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Carcinoma in situ in pregnancy
Carcinoma in situ in pregnancy RICHARD OSBAND, M.D. W. NICHOLSON JONES, M.D. Birmingham, Alabama
C A R c I N o M A of the cervix of the in situ type is an interesting and highly debatable lesion both in diagnosis and in treatment. 1 Broders 2 first introduced the term carcinoma in situ in 1932. At present most authorities agree that these lesions of the cervix are actual cancer and that treatment properly carried out during this preinvasive stage of the disease assures the patient a permanent cure. No attempt is made here to substantiate this opinion, but the literature is full of reliable references. This recognition that invasive cervical carcinoma may be preceded by an in situ type of lesion has provided an impetus toward early diagnosis in cervical carcinoma, perhaps accentuated in recent years by the development of the Papanicolaou smear, 3 which is readily available to all clinicians. In the nonpregnant, as well as in the pregnant woman, the positive diagnosis of carcinoma in situ is sometimes confused with various atypical changes of the cervical epithelium. These have been given names such as basal cell hyperplasia, atypical dysplasia, atypical squamous metaplasia, anaplasia, and anaplasia associated with Trichomonas atypia. We believe that for the positive diagnosis of intraepithelial carcinoma of the cervix, certain criteria should be met. 4 These are: ( 1) loss of stratification and polarity of nuclei; (2) presence of atypical squamous cells which vary in size and shape, with hyperchromatic nuclei and an increased nuclearcytoplasmic ratio; (3) frequent mi-
totic figures, sometimes bizarre; (4) incomplete differentiation; (5) complete replacement of epithelium by these changes; and ( 6) no penetration of basement membranes or underlying stroma. Review of the literature
If the diagnosis is difficult to make in the nonpregnant woman, changes that occur in normal pregnancy are certain to cause increased confusion when it is made at that time. Epperson and associates" reported 4 histologic changes in glandular epithelium of the cervix related to pregnancy. These are glandular hyperplasia, glandular epithelial hyperplasia, adenomatous hyperplasia, and epidermization. In 1951, they reported 5 cases of in situ carcinoma in 4,849 patients during pregnancy (an incidence of 0.1 per cent). All of these patients were allowed to go through pregnancy without interruption and all of the group had normal biopsies in the postpartum period. He believed, therefore, that the diagnosis of carcinoma in situ could not be made during pregnancy. In 1953, Green and associates 6 stated that pregnancy is not responsible for specific changes in cervical epithelium other than those listed above and emphasized that such changes are not peculiar to pregnancy. They reported 12 out of 14 cases diagnosed during pregnancy as being carcinoma in situ in which the lesions persisted after the termination of pregnancy. Peckham and Greene/ in 1957, reported 18 additional cases first recognized during pregnancy, with 78.4 per cent persisting in the postpartum period. Marcus and associates 8 emphasized the
From the Department of Obstetrics and Gynecology, The University of Alabama Medical Center.
599
600
Osbond and Jones
difficulty in the diagnosis of in situ lesions of the cervix during pregnancy and stated that pregnancy need not he interrupted, and definitive therapy for carcinoma in situ need not be undertaken until adequate follow-up studies in the postpartum period are done. TeLinde and associates,~ however, emphasized that conization should be done to rule out a more extensive lesion such as invasive carcinoma of the cervix. Campos and Soihet/ 0 in 1956, studied the cervices of 200 pregnant patients during labor and immediately after childbirth. In 10 patients alterations of the epithelium were "exactly" similar to those of carcinoma in situ. In 2 patients it appeared as though there were incipient stromal infiltration. This was noted in the endocervix. There were no changes present 6 to 12 weeks post partum in these patients. It was their feeling that certain epithelial changes, such as squamous metaplasia, hyperplasia of the basal cell layer of the ectocervical epithelium, and glandular hyperplasia are more frequent in pregnant than nonpregnant women and that these lesions, which are morphologically similar to carcinoma in situ, are transitory changes of pregnancy. Marsh and Fitzgerald 11 studied 4,067 pregnant women (representing 20 per cent of the total pregnancies in that institution) and in these, they found 2 invasive carcinomas of the cervix, 20 in situ carcinomas, 5 debatable lesions, and 16 nonneoplastic changes. Of the 20 cases of carcinoma in situ, in 18 the lesions were found to persist up to as long as 31 months after delivery. These authors' incidence of carcinoma in situ was 0.49 per cent of all pregnant women, with an average age of 30 years. They thought that the disparity in results of studies of carcinoma in situ associated with pregnancy was possibly related to the histologic criteria used in the diagnosis. Important in his conclusions were: ( 1) there was no evidence that the prevalence of in situ lesions increases with the duration of the pregnancy because carcinoma in situ occurs as often at 3 months' gestation as it
~1ard• L l~lh'.! Am. j. <>hst. & (:yw·<'.
does at 8 months; ( 2) pregnancy itself do(·s not g'ive rise to carcinoma in situ lesions (four of his 20 patients with in situ lesions were found to have had prepregnancy biopsies which also rewaled the in situ lesions). Moore and Gusber,g, 1 studying the problem in 1959, re-emphasized the criteria for diagnosis of intraepithelial carcinoma of the cervix, whether in the pregnant or the nonpregnant state. They studied 24,964 deliveries from 1951 to 195 7; 23 of the mothers (0.088 per cent) had atypical cer\'ical changes. Carcinoma in situ was found in 13 (0.052 per cent .1 and basal cell hyperplasia in 10 (0.028 per cent!. No Papanicolaou smears were taken in his studies. His conclusion was that squamous metaplasia and reserve cell hyperplasia, even basal cell hyperplasia, may be conditioned hy pregnancy but that true in situ carcinoma was not. Slate and associates,'" in 1957, studied Papanicolaou smears of 5,935 pregnant women. Suspicious Papanicolaou smears were followed by biopsies. Of these patients, 13 had in situ lesions and one invasive carcinoma previously unsuspected. The average age of the pregnant women with the in situ lesion was 26.9 years and his study indicated that abnormal lesions of the cervix during pregnancy, such as premalignant dysplasia and in situ changes, are definite pathologic changes not related to pregnancy. Peckham and Chung,l'l in 1958, emphasized the value of the Papanicolaou smear in the detection of cervical lesions in pregnancy. Spujt and associatesH studied :i,300 patients, of whom 2:1 had abnormal smears. Of these 23, he found carcinoma in situ in 7, -+ of whom later had the diagnosis confirmed by conization during the pregnancy. In the other 3, conization was donf' post partum. All 7 patients had residual carcinoma in situ in the post partum hysterectomy specimens. His incidence was one carcinoma in situ for every 479 pregnant patients, or not quite 0.2 per rent. Johnson and associatesF· examined 6,074 pre- and postpartum patients and found 20
Carcinoma in situ in pregnancy
Volume 83 Number 5
601
Table I. Outline of patients and treatment Biopsy
Patient
B. A., age 39, 72018 7/11/57 Negro Class I Para 2-0·2 EDC 12/57 Del'd 10/16/57
726978/15/57 Carcinoma in situ 7373810/10/57 Carcinoma in situ 771725/13/58 Chronic cervicitis
E. G., age 32, Negro Para 8-1-3 EDC 8/25/60 Del'd 8/8/60
Conization
Hysterectomy specimen
Slide No. Slide No. and date of and date of Slide No. and original original Papanico· date of original New report New report report report New report report laou smear
P4362 4/22/60 Class III P5463 8/19/60 Class III
779916/28/58 Chronic cervicitis
Cervix with some metaplasia
Carcinoma 92986in situ 11/1/60 Carcinoma Carcinoma in situ in situ in focal areas
Minute focus of carcinoma in situ with assodated atypical metaplasia
Chronic Probable 74442cervicitis carcinoma 11/19/57 in situ but Chronic should cervicitis have conization Probable carcinoma in situ but should have conization Normal cervix
89392-5/2/60 Carcinoma in situ Carcinoma in situ
896175/12/60 Carcinoma in situ 920579/13/60 Carcinoma in situ
I. H., age 38, P2878 10/14/59 white Class IV Para 8-0-7 EDC 5/60
8643211/2/59 Carcinoma in situ
Carcinoma Probable 86529in situ carcinoma 11/7/59 in situ but Invasive should squamous have cell cardconization noma
Treated with irradiation
B. H., age 38, 73461 9/23/57 Negro Class IV Para 9-0-9 Abortion 9/8/57
7378610/12/57 Carcinoma in situ
Atypical metaplasia
Refused hysterectomy
E.
J., age 29, P504 Class IV Negro Para 7-0-6 EDC 11/58
774815/29/58 Carcinoma in situ
Carcinoma in situ
776636/10/58 Carcinoma in situ
Cervicitis with atypical metaplasia
77716Normal cervix 6/12/58 No residual carcinoma seen
R. K., age 30, P3537 1/18/60 white Class III Para 4-0-3 Cesarean section 3/8/60
875851/18/60 Carcinoma in situ
Slide missing
892824/25/60 Carcinoma in situ
Carcinoma in situ
89936Cervix with squamous 5/28/60 metaplasia No residual (no residtumor seen ual tumor)
0. M., age 41, white Para 7-1-6 Abortion 1/15/60
Chronic Chronic 8849087876-2/3/60 Atypical 88000cervtcttts cervicitis 3/10/60 meta2/11/60 Carcinoma with mild No residual plasia not No residual in situ metatumor tumor diagnostic plasia seen seen of carcinoma .in situ
602 Osband and Jones
Am.
March 1, 1962 & Gynec.
J. Obst.
Table 1-Cont'd Biopsy
Patient
Conization
TT.
••.
Slide No. Slide No. and date of and date of Slide No. and original original Papanico- date of original New report New report New report report report report laou smear
(Slide miss- 4190241057ing) focus 8/28/52 7/10/52 of atypi- Chronic Carcinoma cystic cal metain situ plasia and cervicitis 41676-basal hy8/14/52 Focus suspicious perplasia but speciof squamous men too cell small for carcinoma adequate evaluation
M. R., age 41, Negro Para 19-6-11 Del'd 5/25/52
Atypical hy- 43480Chronic cervicitis perplasia 11/15/52 Chronic cervicitis
697163/16/57 Carcinoma in situ
Carcinoma in situ
Lost to follow-up
P. W., age 28, P4188 4/5/60 Negro Class IV Para 4-1-3 Abortion 2/60
891684/16/60 Carcinoma in situ
Carcinoma in situ
899445/28/60 Focal residual Carcinoma in situ
V. V., age 30, 7/59 "Suspiwhite cious" Para 5-0-5 Del'd 11/2/59
8/59 Carcinoma in situ
Slide not 88203available, 2123/60 done in Carcinoma another in situ hospital
Carcinoma in situ
776566/10/58 Carcinoma in situ
Carcinoma in situ
No residual (some sections may be missing)
P. S.,age 32, white Para 6-1-5 EDC 10/26/57 Abortion 3/23/57
69371 693862/27/57 2/27/57 Class IV Carcinoma 70355 in situ 4/17/57 Class I
L.M.W., age 32, Negro Para 7-1-6 Ectopic pregnancy 3/14/58
773925/26/58 Carcinoma in situ
T. B., age 37, 2 positive 11/59 Papanico- Carcinoma white laou Para 3-0-2 in situ smears LMP 8/59 (outlying Abortion hospil/60 tals) G. H., age 36, 5/57 "Questionwhite able" Para 4-1-3 Del'd 7/8/57
Carcinoma in situ
Carcinoma in situ
Carcinoma 87181Slides not in situ 12/18/59 available, done in Carcinoma in situ outlying hospital
7360810/3/58 Carcinoma in situ
Carcinoma in situ
777196/12/58 Carcinoma in situ
Focal residual carcinoma in situ
Chronic 87976-cervicitis 2/10/60 No residual tumor
Lost to follow-up
Volume 83 Number5
Carcinoma in situ in pregnancy 603
Table 1-Cont'd Biopsy
Patient
Conization
Hy•• ~, ~"W"'f J·pecimer>
Slide No. Slide No. and date of Slide No. and and date of Papanico- date of original original original New report laou smear report report New report report New report
412867/23/52 Carcinoma in situ 41451-8/4/52 Chronic cervicitis with severe atypicalities 419038/24/52 Chronic cervicitis 445801/23/53 Chronic cervicitis with epithelial atypism and squamous metaplasia 6782711/28/56 Chronic cervicitis
Slides missing
M.S., age 30, white Para 2-0-0 Del'd 8/19/59
1/30/59 Carcinoma in situ
Slides not 819142/18/59 available, done in Carcinoma in situ outlying hospital
L. 0., age 45, white Para 7-0-7 LMP 3/1/54
4/54 Carcinoma in situ
Slides not available, done in outlying hospital
B. H., age 42, P1402
818072/11/59 Chronic cervicitis
Probable 82036carcinoma 2/24/59 in situ Carcinoma in situ
L.A.T., age 26, Negro Para 8-3-4 LMP 2/12/52 Del'd ll/52
white 2/11/59 Para 11-2-9 Class V LMP 11/58
Slides missing
495801/2/54 Chronic cervicitis
Chronic Lost to cervicitis follow-up
Slides missing Slides missing
in situ lesions. Seventeen of these 20 patients had hysterectomy and in these 12 still had carcinoma in situ in the hysterectomy specimen. Four had early microscopic invasion in either the postpartum biopsies or the surgical specimens, and only one had no evidence of anaplasia or carcinoma in situ in the surgical specimen. He allowed his patients normal delivery if no invasion were noted in the
Carcinoma Probably 86189in situ. carcinoma 10/20/59 in situ Carcinoma in situ
Carcinoma in situ
518085/20/54 Carcinoma in situ
Carcinoma in situ
821352/28/59 Focal residual Carcinoma in situ
Atypical metaplasia
conization specimen, and then re-evaluated them 6 weeks post partum. Data and technique
In this current study the charts of all patients with the diagnosis of carcinoma in situ made either prior to admission or on admission to this hospital were studied from the period Oct. 1, 1950, through Oct. 1, 1960.
604 Osband and Jones
Am.
- - - - - - - - - - - - - - ' ' " ' " . . . . .M
(
trea
March 1, 1962 Obst. & Gynec.
(18)~ Ne!!ative Conizationa (4)
Posi tiva Conizations (11)
~Un flj"'~-..
J.
(5)
wiilie pregnant)
~M'-"'
(')
Positive tterectomies (6} (TWo treat lilii!e pregnant)
Fig. 1. Scheme of therapy. "Negative" means no carcinoma in situ found. "Positive'' means carcinoma in situ.
There was a total of 123 patients with the diagnosis of carcinoma in situ. Of these, 18 were pregnant and 105 were nonpregnant. In the category of pregnant patients were included some in whom the diagnosis was initially made at the checkup 6 weeks post partum. The technique used for study of these patients was as follows: The chart was reviewed and the date of the Papanicolaou smear, biopsy, conization, and hysterectomy was recorded. An effort was made to locate the original slides and pathologic reports. In many cases the slides were not available either because they were missing from the files or, more often, because the original diagnosis, by biopsy or conization, had been made at another hospital prior to admission of the patient to this hospital for more definitive therapy. In all, 41 sets of slides (specimens) were studied; in one instance we believe that some slides are missing because "level" slides were not available. "Levels" are obtained when the diagnosis of carcinoma in situ is made in order to rule out invasion. Each of the available slides was reviewed without knowledge of patient's history, background, or therapy, and an independent diagnosis was placed on the record. A comparison of the diagnosis made on the original report as compared with the new report (read November, 1960) is given in Table I.
Analysis of data As can be seen from the table, of the 18 patients, 8 were Negro and 10 were white. The average age was 34.8 years (compared to 36.9 years given in the literature as the average age in the nonpregnant patient). The average number of pregnancies of these patients was 6.7, with an average parity of 5.4. During this same period of time there were 50,070 deliveries, meaning that almost 1 in 6 patients with carcinoma in situ was also pregnant and that, of every 2,800 pregnant patients, one had carcinoma in situ of the cervix. Of the 18 patients with positive biopsies, one patient had invasive carcinoma of the cervix on conization, 4 had negative conizations, 2 had no conizations, and 11 had conizations positive for carcinoma in situ (Fig. 1). Ten conizations were performed in the postpartum period and were positive for carcinoma in situ in 6 cases (60 per cent). Of the other 4 negative conizations, one specimen was called atypical cervical hyperplasia when reread. Seven conizations were done during pregnancy. One revealed invasive carcinoma of the cervix (now reread as carcinoma in situ) and the other 6 were carcinoma in situ. We had only one patient with conization during pregnancy and after parturition. Carcinoma in situ was found in both specimens. The patient with invasive carcinoma was treated with an Ernst applicator and co-
Volume83 Number5
balt. 60 Of the patients with negative conizations, 2 had no lesion in hysterectomy specimens and 2 had no further treatment. Of the 2 patients with no conizations, one received no treatment of any sort and one patient had a hysterectomy (while pregnant) which revealed carcinoma in situ. Of the 11 patients with positive conizations for carcinoma in situ of the cervix, 6 patients still had active disease noted on the hysterectomy specimen (4 of these hysterectomies being done 6 to 12 weeks following delivery). Three patients showed no further evidence of disease in the hysterectomy specimen (2 of which were done after delivery and one while the patient was still pregnant). Because this study combines hoth private and clinic patients, there was no set pattern of therapy; 4 of the patients had hysterectomy while pregnant. Of the 41 specimens available for comparative study, 7 had an altered diagnosis when reviewed in November, 1960. Five cases previously called carcinoma in situ were now regarded as atypical metaplasia or anaplasia. One case of invasive squamous cell carcinoma was considered as carcinoma in situ showing glandular involvement, with the gland cut in such a manner as to simulate invasion. The seventh slide, which had previously been called chronic cervicitis (by biopsy specimen), was now regarded as probable carcinoma in situ, which corresponded more completely with the conization report. At the time of the reading of these slides, the pathologist regarded many of these as extremely "difficult to interpret." Much depends on the judgment of the pathologist, especially when only focal areas of abnormal cells are present. In no instance, however, did the knowledge of pregnancy alter the criteria for diagnosis in any way. Summary
A review of the literature of carcinoma in situ in pregnant patients has been given. As can be seen, there is a great conflict of opinion as to whether the diagnosis can be made in the pregnant patient. We have hoped to provide by this study more con-
Carcinoma in situ in pregnancy
605
crete evidence that pregnancy itself did not alter the diagnosis of carcinoma in situ. This diagnosis can be made in the pregnant as in the nonpregnant state. It seems more justified to state that interpretation of a slide may change according to the pathologist reading it. Because changes in the cervix, such as basal cell hyperplasia, are often highly indistinguishable from carcinoma in situ, it seems advisable that several pathologists interpret the slide at the time of initial reading to reach common agreement; the pregnancy itself plays no factor in the interpretation. The value of the Papanicolaou smear is to be stressed. Of the 18 cases studied, 11 were initially detected by Papanicolaou smear, reported as from Class III to Class V. The twelfth patient had a Papanicolaou smear reported as Class I but fortunately had a biopsy of the cervix at the same time which revealed carcinoma in situ. Three cases were detected prior to 1955; in none of these had a Papanicolaou smear been taken. Fifteen cases were detected after this time or, more correctly, since 1957. Obviously this increased incidence of detection can be attributed to departmental policy in insisting on complete study of the pregnant as well as the nonpregnant patient. Papanicolaou smears during this time have become readily available for clinic use. In review, it appears that the accepted mode of therapy is as follows: L Immediate conization of the cervix (unless delivery were impending within 6 weeks) for a positive biopsy of carcinoma in situ or cellular anaplasia. This should also be done for Papanicolaou smears, Classes III to V. 2. Vaginal delivery permitted when invasive carcinoma has been ruled out. 3. Definitive therapy consisting of reconization and/or hysterectomy undertaken in the postpartum period. Very special thanks are extended to Dr. Ed· mund A. Dowling, Department of Pathology, The University of Alabama Medical Center, without whose ht>lp this paper could not have been writtPn.
606 Osbond and Jones
REFERENCES
1. Birtch, P. K., and Randall, C. L.: New York, J. Med. 59: 3783, 1959. 2. Broders, A. C.: ].A.M.A. 99: 1670, 1932. 3. Markley, R. L., and Galvin, G. A.: Maryland M. J. 4: 364, 1955. 4. Moore, D. B., and Gusberg, S. B.: Obst. & Gynec. 13: 530, 1959. 5. Epperson, J. W. W., Hellman, L. M., Galvin, G. A., and Busby, T.: AM. J. On sT. & GYNEC. 61: 50, 1951. 6. Greene, R. R., et a!.: Surg. Gynec. & Obst. 96: 71, 1953. 7. Peckham, B. M., and Greene, R. R.: AM. J. 0BST. & GYNEC. 74: 804, 1957. 8. Marcus, N. B., Brandt, M. L., and Cibley, L. J.: Obst. & Gynec. 10: 669, 1957.
Am.
Ma1ch l, 1%2 & Gynec.
J. Obst.
9. TeLinde, R. W., Galvin, G. A., and Jones, H. W., Jr.: AM. J. 0BsT. & GYNEc. 74: 792, 1957. 10. Campos, J., and Soihet, S.: Surg. Gynec. & Obst. 102: 427, 1956. 11. Marsh, M., and Fitzgerald, P. J.: Cancer 9: 1195, 1956. 12. Slate, T. A., Martin, D. L., and Merritt, J. W.: AM. J. OnsT. & GYNEC. 74: 344, 1957. 13. Peckham, B., and Chung, J.: Clin. Obst. & Gynec. 1: 703, 1958. 14. Spujt, H. J., Ruch, W. A., Jr., Martin, P. A., and Hobbs, J. E.: Obst. & Gynec. 15: 19, 1960. 15. Johnson, L. D., Hertig, A. T., Hinman, C. H., and Easterday, C. L.: Obst. & Gynec. 16: 113, 1960.
C A R c I N o M A of the cervix of the in situ type is an interesting and highly debatable lesion both in diagnosis and in treatment. 1 Broders 2 first introduced the term carcinoma in situ in 1932. At present most authorities agree that these lesions of the cervix are actual cancer and that treatment properly carried out during this preinvasive stage of the disease assures the patient a permanent cure. No attempt is made here to substantiate this opinion, but the literature is full of reliable references. This recognition that invasive cervical carcinoma may be preceded by an in situ type of lesion has provided an impetus toward early diagnosis in cervical carcinoma, perhaps accentuated in recent years by the development of the Papanicolaou smear, 3 which is readily available to all clinicians. In the nonpregnant, as well as in the pregnant woman, the positive diagnosis of carcinoma in situ is sometimes confused with various atypical changes of the cervical epithelium. These have been given names such as basal cell hyperplasia, atypical dysplasia, atypical squamous metaplasia, anaplasia, and anaplasia associated with Trichomonas atypia. We believe that for the positive diagnosis of intraepithelial carcinoma of the cervix, certain criteria should be met. 4 These are: ( 1) loss of stratification and polarity of nuclei; (2) presence of atypical squamous cells which vary in size and shape, with hyperchromatic nuclei and an increased nuclearcytoplasmic ratio; (3) frequent mi-
totic figures, sometimes bizarre; (4) incomplete differentiation; (5) complete replacement of epithelium by these changes; and ( 6) no penetration of basement membranes or underlying stroma. Review of the literature
If the diagnosis is difficult to make in the nonpregnant woman, changes that occur in normal pregnancy are certain to cause increased confusion when it is made at that time. Epperson and associates" reported 4 histologic changes in glandular epithelium of the cervix related to pregnancy. These are glandular hyperplasia, glandular epithelial hyperplasia, adenomatous hyperplasia, and epidermization. In 1951, they reported 5 cases of in situ carcinoma in 4,849 patients during pregnancy (an incidence of 0.1 per cent). All of these patients were allowed to go through pregnancy without interruption and all of the group had normal biopsies in the postpartum period. He believed, therefore, that the diagnosis of carcinoma in situ could not be made during pregnancy. In 1953, Green and associates 6 stated that pregnancy is not responsible for specific changes in cervical epithelium other than those listed above and emphasized that such changes are not peculiar to pregnancy. They reported 12 out of 14 cases diagnosed during pregnancy as being carcinoma in situ in which the lesions persisted after the termination of pregnancy. Peckham and Greene/ in 1957, reported 18 additional cases first recognized during pregnancy, with 78.4 per cent persisting in the postpartum period. Marcus and associates 8 emphasized the
From the Department of Obstetrics and Gynecology, The University of Alabama Medical Center.
599
600
Osbond and Jones
difficulty in the diagnosis of in situ lesions of the cervix during pregnancy and stated that pregnancy need not he interrupted, and definitive therapy for carcinoma in situ need not be undertaken until adequate follow-up studies in the postpartum period are done. TeLinde and associates,~ however, emphasized that conization should be done to rule out a more extensive lesion such as invasive carcinoma of the cervix. Campos and Soihet/ 0 in 1956, studied the cervices of 200 pregnant patients during labor and immediately after childbirth. In 10 patients alterations of the epithelium were "exactly" similar to those of carcinoma in situ. In 2 patients it appeared as though there were incipient stromal infiltration. This was noted in the endocervix. There were no changes present 6 to 12 weeks post partum in these patients. It was their feeling that certain epithelial changes, such as squamous metaplasia, hyperplasia of the basal cell layer of the ectocervical epithelium, and glandular hyperplasia are more frequent in pregnant than nonpregnant women and that these lesions, which are morphologically similar to carcinoma in situ, are transitory changes of pregnancy. Marsh and Fitzgerald 11 studied 4,067 pregnant women (representing 20 per cent of the total pregnancies in that institution) and in these, they found 2 invasive carcinomas of the cervix, 20 in situ carcinomas, 5 debatable lesions, and 16 nonneoplastic changes. Of the 20 cases of carcinoma in situ, in 18 the lesions were found to persist up to as long as 31 months after delivery. These authors' incidence of carcinoma in situ was 0.49 per cent of all pregnant women, with an average age of 30 years. They thought that the disparity in results of studies of carcinoma in situ associated with pregnancy was possibly related to the histologic criteria used in the diagnosis. Important in his conclusions were: ( 1) there was no evidence that the prevalence of in situ lesions increases with the duration of the pregnancy because carcinoma in situ occurs as often at 3 months' gestation as it
~1ard• L l~lh'.! Am. j. <>hst. & (:yw·<'.
does at 8 months; ( 2) pregnancy itself do(·s not g'ive rise to carcinoma in situ lesions (four of his 20 patients with in situ lesions were found to have had prepregnancy biopsies which also rewaled the in situ lesions). Moore and Gusber,g, 1 studying the problem in 1959, re-emphasized the criteria for diagnosis of intraepithelial carcinoma of the cervix, whether in the pregnant or the nonpregnant state. They studied 24,964 deliveries from 1951 to 195 7; 23 of the mothers (0.088 per cent) had atypical cer\'ical changes. Carcinoma in situ was found in 13 (0.052 per cent .1 and basal cell hyperplasia in 10 (0.028 per cent!. No Papanicolaou smears were taken in his studies. His conclusion was that squamous metaplasia and reserve cell hyperplasia, even basal cell hyperplasia, may be conditioned hy pregnancy but that true in situ carcinoma was not. Slate and associates,'" in 1957, studied Papanicolaou smears of 5,935 pregnant women. Suspicious Papanicolaou smears were followed by biopsies. Of these patients, 13 had in situ lesions and one invasive carcinoma previously unsuspected. The average age of the pregnant women with the in situ lesion was 26.9 years and his study indicated that abnormal lesions of the cervix during pregnancy, such as premalignant dysplasia and in situ changes, are definite pathologic changes not related to pregnancy. Peckham and Chung,l'l in 1958, emphasized the value of the Papanicolaou smear in the detection of cervical lesions in pregnancy. Spujt and associatesH studied :i,300 patients, of whom 2:1 had abnormal smears. Of these 23, he found carcinoma in situ in 7, -+ of whom later had the diagnosis confirmed by conization during the pregnancy. In the other 3, conization was donf' post partum. All 7 patients had residual carcinoma in situ in the post partum hysterectomy specimens. His incidence was one carcinoma in situ for every 479 pregnant patients, or not quite 0.2 per rent. Johnson and associatesF· examined 6,074 pre- and postpartum patients and found 20
Carcinoma in situ in pregnancy
Volume 83 Number 5
601
Table I. Outline of patients and treatment Biopsy
Patient
B. A., age 39, 72018 7/11/57 Negro Class I Para 2-0·2 EDC 12/57 Del'd 10/16/57
726978/15/57 Carcinoma in situ 7373810/10/57 Carcinoma in situ 771725/13/58 Chronic cervicitis
E. G., age 32, Negro Para 8-1-3 EDC 8/25/60 Del'd 8/8/60
Conization
Hysterectomy specimen
Slide No. Slide No. and date of and date of Slide No. and original original Papanico· date of original New report New report report report New report report laou smear
P4362 4/22/60 Class III P5463 8/19/60 Class III
779916/28/58 Chronic cervicitis
Cervix with some metaplasia
Carcinoma 92986in situ 11/1/60 Carcinoma Carcinoma in situ in situ in focal areas
Minute focus of carcinoma in situ with assodated atypical metaplasia
Chronic Probable 74442cervicitis carcinoma 11/19/57 in situ but Chronic should cervicitis have conization Probable carcinoma in situ but should have conization Normal cervix
89392-5/2/60 Carcinoma in situ Carcinoma in situ
896175/12/60 Carcinoma in situ 920579/13/60 Carcinoma in situ
I. H., age 38, P2878 10/14/59 white Class IV Para 8-0-7 EDC 5/60
8643211/2/59 Carcinoma in situ
Carcinoma Probable 86529in situ carcinoma 11/7/59 in situ but Invasive should squamous have cell cardconization noma
Treated with irradiation
B. H., age 38, 73461 9/23/57 Negro Class IV Para 9-0-9 Abortion 9/8/57
7378610/12/57 Carcinoma in situ
Atypical metaplasia
Refused hysterectomy
E.
J., age 29, P504 Class IV Negro Para 7-0-6 EDC 11/58
774815/29/58 Carcinoma in situ
Carcinoma in situ
776636/10/58 Carcinoma in situ
Cervicitis with atypical metaplasia
77716Normal cervix 6/12/58 No residual carcinoma seen
R. K., age 30, P3537 1/18/60 white Class III Para 4-0-3 Cesarean section 3/8/60
875851/18/60 Carcinoma in situ
Slide missing
892824/25/60 Carcinoma in situ
Carcinoma in situ
89936Cervix with squamous 5/28/60 metaplasia No residual (no residtumor seen ual tumor)
0. M., age 41, white Para 7-1-6 Abortion 1/15/60
Chronic Chronic 8849087876-2/3/60 Atypical 88000cervtcttts cervicitis 3/10/60 meta2/11/60 Carcinoma with mild No residual plasia not No residual in situ metatumor tumor diagnostic plasia seen seen of carcinoma .in situ
602 Osband and Jones
Am.
March 1, 1962 & Gynec.
J. Obst.
Table 1-Cont'd Biopsy
Patient
Conization
TT.
••.
Slide No. Slide No. and date of and date of Slide No. and original original Papanico- date of original New report New report New report report report report laou smear
(Slide miss- 4190241057ing) focus 8/28/52 7/10/52 of atypi- Chronic Carcinoma cystic cal metain situ plasia and cervicitis 41676-basal hy8/14/52 Focus suspicious perplasia but speciof squamous men too cell small for carcinoma adequate evaluation
M. R., age 41, Negro Para 19-6-11 Del'd 5/25/52
Atypical hy- 43480Chronic cervicitis perplasia 11/15/52 Chronic cervicitis
697163/16/57 Carcinoma in situ
Carcinoma in situ
Lost to follow-up
P. W., age 28, P4188 4/5/60 Negro Class IV Para 4-1-3 Abortion 2/60
891684/16/60 Carcinoma in situ
Carcinoma in situ
899445/28/60 Focal residual Carcinoma in situ
V. V., age 30, 7/59 "Suspiwhite cious" Para 5-0-5 Del'd 11/2/59
8/59 Carcinoma in situ
Slide not 88203available, 2123/60 done in Carcinoma another in situ hospital
Carcinoma in situ
776566/10/58 Carcinoma in situ
Carcinoma in situ
No residual (some sections may be missing)
P. S.,age 32, white Para 6-1-5 EDC 10/26/57 Abortion 3/23/57
69371 693862/27/57 2/27/57 Class IV Carcinoma 70355 in situ 4/17/57 Class I
L.M.W., age 32, Negro Para 7-1-6 Ectopic pregnancy 3/14/58
773925/26/58 Carcinoma in situ
T. B., age 37, 2 positive 11/59 Papanico- Carcinoma white laou Para 3-0-2 in situ smears LMP 8/59 (outlying Abortion hospil/60 tals) G. H., age 36, 5/57 "Questionwhite able" Para 4-1-3 Del'd 7/8/57
Carcinoma in situ
Carcinoma in situ
Carcinoma 87181Slides not in situ 12/18/59 available, done in Carcinoma in situ outlying hospital
7360810/3/58 Carcinoma in situ
Carcinoma in situ
777196/12/58 Carcinoma in situ
Focal residual carcinoma in situ
Chronic 87976-cervicitis 2/10/60 No residual tumor
Lost to follow-up
Volume 83 Number5
Carcinoma in situ in pregnancy 603
Table 1-Cont'd Biopsy
Patient
Conization
Hy•• ~, ~"W"'f J·pecimer>
Slide No. Slide No. and date of Slide No. and and date of Papanico- date of original original original New report laou smear report report New report report New report
412867/23/52 Carcinoma in situ 41451-8/4/52 Chronic cervicitis with severe atypicalities 419038/24/52 Chronic cervicitis 445801/23/53 Chronic cervicitis with epithelial atypism and squamous metaplasia 6782711/28/56 Chronic cervicitis
Slides missing
M.S., age 30, white Para 2-0-0 Del'd 8/19/59
1/30/59 Carcinoma in situ
Slides not 819142/18/59 available, done in Carcinoma in situ outlying hospital
L. 0., age 45, white Para 7-0-7 LMP 3/1/54
4/54 Carcinoma in situ
Slides not available, done in outlying hospital
B. H., age 42, P1402
818072/11/59 Chronic cervicitis
Probable 82036carcinoma 2/24/59 in situ Carcinoma in situ
L.A.T., age 26, Negro Para 8-3-4 LMP 2/12/52 Del'd ll/52
white 2/11/59 Para 11-2-9 Class V LMP 11/58
Slides missing
495801/2/54 Chronic cervicitis
Chronic Lost to cervicitis follow-up
Slides missing Slides missing
in situ lesions. Seventeen of these 20 patients had hysterectomy and in these 12 still had carcinoma in situ in the hysterectomy specimen. Four had early microscopic invasion in either the postpartum biopsies or the surgical specimens, and only one had no evidence of anaplasia or carcinoma in situ in the surgical specimen. He allowed his patients normal delivery if no invasion were noted in the
Carcinoma Probably 86189in situ. carcinoma 10/20/59 in situ Carcinoma in situ
Carcinoma in situ
518085/20/54 Carcinoma in situ
Carcinoma in situ
821352/28/59 Focal residual Carcinoma in situ
Atypical metaplasia
conization specimen, and then re-evaluated them 6 weeks post partum. Data and technique
In this current study the charts of all patients with the diagnosis of carcinoma in situ made either prior to admission or on admission to this hospital were studied from the period Oct. 1, 1950, through Oct. 1, 1960.
604 Osband and Jones
Am.
- - - - - - - - - - - - - - ' ' " ' " . . . . .M
(
trea
March 1, 1962 Obst. & Gynec.
(18)~ Ne!!ative Conizationa (4)
Posi tiva Conizations (11)
~Un flj"'~-..
J.
(5)
wiilie pregnant)
~M'-"'
(')
Positive tterectomies (6} (TWo treat lilii!e pregnant)
Fig. 1. Scheme of therapy. "Negative" means no carcinoma in situ found. "Positive'' means carcinoma in situ.
There was a total of 123 patients with the diagnosis of carcinoma in situ. Of these, 18 were pregnant and 105 were nonpregnant. In the category of pregnant patients were included some in whom the diagnosis was initially made at the checkup 6 weeks post partum. The technique used for study of these patients was as follows: The chart was reviewed and the date of the Papanicolaou smear, biopsy, conization, and hysterectomy was recorded. An effort was made to locate the original slides and pathologic reports. In many cases the slides were not available either because they were missing from the files or, more often, because the original diagnosis, by biopsy or conization, had been made at another hospital prior to admission of the patient to this hospital for more definitive therapy. In all, 41 sets of slides (specimens) were studied; in one instance we believe that some slides are missing because "level" slides were not available. "Levels" are obtained when the diagnosis of carcinoma in situ is made in order to rule out invasion. Each of the available slides was reviewed without knowledge of patient's history, background, or therapy, and an independent diagnosis was placed on the record. A comparison of the diagnosis made on the original report as compared with the new report (read November, 1960) is given in Table I.
Analysis of data As can be seen from the table, of the 18 patients, 8 were Negro and 10 were white. The average age was 34.8 years (compared to 36.9 years given in the literature as the average age in the nonpregnant patient). The average number of pregnancies of these patients was 6.7, with an average parity of 5.4. During this same period of time there were 50,070 deliveries, meaning that almost 1 in 6 patients with carcinoma in situ was also pregnant and that, of every 2,800 pregnant patients, one had carcinoma in situ of the cervix. Of the 18 patients with positive biopsies, one patient had invasive carcinoma of the cervix on conization, 4 had negative conizations, 2 had no conizations, and 11 had conizations positive for carcinoma in situ (Fig. 1). Ten conizations were performed in the postpartum period and were positive for carcinoma in situ in 6 cases (60 per cent). Of the other 4 negative conizations, one specimen was called atypical cervical hyperplasia when reread. Seven conizations were done during pregnancy. One revealed invasive carcinoma of the cervix (now reread as carcinoma in situ) and the other 6 were carcinoma in situ. We had only one patient with conization during pregnancy and after parturition. Carcinoma in situ was found in both specimens. The patient with invasive carcinoma was treated with an Ernst applicator and co-
Volume83 Number5
balt. 60 Of the patients with negative conizations, 2 had no lesion in hysterectomy specimens and 2 had no further treatment. Of the 2 patients with no conizations, one received no treatment of any sort and one patient had a hysterectomy (while pregnant) which revealed carcinoma in situ. Of the 11 patients with positive conizations for carcinoma in situ of the cervix, 6 patients still had active disease noted on the hysterectomy specimen (4 of these hysterectomies being done 6 to 12 weeks following delivery). Three patients showed no further evidence of disease in the hysterectomy specimen (2 of which were done after delivery and one while the patient was still pregnant). Because this study combines hoth private and clinic patients, there was no set pattern of therapy; 4 of the patients had hysterectomy while pregnant. Of the 41 specimens available for comparative study, 7 had an altered diagnosis when reviewed in November, 1960. Five cases previously called carcinoma in situ were now regarded as atypical metaplasia or anaplasia. One case of invasive squamous cell carcinoma was considered as carcinoma in situ showing glandular involvement, with the gland cut in such a manner as to simulate invasion. The seventh slide, which had previously been called chronic cervicitis (by biopsy specimen), was now regarded as probable carcinoma in situ, which corresponded more completely with the conization report. At the time of the reading of these slides, the pathologist regarded many of these as extremely "difficult to interpret." Much depends on the judgment of the pathologist, especially when only focal areas of abnormal cells are present. In no instance, however, did the knowledge of pregnancy alter the criteria for diagnosis in any way. Summary
A review of the literature of carcinoma in situ in pregnant patients has been given. As can be seen, there is a great conflict of opinion as to whether the diagnosis can be made in the pregnant patient. We have hoped to provide by this study more con-
Carcinoma in situ in pregnancy
605
crete evidence that pregnancy itself did not alter the diagnosis of carcinoma in situ. This diagnosis can be made in the pregnant as in the nonpregnant state. It seems more justified to state that interpretation of a slide may change according to the pathologist reading it. Because changes in the cervix, such as basal cell hyperplasia, are often highly indistinguishable from carcinoma in situ, it seems advisable that several pathologists interpret the slide at the time of initial reading to reach common agreement; the pregnancy itself plays no factor in the interpretation. The value of the Papanicolaou smear is to be stressed. Of the 18 cases studied, 11 were initially detected by Papanicolaou smear, reported as from Class III to Class V. The twelfth patient had a Papanicolaou smear reported as Class I but fortunately had a biopsy of the cervix at the same time which revealed carcinoma in situ. Three cases were detected prior to 1955; in none of these had a Papanicolaou smear been taken. Fifteen cases were detected after this time or, more correctly, since 1957. Obviously this increased incidence of detection can be attributed to departmental policy in insisting on complete study of the pregnant as well as the nonpregnant patient. Papanicolaou smears during this time have become readily available for clinic use. In review, it appears that the accepted mode of therapy is as follows: L Immediate conization of the cervix (unless delivery were impending within 6 weeks) for a positive biopsy of carcinoma in situ or cellular anaplasia. This should also be done for Papanicolaou smears, Classes III to V. 2. Vaginal delivery permitted when invasive carcinoma has been ruled out. 3. Definitive therapy consisting of reconization and/or hysterectomy undertaken in the postpartum period. Very special thanks are extended to Dr. Ed· mund A. Dowling, Department of Pathology, The University of Alabama Medical Center, without whose ht>lp this paper could not have been writtPn.
606 Osbond and Jones
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