The Bethesda System for Reporting cervical cytology
hyperchromasia or pyknosis, and chromatin smudging and
wrinkling of nuclear contours. Cytoplasmic changes consist
of a well-defined perinuclear cavity, associated with peripheral
thickening of the cytoplasm or cytoplasmic orangeophilia, and
rounding of cellular contours. Specimens with subtle changes
that fall short of definitive LSIL may be categorized as ASC-US.
Cytoplasmic vacuolization (pseudokoilocytosis) alone, in the
absence of any nuclear atypia, is considered a benign change
and should not be classified as LSIL or ASC-US.
of squamous
present a spectrum of morphologic changes within which one
is able, in most cases, to classify lesions as LSIL or HSIL; how-
ever, occasional "borderline" cases occur. In the CAP Interlabo-
ratory Comparison Program in Cervicovaginal Cytology (PAP),
the discrepant rate between low- and high-grade lesions ranged
from 9.8 to 15% for cytotechnologist, pathologist, laboratory,
and all responses.59 Cytology and histology may also be discrep-
ant; 15-25% of women with LSIL cytology are found to have
histologic CIN 2/3 on further work-up.48,59 Features that favor a
high-grade lesion include increased numbers of abnormal cells,
higher nucleus to cytoplasmic ratios, greater irregularities in the
outline of the nuclear envelope and nuclear chromatin distri-
bution, and increased number of chromocenters. The appear-
ance of the cytoplasm may also assist in determining whether
a borderline case is low- or high-grade SIL. LSIL changes typi-
cally involve "mature," intermediate, or superficial type cyto-
plasm with well-defined polygonal borders. Cells of HSIL have
a more immature type of cytoplasm, either delicate and lacy or
dense/metaplastic, with rounded cell borders. Lesions previ-
ously termed "pleomorphic dysplasia," "keratinizing dysplasia,"
or "atypical condyloma," which are composed of single cells
or clusters of cells with enlarged hyperchromatic nuclei and
abundant but abnormally keratinized cytoplasm, are always
considered HSIL.
HSIL, Cannot Exclude Invasion
In rare cases of HSIL, invasive carcinoma may be difficult to
exclude. Examples include atypical keratinized cells without
diathesis/necrosis in the background or cases in which the back-
ground is suspicious but malignant cells are not seen.10 This
terminology may be used in such cases to communicate the
increased concern to the clinician.
Squamous Cell Carcinoma
Squamous cell carcinoma is defined as an invasive malig-
nant tumor with squamous differentiation. TBS does not
subdivide squamous cell carcinoma into keratinizing and non-
keratinizing types, although the atlas does discuss the morphol-
ogy separately. On LBPs, tumor diathesis may be more difficult
to recognize; and as such, in the United States a trend toward
undercalling squamous cell carcinoma as HSIL, especially on
LBP, has been noted.60
Management of SIL
Low-grade SIL. Based on natural history studies of HPV infection,
it is clear that the majority of cytologically detected LSIL regress
within an average of two years.42 After implementation of liquid-
based cervical cytology, there has been a steady increase in the rate
of LSIL in the United States—in 2003 the median rate was 2.4%.31
Anecdotal experiences suggest that this has further increased with
the use of location guided screening. In ALTS, the HPV positivity
rate in LSIL was 83%; a meta-analysis published in 2006 reported
a 76.6% positivity rate.61 Thus HPV DNA testing is not suggested
for initial triage of LSIL. Initial colposcopy identifies preva-
lent CIN 2 or greater in 18% of women with LSIL; subsequent
follow-up over 2 years identified another approximately 10%
CIN 2/3, irrespective of whether the initial colposcopy was
negative or showed histologic CIN 1.54,62
Colposcopy is recommended for managing LSIL; exceptions
include adolescents, postmenopausal, and pregnant women. If
no lesion is identified or colposcopy is unsatisfactory, endocer-
vical sampling is recommended for non-pregnant women. If
CIN 2/3 is not detected, post-colposcopically, either HPV test-
ing at 12 months or repeat cytology at 6 and 12 months is sug-
gested. In adolescents with LSIL, initial colposcopy and/or HPV
testing is not recommended; they should be followed by annual
cytologic testing. Further details can be found in the ASCCP
management guidelines.9
High-grade SIL. The median percentile reporting rate of HSIL
in the United States is estimated at 0.5%,31 and approximately
2% of women with HSIL cytology have invasive carcinoma.63
Follow-up of cytologic HSIL carries a significant risk of a CIN
2/3—a single colposcopy identifies 53-66% of prevalent CIN
2/3; and CIN 2/3 is found in 84-97% of women who proceed to
a loop electrosurgical procedure (LEEP).64 Thus both colposcopy
and LEEP are acceptable for management of cytologic HSIL.9
Epithelial cell Abnormalities: Glandular cell
Cervical cytology is primarily a screening test for cervical squamous
intraepithelial lesions and squamous cell carcinoma; cytology may
have lower sensitivity for detection of glandular lesions has lower
sensitivity due to limitations in sampling and interpretation.
Reporting Glandular Cells in TBS 2001
In TBS 2001, the term atypical glandular cells of undetermined
significance (AGUS) has been eliminated to avoid confusion,
particularly among clinical staff, with ASC-US. Abnormal glan-
dular cells should be subclassified when possible as endocervical
or endometrial; otherwise the generic term "atypical glandular
cells" should be used. It is also advisable to use the qualifiers
"not otherwise specified" or "favor neoplastic" for endocervi-
cal and glandular cells to convey the level of concern about any
abnormality identified. The qualifier "favor reactive" from TBS
1991 has been eliminated as follow-up studies show that results
are similar to those in the NOS category, and as such, this quali-
fier provides no useful predictive value. Atypical endometrial
cells are not further qualified due to difficulty in doing so and
lack of reproducibility of the morphologic criteria. Adenocarci-
noma in situ is a separate interpretive entity in TBS 2001, having
been well described and shown to have moderately good repro-
ducibilty since the 1991 TBS version.65
Atypical Glandular Cells (AGC)
As with its squamous ASC counterpart, this designation applies
to glandular cells that demonstrate changes beyond those
encountered in benign reactive processes, yet which are insuf-
ficient for an interpretation of in situ or invasive adenocarci-
noma. This interpretation should be further qualified, where
possible, to indicate whether the cells are thought to be of
endocervical or endometrial origin. This category includes a
broad morphologic spectrum ranging from atypical-appearing,
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