PART TWO
Diagnostic Cytology
physiologic endometrium. This proliferative activity is often the
result of sustained estrogenic stimulation from either endogenous
(e.g. conversion of androgens by the peripheral adipose organ
to estrogenic compounds) or exogenous (e.g. secondary drug
effects). Endometrial hyperplasia is the morphologic precursor
for type I adenocarcinomas. The cytologic detection of at least the
advanced types of hyperplasia should lead to active treatment,
once a definitive histologic diagnosis has been made. Although
in situ type II adenocarcinomas can be detected cytologically no
precursor lesion for type II adenocarcinomas is recognized.
There is a spectrum of morphologies seen in endometrial
hyperplasia. The World Health Organization (WHO) terminol-
ogy is most often used to subdivide this spectrum into separate
diagnostic entities, and is based upon both the histopathologic
architecture and cytologic appearance of the epithelial cells.10
In simple endometrial hyperplasia without cytologic atypia
there is an abundance of endometrial tissue, and the glands are
enlarged and irregular in outline. The adjacent stroma is also
abundant, and in general the gland/stroma ratio is preserved.
The epithelium of the glands is lined by a single layer of tall
columnar cells with cytologic features similar to those seen in
a normal proliferative endometrium. The nuclei are ovoid to
elongate in shape, are usually basal, and contain small nucleoli
within an evenly spaced chromatin. Simple hyperplasia without
cytologic atypia is associated with a minimal increased risk for
the development of endometrial carcinoma.
In complex endometrial hyperplasia without cytologic atypia
the glands are not only enlarged and irregular, but are increased
in number. The relative amount of stroma is diminished, and the
glands appear to be crowded; occasional back-to-back glands may
be found. Nevertheless, some endometrial-type stroma remains,
and the desmoplastic response that typifies adenocarcinoma is
absent. Glandular complexity is reflected in intraglandular epi-
thelial budding and bridging. Despite these architectural features
the epithelial nuclei still resemble those of a normal prolifera-
tive endometrium. Stratification of the columnar cells is mini-
mal. The nuclei exhibit only small nucleoli. The risk of a woman
with complex endometrial hyperplasia without cytologic atypia
developing endometrial carcinoma is slightly increased.
The most significant endometrial hyperplasia is complex
hyperplasia with cytologic atypia,
or atypical endometrial
hyperplasia. (Simple hyperplasia with cytologic atypia is an
extremely rare lesion.) Women with atypical hyperplasia of the
endometrium are at substantial risk of developing endometrial
carcinoma. In fact, about one-quarter of women with this
form of endometrial hyperplasia diagnosed on endometrial
biopsy will have endometrial carcinoma identified within their
uterus resected within a few weeks of the endometrial biopsy.
The glands of atypical hyperplasia show all the architectural
abnormalities seen in any complex hyperplasia. The distin-
guishing feature is the presence of cytologic atypia character-
ized by enlarged, hyperchromatic nuclei with altered polarity
(Fig. 10.22). The chromatin is clumped, leading to large areas
of clearing. Both micro- and macronucleoli are present. These
nuclear features may be indistinguishable from those seen in
low-grade endometrioid adenocarcinomas.
The cytologic detection of endometrial hyperplasia by exfolia-
tive cervicovaginal specimens may be suspected in three differ-
ent patterns: the presence of normal-appearing endometrial cells
particularly late in the menstrual cycle in the reproductive-age
woman, the detection of normal-appearing endometrial cells
in the postmenopausal woman, and the finding of abnormal
Fig. 10.22 Complex endometrial hyperplasia with cytologic atypia.
Endometrial biopsy, histologic section (H&E x HP). Note the bridges of
epithelium across one of the two glands (arrow), loss of nuclear polarity,
and acquisition of nuclear variability and nucleoli.
endometrial cells at any age. Normal-appearing endometrial cells
in exfoliative cytology specimens in both pre- and postmenopau-
sal women may be associated with a number of conditions other
than endometrial hyperplasia (Table 10.7). In most cases, how-
ever, this finding is not associated with any significant pathologic
finding.42 Nevertheless, the current Bethesda System does require
that endometrial cells in a woman greater than or equal to 40
years of age be reported using an "other" category, separate from
both negative for intraepithelial lesion or malignancy (NILM)
and epithelial cell abnormality.43,57 These endometrial cells often
present as small, tight aggregates with peripheral moulding and
minimal cytoplasm. There are no distinctive cytologic features in
the endometrial cells shed from hyperplasia without cytologic
atypia. In contrast, the spontaneously shed cells from atypical
endometrial hyperplasia show variable degrees of nuclear atypia,
and often arouse the suspicion of adenocarcinoma (Fig. 10.23).
Once again, these nuclear features of atypical endometrial hyper-
plasia can be obscured by degenerative features (Fig. 10.24). In
addition to atypical endometrial hyperplasia and adenocarci-
noma, other conditions have been associated with the presence
of abnormal endometrial cells in exfoliative cytology (Table
10.8). Since there are a number of conditions which can be asso-
ciated with the finding of normal and abnormal endometrial
cells in exfoliative cytology, a definitive diagnosis of endometrial
hyperplasia requires a tissue diagnosis via endometrial biopsy
or curettage. Both clinical findings (symptoms, patient age and
history, and drug intake) and any imaging abnormality alter the
likelihood of finding a significant pathologic lesion, and will
influence the decision to undertake biopsy or curettage.
Key features of endometrial hyperplasia in CV cytology
• NECs late in the menstrual cycle of a premenopausal
woman;
• NECs in a postmenopausal woman's Pap test; and
• Abnormal endometrial cells at any age.
Endometrial Carcinoma in CV Cytology
The ability of exfoliative CV cytology, be it of endocervical or
vaginal type, to detect endometrial carcinoma is dependent upon
spontaneous shedding of cells from higher in the genital tract.
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