“FIELD CANCERIZATION” IN ORAL STRATIFIED

SQUAMOUS EPITHELIUM
Clinical Implications of Multicentric Origin
DANELY M.D., HARRY
P. SLAUGHTER, W. SOUTHWICK,
M.D.,
AND WALTER SMEJKAL, M.D.

ess of lateral cancerization. I n the early lesions

S QUAMOUS-CELL, OR EPIDERMOID carcinoma
the most common cancer affecting the hu-
man body. This tumor prototype may originate
is
this finding was much more striking. Not a
single tumor 2.5 cm. or less in greatest diameter
in more anatomical sites than any other form had downward extension that was as far as lat-
of carcinoma, since it is the usual cancer of the eral growth, the latter usually being three to
skin, lip, oral cavity, pharynx, larynx, bronchi, four times greater. T h e smaller the lesion, the
esophagus, anus, vulva, vagina, cervix, urethra, greater was this differential in measurement.
penis, and even bladder and renal pelvis. Rare-
ly, it may occur primarily or as a metaplastic CONTIGUOUS
PATHOLOGY
variant in other organs. Since the behavior pat-
terns of this morphological entity would seem I n all resected oral tumors it was found that
to have many similar characteristics in its dif- the benign epithelium, beyond the confines of
fering locations and microscopic variations, the malignant tumor was abnormal. This ob-
detailed knowledge of the natural history of servation led to special study of the later speci-
this disease is of some importance. mens, and it was found that rarely, if ever, was
As our most readily available source of normal epithelium included in the tissue ex-
squamous-cell carcinoma, oral cancers were cised. T h e limits of excision were of course
studied from the standpoint of their origins through grossly normal mucosa, except in the
and manner of spread. Tumors of the lip, oral occasional instance in which accompanying
cavity, and pharynx in 783 patients have been leukoplakia extended throughout almost the
reviewed, with findings that reinforce the con- entire oral mucosa precluding total excision of
cept of multifocal growth of these tumors. T h e all visible pathological tissue.
mu1ticen tric origin of epidermoid carcinoma Microscopic examination of the grossly nor-
is not widely accepted, although such occur- mal margins of the totally excised specimens
rence in the skin is generally recognized and revealed, uniformly, marked epithelial hyper-
studies of in situ carcinoma of the cervix uteri plasia and hyperkeratinization, usually with
are indicative of this origin. accompanying fibrosis and atrophy, to some
degree, of the submucosa. I n addition, there
TOPOGRAPHY OF ORALCANCER were frequently found both round-cell infiltra-
tion and some tendency to capillary telangiec-
I n a previous communication1 it was dem- tasia in the submucosa, beyond the apparent
onstrated that the large majority of oral squam- extent of the subacute inflammatory reaction
ous-cell cancers have much greater linear ex- resulting from the tumor itself. I n many of the
tent than extent in depth. Review of this larger sections dyskaryosis, amounting to marked
series strongly confirms that finding. Even in atypism, was found in areas adjacent to the
the far-advanced and hopeless cases, tumors tumor, and in some sections obvious in situ or
that had overgrown and destroyed all evidence intraepithelial epidermoid carcinoma was
of their origins, the majority still had wider found in continuity with or close to the inva-
horizontal spread than infiltration in depth. sive tumor. Serial sections on speciaIly blocked
This is at least suggestive of growth by a proc- whole surgical specimens were then studied,
and, in every instance in which the tumor itself
From the Research and Educational Hospitals and was 1 cm. o r less in diameter, separate foci of
the Tumor Clinic of the University of Illinois College
of Medicine, and the Presbyterian Hospital, Chicago, in situ cancer or isolated islands of invasive
Illinois. squamous-cell carcinoma were found (Figs. 1
Presented at the Sixth Annual Cancer Symposium of to 8). Such independent foci were also found in
the James Ewing Society, March 7, 1953.
Received for publication, April 1, 1953. the epithelium surrounding larger tumors.
963
964 CANCER
September 1953 Vol. 6

(For captions see opposite page.)

No. I; “FIELDCANCERIZATION” EPITHELIUM. Slnughter et nl.
IN ORAL 965
These findings constitute valid evidence of
microscopic multicentric origin. Such micro-
scopically related foci grow independently and
eventually coalesce to produce the clinical pic-
ture of the usual single ulcerating tumor. It is
also our impression that the concept of mul-
tiple contiguous foci of carcinogenesisexplains,
in part at least, one facet of the mechanism of
lateral spread of squamous-cell carcinomas.
In a few patients with very recent and small
oral cancers, grossly multiple tumors have been
seen in a circumscribed area of epithelial
change in which separate tumors are within
iriillimeters or a centimeter or two of each
other. T h e epithelial change surrounding such
tumors is one of two types: either visible and
occasionally palpable leukoplakia or an area
of crinkly atrophy and dryness. Serial sections
of such areas invariably demonstrate grossly
invisible foci of invasive or preinvasive cancer.
The apparent atrophy of the nonleukoplakic
type of epithelial change is seen to be due to
loss of the elastica and thinning of the sub-
mucosa, with a paucity of mucous glands, but
with an accompanying hyperplasia of the over- FIG. 5 . Low-power photomicrograph of mucosa of
floor of mouth with a 3-111m. carcinoma about the papilla
lying epithelium to a degree just short ol of the left Wharton’s duct. At points “A,” “B,” and “C,”
leukoplakia. independent areas of in situ carcinoma are seen. This
patient has since-within eighteen months-developed
another minute focus of infiltrating cancer 1 cm. away
TUMORS
MULTIPLE from this incisional line.
FIG. 6. High-power view of point “A” in Fig. 5.
Because of the accumulating evidence for
microscopic multicentric origin, the records of multiple tumors is represented in Table 1. The
the 783 patients with oral cancer were reviewed pattern of distribution of these multiple pri-
to determine whether or not macroscopically mary lesions is important and interesting, be-
multiple tumors occurred with any frequency cause in forty-three of these eighty-eight pa-
or pattern. Eighty-eight patients in this group tients two separate tumors occurred in the same
were found to have two or more independent anatomical area of the oral cavity. There were
squamous-cell carcinomas involving the mu- fifteen patients with double primaries of the
cosa of the upper alimentary and respiratory lip, one of whom had synchronous cancers of
tracts. This is an incidence of 11.2 per cent, well both the buccal mucosa and the gingiva, and
above the statistical possibility of chance oc- one other had an associated cancer of the lar-
currence. The anatomical distribution of these ynx; fourteen patients had double primary
FIG. 1. Low-power photomicrograph of strip of buccal mucosa from 67-year-old patient with
extensive leukoplakia of tongue and gingiva. In eleven years this patient has had seven separate
foci of epidermoid carcinoma involving the lower and upper lips, gingiva, and buccal mucosa. This
section shows the infiltrating cancer, for which the excision was performed, a t point “A.” At both
ends of the specimen hyperplastic epithelium is present, and at points “B,” “D,” and “E,”in situ
carcinoma is present. At point “C,” a small independent focus of infiltrating cancer is apparent.
FIG. 2. Low-power photomicrograph of superficial cancer of the posterolateral border of the
tongue. At point “A,” an early infiltrating carcinoma is seen and a t point “B,” carcinoma in situ,
shown in higher power in Fig. 3. The remaining epithelium is benign but abnormal and
hyperplastic.
FIG. 3. High-power photominograph of point “B” in Fig. 2, showing epidermoid carcinoma
in situ.
FIG. 4. Two sections of a low-power photomicrograph of a biopsy of extensive leukoplakia of
floor of mouth and lateral border of the tongue, taken in 1946. The pathological specimen was
reported as benign leukoplakia. The patient was again seen in 1950, with an extensive epidemoid
carcinoma of essentially the Same anatomical area, with invasion of the mandible and cervical
node metastases. Review of this original biopsy specimen shows carcinoma in situ at point “A” and
a small focus of infiltrating cancer a t point “B.”
 CANCER
Seplember 1953 Vol. D

FIG. 7. High-power view of point “B” in Fig. 5 .

FIG. 8. High-power view of point “B” and “C” in Fig. 5
No. 5 “FIELDCANCERIZATION” EPITHELIUM. Slntiglrler et 01.
IN ORAL
TABLE1
i\NrZTOMICAI, LOCATIONS OF MI’LTIPLE
PKI MARY ‘TUMORS
4
1
z As is well-known experimentally, the time in-
I cancer at multiple points, related either
X
- X
88 44 38 11 22 5 16 10 11 4 3
X-indicates single primary; X X-indicates
carcinomas of the tongue; four had bilateral
carcinomas of the tonsil; four had bilateral tu-
mors of the buccal mucosa; three had double
primaries of the palate; two had multiple tu-
mors of the floor of the mouth; and one patient
had independent cancers of the gingiva.
This pattern of distribution is of interest
1:ecause i t suggests a regional carcinogenic ac-
tivity of some kind, in which a preconditioned
epithelium has been activated over an area
i n which multiple cell groups undergo a proc-
ess of irreversible change toward cancer. It
also is intriguing because the percentage of
regional multiple oral tumors is almost identi-
cal with that occurring in one organ or tissue
in a study of multiple tumors of all types. In
that study of more than eighteen hundred sep-
arate instances of multiple tumors,’ approxi-
mately 50 per cent were found to arise in the
tissue of one organ or paired organs. This is
indicative of a selective or guided-missile type
of carcinogenic activity.
967
DISCUSSION
From the foregoing observations i t would
appear that epidermoid carcinoma of the oral
stratified squamous epithelium originates IJ\
L
.I
$
c a process of “field cancerization,” in which an
$
B area of epithelium has been preconditioned
4 w by an as-yet-unknown carcinogenic agent. Such
a carcinogenic influence if operative 1011::
enough in time and intense enough in exposurc
produces an irreversible change in cells an(:
cell groups in the given area, so that change o!
the process toward cancer becomes inevitable.
terval between the application of a carcinogen
and the development of cancer can be varied
X
at will by the intensity of the carcinogenic e \ -
X
posure. It is not only conceivable, but it is
X probable, that this same mechanism applies ti i
human cancer material, so that a field of pre-
X conditioned epithelium may break down into
microscopically or macroscopically, and pro-
ducing multiple tumors in the latter instance.
I t is our concept, then, that oral epider-
X
X iiioicl carcinoma arises from inultifocal areas
X
of precancerous change and not from one cell
X
X that suddenly becomes malignant. T h e indi-
vidual malignant cells grow and multiply by
a biologically relative form of geometric pro-
9 5 I gression, but lateral growth of a tumor may be
double primaries. in part by progressive change to cancer of peri-
pheral cells and not solely by expansion and
destruction from pre-existing malignant cells.
Such a concept would explain in part the
high local-recurrence rate in oral cancer.
MJhether radiation therapy or surgery is used,
the same block of tissue must be affected by the
treatment. Since surgically we are seldom be-
yond the limits of abnormal epithelium and
since radiation notoriously is less effective on
Oenign epithelium and leukoplakia than 011
carcinoma cells, local recurrence may be due to
benign epithelium preconditioned to change
toward cancer, which has been apposed in a
suture line after excision of a tumor or has
healed over the site of a tumor destroyed b!
radiation. Support of this thesis is given by
Constance A. P. Wood and J. W. Boag in a
report on oral cancer published by the Medical
Research Council of Great Britain. On page 58
they state precancerous areas respond different-
ly to radiation, and “the development of malig-
nancy is often a gradual process involving quite
large areas.” On page 70 they state that “per-
968 CANCER
September 1953
sistence of precancerous lesions accounts for
one-third of the failures in this series.”
We cannot derive any statistical estimate, but
we believe “field cancerization” to be an im-
portant factor in recurrence or persistence of
oral cancer after therapy. T h e problem of oral
cancer is in contrast to epidermoid carcinoma
of the cervix uteri in that the cervix may be
literally destroyed by intensive irradiation, or
the entire organ may be removed eurgically.
So far it has not proved practical in oral cancer
to apply in reverse the principle of abdomino-
perineal resection for rectal cancer.
One can still extend somewhat the limits of
excision of oral cancer, but eventually preven-
tion of the disease would appear to be a more
practical method of control. We already know
much of the etiological background of epider-
moid carcinoma in many of its manifestations,
such as the carcinogenic effect on the skin of
thermal trauma, sunlight, roentgen-ray and
gamma radiation, industrial exposure to hy-
drocarbons, and arsenic ingestion. Epidermoid
carcinoma of the bladder is known to result
from aniline-dye exposure, and studies have
even been made attempting to implicate non-
circumcision of the male as a factor in cancer
REFERENCES
1. SLAUGHTER, D. P.: T h e multiplicity of origin of
malignant tumors: collective review. Internat. Abstr.
Surg. 79: 89-98, 1944.
2. SLAUGHTER,
D. P.: Multicentric origin of intraoral
VOl. 6
of the cervix. Epidermoid carcinoma of the
lung has been traced to certain industrial haz-
ards and other possible etiological agents are
under review. With this background of knowl-
edge it would seem reasonable that an inten-
sive study of the etiological factors of oral
cancer might be well worth while.
SUMMARY
1. Oral squamous-cell carcinomas in 783 pa-
tients have been reviewed from the gross and
microscopic standpoint.
2. Eighty-eight instances of independent
mu1tiple tumors were found, a n incidence of
11.2 per cent, which is far beyond the statistical
possibility of chance occurrence.
3. Microscopic evidence of multicentric ori-
gin was demonstrated by serial section in all
excised tumors less than 1 cm. in diameter.
4. Abnormal and hyperplastic, often atypi-
cal, epithelium was found to surround all oral
cancers for varying distances.
5. Multicentric origin through a process oE
field cancerization would seem to be an im-
portant factor in the persistence or recurrence
of epidermoid carcinoma following therapy.
carcinoma. Surgery 20: 133-14G, 1946.
3. WOOD,C. A. P., and BOAC,J. W.: Researches o n the
Radiotherapy of Oral Cancer. Medical Research Council,
Special Report Series No. 267. London. His Majesty’s
Stat. Off. 1950.