The Bethesda System for Reporting cervical cytology
was introduced in 1988, this spectrum has always been divided
into low-grade (LSIL) and high-grade (HSIL) categories. LSIL
encompasses changes referred to as "HPV effect," "koilocytosis,"
and mild dysplasia/cervical intraepithelial neoplasia (CIN 1).
HSIL includes moderate dysplasia (CIN 2) and severe dysplasia/
carcinoma in situ (CIN 3). The basis for this bipartite classifica-
tion of SIL in TBS is based on the principles that this division
(a) better reflects natural history and clinical management and
(b) has better intra- and interobserver reproducibility than does
a three-tiered reporting system.
Atypical Squamous Cells (ASC)
The term ASCUS was initially introduced into the earliest ver-
sion of the Bethesda System to reflect the reality and limitations
of light microscopy in classifying borderline cytologic changes.
The use of multiple ASCUS qualifiers such as "not otherwise
specified" (NOS), "favor reactive," and "favor SIL/dysplasia" led
to overuse of this category and by 1996, ASCUS interpretations
accounted for a mean of 5.2% of all cervical cytology reports in
the United States.41 ASCUS interpretations caused dilemmas for
clinicians due to the lack of standardized follow-up and vari-
ability of outcomes.
With advances in the understanding of the biology of HPV
infections and results from various natural history studies,42 as
well as from the NCI ALTS trial,6 the focus of cervical cancer
screening has shifted from detecting and treating any CIN to
focusing on treating high-grade CIN. Based on this concept, in
TBS 2001, the term ASCUS was replaced by ASC, which has a
narrower definition and only two qualifiers: atypical squamous
cells of undetermined significance (ASC-US) and atypical squa-
mous cells, cannot exclude HSIL (ASC-H).7 A subclassification
was aimed at having greater clinical utility by clearly separating
equivocal findings into those that are worrisome for HSIL in dis-
tinction from other types of ASC. As a general guide, the major-
ity of ASC interpretations should fall into the ASC-US qualifier
(90-95% ) with only 5-10% into the ASC-H category.7,10
ASC is not a single biologic or interpretive entity: it encom-
passes a spectrum of cellular changes reflecting a variety of
pathologic processes that for one reason or another cannot be
more definitively categorized. Specifically, ASC should be used
for changes suggestive of SIL, that are either quantitatively or
qualitatively insufficient for a definitive interpretation. For a
cell to be classified as ASC, it should show squamous differen-
tiation, an increase in nuclear cytoplasmic ratio, and minimal
nuclear changes.10 In each case of ASC, the cytopathologist must
consider the summation of the morphologic abnormalities in
terms of quantity and severity within the context of the clinical
information provided.
Atypical Squamous Cells of Undetermined Significance (ASC-US)
Most often, ASC-US involves noninflammatory changes in
squamous cells with mature, superficial/intermediate-type cyto-
plasm. Nuclear enlargement is approximately two-and-a-half to
three times the area of a normal intermediate squamous nucleus,
but the chromatin remains evenly distributed without signifi-
cant hyperchromasia. Nuclear outlines are smooth and regular,
although there may be variation in nuclear size. The differen-
tial diagnosis is usually between a reactive change versus LSIL
but the change(s) quantitatively or qualitatively fall short of
establishing a definitive interpretation of LSIL. Round or ovoid
cells that resemble large metaplastic or small intermediate cells
may also be classified as ASC-US. In liquid-based preparations,
the cells may appear smaller and rounder compared to conven-
tional smears. The cells in question should always be compared
to "normal"-appearing intermediate cells on the same slide.
In distinguishing reactive changes, cells that demonstrate pale
round nuclei and even chromatin distribution favor an interpre-
tation as NILM rather than ASC.
Atypical Squamous Cells, Cannot Exclude High-Grade Squamous
Intraepithelial Lesion (ASC-H)
The ASC-H category is useful for changes suggestive of, but fall
short of a definite interpretation of HSIL. The differential includes
HSIL and mimics of HSIL. A variety of patterns can be recognized:
1. Small cells with a high nuclear to cytoplasmic ratio
or "atypical (immature) metaplasia. Nuclear abnor-
malities such as abnormal shapes, hyperchromasia,
and chromatin irregularity favor HSIL over benign
2. Crowded sheet pattern or so-called hyperchro-
matic cell groups. Dense cytoplasm, polygonal cell
shape, and distinct cell borders favor squamous over
endocervical cells. This cell pattern includes a broad
differential from normal (atrophy, endometrial cells)
to neoplastic (endocervical adenocarcinoma, HSIL, or
HSIL involving glands) changes.
3. Atypical cells in the setting of atrophy, atypia seen
following radiation therapy, poorly preserved endo-
metrial cells or histiocytes, and intrauterine device
users may all show cellular changes that are difficult
to distinguish from HSIL. In such situations, a
designation as ASC-H may be appropriate.
Laboratory Reporting of ASC
Subsequent to the publication and dissemination of TBS 1988/
1991, many clinicians felt overwhelmed by ASCUS interpreta-
tions in their patient practices. This phenomenon was not limited
to the United States or to TBS; greatly increased rates of minor
degrees of abnormality have been observed in countries that do
not use TBS.43 The reasons underlying this real or perceived ASCUS
explosion were twofold: (1) The constant specter of medical-
legal litigation has lowered the threshold for diagnosis of cellu-
lar abnormalities in many laboratories;9,31 and (2) atypical cases
historically may have been camouflaged in vague terms such as
"inflammatory atypia," "benign atypia," "borderline HPV," and
"koilocytotic atypia." The aggregation of all such equivocal cases
under one heading highlighted the subjective, interpretative
nature of cytopathologic diagnosis, something long understood
by laboratorians but not always recognized by clinicians. Some
contend that in TBS 1991, ASCUS merely replaced the old Pap
Class 2 or "inflammatory atypia" designations. However, a study
by Sidawy and Tabbara demonstrated that by using criteria
similar to those outlined above, almost two-thirds of 88 smears
previously interpreted as "inflammatory atypia" could be reclas-
sified as reactive; only 3 out of 57 cases (5%) had CIN (all low
grade) on follow-up colposcopic biopsies. In contrast, among
the smears that fulfilled ASCUS criteria, 61% correlated with
colposcopic biopsies positive for CIN.44
Laboratory rates of ASC will vary depending on the patient
population, the diagnostic criteria used, and the experience
and skill of the microscopist(s). If used appropriately, ASC
should be an infrequent designation employed only when cel-
lular changes elude a more definitive interpretation. Although
previous page 85 ComprehensiveCytopathology 1104p 2008 read online next page 87 ComprehensiveCytopathology 1104p 2008 read online Home Toggle text on/off