Benign Proliferative Reactions, Intraepithelial Neoplasia, and Invasive cancer of the Uterine cervix
Fig. 8.124 Small-cell cancer. Small tumor cells with scanty cytoplasm and
large irregularly shaped nuclei. Compare with superficial and intermediate
squamous cells. Nuclei show large variation in size and shape. Nuclear
chromatin is coarsely granular and hyperchromatic (Papanicolaou x HP).
Immunocytochemistry in Intraepithelial Neoplasia
and Invasive Cancer
To classify cervical intraepithelial neoplasia, cytopathologists
rely on cytomorphological criteria such as nuclear hyperchro-
masia, nuclear atypia, and nucleocytoplasmic ratios. This form
of classification cannot predict the biological behavior of CIN
lesions. A tremendous amount of biological markers or sur-
rogate end-point biomarkers which are largely applicable for
histological cervical tissues are developed. These markers are
usually introduced as "very promising" in correctly predicting
regressive or progressive behavior of cervical lesions. In daily
practice, the applicability of these markers is rather disappoint-
ing. As the earliest observations suggest that CIN involves a
progressive dysfunction of the proliferative activity of cervical
epithelial cells, most of the developed biological markers are
proteins that play a crucial role in the regulatory pathways of
the cell cycle. We refer to Chapter 1 for an extensive overview of
these biological markers, especially equipped for cervical his-
tology. In cervical cytology the choice of biological markers is
historically much more limited, as screening is done with the
Papanicolaou-stained smears and usually there is no rest mate-
rial for additional research. Moreover, if immunocytochemistry
on direct wet cytological specimens such as liquid-based cytol-
ogy wants to be successful, mild short fixation in alcohols or
acetone is necessary. Only in highly skilled and well-controlled
Fig. 8.125 Severe dysplasia of metaplastic type. Positive-staining
reaction for keratin 8 in basal and parabasal cell layers indicating an increase
in cytoplasmic characteristics of simple epithelium in this abnormal, originally
squamous metaplastic epithelium (immunoperoxidase method x MP).
laboratories can this mild fixation be performed properly, so
that reproducible immunocytochemical staining results may
be obtained. This problem does not occur in histology due to
robust routine fixation of tissues in formalin.
The development of chain-specific monoclonal antibodies
(mAbs) to individual keratins allows the immunocytochemical
distinction between reserve cells, immature and mature squamous
metaplasia, and normal ectocervical squamous and endocervical
columnar epithelium as well as between different types of epithe-
lial abnormalities (CIN grades 1, 2, and 3 ).123,228-230
By using several monoclonal antibodies directed against dif-
ferent epitopes of the same keratin polypeptide (e.g. different
mAbs against keratin 18), it is possible to detect structural alter-
ations resulting from biologic activity or neoplastic transforma-
tion. The degree of differentiation in a squamous cell cancer can
be determined by the use of keratin 10 or 13 antibodies. Keratin
10 is a marker of keratinization. It may be expressed in cells of
the more superficial layers of squamous epithelium, even when
no signs of keratinization are detectable light microscopically.
Broadly cross-reacting mAbs give positive reactions in virtu-
ally all epithelial tissues and primary and metastatic epithelial
cancers, including squamous cell carcinomas of different dif-
ferentiation grades and small-cell anaplastic carcinomas. The
antibodies to keratin 18 can, among others, recognize adenocar-
cinomas but do not normally react with squamous cell carcino-
mas.231 Adenocarcinomas almost always are negative for keratins
5, 10, 13, and 16. Squamous cell carcinomas almost always are
positive for keratins 5, 10, and 13. Expression of keratin 16 is
restricted to keratinizing squamous cell carcinomas. Keratin 7
mAbs in general gave no staining reaction with (keratinizing)
squamous epithelia. This antibody reacts with columnar cells
in the cervix.232
Moll and co-workers showed the presence of cytokeratins 5,
7, 8 , 17, 18, and 19 in immature squamous metaplasia and
a changed pattern of keratin expression in mature squamous
epithelium and mild dysplasia233 (Fig. 8.125). They found a
similar pattern in invasive carcinoma as in mature squamous
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