Intestinal type adenocarcinoma of the ethmoid sinus in wood and leather workers: a retrospective study of 153 cases.

Abstract

The purpose of our study was to identify the role of work exposure to organic dusts in patients with malignant paranasal sinus tumors.
We analyzed all patients surgically treated for a malignant paranasal sinus tumor at our institution between 1987 and 2006. All patients were specifically asked about their occupational history. The tumor site was classified as maxillary or ethmoid sinus. Adenocarcinomas were divided into intestinal type (ITAC) and non-ITAC.
The sample included 345 patients with ethmoid sinus and 301 maxillary sinus. Regarding the ethmoid sinus, we found an exposure to organic dusts in 148 of 153 patients with ITAC, in 3 of 16 patients with non-ITAC adenocarcinoma, and in 10 of 176 patients with other tumors. Regarding the maxillary sinus, we found an exposure in 1 of 20 patients with non-ITAC adenocarcinoma and in 4 of 281 patients with other histologies.
Our study demonstrates that only ethmoid ITACs have an indisputable relationship with the exposure to organic dusts.

Full text

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ORIGINAL ARTICLE
INTESTINAL TYPE ADENOCARCINOMA OF THE
ETHMOID SINUS IN WOOD AND LEATHER WORKERS:
A RETROSPECTIVE STUDY OF 153 CASES
Giulio Cantu, MD,1Carlo L. Solero, MD,2Luigi Mariani, MD,3Salvatore Lo Vullo, BSc,3
Stefano Riccio, MD,1Sarah Colombo, MD,1Madia Pompilio, MD,1Federica Perrone, PhD,4
Paolo Formillo, MD,1Pasquale Quattrone, MD5
1Cranio-Maxillo-Facial Unit, Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori, Milan, Italy.
E-mail: giulio.cantu@istitutotumori.mi.it
2Neurosurgical Department, Fondazione I.R.C.C.S. Istituto Neurologico ‘‘Carlo Besta’’, Milan, Italy
3Clinical Epidemiology and Trial Organization, Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori, Milan, Italy
4Unit of Experimental Molecular Pathology, Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori, Milan, Italy
5Pathology Department, Fondazione I.R.C.C.S. Istituto Nazionale dei Tumori, Milan, Italy
Accepted 13 April 2010
Published online 27 July 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21485
Abstract:
identify the role of work exposure to organic dusts in patients
with malignant paranasal sinus tumors.
Methods. We analyzed all patients surgically treated for a
malignant paranasal sinus tumor at our institution between
1987 and 2006. All patients were specifically asked about their
occupational history. The tumor site was classified as maxillary
or ethmoid sinus. Adenocarcinomas were divided into intestinal
type (ITAC) and non-ITAC.
Results. The sample included 345 patients with ethmoid
sinus and 301 maxillary sinus. Regarding the ethmoid sinus,
we found an exposure to organic dusts in 148 of 153 patients
with ITAC, in 3 of 16 patients with non-ITAC adenocarcinoma,
and in 10 of 176 patients with other tumors. Regarding the
maxillary sinus, we found an exposure in 1 of 20 patients with
non-ITAC adenocarcinoma and in 4 of 281 patients with other
histologies.
Conclusion. Our study demonstrates that only ethmoid
ITACs have an indisputable relationship with the exposure to
organic dusts.
V V
535–542, 2011
Background. The purpose of our study was to
C 2010 Wiley Periodicals, Inc. Head Neck 33:
Keywords: intestinal-type
occupational tumors; craniofacial resection; paranasal sinuses
adenocarcinoma; ethmoid sinus;
Malignant tumors of the nasal cavity and paranasal
sinuses account for 3% of the neoplasms occurring in
the head and neck.1In addition to this low incidence
rate, there is a great variety of histologic types. Most
tumors originate in the maxillary sinus or nasal cav-
ity, and only 20% to 25% originate in the ethmoid
sinus. Therefore, sample sizes of previous studies
have generally been small and heterogeneous, pre-
venting any definitive conclusion.
The possible professional etiology of sinonasal can-
cers was hypothesized as long ago as 1890, when a
tumor was detected in a worker exposed to chrome.2
Since then, many etiologic studies on workers exposed
to different materials have been conducted. The carci-
nogenicity in humans of some of these agents has
been demonstrated (wood and leather dusts, nickel,
chrome, isopropyl alcohol, formaldehyde, and arsenic),
whereas the role of other work environments is more
questionable (textile and building industries).3,4For
squamous cell carcinoma, smoking is an important
risk factor.5
The most specific tumor for which an indisputable
occupational etiology has been demonstrated is eth-
moid adenocarcinoma.6–11However, looking to these
articles, we may find 2 possible biases for the correct
approach to the matter regarding histology and site of
origin of the tumor. Some authors use the generic
terms ‘‘nasal cancer,’’7‘‘nasal and sinonasal cancer,’’8
or ‘‘sinonasal cancer,’’9and when the matter is re-
stricted to adenocarcinomas, we find the generic term
‘‘paranasal sinuses.’’6Only 2 of these articles correctly
stated the histology (adenocarcinoma) and site of the
tumor (ethmoid sinuses).10,11
Taking advantage of our large sample of patients
with malignant paranasal sinus tumors—particularly
ethmoid adenocarcinomas—we sought to determine the
impact of the workplace etiology of paranasal sinus
tumors, primarily for ethmoid adenocarcinomas and
wood and leather dust exposure, and whether there is
any difference in occupational etiology between the
various types of adenocarcinomas.
MATERIALS AND METHODS
This study involved 754 consecutive patients with
malignant tumors of the paranasal sinuses that were
Correspondence to: G. Cantu
V V
C 2010 Wiley Periodicals, Inc.
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surgically treated at the Fondazione I.R.C.C.S. Isti-
tuto Nazionale dei Tumori of Milan, Italy, between
January 1987 and November 2007. We initiated our
data analysis in 1987, since that was the year that
our Institute became the most important center in
Italy for craniofacial resection for ethmoid tumors
approaching or involving the anterior skull base.
Thus, due to an increasing number of cases of eth-
moid adenocarcinoma, particularly intestinal-type ad-
enocarcinoma (ITAC), and the previous reports of its
possible association with exposure to organic dusts,
all patients with any malignant paranasal sinus
tumors were specifically asked about their occupa-
tional history from 1987 onward. Excluded from the
analysis were patients with malignant tumors of the
skin with secondary invasion of the sinuses (37
cases), rare tumors of the sphenoid or frontal sinus (4
cases), tumors of the nasal vestibule (23 cases),
patients with previous malignant tumors (25 cases),
patients who died in the perioperative period (17
cases), and patients with tumors originating in the
orbit (2 cases). After removing these patients, the
study involved 646 patients.
Individual information was retrieved from a pro-
spective clinical database. In particular, data on age
at surgery, sex, tumor site, histology, tumor stage,
patient presentation at surgery (previously treated/
untreated), surgical resection, current or previous
occupations, and outcomes were included.
All patients underwent a CT scan and/or MRI to
state the extension of the tumor. The tumor site was
classified as maxillary or ethmoid sinus. Ethmoid
tumors included lesions originating in the ethmoidal
cells, in the middle and/or superior turbinate, or in
the upper septum (vertical lamina of the ethmoid),
according to anatomic attribution of these structures.
Tumors involving more than 1 sinus were classified
according to their epicenter.
All specimens were examined in our pathology
department, and controversial cases were reviewed by
the same pathologist.
Adenocarcinomas were classified according to the
latest pathologic classification of head and neck tumors
by the World Health Organization, which divides sino-
nasal adenocarcinomas into 2 histologic forms: ITACs
and non-ITACs.12
ITACs are divided, according to
Barnes13and Kleinsasser and Schroeder14classifica-
tions, into well-differentiated (papillary, tubular, and
papillary-tubular type), moderately differentiated (pap-
illary-mucinous and papillary-tubular–mucinous type),
and poorly differentiated (mucinous, alveolar goblet cell,
signet-ring type). For tumors not clearly presenting any
of these characteristics, we use the generic term ITAC,
and thesecaseswere
differentiated.
classifiedasmoderately
Statistical Methods.
about main sample characteristics were calculated for
Standard descriptive statistics
categorical data (frequency and percentage) and con-
tinuous data (median and interquartile range [IQR]).
Associations among data concerning exposure to or-
ganic dusts, tumor site, and histology were investi-
gated using the Pearson chi-square test.
The primary endpoints of the study were cause-
specific mortality and incidence of relapse. Both were
estimated in terms of crude cumulative incidence
(CCI) in a competing risk framework, as described by
Marubini and Valsecchi,15and comparisons between
groups were carried out by means of the Gray test.16
Furthermore, multivariable Cox regression models
were fitted for both endpoint events. An event for
cause-specific mortality was defined as death related
to disease, whereas an event for relapse was defined
as the first evidence of recurrent disease. Competing
events included death for other causes and second tu-
mor or death without evidence of disease. For each
endpoint, the time to event was computed from the
date of surgery in our Institute to the date when the
event was recorded or censored at the date of last fol-
low-up assessment in event-free patients.
Because ITAC subtypes in this series presented
only in the ethmoid sinus, analyses on mortality and
recurrence were restricted to this subset.
The factors investigated as potential predictors for
mortality and relapse, chosen before statistical analy-
sis and based on the existing literature, included the
following: ITAC histologic subtype (yes/no), previous
treatment received at another center (yes/no) and
Union Internationale Contre le Cancer (UICC) 2002
staging (4b/4a/3/1-2).
Hazard ratios (HRs), corresponding 95% confi-
dence intervals (95% CIs), and p values of the Wald
test from multivariable Cox regression models were
reported.
We used SAS (SAS Institute, Cary, NC) and R
(http://www.R-project.org) software to perform statis-
tical analysis. For each test, 2-sided p values below
.05 were considered statistically significant.
RESULTS
The sample of 646 study patients included 345 eth-
moid sinus patients (53.4%) and 301 maxillary sinus
patients (46.6%).
The main sample characteristics according to tu-
mor site are summarized in Table 1. Regarding sex,
the male/female ratio was 1.1:1 for the maxillary
sinus, 3.1:1 for all ethmoid sinus tumors, and 20.9:1
for ethmoid ITAC (146/7); overall, the median age
was 58 years. ITAC was the most frequent histologic
typein patientswith ethmoid
whereas squamous cell carcinoma was the most fre-
quent inpatients with
(32.2%).Non-ITAC adenocarcinomas
mainly in the maxillary sinus, rather than in the eth-
moid sinus (6.6% vs 4.6%).
Regarding the surgical treatment of ethmoid
tumors, 315 patients (91.3%) underwent an anterior
tumors (44.4%),
maxillarysinus
were
tumors
found
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craniofacial resection, and 30 patients (8.7%) were
treated with a transfacial ethmoidectomy. Patients
with maxillary sinus tumors underwent an anterior
oranterolateralcraniofacial
20.9%) or a total, subtotal, or enlarged maxillectomy
(238 cases; 79.1%).Overall,
achieved clean margins in 525 cases (81.3%). There
were close margins in 104 cases (16.1%), and macro-
scopic residual disease in 17 cases (2.6%). The rates
of clean margins for ethmoid tumors were 88.3% with
a craniofacial resection versus 80.0% with a transfa-
cial ethmoidectomy.
As of July 2009, the median follow-up duration
(IQR) was 131 months (range, 81–185). Forty-three
patients (6.7%), alive without relapse, were lost to fol-
low-up before the fifth year, with a median follow-up
duration of 40 months (range, 30–51).
resection (63cases;
surgicalresection
Exposure.
148 of 153 patients (96.7%) with ethmoid ITAC (91
wood, 55 leather, 1 textile, and 1 rice). One patient
reported an exposure to asbestos. Four patients did
not report any specific exposure. Regarding non-ITAC
ethmoid adenocarcinoma, 3 patients were exposed to
organic dusts (2 to leather and 1 to wood), whereas
13 of 16 patients (81.3%) did not experience any expo-
sure. For patients with ethmoid malignant tumors
other than adenocarcinoma, we found an exposure to
possible carcinogenic agents in 10 of 176 patients
(5.7%): 3 wood, 2 leather, 2 textile, 2 concrete, and 1
asbestos.
We found an exposure to organic dusts in
For non-ITAC adenocarcinomas of the maxillary
sinus (20 cases), we found an exposure to wood dust in 1
patient (5.0%). Among patients with other histologies
(281),only4(1.4%)wereexposed(2towood,1toleather,
and 1toasbestos).
It wasimpossible to
between tumor presence and smoking because most
patients were or had previously been smokers.
The period of exposure was between 25 and 55
years for the majority of exposed individuals. How-
ever, 16 patients with ITAC had experienced a very
early and limited exposure, followed by a long inter-
val between the end of exposure and the onset of the
ITAC. The mean interval was 33 years (range, 23–
46), and the mean duration of exposure was 7.5 years
(range, 4–18).
Highly significant (p < .0001) were the associa-
tions between ITAC histology and tumor site, and
between ITAC histology and wood/leather exposure.
observearelationship
Cause-Specific Mortality.
were observed, a total of 329 deaths (78%) were due
to disease. Among the 345 ethmoid sinus patients,
179 of 211 deaths (85%) were related to disease.
Overall, the 5-year and 10-year cause-specific mor-
talities for ethmoid sinus patients were 48% and 55%,
respectively (95% CI, 42% to 53% and 49% to 61%,
respectively); according to the histologic subtype, the 5-
year and 10-year mortalities were 44% and 53%,
respectively (95% CI, 36% to 52% and 43% to 62%,
respectively) for ITAC types, and 50% and 57%,
Overall, 421 deaths (65%)
Table 1. Main patient and disease characteristics by site of primary tumor.
Ethmoid, ITAC
Ethmoid,
Non-ITACMaxillary Overall
No.% No.% No.% No.%
Sex
Female
Male
Age at surgery, median (IQR)
Presentation
Treated
Untreated
Histologic subtype
ITAC
Non-ITAC
Other
ITAC differentiation
Well differentiated
Moderately differentiated
Poorly differentiated
Craniofacial resection
No
Yes
UICC 2002
1
2
3
4a
4b
7 4.6
95.4
78
114
55 (44–64)
40.6
59.4
141
160
58 (46–67)
46.8
53.2
226
420
58 (48–67)
35.0
65.0 146
61 (54–68)
102
51
66.7
33.3
120
72
62.5
37.5
164
137
54.5
45.5
386
260
59.8
40.2
153
–
–
100.0
–
–
–
16
176
–
8.3
91.7
–
20
281
–
6.6
93.4
153
36
457
23.7
5.6
70.7
22
73
58
14.4
47.7
37.9
5 3.3
96.7
25
167
13.0
87.0
238
63
79.1
20.9
268
378
41.5
58.5 148
17
19
52
31
34
11.1
12.4
34.0
20.3
22.2
7 3.6
15.1
22.9
26.0
32.3
–– 24
151
120
175
176
3.7
23.4
18.6
27.1
27.2
29
44
50
62
103
24
94
80
34.2
8.0
31.2
26.6
Abbreviations: ITAC, intestinal type adenocarcinomas; IQR, interquartile range; UICC, Union Internationale Contre le Cancer.
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respectively (95% CI, 43% to 58% and 50% to 65%,
respectively) for non-ITAC types, p ¼ .209 (Figure 1).
In the multivariable analysis for ethmoid tumor
patients (Table 2), the histologic subtype was not sig-
nificantly correlated with mortality (p ¼ .677). Among
the other covariates, previous treatment was an
adverse prognostic factor (p < .001; HR, 1.80; 95% CI,
1.33–2.42) and UICC 2002 stage (p value for the over-
all test < .001; for stages 3, 4a, 4b vs 1–2; HR, 1.72,
2.32, 3.84, respectively); in contrast, craniofacial
resection was a favorable predictor (p ¼ .008; HR,
0.46; 95% CI, 0.25–0.82).
According to the ITAC histologic subtypes, cause-
specific mortality estimates at 5 years and 10 years
were: 50% to 50% (95% CI, 28% to 72% and 28% to
72%) for well-differentiated ITAC, 38% to 42% (95% CI,
27% to 50% and 31% to 54%) for moderately differenti-
ated ITAC, and 43% to 48% (95% CI, 30% to 56% and
35% to 61%) for poorly differentiated ITAC. The differ-
ence was not statistically significant (p ¼ .640).
Disease Relapse.
surgery were observed. Most relapses were local (305;
Overall, 373 relapses (58%) after
82%), whereas nodal or distant metastases occurred,
either alone or in combination, in 68 cases (18%).
Among 345 ethmoid sinus patients, 202 experi-
enced relapse (59%). As before, most relapses were
local (178; 88%), followed by nodal (6; 3%) and distant
metastases (18; 9%).
The 5-year and 10-year incidences of relapse for
ethmoid sinus patients were 55% to 62% (95% CI,
50% to 60% and 57% to 68%, respectively). According
to the histologic subtype, the 5-year and 10-year
relapse-CCI were 51% to 58% (95% CI, 43% to 59%
and 48% to 67%, respectively) for ITAC types and
58% to 66% (95% CI, 51% to 65% and 59% to 73%,
respectively) for non-ITAC types, p ¼ .086 (Figure 2).
In the multivariable analysis (Table 3), histologic
subtype was not significantly correlated with disease
relapse (p ¼ .741), whereas previous treatment was
an adverse prognostic factor (p < .001; HR, 1.86; 95%
CI, 1.40–2.47). Craniofacial resection in comparison
with transfacial ethmoidectomy was a favorable prog-
nostic factor (p ¼ .015; HR, 0.50; 95% CI, 0.29–0.88),
but a negative trend was indicated by UICC 2002
stage (p for overall test < .001; for stages 3, 4a, 4b vs
1–2; HR, 1.43; 1.69, and 2.70, respectively).
FIGURE 1. Cause-specific mortality according to histologic sub-
type, in the ethmoid subset.
Table 2. Hazard ratio estimates with 95% confidence intervals and p
values from the multivariable Cox proportional hazard model on cause-
specific mortality for ethmoid subset.
Category (reference)
Cause-specific mortality
Hazard ratio (95% CI)p value*
ITAC histologic subtype:
Yes (no)
Previous treatment:
Yes (no)
Cranio-facial resection:
Yes (no)
UICC 2002
3 (1–2)
4a (1–2)
4b (1–2)
.6765
1.07 (0.78–1.46)
.0001
1.80 (1.33–2.42)
.0083
0.46 (0.25–0.82)
<.0001
1.72 (1.02–2.91)
2.32 (1.31–4.10)
3.84 (2.26–6.54)
Abbreviations: CI, confidence interval; ITAC, intestinal type adenocarcinomas;
UICC, Union Internationale Contre le Cancer.
*The p values for the overall Wald’s test on each factor.
FIGURE 2. Crude cumulative incidence of disease relapse
according to histologic subtype, in the ethmoid subset.
Table 3. Hazard ratio estimates with 95% CIs and p values from the
multivariable Cox proportional hazard model on relapse for ethmoid
subset.
Category (reference)
Relapse
Hazard ratio (95% CI)p value*
ITAC histologic subtype:
Yes (no)
Previous treatment:
Yes (no)
Cranio-facial resection:
Yes (no)
UICC 2002
3 (1–2)
4a (1–2)
4b (1–2)
.7414
0.95 (0.71–1.28)
<.0001
1.86 (1.40–2.47)
.0154
0.50 (0.29–0.88)
.0001
1.43 (0.89–2.32)
1.69 (1.02–2.82)
2.70 (1.68–4.34)
Abbreviations: CI, confidence interval; UICC, Union Internationale Contre le Cancer.
*The p values for the overall Wald’s test on each factor.
538 Intestinal Type Adenocarcinoma of the Ethmoid SinusHEAD & NECK—DOI 10.1002/hedApril 2011

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According to ITACs histologic subtypes, relapse-
CCI estimates at 5 years and 10 years were 59% and
59% (95% CI, 38% to 80% and 38% to 80%, respec-
tively) for well-differentiated, 45% and 56% (95% CI,
33% to 57% and 41% to 71%, respectively) for moder-
ately differentiated, and 54% and 60% (95% CI, 41%
to 67% and 46% to 74%, respectively) for poorly differ-
entiated ITAC. Again, the difference was not statisti-
cally significant (p ¼ .534).
DISCUSSION
It is difficult to describe the incidence of sinonasal
adenocarcinomas due to the lack of consensus among
pathologists and clinicians. Although nearly all pathol-
ogists distinguish between true sinonasal adenocarci-
nomasandsalivary-type
clinical articles on paranasal sinus tumors use the
generic term of adenocarcinoma without subclassifica-
tion.17–20Moreover, most authors reported very small
samples of adenocarcinomas.
Batsakis21divided the adenocarcinomas into 3 ba-
sic clinicopathologic forms: papillary, sessile, and alve-
olar-mucoid, and included
simulate colonic carcinomas in the last subclassifica-
tion. Abecasis et al22used a different clinicopathologic
and immunohistochemical classification for their 14
cases: high-grade and low-grade adenocarcinoma,
papillary, and ITAC. Their results indicated a poor
prognosis for ITACs. Heffner et al23divided 50 adeno-
carcinomas of the sinonasal tract into low-grade and
high-grade and included ITACs in the high-grade
group. On the contrary, Bashir et al24assigned ITACs
to well-differentiated or moderately differentiated
tumors. The last article is paradigmatic about the dif-
ficulties of histologic classification. These authors di-
vided their 11 sinonasal adenocarcinomas into 3
groups: intestinal type, glandular type, and solid
type. However, the authors wrote: ‘‘Judging from
other articles, some of our tumors that we have clas-
sified as SNA-G (glandular) and/or SNA-S (solid),
maybe considered intestinal
Barnes13divided ITACs of the nasal cavity and para-
nasal sinuses into 5 variants: papillary, colonic, solid,
mucinous, and mixed.
The latest pathologic classification of head and
neck tumors by the World Health Organization
divides sinonasal adenocarcinomas into 2 histologic
forms: intestinal-type and nonintestinal type adeno-
carcinoma.12ITACs are divided according to Barnes’
classification.13
As a consequence of the above-mentioned difficul-
ties in pathologic classification and for the possible
selection of the sample, we find a variety of rates of
incidence of adenocarcinomas for malignant sinonasal
tumors in the literature (4% to 9% for Harrison and
Lund,25and 10% to 20% for Bashir et al24).
The role of wood dust has been recognized since
1970 by Hadfield6and numerous other authors.7–11
adenocarcinomas,most
tumorsthat closely
type byothers.’’
However, the role of leather dust has not been so
clearly studied, after the report of Acheson.7Hern-
berg et al8even excluded this role, writing: ‘‘No asso-
ciations were found for a number of exposures,
including agricultural chemicals, textile dust, asbes-
tos, quartz dust, organic solvents, and leather work.’’
The differential role of hardwoods and softwoods
is unclear. Some authors8,9from northern Europe
(where furniture industries use softwoods) described
a minor and different carcinogenetic effect from soft-
woods (conifers) in comparison with hardwoods (such
as beeches, elms, and oaks), which are more often
used in southern Europe. The authors found an asso-
ciation between hardwood dust exposure and adeno-
carcinoma, whereas softwood dust exposure alone was
associated with squamous cell and anaplastic carcino-
mas. However, there is a general consensus concern-
ing the danger of a wood dust level in the working
environment over 5 mg/m3of wood dust,26whereas
some27suggest a lower dust level of 1 mg/m3.
Wolf et al28studied the possible workplace etiol-
ogy of ‘‘adenocarcinoma of the nose’’ among employees
of thewoodworkingindustry
authorsindicatedthat
unequivocally associated with exposure to hardwood
dust and that there is not sufficient evidence of an
epidemiologic association between wood dust and
squamous cell carcinoma. They tried to verify the pos-
sible role of chemical additives (paints and glues) and
wood-preserving agents extensively used in the wood-
working industry and found that 73% of study sub-
jects exposed to wood dust also had contact with
additives and wood-preserving agents.
It is interesting to note a very different histologic
composition of the series of sinonasal tumors treated
with an anterior craniofacial resection between Europe
and North America. The rates of adenocarcinomas in
European series are very high: Roux et al29(France),
74%; Suarez et al30(Spain), 53%; Cantu ` et al31(Italy),
49%; Cheesman et al32(United Kingdom), 27%. On the
contrary, the rates are very lower in American series:
McCutcheon et al33(USA), 17%; Bentz et al34(USA),
12%; Donald35(USA), 6%; and Irish et al36(Canada),
5%. Bridger et al37(Australia) reports a rate of 37% for
adenocarcinoma.
It is difficult to find an unambiguous and exhaus-
tive explanation for these discrepancies. According to
Blot et al,26we may advance some hypotheses. First,
in past years, in many artisan furniture factories and
joineries in Europe, the commonly accepted danger
threshold level of 5 mg/m3for wood dust was probably
often exceeded.
Second, hardwoods (oak and beech), which are
more dangerous than softwoods (coniferous trees), are
probablymore widespread
America.
Third, safety measures (masks and aspiration
devices) became common in America sooner than in
Europe. Therefore, as it was demonstrated, a latent
in Germany.The
were adenocarcinomas
in Europethan in
Intestinal Type Adenocarcinoma of the Ethmoid SinusHEAD & NECK—DOI 10.1002/hedApril 2011 539

Page 6

period of about 30 to 40 years between the beginning
of exposure and the clinical evidence of the tumors in
most patients,11,38,39and we may predict a possible
reduction of the incidence of the disease in Europe in
the upcoming decades as an effect of improved factory
conditions.
The relationship between the various types of ade-
nocarcinoma and the occupational exposure to wood
and leather dust has not been clearly stated. For
example, Choussy et al40report a multicenter study
on 418 ethmoid adenocarcinoma cases collected from
11 French hospitals between 1976 and 2001. They
histologically separated adenocarcinomas into well-
differentiated (107 cases), poorly differentiated (23
cases), and ITACs (215 cases). The ITAC group was
divided into papillary, mucoid, and mixed papillary
and mucoid. Overall, toxic wood exposure was present
in 353 cases (84.7%), whereas leather exposure was
found in only 11 cases (2.6%). No particular exposure
was found in the remaining cases (12.7%). The mean
duration of exposure to wood dust was 27.7 years.
They did not observe any difference in prognosis for
the different pathologic groups, even if the patients
with toxic exposure had better survival rates. Thus,
the conclusion of these authors is that only adenocar-
cinoma of the ethmoid sinus is related to occupational
exposurebut alsothat
relationship.
Barnes13wrote that ITACs of the nasal cavity and
paranasal sinuses may occur sporadically or as an
occupational-related hazard, especially in cases of
wood dust exposure. Among 17 cases of sporadic
ITACs, 8 originated in the maxillary sinus, 7 in the
nasal cavity, and 2 in the ethmoid sinus. In contrast,
ITACs in woodworkers originated almost exclusively
in the nasal cavity or in the ethmoid sinus and had a
better prognosis than sporadic ITACs.
Kleinsasser and Schroeder14,39clearly stated that
only ITACs were developed after exposure to wood
dust and that the location is in the area of the middle
nasal concha and ethmoid bone.
Regarding the location of these tumors in the
nasal cavity, it is necessary to provide an explanation.
It is our opinion that tumors of the nasal cavity are
only those originating in the vestibule, in the mucosa
covering the nasal cartilages and the vomer, and on
the inferior turbinate. It should be remembered that
the middle and superior turbinate anatomically belong
to the ethmoid, like the vertical lamina, the lamina pap-
yracea, and the cribriform plate. Even if many tumors
originating on these structures may vegetate in and
occlude the nasal cavity, it is our opinion that they must
be classified as ethmoid tumors. Thus, many misunder-
standings about the location of these tumors may be
resolvable. Forexample,
Schroeder39use the term ‘‘inner nose’’ but specify that
these tumors ‘‘appear generally in the area of the middle
nasal concha and the ethmoid bone,’’ they are clearly
speaking of ethmoid tumors.
non-ITACshavethis
when Kleinsasserand
Our study attempts to solve some of the aforemen-
tioned problems. It has the advantage of being one of
the largest mono-institutional studies of malignant
tumors of the paranasal sinuses and the largest study
of ITACs. All patients were specifically asked about
their occupational histories, and all specimens were
analyzed in our pathology department.
The results of this study suggest that true ITACs
originate only in the ethmoid sinus, whereas non-
ITACs may also occur in the other paranasal sinuses.
The results of this study are impressive. Only eth-
moid ITACs have an indisputable relationship with
organic dusts, mainly wood and leather, whereas non-
ITAC adenocarcinomas and other histotypes do not
have this relationship. Our study was unable to
define the possible role of chemical additives to wood
and leather dusts.
According to Choussy et al,40we did not find any
statistically significant difference in prognosis among
the 3 subtypes of ITACs.
However, an interesting question remains. Why,
among so many workers exposed to the same high
levels of organic dusts, do so few of them develop an
ITAC?
Starting from the hypothesis that a polymorphism
in xenobiotic metabolizing enzymes may play an im-
portant role in gene–environment interactions and
may contribute to a high degree of variance in an
individual’s susceptibility to cancer risk, the experi-
mental molecular pathology department of our insti-
tute compared the genotypes of the metabolizing
enzymes CYP1A1 and GSTM1 in 30 patients with
ethmoid ITAC with those of 79 healthy blood donors
to verify whether these polymorphisms may identify
subjects with high ITAC risk.41We found that the
CYP1A1 codon 461 polymorphism is overrepresented
in patients with ITAC in comparison with controls
and is often associated with the GSTM1 null geno-
type, thus suggesting that these polymorphisms may
be associated with a high degree of susceptibility to
this tumor.
These results need to be extended to a control
group represented by a cohort of workplace-exposed
individuals who did not develop the disease. If these
future analyses confirm the role of these 2 polymor-
phisms in ITAC susceptibility, the CYP1A1 codon 461
and GSTM null genotype characterization may be
useful in selecting and monitoring individuals at risk
for developing ethmoid ITAC for occupational expo-
sure to carcinogens. The high cost of this research
presents a great difficulty for this study.
Because of the rarity of ethmoid adenocarcinomas,
it is highly unlikely that the various treatment
options could be compared in a clinical trial. However,
surgical radical resection is the most frequent pri-
mary treatment for patients with this tumor. As most
tumors approach or involve the cribriform plate, ante-
rior craniofacial resection is the established gold-
standard.42
Some authorsdemonstratedan
540Intestinal Type Adenocarcinoma of the Ethmoid Sinus HEAD & NECK—DOI 10.1002/hedApril 2011

Page 7

improvement in disease-free survival with craniofa-
cial resection in comparison with transfacial resection
alone.19
In the last decade, a number of articles have dis-
cussed endoscopic resection of malignant tumors
involving the anterior skull base. Although most
include a small number of patients with brief follow-
ups, 1 article from 2 Italian university hospitals
reported 134 patients treated with an endoscopic
approach alone and 50 cases treated with a combined
cranioendoscopic approach.43The 5-year disease-spe-
cific survival was 91% for patients treated with the
endoscopic approach and 58% for those who under-
went cranioendoscopic resection. The tumor size dif-
fered between the 2 groups, with the larger tumors
requiring the cranioendoscopic approach. Neverthe-
less, theauthorsconclude
planned and performed by an experienced surgeon,
endoscopic surgery is a valid alternative to standard
surgical approaches for the management of selected
malignancies of the sinonasal tract.
We believe that regardless of the method, resec-
tion of the sinonasal component of the tumor must be
radical, especially with intestinal-type adenocarcino-
mas. ITAC is a terrible disease that involves the
whole ethmoid sinus and has a prognosis similar to
that of other malignant ethmoid tumors, even after a
craniofacial resection. Because the metaplastic trans-
formation of the ethmoidal mucosa to enteric-type epi-
theliumprecedes the
adenocarcinoma,44,45pre-neoplastic or neoplastic foci
may be present in macroscopically uninvolved sites of
ethmoid. Actually, we found small tumor localizations
in the contralateral ethmoid cells. These foci were
separate from the apparent primary tumor and were
undetected by CT, MRI, and positron emission tomog-
raphy. Even if ITACs may present as an exophytic
pink mass that bulges into the nasal cavity, often
with a gray, necrotic, and friable appearance, they
are locally aggressive tumors that easily infiltrate the
underlying bone.21Thus, we believe that a total eth-
moidectomy must always be performed. If this can be
achieved endoscopically, such an approach should
undoubtedly be used.
However, we must remember that our study dem-
onstrated lower cure rates for patients who under-
went craniofacial resection after previous surgery
performed elsewhere, in comparison with untreated
patients. Also, for these tumors, the first treatment is
often the only treatment.
thatwhenproperly
development of enteric
CONCLUSIONS
Adenocarcinoma of the ethmoid is a rare tumor. ITAC
is the most frequent histologic type in our series, and
it has an indisputable relationship with exposure to
organic dusts, mainly wood and leather. The CYP1A1
codon 461polymorphism
patients with ITAC in comparison with controls and
is overrepresentedin
is often associated with the GSTM1 null genotype,
thus suggesting that these polymorphisms may be
associated with a high degree of susceptibility to this
tumor in wood and leather workers. ITAC is an
aggressive tumor that infiltrates the underlying bone
even when it presents as an exophytic pink mass that
bulges into the nasal cavity. Moreover, we found small
tumor localizations in the contralateral ethmoid cells.
Thus, it is our opinion that a total ethmoidectomy
must always be performed. Also, with an anterior cra-
niofacial resection (the standard treatment), the prog-
nosis ofITACs issimilar
malignancies and is influenced by T classification and
previous unsuitable surgical treatments. An early di-
agnosis is critical to improve the prognosis. The possi-
bility to discover wood and leather workers with a
high degree of susceptibility to this tumor must be
studied further.
toother ethmoid
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