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Results of the Clinical Evaluation of Atypical Glandular Cells of Undetermined Significance (AGCUS) Detected on Cervical Cytology Screening
GYNECOLOGIC ONCOLOGY ARTICLE NO.
63, 14–18 (1996)
0270
Results of the Clinical Evaluation of Atypical Glandular Cells of Undetermined Significance (AGCUS) Detected on Cervical Cytology Screening ALEXANDER W. KENNEDY, M.D., STEPHEN S. SALMIERI, D.O., SUSAN L. WIRTH, B.S.N., CHARLES V. BISCOTTI, M.D., LAURIE J. TUASON, M.S., AND MARY JANE TRAVARCA Departments of Gynecology and Obstetrics, Anatomic Pathology, and Biostatistics, Cleveland Clinic Foundation, Cleveland, Ohio 44195 Received December 29, 1995
bring uniformity to the reporting of cytologic diagnoses [1]. An additional goal of this system was to more stringently define ‘‘atypia’’ so that this term is not overused resulting in overdiagnosis and the unnecessary treatment of patients [2]. The diagnosis of atypical squamous cell of undetermined significance (ASCUS) occurs in up to 5% of routine cervical cytologic smears within the general population. Therefore, by this time, institutions and laboratories have had sufficient experience to determine the underlying clinical conditions and problems related to the diagnosis of ASCUS [3]. A prior unpublished review of the experience at the Cleveland Clinic Foundation with ASCUS revealed that, among premenopausal women, 2% had underlying grade 2–3 cervical intraepithelial neoplasms (CIN) and 9% had grade 1 CIN. No invasive cancers were discovered and no pathologic conditions were noted in postmenopausal women with ASCUS. The clinical significance, however, of a report of atypical glandular cells of undetermined significance (AGCUS) is much less well understood. In large measure this relates to the much lower frequency of glandular abnormalities of the cervix. Additionally, the criteria for the cytologic diagnosis of glandular abnormalities have tended until recently to be more vague and subjective [4, 5]. A previous report by Goff et al. regarding the evaluation of patients with endocervical glandular atypia on Pap smears from the Massachusetts General Hospital Cytopathology Laboratory indicated a substantial rate of underlying cervical and endometrial lesions [6]. Varying degrees of cervical dysplasia were found in 30% of patients and squamous carcinoma in situ in 10% of patients. Additionally, 8% of patients were found to have adenocarcinoma in situ and 3% had invasive adenocarcinoma. The current study was undertaken to improve the understanding of the significance of AGCUS under the current Bethesda System for reporting cytologic results, and to determine the most appropriate management of patients with this finding on routine Pap smears. It was hypothesized based upon prior reports including the study by Goff et al. [6]
Objective: To determine the clinical significance of and underlying pathology among patients with atypical glandular cells of undetermined significance (AGCUS) identified on cervical Pap smear screening. Methods: The computerized files of the Cleveland Clinic Foundation cytology laboratory were searched from 1990 to 1994 to identify all patients with AGCUS. Patients with other significant cytologic diagnoses were considered separately from patients whose only significant finding was reported to be AGCUS. Retrospective chart review was completed to identify associated conditions and to record the results of the clinical evaluations of these patients. Results: One hundred thirty-six patients were identified among the 68,368 (0.2%) specimens from this 5-year period in contrast to 3078 (4.5%) patients with atypical squamous cells (ASCUS). Mean patient age was 43.7 years (range 20–78). Among 77 patients without other significant cytologic findings in addition to AGCUS, without prior gynecologic cancer and who had a recorded gynecologic evaluation, 13 patients (17%) were diagnosed with the following lesions: two (3%) invasive cervical adenocarcinomas, three cervical adenocarcinomas in situ (4%), three grade 1 cervical intraepithelial neoplasms (CIN) (4%), four grade 2–3 CIN (5%), and one (1%) endometrial adenocarcinoma. Additionally, in subsequent follow-up examinations two patients were diagnosed with cervical adenocarcinoma in situ, one with invasive adenocarcinoma of the cervix and one with diffusely metastatic pancreatic cancer. Conclusions: AGCUS on cervical cytologic screening, even in the absence of other associated cytologic findings, is associated with substantial underlying uterine pathology including at least 4% (95% confidence interval (CI) 0.8%, 11.0%) invasive cancers and 13% (95% CI 6.4%, 22.6%) precancerous lesions. Cervical colposcopy, endocervical curettage, and endometrial biopsy are recommended for the complete evaluation of AGCUS. q 1996 Academic Press, Inc.
INTRODUCTION
The Bethesda System for the reporting of cervical/vaginal cytologic diagnoses was developed in 1988 in an attempt to Presented at the 27th Annual Meeting of the Society of Gynecologic Oncologists, New Orleans, LA, February 10–14, 1996. 14
0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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that AGCUS might be associated with significant underlying uterine pathology and that an aggressive diagnostic approach would be warranted. MATERIALS AND METHODS
The computerized records of the Cleveland Clinic Foundation’s Cytology Laboratory were reviewed from January 1, 1990 through December 31, 1994. All patients with a cytologic diagnosis from a cervical/vaginal Papanicolaou smear indicating AGCUS were identified. Consultation cases from outside institutions were not included. The clinical charts from all identified patients were retrieved and abstracted. Standard demographic variables were entered into the computerized database as well as information regarding the following: contraceptive use, sexually transmitted disease history, smoking history, prenatal exposure to diethylstilbestrol (DES), associated medical illnesses, prior cancers, menopausal status, history of hormonal replacement therapy, and history of a prior abnormal Pap smear or therapy to the cervix. The methods of patient evaluation, including colposcopic findings, were reviewed and recorded. Biopsy results were obtained from the patient record as well as from the computerized records of the pathology department. Gynecologic follow-up information was recorded as available from all patient charts. The cytologic preparations were not retrospectively reviewed for this study. The initial diagnosis was made by the staff physicians within the Cleveland Clinic Cytology Laboratory, after routine preparation, using standardized criteria [7]. During this study period, endocervical specimens for Pap smears were obtained with a Cytobrush (Medscand) or Cervex-Brush (Unimar). Exact binomial confidence intervals were determined. RESULTS
During the 5-year time interval of this study, 68,368 cervical/vaginal Papanicolaou smears were analyzed in the Cleveland Clinic Cytology Laboratory. One hundred thirty-six patients (0.2%) were identified as having AGCUS. This is in contrast to 3078 (4.5%) patients found to have atypical squamous cells during this same time interval. The mean patient age was 43.7 years (range 20–78 years). One hundred five patients were Caucasian, 24 were Afro-American, 2 were Hispanic, and 5 were of other racial origin. Thirtythree of the patients (24.3%) were postmenopausal and 15 of these were on hormonal replacement therapy. Among the 136 patients initially identified with AGCUS, 21 had concurrent associated cytologic abnormalities including CIN, adenocarcinoma in situ, and adenocarcinoma. These patients were excluded from further analysis because their associated cytologic findings made them unrepresentative of the finding of AGCUS alone. An additional 4 patients had a prior history of uterine or vaginal carcinomas and
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were excluded because they represented cancer follow-up surveillance rather than a routine gynecologic examination. Three of these patients had recurrent cancer diagnosed simultaneously with or shortly after the finding of AGCUS. Finally, 34 patients were excluded due to chart review not indicating any gynecologic evaluation (colposcopy or uterine biopsy) as well as not indicating any subsequent follow-up exams. The remaining 77 patients had AGCUS reported on routine examination without significant other associated cytologic findings and had further gynecologic evaluation. The mean age of the 77 study patients was 42.4 years (range 23–78 years) with a mean gravidity of 1.8 pregnancies (range 0–6 pregnancies) and a mean parity of 1.5 children (range 0–5 children). Sixty-two (81%) were Caucasian, 11 were Afro-American, and 4 were of other racial origins. Seventeen (22%) were postmenopausal and 11 were receiving hormonal replacement therapy. Among the 60 premenopausal patients, 41 (68%) were employing contraception including 13 using oral contraceptives, 11 using barrier methods, and 15 having had a prior tubal ligation. Thirteen (17%) had a prior history of sexually transmitted disease, most commonly human papilloma virus infection, 20 (26%) were smokers, and 2 (3%) had a history of prenatal DES exposure. Twenty-two (29%) had significant associated medical illnesses, most commonly hypertension or adult onset diabetes mellitus. Four patients had a prior nongynecologic cancer including 2 with colon cancers, 1 with bladder cancer, and 1 with skin cancer. Thirty-six of the 77 study patients (47%) had a history of a previously ‘‘abnormal’’ Pap smear. The following prior abnormal results were able to be documented with chart review: 7 ASCUS, 4 AGCUS, 4 CIN1, 13 CIN2–3, and 1 CIN 2–3 with AGCUS. In 8 cases the specific prior cytologic abnormality could not be documented. Among these 36 study patients with a previously abnormal Pap, 23 had prior treatment of the cervix including the following: 12 cold knife conization, 8 cryotherapy, 2 loop electrical excision procedure (LEEP) conization, and 1 laser ablation. None had a prior hysterectomy. Associated atypical squamous cells were noted in 10 (13%) of the study patients. Colposcopy was performed in 63 (82%) of the 77 patients of which 40 were assessed as satisfactory and 23 were assessed as unsatisfactory. Colposcopic diagnosis of atypia was made in 9 patients and varying degrees of CIN in 8 patients. Endocervical curettage was performed in 35 (45%) patients, directed cervical biopsies in 9 patients, endometrial biopsy in 7 patients, and LEEP conization in 2 patients. The results of these biopsies are presented in Table 1. A summary of the established pathologic diagnosis in the 77 study patients is presented in Table 2. Clinically significant diagnoses were established in 13 (17%) of patients (95% Cl, 9.3%, 27.1%) including precancerous conditions in 10 patients (13%) (95% Cl, 6.4%, 22.6%) and cancer in 3 (4%) patients (95% Cl, 0.8%, 11.0%). Among the 36 patients with a history
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TABLE 1 Pathologic Results by Method of Evaluation in 77 Patients with AGCUS on Routine Pap Smear
Endocervical curettage CINa grade 2–3 Adenocarcinoma in situ, cervix Adenocarcinoma, cervix Atypical squamous epithelium Atypical glandular epithelium Negative Directed biopsy of cervix CIN grade 1 CIN grade 2–3 Atypical glandular epithelium Negative Cervical conization CIN grade 2–3 Negative Endometrial biopsy Adenocarcinoma, endometrium Adenocarcinoma, cervix Negative a
35 2 3 1 1 1 27 9 3 1 1 4 2 1 1 7 1 1 5
CIN, cervical intraepithelial neoplasia.
of a previously abnormal Pap smear, 4 (11%) were diagnosed with significant pathology including 3 with CIN2–3 and 1 with cervical adenocarcinoma in situ. The remaining 9 pathologic diagnoses (Table 2) were established in the 41 patients without a history of a prior abnormal Pap smear for a 22% rate of underlying pathology. Among the 10 patients with concomitant ASCUS, one patient was discovered to have CIN 1 and another patient was diagnosed with cervical adenocarcinoma in situ. Forty-one patients had follow-up information recorded in their medical record with a mean follow-up of 8.5 months (range 1–22 months). During subsequent follow-up exams, two patients were diagnosed with cervical adenocarcinoma in situ, cervical adenocarcinoma was diagnosed in one patient, and diffusely metastatic pancreatic cancer was discovered in one patient. All four of these subsequent lesions were diagnosed within 4 months of the index Pap smear indicating AGCUS. All four had been reevaluated as a result of a persistently abnormal Pap smear. Their initial evaluation consisted of a negative colposcopic evaluation in two patients, negative colposcopy with directed cervical biopsy in one patient, and no further evaluation in the remaining patient.
logic finding of AGCUS have not been well established. The present study reviewed a series of 77 patients with AGCUS on cytologic screening exam and determined that there was underlying cancer and/or precancerous lesions in over 15% of evaluated patients. An aggressive diagnostic approach to the report of AGCUS is therefore recommended. Glandular lesions of the cervix occur with substantially less frequency than their squamous counterparts. Likewise, atypical glandular cells are encountered much less frequently than atypical squamous cells, 0.2% vs 4.5% in our experience. Furthermore, the histologic criteria for precursor lesions of cervical adenocarcinoma have only recently been defined [4, 8]. There is also concern regarding the adequacy of sampling of abnormal endocervical cells that may be located within crypts which may be occluded by squamous metaplasia [5]. As a result of these various factors, the experience of individual cytology laboratories with glandular abnormalities of the cervix has been limited. There appears to be an increasing incidence of adenocarcinoma, adenocarcinoma in situ, and other glandular lesions of the cervix [8, 9]. Laboratories may therefore expect to be encountering these abnormalities with increasing frequency. Recent criteria by van Aspert-van Erp et al. will prove helpful in better describing and diagnosing these abnormalities [10, 11]. The natural history of endocervical glandular atypia is uncertain [12]. Prior reports from the Bellevue Hospital– New York Medical Center Dysplasia Clinic indicated an approximately 50% rate of associated squamous CIN in patients evaluated for endocervical atypia [13, 14]. No glandular abnormalities, however, were reported in this series. A more recent report from the Massachusetts General Hospital reviewed their experience in evaluating women with endocervical glandular atypia on Pap smears [6]. Significant underlying pathology was determined in approximately onehalf of the reported patients. This included squamous lesions in 40% of patients ranging from mild dysplasia to squamous carcinoma in situ. An additional 8% of patients were found to have adenocarcinoma in situ of the cervix and 3% were reported to have invasive adenocarcinoma of the cervix. Based on these findings, an aggressive diagnostic approach TABLE 2 Summary of Pathologic Diagnoses Established in 77 Patients with AGCUS on Routine Pap Smear n (%) Grade 1 CINa Grade 2–3 CIN Adenocarcinoma in situ, cervix Adenocarcinoma, cervix Adenocarcinoma, endometrium
DISCUSSION
Since the introduction in 1988 of the Bethesda System for reporting cervical/vaginal cytologic results, the category AGCUS has been established and defined [1, 7]. The clinical significance and underlying conditions related to the cyto-
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3 4 3 2 1
(4) (5) (4) (3) (1)
13 (17) a
CIN, cervical intraepithelial neoplasia.
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CLINICAL EVALUATION OF AGCUS
was advised and future prospective studies called for [6]. A report from the Bethesda Naval Hospital noted that 20% of patients with AGCUS were found to have grade 2–3 CIN when evaluated colposcopically [15]. The current criteria of AGCUS differ somewhat from the previous diagnosis of endocervical glandular atypia. While the latter is certainly included within AGCUS, this newer term is somewhat broader and also incorporates atypical endometrial cells as well as abnormal glandular cells of undetermined origin. Therefore, with the advent of the Bethesda terminology, the current study was undertaken. We have determined in our overall population of patients that AGCUS represented 0.2% of Pap smear results. This is an identical prevalence as found in the Bethesda Naval Hospital experience [15] but somewhat lower than the 0.46% rate reported from the Massachusetts General Hospital [6]. This rate will vary somewhat depending upon cytologic criteria as well as the population screened but should apparently be less than 0.5%. Although the Cleveland Clinic is a tertiary level institution, the general population served does not have a high rate of cervical lesions as evidenced by our ASCUS rate of 4.5% and CIN rate of 1.8%. The current patients were not evaluated in any systematic fashion because no recommendations for the evaluation of AGCUS had been previously made within our institution. Furthermore, patients were seen within the gynecology department as well as within other departments in the institution. The study is also limited by the available follow-up information recorded within medical records and by the relatively short followup interval. The study population is somewhat selected due to the number of patients receiving treatment of the cervix for prior abnormalities and this may limit the generalization of our findings. However, despite these constraints, a significant rate of underlying uterine pathology was determined, a rate much higher and with more severe lesions than that associated with ASCUS in our experience including two invasive cervix cancers, three adenocarcinomas in situ, four grade 2–3 CINs, and one endometrial adenocarcinoma. Because of the multifocal nature of these neoplastic conditions, thorough uterine evaluation is indicated. In our experience, the patients were diagnosed as a result of a variety of procedures including colposcopy, endocervical curettage, and endometrial biopsy. Therefore, all of these diagnostic studies would seem to be advisable when encountering a patient with AGCUS. It should be noted that the 17% rate of major underlying uterine pathology should be viewed as a minimal figure and would increase to 22% if the 4 patients with subsequent lesions were included. Among 25 patients with endocervical glandular atypia alone in the Massachusetts General Hospital report [6], underlying significant uterine lesions were noted in 15 patients (60%). The discrepancy in these rates is not well understood but may relate to varying cytologic criteria for endocervical glandular atypia versus AGCUS, small patient numbers, and different screening pop-
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ulations as well as the more consistent diagnostic evaluation and more complete follow-up in the Goff et al. report. It also may relate to the number of patients included with prior abnormal Pap smears and associated HPV lesions even if previously treated. Interestingly, the rate of underlying pathology in the patients with a previously abnormal Pap smear was less than in the remaining patients. Nonetheless, substantial underlying uterine pathology was found in our report as well as those from other institutions. Because of the limited follow-up information (time) and the fact that patients may have been diagnosed subsequently at other institutions, additional pathology may have been present within the study group but not found on our chart review. Furthermore, patients with atypical glandular cells are often high-risk patients and, even if initial diagnostic studies are negative, require close follow-up examination. As noted within the study group, four patients after limited initial evaluations were subsequently noted within 4 months to have major lesions including two with adenocarcinoma in situ of the cervix, one with adenocarcinoma of the cervix, and one with diffusely metastatic pancreatic cancer. After becoming aware of our preliminary results we attempted to contact the 34 patients who were not previously evaluated and who did not have any gynecologic follow-up recorded. Among 21 patients who returned for evaluation, two were diagnosed with adenocarcinoma in situ of the cervix 7 and 46 months after the index abnormal Pap smear. Based on this experience, we have established institutional guidelines that patients with AGCUS on cytologic screening undergo immediate intensive diagnostic studies including colposcopy, endocervical curettage, and endometrial biopsy. Additionally, it is recommended that these patients have intensive follow-up examinations to detect incipient lesions including increased cytologic surveillance for 2 years following the report of AGCUS. Potential pitfalls in the diagnosis of AGCUS have been identified and should be borne in mind both by the gynecologist as well as the cytologist [16]. Prior cervical conization has been reported to be associated with the subsequent reporting of atypical glandular cells [17]. It has been hypothesized that the altered microscopic anatomy of the cervix may lead to an altered cytologic appearance of endocervical cells. Inasmuch as 30% of our study patients had prior treatment of the cervix including conization and cryotherapy, this may have affected our results due to repair and regeneration, making their Pap smears difficult to interpret. Additionally, the presence of tubal metaplasia may be misleading [18– 20]. Criteria have been reported which should allow these conditions to be distinguished from true atypical glandular cells. REFERENCES 1. Koss, L. G. The new Bethesda System for reporting cervical/vaginal cytologic diagnoses, J. Am. Med. Assoc. 262, 931–934 (1989).
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2. Kurman, R. J., Malkasian, G. D., Jr., Sedlis, A., and Solomon, D. From Papanicolaou to Bethesda: The rationale for a new cervical cytological classification, Obstet. Gynecol. 77, 779–782 (1991). 3. Jones, D. E., Creasman, W. T., Dombroski, R. A., Lentz, S. S., and Waeltz, J. L. Evaluation of the atypical Pap smear, Am. J. Obstet. Gynecol. 157, 544–549 (1987). 4. Jaworski, R. C., Pacey, N. F., Greenberg, M. L., and Osborn, R. A. The histologic diagnosis of adenocarcinoma in situ and related lesions of the cervix: Adenocarcinoma in situ, Cancer 61, 1171–1181 (1988). 5. Lee, K. R., Manna, E. A., and Jones, M. A. Comparative cytologic features of adenocarcinoma in situ of the uterine cervix, Acta Cytol. 35, 117–126 (1991). 6. Goff, B. A., Atanasoff, P., Brown, E., Muntz, H. G., Bell, D. A., and Rice, L. W. Endocervical glandular atypia in Papanicolaou smears, Obstet. Gynecol. 79, 101–104 (1992). 7. Kurman, R. J., and Solomon, D. The Bethesda System for reporting cervical/vaginal cytologic diagnoses: Definitions, criteria, and explanatory notes for terminology and specimen adequacy. Springer-Verlag, New York (1994). 8. Nicklin, J. L., Wright, R. G., Bell, J. R., Samaratunga, H., Cox, N. C., and Ward, B. G. A clinical pathological study of adenocarcinoma in situ of the cervix. The influence of cervical HPV infection and other factors, and the role of conservative surgery, Aust. NZ J. Obstet. Gynecol. 2, 179–183 (1991). 9. Ursin, G., Peters, R. K., Henderson, B. E., d’Ablaing, G., Monroe, R. K., and Pike, M. C. Oral contraceptive use and adenocarcinoma of the cervix, Lancet 344, 1390–1393 (1994). 10. van Aspert-van Erp, A. J. M., van’t Hof-Grootenboer, A. B., Brugal, G., and Vooijs, G. P. Endocervical columnar cell intraepithelial neoplasia. I. Discriminating cytomorphologic criteria, Acta Cytol. 39, 1199– 1215 (1995).
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11. van Aspert-van Erp, A. J. M., van’t Hof-Grootenboer, A. B., Brugal, G., and Vooijs, G. P. Endocervical columnar intraepithelial neoplasia. II. Grades of expression of cytomorphologic criteria, Acta Cytol. 39, 1216–1232 (1995). 12. Brown, L. J. R., and Wells, M. Cervical glandular atypia associated with squamous intra-epithelial neoplasia: A premalignant lesion? J. Clin. Pathol. 39, 22–28 (1986). 13. Kohan, S., Noumoff, J., Beckman, E. M., Morris, M., Weiner, E., and Douglas, G. W. Colposcopic screening of women with atypical Papanicolaou smears, J. Reprod. Med. 30, 383–387, (1985). 14. Noumoff, J. S. Atypia in cervical cytology as a risk factor for intraepithelial neoplasia, Am. J. Obstet. Gynecol. 156, 628–631 (1987). 15. Taylor, R. R., Guerrieri, J. P., Nash, J. D., Henry, M. R., and O’Connor, D. M. Atypical cervical cytology: Colposcopic follow-up using The Bethesda System, J. Reprod. Med. 38, 443–447 (1993). 16. Pacey, F., Ayer, B., and Greenberg, M. The cytologic diagnosis of adenocarcinoma in situ of the cervix uteri and related lesions. III. Pitfalls in diagnosis, Acta Cytol. 32, 325–330 (1988). 17. Lee, KR. Atypical glandular cells in cervical smears from women who have undergone cone biopsy: A potential diagnostic pitfall, Acta Cytol. 37, 705–709 (1993). 18. Novotny, D. B., Maygarden, S. J., Johnson, P. E., and Frable, W. J. Tubal metaplasia: A frequent potential pitfall in the cytologic diagnosis of endocervical glandular dysplasia on cervical smears, Acta Cytol. 36, 1–10 (1992). 19. Ducatman, B. S., Wang, H. H., Jonasson, J. G., Hogan, C. L., and Antonioli, D. A. Tubal metaplasia: A cytologic study with comparison to other neoplastic and non-neoplastic conditions of the endocervix, Diag. Cytopathol. 9, 98–105 (1993). 20. Hirschowitz, L., Eckford, S. D., Phillpotts, B., and Midwinter, A. Cytologic changes associated with tubo-endometrioid metaplasia of the uterine cervix, Cytopathology 5, 1–8 (1994).
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Results of the Clinical Evaluation of Atypical Glandular Cells of Undetermined Significance (AGCUS) Detected on Cervical Cytology Screening ALEXANDER W. KENNEDY, M.D., STEPHEN S. SALMIERI, D.O., SUSAN L. WIRTH, B.S.N., CHARLES V. BISCOTTI, M.D., LAURIE J. TUASON, M.S., AND MARY JANE TRAVARCA Departments of Gynecology and Obstetrics, Anatomic Pathology, and Biostatistics, Cleveland Clinic Foundation, Cleveland, Ohio 44195 Received December 29, 1995
bring uniformity to the reporting of cytologic diagnoses [1]. An additional goal of this system was to more stringently define ‘‘atypia’’ so that this term is not overused resulting in overdiagnosis and the unnecessary treatment of patients [2]. The diagnosis of atypical squamous cell of undetermined significance (ASCUS) occurs in up to 5% of routine cervical cytologic smears within the general population. Therefore, by this time, institutions and laboratories have had sufficient experience to determine the underlying clinical conditions and problems related to the diagnosis of ASCUS [3]. A prior unpublished review of the experience at the Cleveland Clinic Foundation with ASCUS revealed that, among premenopausal women, 2% had underlying grade 2–3 cervical intraepithelial neoplasms (CIN) and 9% had grade 1 CIN. No invasive cancers were discovered and no pathologic conditions were noted in postmenopausal women with ASCUS. The clinical significance, however, of a report of atypical glandular cells of undetermined significance (AGCUS) is much less well understood. In large measure this relates to the much lower frequency of glandular abnormalities of the cervix. Additionally, the criteria for the cytologic diagnosis of glandular abnormalities have tended until recently to be more vague and subjective [4, 5]. A previous report by Goff et al. regarding the evaluation of patients with endocervical glandular atypia on Pap smears from the Massachusetts General Hospital Cytopathology Laboratory indicated a substantial rate of underlying cervical and endometrial lesions [6]. Varying degrees of cervical dysplasia were found in 30% of patients and squamous carcinoma in situ in 10% of patients. Additionally, 8% of patients were found to have adenocarcinoma in situ and 3% had invasive adenocarcinoma. The current study was undertaken to improve the understanding of the significance of AGCUS under the current Bethesda System for reporting cytologic results, and to determine the most appropriate management of patients with this finding on routine Pap smears. It was hypothesized based upon prior reports including the study by Goff et al. [6]
Objective: To determine the clinical significance of and underlying pathology among patients with atypical glandular cells of undetermined significance (AGCUS) identified on cervical Pap smear screening. Methods: The computerized files of the Cleveland Clinic Foundation cytology laboratory were searched from 1990 to 1994 to identify all patients with AGCUS. Patients with other significant cytologic diagnoses were considered separately from patients whose only significant finding was reported to be AGCUS. Retrospective chart review was completed to identify associated conditions and to record the results of the clinical evaluations of these patients. Results: One hundred thirty-six patients were identified among the 68,368 (0.2%) specimens from this 5-year period in contrast to 3078 (4.5%) patients with atypical squamous cells (ASCUS). Mean patient age was 43.7 years (range 20–78). Among 77 patients without other significant cytologic findings in addition to AGCUS, without prior gynecologic cancer and who had a recorded gynecologic evaluation, 13 patients (17%) were diagnosed with the following lesions: two (3%) invasive cervical adenocarcinomas, three cervical adenocarcinomas in situ (4%), three grade 1 cervical intraepithelial neoplasms (CIN) (4%), four grade 2–3 CIN (5%), and one (1%) endometrial adenocarcinoma. Additionally, in subsequent follow-up examinations two patients were diagnosed with cervical adenocarcinoma in situ, one with invasive adenocarcinoma of the cervix and one with diffusely metastatic pancreatic cancer. Conclusions: AGCUS on cervical cytologic screening, even in the absence of other associated cytologic findings, is associated with substantial underlying uterine pathology including at least 4% (95% confidence interval (CI) 0.8%, 11.0%) invasive cancers and 13% (95% CI 6.4%, 22.6%) precancerous lesions. Cervical colposcopy, endocervical curettage, and endometrial biopsy are recommended for the complete evaluation of AGCUS. q 1996 Academic Press, Inc.
INTRODUCTION
The Bethesda System for the reporting of cervical/vaginal cytologic diagnoses was developed in 1988 in an attempt to Presented at the 27th Annual Meeting of the Society of Gynecologic Oncologists, New Orleans, LA, February 10–14, 1996. 14
0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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that AGCUS might be associated with significant underlying uterine pathology and that an aggressive diagnostic approach would be warranted. MATERIALS AND METHODS
The computerized records of the Cleveland Clinic Foundation’s Cytology Laboratory were reviewed from January 1, 1990 through December 31, 1994. All patients with a cytologic diagnosis from a cervical/vaginal Papanicolaou smear indicating AGCUS were identified. Consultation cases from outside institutions were not included. The clinical charts from all identified patients were retrieved and abstracted. Standard demographic variables were entered into the computerized database as well as information regarding the following: contraceptive use, sexually transmitted disease history, smoking history, prenatal exposure to diethylstilbestrol (DES), associated medical illnesses, prior cancers, menopausal status, history of hormonal replacement therapy, and history of a prior abnormal Pap smear or therapy to the cervix. The methods of patient evaluation, including colposcopic findings, were reviewed and recorded. Biopsy results were obtained from the patient record as well as from the computerized records of the pathology department. Gynecologic follow-up information was recorded as available from all patient charts. The cytologic preparations were not retrospectively reviewed for this study. The initial diagnosis was made by the staff physicians within the Cleveland Clinic Cytology Laboratory, after routine preparation, using standardized criteria [7]. During this study period, endocervical specimens for Pap smears were obtained with a Cytobrush (Medscand) or Cervex-Brush (Unimar). Exact binomial confidence intervals were determined. RESULTS
During the 5-year time interval of this study, 68,368 cervical/vaginal Papanicolaou smears were analyzed in the Cleveland Clinic Cytology Laboratory. One hundred thirty-six patients (0.2%) were identified as having AGCUS. This is in contrast to 3078 (4.5%) patients found to have atypical squamous cells during this same time interval. The mean patient age was 43.7 years (range 20–78 years). One hundred five patients were Caucasian, 24 were Afro-American, 2 were Hispanic, and 5 were of other racial origin. Thirtythree of the patients (24.3%) were postmenopausal and 15 of these were on hormonal replacement therapy. Among the 136 patients initially identified with AGCUS, 21 had concurrent associated cytologic abnormalities including CIN, adenocarcinoma in situ, and adenocarcinoma. These patients were excluded from further analysis because their associated cytologic findings made them unrepresentative of the finding of AGCUS alone. An additional 4 patients had a prior history of uterine or vaginal carcinomas and
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were excluded because they represented cancer follow-up surveillance rather than a routine gynecologic examination. Three of these patients had recurrent cancer diagnosed simultaneously with or shortly after the finding of AGCUS. Finally, 34 patients were excluded due to chart review not indicating any gynecologic evaluation (colposcopy or uterine biopsy) as well as not indicating any subsequent follow-up exams. The remaining 77 patients had AGCUS reported on routine examination without significant other associated cytologic findings and had further gynecologic evaluation. The mean age of the 77 study patients was 42.4 years (range 23–78 years) with a mean gravidity of 1.8 pregnancies (range 0–6 pregnancies) and a mean parity of 1.5 children (range 0–5 children). Sixty-two (81%) were Caucasian, 11 were Afro-American, and 4 were of other racial origins. Seventeen (22%) were postmenopausal and 11 were receiving hormonal replacement therapy. Among the 60 premenopausal patients, 41 (68%) were employing contraception including 13 using oral contraceptives, 11 using barrier methods, and 15 having had a prior tubal ligation. Thirteen (17%) had a prior history of sexually transmitted disease, most commonly human papilloma virus infection, 20 (26%) were smokers, and 2 (3%) had a history of prenatal DES exposure. Twenty-two (29%) had significant associated medical illnesses, most commonly hypertension or adult onset diabetes mellitus. Four patients had a prior nongynecologic cancer including 2 with colon cancers, 1 with bladder cancer, and 1 with skin cancer. Thirty-six of the 77 study patients (47%) had a history of a previously ‘‘abnormal’’ Pap smear. The following prior abnormal results were able to be documented with chart review: 7 ASCUS, 4 AGCUS, 4 CIN1, 13 CIN2–3, and 1 CIN 2–3 with AGCUS. In 8 cases the specific prior cytologic abnormality could not be documented. Among these 36 study patients with a previously abnormal Pap, 23 had prior treatment of the cervix including the following: 12 cold knife conization, 8 cryotherapy, 2 loop electrical excision procedure (LEEP) conization, and 1 laser ablation. None had a prior hysterectomy. Associated atypical squamous cells were noted in 10 (13%) of the study patients. Colposcopy was performed in 63 (82%) of the 77 patients of which 40 were assessed as satisfactory and 23 were assessed as unsatisfactory. Colposcopic diagnosis of atypia was made in 9 patients and varying degrees of CIN in 8 patients. Endocervical curettage was performed in 35 (45%) patients, directed cervical biopsies in 9 patients, endometrial biopsy in 7 patients, and LEEP conization in 2 patients. The results of these biopsies are presented in Table 1. A summary of the established pathologic diagnosis in the 77 study patients is presented in Table 2. Clinically significant diagnoses were established in 13 (17%) of patients (95% Cl, 9.3%, 27.1%) including precancerous conditions in 10 patients (13%) (95% Cl, 6.4%, 22.6%) and cancer in 3 (4%) patients (95% Cl, 0.8%, 11.0%). Among the 36 patients with a history
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TABLE 1 Pathologic Results by Method of Evaluation in 77 Patients with AGCUS on Routine Pap Smear
Endocervical curettage CINa grade 2–3 Adenocarcinoma in situ, cervix Adenocarcinoma, cervix Atypical squamous epithelium Atypical glandular epithelium Negative Directed biopsy of cervix CIN grade 1 CIN grade 2–3 Atypical glandular epithelium Negative Cervical conization CIN grade 2–3 Negative Endometrial biopsy Adenocarcinoma, endometrium Adenocarcinoma, cervix Negative a
35 2 3 1 1 1 27 9 3 1 1 4 2 1 1 7 1 1 5
CIN, cervical intraepithelial neoplasia.
of a previously abnormal Pap smear, 4 (11%) were diagnosed with significant pathology including 3 with CIN2–3 and 1 with cervical adenocarcinoma in situ. The remaining 9 pathologic diagnoses (Table 2) were established in the 41 patients without a history of a prior abnormal Pap smear for a 22% rate of underlying pathology. Among the 10 patients with concomitant ASCUS, one patient was discovered to have CIN 1 and another patient was diagnosed with cervical adenocarcinoma in situ. Forty-one patients had follow-up information recorded in their medical record with a mean follow-up of 8.5 months (range 1–22 months). During subsequent follow-up exams, two patients were diagnosed with cervical adenocarcinoma in situ, cervical adenocarcinoma was diagnosed in one patient, and diffusely metastatic pancreatic cancer was discovered in one patient. All four of these subsequent lesions were diagnosed within 4 months of the index Pap smear indicating AGCUS. All four had been reevaluated as a result of a persistently abnormal Pap smear. Their initial evaluation consisted of a negative colposcopic evaluation in two patients, negative colposcopy with directed cervical biopsy in one patient, and no further evaluation in the remaining patient.
logic finding of AGCUS have not been well established. The present study reviewed a series of 77 patients with AGCUS on cytologic screening exam and determined that there was underlying cancer and/or precancerous lesions in over 15% of evaluated patients. An aggressive diagnostic approach to the report of AGCUS is therefore recommended. Glandular lesions of the cervix occur with substantially less frequency than their squamous counterparts. Likewise, atypical glandular cells are encountered much less frequently than atypical squamous cells, 0.2% vs 4.5% in our experience. Furthermore, the histologic criteria for precursor lesions of cervical adenocarcinoma have only recently been defined [4, 8]. There is also concern regarding the adequacy of sampling of abnormal endocervical cells that may be located within crypts which may be occluded by squamous metaplasia [5]. As a result of these various factors, the experience of individual cytology laboratories with glandular abnormalities of the cervix has been limited. There appears to be an increasing incidence of adenocarcinoma, adenocarcinoma in situ, and other glandular lesions of the cervix [8, 9]. Laboratories may therefore expect to be encountering these abnormalities with increasing frequency. Recent criteria by van Aspert-van Erp et al. will prove helpful in better describing and diagnosing these abnormalities [10, 11]. The natural history of endocervical glandular atypia is uncertain [12]. Prior reports from the Bellevue Hospital– New York Medical Center Dysplasia Clinic indicated an approximately 50% rate of associated squamous CIN in patients evaluated for endocervical atypia [13, 14]. No glandular abnormalities, however, were reported in this series. A more recent report from the Massachusetts General Hospital reviewed their experience in evaluating women with endocervical glandular atypia on Pap smears [6]. Significant underlying pathology was determined in approximately onehalf of the reported patients. This included squamous lesions in 40% of patients ranging from mild dysplasia to squamous carcinoma in situ. An additional 8% of patients were found to have adenocarcinoma in situ of the cervix and 3% were reported to have invasive adenocarcinoma of the cervix. Based on these findings, an aggressive diagnostic approach TABLE 2 Summary of Pathologic Diagnoses Established in 77 Patients with AGCUS on Routine Pap Smear n (%) Grade 1 CINa Grade 2–3 CIN Adenocarcinoma in situ, cervix Adenocarcinoma, cervix Adenocarcinoma, endometrium
DISCUSSION
Since the introduction in 1988 of the Bethesda System for reporting cervical/vaginal cytologic results, the category AGCUS has been established and defined [1, 7]. The clinical significance and underlying conditions related to the cyto-
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3 4 3 2 1
(4) (5) (4) (3) (1)
13 (17) a
CIN, cervical intraepithelial neoplasia.
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CLINICAL EVALUATION OF AGCUS
was advised and future prospective studies called for [6]. A report from the Bethesda Naval Hospital noted that 20% of patients with AGCUS were found to have grade 2–3 CIN when evaluated colposcopically [15]. The current criteria of AGCUS differ somewhat from the previous diagnosis of endocervical glandular atypia. While the latter is certainly included within AGCUS, this newer term is somewhat broader and also incorporates atypical endometrial cells as well as abnormal glandular cells of undetermined origin. Therefore, with the advent of the Bethesda terminology, the current study was undertaken. We have determined in our overall population of patients that AGCUS represented 0.2% of Pap smear results. This is an identical prevalence as found in the Bethesda Naval Hospital experience [15] but somewhat lower than the 0.46% rate reported from the Massachusetts General Hospital [6]. This rate will vary somewhat depending upon cytologic criteria as well as the population screened but should apparently be less than 0.5%. Although the Cleveland Clinic is a tertiary level institution, the general population served does not have a high rate of cervical lesions as evidenced by our ASCUS rate of 4.5% and CIN rate of 1.8%. The current patients were not evaluated in any systematic fashion because no recommendations for the evaluation of AGCUS had been previously made within our institution. Furthermore, patients were seen within the gynecology department as well as within other departments in the institution. The study is also limited by the available follow-up information recorded within medical records and by the relatively short followup interval. The study population is somewhat selected due to the number of patients receiving treatment of the cervix for prior abnormalities and this may limit the generalization of our findings. However, despite these constraints, a significant rate of underlying uterine pathology was determined, a rate much higher and with more severe lesions than that associated with ASCUS in our experience including two invasive cervix cancers, three adenocarcinomas in situ, four grade 2–3 CINs, and one endometrial adenocarcinoma. Because of the multifocal nature of these neoplastic conditions, thorough uterine evaluation is indicated. In our experience, the patients were diagnosed as a result of a variety of procedures including colposcopy, endocervical curettage, and endometrial biopsy. Therefore, all of these diagnostic studies would seem to be advisable when encountering a patient with AGCUS. It should be noted that the 17% rate of major underlying uterine pathology should be viewed as a minimal figure and would increase to 22% if the 4 patients with subsequent lesions were included. Among 25 patients with endocervical glandular atypia alone in the Massachusetts General Hospital report [6], underlying significant uterine lesions were noted in 15 patients (60%). The discrepancy in these rates is not well understood but may relate to varying cytologic criteria for endocervical glandular atypia versus AGCUS, small patient numbers, and different screening pop-
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ulations as well as the more consistent diagnostic evaluation and more complete follow-up in the Goff et al. report. It also may relate to the number of patients included with prior abnormal Pap smears and associated HPV lesions even if previously treated. Interestingly, the rate of underlying pathology in the patients with a previously abnormal Pap smear was less than in the remaining patients. Nonetheless, substantial underlying uterine pathology was found in our report as well as those from other institutions. Because of the limited follow-up information (time) and the fact that patients may have been diagnosed subsequently at other institutions, additional pathology may have been present within the study group but not found on our chart review. Furthermore, patients with atypical glandular cells are often high-risk patients and, even if initial diagnostic studies are negative, require close follow-up examination. As noted within the study group, four patients after limited initial evaluations were subsequently noted within 4 months to have major lesions including two with adenocarcinoma in situ of the cervix, one with adenocarcinoma of the cervix, and one with diffusely metastatic pancreatic cancer. After becoming aware of our preliminary results we attempted to contact the 34 patients who were not previously evaluated and who did not have any gynecologic follow-up recorded. Among 21 patients who returned for evaluation, two were diagnosed with adenocarcinoma in situ of the cervix 7 and 46 months after the index abnormal Pap smear. Based on this experience, we have established institutional guidelines that patients with AGCUS on cytologic screening undergo immediate intensive diagnostic studies including colposcopy, endocervical curettage, and endometrial biopsy. Additionally, it is recommended that these patients have intensive follow-up examinations to detect incipient lesions including increased cytologic surveillance for 2 years following the report of AGCUS. Potential pitfalls in the diagnosis of AGCUS have been identified and should be borne in mind both by the gynecologist as well as the cytologist [16]. Prior cervical conization has been reported to be associated with the subsequent reporting of atypical glandular cells [17]. It has been hypothesized that the altered microscopic anatomy of the cervix may lead to an altered cytologic appearance of endocervical cells. Inasmuch as 30% of our study patients had prior treatment of the cervix including conization and cryotherapy, this may have affected our results due to repair and regeneration, making their Pap smears difficult to interpret. Additionally, the presence of tubal metaplasia may be misleading [18– 20]. Criteria have been reported which should allow these conditions to be distinguished from true atypical glandular cells. REFERENCES 1. Koss, L. G. The new Bethesda System for reporting cervical/vaginal cytologic diagnoses, J. Am. Med. Assoc. 262, 931–934 (1989).
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2. Kurman, R. J., Malkasian, G. D., Jr., Sedlis, A., and Solomon, D. From Papanicolaou to Bethesda: The rationale for a new cervical cytological classification, Obstet. Gynecol. 77, 779–782 (1991). 3. Jones, D. E., Creasman, W. T., Dombroski, R. A., Lentz, S. S., and Waeltz, J. L. Evaluation of the atypical Pap smear, Am. J. Obstet. Gynecol. 157, 544–549 (1987). 4. Jaworski, R. C., Pacey, N. F., Greenberg, M. L., and Osborn, R. A. The histologic diagnosis of adenocarcinoma in situ and related lesions of the cervix: Adenocarcinoma in situ, Cancer 61, 1171–1181 (1988). 5. Lee, K. R., Manna, E. A., and Jones, M. A. Comparative cytologic features of adenocarcinoma in situ of the uterine cervix, Acta Cytol. 35, 117–126 (1991). 6. Goff, B. A., Atanasoff, P., Brown, E., Muntz, H. G., Bell, D. A., and Rice, L. W. Endocervical glandular atypia in Papanicolaou smears, Obstet. Gynecol. 79, 101–104 (1992). 7. Kurman, R. J., and Solomon, D. The Bethesda System for reporting cervical/vaginal cytologic diagnoses: Definitions, criteria, and explanatory notes for terminology and specimen adequacy. Springer-Verlag, New York (1994). 8. Nicklin, J. L., Wright, R. G., Bell, J. R., Samaratunga, H., Cox, N. C., and Ward, B. G. A clinical pathological study of adenocarcinoma in situ of the cervix. The influence of cervical HPV infection and other factors, and the role of conservative surgery, Aust. NZ J. Obstet. Gynecol. 2, 179–183 (1991). 9. Ursin, G., Peters, R. K., Henderson, B. E., d’Ablaing, G., Monroe, R. K., and Pike, M. C. Oral contraceptive use and adenocarcinoma of the cervix, Lancet 344, 1390–1393 (1994). 10. van Aspert-van Erp, A. J. M., van’t Hof-Grootenboer, A. B., Brugal, G., and Vooijs, G. P. Endocervical columnar cell intraepithelial neoplasia. I. Discriminating cytomorphologic criteria, Acta Cytol. 39, 1199– 1215 (1995).
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11. van Aspert-van Erp, A. J. M., van’t Hof-Grootenboer, A. B., Brugal, G., and Vooijs, G. P. Endocervical columnar intraepithelial neoplasia. II. Grades of expression of cytomorphologic criteria, Acta Cytol. 39, 1216–1232 (1995). 12. Brown, L. J. R., and Wells, M. Cervical glandular atypia associated with squamous intra-epithelial neoplasia: A premalignant lesion? J. Clin. Pathol. 39, 22–28 (1986). 13. Kohan, S., Noumoff, J., Beckman, E. M., Morris, M., Weiner, E., and Douglas, G. W. Colposcopic screening of women with atypical Papanicolaou smears, J. Reprod. Med. 30, 383–387, (1985). 14. Noumoff, J. S. Atypia in cervical cytology as a risk factor for intraepithelial neoplasia, Am. J. Obstet. Gynecol. 156, 628–631 (1987). 15. Taylor, R. R., Guerrieri, J. P., Nash, J. D., Henry, M. R., and O’Connor, D. M. Atypical cervical cytology: Colposcopic follow-up using The Bethesda System, J. Reprod. Med. 38, 443–447 (1993). 16. Pacey, F., Ayer, B., and Greenberg, M. The cytologic diagnosis of adenocarcinoma in situ of the cervix uteri and related lesions. III. Pitfalls in diagnosis, Acta Cytol. 32, 325–330 (1988). 17. Lee, KR. Atypical glandular cells in cervical smears from women who have undergone cone biopsy: A potential diagnostic pitfall, Acta Cytol. 37, 705–709 (1993). 18. Novotny, D. B., Maygarden, S. J., Johnson, P. E., and Frable, W. J. Tubal metaplasia: A frequent potential pitfall in the cytologic diagnosis of endocervical glandular dysplasia on cervical smears, Acta Cytol. 36, 1–10 (1992). 19. Ducatman, B. S., Wang, H. H., Jonasson, J. G., Hogan, C. L., and Antonioli, D. A. Tubal metaplasia: A cytologic study with comparison to other neoplastic and non-neoplastic conditions of the endocervix, Diag. Cytopathol. 9, 98–105 (1993). 20. Hirschowitz, L., Eckford, S. D., Phillpotts, B., and Midwinter, A. Cytologic changes associated with tubo-endometrioid metaplasia of the uterine cervix, Cytopathology 5, 1–8 (1994).
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