GYNECOLOGIC
ONCOLOGY
3, 149- 153 (1975)
The Treatment
of Cervical
Dysplasia9
LAMAN A. GRAY, M. D. AND WILLIAM M. CHRISTOPHERSON, M. D. Department of Obstetrics and Gynecology and Department of Pathology University of Louisville School of Medicine Louisville, Kentucky
Received April 4, 1975 Of 111 patients with untreated persistent dysplasia of the cervix, followed longer than 5 yr, 17 progressed to carcinoma in situ, one to in situ carcinoma with questionable invasion, and one to microinvasive carcinoma (17% progression). Sharp cold-knife conization of the cervix was used to treat 62 other patients with dysplasias of the cervix, proved by biopsy and with persistent dysplastic smears. Six had residual or recurrent lesions up to 9 yr later. Cryosurgery was used to treat 66 patients with dysplasia of the cervix. Fifty of these followed for 3- 12 mo had ablation of the lesions, although six required two or three treatments. But 16 had persistent dysplasias as proved by cytology, although seven of the 16 had been retreated (four persisted after two freezes, and three after three freezes). Mild and moderate dysplasias may be observed as they infrequently progress. Severe dysplasias require tissue studies and conservative treatment. Sharp cold-knife conization appears to give a better cure rate than cryosurgery, although cryosurgery is simpler to carry out. All cases with dysplasia must have continuous follow-up examinations.
In the Dysplasia Clinic of the Louisville General Hospital, over 850 patients with dysplasias of the cervix have been studied by us over the past 14 years [ 1,2,3]. Many have had hysterectomies (usually for other reasons), many remain under observation, and unfortunately, many have been lost to follow-up (having changed names, addresses, or desired no further examination). One hundred eleven patients were followed for longer than 5 yr and up to 14 yr. The diagnoses were proven by biopsies, and the patients subsequently had persistent dysplastic smears. One case with reserve cell hyperplasia had a progression of the lesion to microinvasive carcinoma, and one to in situ carcinoma with questionable invasion. Seventeen progressed to carcinoma in situ. Of the 19 total cases which progressed (17%), 12 had atypical reserve cell hyperplasia, four had severe dysplasia, two moderate dysplasia and one mild dysplasia. The progression rate was small over a long period of time. The mild and moderate dysplasias commonly remained in the same phase or regressed when observed over many years. Richart [4] supports the concept of cervical intraepithelial neoplasia (GIN) as an all inclusive concept of the progression from mild dysplasia into invasive cancer. He states that the majority of dysplasias ultimately evolve to carcinoma in situ and invasive carcinoma. Recently Rubio and Lagerlof [5] from the 1 Presented in part at the January 1975 meeting of the Society of Gynecological Oncologists, Key Biscayne, FL. 149 Copyright @ 1975 by Academic Press, Inc. All rights of reproduction in any form reserved
150
GRAY
AND
CHRISTOPHERSON
Karolinska Institute in Stockholm noted the increase of mitotic figures in cervical epithelium from normal squamous epithelium to carcinoma in situ. The differences in the frequency of mitosis between slight and moderate dysplasia were not significant for the whole thickness of the epithelium but when the superficial third of the epithelium was separately analyzed in these two degrees of dysplasia, there was a significant progression. When cervical slices of cone specimens were incubated in vitro with [3H]thymidine, the number of DNAsynthesizing cells increased from normal epithelium to carcinoma in situ stepwise, through slight, moderate and severe dysplasia. They concluded that there exists not only histological but also biological differences in these conditions which indicate that they should be classified separately and not in one generic term, cervical intraepithelial neoplasia. Individualization of the lesions was considered necessary because of the strikingly different risks. Their modes of treatment involved only conservative procedures. This paper presents a comparison of the conservative treatment methods of 128 cases with mild, moderate and severe dysplasia of the cervix. All patients were treated by one of us (L.A.G.). The results indicate further that mild and moderate degrees of dysplasia require little or no treatment other than observation and that sharp cold-knife conization gives a better rate of ablation than cryosurgery. METHODS
The technique of conization of the cervix is not a complicated one. The cervix and vagina are stained with Lugol’s solution, as all nonstaining areas must be excised. Adrenalin, one to 200,000, is injected around the cervical OSlateral to the eversion. Using the small No. 15 Bard Parker blade, an outlining excision extends around and beyond the everted area. The undercutting is superficial, particularly if it is a wide eversion in order not to destroy the cervix. With care, the small circular incisions are deepened with the scalpel, following up the canal, which has been previously probed. The excision can be extended well into the endocervix, ordinarily without destroying the continuity of the cone. In the wide and large everted cervix one may take the cone in two parts. First the eversion up to the external OSis removed. The second higher cone may extend into the canal. Following this, curettage is performed. When the cervix is small, no sutures are necessary. A packing of plain gauze covered with a small portion of Surgicel is inserted tightly into the canal, supported by gauze in the vagina. A new packing is inserted after 48 hr. The patient removes the second packing at the end of the second 48-hr period. This has been followed by infrequent postoperative hemorrhage. With large, open, everted and lacerated cervices, deep sutures are placed at each angle. Commonly in these instances, the external cervical squamous mucosa is undermined and drawn into the canal with Stiirmdorf sutures. The cervix is packed for 48 hr for added precaution. The operation of conization requires care to remove the proper amount of tissue without harming the cervix. The specimen is opened and pinned on cardboard before fixation. In some institutions, only the senior gynecologist performs conization operations, while in others the procedure is carried out by the junior intern.
TREATMENT
OF CERVICAL
151
DYSPLASIAS
TABLE 1 62 DYSPLASIAS: CONIZATION Follow-Up Degree
#
Neg.
1 yr
2-5 yr
6-18 yr
Slight Moderate Severe
15 24 23
15 21 20
2 3 3
4 5 3
9 13 14
Cryosurgery was performed with the KRY/med MT-500 Unit, using the Creasman probe tip. As a rule the cervix was frozen from 3 to 7 min at one sitting. Commonly the application was for 3 min twice in succession. The intent was to freeze the cervix symmetrically and thoroughly. The time of freezing varied with the size of the cervix and the pressure of the nitrous oxide. RESULTS
Sharp Cold-Knife Conization In 62 cases with dysplasia of the cervix, a sharp cold-knife conization was performed. Tables 1 and 2 summarize these findings. One-fourth of the cases had only slight dysplasia, and none of these recurred during the period of observation. Of the 47 cases with moderate and severe dysplasias, as found on sharp conization, six had recurrences. Of three moderate dysplasias with recurrent cytologic findings, one had immediate hysterectomy which revealed incompletely excised dysplasia of moderate degree. A second developed mild dysplasia 3 yr later, proved by cone. A third had mild dysplasia 9 yr later in the hysterectomy specimen performed for other reasons. Of the three recurrences in patients with original severe dysplasia, one had cytology indicating carcinoma in situ after 6 mo, which was proved by hysterectomy. A second developed cells after 3 yr suggesting carcinoma in situ, proved and treated by conization. A third patient after 9 yr developed dysplastic cells and had moderate dysplasia in the second conization. The apparent cure of 56 of 62 cases treated by sharp conization followed from 2 to 18 yr, makes this a satisfactory conservative treatment. Of the 15 cases with mild dysplasia, there were no recurrences. TABLE 2 62 DYSPLASIAS: CONIZATION Residual or Recurrenced Moderate
Severe
1 Hyst. moderate l-3 yr cone, mild l-9 yr hyst., mild
1-6 mo hyst. CIS l-3 yr cone CIS l-9 yr cone dys.
152
GRAY AND CHRISTOPHERSON TABLE 3 66
DYSPLASIAS:
CRYOSURGERY
Degree
Cases
Residual
Mild Moderate Severe
25 31 10
4 10 2
Total
66
16
Cryosurgery
Cryosurgery has been used cautiously for the treatment of dysplasias and carcinoma in situ of the cervix by a few investigators. They indicate failure rates of zero [6], 11.2% [7], 18.7% and 48.5% [8]. In our effort to study this treatment method, a series of patients with cervical dysplasia have been treated and followed short periods (3 mo to 1 yr). In 66 patients with persistent dysplasia of the cervix, as shown by the cytology after multiple biopsies of the cervix, cryosurgery was applied. In 16 of these patients, there was residual or recurrent dsyplasia (Tables 3, 4). Of 25 with mild dysplasia there was residual or recurrence in four. Two of the four were frozen on two and three occasions. In 3 1 patients with moderate dysplasia, there was residual or recurrence in 10. Five of those with moderate dysplasia were treated on two, three and four occasions, but had persistent dysplastic smears. Of the 10 with severe dysplasia, two had persistent dysplastic smears. Thus, seven of the 16 failures continued to have dysplastic cells after two (four patients), three (two patients), and four (one patient) freezes. The freezing was applied from 3 to 7 min. Of the 66 patients treated with cryosurgery, 16 had persistent dysplasia. Cryosurgery may be used in the treatment of this condition with the advantages of outpatient therapy, but the rate of persistence requires close follow-up. DISCUSSION
Sharp conization of the cervix not only provides tissue for diagnostic study, but is indicated particularly for treatment of severe dysplastic lesions. The TABLE 4 66
DYSPLASIAS:
CRYOSURGERY
Follow-Up Duration
Cases
Residual
3 mo 6 mo 9 mo 1 yr +
22 18 15 11
2 6 3 5
Total
66
16
TREATMENT
OF CERVICAL
153
DYSPLASIAS
apparent cure of 56 of 62 patients followed for 2 to 18 yr, illustrates the value in treatment. Otherwise, multiple biopsies alone are sufficient for diagnosis [9]. From this series of 124 patients with dysplasia of the cervix, histologically proven, sharp cold-knife conization gave better results in ablation of the lesions than cryosurgery, although the latter is performed more simply, with less inconvenience to the patient and without hospitalization. Careful follow-up with cytology and colposcopy is indicated with either method. Mild dysplasia as indicated by cytologic smear needs only observation. Moderate dysplasia in the smear should be observed for confirmation over a period of 6 months or longer. Severe dysplasia merits treatment either by sharp cold-knife conization of the cervix or by biopsy followed by cryosurgery. The differentiation of degrees of these lesions allows different approaches to treatment. However, all must have follow-up through the years. REFERENCES 1. Gray, L. A. Dysplasia, carcinoma in situ and microinvasive carcinoma of the cervix uteri, Charles C Thomas, Springfield, IL, (1964). 2. Rutledge, C. E., Jr., Christopherson, W. M., and Parker, J. E. Cervical dysplasia and carcinoma 19, 35 I-354 (1962). in pregnancy, Obstet. Gynecol. 3. Christopherson, W. M. Concepts of genesis and development in early cervical neoplasia. Obstet. Gynecol. Sur. 24, 842-850 (1969). 4. Richart, R. M. Natural history of cervical intraepithelial neoplasia, C/in. Obstet. Gynecok 10, 748-784
(1967).
5. Rubio, C. A. and Lagerlof, 6. Crisp, W. E. Cryosurgical 495-499
B. Identity of cervical dysplasias, Lancer, I386 Dec. 7, 1974. treatment of neoplasia of the uterine cervix. Obstet. Gynecol.
39,
(1972).
7. Townsend,
D. E. and Ostergard, D. R. Cryocauterization for preinvasive cervical neoplasia, J. 6, 171-175 (1971). 8. Creasman, W. T., Weed, J. C., Jr., Curry, S. L., Johnston, W. W., and Parker, R. T. Efficacy of Gynecol. 41, cryosurgical treatment of severe cervical intraepithelial neoplasia, Obstet. Reprod.
Med.
501-506
(1973).
9. Christopherson, W. M., Gray, L. A., and Parker, J. E. Role of punch biopsy in subclinical of the uterine cervix, Obstet. Gynecol. 30, 806-8 11 (1967).
lesions
ONCOLOGY
3, 149- 153 (1975)
The Treatment
of Cervical
Dysplasia9
LAMAN A. GRAY, M. D. AND WILLIAM M. CHRISTOPHERSON, M. D. Department of Obstetrics and Gynecology and Department of Pathology University of Louisville School of Medicine Louisville, Kentucky
Received April 4, 1975 Of 111 patients with untreated persistent dysplasia of the cervix, followed longer than 5 yr, 17 progressed to carcinoma in situ, one to in situ carcinoma with questionable invasion, and one to microinvasive carcinoma (17% progression). Sharp cold-knife conization of the cervix was used to treat 62 other patients with dysplasias of the cervix, proved by biopsy and with persistent dysplastic smears. Six had residual or recurrent lesions up to 9 yr later. Cryosurgery was used to treat 66 patients with dysplasia of the cervix. Fifty of these followed for 3- 12 mo had ablation of the lesions, although six required two or three treatments. But 16 had persistent dysplasias as proved by cytology, although seven of the 16 had been retreated (four persisted after two freezes, and three after three freezes). Mild and moderate dysplasias may be observed as they infrequently progress. Severe dysplasias require tissue studies and conservative treatment. Sharp cold-knife conization appears to give a better cure rate than cryosurgery, although cryosurgery is simpler to carry out. All cases with dysplasia must have continuous follow-up examinations.
In the Dysplasia Clinic of the Louisville General Hospital, over 850 patients with dysplasias of the cervix have been studied by us over the past 14 years [ 1,2,3]. Many have had hysterectomies (usually for other reasons), many remain under observation, and unfortunately, many have been lost to follow-up (having changed names, addresses, or desired no further examination). One hundred eleven patients were followed for longer than 5 yr and up to 14 yr. The diagnoses were proven by biopsies, and the patients subsequently had persistent dysplastic smears. One case with reserve cell hyperplasia had a progression of the lesion to microinvasive carcinoma, and one to in situ carcinoma with questionable invasion. Seventeen progressed to carcinoma in situ. Of the 19 total cases which progressed (17%), 12 had atypical reserve cell hyperplasia, four had severe dysplasia, two moderate dysplasia and one mild dysplasia. The progression rate was small over a long period of time. The mild and moderate dysplasias commonly remained in the same phase or regressed when observed over many years. Richart [4] supports the concept of cervical intraepithelial neoplasia (GIN) as an all inclusive concept of the progression from mild dysplasia into invasive cancer. He states that the majority of dysplasias ultimately evolve to carcinoma in situ and invasive carcinoma. Recently Rubio and Lagerlof [5] from the 1 Presented in part at the January 1975 meeting of the Society of Gynecological Oncologists, Key Biscayne, FL. 149 Copyright @ 1975 by Academic Press, Inc. All rights of reproduction in any form reserved
150
GRAY
AND
CHRISTOPHERSON
Karolinska Institute in Stockholm noted the increase of mitotic figures in cervical epithelium from normal squamous epithelium to carcinoma in situ. The differences in the frequency of mitosis between slight and moderate dysplasia were not significant for the whole thickness of the epithelium but when the superficial third of the epithelium was separately analyzed in these two degrees of dysplasia, there was a significant progression. When cervical slices of cone specimens were incubated in vitro with [3H]thymidine, the number of DNAsynthesizing cells increased from normal epithelium to carcinoma in situ stepwise, through slight, moderate and severe dysplasia. They concluded that there exists not only histological but also biological differences in these conditions which indicate that they should be classified separately and not in one generic term, cervical intraepithelial neoplasia. Individualization of the lesions was considered necessary because of the strikingly different risks. Their modes of treatment involved only conservative procedures. This paper presents a comparison of the conservative treatment methods of 128 cases with mild, moderate and severe dysplasia of the cervix. All patients were treated by one of us (L.A.G.). The results indicate further that mild and moderate degrees of dysplasia require little or no treatment other than observation and that sharp cold-knife conization gives a better rate of ablation than cryosurgery. METHODS
The technique of conization of the cervix is not a complicated one. The cervix and vagina are stained with Lugol’s solution, as all nonstaining areas must be excised. Adrenalin, one to 200,000, is injected around the cervical OSlateral to the eversion. Using the small No. 15 Bard Parker blade, an outlining excision extends around and beyond the everted area. The undercutting is superficial, particularly if it is a wide eversion in order not to destroy the cervix. With care, the small circular incisions are deepened with the scalpel, following up the canal, which has been previously probed. The excision can be extended well into the endocervix, ordinarily without destroying the continuity of the cone. In the wide and large everted cervix one may take the cone in two parts. First the eversion up to the external OSis removed. The second higher cone may extend into the canal. Following this, curettage is performed. When the cervix is small, no sutures are necessary. A packing of plain gauze covered with a small portion of Surgicel is inserted tightly into the canal, supported by gauze in the vagina. A new packing is inserted after 48 hr. The patient removes the second packing at the end of the second 48-hr period. This has been followed by infrequent postoperative hemorrhage. With large, open, everted and lacerated cervices, deep sutures are placed at each angle. Commonly in these instances, the external cervical squamous mucosa is undermined and drawn into the canal with Stiirmdorf sutures. The cervix is packed for 48 hr for added precaution. The operation of conization requires care to remove the proper amount of tissue without harming the cervix. The specimen is opened and pinned on cardboard before fixation. In some institutions, only the senior gynecologist performs conization operations, while in others the procedure is carried out by the junior intern.
TREATMENT
OF CERVICAL
151
DYSPLASIAS
TABLE 1 62 DYSPLASIAS: CONIZATION Follow-Up Degree
#
Neg.
1 yr
2-5 yr
6-18 yr
Slight Moderate Severe
15 24 23
15 21 20
2 3 3
4 5 3
9 13 14
Cryosurgery was performed with the KRY/med MT-500 Unit, using the Creasman probe tip. As a rule the cervix was frozen from 3 to 7 min at one sitting. Commonly the application was for 3 min twice in succession. The intent was to freeze the cervix symmetrically and thoroughly. The time of freezing varied with the size of the cervix and the pressure of the nitrous oxide. RESULTS
Sharp Cold-Knife Conization In 62 cases with dysplasia of the cervix, a sharp cold-knife conization was performed. Tables 1 and 2 summarize these findings. One-fourth of the cases had only slight dysplasia, and none of these recurred during the period of observation. Of the 47 cases with moderate and severe dysplasias, as found on sharp conization, six had recurrences. Of three moderate dysplasias with recurrent cytologic findings, one had immediate hysterectomy which revealed incompletely excised dysplasia of moderate degree. A second developed mild dysplasia 3 yr later, proved by cone. A third had mild dysplasia 9 yr later in the hysterectomy specimen performed for other reasons. Of the three recurrences in patients with original severe dysplasia, one had cytology indicating carcinoma in situ after 6 mo, which was proved by hysterectomy. A second developed cells after 3 yr suggesting carcinoma in situ, proved and treated by conization. A third patient after 9 yr developed dysplastic cells and had moderate dysplasia in the second conization. The apparent cure of 56 of 62 cases treated by sharp conization followed from 2 to 18 yr, makes this a satisfactory conservative treatment. Of the 15 cases with mild dysplasia, there were no recurrences. TABLE 2 62 DYSPLASIAS: CONIZATION Residual or Recurrenced Moderate
Severe
1 Hyst. moderate l-3 yr cone, mild l-9 yr hyst., mild
1-6 mo hyst. CIS l-3 yr cone CIS l-9 yr cone dys.
152
GRAY AND CHRISTOPHERSON TABLE 3 66
DYSPLASIAS:
CRYOSURGERY
Degree
Cases
Residual
Mild Moderate Severe
25 31 10
4 10 2
Total
66
16
Cryosurgery
Cryosurgery has been used cautiously for the treatment of dysplasias and carcinoma in situ of the cervix by a few investigators. They indicate failure rates of zero [6], 11.2% [7], 18.7% and 48.5% [8]. In our effort to study this treatment method, a series of patients with cervical dysplasia have been treated and followed short periods (3 mo to 1 yr). In 66 patients with persistent dysplasia of the cervix, as shown by the cytology after multiple biopsies of the cervix, cryosurgery was applied. In 16 of these patients, there was residual or recurrent dsyplasia (Tables 3, 4). Of 25 with mild dysplasia there was residual or recurrence in four. Two of the four were frozen on two and three occasions. In 3 1 patients with moderate dysplasia, there was residual or recurrence in 10. Five of those with moderate dysplasia were treated on two, three and four occasions, but had persistent dysplastic smears. Of the 10 with severe dysplasia, two had persistent dysplastic smears. Thus, seven of the 16 failures continued to have dysplastic cells after two (four patients), three (two patients), and four (one patient) freezes. The freezing was applied from 3 to 7 min. Of the 66 patients treated with cryosurgery, 16 had persistent dysplasia. Cryosurgery may be used in the treatment of this condition with the advantages of outpatient therapy, but the rate of persistence requires close follow-up. DISCUSSION
Sharp conization of the cervix not only provides tissue for diagnostic study, but is indicated particularly for treatment of severe dysplastic lesions. The TABLE 4 66
DYSPLASIAS:
CRYOSURGERY
Follow-Up Duration
Cases
Residual
3 mo 6 mo 9 mo 1 yr +
22 18 15 11
2 6 3 5
Total
66
16
TREATMENT
OF CERVICAL
153
DYSPLASIAS
apparent cure of 56 of 62 patients followed for 2 to 18 yr, illustrates the value in treatment. Otherwise, multiple biopsies alone are sufficient for diagnosis [9]. From this series of 124 patients with dysplasia of the cervix, histologically proven, sharp cold-knife conization gave better results in ablation of the lesions than cryosurgery, although the latter is performed more simply, with less inconvenience to the patient and without hospitalization. Careful follow-up with cytology and colposcopy is indicated with either method. Mild dysplasia as indicated by cytologic smear needs only observation. Moderate dysplasia in the smear should be observed for confirmation over a period of 6 months or longer. Severe dysplasia merits treatment either by sharp cold-knife conization of the cervix or by biopsy followed by cryosurgery. The differentiation of degrees of these lesions allows different approaches to treatment. However, all must have follow-up through the years. REFERENCES 1. Gray, L. A. Dysplasia, carcinoma in situ and microinvasive carcinoma of the cervix uteri, Charles C Thomas, Springfield, IL, (1964). 2. Rutledge, C. E., Jr., Christopherson, W. M., and Parker, J. E. Cervical dysplasia and carcinoma 19, 35 I-354 (1962). in pregnancy, Obstet. Gynecol. 3. Christopherson, W. M. Concepts of genesis and development in early cervical neoplasia. Obstet. Gynecol. Sur. 24, 842-850 (1969). 4. Richart, R. M. Natural history of cervical intraepithelial neoplasia, C/in. Obstet. Gynecok 10, 748-784
(1967).
5. Rubio, C. A. and Lagerlof, 6. Crisp, W. E. Cryosurgical 495-499
B. Identity of cervical dysplasias, Lancer, I386 Dec. 7, 1974. treatment of neoplasia of the uterine cervix. Obstet. Gynecol.
39,
(1972).
7. Townsend,
D. E. and Ostergard, D. R. Cryocauterization for preinvasive cervical neoplasia, J. 6, 171-175 (1971). 8. Creasman, W. T., Weed, J. C., Jr., Curry, S. L., Johnston, W. W., and Parker, R. T. Efficacy of Gynecol. 41, cryosurgical treatment of severe cervical intraepithelial neoplasia, Obstet. Reprod.
Med.
501-506
(1973).
9. Christopherson, W. M., Gray, L. A., and Parker, J. E. Role of punch biopsy in subclinical of the uterine cervix, Obstet. Gynecol. 30, 806-8 11 (1967).
lesions
