Benign Proliferative Reactions, intraepithelial Neoplasia, and invasive Cancer of the Uterine Cervix
Fundamentally, dysplasia represents a reaction to injury in
the sense that a stimulus acting on a normal epithelium results
in some morphologic alteration of that epithelium.
It is unpredictable where (or when) the stimulus will initi-
ate an abnormal reaction (i.e. in mature stratified squamous
epithelium, mature squamous metaplasia, or immature squa-
mous metaplasia). The form of dysplasia that results may then
depend on the maturity of the epithelium that reacts. The mor-
phologic features of a dysplastic lesion involving an imma-
ture squamous metaplastic epithelium are relatively uniform
and differ from a similar reaction involving mature stratified
squamous epithelium.
The stimulus exerts its effect on the cells of the basal layer
of mature ectocervical stratified epithelium or on the reserve
cells or immature squamous metaplastic cells in the endocer-
vical canal. This would initially be demonstrated by a defect
in the mitotic mechanism of the cell, resulting in scattered
cells with an abnormal DNA content, demonstrated by the
appearance of enlarged nuclei with an abnormally distributed
hyperchromatic chromatinic material. Differentiation of the
cytoplasm is disturbed owing to an abnormal stimulus from
the nucleus.
With a continuing stimulus, persistence of some of the
abnormal cells capable of complete division and survival might
lead to an increase in the number of abnormal cells. Continued
selection and the persistence of the abnormal cells increasingly
involve multiple layers of the lining epithelium, thus increasing
the severity of the lesion.
Cervical intraepithelial Neoplasia
Because of a great deal of confusion about the clinical signifi-
cance of the terms dysplasia and carcinoma in situ, the term
cervical intraepithelial neoplasia was introduced in an effort to
bring a more active approach to the evaluation and treatment of
noninvasive epithelial abnormalities of the cervix.86
The concept of CIN reflects the basic unity of precancerous
changes, regardless of the phenotype of such epithelial abnor-
malities.86-89 It was meant to replace the prior system of nomen-
clature, such as dysplasia and carcinoma in situ.
Data on the progression rate of dysplasias of different grades
of severity and carcinoma in situ emphasize the continuous
nature of the epithelial alterations ultimately leading to inva-
sive squamous cell cancer. On this basis, it seemed advisable to
abandon the artificial distinction between dysplasia and carci-
noma in situ.89
The terminology of CIN subclassified into grades of de-
differentiation essentially has not provided an advantage
over the former subclassification of dysplasias. It has always
been recognized that within the group of dysplasias, a propor-
tion of the lesions may progress to a more severe abnormality,
eventually even to an invasive process. Many cases of CIN are
not truly neoplastic in character but represent a nonspecific
response to injury due to chronic irritation or inflammation.
Although the presence of an inflammatory process does not
preclude the possibility that the epithelial abnormality is not
truly neoplastic in nature, it remains true that in a residue of
cases, nonspecific reactive changes very closely mimic those
of true CIN.7 Richart and Barron apply strict criteria to lesions
before they can be included in the group of CIN.89 How-
ever, these are applicable only in retrospect, when epithelial
changes have proved to persist for a certain period. As stated
by these investigators, the progressive or indolent nature of
dysplastic lesions cannot be judged on the basis of mere light
microscopic examination. This, however, is equally impossible
in grading intraepithelial neoplasias. A relatively large percent-
age of the lesions do not progress during long-term follow-up.
Within the morphologic spectrum of CIN, one must include
lesions known as koilocytotic atypia, recognized as due to
papillomavirus infection. CIN can be graded from 1 to 3 to
reflect the degree of epithelial abnormality, provided that no
prognostic significance is attached to this classification. The
implication of the CIN concept is that all patients with abnor-
malities, whatever their grade, must be referred for colposcopic
examination to be evaluated further.64 Koss advises following
CIN grade 1 (mild dysplasia) with cytology or destroying the
lesion.64 In daily practice, the subclassification into CIN grades
1 through 3 has not reduced the number of women referred
for colposcopic evaluation or biopsies, and the diagnoses CIN
grades 1 through 3 still include a large number of lesions that
spontaneously regress because they were of a reparative or a
reactive nature.
Electron Microscopy
Although it is possible to subclassify CIN into mild, moderate,
and severe dysplasia and carcinoma in situ by light microscopy,
such a subclassification is difficult at the subcellular level.
The nuclear enlargement may reflect the increase in DNA syn-
thesis that accompanies the decreased generation time in dys-
plasia and carcinoma in situ. Mitotic figures are rarely observed
in normal epithelium but are frequently seen in dysplasia and
carcinoma in situ, in keeping with the more rapid growth rate.
The mitotic figures in dysplasias do not generally differ from
those in normal epithelium, but in rare mitotic figures that are
observed, the number of chromosomes in nuclei appear to be
In a comparative study between normal and dysplastic cells
using scanning electron microscopy, Kenemans and co-workers
demonstrated differences in surface architecture between the
basal and luminal side of normal intermediate squamous cells
and between normal and abnormal cells, both in exfoliated
cells and in cells from tissue specimens.91,92 The luminal side
of epithelial cells bears microridges, and the basal side con-
tains microvilli. All cases of histologically established (mod-
erate or severe) dysplasia showed a remarkable increase in the
number of microvilli and a decrease in the number of desmo-
somes. Abnormal configuration of microvilli was also observed
in epithelial abnormalities. These changes have also been
documented in cells from invasive carcinoma. The decrease in
number of desmosomes is in accord with the finding that neo-
plastic cells are more loosely attached to one another than are
normal cells.
The lack of adhesiveness between the epithelial cells in dys-
plasia and carcinoma in situ could also account for the increased
number of leukocytes in the altered epithelium, because it
would facilitate the penetration of the epithelium by inflamma-
tory cells.
Surface cells in dysplasia, although they may appear flattened
under the light microscope, have cytoplasm containing large
numbers of ribosomes, numerous mitochondria, and decreased
or absent storage of glycogen, which is in keeping with their
less-differentiated state. Increased numbers of ribosomes and
polyribosomes have also been reported in cervical squamous
cell carcinoma.90,93
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