Benign Proliferative Reactions, Intraepithelial Neoplasia, and Invasive cancer of the Uterine cervix
In recent years, an increase in the incidence of cervical can-
cer in younger women has been suggested. This may well be
an effect of more frequent screening and screening in younger
age groups, because mortality rates have not (yet) shown an
increase in these age groups.145 In some countries, however, an
increase in mortality rates for cervical cancer in young women
has been reported since the late 1960s,186-188 suggesting the effect
of the introduction of some new risk factors in recent years,
particularly among young women.69 Independently of her age, a
woman's risk of cervical cancer is strongly associated with sexual
activity, more specifically with the number of partners and with
age at first intercourse.189 The epidemiologic pattern strongly
suggests the role of a sexually transmitted agent because of the
striking associations between the temporal, socioeconomic, and
geographic distributions of mortality rates of cervical cancer
and incidence rates of sexually transmitted diseases.190 Although
other factors such as long-term use of oral contraceptives, smok-
ing, specific dietary factors, and immunosuppression may also
be important, the exact role and the relative contribution of
each of these factors can be determined only after the sexually
transmitted agent that may be the main cause of cervical cancer
has been identified with certainty.69
For more than 20 years, much attention has been given to
herpes simplex virus type 2 as an etiologic agent of cervical
neoplasia, but conclusive evidence of a causal role has never
been obtained.191,192 According to a current hypothesis, HPV
is etiologically involved. Although laboratory studies provide
evidence to this effect, it will be very difficult to prove this
hypothesis epidemiologically.69,191,193
Microinvasive carcinoma
Microinvasive carcinoma is the earliest stage in the genesis of an
invasive cancer that can be recognized histologically.
With the implementation of a large-scale population-screen-
ing program, an increasing number of these preclinical, non-
symptomatic processes are being detected. During a 30-year
period, the percentage of microinvasive cancers diagnosed at the
University Hospitals of Cleveland increased from 1.2% of the
squamous cancers seen in the period ending in 1947 to 23.5%
of the cervical cancers detected in a comparable period ending
in 1972. Of the women with microinvasive cancer, 62.1% were
asymptomatic and 56.1% had normal-appearing cervices at the
time of diagnosis.194 These cancers with limited extent have a
very favorable prognosis. Because these cancers occur several
years before the average age of detection of frankly invasive can-
cers, patients are often still younger than 40 years and request
to have as conservative a treatment as possible. Microinvasive
carcinoma in its early stages is often found originating from an
overlying severe epithelial abnormality (CIN grade 3: severe dys-
plasia and carcinoma in situ), but occasionally, particularly in
more extensive lesions, invasion seems to arise from a lesion of
lesser severity. This, however, may be a pseudodifferentiation in
an originally severe lesion. This phenomenon may have caused
the confusion about the potential for progression of mild-to-
moderately atypical epithelial lesions.
The concept of microinvasive carcinoma was introduced by
Mestwerdt for invasive processes with a maximum depth of inva-
sion of 5 mm.195 Microinvasive carcinomas were separated into
a subgroup of stage I invasive cancers because of the much better
survival in patients with this group of lesions. The depth of inva-
sion has since been the crucial parameter for the choice between
a relatively conservative approach and radical treatment. The
subject of microinvasion has been associated with two decades
of confusion. Investigators have reported conflicting results in
what appears to be the same subset of patients.196 The volume of
the tumor, histologically determined by depth of stromal inva-
sion and linear extension along the surface and semiquantitated
from multiple parallel sections, is the real denominator of the
stage of the disease. There has been much confusion about the
exact definition of microinvasive carcinoma. In the literature,
the maximum depth of invasion is given as 1, 3, 5, 7, and 9 mm.
The ideal definition of microinvasive carcinoma should enable a
clear decision between a conservative approach and radical treat-
ment, but unfortunately there is still no internationally accepted
definition of microinvasive carcinoma. Also, the original defini-
tion adopted by the International Federation of Gynecology and
Obstetrics (FIGO) did not fulfill this requirement. In 2000, the
oncology committee of the Federation changed the definition
of limited-stage cervical cancer and better defined microinvasive
carcinoma.197 It is now widely accepted that to be considered as
a microinvasive cancer, the depth of invasion, measured from
the base of the epithelium from which it develops, should not
exceed 5 mm and the largest diameter (lateral extent) should not
exceed 7 mm. Vascular involvement should not alter the staging
but should be specifically recorded, because it may affect treat-
ment decisions in the future.197 The depth of invasion should
be measured from the basement membrane of the neighbor-
ing noninvasive epithelium. Preclinical carcinoma of the cer-
vix should include minimal microscopically evident stromal
invasion as well as small cancers of measurable size. Based on
the histologic evaluation of the tissue removed, which should
include the entire lesion, stage IA tumors are further subdivided
into stage IA1 tumors, which include lesions with minute foci
of invasion visible only microscopically, and stage IA2 tumors,
which are macroscopically measurable. Lesions of greater size
should be staged as IB. Because as a rule it is impossible to esti-
mate clinically whether a cancer of the cervix has extended to
the corpus, extension to the corpus should be disregarded.197
The diagnosis of microinvasive carcinoma should be made only
on a histologic specimen that contains the entire lesion. Punch
biopsy samples taken under colposcopic control and endocer-
vical curettage specimens are inadequate to provide a reliable
diagnosis of microinvasion.
Histologically, two separate entities may be recognized198-200:
• Early stromal invasion; and
• Microinvasive carcinoma.
Early Stromal Invasion
In the early stromal invasion, cell nests protrude from the basal
layer of the overlying epithelium into the surrounding stroma
or single nests are located within 1 mm of the overlying epi-
thelium (Fig. 8.102). These changes are usually too small to be
measured accurately and reproducibly. The earliest sign of inva-
sive growth is a usually rather well-circumscribed small nest of
cells "dropped" from the severely abnormal, essentially nonin-
vasive surface epithelium into the stroma. The cells composing
this protruding peg seem better differentiated owing to a rela-
tively large body of eosinophilic staining cytoplasm, which is
the basis of a lower nucleocytoplasmic ratio in the invading cells
than in the cells of the epithelium of origin (Fig. 8.103).201 The
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