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Introduction
Although the sinonasal cavities occupy a relatively This article focuses on SNSCC and ITAC, which have
small anatomical space (Figure1), they are the site of been the subjects of an increasing number of publica-
origin of one of the most histologically diverse group tions on multiple oncological aspects. In particular,
of tumours observed in the entire human body. The the advances in endoscopic surgical approaches, radio-
sinonasal region is a complex anatomical area, close to therapy and imaging techniques that have improved the
structures that include the eyes and the brain, which is of clinical management of patients with sinonasal cancer
special relevance to surgery and postoperative treatment, are reviewed. In addition, the progress in genetic profil-
as mutilation and aesthetic deformities are difficult to ing and the development of invitro and animal models
avoid. Epithelial tumours are the predominant form of of sinonasal cancers, which is laying the foundations for
malignancy affecting the sinonasal cavities, represent- future targeted anticancer therapies, are discussed.
ing >80% of all sinonasal tumours.1 The most-common
subtypes of epithelial tumour are sinonasal squamous- The epidemiology of sinonasal tumours
cell carcinoma (SNSCC), which predominantly occur in Sinonasal cancers comprise 5% of all cancers of the head
the maxillary sinus and nasal cavity, and intestinal-type and neck, with a worldwide incidence of approximately
adenocarcinoma (ITAC), which almost exclusively arise 1 case per 100,000 inhabitants, annually.24 The average
in the ethmoid sinus (Figure1; Table1).1 Tumours of age at which patients present with sinonasal tumours is
the frontal and sphenoid sinuses are rare.1 Despite the between 5060years.5 In general, SNSCCs account for
anatomical proximity of the nasopharynx to the sino- 5080% of all sinonasal malignancies, while ITAC rep-
nasal cavities (behind the nasal cavities and above the resents 1020%, although these proportions vary geo-
Department of
soft palate), tumours in these regions are considered graphically;4,6 for both these tumour types, the highest
Otolaryngology, separately. Indeed, the aetiology, epidemiology, clinical incidences are reported in European countries.5
Instituto Universitario features, and genetic profile of sinonasal tumours are SNSCC and ITAC occur more commonly in men,
de Oncologa del
Principado de Asturias distinct from those of the main head and neck cancer with a male-to-female ratio of 2:1 in SNSCC, and up to
(IUOPA), Hospital localizations, such as larynx, pharynx, and oral cavity 6:1 in ITAC.1,4,7 The male predominance of sinonasal
Universitario Central
deAsturias,
cancers. Thus, sinonasal tumours should be considered tumours is probably a result of the aetiological involve-
CelestinoVillamil s/n, unique malignancies not to be included in the miscellany ment of occupational hazards;1,4,7 occupational exposure
33006Oviedo, Spain of head and neck cancers. to several industrial compounds has been attributed to
(J.L.L., F.L., C.S.,
M.A.H.). tumorigenesis in around 40% of all sinonasal cancers,
and 30% of SNSCC and 90% of ITAC specifically.710
Correspondence to:
M.A.H. Competing interests Professionals working with wood have up to 500900-
mhermsen@hca.es The authors declare no competing interests. times and 20-times increased risk of developing ITAC
Clinical presentation
and SNSCC, respectively, compared with the general The typical clinical symptoms of sinonasal cancer, such
population.10 In individuals who present with these dis- as nasal obstruction, facial pain, or persistent rhinor-
eases, exposure to such environmental insults usually rhoea (runny nose), or epistaxis (nosebleed), are non-
began at an early age and often persisted for longer specific, and indeed are often indistinguishable from
than 20years.3,11 On the basis of this evidence, in many symptoms of patients with benign sinonasal disease.
European countries ITAC is officially considered a pro- Proptosis (bulging of the eyes), diplopia (double vision),
fessional disease.12 Indeed, the International Agency or neurological symptoms can be present in patients
for Research on Cancer (IARC) designated wood dust with advanced-stage tumours. Owing to thenonspecific
as a human carcinogen in 1995,13 and in 2002, the NIH and the often relatively mild nature of the symptoms
identified wood dust as a known human carcino- at early stages of disease, sinonasal malignancies have
gen.14 Outside of Europe, however, only 20% of patients a prolonged diagnostic latency.7,19 As such, lymphatic
with ITAC have a history of exposure to wood.15 This metastasis at diagnosis occurs in 1020% of patients
EC Intestinal-type
adenocarcinomas
OG
Frontal O
sinus
Sphenoid ES
sinus
Ethmoid S
sinus
Maxillary
sinus NC
MS
OC
Figure 1 | Schematic view of the sinonasal cavities and distribution of the main sinonasal tumour types. Sinonasal
malignancies comprise mostly tumours of epithelial origin, mainly SNSCCs and ITACs, but also esthesioneuroblastomas,
SNUCs, and ACCs.1 Other malignancies affecting the sinonasal region include melanomas, soft-tissue tumours, tumours
ofbone and cartilage, haematolymphoid tumours, germ-cell tumours, and metastases from primary tumours in other
partsof the body. Almost all ITACs are located in the olfactory groove of the ethmoid sinuses, whereas SNSCCs occur
mainly in the nasal cavity and the maxillary sinuses.1 Apart from esthesioneuroblastomas, which originate in the olfactory
epithelium, the other types of sinonasal tumours can occur anywhere within the sinonasal cavities, although tumours with
frontal and sphenoid sinus localizations are rare.1 Given the close proximity of these anatomical areas and the fact that
tumours frequently present at advanced stages,7,19 identifying the exact anatomical localization from which they developed
is often difficult. Of note, the regions affected by sinonasal tumours are situated close to the eyes and brain.
Abbreviations:ACCs, adenoid cystic carcinomas; EC, endocraneum; ES, ethmoid sinuses; ITACs, intestinal-type
adenocarcinomas; MS, maxillary sinus; NC, nasal cavity; O, orbit; OC, oral cavity; OG, olfactory groove; S, septum;
SNSCCs,sinonasal squamous-cell carcinomas; SNUCs, sinonasal undifferentiated carcinomas.
Table 1 | Summary of sinonasal tumour subtypes* also essential because they enable the complete extent of
the tumour to be established and can potentially provide
Histological subtype Proportion of 5-year overall
sinonasal cancers (%) survival rate (%)
information on the benign or malignant nature of the
tumour. Currently, when malignancy is suspected, both
Sinonasal squamous-cell carcinoma 50 50
CT imaging and MRI must be performed to obtain precise
Intestinal-type adenocarcinoma 13 60 anatomical details regarding the tumour localization and
Mucosal melanoma 7 35 extension, which are critical in determining operability
Esthesioneuroblastoma 7 70 or in planning radiotherapy (Figure2). MRI is consid-
Adenoid cystic carcinoma 7 70
ered the standard imaging modality for postoperative
surveillance. The value of PETCT in the assessment of
Sinonasal undifferentiated carcinoma 3 35
sinonasal tumours has not been clearly defined, but this
Other 13 Variable imaging modality is especially important in evaluating
*These data come from a study of patients with sinonasal cancer in the USA; 1 however, similar data have patients with suspected metastasis or tumour recurrence;
been obtained in patient populations in Europe and other regions.5
up to one-third of sinonasal tumours might be accurately
upstaged because of neck or distant-site involvement dis-
with SNSCC (especially if the tumour erodes through the covered using PETCT.22 Once the appropriate imaging
maxillary gingiva), but is a rare occurrence in patients data have been obtained, clinical staging of sinonasal
presenting with ITAC,20,21 perhaps becausethe pattern tumours is performed based on location and extent,
of tumour spread is largely dependent of thesinus according to the current Union for International Cancer
origin and lymphatic drainage. During the follow-up Control (UICC) classificationsystem.23
period after treatment of the primary tumour, 10%
of patients with sinonasal tumours develop distant Tumour histology
metastasis; however, this seldom occurs in absence of The sinonasal cavities are lined with a pseudostratified
locoregionalrecurrence.1921 respiratory epithelium, which changes into pseudo-
Clinical examination of patients with suspected sino- stratified olfactory epithelium at the roof of the nasal
nasal tumour should begin with a thorough medical cavity (Figure3ab); the main difference between these
history and a complete ear, nose, and throat (ENT) epithelia is the presence of olfactory neurons in the latter,
exploration, including assessment of the cranial nerves with the axons of these neurons forming unmyelinated
and neck. Anterior rhinoscopy generally provides limited nerve bundles that traverse the cribiform plate andtrans-
information and, therefore, rigid nasal endoscopy with mit signals to the olfactory bulb. Goblet cellsand sub-
optics at 0 or 45 is mandatory. Nasofibroscopy can also mucosal secretory glands within these epithelia produce
provide useful data, but the image quality is usually worse mucous that captures bacteria and other foreign matter,
than with rigid endoscopes. Noninvasive imaging tests are and is moved toward the pharynx by coordinated
a b c
O O ES
O
ES * ES
MS
MS
MS
*
Figure 2 | Imaging approaches for diagnosis of sinonasal tumours. CT imaging in axial and coronal sections, preferably with
contrast enhancement, enables accurate assessment of sinonasal cancers, especially in terms of bone destruction.
Features of malignancy are invasion of soft tissue and the presence of reactive osteogenesis. MRI is generally indicated
forassessing extension beyond the sinonasal cavities (orbital, intracranial or infratemporal fossa invasion), evaluating
perineural tumour spread, and differentiating tumour from postobstructed secretions. MRI protocols generally include axial
and coronal T1-weighted, T2-weighted, STIR and T1-weighted gadolinium-enhanced scans. a|Coronal CT image showing an
aggressive left maxillary SNSCC with destruction of the maxillary sinus walls. Erosion of the floor of the maxillary sinus and
extension of the tumour into the maxillary alveolus (arrow), buccal space (asterisk), and hard palate (arrowhead) is evident.
b | Coronal CT image of a woodworker, which led to the early diagnosis of a small ITAC of the left olfactory cleft (arrow). The
left olfactory cleft is closed by a slight bulging of the corresponding nasal septum (asterisk) to the right and of the conchal
lamina (arrowhead) to the left. Note the thinning of the left cribiform plate (dotted arrow). c | 3D IR-prepared gradient-echo
sequence coronal MRI image demonstrating a large, heterogeneous ITAC occupying the nasal cavity and ethmoid sinuses
bilaterally, with extension into the anterior cranial fossa (arrow). Abbreviations: ES, ethmoid sinuses; IR, inversion recovery;
ITAC, intestinal-type adenocarcinoma; MS, maxillary sinus; O, orbit; SNSCC, sinonasal squamous-cell carcinoma;
STIR,short tau inversion recovery.
macrophages to secrete a variety of cytokines and chemo- Differentiation or reprogramming the sinonasal epi-
kines involved in the development and maintenance of thelium towards an intestinal-type epithelium, incorpor-
the inflammatory response, including tumour necrosis ating resorptive, goblet, neuroendocrine, and Paneth cells,
factor (TNF).28 The cytokines TNF and IL-1 can result occurs before the development of ITAC (Figure3ef),24
in activation of the transcription factor nuclear factorB but is not unique to the sinonasal cavities: this process
(NFB), which is implicated in tumorigenesis, thus has been reported to precede the development of tumours
connecting inflammation with cancer development.27 at a number of locations, including the stomach, oeso-
Of note, expression of both NFB and downstream phagus, and lung.36,37 Both cuboidal and intestinal meta-
prostaglandin G/H synthase2 (also known as cyclo- plasia have been proposed to be a precursor to ITAC, as
oxygenase-2 [COX2]) have been found to be elevated these metaplastic tissues have been observed adjacent to
in sinonasal carcinomas.29 In addition, upon stimulation such tumours and in sinonasal mucosa of individuals with
by wood dust, alveolar macrophages released reactive exposure to aetiological risk factors (Figure3ef).3840
oxygen species (ROS) and reactive nitrogen species Immunohistochemically, this metaplasia can be detected
(RNS), such as peroxynitrites and nitrogen oxides, which as a switch from a normal cytokeratin-7 (CK-7)+/CK-20/
can generate mutagenic DNA adducts.30,31 Under acute CDX-2/villin sinonasal epithelial cell phenotype to an
inflammatory conditions, these free radicals are released abnormal CK-7/CK-20+/CDX-2+/villin+ intestinal epi-
to combat pathogenic organisms, but in chronic inflam- thelial cell phenotype.41 Expression of p53, which is absent
matory conditions, they can have detrimental effects on in the normal respiratory epithelium, has been also been
the host tissues. A strong relationship between nitric observed, mainly in squamous metaplasia, and seems to
oxide (NO) production through inducible nitric oxide be related to wood-dust exposure.39,40 This observation
synthase (iNOS) activity and G>A nucleotide transi- might be indicative of upregulated expression of func-
tions in the TP53 gene was demonstrated in colorectal tional p53 in response to inflammatory signals in the
cancer.31 Likewise, a dominance of TP53 G>A transitions wood-dust-exposed sinonasal epithelium, rather than of
has been observed almost exclusively in nonsmoking TP53 genemutation.
woodworkers, whereas G>T transversions associated
with tobacco smoking were considerably less frequently Cancer stem cells
observed.3234 Furthermore, G>A transition in KRAS was Another method of investigating the origin of sino-
the most-frequent mutation found in patients with ITAC nasal cancer is the analysis of cancer stem cells (CSC), as
who had a history of exposure to wood and leatherdust.35 proposed for other head and neck tumours.42,43 To our
Together, these data implicate chronic inflammatory knowledge, no research has been published on the role
processes as a causal or promoting factor in the tumori- of CSC in sinonasal cancer. Nevertheless, normal stem
genesis of both SNSCC and ITAC, particularly in indivi- cells in the olfactory epithelium have captured the atten-
duals exposed to industrial compounds. However, more tion of stem-cell researchers, especially with regard to the
studies are needed to confirm this relationship, and ability of these cells to form new olfactory neurons after
also to explain why none of the known sinonasal cavity tissue damage sustained during adulthood.44 The same
inflammatory pathologies, such as rhinitis and polyps, olfactory neuroepithelium stem cells were also found to
seem to be associated with an increased cancer risk. be precursors of non-neuronal, epithelial cell types.44 In
addition to the olfactory epithelium, stem cells have been
Precursor lesions isolated from respiratory epithelium of the lower and
Multistep carcinogenesis through various histological middle turbinate, and these cells were capable of differ-
changes accompanied by accumulating genetic altera- entiating into cells with either neuroectodermal or meso-
tions has not been demonstrated for sinonasal carcino- dermal phenotypes.45 On the basis of specific neuronal
mas. However, any premalignant histological changes markers, esthesioneuroblastoma is the only type of sino-
might be obscured by growth of the tumour mass, which nasal tumour demonstrated to derive from the olfactory
is often detected at advanced stages of progression. At epithelium. Clinical and radiological evidence suggests
an early stage of development of both SNSCCs and that ITACs also originate from the olfactory epithelium
ITACs, the normal respiratory or olfactory epithelium lining the olfactory cleft (Figure1 and Figure2), whereas
undergoes metaplasia, redirecting the normal cell dif- SNSCCs might develop in other sinonasal areas, such
ferentiation pathways toward tissue types that do not as respiratory mucosa in the maxillary sinus or in the
normally exist in the sinonasal cavities. One could specu- pterigopalatine fossa.46,47 Thus, these tumour types could
late that such metaplasia is a histopathological change potentially result from expansion of CSCs localized in
reflecting cellular and tissue responses to a chronic these particular regions.
inflammatorymicroenvironment. Sinonasal tumours could be hypothesized to derive
Squamous metaplasia and subsequent dysplasia are from CSCs capable of undergoing differentiation into
histological changes that precede the development of various cell types, rather than from differentiated, lineage-
SNSCC (Figure3cd).24 In addition, inverted papilloma specific cells that acquire stem-cell properties. Support-
is associated with a small proportion of SNSCCs; HPV- ing this suggestion, many sinonasal tumours have been
16 infection has been described in 38% of benign and described that demonstrate more than one histologi-
31% malignant tumours,17,18 suggesting that inverted cal appearance; for example, adenoid cystic carcinoma
papilloma is a precursor to this subset of SNSCCs. with adenocarcinoma or undifferentiated carcinoma, or
Table 2 | Genetic alterations in SNSCCs/ITACs, and possible targeted therapies adenocarcinomas that arise in patients with inflam-
Genetic aberration ITAC SNSCC Targeted therapeutic agents* matory bowel disease.63,64 Furthermore, mutations in
APC (encoding adenomatous polyposis coli protein) or
EGFR overexpression59,6668 2033% 40% Cetuximab and TKIs
CTNNB1 (encoding -catenin), key components of the
ERBB2 overexpression59,68 ND 37% Trastuzumab and TKIs Wnt cascade that are frequently mutated in colorectal
KRAS mutation 35,58,71,72
15% 1% Deltarasin cancer,65 have not been identified in sinonasal carcino-
Overexpression of ND 50% Sunitinib and TKIs mas.58 Thus, although activation of the Wnt pathway
VEGFR-encoding genes59,116 probably contributes to the development of certain
Overexpression of 36% ND Solithromycin ITACs, the specific mechanisms remain to be identified
NFKB-encoding genes29 and are likely to differ from those underlying the histolo-
FGFR1 amplification73 ND 20% Dovitinib gically similar spontaneous colorectal adenocarcinomas.
PTGS2 (also known as COX2) 4060% 8% NSAIDs In SNSCC, nuclear -catenin expression is rare and the
overexpression29 Wnt pathway is unlikely to have a role in the development
*The list of drugs is not exhaustive and only provides examples of specific agents or classes of agents of this tumour type (unpublished data, M.A.Hermsen).
that target the druggable genetic alterations demonstrated in SNSCC and ITAC to date. Abbreviations: Several studies have demonstrated EGFR overexpres-
ITAC,intestinal-type adenocarcinoma; ND, not determined; NFKB, nuclear factor KB; NSAIDs, non-steroid
anti-inflammatory drugs; SNSCC, sinonasal squamous cell carcinoma; TKIs, tyrosine kinase inhibitors; sion in about 40% of SNSCCs and in 2033% of ITACs
VEGFR,vascular endothelial growth factor receptor.
(Table2).59,6668 Again, these frequencies are lower than
those reported for the histologically similar head and
SNSCC with neuroendocrine carcinoma.48,49 Further- neck and colorectal cancers.69,70 Interestingly, EGFR
more, recurrent tumours can have a different histologi- mutations that have been observed in lung adenocarci-
cal type than the original primary tumour, with reports noma were not found in ITAC. 66 Overexpression of
of ITAC recurrence as undifferentiated carcinoma or HER2 (also known as ErbB2) has also been detected in
esthesioneuroblastoma.50 <10% of SNSCCs.59,68 Mutations in KRAS and HRAS,
The CSC hypothesis provides a model that accommo- which encode proteins downstream of EGFR in the EGF
dates the multiple causes of tumour heterogeneity.51 signalling pathway, have been found in approximately
Accord ing to this hypothesis, tumorigenesis can be 1% in SNSCCs and 15% of ITACs,35,58,71,72 whereas BRAF
considered as a dynamic and plastic process regulated mutations have not been detected in these tumours.71
by microenvironmental factors, rather than as a hier- In SNSCC, 21% of tumours overexpressed p16 INK4A
archical or static concept.52 The study of CSCs and the (also known as cyclin-dependent kinase inhibitor 2A),
tumour microenvironment might, therefore, have clini- and high expression levels of this protein were a surrogate
cal implications for sinonasal cancer, particularly as these marker of a subset of HPV-positive cases.18,73 Conversely,
cells have been implicated in disease recurrence and epigenetic silencing of p16INK4A was reported in 67% and
resistance to chemotherapy,5356 which are both notable loss of heterozygosity at the 9p21 locuswhich har-
characteristics of sinonasal carcinomas.1921 bours the gene encoding this proteinin 45% of ITAC
cases studied.33 Furthermore, microsatellite instability
Genetic characterization can occur in a small proportion of SNSCCs, but does
Sinonasal-cancer-related genes not seem to have a role in ITAC oncogenesis. 62,72,74 In
Studies of the involvement of specific genes in SNSCC addition, using fluorescence insitu hybridization, gene
and ITAC have often been guided by findings from amplification of FGFR1 and SOX2 was demonstrated
more-frequent and better-studied tumours with similar in 20% and 37% of SNSCC cases, respectively, whereas
histology, such as head and neck squamous-cell carci- 0% and 8% of ITACs had amplification of these genes,
noma and colorectal carcinoma, respectively. Mutation respectively (Table2). 73,75 Several studies have also
of the TP53 gene has been associated with exposure to reported NFB and COX2 overexpression in sinonasal
wood dust, with frequencies of TP53 mutation ranging carcinomas, particularly in ITAC, suggesting a role for
from 70% in SNSCC and up to 86% in ITAC. 33,34,57,58 chronic inflammation in tumorigenesis.29
Overexpression of p53 has also been reported in around
50% of SNSCCs and 72% of ITACs.29,33,5860 Interestingly, Genomic profiling of ITAC and SNSCC
the frequency of p53 overexpression seems to be mark- Genome-wide genetic studies have shown that both
edly lower in mucinous-typeITAC compared with the SNSCC and ITAC generally have complex, aneuploid
other ITAC subtypes.60 genomes that carry a wide variety and a large number
Aberration of the canonical Wnt signalling pathway has of chromosomal aberrations (Figure4),7679 similarly to
also been implicated in sinonasal cancer. Activation of most solid tumours. An exception is papillary-typeITAC,
this pathway, detected as nuclear expression of -catenin, which seems to be predominantly diploid with few
has been reported in 3153% of ITACs, with a higher pro- genetic aberrations.76,77 SNSCC and ITAC each have both
portion of activation of Wnt signalling observed in papil- shared and unique genetic abnormalities compared with
lary and colonic ITAC subtypes than in solid-type and other head and neck tumours, such as larynx, pharynx,
mucinous-typeITAC.6062 This proportion is, however, or oral cavity squamous-cell carcinomas, but have a con-
substantially lower than the 90% of sporadic colorectal siderably different genetic profile compared with salivary
adenocarcinoma that demonstrate activation of the Wnt gland tumours, which have characteristic chromosomal
pathway, but is similar to the 40% frequency in colorectal translocations and relatively few geneticchanges.48,80,81
a 5 are less frequent, but some have been reported at 1q, 5p,
7q, 8q2324, 12p, 13q14, and 20q.76,77
4 Using an expression array of 6,864 genes, and vali-
Tumour DNA:normal DNA log2-ratio
Chromosomes
18 20 22 This model suggests that development of mouse ortho-
topic models of SNSCC and ITAC might also be feasi-
Figure 4 | Microarray CGH analysis demonstrating profiles characteristic of SNSCC
and ITAC. The data for each chromosome are ordered continuously from left to ble. These invitro and invivo models, which retain the
right, pter to qter, as chromosomes 1 up to chromosomes X and Y (numbered as biological properties of sinonasal cancer,8486 are impor-
23 and 24, respectively), with the boundaries between chromosomes defined by tant tools for functional studies on the role of CSCs and
dashed vertical lines. All data points are expressed as tumour DNA:normal DNA processes such as proliferation, differentiation, invasion,
log2-ratios; a log2-ratio of 0 is interpreted as a normal copy number, and log2-ratios and metastasis in sinonasal tumours, and might facilitate
of >0 and <0 indicate copy-number gains and losses, respectively. a | CGH analysis the development and testing of new therapeuticagents.
profile of a DNA aneuploid, stage T4aN2bM0, poorly differentiated SNSCC of the
right maxillary sinus with copy-number alterations for most chromosomes. This
case demonstrates many of the recurrent alterations observed in SNSCC (arrows):
Sinonasal-cancer prognosis
high-level amplification at 3q263qter (including SOX2) and at 11q13 (including Independent of the treatment type used, the progno-
CCDN1, EMS1), copy-number gains at 7p, 8q, 17q, 19p, and 20q, and losses at 3p, sis of patients with sinonasal carcinomas is poor, with
8p, 13q, and 17p. b | CGH profile of a DNA aneuploid, stage T3N0M0, colonic- an overall 5-year survival rate of 3050% (Table1).1,2,5
typeITAC of the right ethmoid sinus with copy-number alterations in many The 5-year survival rates depend on disease stage and
chromosomes. This case demonstrates many of the recurrent alterations observed drops from 80% in patients with T1 disease to 30% in
in ITAC (arrows): copy-number gains at 5p, 7p, 8q, 12p, and 20q, and losses at 4q, patients with T4 tumours.1,2,5 Histological grade does
5q, 8p, 17p, and 18q. Abbreviations: CGH, competitive genomic hybridization;
not have prognostic value in patients with SNSCC;25,26
ITAC,intestinal-type adenocarcinoma; SNSCC, sinonasal squamous-cell carcinoma.
among patients with ITACs, however, papillary-type
and colonic-type tumours are associated with more-
In SNSCC, DNA copy number gains are found fre- favourable clinical outcome than the solid or mucinous
quently at chromosomal regions 3q, 7p, 8q, 11q13, 17q, subtypes.24 Molecular markers of poor prognosis include
19p, and 20q, with losses at 3p, 8p, 9p, 13q, 17p, 17q, and EGFR expression and HPV-negativity in SNSCC,17,18,59
18q, whereas recurrent DNA copy number gains in and p53 and nuclear -catenin expression in ITAC.57,61
ITAC genomes include 5p, 6p, 7p, 7q, 8q, 12p, and 20q, Local recurrence often occurs within 2years of follow-
and losses are commonly seen at 4q, 5q, 8p, 17p, and up and is the main contributor to sinonasal cancer
18q (Figure4).7679 Recurrent high-level amplifications mortality.19,21 Lymph node and distant metastases are
of chromosomal loci detected in SNSCC include 7p12, infrequent; however, sinonasal tumours should not be
11p13, 11q13, and 17q21, which contain the suggested considered exclusively as a locoregional disease and
candidate oncogenes EGFR, CD44, CCND1/CTTN, and wider anatomical imaging studies such as PET-CT can
ERBB2, respectively;78 in ITAC high-level amplifications help proper staging.
a FS b c
B FS
B
D O
O O
SS
*
* N * CL
M
PS
Figure 5 | Endoscopic surgery for the treatment of sinonasal tumours. a|Endoscopic nasal view of the anterior cranial
fossa during an endoscopic craniofacial surgery in a patient with ITAC. After debulking the tumour, the cribriform plate, the
dura mater (D), and the tumour implantation area are resected with proper tumour-free margins. The resection limits are:
the frontal sinus (FS), the planum sphenoidale (PS), and sides of the both orbits (O). The frontal lobes (asterisk), falx
cerebri (arrowhead), and dural resection margin (arrow) are indicated. b | Postoperative coronal CT image of a total
endoscopic resection of a bilateral ITAC showing one single sinonasal cavity (asterisk) free of tumour, leaving only the two
inferior turbinates and part of the septum directly below the sinonasal cavity. c | A postoperative sagittal CT image provides
an alternate view of the same resection (asterisk). Abbreviations: B, brain; CL, clivus; D, dura mater; FS, frontal sinus;
ITAC,intestinal-type adenocarcinoma; M, mouth; N, nose; O, orbit; PS, planum sphenoidale; SS, sphenoid sinus.
Precision radiotherapy
Another aspect of sinonasal-cancer therapy that has wit-
nessed undoubted improvements in the past decade is
radiotherapy.8,101 The main difficulty facing radiotherapy
for the treatment of sinonasal tumours, whether used
Figure 6 | Precision radiotherapy for the treatment of sinonasal tumours.
instead of surgery or postoperatively, is the low radi-
a|Coronal CT section showing the clinical target volumes for radiotherapy with ation tolerance of the nearby optical structures (eyes,
VMAT in a patient with a recurrent ITAC of the ethmoid sinus after endoscopic and optic nerves and chiasm) and other adjacent organs,
craniofacial resection. Clinical target volumes were 60 Gy (yellow contour) in the such as the lachrymal glands, the cochlea, the pituitary
high-risk subclinical disease area, and 66 Gy (red contour) in the tumour gland, the frontal and temporal brain lobes, the brain-
implantation area; isodose lines of 57 Gy (brown), 54 Gy (dark blue), 45 Gy stem, the spinal cord, the parotid glands, the mandible,
(mid-blue), 30 Gy (light blue), and 20 Gy (turquoise), as well as the optic nerves and the oral cavity (Figure1). New radiation techniques
(orange contours), are also shown. b | Axial CT section showing the VMAT
such as intensity-modulated radiation therapy (IMRT),
radiation-dose distribution in a patient with a T4bN0 ethmoid ITAC after endoscopic
craniofacial resection. Note the close vicinity of the 60 Gy clinical target volume volumetric modulated arc therapy (VMAT), tomo-
(redcontour) to the optic-system apparatus (eyes and optic nerves, indicated by therapy, and proton-beam therapy enable the achieve-
thegreen and orange contours, respectively). The lachrymal glands are shown ment of well-defined and steep dose gradients close to
bythe pink contours. Isodose lines of 57 Gy (brown), 54 Gy (dark blue), 45 Gy the target volumes.102105 The greater conformality of these
(mid-blue), 30 Gy (light blue), and 20 Gy (turquoise) are also depicted. Abbreviations: new techniques also results in a lower rate of radiation-
ITAC,intestinal-type adenocarcinoma; VMAT, volumetric modulated arc therapy. induced toxicity and increases therapeutic efficiency
compared with conventional approaches.102 Image-guided
and endoscopic surgical approaches. However, endo- radiation therapy (IGRT) has also been introduced
scopic techniques offer a number of advantages over to complement these approaches in ensuring the safe
open surgical methodologies: the endoscope enables a delivery of a highly conformal treatment, by facilitating
more direct approach to the tumour, without altering or convenient and frequent imaging of the patient anatomy
injuring healthy tissues; patient recovery is generally faster throughout the treatmentcourse.106
and less-complicated compared with open surgery; and Indeed, the precision of these sophisticated radiation
facial incisions are avoided, resulting in better cosmetic techniques stresses the importance of proper target
outcomes and the potential prevention of further compli- delineation during the planning process. Thus, a good
cations in irradiated tissues, including naso cutaneous understanding of the patterns of tumour spread and
fistula. To date, the results of many case series support the recurrence by the multidisciplinary teams involved in
endoscopic resection of malignant sinonasal tumours, the management of patients with sinonasal tumours
rather than open surgical treatment.88,96,97 Despite difficul- is required. Such knowledge facilitates not only surgi-
ties associated with standardization of reported outcomes, cal planning, but also the delineation of the treatment
asystematic review that included all types of sinonasal volumes for postoperative radiotherapy to avoid under-
malignancies indicated that the 5-year overall survival rate treatment of areas at risk of microscopic tumour inva-
was considerably increased among patients whounder- sion, while minimizing the radiation dose applied to the
went endoscopic surgery compared with those who unaffected tissues and vital organs (Figure6). With IMRT
were treated using open surgical approaches.98 In some and VMAT, microscopic tumour spread can be targeted
circumstances, however, an open surgical approach will around the site of the primary tumour and through-
be more appropriate than endoscopy, in particular, when out the lymphatic channels to the lymph nodes in the
the tumour (especially SNSCC) has infiltrated the orbital neck, as well as along other routes of dissemination.101
fat or extraocular muscles, orbital apex, the brain, or the In tumours with risk of perineural spread, the nerves at
facial skin, in which case special reconstructive surgery risk can be safely treated.101 Endoscopic surgery and CT
is needed. It must also be recognized that, when properly imaging can precisely define the tumour implantation
indicated, open surgery can be performed with limited site. For example, an ethmoid ITAC involving the whole
subsequent morbiditycertainly without the mutilation nasal cavity on CT scans could be pedicled at only a small
erroneously suggested in many papersand lowmortality. implantation area on the olfactory surface.
Given the new possibilities to deliver different doses not recommended because of toxicity concerns.107,110112
of radiation simultaneously to different anatomical areas Alternative therapeutic schemes for the treatment of
while minimizing the dose at adjacent normal tissues, sinonasal carcinoma are weekly intra-arterial infusions
further studies are need to address a number of clini- of cisplatin delivered rapidly to the tumour bulkwith
cal questions. Firstly, would a higher dose delivered to conventional external-beam irradiation in patients
the tumour implantation area improve local control withSNSCC. Despite encouraging organ-preservation
and patient survival? Secondly, would irradiation of the rates, these approaches have been associated with sub-
hypothetical location of the CSC niches, possibly respon- stantial toxicity, particularly those using intra-arterial cis-
sible for tumour maintenance and recurrence, increase platin and conventional intravenous chemotherapy.107,110
the therapeutic efficiency? Finally, could precision Good results have been reported for patients with ITAC
radiotherapy be applied to modify the microenviron- by combining surgical debulking and repeated topical
ment in the surgical field in a way that blocks or reduces chemotherapy with 5-fluorouracil. 114 Never theless,
the chance of residual tumour regrowth or reseeding of safer and more-effective adjuvant therapies for sino-
circulating tumour cells? nasal tumoursor induction therapies for unresectable
tumoursare clearly needed.
Chemotherapy The use of molecular markers predictive of response
Owing to the low incidence of these tumours, few clini- to adjuvant treatment in patients with sinonasal tumours
cal trials have been performed specifically in patients would represent an important therapeutic advance. For
with sinonasal carcinomas; therefore, chemotherapy or instance, chemotherapy was demonstrated to be highly
chemoradiotherapy protocols are usually administered effective in patients with ITACs carrying wild-type TP53,
by extrapolation of the approaches taken in similar, but ineffective in those carrying TP53 mutations.57 Some
more-common tumours, such as laryngeal-preservation biomarkers, such as low DNA excision repair protein
protocols. In addition, several institutions have experi- ERCC1 scores, have been shown to reflect favourable
mented with regional chemotherapy for sinonasal cancer, responses to chemotherapy.115 In addition, genetic pro-
mainly SNSCC, to try and minimize the complications filing of SNSCCs and ITACs have indicated a number
of radical surgical treatments. of frequently altered genes, such as those encoding
The classic indication for chemotherapy in sinonasal COX2, EGFR, ErbB2, FGFR1, NFB, B,
B, and VEGFR pro-
malignancies is the palliative treatment of patients with teins,29,58,59,6673,116 that could potentially be targets for
locally advanced or metastatic tumours when surgery and treatment with specific antibodies or small-molecule
radiotherapy are contraindicated or no longer control inhibitors (Table1). At present, however, no relevant
the disease effectively. However, new developments in case studies or clinical trials of such approaches to the
radiotherapy techniques have renewed interest in the treatment of sinonasal cancer have been published.
use of chemotherapy as a primary therapy for sinonasal
tumours. Chemotherapy can be used before, concurrent Future directions
with, or as an adjuvant to radiotherapy, depending on the As technology improves, robot-assisted surgery might be
tumour histology or the radiotherapy and chemotherapy the next breakthrough in sinus and skull-base surgery.
protocol used. Currently, patients with advanced-stage With increasing miniaturization of instrumentation to fit
SNSCC have been shown to respond to neoadjuvant the sinonasal area and skull base, imaging-guided, robot-
chemotherapy, and the response to this initial treatment assisted surgery will become more useful, less invasive,
might be predictive of the ultimate outcome of therapy and more precise. Improved radiation therapy techniques,
and prognosis.107 Evidence also suggests that concomi- such as proton-beam and light ions radiotherapy, could
tant radiotherapy and chemotherapy increases survival potentiallyowing to their physical characteristics
and enables locoregional control,108,109 but comparative reduce toxicity and achieve better quality-of-life, and
studies have not been performed and are, therefore, a might improve survival outcomes compared with the
requirement in the future; thus, at present, no clear statis- current standard methodologies; these possibilities might
tically significant survival benefit has been demonstrated be especially relevant in patients with tumours that have
for concomitant chemoradiotherapy versus neoadjuvant dural involvement or that affect structures such as the
chemotherapy protocols. optic nerves and/or chiasm, cavernous sinus, or carotid
The choice of chemotherapy regimen should be indivi- artery. The development of novel approaches to systemic
dualized based on patient characteristics and disease chemotherapy, intra-arterial chemotherapy, and molecu-
presentation. Among the varied regimens used in the lar targeted therapy (guided by genomic profiling of
treatment of sinonasal tumours, induction chemotherapy tumours), alone or in combination with other therapeutic
usually involves docetaxel, cisplatin, or 5-fluorouracil modalities (neoadjuvant, concomitant or adjuvant),
protocols.107,110112 Following induction therapy, weekly might contribute to improve disease control and minimize
carboplatin is used in concurrent chemoradiation proto- the associated morbidity if vital organs are affected.
cols.107,110112 In addition, targeted therapy with cetuximab
every 2 weeks in patients overexpressing EGFR has been Conclusions
described after induction therapy. 113 Cisplatin-based Sinonasal tumours arise in an anatomically complex
induction chemotherapy followed by chemoradiotherapy region of the body. Furthermore, the low incidence of such
with high-dose cisplatin administered every 3 weeks is tumours and their histological diversity have hampered
diagnosis, genetic analyses, classification, and staging, completed trials in patients with other more-common
and prevented the accumulation of clinical experi- tumours that have the same druggable genetic aberra-
ence at individual institutions. Nevertheless, the clini- tions. In addition, invitro and mouse models of sinonasal
cal management of these cancers has improved due to tumours have been developed and are now available for
advances in surgery and radiotherapy, although limited preclinicalstudies.8486
progress has been made in chemotherapy, partly owing Occupational exposure to wood and leather dust is
to the difficulty of recruiting a sufficient number of a strong aetiological factor for SNSCC and especially
patients for clinical trials. Importantly, however, because ITAC, possibly through tumorigenic pathways of chronic
of their distinctive characteristics, sinonasal tumours inflammation. Further investigation of this field is
should not be included in the miscellany of head and needed and might yield tools for chemoprevention (such
neck cancers, as occurs in many published case series. as anti-inflammatory drugs) and for early detection of
Moreover, SNSCCs and ITACs originate in different tumours in individuals at risk. In the case of SNSCC,
sinonasal sublocalizations, and both tumour types have routine HPV-testing in biopsies of patients with inverted
different clinical manage ment options. Many of the papilloma might also be advisable.
advances, improvements, and strategies discussed in this To provide the best possible care, patients with sino-
Review can be applied to other sinonasal tumours, such nasal cancer should be treated in clinical referral centres
as SNUCs, adenoid cystic carcinomas, neuroendocrine specialized in skull-base pathologies; such centres should
carcinomas, or esthesioneuroblastomas; however, these include a multidisciplinary team consisting of ENT sur-
tumours have different clinicopathological and molecu- geons, neurosurgeons, radiotherapists, medical oncolo-
lar genetic features, hence, the therapeutic strategies gists, and pathologists. Local hospital ENT physicians
used might have some peculiarities that would demand need to be aware of the possibility of sinonasal tumours
a separate review. despite their nonspecific symptoms. Outside of local
Currently, increasing knowledge of the genomics of clinical and referral centres, the study of molecular
sinonasal cancer enables a new approach to tumour tumorigenic pathways and the testing of alternative treat-
classification, which is more-refined than classic anato- ment strategies would greatly benefit from wider multi-
mical and histological grouping. Furthermore, genetic institutional collaboration, and we strongly support such
analyses comprising at least of a panel of druggable gene collaborative efforts.
products, if not genome-wide, would be a promising
addition to open up possibilities for targeted anticancer
therapy. On the basis of these advances, combined with Review criteria
the development of novel targeted therapies, personal- Data for this manuscript were obtained by searching the
ized therapeutic opportunities are becoming available. PubMed database for papers published before 27 January
In this context, the low numbers of patients with sino- 2014; the search terms used were sinonasal cancer,
nasal tumours such as SNSCC and ITAC who are avail- sinonasal squamous cell, sinonasal adenocarcinoma,
able for clinical trials might not be an issue, as targeted paranasal sinuses cancer, and nasal cavity.
OnlyEnglish-language articles were considered.
therapy could be based on the results of ongoing or
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