bethesda pap
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The New Bethesda System for
Reporting Results of Smears of
the Uterine Cervix
Leopold G. Koss*
Over 40 years have elapsed since the large-scale introduction
of the cervical-cancer smear as a cancer detection tool. The
smear, which consists of a sample of cells from the epithelial
surfaces of the uterine cervix, is colloquially known as the "Pap
test," after its discoverer, George N. Papanicolaou. The test is
performed annually on many millions of women. It has contrib-
uted in a statistically sign ificant way to the reduction of mo rbidity
and mortality rates from invasive carcinoma of the uterus in
appropriately screened populations {1-4). However, the test is
prone to disturbing failures (5).
Theoretically, at least, the test is quite simple: the cell samples,
placed on microscope slides and appropriately stained, are stud-
ied under the microscope by trained cytotechnologists. The
presence of precancerous lesions is heralded by the appearance of
nuclear and cytoplasmic abnorm alities. Tissue biopsies, prefera-
bly obtained with the colposcope, a magnifying instrument,
provide further information on the scope and size of the lesion,
which is subsequently removed or destroyed to prevent its
progression to invasive cancer.
In practice, there are several problems with the Pap test. They
are (a) the adequacy of the samples, (b ) the difficulty of micro-
scopic screening, based on recognizing few abnormal cellsamong many thousands of cells in each sample, and (c) the
compliance of patients with testing at appropriate intervals or
with follow-up procedures. T hese problems have been the subject
of considerable concern in the lay press and in scientific publica-
tions (5). The failure to discover a precancerous lesion before it
becomes malignant has resulted in invasive cancer and death of
some young patients.
Measures to improve the quality of screening have been
recently proposed (Amendment to the Clinical Laboratory Im-
provement Act: pending), but, without adequate funding, the
implementation and results of these measures are uncertain.
One of the key issues in providing adequate care to patients at
risk for cervical cancer is the manner in which the smears arereported to the primary care physicians and gynecolog ists. Papa-
nicolaou, who was not a trained pathologist, recognized early in
his work that he was not qualified to render diagnostic verdicts
based on smears. He therefore devised a system of reporting
based on five classes. C lass I smears were entirely benign, hence
normal. Class II smears disclosed minor cell abnormalities
("atypia" ), thoug ht to be benign. Class III smears corresponded to
cell abnormalities that were "suspicious," but not definitely
cancerous. Class IV smears were "most likely malignant," and
Class V smears were unequivocally malignant and diagnostic of
cancer.
This reporting system was widely adopted in the United States
and abroad but was rarely used as originally intended . Instead, the
significance of classes was often modified. In some laboratories,
Class II smears w ere considered to be susp icious, C lass III smears
were considered to indicate precancerous lesions, and Class IV
smears were considered to indicate invasive cancer. Other labo-
ratories used only three classes. Still further variations in the
theme existed, including subdivision of the classes by letters,
such as III A and IIIB .
The issue became even m ore complicated once tissue patholo-gists entered the act. It was recognized fairly early in the
mass-screening process that the rate of discovery of precancerous
lesions of the cervical epithelium was much higher than the true or
projected incidence of invasive cancer. Hence, there were at least
some precancerous lesions that did not have the potential for
progression to invasive cancer. Some observers thought that the
cytologic and histologic appearance of these lesions might pro-
vide the clue to their behavior. Thus, despite some dissenting
voices {6,7), the lesions were divided into two broad categories:
dysplasia and carcinoma in situ. Dysplasia referred to lesions
with a lower degree of abnorm ality that w ere implicitly less likely
to progress to invasive cancer. Carcinoma in situ referred to
lesions that were implicitly more likely to progress to invasivecancer. Dysplasia was further subdivided into three grades (mild,
moderate, and severe) that were presumed to reflect the potential
for "good" or "w orse" behavior {8). It was also proposed that one
could accurately interpret the cervical smear in terms of the
underlying tissue pattern.
These additional classifications had a profound impact on the
reporting system. Because of significant peer pressure, patholo-
gists felt co mpel led to add a comment on the nature, and hence the
probable behavior, of the underlying lesion to every abnormal
smear report. This system of reporting was based on the premise
that the interpretation of smears and biopsies was reproducible.
Unfortunately, in spite of some efforts {8), the precancerous
lesions known as dysplasias have never been objectively defined.
Numerous surveys among expert pathologists clearly showed that
the diagnostic system was no t reproducible and that one person's
dysplasia was another pe rson's carcinoma and vice versa {9,10).
Further, long-term follow-up studies documented that the behav-
ior of precancerous lesions could not be predicted by morphology
(6).
The clinicians at the receiving end of the cytologic reports were
often unaware of the substance and nature of the controversy and
acted (or failed to act) according to their interpretation of the
classes and verbal comments. There is evidence that women with
Class III smears or "dysplasia" were not always treated and
subsequently developed invasive cancer {11). Because of thediagnostic chaos, it became impossible to compare the results
from laboratories and individual pathologists.
Received May 1, 1990; accepted May 2, 1990.
*Correspondence to: Leopold G. Koss. M.D., Department of Pathology,
Montefiore Medical Center and Albert Einstein College of Medicine . H I E .
210th St.. Bronx, NY 10467.
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Richart's introduction of the concept of "cervical intraepithe-
lial neoplasia" (CIN) (12), encomp assing all of the precancerous
lesions of the epithelium of the uterine cervix, constituted a major
breakthrough. Many gynecologists recognized that reports on
cervical smears were not always accurate and that many women
with "atypia" or "mild dysplasia" have precancerous lesions
requiring colposcopy and treatment. This knowledge, however,
did not necessarily drift down to the primary care physicians or
alleviate the need for a uniform reporting system of cervical
smears.
A group of expe rts, representing a broad spectrum of interested
professional organizations, met in Bethesda, Md, under the
auspices of the National Cancer Institute on December 12 and 13,
1988. They met in an attempt to redefine the reporting system of
the cervical smears and to address several other pertinent issues
(13). The resulting document, now known as The Bethesda
System (table 1), was adopted by consensus and, hopefully, will
introduce order and uniformity into the diagnostic chaos that
prevailed until now.
The key points of the Bethesda System are as follows:
I. The cytology report is a medical consultation. This state-
ment separates the cervical smear from machine-generated clini-
cal laboratory tests and proposes a different role for the smear in
the cancer prevention system. It holds clinician responsible forobtaining an adequate sample and for providing an adequate
medical history. It obligates the cytopathologist to assess the
adequacy of the sam ple, that is, whether it is representative of the
status of the cervical epithelium. The statement also obligates the
Table 1. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses.
Statement on Specimen Adequacy
Satisfactory for interpretationLess than optimalUnsatisfactory
Explanation for less than optimal/unsatisfactory specimen:
—Scant cellularity
—Poor fixation or preservation—Presence of foreign material (e.g., lubricant)—Partially or completely obscuring inflammation
—Partially or completely obscuring blood—Excessive cytolysis or autolysis—No endocervical component in a premenopausal woman who has a
cervix—Not representative of the anatomic site—Other
General Categorization
Within normal limits
Other:
Se e descriptive diagnoses
Further action recommended
Descriptive Diagnoses
INFECTIONFungal
Fungal organisms morphologically consistent with Candida speciesOther
Bacterial
Microorganisms morphologically consistent with Gardnerella speciesMicroorganisms morphologically consistent with Actinomyces speciesCellular changes suggestive of Chlamydia species infection, subject
to confirmatory studiesOther
Protozoan
Trichomonas vaginalisOther
Viral
Cellular changes associated with cytomegalovirusCellular changes associated with herpesvirus simplexOther
(Note: for human papillomavirus IHPVJ, refer to "Epithelial CellAbnormalit ies , Squamous Cell")
Other
REACTIVE AND REPARATIVE CHANGES
Inflammation
Associated cellular changes
Follicular cervicitisMiscellaneous (as related to patient history)
Effects of therapy
Ionizing radiationChemotherapyEffects of m echanical devices (e.g., intrauterine contraceptive device)
Effects of nonsteroidal estrogen exp osure (e.g., diethylstilbestrol)Other
EPITHELIAL CELL ABNORMALITIES
Squamous Cell• Atypical squamous cells of undetermined significance
(recommended follow-up and/or type of further investigation:specify)
• Squamous intraepithelial lesion (SIL) (comm ent on presence ofcellular changes associated with HPV if applicable)
Low-grade squamous intraepithelial lesion, encompassing:Cellular changes associated with HPVMild (slight) dysplasia/cervical intraepithelial neoplasia
grade 1 (CIN I)High-grade squamous intraepithelial lesion, encompassing:
Moderate dysplasia/CIN IISevere dysplasia/CIN III
Carcinoma in situ/CIN III
• Squamou s cell carcinoma
Glandular Cell
• Presenc e of endom etrial cells in one of the followingcircumstances:
Out of phase in a menstruating womanIn a postmenopausal womanNo menstrual history available
• Atypical glandular cells of undetermined significance(recommended follow-up and/or type of further investigation:specify)
EndometrialEndocervicalNot otherwise specified
• AdenocarcinomaSpecify probable site of origin: endocervical, endometrial,
extrauterineNot otherwise specified
• Other epithelial malignant neoplasm: specify
NONEPITHELIAL MALIGNANT NEOPLASM: SPECIFY
HORMONAL EVALUATION (APPUES TO VAGINAL SMEARS ONLY)
• Hormo nal pattern compatible with age and history• Hormonal pattern incompatible with age and history: specify• Hormonal evaluation not possible
Cervical specimenInflammation
Insufficient patient history
OTHER
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pathologist to provide guidance to the clinician in further evalu-
ation of the patient, if required.
II. The Papanicolaou reporting system of smear classes was
not considered adequate. The lack of uniformity and uncertainty
of the message conv eyed by classes was judged to be ill-suited to
the practice of preventive medicine.
III. A new reporting system was proposed. The proposed
reporting system is the heart of the Bethesda document because it
requires that each report should determine several aspects of the
cervical sample. (The Bethesda System proposal does not pre-clude the use of other nomenclature as an addendum to the
principal reporting system.) Requirements for the report are as
follows:
A. Adequacy of smea rs. The adequacy of each sample must be
assessed. If the sample is thought to be inadequate, an
explanation of the reasons for this judgment must be
provided. This provision has significant fiscal implica-
tions: for a smear to be judged as inadequate, it must be
processed and screened. The costs of this procedure must
be borne by the patients or third-party payers, and obtain-
ing another smear clearly implies additional costs. T hus, it
is in the interest of the clinicians and the patients to provideadequate smears on the first attempt. On the other hand,
rejecting a sme ar as inadequate requires good judgm ent by
the pathologist, and this decision must be based on solid
grounds. Because the makeup of the smear may vary
according to the clinical situation, sampling instruments,
age, and menstrual status of the patient, these factors must
be taken into account. Needless to say, reporting an
inadequate sm ear as negative in a patient who subsequently
develops invasive cervical cancer may have major legal
consequences.
B. Primary assessm ent. The reporting of the sample falls into
two categories: within normal limits and "other," which
calls for descriptive diag nosis.
C. Descriptive diagnosis of benign abnormalities. The de-
scriptive diagnosis of benign abnormalities includes a
broad variety of infections and infestations and reactive
changes.
D. Descriptive diagnosis of precancerous lesions. In reference
to the precancerous intraepithelial lesions, the significant
thrust of the Bethesda System is the classification of these
lesions into two categories: low-grade and high-grade. Th e
low-grade lesions include all neoplastic changes, previ-
ously classified as "mild dy splasia," CIN I, or lesions with
morphologic changes suggestive of human papillomavirus
infections (e.g., flat condylomas). The high-grade lesionscomprise all other precancerous events or lesions previ-
ously classified as moderate or marked dysplasia and
carcinoma in situ (CIN II and III). Thus, the reporting of
precancerous lesions is much simplified.
E. Descriptive diagnosis of cancer. Additional reporting cate-
gories have been provided to encompass other abnormali-
ties, including various types of invasive cancer that can be
recognized in the cervical samples.
The goal of the Bethesda System is to introduce a uniform
reporting system for cervical smears. This is an important first
step in introducing a national system of quality control. The
mandatory reporting of inadequate samples may have a major
impact on the quality of the smears. Patients' compliance with
testing at appropriate intervals and/or with follow-up procedures,
on the other hand, will not be directly affected, short of a major
media campaign.
Is the Bethesda System a final document that will once and for
all eliminate all problems with providing, screening, and report-
ing cervical smears? W ill it introduce uniform clinical han dling of
these lesions? And finally, will the system eliminate invasive
cervical cancer, w hich is a preventable disease? This writer hassome doubts about it. The reporting system as such is only one
part of a complex cancer detection process (5). The reproducibil-
ity of the diagn ostic sys tem, even with the simplified classifica-
tion of low-grade and high-grade precancerous lesions must still
be tested. While this subdivision is possible in the morphologic
sense, it still does not imply that the handling of the patients
should be different.
Although there is fairly good evidence that many of the
low-grade lesions will disappear spontaneously, many exceptions
to this rule exist. F urther, no statistical analysis performed to date
indicates how many high-grade lesions are represented in the
smears classified as low-grade lesions. Anecdotal experience
suggests that this occurrence is not uncommo n. T hus, colposcopy
of all the lesions, whether low- or high-grade, is still the prudent
way to proceed.
Undoubtedly, with the passage of time, perhaps in the next
century, m olecular biologic probes will become available. These
probes will allow an accurate prediction of the behavior of
precancerous lesions, a task that unfortunately is not possible
today by morphologic examination of the cytologic samples or
tissue samples or by typing of human papillomaviruses (14).
However, the Bethesda System is a good beginning. As the
writers of the document stated, like any other human endeavor,
this document can be amended in the future. At this time, it is
worthy of a major trial on a national scale, provided that theresults are collated and evaluated. To my knowledge, no effort
has been made so far to create an agency that would assess the
results.
References
( /) BOYES DA: The value of a Pap smear program and suggestions for itsimplementation. Cancer 48:613-621, 1981
(2 ) MILLER A B , LINDSAY J, HILL GB: Mortality from cancer of the uterus inCanada and its relationship to screening for cancer of the cervix. Int J Cancer17:602-612, 1986
(3 ) GEIRSSON G: Organization of screening in technically advanced countries:
Iceland. In Screening for Cancer of the Uterine Cervix (Hakama M, MillerAB, Day NE, eds). Lyons: 1ARC, 1986, pp 239 -250
(4 ) HAKAMA M: Trends in the incidence of cervical cancer in the Nordiccountries. In Trends in Cancer Inciden ce, Causes and Practical Implications(Magnus K, ed). Washington, DC: Hemisphere 1988, pp 279-292
(5) Koss LG : The Papanicolaou test for cervical cancer detection: A triumphand a tragedy. JAMA 261:737 -743, 1989
(6) Koss LG, STEWART FW , FOOTE FW JR, ET AL: Some histologic aspects ofbehavior of epidermoid carcinom a in situ and related lesions of the uterinecervix: A long-term prospective study. Cancer 12:1171-1193, 1963
(7) Koss LG: Dysplasia: A real concept or a misnomer? Obstet Gynecol51:374-379, 1978
(8 ) PATTEN SF JR: Diagnostic Cytology of the U terine Cervix. 2nd ed. Basel: SKarger, 1978
(9 ) COCKER J, Fox H, LANCLEY FA: Consistency in the histological diagnosis ofepithelial abnormalities of the uterine cervix. J Clin PathoF 21:6 7-70 , 1968
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(10) SEYBOLT JF , JOHNSON WD: Cervical cytodiagnostic problems: A survey.Am J Obstet Gynecol 109:1089-1103, 1971
( / / ) RYLANDER E: Negative smears in women developing invasive cervical
cancer. Acta Obstet Gynecol Scand 56:115-118, 1977(12) RICHART RM: Cervical intraepithelial neoplasia: A review. Pathol Annu
3:301-328, 1973
(13) NATIONAL CANCER INSTITUTE WORKSHOP: The 1988 Bethesda system for
reporting vaginal/cervical cytological diagnoses. JAMA 262:567-576,1989
(14) LORINCZ AT, LANCASTER WD, KURMAN RJ, ET AL : Characterization of
human papillomaviruses in cervical neoplasias and their detection in routineclinical screening. In Viral Etiology of Cervical Cancer: B anbury Report 21(Peto R, zur Hausen H, eds). Cold Spring Harbor, NY: Cold Spring HarborLaboratory, 1986, pp 225-237
Cancer Is Complex
Is Simple
For the lates t cance r informationfrom the National CancerInstitute's Cancer InformationService, write:
The N ational Cancer InstituteBuilding 31, Room 10A24Bethesd a, M aryland 20892-3100U.S.A.
Or Call:1-800-4-CANCER*
( 1 - 8 00 - 422 - 6237 )
Vol. 82, No. 12, June 20, 1990 EDITORIAL 9