[CANCER RESEARCH 36. 2482-2484, July 1976]
Carcinoma, Carcinoma in Situ, and “Early
Lesions―
of the
Uterine Cervix and the Urinary Bladder: Introduction
and Definitions1
Gilbert H. Friedell
Departments of Pathology, St. Vincent Hospital and University of Massachusetts Medical School, Worcester, Massachusetts 01610
At the outset of this combined session on “early
lesions―
of the uterine cervix and the urinary bladder, I should like to
propose some definitions as a basis for the discussions to
follow. First of all, however, I would remind you how the
pathologist gives meaningful names to morphological en
tities. Basically, there are 3 phases to naming such an en
tity.
First, the pathologist applies a descriptive term to the
lesion so that all who hear the term or see it in print will
know what the entity looks like. It is best if the term carries
with it neither pathogenetic nor prognostic implications,
since only a purely descriptive designation is appropriate at
this stage.
In the 2nd phase, the natural history of the lesion in ques
tion is studied. Clinicians and pathologists alike provide in
formation concerning the behavior and biology of the
morphological entity.
When the clinical significance is known, when the natural
history of the lesion has been elucidated, we then enter
Phase 3 of the nomenclature sequence. A name is selected
which will not only convey information about the morphol
ogy of the entity, but will also have pathogenetic and
prognostic significance. The word “cancer,―
for example,
when applied by the pathologist to a biopsy specimen, has
grave prognostic significance and very definite therapeutic
implications. One would be loathe to designate a prolifera
tive epithelial lesion as ‘
‘carcinoma'
‘
without hard data con
cerning the natural history of the entity in question. The
term carcinoma could be appropriately applied in Phase 3
of the nomenclature sequence, but not in Phase 1.
We would restrict the designation of carcinoma to those
epithelial lesions that meet the histological criteria for
malignancy, that invade the subepithelial or supporting
connective tissue, and that metastasize and/or kill the pa
tient (unless prevented from doing so by the introduction
of appropriate treatment). Use of the term carcinoma not
only indicates that the prognosis is poor unless the patient
is treated appropriately, but it also implies that the user of
the term knows what the outcome will be.
If we accept this definition of carcinoma, however, we
then have a problem in giving a name to the superficial
lesion which histologically resembles carcinoma but does
not invade the subepithelial tissue. Some have suggested
“precancer―
as a designation, waiting until invasion is
‘Presented
at
the
Conference.
“Early
Lesions
and
the
Development
of
Epithelial Cancer,―October 21 to 23, 1975, Bethesda, Md. Development of
this manuscript supported by USPHS Grant 15490 from the National Cancer
Institute through the National Bladder Cancer Project.
2482
evident before calling the lesion cancer. Others have ac
cepted the terminological
paradox of a ‘
‘noninvasive
cancer' ‘
and have used ‘
‘superficialcarcinoma―or “carci
noma in situ―when the markedly abnormal epithelium does
not appear to penetrate the basement membrane when
seen with the light microscope. I prefer the term carcinoma
in situ, and use the following definition.
Carcinoma in situ is epithelium that has the histological
features characteristic of cancer, but is noninvasive. It is
related in space or in time to the presence of carcinoma,
and will, if untreated, progress to carcinoma of the same
histological type in a significantly high percentage of cases.
In the cervix, the spatial relationship between invasive
and noninvasive carcinoma was recognized almost a cen
tury ago by SirJohn Williams (19), was noted and illustrated
in 1900 by Cullen (4), and was described in greater detail a
few years later by others (12, 13, 15, 16). They all noted the
presence of noninvasive but histologically malignant epi
thelium adjacent to carcinoma. It was Broders in 1932 (2)
who first termed this epithelium carcinoma in situ.
Subsequent cases were reported in which the presence
of such noninvasive malignant epithelium preceded by
months or years the development of invasive cervical
cancer (6, 17). Gradually, this concept of a sequential
temporal relationship between the presence of carcinoma
in situ and the development of cervical carcinoma was ac
cepted. Based on data concerning the peak age incidence
of both in situ and Stage I carcinoma, it has been esti
mated that the progression of in situ to invasive carcinoma
of the cervix takes an average of 10 years (6, 18).
That such progression is not inevitable, however, was
clearly pointed out by the work of Dr. Olaf Petersen (11).
Indeed, through personal communication with him and
with Professor Johannes Clemmesen since 1960, it is clear
that, in some of Petersen's cases, carcinoma in situ has
persisted —without either progressing or regressing —
for
many years, and may possibly do so through the remaining
lifetime of these patients. Others have also found that pro
gression is not inevitable in untreated cases of carcinoma
in situ, and at this time it is probably fair to say that
carcinoma in situ of the cervix, if not treated, will progress
to carcinoma in some 50 to 60% of cases over a period of 5
to 20 years. This is not to say that the lesion regresses
spontaneously in 40 to 50% of cases, but simply that it does
not progress in these cases. “Spontaneous
disappearance
of carcinoma in situ apparently does occur, but it is an ex
traordinarily rare event―(9).
Thus, as we define carcinoma in situ of a given organ, it
CANCER RESEARCHVOL. 36
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Early Lesions of Uterine Cervix and Urinary Bladder
becomes important to know just what constitutes a ‘
‘sig
nificantly high percentage of cases.―If we take as a stand
ard the 50 or 60% progression that we have just given for
cervical carcinoma in situ, how many lesions now called
carcinoma in situ in other organs will meet this part of the
definition? Suppose we find that in some organ a given
noninvasive lesion which histologically resembles carci
noma, if left untreated, will progress to carcinoma only in
15% of cases. Is this a sufficiently high figure to justify
the diagnosis of carcinoma in situ? If not, how should this
lesion be designated? As “precarcinoma
in situ―?Another
possibility, of course, is that we should have a sliding scale
for “significantlyhigh percentage of cases―so that we
would diagnose carcinoma in situ in one organ if the figure
is 15 or 20%, while in another organ the diagnosis would
have a 70% figure attached to it.
The spatial and temporal relationship between nonin
vasive and invasive carcinoma of the bladder is also clearly
evident. The study of giant tissue sections illustrates the
spatial relationship particularly well (1, 14). The temporal
relationship has been shown by information from longitu
dinal studies of patients with bladder cancer (7, 8, 10).
These studies indicate that an'in situ phase precedes the
development of invasive cancer in the bladder as it does in
the uterine cervix, but the in situ entity is less well defined
and the relationship between noninvasive flat and papillary
lesions remains to be worked out. Nevertheless, in many
ways the principles derived from the study of cervical carci
noma in situ would seem to be applicable, and the defini
tions just given can probably be used as we discuss pro
liferative lesions of the bladder (5).
In studies of the cervix, attention has also been devoted
to characterizing the early lesion which precedes the de
velopment of histologically recognizable carcinoma in situ.
Terms applied to it include atypical hyperplasia, anaplasia,
dysplasia, and others. This early lesion might be defined
as an epithelial proliferation with characteristic, but non
neoplastic, histological features which, if untreated, will be
followed in a significantly high percentage of cases by car
cinoma in situ or carcinoma. It represents the induction by
a simple or complex carcinogenic stimulus of an irreversi
ble but not necessarily progressive lesion which must be
distinguished from reversible hyperplastic lesions.
However, if the definition of carcinoma in situ in various
organs is somewhat clouded by our lack of knowledge con
cerning the percentage of cases which would go on to in
vasive neoplasms, the same problem confronts us as we
try to use our definition of the early lesion in discussing
the pathogenesis of cervical and bladder cancer. If the
definition requires that the lesion, comprised of epithelial
cells with defineable, but nonneoplastic, cytological or
histological characteristics will, if untreated, go on to carci
noma in situ or carcinoma in a significantly high percentage
of cases, what figure would constitute a significantly high
percentage of cases? —
5%? 25%? 50%?
Finally, we should note what is not an early lesion in our
terminology. This would be a reversible, proliferative epi
thelial change that can be characterized in histological or
cytological terms and that will provide a more-than-usually
susceptible substrate for a carcinogenic stimulus—but that,
JULY 1976
without this stimulus, will not go on to carcinoma. Some
epithelial hyperplasias of the cervix and bladder would fall
into this category of precursor or preneoplastic lesions.
Morphologically, the early and precursor lesions will be
similar, but the irreversibility of the 1st and reversibility
of the 2nd would distinguish them biologically. A biochemi
cal, biological, or other marker would be most helpful in
making this distinction.
During this first conference session dealing with early
lesions of the uterine cervix and the urinary bladder, there
will be references made to experimental models. Such
models may be defined as experimental systems, either
in vitro or in vivo, in which some aspect of the natural
history of a human cancer can be studied. Generally, the
model will be the growing tumor or the tumor interacting
with the host, but it might also be the host itself, as in the
development of a model for screening carcinogenic com
pounds. For example , a N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced bladder tumor in the Fischer rat might
be a good model for the study of the pathogenesis of
human bladder cancer (3), but the Fischer rat itself might
be a model for screening carcinogenic compounds.
During this meeting we will be discussing models in
which tumor cell markers or the markers of host response
to tumors (or early lesions) can be identified and followed.
A marker of an epithelial tumor, or of the epithelial cell com
prising the early lesion is that structural or functional cellu
lar characteristic which can be used to identify a tumor
cell or the cellular components of an early lesion. The latter
would be called early lesion markers and might include
cytological, histological, or ultrastructural characteristics
of epithelial cells, or the identification of some product
elaborated by the cells in question and detected locally or
systemically.
At the same time, we will be discussing host markers,
i.e. , the structural or functional characteristics of host tis
sues that appear in response to the presence of tumors or
early lesions. These might be specific or nonspecific, or
perhaps both, in response to a tumor or early lesion.
I would hope that during the course of this conference
we will be provided with some qualitative evidence of the
presence of such tumor or host markers in various experi
mental systems and in human patients with tumors or early
lesions. This would be the first step in the development of
quantifiable means of assessing the biological potential of
proliferative epithelial lesions of the cervix and bladder.
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CANCER
RESEARCH
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1976 American Association for Cancer Research.
VOL. 36
Carcinoma, Carcinoma in Situ, and ''Early Lesions'' of the
Uterine Cervix and the Urinary Bladder: Introduction and
Definitions
Gilbert H. Friedell
Cancer Res 1976;36:2482-2484.
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