PART TWO
Diagnostic Cytology
Moreover, in cases in which sampling of the cervix has been
done less expertly, the number of abnormal cells may be rela-
tively low. In routine screening situations, this low number
of cells may remain unobserved or, because of the paucity of
abnormal cells, may erroneously lead to an underestimation of
the severity of the lesion.
The initial cellular sample collected from the cervix usually
contains the greatest number of abnormal cells. Subsequent
samples may contain few abnormal cells even after an interval
of 2 to 3 weeks. Because after only a short interval samples are
taken from less-matured lesions, diagnoses on repeat studies
made after too short an interval are likely to overestimate the
severity of the lesion. Therefore, when follow-up of the lesion is
done cytologically or when confirmation of the lesion is required
before biopsy, the repeat study should not be performed within
4 weeks.
In all cases of discrepancies between cytologic and histologic
diagnoses, both the cytologic and the histologic specimens must
be reviewed. When the original cytologic diagnosis is confirmed
at review, a repeat histologic examination should be requested.
Carcinoma In situ
Broders introduced the term carcinoma in situ (CIS) to describe
epithelial lesions composed entirely of cells that have all the fea-
tures of malignant cells but that do not exhibit invasive growth.141
This term has become widely used since. Other terms that have
been in use are incipient cancer, surface cancer, Bowen's disease
of the cervix, intraepithelial cancer, carcinomatoid change, and
preinvasive or noninvasive cancer.12,79,142
Carcinoma in situ is now generally accepted as a precursor of
invasive squamous cell carcinoma.
O rigin, Localization, and Extent
The morphologic variations that can be observed when studying
the spectrum of lesions directly associated with carcinoma in
situ suggest a common pathway in the development of dysplasia
and carcinoma in situ. The basic factor in the mechanism of
the genesis of carcinoma in situ is reserve cell hyperplasia. The
cells arising in reserve cell hyperplasia are noteworthy, because
in some instances they are reminiscent of those seen in carci-
noma in situ. A proliferation of the subcolumnar reserve cells
may involve only one or two layers of cells beneath columnar
epithelium or may attain considerable thickness. The latter not
only simulates carcinoma in situ but actually may represent a
developmental stage of this process.14
The stimulus that has induced a proliferation of reserve cells
as such also blocks the differentiation of these reserve cells into
immature and then mature squamous metaplastic cells. Thus,
by proliferation, primitive undifferentiated cells finally compose
the entire lesion. Each pathway in the development of carcinoma
in situ, localized in the endocervical canal, begins with or mim-
ics reserve cell hyperplasia. If some differentiation occurs in the
epithelial substrate before conversion to carcinoma in situ, such
as occurs in squamous metaplasia or dysplasia of metaplastic
type, the ensuing lesion is of large cell type. A lack of differentia-
tion of the epithelial substrate would result in an in situ lesion
composed entirely of small primitive cells.12
The majority of cases of carcinoma in situ originate in the
area of the transformation zone, bordering the original ana-
tomic separation between stratified squamous epithelium and
columnar epithelium. The farthest limit of CIN is determined
by the farthest limit of reserve cell hyperplasia (squamous
metaplasia, repair epithelium).22 In the most distal part of this
area, the stimulus for a metaplastic change of the columnar epi-
thelium is apparently the strongest. This may also be the rea-
son why large-cell carcinomas in situ are much more frequent
distally in the canal than proximally, where small-cell variants
are more often seen. It may well be that the potential for meta-
plastic change in the more proximal parts of the canal is lower,
resulting in a lower frequency of mature squamous metaplastic
changes and a higher frequency of poorly differentiated epithe-
lial abnormalities.
Epithelial changes preceding a small-cell carcinoma in situ
likely do not develop through precursor lesions showing some
squamous differentiation. It is probably very difficult to differ-
entiate between early small-cell intraepithelial changes and the
finally resulting small-cell carcinoma in situ. In a small number
of women participating in the Nijmegen population-screening
program, a small-cell lesion was identified as composed of rather
immature small cells, which histologically showed a pseudo-
stratified, somewhat columnar arrangement. In a few women
who had no intercurrent smears or biopsy specimens taken for
various reasons, classic small-cell carcinomas in situ were found
at repeat examination 3 to 4 years later.
The biologic significance of these pseudostratified small-cell
precursor lesions, which biologically may be comparable to the
more distally located severe dysplasias, needs further clarifica-
tion. On a cytomorphologic as well as on a histologic basis, it is
possible to subclassify abnormal intraepithelial lesions specifi-
cally into categories that can be arbitrarily labeled dysplasia and
carcinoma in situ.
A ge at Detection
Most researchers report an average age at detection of about
40 years (41.6 years12,79,142-144 and 42.5 years, with a range of 22
to 91 years).12 In our own material, average age at first histologic
diagnosis of carcinoma in situ was 39.4 years, with a range of 17
to 82 years (Fig. 8.80). More recently the mean age at detection
has been reported to be earlier. This reduction in average age has
Years
CIS
INV CA
Fig. 8.80 Carcinoma in situ (CIS) and invasive cancer (INV CA).
Histologic diagnoses. Age distribution-average age of patients with
carcinoma in situ was 39.2 years (SD 9.8) and
n
= 879. Average age of patients
with invasive cancer was 53.0 years (SD 13.9) and
n
= 435. (Data from the
Nijmegen Registry of Cervical Cytology, 1970-1987.)
172
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