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The fate of cervical dysplasia
GYNECOLOGY
The fate of cervical dysplasia ALEXANDER
SEDLIS,
ABRAHAM
COHEN,
SANFORD New
York,
SALL, New
M.D. M.D
M.D.
York
A total of 168 patients with cervical dysplasia were followed for from 6 weeks to 5 years. In 71 women (42 per cent), a regression of dysplasia was observed. In 59 patients (35 #er cent), dysplasia persisted. Progression to or coexistence with carcinoma in situ was found in 30 women (18 per cent). In 8 patients (6 per cent), an invasive carcinoma has finally developed. In view of these findings it is recommended that the treatment of moderate or severe dysplasia should be sharp knife conization. Hysterectomy should be considered in older women and those of high parity.
CERVICAL DYSPLASIA is a lesion thought to precede invasive carcinoma, but not defined by the criteria established for carcinoma in situ.4 In carcinoma in situ, the entire thickness of the epithelium is composed of tumor cells; in dysplasia, only part of the epithelium is replaced by the neoplastic cells (Figs. 1 and 2) . The morphology of dysplasia on tissue sections and cytologic smears is very similar to carcinoma, and the difference between the two lesions is only quantitative. Earlier studies of follow-up of patients with dysplasia suggested the malig-
nant potential of dysplasia, since in 5 to 6 per cent of those women the eventual diagnosis of carcinoma in situ or invasion was made within 5 years. 3, 6 Since then, numerous studies utilizing various methods have been conducted in order to estimate the odds of the occurrence of invasive cervical malignancy in women with dysplasia and to establish the time interval between dysplasia and carcinoma.ls 2y 4p3, lo This report presents the results of follow-up and final diagnosis in 169 patients with dysplasia observed for periods ranging from 6 weeks to 5 years, at the New York Medical College.
From the Department of Obstetrics and Gynecology, and the Cytology Laboratory of the New York Medical College-Metropolitan Hospital Center.
Material
and
methods
Between 1960 and 1967, in the mass screening of 111,713 women for cervical neoplasia conducted at the Metropolitan Hospital Medical Center, cervical dysplasia, as defined by criteria of Reagan and Patten3 was diagnosed in 246 patients. This
Supported in part by United States Public Health Service Grants No. 3429-B-66-67, No. 41-262-6, and No. 23069-03-69. Presented at a meeting of the New York Obstetrical Society Jan. 13, 1970.
1065
1066
Sedlis,
Cohen,
and
Sall
Amer.
August J. Obstet.
1, 1970 Gynec.
B
Fig. 1. Cervical dysplasia. Cytology numerous mitotic figures are present (From Sedlis, A., and Stone, D.: Clin.
figure noted tomy in situ
(A) and histology (B). Nuclear pleomorphism and while the normal epithelial differentiation is maintained. Obstet. Gynec. 12: 303, 1969.)
does not include cases of dysplasia, as an incidental finding, on hysterecspecimens. Concurrently, carcinoma was diagnosed in 233 women and invasive carcinoma in 182. The details of the organization of the screening program, the results, and the procedure in follow-up of patients have been previvously reported.5y 7, 8 In accordance with our procedure, multiple cervical punch biopsies were performed in all patients with suspicious, positive, and repeated atypical smears. An attempt was always made to obtain 6 to 8 adequate tissue fragments from the squamocolumnar junction using Schubert biopsy forceps. Patients in whom the diagnosis of cervical dysplasia was established on biopsy were kept under observation with repeat smears and biopsies. Sharp knife conizations were performed only when cytologic findings were suggestive of progression of the neoplastic process. The
conization specimens were studied on multiple sections; usually approximately 10 to 12 blocks were obtained from a single conization specimen. Similarly, when hysterectomy was performed on patients with a previous diagnosis of dysplasia, the entire cervix was sectioned along the long axis into 10 to 12 fragments which were blocked separately and examined on multiple sections. To insure the uniformity of pathologic diagnoses, all slides were reviewed by the author prior to their signing out by the department of pathoIogy. The records of patients screened by the Cancer Detection Service have been kept by a unit system so that accurate information could be obtained about each diagnostic or therapeutic procedure on every patient subsequent to the first visit. Of 246 patients with dysplasia, follow-up information was available for 168 patients; in the remaining 78 patients, no adequate data
Volume Number
107 7
Fate
of
cervical
dysplasia
1067
B
Fig. 2. Carcinoma in situ. Cytology (A) and differentiation along with cellular pleomorphism. Gynec. 12: 303, 1969.)
were obtained, either because the diagnosis was recent or because the patient did not return for follow-up examination. The 168 patients on whom information was available were grouped into 4 categories according to the duration of observation and the specimen utilized for tissue diagnosis: (1) patients who had conization or hysterectomy within 1 year, (2) patients who had conization or hysterectomy after 1 year, (3) patients who were followed with repeat biopsies, and (4) patients who had been followed only by repeat Papanicolaou smears. The findings of follow-up were interpreted in the following manner. Absence of neoplastic changes on the cone or hysterectomy specimen was considered a definite regression; negative cytology on a repeat smear, a probable regression. Dysplasia on the surgical specimen was considered a persistence of the process. Carcinoma, invasive or in situ, found
histology (B). There is loss of polarity and (From Sedlis, A., and Stone, D.: Clin. Obstet.
on the surgical specimen within one year of the initial diagnosis was interpreted as a coexistent lesion, and carcinoma found after more than 1 year, either a coexistent malignancy or a progression of the process. Results
Conization or hysterectomy within one year after the initial diaposis (Table I). In a total of 78 patients, there was no evidence of neoplasia in 17 (22 per cent), which probably indicates that the small area of dysplasia was either totally removed with biopsy or regressed. In 28 patients (36 per there was persistent dysplasia. cent), Twenty-six patients (33 per cent) showed carcinoma in situ and 7 patients (9 per cent) had an invasive carcinoma. Since it is unlikely that carcinoma in situ or invasive could develop de novo within a period of one year, it was assumed that in these 33
1068
Sedlis,
Cohen,
and
Sal1
Amer.
Table I. Findings on conization hysterectomy within one year the initial biopsy Pathologic findings on a cone or hysterectomy specimen No neoplasia Persistent dyspkia Carcinoma in situ Invasive carcinoma
% 22 36 33 9
?s
TabIe II. Findings on conization or hysterectomy within one year or more after the initial diagnosis of dysplasia Pathologic findings on a cone or hysterectomy
specimen
%
No neoplasia Persistent dysplasia Carcinoma in situ Invasive carcinoma Total
44 21 28 7
Ti
Table III.
Findings
Findings on follow-up examination Atypical sistent Negative
6 3 4 1
cytology (conwith dysplasia) cytology
Total
on repeat
cytology
No. of patients
70
15 48
24 76
iz
Table IV. Progression cervical
and regression of dysphasia in 168 observed patients
Outcome Regression Persistence of dysplasia Progression, or association with carcinoma in situ Progression or association with invasive carcinoma Total
No. of patients
%
71 59
42 35
30
18
8
5
168
was already biopsy.
present
1, 1970 Gynec.
but
Conization or hysterectomy after one year or more following the initial diagnosis (Table II). Fourteen patients underwent
No. of patients 17 28 26 7
Total
patients, carcinoma missed by the initial
or after
August J. Obstet.
conization between one and 5 years after the initial diagnosis of dysplasia. In 6 patients (44 per cent) there was no evidence of dysplasia on conization. The lesion had either regressed or was completely removed with biopsy. There was persistent dysplasia on conization in 3 patients (2 1 per cent). Four patients showed carcinoma in situ and one showed invasive carcinoma. The interval elapsed between the initial cervical biopsy and the diagnosis of carcinoma in situ was 20, 24, 27, and 40 months, respectively. In one patient, 15 months elapsed between the initial diagnosis of dysplasia and the development of an invasive carcinoma. Repeat biopsy. All biopsies were repeated within one year. Thirteen patients had persistent cervicai dysplasia on a second biopsy.
Patients followed by Papanicolaou smear (Table III). Sixty-three patients were observed and followed only by cervical smears. Forty-eight patients had negative Papanicolaou smears during their periods of follow-up. The smears were repeated in an interval ranging from 3 months to 5 years after the initial biopsy. In this group there were 21 patients with a follow-up period of less than one year and 27 patients with 1 to 5 years follow-up. In 15 women, the smears were consistent with dysplasia. The period of observation in 4 of these patients was less than one year and in 11 women from 1 to 5 years after the cervical biopsy. It was presumed that the cervical dysp!asia had persisted in this category. Final outcome of dysplasia (Table IV). In 71 patients (42 per cent), a regression of dysplasia was observed. The positive evidence of regression, namely, absence of a neoplastic lesion on the conization or hysterectomy specimen was found in 23 of these women. In the remaining 48 women (Table negative smears were interpreted as III), probable evidence of regression. Since the estimated incidence of false negative smears
Volume Number
107 7
in our institution is 0.5 per cent,7 this figure can be considered 99.5 per cent accurate. Persistence of dysplasia was noted in 59 women (35 per cent). In 44 of these, it was proved by pathologic diagnosis on a conization or hysterectomy specimen, and in 15 women, it was indicated by smears interpreted as being consistent with dysplasia (Table III). C arcinoma in situ was found in 30 women (18 per cent). In 26 women, on whom the diagnosis was made in less than one year (Table I) the carcinoma had probably been associated with dysplasia and missed by initial biopsy. In 4 patients the interval between the initial diagnosis of dysplasia and carcinoma in situ found on the conization section was more than 20 months (Table II). It is possible that in these 4 patients, the lesion had progressed to carcinoma during the period of observation. In 8 patients (6 per cent), the final diagnosis was invasive carcinoma. Of these, 7 were diagnosed within one year after the initial biopsy (Table I), and dysplasia and carcinoma probably coexisted at the time of the biopsy. In one patient (Table II), invasive carcinoma was diagnosed 15 months after the first biopsy and it is assumed that a progression to an invasive lesion had occurred during the period of observation. Comment
In spite of the accumulating evidence in support of the proposition that cervical dysplasia is a phase in the development of cervical carcinoma, direct proof is still not available and seerns almost impossible to establish. To prove this theory it is essential that the following conditions be met: (1) there must be reliable evidence that no carcinoma is present at the time of the original diagnosis of dysplasia; (2) the dysplasia must be observed by means other than biopsy, so that the natural course of the disease is not disturbed; and (3) if a suspicion of carcinoma appears during the course of observation, it must be promptly diagnosed so that therapy is not delayed. Since at the present time the only acceptable means for a positive diagnosis of
Fate
of
cervical
dysplasia
1069
dysplasia or carcinoma is histologic examination of tissue, it is not possible either to rule out coexisting carcinoma at the time of the initial biopsy or to diagnose accurately the pathology at the follow-up examination, without removing the lesion. In view of these difficulties, indirect approaches to the study of the fate of dysplasia have been made. Colpomicroscopy has been used both for the original diagnosis and for the follow-up, so as not to interfere with the natural development of the lesion.?, 4 While the accuracy of morphologic diagnoses in vivo by colpomicroscopy may be equal to the light microscopy on histologic section, the examination is incomplete because the whole extent of the lesion cannot be scanned by the instrument; especially the area of the endocervical canal which remains outside the field of vision. To overcome this difficulty the colpomicroscopic method was supplemented by the study of cytologic material obtained by cervical scraping and endocervical aspiration, It has been shown that the differential count of neoplastic cells on the cytologic spreads makes it possible to differentiate cervical dysplasia from in situ carcinoma in over 97 per cent of the patients.’ Through the combined use of colpomicroscopy and cytology, 22 1 patients with dysplasia were observed and progression to carcinoma was demonstrated in 22.4 Statistical methods were used by Stern and Neelyg to demonstrate the malignant propensity of dysplasia. They report that patients with dysplasia who returned for follow-up examinations had an incidence of carcinoma in situ 20 times and of invasive carcinoma, 10 times greater than the patients with previously negative cytology. As further evidence in favor of the premalignant nature of dysplasia, similar tissue cultures and electron microscopic characteristics of dysplasia and cancer cells have also been cited.” A follow-up of patients with dysplasia by smears and conization after progression noted on smears has been practiced by some investigators. The reported incidence of carcinoma in these patients varied from 6.8 to 64 per cent.‘jl lo
1070
Sedlis, Cohen, and Sall
In our study, in more than 40 per cent of the patients with dysplasia, the lesion regressed and no definitive therapy was required. In 35 per cent of the patients, the dysplasia persisted and there are no means at present to predict the final outcome in this group. In the third category, which comprises 28 per cent of the patients, carcinoma in situ or invasion developed during the course of observation or perhaps, a small focus of cancer eluded detective measures at biopsy. Patients in this group deserve prompt therapeutic action. In a great majority of these patients it is possible to detect the progression of the lesion by means of desquamative cytology. However, when the first diagnosis of dysplasia is made, it is impossible to predict which of these will progress to carcinoma. Under ideal circumstances, therefore, if the cytologic examination is highly reliable, the management of the patients with dysplasia could consist of careful observation with frequent cervical smears. A conization would be resorted to when cytologic findings indicated a higher than previous rank of neoplasia. There are several drawbacks to such a plan: (1) much time and effort is involved in the multiple visits and cytologic tests, (2) patients fail to adhere to the follow-up schedule and eventually drop out, and (3) There is always a chance of an error in evaluation of the cytologic findings. The risks resulting from such a procedure may be justified only when there is an attempt to study the natural history of the dysplasia, the maximum cooperation of the patients is assured, and a well-organized cytology laboratory is available. The status of patients with dysplasia and
REFERENCES
Hall, J. E., and Walton, L.: AMER. J. OBSTET. GYNEC. 100: 662, 1968. Lerch, V., Okagaki, T., Austin, J. H. A., Kevorkian, A. T., and Younge, P. A.: Acta Cytol. 7: 183, 1963. Reagan, J. W., and Patten, S. F., Jr.: Ann. N. Y. Acad. Sci. 97: 662, 1962. Richart, R. M.: Clin. Obstet. Gynec. 10: 748, 1967.
Amer.
August J. Obstet.
1, 1970 Gynec.
carcinoma in situ has many points in common. In both instances the question of whether in all patients the lesion is in a preinvasive stage of invasive carcinoma remains unanswered. It is known that the incidence of coexistent and subsequent invasive cancer is much higher in patients with dysplasia or cacinoma in situ than in the normal population. In view of so many similarities between these 2 conditions, it has been suggested that the terminology of carcinoma in situ and dysplasia should be abandoned in favor of a common denominator, preinvasive cervical neoplasia.4 Our study employing simple clinical methods does not attempt to answer the question of whether or not dysplasia precedes cervical malignancy. The study does, however, lead to several practical conclusions which help in the management of the patient with dysplasia. Since the exact malignant potential of the preinvasive lesions is not known, the practical management of patients with preinvasive neoplasia is aimed at ruling out the coexisting malignancy and safeguarding against its development. In line with this present concept, our management of dysplasia has been modified. The continued observation of patients with moderate or severe dysplasia without further tissue diagnosis is no longer justified. A sharp knife conization is practiced now in these cases. In patients with mild dysplasia, conization is omitted and the follow-up with smears is practiced since it is difficult to distinguish mild dysplasia from inflammatory changes. Hysterectomy is performed in older women and in women of high parity. Periodic cytologic follow-up is performed in those women who had only conizations.
5. 6. 7. 8. 9. 10.
Sail, S., Olivo, E., and Sedlis, A.: Cancer 21: 1180, 1968. Scott, R. B., and Ballard, L. A.: Ann. N. Y. Acad. Sci. 97: 767, 1962. 17: 2, 1963. Sedlis, A.: Cancer 7: 224, 1963. Sedlis, A.: Acta Cytol. Stern, E., and Neely, P. M.: Acta Cytol. 7: 357, 1963. Varga, A.: AMER. J. OBSTET. GYNEC. 95: 759, 1966.
The fate of cervical dysplasia ALEXANDER
SEDLIS,
ABRAHAM
COHEN,
SANFORD New
York,
SALL, New
M.D. M.D
M.D.
York
A total of 168 patients with cervical dysplasia were followed for from 6 weeks to 5 years. In 71 women (42 per cent), a regression of dysplasia was observed. In 59 patients (35 #er cent), dysplasia persisted. Progression to or coexistence with carcinoma in situ was found in 30 women (18 per cent). In 8 patients (6 per cent), an invasive carcinoma has finally developed. In view of these findings it is recommended that the treatment of moderate or severe dysplasia should be sharp knife conization. Hysterectomy should be considered in older women and those of high parity.
CERVICAL DYSPLASIA is a lesion thought to precede invasive carcinoma, but not defined by the criteria established for carcinoma in situ.4 In carcinoma in situ, the entire thickness of the epithelium is composed of tumor cells; in dysplasia, only part of the epithelium is replaced by the neoplastic cells (Figs. 1 and 2) . The morphology of dysplasia on tissue sections and cytologic smears is very similar to carcinoma, and the difference between the two lesions is only quantitative. Earlier studies of follow-up of patients with dysplasia suggested the malig-
nant potential of dysplasia, since in 5 to 6 per cent of those women the eventual diagnosis of carcinoma in situ or invasion was made within 5 years. 3, 6 Since then, numerous studies utilizing various methods have been conducted in order to estimate the odds of the occurrence of invasive cervical malignancy in women with dysplasia and to establish the time interval between dysplasia and carcinoma.ls 2y 4p3, lo This report presents the results of follow-up and final diagnosis in 169 patients with dysplasia observed for periods ranging from 6 weeks to 5 years, at the New York Medical College.
From the Department of Obstetrics and Gynecology, and the Cytology Laboratory of the New York Medical College-Metropolitan Hospital Center.
Material
and
methods
Between 1960 and 1967, in the mass screening of 111,713 women for cervical neoplasia conducted at the Metropolitan Hospital Medical Center, cervical dysplasia, as defined by criteria of Reagan and Patten3 was diagnosed in 246 patients. This
Supported in part by United States Public Health Service Grants No. 3429-B-66-67, No. 41-262-6, and No. 23069-03-69. Presented at a meeting of the New York Obstetrical Society Jan. 13, 1970.
1065
1066
Sedlis,
Cohen,
and
Sall
Amer.
August J. Obstet.
1, 1970 Gynec.
B
Fig. 1. Cervical dysplasia. Cytology numerous mitotic figures are present (From Sedlis, A., and Stone, D.: Clin.
figure noted tomy in situ
(A) and histology (B). Nuclear pleomorphism and while the normal epithelial differentiation is maintained. Obstet. Gynec. 12: 303, 1969.)
does not include cases of dysplasia, as an incidental finding, on hysterecspecimens. Concurrently, carcinoma was diagnosed in 233 women and invasive carcinoma in 182. The details of the organization of the screening program, the results, and the procedure in follow-up of patients have been previvously reported.5y 7, 8 In accordance with our procedure, multiple cervical punch biopsies were performed in all patients with suspicious, positive, and repeated atypical smears. An attempt was always made to obtain 6 to 8 adequate tissue fragments from the squamocolumnar junction using Schubert biopsy forceps. Patients in whom the diagnosis of cervical dysplasia was established on biopsy were kept under observation with repeat smears and biopsies. Sharp knife conizations were performed only when cytologic findings were suggestive of progression of the neoplastic process. The
conization specimens were studied on multiple sections; usually approximately 10 to 12 blocks were obtained from a single conization specimen. Similarly, when hysterectomy was performed on patients with a previous diagnosis of dysplasia, the entire cervix was sectioned along the long axis into 10 to 12 fragments which were blocked separately and examined on multiple sections. To insure the uniformity of pathologic diagnoses, all slides were reviewed by the author prior to their signing out by the department of pathoIogy. The records of patients screened by the Cancer Detection Service have been kept by a unit system so that accurate information could be obtained about each diagnostic or therapeutic procedure on every patient subsequent to the first visit. Of 246 patients with dysplasia, follow-up information was available for 168 patients; in the remaining 78 patients, no adequate data
Volume Number
107 7
Fate
of
cervical
dysplasia
1067
B
Fig. 2. Carcinoma in situ. Cytology (A) and differentiation along with cellular pleomorphism. Gynec. 12: 303, 1969.)
were obtained, either because the diagnosis was recent or because the patient did not return for follow-up examination. The 168 patients on whom information was available were grouped into 4 categories according to the duration of observation and the specimen utilized for tissue diagnosis: (1) patients who had conization or hysterectomy within 1 year, (2) patients who had conization or hysterectomy after 1 year, (3) patients who were followed with repeat biopsies, and (4) patients who had been followed only by repeat Papanicolaou smears. The findings of follow-up were interpreted in the following manner. Absence of neoplastic changes on the cone or hysterectomy specimen was considered a definite regression; negative cytology on a repeat smear, a probable regression. Dysplasia on the surgical specimen was considered a persistence of the process. Carcinoma, invasive or in situ, found
histology (B). There is loss of polarity and (From Sedlis, A., and Stone, D.: Clin. Obstet.
on the surgical specimen within one year of the initial diagnosis was interpreted as a coexistent lesion, and carcinoma found after more than 1 year, either a coexistent malignancy or a progression of the process. Results
Conization or hysterectomy within one year after the initial diaposis (Table I). In a total of 78 patients, there was no evidence of neoplasia in 17 (22 per cent), which probably indicates that the small area of dysplasia was either totally removed with biopsy or regressed. In 28 patients (36 per there was persistent dysplasia. cent), Twenty-six patients (33 per cent) showed carcinoma in situ and 7 patients (9 per cent) had an invasive carcinoma. Since it is unlikely that carcinoma in situ or invasive could develop de novo within a period of one year, it was assumed that in these 33
1068
Sedlis,
Cohen,
and
Sal1
Amer.
Table I. Findings on conization hysterectomy within one year the initial biopsy Pathologic findings on a cone or hysterectomy specimen No neoplasia Persistent dyspkia Carcinoma in situ Invasive carcinoma
% 22 36 33 9
?s
TabIe II. Findings on conization or hysterectomy within one year or more after the initial diagnosis of dysplasia Pathologic findings on a cone or hysterectomy
specimen
%
No neoplasia Persistent dysplasia Carcinoma in situ Invasive carcinoma Total
44 21 28 7
Ti
Table III.
Findings
Findings on follow-up examination Atypical sistent Negative
6 3 4 1
cytology (conwith dysplasia) cytology
Total
on repeat
cytology
No. of patients
70
15 48
24 76
iz
Table IV. Progression cervical
and regression of dysphasia in 168 observed patients
Outcome Regression Persistence of dysplasia Progression, or association with carcinoma in situ Progression or association with invasive carcinoma Total
No. of patients
%
71 59
42 35
30
18
8
5
168
was already biopsy.
present
1, 1970 Gynec.
but
Conization or hysterectomy after one year or more following the initial diagnosis (Table II). Fourteen patients underwent
No. of patients 17 28 26 7
Total
patients, carcinoma missed by the initial
or after
August J. Obstet.
conization between one and 5 years after the initial diagnosis of dysplasia. In 6 patients (44 per cent) there was no evidence of dysplasia on conization. The lesion had either regressed or was completely removed with biopsy. There was persistent dysplasia on conization in 3 patients (2 1 per cent). Four patients showed carcinoma in situ and one showed invasive carcinoma. The interval elapsed between the initial cervical biopsy and the diagnosis of carcinoma in situ was 20, 24, 27, and 40 months, respectively. In one patient, 15 months elapsed between the initial diagnosis of dysplasia and the development of an invasive carcinoma. Repeat biopsy. All biopsies were repeated within one year. Thirteen patients had persistent cervicai dysplasia on a second biopsy.
Patients followed by Papanicolaou smear (Table III). Sixty-three patients were observed and followed only by cervical smears. Forty-eight patients had negative Papanicolaou smears during their periods of follow-up. The smears were repeated in an interval ranging from 3 months to 5 years after the initial biopsy. In this group there were 21 patients with a follow-up period of less than one year and 27 patients with 1 to 5 years follow-up. In 15 women, the smears were consistent with dysplasia. The period of observation in 4 of these patients was less than one year and in 11 women from 1 to 5 years after the cervical biopsy. It was presumed that the cervical dysp!asia had persisted in this category. Final outcome of dysplasia (Table IV). In 71 patients (42 per cent), a regression of dysplasia was observed. The positive evidence of regression, namely, absence of a neoplastic lesion on the conization or hysterectomy specimen was found in 23 of these women. In the remaining 48 women (Table negative smears were interpreted as III), probable evidence of regression. Since the estimated incidence of false negative smears
Volume Number
107 7
in our institution is 0.5 per cent,7 this figure can be considered 99.5 per cent accurate. Persistence of dysplasia was noted in 59 women (35 per cent). In 44 of these, it was proved by pathologic diagnosis on a conization or hysterectomy specimen, and in 15 women, it was indicated by smears interpreted as being consistent with dysplasia (Table III). C arcinoma in situ was found in 30 women (18 per cent). In 26 women, on whom the diagnosis was made in less than one year (Table I) the carcinoma had probably been associated with dysplasia and missed by initial biopsy. In 4 patients the interval between the initial diagnosis of dysplasia and carcinoma in situ found on the conization section was more than 20 months (Table II). It is possible that in these 4 patients, the lesion had progressed to carcinoma during the period of observation. In 8 patients (6 per cent), the final diagnosis was invasive carcinoma. Of these, 7 were diagnosed within one year after the initial biopsy (Table I), and dysplasia and carcinoma probably coexisted at the time of the biopsy. In one patient (Table II), invasive carcinoma was diagnosed 15 months after the first biopsy and it is assumed that a progression to an invasive lesion had occurred during the period of observation. Comment
In spite of the accumulating evidence in support of the proposition that cervical dysplasia is a phase in the development of cervical carcinoma, direct proof is still not available and seerns almost impossible to establish. To prove this theory it is essential that the following conditions be met: (1) there must be reliable evidence that no carcinoma is present at the time of the original diagnosis of dysplasia; (2) the dysplasia must be observed by means other than biopsy, so that the natural course of the disease is not disturbed; and (3) if a suspicion of carcinoma appears during the course of observation, it must be promptly diagnosed so that therapy is not delayed. Since at the present time the only acceptable means for a positive diagnosis of
Fate
of
cervical
dysplasia
1069
dysplasia or carcinoma is histologic examination of tissue, it is not possible either to rule out coexisting carcinoma at the time of the initial biopsy or to diagnose accurately the pathology at the follow-up examination, without removing the lesion. In view of these difficulties, indirect approaches to the study of the fate of dysplasia have been made. Colpomicroscopy has been used both for the original diagnosis and for the follow-up, so as not to interfere with the natural development of the lesion.?, 4 While the accuracy of morphologic diagnoses in vivo by colpomicroscopy may be equal to the light microscopy on histologic section, the examination is incomplete because the whole extent of the lesion cannot be scanned by the instrument; especially the area of the endocervical canal which remains outside the field of vision. To overcome this difficulty the colpomicroscopic method was supplemented by the study of cytologic material obtained by cervical scraping and endocervical aspiration, It has been shown that the differential count of neoplastic cells on the cytologic spreads makes it possible to differentiate cervical dysplasia from in situ carcinoma in over 97 per cent of the patients.’ Through the combined use of colpomicroscopy and cytology, 22 1 patients with dysplasia were observed and progression to carcinoma was demonstrated in 22.4 Statistical methods were used by Stern and Neelyg to demonstrate the malignant propensity of dysplasia. They report that patients with dysplasia who returned for follow-up examinations had an incidence of carcinoma in situ 20 times and of invasive carcinoma, 10 times greater than the patients with previously negative cytology. As further evidence in favor of the premalignant nature of dysplasia, similar tissue cultures and electron microscopic characteristics of dysplasia and cancer cells have also been cited.” A follow-up of patients with dysplasia by smears and conization after progression noted on smears has been practiced by some investigators. The reported incidence of carcinoma in these patients varied from 6.8 to 64 per cent.‘jl lo
1070
Sedlis, Cohen, and Sall
In our study, in more than 40 per cent of the patients with dysplasia, the lesion regressed and no definitive therapy was required. In 35 per cent of the patients, the dysplasia persisted and there are no means at present to predict the final outcome in this group. In the third category, which comprises 28 per cent of the patients, carcinoma in situ or invasion developed during the course of observation or perhaps, a small focus of cancer eluded detective measures at biopsy. Patients in this group deserve prompt therapeutic action. In a great majority of these patients it is possible to detect the progression of the lesion by means of desquamative cytology. However, when the first diagnosis of dysplasia is made, it is impossible to predict which of these will progress to carcinoma. Under ideal circumstances, therefore, if the cytologic examination is highly reliable, the management of the patients with dysplasia could consist of careful observation with frequent cervical smears. A conization would be resorted to when cytologic findings indicated a higher than previous rank of neoplasia. There are several drawbacks to such a plan: (1) much time and effort is involved in the multiple visits and cytologic tests, (2) patients fail to adhere to the follow-up schedule and eventually drop out, and (3) There is always a chance of an error in evaluation of the cytologic findings. The risks resulting from such a procedure may be justified only when there is an attempt to study the natural history of the dysplasia, the maximum cooperation of the patients is assured, and a well-organized cytology laboratory is available. The status of patients with dysplasia and
REFERENCES
Hall, J. E., and Walton, L.: AMER. J. OBSTET. GYNEC. 100: 662, 1968. Lerch, V., Okagaki, T., Austin, J. H. A., Kevorkian, A. T., and Younge, P. A.: Acta Cytol. 7: 183, 1963. Reagan, J. W., and Patten, S. F., Jr.: Ann. N. Y. Acad. Sci. 97: 662, 1962. Richart, R. M.: Clin. Obstet. Gynec. 10: 748, 1967.
Amer.
August J. Obstet.
1, 1970 Gynec.
carcinoma in situ has many points in common. In both instances the question of whether in all patients the lesion is in a preinvasive stage of invasive carcinoma remains unanswered. It is known that the incidence of coexistent and subsequent invasive cancer is much higher in patients with dysplasia or cacinoma in situ than in the normal population. In view of so many similarities between these 2 conditions, it has been suggested that the terminology of carcinoma in situ and dysplasia should be abandoned in favor of a common denominator, preinvasive cervical neoplasia.4 Our study employing simple clinical methods does not attempt to answer the question of whether or not dysplasia precedes cervical malignancy. The study does, however, lead to several practical conclusions which help in the management of the patient with dysplasia. Since the exact malignant potential of the preinvasive lesions is not known, the practical management of patients with preinvasive neoplasia is aimed at ruling out the coexisting malignancy and safeguarding against its development. In line with this present concept, our management of dysplasia has been modified. The continued observation of patients with moderate or severe dysplasia without further tissue diagnosis is no longer justified. A sharp knife conization is practiced now in these cases. In patients with mild dysplasia, conization is omitted and the follow-up with smears is practiced since it is difficult to distinguish mild dysplasia from inflammatory changes. Hysterectomy is performed in older women and in women of high parity. Periodic cytologic follow-up is performed in those women who had only conizations.
5. 6. 7. 8. 9. 10.
Sail, S., Olivo, E., and Sedlis, A.: Cancer 21: 1180, 1968. Scott, R. B., and Ballard, L. A.: Ann. N. Y. Acad. Sci. 97: 767, 1962. 17: 2, 1963. Sedlis, A.: Cancer 7: 224, 1963. Sedlis, A.: Acta Cytol. Stern, E., and Neely, P. M.: Acta Cytol. 7: 357, 1963. Varga, A.: AMER. J. OBSTET. GYNEC. 95: 759, 1966.