Cancer of the nose and paranasal sinuses (SNC) has been attributed to

occupational exposure to nickel, chromium, radium, dichlordiethyl sulphide,

isopropyl oil, and hydrocarbons. Occupational groups with an increased
SNC risk include furniture, boot and shoe workers, and workers in U S .
counties heavily involved in both petroleum and chemical manufacturing;
specific agents have not been identifiedwith certainty. In most of the studies,
the risk for developing SNC in the exposed workers was 21 to 100+ times
greater than the risk for SNC in those who were not exposed. Undifferen-
tiated and squamous histologies are associated with nickel refining; aden-
ocarcinomas are found in woodworkers, boot and shoe manufacturers, and
textile workers. Most occupations at risk for SNC were also at risk for cancer
of other sites, particularly lung and skin cancer. Study of the epidemiology
of SNC may identify unrecognized carcinogens and occupational groups at
increased cancer risk.
HEAD & NECK SURGERY 2:3-11 1979

EPIDEMIOLOGY OF CANCER
OF THE NOSE AND
PARANASAL SINUSES:
CURRENT CONCEPTS
GEORGE C. ROUSH, MD, MPH

Less than 1% of cancer deaths in the United
States from 1950 through 1969 were attributed
to sinonasal cancer, i.e., cancer of the internal
nose and paranasal sinuses (SNC).77It is precisely
the rarity of this tumor and its unique epidemi-
ologic features that make SNC useful in the study
of cancer etiology and prevention.
CLINICAL FEATURES
Hospital studies characteristically report that
about 55% of SNC arises in the maxillary an-
trum, 35% in the nasal cavity, 9% in the ethmoid
sinuses, and 1%in the sphenoid and frontal sin-
uses.17.i0.72 Although the above distinctions may
often be difficult to make, it is frequently possible
to distinguish sinonasal cancers as a group from
From the Department of Epidemiology and Public Health, Yale University
Schooi of Medicine and the Connecticut Cancer Epidemiology Unit, New
Haven, CT
Acknowledgments This work was supported by National Cancer Institute
contract NO1 CP 33235 and PHS grant 1 R01 CA 24304. The assistance
of Clarence T Sasaki, MD, in reviewing this manuscript is gratefully
acknowledged.
Address reprint requests to Dr. Roush at Connecticut Cancer Epide-
miology Unit, 30 College St., New Haven, CT 06510.
Accepted for publication April 19, 1979
0148-64031020110003 $00.0010
1979 Houghton Mifflin Professional Publishers
those cancers arising in adjacent anatomic areas,
(such as the skin of the external nose, the naso-
pharynx, and the oropharyngeal surfaces of the
hard palate and upper alveolar ridge). The his-
tologic distribution reported in United States hos-
pitals shows a predominance of squamous-cell
and anaplastic-cell types, while about 15% are
adenocarcinomas.
Symptoms of SNC are usually present one to
six months before diagnosis is rnade.l2 Clinical
manifestations include periorbital swelling, nasal
discharge, or nasal obstruction.'""2,'i Intraopera-
tive biopsy is the usual method of diagnosing both
sinus and nasal cavity cancers, although occa-
sionally tumors exhibiting exterior growth may
be first diagnosed by a biopsy performed in the
physician's 0ffice.l') X ray may reveal erosion of
facial bones, particularly in cancers that are pri-
mary to the antrum. SNC is usually diagnosed in
the localized stage. The relative five-year sur-
vival rate (a figure that includes deaths from
causes other than SNC) is 25% to 50%, and pa-
tients with nasal cavity cancer have a better
prognosis than those patients with maxillary
cancer.8-10,12,46,52,72
DEMOGRAPHIC
CHARACTERISTICS
The incidence rate of SNC, adjusted for age and
sex, is 0.3 to 1.0 cases per 100,000 people a year

Epidemiology of Nasal Cancer HEAD & NECK SURGERY Sep/Oct 1979 3

in most countries*'H.2Y,."Y,l
11,112 (Rates in this para-
graph follow the custom of tumor registries in re-
porting SNC under ICDA code 160, thus includ-
ing cases of eustachian tube and middle ear
neoplasms in the rates. However, these two sub-
sites constitute only 6% of the ICDA 160 category
in Connecticut.) Exceptions are Uganda and Ja-
pan, which have reported rates between 2.0 and
3.6 cases per one hundred thousand annual-
ly.'5.39.1I2 Except for nonepithelial neoplasms, SNC
is virtually nonexistent in children. The inci-
dence rate increases steadily after age 35,reach-
ing about 5 to 7 per one hundred thousand by age
80. The incidence rate in males is 1.5 times greater
than that found in females. No studies on social
class variation are available. The death rate in
the United States among the Negro population
appears to be about 1.5 times greater than that
found among Caucasians. 75
OCCUPATIONAL
FACTORS
As table 1 indicates, chemical agents in occupa-
tional settings often play a causal role in the de-
velopment of sinonasal cancer. This table in-
cludes only those chemical agents whose
association with SNC had been supported by both
epidemiologic and animal studies. Nickel (Ni),
chromium (Cr), radium (Ra), and isopropyl oil
have each been associated with SNC in two or
more factories.
Evidence for a chemical agent in the etiology
of SNC is strongest for nickel exposure; in nickel
refining, risks exceeded 100 in retrospective co-
hort studies in Wales, Norway, and Canada. Each
of these studies also found elevated risks for lung
cancer, while five cases of laryngeal cancer were
found among the Norwegian refinery workers.
For patients with SNC, the minimum duration of
exposure t o the chemical was six months, but
most subjects had worked in the refineries nine
or more years. The risk for SNC increased with
duration of exposure and age at first exposure. An
interesting historical note is that, in each of the
three countries in which nickel refinery- related
cancers have been well studied, the risk for res-
piratory cancer appeared to have been largely
eliminated before the first epidemiologic study in-
dicated that there had been a carcinogenic hazard
in that country's i n d ~ s t r y . ~ ~ . " . " ' ~
Experiments in animals have confirmed that
inhaled nickel subsulphide and nickel carbonyl
may cause lung carcinoma,x""""and that subcu-
taneously injected nickel subsulphide, nickel car-
4 Epidemiology of Nasal Cancer
bonyl, and other nickel compounds may produce
sarcoma at the site of injection.'7,fi2,63,~1,101,102
Lab-
oratory models of tumorogenesis suggest that
nickel has a direct effect on nucleic acid, and/or
protein, ~ y n t h e ~ i ~Although . ~ ~ both
~ ~ the
~ ~ ~ ~ , ~
laboratory and epidemiologic results point to the
carcinogenicity of nickel, Sunderman has noted
that other carcinogens, chromium and arsenic
(As), were also present in those nickel refining
processes.
Little data are available on the possible car-
cinogenic effects of nickel in manufacturing (as
distinguished from refining) occupations. The first
such epidemiologic study found no deaths from
SNC among workers in an aircraft engine plant
and no increased risk for lung cancer; however,
the quantity of nickel exposure was felt to be less
than the current Occupational Safety and Health
Act (OSHA)threshold limit value of 1mg Ni/m3.I3
Furthermore, these authors pointed out that evi-
dence from the laboratory and from the nickel re-
finery indicated that both nickel subsulphide and
nickel carbonyl are more carcinogenic than the
nickel in the dusts and aerosols the aircraft work-
ers were exposed to.
Further epidemiologic studies in manufactur-
ing settings that employ nickel as a component
(e.g., silverware, aircraft, paint, and dye prod-
ucts) or as an intermediate-such as nickel ca-
talysts-may help in identifying those forms of
nickel that are carcinogenic in humans. Case re-
ports of lung and sinonasal cancer suggest that
a hazard may exist when nickel products are
being ground, stripped (pickled, degreased), or
plated.18~100~102~1"6
Welding, smelting, and casting
operations have also been held suspect."
Table 2 provides epidemiologic evidence for
occupationally induced sinonasal cancer (no lab-
oratory experiments in animals were done to sup-
port these data.) Otolaryngologist Esme Hadfield
first discovered an apparent SNC risk among
woodworkers.." While the risk for SNC among
boot and shoe workers in England and among fur-
niture makers appears to be well established ep-
idemiologically, the complexity of occupational
exposure has created uncertainty as to which are
the responsible agents (these are discussed later
in this article). The excess cancer deaths in coun-
ties heavily involved in both the petroleum and
chemical industries is consistent with the finding
of an increased risk for lung cancer in machine
setters, gashouse workers, steelworkers, etc., who
are exposed to polyaromatic hydrocarbons. A case
of skin cancer of the nose has been reported in an
HEAD & NECK SURGERY SepiOct 1979
individual who had previously been diagnosed
with scrota1 cancer caused by cutting oils.6oAn
excess risk for cancer primary to the sinonasal
mucous membrane has been attributed to such
e x p o ~ u r e ;however,
~ ~ , ~ ~ little data on the relation- the relative risk for cancer of other sites in the
ship are available, although there are several re-
ports on the risk for skin and lung cancer.32~33,10gJ*0tive risk for SNC in refinery workers in Wales
A report of two cases of SNC among asbestos
workers has apparently not been supported by
any additional occurrence^.'^*^^ Six cases of SNC
have been documented in the baking industry,
and a seventh case involved exposure to flour
in a mill. Three of these cases were transitional
cell carcinomas and three were adenocarcinomas.
These findings are being studied to determine
their significance.
A deficiency of many of the occupational stud-
ies has been the absence of data on possible con-
founding variables. It is conceivable that tobacco
use, for example, could have contributed to the
elevated risks found among nickel refinery or
chrome pigment workers-if tobacco is causative
for SNC and if the particular cohort used tobacco
in excess of the comparison group. However, the
relative risk for SNC appeared to be higher than
same occupational group. For example, the rela-
exceeded 100, while their relative risk for lung
cancer was no higher than 13. The high relative
risk for SNC minimizes the possibility that can-
cer has been spuriously attributed to occupational
hazards in industries involving nickel, chromi-
um, mustard gas, wood and petrochemicals.
The association of the sinonasal tumor with
the manufacturing of mustard gas, isopropyl oil,
and hydrocarbon gas is based on a small number
of cases of SNC. The argument that these few
cases do not represent chance clustering is sup-
ported by excess risks for other tumors in each of
these manufacturing settings, including tumors
of the lung, larynx, and bone. Furthermore, the

Table 1. Occupational agents correlated with sinonasal cancer in epidemiologic studies, with laboratory confirmation
Other cancers
associated with
Occupational Suspect No. of SNC Relative Latent the exposure
setting carcinogen cases riska Anatomic site Histology periodh (no. of cases)
Nickel refiningb Nickel subsulphide, 143c Up to Nose, Squamous, 24 Lung (447)c
oxide, or carbonyl 800 ethmoids anaplastic (5-40) Larynx (5)
Chrome pigment Calcium chromate, 9' 2 21 Sinuses, nose Adenocarcinoma and -' Lung (180)
manufacturingd zinc potassium not specified
chromate
Dial Radium 49 - Antrum Squamous 15 Osteosarcoma (22)
painting7,21,97.95 (18-25) Mastoid
carcinoma (4)9
Mustard gas pp dichlordiethyl 3e 3 30 Sphenoid Squamous 25 Tongue (1)
manufactur- subhide Pharynx (3)
in955.'08 Larynx (8)
Lung (34)
lsopropyl alcohol lsopropyl oil 6' 2 21 Ethmoid Adenocarcinoma and <20 Larynx (3)
manufactur- not specified
ing41.65.80.113
Gas rnanufactur- Hydrocarbons 3" - Paranasal -f -f Lung (1 1)
iw22,62 sinus Larynx (3)
Pharynx (3)
Bladder (5)
Esophagus (3)
"he estimated usk for SNC among those with the given exposure divided by the risk in the unexposed; for example, the risk
in nickel refinery workers was up to 800 times greater than the risk in other occupations.
bData obtained from references 24, 27, 36, 38, 56, 62, 79, 81, 85-87. 98-105
"Two-sided p < 0.05 for SNC and for all respiratory cancers combined.
9 a t a obtained from references 43. 62, 69, 71, 83, 92.
eTwo-sided p < 0.05 for respiratory cancers combined
'Data not available
* Thirty-three cases of carcinoma primary to the nasopharyngeal area, paranasal sinus, and mastoid region have been
documented in a cohort of about 5,000 individuals, most of whom were occupationally exposed and were females."
hLatent period IS defined as the number of years from the first entry into a high-risk occupation to the development of
cancer (with numbers in oarentheses indicatma the ranae in observed vears)

Epidemiology of Nasal Cancer HEAD & NECK SURGERY SepiOct 1979 5

 Table 2. Occupational agents correlated with sinonasal cancer in epidemiologic studies, without laboratory confirmation
Other cancers
Occupational Suspect No. of Relative Anatomic Latent associated with
setting carcinogen SNC cases riska site Histology period (yr) the exposure
Furniture and other Wood dust 34" Up to 70 Ethmoids. Adenocarcinoma 43 None
woodworkt ng constituents nose (27-69)
(beech, oak)
Boot and shoe Wood dust 17" 8-87 Ethmoids, Adenocarcinoma 55 Bladder
manufacturing and constituents nose Squamous 42
repair'.3
Textile and clothing Wool dust 20" 5-8d -e Adenocarcinoma -e Tongue, mouth,
manufacturing4 constituents and melanoma pharynx
Chemical Nitrosamines. - Men 1.1 -e -e -e Lung, larynx,
manufacturing dioxane, aromiltlC Women. 1 2 skin. bladder,
( U S counties hydrocarbons, liver, bonef
heavily nickel catalysts
Both petroleum and Aromatic -e 2.0 ~
Lung, skin
chemical hydrocarbons,
manufacturing nickel catalysts
( U S counties
heavily i n ~ o l v e d ) ' ~
~ ~~

'The risk for SNC among those with the given exposure divided by the risk in the unexposed, for example, the risk for SNC in
woodworkers is up to 70 times greater than the risk among those in other occupations
bData obtained from references 2 4-6, 20. 34, 35, 44, 47-49, 66
' p < 0 05
dAcheson e t a / noted that it was extremely difficult to calculate a rea/ishc expected figure, and the relative risk given here
IS our approximation
'Data not avai/ab/e
'This listing includes excesses for males on/y

anatomic distribution of the accompanying tu- cinogens which act directly on the cells of the si-
mors is generally compatible with observations nonasal and pulmonary epithelium. For example,
on routes of exposure to the suspect agents. simple occlusion of one nostril has been shown to
induce squamous metaplasia in the other nostril,
ROUTES OF EXPOSURE and this could interfere with the clearing mech-
TO OCCUPATIONAL AGENTS anism of the upper airway.3'' Compared to plastic
Airborne particulates or vapors of the suspect car- dust, wood dust has been shown to slow muco-cil-
cinogens have been observed in workplaces in- iary transport in the nasal epithelium.fi The im-
volved with nickel, chromates, mustard gas, iso- plication that such alterations predispose to si-
propyl oil, shoes, furniture and hydrocarbon gas; nonasal cancer is analogous to the concept of
exposure appears to occur by direct inhalation of increased susceptibility to lung cancer when the
these substances. In five of these seven work sit- respiratory cilia and muco-ciliary blanket have
uations, the occurrence of tumors in other parts been destroyed or compromised.R2
of the respiratory tract-but not in other ana- While direct exposure via inhalation is an im-
tomic sites-supports this concept of exposure via portant factor, other mechanisms need consider-
direct inhalation. Excesses of laryngeal and lung ation. In radium dial painters, the radioactive
tumors were not found among woodworkers or metal was probably absorbed by the oral mucosa
among boot and shoe workers; this may be a func- and deposited in body and facial bone; from these
tion of the trapping of carcinogenic agents by the sites, constant radiation to adjacent tissue led to
hair and ciliated pseudostratified columnar epi- tumors of the nasal epithelium, the mastoid air
thelium of the nasal passages. Trapping appears cells, and, most commonly, the osteoid tissue it-
to depend on particle diameter (>5pm), particle self.g' In laboratory animals, oral, subcutaneous,
density, and the breathing habits of the subje~t.''~ and intravenous administration of dioxane, qui-
Hazardous exposure may act by disturbing the noxaline 1 , 4 dioxide, or any of several nitrosa-
normal physiology of the nasal epithelium, and mines has induced cancers of ethmoid and nasal
thus lead to increased susceptibility to other car- epithelium as well as cancers of various internal

6 Epidemiology of Nasal Cancer HEAD & NECK SURGERY SepiOct 1979

organs, including the lung, liver, bile duct, pan-
creas, and kidney."",8,64,7"76,RX.90.107
These observations are intriguing in view of
findings in counties heavily involved in chemical
industries: SNC deaths were elevated in both
men and women (10% and 20% excesses, respec-
tively) and death rates for lung and liver tumors
were elevated in men (table 2). These correlations
were the result of multiple comparisons, which
increase the possibility of correlations occurring
by chance. However, the similarities between lab-
oratory and epidemiologic findings suggest the
presence of a carcinogenic hazard. In SNC as in
lung cancer, a negative history of exposure to air-
borne carcinogens does not eliminate the possi-
bility of exposure via other routes.
NONOCCUPATIONAL
FACTORS
In 1928, thorium dioxide (thorotrast) was intro-
duced into medical diagnosis as a radio-contrast
material (table 3). It was used extensively to out-
line vessels, bronchial tubes, bile ducts, and the
ventricles of the brain, as well as in mammog-
raphy. It was used in the United States as re-
cently as 1954. This radiopaque material is also
radioactive. Upon injection into the maxillary
sinus (again for purposes of radiologic diagnosis),
thorium decays to mesothorium with concurrent
release of alpha, beta, and gamma rays. Radio-
activity reaches its peak after 15 years.
The relationship between thorium and SNC is
based on a series of case reports. Almost all of the
subjects have been found to have radiopaque (and
radioactive) material in the maxillary sinus. The
material had been injected 10 to 21 years earlier,
and it is reported that virtually all of the thorium
is retained in the sinuses for life.89The first case
was reported in 1952.j9
Evidence for snuff-taking as a risk factor for
SNC consists of clinical observations and geo-
Table 3. Nonoccupational agents suspected of causing sinonasal cancer
Type of Suspect No. of SNC
exposure carcinogen cases
Thorium dioxide Mesothorium 14
for x-ray ff, B* Y
diagnosis' s ~ . rays
~ ~
Snuff5' .68 Nickel. chromium,
hydrocarbons
'Data not available.
bTumors in these four locations were associated with intravenous administration of thorium.
Epidemiology of Nasal Cancer
graphic correlations of SNC and this habit (com-
mon in parts of Africa):" Snuff-taking does not
appear to be a risk factor according to two Euro-
pean reports on SNC in woodworkers,1,6and one
report suggests that the European varieties of to-
bacco snuff have lower concentrations of aromatic
hydrocarbons, nickel, and chromium than the
African varieties.68
Data on the relationship of cigarette smoking
and SNC are needed. Several large cohort studies
on cigarette smoking have failed to report an el-
evated risk for SNC, although this may have been
the result of the inattention given this rare
cancer and the policy of combining cancer
sites. 14,37,50.~Y.Si.67.1 I 1 Smoking among Danish and
English woodworkers who developed SNC may
have been less than in the general population,
since the habit was prohibited a t work because of
fire regulations.2,6
I n their study of Welsh refinery workers, Doll
et a1 discovered differences between trends in
lung cancer risks and trends in SNC risks based
on date of diagnosis and age at first occupational
e x p o ~ u r eTo. ~ ~explain these phenomena, the au-
thors proposed that cigarette smoking may inter-
act in a synergistic fashion with nickel exposure
in the production of lung cancer, but smoking
may act independently of nickel (or have no ef-
fect) on SNC risks. Case reports of SNC occurring
in individuals who abstained from snuff and cig-
arette smoking merely imply that tobacco use is
not a necessary condition for the development of
SNC.2,6,'7.9'Clearly, occupational factors should
be included in epidemiologic studies focusing on
tobacco as a possible etiologic agent.
HISTOLOGY, ANATOMY,
AND ETIOLOGY
The geographic distribution of sinonasal cancer
may provide clues to the etiologic agent in a given
setting (table 4).The high proportion of sinonasal
Other cancers
Relative Anatomic Latent associated with
risk site Histology period (yr) the exposure
-a Antrum Squamous, 15 Liver, kidney,
mucoepidermoid pancreas, boneb
-a Antrum Squamous -a None
HEAD & NECK SURGERY SepiOct 1979 7
 Table 4. Histologic distribution of sinonasal cancer reported from various studies
No of cases with
Geographic Type of sample
region (no of cases)
New York City46 Hospital based (416)
U g andaB4 Population based (236)
Bucks, England48 Population based (37)
Diverse regions
(nickel workers)'aa Various studies (49)
aNone reported
Tompnses 7 06 lymphomas and 52 other nonep/fhe/iai tumors
c/nc/udes6 anaplasoc, 75 pleomorphfc,and 22 squamous-celi carcinomas
lymphomas in Uganda reflects the occurrence
of Burkitt's lymphoma, which is believed to be
caused by the Epstein-Barr virus. The high pro-
portion of adenocarcinomas in Bucks, England, is
associated with furniture making in this region.
In contrast, anaplastic and squamous-cell types
of SNC are characteristic of nickel-refinery work-
ers, while adenocarcinomas are apparently rare.
Standardizing histologic classification may help
t o identify the etiologic agents present in a given
populati~n.'~
The percentages of adenocarcinomas among
furniture makers and among boot and shoe man-
ufacturers are approximately 85% and 40%, re-
spectively. A chemical agent common to both in-
dustries has been suggested.'.",49Suspects include
aldehyde compounds, aflatoxin (fungi metabo-
lites),and chromium that is found in dye and tan-
ning agents.g3It is interesting that two of the nine
SNC cases found in chromate workers have been
adenocarcinomas. 69*X3392
The epidemiology of SNC differs from that of
cancers arising from neighboring anatomic sites.
Skin cancer of the external nose may occur more
frequently among persons exposed to ~ u n l i g h t . ~ "
Cancers primary to the oral mucosa of the upper
alveolar ridge (bordering on the floor of the max-
illary antrum) may be related to tobacco usage.
Although nasopharyngeal carcinoma occurs more
frequently among Chinese with an A-2lsin2 HLA
type, sinonasal cancer has not been correlated
with specific HLA types, nor do international
variations suggest the presence of strong genetic
determinants for SNC. Elevated antibody titers
to Epstein-Barr virus have been repeatedly found
in patients with nasopharyngeal carcinoma, while
such titers have been reported to be normal in
those with sinonasal cancer, with the exception
of one report.'4 However, clusters of nasal cavity
cancer in animals have suggested the presence of
8 Epidemiology of Nasal Cancer
No of
squamous or No of cases with
anaplastic cases with other types
carcinoma ("A) adenocarcinorna (%) of cancer (%)
337 (81) 79 (19) 0"
66 (28) 12 (5) 158 (67)b
18 (49) 19 (51) 0"
43 (88)' 0 6 (12)
an infectious agent, and other viral agents need
consideration.31
CONCLUSION
The proportion of all malignancies attributable to
occupational agents is currently a subject of de-
bate, with estimates ranging from 5% to greater
than 20~0.19.423115However, it is likely that the
proportion of SNC cases attributable to occupa-
tional agents is substantially greater than 5%
and has approached 50% in some region^.^'^^'""
Additionally, epidemiologic studies are needed to
determine the role of tobacco and alchohol usage
in the etiology of sinonasal cancer.
The few occurrences of this rare tumor in in-
dividuals with a common exposure may act as a n
alarm and permit the detection of previously un-
recognized carcinogens; the practicing otolaryn-
gologist may play a key role in this process. The
verification of a carcinogenic hazard should in-
clude examination of possible excess risks for ma-
lignancies in other anatomic sites. Excess risks
for SNC are frequently accompanied by elevated
risks for lung and skin cancer, but the experi-
ences of radium dial painters and the results in
laboratory animals indicate that excess risks can
occur for other tumors as well.
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