was esti- earlier. mated using the formula for a casecontrol study Women with benign breast lesions showed an inverse relationship. The relative risk with the first marriage at the age of 25 or older was 0.5 compared with those who married earlier. T h e relative risks of where XI,is the number of cases with a selected charac- breast cancer and benign lesions for nulliparous teristic, X,,the number of controls with the same charac- women in terms of unit risk for parous women with teristic, X,, and XZZthe numbers of cases and controls their first birth under 25 years of age were 1.7 and withoutthis characteristic. Confidence intervals for the 0.9, respectively. The total number of.full-term relative risks were estimated using the method proposed births also had an effect o n cancer risk, but only by Gart (9). Three classes of socioeconomic status were based on when women had more than two births ' ( ~ i g .2). the occupation of the woman or her husband and desig- hlultiparity had only a minor effect(RR=O.S) on the nated as low, average, and high, according to the classifi- risk of a benign lesion. Women aged 25 o r over at cation used by Finnish sociologists (23). When the risk of breast cancer and benign diseases the first full-term birth had a lower r i s k ' ( ~ ~ = 0 . 6of) associated with hereditary factors was estimated, the benign breast lesions than women with a n earlier female maternal relatives considered were the mother, first birth. grandmother, sisters and aunts. Paternal female relatives There was an excess of cancer cases in women were not included. reporting one o r more abortions. T h e relative risk The size of the women was taken as the product height abor2.1 compared with (cm)xweight (kg). The size of the breast was evaluated tion. Benign breast lesions had no relation to aborusing the brassikre cup size. A was the smallest and D the largest size. tions. Table 11. Nrrrnber nrrd screerrirtg p r c ~ ~ ~ l e r (/lo5) l c e o f berligri trrrd rrinligrrnrrt lesiorrs artrorrg tlre scrcerrerl poprrlntiorr by nge Age (years)
S r n r ~ dJ Soc Aied 7
No. of women invited
No. of controls
Benign lesions
hlalignant lesions
Number
Number
110'
/lOi
kt.d
Aarital status: Single vs. ever married
no i so lmnebo I malignant lesion
denarche: At 14 yrs. or earlier vs. at older age First marriage: At 25 yrs. or later vs. younger marriage First birth: At 25 yrs. or later vs. at earlier age First birth: N o birth vs. first birth under 25 yrs.
Uumber of births: 3 or more vs. no birth hbortions: 1 or more vs. no abortions
,actation periodlone child: Over 6 months vs. a shorter period Uenstrual cycle: Irregular vs. normal
! Fig. I. Relative risks of benign and malignant breast le-
0.3
0.5
1
2
3
relative risk
$ions distributed by reproductive and hormonal characteristics.
A relationship was found between the duration of actation and cancer risk. An average lactation period per child of more than 6 months was associated with decreased risk of cancer (RR=0.4) relative to women with a shorter lactation period. In benign breast lesions the decrease in risk was slight when the lactation period per child was longer. Women with an irregular menstrual cycle had a smaller risk of breast cancer (RR=0.3) and benign disease (RR=0.5) than women with a normal cycle. No association was found between the age at menarche and the risk of breast cancer or between the age at menarche and the risk of a benign lesion. Women who were given exogenous female hormones for therapy (in these age groups no oral contraceptives were used) for 6 months or more also had a lower risk of cancer (RR=0.4) than women who received no hormonal therapy. No relationship between exogenous female hormones and the risk of benign breast disease was found. 28 controls were oophorectomized, while 2 benign and 2 malignant cases were subjected to oophorectomy.
anamnesis. This risk of breast cancer was not increased for women with anamnestic breast disease (RR=0.2) Socioecononlic strrtits There were more cancer patients (RR=3.3) in the highest socioeconomic class than in the other two classes (Fig. 3). The effect of socioeconomic status was not as strong among women with benign breast diseases as among women with carcinomas. Hcretfity
The cancer patients had no breast cancer patients among their female maternal relatives. Women with benign breast diseases had more relatives with breast cancer than expected (RR=2.5) (Fig. 3).
relative
0 benrgn
1111
l m a l ~ g n a n t
Earlier breast cliseases
Women with acute mastitis in their anamnesis did not have an increased risk of cancer or of other breast diseases. Women who were operated on earlier for a benign breast tumour had 2. l times the risk of benign breast disease of women without this
1-2
3 or
more
2
number of btrlhs
Fig. 2. Estimates of relative risks of benign and malignant breast lesions distributed by number of full-term biths. Sro~rdJ Sor .\led 7
pk-
Socioeconomic status: High vs. average or low
I=-
Relatives with breast cancer vs. not Height x weight: over Size of
10700 vs. 10700 or less
33
2-5
breasts: Large vs. small a5
0.7
I 1
2
3
relative risk
0 benign lesion malignant lesion
Fig. 3 . Estimates of relative risks of benign and malignant
breast lesions distributed by socioeconomic status, fa-
Size
Cancer patients were somewhat smaller than the controls, and patients with benign breast lesions were clearly smaller than the controls (Fig. 3). Women with large breasts had a smaller risk of breast cancer (RR=0.4) and benign disease (RR= 0.7) than women with small breasts (Fig. 3).
DISCUSSION The risk of breast cancer depends on the age of the woman and increases up to the age of menopause, after which there is a IevelIing off for the next few years. Depending on the population, the risk increases, decreases, o r remains unchanged from the age of 50 years upwards. This irregularity around the menopausal age is known as 'Clemesen's hook' (3) and is an indication of two components of the disease possibly with different aetiology (1 1). In Finland the risk of breast cancer continues to rise after menopause (29). In the present study the prevalence of benign breast diseases decreased from the age of 50 upwards. This decrease indicates that either benign lesions become malignant, benign lesions regress in older age groups, or else benign lesions are more difficult to diagnose in older than in younger age groups. The last alternative has least credibility because the breast parenchyma becomes atrophic after menopause and its lesions are thus easier to detect. Because the population screened in this study was partly around the age of menopause, it was considered necessary to repeat the analyses separately for the age groups 41-50 and 51-60. The Scand J Soc .\lei/ 7
rnilial breast cancer anamnesis, and size of woman and breasts.
results were essentially the same for the risk of both benign and malignant lesions. However, the material was too small for detailed analysis by age. It is proposed that atypia of the ductal cells of the female breast is positively correlated with breast cancer (2). Gallager et al. (8) concluded that benign hyperplastic epithelial lesion and carcinoma are causally related, and that epithelial hyperplasia is premalignant in a non-obligate sense. On the other hand, Haagensen (10) proposed that though carcinoma is more common in women with a benign lesion, it does not especially arise from the dysplastic tissue. Women who previously had a breast biopsy because of benign breast disease..were proposed to have a 7-fold risk of a new breast lesion (31). In this series the risk was double. The frequency of benign disease in breast tissue removed at mastectomy for carcinoma varies from 39% to 46% (4, 24). Benign disease without malignancy was confirmed in 53% of autopsied women without breast symptoms during life (7). Consequently benign lesions are very common in the population. However, women with an earlier benign lesion confirmed histologically comprise only a small proportion (1.2%) of breast cancer patients (4). It is known that an increased risk of breast cancer is linked with hormone-associated factors such as early menarche (34), late first confinement (19). abortions (35) and an unmarried state (20). A high risk of breast cancer is also associated with a high standard of living (l7,21,30,35) and d i t h a familial breast cancer anamnesis (15,26). Different opinions exist as to lactation (20, 34), the size of the woman (5, 21) and the size of the breasts (30,33). In this material the mean age at first marriage and
Risk frtctot-s ofboiigrt lit-eotst lc~sioi~s 83
Table 111. Re1rrrh.e risks (RR) ~t'itlr95 % cortfitlcrtce litrtiis ( R R . RH)of bertigtr lesiorrs it1 ilre present strrrfj risks of hrcrrs~ccrrtcer l7rrsrtl oft sclcctrd rc.f~rcrtcesb j rc~prot1rrcti1.e clrarocterisrics trttol relrrti~~c Benign lesion Number
hialignant lesion
Cases Risk factor hlarital status: Single vs. ever married hlenarche: At 14 yrs. or earlier vs. at older age First marriage: At 25 yrs. or later vs. younger mamage First birth: At 25 yrs. or later vs. at an earlier age First birth: No birth vs. first birth under 25 yrs. Number of births: 3 or more vs. no birth Abortions: 1 o r more vs. no abortions
Controls RR
References
2.4
1.2-1.5
18
1.0
1.6
1.3-1.5
27,24
0.3
0.5
0.8
1.7
15
208
0.4
0.6
1.0
1.5
17
121
208
0.6
0.9
1.5
1.7
17
32
171
I21
0.5
0.8
1.4
0.4-0.5
14, 15
101
130
40-1
0.6
0.9
1.5
1.2
27
Exposed
Nonexp.
Exposed
23
108
69
465
0.9
1.4
74
57
303
23 1
0.7
24
85
175
290
38
61
205
32
61
37 30
at first birth was 22.1 and 25.3 years, respectively (27). The mean age at menarche for controls was 14.3 years (27). Among younger cohorts the age at menarche is lower. For the Finnish females born in 1949-59, it was estimated to be 13.2 years (12). Table 111 shows a summary from published reports on the most important reproductive factors associated with the risk of breast cancer. Even though the present series is small, many of these associations were confirmed (socioeconomic status, age at marriage, parity, abortions). A twofold risk was associated with short lactation. The risk was not affected by the size of the woman. The association of breast cancer with the period of lactation was possibly confounded by other hormonal and reproductive characteristics. Hormonal therapy was found to be associated with reduced risk of breast cancer (RR=0.4), which is consistent with the results of no increase in risk (I). Even though socioeconomic status, parity, and abortions were associated with the risk of breast cancer, no such association was found for benign lesions. The relative risks for benign lesions varied between 0.8 and 1.3 and were consistently closer to I as compared with breast cancer. Hormonal therapy was not associated with the risk of benign lesions, either (RR= 1.2). One of the most important high-risk factors for breast cancer, late first marriage and late age at birth of first child (19), was
Nonexp.
RR
inversely associated with benign lesions. Those with marriage or first birth at the age of 25 or younger had a ?-fold risk of benign breast disease as compared with those 25 o r older. There are only a few published reports dealing with the risk factors of benign breast lesions. Exogenous female hormones are likely to be associated with a reduced risk of benign lesions (25). In t\do earlier reports (13, 22) benign breast disease appeared to be unrelated to the age at first birth, whereas low parity was related to the increased risk of benign lesion (13). In the present study the epidemiological dharacteristics of benign and malignant lesions were dissimilar. However, the risk factors should also be related if benign and malignant lesions are causally related (8) or if they are associated without the transition of a benign lesion into breast cancer (10). The results published are markedly influenced by diagnostic difficulties. The prevalence of benign breast disease depends on the diagnostic facilities and diagnostic criteria (4). In the present series the prevalence of benign breast disease was less than 1 %, indicating marked underdiagnosis (7). If diagnostic errors affect the relative risks, thi? effect should decrease the observed inverse relationship rather than cause one. We therefore conclude that benign and malignant lesions of the female breast either are not associated o r else an associated subSccrricl J Soc ,\led 7
g r o u p o f benign lesions is small e n o u g h to remain undetected without detailed morphological o r o t h e r classification o f t h e lesions ( 2 , 14). Consequently t h e d e c r e a s e in t h e prevalence o f benign breast les i o n s after menopause is m o r e likely t o be d u e t o regression than t o transition t o carcinoma. T h e n u m e r o u s results in t h e literature s h o w i n g t h e reverse m a y b e d u e t o methodological artefacts, a s it is likely t h a t w o m e n with breast c a n c e r are m o r e accurately diagnosed f o r earlier benign breast dise a s e , which is v e r y prevalent in a n unselected population.
ACKNOWLEDGEhlENT This study was supported (I. S.) by the Pirkanmaa Cancer Society, Finland
14. IS. 16. 17. 18. 19.
20.
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Risk firctors of D r r i i . ~Bretrst ~~ lesiorls
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85
Adrlrcssfor rcprinls:
Irma Soini, h1.D. Department of Public Iiealth of Tampere Vuolteenkatu I I P . ~ Box . 607 SF-33101T~~~~~~10 Finland
Sccrr~dJ Sor ,\led 7
