The Etiologyand Pathogenesis
of Oral Cancer
Roy W. Osterkamp, D.O.S.
and J. B. Whitten, D.O.S.
Etiology
The etiology of oral cancer in man is
unknown. However, several pre-exist
ing conditions have been found with
such frequency in patients with oral
cancer that they may be considered, at
least in part. as contributory factors. For
instance, chronic irritation seems to be
related to the development of cancer,
whereas a single episode of trauma
does not.
Other factors which may lead to the
development of oral cancer include:
El Ionizing radiation at therapeutic, not
diagnostic, dosage levels. Fortunately,
because of stricter rad iotherape utic
guidelines, few patients are today ex
posed to sufficient quantities of ionizing
radiation to produce cancers of the oral
cavity.
El Chronic exposure to actinic radia
tion. Chronic exposure to the sun is a
significant factor in the development of
cancer of the lower lip, the most com
mon form of oral cancer. The high inci
dence of “¿Farmer'slip― and “¿Sailor's factor in the development of oral cancer,
lip,― as well as epidermoid carcinoma
of the lip in hot climates attests to the
etiologic significance of long-term expo
sure to sunlight. Apparently, repeated
exposure to ultraviolet solar rays over a
period of 15-30 years results in atrophic
alterations of the exposed aspect of the
lower lip, which may develop into car
cinoma. The carcinogenic action of
solar rays varies according to intensity
Dr. Osterkamp is in general dental practice in
St. Louis, Missouri.
Dr. Whitten is Associate Professor and Chairman.
Department of Pathology, School of Dental Medi
cine, Southern Illinois University.
28
and length of exposure and is probably
limited by pigmentation. In black peo
ple, for example, epidermoid carcinoma
of the lip is extremely rare.
El The use of chewing tobacco and
snuff. The prolonged use of these agents
may lead to benign, premalignant and
malignant lesions of the base of the
tongue and the buccal mucosa. These
habits, which involve holding unburned
tobacco directly against the tissue in one
area of the mouth, may produce a local
concentration of the chemical constit
uents of tobacco, resulting in changes in
the mucous membrane. In addition,
other tobacco-related habits, such as
chewing betel nut and pan, have been as
sociated with dysplastic or neoplastic
disease as a result of chemical irritation.
A number of toxic agents, such as the lye
used in the betel nut cud, have also been
shown to have a contributory relation
ship to oral cancer.
El The chronic ingestion of alcohol.
This has been found to be a causative
especially cancer of the floor of the
mouth and tongue. The decreased inci
dence of oral cancer in Great Britain in
the last few years, in direct proportion to
a decrease in alcohol consumption, sup
ports this association.
El The action of specific infectious
agents. Atrophic leutic glossitis found in
tertiary syphilis has, for instance, been
associated with the development of
cancer of the tongue.
Epidemiological studies have found
an increased incidence of oral cancer for
cigarette smokers, as well as pipe and
cigar smokers.2 Long-term exposure to
the chemical carcinogens in tobacco and
icigure 1 Chemical burns Figure 3 Leukoplakia

,Figure2@Moniliasis Figure4 Epidermoidcarcinoma

29
 the trauma from heat and drying gen
erated by cigarette smoking are of etio
logical significance in the development
of cancer of the oral cavity and pharynx.
The role of metabolic and dietary de
ficiencies in the development of oral
cancer has not been determined, al
though an increased incidence of cancer
of the gastrointestinal tract, including
cancer of the oral cavity, has been
reported in Plummer-Vinson syndrome
and other disturbances in which atrophy
of the mucous membrane occurs.
In all probability, however, most of
these etiological factors are co-carcino
gens working symbiotically with a pri
mary carcinogen in the production of
cancer. The primary carcinogen, many
investigators believe, may be a virus. It
is theorized that the nuclear protein of a
cell infected by a virus is altered to fit the
purposes of the virus. This altered nu
cleoprotein is then transmitted to future
generations of cells. Eventually, a co
carcinogen (or co-carcinogens) acts to
initiate malignant change.

Pathogenesis
The most common type of oral cancer
is epidermoid carcinoma (squamous cell
carcinoma). Epidermoid carcinoma
originates in abnormal mucosa as either
leukoplakia, erythroplakia or speckled
leukoplakia. This disease most com
FigureS Speckled leukoplakia
monly begins in a leukoplakic lesion
which can be smooth or rough, flat or
elevated, ulcerated or intact.
Leukoplakia is manifested histologi
cally by a thickening of the mucosa.
When the thickened surface layer con
tains cells with retained nuclei it is
termed hyperparakeratosis; if the thick
ened surface layer cells do not contain
nuclei it is termed hyperorthokeratosis.
A thickened spinous layer is called

30
acanthosis; a thickened basal layer, ba
salar hyperplasia. Actually, many leu
koplakic lesions result from combina
tions of the various thickenings, for in
stance, hyperparakeratosis with acanth
osis. These hyperplastic lesions of oral
mucosa—hyperparakeratosis, hyper
orthokeratosis, acanthosis or combina
tions—generally have a benign course
for at least some phases of their biology.
The stage following hyperplasia in the
pathogenesis of oral cancer is dysplasia.
This is evidenced histologically by cyto
logically atypical cells and an alteration
in the sequence of maturation and orga
nization of the epithelium. It is not
proven if the removal of the cause of
dysplasia in the oral cavity will result in
resolution of the disease; therefore, dys
plastic areas are considered irreversible
precancerous lesions.
Carcinoma in situ, cancer confined to
the surface epithelium, shows all of the
histological criteria of cancer. However,
this process has not spread beyond the
boundaries of the surface epithelium.
Therefore, invasion and metastasis are
not present in carcinoma in situ. In other
sites of the body (uterine cervix, for ex
ample), and perhaps the oral cavity, car
cinoma in situ can persist for some time,
even years, before progressing into in
vasive carcinoma.
Epidermoid carcinoma can be of
varying levels of differentiation which
exhibit all the clinical and histologic fea
tures of cancer. The sequence in the de
velopment of carcinoma seems to be
similar regardless of origin (leukopla
kia, erythroplakia or speckled leukopla
kia). This disease shows invasion and
later metastasis.
Metastases, which generally occur
via the lymphatics of the neck, produce
fixed, indurated, matted swellings of the
neck. These neck metastases can obtain
considerable size, produce fistulation
and cause marked discomfort. When the
disease spreads beyond the neck, target
organs are usually the lungs.
Metastases to the oral cavity from
other sites of the body—generally from
cancers of the breast, lung or prostate
frequently present as a nonsymptomatic
radiolucency of the posterior aspect of
the mandible often associated with the
teeth. These radiolucencies are irregu
lar, with a “¿motheaten―pattern. Al
though the patient is usually aware of his
disease, cases of unsuspected cancers
have been diagnosed as a result of
“¿periapicalgranulomas― or “¿atypical
periodontitis― submitted for histopatho
logic examination.
The differential diagnosis of white le
sions relies on an adequate history and
thorough physical examination, as well
as histopathological investigation.
Some of the more common diseases
which may present as a white or whitish
lesion are listed below:
(I) Ectopic sebaceous glands (For
dyce ‘¿s
disease) presents as yellowish,
small elevations which, when clustered,
may resemble a white patch and occur
on the lips, buccal mucosa or vestibular
mucosa;
(2) Leukoedema appears as a filmy,
bluish-white lesion which is usually bi
lateral, confined to the buccal mucosa
and most frequently observed in black
patients;
(3) Chemical burns (Fig. 1.)produce
a lesion with necrotic surface epithelial
cells which can, at least in part, be
scraped clean, leaving a raw red surface,
and, in most instances, are associated
with a history of topical application of
some medication, often acetylsalicylic
acid;
31
 (4) Moniliasis (Fig. 2.) also presents
as a white lesion with surface fibrin and
organisms that can be scraped from the
underlying connective tissues; cytologi
cal examination of these scrapings are
usually diagnostic;
(5) Lichen planus produces multiple
lesions of bluish-white color (mother
of-pearl) composed (at least on the buc
cal mucosa) of many fine lines connect
ing to form beads. Since there are no
clinical features to distinguish lichen
planus from leukoplakia when it in
volves other sites, e.g., the tongue,
definitive diagnosis must be made by
histopathological examination;
(6) Leukoplakia (Fig. 3.)as the
name implies, is a white patch, usually
solitary, which may be smooth or rough
surfaced, ulcerated or nonulcerated and
which can only be diagnosed by histo
pathological examination;
(7) Erythroplakia is a red patch of the
mucosa which represents an area of dys
plasia, carcinoma in situ or epidermoid
carcinoma. It is necessary to distinguish
the common injury erythemas from the
precancerous lesions. In most instances
healing of inflammatory lesions occurs
within one to two weeks; if the lesion
persists longer, biopsy should be per
formed;
(8) Speckled leukoplakia (Fig. 5.) is
a combination of red and white areas and
must be considered a potential premalig
nant lesion and as such should have
histopathological examination;
32
(9) Verrucous carcinoma is a locally
aggressive cancer which metastasizes
only late in the course of the disease.
This lesion presents as an irregularly ele
vated, rough surfaced lesion which is
white to whitish yellow in color. Often
on radiographs superficial invasion into
the associated bones is evident. The
diagnosis of verrucous carcinoma is es
tablished by a combination of clinical
and histopathological examinations;
(10) Epidermoid carcinoma (Fig. 4.)
occurs most often in patients over 40
years of age, is usually a solitary lesion
and is capable of killing the patient by
local or systemic involvement. Epi
dermoid carcinoma can present as a
white lesion, a red lesion, an ulceration
or combinations. In later stages of the
disease the ulcerated lesion has ele
vated, indurated margins and is fixed to
the underlying tissues. If invasion or re
gional spread has occurred, clinical rec
ognition is facilitated. Almost all early
lesions or epidermoid carcinomas are
discovered by histopathological exami
nation. The definitive diagnosis of car
cinoma can only be established by histo
logical procedures.
References
1. Binnie, W. H.. etal.: Oral Cancer in England and
Wales. Her Majesty's Stationery Office, London,
l9'72,pp. 18-20.
2. U.S. DepartmentofHealth.Education,andWel
fare,PublicHealthService:TheHealthConse
quencesofSmoking.A ReportoftheSurgeonGen
eral:290.39l-392, 1971.