Benign Proliferative Reactions, Intraepithelial Neoplasia, and Invasive cancer of the Uterine cervix
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Fig. 8.129 (A) In a CIN 2 lesion, Mibl-positive cells are present in the lower and middle thirds of the cervical epithelium. (B) In a CIN 3 lesion, the dysplastic
epithelium shows Mib 1-positive cells throughout the whole thickness of the epithelium (indirect immunoperoxidase method x MP).
a third of cases show some dispersed positivity for keratins 8
and 18, whereas keratin 19, which in mature squamous epithe-
lium stains basal layers, now shows loss of polarity and stains
an increasing part of the entire thickness of the dysplastic epi-
thelium, often in an irregular pattern.
Compared with mature squamous epithelium, the expression
of keratins 4, 5, 13, and 14 decreased and the staining pattern
became variable (Figs 8.127 and 8.128). This indicated that dys-
plastic epithelium related to the progression of the severity of
the abnormality progressively lost its squamous keratin pheno-
type and acquired keratin characteristics of simple epithelium.
These changes were even more evident in cases of CIN grade
3; in all cases, the expression of keratins 8 and 18 was abundant
and expression of keratins 13 and 14 decreased, in some areas
becoming completely absent. This emphasized the increased
expression of a keratin pattern characteristic of simple epithe-
lium with increasing dysplastic change.
Keratins 8 , 18, and 19 have been found in cervical squamous
cell carcinomas as well as in adenocarcinoma. The expression of
these keratins in reserve cells might indicate that these cells are the
common progenitor cells with a dual differentiation potential,
on the one hand through a phase of metaplasia into squamous
epithelial abnormalities and, on the other, through differentia-
tion into a columnar cell-type abnormality. The dual expression
of squamous cell-type and columnar cell-type keratins in imma-
ture squamous metaplasia seems to support this hypothesis.228,229
Ki-67 and p16INK4a
In cervical cytology and histology, two widely used cell cycle-
related oncoproteins are Ki-67 and p16INK4a. These proteins are
up-regulated in the dysplastic cervical epithelial cell through the
actions of high-risk HPV (for instance: HPV 16, 18, 31, 33, 45,
51, 56, and 6 8 ). Infection with high-risk HPV is an early event
in the multistep process of cervical carcinogenesis. Because of
integration of high-risk HPV in the host genome, the E2 region
of the HPV DNA is disrupted and the E6 and E7 viral proteins
are expressed. E6 and E7 proteins interfere with two pathways
of the host cell that are critical in tightly regulating cell division:
the pRb pathway and the p53 pathway. E6 disrupts the activities
of p53, the "guardian of the genome." This degradation of p53
makes repair of DNA synthesis errors impossible.239 Enhanced
expression of the E7 oncoprotein leads to inactivation of pRb,
which induces cell proliferation of the cervical dysplastic epi-
thelium.240 Both effects of HPV—genetic instability and hyper-
proliferation of the cervical epithelium—may finally lead to an
invasive phenotype or cervical cancer.
The monoclonal antibody Mib1 recognizes
a formalin fixation-resistant epitope on the cell
proliferation-associated Ki-67 antigen. Ki-67 is
expressed in dividing or proliferating cells and is
normally expressed in basal or suprabasal cells of the
cervical epithelium.241 Atrophic cells do not prolif-
erate and can be distinguished from dysplastic and
neoplastic cells by loss of Ki-67 expression.242,243
This phenomenon can be used in the evaluation of
Pap smears of postmenopausal women that may
be difficult to interpret. Atrophic cell groups show
no staining with M ib1, whereas dysplastic (highly
proliferative) cervical cells will stain strongly positive.
Cytomorphologically, these cell groups may not be
differentiated easily. A simple restaining procedure
of the difficult Pap smear with Mib1 may aid in the
diagnosis and thus prevent an unnecessary estrogen
treatment followed by a second Pap smear.244 More-
over, the extent of Mib1 expression correlates very well
with the grade of CIN in histology (Fig. 8.129) as
well as with the severity of cytological abnormalities
in cytological specimens.245,246
HPV E7 blocks pRb function and via a
negative feedback-loop mechanism p16INK4a will ac-
cumulate in the dysplastic cervical cell (nucleus and
cytoplasm). Overexpression of p16INK4a protein (p16)
is considered to be a marker for progression of CIN to
cervical carcinoma.247 In fact, the extent of p16 stain-
ing resembles the Mib1 expression in dysplastic squa-
mous epithelium as well as in atypical endocervical
epithelium. A good explanation for this phenomenon
is given by the viral oncogenesis model. When both
types of epithelium around the cervical transformation
zone become infected with high-risk HPV, the viral
oncoproteins will simultaneously induce
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