Critical Reviews in Oncology/Hematology 79 (2011) 265–277

Sinonasal carcinomas: Recent advances in molecular and phenotypic

characterization and their clinical implications
Alessandro Franchi a,∗ , Lucia Miligi b , Annarita Palomba a ,
Lucia Giovannetti b , Marco Santucci a
a Division of Anatomic Pathology, Department of Critical Care Medicine and Surgery, University of Florence, Italy
b Unit of Environmental and Occupational Epidemiology, ISPO – Cancer Prevention and Research Institute, Florence, Italy
Accepted 19 August 2010

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
2. Incidence, mortality and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
2.1. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
2.2. Data by subsite and morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
2.3. Survival and mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
3. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
3.1. Woodworking and wood-dust exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
3.2. Shoe and leather industry and leather dust exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
3.3. Other occupational exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
3.4. Smoking habits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
3.5. Attributable risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
4. Advances in the histopathologic diagnosis of sinonasal carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
4.1. Adenocarcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
4.2. Poorly differentiated and undifferentiated carcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
4.3. Nuclear protein in testis (NUT) midline carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
4.4. Sinonasal metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
5. Molecular changes implicated in the pathogenesis of sinonasal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
5.1. Whole genome analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
5.2. TP53 gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
5.3. Other genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
5.4. HPV and sinonasal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
6. Molecular markers for screening and prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
7. Predictive factors and new therapeutic targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

∗ Corresponding author at: Unit of Pathological Anatomy, Department of Critical Care Medicine and Surgery, University of Florence,

Viale G.B. Morgagni 85, 50134 Firenze, Italy. Tel.: +39 055 4478102; fax: +39 055 4379868.
E-mail address: franchi@unifi.it (A. Franchi).

1040-8428/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.critrevonc.2010.08.002
266 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277

Abstract
Sinonasal carcinomas are rare tumors with an aggressive clinical behaviour which frequently pose a number of problems regarding the
interpretation of diagnostic findings and the treatment. In addition, in comparison with other malignancies of the head and neck region, an
elevated fraction of sinonasal carcinomas can be attributed to occupational exposure. This review is focused on the recent advances in the
molecular and phenotypic characterization of sinonasal carcinomas, and their possible implications for the interpretation of epidemiological
data, as well as for the diagnosis and treatment of these rare malignancies. The increasing knowledge on their phenotypic and genotypic
features is progressively leading to a refinement in diagnosis, especially for poorly differentiated and undifferentiated lesions, as well as to
the identification of markers which can be potentially useful to identify the early phases of carcinogenesis, to detect subclinical disease, to
predict the response to therapy, and finally, that may represent potential targets for alternative treatments.
© 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords: Carcinoma; Adenocarcinoma; Nasal cavity; Paranasal sinuses; Molecular markers

1. Introduction resident population) was 105 among males and 53 among

Malignant tumors of the nasal cavities and paranasal
sinuses represent about 3.6% of all malignancies arising
in the head and neck area, and carcinomas are the most
frequent subtypes [1]. The complexity of the anatomic
region and the rare occurrence pose a number of prob-
lems regarding the diagnostic interpretation and the treatment
of these neoplasms. In general, they represent a group of
clinically aggressive tumors, although the knowledge has
progressively evolved towards the need for careful differ-
ential diagnosis, because some of these entities present
distinct clinico-pathologic features and biologic behaviour
warranting individualised treatment strategies. In addition,
in comparison with other malignancies of the head and neck
region, an elevated fraction of sinonasal carcinomas can
be attributed to occupational exposure, as documented by
several epidemiological studies conducted worldwide. This
review is focused on the recent advances in the molecular
and phenotypic characterization of sinonasal carcinomas, and
their possible implications for the interpretation of epidemio-
logical data, and for the diagnosis and treatment of these rare
malignancies.
2. Incidence, mortality and survival
2.1. Incidence
Studies presenting data of descriptive epidemiology of
sinonasal cancer must be interpreted considering that the
ICD-O-3 codes for these sites (C30–C31) take into account
also the middle ear.
According to the National Program of Cancer Registries
(NPCR) that covers approximately 93% of the United States
population, the annual incidence rates were lower than
1/100,000 inhabitants (0.8 in males and 0.6 in females) in
the period 1998–2002 [2]. The mean number of new cases
per year by cancer type C30–C31 reported by Italian Net-
work of Cancer Registries (AIRTUM) (population included
is about 15 million inhabitants, 25.5% of the whole Italian
females in the period 1998–2002 [3]. Long term incidence
rates for cancer of the sinonasal tract showed only little
changes, and in Italian areas covered by a general can-
cer registry (years 1985–2002), incidence age-standardised
rates (ASR) showed a small increase in males in the two
more recent periods [3]. Finally, population-based rates for
sinonasal cancer have been described to increase with age
and, according to the US SEER Program, in 1986–1990 the
median age at diagnosis was 63 years in men and 65 years
in women [4], while in Italian areas, in the years 1998–2002,
the median age of diagnosis was 66 years in men and 70.5 in
women [3].
2.2. Data by subsite and morphology
According to data from AIRTUM and SEER [3,5], tumors
originate more often in the nasal cavities in both genders,
while maxillary and ethmoidal sinuses are the next most com-
mon subsites (Table 1). Malignant epithelial neoplasms are
the most frequent subtypes in both pooled data and in both
genders (59–75% of all malignant cancers of this site), and
squamous cell carcinomas outnumbered all other carcinomas
(Table 2). However, there are some relevant differences in the
two groups. Considering the incidence of malignant epithe-
lial neoplasms, ASR (per 100,000) in females from SEER is
higher than ASR from AIRTUM: 0.24 (95% CI 0.22–0.27)
vs 0.18 (95% CI 0.15–0.21) and the difference is statisti-
cally significant (p < 0.05). Moreover, adenocarcinomas are
more represented among Italian cases than among US cases
in males (24% vs 9%), while in females they represent 13% in
both pools of data. Considering the incidence of adenocarci-
nomas, ASR (per 100,000) in males from AIRTUM database
is higher than ASR from SEER: 0.19 (95% CI 0.16–0.23) vs
0.07 (95% CI 0.06–0.09) and the difference is statistically
significant (p < 0.05). The group of malignant non-epithelial
neoplasms is larger among US cases than among Italian
cases both in males (38% vs 17%) and in females (40%
vs 26%). For this group of histotypes, incidence ASR (per
100,000) from SEER is higher than ASR from AIRTUM
both in males: 0.28 (95% CI 0.25–0.32) vs 0.16 (95% CI
 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277 267

Table 1
Carcinomas of the nasal cavity, middle ear and paranasal sinuses (codes ICD-O-3: C30–C31). Number of new cases in 5 years, crude rates (per 100,000
inhabitants), age-standardised rates (per 100,000 inhabitants) by Registries Association. Males and females, years 1998–2002.
Subsites Males Females

AIRTUM SEER AIRTUM SEER

No % No % No % No %
C30.0 Nasal cavity 270 51% 372 44% 153 58% 288 45%
C30.1 Middle ear 12 2% 23 3% 9 3% 23 4%
C31.0 Maxillary sinus 103 20% 249 29% 53 20% 191 30%
C31.1 Ethmoidal sinus 66 13% 91 11% 21 8% 53 8%
C31.2 Frontal sinus 5 1% 12 1% 3 1% 7 1%
C31.3 Sphenoidal sinus 10 2% 28 3% 2 1% 23 4%
C31.8 Overlapping lesion 14 3% 31 4% 4 2% 16 3%
C31.9 Sinus, unspecified 47 9% 49 6% 19 7% 33 5%
All 527 100% 855 100% 264 100% 634 100%

Table 2
Malignant tumors of the nasal cavity, middle ear and paranasal sinuses (codes ICD-O-3: C30–C31). Number of new cases in 5 years by morphology and by
Registries Association. Males and females, years 1998–2002.
Morphology Males Females

AIRTUM SEER AIRTUM SEER

N % N % N % N %
Epithelial neoplasms 395 75 526 62 168 64 372 59
Epithelial NOS 52 10 62 7 24 9 37 6
Squamous cell 178 34 354 41 93 35 222 35
Adenocarcinomas 129 24 81 9 33 13 82 13
Others epithelial 36 7 29 3 18 7 31 5
Non-epithelial neoplasms 92 17 325 38 69 26 255 40
Malignant neoplasm, unspecified 40 8 4 0 27 10 7 1
All 527 100 855 100 264 100 634 100

0.12–0.21) and females: 0.19 (95% CI 0.17–0.22) vs 0.08
(95% CI 0.05–0.10); the differences are statistically signifi-
cant (p < 0.05).
2.3. Survival and mortality
In US mortality, rates were 0.2/100,000 in men and
0.1/100,000 in women (year 2002) [6] and showed declines
by year of birth [4]. In the data from the pool of Italian Cancer
Registries (1998–2002) the 5-year age-standardised relative
survival was equal to 48% (CI 95%: 43–53%) for both gen-
ders combined [7]. In a recent analysis conducted on adult
European patients with ethmoid adenocarcinoma, survival
was 83%, 58% and 46%, at 1, 3 and 5 years after diagnosis,
respectively [8]. In addition, no survival improvement with
time was evidenced in this study [8].
3. Risk factors
Malignant tumors of the nose and paranasal sinuses are
uncommon neoplasms. This low absolute risk in the general
population has been accompanied by an high relative risk
for specific chemical exposures and occupational settings,
particularly for epithelial tumors.
3.1. Woodworking and wood-dust exposures
At the end of the 60s a cluster of patients with sinonasal
adenocarcinoma was reported in the furniture industry in
Great Britain [9,10], and since then studies of sinonasal
cancer among workers with job entailing potential wood
exposure were published in several other countries indicating
an increased risk for nasal adenocarcinoma in woodwork-
ers [11–13]. A pooled reanalysis of cancer mortality among
five cohorts of wood workers (furniture workers, plywood
workers and wood model makers) including 28,704 subjects,
observed a significant excess of nasal cancer (SMR 3.1 95%
CI 1.6–5.6) [14]. Conversely, in a review of North American
cohort studies published in 1997, rates of nasal cancer were
not significantly elevated [15], indicating a significant a geo-
graphic discrepancy. Similar differences have been observed
in case–control studies conducted in Europe and in North
America [15,16], and could be explained considering a vari-
able concentration or types of wood dust, wood processing
methods and/or presence of other carcinogenic exposures in
the European workplaces [16].
In a pooled analysis of twelve case–control studies, seven
categories of jobs with potential exposure to wood dust were
defined combining occupation and industry title: forestry
workers, loggers, pulp and paper workers, sawmill workers,
268 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277
furniture makers other wood product workers and carpenters
[17]. In addition, the jobs were classified according to the
level of wood-dust exposure on the basis of an ad hoc job-
exposure matrix. Overall, men employed in any wood-related
job had an OR of 2.0 (95% CI 1.6–2.5) for all histologies
combined, the highest risk being for furniture workers (OR
4.5, 95% CI 3.2–6.5), sawmill workers (OR 2.5 95% CI
1.8–3.4), wood product workers (OR 2.8 95% CI 1.7–4.6)
and carpenters (OR 2.9 95% CI 2.1–3.9) [17]. Consider-
ing histologic subtypes, an high risk for adenocarcinoma
(OR 13.5 95% CI 9.0–20.0) was associated with employ-
ment in wood-related jobs, and the risk was highest for
furniture workers (OR 41.1, 95% CI 24.5–68.7). No asso-
ciation was observed among men between squamous cell
carcinoma and employment in all wood-related occupations.
The OR for all sinonasal cancer and adenocarcinoma among
women were elevated but lower than those observed in men,
while the risk for squamous cell carcinoma was similar to
men. The results for men by high level of wood exposure
showed an OR of 5.8 (95% CI 4.2–8.0) for all histologies
considered, and 45.5 (95% CI 28.3–72.9) for adenocarci-
noma. Considering women, very few were included in the
high level of wood exposure and the risk for any expo-
sure level was 1.5 (95% CI 0.7–3.2); analysis by subtype
showed an OR of 2.5 (95% CI 0.5–12.3) for adenocarci-
noma and 2.1 (95% CI 0.8–5.5) for squamous cell carcinoma.
In addition, the highest risk was observed in the European
studies, in comparison with the American and Shanghai stud-
ies. Indeed, 77% of the European adenocarcinoma cases had
worked in wood-dust exposed jobs as compared with the 20%
of non-European studies. Furthermore, the authors pointed
out that the evidence regarding squamous cell carcinoma
was ambiguous and there was a great deal of heterogene-
ity observed in individual study results. This may be due
to differences in risk associated with exposure to hard-
wood and softwoods or with other aspects of exposures
[17].
Adenocarcinoma of the nasal cavity and paranasal sinuses
is clearly associated with exposures to hardwood dust. In sev-
eral series of adenocarcinoma from different countries, a high
proportion of cases were exposed to hard wood and these
findings were confirmed in several case–control studies [16].
Considering the risk for exposure to soft woods, there are too
few studies to draw definitive conclusions. In these studies,
the risk for sinonasal cancer was elevated but lower than that
in studies with exposure to hard wood or mixed [16]. The
overall evaluation of the IARC working group was that wood
dust is carcinogenic to humans (Group 1) considering that
there is sufficient evidence in humans for the carcinogenicity
of wood dust and inadequate evidence in experimental ani-
mals for the carcinogenicity of wood dust [16]. As pointed
out by the IARC working group, the excess appears to be
attributable to wood dust per se, rather than to other exposures
in the workplaces, since the excess was observed in vari-
ous countries during different periods and among different
occupational groups, and because direct exposures to other
chemicals do not produce RR of the magnitude associated
with exposure to wood dust [16].
In an industry based case–control study on sinonasal
adenocarcinoma in the Germany wood industry, adenocar-
cinoma occurred more frequently among workers that had
ever worked as cabinetmakers or joiners (OR 2.96, 95%
CI 1.46–6.01) [18]. Average exposure to inhalable wood
dust ≥5 mg/m3 was associated with an high risk (OR 48.47
95% CI 13.30–176.63) compared to levels below 3.5 mg/m3 .
Exposure between 3.5 and 5 mg/m3 was also found to pose a
risk (OR 10.54 95% CI 3.34–33.27) [18]. In a recent Italian
study a very elevated risk was observed for adenocarcinoma
and exposure to wood dust (OR 58.6 95% CI 23.74–144.8),
among subjects exposed to high levels of wood dust the OR
was 179.9 (95%CI 55.37–584.4) [19].
3.2. Shoe and leather industry and leather dust exposure
In 1981, and again in 1987, the International Agency for
Research on Cancer concluded that there is an excess risk of
cancer among people employed in the boot and shoe man-
ufacture and repair industry. The strongest evidence cited
was for excess risks of nasal cancer and leukemia [20,21].
Nasal adenocarcinoma has been associated with employment
in boot and shoe manufacture and repair. Elevated risks in
excess of 10-fold have been reported from studies in the boot
and shoe manufacturing industry in England and in Italy
[21]. A far higher risk of nasal cancer was found for sub-
jects who worked in the dustiest operations and for those
classified into the category of “heavy” exposure to leather
dust. There have also been indications of an association for
tannery workers [22–26], but in some cases results were non-
significant and based on very few cases. Adenocarcinoma
was the most frequent histologic type observed, and expo-
sure other than leather dust was suggested such as chromium
salts and natural tannins [26]. For leather dust exposure, the
pooled analysis of European case–control studies found an
excess risk for sinonasal cancer of 1.7 (95% CI 1.10–3.35)
among men and an OR of 2.71 (95% CI 0.78–9.43) among
women [27]. Leather dust exposure was principally asso-
ciated with adenocarcinoma (OR 2.99 95% CI 1.33–6.73)
and lower and non-significant excess risk was seen for squa-
mous cell carcinoma (OR 1.45 95% CI 0.70–2.99) [27]. In
a recent review on sinonasal cancer and exposure to leather
dust, four out of five of the case–control studies found an
excess risk associated with exposure to leather dust, and of
five cohort mortality studies, an excess risk was found in
all studies conducted in shoe trades [28]. The excess was
observed especially among those working in shining, finish-
ing and shoe repair in which exposure levels to leather dust
was particularly high. A significant dose–response effect (all
histological subtypes) in the profession was observed [22].
Histological classification was provided in several studies
focusing on the shoe trades: adenocarcinoma accounted for
80% of cases according to Battista et al. [26], 88% accord-
ing to Acheson et al. [29] and 75% according to Cecchi et
 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277
al. [30]. A recent Italian study observed an OR of 14.4 (95%
CI 3.03–68.87 all histological subtypes) with the adenocarci-
noma subtypes particularly associated with leather dust (OR
26.6 95% CI 5.09–139.0) [19]. A series of cases of sinonasal
carcinoma has been observed among shoe makers (11 cases)
and tannery workers (8 cases) in the leather production area in
Tuscany (Italy) in the period 1990–2002, and the possible eti-
ologic role of tannins both in leather and in wood industry was
stressed [31]. In the SNC cancer registry operating in Brescia
(Italy) 7% of the cases exposed to occupational carcinogens
(IARC group 1) was exposed to leather dust (particular in the
shoe repair) and among these 85% was an adenocarcinoma
[32].
3.3. Other occupational exposures
In volume 88 of IARC Monographs, formaldehyde was
evaluated as carcinogenic to humans (Group 1), showing
that in six case–control studies there was increased risk for
adenocarcinoma in both men and women, while there was
little evidence for an association with squamous cell carci-
noma [33]. No excess of mortality from sinonasal cancer
was observed in cohort studies of formaldehyde-exposed
workers, except for a Danish cohort of industrial workers
in which an decreased risk for squamous cell carcinoma was
found [33]. Due to this discrepancy between the results of
case–control and the cohort studies the working group con-
cluded that there is only limited epidemiological evidence
that formaldehyde causes sinonasal cancer in humans [33].
Cases of sinonasal cancer were reported in epidemiological
studies of primary chromate production workers in Japan,
UK and USA, of chromate pigment production workers in
Norway and in chromium platters in the UK, indicating a
pattern of excess risk for these rare tumors, and IARC eval-
uated chromium IV as carcinogenic to humans (Group 1)
[34]. Nickel exposure has also been associated with nasal
cancer [34], and nickel compounds were evaluated as carcino-
genic to humans. Radiation exposure has also been suggested
to be associated with SNC in radium dial painting [35,36].
Increased risks have also been observed with some incon-
sistencies for many occupations including farm and textile
workers [37–40]. A pooled analysis showed that exposure
to textile dust was associated with non-significantly elevated
risk of adenocarcinoma, among women only, with an OR
for the high level of cumulative exposure of 2.5 (95% CI
0.7–9.0) [40]. Also chemical workers and welders were sug-
gested to be at risk for sinonasal cancer [41]. An OR of 4.1
(95% CI 1.66–10.13) for squamous cell carcinoma subtypes
was found among those exposed to welding fumes in a recent
Italian study [19].
3.4. Smoking habits
Despite occupational agents are the most important eti-
ological agents for sinonasal carcinomas, an excess risk
was also observed in some studies in association with
269
cigarette smoking. The pooled analysis of the European stud-
ies showed an OR of 1.72 (95% CI 1.16–2.56) for current
smokers for the squamous cell carcinoma subtypes [27]. In
2004 the IARC working group, that reviewed data on the car-
cinogenicity of tobacco smoke considering in particular nine
case–control studies, concluded that there is sufficient evi-
dence in humans that smoking causes cancer of nasal cavity
and paranasal sinuses [42].
When the histological types were combined, all studies
found an increased risk associated with cigarette smoking but
only one was statistically significant. Seven of the nine studies
analyzed dose–response relationships, in terms of intensity
of smoking (cigarettes/day), duration of smoking or pack-
years. A positive significant trend was found in five and was
suggest in others two [27].
One study examined the residual risk after cessation of
smoking and found a significant decrease in risk of sinonasal
cancer associated with increasing number of years since ces-
sation.
In all the five studies that have analyzed squamous cell car-
cinoma and adenocarcinoma separately the relative risk was
clearly increased for squamous cell carcinoma. The IARC
working group concluded that the evidence of an association
between tobacco smoking and sinonasal cancer is based on
the results from case–control studies, each of which may be
subject to different sources of bias. However, several argu-
ments supports the existence of a causal association: (1)
presence of a dose–response relationship in most studies; (2)
decrease in relative risk associated with time since quitting;
(3) consistently higher relative risks for squamous cell carci-
noma than for adenocarcinoma; and (4) the lack of potential
confounders.
The recent Italian case–control study [19], however, found
that smoking was not a significant risk factor for sinonasal
cancer after accounting for exposure to occupational hazards,
but the authors also state that smoking habits in particular
information on duration and intensity was incomplete for
many study participants.
Finally, some studies have focused on involuntary smok-
ing but data are conflicting and sparse [27].
3.5. Attributable risk
The pooled analysis of the European case–control stud-
ies has produced attributable risk estimates for occupations,
exposures and smoking [27]. The attributable risk for
sinonasal cancer associated with occupations was 33% (95%
CI 12–89%), and considerable differences were observed
between men and women. In men, up to 39% (95% CI
18–92%) of cases could be attributed to occupational expo-
sure, while in women occupation explained 11% (95% CI
0.1–100%). Considering histological subtypes, occupational
exposures were related to 77% (95% CI 60–100%) of all
adenocarcinomas, while a lower attributable risk of 22 (95%
CI 3–100%) was observed for squamous cell carcinoma,
mainly due to exposures in other than wood or leathers related
270 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277

Table 3
Summary of the potential etiological factors, genetic abnormalities, and diagnostic markers in undifferentiated and poorly differentiated sinonasal carcinomas.
Tumor type
Squamous cell carcinoma
Non-keratinising carcinoma
Nasopharyngeal-type
undifferentiated carcinoma
Sinonasal undifferentiated
carcinoma
Small cell neuroendocrine
carcinoma
NUT midline carcinoma
Etiology
Cigarette smoking;
occupational exposures; HPV
(detected in 10–20% of cases)
HPV (detected in 50% of
cases)
EBV
Association to previous
radiotherapy for
nasopharyngeal carcinoma,
HPV (detected in 10%)
Association to previous
radiotherapy for
nasopharyngeal carcinoma
Unknown
Genetic changes
Similar to other head and neck sites,
TP53 mutation (detected in 30–75%)
Only few cases examined
cytogenetically, no specific
abnormalities identified
Unknown
Only few cases examined
cytogenetically, no specific
abnormalities identified
Unknown
t(15;19)
Diagnostic markers
Cytokeratin immunohistochemical
pattern
Cytokeratin immunohistochemical
pattern
EBV detection; cytokeratin
immunohistochemical pattern
Cytokeratin immunohistochemical
pattern; low or absent p63
immunohistochemical expression;
absence of EBV
Immunohistochemistry for
cytokeratins, neuroendocrine
markers, CD57
Detection of t(15;19);
immunohistochemistry for NUT

occupations. Fifteen % of sinonasal carcinomas could be
attributed to smoking, this proportion being higher for squa-
mous cell carcinoma (23%).
4. Advances in the histopathologic diagnosis of
sinonasal carcinomas
Several of the malignant tumors occurring in the sinonasal
tract may present with an undifferentiated or poorly differ-
entiated morphology and with overlapping clinical findings,
making their distinction challenging, especially in limited
biopsy material. However, establishing the correct patholog-
ical diagnosis is the prerequisite for treating the patient and
for the interpretation of epidemiological data. In recent years,
a number of studies have defined the use of novel diagnos-
tic markers for sinonasal carcinomas, and there is increasing
evidence of the importance of the role of immunophe-
notyping and genotyping for differentiating among these
neoplasms.
4.1. Adenocarcinomas
The differential diagnosis among sinonasal adeno-
carcinomas is clinically relevant, because intestinal-type
adenocarcinoma (ITAC) is characteristically associated with
occupational exposure to wood and leather dusts and has
an aggressive behaviour characterized by repeated local
recurrences and ominous outcome, while low grade adeno-
carcinomas and salivary gland-type carcinomas tend to have
a more indolent clinical course and lack the evidence for an
excess risk related to occupational exposures.
The distinction of ITAC from sinonasal non-intestinal-
type adenocarcinomas may be facilitated by studying the
expression of immunophenotypic markers of intestinal dif-
ferentiation, including cytokeratin 20 [43,44], CDX-2 (a
nuclear transcription factor involved in the differentiation of
intestinal epithelial cells) [43–45], and villin (a cytoskeletal
protein required for the formation of the brush border in the
normal intestine) [43]. These markers are characteristically
expressed by ITACs but not by sinonasal non-intestinal-type
adenocarcinomas.
4.2. Poorly differentiated and undifferentiated
carcinomas
Table 3 summarises the potential etiological factors,
genetic and molecular abnormalities, and diagnostic mark-
ers in poorly differentiated and undifferentiated sinonasal
carcinomas. The group of high grade poorly differen-
tiated and undifferentiated sinonasal carcinomas include
nasopharyngeal-type undifferentiated carcinoma (lymphoep-
ithelioma), sinonasal undifferentiated carcinoma (SNUC),
small cell neuroendocrine carcinoma, and poorly differenti-
ated keratinising and nonkeratinising variants of squamous
cell carcinoma. Nasopharyngeal-type undifferentiated car-
cinoma is typically associated with EBV infection, and
this is a useful feature to separate this entity from other
sinonasal undifferentiated carcinomas, which are typically
EBV negative [46]. By definition SNUC does not show
any overt squamous or glandular differentiation, whereas
neuroendocrine features have been frequently noted, both
histologically and immunohistochemically. Indeed, some
Authors consider these tumors as part of the spectrum of
neuroendocrine carcinomas, representing the large cell vari-
ant of sinonasal neuroendocrine carcinoma [47]. SNUC
can be distinguished from poorly differentiated squamous
cell carcinoma variants for the different pattern of cytok-
eratins subtypes expression, since SNUC is positive for
simple epithelia cytokeratins and lacks the expression of
cytokeratins 5/6 and 13, which instead are expressed by squa-
mous cell carcinoma variants [48]. In addition, SNUC has
a limited expression of p63, which is present in squamous
 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277
cell carcinoma variants [49]. Small cell carcinoma of the
sinonasal tract is histologically indistinguishable from its
pulmonary counterpart. Immunohistochemically, it is pos-
itive for cytokeratins and neuroendocrine markers such as
NSE (neuron specific enolase), synaptophysin, and chromo-
granin, although with variable intensity [50]. As small cell
neuroendocrine carcinomas of other sites, sinonasal tumors
express CD57 [51]. These features allow the distinction from
SNUC, malignant melanoma, olfactory neuroblastoma, lym-
phoma, Ewing’s sarcoma/PNET and rhabdomyosarcoma.
In undifferentiated sinonasal tumors ultrastructural eval-
uation still has a place in resolving complex diagnostic
cases.
4.3. Nuclear protein in testis (NUT) midline carcinoma
NUT midline carcinoma (NMC) is a rare, clinically
aggressive carcinoma, which is defined by a translocation
involving the NUT (nuclear protein in testis) gene on chro-
mosome 15q14 and, in most cases, the BRD4 gene on
chromosome 19p13.1, resulting in a BRD4-NUT fusion gene.
Initial cases were reported in young patients affected by
intrathoracic carcinomas, but it is now well established that
these tumors may occur in adults and involve other anatomic
sites, including the sinonasal tract. So far less than 10 cases
have been described in the nasal cavity and paranasal sinuses
[52–54]. These tumors affected young adults of both sexes
and showed an aggressive clinical behaviour. However, there
is certainly an underestimation of their occurrence due to
the lack of specific diagnostic features. Histologically, these
carcinomas are composed of undifferentiated basaloid cells
with focal, often abrupt, squamous differentiation. There-
fore, the diagnosis of NMC requires the demonstration of the
NUT translocation, which can be achieved by karyotyping,
reverse transcription polymerase chain reaction (RT-PCR),
and FISH. Recently, a monoclonal antibody to NUT for use
in immunohistochemistry has been developed, which showed
a sensitivity of 87%, a specificity of 100%, a negative predic-
tive value of 99%, and a positive predictive value of 100%
when tested in a large panel of carcinoma tissues [55]. More-
over, the expression of normal NUT protein is limited to the
germ cells of the testis and ovary, thus increasing the relia-
bility of the use of immunohistochemistry in the diagnosis of
NMC. The use of this antibody may help to separate NMC
from other poorly differentiated sinonasal carcinomas, thus
contributing to their clinico-pathologic characterization. In
addition, it appears that the distinction of NMC from other
sinonasal carcinomas is of clinical relevance, in view of the
favourable response to certain treatment regimes, including
chemotherapy according to Ewing’s sarcoma protocols [56]
or docetaxel and radiotherapy [57].
4.4. Sinonasal metastases
Secondary epithelial malignancies involving the sinonasal
region are exceedingly rare. Prescher and Brors reviewed 169
271
cases of carcinoma metastatic to the paranasal sinuses, and
found that most primary tumors were located in the kid-
ney (40%), followed by lung, breast, thyroid, and prostate
(approximately 10% each site) [58]. The maxillary sinus was
the most commonly affected site, followed by the sphenoid
sinus, the ethmoid sinus, and the frontal sinus; in 22% of
the cases multiple sinuses were involved [58]. The differen-
tial diagnosis with primary malignancies requires correlation
with clinical data, due to the overlapping morphology with
several primary carcinomas and adenocarcinomas. Immuno-
histochemistry may be helpful in selected cases. For example,
double positivity for cytokeratin 7 and 20 allows the
distinction of ITAC from a metastasis of colorectal adeno-
carcinoma, which is usually positive only for cytokeratin 20
[43,44].
5. Molecular changes implicated in the pathogenesis
of sinonasal cancer
5.1. Whole genome analysis
To date only few studies have been published specifically
focused on sinonasal carcinomas, and they mostly consid-
ered tumors related to the professional exposure to wood
dust. Chromosomal imbalances that occur in adenocarcino-
mas of the ethmoid related to occupational exposure to wood
dust have been studied by Comparative Genomic Hybridiza-
tion (CGH), a powerful molecular cytogenetic technique for
screening the entire tumor genome. Gains were more fre-
quently detected than losses and occurred at 7q11-21 in 71%
of cases, at 18p11-2 in 66%, at 8q11-22 in 62%, at 5p11-13
in 57%, at 12q11-13 and at 19p in 52% [59]. On the other
hand, losses were more frequent at loci 8p22-23, 18q22-23,
17p13 and 5q31-qter [59]. Interestingly, this pattern of chro-
mosomal abnormalities is considerably different from that
of other tumors of the head and neck region, but it shows
similarities with that of gastric and colonic adenocarcino-
mas [60,61], that have a completely different aetiology, but
similar morphology. Some of these loci showing gains in
nasal adenocarcinomas contain genes that codify for growth
factors and for growth factor receptors, such as hepatocyte
growth factor (HGF) gene at 7q21-22, and MOS and MYCC
at 8q. Conversely, tumor suppressor genes, such as DCC and
SMAD4 at locus 18q, APC at 5q and TP53 at 17p13, local-
ize in regions of chromosomal losses [59]. Finally, a higher
number of gains have been noted in poorly differentiated
adenocarcinomas in comparison with well and moderately
differentiated tumors, indicating the involvement of gene
amplification in the process of loss of differentiation in ITAC
[62].
More recently, microarray CGH, a method with better res-
olution and sensitivity than chromosome CGH, was applied
to the study of a series of wood dust related sinonasal adeno-
carcinomas [63]. The most frequent gains localized at 5p15,
20q13, and 8q24, while losses occurred most frequently at
272 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277
4q31-qter, 18q12-22, 8p12-pter, and 5q11-qter [63]. Again,
this pattern bears some similarities to the genetic changes
observed in colorectal adenocarcinoma.
In a study of gene expression profiling of a small series
of sinonasal adenocarcinomas, cancer dedicated microar-
rays and subsequent validation by quantitative RT-PCR and
immunohistochemistry were employed [64]. Overexpres-
sion of LGALS4 (galectin 4) and the downregulation of
CLU (clusterin) were the two most consistent alterations
observed in comparison with normal tissue [65]. If these data
will be confirmed in a larger set of tumors, these markers
could be potentially useful in the differential diagnosis of
sinonasal adenocarcinomas and in the identification of early
lesions.
Although no significant correlation with clinical param-
eters as well as with occupational exposure can be drawn
from these studies, the molecular pathways relevant for the
pathogenesis of sinonasal ITAC begin to be unravelled, and
this may lead in the next future to the identification of poten-
tial markers for early diagnosis in occupationally exposed
subjects.
5.2. TP53 gene
TP53 gene alteration is a common event in head and neck
carcinoma, which occurs in the early phases of neoplas-
tic progression. The overall frequency of TP53 mutations
in sinonasal cancer varied between 18% and 77% in dif-
ferent series [65–68]. The rate of TP53 mutations differed
significantly according to histology, being higher in ade-
nocarcinomas than in squamous cell carcinomas [68]. In
addition, a high overall occurrence of TP53 mutations in asso-
ciation to wood dust has been observed, with an increase over
5- to 3-fold in association to a long duration and high level
of wood-dust exposure [68].
In a recent study analysing a large series of sinonasal car-
cinomas, the majority of the identified TP53 mutations were
missense base substitutions (60%), which occurred at a sim-
ilar rate of carcinomas involving the head and neck anatomic
site [69]. However, some specific features of TP53 mutation
emerged from this study, including a higher frequency of mis-
sense base substitutions in wood-dust exposed patients and
an excess of multiple mutations, and of frameshift and silent
mutations in smokers. Moreover, another peculiar aspect of
TP53 mutation profile in sinonasal carcinomas is a rela-
tively high frequency of codon 135 involvement, which could
be related to a high genotoxic stress generated by a regu-
lar exposure to carcinogenic substances, such as wood dust
[69].
Finally, loss of heterozygosity at the 17p13 locus that har-
bours the TP53 gene, was observed at a similar rate of gene
mutation in ITAC (58%) [67].
Given the close relationship of TP53 gene alterations
with occupational exposure and its relatively high fre-
quency in sinonasal carcinomas, this gene may represent
a potential marker of the early phases of carcinogenesis
which could be employed in screening of exposed subjects
(see Section 6).
5.3. Other genes
The ras proto-oncogenes (H-ras, K-ras, and N-ras) are acti-
vated in approximately 20% of human cancers through point
mutations in the codifying sequences, that generally consist
of exchanges of pairs of bases in codons 12, 13 and 61 [70].
K-ras mutations have been detected with variable, generally
low frequency in sinonasal carcinomas, being more frequent
in adenocarcinomas (0–50% of cases) than in squamous cell
carcinomas (1% of cases) [68–70,65,71–73]. Interestingly,
Kras mutations consisted prevalently of G → A transitions, a
type of mutation typically produced by alkylating agents in
experimental systems, and this could be related to a combi-
nation of exposure to tobacco, wood dust, and possibly other
occupational agents [71].
Methylation of CpG islands is a frequent mechanism of
tumor suppressor gene inactivation which has been related to
dust genotoxic agents. Accordingly, ITACs related to work
exposure present a high frequency of p14ARF and p16INK4a
aberrant methylation, suggesting that simultaneous deregu-
lation of these tumor suppressor genes is an important event
in the development of these tumors [67].
5.4. HPV and sinonasal cancer
There is increasing evidence that the human papillo-
mavirus (HPV) is associated with a subset of sinonasal
carcinomas. Early studies focused on sinonasal inverted
papillomas and evidence on the involvement of HPV in
carcinoma was obtained soon after [74,75]. Using differ-
ent detection methods, HPV DNA has been demonstrated in
approximately 20% of sinonasal carcinomas [74–76], with
HPV-16 being the most frequent HPV type, followed by
HPV-18.
Recent studies have established a clear relationship
between HPV infection and a subtype of sinonasal car-
cinoma, the nonkeratinising (cylindrical cell) carcinoma.
In this histologic subtype, the prevalence of HPV infec-
tion, particularly of HPV 16, is 50%, while in keratinising
squamous cell carcinoma it ranges between 16% and 19%
[77,78]. In addition, HPV-positive tumors are positive for
p16 immunostaining, analogously to HPV related carcino-
mas of the female genital tract, and frequently show a high
proliferative score [77,78]. Conversely, p53 immunohisto-
chemical overexpression is significantly more frequent in
HPV-negative than in HPV-positive sinonasal SCCs [77,78].
Therefore, nonkeratinising sinonasal carcinoma appears to
be a distinct histopathologic and molecular disease entity
characterized by high prevalence of high risk HPV DNA,
overexpression of p16 protein, high Ki-67 labeling index,
and negative or low p53 reactivity [77], whereas keratinising
squamous cell carcinoma is a tumor more frequently related
to cigarette smoking with high frequency of p53 anomalies.
 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277
The identification of HPV in sinonasal carcinomas has
important clinical implications, because the presence of HPV
is a prognostic factor associated with a favourable outcome.
Alos et al. have recently shown that patients with HPV-
positive tumors have a significantly better prognosis than
those with HPV-negative neoplasms, analogously to what it
has been previously reported in oropharyngeal carcinomas
[78]. The improved survival in HPV-positive oropharyngeal
tumors has been related to a better response to current regimes
of chemo- and radiotherapy. Therefore, characterization of
HPV status in sinonasal squamous cell carcinoma prior to
therapy might help to define subpopulations of responsive
patients.
6. Molecular markers for screening and prevention
Studies focused on the morphologic precursors of
sinonasal squamous cell carcinoma and the molecular
changes associated with the early steps of cancerogenesis
at this site are currently lacking. On the other hand, the well
documented association of ITAC with occupational exposure
to wood and leather dusts, has prompted a number of stud-
ies aiming to identify precursor lesions developing in exposed
subjects. Indeed, these efforts could be relevant to define mor-
phologic markers to be employed in screening programs in
occupationally exposed individuals, which could be useful
to identify subjects at risk to develop sinonasal adenocarci-
noma. Earlier studies were mainly conducted on the nasal
mucosa of woodworkers [79–81], and the most frequently
observed morphologic alteration was squamous metaplasia
with or without dysplasia. However, these are non-specific
changes that can be induced by a number of agents, although
they may contribute to tumor development, because substi-
tution of ciliated with non-ciliated epithelium prolongs the
action of carcinogens on the mucosa. In addition, the so-
called cuboidal metaplasia has been reported as a significant
histologic finding in nasal mucosa of woodworkers [80], but
this is more likely to be part of the morphologic spectrum of
squamous metaplasia of nasal respiratory epithelium.
In a recent study, we investigated the histologic changes
and modifications in the phenotype of epithelial cells of
the nasal mucosa in cohort of 139 leather workers [82].
In addition to squamous metaplasia, which was detected in
approximately 2/3 of samples and was often associated with
dysplasia, we observed the presence of goblet cell hyper-
plasia in 20% of the cases. This was often associated with
expression of MUC-2, a glycosylated apomucin which con-
stitutes one of the major components of mucus covering the
surface of epithelial tissues, including the upper respiratory
tract [83,84]. In addition, the presence of goblet cell hyper-
plasia and of MUC-2 immunopositivity were significantly
associated with longer occupational exposure in leather tan-
ning activities, but not in shoe manufacturing, indicating that
these could be work-related alterations of nasal mucosa in
leather workers.
273
Intestinal metaplasia of sinonasal mucosa has been con-
sidered a potential morphologic precursor of ITAC, but it
has been recognised only in few cases and in non-neoplastic
mucosa near adenocarcinoma areas [43,85]. In our previ-
ous study, we did not identify intestinal metaplasia of nasal
mucosa, even employing immunostaining for markers of
intestinal differentiation, such as cytokeratin 20, CDX-2
and MUC-2 [82]. Conversely, others were able to identify
metaplastic foci in normal mucosa adjacent to the tumor,
which showed positivity for cytokeratin 20, CDX-2, and villin
[43,85]. Overall, the absence of intestinal metaplasia in nasal
mucosa of exposed workers and its identification only in areas
adjacent to ITAC, could be explained considering that the
acquisition of the intestinal phenotype is a late event in the
development of ITAC from nasal epithelia which is preceded
by a number of other molecular alterations in schneiderian
mucosa, or alternatively it could represent an intraepithelial
extension of neoplastic cells rather than a true metaplastic
process.
Since no morphological precursor of sinonasal ITAC has
been so far identified with certainty, the attention has moved
to the analysis of molecular changes that may precede the
onset of the tumor. Valente et al. examined the expression
of p53 protein in epithelial cells of ethmoid mucosa from
a group of 60 woodworkers [86]. They found an overex-
pression of p53 in squamous metaplastic epithelium, ciliated
epithelium, and seromucous glands of the nasal stroma in
comparison with non-exposed controls, and concluded that
evaluation of p53 could be useful to detect subjects at risk to
develop adenocarcinoma among woodworkers. We obtained
similar results in a series of biopsies of nasal mucosa from
subjects occupationally exposed to leather dusts, where we
observed a significant overexpression of p53, particularly in
surface epithelial cells, in comparison with non-exposed con-
trols [87]. In addition, we noted a significantly higher p53
expression in subjects with long exposure to leather tanning
activities, supporting the concept that altered p53 expression
may be related to the damage to nasal epithelia determined
by substances employed in these activities, rather than being
a non-specific phenomenon related to irritation of the nasal
mucosa [87].
7. Predictive factors and new therapeutic targets
The treatment for sinonasal carcinomas remains currently
based on surgical excision with wide free margins. However
the high rate of failures and the complications of surgery
have prompted the use of radiotherapy and chemotherapy
as neoadjuvant or adjuvant treatments in different combina-
tions, resulting in improved results. In this setting it would
important to select patients who could benefit of adjuvant
treatments according to the status of predictive tumor bio-
logic markers. An analysis of the predictive value of TP53
gene status on the response to chemotherapy has been con-
ducted on a series of patients affected by ITAC [88]. The
274 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277
rationale for this study is that most of DNA-damaging
chemotherapeutic regimes are ineffective if TP53 gene alter-
ations compromise the apoptotic pathway involved in the
drug apoptosis-mediated cell killing mechanism. Accord-
ingly, chemotherapy was highly effective in tumors bearing
wild type or a still-efficient p53 protein, but ineffective in
those carrying a disabled p53 protein [88], indicating that p53
status represents a promising biomarker to predict response
to chemotherapy in ITACs.
Similarly, in study of 70 Japanese patients affected by
maxillary sinus squamous cell carcinoma, p53 mutation in
the pretreatment tissues correlated with low histologic effec-
tiveness of radiochemotherapy and with worst prognosis [89].
Recent advances in cancer treatment with the introduction
of molecular targeted therapies may in the next future prompt
a significant improvement of the current status in patients
affected by sinonasal carcinomas. Molecular targeted ther-
apies aim to interfere with specific molecular mechanisms
involved in tumor growth, optimizing the efficacy and min-
imizing the side effects of anticancer treatment. In recent
years, several drugs have been developed which can interfere
successfully with neoplastic growth, including molecules that
target tyrosine kinase receptor proteins, such as HER-2, KIT,
PDGFR, ABL and EGFR, from which promising results have
been obtained in the treatment of different types of can-
cers. A prerequisite for the efficacy of targeted therapy is the
expression of the target-molecule, which can be preliminarily
assessed in different ways on tumor tissue.
Currently, only few studies have aimed to identify the pres-
ence of possible targets for these types of drugs in sinonasal
carcinomas. Our group analyzed the expression of c-erb-B2
(HER-2/neu) in a series of 28 ITACs, and we observed that
about one-third overexpressed the receptor, and these tumors
were characterized by a more aggressive clinical course [90].
These preliminary data indicate that c-erbB-2 oncogene acti-
vation could be involved in sinonasal tract oncogenesis, with
potential implication for treatment, since HER-2 has become
an important target for novel therapeutic strategies, such as
trastuzumab (Herceptin® ), a monoclonal antibody that acts
as an HER-2 antagonist.
In a recent study, we evaluated epidermal growth factor
receptor (EGFR) protein expression and epidermal growth
factor receptor gene copy gains, through immunohistochem-
istry and fluorescence in situ hybridization in a series of
55 ITACs [91]. Approximately one-third of tumors showed
EGFR positivity, 7 of which exhibited high expression levels
of the receptor. The frequency of EGFR overexpression was
significantly higher in tumors from woodworkers (42.8%)
than in tumors from leatherworkers (9.5%), or arising in sub-
jects with no known occupational history (0 of 8). In cases
with EGFR overexpression, fluorescent in situ hybridization
analysis revealed disomy in three adenocarcinomas, chro-
mosome 7 polysomy in two, and EGFR gene amplification
in three. These data may therefore furnish the basis for future
studies in which EGFR targeted therapies could be tested
prospectively in this group of tumors.
8. Conclusions
Sinonasal carcinomas are rare tumors, for which a
relationship to work exposures is well documented. No sig-
nificant improvement in survival has been registered in recent
years, indicating that efforts should be made to improve early
diagnosis, especially by monitoring exposed workers. On the
other hand, increasing knowledge on their phenotypic and
genotypic features is progressively leading to a refinement in
diagnosis, especially for poorly differentiated and undiffer-
entiated lesions, as well as to the identification of markers
which can be potentially useful to identify the early phases
of carcinogenesis, to detect subclinical disease, to predict the
response to therapy, and finally, that may represent potential
targets for alternative treatments.
Conflict of interest statement
The authors declare they have no conflict of interest.
Reviewers
Nina Gale, M.D., University of Ljubljana, Medical Fac-
ulty, Pathology Institute, Korytkova 2, SI-1000 Ljubljana,
Slovenia.
Antonio Cardesa, M.D., Hospital Clinic/University of
Barcelona, Department of Pathological Anatomy, Villarroel
170, E-08036 Barcelona, Spain.
Acknowledgments
The AIRTUM data presented here are derived from AIR-
TUM database; we thank Dr. Carlotta Buzzoni and Dr.
Emanuele Crocetti, from AIRTUM Working Group, who
made available and processed data from Italy (AIRTUM) and
from US (SEER 13). This work was supported by Istituto
Toscano Tumori (ITT).
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Biographies
Alessandro Franchi, M.D., received his degree “cum
laude” from University of Florence Medical School (Italy) in
 A. Franchi et al. / Critical Reviews in Oncology/Hematology 79 (2011) 265–277
1987. His post-graduate specialty was in Anatomic Pathol-
ogy. Since 2001 he is Associate Professor of Pathology
at the University of Florence Medical School. During his
post-graduate training he has attended the Department of
Pathology at the Hospital for Special Surgery, New York (NY)
as Research Fellow in 1990. In 1996 he was a visiting fellow at
the Department of Pathology, Memorial Sloan Kettering Can-
cer Center, New York (NY). He has been involved as principal
investigator or co-investigator in several research projects
on head & neck tumor pathology, particularly focused on
angiogenesis, lymphangiogenesis, and molecular pathology.
He has developed a particular interest for the pathology of
sinonasal carcinomas, and in this field he contributed to the
2005 WHO Classification of tumors of the Head and Neck
with a co-authored chapter on sinonasal adenocarcinomas.
He is the author of 150 publications in top-rated oncology
and pathology journals.
Lucia Miligi, ScD, received her degree from the Univer-
sity of Florence, Italy, in 1979. Since 1989 she has been
chief assistant at the Unit of Environmental and Occupa-
tional epidemiology of the Cancer Research and Prevention
Institute (ISPO), Florence, Italy. She developed experience
in occupational and environmental epidemiology and in
methods used in exposure assessment particularly in the
contest of case–control studies. She has been involved,
as principal or co-investigator in several projects in the
fields of cancer epidemiology, in particular in case–control
studies on hematolymphopoietic malignancies: “The Ital-
ian multicenter case–control study on hematolymphopoietic
malignancies” that involved eleven areas in Italy, “The
multicenter case–control study on etiological factors for
childhood leukemia, non-Hodgkin lymphoma and neuroblas-
tomain Italy (SETIL)” that involved fourteen Italian regions,
“The Italian study on gene-environment interaction in lym-
phoma etiology” that involved five areas in Italy, and in the
International Hodgkin lymphoma (HL) pooling project. Fur-
thermore, she is involved in the international MOBI-Kids
study on risk of brain cancer from exposure to radiofrequency
fields in childhood and adolescence. She is the coordinator
of Tuscan Regional SinoNasal Cancer Registry and collabo-
rate with ISPESL (National Institute for Occupational Safety
and Prevention) to implement the SinoNasal Cancer National
Registry (ReNaTuNS) aiming to estimate the incidence of
these cancers in the areas with the prevalence of occupational
exposure to wood and leather dust, to describe the frequency
277
of cases by industrial activity and job title, to describe the
modalities of exposure to wood and leather dust, to describe
frequency of histological subtypes for age, gender and kind
of exposure. She has authored 48 peer-reviewed publications
listed on Medline-PubMed.
Annarita Palomba, M.D., received her degree from the
University of Florence Medical School (Italy) in 1991.
Her post-graduate specialty was in Anatomic Pathology.
In 2001 she obtained a Ph.D. degree in at the University
of Florence, Italy. She is currently a staff pathologist at
the “Azienda Ospedaliera Universitaria Careggi”, Florence,
Italy. Her relevant studies concern the molecular and phe-
notypic characterization of colorectal cancer and head and
neck tumors. She is the author of more than 15 publications
in top-rated cancer journals.
Lucia Giovannetti, M.D., received her degree “cum laude”
from the University of Florence Medical School (Italy) in
1985. Her post-graduate specialty was in Epidemiology and
Public Health. Since 1989 she has been medical consul-
tant at the Cancer Research and Prevention Institute (ISPO),
Florence, where she has been mainly involved in Tus-
can Regional Mortality Registry (RMR), Tuscan Regional
Mesothelioma Registry (participating in the network of
the National Mesothelioma Registry: ReNaM) and in Tus-
can Regional Sinonasal Cancer Registry (participating in
the network of the National Sinonasal Cancer Registry:
ReNaTuNS). She has authored 15 peer-reviewed publications
listed on Medline-PubMed.
Marco Santucci, M.D., is Full Professor of Anatomic
Pathology at the University of Florence Medical School and
Head of the Division of Anatomic Pathology, Department of
Critical Care Medicine and Surgery, University of Florence.
He performs his clinical activities in dermatopathology and
head and neck pathology. After receiving his medical degree
“cum laude” in 1976, he obtained the post-graduate special-
ties in Oncology and Anatomic Pathology. In 1996 he was
Visiting Professor and Visiting Investigator at the Depart-
ment of Pathology, Memorial Sloan Kettering Cancer Center,
New York, N.Y. He has authored more than 200 scientific
publications in oncology and pathology journals, and is a
manuscript reviewer for several international journals. He
has been involved, as principal or co-investigator, in several
projects in the field of pathology of tumors funded by the
Italian Ministry of Health.