PART TWO
Diagnostic Cytology
Table 10.6
Comparison of the cytomorphology of endometrial cells, endocervical cells, and high-grade squamous intraepithelial lesion
Endometrial cells
Endocervical cells
HSIL
Size
Comparable to intermediate cell
Larger
Pleomorphic
Pattern
Overlapping, crowded, 3-dimensional
Often sheets, honeycomb, 2-dimensional
Can form tight groups but disorganized
Chromatin
Dense, degenerated
Vesicular, even
Hyperchromatic, coarse
Cytoplasm
Scant, wispy
Abundant, distinct cell borders, larger
vacuoles
Usually denser and cell shape varies
Additional findings
Neutrophil infiltration, presence of
stroma
Multinucleation may be present
Single atypical cells may be present
in the background
Table 10.7
Conditions associated with the presence
of normal-appearing endometrial cells in exfoliative
cervicovaginal cytology specimens (all ages)
Normal cycling and menstrual endometriuma
Benign endometrial polyps
Leiomyomas (submucosal)
Atrophic endometrium
Proliferating endometrium
Early post-partum period
Early post- or pre-abortion periods
Acute endometritis
Recent intrauterine instrumentation
Intrauterine device use
Hormonal and tamoxifen use
Cervical and vaginal endometriosis
Endometrial hyperplasia with, and without, cytologic atypia
Adenocarcinoma, low and high grade
‘See text for discussion of normal endometrial cells during reproductive years.
the presence of NECs, even in the second half of the cycle, is
not associated with significant endometrial pathology in the
vast majority of cases.42,53
The possibility of NECs in cervical cytology being associ-
ated with significant endometrial disease increases with age of
the patient and more importantly menopausal status. Many
studies have shown that postmenopausal women with NECs
in cervical cytology have a significant incidence of underlying
endometrial pathology (hyperplasia and adenocarcinoma), as
compared to women without NECs42,46,47,53-55 and as compared
to premenopausal women.56 However, many of these studies
lack an appropriate comparison group and are not controlled
for confounding variables such as use of hormone replacement
therapy.44 Furthermore, there is wide variation in histologic fol-
low-up, age range, criteria for menopausal status, and definition
of significant endometrial pathology. In addition, the signifi-
cance of NECs may have evolved over the past few decades along
with changing practice patterns. Studies from the 1970s using
conventional cytology showed an increased rate of abnormal
follow-up for NECS53,54 as compared to more recent studies in
the past 10 years.42,46,47,55 The presence and significance of NECs
may have been altered over this time period with increased use
of hormone replacement therapy and with changes in cytology
sampling devices and preparation methods.48
The majority of women diagnosed with endometrial adeno-
carcinoma will have symptoms such as abnormal vaginal
bleeding. In fact most women with NECs who are subsequently
found to have an endometrial lesion are also symptomatic.57
The significance of NECs in asymptomatic women is uncertain,
although some studies have shown a small but significant pro-
portion of women with endometrial hyperplasia/adenocarci-
noma will have NECs as their only presenting finding.42,58
Despite these drawbacks in the reported literature some con-
clusions can be drawn. The majority of both pre- and postmeno-
pausal women with NECs in their cervicovaginal cytology will
have no clinical abnormality. Nevertheless, there is an oppor-
tunity to detect endometrial neoplasia in a small proportion of
these women, especially those who are postmenopausal.
These controversies are mirrored in the development of many
of the current terminology systems used for reporting of cervi-
cal cytology43,59,60 (Table 10.4). In the 1990s, the first version
of the Bethesda System included the finding of endometrial
cells in postmenopausal women in the epithelial abnormal-
ity category.61 With the 2001 revision, this finding was moved
in the category of "Other" to be combined with "Negative for
Squamous Intraepithelial Lesion."43 It was recommended that
NECs be reported in all women over the age of 40. Although it
was recognized that NECs have the most significance in post-
menopausal women, this age-based cutoff was chosen largely
because menopausal status is frequently not available to the
laboratory, whereas patient age is reliably given. The average
age of menopause is approximately 51 years62 but there is wide
individual variation. In recommending the reporting of NECs
over the age of 40, an explanatory note listing the many condi-
tions, most of which are benign, that can be associated with
this finding was included. If a date of last menstrual period
is submitted and the woman is in the first half of her cycle, a
comment should be added that this finding is consistent with
provided menstrual data. Clinicians were expected to interpret
the finding of NECs in light of the patient's history and findings
and determine the most appropriate follow-up. Many coun-
tries that use the Bethesda System or a modified version have
adopted this recommendation for reporting of NECs in women
over the age of 4 0 .43,55,60,63
Since the adoption of these recommendations, there are con-
cerns that the reporting rates of NECs continue to rise, leading to
an increased number of investigative endometrial biopsies.48,64
Consequently some screening programs, for example Australia,
do not attach any significance to the finding of NECs at any
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