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Diagnosis of cervical neoplasia
GYNECOLOGIC
ONCOLOGY
12, S277-S279 (1981)
Session IV: Diagnosis of Cervical Neoplasia HERVY AVERETTE Department of Obstetrics and Gynecology, Jackson Memorial Hospital, University of Miami, Miami, Florida 33101
Dr. Stafl questioned whether Dr. Fu was able to detect polyploidy with sufficient sensitivity using microspectrophotometric methods. He pointed out that he, Katayama, and Jones had studied moderate and severe dysplasia and found that many had normal chromosome numbers, commonly tetraploid, but that some were pseudoeuploid. He agreed that in most instances, there were widespread DNA values but felt the errors using a direct chromosomal squash technique were of the order of 5-10%. Dr. Koss joined Dr. Stafl in expressing concern about the conclusions reached from the DNA studies. He indicated that he was not persuaded that with the available technology, it is possible to conclude that lesions which appear to be in the diploid range are benign. He suggested that unless a quick stop is put to this concept, patients may be paying with their lives as they paid in the past, because of erroneous concepts of dysplasia. He indicated that the concept of dysplasia should be put to rest forever and was concerned that there was no prognostic value to the DNA measurements. Dr. Richart suggested that there were two separate issues involved. The first was the question of the sensitivity of the microspectrophotometric method. In this respect, he agreed that the method has an error rate and that it is insufficiently sensitive to detect small differences in DNA values for the pseudoeuploid configurations about which Dr. Stafl spoke. On the other hand, he believed that the clinical behavior of aneuploid lesions as a group is strikingly different from euploid and polyploid lesions as a group and stated that, in his opinion, there is adequate data to conclude that aneuploid lesions are precursors. There is also adequate data to suggest that most, if not all, euploid epithelia should be considered benign. The polyploid lesions are more complex, but it seems to be clear that the vast majority of them behave as a benign lesion. Dr. Koss reiterated that it was his opinion that there was insufficient information to assume that lesions which are not aneuploid will not contain gene mutations which may make them progress to invasive cancer. Dr. Meisels indicated that the condylomata are polyploid, but that in some of the cases, there are abnormal mitotic figures and aneuploidy. He asked Dr. Fu to define what happens to polyploid lesions which are present for a prolonged period of time and indicated he was concerned that if a lesion was polyploid in one place, that it might be aneuploid in another. Dr. Fu responded that one of the main values of DNA microspectrophotometric studies has been to redefine the morphologic criteria usually used to define the S277 0090-8258/81/05S277-03$01.00/0 Copyright B 1981 by Academic Press, Inc. All rights of reproduction in any form reserved.
S278
HERVY
AVERETTE
dysplasias which, under the old histological definitions, included an extremely broad spectrum of morphologic change. In his studies, an attempt was made to separate lesions into polyploid, euploid and aneuploid lesions and to define histological criteria which correspond to these three ploidy groups. He pointed out that in both prospective and retrospective studies, the pofypioid lesions generally regress after biopsy and that in the great majority of cases, they do not recur after biopsy or treatment. In contrast, the aneuploid lesions tend to persist or progress and have a higher incidence of recurrence in patients who are treated. Dr. Rapp asked Dr. Gupta why two different antigens were being used and how they correlate. Dr. Lopez asked whether ICP 10, 12, and 14 were induced by the virus or whether they were structural proteins. Dr. Zurhausen asked whether the proteins which were used for immunization were purified before they were injected, and Courtney asked whether there were controls to prove that ICP 10, 12, and 14 were the only antigens produced and hence were not part of a productive infection. Dr. Aurelian responded that the percentage of cases with cells positive for ICP 10 were almost identical to the percentage of cases who were serologically positive for antibodies to the antigen. She stated that ICP 10 and 12 are early proteins and that she believed they are not expressed in normal cells. She stated that that had been confirmed for ICP 10. Dr. Courtney then asked whether there was nuclear fluorescence in the cells; Dr. Aurelian answered that there was no nuclear fluorescence. Dr. Wilbanks stated that he believed that it was unfortunate that the endocervical curettage was dropped from the routine workup of the patient with the abnormal Papanicolaou smear and that he wished to stress that it is an essential part of patient evaluation. Dr. Averette added that an endocervical curettage may make a subsequent conization difficult to interpret if the whole lesion cannot be seen colposcopically and questioned whether it was appropriate to perform the endocervical curettage under those circumstances. Dr. Wilbanks asked why it is necessary to take a biopsy if the colposcopic examination is unsatisfactory since a cone will be performed anyway. Dr. Stafl responded that in the Wisconsin program there were 19 cases of invasive cancer in which an endocervical curettage was not performed. Dr. Townsend supported Dr. Stafl’s observation that invasive cancer may be missed if an endocervical curettage is not performed. It was his opinion that a rigorous triage scheme is essential to minimize the risk of missing invasive carcinoma. Dr. Gusberg said that there had been a great deal of discussion of the lack of sophistication in colposcopy and the errors which can occur when a patient with an abnormal smear is evaluated by a physician with less than adequate colposcopic skills. He wondered why colposcopy courses continue to be presented under these circumstances. Dr. Richart responded that most students attending basic colposcopy courses have already purchased a colposcope and begun using them and that it was his opinion that colposcopy would be done whether or not the courses were given. He believed that it was more appropriate to try to educate the gynecologists in well-designed formal courses, than to have them educated by picture books and detail men. Dr. Christopherson asked how
DIAGNOSIS OF CERVICAL
NEOPLASIA
S279
much a colposcopic examination costs. Dr. Townsend replied that the general charges are from $100 to $150, but that there was considerable variability. Dr. Townsend pointed out further, that problems exist not only in the field of colposcopy, but also cytopathology and that, in his opinion, many pathologists do not know how to diagnose cervical intraepithelial neoplasia. He granted the contention that metaplasias may be treated by cryotherapy but suggested that this is preferable to treating metaplasia by conization. Dr. Averette asked whether the CO, laser should be a part of the private-practice setting. Dr. Townsend indicated that the laser was a sophisticated instrument which required colposcopic skills as well as laser skills and that its indicated uses were rather restricted. He believes that the laser is more appropriate to an institutional or referral setting than as a fixture in every private office. Dr. Wilbanks pointed out that there are risks of underdiagnosis using colposcopy but that there are equivalent risks in a large number of women having diagnostic conizations or hysterectomies. He felt it was important to weigh the errors which are being reported subsequent to colposcopy against the number of patients which might have died from operative anesthesia or other complications which occur during surgical procedures. In closing, Dr. Boyes pointed out that in British Columbia, they feel that colposcopy should be restricted to centers, thereby reducing the chance of missing invasive cancer. Although they have missed early invasive cancer, they have no major catastrophes with the outpatient approach. He hoped that more physicians in North America would become cognizant of the colposcopic evaluation’s potential hazards and carefully follow the evaluation scheme presented at this meeting.
ONCOLOGY
12, S277-S279 (1981)
Session IV: Diagnosis of Cervical Neoplasia HERVY AVERETTE Department of Obstetrics and Gynecology, Jackson Memorial Hospital, University of Miami, Miami, Florida 33101
Dr. Stafl questioned whether Dr. Fu was able to detect polyploidy with sufficient sensitivity using microspectrophotometric methods. He pointed out that he, Katayama, and Jones had studied moderate and severe dysplasia and found that many had normal chromosome numbers, commonly tetraploid, but that some were pseudoeuploid. He agreed that in most instances, there were widespread DNA values but felt the errors using a direct chromosomal squash technique were of the order of 5-10%. Dr. Koss joined Dr. Stafl in expressing concern about the conclusions reached from the DNA studies. He indicated that he was not persuaded that with the available technology, it is possible to conclude that lesions which appear to be in the diploid range are benign. He suggested that unless a quick stop is put to this concept, patients may be paying with their lives as they paid in the past, because of erroneous concepts of dysplasia. He indicated that the concept of dysplasia should be put to rest forever and was concerned that there was no prognostic value to the DNA measurements. Dr. Richart suggested that there were two separate issues involved. The first was the question of the sensitivity of the microspectrophotometric method. In this respect, he agreed that the method has an error rate and that it is insufficiently sensitive to detect small differences in DNA values for the pseudoeuploid configurations about which Dr. Stafl spoke. On the other hand, he believed that the clinical behavior of aneuploid lesions as a group is strikingly different from euploid and polyploid lesions as a group and stated that, in his opinion, there is adequate data to conclude that aneuploid lesions are precursors. There is also adequate data to suggest that most, if not all, euploid epithelia should be considered benign. The polyploid lesions are more complex, but it seems to be clear that the vast majority of them behave as a benign lesion. Dr. Koss reiterated that it was his opinion that there was insufficient information to assume that lesions which are not aneuploid will not contain gene mutations which may make them progress to invasive cancer. Dr. Meisels indicated that the condylomata are polyploid, but that in some of the cases, there are abnormal mitotic figures and aneuploidy. He asked Dr. Fu to define what happens to polyploid lesions which are present for a prolonged period of time and indicated he was concerned that if a lesion was polyploid in one place, that it might be aneuploid in another. Dr. Fu responded that one of the main values of DNA microspectrophotometric studies has been to redefine the morphologic criteria usually used to define the S277 0090-8258/81/05S277-03$01.00/0 Copyright B 1981 by Academic Press, Inc. All rights of reproduction in any form reserved.
S278
HERVY
AVERETTE
dysplasias which, under the old histological definitions, included an extremely broad spectrum of morphologic change. In his studies, an attempt was made to separate lesions into polyploid, euploid and aneuploid lesions and to define histological criteria which correspond to these three ploidy groups. He pointed out that in both prospective and retrospective studies, the pofypioid lesions generally regress after biopsy and that in the great majority of cases, they do not recur after biopsy or treatment. In contrast, the aneuploid lesions tend to persist or progress and have a higher incidence of recurrence in patients who are treated. Dr. Rapp asked Dr. Gupta why two different antigens were being used and how they correlate. Dr. Lopez asked whether ICP 10, 12, and 14 were induced by the virus or whether they were structural proteins. Dr. Zurhausen asked whether the proteins which were used for immunization were purified before they were injected, and Courtney asked whether there were controls to prove that ICP 10, 12, and 14 were the only antigens produced and hence were not part of a productive infection. Dr. Aurelian responded that the percentage of cases with cells positive for ICP 10 were almost identical to the percentage of cases who were serologically positive for antibodies to the antigen. She stated that ICP 10 and 12 are early proteins and that she believed they are not expressed in normal cells. She stated that that had been confirmed for ICP 10. Dr. Courtney then asked whether there was nuclear fluorescence in the cells; Dr. Aurelian answered that there was no nuclear fluorescence. Dr. Wilbanks stated that he believed that it was unfortunate that the endocervical curettage was dropped from the routine workup of the patient with the abnormal Papanicolaou smear and that he wished to stress that it is an essential part of patient evaluation. Dr. Averette added that an endocervical curettage may make a subsequent conization difficult to interpret if the whole lesion cannot be seen colposcopically and questioned whether it was appropriate to perform the endocervical curettage under those circumstances. Dr. Wilbanks asked why it is necessary to take a biopsy if the colposcopic examination is unsatisfactory since a cone will be performed anyway. Dr. Stafl responded that in the Wisconsin program there were 19 cases of invasive cancer in which an endocervical curettage was not performed. Dr. Townsend supported Dr. Stafl’s observation that invasive cancer may be missed if an endocervical curettage is not performed. It was his opinion that a rigorous triage scheme is essential to minimize the risk of missing invasive carcinoma. Dr. Gusberg said that there had been a great deal of discussion of the lack of sophistication in colposcopy and the errors which can occur when a patient with an abnormal smear is evaluated by a physician with less than adequate colposcopic skills. He wondered why colposcopy courses continue to be presented under these circumstances. Dr. Richart responded that most students attending basic colposcopy courses have already purchased a colposcope and begun using them and that it was his opinion that colposcopy would be done whether or not the courses were given. He believed that it was more appropriate to try to educate the gynecologists in well-designed formal courses, than to have them educated by picture books and detail men. Dr. Christopherson asked how
DIAGNOSIS OF CERVICAL
NEOPLASIA
S279
much a colposcopic examination costs. Dr. Townsend replied that the general charges are from $100 to $150, but that there was considerable variability. Dr. Townsend pointed out further, that problems exist not only in the field of colposcopy, but also cytopathology and that, in his opinion, many pathologists do not know how to diagnose cervical intraepithelial neoplasia. He granted the contention that metaplasias may be treated by cryotherapy but suggested that this is preferable to treating metaplasia by conization. Dr. Averette asked whether the CO, laser should be a part of the private-practice setting. Dr. Townsend indicated that the laser was a sophisticated instrument which required colposcopic skills as well as laser skills and that its indicated uses were rather restricted. He believes that the laser is more appropriate to an institutional or referral setting than as a fixture in every private office. Dr. Wilbanks pointed out that there are risks of underdiagnosis using colposcopy but that there are equivalent risks in a large number of women having diagnostic conizations or hysterectomies. He felt it was important to weigh the errors which are being reported subsequent to colposcopy against the number of patients which might have died from operative anesthesia or other complications which occur during surgical procedures. In closing, Dr. Boyes pointed out that in British Columbia, they feel that colposcopy should be restricted to centers, thereby reducing the chance of missing invasive cancer. Although they have missed early invasive cancer, they have no major catastrophes with the outpatient approach. He hoped that more physicians in North America would become cognizant of the colposcopic evaluation’s potential hazards and carefully follow the evaluation scheme presented at this meeting.