Atypical Glandular Cells Forum –Recommendations revised post-meeting



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Atypical Glandular Cells Forum –Recommendations revised post-meeting



Issue 1: AIS as a discrete entity; Atypical Glandular Cell Qualifiers



Background and Workshop Discussion:

  1. In the 1991 terminology, AIS was included in “AGUS, probably neoplastic”. Since that time, studies have clearly documented the excellent predictive value and reproducibility of properly applied cytologic criteria for the diagnosis of AIS. (Solomon DS, Acta Cytol 1998;42:16-24)

  2. Due to the finding of neoplastic processes in a significant number of cases following an interpretation of “AGUS, favor reactive,” and the inherent false sense of security that such a “benign” sounding interpretation might transmit to the clinician, the use of this qualifier in any case has been questioned. Study results show significant levels of positive follow-up in cases categorized as AGUS, favor reactive. Follow-up diagnoses of high grade lesions (any type) may be seen in 5 to 39% of such cases (Appendix A- multiple references as listed in table). Anecdotal evidence (Bethesda website) suggests that an interpretation of “AGUS, favor reactive” does not uniformly elicit an appropriate clinical response and hence some patients harboring unrecognized lesions may not be properly managed.

2&3) It was reported at the meeting that there are significant problems with overlap confusion between the categories of ASCUS and AGUS, particularly with regard to the similarity of terminology. Pooling of these results for management purposes in many offices creates a situation where the more problematic category of AGUS may be therefore undermanaged.
Recommendations:

  1. “Endocervical adenocarcinoma in situ” should be added as a discrete interpretation/diagnosis when criteria are adequate for this interpretation. In cases showing near complete features (criteria) of AIS, an intermediate category of “Atypical endocervical cells, probably AIS” is appropriate as it will convey a significant level of concern to the clinician in order to prompt appropriate follow-up.

  2. The category “Atypical glandular/endocervical/endometrial cells” should be retained, however, the qualifier “of undetermined significance” (AGUS) should be eliminated to avoid confusion with ASCUS. Where appropriate, add a qualifying statement to “atypical glandular cells” which transmits more specific information to the clinician.

In addition, the qualifier “favor reactive” should be eliminated. The qualifier “favor neoplastic” should be retained; where appropriate, the interpretation may be further specified. Categories under the “atypical glandular” heading:


Atypical Glandular/Endocervical/Endometrial Cells (unqualified)
Atypical Glandular/Endocervical Cells, Favor Neoplastic

- specify further in description

The caveat in this approach is that the criteria for “atypical glandular cells” are less reproducible and predictive than for AIS or adenocarcinoma, with greater range of morphologies and processes found on follow-up. Close attention to laboratory interpretation/diagnosis rates (discussed below) must be maintained in order that overuse of the “Atypical glandular cell” category does not lead to aggressive management of the “benign/reactive” end of the interpretative spectrum.
3) To highlight the glandular nature of the findings, it was proposed that the General Categorization include, in addition to “Epithelial cell abnormality,” the specific cell type (i.e. squamous or glandular). Therefore, the General Categorization for a glandular cell abnormality would be as follows:

Epithelial Cell Abnormality, Glandular

It was felt that this distinction would better allow clinicians (and their support staff) to more appropriately triage such cases.

Issue 2: Atypical Glandular Cell Classification as of Endocervical, Endometrial, or Undetermined Origin
Background:


  1. Can “Atypical glandular cells” be reliably subcategorized as endocervical or endometrial in origin? In the 1991 TBS, cytologic criteria have been clearly defined allowing for differentiation between endometrial and endocervical origin. The work-up and follow-up of patients with glandular abnormalities may vary significantly depending upon cell type and clinical findings (e.g. age, menstrual status, prior Pap smear findings). These facts justify the continued differentiation of cell abnormalities between endocervical and endometrial origin whenever possible (Wilbur DC, Gynecologic Cytopathology,1997,107-156);

2) A question has been raised as to whether a separate category of “atypical epithelial cells” should be added to the terminology for use in cases where a specific origin (squamous, endocervical, endometrial) cannot be reliably determined. Currently, “atypical epithelial cells” may be used when the histologic cell type is uncertain. Further studies are needed to identify criteria that better distinguish squamous lesions with glandular features (often due to gland involvement) from true glandular abnromalities.


Recommendations:

  1. Atypical glandular cells can and should be qualified as to endocervical or endometrial origin whenever possible. This will occur in the majority of cases. When the distinction cannot be made, the cytology report should indicate the uncertainty;

  2. The possibility of reporting “atypical epithelial cells (NOS)” currently exists within the 1991 TBS by using the free text provision of TBS – no new recommendation.



Issue 3: The Presence of Benign Glandular Cells in the Specimens from Post-Hysterectomy Women
Background: Benign-appearing glandular cells, including squamous-metaplastic-like cells, endocervical-type cells, and glandular cells, NOS, are infrequently identified in vaginal smears from patients who are post-hysterectomy. Questions have been raised about the origin of these cells and their significance in relation to neoplastic cells or precursors. Should such cases warrant a cytologic interpretation of AGUS or other “benign” category.
Data from the literature show that no patient having benign glandular cells in vaginal smears post-hysterectomy developed recurrent or de novo neoplastic lesions regardless of the history of prior malignancy. (Ponder TB, Acta Cytol 1997;41:1701-1704; Tambouret R, Acta Cytol 1998;42:1403-1408; Ramirez NC, Eur J Gynaecol Oncol 2000;21:43-48). The likely origins of these benign cells include: prolapse of uterine tube, vaginal endometriosis, fistula, vaginal adenosis not associated with DES exposure, or glandular metaplasia associated with prior radiation or chemotherapy. (Tambouret R, Acta Cytol 1998;42:1403-1408; Ramirez NC, Eur J Gynaecol Oncol 2000;21:43-48)
Recommendations:

At the Workshop, it was agreed that reporting benign glandular cells in specimens from post-hysterectomy patients may convey useful information to clinicians and will therefore be included in the Bethesda lexicon under Non Neoplastic findings. These findings are considered benign and do NOT warrant an interpretation/diagnosis of “atypical glandular cells”. The General Categorization of such cases should be “Negative for intraepithelial lesion or malignancy”.



Issue 4: Morphologic Criteria for Atypical Glandular Cells and AIS



Background: The 1991 Bethesda System terminology provides criteria for the following under AGUS (see Appendix B):


  1. Atypical Endometrial Cells of Undetermined Significance

  2. Atypical Endocervical Cells, Favor Reactive

  3. Atypical Endocervical Cells, Probably Neoplastic

1) Is there a rationale for utilizing the term “endocervical glandular dysplasia” or “low grade glandular intraepithelial lesion” as for squamous lesions? 2) Do AGUS (to be changed to Atypical Glandular Cells) criteria require revision in light of increased knowledge? 3) Is revision of these criteria required in light of the widespread use of the new liquid-based methods of specimen preparation?


Recommendations:

1) “Low grade glandular intraepithelial lesion” and/or “endocervical glandular dysplasia” should not be utilized. 2) Proposed criteria for AIS and Atypical Glandular Cells were presented at the meeting. These criteria will serve as a starting point for the criteria committee to use in updating the Bethesda System Atlas. (see Appendix C). 3) Criteria for AIS in liquid-based specimens should be altered slightly from the criteria for conventional smears. (see Appendix D). Criteria cited in the Appendix are for the most common (“endocervical”) variant of AIS. Other variants exist in a minority of cases for which the criteria may be altered.

Rationale:

1) There is no evidence to suggest that “endocervical glandular dysplasia” or “low grade glandular intraepithelial lesion” should be adopted as a separate category. Interpretations of “endocervicval dysplasia” have shown significantly lower levels of HPV-positivity than have interpretations of AIS or endocervical adenocarcinoma, strongly supporting a non-neoplastic etiology for many such cases. (Leary J, Pathologica 1991;23:85-89; Farnsworth A. Int J Gynecol Pathol 1989;8:321-330) Using such terminology would mislead clinicians accustomed to high rates of specificity for interpretations of low grade squamous lesions. 2) Criteria have been well-established for AIS and the literature shows both high predictive value for a histologic followup of AIS (Solomon DS, Acta Cytol 1998;42:16-24, Betsill W, Acta Cytol 1986;30:115-26, Lee KR, Acta Cytol 1991;35:117-26; Selvaggi S, Diagn Cytopath 1997;16:168-73; Biscotti CV, Diagn Cytopathol 1997;17:326-32). Criteria for “Atypical endocervical cells, favor neoplastic” or “Atypical glandular cells” are considered to be the presence of some but not all the criteria as outlined for AIS, or other “atypical” presentation which should be individually categorized in a qualifying statement. Criteria which have been shown to be of use in differentiating benign from neoplastic outcomes in cases classified as Atypical Glandular Cells are: irregular nuclear membranes, atypical single cells, and decreased cytoplasm. (Raab SS, Am J Clin Pathol 1995;104:574-582. 3) Although most criteria for AIS directly translate to liquid-based specimens, some differences in the presentation of cases of AIS in liquid-based specimens have been documented in the literature. (Wilbur DC, Diagn Cytopathol 1996;14:201-211, Roberts JM, Acta Cytol 1999;43:74-80, Johnson JE, Acta Cytol 1999;43:369-75)




Issue 5: Prevalence of AGUS and Histologic Outcomes Following an AGUS Interpretation

Background:

1) What is an acceptable rate of AGUS interpretations in the typical cytology laboratory? Monitoring of this rate is important to prevent overuse with subsequent inappropriate clinical interventions. 2) What has been found in the histologic and/or clinical followup of cases interpreted as AGUS?


Recommendations:

AGUS (to be changed to “atypical glandular cells”—see issue #1) rates in the typical cytology laboratory should be less than 1%, with compiled series showing means between 0.3 and 0.5%. Atypical Glandular Cells” prevalence and follow up data can be used to monitor laboratory performance in these areas. Careful examination should take place regarding the use of proper cytologic criteria and of followup of outcomes in laboratories showing AGUS (to become “atypical glandular cells”) rates falling above 1% to avoid overuse. These data are given for use in laboratories as quality assurance baselines. Deviations from these figures should be explained as part of a laboratory’s overall quality assurance program.


Rationale: 1) AGUS Rates – The reported incidence of AGUS from the literature varies from 0.1% to 1.8%, with a mean near 0.5%. (Table 2 in Appendix E) In the CAP survey, the median AGUS rate was 0.3%, with the 10th and 90th percentiles at 0% and 1.3%, respectively. (Jones B, Arch Pathol Lab Med 1996;120:523-531) In liquid-based specimens, AGUS rates are similar to conventional smears, however, follow-up with more significant lesions appears to be greater. (Roberts JM, Acta Cytol 1999;43:74-80; Ashfaq R, Acta Cytol 1999;43:81-85; Eltabbakh G,Gynecol Oncol 2000;78:245-250)
2) AGUS Followup - According to the CAP Q probes survey, 39.6% of AGUS on follow-up were found to have squamous intraepithelial lesions, 5.8% with adenocarcinoma in situ and 5.8% with carcinoma (Jones B, Arch Pathol Lab Med 2000;124:672-681). Follow-up with SIL ranges from a low of 9.1% (Kennedy AW, Gynecol Oncol 1996;63:14-18) to a high of 43.7% (Nasu I, Int J Gynecol Pathol 1993;12:208-218). Follow-up with carcinomas ranged from a low of 3.2% (Goff BA, Obstet Gynecol 1992;79:101-104) to a high of 9.4% (Zweizig S, Gynecol Oncol 1997;65:314-318). Follow-up with adenocarcinoma in situ ranged from a low of 1.2% (Zweizig S, Gynecol Oncol 1997;65:314-318) to a high of 7.9% (Goff BA, Obstet Gynecol 1992;79:101-104). In the post-menopausal population, the frequency of follow-up of AGUS with endometrial and endocervical polyps was greater than that of either endometrial hyperplasias or adenocarcinomas. A small number of SIL and other carcinomas were detected (7%). The carcinoma detected in post-menopausal patients with AGUS was endometrial or extrauterine. (Oberson K, Acta Cytol 2000;44:141-145)

Issue 6: Clinical management of AGUS (NOTE: THE FOLLOWING IS INCLUDED AS AN APPENDIX FOR DISCUSSION PURPOSES AND TO PROVIDE INPUT FOR THE MANAGEMENT CONFERENCE TO BE HELD SEPTEMBER 6-9, 2001. THE BETHESDA CONFERENCE WILL NOT BE DEVELOPING MANAGEMENT GUIDELINES, HOWEVER CONSIDERATION OF MANAGEMENT IS IMPORTANT IN DEVELOPING TERMINOLOGY.)

(See Appendix F)

References:




  1. Eddy GL, Stumpf 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;177:1188-1195.

  2. Goff BA, Atanasoff P, Brown E, Muntz HG, Bell DA, Rice LW. Endocervical glandular atypia in Papanicolaou smears. Obstet Gynecol 1992;79:101-104.

  3. Kim TJ, Kim HS, Park CT, Hong SR, Park JS, Shim JU. Clinical evauation of follow-up methods and results of atypical glandular cells of undetermined signifcance (AGUS) detected on cervicovaginal pap smears. Gynecol Oncol 1999;73:292-298.

  4. Lee KR, Manna EA, St. John T. Atypical endocervical glandular cells: accuracy of cytologic diagnosis. Diagn Cytopathol 1995;13:202-208.

  5. Nasu I, Meurer W, Fu YS. Endocervical glandular atypia and adenocarcinoma: a correlation of cytology and histology. Int J Gynecol Pathol 1993;12:208-218.

  6. Manetta A, Keefe K, Lin F, Ahdoot D, Kaleb V. Atypical glandular cells of undetermined significance in cervical cytologic findings. Am J Obstet Gynecol 1999;180:883-888.

  7. Raab SS, Isacson C, Layfield LJ, Lenel JC, Slagel DD, Thomas PA. Atypical glandular cells of undetermined significance: cytologic criteria to separate clinically signifcant from benign lesions. Am J Clin Pathol 1995;104:574-582.

  8. Raab SS, Snider TE, Potts SA, McDaniel HL, 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;107:299-307.

  9. Ronnette B, Manos MM, Ransley JE, Fetterman BJ, Kinney WK, Hurley LB et al. Atypical glandular cells of undetermined significance (AGUS):cytopathologic features, histopathologic results, and human papillomavirus DNA detection. Hum Pathol 1999;30:816-825.

  10. Schindler S, Pooley RJ, De Frias DVS, Yu GH, Bedrossian CW. Follow-up of atypical glandular cells in cervical-endocervical smears. Ann Diagn Pathol 1998;312-317.

  11. 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;38:443-447.

  12. Veljovich DS, Stoler MH, Andersen WA, Covell JL, Rice LW. Atypical glandular cells of undetermined significance: a five-year retrospective histopathologic study. Am J Obstet Gynecol 1998;179:382-390.

  13. Korn AP, Judson PL, Zaloudek CJ. The importance of atypical glandular cells of uncertain significance in cervical cytology smear. J Reprod Med 1998;43:774-778.

  14. Burja IT, Thompson SK, Sawyer WL, Shurbaji MS. Atypical glandular cells of undetermined significance in cervical smear. Acta Cytol 1999;43:351-356.

  15. Gornall RJ, Singh N, Noble W, Boyd IE, Hitchcock A. Glandular abnormalities on cervical smear: a study to compare the accuracy of cytologic diagnosis with underlying pathology. Eur J Gynaecol Oncol 2000;21:49-52.

  16. Roberts JM, Thurloe JK, Bowditch RC, Humcevic J, Laverty CRA. Comparison of ThinPrep and Pap smear in relation to prediction of adenocarcinoma in situ. Acta Cytol 1999;43:74-80.

  17. Solomon DS, Frable WJ, Vooijs GP, Wilbur DC, Amma NS, Collins RJ et al. ASCUS and AGUS Criteria: IAC Task Force Summary. Acta Cytol 1998;42:16-24.

  18. Wilbur DC. The cytology of the endocervix, endometrium, and upper female genital tract. In Gynecologic Cytopathology, Bonfiglio TA and Erozan YS (eds). Philadelphia: Lippincott-Raven, 1997, pp. 107-156.

  19. Betsill WL, Clark AH. Early endocervical glandular neoplasia. I. Histomorphology and cytomorphology.. Acta Cytol 1986;30:115-26.

  20. Lee KR, Manna EA, Jones MA. Comparative cytologic features of adenocarcinoma in situ of the uterine cervix. Acta Cytol 1991;35:117-26.

  21. Selvaggi S, Haefner HK. Microglandular endocervical hyperplasia and tubal metaplasia: pitfalls in the diagnosis of adenocarcinoma on cervical smears. Diagn Cytopath 1997;16:168-73.

  22. Biscotti CV, Gero MA, Toddy SM, Fischler DF, Easley KA. Endocervical adenocarcinoma in situ: an analysis of cellular features. Diagn Cytopathol 1997;17:326-32.

  23. Farnsworth A, Laverty C, Stoler MH. Human papillomavirus messenger RNA expression in adenocarcinoma in situ of the uterine cervix. Int J Gynecol Pathol 1989;8:321-330.

  24. Leary J, Jaworski R, Houghton R. In-situ hybridization using biotinylated DNA probes to human papillomavirus in adenocarcinoma-in-situ and endocervical glandular dysplasia of the uterine cervix. Pathologica 1991;23:85-89.

  25. Wilbur DC, Dubeshter B, Angel C, Atkison KM. Use of thin-layer preparation s for gynecologic smears with emphasis on the cytomorphology of high-grade intraepithelial lesions and carcinomas. Diagn Cytopathol 1996;14:201-211.

  26. Johnson JE, Rahemtulla A. Endocervical Glandular Neoplasia and its Mimics in ThinPrep Pap Tests: A Descriptive Study. Acta Cytol 1999;43:369-75.

  27. Jones B, Novis D. cervical biopsy-cytology correlation: a College of American Pathologists Q-Probes study of 22,439 correlations in 348 laboratories. Arch of Pathol and Lab Med 1996;20:523-531.

  28. Kennedy AW, Salmieri SS, Wierth SL, Biscotti CV, Tuason LJ, Travarca MG. Results of the clinical evaluation of atypical glandular cells of undetermined significance (AGCUS) detected on cervical cytology screening. Gynecol Oncol 1996;63:14-8.

  29. Zweizig S, Noller K, Real EF, Collin S, Ressegue L. Neoplasia associated with atypical glandular cells of undetermined significance on cervical cytology. Gynecol Oncol 1997;65:314-8.

  30. 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;91:278-82.

  31. Soofer S and Sidawy M. Atypical glandular cells of undetermined significance: clinically significant lesions and means of patient follow-up. Cancer Cytopathol 2000;90:4; 207-213.

  32. Obenson Ken, Abrero F and Grafton W. Cytohistologic correlation between AGUS and biopsy- detected lesions in post-menopausal women. Acta Cytologica 2000;44:1;41-45.

  33. Ashfaq R, Gibbons D, Vela C, Saboorian H, Iliya F. Thin Prep pap test: Accuracy for glandular disease. Acta Cytol 1999;43:81-85, 1999.

  34. Eltabbakh GH, Lipman JN, Mount SL, Morgan A. Significance of atypical glandular cells of undetermined significance on ThinPrep Papanicolaou smears. Gynecol Oncol 2000;78:245-50.

  35. Ponder TB, Easley KO, Davila RM. Glandular cells in vaginal smears from posthysterectomy patients. Acta Cytol 1997;41:1701-1704.

  36. Tambouret R, Pitman MB, Bell DA. Benign glandular cells in posthysterectomy vaginal smears. Acta Cytol 1998;42:1403-1408.

  37. Ramirez NC, Sastry LK, Pisharodi LR. Benign glandular and squamous metaplastic-like cells seen in vaginal Pap smears of post hysterectomy patients: incidence and patient profile. Eur J Gynaecol Oncol 2000;21:43-48.

  38. American College of Obstetricians and Gynecologists. Cervical cytology: Evaluation and management of abnormalities. ACOG Technical Bulletin No. 183. Washington DC. The American College of Obstetricians and Gynecologists,1993.

  39. Cox JT (lead author). ASSCP Practice Guideline: Management of glandular

abnormalities in the cervical smear. J Lower Gen Tract Dis 1997;1:41-45.

40) Partridge E. NCCN Practice Guidelines for cervical cancer screening. Oncology 1999;13:550-74.



  1. Chin AB, Bristow RE, Korst LM, Walts A, Lagasse LD. He significance of atypical glandular cells on routine cervical cytologic testing in a community-based population. Amer J Obset Gynecol 2000;182:1278-82.

  2. Cheng RF, Hernandez E, Anderson LL, Heller PB, Shank R. Clinical significance of a cytologic diagnosis of atypical glandular cells of undetermined significance. J Reprod Med 1999;44:922-28).




  1. Ronnett BM, Mano MM, Ransley JE, Fettterman BJ, Kinney WK, Hu LB, Ngai JS, Kurman RJ, Sherman ME. Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papilomavirus DNA detection. Hum Pathol 1999;30:816-25.

  2. Chhieng DC, Elgert PA, Cangiarella JF, Cohen J-M: Clinical significance of atypical glandular cells of undetermined significance: A follow-up study from an academic medical center. Acta Cytol 2000;44:557-566.

  3. van Aspert van Erp AJ, van't Hof Grootenboer AE, Brugal G, Vooijs GP:Individual use of cytomorphologic characteristics in the diagnosis of endocervical columnar cell abnormalities: selection of preferred features with help of the 'Navigator' microscope. Anal Cell Pathol 1996;11:73-95.

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