Benign Cellular Changes: Recommendations after the Bethesda Conference forum: Benign Cellular Changes and Infections

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Benign Cellular Changes: Recommendations after the Bethesda Conference

FORUM: Benign Cellular Changes and Infections


What terminology should be used for negative and reactive specimens in the General Categorization?
Benign cellular changes (BCC) used as a General Categorization in the 1991 TBS was felt to be ambiguous to clinicians. It was suggested that this be eliminated. Various options based on bulletin board responses were presented to the meeting participants. The almost unanimous consensus was to combine Benign Cellular Changes and Within Normal Limits into one "negative" category, "Negative for intraepithelial lesion or malignancy". "Intraepithelial lesion" terminology was preferred over "dysplasia" or "CIN" in order to be uniform with the rest of The Bethesda System. "Negative" was suggested as a concise term for verbal communication, however the entire phrase "Negative for intraepithelial lesion or malignancy" is preferred in the report so that organisms and other benign cellular changes may be included under this general category.



Negative for intraepithelial lesion or malignancy (includes organisms and reactive cellular changes)

Epithelial cell abnormality: (Specify squamous or glandular as appropriate) (See interpretation/diagnosis)

Other: (See interpretation/diagnosis) (includes conditions that do not fit under the first two categories such as exfoliated endometrial cells in a woman over 40 years of age and non-epithelial malignancies)
Use of the General Categorization is still considered optional. Note that the General Categorical heading of "Negative for intraepithelial lesion or malignancy" can also be used as an interpretation/diagnosis. However, the categories of “Epithelial Cell Abnormality” and/or “Other” require an additional interpretation/diagnosis be included in the report.
The workshop participants also recommended that “Epithelial Cell Abnormality be qualified as squamous or glandular as appropriate.

Issue 2: Should non neoplastic cellular changes be included in the report and if so, where? Should the list of non-neoplastic cellular changes be modified?
There have been published criticisms of the overuse of reactive changes in cytology reports. 13, 17 A 1992 survey questionnaire from the CAP sent to laboratories participating in the Interlaboratory Comparison Program in Cervicovaginal Cytology (PAP) found wide interlaboratory variation in the percentage of cases reported as reactive10 and the least concordant response rate for participant responses in the PAP program has consistently been for reactive/reparative changes. 3, 4, 11 Cases that are clearly reactive should be downgraded to a negative diagnosis, and those that are questionably neoplastic should be upgraded to "atypical".
Clinicians attending this Bethesda conference were not as interested in retaining reactive terminology as the laboratorians. Clinicians at the meeting were not able to identify one reactive cellular change that was clinically useful to document on the report. However as a concept and as a reporting vocabulary, reactive terminology creates a discipline in applying criteria during screening and sign out. It also sensitizes and educates clinicians to the pitfalls and diagnostic issues that we encounter. Documentation of reactive changes in the report may allow one to spot trends in a series of smears. Another argument for explicitly commenting on reactive cellular changes is that studies have reported a small increased incidence of SIL in reactive cases over those diagnosed as "WNL".2, 14, 16 Retrospectively we may be able to identify certain types of reactive cellular changes or other non-neoplastic cellular changes that do have clinical significance and should be recognized. However, there are no current guidelines that differentiate management of patients with reactive cellular changes from those who have "within normal limits" smears. Clinicians accepted having reactive terminology in the report as long as it would be accompanied by the general category/interpretation "negative for intraepithelial lesion or malignancy".

Another interest pathologists have in retaining reactive terminology in the report is for medical legal documentation. Interpretive errors are a factor in false negative Pap tests originally diagnosed as reactive. 12 It was felt that if one documents observations in the report, liability may be lessened by showing that although an interpretive error was made, one was not negligent in missing cells.

Finally, reactive terminology is useful for the laboratory as a triage tool to satisfy CLIA regulations that stipulate referral of reactive /reparative changes to a pathologist for review. However the 1991 Bethesda Classification System was published prior to the 1992 Federal Register containing the CLIA regulations. The inclusion of certain non-neoplastic conditions, including infections, under Benign Cellular Changes in the 1991 Bethesda Classification has caused confusion for laboratories in their attempts to comply with the law.


For General Categorization: Include reactive cellular changes and other non-neoplastic findings within "Negative for intraepithelial lesion or malignancy"
For Interpretations/Diagnoses include in Bethesda 2001 the following:

Reactive cellular changes associated with:

Inflammation (includes typical repair)


Intrauterine contraceptive device (IUD)

Other Findings
A compromise derived at the meeting is to retain “Reactive Cellular Changes associated with inflammation, radiation, and IUD” in the Bethesda lexicon, but such interpretations/diagnoses fall under the General Categorization of “Negative for intraepithelial lesion or malignancy”. Use of reactive diagnoses is optional as is the reporting format. Reactive cellular changes may be included in the interpretation/diagnosis section of the report or in a separate "slide characteristics" section which may also include other non-neoplastic findings such as inflammation or blood. However, any reference to factors obscuring adequate visualization of the specimen belongs in the Adequacy section of the report.
Atrophy is not a reactive condition and would no longer be in the list of reactive cellular changes. Questionably atypical cellular changes associated with atrophy or atrophy with inflammation should be dealt with as a possible epithelial cell abnormality and warrant hierarchical review. Description of other non-neoplastic findings such as atrophy would be included for educational purposes in a revised Bethesda Manual, but would not be listed in the 2001 Bethesda Classification system. Additional non-neoplastic cellular changes can be documented in the report at the discretion of the pathologist in the diagnostic field or in a "slide characteristics" section. Procedures for hierarchical review of non-neoplastic cellular changes other than reactive and reparative cellular changes will be left to the discretion of individual laboratory policy.

Issue 3: Where should infections be listed within the terminology and in the report?

Not all organisms cause infections but may represent colonization. Furthermore, organisms may occur with or without accompanying cellular changes. Inclusion of organisms in the Benign Cellular Changes category in the 1991 Bethesda System has been confusing to both laboratorians and clinicians.

The consensus of opinion at the conference was to change the "infections" category to "organisms".
In the absence of epithelial cell abnormalities or conditions that would justify the general category of "Other", organisms belong under the general category and descriptive interpretation "negative for intraepithelial lesion or malignancy". It should be listed prominently in the diagnosis/Interpretation section of the report to avoid a significant infection from being overlooked. Reactive cellular changes or other non-neoplastic cellular changes may be listed as well at the discretion of the pathologist, but under the general category of negative for intraepithelial lesion or malignancy.

Issue 4:

Should there be a modification of the infection list?
There was not much controversy surrounding the infection list. The question was raised by the BCC/Infection committee whether Chlamydia spp should be added to the list of infections to be diagnosed by Papanicolaou smear. The reliablility of the diagnosis of Chlamydia by Pap smear is still an area of controversy in the literature1, 6. However the almost universal consensus among bulletin board and meeting participants was that Chlamydia is not a reliable diagnosis on Pap smear. One individual made the point that we would not want to introduce the idea to clinicians that the Pap smear can be used in lieu of standard Chlamydia testing because it is cheaper.
There was a limited discussion surrounding the term "Predominance of coccobacilli consistent with shift in vaginal flora". Some consider “true” Clue cells (defined as a squamous cell completely covered with coccobacillary organisms that stretch beyond the outline of the cell ) to be diagnostic of G. vaginalis infection while a simple shift in vaginal flora or less extensive coverage of the cell is not as specific for this infection.9
Specifying the organism “Gardnerella vaginalis" was suggested; however, other bacteria such as Bacteroides, Mobiluncus, peptococci and peptostreptococci have been associated with bacterial vaginosis.7, 8 The current Bethesda system terminology does not specify an organism for this reason. The overwhelming majority of meeting participants agreed that the current terminology "shift in vaginal flora" is vague and the possibility of the clinical condition, bacterial vaginosis (which has been associated with pelvic inflammatory disease, preterm birth, postoperative gynecologic infections, and abnormal Pap smears5, 15) should be mentioned.

Trichomonas Vaginalis

Fungal organisms morphologically consistent with Candida spp

Shift in vaginal flora suggestive of bacterial vaginosis

Bacteria morphologically consistent with Actinomyces spp

Cellular changes associated with Herpes simplex virus

Chlamydia should not be listed as an infectious entity in the Bethesda System to be diagnosed routinely on Pap smear. (No change)
Change the term "Predominance of coccobacilli consistent with shift in vaginal flora" to "Shift in vaginal flora suggestive of bacterial vaginosis" The clinician can then use clinical judgment to determine if additional tests or treatment is indicated.

Example: A"Negative for intraepithelial lesion or malignancy" report that contains an organism and reactive cellular changes:

  • Specimen Adequacy

Satisfactory for evaluation

  • General Negative Statement

Negative for intraepithelial lesion or malignancy

  • Organisms

Trichomonas Vaginalis

  • Reactive/reparative statement (optional)

Reactive cellular changes associated with inflammation

The Forum Moderators

Nancy Young, M.D., Marluce Bibbo, M.D., Sally-Beth Buckner, CT(ASCP), Terence Colgan, M.D., Dorothy Rosenthal, M.D., and Edward Wilkinson, M.D.

1. Banuelos Panuco CA, Deleon Rodriguez I, Hernandez Mendez JT, Martinez Guzman LA, Akle Fierro D, Miranda Murillo J, et al. Detection of Chlamydia trachomatis in pregnant women by the Papanicolaou technique, enzyme immunoassay and polymerase chain reaction. Acta Cytol 2000;44(2):114-23.

2. Barr Soofer S, Sidawy MK. Reactive cellular change: is there an increased risk for squamous intraepithelial lesions? [see comments]. Cancer 1997;81(3):144-7.

3. Colgan TJ, Woodhouse SL, Styer PE, Kennedy M, Davey DD. Reparative Changes and the False-Positive/False-Negative Papanicolaou Test. Arch Pathol Lab Med 2001;125(1):134-40.

4. Davey DD, Nielsen ML, Frable WJ, Rosenstock W, Lowell DM, Kraemer BB. Improving accuracy in gynecologic cytology. Results of the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology [see comments]. Arch Pathol Lab Med 1993;117(12):1193-8.

5. Donders GG, Van Bulck B, Caudron J, Londers L, Vereecken A, Spitz B. Relationship of bacterial vaginosis and mycoplasmas to the risk of spontaneous abortion. Am J Obstet Gynecol 2000;183(2):431-7.

6. Edelman M, Fox A, Alderman E, Neal W, Shapiro A, Silver EJ, et al. Cervical papanicolaou smear abnormalities and Chlamydia trachomatis in sexually active adolescent females. J Pediatr Adolesc Gynecol 2000;13(2):65-9.

7. Giacomini G, Paavonen J, Rilke F. Microbiologic classification of cervicovaginal flora in Papanicolaou smears. Acta Cytol 1989;33(2):276-8.

8. Giacomini G, Schnadig VJ. The cervical Papanicolaou smear: bacterial infection and the Bethesda System. Acta Cytol 1992;36(1):109-10.

9. Gupta PK. Microbiology,Inflammation, and Viral Infections. In: Bibbo M, editor. Comprehensive Cytopathology. Philadelphia: W.B.Saunders Company; 1991.

10. Interlaboratory Comparison Program in Cervicovaginal Cytopathology (PAP)1992 PAP Supplementary Questionnaire Summary. Northfield: College of American Pathologists; 1992. p. 9.

11. Interlaboratory Comparison Program in Cervicovaginal Cytopathology (PAP)1999 PAP Year End Summary. Northfield: College of American Pathologists; 2000. p. 22.

12. Jones BA. Rescreening in gynecologic cytology. Rescreening of 3762 previous cases for current high-grade squamous intraepithelial lesions and carcinoma-- a College of American Pathologists Q-Probes study of 312 institutions. Arch Pathol Lab Med 1995;119(12):1097-103.

13. Luff RD. Benign cellular changes: have we inadvertently reinvented the class II cytology sign-out? [editorial]. Diagn Cytopathol 1994;10(4):309-10.

14. Malik SN, Wilkinson EJ, Drew PA, Hardt NS. Benign cellular changes in Pap smears. Causes and Signficance. Acta Cytol 2001;45(1):5-8.

15. Schwebke JR. Bacterial Vaginosis. Curr Infect Dis Rep 2000;2(1):14-17.

16. Sidawy MK, Tabbara SO. Reactive change and atypical squamous cells of undetermined significance in Papanicolaou smears: a cytohistologic correlation [see comments]. Diagn Cytopathol 1993;9(4):423-7; discussion 27-9.

17. Young NA, Kline TS. Benign cellular changes: allied ambiguity in CLIA '88 and the Bethesda System [editorial]. Diagn Cytopathol 1994;10(4):307-8.

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