Clinical implications of atypical glandular cells of undetermined significance, favor endometrial origin
The Bethesda System recommends qualifying atypical glandular cells with regard to their possible origin: endocervical versus endometrial. This study was undertaken to determine the clinical significance of atypical glandular cells of undetermined significance that favor an endometrial origin (AGUS-EM).METHODSA computer search identified 62 cervicovaginal smears (5.25% of all smears classified as AGUS) with a diagnosis of AGUS-EM in the files of Shared Cytopathology Laboratory of New York University Medical Center/Bellevue Hospital Medical Center between January 1995 and December 1999. The patients ranged in age from 29 years to 88 years (mean age, 53 years). Thirty-four patients were postmenopausal (55%), and 5 patients were on hormonal replacement therapy. Follow-up was available for 56 patients (90%); 45 patients (73%) underwent biopsy, and 11 patients (17%) had repeat cervicovaginal smears. Six patients were lost to follow-up.RESULTSAmong patients who underwent biopsy, 14 patients (31%) had a clinically significant uterine lesions, including 6 (13%) endometrial adenocarcinomas, 5 (11%) endometrial hyperplasias, and 3 (7%) squamous lesions (2 high-grade squamous intraepithelial lesions and 1 squamous cell carcinoma). Ten of 11 patients with significant endometrial pathology findings were postmenopausal. The remaining 31 patients had benign pathology results, which included chronic cervicitis, endometritis, endometrial polyps, microglandular hyperplasia, and tubal metaplasia. Among the patients with repeat cervicovaginal smears, one patient had atypical squamous cells of undetermined significance; the remaining patients were within normal limits.CONCLUSIONS
Approximately one-third of women with a diagnosis of AGUS-EM had a significant uterine lesion on subsequent biopsy; the majority of these lesions were endometrial in origin. Patients with a diagnosis of AGUS-EM on cervicovaginal smears should be followed closely, and endometrial curettage or biopsy should be included in their initial work-up. Cancer (Cancer Cytopathol) 2001;93:351–6. © 2001 American Cancer Society.
- SourceAvailable from: utilis.net
Article: Endometrial hyperplasia: a review.[Show abstract] [Hide abstract]
ABSTRACT: Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women: endometrial cancer of endometrioid histology. It is most often diagnosed in postmenopausal women, but women at any age with unopposed estrogen from any source are at an increased risk for developing endometrial hyperplasia. Hyperplasia with cytologic atypia represents the greatest risk for progression to endometrial carcinoma and the presence of concomitant carcinoma in women with endometrial hyperplasia. Abnormal uterine bleeding is the most common presenting symptom of endometrial hyperplasia. Specific Pap smear findings and endometrial thickness per ultrasound could also suggest the diagnosis. Unopposed estrogen in women taking hormone replacement therapy increases the risk of endometrial hyperplasia. Tamoxifen has demonstrated its efficacy in treating women at risk for breast cancer, but it increases the risk of endometrial hyperplasia. The choice of treatment for endometrial hyperplasia is dependent on patient age, the presence of cytologic atypia, the desire for future childbearing, and surgical risk. Endometrial hyperplasia without atypia responds well to progestins. However, women with atypical hyperplasia should be treated with hysterectomy unless other factors preclude surgery. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to describe the definition and classification of endometrial hyperplasia, to outline the clinical features of a patient with endometrial hyperplasia, to point out the natural history of endometrial hyperplasia, and to summarize the diagnostic options for patients with endometrial hyperplasia.Obstetrical and Gynecological Survey 06/2004; 59(5):368-78. · 2.51 Impact Factor
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ABSTRACT: The 2001 Bethesda System for Reporting Cervical Cytology recommends reporting benign exfoliated endometrial cells in women age 40 and older, and a review of the literature supports this recommendation. Stromal cells and histiocytes do not need to be reported. The effect of hormonal therapy on endometrial shedding is reviewed. Clinical information should be provided to the laboratory so that appropriate educational notes can be appended to the cytology report. Benign endometrial cells in premenopausal women in the first half of the cycle are not associated with significant pathology and such women do not need additional evaluation. Significant pathology is also unlikely in the second half of the cycle and evaluation may not be required unless clinically indicated. Initial evaluation of other women with benign endometrial cells may include either endometrial sampling or transvaginal ultrasound. Atypical endometrial cells are associated with a higher rate of significant pathology and should lead to additional evaluation. Additional prospective studies on the management of patients with endometrial cells on Pap tests are needed.Journal of Lower Genital Tract Disease 05/2006; 10(2):111-22. · 1.21 Impact Factor
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ABSTRACT: To assess the clinical significance of a cervical cytological diagnosis of atypical glandular cells of undetermined significance and to formulate the most appropriate management guidelines for patients with such a diagnosis. Retrospective study. Regional hospital, Hong Kong. Seventy-two patients with diagnoses of atypical glandular cells of undetermined significance who were managed in a colposcopy clinic between January 1998 and December 1999. Age, cytological diagnoses of atypical glandular cells of undetermined significance and its subtypes, method of evaluation, final diagnosis, and outcome after 2 years. Atypical glandular cells of undetermined significance were diagnosed in 83 (0.4%) of 21 854 cervical smear samples taken during the 2-year study period. Follow-up data were available from 72 patients, whose mean age was 43 years (range, 22-69 years). Forty-three percent of these patients had significant diseases of the genital tract. Patients with the subtype diagnosis of atypical glandular cells of undetermined significance-favour neoplasia had the worst outcome, with 90% of patients having significant disease, followed by patients with atypical glandular cells of undetermined significance "not otherwise specified" (43%), and atypical glandular cells of undetermined significance-favour reactive (8%). Patients with atypical glandular cells of undetermined significance should be investigated early and thoroughly, because many of them will have premalignant or malignant disease.Hong Kong medical journal = Xianggang yi xue za zhi / Hong Kong Academy of Medicine 11/2003; 9(5):346-51.
Clinical Implications of Atypical Glandular Cells of
Undetermined Significance, Favor Endometrial Origin
David C. Chhieng, M.D.1
Paul Elgert, C.T.2
Jean-Marc Cohen, M.D.3
Joan F. Cangiarella, M.D.4
1Department of Pathology, University of Alabama
at Birmingham, Birmingham, Alabama.
2Cytopathology Laboratory, New York University
Medical Center, New York, New York.
3Department of Pathology, Beth Israel Medical
Center, New York, New York.
4Department of Pathology, New York University
Medical Center, New York, New York.
Presented at the 48th annual meeting of the Amer-
ican Society of Cytopathology, Philadelphia, Penn-
sylvania, November, 7–11, 2000.
Address for reprints: David C. Chhieng, M.D., De-
partment of Pathology, University of Alabama at
Birmingham, KB 627 619 19 Street S, Birmingham
AL 35249-6823; Fax: 205-975-7284; Email:
Received December 28, 2000; revision received
June 14, 2001; accepted June 28, 2001.
BACKGROUND. The Bethesda System recommends qualifying atypical glandular
cells with regard to their possible origin: endocervical versus endometrial. This
study was undertaken to determine the clinical significance of atypical glandular
cells of undetermined significance that favor an endometrial origin (AGUS-EM).
METHODS. A computer search identified 62 cervicovaginal smears (5.25% of all
smears classified as AGUS) with a diagnosis of AGUS-EM in the files of Shared
Cytopathology Laboratory of New York University Medical Center/Bellevue Hos-
pital Medical Center between January 1995 and December 1999. The patients
ranged in age from 29 years to 88 years (mean age, 53 years). Thirty-four patients
were postmenopausal (55%), and 5 patients were on hormonal replacement ther-
apy. Follow-up was available for 56 patients (90%); 45 patients (73%) underwent
biopsy, and 11 patients (17%) had repeat cervicovaginal smears. Six patients were
lost to follow-up.
RESULTS. Among patients who underwent biopsy, 14 patients (31%) had a clinically
significant uterine lesions, including 6 (13%) endometrial adenocarcinomas, 5
(11%) endometrial hyperplasias, and 3 (7%) squamous lesions (2 high-grade squa-
mous intraepithelial lesions and 1 squamous cell carcinoma). Ten of 11 patients
with significant endometrial pathology findings were postmenopausal. The re-
maining 31 patients had benign pathology results, which included chronic cervi-
citis, endometritis, endometrial polyps, microglandular hyperplasia, and tubal
metaplasia. Among the patients with repeat cervicovaginal smears, one patient had
atypical squamous cells of undetermined significance; the remaining patients were
within normal limits.
CONCLUSIONS. Approximately one-third of women with a diagnosis of AGUS-EM
had a significant uterine lesion on subsequent biopsy; the majority of these lesions
were endometrial in origin. Patients with a diagnosis of AGUS-EM on cervicovagi-
nal smears should be followed closely, and endometrial curettage or biopsy should
be included in their initial work-up. Cancer (Cancer Cytopathol) 2001;93:351–6.
© 2001 American Cancer Society.
KEYWORDS: cervicovaginal smears, atypical, glandular cells, endometrial cells,
1988 to denote cytologic changes in glandular cells that exceed those
typical of reactive changes but are quantitatively and/or qualitatively
not diagnostic of adenocarcinoma.1These changes may represent a
florid response to inflammation, a precursor neoplastic lesion, or a
nonrepresentative sampling of a neoplastic lesion. The Bethesda sys-
tem also recommends subclassifying the atypical glandular cells ac-
cording to their possible anatomic origin: endocervical versus endo-
metrial.2There have been a number of studies addressing the
he diagnostic category atypical glandular cells of undetermined
significance (AGUS) was introduced by the Bethesda System in
© 2001 American Cancer Society
implications and management of patients with AGUS
in general as well as patients with AGUS, favor endo-
cervical origin in particular.3–17Little is known about
the clinical significance of AGUS, favor endometrial
origin (AGUS-EM). In this retrospective study, we de-
termined the rate of a diagnosis of AGUS-EM and the
incidence of clinically significant lesions in women
with this cytologic diagnosis on subsequent follow-up.
We also suggested guidelines for the clinical manage-
ment of patients with this diagnosis.
MATERIALS AND METHODS
From January 1995 to December 1999, 211,220 cervi-
covaginal smears were screened at the Shared Cyto-
pathology Laboratory at New York University Medical
Center/Bellevue Hospital Medical Center. All cervico-
vaginal smears were collected using an endocervical
brush, an Ayre spatula, or a cervical brush. One or two
slides per patient were prepared, depending on the
preferences of the health care providers who obtained
the smears. All smears were fixed immediately with
nonaerosal spray fixative and sent to the cytopathol-
Patients with a cytologic diagnosis of AGUS-EM,
were identified during the study period. Patients with
benign appearing endometrial cells were excluded.
The diagnoses were made by staff pathologists using
the criteria listed in Table 1.
Information regarding previous gynecologic his-
tory and hormone replacement therapy was obtained.
The methods and results of patient evaluation, which
included repeat cervicovaginal smears, colposcopic
examination along with endocervical curettage and/or
cervical biopsy, and endometrial biopsy, were re-
viewed and recorded. Follow-up smears were ob-
tained 6–12 months after the initial abnormal smear;
all biopsies and curettages were performed within 1
During the 5-year study period, 1179 cervicovaginal
smears (0.56%) had a cytologic diagnosis of AGUS.
Among these smears, 62 (5.25%) had a diagnosis of
AGUS-EM. The mean age of this group of patients was
53 years, with a range of 29–88 years. Thirty-four
patients (55%) were postmenopausal. Five of 34 pa-
tients (15%) were receiving hormone replacement
therapy at the time of the AGUS diagnosis. Seven
patients presented with abnormal vaginal bleeding:
Six patients were postmenopausal, and one patient
was premenopausal. One patient had a history of en-
dometrial adenocarcinoma and was status posthyster-
ectomy. An additional patient presented with a history
of an ovarian mucinous neoplasm of low malignant
Follow-up information was available for 56 pa-
tients (90%): Forty-five patients (73%) had histologic
follow-up, and 11 patients (17%) had repeat cervico-
vaginal smears. Six patients were lost to follow-up.
The types of procedures performed for patients who
underwent histologic evaluation are shown in Table 2.
All but six patients underwent endometrial biopsy.
The patient who was status posthysterectomy for en-
dometrial carcinoma had biopsy of the vaginal cuff.
Fourteen of 45 patients (31%) with subsequent
histologic follow-up had a clinically significant uterine
lesion that was defined as a preneoplastic or neoplas-
tic, glandular or squamous lesion. Eleven patients
(24%) had a glandular lesion, including 6 endometrial
adenocarcinomas (Fig. 1) and 5 endometrial hyperpla-
sias. Three patients (7%) had squamous lesions, in-
cluding two high-grade squamous intraepithelial le-
sions (Fig. 2) and one invasive squamous cell
carcinoma. Table 3 shows the results of histologic
diagnoses in relation to the patients’ hormonal status.
Ten of 11 patients with significant endometrial pathol-
ogy and all patients with squamous lesions were post-
menopausal. In addition, four of five patients who
presented with abnormal vaginal bleeding and under-
went histologic evaluation had significant endometrial
lesions. The remaining 31 patients with biopsies had
Criteria of Atypical Glandular Cells, Favor Endometrial Origin
Arranged in loose and tight clusters
?/? Irregular nuclear contours
?/?: With or without.
Methods No. of patients (%)
EMB and ECC
Cervical biopsy and ECC
Cervical biopsy, ECC, and EMB
EMB: endometrial biopsy; ECC: endocervical curettage.
352 CANCER (CANCER CYTOPATHOLOGY) December 25, 2001 / Volume 93 / Number 6
benign pathology that included chronic cervicitis with
squamous metaplasia, endometritis (Fig. 3), endome-
trial polyps, mircoglandular hyperplasia (Fig. 4), and
tubal metaplasia. None of them demonstrated any
significant endocervical lesions. Among the patients
with repeat cervicovaginal smears, one patient had a
diagnosis of atypical squamous cells of undetermined
significance. The repeat smears of the remaining 10
patients were interpreted as within normal limits or as
benign cellular changes.
Among all patients with an AGUS diagnosis, 62%
underwent histologic evaluation. Twenty-nine percent
had a significant uterine lesion on subsequent follow-
up: Twenty-two percent were squamous lesions, 2%
were endocervical lesions, and 5% were endometrial
FIGURE 3. A large, three-dimensional group of glandular cells with mild
nuclear crowding and overlapping as well as mild nuclear hyperchromasia.
Subsequent biopsy revealed marked chronic endometritis (Papanicolaou stain;
original magnification, ?600).
FIGURE 4. A small cluster of glandular cells with scant cytoplasm and mild
nuclear hyperchromasia and pleomorphism. Subsequent biopsy revealed mi-
croglandular hyperplasia; the patient was on hormone replacement therapy
(Papanicolaou stain; original magnification, ?600).
FIGURE 1. Three-dimensional cluster of glandular cells with hyperchromatic
nuclei and scant-to-moderate, sometimes vacuolated cytoplasm. Endometrial
biopsy revealed a well-differentiated endometrial adenocarcinoma (Papanico-
laou stain; original magnification, ?600).
FIGURE 2. Haphazardly arranged glandular cells with coarse chromatin and
an increased nuclear-to-cytoplasmic ratio. It was determined that the patient
had a high-grade squamous intraepithelial lesion that involved the endocervical
gland (Papanicolaou stain; original magnification, ?600).
Results of Histologic Follow Up and Menopausal Status
Histologic diagnosis PostmenopausalPremenopausalTotal
Significant uterine lesions
SCC or HGSIL
SCC: squamous cell carcinoma; HGSIL: high-grade squamous intraepithelial lesion.
Significance of AGUS, Favor Endometrial Origin/Chhieng et al. 353
Since the introduction of the diagnostic category
AGUS by the Bethesda System in 1988, there have
been a number of studies addressing the incidence
and the clinical significance of AGUS.3–17The reported
rates of AGUS among the general patient population
ranged from 0.17% to 1.83%. Most laboratories report
an AGUS rate ? 1%.3–17The AGUS rate of 0.56% ob-
served among the general patient population in our
laboratory was in agreement with the current litera-
Few studies have investigated the incidence of
atypical endometrial cells in cervicovaginal smears.
One study was carried out by Cherkis et al.18before
the introduction of the Bethesda system. Those au-
thors identified 177 women with atypical endometrial
cells from a screening pool of approximately 300,000
cervicovaginal smears, resulting in a frequency of 1 in
1700 or 0.06%. In another study, the incidence of
atypical endometrial cells was 6.2% (5 of 81 smears)
among all cervicovaginal smears with a diagnosis of
AGUS.19In a more recent study, Soofer and Sidaway17
reported that the incidence of atypical endometrial
cells was 12% among all AGUS smears and 0.01%
among all cervicovaginal smears screened during the
study period. In the current study, atypical endome-
trial cells accounted for 5.25% of smears with a diag-
nosis of AGUS or 0.03% of all smears screened in our
laboratory during the study period, findings consistent
with those in the literature. It is interesting to note that
many studies did not subclassify the origin of the
atypical glandular cells according to their possible an-
Thirty-one percent of our patients with histologic
follow-up had a significant uterine lesion; 11 lesions
(24%) were of endometrial origin, and 3 lesions (7%)
were of squamous origin. These findings are similar to
those reported by Cherkis et al.18: 32 of 134 patients
(31.1%) with atypical endometrial cells had a signifi-
cant uterine lesion. Duska et al.19also reported that 2
of 5 patients (40%) with atypical endometrial cells had
a significant uterine lesion on subsequent follow-up.
In both studies, the significant uterine lesions were
exclusively of endometrial origin. Soofer and Sid-
away,17in a different study, identified 2 (18%) signif-
icant uterine lesions, 1 high-grade squamous intraepi-
thelial lesion (HGSIL), and 1 endometrial lesion in 11
patients with atypical endometrial cells. The incidence
of a significant endometrial lesion (either hyperplasia
or adenocarcinoma) on subsequent follow-up when
normal endometrial cells were identified in the pre-
ceding cervicovaginal smears ranged from 10.5% to
24.1%, with an average of 14.8%.20–23Therefore, the
incidence of a significant uterine lesion on subsequent
follow-up is higher for patients with atypical endome-
trial cells on their cervicovaginal smears compared
with patients with smears that show normal endome-
In a previous study, we reported that 75% of the
significant uterine lesions that were identified after a
diagnosis of AGUS were of squamous origin.3In the
current study, the majority of significant uterine le-
sions (79%) were endometrial in origin after a diagno-
sis of atypical endometrial cells. This may be ex-
plained by the fact that patients with atypical
endometrial cells tended to be older (average age, 53
years vs. 45 years in a previous study3) and were more
likely to be postmenopausal (55% vs. 40% in a previ-
ous study3) compared with patients who were diag-
nosed with AGUS. Similar observations were made by
other authors.18,19Cherkis et al.18reported that all of
the significant uterine lesions after a diagnosis of atyp-
ical endometrial cells were of endometrial origin.
Therefore, our findings and findings from other re-
ports justify the subclassification of AGUS-EM.
Twenty-seven of 45 postmenopausal women
(60%) with atypical endometrial cells had a significant
uterine lesion on subsequent follow-up, whereas 1 of
18 premenopausal women (6%) with atypical endo-
metrial cells had a significant uterine lesion on follow-
up. There was a 10-fold increase in the frequency of
significant uterine lesions in postmenopausal women
compared with premenopausal women. The differ-
ence was statistically significant (P ? 0.003; Fisher
exact test). Other authors also have observed an in-
creased incidence of endometrial adenocarcinoma as-
sociated with increasing age in patients with atypical
endometrial cells.18Patients age ? 59 years were more
likely to have an endometrial adenocarcinoma than
patients age ? 59 years, with a relative ratio of 2.3.
In the current study, among the five patients who
presented with vaginal bleeding and had histologic
follow-up, four women were postmenopausal and had
either endometrial hyperplasia or endometrial carci-
noma after a diagnosis of atypical endometrial cells in
cervicovaginal smears. The remaining patient was pre-
menopausal and had an endometrial polyp on histo-
logic evaluation. It is not surprising that symptomatic
postmenopausal women with atypical endometrial
cells were at risk of harboring a significant endome-
trial lesion. It is more important to note that more
than half (64%) of the patients with significant endo-
metrial lesions were asymptomatic. The cytologic
finding of atypical endometrial cells triggered a sub-
sequent work-up, resulting in the identification of the
occult endometrial lesions.
Three of our patients with atypical endometrial
354CANCER (CANCER CYTOPATHOLOGY) December 25, 2001 / Volume 93 / Number 6
cells had an HGSIL or invasive squamous cell carci-
noma on follow-up. Other authors also have reported
the finding of HGSIL on follow-up of a patient with
AGUS-EM.17HGSIL often is characterized by the pres-
ence of three-dimensional, hyperchromatic, crowded
groups that can mimic endometrial cells.24In a recent
study, Zhou et al.25reported that small cell carcinoma
of the cervix can form ball-like clusters of cells with
scant cytoplasm resembling endometrial cells. The
finding of dysplastic squamous cells should provide
evidence that the hyperchromatic, crowded groups
most probably are of squamous origin.24In addition,
the identification of a squamous cervical lesion does
not necessarily preclude the possibility of a concur-
rent endometrial lesion.
Various investigators have attempted to qualify
the diagnosis of AGUS to favor a reactive/benign pro-
cess or a premalignant/malignant condition.11,26–31
The majority of these studies focused on atypical glan-
dular cells of endocervical origin, particularly the cri-
teria for separating endocervical adenocarcinoma in
situ from benign lesions. There was only one study
that attempted to subclassify atypical endometrial
cells into three categories based on the nuclear size
and hyperchromasia, chromatin pattern, and pres-
ence or absence of nucleoli.18Those authors reported
that 40% of patients with markedly atypical endome-
trial cells, 20% of patients with moderately atypical
endometrial cells, and none of the patients with mildly
atypical endometrial cells had an endometrial carci-
noma on follow-up, with a risk ratio of 1.7. Both the
Bethesda System and the International Academy of
Cytology Task Force did not recommend the subclas-
sification of atypical endometrial cells because of the
lack of well-defined criteria.2,32Therefore, it is our
routine practice not to qualify further the atypical
endometrial cells according to whether they favor a
reactive or neoplastic process.
Ronnett et al.33have assessed the value of human
papillomavirus (HPV) DNA testing in the management
of patients with cervicovaginal smears classified as
AGUS.33HPV testing identified 92% of women with
histologically confirmed HGSIL, all patients with en-
docervical adenocarcinoma in situ, but none of the
patients with endometrial adenocarcinoma. There-
fore, HPV DNA testing did not provide useful informa-
tion for evaluating the status of the endometrium.
Currently, there is no clear consensus regarding
the management of patients with atypical endometrial
cells. Based on the findings of our study, we would like
to suggest the following guidelines: A complete endo-
metrial evaluation should be included as part of the
initial examination, particularly for postmenopausal
women. Colposcopic examination with endocervical
curettage should be considered part of the initial ex-
amination, because a small but significant number of
patients can have a high-grade squamous lesion.
Asymptomatic premenopausal patients may be fol-
lowed conservatively. In patients with an otherwise
negative initial histologic evaluation and persistent
glandular atypia on repeat cervicovaginal smears, the
clinician should consider more aggressive evalua-
tion.3,18,19It cannot be overemphasized that commu-
nication between clinicians and cytopathologists must
be established to convey the degree of concern about
possible neoplasia for a cytologic interpretation of
In summary, the incidence of atypical endome-
trial cells was low: 5.25% of all AGUS smears diag-
nosed in our laboratory. About one-third of these pa-
tients had a significant uterine lesion on follow-up,
with the majority of endometrial origin. Close fol-
low-up is indicated in patients with a cytologic diag-
nosis of AGUS-EM.
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356 CANCER (CANCER CYTOPATHOLOGY) December 25, 2001 / Volume 93 / Number 6