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Atypical glandular cells of undetermined significance: A five-year retrospective histopathologic study
Atypical glandular cells of undetermined significance: A fiveyear retrospective histopathologic study Dan S. Veljovich, MD,a Mark H. Stoler, MD,b Willie A. Andersen, MD,a Jamie L. Covell, BS, CT(ASCP),b and Laurel W. Rice, MDa Charlottesville, Virginia OBJECTIVE: Our purpose was to ascertain the types and frequency of pathologic conditions associated with atypical glandular cells of undetermined significance on Papanicolaou smears. STUDY DESIGN: A 5-year retrospective review of screening cervical cytologic examinations diagnosed as atypical glandular cells of undetermined significance was performed at the University of Virginia to determine pathologic findings associated with atypical glandular cells of undetermined significance on Papanicolaou smears stratified by subtype and overall. RESULTS: Pathologic findings for the respective Papanicolaou smears with the diagnosis of atypical glandular cells of undetermined significance not otherwise specified, favor benign, squamous intraepithelial lesions, and favor neoplasia through the follow-up interval were as follows: squamous intraepithelial lesions in 11%, 8%, 38%, and 20%; adenocarcinoma in situ in 3%, 0%, 0%, and 10%; endometrial hyperplasia in 3%, 5%, 1%, and 2%; and cancer in 8%, 3%, 1%, and 7%. Overall, 63 patients (32%) had preinvasive or invasive lesions. Conclusions: Atypical glandular cells of undetermined significance on Papanicolaou smears were correlated with significant findings in 45% of patients (32% with preinvasive or invasive lesions and 13% with benign lesions). A prompt and aggressive workup is recommended. (Am J Obstet Gynecol 1998;179:382-90.)
Key words: Cervical cytology, atypical glandular cells of undetermined significance, the Bethesda system
In 1988 the Bethesda system of Papanicolaou smear classification proposed atypical glandular cells of undetermined significance as a diagnostic subcategory of epithelial glandular abnormalities.1, 2 This descriptive diagnosis is made when cells interpreted as having glandular differentiation are present on cytologic smears and demonstrate changes beyond those encountered in benign reactive processes yet that are insufficient for a diagnosis of invasive adenocarcinoma. Therefore this cytologic category includes a morphologic spectrum ranging from a possibly benign reactive process to adenocarcinoma in situ. Qualifiers such as whether the cells appear endocervical or endometrial in origin and whether a reactive or neoplastic process (adenocarcinoma in situ) is favored in the case of endocervical cells were recommended when possible after the 1991 revision of the Bethesda system.3 From the Departments of Obstetrics and Gynecologya and Pathology,b University of Virginia Health Sciences Center. Presented as Invited Guest at the Sixtieth Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Lake Buena Vista, Florida, January 24-27, 1998. Reprint requests: Laurel W. Rice, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Health Sciences Center, PO Box 10016, Charlottesville, VA 22906. Copyright © 1998 by Mosby, Inc. 0002-9378/98 $5.00 + 0 6/6/92296
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In contrast to both preinvasive and neoplastic squamous lesions of the cervix, where the evaluation and treatment is usually straightforward, glandular lesions of the cervix are diagnostically and therapeutically more challenging to the cytopathologist and clinician because of their relative rarity, relative absence of colposcopic findings, irregular shedding, small size, endocervical location (making lesions less amenable to cytologic sampling), and broader differential diagnosis.4 Several investigators have established the value of using key cytologic criteria in differentiating benign atypical glandular cells of undetermined significance on Papanicolaou smears from clinically significant lesions.5-10 However, benign conditions such as cervical endometriosis, tubal metaplasia, history of cone biopsy, Gartner’s ducts, microglandular hyperplasia, deciduosis, and even endometrial glands in the upper cervical canal can make the differential diagnosis difficult.11-13 Numerous reviews have shown an association between atypical glandular cells of undetermined significance on Papanicolaou smears and significant neoplastic squamous and glandular lesions of the cervix.14-20 The complex management and follow-up of this cytopathologic diagnosis is compounded by the multiple approaches for diagnostic confirmation, including endocervical curettage, ectocervical biopsy, endometrial biopsy, cervical conization, and loop electrosurgical excision procedure.
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To assess these issues, we retrospectively reviewed all atypical glandular cells of undetermined significance on Papanicolaou smears at the University of Virginia Health Sciences Center over a 5-year interval, stratifying findings by subtypes to evaluate not only the significance of these findings in our population but also whether stratification yields useful clinical information. Methods The computerized cytopathology archives of the University of Virginia Health Sciences Center were analyzed to identify women with atypical endocervical cells or atypical glandular cells of undetermined significance on Papanicolaou smears diagnosed between June 1990 and June 1995. During that time period 354 patients from a total of 84 442 smears were identified who met the criteria. The cytologic preparations were not submitted for a second review as a part of this study. Smears were subclassified on the basis of the cytopathology report diagnosis or comment into 1 of 4 subtypes: (1) atypical glandular cells of undetermined significance, not otherwise specified, when no other qualification was present, (2) atypical glandular cells of undetermined significance, favor benign, when a reactive or inflammatory process was favored, (3) atypical glandular cells of undetermined significance with associated squamous intraepithelial lesion when both diagnoses were present, and (4) atypical glandular cells of undetermined significance, favor neoplasia, when a glandular neoplasm of endocervical (or, less frequently, endometrial) origin was suspected but could not be definitively diagnosed. The method by which tissue was obtained in the evaluation of these smears varied and included ectocervical biopsy, endocervical curettage, cervical conization, loop electrosurgical excision procedure, polypectomy, endometrial biopsy, and hysterectomy. All histopathologic specimens were correlated with the cytologic diagnosis on the basis of the above stratification schema. Follow-up was analyzed through May 1997 for all patients. Results Three hundred fifty-four patients were identified between June 1990 and June 1995 as having cytologic findings consistent with atypical glandular cells of undetermined significance. A total of 84,442 Papanicolaou smears were obtained at the University of Virginia Health Science Center. Nine of these patients had atypical glandular cells of undetermined significance consistent with adenocarcinoma on their index Papanicolaou smears and were excluded. Three hundred forty-five remaining patients had a total of 449 Pap smears revealing atypical glandular cells of undetermined significance, establishing an incidence of 0.53%. Of these 345 patients, the following patients were excluded from analysis: 19 with a
Fig 1. Bar graph depicting number and percentage of each case of atypical glandular cells of undetermined significance (AGUS) on Papanicolaou smear subtype of 199 patients with this finding. SIL, Squamous intraepithelial lesions; NOS, not otherwise specified.
Table I. Patient follow-up intervals after finding atypical glandular cells of undetermined significance on Papanicolaou smear From Papanicolaou smear
Mean (mo)
Range (mo)
To first histologic specimen To last histologic specimen To last Papanicolaou smear
9.97 16.51 36.80
1-59 1-75 0-82
history of cancer, 27 with no follow-up histologic studies, and 100 with histologic specimens obtained the same day as the Papanicolaou smear. This latter group was omitted because of potential bias given the absence of a screening Papanicolaou smear before histologic follow-up. One hundred ninety-nine patients remained with histopathologic follow-up evaluation; it was this group that comprised our study population. The mean age of patients in the study was 43.7 years, with a range of 17 to 85 years. The number and relative percentage of the total population with atypical glandular cells of undetermined significance for each of the 4 subtypes used in our study are shown in Fig 1. Follow-up intervals for the study population from the day of the screening Papanicolaou smear to the first follow-up visit where biopsies were performed (first histologic specimen) and the last visit in the study interval where biopsies were performed (last histologic specimen) and the last Papanicolaou smear performed in the study interval are shown in Table I. The number of patients and percent of the total 199 patients with corre-
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Fig 2. Bar graph depicting final number and percentage of each histologic diagnosis in 199 patients with atypical glandular cells of undetermined significance (AGUS) on Papanicolaou smears through follow-up interval. SIL, High- or low-grade squamous intraepithelial lesions; CA, cancer; AIS, adenocarcinoma in situ.
Table II. Histologic specimens obtained at first follow-up and through total follow-up of 199 patients after finding atypical glandular cells of undetermined significance on Papanicolaou smear Specimen Endocervical curettage Cervical biopsy Endometrial biopsy Hysterectomy Polypectomy Endometrial curettage Cervical conization LEEP biopsy
First follow-up (No. [%]) 125 (62.8) 71 (35.7) 52 (26.1) 15 (7.5) 14 (7.0) 10 (5.0) 5 (2.5) 4 (2.0)
Total follow-up (No. [%]) 134 (67.3) 79 (39.7) 72 (36.2) 33 (16.6) 17 (8.5) 27 (13.6) 27 (13.6) 16 (8.0)
LEEP, Loop electrosurgical excision procedure.
sponding histologic specimens obtained at the first follow-up visit and through the last visit in the study interval are shown for the study population in Table II. The difference in the number of patients between the column showing first follow-up and the column showing total follow-up represents additional patients undergoing biopsy through the study interval. Of patients having endocervical curettage (67.3%), cervical biopsy (39.7%), and endometrial biopsy (36.2%) through the follow-up interval, the mean number of biopsies performed per patient were 1.28 (range 1 to 5), 1.14 (range 1 to 3), and 1.34 (range 1 to 6), respectively. The mean number of Papanicolaou smears repeated per patient after the screening smear in the study interval was 4.4, with a range of 0 to 15 repeat smears for the 199 patients studied. Tables III, IV, V, and VI show the results of histologic evaluation of the study group stratified by Papanicolaou
smear subtypes of atypical glandular cells of undetermined significance not otherwise specified, favor benign, squamous intraepithelial lesions, and favor neoplasia, respectively. Initial diagnosis represents the pathologic diagnosis of all patients with a given subtype at the first follow-up visit where biopsy was performed. Final diagnosis represents the cumulative final pathologic diagnoses of all study patients with a given subtype through the study interval of evaluation. The difference between the initial diagnosis and final diagnosis columns represents the diagnoses established with follow-up biopsy specimens after initial biopsies were performed. Of 8 cancers diagnosed in follow-up, all but 1 was detected at the first follow-up visit with biopsy after the screening diagnosis of atypical glandular cells of undetermined significance. Cancers found on initial biopsy were as follows: 2 endometrial adenocarcinomas (not otherwise specified type and favor neoplasia), 1 synchronous ovarian and endometrial carcinoma (not otherwise specified type), 1 ovarian carcinoma (favor neoplasia), 1 squamous cell carcinoma of the cervix (not otherwise specified type), 1 uterine stromal sarcoma (favor benign), and 1 metastatic adenocarcinoma of the breast (squamous intraepithelial lesion). One adenosquamous carcinoma of the cervix was detected on follow-up of a patient with atypical glandular cells of undetermined significance (favor neoplasia) subtype after initial workup with endocervical curettage showed only “adenocarcinoma in situ with detached high-grade squamous dysplasia with endocervical involvement.” The mean follow-up interval from the initial Papanicolaou smear to the diagnosis of cancer was 3.1 months for all patients diagnosed with cancer in the study interval.
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Fig 3. Bar graph depicting percentage of each subtype of atypical glandular cells of undetermined significance (AGUS) on Papanicolaou smear associated with preinvasive or invasive versus benign findings through follow-up interval. SIL, Squamous intraepithelial lesions; NOS, not otherwise specified. Preinvasive or invasive: Squamous intraepithelial lesion, adenocarcinoma in situ, endometrial hyperplasia, or cancer; benign: polyp or benign ovarian lesion.
Table III. Pathologic findings in women with findings of atypical glandular cells of undetermined significance subtype not otherwise specified on Papanicolaou smear (n = 38) on initial follow-up biopsy specimen and through follow-up interval Pathologic diagnosis Squamous intraepithelial lesions, high-grade Adenocarcinoma in situ Endometrial hyperplasia Cancer Polyp Total with pathologic features No pathologic features Total patients
Initial diagnosis
Final diagnosis
1 (2.6%) 0 0 3 (7.9%) 7 (18.4%) 11 (28.9%) 27 (71.1%) 38 (100%)
4 (10.5%) 1 (2.6%) 1 (2.6%) 3 (7.9%) 8 (21%) 17 (44.7%) 21 (55.3%) 38 (100%)
Table IV. Pathologic findings in women with findings of atypical glandular cells of undetermined significance subtype favor benign on Papanicolaou smear (n = 40) on follow-up initial biopsy specimen and through follow-up interval Pathologic diagnosis
Initial diagnosis
Final diagnosis
Squamous intraepithelial lesions High-grade Low-grade Endometrial hyperplasia Cancer Polyp Total with pathologic features No pathologic features Total patients
2 (5%) 1 (2.5%) 2 (5%) 1 (2.5%) 5 (12.5%) 11 (27.5%) 29 (72.5%) 40 (100%)
2 (5%) 1 (2.5%) 2 (5%) 1 (2.5%) 6 (15%) 12 (30%) 28 (70%) 40 (100%)
Comment The literature supports the premise that atypical glandular cells of undetermined significance represent a cytologic diagnosis associated with a high percentage of underlying pathologic conditions. Table VII shows findings of previous investigators and this study with respect to the number of total Papanicolaou smears evaluated and
the number of Papanicolaou smears with atypical glandular cells of undetermined significance evaluated, the incidence of atypical glandular cells of undetermined significance, the number of patients undergoing biopsy evaluation, and prevalence of pathologic findings on follow-up evaluation.14-20 These investigators all recommend that patients with a Papanicolaou smear diagnosed
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Fig 4. Bar graph depicting percentage of preinvasive or invasive lesions associated with each subtype of atypical glandular cells of undetermined significance (AGUS) on Papanicolaou smear through follow-up interval. CA, Cancer; AIS, adenocarcinoma in situ; SIL, squamous intraepithelial lesion; NOS, not otherwise specified.
Table V. Pathologic findings in women with findings of atypical glandular cells of undetermined significance subtype squamous intraepithelial lesions on Papanicolaou smear (n = 80) on follow-up initial biopsy specimen and through follow-up interval Pathologic diagnosis
Initial diagnosis
Final diagnosis
Squamous intraepithelial lesions High-grade Low-grade Endometrial hyperplasia Cancer Polyp Teratoma Total with pathologic features No pathologic features Total patients
14 (17.5%) 9 (11.25%) 1 (1.25%) 1 (1.25%) 4 (5%) 0 29 (36.25%) 51 (63.75%) 80 (100%)
16 (20%) 14 (17.5%) 1 (1.25%) 1 (1.25%) 6 (7.5%) 1 (1.25%) 39 (48.75%) 41 (51.25%) 80 (100%)
Table VI. Pathologic findings in women with findings of atypical glandular cells of undetermined significance subtype favor neoplasia on Papanicolaou smear (n = 41) on follow-up initial biopsy specimen and through follow-up interval Pathologic diagnosis
Initial diagnosis
Final diagnosis
Squamous intraepithelial lesions High-grade Low-grade Adenocarcinoma in situ Endometrial hyperplasia Cancer Polyp Brenner tumor Total with pathologic features No pathologic features Total patients
4 (9.8%) 2 (4.9%) 4 (9.8%) 1 (2.4%) 2 (4.9%) 1 (2.4%) 1 (2.4%) 15 (36.6%) 26 (63.4%) 41 (100%)
6(14.6%) 2 (4.9%) 4 (9.8%) 1 (2.4%) 3 (7.3%) 4 (9.8%) 1 (2.4%) 21 (51.2%) 20 (48.8%) 41 (100%)
as having atypical glandular cells of undetermined significance undergo colposcopy with directed cervical biopsies and endocervical curettage. The question of whether endometrial biopsy should be used routinely is contro-
versial, but it is generally recommended in older women. In the current study, when the group with atypical glandular cells of undetermined significance is considered as a whole, the associated histopathologic findings
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Table VII. Comparison of incidence of atypical glandular cells of undetermined significance and prevalence of pathologic findings on follow-up in literature Study Goff et al14 (1992) Nasu et al16 (1993) Taylor et al15 (1993) Kennedy et al17 (1996) Zweizig et al18 (1997) Eddy et al19 (1997) Duska et al20 (1998) TOTAL
Veljovich et al
Total Pap smears
AGUS Pap smears
Incidence (%)
21,930 34,384 17,000 68,368 46,804 177,715 120,338 486,539 84,442
100 620 30 136 127 1117 201 2331 345
0.46 1.8 0.18 0.20 0.27 0.63 0.17 0.48 0.53
No.
SIL (%)
AIS (%)
EMH (%)
CA (%)
63 277 30 77 85 531 73 1136 199
39.7 43.7 37 9.1 21.2 27 26 29.1 22.6
7.9 3.3
3.2
3.2 4
3.9 1.2 1.9
11.8 1.1
3.6 2.5
5.4 2.5
3.9 9.4 6 8.2 5.8 4
Pap, Papanicolaou smear; AGUS, atypical glandular cells of undetermined significance; Incidence, incidence of atypical glandular cells of undetermined significance on Papanicolaou smears; No., number of patients evaluated with biopsy specimens; SIL, high- and lowgrade squamous intraepithelial lesions; AIS, adenocarcinoma in situ; EMH, endometrial hyperplasia; CA, cancer.
for the 199 patients are represented in Fig 2. As can be seen in Table VII, the incidence of atypical glandular cells of undetermined significance and the prevalence of squamous intraepithelial lesions, adenocarcinoma in situ, endometrial hyperplasia, and cancer are within the range of previous studies. Atypical glandular cells of undetermined significance detected on cervical cytologic examination were associated with pathologic conditions in the final diagnosis of between 30% (favor benign) and 51% (favor neoplasia) of women (Tables III to VI). Among the 4 stratifications, the subset interpreted as favoring a benign process, representing approximately 20% of smears in our study, had the lowest incidence of pathologic conditions (30%). In contrast, the subset favoring a neoplastic process, also comprising approximately 20% of smears, had the highest incidence of pathologic conditions (51.1%). Fig 3 shows the incidence of preinvasive or invasive lesions (squamous intraepithelial lesion, adenocarcinoma in situ, endometrial hyperplasia, and cancer) and benign lesions (polyps or benign ovarian lesions) stratified by subtype of atypical glandular cells of undetermined significance. As can be seen, a higher incidence of preinvasive or invasive lesions was associated with squamous intraepithelial lesions and favor neoplasia than for favor benign and not otherwise specified subtypes. However, it is noteworthy that even in the group of women in whom the Papanicolaou smear was interpreted as representing a benign process or was not otherwise specified, there still existed a 15% to 24% incidence of preinvasive or invasive lesions confirmed by histopathologic analysis. Only in the favor benign stratification was there equal likelihood of finding a benign versus preinvasive or invasive lesion. In all other subgroups if a lesion was found it was more likely to be preinvasive or invasive than benign. Fig 4 illustrates the incidence of each preinvasive or invasive finding for each subclassification. In 8% to 20% of patients without associated squamous lesions on the
Papanicolaou smear, a squamous lesion was diagnosed on biopsy. The association between squamous lesions and glandular lesions of the cervix is undoubtedly related to 2 factors. First, as in cases of atypical squamous cells of undetermined significance, cases of atypical glandular cells of undetermined significance may be misclassified because of difficulty in seeing cellular detail because of poor preservation or obscuring inflammation. Second, and probably more important, both cervical glandular and squamous neoplasms are etiologically linked to human papillomavirus infection; hence the 2 lesions tend to coexist, although squamous lesions are diagnosed and confirmed approximately 20% to 100% more frequently than true glandular neoplasms are.21 Adenocarcinoma in situ, the final diagnosis in only 5 patients, was found in subtypes not otherwise specified and favor neoplasia only (Fig 4). However, of the 8 patients diagnosed with an invasive malignancy, 1 was included in the favor benign subgroup and 3 in the not otherwise specified category. This points to the fact that a diagnosis of atypical glandular cells of undetermined significance of any type may represent serious pathologic conditions. Recommendations have been made for aggressive workup of Papanicolaou smears with these glandular cells to rule out potential endocervical, endometrial, and, much more rarely, gastrointestinal, tubal, ovarian, or breast pathologic conditions. The American Society for Colposcopy and Cervical Pathology recently published guidelines for management of patients with atypical glandular cells of undetermined significance on Papanicolaou smears. All women with this diagnosis should undergo cervical and vaginal colposcopy and endocervical curettage. Those patients with unqualified atypical glandular cells of undetermined significance who have negative colposcopic examinations and endocervical curettage should have repeat Papanicolaou smears every 4 to 6 months until 4 normal smears have
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been obtained. Those patients with either atypical glandular cells of undetermined significance favoring neoplasia with negative colposcopy and endocervical curettage or unqualified atypical glandular cells of undetermined significance with an endocervical curettage positive for neoplasia should undergo cervical conization. Endometrial biopsy, hysteroscopy, or a curettage is recommended if cells appear to be of endometrial origin.4 Until we can better understand the relationship between atypical glandular cells of undetermined significance on Papanicolaou smears and the underlying pathologic conditions through prospective trials evaluating follow-up for patients with this diagnosis, we support these guidelines for evaluation. This review contributes to the understanding of this diagnosis in 3 ways. First, our study reinforces the previously published concept that atypical glandular cells of undetermined significance on Papanicolaou smears represent a cytologic diagnosis with an associated high incidence of underlying malignant or premalignant lesions on follow-up histologic examination; thus this diagnosis should be worked up appropriately in accordance with the guidelines of the American Society for Colposcopy and Cervical Pathology. Second, the stratification of these smears by subtype may be valuable in assessing the risk of underlying pathologic conditions. Development of well-defined criteria for the diagnosis of various subtypes of atypical glandular cells of undetermined significance could potentially identify women at higher or lower risk for significant pathologic conditions and thus assist in triage of patients on the basis of subtypes. Careful discussion with the interpreting cytopathologist is crucial, however, in any situation when a management plan is being developed. Finally, our study further underscores the importance of diligent and persistent followup of the patient with atypical glandular cells of undetermined significance on cervical cytologic studies. Although the initial evaluation of patients failed to reveal significant pathologic conditions in 133 patients (67%), follow-up revealed significant conditions in 25 new patients (12.6%), with 12 of these 25 having squamous lesions, 1 adenocarcinoma in situ, and 1 cancer (adenosquamous carcinoma of the cervix). REFERENCES
1. National Cancer Institute Workshop. The 1988 Bethesda system for reporting cervical/vaginal cytological diagnoses. JAMA 1989;262:931-4. 2. International Academy of Cytology. The Bethesda system for reporting cervical/vaginal cytologic diagnoses. Acta Cytol 1993;37:115-24. 3. Kurman RJ, Solomon D. The Bethesda system for reporting cervical/vaginal cytologic diagnoses: definitions, criteria and explanatory notes for terminology and specimen adequacy. New York: Springer Verlag; 1994. 4. Cox JT. ASCCP practice guidelines: management of glandular abnormalities in the cervical smear. J Lower Genital Tract Dis 1997;1:41-5.
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5. Bose S, Kannan V, Kline T. Abnormal endocervical cells: really abnormal? really endocervical? Am J Clin Pathol 1994;101:70813. 6. Raab SS, Isacson C, Layfield LJ, Lenel JC, Slagel DD, Thomas PA. Atypical glandular cells of undetermined significance: cytologic criteria to separate clinically significant from benign lesions. Am J Clin Pathol 1995;104:574-82. 7. DiTomasso JP, Ramzy I, Mody DR. Glandular lesions of the cervix: validity of cytologic criteria used to differentiate reactive changes, glandular intraepithelial lesions and adenocarcinoma. Acta Cytol 1996;40:1127-35. 8. Raab SS, Snider TE, Potts SA, McDaniel H, Robinson RA, Nelson DL, et al. Atypical glandular cells of undetermined significance: diagnostic accuracy and interobserver variability using select cytologic criteria. Am J Clin Pathol 1997;107:299307. 9. van Aspert-van Erp AJM, van’t Hof-Grootenboer AB, Brugal G, Vooijs GP. Endocervical columnar cell intraepithelial neoplasia, I: discriminating cytomorphologic criteria. Acta Cytol 1995;39:1199-215. 10. van Aspert-van Erp AJM, van’t Hof-Grootenboer AB, Brugal G, Vooijs GP. Endocervical columnar cell intraepithelial neoplasia, II: grades of expression of cytomorphologic criteria. Acta Cytol 1995;39:1216-32. 11. Pacey F, Ayer B, Greenberg M. The cytologic diagnosis of adenocarcinoma in situ of the cervix uteri and related lesions, III: pitfalls in diagnosis. Acta Cytol 1988;32:325-30. 12. Lee KR. Atypical cells in cervical smears from women who have undergone cone biopsy: a potential diagnostic pitfall. Acta Cytol 1993;37:705-9. 13. Novotny DB, Maygarden SJ, Johnson DE, Frable WJ. Tubal metaplasia: a frequent potential pitfall in the cytologic diagnosis of endocervical glandular dysplasia on cervical smears. Acta Cytol 1992;36:1-10. 14. Goff BA, Atanasoff P, Brown E, Muntz HG, Bell DA, Rice LW. Endocervical glandular atypia in Papanicolaou smears. Obstet Gynecol 1992;79:101-4. 15. Taylor RR, Guerrieri JP, Nash JD, Henry MR, O’Connor DM. Atypical cervical cytology: colposcopic follow-up using the Bethesda system. J Reprod Med 1993;38:443-7. 16. Nasu I, Meurer W, Fu YS. Endocervical glandular atypia and adenocarcinoma: a correlation of cytology and histology. Int J Gynecol Pathol 1993;12:208-18. 17. Kennedy AW, Salmieri SS, Wirth SL, Biscotti CV, Tuason LJ, Travarca MJ. Results of the clinical evaluation of atypical glandular cells of undetermined significance (AGCUS) detected on cervical cytology screening. Gynecol Oncol 1996;63:14-8. 18. Zweizig S, Noller K, Reale F, Collis S, Resseguie L. Neoplasia associated with atypical glandular cells of undetermined significance on cervical cytology. Gynecol Oncol 1997;65:314-8. 19. Eddy GL, Strumpf KB, Wojtowycz MA, Piraino PS, Mazur MT. Biopsy findings in five hundred thirty-one patients with atypical glandular cells of uncertain significance as defined by the Bethesda system. Am J Obstet Gynecol 1997;177:1188-95. 20. Duska LR, Flynn CF, Chen A, Whall-Strojwas D, Goodman A. Clinical evaluation of atypical glandular cells of undetermined significance on cervical cytology. Obstet Gynecol 1998;91:27882. 21. Stoler MH. The biology of human papillomavirus. Pathol Case Rev 1997;2:1-13.
Discussion DR LAURIE HUDGINS, Blacksburg, Virginia (Official Guest). Fifty-five years ago Papanicolaou published his study demonstrating the value of cervical cytologic examination as a screening test for cancer of the cervix. Many adjustments in Papanicolaou smear categories and interpretation have been made over the years. The National Cancer Institute developed the Bethesda system in 1988 to establish consistent terminology for the reporting of
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Papnicolaou smears and to develop more specificity in categorizing abnormalities. Atypical glandular cells of undetermined significance was one of the new diagnostic categories. Once identified as a separate entity, we have been able to stud it regarding its clinical implications. The study of Veljovich et al contributes greatly to our understanding of the clinical relevance and therefore management of the Papanicolaou smear with atypical glandular cells of undetermined significance. First, it is worthy to note that this study’s incidence of atypical glandular cells of undetermined significance among all Papanicolaou smears is 0.53%, which is in the range of other study findings, about 0.3% to 0.8%. In comparison, the incidence of atypical squamous cells of undetermined significance, among all Papanicolaou smears, is quoted in the 3% to 10% range. Therefore the category of atypical glandular cells is much less likely to be encountered in a clinical setting than is the category of atypical squamous cells. However, the major “take-home” lesson is that when atypical glandular cells of undetermined significance are reported on a Papanicolaou smear it is a red flag that there is a very high risk of the existence of pathologic conditions. This study reveals overall significant pathologic findings in 45% of patients who had atypical glandular cells of undetermined significance on a Papanicolaou smear. Other studies find similar rates of pathologic conditions from 42% to as high as 83% in the workup of these reports. Again, to compare it with the category of atypical squamous cells of undetermined significance with which we are all so familiar, the squamous cells convey a much lower rate of underlying pathologic conditions of 10% to 40%. Another important clinical point of this study is the high incidence of squamous intraepithelial lesions uncovered in patients with atypical glandular cells of undetermined significance on Papanicolaou smear. There is a 38% incidence of squamous intraepithelial lesions in the subtype. In other subtypes where squamous intraepithelial lesions are not specifically noted on the Papnicolaou smear, there is still an 8% to 20% incidence of squamous lesions detected with histologic workup. Thus it is imperative that colposcopy and ectocervical biopsies as indicated be performed as part of the overall workup when atypical glandular cells of undetermined significance are detected on Papanicolaou smears. This study includes 199 patients with atypical glandular cells of undetermined significance on Papanicolaou smears with histologic follow-up. This series is at least twice as large as most of the other studies that have examined this issue and thus it substantially contributes to the accumulated data. In that this study does not include control groups, it is important to bear in mind that the reported percentages of pathologic conditions represent associations but do not necessarily have precise predictive values. One of the unique features of this study is the stratification of atypical glandular cells of undetermined significance into the 4 subtypes previously described and the conclusions regarding the clinical importance of such
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subtyping. The author concludes that subtyping may allow for the assessment of underlying pathologic conditions because the subtype favoring neoplasia had the highest percentage of both pathologic conditions and severity of pathologic conditions. However, I believe that it is important to recognize that classifying by subtype has no impact on the necessity of working up every case because even the “benign” subtype has a 30% risk of pathologic conditions. I have 2 specific questions. Was the histologic outcome of atypical glandular cells of undetermined significance on Papanicolaou smears correlated with patient factors such as age or hormone usage to see whether these factors might be associated with an increased risk of pathologic findings? Second, in light of recommendations by the American Society for Colposcopy and Cervical Pathology that the most vigilant follow-up should fall within the first 2 years after a Papnicolaou smear with atypical glandular cells of undetermined significance, were any trends noted as to a mean time frame during which pathologic conditions were eventually detected after an initial negative workup? Aside from this study, I am also concerned regarding new techniques for cervical cytologic studies such as liquid collection systems and thin-layer preparations and what impact they may have on interpretation and possibly on rates of underlying pathologic conditions. Future studies will be necessary to assess this. Because the frequency of cervical adenocarcinoma is increasing, studies regarding screening and detection of precursors and related lesions are very important. This study adds much to our understanding of the implications of the category of atypical glandular cells of undetermined significance found on the Papnicolaou smear. It also compels us to adhere strictly to the relatively recent protocol of the American Society of Colposcopy and Cervical Pathology for the workup of this finding. DR RAMEZ S. AZOURY, Norfolk, Virginia. Is there any correlation between atypical glandular cells of undetermined significance on the Papanicolaou smear and microglandular hyperplasia of the endocervix? Is there an association between the atypical glandular lesions and the atypical squamous lesions? DR VELJOVICH (Closing). I agree with Dr Hudgins that subtyping of all lesions would not be helpful in determining the management plan because all subtypes in our study had significant pathologic conditions and thus we would not recommend working up any one subgroup less aggressively at this point. Initially our pathologist felt that we would show that he could differentiate the more benign lesions from the more significant ones, but, as the study showed, this turned out to not always be the case. The smears with atypical glandular cells with squamous involvement did show much more squamous involvement than did those without squamous involvement, however. Dr Hudgins pointed out that typing would not affect your management very much at this point because any of these lesions can be associated with significant pathologic features. All people involved in obtaining Papanicolaou smears need to be aware of the discrep-
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ancy between smears with atypical glandular cells in which a benign process is favored by the pathologist but follow-up shows a significant lesion. The person who is reading the smear must communicate well with the clinician. With respect to Dr Hudgins’ question regarding patient factors such as age or hormone usage and their association with pathologic findings, our study did not evaluate age or hormonal status in the patient population with respect to lesions. Zweizig et al1 looked at age, parity, gravidity, menopausal status, abnormal bleeding, current hormone replacement therapy, and oral contraceptive use and did not find any significant association between these factors and more advanced lesions. They did find, however, that no woman <35 years old had endometrial pathologic findings and thus they recommend an endometrial biopsy for the subset of women >35 years old. We did not evaluate what features of follow-up would allow a person to return to a routine screening category, but this would be a very interesting study, ideally in a randomized controlled trial of follow-up. In reference to the newer “thin prep” technique, there is considerable “brush artifact” in conventional smear technique with large sheets of normal endocervical cells that can mimic nuclear overlap, which can be confused with atypical glandular cells. With the new cell suspension systems, if the cells were placed on a monolayer, it would likely prove less confusing for the pathologist reading the smear. In reference to Dr Azoury’s question, we did not find
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microglandular hyperplasia in any of our patients as others have.2 In reference to the question about whether there is an association between the atypical glandular lesions and the atypical squamous lesions, this does suggest a “field” effect of human papillomavirus. A large number of atypical endocervical neoplasms do have human papillomavirus–positive typing.3, 4 In the glandular lesions the human papillomavirus types tend to be type 18 as opposed to type 16, which is more common in squamous lesions.5 Additionally, many squamous cell carcinoma in situ lesions will extend into a gland crypt, and this may lead to confusion when these cells are examined microscopically.6 REFERENCES
1. Zweizig S, Noller K, Reale F, Collis S, Resseguie L. Neoplasia associated with atypical glandular cells of undetermined significance on cervical cytology. Gynecol Oncol 1997;65:314-8. 2. Nasu I, Meurer W, Fu YS. Endocervical glandular atypia and adenocarcinoma: a correlation of cytology and histology. Int J Gynecol Pathol 1993;12:208-18. 3. Alejo M, Macedo I, Matias-Guiu X, Prat J. Adenocarcinoma in situ of the uterine cervix: clinicopathological study of nine cases with detection of human papillomavirus DNA by in situ hybridization and polymerase chain reaction. Int J Gynecol Pathol 1993;12:219-23. 4. Samaratunga H, Cox N, Wright RG. Human papillomavirus DNA in glandular lesions of the uterine cervix. J Clin Pathol 1993;46:718-21. 5. Stoler MH. The biology of human papillomavirus. Pathol Case Rev 1997;2:1-13. 6. Selvaggi SM. Cytologic features of squamous cell carcinoma in situ involving endocervical glands in endocervical Cytobrush specimens. Acta Cytol 1994;38:687-92.
Make researching easier with the Ten-Year Cumulative Index (1978-1987) to the American Journal of Obstetrics and Gynecology The Ten-Year Cumulative Index is a complete guide to more than 30,000 pages of original articles, case reports, letters, and editorials published in the American Journal of Obstetrics and Gynecology from 1978 through 1987 (volumes 130 to 157). Numbering more than 800 pages, the Cumulative Index includes both a subject and an author index. This hard-cover volume is $64.50 ($69 international). Prices include shipping. Payment must accompany all orders and must be in US funds, drawn on a US bank. Contact Mosby, Inc, Subscription Services, 11830 Westline Industrial Dr, St. Louis, MO 63146-3318, USA; telephone (314)453-4351. In the US call toll-free: (800)453-4351. Please allow 6 weeks for delivery.
Key words: Cervical cytology, atypical glandular cells of undetermined significance, the Bethesda system
In 1988 the Bethesda system of Papanicolaou smear classification proposed atypical glandular cells of undetermined significance as a diagnostic subcategory of epithelial glandular abnormalities.1, 2 This descriptive diagnosis is made when cells interpreted as having glandular differentiation are present on cytologic smears and demonstrate changes beyond those encountered in benign reactive processes yet that are insufficient for a diagnosis of invasive adenocarcinoma. Therefore this cytologic category includes a morphologic spectrum ranging from a possibly benign reactive process to adenocarcinoma in situ. Qualifiers such as whether the cells appear endocervical or endometrial in origin and whether a reactive or neoplastic process (adenocarcinoma in situ) is favored in the case of endocervical cells were recommended when possible after the 1991 revision of the Bethesda system.3 From the Departments of Obstetrics and Gynecologya and Pathology,b University of Virginia Health Sciences Center. Presented as Invited Guest at the Sixtieth Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Lake Buena Vista, Florida, January 24-27, 1998. Reprint requests: Laurel W. Rice, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Health Sciences Center, PO Box 10016, Charlottesville, VA 22906. Copyright © 1998 by Mosby, Inc. 0002-9378/98 $5.00 + 0 6/6/92296
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In contrast to both preinvasive and neoplastic squamous lesions of the cervix, where the evaluation and treatment is usually straightforward, glandular lesions of the cervix are diagnostically and therapeutically more challenging to the cytopathologist and clinician because of their relative rarity, relative absence of colposcopic findings, irregular shedding, small size, endocervical location (making lesions less amenable to cytologic sampling), and broader differential diagnosis.4 Several investigators have established the value of using key cytologic criteria in differentiating benign atypical glandular cells of undetermined significance on Papanicolaou smears from clinically significant lesions.5-10 However, benign conditions such as cervical endometriosis, tubal metaplasia, history of cone biopsy, Gartner’s ducts, microglandular hyperplasia, deciduosis, and even endometrial glands in the upper cervical canal can make the differential diagnosis difficult.11-13 Numerous reviews have shown an association between atypical glandular cells of undetermined significance on Papanicolaou smears and significant neoplastic squamous and glandular lesions of the cervix.14-20 The complex management and follow-up of this cytopathologic diagnosis is compounded by the multiple approaches for diagnostic confirmation, including endocervical curettage, ectocervical biopsy, endometrial biopsy, cervical conization, and loop electrosurgical excision procedure.
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To assess these issues, we retrospectively reviewed all atypical glandular cells of undetermined significance on Papanicolaou smears at the University of Virginia Health Sciences Center over a 5-year interval, stratifying findings by subtypes to evaluate not only the significance of these findings in our population but also whether stratification yields useful clinical information. Methods The computerized cytopathology archives of the University of Virginia Health Sciences Center were analyzed to identify women with atypical endocervical cells or atypical glandular cells of undetermined significance on Papanicolaou smears diagnosed between June 1990 and June 1995. During that time period 354 patients from a total of 84 442 smears were identified who met the criteria. The cytologic preparations were not submitted for a second review as a part of this study. Smears were subclassified on the basis of the cytopathology report diagnosis or comment into 1 of 4 subtypes: (1) atypical glandular cells of undetermined significance, not otherwise specified, when no other qualification was present, (2) atypical glandular cells of undetermined significance, favor benign, when a reactive or inflammatory process was favored, (3) atypical glandular cells of undetermined significance with associated squamous intraepithelial lesion when both diagnoses were present, and (4) atypical glandular cells of undetermined significance, favor neoplasia, when a glandular neoplasm of endocervical (or, less frequently, endometrial) origin was suspected but could not be definitively diagnosed. The method by which tissue was obtained in the evaluation of these smears varied and included ectocervical biopsy, endocervical curettage, cervical conization, loop electrosurgical excision procedure, polypectomy, endometrial biopsy, and hysterectomy. All histopathologic specimens were correlated with the cytologic diagnosis on the basis of the above stratification schema. Follow-up was analyzed through May 1997 for all patients. Results Three hundred fifty-four patients were identified between June 1990 and June 1995 as having cytologic findings consistent with atypical glandular cells of undetermined significance. A total of 84,442 Papanicolaou smears were obtained at the University of Virginia Health Science Center. Nine of these patients had atypical glandular cells of undetermined significance consistent with adenocarcinoma on their index Papanicolaou smears and were excluded. Three hundred forty-five remaining patients had a total of 449 Pap smears revealing atypical glandular cells of undetermined significance, establishing an incidence of 0.53%. Of these 345 patients, the following patients were excluded from analysis: 19 with a
Fig 1. Bar graph depicting number and percentage of each case of atypical glandular cells of undetermined significance (AGUS) on Papanicolaou smear subtype of 199 patients with this finding. SIL, Squamous intraepithelial lesions; NOS, not otherwise specified.
Table I. Patient follow-up intervals after finding atypical glandular cells of undetermined significance on Papanicolaou smear From Papanicolaou smear
Mean (mo)
Range (mo)
To first histologic specimen To last histologic specimen To last Papanicolaou smear
9.97 16.51 36.80
1-59 1-75 0-82
history of cancer, 27 with no follow-up histologic studies, and 100 with histologic specimens obtained the same day as the Papanicolaou smear. This latter group was omitted because of potential bias given the absence of a screening Papanicolaou smear before histologic follow-up. One hundred ninety-nine patients remained with histopathologic follow-up evaluation; it was this group that comprised our study population. The mean age of patients in the study was 43.7 years, with a range of 17 to 85 years. The number and relative percentage of the total population with atypical glandular cells of undetermined significance for each of the 4 subtypes used in our study are shown in Fig 1. Follow-up intervals for the study population from the day of the screening Papanicolaou smear to the first follow-up visit where biopsies were performed (first histologic specimen) and the last visit in the study interval where biopsies were performed (last histologic specimen) and the last Papanicolaou smear performed in the study interval are shown in Table I. The number of patients and percent of the total 199 patients with corre-
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Fig 2. Bar graph depicting final number and percentage of each histologic diagnosis in 199 patients with atypical glandular cells of undetermined significance (AGUS) on Papanicolaou smears through follow-up interval. SIL, High- or low-grade squamous intraepithelial lesions; CA, cancer; AIS, adenocarcinoma in situ.
Table II. Histologic specimens obtained at first follow-up and through total follow-up of 199 patients after finding atypical glandular cells of undetermined significance on Papanicolaou smear Specimen Endocervical curettage Cervical biopsy Endometrial biopsy Hysterectomy Polypectomy Endometrial curettage Cervical conization LEEP biopsy
First follow-up (No. [%]) 125 (62.8) 71 (35.7) 52 (26.1) 15 (7.5) 14 (7.0) 10 (5.0) 5 (2.5) 4 (2.0)
Total follow-up (No. [%]) 134 (67.3) 79 (39.7) 72 (36.2) 33 (16.6) 17 (8.5) 27 (13.6) 27 (13.6) 16 (8.0)
LEEP, Loop electrosurgical excision procedure.
sponding histologic specimens obtained at the first follow-up visit and through the last visit in the study interval are shown for the study population in Table II. The difference in the number of patients between the column showing first follow-up and the column showing total follow-up represents additional patients undergoing biopsy through the study interval. Of patients having endocervical curettage (67.3%), cervical biopsy (39.7%), and endometrial biopsy (36.2%) through the follow-up interval, the mean number of biopsies performed per patient were 1.28 (range 1 to 5), 1.14 (range 1 to 3), and 1.34 (range 1 to 6), respectively. The mean number of Papanicolaou smears repeated per patient after the screening smear in the study interval was 4.4, with a range of 0 to 15 repeat smears for the 199 patients studied. Tables III, IV, V, and VI show the results of histologic evaluation of the study group stratified by Papanicolaou
smear subtypes of atypical glandular cells of undetermined significance not otherwise specified, favor benign, squamous intraepithelial lesions, and favor neoplasia, respectively. Initial diagnosis represents the pathologic diagnosis of all patients with a given subtype at the first follow-up visit where biopsy was performed. Final diagnosis represents the cumulative final pathologic diagnoses of all study patients with a given subtype through the study interval of evaluation. The difference between the initial diagnosis and final diagnosis columns represents the diagnoses established with follow-up biopsy specimens after initial biopsies were performed. Of 8 cancers diagnosed in follow-up, all but 1 was detected at the first follow-up visit with biopsy after the screening diagnosis of atypical glandular cells of undetermined significance. Cancers found on initial biopsy were as follows: 2 endometrial adenocarcinomas (not otherwise specified type and favor neoplasia), 1 synchronous ovarian and endometrial carcinoma (not otherwise specified type), 1 ovarian carcinoma (favor neoplasia), 1 squamous cell carcinoma of the cervix (not otherwise specified type), 1 uterine stromal sarcoma (favor benign), and 1 metastatic adenocarcinoma of the breast (squamous intraepithelial lesion). One adenosquamous carcinoma of the cervix was detected on follow-up of a patient with atypical glandular cells of undetermined significance (favor neoplasia) subtype after initial workup with endocervical curettage showed only “adenocarcinoma in situ with detached high-grade squamous dysplasia with endocervical involvement.” The mean follow-up interval from the initial Papanicolaou smear to the diagnosis of cancer was 3.1 months for all patients diagnosed with cancer in the study interval.
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Fig 3. Bar graph depicting percentage of each subtype of atypical glandular cells of undetermined significance (AGUS) on Papanicolaou smear associated with preinvasive or invasive versus benign findings through follow-up interval. SIL, Squamous intraepithelial lesions; NOS, not otherwise specified. Preinvasive or invasive: Squamous intraepithelial lesion, adenocarcinoma in situ, endometrial hyperplasia, or cancer; benign: polyp or benign ovarian lesion.
Table III. Pathologic findings in women with findings of atypical glandular cells of undetermined significance subtype not otherwise specified on Papanicolaou smear (n = 38) on initial follow-up biopsy specimen and through follow-up interval Pathologic diagnosis Squamous intraepithelial lesions, high-grade Adenocarcinoma in situ Endometrial hyperplasia Cancer Polyp Total with pathologic features No pathologic features Total patients
Initial diagnosis
Final diagnosis
1 (2.6%) 0 0 3 (7.9%) 7 (18.4%) 11 (28.9%) 27 (71.1%) 38 (100%)
4 (10.5%) 1 (2.6%) 1 (2.6%) 3 (7.9%) 8 (21%) 17 (44.7%) 21 (55.3%) 38 (100%)
Table IV. Pathologic findings in women with findings of atypical glandular cells of undetermined significance subtype favor benign on Papanicolaou smear (n = 40) on follow-up initial biopsy specimen and through follow-up interval Pathologic diagnosis
Initial diagnosis
Final diagnosis
Squamous intraepithelial lesions High-grade Low-grade Endometrial hyperplasia Cancer Polyp Total with pathologic features No pathologic features Total patients
2 (5%) 1 (2.5%) 2 (5%) 1 (2.5%) 5 (12.5%) 11 (27.5%) 29 (72.5%) 40 (100%)
2 (5%) 1 (2.5%) 2 (5%) 1 (2.5%) 6 (15%) 12 (30%) 28 (70%) 40 (100%)
Comment The literature supports the premise that atypical glandular cells of undetermined significance represent a cytologic diagnosis associated with a high percentage of underlying pathologic conditions. Table VII shows findings of previous investigators and this study with respect to the number of total Papanicolaou smears evaluated and
the number of Papanicolaou smears with atypical glandular cells of undetermined significance evaluated, the incidence of atypical glandular cells of undetermined significance, the number of patients undergoing biopsy evaluation, and prevalence of pathologic findings on follow-up evaluation.14-20 These investigators all recommend that patients with a Papanicolaou smear diagnosed
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Fig 4. Bar graph depicting percentage of preinvasive or invasive lesions associated with each subtype of atypical glandular cells of undetermined significance (AGUS) on Papanicolaou smear through follow-up interval. CA, Cancer; AIS, adenocarcinoma in situ; SIL, squamous intraepithelial lesion; NOS, not otherwise specified.
Table V. Pathologic findings in women with findings of atypical glandular cells of undetermined significance subtype squamous intraepithelial lesions on Papanicolaou smear (n = 80) on follow-up initial biopsy specimen and through follow-up interval Pathologic diagnosis
Initial diagnosis
Final diagnosis
Squamous intraepithelial lesions High-grade Low-grade Endometrial hyperplasia Cancer Polyp Teratoma Total with pathologic features No pathologic features Total patients
14 (17.5%) 9 (11.25%) 1 (1.25%) 1 (1.25%) 4 (5%) 0 29 (36.25%) 51 (63.75%) 80 (100%)
16 (20%) 14 (17.5%) 1 (1.25%) 1 (1.25%) 6 (7.5%) 1 (1.25%) 39 (48.75%) 41 (51.25%) 80 (100%)
Table VI. Pathologic findings in women with findings of atypical glandular cells of undetermined significance subtype favor neoplasia on Papanicolaou smear (n = 41) on follow-up initial biopsy specimen and through follow-up interval Pathologic diagnosis
Initial diagnosis
Final diagnosis
Squamous intraepithelial lesions High-grade Low-grade Adenocarcinoma in situ Endometrial hyperplasia Cancer Polyp Brenner tumor Total with pathologic features No pathologic features Total patients
4 (9.8%) 2 (4.9%) 4 (9.8%) 1 (2.4%) 2 (4.9%) 1 (2.4%) 1 (2.4%) 15 (36.6%) 26 (63.4%) 41 (100%)
6(14.6%) 2 (4.9%) 4 (9.8%) 1 (2.4%) 3 (7.3%) 4 (9.8%) 1 (2.4%) 21 (51.2%) 20 (48.8%) 41 (100%)
as having atypical glandular cells of undetermined significance undergo colposcopy with directed cervical biopsies and endocervical curettage. The question of whether endometrial biopsy should be used routinely is contro-
versial, but it is generally recommended in older women. In the current study, when the group with atypical glandular cells of undetermined significance is considered as a whole, the associated histopathologic findings
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Table VII. Comparison of incidence of atypical glandular cells of undetermined significance and prevalence of pathologic findings on follow-up in literature Study Goff et al14 (1992) Nasu et al16 (1993) Taylor et al15 (1993) Kennedy et al17 (1996) Zweizig et al18 (1997) Eddy et al19 (1997) Duska et al20 (1998) TOTAL
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Total Pap smears
AGUS Pap smears
Incidence (%)
21,930 34,384 17,000 68,368 46,804 177,715 120,338 486,539 84,442
100 620 30 136 127 1117 201 2331 345
0.46 1.8 0.18 0.20 0.27 0.63 0.17 0.48 0.53
No.
SIL (%)
AIS (%)
EMH (%)
CA (%)
63 277 30 77 85 531 73 1136 199
39.7 43.7 37 9.1 21.2 27 26 29.1 22.6
7.9 3.3
3.2
3.2 4
3.9 1.2 1.9
11.8 1.1
3.6 2.5
5.4 2.5
3.9 9.4 6 8.2 5.8 4
Pap, Papanicolaou smear; AGUS, atypical glandular cells of undetermined significance; Incidence, incidence of atypical glandular cells of undetermined significance on Papanicolaou smears; No., number of patients evaluated with biopsy specimens; SIL, high- and lowgrade squamous intraepithelial lesions; AIS, adenocarcinoma in situ; EMH, endometrial hyperplasia; CA, cancer.
for the 199 patients are represented in Fig 2. As can be seen in Table VII, the incidence of atypical glandular cells of undetermined significance and the prevalence of squamous intraepithelial lesions, adenocarcinoma in situ, endometrial hyperplasia, and cancer are within the range of previous studies. Atypical glandular cells of undetermined significance detected on cervical cytologic examination were associated with pathologic conditions in the final diagnosis of between 30% (favor benign) and 51% (favor neoplasia) of women (Tables III to VI). Among the 4 stratifications, the subset interpreted as favoring a benign process, representing approximately 20% of smears in our study, had the lowest incidence of pathologic conditions (30%). In contrast, the subset favoring a neoplastic process, also comprising approximately 20% of smears, had the highest incidence of pathologic conditions (51.1%). Fig 3 shows the incidence of preinvasive or invasive lesions (squamous intraepithelial lesion, adenocarcinoma in situ, endometrial hyperplasia, and cancer) and benign lesions (polyps or benign ovarian lesions) stratified by subtype of atypical glandular cells of undetermined significance. As can be seen, a higher incidence of preinvasive or invasive lesions was associated with squamous intraepithelial lesions and favor neoplasia than for favor benign and not otherwise specified subtypes. However, it is noteworthy that even in the group of women in whom the Papanicolaou smear was interpreted as representing a benign process or was not otherwise specified, there still existed a 15% to 24% incidence of preinvasive or invasive lesions confirmed by histopathologic analysis. Only in the favor benign stratification was there equal likelihood of finding a benign versus preinvasive or invasive lesion. In all other subgroups if a lesion was found it was more likely to be preinvasive or invasive than benign. Fig 4 illustrates the incidence of each preinvasive or invasive finding for each subclassification. In 8% to 20% of patients without associated squamous lesions on the
Papanicolaou smear, a squamous lesion was diagnosed on biopsy. The association between squamous lesions and glandular lesions of the cervix is undoubtedly related to 2 factors. First, as in cases of atypical squamous cells of undetermined significance, cases of atypical glandular cells of undetermined significance may be misclassified because of difficulty in seeing cellular detail because of poor preservation or obscuring inflammation. Second, and probably more important, both cervical glandular and squamous neoplasms are etiologically linked to human papillomavirus infection; hence the 2 lesions tend to coexist, although squamous lesions are diagnosed and confirmed approximately 20% to 100% more frequently than true glandular neoplasms are.21 Adenocarcinoma in situ, the final diagnosis in only 5 patients, was found in subtypes not otherwise specified and favor neoplasia only (Fig 4). However, of the 8 patients diagnosed with an invasive malignancy, 1 was included in the favor benign subgroup and 3 in the not otherwise specified category. This points to the fact that a diagnosis of atypical glandular cells of undetermined significance of any type may represent serious pathologic conditions. Recommendations have been made for aggressive workup of Papanicolaou smears with these glandular cells to rule out potential endocervical, endometrial, and, much more rarely, gastrointestinal, tubal, ovarian, or breast pathologic conditions. The American Society for Colposcopy and Cervical Pathology recently published guidelines for management of patients with atypical glandular cells of undetermined significance on Papanicolaou smears. All women with this diagnosis should undergo cervical and vaginal colposcopy and endocervical curettage. Those patients with unqualified atypical glandular cells of undetermined significance who have negative colposcopic examinations and endocervical curettage should have repeat Papanicolaou smears every 4 to 6 months until 4 normal smears have
388 Veljovich et al
been obtained. Those patients with either atypical glandular cells of undetermined significance favoring neoplasia with negative colposcopy and endocervical curettage or unqualified atypical glandular cells of undetermined significance with an endocervical curettage positive for neoplasia should undergo cervical conization. Endometrial biopsy, hysteroscopy, or a curettage is recommended if cells appear to be of endometrial origin.4 Until we can better understand the relationship between atypical glandular cells of undetermined significance on Papanicolaou smears and the underlying pathologic conditions through prospective trials evaluating follow-up for patients with this diagnosis, we support these guidelines for evaluation. This review contributes to the understanding of this diagnosis in 3 ways. First, our study reinforces the previously published concept that atypical glandular cells of undetermined significance on Papanicolaou smears represent a cytologic diagnosis with an associated high incidence of underlying malignant or premalignant lesions on follow-up histologic examination; thus this diagnosis should be worked up appropriately in accordance with the guidelines of the American Society for Colposcopy and Cervical Pathology. Second, the stratification of these smears by subtype may be valuable in assessing the risk of underlying pathologic conditions. Development of well-defined criteria for the diagnosis of various subtypes of atypical glandular cells of undetermined significance could potentially identify women at higher or lower risk for significant pathologic conditions and thus assist in triage of patients on the basis of subtypes. Careful discussion with the interpreting cytopathologist is crucial, however, in any situation when a management plan is being developed. Finally, our study further underscores the importance of diligent and persistent followup of the patient with atypical glandular cells of undetermined significance on cervical cytologic studies. Although the initial evaluation of patients failed to reveal significant pathologic conditions in 133 patients (67%), follow-up revealed significant conditions in 25 new patients (12.6%), with 12 of these 25 having squamous lesions, 1 adenocarcinoma in situ, and 1 cancer (adenosquamous carcinoma of the cervix). REFERENCES
1. National Cancer Institute Workshop. The 1988 Bethesda system for reporting cervical/vaginal cytological diagnoses. JAMA 1989;262:931-4. 2. International Academy of Cytology. The Bethesda system for reporting cervical/vaginal cytologic diagnoses. Acta Cytol 1993;37:115-24. 3. Kurman RJ, Solomon D. The Bethesda system for reporting cervical/vaginal cytologic diagnoses: definitions, criteria and explanatory notes for terminology and specimen adequacy. New York: Springer Verlag; 1994. 4. Cox JT. ASCCP practice guidelines: management of glandular abnormalities in the cervical smear. J Lower Genital Tract Dis 1997;1:41-5.
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5. Bose S, Kannan V, Kline T. Abnormal endocervical cells: really abnormal? really endocervical? Am J Clin Pathol 1994;101:70813. 6. Raab SS, Isacson C, Layfield LJ, Lenel JC, Slagel DD, Thomas PA. Atypical glandular cells of undetermined significance: cytologic criteria to separate clinically significant from benign lesions. Am J Clin Pathol 1995;104:574-82. 7. DiTomasso JP, Ramzy I, Mody DR. Glandular lesions of the cervix: validity of cytologic criteria used to differentiate reactive changes, glandular intraepithelial lesions and adenocarcinoma. Acta Cytol 1996;40:1127-35. 8. Raab SS, Snider TE, Potts SA, McDaniel H, Robinson RA, Nelson DL, et al. Atypical glandular cells of undetermined significance: diagnostic accuracy and interobserver variability using select cytologic criteria. Am J Clin Pathol 1997;107:299307. 9. van Aspert-van Erp AJM, van’t Hof-Grootenboer AB, Brugal G, Vooijs GP. Endocervical columnar cell intraepithelial neoplasia, I: discriminating cytomorphologic criteria. Acta Cytol 1995;39:1199-215. 10. van Aspert-van Erp AJM, van’t Hof-Grootenboer AB, Brugal G, Vooijs GP. Endocervical columnar cell intraepithelial neoplasia, II: grades of expression of cytomorphologic criteria. Acta Cytol 1995;39:1216-32. 11. Pacey F, Ayer B, Greenberg M. The cytologic diagnosis of adenocarcinoma in situ of the cervix uteri and related lesions, III: pitfalls in diagnosis. Acta Cytol 1988;32:325-30. 12. Lee KR. Atypical cells in cervical smears from women who have undergone cone biopsy: a potential diagnostic pitfall. Acta Cytol 1993;37:705-9. 13. Novotny DB, Maygarden SJ, Johnson DE, Frable WJ. Tubal metaplasia: a frequent potential pitfall in the cytologic diagnosis of endocervical glandular dysplasia on cervical smears. Acta Cytol 1992;36:1-10. 14. Goff BA, Atanasoff P, Brown E, Muntz HG, Bell DA, Rice LW. Endocervical glandular atypia in Papanicolaou smears. Obstet Gynecol 1992;79:101-4. 15. Taylor RR, Guerrieri JP, Nash JD, Henry MR, O’Connor DM. Atypical cervical cytology: colposcopic follow-up using the Bethesda system. J Reprod Med 1993;38:443-7. 16. Nasu I, Meurer W, Fu YS. Endocervical glandular atypia and adenocarcinoma: a correlation of cytology and histology. Int J Gynecol Pathol 1993;12:208-18. 17. Kennedy AW, Salmieri SS, Wirth SL, Biscotti CV, Tuason LJ, Travarca MJ. Results of the clinical evaluation of atypical glandular cells of undetermined significance (AGCUS) detected on cervical cytology screening. Gynecol Oncol 1996;63:14-8. 18. Zweizig S, Noller K, Reale F, Collis S, Resseguie L. Neoplasia associated with atypical glandular cells of undetermined significance on cervical cytology. Gynecol Oncol 1997;65:314-8. 19. Eddy GL, Strumpf KB, Wojtowycz MA, Piraino PS, Mazur MT. Biopsy findings in five hundred thirty-one patients with atypical glandular cells of uncertain significance as defined by the Bethesda system. Am J Obstet Gynecol 1997;177:1188-95. 20. Duska LR, Flynn CF, Chen A, Whall-Strojwas D, Goodman A. Clinical evaluation of atypical glandular cells of undetermined significance on cervical cytology. Obstet Gynecol 1998;91:27882. 21. Stoler MH. The biology of human papillomavirus. Pathol Case Rev 1997;2:1-13.
Discussion DR LAURIE HUDGINS, Blacksburg, Virginia (Official Guest). Fifty-five years ago Papanicolaou published his study demonstrating the value of cervical cytologic examination as a screening test for cancer of the cervix. Many adjustments in Papanicolaou smear categories and interpretation have been made over the years. The National Cancer Institute developed the Bethesda system in 1988 to establish consistent terminology for the reporting of
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Papnicolaou smears and to develop more specificity in categorizing abnormalities. Atypical glandular cells of undetermined significance was one of the new diagnostic categories. Once identified as a separate entity, we have been able to stud it regarding its clinical implications. The study of Veljovich et al contributes greatly to our understanding of the clinical relevance and therefore management of the Papanicolaou smear with atypical glandular cells of undetermined significance. First, it is worthy to note that this study’s incidence of atypical glandular cells of undetermined significance among all Papanicolaou smears is 0.53%, which is in the range of other study findings, about 0.3% to 0.8%. In comparison, the incidence of atypical squamous cells of undetermined significance, among all Papanicolaou smears, is quoted in the 3% to 10% range. Therefore the category of atypical glandular cells is much less likely to be encountered in a clinical setting than is the category of atypical squamous cells. However, the major “take-home” lesson is that when atypical glandular cells of undetermined significance are reported on a Papanicolaou smear it is a red flag that there is a very high risk of the existence of pathologic conditions. This study reveals overall significant pathologic findings in 45% of patients who had atypical glandular cells of undetermined significance on a Papanicolaou smear. Other studies find similar rates of pathologic conditions from 42% to as high as 83% in the workup of these reports. Again, to compare it with the category of atypical squamous cells of undetermined significance with which we are all so familiar, the squamous cells convey a much lower rate of underlying pathologic conditions of 10% to 40%. Another important clinical point of this study is the high incidence of squamous intraepithelial lesions uncovered in patients with atypical glandular cells of undetermined significance on Papanicolaou smear. There is a 38% incidence of squamous intraepithelial lesions in the subtype. In other subtypes where squamous intraepithelial lesions are not specifically noted on the Papnicolaou smear, there is still an 8% to 20% incidence of squamous lesions detected with histologic workup. Thus it is imperative that colposcopy and ectocervical biopsies as indicated be performed as part of the overall workup when atypical glandular cells of undetermined significance are detected on Papanicolaou smears. This study includes 199 patients with atypical glandular cells of undetermined significance on Papanicolaou smears with histologic follow-up. This series is at least twice as large as most of the other studies that have examined this issue and thus it substantially contributes to the accumulated data. In that this study does not include control groups, it is important to bear in mind that the reported percentages of pathologic conditions represent associations but do not necessarily have precise predictive values. One of the unique features of this study is the stratification of atypical glandular cells of undetermined significance into the 4 subtypes previously described and the conclusions regarding the clinical importance of such
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subtyping. The author concludes that subtyping may allow for the assessment of underlying pathologic conditions because the subtype favoring neoplasia had the highest percentage of both pathologic conditions and severity of pathologic conditions. However, I believe that it is important to recognize that classifying by subtype has no impact on the necessity of working up every case because even the “benign” subtype has a 30% risk of pathologic conditions. I have 2 specific questions. Was the histologic outcome of atypical glandular cells of undetermined significance on Papanicolaou smears correlated with patient factors such as age or hormone usage to see whether these factors might be associated with an increased risk of pathologic findings? Second, in light of recommendations by the American Society for Colposcopy and Cervical Pathology that the most vigilant follow-up should fall within the first 2 years after a Papnicolaou smear with atypical glandular cells of undetermined significance, were any trends noted as to a mean time frame during which pathologic conditions were eventually detected after an initial negative workup? Aside from this study, I am also concerned regarding new techniques for cervical cytologic studies such as liquid collection systems and thin-layer preparations and what impact they may have on interpretation and possibly on rates of underlying pathologic conditions. Future studies will be necessary to assess this. Because the frequency of cervical adenocarcinoma is increasing, studies regarding screening and detection of precursors and related lesions are very important. This study adds much to our understanding of the implications of the category of atypical glandular cells of undetermined significance found on the Papnicolaou smear. It also compels us to adhere strictly to the relatively recent protocol of the American Society of Colposcopy and Cervical Pathology for the workup of this finding. DR RAMEZ S. AZOURY, Norfolk, Virginia. Is there any correlation between atypical glandular cells of undetermined significance on the Papanicolaou smear and microglandular hyperplasia of the endocervix? Is there an association between the atypical glandular lesions and the atypical squamous lesions? DR VELJOVICH (Closing). I agree with Dr Hudgins that subtyping of all lesions would not be helpful in determining the management plan because all subtypes in our study had significant pathologic conditions and thus we would not recommend working up any one subgroup less aggressively at this point. Initially our pathologist felt that we would show that he could differentiate the more benign lesions from the more significant ones, but, as the study showed, this turned out to not always be the case. The smears with atypical glandular cells with squamous involvement did show much more squamous involvement than did those without squamous involvement, however. Dr Hudgins pointed out that typing would not affect your management very much at this point because any of these lesions can be associated with significant pathologic features. All people involved in obtaining Papanicolaou smears need to be aware of the discrep-
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ancy between smears with atypical glandular cells in which a benign process is favored by the pathologist but follow-up shows a significant lesion. The person who is reading the smear must communicate well with the clinician. With respect to Dr Hudgins’ question regarding patient factors such as age or hormone usage and their association with pathologic findings, our study did not evaluate age or hormonal status in the patient population with respect to lesions. Zweizig et al1 looked at age, parity, gravidity, menopausal status, abnormal bleeding, current hormone replacement therapy, and oral contraceptive use and did not find any significant association between these factors and more advanced lesions. They did find, however, that no woman <35 years old had endometrial pathologic findings and thus they recommend an endometrial biopsy for the subset of women >35 years old. We did not evaluate what features of follow-up would allow a person to return to a routine screening category, but this would be a very interesting study, ideally in a randomized controlled trial of follow-up. In reference to the newer “thin prep” technique, there is considerable “brush artifact” in conventional smear technique with large sheets of normal endocervical cells that can mimic nuclear overlap, which can be confused with atypical glandular cells. With the new cell suspension systems, if the cells were placed on a monolayer, it would likely prove less confusing for the pathologist reading the smear. In reference to Dr Azoury’s question, we did not find
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microglandular hyperplasia in any of our patients as others have.2 In reference to the question about whether there is an association between the atypical glandular lesions and the atypical squamous lesions, this does suggest a “field” effect of human papillomavirus. A large number of atypical endocervical neoplasms do have human papillomavirus–positive typing.3, 4 In the glandular lesions the human papillomavirus types tend to be type 18 as opposed to type 16, which is more common in squamous lesions.5 Additionally, many squamous cell carcinoma in situ lesions will extend into a gland crypt, and this may lead to confusion when these cells are examined microscopically.6 REFERENCES
1. Zweizig S, Noller K, Reale F, Collis S, Resseguie L. Neoplasia associated with atypical glandular cells of undetermined significance on cervical cytology. Gynecol Oncol 1997;65:314-8. 2. Nasu I, Meurer W, Fu YS. Endocervical glandular atypia and adenocarcinoma: a correlation of cytology and histology. Int J Gynecol Pathol 1993;12:208-18. 3. Alejo M, Macedo I, Matias-Guiu X, Prat J. Adenocarcinoma in situ of the uterine cervix: clinicopathological study of nine cases with detection of human papillomavirus DNA by in situ hybridization and polymerase chain reaction. Int J Gynecol Pathol 1993;12:219-23. 4. Samaratunga H, Cox N, Wright RG. Human papillomavirus DNA in glandular lesions of the uterine cervix. J Clin Pathol 1993;46:718-21. 5. Stoler MH. The biology of human papillomavirus. Pathol Case Rev 1997;2:1-13. 6. Selvaggi SM. Cytologic features of squamous cell carcinoma in situ involving endocervical glands in endocervical Cytobrush specimens. Acta Cytol 1994;38:687-92.
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