British Journal of Obstetrics and Gynaecology July 1976. V O 83. ~ pp 554-559
THE MANAGEMENT AND NATURAL HISTORY OF SEVERE DYSPLASIA AND CARCINOMA IN SITU OF THE UTERINE CERVIX BY
C . GAD,Senior Registrar Department of Gynaecology and Obstetrics, Frederiksberg Hospital, Copenhagen, Denmark Summary This report concerns 375 patients seen in Frederiksberg, Denmark, between 1951 and 1972: 103 of them had severe dysplasia and 272 of them carcinoma in situ of the uterine cervix. Thirty patients had no primary treatment: 9 of them developed invasive carcinoma, and 2 of these died; 12 patients had persistent intraepithelial abnormality of the ceivix and the other 9 patients showed no abnormality after varying periods of observation. Recurrences after cone biopsy were noted in 9 * 5 and 10.1 per cent of patients with severe dysplasia and carcinoma in situ respectively, and in 2 per cent of patients who had an in sitii carcinoma treated by hysterectomy. This made a total of 15 patients with recurrences. All were ultimately cured although two patients were found to have invasive carcinoma.
seen, three during the first year and three from five to six years after diagnosis. Because of the method of follow-up the recurrence figures represent minimum values.
THIS paper describes 90 patients treated for severe dysplasia and 255 treated for carcinoma in situ of the uterine cervix. In addition 30 patients with untreated lesions are presented. PATIENTS All 375 patients were citizens of the Frederiksberg Borough of Copenhagen between 1951 and 1972. In this Borough, the number of women over 20 years of age was 52 289 in 1950 and 45 543 in 1972. The patients were collected from the Department of Gynaecology, Frederiksberg Hospital, from the Radium Station, Copenhagen, and from the Danish Cancer Registry listings. In addition to the 375 patients in the study another 40 are mentioned in whom precancerous changes were found before surgical intervention for invasive carcinoma. Patients first treated between 1951 and 1960 were followed until 1970, and the remainder until the end of 1973. Patients who had a hysterectomy were discharged after five years but information about them was obtained by postal inquiry or by reference to a community register. Only six patients were not traced or
RESULTS Tables I and I1 summarize information about the method and timing of diagnosis. Diagnosis and treatment The initial diagnosis was invariably made by biopsy and/or curettage but the final classification depended on the most severe lesion seen during histological examination of biopsy, cone biopsy or hysterectomy specimens. In addition to the 375 patients in the series there were 40 patients in whom invasive carcinoma was found making a total of 415 patients. Of these 415 patients, 229 (55.2 per cent) had a conization; 31 of them (13.5 per cent) had an invasive growth (22 stage Ia carcinoma and 9 stage Ib), the initial diagnosis being carcinoma in situ in 29 patients and severe dysplasia in 2 patients. A total of 235 patients was treated by simple 554
555
DYSPLASIA AND IN SITU CARCINOMA OF CERVIX
TABLEI The 375 patients according to year of diagnosis and method of detection Severe dysplasia Year of diagnosis
1951-52 1953-54 1955-56 1957-58 1959-60 1961-62 1963-64 1965-66 1967-68 1969-70 1971-72 1951-72
Population screening
Other routine cytology* -
-
-
-
-
-
Gynaecological clinic
7 14
26
27
50
6
Population screening
2 1 3 4 1
-
-
-
-
2
2 7 8 7 2
Other Gynaeroutine cological cytology* clinic
Total
-
I 3 4 1 2 3 10 13 11
-
Carcinoma in situ
10 24 27 27
8 61 32 16 5 3
103
125
4
Total
2 2 2 6 14 9
7 1 2 2 14 13 11 12 17 13 20
7 1 2 2 14 23 74 46 39 32 32
35
112
212
* Includes a cancer prevention clinic for women aged 55 to 59. TABLEI1 The 375 patients according to age at diagnosis and method of deteciion
Severe dysplasia
Carcinoma in situ -
Age Population screening
20 -24 25-29 30-34 35-39 40-44 3549 50-54 55-59 60-64 65-69 70 4Total
-
3 3 11 9
26
Other routine cytology
Gynaecological clinic
1 3 10 2 3 2 6
3 8
27
Other routine cytology
Total
2 10 6 9 3 4 2 2 1
4 11 15 15 20 20 3 10 2 2 1
50
103
hysterectomy with or without preceding conization; 9 of them ( 3 - 8 per cent) had an invasive growth (6 stage Ia carcinoma and 3 stage Ib), the initial diagnosis having been carcinoma in situ in 5 patients and severe dysplasia in 4 patients; only one of these 9 patients had had a cone biopsy before hysterectomy. These patients are now excluded from this study but are dealt with elsewhere (Gad, 1976).
Total
-
-
20 52 52 61
1
16 16 20 19 22 10 3 2 3 1
35
112
272
29 29 36 31
-
125
Gynaecological clinic
57
13 9 3 3 2
Thirty patients (13 with severe dysplasia and 17 with carcinoma in situ) were not treated immediately, and Table 111shows what happened to the other 345 patients. Recurrences A later finding of severe dysplasia, carcinoma in situ or invasive carcinoma of the uterine cervix or vaginal vault was defined as a recur-
556
GAD
TABLEI11 The methods of treatment in 345 patienis with information about the number of recurrences
Severe dysplasia
Carcinoma in situ
TIeatmen t No. Conization only Simple hysterectomy previous conization no previous conization Radical hysterectomy Amputation of cervix Electrocoagulation Radium Radium and external irradiation
No.
Recurrences
42
59
15
81 1023* 2
28l* 0 3l* 1 1 0
Total
Recurrences
5l* 1
4 1 6 (6.6 per cent)
90
9 (3.5 per cent)
255
_
The asterisked figures show the number of patients not known to have a lesion until after operation-none developed a recurrence
~~
_
of them
TABLEIV Details of15 patients with severe dysplasia or carcinoma in situ who developed recurrence after treatment
Record No. Age
TF diagnosis
Interval between Primary diagnosis
Primary treatment
diagnosis primary and
Duration of Secondary diagnosis
Secondary treatment
recurrence (years)
follOw-up after primary treatment* (years)
184
32
1959
s.d.
305
47
1958
s.d.
911 924 949 957
58 29 59 40
1971 1971 1971 1970
s.d. s.d. s.d. s.d.
Electrocoagulation Amputation of cervix Conization Conization Conization Conization
110
45
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1956 c.i.s. ElectroOt Stage Ib Radical hysterectomy 13
459 732 852 871 904 942 946 950
41 59 33 55 30 43 31 46
1963 1967 1970 1970 1970 1971 1972 1971
c.i.s. c.i.s. c.i.s. cis. c.i.s. c.i.s. c.i.s. c.i.s.
- -- ----
s.d.
=
* A11 patients were alive when last seen
0
s.d.
Hysterectomy
10
3
Stage IIa
12
0 0 1 1
C.I.S. c.i.s. c.i.s. C.I.S.
Radium and external irradiation Hysterectomy Reconization Hysterectomy Hysterectomy
coagulation Hysterectomy Hysterectomy Conization Conization Conization Conization Conization Conization
6 0 2 0 1 0 0
c.i.s. c.i.s. c.i.s. cis. s.d. cis. c.i.s. cis.
Radium Radium Hysterectomy Hysterectomy Hysterectomy Hysterectomy Hysterectomy Hysterectomy
10 5 3 3 3 2
severe dysplasia;
cis.
I
1 =
2 2 2 2
1 2
carcinoma in situ
t Invasive carcinoma probably present
at time of initial diagnosis
~
DYSPLASIA AND IN SITU CARCINOMA OF CERVIX
rence and the latter were much more common after conization than after hysterectomy (Table 111). Table IV shows details of the 15 patients who had recurrences, and in only three of them was there an interval of two years or more. Only two patients developed an invasive lesion and in one of them (No. 110) it was probably overlooked a t the time of electrocoagulation. The period of follow-up is rather limited and more recurrences may yet come to light. Untreated patients Tables V and VI show the fate of 30 patients who were not treated after the initial diagnosis was made; 14 of them were seen in the first three years of the study. Nine patients progressed to invasive carcinoma, and two of them died. Twelve patients developed ‘precancerous’ conditions again, and nine remained free of disease.
DISCUSSION The experience gained in handling precancerous disease of the cervix in a limited population
557
over a 22-year period has been presented. Cone biopsy is undoubtedly preferable to punch biopsy in the investigation and treatment of patients with malignant cells in a cervical smear; a 13.5 per cent incidence of microinvasive or frankly invasive carcinomas is in line with the results reported by Koch and Albrechtsen (1972) and Karjalainen et al (1974), but is higher than that found by Selim et a1 (1973). The incidence of recurrence after cone biopsy in this series was 10.1 per cent while the figures were 13 per cent for Kullander and Sjoberg (1971), 8 per cent for Villa Santa (1971), 7 per cent for Creasman and Rutledge (1971) and 4 per cent for Selim et a1 (1974). The incidence of vaginal vault recurrences after hysterectomy was 2 per cent in the current series, and rates of 0.5 to 2 - 9 per cent have been quoted by others (Creasman and Rutledge, 1971; Selim et al, 1974). All our recurrences were curable and so their occurrence is no argument against conization provided that patients are seen regularly afterwards.
TABLE V DetaiIs of 13 patients who had severe dysplasia and received no primary treatment
Record No. Age
Interval between Year primary of and primary secondary diagnosis diagnosis (years)
26
48
1951
2
193 213
26 74
1959 1952
0 17*
311 436 545 641 679 714 824 841
35 48 29 34 44 67 24 61
1956 1962 1963 1965 1963 1967 1969 1969
889 982
53 30
1971 1972
Secondary treatment
Secondary diagnosis
~______
s.d.
Hysterectomy
c.i.s. Stage 111 carcinoma of cervix s.d. s.d. c.i.s. s.d. cis.
Hysterectomy Radium and external irradiation
-
Amputation of cervix Conization Amputation of cervix Hysterectomy Radium -
-
-
0
Stage Ia carcinoma of cervix
s.d. = severe dysplasia;
* Discharged from follow-up 5 years after initial diagnosis
Hysterectomy
c.i.s.
=
carcinoma in siru
Outcome and duration of follow-up after secondary treatment or after primary diagnosis -
Died of unknown causes, 15 years Alive, 10 years Died of cervical carcinoma, 0 years Alive, 14 years Alive, 6 years Alive, 9 years Alive, 8 years Alive, I years Alive, 6 years Alive, 4 years Died of intercurrent disease, 1 year Alive, 2 years Alive, 1 year
558
GAD
TABLEVI Details of'l7patients w41o had carcinonia in situ and received no primary treatment Interval between primary and
Year of primary diagnosis secondary diagnosis (years)
Record No.
Age
8 28
29 42
1951 1953
-
51
46
1952
2
98
65
1951
4
114 162 216
35 35 45
1951 1951 1952
4 7 3
304
36
1959
2
42 1 423
37 38
1961 1961
-
446 691 701 843 909
25 39 31 52 38
1962 1965 1967 1962 1963
1 7 8
928 1077
32 42
1964 1963
7 6
* Invasive carcinoma
O*
Secondary diagnosis
Secondary treat men t
-
Stage Ib carcinoma of cervix Stage Ib carcinoma Stage IIb carcinoma cis. cis. Stage Ib carcinoma Stage l a carcinoma c.i.s. c.i.s. Stage 111 carcinoma c.i.s. Stage Ia carcinoma
Radium and external irradiation Radium and external irradiation Radium and external irradiation Electrocoagulation Hysterectomy Radium and external irradiation Radium and external irradiation
Conization Conization Radium and external irradiation Conization Radium
Outcome and duration of follow-up after secondary treatment or primary diagnosis
Alive, 17 years Died of cervical carcinoma, 7 years Alive, 15 years Died of intercurrent disease, 14 years Alive, 13 years Alive, 10 years Alive, 13 years Alive, 10 years Alive, 12 years Emigrated 6 months after diagnosis Alive, 1 1 years Alive, 8 years Alive, 10 years Alive, 3 years Alive, 2 years Alive, 1 year Alive, 3 years
c.i.s. =- carcinoma in situ probably present at tim:: of initial diagnosis
Chanen and Hollyock (1974) proposed an even more conservative attitude and stated that routine colposcopy saved more than half of the patients with dysplasia or carcinoma in situ from cone biopsy, electrocoagulation being used instead. Only if pathological changes appeared to extend beyond the range of the colposcope was conization performed. Ninety per cent of patients who had an electrocoagulation developed a normal cervical smear but more than 50 per cent of them had had mild or moderate dysplasias while the period of follow-up was Iess than 12 months in 30 per cent of cases. Also Fowler and Shingleton (1971) advocated the use of colposcopy and claimed to have reduced the frequency of conization by 69 per cent. In
the Danish series colposcopy was used only sporadically. There have been numerous surveys of the relationship between carcinoma in situ or severe dysplasia and invasive carcinoma (see Te Linde, 1973 and Koss, 1969), and there are some reports which attempt to elucidate the natural history of intraepithelial disease of the cervix. Spriggs (1971) collected 26 patients with class IV or V Papanicolaou smears who were not treated; 13 were lost to follow-up; 4 of the remaining 13 developed invasive carcinoma after three years and 2 of them died; 4 showed persistent disease, one had mild dysplasia and in 4 the smears became normal. Jones et a1 (1957) reported a series of 24 patients who had had a
DYSPLASIA AND IN SITU CARCINOMA OF CERVIX
biopsy of the cervix 12 months to 20 years before a diagnosis of carcinoma was made; 17 of the old biopsy specimens showed carcinoma in situ, 4 were normal and 3 showed basal cell hyperplasia. Koss et a1 (1963) made a 6 to 84 months cytological follow-up study of 67 patients with carcinoma in situ and of 26 ‘borderline cases’: 29 per cent developed a normal smear, 11 per cent progressed to certain or questionable invasion, while the rest retained abnormal smears. Eleven ‘borderline cases’ (42 per cent) progressed to carcinoma in situ. Masterson (1957) followed 25 patients with untreated intraepithelial carcinoma. All but one of them were below 30 years of age and the diagnoses were made by quadrant biopsies. Five patients developed invasive cancer and 5 were suspected of an early invasive lesion; 14 patients had persistent carcinoma in situ and in one the disease disappeared. Two Danish prospective studies exist. Petersen (1955) and Petersen and Wiklund (1959) followed up 127 women, 87 per cent for 10 years and 32 per cent for 15 years or more. Progression to invasive disease was reported in about 30 per cent. Petersen (1955) classified his patients into those with ‘epithelial hyperplasia with nuclear abnormalities’ and those with ‘borderline’ appearances. Clemmesen and Poulsen (1971) later revised this series using modern histological terminology and concluded that at least 40 per cent of patients with carcinoma in Aitu would develop invasive carcinoma. Lange (1960) studied 100 patients and 24 of them progressed to invasive cancer, the figure being 50 per cent for those over 35 years of age; the mean duration of follow-up was 7 - 5 years. It is thus generally agreed that a sizeable proportion of patients with severe dysplasia or carcinoma in situ will, without treatment, develop an invasive carcinoma of the cervix. On the other hand, conization is adequate therapy in about 90 per cent of patients and there is no doubt about the need for adequate follow-up to detect recurrences which can be easily and successfully treated. ACKNOWLEDGEMENTS The study was supported by a grant from the Danish Hospital Foundation for Medical Research, Region of Copenhagen, The Faroe
559
Islands and Greenland. I thank the Danish Cancer Registry for valuable help and the Radium Centre, Copenhagen, for permission to use clinical material. REFERFNCES Chanen, W., and Hollyock, V. E. (1974): Obstetrics and Gynecology, 43, 527. Clemmesen, J., and Poulsen, H. (1971): Report of Ministry of the Interior, Document 3, Copenhagen. Creasrnan, W. T., and Rutledge, F. (1971): Obstetrics and Gynecology, 39, 373. Fowler, W. C., and Shingleton, €1. (1971): Obstetrics and Gynecology, 38, 609. Gad, C. (1976): British Journal of Obstetrics and Gynaecology, 83, 560. Jones, H. W., Calvin, G. A., and Te Linde, R. W. (1957): Proceedings of the Third National Cancer Conference (Detroit 1956). Lippincott, Philadelphia, p 678. Karjalainen, O., Jarvilehto, U., Nieminen, U., and Timonen, S. (1974): Annales chirurgiae et gynaecologiae Fenniae, 63, 1 13. Koch, F., and Albrechtsen, R. (1972): Danish Medical Bulletin, 19, 127. Koss, L. G . (1969): Obsterrical and Gynecologica Survey, 24, 850. Koss, L. G., Stewart, F. W., Foote, F. W., Jordan, M. J., Bader, G. M., and Day, E. (1963): Cancer (Philadelphia), 16, 1160. Kullander, S., and Sjoberg, N.-0. (1971) : Acta obstetricia et gynecologica Scandinavica, 50, 153. Lange, P. (1960): Clinical and Histological Studies on Cervical Carcinoma. Precancerosis, Early Metastases and Tubular Structures in the Lymph Nodes. Munksgaard. Copenhagen, p 27. Masterson, J. G. (1957): Proceedings of the Third National Cancer Conference (Detroit 1956). Lippincolt, Philadelphia, p 671. Petersen, 0.(1955) : Precancerous Changes ofthe Cervical Epithelium in Relation to Manijest Cervical Carcinoma. Clinical and Histopathological Aspects. Danish Science Press Ltd, Copenhagen, p 49. Petersen, O., and Wiklund, E. (1959): Acta rudiologica, Supplementurn 188, 21 0. Selim, M. A., So-Bosita, J. L., Blair, 0. M., and Little, B. A. (1973): Obstetrics and Gynecology, 41, 177. Selim, M. A., S-Bosita, J. L., and Neuman, M . R . (1974): Surgery, Gynecology and Obstetrics, 139, 697. Spriggs, A. J. (1971): Lancet, 2. 599. Te Linde, R. W. (1973): American Journal of Obstetrics and Gynecology, 115, 1022. Villa Santa, U. (1971): Obstetrics and Gynecology, 38, 811.
THE MANAGEMENT AND NATURAL HISTORY OF SEVERE DYSPLASIA AND CARCINOMA IN SITU OF THE UTERINE CERVIX BY
C . GAD,Senior Registrar Department of Gynaecology and Obstetrics, Frederiksberg Hospital, Copenhagen, Denmark Summary This report concerns 375 patients seen in Frederiksberg, Denmark, between 1951 and 1972: 103 of them had severe dysplasia and 272 of them carcinoma in situ of the uterine cervix. Thirty patients had no primary treatment: 9 of them developed invasive carcinoma, and 2 of these died; 12 patients had persistent intraepithelial abnormality of the ceivix and the other 9 patients showed no abnormality after varying periods of observation. Recurrences after cone biopsy were noted in 9 * 5 and 10.1 per cent of patients with severe dysplasia and carcinoma in situ respectively, and in 2 per cent of patients who had an in sitii carcinoma treated by hysterectomy. This made a total of 15 patients with recurrences. All were ultimately cured although two patients were found to have invasive carcinoma.
seen, three during the first year and three from five to six years after diagnosis. Because of the method of follow-up the recurrence figures represent minimum values.
THIS paper describes 90 patients treated for severe dysplasia and 255 treated for carcinoma in situ of the uterine cervix. In addition 30 patients with untreated lesions are presented. PATIENTS All 375 patients were citizens of the Frederiksberg Borough of Copenhagen between 1951 and 1972. In this Borough, the number of women over 20 years of age was 52 289 in 1950 and 45 543 in 1972. The patients were collected from the Department of Gynaecology, Frederiksberg Hospital, from the Radium Station, Copenhagen, and from the Danish Cancer Registry listings. In addition to the 375 patients in the study another 40 are mentioned in whom precancerous changes were found before surgical intervention for invasive carcinoma. Patients first treated between 1951 and 1960 were followed until 1970, and the remainder until the end of 1973. Patients who had a hysterectomy were discharged after five years but information about them was obtained by postal inquiry or by reference to a community register. Only six patients were not traced or
RESULTS Tables I and I1 summarize information about the method and timing of diagnosis. Diagnosis and treatment The initial diagnosis was invariably made by biopsy and/or curettage but the final classification depended on the most severe lesion seen during histological examination of biopsy, cone biopsy or hysterectomy specimens. In addition to the 375 patients in the series there were 40 patients in whom invasive carcinoma was found making a total of 415 patients. Of these 415 patients, 229 (55.2 per cent) had a conization; 31 of them (13.5 per cent) had an invasive growth (22 stage Ia carcinoma and 9 stage Ib), the initial diagnosis being carcinoma in situ in 29 patients and severe dysplasia in 2 patients. A total of 235 patients was treated by simple 554
555
DYSPLASIA AND IN SITU CARCINOMA OF CERVIX
TABLEI The 375 patients according to year of diagnosis and method of detection Severe dysplasia Year of diagnosis
1951-52 1953-54 1955-56 1957-58 1959-60 1961-62 1963-64 1965-66 1967-68 1969-70 1971-72 1951-72
Population screening
Other routine cytology* -
-
-
-
-
-
Gynaecological clinic
7 14
26
27
50
6
Population screening
2 1 3 4 1
-
-
-
-
2
2 7 8 7 2
Other Gynaeroutine cological cytology* clinic
Total
-
I 3 4 1 2 3 10 13 11
-
Carcinoma in situ
10 24 27 27
8 61 32 16 5 3
103
125
4
Total
2 2 2 6 14 9
7 1 2 2 14 13 11 12 17 13 20
7 1 2 2 14 23 74 46 39 32 32
35
112
212
* Includes a cancer prevention clinic for women aged 55 to 59. TABLEI1 The 375 patients according to age at diagnosis and method of deteciion
Severe dysplasia
Carcinoma in situ -
Age Population screening
20 -24 25-29 30-34 35-39 40-44 3549 50-54 55-59 60-64 65-69 70 4Total
-
3 3 11 9
26
Other routine cytology
Gynaecological clinic
1 3 10 2 3 2 6
3 8
27
Other routine cytology
Total
2 10 6 9 3 4 2 2 1
4 11 15 15 20 20 3 10 2 2 1
50
103
hysterectomy with or without preceding conization; 9 of them ( 3 - 8 per cent) had an invasive growth (6 stage Ia carcinoma and 3 stage Ib), the initial diagnosis having been carcinoma in situ in 5 patients and severe dysplasia in 4 patients; only one of these 9 patients had had a cone biopsy before hysterectomy. These patients are now excluded from this study but are dealt with elsewhere (Gad, 1976).
Total
-
-
20 52 52 61
1
16 16 20 19 22 10 3 2 3 1
35
112
272
29 29 36 31
-
125
Gynaecological clinic
57
13 9 3 3 2
Thirty patients (13 with severe dysplasia and 17 with carcinoma in situ) were not treated immediately, and Table 111shows what happened to the other 345 patients. Recurrences A later finding of severe dysplasia, carcinoma in situ or invasive carcinoma of the uterine cervix or vaginal vault was defined as a recur-
556
GAD
TABLEI11 The methods of treatment in 345 patienis with information about the number of recurrences
Severe dysplasia
Carcinoma in situ
TIeatmen t No. Conization only Simple hysterectomy previous conization no previous conization Radical hysterectomy Amputation of cervix Electrocoagulation Radium Radium and external irradiation
No.
Recurrences
42
59
15
81 1023* 2
28l* 0 3l* 1 1 0
Total
Recurrences
5l* 1
4 1 6 (6.6 per cent)
90
9 (3.5 per cent)
255
_
The asterisked figures show the number of patients not known to have a lesion until after operation-none developed a recurrence
~~
_
of them
TABLEIV Details of15 patients with severe dysplasia or carcinoma in situ who developed recurrence after treatment
Record No. Age
TF diagnosis
Interval between Primary diagnosis
Primary treatment
diagnosis primary and
Duration of Secondary diagnosis
Secondary treatment
recurrence (years)
follOw-up after primary treatment* (years)
184
32
1959
s.d.
305
47
1958
s.d.
911 924 949 957
58 29 59 40
1971 1971 1971 1970
s.d. s.d. s.d. s.d.
Electrocoagulation Amputation of cervix Conization Conization Conization Conization
110
45
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1956 c.i.s. ElectroOt Stage Ib Radical hysterectomy 13
459 732 852 871 904 942 946 950
41 59 33 55 30 43 31 46
1963 1967 1970 1970 1970 1971 1972 1971
c.i.s. c.i.s. c.i.s. cis. c.i.s. c.i.s. c.i.s. c.i.s.
- -- ----
s.d.
=
* A11 patients were alive when last seen
0
s.d.
Hysterectomy
10
3
Stage IIa
12
0 0 1 1
C.I.S. c.i.s. c.i.s. C.I.S.
Radium and external irradiation Hysterectomy Reconization Hysterectomy Hysterectomy
coagulation Hysterectomy Hysterectomy Conization Conization Conization Conization Conization Conization
6 0 2 0 1 0 0
c.i.s. c.i.s. c.i.s. cis. s.d. cis. c.i.s. cis.
Radium Radium Hysterectomy Hysterectomy Hysterectomy Hysterectomy Hysterectomy Hysterectomy
10 5 3 3 3 2
severe dysplasia;
cis.
I
1 =
2 2 2 2
1 2
carcinoma in situ
t Invasive carcinoma probably present
at time of initial diagnosis
~
DYSPLASIA AND IN SITU CARCINOMA OF CERVIX
rence and the latter were much more common after conization than after hysterectomy (Table 111). Table IV shows details of the 15 patients who had recurrences, and in only three of them was there an interval of two years or more. Only two patients developed an invasive lesion and in one of them (No. 110) it was probably overlooked a t the time of electrocoagulation. The period of follow-up is rather limited and more recurrences may yet come to light. Untreated patients Tables V and VI show the fate of 30 patients who were not treated after the initial diagnosis was made; 14 of them were seen in the first three years of the study. Nine patients progressed to invasive carcinoma, and two of them died. Twelve patients developed ‘precancerous’ conditions again, and nine remained free of disease.
DISCUSSION The experience gained in handling precancerous disease of the cervix in a limited population
557
over a 22-year period has been presented. Cone biopsy is undoubtedly preferable to punch biopsy in the investigation and treatment of patients with malignant cells in a cervical smear; a 13.5 per cent incidence of microinvasive or frankly invasive carcinomas is in line with the results reported by Koch and Albrechtsen (1972) and Karjalainen et al (1974), but is higher than that found by Selim et a1 (1973). The incidence of recurrence after cone biopsy in this series was 10.1 per cent while the figures were 13 per cent for Kullander and Sjoberg (1971), 8 per cent for Villa Santa (1971), 7 per cent for Creasman and Rutledge (1971) and 4 per cent for Selim et a1 (1974). The incidence of vaginal vault recurrences after hysterectomy was 2 per cent in the current series, and rates of 0.5 to 2 - 9 per cent have been quoted by others (Creasman and Rutledge, 1971; Selim et al, 1974). All our recurrences were curable and so their occurrence is no argument against conization provided that patients are seen regularly afterwards.
TABLE V DetaiIs of 13 patients who had severe dysplasia and received no primary treatment
Record No. Age
Interval between Year primary of and primary secondary diagnosis diagnosis (years)
26
48
1951
2
193 213
26 74
1959 1952
0 17*
311 436 545 641 679 714 824 841
35 48 29 34 44 67 24 61
1956 1962 1963 1965 1963 1967 1969 1969
889 982
53 30
1971 1972
Secondary treatment
Secondary diagnosis
~______
s.d.
Hysterectomy
c.i.s. Stage 111 carcinoma of cervix s.d. s.d. c.i.s. s.d. cis.
Hysterectomy Radium and external irradiation
-
Amputation of cervix Conization Amputation of cervix Hysterectomy Radium -
-
-
0
Stage Ia carcinoma of cervix
s.d. = severe dysplasia;
* Discharged from follow-up 5 years after initial diagnosis
Hysterectomy
c.i.s.
=
carcinoma in siru
Outcome and duration of follow-up after secondary treatment or after primary diagnosis -
Died of unknown causes, 15 years Alive, 10 years Died of cervical carcinoma, 0 years Alive, 14 years Alive, 6 years Alive, 9 years Alive, 8 years Alive, I years Alive, 6 years Alive, 4 years Died of intercurrent disease, 1 year Alive, 2 years Alive, 1 year
558
GAD
TABLEVI Details of'l7patients w41o had carcinonia in situ and received no primary treatment Interval between primary and
Year of primary diagnosis secondary diagnosis (years)
Record No.
Age
8 28
29 42
1951 1953
-
51
46
1952
2
98
65
1951
4
114 162 216
35 35 45
1951 1951 1952
4 7 3
304
36
1959
2
42 1 423
37 38
1961 1961
-
446 691 701 843 909
25 39 31 52 38
1962 1965 1967 1962 1963
1 7 8
928 1077
32 42
1964 1963
7 6
* Invasive carcinoma
O*
Secondary diagnosis
Secondary treat men t
-
Stage Ib carcinoma of cervix Stage Ib carcinoma Stage IIb carcinoma cis. cis. Stage Ib carcinoma Stage l a carcinoma c.i.s. c.i.s. Stage 111 carcinoma c.i.s. Stage Ia carcinoma
Radium and external irradiation Radium and external irradiation Radium and external irradiation Electrocoagulation Hysterectomy Radium and external irradiation Radium and external irradiation
Conization Conization Radium and external irradiation Conization Radium
Outcome and duration of follow-up after secondary treatment or primary diagnosis
Alive, 17 years Died of cervical carcinoma, 7 years Alive, 15 years Died of intercurrent disease, 14 years Alive, 13 years Alive, 10 years Alive, 13 years Alive, 10 years Alive, 12 years Emigrated 6 months after diagnosis Alive, 1 1 years Alive, 8 years Alive, 10 years Alive, 3 years Alive, 2 years Alive, 1 year Alive, 3 years
c.i.s. =- carcinoma in situ probably present at tim:: of initial diagnosis
Chanen and Hollyock (1974) proposed an even more conservative attitude and stated that routine colposcopy saved more than half of the patients with dysplasia or carcinoma in situ from cone biopsy, electrocoagulation being used instead. Only if pathological changes appeared to extend beyond the range of the colposcope was conization performed. Ninety per cent of patients who had an electrocoagulation developed a normal cervical smear but more than 50 per cent of them had had mild or moderate dysplasias while the period of follow-up was Iess than 12 months in 30 per cent of cases. Also Fowler and Shingleton (1971) advocated the use of colposcopy and claimed to have reduced the frequency of conization by 69 per cent. In
the Danish series colposcopy was used only sporadically. There have been numerous surveys of the relationship between carcinoma in situ or severe dysplasia and invasive carcinoma (see Te Linde, 1973 and Koss, 1969), and there are some reports which attempt to elucidate the natural history of intraepithelial disease of the cervix. Spriggs (1971) collected 26 patients with class IV or V Papanicolaou smears who were not treated; 13 were lost to follow-up; 4 of the remaining 13 developed invasive carcinoma after three years and 2 of them died; 4 showed persistent disease, one had mild dysplasia and in 4 the smears became normal. Jones et a1 (1957) reported a series of 24 patients who had had a
DYSPLASIA AND IN SITU CARCINOMA OF CERVIX
biopsy of the cervix 12 months to 20 years before a diagnosis of carcinoma was made; 17 of the old biopsy specimens showed carcinoma in situ, 4 were normal and 3 showed basal cell hyperplasia. Koss et a1 (1963) made a 6 to 84 months cytological follow-up study of 67 patients with carcinoma in situ and of 26 ‘borderline cases’: 29 per cent developed a normal smear, 11 per cent progressed to certain or questionable invasion, while the rest retained abnormal smears. Eleven ‘borderline cases’ (42 per cent) progressed to carcinoma in situ. Masterson (1957) followed 25 patients with untreated intraepithelial carcinoma. All but one of them were below 30 years of age and the diagnoses were made by quadrant biopsies. Five patients developed invasive cancer and 5 were suspected of an early invasive lesion; 14 patients had persistent carcinoma in situ and in one the disease disappeared. Two Danish prospective studies exist. Petersen (1955) and Petersen and Wiklund (1959) followed up 127 women, 87 per cent for 10 years and 32 per cent for 15 years or more. Progression to invasive disease was reported in about 30 per cent. Petersen (1955) classified his patients into those with ‘epithelial hyperplasia with nuclear abnormalities’ and those with ‘borderline’ appearances. Clemmesen and Poulsen (1971) later revised this series using modern histological terminology and concluded that at least 40 per cent of patients with carcinoma in Aitu would develop invasive carcinoma. Lange (1960) studied 100 patients and 24 of them progressed to invasive cancer, the figure being 50 per cent for those over 35 years of age; the mean duration of follow-up was 7 - 5 years. It is thus generally agreed that a sizeable proportion of patients with severe dysplasia or carcinoma in situ will, without treatment, develop an invasive carcinoma of the cervix. On the other hand, conization is adequate therapy in about 90 per cent of patients and there is no doubt about the need for adequate follow-up to detect recurrences which can be easily and successfully treated. ACKNOWLEDGEMENTS The study was supported by a grant from the Danish Hospital Foundation for Medical Research, Region of Copenhagen, The Faroe
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Islands and Greenland. I thank the Danish Cancer Registry for valuable help and the Radium Centre, Copenhagen, for permission to use clinical material. REFERFNCES Chanen, W., and Hollyock, V. E. (1974): Obstetrics and Gynecology, 43, 527. Clemmesen, J., and Poulsen, H. (1971): Report of Ministry of the Interior, Document 3, Copenhagen. Creasrnan, W. T., and Rutledge, F. (1971): Obstetrics and Gynecology, 39, 373. Fowler, W. C., and Shingleton, €1. (1971): Obstetrics and Gynecology, 38, 609. Gad, C. (1976): British Journal of Obstetrics and Gynaecology, 83, 560. Jones, H. W., Calvin, G. A., and Te Linde, R. W. (1957): Proceedings of the Third National Cancer Conference (Detroit 1956). Lippincott, Philadelphia, p 678. Karjalainen, O., Jarvilehto, U., Nieminen, U., and Timonen, S. (1974): Annales chirurgiae et gynaecologiae Fenniae, 63, 1 13. Koch, F., and Albrechtsen, R. (1972): Danish Medical Bulletin, 19, 127. Koss, L. G . (1969): Obsterrical and Gynecologica Survey, 24, 850. Koss, L. G., Stewart, F. W., Foote, F. W., Jordan, M. J., Bader, G. M., and Day, E. (1963): Cancer (Philadelphia), 16, 1160. Kullander, S., and Sjoberg, N.-0. (1971) : Acta obstetricia et gynecologica Scandinavica, 50, 153. Lange, P. (1960): Clinical and Histological Studies on Cervical Carcinoma. Precancerosis, Early Metastases and Tubular Structures in the Lymph Nodes. Munksgaard. Copenhagen, p 27. Masterson, J. G. (1957): Proceedings of the Third National Cancer Conference (Detroit 1956). Lippincolt, Philadelphia, p 671. Petersen, 0.(1955) : Precancerous Changes ofthe Cervical Epithelium in Relation to Manijest Cervical Carcinoma. Clinical and Histopathological Aspects. Danish Science Press Ltd, Copenhagen, p 49. Petersen, O., and Wiklund, E. (1959): Acta rudiologica, Supplementurn 188, 21 0. Selim, M. A., So-Bosita, J. L., Blair, 0. M., and Little, B. A. (1973): Obstetrics and Gynecology, 41, 177. Selim, M. A., S-Bosita, J. L., and Neuman, M . R . (1974): Surgery, Gynecology and Obstetrics, 139, 697. Spriggs, A. J. (1971): Lancet, 2. 599. Te Linde, R. W. (1973): American Journal of Obstetrics and Gynecology, 115, 1022. Villa Santa, U. (1971): Obstetrics and Gynecology, 38, 811.
