Anatomic Pathology / ATYPICAL SQUAMOUS CELLS, CANNOT EXCLUDE HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION
Atypical Squamous Cells, Cannot Exclude High-Grade
Squamous Intraepithelial Lesion
A Follow-up Study of Conventional and Liquid-Based Preparations
in a High-Risk Population
Ana Paula Louro, MD, Janie Roberson, SCT(ASCP), Isam Eltoum, MD, and David C. Chhieng, MD
Key Words: Cervicovaginal smears; Liquid-based preparation; Atypical squamous cells; High-grade squamous intraepithelial lesions;
Cervical dysplasia
DOI: 10.1309/NPU3WRQCTAB81XLW
We compared the histologic follow-up of 368
smears or slides with an interpretation of “atypical
squamous cells, cannot rule out high-grade squamous
intraepithelial lesion” (ASC-H) based on conventional
and liquid-based preparations and age groups in a
high-risk population. Patients with an ASC-H
interpretation were 17 to 87 years old (mean, 36.8
years). The specimens were 52 liquid-based
preparations and 316 conventional smears. For 218
cases (59.2%), including 28 liquid-based preparations
(65%) and 190 conventional smears (58%), histologic
follow-up was available. In 20 liquid-based
preparations (71%) and 152 conventional smears
(80.0%), cervical intraepithelial neoplasia (CIN) or
higher was revealed on subsequent biopsy. Other
results were as follows: liquid-based preparations,
CIN1, 11 (55%); CIN2/3, 9 (45%); conventional
smears, CIN1, 78 (51.3%); CIN2/3, 70 (46.1%);
squamous cell carcinoma, 4 (2.6%). There was no
statistically significant difference in the incidence of
CIN or higher on subsequent biopsy after an
interpretation of ASC-H based on preparation types.
The incidences of CIN in patients 40 years old or older
and patients younger than 40 years were 66% and
84%, respectively, a statistically significant difference.
Because of the high incidence of clinically significant
lesions noted on subsequent follow-up, patients with an
interpretation of ASC-H should be observed closely
and referred for colposcopic examination regardless of
their age.
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The category of ASCUS (atypical squamous cells of
undetermined significance) was created by the Bethesda
System in 1988 to denote squamous cellular changes that
were more marked than those attributable to reactive or
inflammatory changes but were not quantitatively or qualitatively diagnostic of a preneoplastic or neoplastic condition.1
When the Bethesda system was revised in 1991, it was
recommended that the category of ASCUS be qualified as
“favor reactive” or “favor SIL” (squamous intraepithelial
lesion) to facilitate subsequent patient management. 2,3
However, “atypical squamous cells” (ASC) is a heterogeneous entity and can be superficial or intermediate squamous
cells or squamous metaplastic cells.4 The incidence of SIL
correlates inversely with the degree of cytoplasmic maturity.
In addition, atypical squamous cells of the superficial or
intermediate subtype are more likely to be associated with
low-grade SIL (LSIL), whereas atypical squamous cells of
the metaplastic subtype are more likely to be associated with
a high-grade SIL (HSIL) on subsequent follow-up.
LSIL often regresses spontaneously, especially in
young women, whereas HSIL is more likely to persist or
even progress to more severe lesions.5 Therefore, early
cytologic detection and treatment of HSIL are highly desirable. As a result, our laboratory has separated atypical squamous cells of the metaplastic subtype from the other ASC.
The former has been arbitrarily designated by various
authors as “atypical metaplastic cells,” “ASC, equivocal
HSIL,” “ASC, cannot rule out HSIL,” and “inconclusive,
possible high-grade epithelial abnormality.”6-11 In 2001, the
category “ASC-H” or “ASC, cannot rule out HSIL” was
adopted officially in the latest version of the Bethesda
System (Bethesda 2001). 12 Various studies, based on
© American Society for Clinical Pathology
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Abstract
Anatomic Pathology / ORIGINAL ARTICLE
conventional or liquid-based preparations, have shown that
ASC-H is associated with a significant incidence of HSIL
on subsequent follow-up compared with ASC as a group.6-11
Few studies have studied whether there is any difference in
the outcome of ASC-H between the 2 preparations and
among different age groups.
We determined the incidence of ASC-H in conventional and liquid-based preparations in a high-risk population (we considered our population high risk because the
incidence of SIL detected by our laboratory was 7.2%
during the study period). We also compared the rate of clinically significant cervical lesions after such an interpretation between conventional and liquid-based preparations
and among different age groups.
A computer search of the archives of the Department of
Pathology, University of Alabama at Birmingham Hospital,
identified all gynecologic specimens, both conventional and
ThinPrep (Cytyc, Boxborough, MA) specimens, diagnosed
as ASC-H or equivalent, such as atypical metaplastic cells,
during the period January 2000 through December 2001.
During the study period, 70% of our workload involved
conventional smears and the remaining 30%, ThinPrep
preparations. Conventional smears were obtained with a
modified Ayre spatula alone or along with an endocervical
brush. The smears were fixed using a spray fixative. Specimens for ThinPrep Papanicolaou (Pap) tests were obtained
using an endocervical brush, which then was rinsed into a
vial of PreservCyt Solution (Cytyc). The solution was
processed with the ThinPrep 2000 automated slide
processor (Cytyc).
An interpretation of ASC-H or atypical metaplastic cells
was made when the atypical squamous cells resembled squamous metaplastic cells. These atypical metaplastic cells
occurred singly, in loosely cohesive groups, or in syncytial
fragments. Individual cells demonstrated an increased
nuclear/cytoplasmic ratio. In addition, these cells might be
euchromatic or slightly hyperchromatic with variable nuclear
enlargement and/or nuclear irregularity.
The methods and results of patient evaluation, which
included repeated Pap tests, colposcopic examination along
with endocervical curettage and cervical biopsy, vaginal
biopsy, loop electrosurgical excision procedure, and
hysterectomy, were reviewed and recorded. Follow-up Pap
tests were obtained 6 to 12 months after the initial
abnormal smear; all biopsies and curettages were
performed within 1 year. Statistical analysis was performed
using the z test and the t test. The significance level was set
at P of less than or equal to .5.
During the study period, the total number of Pap tests
accessioned in our laboratory was 43,840. A total of 368
smears or slides were identified with an interpretation of
ASC-H or equivalent, accounting for 0.84% of all Pap tests
screened during the study period. During the same period,
10.8% of the specimens were classified as ASC. As a result,
ASC-H accounted for 7.8% of specimens with an ASC interpretation. The incidence of SIL was 7.2%, resulting in an
ASC/SIL ratio of 1.5. This finding also indicated that our
population was at risk for developing SIL. The age of
patients with an ASC-H interpretation ranged from 17 to 87
years (mean, 36.8 years). Of the specimens, 52 (14.1%) were
liquid-based preparations, and 316 (85.9%) were conventional smears. There was no difference in the age distribution
of patients for the 2 preparations (P = .14; t test).
Of the 368 smears and slides with an interpretation of
ASC-H or equivalent, 218 (59.2%) had histologic follow-up
and 61 (16.6%) repeated Pap test results. Eighty-nine
patients (24.2%) were lost to follow-up. ❚Table 1❚ summarizes the follow-up according to the type of preparation.
There was no statistically significant difference in the choice
of follow-up between conventional and liquid-based preparations (P > .05; z test). Among the patients with a repeated
Pap test, findings were as follows: “negative for intraepithelial lesions or malignancy,” 38; persistent atypical squamous
or glandular cells, 19; LSIL, 1; and HSIL, 3. The average
number of follow-up Pap smears was 1.6 (range, 1-3).
A clinically significant lesion was detected in 172
patients (78.9%) with histologic follow-up: cervical intraepithelial neoplasia (CIN) 1, 89 (51.7%); CIN2/3, 79 (45.9%);
and invasive squamous cell carcinoma, 4 (2.3%). Table 1 also
summarizes the results of histologic follow-up for patients
with ASC-H with different preparations. The incidence of
clinically significant lesions after an interpretation of ASC-H
was higher with conventional preparations than with liquidbased preparations. However, the difference was not statistically significant (P > .05; z test). Similarly, no statistically
significant differences were noted in the incidences of CIN1
and CIN2 or higher between the 2 preparations.
❚Table 2❚ summarizes the types and the results of follow-up
among different age groups. Of the patients, 128 (34.8%) were
40 years old or older and 240 (65.2%) were younger than 40
years. There was no statistically significant difference in the
percentage for use of liquid-based preparations between the 2
groups (P = .56; z test). Approximately 66% of patients younger
than 40 years had histologic follow-up, whereas only 46.1% of
patients 40 years old or older had histologic follow-up. The
difference was statistically significant (P < .001; z test). Patients
40 years old or older were less likely to have a clinically significant lesion detected on subsequent histologic follow-up than
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Materials and Methods
Results
Louro et al / ATYPICAL SQUAMOUS CELLS, CANNOT EXCLUDE HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION
❚Table 1❚
Summary of Follow-up Results for Patients With ASC-H According to Type of Preparation*
Mean age (SD), y
No follow-up
Repeated Papanicolaou test
NIL
ASC/AGC
LSIL
HSIL
Histologic findings
Negative or reactive condition
Clinically significant lesion
CIN1
CIN2/3
Squamous cell carcinoma
Total
Conventional Smear
Liquid-Based Preparation (ThinPrep)
Total
37.3 (14.83)
79 (25.0)
47 (14.9)
27 (57.4)
16 (34.1)
1 (2.1)
3 (6.4)
190 (60.1)
38 (20.0)
152 (80.0)
7 8 (51.3)
70 (46.1)
4 (2.6)
316 (100.0)
34.08 (12.32)
10 (19.2)
14 (26.9)
11 (78.6)
3 (21.4)
0 (0.0)
0 (0.0)
28 (53.8)
8 (28.6)
20 (71.4)
11 (55.0)
9 (45.0)
0 (0.0)
52 (100.0)
36.84 (14.53)
89 (24.2)
61 (16.6)
38 (62.3)
19 (31.2)
1 (1.6)
3 (4.9)
218 (59.2)
46 (21.1)
172 (78.9)
89 (51.7)
79 (45.9)
4 (2.3)
368 (100.0)
❚Table 2❚
Summary of Follow-up Results for Patients With ASC-H According to Age*
Age ≥40 y
ThinPrep specimen
No follow-up
Repeated Papanicolaou test
NIL
ASC/AGC
LSIL
HSIL
Histologic findings
Negative or reactive condition
Clinically significant lesion
CIN1/HPV
CIN2/3
Squamous cell carcinoma
Total
Age <40 y
40-49 y
50-59 y
32 (13.3)
48 (20.0)
33 (13.8)
17 (52)
13 (39)
1 (3)
2 (6)
159 (66.3)
26 (16.4)
133 (83.6)
67 (50.4)
66 (49.6)
0 (0.0)
240 (100.0)
12 (21)
16 (28)
8 (134)
6 (75)
2 (25)
0 (0)
0 (0)
34 (59)
12 (35)
22 (65)
12 (55)
8 (36)
2 (9)
58 (100)
7 (19)
12 (32)
11 (30)
10 (91)
1 (9)
0 (0)
0 (0)
14 (38)
4 (29)
10 (71)
5 (50)
4 (40)
1 (10)
37 (100)
≥60 y
1 (3)
13 (39)
9 (27)
5 (56)
3 (33)
0 (0)
1 (11)
11 (33)
4 (36)
7 (64)
5 (71)
1 (14)
1 (14)
33 (100)
≥40)
Total (≥
20 (15.6)
41 (32.0)
28 (21.9)
21(75)
6 (21)
0 (0)
1 (4)
59 (46.1)
20 (34)
39 (66)
22 (56)
13 (33)
4 (10)
128 (100.0)
Total
52 (14.1)
89 (24.2)
61 (16.6)
38 (62)
19 (31)
1 (2)
3 (5)
218 (59.2)
46 (21.1)
172 (78.9)
89 (51.7)
79 (45.9)
4 (2.3)
368 (100.0)
AGC, atypical glandular cells; ASC, atypical squamous cells; ASC-H, atypical squamous cells, cannot rule out high-grade squamous intraepithelial lesion; CIN, cervical
intraepithelial neoplasia; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; NIL, negative for
intraepithelial lesions or malignancy.
* Data are given as number (percentage). Percentages are based on the category total, ie, repeated Papanicolaou test, histologic findings, clinically significant lesion. Numbers in
the ThinPrep specimen row are not included in the Total row. ThinPrep, Cytyc, Boxborough, MA.
were patients younger than 40 years (P = .01; z test). The
proportion of clinically significant lesions that were CIN2 or
higher was similar in both age groups. However, among patients
with invasive squamous cell carcinoma detected on subsequent
follow-up, all 4 patients were age 40 or older.
Discussion
Since its introduction by the Bethesda System in 1988,
the diagnostic category of atypical squamous cells has been
an evolving entity. For example, the second Bethesda System
(1991) recommended the subclassification of ASCUS as to
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whether a “reactive” process or a “neoplastic” process is
favored.3 Bethesda 2001 has proposed to drop the phrase
“undetermined significance” from the atypical squamous
cells category. In addition, it also proposed elimination of the
subclassifications of ASC.12 In addition to the aforementioned changes, Bethesda 2001 created a new diagnostic
category, atypical squamous cells, cannot rule out a HSIL (or
ASC-H) to denote cases that demonstrate some but not all
features of HSIL.12 The ASC-H category was introduced in
our laboratory in January 2000, and initially was termed “atypical metaplastic squamous cells, HSIL cannot be excluded.”
The term was replaced by ASC-H when our laboratory
implemented Bethesda 2001 in January 2002.
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AGC, atypical glandular cells; ASC, atypical squamous cells; ASC-H, atypical squamous cells, cannot rule out high-grade squamous intraepithelial lesion; CIN, cervical
intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; NIL, negative for intraepithelial lesions or
malignancy.
* Data are given as number (percentage) unless otherwise indicated. Percentages are based on the category total, ie, repeated Papanicolaou test, histologic findings, clinically
significant lesion. ThinPrep, Cytyc, Boxborough, MA.
Anatomic Pathology / ORIGINAL ARTICLE
nuclear contour and mild hyperchromasia. In our experience,
the cells of ASC-H were more likely to present as isolated
single cells and appear more euchromatic in liquid-based
preparations than in conventional smears ❚Image 3❚ and
❚Image 4❚.
The lack of well-defined criteria for ASC-H is reflected
in its poor interobserver agreement. In one study in which 20
cases previously diagnosed as ASC-H were reviewed by 4
❚Image 1❚ Atypical metaplastic squamous cells with nuclear
enlargement and increased nuclear/cytoplasmic ratio. Followup cervical biopsy revealed immature squamous metaplasia
(conventional smear, Papanicolaou, ×600).
❚Image 2❚ A syncytial group of metaplastic squamous cells
with nuclear enlargement and high nuclear/cytoplasmic ratio.
Subsequent biopsy revealed cervical intraepithelial neoplasia
3 (conventional smear, Papanicolaou, ×600).
❚Image 3❚ A group of atypical immature metaplastic
squamous cells with increased nuclear/cytoplasmic ratio and
hyperchromasia. Results of the follow-up cervical biopsy were
negative (ThinPrep [Cytyc, Boxborough, MA] preparation,
Papanicolaou, ×600).
❚Image 4❚ Loosely cohesive group of metaplastic squamous
cells with increased nuclear/cytoplasmic ratio. Biopsy of the
cervix revealed cervical intraepithelial neoplasia 3 (ThinPrep
[Cytyc, Boxborough, MA] preparation, Papanicolaou, ×600).
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The diagnostic criteria for ASC-H have not been well
established. Most authors agree that atypical squamous cells
classified as ASC-H resemble metaplastic squamous cells
and have an increased nuclear/cytoplasmic ratio6,7,10 ❚Image
1❚ and ❚Image 2❚. In contrast with ASC, with nuclei 2.5 to 3
times that of intermediate squamous cells, nuclear size is not
helpful in defining ASC-H because of the wide variation in
nuclear size.6,10 Other features include mild irregularity in
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uniform protocol for managing patients with ASC-H. In
addition, the present study was a retrospective review, and
the study period occurred before the publication of American Society for Colposcopy and Cervical Pathology
(ASCCP) guidelines. Many clinicians may have managed
patients with ASC-H as if they had a diagnosis of ASC-not
otherwise specified and provided less aggressive follow-up.
We also observed that patients 40 years old or older were
significantly less likely to have histologic follow-up than
those younger than 40 years. One possible explanation is
that physicians and health care providers might have the
false sense of security that older patients with ASC-H, like
their counterparts with ASC-not otherwise specified, were
less likely to have SIL on follow-up and, therefore, should
not be subjected to colposcopic examination and biopsy but
rather a repeated Pap test.
Among patients with histologic follow-up, more than
60% in either age group had a CIN lesion. The incidence of
CIN in patients 40 years old or older was less than that in
patients younger than 40 years. The difference was statistically significant. The occurrence of atrophy-related cytologic changes in the older population may explain the difference. Interestingly, the proportion of clinically significant
lesions that were CIN2 or higher, however, was similar in
both age groups.
Sheils and Wilbur10 noted no difference in the SIL
detection rate in patients younger than 41 years and older
than 40 years (28% vs 27%) after an interpretation of atypical squamous metaplastic cells or atypical immature squamous metaplastic cells. However, Quddus et al7 observed
that patients who had SIL histologic diagnoses were
younger than patients who had benign histologic diagnoses
after a cytologic interpretation of atypical squamous metaplastic cells. Therefore, their experience, as well as ours,
suggests that older women with an interpretation of ASC-H
are less likely to have SIL detected on subsequent biopsy
than younger women. In addition, these observations are
parallel with the findings of a lower detection rate of SIL
after a cytologic interpretation of ASC in older, postmenopausal women than in younger, premenopausal
women.10,20-22
In 2002, the ASCCP published updated guidelines for
the management of patients with abnormal Pap test results.23
Patients with a cytologic interpretation of ASC should
undergo reflex human papillomavirus DNA testing or
repeated Pap testing, whereas patients with a cytologic interpretation of ASC-H should undergo a colposcopic examination and cervical biopsy if indicated. Data from this study
support the ASCCP-recommended management for patients
with ASC-H since 78.8% of patients with ASC-H had SIL
on subsequent follow up and almost half of the SILs were
high grade. Although the detection rate of SIL for the subset
© American Society for Clinical Pathology
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pathologists, overall agreement among reviewers was 20%
with a κ value of 0.11.7 Sherman et al9 reported a κ value of
0.19 for the ASC-H category, similar to the reproducibility of
ASC. This lack of interobserver reproducibility of ASC-H
may be explained by pathologists’ personal uncertainty and
diagnostic thresholds.
ASC-H is an uncommon interpretation. We reported an
incidence of 0.84% of all Pap tests screened during the study
period and 7.8% of specimens with an ASC interpretation.
Other authors reported that the incidence of ASC-H or
equivalent ranged from 0.13% to 0.20% of all gynecologic
cytology specimens and from 6% to 9% of all specimens
classified as ASC.6,7,13 Therefore, our laboratory experienced
a higher overall rate of ASC-H among all Pap tests despite
our ASC/SIL ratio of 1.5. However, our percentage of ASCH among specimens reported as ASC was similar to those
reported in the literature. One possible explanation for our
higher overall ASC-H rate was that our population was at
high risk for SIL, with an incidence of 7.2%.
The reported incidence of CIN after an interpretation of
ASC-H or equivalent ranged from 27% to 62%, among
which 32% to 71% were CIN2 or higher.7,9,10,14 Our results
were similar to those reported in the literature. Of our
patients with histologic evaluation, CIN was found in almost
79%, and almost half of these patients (or 37.2% of all
patients with histologic follow-up) had a diagnosis of CIN2
or higher. According to the ASCUS LSIL Triage Study, the
incidences of biopsy-proven CIN2 or higher following a
cytologic interpretation of ASC-L (ASC, equivocal LSIL)
and HSIL were 11.6% and 59.2%, respectively.9 Others also
reported that the rate of CIN2 or higher following an ASC
interpretation ranged from 5% to 25%.13,15-19 Therefore, the
incidence of a clinically significant lesion following an interpretation of ASC-H was somewhere between that of ASC
and HSIL. These findings justified the creation and validated
the clinical relevance of the subcategory ASC-H.
We did not observe a significant difference in the incidence of CIN on follow-up between conventional and liquidbased preparations. There also was no difference in the rate
of CIN2 or higher lesions between the 2 preparations.
Sherman et al,9 however, reported that the incidence of
lesions diagnosed as CIN2 or higher was significantly higher
in patients for whom ThinPrep preparations were used than
in patients for whom conventional preparations were used. It
is interesting to note that in their study, women with ASC-H
for whom conventional smears had been used tended to be
older than those with ASC-H for whom ThinPrep Pap tests
had been used, whereas in the present study, age distribution
for the 2 types of preparations was similar.
Our patients were referred from various sources, and the
methods of evaluation were entirely at the discretion of their
physicians and health care providers. Therefore, there was no
Anatomic Pathology / ORIGINAL ARTICLE
of patients who were 40 years old or older was lower than
that for patients younger than 40 years, the incidence of SIL
for the former group was still quite significant, 66.1%. In
addition, all 4 invasive squamous cell carcinomas occurred
in patients 40 years old or older. Therefore, all patients with
a cytologic interpretation of ASC-H should undergo aggressive follow-up regardless of their age.
ASC-H was an uncommon interpretation in gynecologic
cytology and accounted for 7.8% of all Pap tests interpreted as
ASC. Follow-up biopsy revealed SIL in approximately 79%
of patients with ASC-H; half of the SILs were CIN2 or
higher. The incidence of SIL was similar in conventional and
liquid-based preparations. Therefore, patients with a cytologic
interpretation of ASC-H should be followed up aggressively.
Presented in part at the 91st Annual Meeting of the
American Society of Cytopathology, Salt Lake City, UT,
November, 5-9, 2002.
Address reprint requests to Dr Chhieng: Dept of Pathology,
University of Alabama at Birmingham, 619 19 St S, KB 627,
Birmingham, AL 35249-6823.
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