Carcinoma of the cervix in oral contraceptive steroid and IUD users and nonusers HERBERT
F.
SANDMIRE,
STEPHEN
D.
AUSTIN,
RICHARD
C.
BECHTEL,
M.D. M.D. M.D.
Green Buy, Wisconsin
A total of 40,211 cytologic examinations and subsequent diagnostic procedures resulted in the diagnosis of carcinoma of the cervix in 76 patients. The 74 patients did not demonstrate any variations in use of oral contraceptive steroids or intrauterine deuices when compared to 780 randomly selected control patients, This study is in agreement with our earlier report demonstrating no increased risk of carcinoma of the cervix in oral contraceptive
steroid
users
compared
to nonusers.
C ON s I DE RA B LE interest has arisen concerning the possible carcinogenic properties of oral contraceptive steroids. In particular, the effect of these compounds on the uterine cervix and breasts has been widely speculated upon. Dunn’ demonstrated the development of cervical carcinoma in mice given an oral contraceptive containing both the estrogen, mestranol, and the progestogen, norethynodrel, for a prolonged period of time in daily doses roughly equivalent to the amounts received by women using the early oral contraceptives. Dougherty: in an uncontrolled study, reported a rate of occurrence of cytologic atypia twice as high as expected in 1983 women using sequential oral contraceptive steroids. Kline and associates3 demonstrated a 2.0 per cent rate of abnormal smears in pill users compared to 1.0 per cent in nonusers. It should be noted, however, that 19 of the 45 abnormal smears from pill users reverted to normal, 15 while continuing to use the pill and 4 after cessation of the pill. In addition, biopsy was performed on only nine of the 45 abnormal smear patients, resulting in the following diagnoses: mild dysplasia, four; endocervical hyperplasia., two; severe dysplasia, three. Biopsy data on nonusers were not tabulated, preventing any comparison of histologic findings in pill users and nonusers. Melamed and associate& observed a small but statistically significant increase in carcinoma of the cervix among both pill choosers and pill users when
compared to diaphragm choosers and users. He indicated that his results “can be attributed either to a decreased prevalence rate for women using a diaphragm or to an increased rate for women using oral steroids.” He further indicated that the difference is consistently present in subsets corrected for each of five factors known to influence the prevalence rate of cervical carcinoma: age, ethnic orgin, age at first pregnancy (as a reflection of early sexual experience), number of live births, and family income. Our previous analysid of 15,000 consecutive Pap smears failed to demonstrate an increased risk of carcinoma of the cervix in pill users compared to nonusers. Wied and associates6 in 1966 reported on 1,628 patients-on oral contraceptives for at least one year-,and found no statistically significant increase of even slight atypia in pill users compared to nonusers. Similar studies by Boyce and associates,7 Miller,’ and Courey and Powell’ all reported equal risks of cervical neoplasia in pill users and nonusers. Thomas” compared the contraceptive history of 324 women with cytologic smears suggestive of neoplasia with 302 matched control patients. His results led him to conclude that women using oral contraceptives for an average of 20 months are no more likely to develop squamous dysplasia or carcinoma in situ within 2% to 3 years after initial use than are women who do not use oral contraceptives. Melamed and Flehinger,” in a more recent article, reported on estimated incidence rates of carcinoma in situ and other precancerous cervical lesions in carefully matched diaphragm and steroid users in one group and IUD and steroid users in another group. The data
Pmrnted at the Forty-third Annual Meeting of the Central Association of Obstetricians and Gynecologists, Coloro.do Springs, Colorado, September 26-28, 1975. Reprint requests: Dr. Herbert F. Sandmire, 704 S. Webster Ave., Green Bay, Wisconsin 54301.
339
340
Sandmire,
Austin,
Table I. Findings 1960-1975*
Class I
June 1. 1976 hn. J. Obstet. Gynecol.
and Bechtel
in 40,2 I 1 consecutive
39,867
99. 14
“(i2
Class II Class III Class IV Class V Total
Pap smears:
0.6.3
50 I1 18
I : 1.53 1 : 801 112x72 1 : 2233 I:117
0.12 0.03 0.0-l
344
0.8,4
II. Average
number
of smears
in control
patients* No.
Current IUD users
4.35 ti.33
Previous Previous Non-pill Total
4.50 .5.75 24.7” 4.77
Current
pill users pill users IUD users and IUD users a11 controls
*Calculations based upon number of smears performed control patients from the total
Table
III. Median
the actual counting on 240 randomly of 807 controls.
age of control
Pill users IUD users Non-pill and IUD users Total control patients
Table
IV. Median
age of carcinoma
Carcinoma in situ Carcinoma in situ with microinvasion Invasive carcinoma Total carcinomas
use
on
the
dysplasia dysplasia
transit
time
to carcinoma to carcinoma
in
the
progression
of
in situ (86 months) in situ (12 months).
mild
and severe
Materials and method
*Carcinomas, 1 : 529 Pap smears. Table
cytologic evaluations. Nine patients showed cytologic evidence of regression: five from marked dysplasia OI carcinoma in situ to mild or moderate dysplasia and four from moderate or marked dysplasia to negative smears. Kichart and Barn)@ reported no influence of IUD
In 1960 a cytology registry was organized by two of the three present authors in their practice in Green Bay, Wisconsin. Our present analysis (Table I) includes the first 40,211 consecutive (1960-1975) Pap smears registered and 807 randomly selected control patients. In 27 of the control patients contraceptive data were missing, leaving 780 patients for analysis. Pap smears in our year,
of the selected
patients
27.5 31..5 31.5 3o.j
patients
29.5 35.0 55.0 35.0
are derived from patients having two consecutive annual negative Pap smears who subsequently develop precancerous cervical lesions. The more recent study did not reveal any increase in incidence of carcinoma in situ and other precancerous cervical lesions in pill users compared to diaphragm and II:D users. Ayre and associates I* followed 27 patients using oral contraceptive steroids cytologically diagnosed as having dysplasia, moderate or marked, and beginning carcinoma in situ. None of the patients progressed to a more advanced lesion demonstrable by periodic
registry with
are the
numbered
first
two
in sequential numbers
being
fashion the
last
by two
numbers of the year in which the smear was obtained. As an example, Pap smears obtained during 1974 were numbered from 74-l through 74-5157. In order to randomize our controls, an outside person selected two two-digit numbers, 14 and 52, and every Pap smear number in our registry ending in 14 and 52 M~S selected as a tontrol patient. This “index” smear selects the patient and the collected data apply to the time of the index smear even though the patient may have had other
smears
during
the
study.
In
this
manner
a
control patient was selected by- picking every fiftieth Pap smear I’or each year. A correction factor was necessary because the average number of Pap smears per patient was different for various categories ot patients (Table 1I). ‘The correction factor will be explained later but was necessary because the number of Pap smears in our registry per patient could influence the probability of any given patient being selected as a control (every fiftieth Pap). Duplication was avoided by selecting the next Pap smear number following the one ending in It or 52 when a patient had already been selected as a control; in the same manner all abnormal smears were avoided in control selection. In addition, through human error two patients, 62-452 and 73-2552. were not included in our control groups. We do not know directly the total number of patients involved in the study. Indirectly, by dividing the total number of Pap smears (40,2 11) by the average number of Pap smears per patient of 4.77, we have a total of‘ 8,386 patients. The control and carcinoma patients were predominately
white
and
middle
class on a socioeconomic
scale.
Cervical carcinoma in oral contraceptive and IUD users and nonusers
Volume Number
125 3
Table
V. Total
carcinomas
in 40,211
Diag7Losis
Pap smears No. of pltients
Carcinoma insitu Carcinoma in situ
41
Table VII. Carcinoma of the cervix in patients previously using oral contraceptive steroids Carcinoma
had previously used the pill
86/377t
Controls
Carcinoma
of the cervix in oral users
20176
26.3%
of carcinoma patients were on the pill
Controls
196/780
25.1%
of control patients were on the pill
Corrected controls*
214/780
27.4%
of control patients were on the pill
*Corrected per patient
22.8% of control patients
26 76 Corrected controlsf
Table VI. Carcinoma contraceptive steroid
9.8% of carcinoma patients
5/51*
9
with microinvasion Invasive carcinoma Total
for the disproportionate category in the 40,211
number of Pap smears total smears.
The median age for each group is tabulated in Tables III and IV. Since the present paper deals only with the question of the possible effect of oral contraceptive steroids and intrauterine devices on the risk of carcinoma of the cervix, a subsequent communication will report on the remainder of our experience with the 40,211 smears, including an analysis of dysplasia patients in oral contraceptive steroid users. The main goal of the present study was to detec,t any variation in contraceptive use in the 76 carcinoma patients (Table V) when compared to the 780 control patients. Although we recorded data on the condom and diaphragm, their use was too infrequent to produce statistically significant results and will not be included. The present data are limited to use or nonuse of the oral contraceptive steroids and the intrauterine contraceptive device (IUD) in cervical carcinoma patients. For each of thea#e agents we are reporting on previous as well as current use and the duration of use in both categories in the comparison of the carcinoma patients with the controls.
Results and comment Twenty (26.3 per cent) of the 76 carcinoma subjects (Table VI) were currently using oral contraceptive steroids at the time of discovery of their lesions. Two of these patients had invasive lesions and the remaining 18 carcinoma in situ. Of 780 control patients, 196 (25.1 per cent) were using oral contraceptives. The pill users in the control patients had an average of 4.35 smears in our registry whereas the over-all average number of smears per control patient was 4.77. This would result in fewer pill users being selected as controls (every
341
91/377?
had previously used the pill of control patients had previously used the pill
24.1%
*Previous contraceptive history missing in 25 patients. TPrevious contraceptive history missing in 403 control patients. SCorrected for the disproportionate number of Pap smears per patient category in the 40,2 11 total patients.
Table VIII. Carcinoma previously or presently steroids Carcinoma
36.1%
of carcinoma patients were using or had previously used the pill 47.9% of control patients were using or had previously used the pill 5 1.5 % of control patients were using or had previously used the pill
Controls
Corrected controls*
*Corrected per patient
of the cervix in patients using oral contraceptive
for the disproportionate number of Pap smears category in the 40.2 11 total smears.
fiftieth Pap) and can be corrected for by multiplying 4.77/4.35 x 196 and obtaining 214, which is the number of pill-using patients that should have been selected as controls and will be designated as corrected controls in Table VI. Similar corrections were made for other categories of control patients and are identified in all tables as corrected controls. Actually there was very little difference in the results obtained when using corrected controls, as compared to actual controls, except in IUD users. There were five (9.8 per cent) patients (Table VII) with carcinoma who were not currently using the birth control pill but had used it in the past. Of the control patients 22.8 per cent had used the pill previously. By combining current and previous pill users (Table VIII) we have 36.1 per cent of the carcinoma
patients
with
a positive
pill
history
whereas
47.9 per cent of control patients had either current or previous use of the pill. It can be seen from these findings
that
there
was
no
increase
in
the
carcinoma of the cervix when comparing pill nonusers. By multiplying the percentage of control (corrected) with a positive pill history, 51.5 times the total number of patients. 8,386, we
risk
of
users to patients per cent, calculate
342
Sandmire, Austin, and Bechtel
Am. J.
Table IX. Carcinoma of the cervix correlated duration of use of oral contraceptive steroids current users Duration
Carcinoma
of
use (yr) O-l 1-3 3-6 Over 6 Total
(20)
with in
No.
%
4 10 5 1 20
2n 50 23 5
37 90 34 12 173
21.3 51 19.6 6.9
Table X. Carcinoma of the cervix correlated with duration of use of oral contraceptive steroids combining previous and present users in the calculations
I
I
5
1-3 3-6
12 7
20 48 2x
I
70 133 39
usage with cervical
Total
5%
1
of IUD
c llrrrllt uxr.,
(I 73)
Control
NO.
O-1
Table XI. Correlation carcinoma
June 1. 1976 Ohstet. Gvnerol.
27.4 52. I 1.5.2
the total number of patients in the Pap smear registry currently or previously using the birth control pill as 4319. Table IX relates duration of use of oral contraceptive steroids to the risk of carcinoma and demonstrates no higher risk in long-term users when compared to long-term control users (expressed in per cent of total lesions in each group when broken down into duration of usage). Table X combines present and previous pill users in the duration of usage correlation and demonstrates some increase risk of carcinoma in the 3 to 6 year duration group compared to control patients. Because of the small numbers this is not statistically significant but will need to be watched as the study continues and the number of patients in the longer duration groups increase. Table XI demonstrates no statistically significant increased risk of carcinoma in IUD users. Carcinoma correlated with duration of IUD usage is tabulated in Table XII and demonstrates no statistically significant increased risk of carcinoma with longer usage. Previous studies concerning carcinogenic properties of oral contraceptive steroids have had the following weaknesses: (1) studies based on cytology and conclusions drawn without tissue examination2v 3, 8: (2) no controls, insufficient controls, or poorly matched controls’: (3) insufficient number of cases of carcinoma
Carcinoma patients Controls
5176
Prrvious UMI.7 1 (%j 4142* (9.5%) 221377T (5.8%) I81377114.7%)
(6.5%)
6417HO (8.2%)
Corrected controlsf
481780 (6.1 B)
16.0 14.0 10.X
*Previous contraceptive history missing in 34 patients. tPrevious contraceptive history missing in 403 control patients. Korrected tin- the disproportionate number of Pap smear\ per patient category in the 40,2 11 total smears.
Table XII. Carcinoma of’ the cervix correlated with duration of use of the IUD combining previous and present users in the calculations Duration
of
Carcinoma
(9)
O-I
3
33.3
17
1 -?I
5
55.5
4.5
3-6 Over 6
0 I 9
00.0 Il.2
16 .1 x2
20.7 54.x 19.5 4.x
patients and pill users2. “* ‘* 6; and (4) duration of usage and length of follow-up period inadequate in pill users considering the latent period involved in carcinogenesis.2* I’ Although this study is not free of’ all of the weaknesses enumerated above, it does represent an evaluation of a large number of patients (4,319) with a positive pill history followed for up to I4 years. In addition, the duration of usage extends to a maximum of 15 years. The numbers involved in our IUD group are smaller and permit less definite conclusions. In conclusion we did not detect any variation in use of oral contraceptive steroids or intrauterine devices in our 76 carcinoma patients when compared to 780 randomly selected control patients. This confirms ow previous experience and remains at variance with an earlier report bv Melamed. who reported an increase in carcinoma of the cervix among pill users when compared to diaphragm users. This difference could be explained by some protective effect ot‘ the diaphragm against the development of‘ cervical carcinctma. A more recent report by Melamed and Flehinger *’ did not reveal any increase in incidence of carcinoma in situ and other precancerous cervical lesions in pill users compared to diaphragm and IUD users.
Volume Number
125 3
Cervical carcinoma in oral contraceptive and IUD users and nonusers
REFERENCES
Dunn, T. B.: Cancer of the uterine cervix in mice fed a liquid diet containing an antifertility drug, J. Natl. Cancel Inst. 43: 671, 1969. 2. Dougherty, C. M.: Cervical cytology and sequential birth control pills, Obstet. Gynecol. 36: 741, 1970. 3. Kline, T. S., Holland, M., and Wemple, D.: Atypical cytology with contraceptive hormone medication, Am. J, 1.
Clin.
Pathol.
53: 215,
1970.
4. Melamed, M. R., Koss, L. G., Flehinger, B. J., Kelisky, R.
5.
P., and DuBrow, H.: Prevalence rate of uterine cervical carcinoma in situ for women using the diaphragm or contraceptive oral steroids, Br. Med. J. 3: 195, 1969. Sandmire, H. F.: Experience with fifteen thousand
consecutive Pap smears, Wis. Med. J. 71: 130, 1972. 6. Wied, G. L., Davis, M. E., Frank, R., Segal, P. B., Meier, P., and R.osenthal, E.: Statistical evaluation of the effect of hormonal contraceptives on the cytologic smear pattern, Obstet. Gynecol. 27: 327, 1966.
Discussion E. EICHNER, Cleveland, Ohio. In reviewing this paper two immediate statistical problems present themselves. Nowhere is there a statement of the actual number of patients serviced by the over 40,000 Pap smears so that a true incidence of malignancy might be obtained. Assuming there were no in situ in those patients with Class II smears or less, and no patients with repeated smears in those with Class III-V, the authors show a remarkable accuracy, with 76 carcinomas in 82 smears, something my cytologists do not approached. The original draft did not state the method of selection of controls. Were the patients with cancer included or excluded in the final group tally? This could affect the final results. Complete evaluation requires this information. Insofar as the paper itself is concerned, I doubt that the authors have either proved or disproved their contentions. Cervical carcinoma, to the best of my knowledge, is a slowly developing disease, probably taking 10 or more years for identification. Since the pill has been in use only slightly more than 15 years, we should just be beginning to find those related to pill use unless there is evidence that the pill or the intrauterine device actually speed up the development of malignancy. Pincus and Garcia’ reported that the development of cervical anaplasia may be prevented in users of oral ovulation-inhibiting estrogen-progestin mixtures as identified in biopsies or smears. The present trend to lower dose tablets started over 5 years ago. Shortly thereafter, ,an increase in papillary cervicitis and in developing cervical dysplasias was noted. The current pill has a disproportionately high estrogen which might stimulate cellular growth and metabolism. This could be in keeping with the authors’ higher incidence in the 3 to 6 year users, most of whom were also current users. Although this interval might be long enough for the development of cervical dysplasia, I still believe it is too short for proof of its relationship to cervical cancer. However, I must add DR.
343
7. Boyce, J. G., Lu, T., Nelson, J. H., and Joyce, D.: Cervical carcinoma and oral contraception, Obstet. Gynecol. 40: 139, 1972. D. F.,: The impact of hormonal contraceptive 8. Miller, therapy on a community and effects on cytopathology of the cervix, AM. J. OBSTET. GYNECOL. 115: 978, 1973. 9. Courey, N. G., and Powell, A. S.: The pill, the smear and cancer, N. Y. J. Med. 71: 2513, 1971. 10. Thomas, D. B.: Relationship of oral contraceptives to cervical carcinogenesis, Obstet. Gynecol. 40: 508, 1972. 11. Melamed, M. R., and Flehinger, B. J.: Early incidence rates of precancerous cervical lesions in women using contraceptives, Gynecol. Oncol. 1: 290, 1973. J. E.. Reyner, F. C., Fagundes, W. B., and 12. Ayre, LeGuerrier, J. M.: Oral progestins and regression of carcinoma in situ and cervical dysplasia, Obstet. Gynecol.
34: 545, 1969. R. M., and Barron, 13. Richart, device and cervical neoplasia,
B. A.,: The intrauterine J. A. M. A. 199: 817, 1967.
here that my own statistics agree with those of the authors as regards steroidal contraceptives. Another item for statistical evaluation is the relative median age of the various subgroups. This was 35 for the cancer patients, 29.5 for the in situs, 30.5 for the controls, but only 27.5 for the pill users. Does this suggest that more pill users might have developed cancer had their median age been higher? The fact that control patients had more smears done than did the study group is merely an indication of the increased age in the controls. My patients with IUD’s have been too few for statistical analysis, but I have had several wearing stringed devices who did develop carcinoma in situ of the cervix within 2 to 3 years of the insertion. I must remind all of the wing-type contraceptive stem pessary outlawed by Washington a few years back because of its relationship to severe cervical infection and malignancy. Concomitant malignancy was reported by Frank’ in the early 1930’s. Therefore, there may be an association between devices and cervical cancer, but this remains to be shown. In conclusion, I do not believe that the material presented by the authors proves or disproves any relationship between steroid or intrauterine device contraceptives to cervical malignancy. I do believe that studies of this type must be repeated at intervals until we are able to get truly significant data. REFERENCES
1. Pincus, G., and Garcia, C.-R.: Studies on vaginal, cervical and uterine histology, Metabolism 14: 344, 1965. 2. Frank, R. T., editor: Vol. 12, Gynecological and Obstetrical Monographs, Ed. 2, New York, 193 1, D. Appleton & Co. p. 128. DR. JOHN G. MASTERSON, Maywood, Illinois. As the authors have pointed out in their brief review of the iiterature, there is considerable difference of opinion about the possible carcinogenic properties of the oral
344
Sandmire,
Austin,
and Bechtel
contraceptive steroids. At first blush, their study based on 40,211 cytologic examinations of possibly 8,386 patients would suggest that there is no increased risk of carcinoma of the cervix in oral contraceptive users compared to nonusers. Unfortunately, their study is not free of some of the weaknesses noted in previous reports on this subject. Although the random selection of their controls is a statistically valid approach, I just wonder whether the controls could have been more carefully selected so that other factors in the development of carcinoma of the cervix such as age, parity, and social status were matched in the cancer and control groups of patients. For example, I noted in Table V that the median age of the carcinoma patients was 35 compared with a median age of 30 in the control group. I raise this particular issue because of my personal experience during the past 6 years in which I have seen seven white patients under the age of 25, from upper and middle social status, with invasive carcinoma of the cervix; all of them gave a history of being users of the oral contraceptives for 2 or more years. Although I had previously seen black patients under the age of 25 from lower social status with invasive carcinoma, I had not seen this condition in white patients of this age group from upper or middle social status. Therefore. I would be interested in the authors’ experience. Also I would like to know whether they have any evidence to determine what influence the gynecologic care of the cervix and vagina might have on the development ot carcinoma in a patient. Although it was not stated. I presume all of the lesions in this series were of the squamous-cell variety. But if they were not, I would be curious to know whether any adenocarcinomas o.curred in the users of the oral contraceptives. Just as the authors have suggested in Table XI that the duration of oral contraceptive use may increase the incidence of carcinoma, I would also suggest that the duration of follow-up of the patients may be equally or more important. The experience with diethystilbestrol has demonstrated that we sometimes have to wait many years to demonstrate the possible carcinogenic effect of a medication. At this juncture. I do not believe that we have sufficient data to come to any definitive ciimclusions. Perhaps the problem may really rest with the exposure of the user of the oral contraceptives to an earlier and more frequent coital experience as well as the other factors that have been previously demonstrated to play a role in the development of carcinoma of the cervix. I would hope that their fine report stimulates them to conduct further investigations that are designed to provide us with conclusions that would resolve the controversies that have been raised by the various reports on this subject. DR. ALBERT MT. DIDDLE. Knoxville. Tennessee. ‘The first comment concerns the controversy started in 1933 when Overholser and Edgar Allen did their experi-
merits on primates. They were of the opinion that estrogens predisposed to neoplasia of the cervix uteri. But I would point out something that Dr. Masterson referred to-That is, Janet Towne and Gagnon gave us another idea: this kind of neoplasm may be a social disease. The second comment tends to support the essayist’s contention. 1 analyzed the records of 7,423 patienrs seen by six gynecologists within the last 30 months. The women had been followed for 1 to ‘LO years. The\ ranged in age from 15 to 46 years. Of these 4,261 hah been on progestogens for one month up to twelve years each; 2.156 others had never taken these drugs while this information was in question for the other 1,025 women. Over all, there were 47 that had dysplasia, 88 others had carcinoma in situ, and another 24 women had invasive disease. The incidence of neoplasia ill the different groups ranged from 1 in 46 to 1 in 48. At this reporting, I do not see any indication that the pill has changed the incidence. But I will agree with the two previous discussants; we need to take cognizance of Roy Hertz’ work. Another 10 to 20 years must elapse before we know whether or not progestogens do have an effect on the incidence of carcinoma of the cervix uteri. DR. GARY M. DOUGHEKT~., Baton Rouge. Louisiana. I have to idemit’! myself as the person who wrote the article refel-red to as “Doughertr. and associates,“ a11d the title of it is, “Cervical cytology and sequential birth control pills.” L’nfortunately. there were a few editorial mistakes. I did not get a chance to see the proofs before thev were put into print. For example, one of the statements erroneously published as mine was that a certain difference was significant. What I actually wrote was “not significant.” The editor left out the word “not.” I did use prevalence and incidence studies as controls: The rate of cervical disease in the fenlalc population of the Baton Rouge area vs. the ratr of occurrence of in situ carcinoma and dysplasia itt birth control pill users. The rate of occurrence among the birth control pill users was higher than expected. judging by the prevalence rates of the population as a whole. and my conclusion from this was that there is ;t difference, though possibly not significant, due 10 thca low number of cases of disease that I encountered: some 30-odd. DR. JOSEPH (1. Scour. JR., Omaha. Nebraska. ;\Ithough it was not the primary focus of the presentation, I wonder if Dr. Sandmire would comment as to whether or not any other forms of genital carcinoma were found in the user group. DR. RAYMOND H. KAUFMAN. Houston, I‘exas. I would just like IO emphasize what the two discussants have already mentioned. I think that any study of this type cannot i,gnorc the so-called sex-related factors. It is of paramount importance that you take into considcK1tion such factors as age of onset of intercourse ant1 number of sexual partners, because these are factors
Volume Number
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Cervical carcinoma in oral contraceptive and IUD users and nonusers
that we all agree may well be related to the genesis of cervical carcinoma. If cases and controls are not matched along these lines, the study will not be of any significance and will not tell us what we want to know. What really is needed is a good, controlled, prospective study. DR. SANDMIRE (Closing). We did not have incidence figures because patients move, doctors’ offices move, and the only thing we had was our cytology register which was firm throughout the 15 years of the study. We found a large number of cases of cancer in our Class II smears. Our cytologists are no more accurate than Dr. Eichner’s. In fact, there were 25 of the 76 cancers from patients who had Class II smears and in whom the smears never progressed to a higher level of abnormality. The median age of the cancer patients was 35 years; of control pill users, 27.5 years; however, the 50 carcinoma in situ patients, with a median age of 29.5, compared closely to the control pill users.
345
Dr. Masterson asked about other than squamous-cell carcinomas. We had one carcinosarcoma, a couple of adenocarcinomas of the cervix, one adenocarcinoma of the endometrium, one metastatic ovarian carcinoma, and one mesothelial carcinoma. Dr. Scott asked about other carcinomas in the pill users. I presume he means ovary, etc. We do not have information on that. In order to get into this study, the patient had to have had an abnormal Pap smear. Cancer patients who did not have a positive Pap smear are not included in this study. This study comes from 40,2 11 consecutive Pap smears. Dr. Kaufman talked about the relationship between sexual practices and the risk of development of carcinoma of the cervix. I believe there is only one factor important in whether a patient will or will not develop squamous-cell carcinoma of the cervix, and that is her early sexual experience: age of onset and number of partners.
F.
SANDMIRE,
STEPHEN
D.
AUSTIN,
RICHARD
C.
BECHTEL,
M.D. M.D. M.D.
Green Buy, Wisconsin
A total of 40,211 cytologic examinations and subsequent diagnostic procedures resulted in the diagnosis of carcinoma of the cervix in 76 patients. The 74 patients did not demonstrate any variations in use of oral contraceptive steroids or intrauterine deuices when compared to 780 randomly selected control patients, This study is in agreement with our earlier report demonstrating no increased risk of carcinoma of the cervix in oral contraceptive
steroid
users
compared
to nonusers.
C ON s I DE RA B LE interest has arisen concerning the possible carcinogenic properties of oral contraceptive steroids. In particular, the effect of these compounds on the uterine cervix and breasts has been widely speculated upon. Dunn’ demonstrated the development of cervical carcinoma in mice given an oral contraceptive containing both the estrogen, mestranol, and the progestogen, norethynodrel, for a prolonged period of time in daily doses roughly equivalent to the amounts received by women using the early oral contraceptives. Dougherty: in an uncontrolled study, reported a rate of occurrence of cytologic atypia twice as high as expected in 1983 women using sequential oral contraceptive steroids. Kline and associates3 demonstrated a 2.0 per cent rate of abnormal smears in pill users compared to 1.0 per cent in nonusers. It should be noted, however, that 19 of the 45 abnormal smears from pill users reverted to normal, 15 while continuing to use the pill and 4 after cessation of the pill. In addition, biopsy was performed on only nine of the 45 abnormal smear patients, resulting in the following diagnoses: mild dysplasia, four; endocervical hyperplasia., two; severe dysplasia, three. Biopsy data on nonusers were not tabulated, preventing any comparison of histologic findings in pill users and nonusers. Melamed and associate& observed a small but statistically significant increase in carcinoma of the cervix among both pill choosers and pill users when
compared to diaphragm choosers and users. He indicated that his results “can be attributed either to a decreased prevalence rate for women using a diaphragm or to an increased rate for women using oral steroids.” He further indicated that the difference is consistently present in subsets corrected for each of five factors known to influence the prevalence rate of cervical carcinoma: age, ethnic orgin, age at first pregnancy (as a reflection of early sexual experience), number of live births, and family income. Our previous analysid of 15,000 consecutive Pap smears failed to demonstrate an increased risk of carcinoma of the cervix in pill users compared to nonusers. Wied and associates6 in 1966 reported on 1,628 patients-on oral contraceptives for at least one year-,and found no statistically significant increase of even slight atypia in pill users compared to nonusers. Similar studies by Boyce and associates,7 Miller,’ and Courey and Powell’ all reported equal risks of cervical neoplasia in pill users and nonusers. Thomas” compared the contraceptive history of 324 women with cytologic smears suggestive of neoplasia with 302 matched control patients. His results led him to conclude that women using oral contraceptives for an average of 20 months are no more likely to develop squamous dysplasia or carcinoma in situ within 2% to 3 years after initial use than are women who do not use oral contraceptives. Melamed and Flehinger,” in a more recent article, reported on estimated incidence rates of carcinoma in situ and other precancerous cervical lesions in carefully matched diaphragm and steroid users in one group and IUD and steroid users in another group. The data
Pmrnted at the Forty-third Annual Meeting of the Central Association of Obstetricians and Gynecologists, Coloro.do Springs, Colorado, September 26-28, 1975. Reprint requests: Dr. Herbert F. Sandmire, 704 S. Webster Ave., Green Bay, Wisconsin 54301.
339
340
Sandmire,
Austin,
Table I. Findings 1960-1975*
Class I
June 1. 1976 hn. J. Obstet. Gynecol.
and Bechtel
in 40,2 I 1 consecutive
39,867
99. 14
“(i2
Class II Class III Class IV Class V Total
Pap smears:
0.6.3
50 I1 18
I : 1.53 1 : 801 112x72 1 : 2233 I:117
0.12 0.03 0.0-l
344
0.8,4
II. Average
number
of smears
in control
patients* No.
Current IUD users
4.35 ti.33
Previous Previous Non-pill Total
4.50 .5.75 24.7” 4.77
Current
pill users pill users IUD users and IUD users a11 controls
*Calculations based upon number of smears performed control patients from the total
Table
III. Median
the actual counting on 240 randomly of 807 controls.
age of control
Pill users IUD users Non-pill and IUD users Total control patients
Table
IV. Median
age of carcinoma
Carcinoma in situ Carcinoma in situ with microinvasion Invasive carcinoma Total carcinomas
use
on
the
dysplasia dysplasia
transit
time
to carcinoma to carcinoma
in
the
progression
of
in situ (86 months) in situ (12 months).
mild
and severe
Materials and method
*Carcinomas, 1 : 529 Pap smears. Table
cytologic evaluations. Nine patients showed cytologic evidence of regression: five from marked dysplasia OI carcinoma in situ to mild or moderate dysplasia and four from moderate or marked dysplasia to negative smears. Kichart and Barn)@ reported no influence of IUD
In 1960 a cytology registry was organized by two of the three present authors in their practice in Green Bay, Wisconsin. Our present analysis (Table I) includes the first 40,211 consecutive (1960-1975) Pap smears registered and 807 randomly selected control patients. In 27 of the control patients contraceptive data were missing, leaving 780 patients for analysis. Pap smears in our year,
of the selected
patients
27.5 31..5 31.5 3o.j
patients
29.5 35.0 55.0 35.0
are derived from patients having two consecutive annual negative Pap smears who subsequently develop precancerous cervical lesions. The more recent study did not reveal any increase in incidence of carcinoma in situ and other precancerous cervical lesions in pill users compared to diaphragm and II:D users. Ayre and associates I* followed 27 patients using oral contraceptive steroids cytologically diagnosed as having dysplasia, moderate or marked, and beginning carcinoma in situ. None of the patients progressed to a more advanced lesion demonstrable by periodic
registry with
are the
numbered
first
two
in sequential numbers
being
fashion the
last
by two
numbers of the year in which the smear was obtained. As an example, Pap smears obtained during 1974 were numbered from 74-l through 74-5157. In order to randomize our controls, an outside person selected two two-digit numbers, 14 and 52, and every Pap smear number in our registry ending in 14 and 52 M~S selected as a tontrol patient. This “index” smear selects the patient and the collected data apply to the time of the index smear even though the patient may have had other
smears
during
the
study.
In
this
manner
a
control patient was selected by- picking every fiftieth Pap smear I’or each year. A correction factor was necessary because the average number of Pap smears per patient was different for various categories ot patients (Table 1I). ‘The correction factor will be explained later but was necessary because the number of Pap smears in our registry per patient could influence the probability of any given patient being selected as a control (every fiftieth Pap). Duplication was avoided by selecting the next Pap smear number following the one ending in It or 52 when a patient had already been selected as a control; in the same manner all abnormal smears were avoided in control selection. In addition, through human error two patients, 62-452 and 73-2552. were not included in our control groups. We do not know directly the total number of patients involved in the study. Indirectly, by dividing the total number of Pap smears (40,2 11) by the average number of Pap smears per patient of 4.77, we have a total of‘ 8,386 patients. The control and carcinoma patients were predominately
white
and
middle
class on a socioeconomic
scale.
Cervical carcinoma in oral contraceptive and IUD users and nonusers
Volume Number
125 3
Table
V. Total
carcinomas
in 40,211
Diag7Losis
Pap smears No. of pltients
Carcinoma insitu Carcinoma in situ
41
Table VII. Carcinoma of the cervix in patients previously using oral contraceptive steroids Carcinoma
had previously used the pill
86/377t
Controls
Carcinoma
of the cervix in oral users
20176
26.3%
of carcinoma patients were on the pill
Controls
196/780
25.1%
of control patients were on the pill
Corrected controls*
214/780
27.4%
of control patients were on the pill
*Corrected per patient
22.8% of control patients
26 76 Corrected controlsf
Table VI. Carcinoma contraceptive steroid
9.8% of carcinoma patients
5/51*
9
with microinvasion Invasive carcinoma Total
for the disproportionate category in the 40,211
number of Pap smears total smears.
The median age for each group is tabulated in Tables III and IV. Since the present paper deals only with the question of the possible effect of oral contraceptive steroids and intrauterine devices on the risk of carcinoma of the cervix, a subsequent communication will report on the remainder of our experience with the 40,211 smears, including an analysis of dysplasia patients in oral contraceptive steroid users. The main goal of the present study was to detec,t any variation in contraceptive use in the 76 carcinoma patients (Table V) when compared to the 780 control patients. Although we recorded data on the condom and diaphragm, their use was too infrequent to produce statistically significant results and will not be included. The present data are limited to use or nonuse of the oral contraceptive steroids and the intrauterine contraceptive device (IUD) in cervical carcinoma patients. For each of thea#e agents we are reporting on previous as well as current use and the duration of use in both categories in the comparison of the carcinoma patients with the controls.
Results and comment Twenty (26.3 per cent) of the 76 carcinoma subjects (Table VI) were currently using oral contraceptive steroids at the time of discovery of their lesions. Two of these patients had invasive lesions and the remaining 18 carcinoma in situ. Of 780 control patients, 196 (25.1 per cent) were using oral contraceptives. The pill users in the control patients had an average of 4.35 smears in our registry whereas the over-all average number of smears per control patient was 4.77. This would result in fewer pill users being selected as controls (every
341
91/377?
had previously used the pill of control patients had previously used the pill
24.1%
*Previous contraceptive history missing in 25 patients. TPrevious contraceptive history missing in 403 control patients. SCorrected for the disproportionate number of Pap smears per patient category in the 40,2 11 total patients.
Table VIII. Carcinoma previously or presently steroids Carcinoma
36.1%
of carcinoma patients were using or had previously used the pill 47.9% of control patients were using or had previously used the pill 5 1.5 % of control patients were using or had previously used the pill
Controls
Corrected controls*
*Corrected per patient
of the cervix in patients using oral contraceptive
for the disproportionate number of Pap smears category in the 40.2 11 total smears.
fiftieth Pap) and can be corrected for by multiplying 4.77/4.35 x 196 and obtaining 214, which is the number of pill-using patients that should have been selected as controls and will be designated as corrected controls in Table VI. Similar corrections were made for other categories of control patients and are identified in all tables as corrected controls. Actually there was very little difference in the results obtained when using corrected controls, as compared to actual controls, except in IUD users. There were five (9.8 per cent) patients (Table VII) with carcinoma who were not currently using the birth control pill but had used it in the past. Of the control patients 22.8 per cent had used the pill previously. By combining current and previous pill users (Table VIII) we have 36.1 per cent of the carcinoma
patients
with
a positive
pill
history
whereas
47.9 per cent of control patients had either current or previous use of the pill. It can be seen from these findings
that
there
was
no
increase
in
the
carcinoma of the cervix when comparing pill nonusers. By multiplying the percentage of control (corrected) with a positive pill history, 51.5 times the total number of patients. 8,386, we
risk
of
users to patients per cent, calculate
342
Sandmire, Austin, and Bechtel
Am. J.
Table IX. Carcinoma of the cervix correlated duration of use of oral contraceptive steroids current users Duration
Carcinoma
of
use (yr) O-l 1-3 3-6 Over 6 Total
(20)
with in
No.
%
4 10 5 1 20
2n 50 23 5
37 90 34 12 173
21.3 51 19.6 6.9
Table X. Carcinoma of the cervix correlated with duration of use of oral contraceptive steroids combining previous and present users in the calculations
I
I
5
1-3 3-6
12 7
20 48 2x
I
70 133 39
usage with cervical
Total
5%
1
of IUD
c llrrrllt uxr.,
(I 73)
Control
NO.
O-1
Table XI. Correlation carcinoma
June 1. 1976 Ohstet. Gvnerol.
27.4 52. I 1.5.2
the total number of patients in the Pap smear registry currently or previously using the birth control pill as 4319. Table IX relates duration of use of oral contraceptive steroids to the risk of carcinoma and demonstrates no higher risk in long-term users when compared to long-term control users (expressed in per cent of total lesions in each group when broken down into duration of usage). Table X combines present and previous pill users in the duration of usage correlation and demonstrates some increase risk of carcinoma in the 3 to 6 year duration group compared to control patients. Because of the small numbers this is not statistically significant but will need to be watched as the study continues and the number of patients in the longer duration groups increase. Table XI demonstrates no statistically significant increased risk of carcinoma in IUD users. Carcinoma correlated with duration of IUD usage is tabulated in Table XII and demonstrates no statistically significant increased risk of carcinoma with longer usage. Previous studies concerning carcinogenic properties of oral contraceptive steroids have had the following weaknesses: (1) studies based on cytology and conclusions drawn without tissue examination2v 3, 8: (2) no controls, insufficient controls, or poorly matched controls’: (3) insufficient number of cases of carcinoma
Carcinoma patients Controls
5176
Prrvious UMI.7 1 (%j 4142* (9.5%) 221377T (5.8%) I81377114.7%)
(6.5%)
6417HO (8.2%)
Corrected controlsf
481780 (6.1 B)
16.0 14.0 10.X
*Previous contraceptive history missing in 34 patients. tPrevious contraceptive history missing in 403 control patients. Korrected tin- the disproportionate number of Pap smear\ per patient category in the 40,2 11 total smears.
Table XII. Carcinoma of’ the cervix correlated with duration of use of the IUD combining previous and present users in the calculations Duration
of
Carcinoma
(9)
O-I
3
33.3
17
1 -?I
5
55.5
4.5
3-6 Over 6
0 I 9
00.0 Il.2
16 .1 x2
20.7 54.x 19.5 4.x
patients and pill users2. “* ‘* 6; and (4) duration of usage and length of follow-up period inadequate in pill users considering the latent period involved in carcinogenesis.2* I’ Although this study is not free of’ all of the weaknesses enumerated above, it does represent an evaluation of a large number of patients (4,319) with a positive pill history followed for up to I4 years. In addition, the duration of usage extends to a maximum of 15 years. The numbers involved in our IUD group are smaller and permit less definite conclusions. In conclusion we did not detect any variation in use of oral contraceptive steroids or intrauterine devices in our 76 carcinoma patients when compared to 780 randomly selected control patients. This confirms ow previous experience and remains at variance with an earlier report bv Melamed. who reported an increase in carcinoma of the cervix among pill users when compared to diaphragm users. This difference could be explained by some protective effect ot‘ the diaphragm against the development of‘ cervical carcinctma. A more recent report by Melamed and Flehinger *’ did not reveal any increase in incidence of carcinoma in situ and other precancerous cervical lesions in pill users compared to diaphragm and IUD users.
Volume Number
125 3
Cervical carcinoma in oral contraceptive and IUD users and nonusers
REFERENCES
Dunn, T. B.: Cancer of the uterine cervix in mice fed a liquid diet containing an antifertility drug, J. Natl. Cancel Inst. 43: 671, 1969. 2. Dougherty, C. M.: Cervical cytology and sequential birth control pills, Obstet. Gynecol. 36: 741, 1970. 3. Kline, T. S., Holland, M., and Wemple, D.: Atypical cytology with contraceptive hormone medication, Am. J, 1.
Clin.
Pathol.
53: 215,
1970.
4. Melamed, M. R., Koss, L. G., Flehinger, B. J., Kelisky, R.
5.
P., and DuBrow, H.: Prevalence rate of uterine cervical carcinoma in situ for women using the diaphragm or contraceptive oral steroids, Br. Med. J. 3: 195, 1969. Sandmire, H. F.: Experience with fifteen thousand
consecutive Pap smears, Wis. Med. J. 71: 130, 1972. 6. Wied, G. L., Davis, M. E., Frank, R., Segal, P. B., Meier, P., and R.osenthal, E.: Statistical evaluation of the effect of hormonal contraceptives on the cytologic smear pattern, Obstet. Gynecol. 27: 327, 1966.
Discussion E. EICHNER, Cleveland, Ohio. In reviewing this paper two immediate statistical problems present themselves. Nowhere is there a statement of the actual number of patients serviced by the over 40,000 Pap smears so that a true incidence of malignancy might be obtained. Assuming there were no in situ in those patients with Class II smears or less, and no patients with repeated smears in those with Class III-V, the authors show a remarkable accuracy, with 76 carcinomas in 82 smears, something my cytologists do not approached. The original draft did not state the method of selection of controls. Were the patients with cancer included or excluded in the final group tally? This could affect the final results. Complete evaluation requires this information. Insofar as the paper itself is concerned, I doubt that the authors have either proved or disproved their contentions. Cervical carcinoma, to the best of my knowledge, is a slowly developing disease, probably taking 10 or more years for identification. Since the pill has been in use only slightly more than 15 years, we should just be beginning to find those related to pill use unless there is evidence that the pill or the intrauterine device actually speed up the development of malignancy. Pincus and Garcia’ reported that the development of cervical anaplasia may be prevented in users of oral ovulation-inhibiting estrogen-progestin mixtures as identified in biopsies or smears. The present trend to lower dose tablets started over 5 years ago. Shortly thereafter, ,an increase in papillary cervicitis and in developing cervical dysplasias was noted. The current pill has a disproportionately high estrogen which might stimulate cellular growth and metabolism. This could be in keeping with the authors’ higher incidence in the 3 to 6 year users, most of whom were also current users. Although this interval might be long enough for the development of cervical dysplasia, I still believe it is too short for proof of its relationship to cervical cancer. However, I must add DR.
343
7. Boyce, J. G., Lu, T., Nelson, J. H., and Joyce, D.: Cervical carcinoma and oral contraception, Obstet. Gynecol. 40: 139, 1972. D. F.,: The impact of hormonal contraceptive 8. Miller, therapy on a community and effects on cytopathology of the cervix, AM. J. OBSTET. GYNECOL. 115: 978, 1973. 9. Courey, N. G., and Powell, A. S.: The pill, the smear and cancer, N. Y. J. Med. 71: 2513, 1971. 10. Thomas, D. B.: Relationship of oral contraceptives to cervical carcinogenesis, Obstet. Gynecol. 40: 508, 1972. 11. Melamed, M. R., and Flehinger, B. J.: Early incidence rates of precancerous cervical lesions in women using contraceptives, Gynecol. Oncol. 1: 290, 1973. J. E.. Reyner, F. C., Fagundes, W. B., and 12. Ayre, LeGuerrier, J. M.: Oral progestins and regression of carcinoma in situ and cervical dysplasia, Obstet. Gynecol.
34: 545, 1969. R. M., and Barron, 13. Richart, device and cervical neoplasia,
B. A.,: The intrauterine J. A. M. A. 199: 817, 1967.
here that my own statistics agree with those of the authors as regards steroidal contraceptives. Another item for statistical evaluation is the relative median age of the various subgroups. This was 35 for the cancer patients, 29.5 for the in situs, 30.5 for the controls, but only 27.5 for the pill users. Does this suggest that more pill users might have developed cancer had their median age been higher? The fact that control patients had more smears done than did the study group is merely an indication of the increased age in the controls. My patients with IUD’s have been too few for statistical analysis, but I have had several wearing stringed devices who did develop carcinoma in situ of the cervix within 2 to 3 years of the insertion. I must remind all of the wing-type contraceptive stem pessary outlawed by Washington a few years back because of its relationship to severe cervical infection and malignancy. Concomitant malignancy was reported by Frank’ in the early 1930’s. Therefore, there may be an association between devices and cervical cancer, but this remains to be shown. In conclusion, I do not believe that the material presented by the authors proves or disproves any relationship between steroid or intrauterine device contraceptives to cervical malignancy. I do believe that studies of this type must be repeated at intervals until we are able to get truly significant data. REFERENCES
1. Pincus, G., and Garcia, C.-R.: Studies on vaginal, cervical and uterine histology, Metabolism 14: 344, 1965. 2. Frank, R. T., editor: Vol. 12, Gynecological and Obstetrical Monographs, Ed. 2, New York, 193 1, D. Appleton & Co. p. 128. DR. JOHN G. MASTERSON, Maywood, Illinois. As the authors have pointed out in their brief review of the iiterature, there is considerable difference of opinion about the possible carcinogenic properties of the oral
344
Sandmire,
Austin,
and Bechtel
contraceptive steroids. At first blush, their study based on 40,211 cytologic examinations of possibly 8,386 patients would suggest that there is no increased risk of carcinoma of the cervix in oral contraceptive users compared to nonusers. Unfortunately, their study is not free of some of the weaknesses noted in previous reports on this subject. Although the random selection of their controls is a statistically valid approach, I just wonder whether the controls could have been more carefully selected so that other factors in the development of carcinoma of the cervix such as age, parity, and social status were matched in the cancer and control groups of patients. For example, I noted in Table V that the median age of the carcinoma patients was 35 compared with a median age of 30 in the control group. I raise this particular issue because of my personal experience during the past 6 years in which I have seen seven white patients under the age of 25, from upper and middle social status, with invasive carcinoma of the cervix; all of them gave a history of being users of the oral contraceptives for 2 or more years. Although I had previously seen black patients under the age of 25 from lower social status with invasive carcinoma, I had not seen this condition in white patients of this age group from upper or middle social status. Therefore. I would be interested in the authors’ experience. Also I would like to know whether they have any evidence to determine what influence the gynecologic care of the cervix and vagina might have on the development ot carcinoma in a patient. Although it was not stated. I presume all of the lesions in this series were of the squamous-cell variety. But if they were not, I would be curious to know whether any adenocarcinomas o.curred in the users of the oral contraceptives. Just as the authors have suggested in Table XI that the duration of oral contraceptive use may increase the incidence of carcinoma, I would also suggest that the duration of follow-up of the patients may be equally or more important. The experience with diethystilbestrol has demonstrated that we sometimes have to wait many years to demonstrate the possible carcinogenic effect of a medication. At this juncture. I do not believe that we have sufficient data to come to any definitive ciimclusions. Perhaps the problem may really rest with the exposure of the user of the oral contraceptives to an earlier and more frequent coital experience as well as the other factors that have been previously demonstrated to play a role in the development of carcinoma of the cervix. I would hope that their fine report stimulates them to conduct further investigations that are designed to provide us with conclusions that would resolve the controversies that have been raised by the various reports on this subject. DR. ALBERT MT. DIDDLE. Knoxville. Tennessee. ‘The first comment concerns the controversy started in 1933 when Overholser and Edgar Allen did their experi-
merits on primates. They were of the opinion that estrogens predisposed to neoplasia of the cervix uteri. But I would point out something that Dr. Masterson referred to-That is, Janet Towne and Gagnon gave us another idea: this kind of neoplasm may be a social disease. The second comment tends to support the essayist’s contention. 1 analyzed the records of 7,423 patienrs seen by six gynecologists within the last 30 months. The women had been followed for 1 to ‘LO years. The\ ranged in age from 15 to 46 years. Of these 4,261 hah been on progestogens for one month up to twelve years each; 2.156 others had never taken these drugs while this information was in question for the other 1,025 women. Over all, there were 47 that had dysplasia, 88 others had carcinoma in situ, and another 24 women had invasive disease. The incidence of neoplasia ill the different groups ranged from 1 in 46 to 1 in 48. At this reporting, I do not see any indication that the pill has changed the incidence. But I will agree with the two previous discussants; we need to take cognizance of Roy Hertz’ work. Another 10 to 20 years must elapse before we know whether or not progestogens do have an effect on the incidence of carcinoma of the cervix uteri. DR. GARY M. DOUGHEKT~., Baton Rouge. Louisiana. I have to idemit’! myself as the person who wrote the article refel-red to as “Doughertr. and associates,“ a11d the title of it is, “Cervical cytology and sequential birth control pills.” L’nfortunately. there were a few editorial mistakes. I did not get a chance to see the proofs before thev were put into print. For example, one of the statements erroneously published as mine was that a certain difference was significant. What I actually wrote was “not significant.” The editor left out the word “not.” I did use prevalence and incidence studies as controls: The rate of cervical disease in the fenlalc population of the Baton Rouge area vs. the ratr of occurrence of in situ carcinoma and dysplasia itt birth control pill users. The rate of occurrence among the birth control pill users was higher than expected. judging by the prevalence rates of the population as a whole. and my conclusion from this was that there is ;t difference, though possibly not significant, due 10 thca low number of cases of disease that I encountered: some 30-odd. DR. JOSEPH (1. Scour. JR., Omaha. Nebraska. ;\Ithough it was not the primary focus of the presentation, I wonder if Dr. Sandmire would comment as to whether or not any other forms of genital carcinoma were found in the user group. DR. RAYMOND H. KAUFMAN. Houston, I‘exas. I would just like IO emphasize what the two discussants have already mentioned. I think that any study of this type cannot i,gnorc the so-called sex-related factors. It is of paramount importance that you take into considcK1tion such factors as age of onset of intercourse ant1 number of sexual partners, because these are factors
Volume Number
125 3
Cervical carcinoma in oral contraceptive and IUD users and nonusers
that we all agree may well be related to the genesis of cervical carcinoma. If cases and controls are not matched along these lines, the study will not be of any significance and will not tell us what we want to know. What really is needed is a good, controlled, prospective study. DR. SANDMIRE (Closing). We did not have incidence figures because patients move, doctors’ offices move, and the only thing we had was our cytology register which was firm throughout the 15 years of the study. We found a large number of cases of cancer in our Class II smears. Our cytologists are no more accurate than Dr. Eichner’s. In fact, there were 25 of the 76 cancers from patients who had Class II smears and in whom the smears never progressed to a higher level of abnormality. The median age of the cancer patients was 35 years; of control pill users, 27.5 years; however, the 50 carcinoma in situ patients, with a median age of 29.5, compared closely to the control pill users.
345
Dr. Masterson asked about other than squamous-cell carcinomas. We had one carcinosarcoma, a couple of adenocarcinomas of the cervix, one adenocarcinoma of the endometrium, one metastatic ovarian carcinoma, and one mesothelial carcinoma. Dr. Scott asked about other carcinomas in the pill users. I presume he means ovary, etc. We do not have information on that. In order to get into this study, the patient had to have had an abnormal Pap smear. Cancer patients who did not have a positive Pap smear are not included in this study. This study comes from 40,2 11 consecutive Pap smears. Dr. Kaufman talked about the relationship between sexual practices and the risk of development of carcinoma of the cervix. I believe there is only one factor important in whether a patient will or will not develop squamous-cell carcinoma of the cervix, and that is her early sexual experience: age of onset and number of partners.
