PART TWO
Diagnostic Cytology
there is no "correct" percentage rate of ASC, benchmarks were
provided when ASCUS was introduced in the Bethesda termi-
nology. In a low-risk population, it was suggested that the rate
of ASCUS should be less than 5%. For laboratories that serve
high-risk populations (e.g., sexually transmitted disease clinics
or colposcopy clinics), the rate of ASCUS could be higher, but
by 1991 guidelines should not exceed two to three times the rate
of SIL; thus the ratio of ASCUS/SIL suggested was in the range
of 2-3:1. A 1993 CAP survey focusing on laboratory utilization
of ASCUS found that 86% of responding laboratories used the
term ASCUS and the median ASCUS rate was 2.8%, with 90% of
laboratories reporting rates of less than 9%. The median ASCUS/
SIL ratio was 1.7; for 90% of laboratories, the calculated ratio
was less than 3.6.41 In 2003, a follow-up CAP survey on Bethesda
2001 implementation and reporting rates showed a decrease in
the average ASC/SIL ratio (from a median of 2.0 in 1996 to 1.4
in 2002). This can be explained by increased LSIL detection on
LBP and also possibly by using Bethesda 2001 criteria more
stringently.31
Sherman and colleagues, in a study correlating cytopatho-
logic diagnoses with detection of HPV DNA, also found that use
of TBS criteria reduced the percentage of inconclusive "atypi-
cal" smears. Overall, a consistent relationship between high-risk
HPV detection and TBS diagnostic categories was evident. High-
risk HPV types were detected in 10% of negative smears, 30%
of ASCUS, and 60% of SIL specimens. Based on these data, the
authors proposed using high-risk HPV testing as an objective
quality assurance measure to assess the performance of a cytopa-
thology laboratory.45 These results were substantiated by ALTS.5,6
It is well established that ASC-US is one of the least repro-
ducible cytologic interpretations.12,46 Various quality assurance
monitors may be utilized to evaluate the laboratory s utilization
of ASC. These include the following:
1. Correlation of ASC-US cases with high-risk HPV posi-
tivity rates; results from ALTS indicate that this should
be in the range of 40-60% , or in essence that ASC-US
is a 50-50 proposition between SIL (usually LSIL) and
cellular changes unrelated to HPV;47, 48
2. Correlation of ASC cases with results of colposcopi-
cally directed biopsy;
3. Review of ASC cases by a second cytopathologist; and
4. Calculation of ASC/SiL ratio.
The ASC-HPV+/ASC ratio closely mirrors the ASC/SIL ratio.
However, the ASC-HPV+/ASC ratio offers the additional advan-
tage of identification of aberrant trends where ASC and SIL are
both being misinterpreted, which may allow ASC/SIL ratios to
remain within "acceptable" ranges despite the erroneous trend.49
After implementation of LBPs, many laboratories have reported
an increase in SIL rates over the increase in ASC rates, such that
lower ASC/SIL ratios are being seen in many laboratories.31 The
prior 2-3:1 suggested ratio for ASC/SIL may undergo revision as
future benchmarking results are gathered.
Clinical Management of ASC
Women with ASC have a low prevalence of invasive cancer, esti-
mated at 0.1-0.2% .50 The prevalence of CIN 2/3 is substantially
higher in women with ASC-H (37-40% )51,52 than in those with
ASC-US (11.6%).51 ASC-US/high-risk HPV-positive cases over
2-years follow-up in ALTS have the same cumulative risk of CIN
2/3, about 27-28% , as a cytologic LSIL.47 In contrast women
in the ALTS who were ASC-US/high-risk HPV-negative showed
a very low (1.4%) absolute risk of subsequently detected CIN
3 or worse and no cancers were detected in the two-year study
period, similar to women with negative cytology in the absence
of HPV testing.53
The ASCCP consensus guidelines8,9 for ASC follow-up have
seen widespread penetration into US practice. For ASC-US, HPV
DNA testing, repeat cytological testing, and colposcopy are all
acceptable methods for managing women over 20 years of age.
When liquid-based cytology is used, reflex oncogenic or high-
risk HPV DNA testing is the preferred management approach.
ASC-US/high-risk HPV positive women should be managed in a
fashion similar to those with LSIL. In adolescents (20 years and
younger), follow-up with annual cytology is suggested due to
the high prevalence of HPV in this age group and the low risk
of persistence.9
ASC-H on the other hand needs more aggressive follow-up,
with colposcopic evaluation at the first interpretation. HPV test-
ing is not recommended for triage of ASC-H. However, if a CIN
2/3 lesion is not identified at colposcopy, follow-up with either
HPV testing at 12 months or cytology testing at 6 and 12 months
is recommended.9
Squamous intraepithelial Lesions (SiL)
In TBS, LSIL and HSIL encompass the spectrum of precursors to
squamous carcinoma of the cervix. Unlike CIN and dysplasia
classifications that maintain HPV as a separate diagnostic cate-
gory, low-grade SIL incorporates changes of HPV as well as mild
dysplasia/CIN 1. High-grade SIL includes moderate dysplasia/
CIN 2, severe dysplasia/CIN 3, and carcinoma in situ/CIN 3.
Cytologists are of course free to append degrees of dysplasia or
CIN classifications to a SIL interpretation.
Conceptual Basis for Two-Tiered Terminology of SIL
Previous terminology classifications—degrees of dysplasia and
grades of CIN 1 to 3—have emphasized the morphologic con-
tinuum of squamous lesions that was thought to reflect a con-
tinuous process in the development of cervical cancer. Natural
history studies42 and HPV research have since established that
HPV infection is a necessary cause for cervical carcinogene-
sis;55,56 however, even most oncogenic or high-risk HPV types
cause transient low-risk lesions that regress, and cervical carci-
noma develops in a small subset of persistent/progressive HPV
infections.57 It is estimated that approximately 70% of cervical
cancers are associated with HPV 16 or 18.58
The two-tiered LSIL/HSIL Bethesda approach attempts to
morphologically distinguish minor from significant lesions;
however, morphology is an imperfect reflection of biologic
potential. Low-grade lesions, particularly those that persist, may
progress or be associated with the development of high-grade
lesions, and some high-grade lesions may regress.57 Some have
questioned setting TBS division of LSIL and HSIL at the break-
point of CIN 1-2, or mild/moderate dysplasia, arguing that
some CIN 2/moderate dysplasias should be considered low-
grade lesions. However, because some CIN 2 lesions represent
high-grade disease processes, conservatism dictated its inclusion
into the more severe TBS category to ensure maximal sensitivity
of the process.
Morphologic Features
An interpretation of LSIL based on cellular changes asso-
ciated with HPV requires nuclear as well as cytoplasmic
abnormalities. Nuclear changes may include enlargement with
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