Colposcopy and the management of cervical intraepithelial neoplasia

GYNECOLOGlC

ONCOLOGY

5, 27-39 (1977)

Colposcopy

and the Management of Cervical lntraepithelial Neoplasia

SILVIU KOHAN, M.D., E. MARK BECKMAN, BRADLEY BIGELOW, M.D., MASON CARP, AND GORDON W. DOUGLAS, M.D. The Department Division

of Obstetrics and Gynecology of Gynecologic Oncology, New 5.50 First

Avenue,

New

M.D., M.D.,

and the Department York University Medical York, New York 11016

of Pathology, Center,

Received June 29, 1976 The accuracy of the colposcopically directed punch biopsy and its value in the management of cervical intraepithelial neoplasia (C.I.N.) was evaluated among 272 consecutive patients with abnormal Pap smears who were followed in a cervical dysplasia clinic (Bellevue Hospital, New York University Medical Center). The authors conclude that many unnecessary surgical operations were eliminated with this technique. One hundred and eighty-five patients (68%) underwent a colposcopically directed punch biopsy, usually followed by endocervical curettage. Only 22 patients (8%) had subsequent surgical conizations and 11 patients (4%) underwent hysterectomies. All cases diagnosed as mild or moderate dysplasia were treated by cryocauterization. For the cases with severe dysplasia or C.I.N. the treatment was individualized. Surgical conization or hysterectomy was performed in those cases with additional indications such as uterine prolapse, desire for sterilization, or advanced age. To minimize the risk of a later invasive carcinoma, a continuous follow-up with colposcopy and cytology is necessary.

In the last few years, colposcopy has been used increasingly in the United States for the diagnosis and management of cervical intraepithelial neoplasia (C.I.N.) [l-31. The aim of this study is to define the accuracy of colposcopically directed punch biopsies, and their value in the management of C.I.N. We also wish to demonstrate that colposcopy can accurately differentiate between invasive carcinoma and C.I.N. Consequently, an important use of the colposcope, in our institution, is the selection of patients for conservative treatment. The rationale is that its use in an outpatient clinic will save the patients the expense of hospitalization and will eliminate the complications of the cone biopsy r41.

Previous studies have indicated that in approximately 85% of cases with abnormal Papanicolau smears, cone biopsies can be successfully replaced by colposcopically directed punch biopsies [5-71. These “target” biopsies can find the worst lesion and define its extent. In 1910, Rubin [8] was the first to describe the entity known as carcinoma in situ of the cervix, and it is more than half a century since Hinselman [9] described the use of his colposcope. However, it is less than a decade since the concept of cervical intraepithelial neoplasia was popularized [ 10, 1 I]. This term encompasses dysplasia of varying severity, as well as carcinoma in situ. 27 Copyright All rights

@ 1977 by Academic Press, Inc. of reproduction m any form reserved.

28

KOHAN

ET AL.

The combined use of cytology and colposcopy permits the diagnosis of C.I.N. to be made in an early stage and the treatment to be the relatively simple procedure of cryosurgery [ 12-141. MATERIALS

AND METHODS

The study group consisted of 272 patients who had at least one suspicious Pap smear. The patients were referred to the Bellevue Cervical Dysplasia Clinic (New York University Medical Center) from other gynecology and family planning clinics of the hospital, or by private physicians. They were seen over a 16-mon period between October 1974 and January 1976. Repeat Pap smear tests were obtained from all patients. Prior to the colposcopic examination, the cervix was thoroughly cleansed with 4% acetic acid solution in order to remove the mucus and to accentuate the colposcopic patterns. Abnormal colposcopic findings which necessitated target biopsies were the following (Fig. 1): 1. White focal lesions observed after acetic acid test. 2. Punctation. 3. Mosaicism. 4. Leukoplakia: white lesions observed before acetic acid test. 5. Abnormal pattern of blood vessels, e.g., a. Irregular, branched pattern. b. Sharp, irregular bends. c. Abrupt, sharp, intermingled dilations and constrictions. In addition to the above, findings suggestive of invasion were (Fig. 2): 1. Abnormal blood vessels running parallel to the surface and covered by only a few cell layers. 2. Uneven, slightly elevated surface of the lesion. 3. Sharply circumscribed border of the lesion. 4. A lesion darker and shinier than the surrounding surface when viewed through a green filter. Following the target biopsy(ies), endocervical curettage was performed and submitted as a separate specimen to the laboratory. Endocervical curettage was performed in all patients with the exception of gravidas, or when invasive carcinoma was evident at the colposcopic examination. The specimens were fixed in 10% formalin and each was examined by a minimum of four levels through the tissue block (Figs. 3-5). Patients who had colposcopic findings of mild to moderate dysplasia, in whom the entire lesion was visualized and the endocervical curettings were negative, were treated by cryocauterization alone. Histological confirmation of the colposcopic findings was always obtained prior to the treatment. The cryocauterization was performed with nitrous oxide for two periods of 3 min, separated by a 5-min thawing interval. Cone biopsy was performed under any of the following circumstances: if the entire squam+columnar junction was not visualized, if the colposcopically abnormal areas extended up the endocervical canal, out of view, or if the endocervical curettings contained dysplastic epithelium. Cone biopsy was also indicated when a negative, or minimally abnormal,

COLPOSCOPY

AND

CERVICAL

NEOPLASIA

29

FIG. 1. Abnormal colposcopic findings indicative of C.I.N., including punctation (bottom of figure), leukoplakia (center of figure), and mosaicism (top of figure).

30

Cl

KOHAN

ET AL.

FIG. 2. Abnormal colposcopic findings suggestive of invasive neoplasia. Note sharply cirlmscribed border of the lesion, the uneven, elevated surface and abnormally dilated “corkscr .ew” ‘pe of vessels running superficially, and parallel to the surface (center).

COLPOSCOPY

AND CERVICAL

NEOPLASIA

31

FIG. 3. Dysplasia of moderate degree in a colposcopically directed biopsy. The abnormal nut :lei become less numerous as the surface of the epithelium is approached at top.

32

KOHAN ET AL.

FFIG. 4. Carcinoma in situ. The abnormal nuclei extend through epicthelium from bottom to the surface at top.

the full thickness of the

COLPOSCOPY

AND CERVICAL

NEOPLASIA

33

FIG. 5. Endocervical curettings obtained following colposcopic biopsy. A strip of dysplastic epithelium is associated with red blood cells and bits of endocervical mucosa at upper right left.

s quamous aInd lower

34

KOHAN

ET AL.

colposcopic examination conflicted with a more abnormal cytologic or histologic diagnosis. When a colposcopically directed biopsy showed severe dysplasia or carcinoma in situ, a therapeutic cervical conization was performed in those patients desiring preservation of fertility, but in whom continuous follow-up was not assured. When there were such indications as uterine prolapse, desire for sterilization, or a patient over 40 years of age, a total hysterectomy was performed. Both the conization and the hysterectomy specimens were examined by multiple step sections of the entire squamo-columnar juction. For younger patients who demonstrated dependability for continuous followup, cryosurgery was performed, even when severe dysplasia or carcinoma in situ was diagnosed. All the patients treated by cryocauterization or surgical conization were followed by Pap smear and colposcopy at 3-month intervals. Hysterectomized patients were similarly followed at 6-month intervals. RESULTS

As seen in Table 1, of 272 patients, 87 (32%) had normal epithelium or inflammatory changes on colposcopy. The total number of patients with dysplastic lesions, carcinoma in situ, or invasive carcinoma was 185 (68%). Table 2 shows the histology of the colposcopically directed biopsies in these 185 patients. Thirty-seven patients (20%) had normal or inflammatory changes in the colposcopically directed biopsy. One hundred forty-three patients (77%) were found to have various degrees of dysplastic lesions or carcinoma in situ: 59 patients (32%) were found to have severe dysplasia or carcinoma in sitcl and 84 cases (45%) had mild to moderate dysplasia. Five patients (3%) had invasive carcinoma. In Table 3, which compares the referral Pap smears with the impression on colposcopy, we have divided the 272 patients into two groups. The first group of 213 patients, whose smears showed all degrees of dysplasia from minimal to severe, is defined as suspicious. Eighty-seven patients (40%) had normal or inflammatory changes on colposcopic examination, while 123 (58%) had mild to moderate dysplasia, and 3 (2%) had severe dysplasia or carcinoma in situ. The second group of 59 patients had smears classified as positive. Here colposcopy revealed severe dysplasia, or worse, in all cases, with severe dysplasia or carTABLE 1 RESULTS OF COLPOSCOPIC EXAMINATION Normal or inflammatory changes Mild to moderate dysplasia Severe dysplasia or carcinoma in situ Invasive carcinoma

81 123

Total

272

Total number of patients with colposcopically carcinomatous lesions

51

5

dysplastic or 185 (68%)

COLPOSCOPY

AND CERVICAL TABLE

RESULTS OF BIOPSY SUGGESTED

35

NEOPLASIA

2

IN PATIENTS WITH C.I.N. OR INVASIVE

COLPOSCOPICALLY CARCINOMA

Normal or inflammatory changes Mild to moderate dysplasia Severe dysplasia or carcinoma in situ Invasive carcinoma

37 (20%) 84 (45%) 59 (32%) 5 (3%)

Total

185

cinema in situ in 54 patients (92%). The remaining 5 cases (8%) were felt to be invasive cancer, subsequently proven by biopsy. Table 4 compares the colposcopic impression with the directed biopsy results in 185 cases. Of 123 patients with colposcopic findings suggestive of mild to moderate dysplasia, 82 (67%) were confirmed by histology. In 32 patients (26%) histology showed only normal or inflammatory changes, and in the other 9 (7%), severe dysplasia or carcinoma in situ. Of the 57 cases with severe dysplasia or carcinoma in situ on colposcopy, histology showed 5 cases (9%) to be normal or inflammatory, 2 (4%) to be mild or moderate dysplasia, and the remaining 50 (87%) were confirmed. All 5 cases of invasive carcinoma were histologically confirmed. In Table 5, the directed biopsies showing severe dysplasia or worse are compared with the specimens from subsequent cones and hysterectomies. Of the 33 patients with severe dysplasia or carcinoma in situ on biopsy, 23 (67%) had similar findings in the subsequent specimens. Ten (33%) had mild to moderate dysplasia. All 5 cases with invasive cancer on biopsy had confirmation in the radical hysterectomy specimens. COMMENTS

The first point to be discussed is the large number of patients (87 or 32%) whose suspicious Pap smears were not confirmed by colposcopy. These cases reflect both the low threshold of suspicion in the interpretation of cytology and a low threshold of indication for referral of cases to the colposcopy clinic. However, we TABLE COMPARISON

BETWEEN

CYTOLOGY

3 AND

COLPOSCOPY

RESULTS

Colposcopy results Number of patients

Cytology results (Pap smears)

213 59

Suspicious Positive

Total 272

Severe dysplasia or carcinoma

Normal or inflammatory changes

Mild to moderate dysplasia

87 0

123 0

3 54

0 5

87

123

57

5

in situ

Invasive carcinoma

KOHAN

36

TABLE COMPARISON

BETWEEN

COLPOSCOPY

ET

AL.

4 AND

DIRECTED

BIOPSY

RESULTS

Directed biopsy results Number of Patients 123

57

colposcopy results

Severe dysplasia or carcinoma

Normal or inflammatory changes

Mild to moderate dysplasia

32

82

9

0

5

2

50

0

0

0

0

5

37

84

59

5

Mild to moderate dysplasia Severe dysplasia or carcinoma in

in situ

Invasive carcinoma

situ

5

Invasive carcinoma

Totals 185

still find it necessary to evaluate by colposcopy every patient with a Pap smear that is not reported as entirely free of dysplastic cells, since 68% dysplastic lesions, found colposcopically in the whole group, is a significant proportion. Table 2 shows the histology of the 185 colposcopically directed biopsies. The 37 patients (20%) with no histologically proven C.I.N. deserve serious consideration. The value of colposcopy, despite this relatively high figure, is incontestable. We are convinced that minimally dysplastic lesions will escape the eye even of an experienced colposcopist, unless a generous number of biopsies are performed. Consequently, an excess in the number of directed biopsies is justifiable. Since scrupulous attention was paid toward the biopsy of the most colposcopically TABLE COMPARISON

BETWEEN AND

DIRECTED HYSTERECTOMY

5 BIOPSY

AND

CONIZATION

RESULTS

Conization and hysterectomy results Number of Patients 33

Directed biopsy results Severe dysplasia or carcinoma

Normal or inflammatory changes

Mild to moderate dysplasia

Severe dysplasia or carcinoma in situ

Radical Hysterectomy results Invasive carcinoma

0

10

23

0

0’

0

0

5

0

10

23

5

in situ

5 Totals 38

Invasive carcinoma -

COLPOSCOPY

AND

CERVICAL

NEOPLASIA

37

suspicious area, we believe that the 20% negative biopsy rate does not represent a failure of technique, but rather, a high level of suspicion on the part of the colposcopist. The accuracy of the technique is further confirmed, in Table 4, by the absence of histologically invasive lesions which were not suspected colposcopically. Excluding the 5 cases with invasive carcinoma, who were treated radically for this disease, the rest of the patients underwent more conservative treatment. Recent publications [ 15, 161 have reported a marked reduction of surgical conization and the successful treatment of cervical intraepithelial neoplasia with electrocauterization [ 17, 181 or cryosurgery [ 19,201 after colposcopically directed punch biopsy. At this point, we want to stress once more, that an incomplete colposcopic examination could lead to the inadequate diagnosis and treatment of the patient with early invasive neoplasia. In our clinic, the patients with histologically conIirmed mild or moderate dysplasia were treated only by cryocauterization. Other authors have concluded in recent studies [ 121 that severe dysplasia and even carcinoma in situ can be adequately treated by cryocauterization alone. In our study, we tried to be more selective. Of the 59 cases with severe dysplasia or carcinoma in situ, 26 young, nulliparous patients (44%) were treated by cryocauterization. At the time of this study, no signs of recurrent disease have been found in our patients, although the follow-up is admittedly short. Of the remaining 33 patients (56%), 22 had cone biopsies and 11 had hysterectomies. The 22 cases with surgical cones represent only 8% of the total of 272 cases screened and only 12% of the 180 cases of colposcopically suggested C.I.N. We believe that by our management a great number of unnecessary cone biopsies were avoided. As presented in Table 3, of 213 patients with one suspicious Pap smear, 87 (40%) showed only normal or inflammatory changes on colposcopy. These patients will be carefully followed by colposcopy and repeat cytology. Despite the high incidence of negative colposcopies, we are impressed by the 3 patients (2%) in this group with severe dysplasia or carcinoma in situ. Table 3 shows that Pap cytology is a very efficient method of screening for intraepithelial neoplasia in a more advanced stage. Of 59 cases with positive Pap smears, none were considered as less than severe dysplasia by colposcopy. All 5 cases of invasive carcinoma, detected by Pap smears, were confirmed by colposcopy and biopsy (Table 4). With respect to the data shown in Table 4, we found a discrepancy of at least one histologic grade, between colposcopy and histology in 7 patients (12%) of the 57 with severe dysplasia or carcinoma in situ, and in 41 cases (33%) of 123 with mild to moderate dysplasia. Overall, there were 48 discrepancies (approximately 25%) in all 185 cases. However, no invasive carcinoma was missed. While these data emphasize that colposcopy cannot be a substitute for biopsy of the lesion, it does give enough information to avoid missing an invasive carcinoma. Finally, in Table 5, a comparison is made between the histology of the directed biopsies and the subsequent cone and hysterectomy specimens. Of 33 patients with severe dysplasia or carcinoma in situ, 23 were confirmed and 10 showed

38

KOHAN

ET AL,

residual dysplastic lesions of a lesser degree. In the latter cases, it must be presumed that the worst area of the lesion was completely removed by colposcopic biopsy. CONCLUSION

Careful colposcopic examination in a series of patients seen in a cervical dysplasia clinic (Bellevue Hospital Center, New York, New York) has eliminated many unnecessary surgical procedures. One hundred eighty-five patients had a colposcopically directed punch biopsy and endocervical curettage. Twenty-two patients (8%) had subsequent surgical conizations of the cervix and 11 patients (4%) underwent hysterectomy. All the cases diagnosed as mild to moderate dysplasia were treated by cryocauterization. This was contingent upon the availability of continuous follow-up. This study supports the opinion that colposcopy is a reliable method for the investigation of abnormal cervical cytology by selecting the site of biopsy. In our view, colposcopy is an indispensable tool in the follow-up and the conservative management of mild to moderate dysplasia. Reliance on colposcopy is contingent upon visualization of the whole lesion, as well as the entire squamo-columnar junction, and upon a negative endocervical curettage. If adequate follow-up is assured, we believe that all cervical intraepithelial neoplasias, including carcinoma in situ, can be followed colposcopically and managed conservatively, without resort to surgical conization or hysterectomy. As long as colposcopic and cytologic evaluation can be maintained in a long follow-up, the risk of missing invasive carcinoma will be minimal. REFERENCES 1. Coppleson, M., Poxley, E., and Reid, B. Colposcopy, Charles C Thomas, Springfield, Illinois (1971). 2. Creasman, W. T., Weed, J. C., Jr., Curry, S. S., Johnson, W. W., and Parker, R. T. Efficiency of cryosurgical treatment of severe cervical intraepithelial neoplasia, Gbster. Gynecol. 41,501-X% (1973). 3. Donohue, D. R., and Meriwether, P. E. Colposcopy as a diagnostic tool in the investigation of cervical neoplasias, Amer. J. Obstet. Gynecol. 113, 107 (1972). 4. Ahlgren, M., Ingemarsson, I., Lindberg, L. G., and Nordquist, S. R. B. Conization as treatment of carcinoma in situ of the uterine cervix, Obstet. Gynecol. 46, 135-139 (1975). 5. Boelter, W. C., and Newman, R. The correlation between colposcopical grading, directed punch biopsy and conization, Amer. J. Obstet. Cynecol. 110, 945-946 (1971). 6. Hollyock, V. E., and Chanen, W. The use of colposcopy in the selection of patients for cervical cone biopsy, Amer. J. Obstet. Gynecol. 114, 185-189 (1972). 7. Van Nagell, J. R., Parker, J. C., Hicks, L. P., Conrad, R. P., and England, C. Diagnostic and therapeutic efficacy of cervical conization, Amer. J. Obstet. Gynecol. 124, 134-140 (1976). 8. Rubin, I. C. The pathological diagnosis of incipient carcinoma of the cervix, Amer. J. Obstet. Dis. Women, 62, 66 (1910). 9. Hinselman, H. Mum. Med. Wochenschr. 72, 1733 (1925). 10. Chanen, W., and Hollyock, V. E. Colposcopy and the conservative management of cervical dysplasia and carcinoma in situ, Obstet. Gynecol. 43, 527-534 (1974). 11. Creasman, W. T., and Rutledge, F. Carcinoma in situ of the cervix, Obstet. Gynecol. 39,373-380 (1972).

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AND

CERVICAL

NEOPLASIA

39

12. Creasman, W. T., and Parker, R. T. Management of early cervical neoplasia, C/in. Obster. Gynecol. 18, 233-246 (1975). 13. Kaufman, R. H., Strama, T., Norton, P. K., and Conner, J. S. Cryosurgical treatment of surgical intraepithelial neoplasia, Obstet. Gynecol. 42, 881-886 (1973). 14. Thredway, D. R., Townsend, D. E., Howland, D. N., and Upton, R. T. Colposcopy and cryosurgery in cervical intraepithelial neoplasia, Amer. 1. Obstet. Gynecol. 114, 1020-1024 (1972). 15. Gray, L. A., and Cristopherson, W. Treatment of cervical dysplasia, Gynecol. Oncol. 3, 149-153 (1975). 16. Kolstad, P. Carcinoma of the cervix, Stage 0: Diagnosis and treatment, Amer. J. Obstet. Gynecol. 96, 1098 (1966). 17. Chanen, W., and Hollyock, V. E. Colposcopy and electrocoagulation diathermy for cervical dysplasia and carcinoma in situ, Obstet. Gynecol. 37, 623-628 (1971). 18. Krumholtz, B. A., and Knapp, R. C. Colposcopical selection of biopsy sites, Obstet. Gynecol. 39, 22-26 (1972). 19. Stafl, A., Mattingly, R. F. Colposcopic diagnosis of cervical neoplasia, Obstet. Gynecol. 41, 168-176 (1973). 20. Townsend, D. E., and Ostergard, D. R. Cryocauterization for preinvasive cervical neoplasia, J. Reprod. Med. 6, 171-175 (1971).