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The assessment of radioresponse of cervical carcinoma by colposcopy
GYNECOLOGIC
ONCOLOGY
18,
28-37 (1984)
The Assessment of Radioresponse of Cervical Carcinoma by Colposcopy YEW CHEONG CHOO, M.B., B.S., FACOG,” CHIH Hsu, B.Sc., DIP. MED. ,t AND HO-KEI MA, M.B., B.S., FRCOGS *‘$Departments
of Obstetrics
and Gynaecology and Pathology, fQueen Mary Hospital, of Hong Kong, Hong Kong
University
Received June 1, 1982 Ninety-four patients with invasive carcinoma of the cervix were investigated for radioresponse during treatment using colposcopy and serial biopsies. In 31 patients, the results were further correlated with pathological examination of the Wertheim hysterectomy specimen. It is established that colposcopy can be as reliable as biopsy in predicting radioresponse and can be employed complementary to serial biopsies and clinical examinations. The colposcopic features of cervical carcinomas undergoing irradiation are described.
INTRODUCTION
The study of tumor response to radiation has been historical; no other tumor in the body has been studied in this regard to the extent of carcinoma of the cervix. Cytology, a cytochemical method, autoradiography, and serial biopsies have all been employed, but unfortunately the idea has not gained widespread acceptance. The cytological method was propounded by Graham and Graham [l] in 1953. They studied normal vaginal cells from smears for radioresponse as an indirect means of testing tumor response to radiation. Gusberg [2] in 1956 utilized a cytochemical method to study the DNA/RNA content of tumor cells following a test dose of irradiation; an RNA predominence would indicate radioresponse. Yanagita et al. [3] introduced autoradiography in 1966 and studied the labeling index of irradiated tumor cells after incubation in [3H]TDR. By far, however, the histological method was the most often tested method. Glucksman and Cherry [4] was able to identify four categories of irradiated tumor cells: the degenerating and differentiating cells which signified good radioresponse, and the resting and mitotic cells which denoted poor radioresponse. Their extensive studies, together with that of others [5-71 have attested the applicability of the histological method. In addition to the abovementioned methods, a clinical assessment of the regression in bulk of the tumor is also said to be a valuable and reliable index of radioresponse and survival [81. The prognostic accuracy of radioresponse can further be enhanced when a combination of methods incorporating biopsies are employed. Although colposcopy has been established in the screening and diagnosis of cervical carcinoma, its role in the assessment of 28 0090-8258/84 $1SO Copyright All rights
0 1984 by Academic Press, Inc. of reproduction in any form reserved
COLPOSCOPIC RADIORESPONSE ASSESSMENT
29
radioresponse in cervical carcinoma was previously untested. To determine its possible adjunctive role, we have employed colposcopy in conjunction with serial biopsies on cervical carcinoma undergoing irradiation. The results are further compared with the tissue report of a Wertheim hysterectomy performed at the end of irradiation on suitable patients with stages IB, IIA, and early IIB disease. METHODS
Ninety-four patients with cervical carcinoma irradiated between February 1981 and April 1982 at Queen Mary Hospital, University of Hong Kong, formed the basis of this study. Thirty patients had stage I, 43 had stage II, 17 had stage III, and 4 had stage IVA disease. All patients had a clinical assessment on the size and extent of the lesion, as well as colposcopic mapping of the lesion and a biopsy. The vagina was also examined colposcopically in order to detect a subclinical extension of carcinoma or a possible separate multicentric lesion. Radiotherapy was begun with external irradiation to a total dose of 4000 rad, at 1000 rad per week given in four fractions. This was then followed by two radium implants of 3500 and 2500 to 3000 mg hr, respectively, for stages IB, IIA, and IIB lesions, while one implant of 4000 mg hr was given for stages III and IVA disease. The intervals between the completion of external irradiation and the first radium implant, and between first and second radium implants was 7 days. The Wertheim hysterectomy was performed as soon as possible, usually within 10 days following radium implant. Serial colposcopy and biopsies were performed initially at weekly intervals during external irradiation and at the first radium implant. At the second implant, since colposcopy could not be satisfactorily performed following trauma from the previous implant, only biopsy of the cervix within the previously mapped area was taken. RESULTS Colposcopy
Findings
Characteristic features of invasive carcinoma were typified by finding atypical branching vessels which showed abrupt changes in caliber, shape, and direction, as well as a much darker light reflection and nodularity of the lesion. Following about 1000 to 1500 rad of external pelvic irradiation, an intense flush of the tumor bed could be seen; this often’persisted until some 3000 rad of irradiation were reached. During this stage, easy contact bleeding frequently occurred because of the fragility of the surface vessels. The vessels themselves often showed transient increased tortuosity but they gradually diminished in size until complete regression occurred, or persisted as normal network vessels. Concomitant with these changes in the vessels, the lesion became smooth and regular until an erythematous patch reminiscent of the original lesion and showing no atypical vessels was seen, at which time a diagnosis of no evidence of carcinoma could be made. Prior to this stage, the presence of retrogressive changes in the lesion was interpreted as showing radiosensitive response. In the absence of these changes, the tumor was regarded as radioresistant (Figs. l-5).
FIG. 1. Colpophotograph numerous atypical vessels.
showing
cervical
carcinoma
with white lesion, irregular
surface,
and
FIG. 2. Following 2500 rad of irradiation, the lesion became less irregular and atypical vessels were less numerous. A mild flush could be seen in the tumor bed. Colposcopy and biopsy indicated radiosensitive tumor.
30
FIG. 3. Following completion of 4000 rad of irradiation, the lesion became smooth; a few dilated surface vessels were seen but they appeared regular. Colposcopic and biopsy diagnosis-radiosensitive carcinoma.
FIG. 4. Colpophotograph showing adenocarcinoma of the cervix with abundant mucin, large atypical vessels, and irregular surface. 31
32
CHOO,
IISU, AND MA
FIG. 5. Following 4000 rad of irradiation, atypical vessels persisted. Colposcopic and biop diagnosis-radioresistant carcinoma.
Histological Interpretation The colposcopically directed pre- and postirradiation biopsies were fixed in 10% Formalin and processed as routine paraffin embedding, and sections were stained by hematoxylin and eosin stain. Each tumor was classified according to the WHO Classification and graded. The difference in degree of differentiation between the pre- and postirradiation sections was noted at each stage of external irradiation and radium implant. Increased differentiation, nuclear and cytoplasmic vacuolations, prominent nucleoli, as well as dispersion of nuclear chromatin and absence of mitosis, were indications of favorable response to irradiation (Fig. 6), while presence of many viable cells, little maturation, and presence of mitosis were considered as unfavorable radioresponse or radioresistant (Fig. 7). It is noteworthy that six patients (6.4%) were found to have a separate focus of carcinoma in situ in the upper vagina as demonstrated by colposcopy and confirmed by biopsy, illustrating the possible multicentric nature of the disease. Table 1 shows the prediction of radioresponse by colposcopy compared with biopsy during the different phases of external irradiation. Prior to 2000 rad, colposcopy and biopsy were not helpful in predicting tumor response, hence these examinations were abandoned subsequently. Between 3000 to 4000 rad of external irradiation alone, seven patients demonstrated complete resolution of carcinoma on colposcopy as well as by biopsy. One patient was diagnosed as
COLPOSCOPIC
RADIORESPONSE
ASSESSMENT
33
FIG. 6. Tumor cells showing favorable response to irradiation after 3000 rad. Note increased differentiation of the tumor cells with nuclear and cytoplasmic vacuolations and absence of mitosis (H & E, x 420). Insert-poorly differentiated squamous carcinoma, preirradiation biopsy of the same patient (H & E, x370).
having a radiosensitive carcinoma on colposcopy while the biopsy showed radioresistant features; this patient subsequently was found to have a radioresistant tumor. Overall, between 3000 and 4000 rad, the colposcopic finding agreed with that of the biopsy in 81.5% of the patients. The colposcopic finding and biopsy result at the time of first radium application are shown in Table 2. The results are compatible in 83 of 94 (88.3%) patients. Six patients with radioresistant carcinoma were correctly diagnosed by both the colposcopy and biopsy. Two radioresistant carcinomas were correctly predicted by biopsy but were interpreted as radiosensitive by colposcopy; on the other hand, two radiosensitive carcinomas were correctly interpreted by colposcopy but were reported to be radioresistant by biopsy. Thirty-one patients with stage IB (large growth), IIA, and IIB (early) lesions subsequently underwent a Wertheim hysterectomy. The surgical specimen permitted a direct evaluation of the predicting accuracy of radioresponse by both colposcopy and biopsy. Table 3 shows the colposcopic prediction of radioresponse at the time of first radium implant compared with the pathological diagnosis of the Wertheim hysterectomy specimen. Correlation of results was found in 22 of 31 (71.0%) patients. Similarly, when the results of radioresponse by biopsy taken at first radium implant were compared with that of the Wertheim hysterectomy (Table 4), the correlation was also found in 22 out of 31 (71.0%) patients. It should be noted that all of these patients received a second radium implant before
34
CHOO, HSU, AND MA
FIG. 7. Viable mucin-secreting adenocarcinoma is radioresistant (H & E, x 133).
following
completion
of radiotherapy.
The tumor
undergoing surgery, thus further sterilization of tumor is possible. This may explain a tumor that is interpreted as radiosensitive at the time of first radium implant showing no evidence of carcinoma at Wertheim hysterectomy. Whereas, the 8 patients diagnosed as having radioresistant carcinoma persisted to have evidence of radioresistance at Wertheim hysterectomy. During radium implant, all patients also underwent a pelvic examination under anesthesia to assess the changes in the size, consistency of the lesion, and paracervical tumor extension. While clinical examination was found to be useful in tumors showing favorable radioresponse, it failed to predict four of the eight patients with proven radioresistance. The follow-up of patients ranged from 1 to 2 years. Of the eight patients who had radioresistant tumor, three underwent Wertheim hysterectomy and two had surgery abandoned because of unresectable disease. Six have died of progressive disease, all with local and distant metastases. The two survivors had surgical clearance of their disease made possible by Wertheim hysterectomy. With respect to patients who had radiosensitive carcinoma, only four have died of recurrencesthree had distant recurrences only while the fourth also had vaginal recurrence as well. DISCUSSION
Despite the reduction in the incidence of invasive carcinoma of the cervix which has been due largely to the early diagnosis and treatment of preinvasive disease, the absolute survival of patients with invasive carcinoma has remained
Biopsy Wertheim hysterectomy Patient No.
colposcopy Wertheim hysterectomy Patient No.
coIposcopy Biopsy Patient No.
1
1
Radiosensitive Radiosensitive 32
Radioresistant Radioresistant 6 No carcinoma Radiosensitive 3
Radiosensitive No carcinoma 4
7
No carcinoma, no carcinoma
IMPLANT (94 PATIENTS)
1 1
Radioresistant, radiosensitive
8
Radiosensitive Radiosensitive
Radioresistant Radioresistant 6
No carcinoma No carcinoma
11
IMPLANT
TABLE
5
4
5
No carcinoma Radiosensitive
AND WERTHEIM
4
Radioresistant Radioresistant
Radiosensitive Radiosensitive
CORRELATION BETWEEN BIOPSY AT FIRST RADIUM
10
No carcinoma No carcinoma
2
1
Radioresistant Radiosensitive
(31 PATIENTS)
4
Radiosensitive No carcinoma
SPECIMEN
Radiosensitive No carcinoma
HYSTERECTOMY
3
No carcinoma Radiosensitive
TABLE 3 CORRELATION BETWEEN COLPOSCOPYAT FIRST RADIUM IMPLANT AND WERTHEIM HYSTERECTOMY SPECIMEN (31 PATIENTS)
No carcinoma No carcinoma 45
TABLE 2 CORRELATION BETWEENCOLPOSCOPYAND BIOPSY AT FIRST RADIUM
3
5 3
1 6 15 14
0- 999 1000-1999 2000-2999 3000-4000
rad rad rad rad
Radiosensitive, radioresistant
Radioresistant, radioresistant
Radiosensitive, radiosensitive
colposcopy, biopsy
TABLE 1 CORRELATION BETWEEN COLPOSCOPYAND BIOPSY DURING EXTERNAL IRRADIATION
1
Radioresistant No carcinoma
2
Radiosensitive Radioresistant
Radiosensitive Radioresistant 4
4
No carcinoma, radiosensitive
E
36
CHOO, HSU, AND MA
unchanged over the past few decades. This could be explained on the basis of two factors: (1) the failure to detect micrometastasis outside the regional treatment field, and (2) radioresistance in patients treated by irradiation. This latter factor has been found to occur in 8.5% of our patients studied. To salvage this group of patients, some form of reliable radiosensitivity tests could be instituted so that such patients ay receive alternative treatment in the form of neutrons or high-energy electrons, have an additional boost of irradiation to the tumor, or be treated with the addition of a hypoxic radiosensitizer. In patients deemed to be operable, surgery may also be substituted. Regarding radiosensitivity testing, one should adopt the view that there is no one absolute method of identifying radioresistant or radiosensitive tumor. Histology should, however, form the basis of such an evaluation as it is simple, can be readily performed, and the interpretation of radioresponse can be carried out by any pathologist interested in this area. Colposcopy has been shown in this study to be as reliable as biopsies in the interpretation of radioresponse. The examination can be carried out by any experienced colposcopist. A pretreatment colposcopie examination is mandatory, and a single colposcopic evaluation for radioresponse can be carried out following the completion of external irradiation and before radium implant. In addition to enhancing the accuracy of the histological method by guiding a more precise biopsy, colposcopy serves as a useful adjunct to other methods of assessment of radioresponse like biopsy and clinical examination. When such a combination of methods are used, the accuracy of predictability of radiosensitivity can be greatly enhanced. The existance of multicentric foci of carcinoma in the cervix and vagina is well known. An added advantage of colposcopic examination is the finding of a 6.4% incidence of a separate primary focus of carcinoma in situ in our patients with cervical carcinoma. Should these patients be subjected to surgical treatment alone, such a lesion, if missed, could result in “residual” carcinoma or even a subsequent invasive carcinoma in the vagina. We have therefore demonstrated the reliability of colposcopy and biopsies in radiosensitivity prediction in patients in whom we have performed a Wertheim hysterectomy. On this group of 31 patients who had a Wertheim hysterectomy following full radiation, we have not observed any surgical complications. Our experience on combined radiation and surgery based on prediction of radiosensitivity by biopsy has previously been reported [7]. Thus, using colposcopy as a simple examination complementary to biopsy, should radioresistance be demonstrated on patients receiving irradiation for cervical carcinoma-especially the bulky and stage II lesions, the addition of a Wertheim hysterectomy is a feasible approach. REFERENCES 1. Graham, R. M., and Graham, J. B. A cellular index of sensitivity to ionizing radiation, Cancer 6, 215-223 (1953). 2. Gusberg, S. B. A consideration of the problems of radiosensitivity in cancers of the cervix, Amer. J. Obstet. Gynecol. 72, 804-819 (1956). 3. Yanagita, T., Herman, G. G., and Gusberg, S. B. Autoradiographic studies in cervical cancer before and after a test dose of irradiation, Amer. J. Obstet. Gynecol. 95, 1051-1058 (1966).
COLPOSCOPIC
RADIORESPONSE
ASSESSMENT
37
4. Glucksmann, A., and Cherry, C. P. The ten year results of individualized treatment of cancer of the cervix based on the analysis of serial biopsies, J. Obsrer. Gynaecol. &it. Commonw. 71, 198-201 (1964). 5. Gusberg, S. B., and Herman, G. G. Radiosensitivity testing of cervix cancer by the test dose technique, Amer. J. Roentgenol. 87, 60-68 (1962). 6. Walter, L., Harrison, C. V., Glucksmann, A., and Cherry, C. P. Assessment of response of cervical cancers to irradiation by routine histological methods, hit. Med. J. 1, 1673-1675 (1965). 7. Ma, H. K., Wong, L. C., Chan, W. C., and Wong V. Can treatment of carcinoma of the cervix be individualized? Gynecol. Oncol. 6, 206-215 (1978). 8. Grossman, I., Kurohara, S. S., Webster, .I. H., and George, F. W. The prognostic significance of tumor response during radiotherapy in cervical carcinoma, Radiology 107, 411-415 (1973).
ONCOLOGY
18,
28-37 (1984)
The Assessment of Radioresponse of Cervical Carcinoma by Colposcopy YEW CHEONG CHOO, M.B., B.S., FACOG,” CHIH Hsu, B.Sc., DIP. MED. ,t AND HO-KEI MA, M.B., B.S., FRCOGS *‘$Departments
of Obstetrics
and Gynaecology and Pathology, fQueen Mary Hospital, of Hong Kong, Hong Kong
University
Received June 1, 1982 Ninety-four patients with invasive carcinoma of the cervix were investigated for radioresponse during treatment using colposcopy and serial biopsies. In 31 patients, the results were further correlated with pathological examination of the Wertheim hysterectomy specimen. It is established that colposcopy can be as reliable as biopsy in predicting radioresponse and can be employed complementary to serial biopsies and clinical examinations. The colposcopic features of cervical carcinomas undergoing irradiation are described.
INTRODUCTION
The study of tumor response to radiation has been historical; no other tumor in the body has been studied in this regard to the extent of carcinoma of the cervix. Cytology, a cytochemical method, autoradiography, and serial biopsies have all been employed, but unfortunately the idea has not gained widespread acceptance. The cytological method was propounded by Graham and Graham [l] in 1953. They studied normal vaginal cells from smears for radioresponse as an indirect means of testing tumor response to radiation. Gusberg [2] in 1956 utilized a cytochemical method to study the DNA/RNA content of tumor cells following a test dose of irradiation; an RNA predominence would indicate radioresponse. Yanagita et al. [3] introduced autoradiography in 1966 and studied the labeling index of irradiated tumor cells after incubation in [3H]TDR. By far, however, the histological method was the most often tested method. Glucksman and Cherry [4] was able to identify four categories of irradiated tumor cells: the degenerating and differentiating cells which signified good radioresponse, and the resting and mitotic cells which denoted poor radioresponse. Their extensive studies, together with that of others [5-71 have attested the applicability of the histological method. In addition to the abovementioned methods, a clinical assessment of the regression in bulk of the tumor is also said to be a valuable and reliable index of radioresponse and survival [81. The prognostic accuracy of radioresponse can further be enhanced when a combination of methods incorporating biopsies are employed. Although colposcopy has been established in the screening and diagnosis of cervical carcinoma, its role in the assessment of 28 0090-8258/84 $1SO Copyright All rights
0 1984 by Academic Press, Inc. of reproduction in any form reserved
COLPOSCOPIC RADIORESPONSE ASSESSMENT
29
radioresponse in cervical carcinoma was previously untested. To determine its possible adjunctive role, we have employed colposcopy in conjunction with serial biopsies on cervical carcinoma undergoing irradiation. The results are further compared with the tissue report of a Wertheim hysterectomy performed at the end of irradiation on suitable patients with stages IB, IIA, and early IIB disease. METHODS
Ninety-four patients with cervical carcinoma irradiated between February 1981 and April 1982 at Queen Mary Hospital, University of Hong Kong, formed the basis of this study. Thirty patients had stage I, 43 had stage II, 17 had stage III, and 4 had stage IVA disease. All patients had a clinical assessment on the size and extent of the lesion, as well as colposcopic mapping of the lesion and a biopsy. The vagina was also examined colposcopically in order to detect a subclinical extension of carcinoma or a possible separate multicentric lesion. Radiotherapy was begun with external irradiation to a total dose of 4000 rad, at 1000 rad per week given in four fractions. This was then followed by two radium implants of 3500 and 2500 to 3000 mg hr, respectively, for stages IB, IIA, and IIB lesions, while one implant of 4000 mg hr was given for stages III and IVA disease. The intervals between the completion of external irradiation and the first radium implant, and between first and second radium implants was 7 days. The Wertheim hysterectomy was performed as soon as possible, usually within 10 days following radium implant. Serial colposcopy and biopsies were performed initially at weekly intervals during external irradiation and at the first radium implant. At the second implant, since colposcopy could not be satisfactorily performed following trauma from the previous implant, only biopsy of the cervix within the previously mapped area was taken. RESULTS Colposcopy
Findings
Characteristic features of invasive carcinoma were typified by finding atypical branching vessels which showed abrupt changes in caliber, shape, and direction, as well as a much darker light reflection and nodularity of the lesion. Following about 1000 to 1500 rad of external pelvic irradiation, an intense flush of the tumor bed could be seen; this often’persisted until some 3000 rad of irradiation were reached. During this stage, easy contact bleeding frequently occurred because of the fragility of the surface vessels. The vessels themselves often showed transient increased tortuosity but they gradually diminished in size until complete regression occurred, or persisted as normal network vessels. Concomitant with these changes in the vessels, the lesion became smooth and regular until an erythematous patch reminiscent of the original lesion and showing no atypical vessels was seen, at which time a diagnosis of no evidence of carcinoma could be made. Prior to this stage, the presence of retrogressive changes in the lesion was interpreted as showing radiosensitive response. In the absence of these changes, the tumor was regarded as radioresistant (Figs. l-5).
FIG. 1. Colpophotograph numerous atypical vessels.
showing
cervical
carcinoma
with white lesion, irregular
surface,
and
FIG. 2. Following 2500 rad of irradiation, the lesion became less irregular and atypical vessels were less numerous. A mild flush could be seen in the tumor bed. Colposcopy and biopsy indicated radiosensitive tumor.
30
FIG. 3. Following completion of 4000 rad of irradiation, the lesion became smooth; a few dilated surface vessels were seen but they appeared regular. Colposcopic and biopsy diagnosis-radiosensitive carcinoma.
FIG. 4. Colpophotograph showing adenocarcinoma of the cervix with abundant mucin, large atypical vessels, and irregular surface. 31
32
CHOO,
IISU, AND MA
FIG. 5. Following 4000 rad of irradiation, atypical vessels persisted. Colposcopic and biop diagnosis-radioresistant carcinoma.
Histological Interpretation The colposcopically directed pre- and postirradiation biopsies were fixed in 10% Formalin and processed as routine paraffin embedding, and sections were stained by hematoxylin and eosin stain. Each tumor was classified according to the WHO Classification and graded. The difference in degree of differentiation between the pre- and postirradiation sections was noted at each stage of external irradiation and radium implant. Increased differentiation, nuclear and cytoplasmic vacuolations, prominent nucleoli, as well as dispersion of nuclear chromatin and absence of mitosis, were indications of favorable response to irradiation (Fig. 6), while presence of many viable cells, little maturation, and presence of mitosis were considered as unfavorable radioresponse or radioresistant (Fig. 7). It is noteworthy that six patients (6.4%) were found to have a separate focus of carcinoma in situ in the upper vagina as demonstrated by colposcopy and confirmed by biopsy, illustrating the possible multicentric nature of the disease. Table 1 shows the prediction of radioresponse by colposcopy compared with biopsy during the different phases of external irradiation. Prior to 2000 rad, colposcopy and biopsy were not helpful in predicting tumor response, hence these examinations were abandoned subsequently. Between 3000 to 4000 rad of external irradiation alone, seven patients demonstrated complete resolution of carcinoma on colposcopy as well as by biopsy. One patient was diagnosed as
COLPOSCOPIC
RADIORESPONSE
ASSESSMENT
33
FIG. 6. Tumor cells showing favorable response to irradiation after 3000 rad. Note increased differentiation of the tumor cells with nuclear and cytoplasmic vacuolations and absence of mitosis (H & E, x 420). Insert-poorly differentiated squamous carcinoma, preirradiation biopsy of the same patient (H & E, x370).
having a radiosensitive carcinoma on colposcopy while the biopsy showed radioresistant features; this patient subsequently was found to have a radioresistant tumor. Overall, between 3000 and 4000 rad, the colposcopic finding agreed with that of the biopsy in 81.5% of the patients. The colposcopic finding and biopsy result at the time of first radium application are shown in Table 2. The results are compatible in 83 of 94 (88.3%) patients. Six patients with radioresistant carcinoma were correctly diagnosed by both the colposcopy and biopsy. Two radioresistant carcinomas were correctly predicted by biopsy but were interpreted as radiosensitive by colposcopy; on the other hand, two radiosensitive carcinomas were correctly interpreted by colposcopy but were reported to be radioresistant by biopsy. Thirty-one patients with stage IB (large growth), IIA, and IIB (early) lesions subsequently underwent a Wertheim hysterectomy. The surgical specimen permitted a direct evaluation of the predicting accuracy of radioresponse by both colposcopy and biopsy. Table 3 shows the colposcopic prediction of radioresponse at the time of first radium implant compared with the pathological diagnosis of the Wertheim hysterectomy specimen. Correlation of results was found in 22 of 31 (71.0%) patients. Similarly, when the results of radioresponse by biopsy taken at first radium implant were compared with that of the Wertheim hysterectomy (Table 4), the correlation was also found in 22 out of 31 (71.0%) patients. It should be noted that all of these patients received a second radium implant before
34
CHOO, HSU, AND MA
FIG. 7. Viable mucin-secreting adenocarcinoma is radioresistant (H & E, x 133).
following
completion
of radiotherapy.
The tumor
undergoing surgery, thus further sterilization of tumor is possible. This may explain a tumor that is interpreted as radiosensitive at the time of first radium implant showing no evidence of carcinoma at Wertheim hysterectomy. Whereas, the 8 patients diagnosed as having radioresistant carcinoma persisted to have evidence of radioresistance at Wertheim hysterectomy. During radium implant, all patients also underwent a pelvic examination under anesthesia to assess the changes in the size, consistency of the lesion, and paracervical tumor extension. While clinical examination was found to be useful in tumors showing favorable radioresponse, it failed to predict four of the eight patients with proven radioresistance. The follow-up of patients ranged from 1 to 2 years. Of the eight patients who had radioresistant tumor, three underwent Wertheim hysterectomy and two had surgery abandoned because of unresectable disease. Six have died of progressive disease, all with local and distant metastases. The two survivors had surgical clearance of their disease made possible by Wertheim hysterectomy. With respect to patients who had radiosensitive carcinoma, only four have died of recurrencesthree had distant recurrences only while the fourth also had vaginal recurrence as well. DISCUSSION
Despite the reduction in the incidence of invasive carcinoma of the cervix which has been due largely to the early diagnosis and treatment of preinvasive disease, the absolute survival of patients with invasive carcinoma has remained
Biopsy Wertheim hysterectomy Patient No.
colposcopy Wertheim hysterectomy Patient No.
coIposcopy Biopsy Patient No.
1
1
Radiosensitive Radiosensitive 32
Radioresistant Radioresistant 6 No carcinoma Radiosensitive 3
Radiosensitive No carcinoma 4
7
No carcinoma, no carcinoma
IMPLANT (94 PATIENTS)
1 1
Radioresistant, radiosensitive
8
Radiosensitive Radiosensitive
Radioresistant Radioresistant 6
No carcinoma No carcinoma
11
IMPLANT
TABLE
5
4
5
No carcinoma Radiosensitive
AND WERTHEIM
4
Radioresistant Radioresistant
Radiosensitive Radiosensitive
CORRELATION BETWEEN BIOPSY AT FIRST RADIUM
10
No carcinoma No carcinoma
2
1
Radioresistant Radiosensitive
(31 PATIENTS)
4
Radiosensitive No carcinoma
SPECIMEN
Radiosensitive No carcinoma
HYSTERECTOMY
3
No carcinoma Radiosensitive
TABLE 3 CORRELATION BETWEEN COLPOSCOPYAT FIRST RADIUM IMPLANT AND WERTHEIM HYSTERECTOMY SPECIMEN (31 PATIENTS)
No carcinoma No carcinoma 45
TABLE 2 CORRELATION BETWEENCOLPOSCOPYAND BIOPSY AT FIRST RADIUM
3
5 3
1 6 15 14
0- 999 1000-1999 2000-2999 3000-4000
rad rad rad rad
Radiosensitive, radioresistant
Radioresistant, radioresistant
Radiosensitive, radiosensitive
colposcopy, biopsy
TABLE 1 CORRELATION BETWEEN COLPOSCOPYAND BIOPSY DURING EXTERNAL IRRADIATION
1
Radioresistant No carcinoma
2
Radiosensitive Radioresistant
Radiosensitive Radioresistant 4
4
No carcinoma, radiosensitive
E
36
CHOO, HSU, AND MA
unchanged over the past few decades. This could be explained on the basis of two factors: (1) the failure to detect micrometastasis outside the regional treatment field, and (2) radioresistance in patients treated by irradiation. This latter factor has been found to occur in 8.5% of our patients studied. To salvage this group of patients, some form of reliable radiosensitivity tests could be instituted so that such patients ay receive alternative treatment in the form of neutrons or high-energy electrons, have an additional boost of irradiation to the tumor, or be treated with the addition of a hypoxic radiosensitizer. In patients deemed to be operable, surgery may also be substituted. Regarding radiosensitivity testing, one should adopt the view that there is no one absolute method of identifying radioresistant or radiosensitive tumor. Histology should, however, form the basis of such an evaluation as it is simple, can be readily performed, and the interpretation of radioresponse can be carried out by any pathologist interested in this area. Colposcopy has been shown in this study to be as reliable as biopsies in the interpretation of radioresponse. The examination can be carried out by any experienced colposcopist. A pretreatment colposcopie examination is mandatory, and a single colposcopic evaluation for radioresponse can be carried out following the completion of external irradiation and before radium implant. In addition to enhancing the accuracy of the histological method by guiding a more precise biopsy, colposcopy serves as a useful adjunct to other methods of assessment of radioresponse like biopsy and clinical examination. When such a combination of methods are used, the accuracy of predictability of radiosensitivity can be greatly enhanced. The existance of multicentric foci of carcinoma in the cervix and vagina is well known. An added advantage of colposcopic examination is the finding of a 6.4% incidence of a separate primary focus of carcinoma in situ in our patients with cervical carcinoma. Should these patients be subjected to surgical treatment alone, such a lesion, if missed, could result in “residual” carcinoma or even a subsequent invasive carcinoma in the vagina. We have therefore demonstrated the reliability of colposcopy and biopsies in radiosensitivity prediction in patients in whom we have performed a Wertheim hysterectomy. On this group of 31 patients who had a Wertheim hysterectomy following full radiation, we have not observed any surgical complications. Our experience on combined radiation and surgery based on prediction of radiosensitivity by biopsy has previously been reported [7]. Thus, using colposcopy as a simple examination complementary to biopsy, should radioresistance be demonstrated on patients receiving irradiation for cervical carcinoma-especially the bulky and stage II lesions, the addition of a Wertheim hysterectomy is a feasible approach. REFERENCES 1. Graham, R. M., and Graham, J. B. A cellular index of sensitivity to ionizing radiation, Cancer 6, 215-223 (1953). 2. Gusberg, S. B. A consideration of the problems of radiosensitivity in cancers of the cervix, Amer. J. Obstet. Gynecol. 72, 804-819 (1956). 3. Yanagita, T., Herman, G. G., and Gusberg, S. B. Autoradiographic studies in cervical cancer before and after a test dose of irradiation, Amer. J. Obstet. Gynecol. 95, 1051-1058 (1966).
COLPOSCOPIC
RADIORESPONSE
ASSESSMENT
37
4. Glucksmann, A., and Cherry, C. P. The ten year results of individualized treatment of cancer of the cervix based on the analysis of serial biopsies, J. Obsrer. Gynaecol. &it. Commonw. 71, 198-201 (1964). 5. Gusberg, S. B., and Herman, G. G. Radiosensitivity testing of cervix cancer by the test dose technique, Amer. J. Roentgenol. 87, 60-68 (1962). 6. Walter, L., Harrison, C. V., Glucksmann, A., and Cherry, C. P. Assessment of response of cervical cancers to irradiation by routine histological methods, hit. Med. J. 1, 1673-1675 (1965). 7. Ma, H. K., Wong, L. C., Chan, W. C., and Wong V. Can treatment of carcinoma of the cervix be individualized? Gynecol. Oncol. 6, 206-215 (1978). 8. Grossman, I., Kurohara, S. S., Webster, .I. H., and George, F. W. The prognostic significance of tumor response during radiotherapy in cervical carcinoma, Radiology 107, 411-415 (1973).