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2001 Bethesda System PDF
2001 Bethesda System PDF
2114 JAMA, April 24, 2002—Vol 287, No. 16 (Reprinted) ©2002 American Medical Association. All rights reserved.
System the term “diagnosis” has been gued for elimination of the ASCUS cat- Squamous Intraepithelial Lesions. The
replaced by “interpretation” or “re- egory. However, the participants 1988 Bethesda System introduced a
sult” to convey that cervical cytology decided that it was essential to main- 2-tiered terminology, LSIL and HSIL, for
provides an interpretation of morpho- tain an equivocal category because of reporting the spectrum of noninvasive
logical findings that must be inte- the large number of women with un- squamous cervical abnormalities.
grated into a clinical context. derlying CIN 2 and 3 who are discov- After thorough consideration by the
Negative for Intraepithelial Lesion ered through a workup for an equivo- Bethesda 2001 Workshop, the 2-tiered
or Malignancy. Specimens for which no cal cytological reading. Estimates LSIL /HSIL terminology remains un-
epithelial abnormality is identified are suggest that 10% to 20% of women with changed.
reported as “negative for intraepithe- ASC have underlying CIN 2 or 3 and The dichotomous division of SIL re-
lial lesion or malignancy.” Reporting that 1 in 1000 may have invasive can- flects the substantial virological, mo-
non-neoplastic findings, other than the cer.6 The elimination of an equivocal lecular, and clinical evidence that LSIL
listed organisms, is optional; Box 2 in- cytology category seemed imprudent is generally a transient infection with
cludes a partial list of findings. given the high expectations for very sen- HPV, while HSIL is more often associ-
Epithelial Cell Abnormalities. Atypi- sitive cervical cytological screening in ated with viral persistence and higher
cal Squamous Cells. The 1988 Bethesda the United States. risk for progression.10-13 In addition,
System included the term “atypical The 2001 Bethesda System differs in data from the ASCUS LSIL Triage Study
squamous cells of undetermined sig- several fundamental ways with regard to demonstrate the following: (1) LSIL vs
nificance” (ASCUS) to designate “cel- reporting equivocal results. First, “atypi- HSIL is a fairly reproducible diagnos-
lular abnormalities that were more cal squamous cells” are now qualified tic breakpoint, (2) subdividing cyto-
marked than those attributable to re- as “of undetermined significance logical HSIL into moderate and severe
active changes but that quantitatively (ASC-US)” or “cannot exclude HSIL” dysplasia or CIN 2 and 3 is not very re-
or qualitatively fell short of a defini- (ASC-H). The qualifier “undetermined producible, and (3) HPV cytopathic
tive diagnosis of ‘squamous intraepi- significance” was retained to empha- effect cannot be reliably separated from
thelial lesion’ (SIL).” Pathologists were size that some cases of ASC-US are as- mild dysplasia or CIN 1 (M. Schiff-
encouraged to qualify ASCUS with re- sociated with underlying CIN 2 or 3. Sec- man, written communication, 2001).
spect to whether a reactive process or ond, ASC is not a diagnosis of exclusion; However, the 3-tiered CIN 1-2-3 des-
SIL was favored. In practice, patholo- all ASC is considered to be suggestive ignations may be helpful in managing
gists reported a significant proportion of SIL. Accordingly, the category of some individual patients, in correlat-
of smears as “ASCUS, not otherwise “ASCUS, favor reactive” was elimi- ing cytopathologic and histopatho-
specified.” nated. Pathologists are encouraged to logic findings, or in reporting cytol-
When the 1988 Bethesda System was judiciously downgrade to “negative for ogy results outside the United States.
drafted, clinical management in the intraepithelial lesion or malignancy” a Some members of the European cyto-
United States focused on identifying all portion of the cases previously termed pathology community in particular fa-
SIL, including low-grade SIL (LSIL), “ASCUS favor reactive.” vor use of CIN terminology. As in pre-
based on the view that all grades of SIL The new term “ASC-H” is thought to vious versions of the Bethesda System,
represented closely linked precursors include approximately 5% to 10% of CIN or dysplasia terminology can be
that required colposcopy and treat- ASC cases overall.7-9 This category re- used, either as a substitute for SIL or
ment. However, there has been a shift flects a mixture of true HSIL and its as an additional descriptor.
in the United States with regard to man- mimics. Although the interpretation is Atypical Glandular Cells.The classi-
agement based on the recognition that not highly reproducible among patholo- fication of glandular abnormalities has
most LSIL, especially in young women, gists, studies suggest that ASC-H has a been significantly revised in the 2001
represents a self-limited human papil- positive predictive value for histologi- Bethesda System, reflecting a reap-
lomavirus (HPV) infection.5 Accord- cal CIN 2 or 3 that is intermediate be- praisal of the strengths and weak-
ingly, the current emphasis is on de- tween ASC-US and HSIL. It is hoped nesses of cytology in assessing these
tection and treatment of histologically that by highlighting such cases, ASC-H findings.
confirmed high-grade disease (particu- will aid in more rapid detection and The term “atypical glandular cells of
larly cervical intraepithelial neoplasia treatment of some cases of CIN 2 and undetermined significance” (AGUS) has
[CIN] 3). Therefore, it is logical for the 3. However, the equivocal nature of the been eliminated to avoid confusion with
ASC category qualifiers to emphasize ASC-H designation should encourage ASC-US. Glandular cell abnormalities
the importance of detecting high- comprehensive review of all pathol- are classified as “atypical endocervi-
grade SIL (HSIL), which has emerged ogy and colposcopic findings prior to cal, endometrial, or glandular cells.”
as the central purpose of screening. performing a diagnostic loop electro- In the majority of cases, morpho-
At the 2001 workshop, a small mi- surgical excision procedure in women logical features permit differentiation
nority of workshop participants ar- with negative histology results. between atypical endometrial and en-
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, April 24, 2002—Vol 287, No. 16 2117
docervical cells.14 The management of menstrual/menopausal status, exog- tive, consistent with clinical follow-up
patients with glandular abnormalities enous hormone therapy, and other guidelines published by professional or-
may vary significantly depending on cell clinical risk factors are often un- ganizations, and phrased in the form of
type and justifies making this distinc- known or unclear. Although usually a suggestion. A qualifying phrase (eg,
tion when possible. The term “atypi- benign in nature, identification of “as clinically indicated”) should gen-
cal epithelial cells” may be used for endometrial cells, particularly if not as- erally be added since the pathologist
cases where a squamous vs glandular sociated with menses or after meno- may be unaware of other pertinent clini-
origin cannot be determined. pause, may indicate risk for an endo- cal information. One study has shown
The finding of atypical glandular cells metrial abnormality.22-25 As noted above, that including suggestions for further
(AGC) is important clinically because this finding is categorized as “other.” evaluation improves the likelihood that
the percentage of cases associated with It is important to emphasize that cer- appropriate follow-up occurs.26 Pro-
underlying high-grade disease is higher vical cytology is primarily a screening viding references for consensus clini-
than for ASC-US. On follow-up, high- test for squamous epithelial lesions and cal follow-up guidelines for abnormal
grade lesions (either squamous or glan- squamous cancer. It is unreliable for the cervical cytology results published by
dular) may be seen in 10% to 39% of detection of endometrial lesions and medical organizations (eg, American
such cases.15-17 Based on such data, the should not be used to evaluate sus- College of Obstetricians and Gynecolo-
qualifier “favor reactive” was consid- pected endometrial abnormalities. gists, American Society for Colpos-
ered misleading and it has been elimi- copy and Cervical Pathology) may also
nated: such cases are now included in Automated Review be helpful.27
the AGC category. and Ancillary Testing
In the 1991 terminology, adenocar- “Automated review and ancillary test- SUMMARY
cinoma in situ (AIS) was included in ing” are elements of the report that are The goal of the Bethesda System is to
“AGUS, probably neoplastic.” Since that included as appropriate. For slides promote more effective communica-
time, studies have clearly documented scanned by automated computer sys- tion of cervical cytology results from the
predictive value and reproducibility of tems, the instrumentation used and the laboratory to clinicians. The 2001 re-
properly applied cytological criteria for automated review result should be in- vision of the terminology was devel-
this interpretation.18-20 “Endocervical ad- cluded in the cervical cytology report. oped through a process designed to in-
enocarcinoma in situ” is therefore now If an ancillary molecular test has been corporate new scientific data and
a separate category. However, there is performed, the type of assay should be encourage input from a broad range of
considerable morphological overlap be- specified in addition to the results. Ide- individuals involved in cervical can-
tween AIS and well-differentiated inva- ally, cytology and ancillary testing re- cer screening. Management guide-
sive endocervical adenocarcinoma; a per- sults should be reported concur- lines for women with abnormal cytol-
centage of cases interpreted as AIS will rently; however, this may not always be ogy results, based on the 2001 Bethesda
demonstrate invasion on histological possible. System, have been developed at a con-
evaluation. sensus conference sponsored by the
For cases showing some features sug- Educational Notes and Suggestions American Society for Colposcopy and
gestive of, but not sufficient to reach an Written comments regarding the va- Cervical Pathology.28 Such collabora-
interpretation of AIS, an intermediate lidity and significance of a cytology re- tive and integrated development of re-
category of “atypical endocervical cells, sult are the responsibility of the pa- porting terminology and management
favor neoplastic” conveys a significant thologist and are directed to the guidelines should provide more uni-
level of concern. There is no basis for es- clinician who requested the test. The form, evidence-based care of women
tablishing a category of “endocervical laboratory should avoid communi- with cervical abnormalities.
glandular dysplasia” or “low grade glan- cating results directly to the patient, as
dular intraepithelial lesion.”21 A mor- this may interfere with the patient- The Forum Group Members include the following:
Specimen Adequacy: Diane D. Davey, MD, George
phological spectrum of bona fide pre- clinician relationship. Direct contact be- Birdsong, MD, Henry W. Buck, MD, Teresa Darragh,
cursors of AIS has not been identified for tween the patient and the laboratory MD, Paul Elgert, CT(ASCP), Michael Henry, MD,
Heather Mitchell, MD, Suzanne Selvaggi, MD; Be-
endocervical glandular lesions. may be acceptable, however, if specifi- nign Cellular Changes and Infections: Nancy Young,
Other. In the previous version of the cally requested by the clinician. MD, Marluce Bibbo, MD, Sally-Beth Buckner, CT
Bethesda System, the finding of endo- The use of educational notes or sug- (ASCP), Terence Colgan, MD, Dorothy Rosenthal, MD,
Edward Wilkinson, MD; ASCUS: Mark Sherman, MD,
metrial cells was reported only for post- gestions is optional. If used, the for- Fadi Abdul-Karim, MD, Jonathan Berek, MD, Patri-
menopausal women. However, in the mat and style may vary depending on cia Braly, MD, Robert Gay, CT(ASCP), Celeste Pow-
ers, MD, Mary Sidawy, MD, Sana Tabbara, MD; AGUS:
2001 Bethesda System, endometrial the preferences of the laboratory and its David Wilbur, MD, David Chhieng, MD, J. Thomas
cells are noted if the woman is 40 years clinicians. Nevertheless, any com- Cox, MD, Jamie Covell, BS, CT(ASCP), Barbara Gui-
dos, SCT(ASCP), Kenneth Lee, MD, Dina Mody, MD;
of age or older, regardless of the date ments should be carefully and thought- HPV Triage: Stephen Raab, MD, Karen Allen, CT
of the last menstrual period, because fully crafted, concise but not direc- (ASCP), Christine Bergeron, MD, PhD, Diane Harper,
2118 JAMA, April 24, 2002—Vol 287, No. 16 (Reprinted) ©2002 American Medical Association. All rights reserved.
MD, Walter Kinney, MD, Alexander Meisels, MD; En- mined significance: baseline results from a random- nificance as defined by the Bethesda System. Am J Ob-
dometrial Cells: Ann Moriarty, MD, Edmund Cibas, ized trial. J Natl Cancer Inst. 2001;93:293-299. stet Gynecol. 1997;177:1188-1195.
MD, Gary Gill, CT(ASCP), Meg McLachlin, MD, Ellen 7. Sherman ME, Solomon D, Schiffman M, for the 18. Betsill WL, Clark AH. Early endocervical glandu-
Sheets, MD, Theresa Somrak, CT(ASCP), Rosemary ALTS Group. Qualification of ASCUS: a comparison lar neoplasia, I: histomorphology and cytomorphol-
Zuna, MD; LSIL /HSIL: Tom Wright, MD, Richard De- of equivocal LSIL and equivocal HSIL cervical cytol- ogy. Acta Cytol. 1986;30:115-126.
May, MD, Rose Marie Gatscha, CT(ASCP), Lydia How- ogy in the ASCUS LSIL Triage Study. Am J Clin Pathol. 19. Lee KR, Manna EA, Jones MA. Comparative cy-
ell, MD, Ronald Luff, MD, MPH, Volker Schneider, MD, 2001;116:386-394. tologic features of adenocarcinoma in situ of the uter-
Leo Twiggs, MD; Computer-Assisted Diagnosis: Mari- 8. Quddus MR, Sung CJ, Steinhoff MM, et al. Atypi- ine cervix. Acta Cytol. 1991;35:117-126.
anne Prey, MD, Mike Facik, CT(ASCP), Albrecht Reith, cal squamous metaplastic cells: reproducibility, out- 20. Biscotti CV, Gero MA, Toddy SM, Fischler DF, Ea-
MD, Max Robinowitz, MD, Mary Rubin, NP, PhD, Sue come, and diagnostic features on ThinPrep Pap test. sley KA. Endocervical adenocarcinoma in situ: an analy-
Zaleski, SCT(ASCP); Recommendations, Educational Cancer. 2001;93:16-22. sis of cellular features. Diagn Cytopathol. 1997;17:
Notes, and Disclaimers: Dennis O’Connor, MD, Mar- 9. Sherman ME, Tabbara SO, Scott DR, et al. “ASCUS, 326-332.
shall Austin, MD, PhD, Lisa Flowers, MD, Blair rule out HSIL”: cytologic features, histologic corre- 21. Farnsworth A, Laverty C, Stoler MH. Human pap-
Holladay, PhD, CT(ASCP), Dennis McCoy, JD, Paul lates and human papillomavirus detection. Mod Pathol. illomavirus messenger RNA expression in adenocar-
Krieger, MD, Gabriele Medley, MD, Jack Nash, MD, 1999;12:335-343. cinoma in situ of the uterine cervix. Int J Gynecol
Mark Sidoti, JD; Electronic Bulletin Board Program- 10. Park TJ, Richart RM, Sun X-W, et al. Association Pathol. 1989;8:321-330.
mer: Lomi Kil, BA. between HPV type and clonal status of cervical squa- 22. Montz FJ. Significance of “normal” endometrial
mous intraepithelial lesions (SIL). J Natl Cancer Inst. cells in cervical cytology from asymptomatic post-
1996;88:355-358. menopausal women receiving hormone replacement
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©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, April 24, 2002—Vol 287, No. 16 2119