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Preclinical cervical carcinoma, colposcopy, and the “negative” smear
Preclinical cervical carcinoma, colposcopy, and the “negative” smear EDWARD San
Francisco,
C.
HILL,
M.D.*
California
CAREFUL MACROSCOPIC inspection of the cervix is universally considered an essential part of a gynecological examination, yet it fails to detect the earliest stages of carcinoma of the cervix. Since its introduction by Papanicolaou and Traut,18 in 1941> as a useful method in the early detection of cervical cancer, cytological examination has proved clinically effective and has found widespread acceptance. Prior to that time, however, Hinselmanng in an effort to find a satisfactory method of diagnosing carcinoma early in its course, had developed colposcopy, the technique of inspecting the cervix under low-power magnification. This method gradually came to be used extensively in most European countries and in South America: and despite the advent of cytology, continues to occupy a prominent place in gynecologic practice in these areas. In the United States, Canada, and in England, on the other hand, colposcopy found little acceptance. This was? in part perhaps, due to the confusion which occurred as a result of Hinselmann’s use of the term, “leukoplakia,” in describing lesions which he considered possibly precancerous and also because of his somewhat confusing histologic classifica-
tion.‘” It is only within recent years that there appears to be a renewed interest in colposcopy in this country, and with it? controversy regarding its merits as a screening technique in the early detection of cervical cancer when compared with the cytological 7. I”, 16, 17, 19. “u, 23 method.ll The accuracy of both techniques has been shown to be about the same. Neither cytology nor colposcopy is perfect, and each has its advantages and disadvantages. Navratil’” has recommended that, if the use of only one is practical, then cytology should be used because it is easily accomplished and samples cells shed not only from the vagina and portio vaginalis of the cervix but from the cervical canal and endometrial cavity as well. Rut, even in expert hands, the cytologic method fails to detect a certain percentage of early carcinomas.” This occurs through error on the part of the physician in taking the smear: through laboratory error: or because the tumor fails to desquamate cells in sufficient numbers to be detected. The incidence of such false negative smears is reported to range from 6 to 28 per cent.” Colposcopy, on the other hand, has the disadvantages of requiring special training on the part of the physician, of requiring relatively large numbers of cervical biopsies in relation to yield, and of failing to visualize and detect lesions which are primarily endocervical in location. The latter two are, perhaps, the greater drawbacks of this method. The frequency of indicated biopsies in relation to the number of colposcopic examinations has been reported to range from 10 per cent in some clinics to as high as 50 per cent
From the Clinic of Obstetrics and Gynecology, University of Grat, Austria. Presented at the Thirty-second Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Vancouuer, British Columbia, Canada, Sept. 29-O&. 2, 1965. *Department of Obstetrics and Gynecology, University of California Medical Center, San Francisco, California.
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in 0thers.l” I5 Preclinical cervical cancer is detected in from 2.5 to 10 per cent of those lesions in which biopsies are taken, the smaller yield being related to the greater number of biopsies .3s24 It has been pointed out by experienced colposcopists, however, that a colposcopically indicated biopsy rarely results in the finding of normal squamous or columnar epithelium and that a very high percentage of these lesions are demonstrated histologically to be dysplasias of the cervical epithelium of low or high degree. This is considered to be of value in the recognition, study, and follow-up of these possibly precancerous epithelial changes. This is all the more cogent in the light of recent evidence that the risk of carcinoma in situ in women with dysplasia is about 1,000 times greater than that for patients who have been observed to be negative for both cancer and dysplasia.21 Moreover, it is said that with greater experience in the correlation of colposcopic findings and pathologic material, one can be more selective in choosing tissue in which biopsy is deemed necessary.4 The early carcinoma of the cervix which exists only in the colposcopically inaccessible portion of the cervical canal is not common, but it does exist and poses a problem for the individual who relies solely upon colposcopy for detection. The reported incidence of preclinical carcinoma which is confined to the endocervix ranges from “very rare” to 33 per cent.2, 2G Thus, both methods have limitations, but because these limitations are different for each technique, the simultaneous use of both cytology and colposcopy has resulted in a higher rate of detection than when either one is used alone.6’ ‘9 I5 One of the largest series is that reported by Navratill’ in which more than 55,000 patients were seen in the University of Graz from 1949 through 1960, with the discovery of 83% cases of preclinical carcinoma of the cervix. In this report it was estimated that 729 (87.0 per cent) would have been detected from cy tologic examination alone. Had colposcopy been the sole method used, 663 (79.1 per
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cent) would have been diagnosed. Through the simultaneous use of both methods, however, 82% (98.8 per cent) were discovered. The remaining 10 cases were missed both by cytologic and by colposcopic examination, the diagnosis having been made on routine pathologic examination of the cervix which had been removed for apparently benign disease. This study was undertaken to elucidate the details of such cases in which early cancers of the cervix were missed by cytologic screening yet demonstrated some colposcopically visible manifestation, biopsy of which resulted in the diagnosis. It was thought that such a study would help to determine, perhaps, what factors were responsible for the failure of the cytologic method as well as those factors resulting in the success of colposcopy. It was carried out during a recent visit to the Clinic of Obstetrics and Gynecology, University of Graz. Material
The records of all patients admitted to the Frauenklinik, University of Graz, subsequent to Jan. 1, 1954, were available for this study. During the 7 year period through Dec. 31, 1960, there were 42,357 colposcopic examinations done for the purpose of cancer deIn this group 59 patients with tection. cytologically negative or unsatisfactory smears were found to have preclinical cervical cancer as a result of biopsies taken from colposcopically suspicious areas. The records of thes patients were analyzed, and selected pathologic material from punch and cone biopsies in these women were reviewed. At the Frauenklinik, University of Graz, all patients admitted to the hospital or to the outpatient department are seen in the Colposcopy Clinic where a smear is taken directly from the cervix with an Ayre spatula, and a careful colposcopic examination, including Schiller staining of the mucous membrane, is performed. The technique used at this clinic has been reported elsewhere by Navratil.15 A punch biopsy is taken of all colposcopically suspicious areas. These include true erosions; regions showing a ground
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or mosaic pattern; any area, particularly in the transformation zone, which demonstrates thickened, opaque, or yellowish epithelium or an atypical vascular pattern (atypical transformation zone) ; and iodine-negative areas which are sharply demarcated. The results of the cytologic and colposcopic examinations are reviewed. If either the smear or the biopsy demonstrates findings which are suspicious of malignancy, a cold-knife cone biopsy is done. Step sections from the cone are carefully examined for evidence of intraepithelial or early invasive cancer. Unless there is unequivocal invasion, the colposcopically directed punch biopsy is not considered an adequate substitute for a full conization of the cervix. Results
Table I. Results
of cytologic
Initial interpretation Unsatisfactory smear
esamina
ticm ----
“negative”
.54 5 5 !3
Review of “negative” smears Negative Atypical (not suspicious) Suspicious
44 5 5 54
Table II. Colposcopic with
preclinical
findings in 59 patients carcinoma of cervix
Erosio vera Iodine negative zone Vascular atypia Mosaic pattern Ground pattern Thickened epithelium
2 9 10 11 18 26 76
Age. These
patients ranged in age from 22 to 74 years with an average age of 40 years. Clinical findings. “Erythroplakia” (Navratill, or a nonspecific reddened area involvina the portio vaginalis of the cervix, was found in 47 (80 per cent) of these patients, but only in 8 was the notation made that it was suspicious of malignancy. In 12 patients the cervix was described as grossly normal in appearance. Cytologic examination. The results of the cytologic examination are shown in Table I. The review of the negative smears was carried out after the diagnosis of malignancy had been established. Colposcopic findings. All of these patients had abnormalities of the cervix under colposcopic examination, some of them presenting a combination of two or more findings. These are tabulated in Table II. Such abnormalities were considered possible areas of early malignant change in the epithelium. A true loss of epithelium (erosio Vera) was the least common finding, occurring in only 2 patients whereas 36 demonstrated an atypical transformation zone. The mosaic and ground patterns were seen in 29 patients. Biopsy findings. Table III shows the diagnoses made on colposcopically directed punch biopsies performed in 55 patients. It
also shows the results of the cone biopsies done on these patients as well as the 4 women whose records did not indicate that a punch biopsy had been done. Dysplasia was a frequent finding in the punch biopsy ( 17 cases) and was considered to be of high degree in all instances except 2 (Fig. 1). In subsequent cone biopsy, these cervices demonstrated additional areas with sufficient criteria of malignancy to warrant a diagnosis of carcinoma in situ (Fig. 2)) and in 3 cases, foci of early stromal invasion were seen. One of these, in fact, was discovered in a patient whose original punch biopsy had shown dysplasia of low degree. Carcinoma in situ was diagnosed in 27 patients on the basis of the colposcopically directed biopsy, and this diagnosis was made also in the conization specimen of half of them. In 12 patients, there was no residual malignant epithelium in the cervical cone (Fig. 3)) but 3 showed dysplastic epithelium. Early invasive carcinoma was found in two of the patients whose putich biopsies had demonstrated carcinoma in situ (Figs. 4 and5). The cone biopsy specimens in 6 of the 11 patients in whom early invasive carcinoma was diagnosed on punch biopsy failed to
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Table III Colposcopically
directed
punch
Carcinoma in situ
Dysplasia
biopsy Early
invasion
Cold-knife Dysplasia
17* 27 11 No 7
tTwo 1.One
biopsy
3 1
cone Carcinoma in situ
biopsy
with Early
14 13 2
step
sections No residual carcinoma
invasion 3t 2 5
9 3
(4)
with dysplasia of low degree. with dysplasia of low degree.
Fig. 1. clinically.
-4.
E., aged 42. Ground pattern on colposcopic examination. Nonspecific Cytology negative. Punch biopsy above interpreted as dysplasia of high
Fig. 2. Cone ment consisted
biopsy of the of conization
cervix only.
of patient Four-year
in Fig. follow-up
1 interpreted as carcinoma with no recurrence.
“erosion” degree.
in situ.
Treat-
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Fig. 3. M. P., aged 33. Opaque, thickened transitional zone on colposcopic Nonspecific “erosion” clinically. Cytology negative. Punch biopsy at colposcopy carcinoma in situ. Subsequent conization failed to demonstrate abnormal further therapy. Seven-year follow-up without evidence of recurrence.
examination. demonstrated epithelium. I\io
Fig. 4. M. J., aged 40. Ground pattern and sharply demarcated iodine negative zone on colposcopic examination. Suspicious erosion clinically. Cytology negative. Punch biopsy revealed carcinoma in situ with an equivocally invasive focus. Low-power magnification of conization specimen demonstrating early stromal invasion.
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cervical
carcinoma
Fig. 5. Same patient as Fig. 4 with higher power showing definite early stromal invasion on cone biopsy. Treatment consisted of Schauta-Amreich operation (no residual carcinoma in the operative specimen). Four-year follow-up with no evidence of recurrence.
Fig. 6. M. T.,
aged 35. Fine mosaic pattern on colposcopic cervix clinically. Cytology negative. Punch biopsy revealed quent cone biopsy demonstrated dysplasia only without Treatment consisted of Schauta-Amreich operation. Six-year recurrence.
examination. Normal-appearing early invasive carcinoma. Subseevidence of invasive carcinoma. follow-up with no evidence of
313
314 Hill
Fig. 7. G. K., aged 45. Ground and coarse mosaic specific “erosion” clinically. Cytology negative. high degree.
patterns Punch
Fig. 8. Same patient as Fig. 7. Cone biopsy revealed Schauta-Amreich operation recommended but patient later, cause undetermined.
ShOW
had (Fig. In puncl situ cinon
other Ino
areas of invasion, and 4, indeed of any residual carcinoma
evidence
6). the 4 patients without a preliminary n biopsy, the diagnosis of carcinoma in 1Nas made in 3 and early invasive carla in one.
on colposcopic biopsy interprrted
area suspicious refused further
of early therapy.
f.xamination. Nonas dysplasia of
stromal Died
invasion. 6 months
The final diagnosis in these 59 pat .ients was carcinoma in situ in 42 and carcir koma with early invasion in 17. Treatment and follow-up. Treatment given to these 59 patients and follow-up fij ;ures are given in Tables IV and V. In tl he 3 patients with diagnoses of invasive carcin Loma
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Table IV. Treatment of therapy
Form Diagnosis
Coniration
Carcinoma in situ Early invasive carcinoma Total
Table V. Survival
Carcinoma in situ Early invasive carcinoma patient
refused
25 3
4
28
4
(4 or more
Diagnosis
*One
Cervical amputation
further
Total hysterectomy
WertheimMeigs
Radiation
12
12
11
1
1 2
11
1
3
Total 42 17 59
-
years)
No.
Living and well
42 17
42 14
therapy:
SchautaAmreich
died
6 months
Died of carcinoma’ or cause unknown 2” later,
in whom conization was the only therapy given, one had evidence of early stromal invasion in the punch biopsy only without any evidence of malignant epithelium in the cone. She was young, and conization was considered adequate therapy in this instance. There was no evidence of recurrence 8 years after treatment. The second patient’s cone specimen revealed penetration beyond the basement membrane in one small area only, and she is well 5 years later. The third patient had an equivocally invasive focus in the cone specimen but failed to return for further treatment (Figs. 7 and 8). She died 6 months later of an undetermined cause. Comment About once in every 700 examinations in which both methods were used, a preclinical carcinoma of the cervix was discovered by colposcopy which, presumably, would have been missed in a single cytologic examination. If one presumes that a repeat smear would have demonstrated malignant cells in the 5 instances in which the initial preparation was considered unsatisfactory, then the frequency of a postitive colposcopy, negative smear combination in the face of a cervical malignancy of an occult type is reduced to one in 800 screening examinations. The fact remains, however, that with a negative cytology report, it is probable the remaining 54 patients would have been released with
cause
Died
intercurrent disease
%
1
100.0 82.4
unknown.
the assurance that there was no malignant disease involving the cervix. Perhaps one can afford to be optimistic regarding the occurrence of false negative smears in patients who are reporting regularly and frequently for examinations. The probability of missing an early carcinoma is sharply reduced by the application of repeated cytologic sampling. It is believed that intraepithelial carcinoma, in most instances, exists for approximately 9 years before it becomes invasive, and a delay of a few months in diagnosis, in most cases, is relatively unimportant. Not all invasive carcinomas of the cervix stem from pre-existing it is quite likely in situ cancers, although that the vast majority of them do. Furthermore, the results of this study demonstrate that a significant number of these patients, despite the normal gross appearance of the cervix, had early invasive foci. One cannot, under these circumstances, be as casual in the detection and management of this lesion as in the case of intraepithelial disease. Early recognition is considered paramount in order to insure a successful result of treatment. The occurrence of an advanced Stage I lesion in a patient with a grossly normalappearing cervix and a negative cytoloLgic examination one year previously is most certainly a disquieting and thought-provoking event. The fact that 29 per cent of these patients had lesions which demonstrated pen-
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etration of the basement membrane by cancer cells is considered highly significant. The majority (80 per cent) of these patients had grossly visible “erosions,” or “erythroplakia,” which were not suspected of harboring malignant epithelium. This coincides with the 80 per cent of cervical “erosions” in the 135 cases of carcinoma in situ reported by Younge, Hertig, and Armstrong.“j Stoddardz? has pointed out that carcinoma in situ usually develops within the portio epithelium of the transformation zone of an endocervical ectopia. It is not possible macroscopically to distinguish between benign areas of erythroplakia and those in which the epithelium has undergone malignant change. The Chrobak test may be helpful in arousing a suspicion as may the history of contact bleeding. On the other hand, the finding in an “erosion” on colposcopic examination of typical endocervical epithelium or a normal transformation zone only is a reassuring finding, and, for all practical purposes, in combination with a negative cytologic examination, rules out a malignant process of the cervix. The finding on cone biopsy of no residual carcinoma in 12 of the 27 patients who demonstrated intraepithelial carcinoma on colposcopically directed punch biopsy would imply that these lesions were very small, isolated foci. Presumably, a smear from such a cervix would contain few or no malignant cells, thus escaping detection. Likewise, no residual carcinoma in four of the 11 patients who showed early invasion on punch biopsy indicates small lesions probably desquamating very few cells. Thus, in almost one third of these cases the lesion was SO small that it was removed in the performance of a diagnostic punch biopsy under colposcopic control. Another possible explanation is that the manipulation of the cervix incidental to the punch biopsy brought about a mass shedding of intraepithelial carcinoma, a phenomenon observed by Koss and his associates.” In those patients in whom carcinoma in situ was found in the cone biopsy, it was noteworthy that the focus of malignant epithelium in several in
whom the pathologic, material was rc&wecl was \-cry small, somotifnes esisting ~II only a small area on two or three step sections. In other cases, the epithelial layer of rnalignant cells was covered by a very thin, superficial layer of parakeratotic cells with pyknotic nuclei. Although in these instances there may be some question regarding the differential diagnosis of intraepithelial carcinoma versus dysplasia of high degree (according to the opinion of the Clinic in Graz, such a surface layer does not interfere with the diagnosis of carcinoma in situ*“), such a differentiated surface layer may prevent the desquamation of deeper cells with more typical nuclear abnormalities. Such cases may be missed on a single cytologic examination. It would appear from this study that routine colposcopic examination with biopsy of suspicious areas does fulfill the function of serving as a secondary screening method and “cover” for cytologic examination in the detection of preclinical carcinoma of the cervix. Its effectiveness lies in its ability to find small areas of malignant epithelium which, for one reason or another. are not represented in a sampling of superficial cells shed or scraped from the cervix. Furthermore, it also appears to be a useful method for detecting areas of epithelial dysplasia and helping to clarify the interpretation of the atypical smear report. The technique of colposcopic examination is not difficult, and it is not time-consuming when applied by an experienced observer in a routine fashion. There is still some question regarding its practicability, however, because of the relatively large numbers of biopsies which are required. For this reason, in the average gynecologic practice, the cytologic method undoubtedly will continue to occupy the major role in early cancer detection. Certainly it is important, though, for certain centers in the United States and in Canada to pursue the question and to develop their own experiences in colposcopy. Only by doing this can we fairly judge the part that it plays in complementing cytology in the the detection of precancerous lesions and early carcinoma of the cervix. Knowledge of
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the pathogenesis and the relationship of these conditions will be furthered thereby. Summary
1. Fifty-nine cases of preclinical carcinoma of the cervix with negative cytologic smears detected by colposcopic examination in the Clinic of Obstetrics and Gynecology, University of Graz, have been reviewed. 2. These cases were found in 42,357 screening examinations over a 7 year period, an occurrence of 1: 700 examinations. 3. There were 42 cases of intraepithelial carcinoma and 17 with early stromal invasion. 4. Almost one third of these carcinomas
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were such small lesions, they were found only in the colposcopically directed punch biopsy, step sections of subsequent cold-knife cone biopsy demonstrating no residual carcinoma. 5. Colposcopic examination is considered to be an effective method of complementing the cytologic examination in the early detection of incipient carcinoma. Because of the need for large numbers of biopsies, however, its practicability remains in question. The help of Professor Dr. Ernst Navratil in the preparation of the manuscript and of Dozend Dr. E. Burghardt in providing the photomicrographs is gratefully acknowledged.
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8.
9. 10. 11.
12. 13.
Bolten, K.: Introduction to colposcopy, New York, 1960, Grune & Stratton. Bret, J. A., and Coupez, F. J.: Acta cytol. 5: 407, 1961. Burghardt, E., and Bajardi, F.: Arch. Gynsk. 187: 621, 1956. Burghardt, E.: Personal communication, 1965. Coppleson, M.: J. Obst. & Gynaec. Brit. Emp. 67: 11, 1960. Coppleson, M.: J. Obst. & Gynaec. Brit. Comm. 71: 854, 1964. Dampeer, T. K., Jr.: South. M. J. 55: 445, 1962. Graham, J. G., Sotto, L. S. J., and Paloucek, F. P.: Carcinoma of the Cervix, Philadelphia and London, 1962, W. B. Saunders Company. Hinselmann, H.: Miinchen. med. Wchnschr. 7: 1733, 1925. Hinselmann, H.: Ztschr. Geburtsh. u. Gyngk. 101: 142, 1932. Koss, L. G., Stewart, F. W., Foote, F. W., Jordan, M. J., Bader, G. M., and Day, E.: Cancer 16: 1160, 1963. Lang, W. R.: J. A. M. A. 166: 893, 1958. Limburg, H.: In La prophylaxie en gyne-
14. 15.
16. 17. 18. 19. 20. 21. 22.
23. 24. 25. 26.
cologie et obstetrique, Librairie de l’UniversitC, Gentve, 1954, Georg. Martzloff, K. H.: West. J. Surg. 67: 160, 1959. Navratil, E.: In Dysplasia, Carcinoma in Situ, Gray, Laman A., kditor: Springfield, 1964, Charles C Thomas. Publisher. Navratil, E.: Per&al communication, 1965. Olson, A. W., and Nichols, E. E.: Obst. & Gynec. 15: 372, 1960. Papanicolaou, G. N., and Traut, H. F.: AM. J. OBST. & GYNEC. 42: 193, 1941. Salzer, R. B.: Obst. & Gynec. 13: 451, 1959. Scheffey, L. C., Lang, W. R., and Tatarian, G.: AM. T. OBST. & GYNEC. 70: 876. 1955. Stern, E.: and Neely, P. M.: Can&r 17: 508, 1964. Stoddard, L. D.: In Progress in Fundamental Medicine, McManus, J. F. A., editor: Philadelphia. 1952. Lea & Febiger. W&d, G. L.1 Acta cyto[ 8: 321, 1964. Wyss, H. J.: Arch. Gyngk. 194: 365, 1961. Younge, PI, Hertig, A., and Armstrong, D.: AIVK. 1. OBST. & GYNEC. 58: 867. 1949. Zinse;, H. K., Meissner, H., and Botzelen, H.: Geburtsh. u. Frauenh. 23: 321, 1963.
Discussion
DR. PURVIS L. MARTIN, San Diego, California. Dr. Hill has reaffirmed the accuracy of colposcopy as a double check on cytology. On the other hand, he questions its practicability for clinical practice and with this, we heartily agree. As institutional research tools, cytology and colposcopy appear to yield comparable percentages of preclinical carcinoma. But as useful tools for clinical practice, these two methods simply
cannot screen
be compared. Cytology can be used to entire populations and virtually to eliminate carcinoma of the cervix. Colposcopy with biopsy may be almost as accurate, but aside from its built in defect of missin,% all endocerviral and fundal carcinomas, colposcopy is simply too unwieldy for use in population screening. Colposcopy appears to have retarded the developmrnt of cytology in Europe. There, in
318
HIII
traching centers, it remains the primary dctc~ct~lr of prcclinical cervical cancer. American women arc fortunate, indeed, that in this country cytology has flowered and spread into ordinary clinical practice, without the time-consuming hottleneck of colposcopy tied to it. An increasing percentagc of our women have been screened for cervical cancer by cytology, 75 prr cent in San Dicgo County. In Austria, we are told, less than 1 pctr cent have had cytology. Dr. Hill studied 59 cases of early cervical carcinoma that were missed by cytology but were detected by performing 42,357 colposcopic exarninations, followed by the necessary large numbers of biopsies with tissue study. One wonders how many cancers could have been detected, had all of this colposcopic effort been directed into primary cytologic screening of the women of Austria. In Navratil’s clinic, primary screening yicldcd 838 preclinical cancers out of 55,000 patients. Since colposcopy-biopsy is at least trn times as time-consuming to perform as cytology, it follows that with the same amount of clinical rffort 550,000 women could have received primary cytologic screening. At Navratil’s 1.5 per cent yield for primary screening, some 8,380 prrrlinical cancers should have been detected. One might, therefore, conclude that while 59 cancers were missed by cytology and saved by colposcopy, more than 8,000 were lost by being denied cytology. Thr false negative smear is a frightening complication which is always lurking in the practice of cytology. We, too, have had experience with the false negative smear, much as we would wish it other&r. Almost any effort seems justified if it will rcaduce the chance of missing an early canrcr bcrause of a negative report. But there are at lc‘ast three double checks within the practice of cytology itself, all simpler and better than colposcopy. One effective check is the annual repeat smear. Every patient in our practice is twice reminded she should have an annual repeat smear, first at the time of her initial smear, and again when she rcccives her negative report in the mail. Since most cerviral cancers are thought to exist in an in situ stage for from 5 to 10 years before bcc,olllinq iuvasivt,, this gives us se\rrral c~haiict~ tcb 1jit.k up camrr wc rnigbt have missed tlr13 lit.st time around. A second useful check is the special significallce attached to our CIass II smear. This work was prrsrnted for the first time bcforc this so-
,.iecy last year by Dr. ‘l‘hornas A. Slate.. hrnc’ars that show rells which arc* atypil.al, yrht Ilclt SIIP picious of cancer, are placc>d in a wpnratc~ catc‘gory for closer follow-up and evaluation. ‘I‘hcsc patients, listed in our recall file, rc~c&c :ln automatic recall notice in 6 months rather than in a year. The chances for a woman with a Class 11 smear report turning up later with cancer are several times as high as those of her sister with an initial Class I smear. Laboratories that omit reporting these Class II or atypical smears. rrgardless of what name they may us?‘, arr reducing thr efficiency of the cytologic method of uterine cancer detection. A third way of reducing false negatives is ttr improve the quality of the smears thrmselves. In our laboratory, all slides are kept in permanent file. Whenever later studies are a false nrgative. that slide is reviewed in great detail, and an attempt is made to fix responsibility for the miss. In some cases, the slide will show a sparsr distribution of cells without representative crlls from both the canal and the portio. Such slides should not he accepted by the laboratory, but should be rejected with a request for a repeat smear more carefully obtained. Sometimes a thorough review shows malignant cells which the laboratory itself has missed in the initial scanning. This serves as a valuable lesson to the rytotechnicians and makes them more c;lrcful for the future. The relatively high percentage of false negative smears in Dr. Navratil’s laboratory would lead us to question the quality of his cytology. Missing 13 per cent of positive cases would br ronsidpred unacceptable cytology practice today in this country. Are wc comparing the results of the best in colposcopy with the results of less than the best in cytology? DR. HILL (Closing). Colposcopy is unwieldy for large population screening and would be difficult to use in a routine fashion in private practice, particularly because of the cost of the instrument but also because of the time required for performance of the examination. We may, however, have an exaggerated idea of how much time colposcopy does involve. Even with the Srhillpr staining of thp cervix, which is routine., the total time sprnt in inspcticting the c,tarvix and taking thr smear at the (:raz Clinic: is just a few minutes more than the Gmplr inspection of the cervix that we carry out along with the cytology and the scraping front the, cervix which is rccommendcd.
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As far as Class II smears are concerned I am reminded of the discussion of Dr. Slate’s paper of last year in which Dr. Lyons said, “Whose II are you?” indicating that Class II means different things to different people and different laboratories. At the University of Graz they attempt merely to report smears as either negative or positive. In the borderline situations they still try to assign either a negative or a positive aspect to the report of the smear. The reason that there
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are more negative reports is, perhaps, because they don’t break down the reports into five separate categories. All of us could improve the quality of our smears. Patients do come in having douched prior to the examination. Inadvertently, the cervix may be wiped prior to taking a smear. There are undoubtedly many reasons why a smear might be false negative.
Francisco,
C.
HILL,
M.D.*
California
CAREFUL MACROSCOPIC inspection of the cervix is universally considered an essential part of a gynecological examination, yet it fails to detect the earliest stages of carcinoma of the cervix. Since its introduction by Papanicolaou and Traut,18 in 1941> as a useful method in the early detection of cervical cancer, cytological examination has proved clinically effective and has found widespread acceptance. Prior to that time, however, Hinselmanng in an effort to find a satisfactory method of diagnosing carcinoma early in its course, had developed colposcopy, the technique of inspecting the cervix under low-power magnification. This method gradually came to be used extensively in most European countries and in South America: and despite the advent of cytology, continues to occupy a prominent place in gynecologic practice in these areas. In the United States, Canada, and in England, on the other hand, colposcopy found little acceptance. This was? in part perhaps, due to the confusion which occurred as a result of Hinselmann’s use of the term, “leukoplakia,” in describing lesions which he considered possibly precancerous and also because of his somewhat confusing histologic classifica-
tion.‘” It is only within recent years that there appears to be a renewed interest in colposcopy in this country, and with it? controversy regarding its merits as a screening technique in the early detection of cervical cancer when compared with the cytological 7. I”, 16, 17, 19. “u, 23 method.ll The accuracy of both techniques has been shown to be about the same. Neither cytology nor colposcopy is perfect, and each has its advantages and disadvantages. Navratil’” has recommended that, if the use of only one is practical, then cytology should be used because it is easily accomplished and samples cells shed not only from the vagina and portio vaginalis of the cervix but from the cervical canal and endometrial cavity as well. Rut, even in expert hands, the cytologic method fails to detect a certain percentage of early carcinomas.” This occurs through error on the part of the physician in taking the smear: through laboratory error: or because the tumor fails to desquamate cells in sufficient numbers to be detected. The incidence of such false negative smears is reported to range from 6 to 28 per cent.” Colposcopy, on the other hand, has the disadvantages of requiring special training on the part of the physician, of requiring relatively large numbers of cervical biopsies in relation to yield, and of failing to visualize and detect lesions which are primarily endocervical in location. The latter two are, perhaps, the greater drawbacks of this method. The frequency of indicated biopsies in relation to the number of colposcopic examinations has been reported to range from 10 per cent in some clinics to as high as 50 per cent
From the Clinic of Obstetrics and Gynecology, University of Grat, Austria. Presented at the Thirty-second Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Vancouuer, British Columbia, Canada, Sept. 29-O&. 2, 1965. *Department of Obstetrics and Gynecology, University of California Medical Center, San Francisco, California.
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in 0thers.l” I5 Preclinical cervical cancer is detected in from 2.5 to 10 per cent of those lesions in which biopsies are taken, the smaller yield being related to the greater number of biopsies .3s24 It has been pointed out by experienced colposcopists, however, that a colposcopically indicated biopsy rarely results in the finding of normal squamous or columnar epithelium and that a very high percentage of these lesions are demonstrated histologically to be dysplasias of the cervical epithelium of low or high degree. This is considered to be of value in the recognition, study, and follow-up of these possibly precancerous epithelial changes. This is all the more cogent in the light of recent evidence that the risk of carcinoma in situ in women with dysplasia is about 1,000 times greater than that for patients who have been observed to be negative for both cancer and dysplasia.21 Moreover, it is said that with greater experience in the correlation of colposcopic findings and pathologic material, one can be more selective in choosing tissue in which biopsy is deemed necessary.4 The early carcinoma of the cervix which exists only in the colposcopically inaccessible portion of the cervical canal is not common, but it does exist and poses a problem for the individual who relies solely upon colposcopy for detection. The reported incidence of preclinical carcinoma which is confined to the endocervix ranges from “very rare” to 33 per cent.2, 2G Thus, both methods have limitations, but because these limitations are different for each technique, the simultaneous use of both cytology and colposcopy has resulted in a higher rate of detection than when either one is used alone.6’ ‘9 I5 One of the largest series is that reported by Navratill’ in which more than 55,000 patients were seen in the University of Graz from 1949 through 1960, with the discovery of 83% cases of preclinical carcinoma of the cervix. In this report it was estimated that 729 (87.0 per cent) would have been detected from cy tologic examination alone. Had colposcopy been the sole method used, 663 (79.1 per
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cent) would have been diagnosed. Through the simultaneous use of both methods, however, 82% (98.8 per cent) were discovered. The remaining 10 cases were missed both by cytologic and by colposcopic examination, the diagnosis having been made on routine pathologic examination of the cervix which had been removed for apparently benign disease. This study was undertaken to elucidate the details of such cases in which early cancers of the cervix were missed by cytologic screening yet demonstrated some colposcopically visible manifestation, biopsy of which resulted in the diagnosis. It was thought that such a study would help to determine, perhaps, what factors were responsible for the failure of the cytologic method as well as those factors resulting in the success of colposcopy. It was carried out during a recent visit to the Clinic of Obstetrics and Gynecology, University of Graz. Material
The records of all patients admitted to the Frauenklinik, University of Graz, subsequent to Jan. 1, 1954, were available for this study. During the 7 year period through Dec. 31, 1960, there were 42,357 colposcopic examinations done for the purpose of cancer deIn this group 59 patients with tection. cytologically negative or unsatisfactory smears were found to have preclinical cervical cancer as a result of biopsies taken from colposcopically suspicious areas. The records of thes patients were analyzed, and selected pathologic material from punch and cone biopsies in these women were reviewed. At the Frauenklinik, University of Graz, all patients admitted to the hospital or to the outpatient department are seen in the Colposcopy Clinic where a smear is taken directly from the cervix with an Ayre spatula, and a careful colposcopic examination, including Schiller staining of the mucous membrane, is performed. The technique used at this clinic has been reported elsewhere by Navratil.15 A punch biopsy is taken of all colposcopically suspicious areas. These include true erosions; regions showing a ground
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or mosaic pattern; any area, particularly in the transformation zone, which demonstrates thickened, opaque, or yellowish epithelium or an atypical vascular pattern (atypical transformation zone) ; and iodine-negative areas which are sharply demarcated. The results of the cytologic and colposcopic examinations are reviewed. If either the smear or the biopsy demonstrates findings which are suspicious of malignancy, a cold-knife cone biopsy is done. Step sections from the cone are carefully examined for evidence of intraepithelial or early invasive cancer. Unless there is unequivocal invasion, the colposcopically directed punch biopsy is not considered an adequate substitute for a full conization of the cervix. Results
Table I. Results
of cytologic
Initial interpretation Unsatisfactory smear
esamina
ticm ----
“negative”
.54 5 5 !3
Review of “negative” smears Negative Atypical (not suspicious) Suspicious
44 5 5 54
Table II. Colposcopic with
preclinical
findings in 59 patients carcinoma of cervix
Erosio vera Iodine negative zone Vascular atypia Mosaic pattern Ground pattern Thickened epithelium
2 9 10 11 18 26 76
Age. These
patients ranged in age from 22 to 74 years with an average age of 40 years. Clinical findings. “Erythroplakia” (Navratill, or a nonspecific reddened area involvina the portio vaginalis of the cervix, was found in 47 (80 per cent) of these patients, but only in 8 was the notation made that it was suspicious of malignancy. In 12 patients the cervix was described as grossly normal in appearance. Cytologic examination. The results of the cytologic examination are shown in Table I. The review of the negative smears was carried out after the diagnosis of malignancy had been established. Colposcopic findings. All of these patients had abnormalities of the cervix under colposcopic examination, some of them presenting a combination of two or more findings. These are tabulated in Table II. Such abnormalities were considered possible areas of early malignant change in the epithelium. A true loss of epithelium (erosio Vera) was the least common finding, occurring in only 2 patients whereas 36 demonstrated an atypical transformation zone. The mosaic and ground patterns were seen in 29 patients. Biopsy findings. Table III shows the diagnoses made on colposcopically directed punch biopsies performed in 55 patients. It
also shows the results of the cone biopsies done on these patients as well as the 4 women whose records did not indicate that a punch biopsy had been done. Dysplasia was a frequent finding in the punch biopsy ( 17 cases) and was considered to be of high degree in all instances except 2 (Fig. 1). In subsequent cone biopsy, these cervices demonstrated additional areas with sufficient criteria of malignancy to warrant a diagnosis of carcinoma in situ (Fig. 2)) and in 3 cases, foci of early stromal invasion were seen. One of these, in fact, was discovered in a patient whose original punch biopsy had shown dysplasia of low degree. Carcinoma in situ was diagnosed in 27 patients on the basis of the colposcopically directed biopsy, and this diagnosis was made also in the conization specimen of half of them. In 12 patients, there was no residual malignant epithelium in the cervical cone (Fig. 3)) but 3 showed dysplastic epithelium. Early invasive carcinoma was found in two of the patients whose putich biopsies had demonstrated carcinoma in situ (Figs. 4 and5). The cone biopsy specimens in 6 of the 11 patients in whom early invasive carcinoma was diagnosed on punch biopsy failed to
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Table III Colposcopically
directed
punch
Carcinoma in situ
Dysplasia
biopsy Early
invasion
Cold-knife Dysplasia
17* 27 11 No 7
tTwo 1.One
biopsy
3 1
cone Carcinoma in situ
biopsy
with Early
14 13 2
step
sections No residual carcinoma
invasion 3t 2 5
9 3
(4)
with dysplasia of low degree. with dysplasia of low degree.
Fig. 1. clinically.
-4.
E., aged 42. Ground pattern on colposcopic examination. Nonspecific Cytology negative. Punch biopsy above interpreted as dysplasia of high
Fig. 2. Cone ment consisted
biopsy of the of conization
cervix only.
of patient Four-year
in Fig. follow-up
1 interpreted as carcinoma with no recurrence.
“erosion” degree.
in situ.
Treat-
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Fig. 3. M. P., aged 33. Opaque, thickened transitional zone on colposcopic Nonspecific “erosion” clinically. Cytology negative. Punch biopsy at colposcopy carcinoma in situ. Subsequent conization failed to demonstrate abnormal further therapy. Seven-year follow-up without evidence of recurrence.
examination. demonstrated epithelium. I\io
Fig. 4. M. J., aged 40. Ground pattern and sharply demarcated iodine negative zone on colposcopic examination. Suspicious erosion clinically. Cytology negative. Punch biopsy revealed carcinoma in situ with an equivocally invasive focus. Low-power magnification of conization specimen demonstrating early stromal invasion.
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Preclinical
cervical
carcinoma
Fig. 5. Same patient as Fig. 4 with higher power showing definite early stromal invasion on cone biopsy. Treatment consisted of Schauta-Amreich operation (no residual carcinoma in the operative specimen). Four-year follow-up with no evidence of recurrence.
Fig. 6. M. T.,
aged 35. Fine mosaic pattern on colposcopic cervix clinically. Cytology negative. Punch biopsy revealed quent cone biopsy demonstrated dysplasia only without Treatment consisted of Schauta-Amreich operation. Six-year recurrence.
examination. Normal-appearing early invasive carcinoma. Subseevidence of invasive carcinoma. follow-up with no evidence of
313
314 Hill
Fig. 7. G. K., aged 45. Ground and coarse mosaic specific “erosion” clinically. Cytology negative. high degree.
patterns Punch
Fig. 8. Same patient as Fig. 7. Cone biopsy revealed Schauta-Amreich operation recommended but patient later, cause undetermined.
ShOW
had (Fig. In puncl situ cinon
other Ino
areas of invasion, and 4, indeed of any residual carcinoma
evidence
6). the 4 patients without a preliminary n biopsy, the diagnosis of carcinoma in 1Nas made in 3 and early invasive carla in one.
on colposcopic biopsy interprrted
area suspicious refused further
of early therapy.
f.xamination. Nonas dysplasia of
stromal Died
invasion. 6 months
The final diagnosis in these 59 pat .ients was carcinoma in situ in 42 and carcir koma with early invasion in 17. Treatment and follow-up. Treatment given to these 59 patients and follow-up fij ;ures are given in Tables IV and V. In tl he 3 patients with diagnoses of invasive carcin Loma
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Table IV. Treatment of therapy
Form Diagnosis
Coniration
Carcinoma in situ Early invasive carcinoma Total
Table V. Survival
Carcinoma in situ Early invasive carcinoma patient
refused
25 3
4
28
4
(4 or more
Diagnosis
*One
Cervical amputation
further
Total hysterectomy
WertheimMeigs
Radiation
12
12
11
1
1 2
11
1
3
Total 42 17 59
-
years)
No.
Living and well
42 17
42 14
therapy:
SchautaAmreich
died
6 months
Died of carcinoma’ or cause unknown 2” later,
in whom conization was the only therapy given, one had evidence of early stromal invasion in the punch biopsy only without any evidence of malignant epithelium in the cone. She was young, and conization was considered adequate therapy in this instance. There was no evidence of recurrence 8 years after treatment. The second patient’s cone specimen revealed penetration beyond the basement membrane in one small area only, and she is well 5 years later. The third patient had an equivocally invasive focus in the cone specimen but failed to return for further treatment (Figs. 7 and 8). She died 6 months later of an undetermined cause. Comment About once in every 700 examinations in which both methods were used, a preclinical carcinoma of the cervix was discovered by colposcopy which, presumably, would have been missed in a single cytologic examination. If one presumes that a repeat smear would have demonstrated malignant cells in the 5 instances in which the initial preparation was considered unsatisfactory, then the frequency of a postitive colposcopy, negative smear combination in the face of a cervical malignancy of an occult type is reduced to one in 800 screening examinations. The fact remains, however, that with a negative cytology report, it is probable the remaining 54 patients would have been released with
cause
Died
intercurrent disease
%
1
100.0 82.4
unknown.
the assurance that there was no malignant disease involving the cervix. Perhaps one can afford to be optimistic regarding the occurrence of false negative smears in patients who are reporting regularly and frequently for examinations. The probability of missing an early carcinoma is sharply reduced by the application of repeated cytologic sampling. It is believed that intraepithelial carcinoma, in most instances, exists for approximately 9 years before it becomes invasive, and a delay of a few months in diagnosis, in most cases, is relatively unimportant. Not all invasive carcinomas of the cervix stem from pre-existing it is quite likely in situ cancers, although that the vast majority of them do. Furthermore, the results of this study demonstrate that a significant number of these patients, despite the normal gross appearance of the cervix, had early invasive foci. One cannot, under these circumstances, be as casual in the detection and management of this lesion as in the case of intraepithelial disease. Early recognition is considered paramount in order to insure a successful result of treatment. The occurrence of an advanced Stage I lesion in a patient with a grossly normalappearing cervix and a negative cytoloLgic examination one year previously is most certainly a disquieting and thought-provoking event. The fact that 29 per cent of these patients had lesions which demonstrated pen-
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etration of the basement membrane by cancer cells is considered highly significant. The majority (80 per cent) of these patients had grossly visible “erosions,” or “erythroplakia,” which were not suspected of harboring malignant epithelium. This coincides with the 80 per cent of cervical “erosions” in the 135 cases of carcinoma in situ reported by Younge, Hertig, and Armstrong.“j Stoddardz? has pointed out that carcinoma in situ usually develops within the portio epithelium of the transformation zone of an endocervical ectopia. It is not possible macroscopically to distinguish between benign areas of erythroplakia and those in which the epithelium has undergone malignant change. The Chrobak test may be helpful in arousing a suspicion as may the history of contact bleeding. On the other hand, the finding in an “erosion” on colposcopic examination of typical endocervical epithelium or a normal transformation zone only is a reassuring finding, and, for all practical purposes, in combination with a negative cytologic examination, rules out a malignant process of the cervix. The finding on cone biopsy of no residual carcinoma in 12 of the 27 patients who demonstrated intraepithelial carcinoma on colposcopically directed punch biopsy would imply that these lesions were very small, isolated foci. Presumably, a smear from such a cervix would contain few or no malignant cells, thus escaping detection. Likewise, no residual carcinoma in four of the 11 patients who showed early invasion on punch biopsy indicates small lesions probably desquamating very few cells. Thus, in almost one third of these cases the lesion was SO small that it was removed in the performance of a diagnostic punch biopsy under colposcopic control. Another possible explanation is that the manipulation of the cervix incidental to the punch biopsy brought about a mass shedding of intraepithelial carcinoma, a phenomenon observed by Koss and his associates.” In those patients in whom carcinoma in situ was found in the cone biopsy, it was noteworthy that the focus of malignant epithelium in several in
whom the pathologic, material was rc&wecl was \-cry small, somotifnes esisting ~II only a small area on two or three step sections. In other cases, the epithelial layer of rnalignant cells was covered by a very thin, superficial layer of parakeratotic cells with pyknotic nuclei. Although in these instances there may be some question regarding the differential diagnosis of intraepithelial carcinoma versus dysplasia of high degree (according to the opinion of the Clinic in Graz, such a surface layer does not interfere with the diagnosis of carcinoma in situ*“), such a differentiated surface layer may prevent the desquamation of deeper cells with more typical nuclear abnormalities. Such cases may be missed on a single cytologic examination. It would appear from this study that routine colposcopic examination with biopsy of suspicious areas does fulfill the function of serving as a secondary screening method and “cover” for cytologic examination in the detection of preclinical carcinoma of the cervix. Its effectiveness lies in its ability to find small areas of malignant epithelium which, for one reason or another. are not represented in a sampling of superficial cells shed or scraped from the cervix. Furthermore, it also appears to be a useful method for detecting areas of epithelial dysplasia and helping to clarify the interpretation of the atypical smear report. The technique of colposcopic examination is not difficult, and it is not time-consuming when applied by an experienced observer in a routine fashion. There is still some question regarding its practicability, however, because of the relatively large numbers of biopsies which are required. For this reason, in the average gynecologic practice, the cytologic method undoubtedly will continue to occupy the major role in early cancer detection. Certainly it is important, though, for certain centers in the United States and in Canada to pursue the question and to develop their own experiences in colposcopy. Only by doing this can we fairly judge the part that it plays in complementing cytology in the the detection of precancerous lesions and early carcinoma of the cervix. Knowledge of
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the pathogenesis and the relationship of these conditions will be furthered thereby. Summary
1. Fifty-nine cases of preclinical carcinoma of the cervix with negative cytologic smears detected by colposcopic examination in the Clinic of Obstetrics and Gynecology, University of Graz, have been reviewed. 2. These cases were found in 42,357 screening examinations over a 7 year period, an occurrence of 1: 700 examinations. 3. There were 42 cases of intraepithelial carcinoma and 17 with early stromal invasion. 4. Almost one third of these carcinomas
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were such small lesions, they were found only in the colposcopically directed punch biopsy, step sections of subsequent cold-knife cone biopsy demonstrating no residual carcinoma. 5. Colposcopic examination is considered to be an effective method of complementing the cytologic examination in the early detection of incipient carcinoma. Because of the need for large numbers of biopsies, however, its practicability remains in question. The help of Professor Dr. Ernst Navratil in the preparation of the manuscript and of Dozend Dr. E. Burghardt in providing the photomicrographs is gratefully acknowledged.
REFERENCES
1. 2. 3. 4. 5. 6. 7. 8.
9. 10. 11.
12. 13.
Bolten, K.: Introduction to colposcopy, New York, 1960, Grune & Stratton. Bret, J. A., and Coupez, F. J.: Acta cytol. 5: 407, 1961. Burghardt, E., and Bajardi, F.: Arch. Gynsk. 187: 621, 1956. Burghardt, E.: Personal communication, 1965. Coppleson, M.: J. Obst. & Gynaec. Brit. Emp. 67: 11, 1960. Coppleson, M.: J. Obst. & Gynaec. Brit. Comm. 71: 854, 1964. Dampeer, T. K., Jr.: South. M. J. 55: 445, 1962. Graham, J. G., Sotto, L. S. J., and Paloucek, F. P.: Carcinoma of the Cervix, Philadelphia and London, 1962, W. B. Saunders Company. Hinselmann, H.: Miinchen. med. Wchnschr. 7: 1733, 1925. Hinselmann, H.: Ztschr. Geburtsh. u. Gyngk. 101: 142, 1932. Koss, L. G., Stewart, F. W., Foote, F. W., Jordan, M. J., Bader, G. M., and Day, E.: Cancer 16: 1160, 1963. Lang, W. R.: J. A. M. A. 166: 893, 1958. Limburg, H.: In La prophylaxie en gyne-
14. 15.
16. 17. 18. 19. 20. 21. 22.
23. 24. 25. 26.
cologie et obstetrique, Librairie de l’UniversitC, Gentve, 1954, Georg. Martzloff, K. H.: West. J. Surg. 67: 160, 1959. Navratil, E.: In Dysplasia, Carcinoma in Situ, Gray, Laman A., kditor: Springfield, 1964, Charles C Thomas. Publisher. Navratil, E.: Per&al communication, 1965. Olson, A. W., and Nichols, E. E.: Obst. & Gynec. 15: 372, 1960. Papanicolaou, G. N., and Traut, H. F.: AM. J. OBST. & GYNEC. 42: 193, 1941. Salzer, R. B.: Obst. & Gynec. 13: 451, 1959. Scheffey, L. C., Lang, W. R., and Tatarian, G.: AM. T. OBST. & GYNEC. 70: 876. 1955. Stern, E.: and Neely, P. M.: Can&r 17: 508, 1964. Stoddard, L. D.: In Progress in Fundamental Medicine, McManus, J. F. A., editor: Philadelphia. 1952. Lea & Febiger. W&d, G. L.1 Acta cyto[ 8: 321, 1964. Wyss, H. J.: Arch. Gyngk. 194: 365, 1961. Younge, PI, Hertig, A., and Armstrong, D.: AIVK. 1. OBST. & GYNEC. 58: 867. 1949. Zinse;, H. K., Meissner, H., and Botzelen, H.: Geburtsh. u. Frauenh. 23: 321, 1963.
Discussion
DR. PURVIS L. MARTIN, San Diego, California. Dr. Hill has reaffirmed the accuracy of colposcopy as a double check on cytology. On the other hand, he questions its practicability for clinical practice and with this, we heartily agree. As institutional research tools, cytology and colposcopy appear to yield comparable percentages of preclinical carcinoma. But as useful tools for clinical practice, these two methods simply
cannot screen
be compared. Cytology can be used to entire populations and virtually to eliminate carcinoma of the cervix. Colposcopy with biopsy may be almost as accurate, but aside from its built in defect of missin,% all endocerviral and fundal carcinomas, colposcopy is simply too unwieldy for use in population screening. Colposcopy appears to have retarded the developmrnt of cytology in Europe. There, in
318
HIII
traching centers, it remains the primary dctc~ct~lr of prcclinical cervical cancer. American women arc fortunate, indeed, that in this country cytology has flowered and spread into ordinary clinical practice, without the time-consuming hottleneck of colposcopy tied to it. An increasing percentagc of our women have been screened for cervical cancer by cytology, 75 prr cent in San Dicgo County. In Austria, we are told, less than 1 pctr cent have had cytology. Dr. Hill studied 59 cases of early cervical carcinoma that were missed by cytology but were detected by performing 42,357 colposcopic exarninations, followed by the necessary large numbers of biopsies with tissue study. One wonders how many cancers could have been detected, had all of this colposcopic effort been directed into primary cytologic screening of the women of Austria. In Navratil’s clinic, primary screening yicldcd 838 preclinical cancers out of 55,000 patients. Since colposcopy-biopsy is at least trn times as time-consuming to perform as cytology, it follows that with the same amount of clinical rffort 550,000 women could have received primary cytologic screening. At Navratil’s 1.5 per cent yield for primary screening, some 8,380 prrrlinical cancers should have been detected. One might, therefore, conclude that while 59 cancers were missed by cytology and saved by colposcopy, more than 8,000 were lost by being denied cytology. Thr false negative smear is a frightening complication which is always lurking in the practice of cytology. We, too, have had experience with the false negative smear, much as we would wish it other&r. Almost any effort seems justified if it will rcaduce the chance of missing an early canrcr bcrause of a negative report. But there are at lc‘ast three double checks within the practice of cytology itself, all simpler and better than colposcopy. One effective check is the annual repeat smear. Every patient in our practice is twice reminded she should have an annual repeat smear, first at the time of her initial smear, and again when she rcccives her negative report in the mail. Since most cerviral cancers are thought to exist in an in situ stage for from 5 to 10 years before bcc,olllinq iuvasivt,, this gives us se\rrral c~haiict~ tcb 1jit.k up camrr wc rnigbt have missed tlr13 lit.st time around. A second useful check is the special significallce attached to our CIass II smear. This work was prrsrnted for the first time bcforc this so-
,.iecy last year by Dr. ‘l‘hornas A. Slate.. hrnc’ars that show rells which arc* atypil.al, yrht Ilclt SIIP picious of cancer, are placc>d in a wpnratc~ catc‘gory for closer follow-up and evaluation. ‘I‘hcsc patients, listed in our recall file, rc~c&c :ln automatic recall notice in 6 months rather than in a year. The chances for a woman with a Class 11 smear report turning up later with cancer are several times as high as those of her sister with an initial Class I smear. Laboratories that omit reporting these Class II or atypical smears. rrgardless of what name they may us?‘, arr reducing thr efficiency of the cytologic method of uterine cancer detection. A third way of reducing false negatives is ttr improve the quality of the smears thrmselves. In our laboratory, all slides are kept in permanent file. Whenever later studies are a false nrgative. that slide is reviewed in great detail, and an attempt is made to fix responsibility for the miss. In some cases, the slide will show a sparsr distribution of cells without representative crlls from both the canal and the portio. Such slides should not he accepted by the laboratory, but should be rejected with a request for a repeat smear more carefully obtained. Sometimes a thorough review shows malignant cells which the laboratory itself has missed in the initial scanning. This serves as a valuable lesson to the rytotechnicians and makes them more c;lrcful for the future. The relatively high percentage of false negative smears in Dr. Navratil’s laboratory would lead us to question the quality of his cytology. Missing 13 per cent of positive cases would br ronsidpred unacceptable cytology practice today in this country. Are wc comparing the results of the best in colposcopy with the results of less than the best in cytology? DR. HILL (Closing). Colposcopy is unwieldy for large population screening and would be difficult to use in a routine fashion in private practice, particularly because of the cost of the instrument but also because of the time required for performance of the examination. We may, however, have an exaggerated idea of how much time colposcopy does involve. Even with the Srhillpr staining of thp cervix, which is routine., the total time sprnt in inspcticting the c,tarvix and taking thr smear at the (:raz Clinic: is just a few minutes more than the Gmplr inspection of the cervix that we carry out along with the cytology and the scraping front the, cervix which is rccommendcd.
Volume 95 Number 3
As far as Class II smears are concerned I am reminded of the discussion of Dr. Slate’s paper of last year in which Dr. Lyons said, “Whose II are you?” indicating that Class II means different things to different people and different laboratories. At the University of Graz they attempt merely to report smears as either negative or positive. In the borderline situations they still try to assign either a negative or a positive aspect to the report of the smear. The reason that there
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319
are more negative reports is, perhaps, because they don’t break down the reports into five separate categories. All of us could improve the quality of our smears. Patients do come in having douched prior to the examination. Inadvertently, the cervix may be wiped prior to taking a smear. There are undoubtedly many reasons why a smear might be false negative.