Diagnostic Cytology
and are likely to lead to new discoveries regarding the interaction
of virus type, type variants, and other cofactors which may con-
trol both cancer development and the ultimate histogenesis.
Endocervical Adenocarcinoma in Situ
Endocervical adenocarcinoma in situ represents the most dif-
ferentiated neoplastic lesion that can be specifically recognized
on histologic and cytologic preparations. AIS was originally
described in 1953 by Friedell and Mackay.31 Although many
attempts have been made to identify precursor lesions to AIS,
no system has yet been devised to reliably classify and predict
the behavior of so-called "low-grade endocervical dysplasias."
Of note, in the first edition of
The Bethesda System
manual pub-
lished in 1994,32 AIS itself was not felt to be well enough defined
morphologically as to be reproducible enough to warrant its
own cytologic classification. Hence it was placed in the category
of "atypical glandular cells of undetermined significance, prob-
ably neoplastic." In the explanatory notes the authors make the
following statement which accurately reflected the general state
of practice at the time:
The category of atypical endocervical cells encompasses a broad
morphologic spectrum of changes that exceed reactive change
but fall short of frankly invasive adenocarcinoma. Accordingly,
lesions in this category can range from benign, but atypical-
appearing reactive processes, to adenocarcinoma in situ (AIS).32
In the conference leading up to the second edition of
Bethesda System
published a decade later,9 a review of the ensu-
ing literature and practice in cytopathology made clear that rec-
ognition of the cytologic features representative of AIS and the
reliability and reproducibility with which they could be detected
in routine conventional or liquid-based specimens made a sepa-
rate categorization of AIS appropriate. However, based on review
of available data, lesions less than AIS could still not be reliably
detected and categorized, and hence such cytologic presenta-
tions remained in the "atypical glandular cells" category (to be
discussed later).
AIS has been well characterized as a precursor lesion of inva-
sive endocervical adenocarcinoma. Its mean age of presentation
is substantially lower than that of invasive adenocarcinoma,
with reported ranges as much as 1233 to 18 years,34,35 indicating
that it long precedes the development of the invasive lesion. AIS
shares many of the same epidemiologic risk factors as invasive
endocervical adenocarcinoma, is associated with HPV in virtu-
ally all cases, and shows HPV type 18 to 16 ratios similar to
those of its invasive counterpart.11 In addition, resected speci-
mens of invasive adenocarcinoma typically show adjacent areas
of well-defined AIS. Squamous dysplasias are commonly identi-
fied in association with AIS. Some studies report the figure to be
as common as 50%,36 although in recent experience, this author
has noted more than 50% of cases unassociated with a squa-
mous component.
Histologically, the characteristic features of AIS involve a
completely or partially replaced area of surface epithelium and/
or endocervical glands, with no evidence of stromal invasion.
The epithelium is typically pseudostratified, with nuclei that
are enlarged and elongated, showing hyperchromasia and an
evenly distributed, but coarsely granular chromatin. Architec-
turally, intraepithelial gland formation and cribriform features
can be seen. Mitoses and apoptotic bodies are commonly noted
(Fig. 9.10).
The cytologic features were described (if not well recognized
or applied) in the early 1970s.37,38 The first organized descrip-
tions of the cytologic features of AIS appeared in the late 1970s
and 1980s.33,39,40 Derived from these earlier works, the currently
recognized cytologic criteria for AIS are compiled in the second
edition of
The Bethesda System
10 and include both architectural
and cytologic features. Architectural features include the pres-
ence of hyperchromatic crowded groupings of cells with promi-
nent cellular and nuclear overlapping. Additional groupings may
include pseudostratified strips of cells, the formation of epithe-
lial rosettes, and honeycombed arrangements with disorganiza-
tion and nuclear overlapping (not showing the uniform rigidity
noted with honeycombed groupings of benign endocervical
cells). Margins of the groupings may show palisading and a char-
acteristic protrusion of cytoplasmic and nuclear "tags," a feature
aptly named "feathering." This change occurs when the basal
portion of the cell is stripped from the underlying basement
membrane, leaving a portion of the cell elongated. Nuclei are
enlarged—on average about twofold the size of the intermediate
squamous cell nucleus—but significant size pleomorphism can
be present. The nucleus to cytoplasmic ratio (N:C) is higher than
for normal endocervical cells. The nuclei are oval to elongate,
hyperchromatic, and show chromatin patterns which are evenly
dispersed, but coarsely granular. Nucleoli are small and incon-
spicuous. Mitoses and apoptotic bodies are commonly found.
Occasional isolated abnormal columnar cells can be present, but
these are generally far less in number than cells that present as
groups. Slide backgrounds are generally clean, but occasionally
an inflammatory background can be noted. Examples of these
criteria are illustrated in Figs. 9.11 and 9.12. Dysplastic squamous
cells are present in association in a significant number of cases,
and focusing on this more commonly seen lesion can lead to
lack of identification of the extant abnormal glandular process.
Key features of endocervical adenocarcinoma in situ
• Hyperchromatic crowded groupings of cells;
• Pseudostratified strips of columnar cells;
• Epithelial rosettes (gland formations);
• Nuclear and cytoplasmic "feathering";
• Nuclear size twofold greater than normal endocervical
• N:C increased beyond normal endocervical cells;
• Coarsely granular, evenly distributed hyperchromatic
• Possible presence of small nucleoli;
• Presence of mitotic figures and apoptotic bodies; and
• Not associated with a background "tumor" diathesis.
Most original reports of the cytologic features of AIS were
from conventionally smeared Papanicolaou slides. Recently,
reports detailing the differences that can be present in the now
far more common liquid-based cytology preparations (LBP)
have appeared. Although virtually all reports have indicated that
AIS can be identified in LBP specimens with a high degree of
accuracy and reproducibility,41-44 the Bethesda System reported
LBP criteria that indicated that AIS may present in smaller and
denser 3-dimensional groupings, making visualization of indi-
vidual cells (and hence their specific cytology features) more
difficult.9 Pseudostratified strips of cells, often in a "bird-tail"-
like arrangement (Fig. 9.12), as opposed to the more commonly
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