Benign Proliferative Reactions, Intraepithelial Neoplasia, and Invasive cancer of the Uterine cervix
medications, particularly those used in the systemic treatment
of malignancies or in the course of immunosuppression in
organ transplant recipients, may also induce cellular changes
of a dysplastic nature. In rare instances, folic acid deficiency
may cause an increase of both cytoplasm and nucleus. Even
though extremely large nuclei may be found, the nucleocyto-
plasmic ratio remains within the limits of a minimal abnor-
mality because of a correlated increase of the cytoplasmic
body, often creating rather characteristic giant cells. In contrast
to dysplastic changes, nuclei are hypochromatic.130 Similar
changes may be found as an effect of radiotherapy or treatment
with alkylating drugs.64
Prognosis of Dysplasia and DNA Cytophotometry
Light microscopically observed severely abnormal epithelial
lesions cannot be subdivided into regressive, persistent, or pro-
gressive subtypes. An alternative to visual light microscopic
evaluation of these lesions is the study of DNA ploidy.131 In
one study, the DNA content in dysplasia proved to be higher
than normal, but the mode of the DNA index distribution fell
entirely within the diploid range. Some cells had DNA values in
the tetraploid and the hyperdiploid range, but a significant rela-
tionship between aberrant DNA values in dysplasia and DNA
profiles of carcinoma in situ and invasive carcinoma could not
be established.132
The wide range of DNA values found in dysplasia and car-
cinoma in situ indicates that dysplasia and carcinoma in situ
contain a highly variable population of cells whose range of
DNA content is similar to that found in invasive cancer. A high
proportion of cells in these lesions have abnormal chromo-
some numbers, but no chromosomal feature is distinctive of
dysplasia, carcinoma in situ, or microcarcinoma, nor is any
marker chromosome characteristic for early cervical neopla-
sia.107 In some studies, DNA ploidy analyses indicated a high
percentage of aneuploidy in CIN grade 3 lesions. On this basis,
DNA aneuploidy was considered to be a marker for progres-
sion.133,134 In dysplasia and carcinoma in situ, clonal prolifera-
tion may already be occurring. However, there is also much
evidence of the opposite kind: wide scatter of chromosome
counts without a recognizable similarity from cell to cell. DNA
estimations usually do not indicate a dominant aneuploid
stem line. Evidence suggests that by the time microinvasion is
identifiable, a new clone has overgrown the rest of the epithe-
lium. Most cases have one distinct stem line, but some can have
According to some investigators, quantitative DNA determi-
nations in cytomorphologically equivalent dysplastic cervical
cells do not offer additional means of predicting the outcome
of the epithelial change. In patients with moderate cervical dys-
plasia, no significant differences between cell populations from
moderate dysplasias that subsequently progressed to carcinoma
in situ and those from lesions that regressed to normality were
observed. The DNA distribution pattern of both groups was dif-
ferent from that of normal cells.137
A striking association was found between DNA ploidy and
age. In women who were younger than 35 years and who had
CIN grade 3 lesions, aneuploidy was present in 27%, and the
majority of the lesions showed a polyploid pattern. In women
older than 50 years, aneuploidy was found in 88%. These
findings suggest that processes finally progressing to invasive
cancer may have different biologic characteristics in these two
age groups. A diploid-like DNA pattern does not necessarily
imply a regressive or persistent behavior of intraepithelial
Postirradiation Dysplasia
After successful radiotherapy for a malignancy of the cervix, a
small percentage of patients, following a latent period varying
from 6 months to more than 20 years, develop an abnormality
of the cervical or vaginal mucosa that has the characteristics
of dysplasia. The characteristics of a postirradiation dysplasia
are essentially those of classic dysplasia. Accompanying the
cellular evidence of dysplasia is the evidence of increased
maturation of squamous cells, comparable to estrogen-induced
maturation and the characteristics of irradiation changes such
as multinucleation, dual staining reaction, and vacuolation of
the cytoplasm. The appearance of superficial squamous cells
may antedate the appearance of a cellular abnormality.140 The
biologic significance of a postirradiation dysplasia remains
With the exception of invasion, the basic changes of importance
in the recognition of primary cancer are apparent in both tis-
sues and cells.14 Because there is no single distinguishing feature
that is in itself invariably pathognomonic of cancer in the cell
or the epithelial lesion of origin, more than one fundamental
change must be present to warrant an interpretation of cancer.
Cell samples usually show dysplastic cells with a variable degree
of atypia.
A prerequisite for the study of cellular pathology is an inti-
mate knowledge of the component cells in the parent tissues
in order to learn the origin of various cells identified in cellular
preparations. Because the cellular sample represents a very com-
prehensive sample of the surface changes, in many instances the
cellular evidence of a change is not apparent on so-called punch
biopsy samples. For this reason, the presence of a lesion can
be precluded only when the pathologic study is comprehensive.
This is an important consideration when dealing with evidence
gained by cell studies.14
Clinicians increasingly show an inclination to reduce the
amount of tissue removed for diagnostic or even therapeutic
purposes. For diagnostic purposes, multiple biopsy specimens
preferably taken under colposcopic control or a very shallow
conus are most often used. Thus, a severe lesion of limited
extent bordered by less severe changes may not be present in the
histologic material. When comparing cytologic and histologic
findings, this may lead to the conclusion that a severe lesion
diagnosed cytologically apparently was overestimated: a
positive diagnosis.
With the use of collection techniques that provide compre-
hensive samples in the uterine cervix, most reactions occur-
ring in the cervix can be recognized on the basis of the cellular
changes alone.12 The number of cells diagnostic for a specific,
benign proliferative reaction depends on the extent of the epi-
thelial change and the method used for collecting the cells. In
a well-sampled specimen, cells from these multiple atypical
mucosal changes may be found next to one another. In a less
adequate sample in which only part of the circumference of the
ectocervix and the endocervical canal is represented by the cells
in the sample, only part of the abnormal changes may be recog-
nizable. This may lead to an underestimation of the severity of
the lesion or, when the sample is highly inadequate, to a
negative diagnosis.
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