Benign Proliferative Reactions, Intraepithelial Neoplasia, and Invasive cancer of the Uterine cervix
keratinizing epithelium. In the uterine cervix, with its nonkerat-
inizing stratified squamous epithelium, keratinization should
be regarded as a sign of abnormal differentiation. Keratinized
cells are not sensitive to radiation. This is the underlying cause
of the discrepancy between histologic grade of differentiation,
which suggests a relatively favorable prognosis for a patient,
and the poor reaction of the tumor to radiotherapy. As Patten
stated, "When keratinization is used as an index of differentia-
tion for the classification of invasive carcinoma of the uterine
cervix, there is relatively little correlation between differen-
tiation and biologic behavior and/or radiocurability."12 Reagan
and co-workers and Sidhu and colleagues found no correlation
between histologic grade and survival.222,223
In view of the poor correlation between differentiation grade
and biologic behavior, Wentz and Reagan proposed a classifica-
tion of squamous cell cancers of the cervix based on histologic
characteristics.224 Subclassification of the tumors was based on
growth pattern, cellular characteristics, and stromal reaction at
the site of infiltration. One of the major advantages of this grad-
ing system is that it permits a morphologic correlation between
cytologic and tissue specimens and it refers to the cells from
which the malignant tumor was derived. Based on the reaction
to radiotherapy, this classification correlates better with the bio-
logic behavior of the neoplasms. Wentz and Reagan's classifica-
tion of squamous cell cancers of the cervix included large-cell
nonkeratinizing cancers, keratinizing cancers, and small-cell
cancers. Wentz and Lewis found 5-year survival in large-cell non-
keratinizing cancers to be 78.6%, in keratinizing cancers to be
47.8%, and in small-cell cancers to be 20% .220 Survival was best
in large-cell nonkeratinizing tumors and poorest in small-cell
cancers. Later, in view of the wide variation in cell sizes present
in large-cell nonkeratinizing squamous cell cancers, the prefix
large cell was dropped.12 In 1973, this classification was adopted
by the World Health Organization.225
Cell Size and Shape
The cells originating in squamous cell carcinoma are smaller
than normal squamous cells. Round and oval forms are more
numerous than in dysplasia. Elongated cells are common in
invasive cancer, many of them containing intracytoplasmic
fibrils. The configuration of a cell depends in part on surface ten-
sion, the viscosity of cytoplasm, the mechanical action exerted
by adjoining cells, the rigidity of the cell membrane, and the
functional adaptation.
A rrangem ent o f Cells
Cells are often arranged in syncytial masses in which cells have
indistinct boundaries. This aggregation form is also a "microbi-
opsy" demonstrating altered cellular polarity. Cytoplasmic eosi-
nophilia is more often observed in the cells of invasive cancer.
N uclear M orphology
The nuclear configuration is in part related to the shape of the
cell. Invasive cancer has the largest proportion of nonisodiamet-
ric nuclear forms.222 Cytologic specimens do not always reflect
underlying disease. This is particularly important in regard to
invasive cancer. In improperly made smears, the sampled mate-
rial may be composed almost exclusively of the debris cover-
ing the invasive lesion owing to necrosis of the most superficial
layer and may thus fail to reflect the true nature of the disease.
Scattered abnormal cells may remain undetected during routine
screening, leading to a false-negative diagnosis. This is still
not very well recognized. Specimens of unsatisfactory quality
because of admixture of debris, blood, and leukocytes should
be carefully rescreened by a second observer, and the cytologic
examination should be repeated shortly.
Relative N uclear A rea
The mean nuclear area of tumor cells is more than twice the
mean area of normal squamous cells. This is significantly differ-
ent from the larger mean nuclear area of cells in dysplasia and
carcinoma in situ.
Cells in dysplasia have the highest absolute nuclear size, but
their relative nuclear area is relatively low. In general, the rela-
tive nuclear area is larger in more primitive cells and smaller in
mature cells.
Nonkeratinizing Cancer
Nonkeratinizing cancer characteristically invades with large
masses that have round, well-demarcated, blunt borders and
that are separated by thick bands of stromal cells (Fig. 8.109).
The surrounding stroma usually contains a moderately cellular
mononuclear infiltrate. Epithelial pearl formation by definition
may occur.
microscopically, it may be difficult to classify these tumors as
squamous in origin. In those cases, the immunocytochemical
demonstration of keratin 14 may be of assistance. Keratin 14 can
be demonstrated only in keratinizing cells. In nonkeratinizing
cancers, positivity in scattered cells can often be demonstrated,
even when individual cell keratinization is not recognizable by
light microscopy. A moderate number of mitoses can usually
be observed. In cytologic specimens, cells most often occur in
syncytial aggregates with usually ill-defined cytoplasmic borders
(Fig. 8.110). Owing to the often extensive necrosis of these neo-
plasms, cellular debris, blood cells, and proteinaceous material
cause a dirty background in the smear, which even in the absence
of diagnostic tumor cells should raise suspicion of a malignant
process (Fig. 8.111). The majority of cells are round to oval, some-
times polygonal. Moderate variation in size and shape is usually
present. Tumor cells having phagocytosed inflammatory cells or
Fig. 8.109 Nonkeratinizing squamous cell cancer. Tumor nests invade
with blunt edges. The stroma contains a dense inflammatory infiltrate. Tumor
cells are relatively rich in cytoplasm. Mitoses are frequently seen. No evidence
of keratinization. Nuclei vary greatly in size. Nucleoli are conspicuous (H&E x HP).
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