State of the Art Oncology in EuropeFont: aaa

Paranasal sinus cancer – 2015



1.1 Epidemiology

1.1.1 Incidence

Nasal cavity and paranasal sinus cancers comprise a small proportion of head and neck (H&N) cancers, representing about 5% of all H&N cancer patients. They are very rare cancers, with an incidence of about 1 case every 100,000, with an average age at comparison between 50 and 60 years (Youlden 2013). There are geographical differences in the occurrence of the disease, with the highest incidence in Eastern Europe and the lowest in the UK and Ireland. During the period 1999-2007, the incidence rate remained stable, being twice as high in males than in females (RARECAREnet).

1.1.2 Survival

Survival from nasal cavity and paranasal sinuses cancers in European adults diagnosed during 2000-2007 was 76% at one year after diagnosis and 47% at 5 years (RARECAREnet). Survival slightly reduces with age at diagnosis: 5-year survival was 51% in people who were under 65 years old at the moment of diagnosis and 42% in people aged +65 at diagnosis. (RARECAREnet; AIRTUM 2007).

1.1.3 Prevalence

In Europe, about 14,500 people are living with a diagnosis of an epithelial tumour of the nasal cavities and paranasal sinuses (Van Dijk 2012). This includes people who are considered cured, under treatment, or in clinical follow-up (15 years or more after diagnosis). Cured patients are estimated to comprise about 22% of the total, while patients in treatment or in clinical follow represent 21%, (Van Dijk 2012).

1.2 Environmental factors

According to the International Agency for Research on Cancer (IARC), occupational exposure to several agents contributes to carcinogenesis in the nasal cavities and paranasal sinuses, for some there is strong evidence (isopropyl alcohol production, leather dust, nickel compounds, radium, wood dust) and others are supported by only limited evidence (carpentry and joinery, chromium (VI) compounds, formaldehyde,textile manufacture (Charbotel 2014).
Epidemiological studies have consistently associated cancer of the nasal cavity and paranasal sinuses with wood dust, leather dust, nickel and radium (Demers 1995; d’Errico 2009; Grimsrud 2006; Carnes 1997; IARC 2013). Adenocarcinomas have been associated with wood dust, leather dust, and formaldehyde (Demers 1995; Luce 2002), whereas squamous cell carcinomas have been linked to arsenic and welding fumes (d’Errico 2009). The risk (odds ratio) of wood-related occupations of developing an adenocarcinoma was about 14 and increased to 46 in proportion to the quantity and duration of exposure (Gordon 1998).
Studies published in IARC Monographs starting in 1986 provide sufficient evidence to establish a causal association between cigarette smoking and cancer of the nasal cavities and paranasal sinuses, among the other cancer sites (IARC 1986; IARC 2004). The association was based primarily on epidemiological studies, conducted in different countries throughout the world.
The meta-analysis by Gandini et al reported a relative risk of 2.77 (95% CI: 2.17–3.54) for cancer of the nasal cavity in current smokers (Gandini 2008).

1.3 Pathogenesis

Several studies have established a causal role of exposure to hard wood dust and leather in the development of sinonasal cancer, with particular association with intestinal-type adenocarcinoma (Hayes 1986; Luce 2002).
In 2001-2003 it was estimated that about 3.6 million workers were occupationally exposed to inhalable wood dust in the European Union alone (Dulguerov 2006).
Wood dust is a complex mixture of organic and inorganic components, including genotoxic and carcinogenic factors (Hawkins 1988; Bhattacharyya 2002a). Its capacity to induce DNA damage has been attributed in part to its particulate nature, which induces the generation of reactive oxygen species in the cells (Chen 2007; Guntinas-Lichius 2007).
However there are few experimental data on cellular mechanisms of wood dust related sinonasal carcinogenesis (Hawkins 1988; Bhattacharyya 2002a).
In a retrospective review of 125 cases of patients with ethmoid adenocarcinoma, more than 90% had a history of wood- or leather-dust exposure, in contrast to 1.6% of patients with other types of sinonasal malignancies (Khademi 2009).
Other proposed aetiological factors include industrial fumes, exposure to nickel refining processes, mineral oils, chromium and chromium compounds, isopropyl oils, exposure to soldering materials or paint.
Although occupational agents are the most important aetiological factors for sinonasal carcinomas, some studies have observed an increased risk in association with cigarette smoking. Other studies, that have analysed squamous cell carcinoma and adenocarcinoma separately, reported that the relative risk associated with smoking was clearly higher for squamous cell carcinoma.

1.3.1 Biomolecular alterations

Little is known about the genetic alterations in human sinonasal cancer because of the rarity of this neoplasm. The majority of studies, despite being few in number, involve intestinal-type adenocarcinoma (ITAC). Molecular alterations seen in ITAC mainly focused on TP53, K-ras and H-ras gene mutations and EGFR or HER2 over-expression. Ras genes were found to be mutated only in rare cases (0-16% of the series), with conflicting reports about a possible prognostic role (Saber 1998; Pérez 1999; Perrone 2003). No BRAF mutations were identified (Lopez 2012a).
EGFR and HER2 are over-expressed in about 30% of cases (Franchi 2009).
TP53 gene alteration is a common event in head and neck carcinoma, which occurs in the early phases of neoplastic progression. The rate of TP53 mutations in ITAC is about 60% and it is significantly higher than in squamous cell carcinomas; TP53 mutation rate in ITAC is directly correlated with duration, average and cumulative level of wood dust exposure (Holmila 2010).
Sinonasal undifferentiated cancer (SNUC) has previously shown over-expression of cKIT in a limited number of cases but without corresponding activating mutations; moreover, over-expression of EGFR but no of HER2 has been reported (Chernock 2009). From a mutational point of view, SNUC has not been associated with mutations in a selection of 12 potentially oncogenes and tumour suppressor genes that may be targeted with currently available or emerging agents (Gelbard 2014).
EGFR and HER2 copy number in sinonasal squamous cell cancer (SCC) is increased in about 40% and 20% of the cases, respectively, and their occurrence is mutually exclusive; positivity to immunochemistry has been recently reported in 82% of the cases, harbouring a worse outcome (Takahashi 2014; Lopez 2012b).

Table 1. Molecular alterations and possible clinical meanings


Histologic subtype Gene Reported alteration Possible clinical application Reference
ITAC TP53 60% mutated If wild type: responsiveness to chemo Licitra 2004
Ras 0%-16% mutated Doubtful prognostic role Saber 1998; Pérez 1999; Perrone 2003; Lopez 2012a
EGFR-HER2 30% overexpressed Not specified Franchi 2009
SCC EGFR 82% IHC positivity worse outcome Takahashi 2014
40% overexpressed not specified Lopez 2012b
HER2 20% overexpressed not specified Lopez 2012b
HPV 10%-20% improved outcome Takahashi 2014; Alos 2009
FGFR1 20% amplification higher metastatic risk Schröck 2014
SNUC cKit 80% ICH positivity.
No activating mutation
Not clear Chernock 2009
HPV 7%-65% positivity Improved outcome? Gray 2015
Salivary gland-like cancer AR unknown Androgen deprivation therapy Higo 2007; Locati 2014
1.3.2 Role of Human Papillomavirus (HPV)

There is increasing evidence that the Human Papillomavirus (HPV) is associated with a subset of sinonasal carcinomas. HPV has been detected in about 30% of sinonasal carcinomas, as shown in a recent meta-analysis (Syrjänen 2013). HPV 16 seems to be the most frequent HPV type (Syrjänen 1987; Syrjänen 2003). Recent studies have reported a possible relationship between HPV infections and a subtype of sinonasal cancer: non-keratinizing carcinoma. However, current histological classification and the limited number of the published series do not strongly justify such an association. HPV positive cancers have been detected more in the nasal cavity than in paranasal sinuses and, from a pathogenetic point of view there is no clear progression from inverted papilloma to cancer.
The identification of HPV in sinonasal carcinomas has important clinical implications, because the presence of HPV could be a prognostic factor associated with a favourable outcome (Alos 2009).
Prospective trials are needed to better evaluate the pathogenic role of HPV and to draw conclusions regard the prognostic role of HPV.


Pathological examinations of sinonasal cancer often present difficulties in interpretation and differential diagnosis. There are several reasons for this: the rarity of the disease, the variety of histological types, the presence of overlapping pathological features with other entities, the high histological spectrum of differentiation among the same histological type, the difficulty in obtaining a pathological complete specimen – without fragmentation or degradation artifacts – which may also occur with new endoscopic techniques, and the sometimes confusing classification reported in published trials. In this regard, the importance of having a skilled pathologist or opportunity to access a second opinion in these rare cancers should be stressed.
In Table 2, a simplified classification, modified by the World Health Organization (WHO) classification, is reported.

 Table 2. Classification of nasal and paranasal sinus tumours (modified by the World Health Organization histological classification of nasal and paranasal sinus cancer). (Barnes 2005)


Type of tumour Subtypes
1. Malignant epithelial tumours
1.1. Squamous cell carcinoma Verrucous carcinoma
Papillary squamous cell carcinoma
Basaloid squamous cell carcinoma
Spindle cell carcinoma
Adenoid squamous cell carcinoma
1.2. Lymphoepithelial carcinoma
1.3. Adenocarcinoma Intestinal type adenocarcinoma
non-intestinal type adenocarcinoma
1.4. Salivary gland-type carcinoma Acinic cell carcinoma
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Polymorphic low-grade adenocarcinoma
Carcinoma in pleomorphic adenoma
Malignant myoepithelioma
Epithelial-myoepithelial carcinoma
Clear cell carcinoma
1.5. Neuroendocrine tumours Carcinoid tumours
Atypical carcinoids
Small cell carcinoma, neuroendocrine type
2. Malignant soft tissue tumours
2.1. Fibrosarcoma
2.2 Malignant fibrous histiocytoma
2.3. Leiomyosarcoma
2.4. Rhabdomyosarcoma
2.5. Angiosarcoma
2.6. Malignant peripheral nerve sheath tumour
3. Malignant tumours of bone and cartilage
3.1. Chondrosarcoma
3.2. Osteosarcoma
3.3. Chordoma
4. Neuroectodermal tumours
4.1. Ewing sarcoma
4.2. Primitive neuroectodermal tumour
4.3. Esthesioneuroblastoma
4.4. Melanotic neuroectodermal tumour of infancy
4.5. Mucosal malignant melanoma

2.1 Other pathological classification and particular histotypes

Sinonasal neuroendocrine cancers can be divided according to the different amount of neuroendocrine differentiation into well differentiated (typical), moderately differentiated (atypical carcinoids), and poorly differentiated (small and non-small cell types).
Sinonasal undifferentiated carcinoma (SNUC) has been described as a clinical-pathological entity with a surface epithelial-derived origin and undifferentiated characteristics. The presence of limited differentiated foci (i.e., squamous differentiation), as well as some grade of neuroendocrine characteristics, still allows classification as a SNUC without placing that specific tumour type into another tumour category (Ejaz 2005).
Esthesioneuroblastoma (or olfactory neuroblastoma) can be divided according to pathological features into 4 different grades (Hyam’s system). The grade of differentiation affects prognosis.
NUT (Nuclear protein of the testis) midline carcinoma is a very rare and aggressive tumour, whose diagnosis could be made on the bases on the chromosomal rearrangement of the gene encoding the NUT protein.


3.1 Signs and symptoms

Early symptoms of nasal cavity and paranasal sinus cancers, such as nasal obstruction, nasal discharge, epistaxis, and facial pain, are similar to those typical of inflammatory conditions; these complaints, therefore, may be overlooked for a long time by patients and clinicians, causing a significant delay in the diagnosis. Unilateral, persistent symptoms and absence of response to medical treatment must raise the suspicion of a sinonasal expansile lesion. Extension beyond the sinuses and nasal cavity, in addition to the aforementioned sinonasal symptoms, may cause neurological (headache, anaesthesia and/or pain in the territory of the trigeminal nerve, or smell disturbances), ophthalmological (exophthalmos, epiphora, diplopia, loss of vision) or dental (pain or mobility of maxillary teeth) symptoms. In such cases, the patient should be referred for nasal endoscopy or imaging. It has been estimated that a mean period of 6-8 months occurs between the onset of symptoms and rendering a definitive diagnosis and, at this time, more than half of the tumours have reached an advanced stage with a poor prognostic outcome (Bhattacharyya 2002a; Thorup 2010; Dulguerov 2001). Regional and distant metastases are not frequent even in presence of advanced stage tumours. Rates of cervical lymph node metastases at the time of initial diagnosis tend to vary across studies with a range of 3- 33% (Cantù 2008; Jiang 1991; Kim 1999). Distant metastases on initial presentation are even less common, with most series presenting an incidence of 1-7% (Dulguerov 2001).

3.2 Diagnostic strategy

The mainstay of clinical examination in patients with a suspected sinonasal expansile lesion is nasal endoscopy by flexible and/or rigid scopes. Nasal endoscopy allows visualisation of the lesion and may help in differentiating an inflammatory polyp from a neoplasm, benign or malignant. At endoscopy, unilateral expansile lesions with an irregular surface, necrotic areas, and contact bleeding should be considered as suspicious and possibly suggestive of cancer; it is however worth mentioning that endoscopic appearance per se is not exclusive to malignancy, since the same endoscopic features may also be observed in some benign neoplasms. Moreover, it is important to remember that inflammatory polyps may be associated with or hide an otherwise invisible tumour. Endoscopic evaluation may also allow, especially in those cases not completely filling the nasal fossa, identification or suggestion of the possible site of origin of the lesion, its local extension and to assess the presence of satellite lesions. Finally, the rigid scopes are essential to perform a guided biopsy under local anaesthesia; as a general rule, biopsy of a sinonasal lesion should only be performed after imaging evaluation has been completed, to minimize the risk of massive and uncontrolled bleeding in hypervascularised lesions. Examination of the oral cavity must be accomplished to evaluate the presence of areas of mucosal ulceration and possible oro-antral or oronasal communication; maxillary sinus tumours may also present as a submucosal swelling at level of the cheek, gingiva-buccal sulcus, alveolar process and/or hard palate. A recent history of an otherwise unexplainable tooth extraction or mobility should not be overlooked.

Figure 1. Post-contrast axial VIBE T1 (a); sagittal (b) and coronal (c-d) TSE T2; axial DWI (e-f).

In Figure 1, the ethmoid labyrinth is completely filled by solid tumor tissue (N) which shows contrast enhancement, though less bright than the mucosal lining of the air cells (ML, Figure a). The mass obstructs the left middle meatus and the maxillary sinus ostium (MO, Figure 1d), resulting in inflammatory changes in the sinus cavity (thickening of the mucosa with retained secretions). The sphenoethmoid recess is not clearly visualised, however, the sphenoid sinus (SS, Figures 1a-b) is completely filled by material with signal characteristics different from tumour, indicating chronically entrapped fluid. The left frontal recess (FR, Figure 1c) is narrowed by the vertical lamella of the middle turbinated (divergent arrows, Figure 1c), remodeled and laterally displaced by the mass; the hyperintense signal with the recess corresponds to inflamed mucosa. The orbit is not invaded: a continuous hypointense layer (created by bone and periosteum) creates a clear-cut separation between the tumour and the extra-conal fat pad (arrowheads, Figure 1d). Over the midline, the hypointense bone of the anterior cranial fossa floor is intact and both the olfactory bulb (OB, Figure 1b) and the surrounding hyperintense CSF are preserved; however, a minimal remodeling of the left ethmoid fovea (EF, Figure 1d) suggests the possibility of marginal intracranial spread. Despite its intrinsically poor anatomic detail, DWI technique (Figures 1e-f) provides additional information: the combination of high signal on b1000 (Figure 1e) and low signal on ADC map (Figure 1f) suggests a densely cellular, malignant lesion.
Whenever a history of a recurrent otitis media is reported, an endoscopic and imaging evaluation is mandatory to rule out a nasopharyngeal involvement with possible Eustachian tube obstruction.
All cervical lymph node stations must be palpated in order to look for neck swelling; it is worth remembering that, when dealing with sinonasal malignancies, the risk of nodal metastasis at presentation is very low with the exception of those lesions involving the oral mucosa and/or with aggressive histologic behaviour and high risk of lymphatic spreading (i.e., sinonasal undifferentiated carcinoma, high-grade olfactory neuroblastoma). In these cases, clinical evaluation of the neck must be completed by ultra sound (US) (with or without US-guided fine needle aspiration cytology – FNAC).
Clinical examination of cranial nerves (from I to VI) should be also performed. Proptosis with or without diplopia, may suggest orbit compression and possible intraorbital extension. Optic nerve and extrinsic muscle impairment may cause visual disturbance and ophthalmoplegia, respectively, and generally reflect orbit apex and/or cavernous sinus involvement. Trigeminal nerve numbness or hyperesthesia may be reported, especially in lesions extending into the pterygopalatine fossa and/or masticatory space, or directly involving the infraorbital branch of the maxillary nerve (V2) (Jégoux 2013).
Imaging studies are not used to characterise sinonasal tumours: only a minority of lesions display such a particular CT or MRI appearance to allow a reliable diagnosis; inverted papilloma (columnar pattern on MRI), melanotic melanoma (sometimes hyperintense on basal T1 sequences), juvenile angiofibroma (intense enhancement with intralesional vascular structures on both techniques), osteoma and fibrous dysplasia (CT hyperdensity) are some examples.
In the vast majority of cases, however, CT and MRI findings are so aspecific as to prevent not only the differentiation between different malignant histotypes, but even the discrimination among these ones and benign neoplasms or some inflammatory lesions.
Similarly, bone changes may be misleading. As a general rule, remodelling and distortion indicate a slow-growing benign entity, whereas erosion and destruction suggest malignant behaviour. Not infrequently, however, aggressive inflammatory lesions (chronic invasive fungal sinusitis, Wegener’s granulomatosis, myofibroblastic tumour) may mimic a malignancy.
Tumour staging essentially focuses on four issues, namely: orbital infiltration, anterior cranial fossa invasion, posterior extension to pterygopalatine and infratemporal fossa, and perineural spread.
The key element in the assessment of orbital invasion is represented by periorbital MRI (particularly on TSE T2 sequences) which identifies this periosteal layer as a hypointense line interposed between the hyperintense extraconal fat and the tumour, generally intermediate. Effacement of this barrier and the demonstration of an unsharp or nodular tumour/fat interface predict orbital invasion with high accuracy (Maroldi 1997). On the other hand, CT, being unable to detect this oncologic barrier, lacks accuracy whenever the mineralised component of bone is breached by the neoplasm.
Cranially, the interface between sinus cavities and brain is composed of three different elements: bone, dura and cerebrospinal fluid (CSF). TSET2 sequence offers excellent contrast between bone (hypointense), CSF (hyper) and olfactory bulbs and tracts (intermediate), hence providing accurate information on invasion of the ethmoid roof and infiltration of I cranial nerve. Dura is only visible after the administration of contrast; linear enhancement at the site of contact with the tumour is generally a reactive change whilst dural thickening (>5mm), irregular (nodular) profile or interruption predict infiltration, with sensitivity and specificity of 88% and 100%, respectively (Eisen 1996; Yousem 2006). Demonstration of intra-axial tumour growth is more challenging, brain oedema being the more reliable predictor of such an event. As in orbital assessment, CT findings are much less sophisticated: in particular the demonstration of subtle dural changes (essential for planning of surgical route and treatment) is hindered by the inherently inferior contrast resolution of the technique.
Posterior extension to the pterygopalatine and infratemporal fossa is shown equally by both CT and MRI. Bone lysis and erosion are quite often associated with partial or complete effacement of fat pads in both fossae and encasement of the sphenopalatine artery (appearing as a contrast filled serpiginous structure or, on MRI SE sequences, as a signal void).
Perineural tumour spread along named cranial nerves manifests as thickening or altered enhancement of a nerve segment, widening or erosion of skull base foramina and fissures, enlargement and bulging of the cavernous sinus. Detection on MRI requires contrast administration and high-resolution acquisition, best obtained with 3D isotropic sequences with submillimetric pixel size. CT demonstrates segmental changes in nerve tracts surrounded by fat pads, but may miss perineural spread in a foraminal segment when bone is intact. This is due to the blooming artifacts produced by the high density of skull base bone, which may partially (or even completely) efface the density of soft tissue structures contained in the foramen of fissure (Moonis 2012).
Perineural spread along motor branches may also be indirectly heralded by denervation atrophy of muscles, easily detected with both techniques as fatty replacement and, in the subacute phase, enhancement of muscle.
The evaluation of follow-up scans of patients treated for sinonasal malignancies requires detailed knowledge of treatment. Surgery (both resection and reconstruction) and, to a lesser extent, chemoradiation significantly remodel the anatomy; thus, the first step in the interpretation is the consideration of the expected changes (Farina 2010).
The superior contrast resolution of MRI can be exploited, for example, to unravel the different layers used to separate the nasal cavity for the anterior cranial fossa after open or endoscopic craniofacial resection. Surgery and chemoradiation also produce variable amounts of scar tissue – again, MRI has greater potential in the differentiation between scar, complication, and recurrence. The wide array of pulse sequences available (including DWI) allows collection of information quantitatively and qualitatively superior to that obtained with multislice CT (MSCT).
Functional imaging (PET-CT and the newly emerging PET-MRI) plays an essential role during follow up of advanced tumours, because they allow whole body survey of the disease. The high negative predictive value of the technique allows recurrent tumours to be safely ruled out, whereas positive studies need to be viewed cautiously, in conjunction with clinical examination, endoscopic assessment, and focused biopsies, given the high rate of false-positive studies (Lamarre 2012).

3.3 Pathological diagnosis

Biopsy and histopathological examination are mandatory for a correct diagnosis. Using endoscopic biopsy, a small piece of the suspicious area can be removed through the endoscope. This procedure is generally performed under local anaesthesia, but general anaesthesia is sometimes requested. If the suspicious area is in the paranasal sinus cavity, the surgeon may need to cut into the sinus through the bones to reach it. A small piece of the tumour is cut out and removed for examination (incisional biopsy). A fine needle aspiration by use of a thin needle inserted into a lump to remove cells may be used to check a lump in the neck, or to see if the nasal cavity or paranasal sinus cancer has spread to the lymph nodes in the neck (cervical lymph nodes).


Classification of paranasal sinus carcinoma poses a great challenge, due to the complexity of the anatomical site and the heterogeneity of the tumours. The Union Internationale Contre le Cancer/American Joint Committee on Cancer (UICC/AJCC) classification is the most commonly used staging system. It employs the concept that different prognostic values should be applied for tumour involvement of the anterior orbit and the apex. The seventh edition of this classification includes two different grouping systems, one for carcinoma of the maxillary sinus and one for malignant tumours of the ethmoid sinuses and the nasal cavity, thus finding a solution for the difficult distinction of the site of origin of tumours of these two regions. This classification divides T4 lesions into T4a (moderately advanced local disease) and T4b (very advanced local disease), leading to the stratification of stage 4 into stage 4A (moderately advanced local/regional disease), stage 4B (very advanced local/regional disease), and stage 4C (distant metastatic disease) (Patel 2009). While the TNM classification for tumours arising in the maxillary sinus has been examined, the prognostic quality of the TNM classification and the stage grouping for tumours of the ethmoid sinuses and the nasal cavity is not as well established. Recently, Kreppel stated that the UICC-stage grouping of the sixth edition is a good prognostic index for malignant tumours of the ethmoid sinuses and the nasal cavity (Kreppel 2013). Besides, the 7th edition of the AJCC staging of head and neck cancers includes mucosal malignant melanomas, approximately two-thirds of which arise in the sinonasal tract (Table 3).

 Table 3. UICC classification – Seventh edition. (Patel 2009)


Type of tumour Stage
For all carcinomas excluding mucosal malignant melanoma
Primary tumour: Maxillary sinus Tx: Cannot be assessed
T0: No evidence of primary tumour
Tis: Carcinoma in situ
T1: Tumour limited to the maxillary sinus mucosa with no erosion or destruction of bone
T2: Tumour causing bone erosion or destruction including extension into the hard palate and/or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates
T3: Tumour invades any of the following: bone of the posterior wall of maxillary sinus, subcutaneous tissues, floor or medial wall of orbit, pterygoid fossa, ethmoid sinuses
T4a: Tumour invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid or frontal sinuses
T4b: Tumour invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx, or clivus
Primary tumour: Nasal cavity and Ethmoid sinus Tx: Cannot be assessed
T0: No evidence of primary tumour
Tis: Carcinoma in situ
T1: Tumour restricted to any one subsite, with or without bone invasion
T2: Tumour invading two subsites in a single region or extending to involve an adjacent region within the nasoethmoidal complex, with our without bone invasion
T3: Tumour extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate
T4a: Tumour invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses
T4b: Tumour invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2),
nasopharynx, or clivus
Regional lymph nodes Nx: Cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral nodes, none more than 6 cm in greatest dimension
N2a: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3: Metastasis in a lymph node more than 6 cm in greatest dimension
Metastases at level VII are considered regional lymph node metastases. Midline nodes are considered ipsilateral nodes
Distant Metastasis M0: No distant metastasis
M1: Distant metastasis
For Mucosal Malignant Melanoma
Primary Tumour T3: Mucosal disease
T4a: Moderately advanced disease. Tumour involving deep soft tissue, cartilage, bone, or overlying skin
T4b: Very advanced disease.
Tumour involving brain, dura, skull base,
lower cranial nerves (IX, X, XI, XII), masticator space,
carotid artery, prevertebral space, or mediastinal structures
Regional Lymph Nodes Nx: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastases
N1: Regional lymph node metastases present
Distant Metastasis M0: No distant metastasis
M1: Distant metastasis
Stage groupings for all cancers
except mucosal malignant melanoma
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T1 N1 M0
Stage III T2 N1 M0
Stage III T3 N0, N1 M0
Stage IVa T1, T2, T3 N2 M0
Stage IVa T4a N0, N1, N2 M0
Stage IVb T4b Any N M0
Stage IVb Any T N3 M0
Stage IVc Any T Any N M1
Stage groupings for mucosal malignant melanoma
Stage III T3 N0 M0
Stage IVa T4a N0 M0
Stage IVa T3-T4a N1 M0
Stage IVb T4a Any N M0
Stage IVc Any T Any N M1

Besides the UICC classification, various staging systems have been proposed for ethmoid tumours. Dulguerov and Calcaterra distinguish between tumours that do not involve the most superior ethmoid cells (T1) and those that extend to or erode the cribriform plate (T2), but include generically in the T3 category tumours invading the orbit without a distinction between tumours with invasion in the anterior two thirds of the orbit and those with orbit apex involvement. This classification has been proposed only for esthesioneuroblastomas (Dulguerov 1992). The advantage of this classification is that tumours are classified taking into account lymph node involvement and distant metastases. For esthesioneuroblastoma, Kadish and his co-workers, from the Massachusetts General Hospital, proposed a classification system based on their experience into three groups:

  • group A: extension to the nasal cavity only;
  • group B: extension to the nasal and paranasal cavity;
  • group C: extension beyond the paranasal cavity (Kadish 1976).

However, the inadequacies of this classification have been pointed out by several authors (Dulguerov 1992; Dulguerov 2001; Bachar 2008). Finally, Cantù et al. proposed their classification (INT staging) for malignant ethmoid tumour based on the most commonly accepted unfavourable prognostic factors involvement of dura mater; intradural extension; involvement of the orbit and, in particular, of its apex; invasion of maxillary, frontal, and/or sphenoidal sinus; and invasion of the infratemporal fossa. They evaluated 123 consecutive patients undergoing craniofacial resection for malignant ethmoid tumours involving the anterior skull base with a mean follow-up of 60 months. The prognostic difference among INT stages was statistically significant and more reliably correlated with various survival outcome as compared with 1977 staging system (Cantù 1999).


Various potential prognostic factors affecting disease-free, local and overall survival have been investigated in the literature. In a series of 220 patients, Dulguerov found that T classification, histology, localization and treatment were independent prognostic factors for survival. The 5-year actuarial specific survival were 91%, 64%, 72%, and 49% for patients with T1, T2, T3, and T4 tumours, respectively; 78% and 60% for patients with adenocarcinoma, and undifferentiated carcinoma, respectively; 77%, 62% and 48% for tumours of the nasal cavity, maxillary sinus, and ethmoid sinus, respectively.
Considering histology, in an international collaborative study on craniofacial resection for malignant paranasal sinus tumours, squamous cell carcinoma and adenocarcinoma, were found to have a similar outcome for overall survival, even though a better disease-specific and recurrence-free survival was observed for adenocarcinoma. In contrast, olfactory neuroblastoma may be associated with late local relapses, appearing many years after primary treatment, while adenoid cystic carcinoma displays some characteristic features, such as perineural spread, slow growth, and frequent distant metastasis (Ganly 2005). In addition, the authors found that the status of surgical margins, intracranial extent and orbital involvement were prognostic factors of overall, disease-specific, and recurrence-free survival. Moreover, Dulguerov included among local factors that were associated with a worse prognosis the extension to the pterygomaxillary fossa, extension to the frontal and sphenoid sinuses, the erosion of the cribriform plate, and invasion of the dura (Dulguerov 2001). Finally, several publications have reported that the presence of neck metastases at presentation is also associated with poor prognosis and usually indicates tumour extension outside the sinonasal cavity (Koivunen 2012; Blanch 2004; Mirghani 2014).
By contrast, evidence of neural invasion that is reported to be associated with positive margins and maxillary origin is not an independent predictor of outcome (Gil 2009). With regard to biological parameters, Airoldi et al, by analysing data from 179 consecutive patients, found a strong association between Ki-67 expression and microvessel density and overall survival (p =0.05 and p =0.039, respectively), while VEGF-C was a prognostic factor in squamous cell carcinoma patients only (p =0.05) (Airoldi 2009).
Hyams grading confirmed to be a prognostic indicator in a large series of esthesioneuroblastoma (Bell 2014). In addition to stage and histology, treatment is a very important clinical prognostic factor. Surgery and radiotherapy alone rarely cures these tumours. In fact, a significant survival gain has been observed over recent decades with the postoperative radiotherapy following surgery, but not with other treatment modalities. Survival rates were 79% for patients who underwent surgery alone, 66% for patients who were treated with a combination of surgery and radiation, and 57% for patients who were treated exclusively with radiotherapy (Dulguerov 2001). Regarding radiotherapy dose, Hoppe et al. reported that a radiation dose ≥ 65 Gy was the only significant prognostic factor predicting improvement in local control and overall survival in unresectable cases (Hoppe 2008).
In the postoperative setting, a total dose of at least 60 Gy following incomplete surgery (close or positive margins) can provide satisfactory local control for patients with squamous cell carcinoma of the maxillary sinus (Kawashima 2001). Concerning radiotherapy technique, postoperative intensity modulated radiotherapy (IMRT) is suggested by some authors (Dirix 2010; Chargari 2009; Combs 2006; Duthoy 2005). These studies demonstrated an improved survival with IMRT compared to historical series without IMRT. Moreover, a meta-analysis showed an increase in local control of tumour with proton ion therapy compared to photon RT (p =0.035) (Ramaekers 2011); more recently, a systematic review and meta-analysis confirmed the better outcomes obtained with charged particle therapy in comparison with photons, in overall and disease free survival, even if the need for larger prospective trials should be emphasized (Patel 2014).


6.1 Radiotherapy

No standard treatment has been reported, given the rarity of the condition, the absence of prospective studies and the heterogeneity of histology and disease stages.
In the absence of such Class I evidence, therapeutic decisions must be made on the basis of retrospective studies.

6.1.1 Early stage disease

T1 tumours of maxillary sinus are preferentially treated by surgery alone. Postoperative radiotherapy is indicated when the surgical margin is close or positive, in cases of histological features suggestive of intrinsic aggressiveness (i.e., perineural spread, vascular emboli) or unfavourable histology, i.e., adenoid cystic carcinoma (Nicolai 2007; Seong 2014).

6.1.2 Locally advanced disease

In more advanced resectable tumours, surgery plus radiotherapy, with or without chemotherapy, has been the usual approach (Hu 1982; Lindeman 1987; Sisson 1989; Waldron 2003). In a publication from a collaborative study group, Ganly reported that a preoperative radiation therapy in patients requiring craniofacial resection had a negative impact on recurrence-free survival, with a 1.6 increase in relative risk of recurrence compared with no previous radiation (Ganly 2005). Probably, the assessment of the extent of surgical resection required to obtain clear margins might have been more difficult in the previously irradiated patients. Thus, radiotherapy is generally given in the postoperative setting. Unresectable cases are generally treated with definitive RT or radiochemotherapy (CRT).
The proximity or involvement of several critical structures (i.e., dura, brain, middle cranial fossa, clivus, optic nerves, orbit, optic chiasm) and the horseshoe-shaped target volume – including in selected cases cervical nodal levels – make these cancers optimal candidates for modern RT techniques, such as Intensity Modulated Radiation Therapy (IMRT) either as in adjuvant with surgery or as a primary therapy. Historically, RT delivered via conventional techniques has been associated with significant complications. Severe visual toxicity has been observed with unilateral and bilateral blindness rates reported to be as high as 30% and 10%, respectively (Katz 2002; Parsons 1994; Takeda 1999). Subsequent improvements in three-dimensional conformal RT (3D-CRT) techniques appeared to reduce the risk on optical pathways, but not to modify outcome with respect to conventional RT (Gabriele 2008; Roa 1994; Pommier 2000). The 18-year experience from Memorial Sloan-Kettering Cancer Centre in 85 patients concluded that severe ophthalmic toxicities were not observed in any of the 53 patients receiving postoperative 3D and IMRT (Hoppe 2007).
Another opportunity to compare treatment techniques comes from Chen et al., who reported the results of 127 patients who underwent radiotherapy with planning and delivery techniques available between 1960 and 2005. A total of 59 patients received conventional radiotherapy; 45 patients 3D-RT, and 23 patients IMRT. Most of these patients were treated with radiotherapy after gross total tumour resection for squamous cell carcinoma. Even if there were no significant differences in survival and tumour control with respect to decade of treatment or radiotherapy technique, the incidence of complications had significantly declined, resulting in an improved therapeutic ratio (Chen 2007). IMRT significantly preserved vision as compared with three-dimensional conformal or conventional radiotherapy (Grade 3 late ocular toxicity in 0%, 9%, and 20%, respectively).
An important feature of IMRT for sinonasal cancer is the ability to prevent “dry eye syndrome”, a well-documented complication of conventional radiotherapy.
Although a more precise administration of RT treatments is currently possible due to the advances in imaging and treatment planning, radiation-induced side effects to healthy structures still remain a strong concern. Recently, the use of charged particle therapy, such as protons or carbon ions, has gained particular interest. Their physical advantage consists in the absence of exit dose, which offers the opportunity for higher conformal dose distributions and greater sparing of normal tissue compared to photon therapy allowing an escalation of dose, in order to increase tumour control and survival, with lower incidence and lower severity of toxic effects.
Two recent meta-analyses showed an increase in disease control with charged particle therapy compared to photon RT (Ramaekers 2011; Patel 2014), both in treatment-naive cohort patients (both primary and adjuvant radiation therapy) and in patients with recurrent disease. In particular, a subgroup analysis by Patel showed a significantly higher disease-free survival at 5 years (relative risk 1.44, 95%CI 1.01-2.05; p=0.045) and loco-regional control at longest follow-up (p=0.011 with proton therapy compared to IMRT). The use of particle therapy can potentially help in organ preservation strategies when exenteratio orbitae is planned by surgeon. However, the comparison of the overall (acute and late) occurrence of toxic effects induced by charged particle therapy vs. photon therapy revealed that there were more significant neurological side effects in the charged particle therapy group than in the photon therapy group (p=0.0002), probably because of a greater proportion of anatomically challenging cases referred to charged particle therapy institutions and a higher proportion of studies about charged particle therapy toxic effects. No differences were found with respect to other types of morbidity (Patel 2014).
More data about acute and late adverse events are needed before being able to draw a conclusion about safety and efficacy of charged particle therapy.


6.1.3 Unresectable disease

Definitive RT or radiochemotherapy (CRT) represent the usual treatment approach for unresectable paranasal sinus cancer. Outcomes following IMRT treatments for patient with PNSC staged IVB are rarely reported (Hoppe 2008; Duthoy 2005). In one study, Hoppe et al. reported that a radiation dose ≥65 Gy was the only significant prognostic factor predicting improvement in local control and overall survival, stressing the need for further dose escalation (Hoppe 2008). However potential treatment-related toxicity has so far limited attempts of dose escalation. Recently, Orlandi et al. reported that volumetric modulated arc therapy (VMAT) could offer significant improvement of treatment for all unresectable PNSCs over existing IMRT techniques. This was particularly evident for patients with sinonasal cancers and involvement of the nodes in whom large volumes and complex/irregular shape have to be irradiated, even if clinical benefit has yet to be established (Orlandi 2014).
Proton or carbon ion therapy may represent an advantage in treating these patients, since they can achieve an increased biologically effective dose without increasing the dose to neurological structures (Zenda 2011; Jensen 2011). Unfortunately, this form of radiotherapy is not yet commonly available.

6.1.4 Radiotherapy technical notes Target volume and doses

It is recommended on a type C basis that the planned target volume of irradiation is delineated. Radical radiotherapy

A compartment-related definition should be adopted for target volume definition in 3D and IMRT treatments. It is based on MRI imaging as follows: in regions where macroscopic disease is flanked by intact bone or by cranial nerves, no margin is added to obtain high risk target volume; in regions where macroscopic disease invades compartments enclosed by bone, such as other paranasal sinuses, or extended up to their ostia, the whole compartment is included in the high risk volume; in those regions where macroscopic disease invades radiologically defined spaces known to be poorly resistant to invasion of malignant tumours (e.g., masticator or parapharyngeal spaces), and where macroscopic disease invades the orbit or extends intracranially, either the entire space or a margin of 0.5-1.0 cm is added to visible disease edge (Claus 2001).
If perineural invasion is reported, this volume can be larger than the former, including the base of skull and foramina (intermediate risk volume). In stages N2a-b, node(s) adjacent to involved node(s) should be included in high-risk volumes. In case of clinically positive monolateral neck nodes, uninvolved ipsilateral nodes could be included in an intermediate risk volume.
An elective nodal volume can be considered in some clinical situations (see paragraph “Management of the clinically negative neck”).

  • High risk volume, 66-70 Gy/ 2 Gy-fraction;
  • Intermediate risk volume, 60 Gy/ 2 Gy-fraction;
  • Low risk volume, 50-54Gy/ 2 Gy-fraction. Postoperative radiotherapy

For patients who have undergone macroscopically complete surgical resection, postoperative target volume consists of the edges of resection plus a variable margin according to the principles of a “compartment-related volume” as described above (Claus 2001). If perineural invasion is reported, this volume can be larger than the former and the inclusion of the base of skull and foramina is recommended (intermediate risk volume). If multiple nodes with ECE are found, high-risk volume should include these nodes. If nodes are without ECE, adjacent node levels should be included in the volume of intermediate risk. An elective nodal volume can be considered in some clinical situations (see paragraph “Management of the neck”).

  • High risk volume (R1, ECE+), 66 Gy/ 2 Gy-fraction;
  • Intermediate risk volume, 60 Gy/ 2 Gy-fraction;
  • Low risk volume, 50-54Gy/ 2 Gy-fraction.
6.1.5 Management of the clinically negative neck with radiotherapy

Management of the clinically N0 neck is debatable. A relativity high rate of failure in the clinically N0 neck has been reported in several retrospective series. Rate of cervical nodal involvement depends on anatomical site and histology. When the neck is not treated electively, the reported rate of failure ranged from 9% to 33% (Le 2000; Paulino 1997; Jiang 1991). In 2008, Cantu et al. reported 704 cases of paranasal sinus cancer treated between 1968 and 2003 and reported an analysis of nodal involvement. With regard to squamous cell carcinoma, high incidences of nodal metastasis were found for T2 stage of the maxillary sinus. This last finding is not in agreement with other authors. In fact, Le et al. recommended elective nodal irradiation in patients with T3-T4 squamous cell carcinoma (Le 2000). This recommendation is endorsed by Snyers et al (Snyers 2009). By contrast, Paulino recommended ipsilateral neck irradiation in all T stage SCCC of the maxillary sinus (Paulino 1997).
In cases of undifferentiated carcinoma, Tanzler et al. (Tanzler 2008) proposed that the entire neck should be electively irradiated in patients with a clinically negative neck, because of the high risk of subclinical regional disease. In cases of esthesioneuroblastoma, as in squamous cell carcinoma, management of the neck is controversial. However, several authors found that elective neck RT is effective in preventing cervical recurrences and recommended that it should be considered in all patients with Kadish Stages B and C (Monroe 2003; Demiroz 2011). In cases of adenocarcinoma, Cantu et al. reported a 2 year and 5-year nodal relapse incidence > 20% (Cantù 2008). This can suggest a prophylactic cervical nodal irradiation. Finally, in cases of adenoidocystic carcinoma, no cervical irradiation is recommended (Garden 1995). Regarding nodal volume extension, regardless of histological type, levels IB, II, III and the lateral retropharyngeal node should be included in the elective nodal volume (Cantù 2008; Guan 2013; Maghami 2004).

6.1.6 Recurrent disease

The first and predominant site of treatment failure in paranasal sinus and nasal cavity cancer remains in the treatment field (Chen 2007; Hoppe 2008). Given the rarity of this pathology, few cases of recurrent sinonasal cancer are reported among heterogeneous series of head and neck cancer recurrences. Only about 20% of these patients are candidates for curative salvage surgery, since recurrent disease usually spreads extensively and involves critical organs. When treated with salvage surgery alone, treatment outcome for more advanced recurrent stages is worse (Mabanta 1999). Furthermore, patient’s quality of life could be impaired because of the possibility of severe postoperative dysfunction. Regional recurrences can be treated successfully with neck dissection, with or without postoperative radiotherapy, depending on pathologic features. Chemotherapy alone produces nondurable responses and is reserved for palliation (Gibson 2005). Treatment options are limited for tumours that occur after combined modality therapy. Many authors have investigated reirradiation with or without chemotherapy delivered by standard conventional fractionation; the reported 3-year overall survival rate is only 10-20% and the local control rate is 20-30% (Langendijk 2006; Kasperts 2006). Better overall survival and local control using reirradiation plus chemotherapy has been reported by multi-institutional prospective trials, but with 8% of treatment-related deaths and high incidence of Grade 4 or higher toxicities (Spencer 2008; Langer 2007). Newer techniques such as Image-Guided IMRT and salvage stereotactic radiosurgery using CyberKnife, delivering very precise radiotherapy to the designated target volume, resulted in feasible and effective results for the reirradiation of local recurrence of nasal and paranasal carcinomas (Thiagarajan 2011; Roh 2009; Iwata 2012). Cumulative doses of radiotherapy to neural tissues (spinal cord, brainstem, brain, optic structures) are the main limitation to reirradiation.


The role of chemotherapy in paranasal cancer sinus tumours is considered within multimodal treatment with curative purposes, or as single therapeutic modality in the palliative setting.

6.2.1 Curative purposes

There are some suggestions that trimodality treatment comprising chemotherapy, surgery and radiation could exert the highest effect on locally advanced paranasal sinus cancer with epithelial non-glandular histologies. Due to the rarity of the disease, this trimodality approach is suitable for individual clinical use on a type R basis.
Timing of this approach has not been strictly defined. Induction chemotherapy followed by concurrent chemotherapy with a radiosensitizing effect have been employed in small trials (Rosen 1993; Lee 1999; Musy 2002; Mendenhall 2009; Hanna 2011) and can be suggested for individual use on a type R basis. Favourable response to induction chemotherapy is a strong prognostic factor (Hanna 2011; Licitra 2003; LoRusso 1988). In the specific case of intestinal type adenocarcinoma showing functional p53 status, the employment of induction chemotherapy with cisplatin, 5-fluorouracil and leucovorin can be employed as neoadjuvant treatment before surgery, showing high response rate and better prognosis in comparison to historical controls receiving surgery as first treatment (individual clinical use, level of evidence 3) (Licitra 2004; Bossi 2013).
Other therapeutic strategies employed concurrent chemoradiation followed by surgical resection or the employment of intra-arterial cisplatin chemotherapy followed by locoregional treatment (Papadimitrakopoulou 2003; Samant 2004; Homma 2009), that should be considered for individual use on a type R basis.
There is histological evidence showing higher response rates (ranging from 36% to 84%) to chemotherapy in the induction setting, in nasal cavity subtypes such as SNUC, SNEC, small cell carcinoma of neuroendocrine type, squamocellular cancer and ITAC where there is functional p53.
Most chemotherapy schemes are platinum-based, in association with 5-fluorouracil or a taxane; ifosfamide, etoposide, cyclophosphamide, doxorubicin and vincristine have been also included within polychemotherapy treatments.
In selected cases, when disease is close to orbital structures, the employment of chemotherapy could theoretically provide an organ preservation strategy, followed by radiation or chemoradiation. This conservative approach should be considered for individual use on a type R basis and further trials are required to justify such a therapeutic strategy.
Unresectable diseases, due to the extension into structures that cannot be removed, are treated with a combination of radiation and chemotherapy.
The employment of different radiotherapy techniques or energy levels is described in the specific paragraphs.

6.2.2 Palliative setting

Chemotherapy may be employed in patients with local-regional recurrence not amenable to surgical salvage or reirradiation, with palliative intent, for individual use, level of evidence 3. There are no trials comparing chemotherapy with best supportive care in this setting.
The choice of giving chemotherapy or not depends on performance status, age, previous treatment received, time to disease recurrence and amount of benefit expected from systemic treatment.
The type of chemotherapy to be employed is based on intrinsic chemosensitivity of each single histological type.

6.2.3 Treatment by histological type

In the following paragraphs, the role of chemotherapy either added to locoregional treatment or employed as palliative therapy is analysed, considering individual histological types, when the rarity of disease allows the evaluation of homogeneous series. The main focus is on malignant epithelial tumours. Esthesioneuroblastoma

Response to chemotherapy of this histotype is related to tumour dedifferentiation , with higher grade tumours more responsive to systemic therapy. The chemotherapy employed is platinum-based (McElroy 1998).
A small retrospective trial postulated the possibility of adopting an adjuvant chemotherapeutic therapy in higher-grade tumours and those of an advanced stage after locoregional treatment. This strategy is suitable for individual use on a type R basis (Porter 2008). SinoNasal Undifferentiated Cancer (SNUC)

SNUCs have a high local aggressiveness and a greater propensity to metastasise than other histologies. It is therefore logical to adopt a therapeutic approach that maximizes the benefit of anticancer drugs administered systemically.
Recently, a meta-analysis of published trials on SNUCs found the adjunct of chemotherapy and/or radiation to surgery was able to achieve an improved survival, especially in locally or regionally advanced stages (Reiersen 2012); this approach is recommended for individualized use on a type 3 basis. The most suitable approach in locally advanced cases is the employment of induction chemotherapy (platinum-based), followed by surgery and postoperative radiation, as witnessed by some trials showing the feasibility and the activity of this multimodal treatment (Musy 2002; Rischin 2004; Mourad 2013). Response to induction chemotherapy was a favourable prognostic factor. Most commonly employed chemotherapeutic agents with cisplatin were doxorubicin and vincristine, or docetaxel and 5-fluorouracil. Sinonasal NeuroEndocrine Carcinoma (SNEC)

Survivals similar to those achieved in SNUC were noted in sinonasal neuroendocrine cancer (SNEC), which can also potentially benefit from systemic treatment, by virtue of the local aggressiveness and the increased risk of systemic dissemination (Rosenthal 2004). This approach could be suggested for tumours with higher proliferation activity, for individualized use with a type R evidence.
An approach using induction chemotherapy with cisplatin and etoposide, followed by radiotherapy or surgery in unresponsive cases, showed good survival (74% at 5 years) in a prospective study with a mixed series including esthesioneuroblastoma and neuroendocrine carcinomas (Fitzek 2002).
Despite the use of integrated strategies also including chemotherapy, even in limited cases, the prognosis is worse for small-cell carcinomas, with an higher rates of distant metastases (Rosenthal 2004). Squamous cell carcinoma (SCC)

Squamous cell tumours are usually detected at advanced stages. The role of chemotherapy in multimodality treatment has so far not been extensive, with few studies in this regard. In those limited studies 5-year survival was less than 50% (McKay 2007). The use of all treatment modalities (surgery, chemotherapy and radiation) has been suggested, similar to regimens for squamous cell cancer of other head and neck regions and is suitable for individual use on a type R basis. The most feasible and preferred timing of treatment in stage III-IV should be induction chemotherapy (platinum based, plus docetaxel and 5-fluorouracil), followed by surgery and radiation. Carcinomas of salivary type

Tumours of a salivary-gland type have an unremarkable chemosensitivity, so an approach with antineoplastic drugs is reserved only for advanced cases not susceptible to surgery and radiotherapy, and with a palliative intent. The mostly frequently used therapeutic combinations are platinum-based, anthracycline and cyclophosphamide, but indications of modest activities with other drugs, including taxanes and vinorelbine have been reported (Laurie 2006). In case of adenocarcinoma or ductal carcinoma expressing androgen receptors, the use of an androgen-blockage strategy could be adopted, for individual use on a type R basis (Jaspers 2011; Locati 2014). Ethmoid carcinoma of intestinal type (ITAC)

The approach of induction therapy with a PFL scheme (cisplatin, 5-fluorouracil, lederfolin) in advanced stage disease was studied in intestinal type adenocarcinomas of the ethmoid sinus (ITAC) (Licitra 2004). The results in terms of complete pathological response (pCR) are strongly related to the presence of a functional p53 protein (80% of pCR with functional p53, compared with no response with an inactivating mutation of TP53 gene). Obtaining a pCR was a strong prognostic factor for survival. The use of induction chemotherapy in p53 functional tumours is suitable for individual use on a type 3 level. Conclusions of systemic treatment

Overall, the use of systemic therapy in carcinomas of the paranasal sinuses derived from the unsatisfactory results obtained with a single therapeutic strategy (radiotherapy or surgery).
Some studies have shown the feasibility of the incorporation of chemotherapy, in particular in the induction phase (Mhawech 2004; Björk-Eriksson 1992; Licitra 2003), where the achievement of a complete response was found to have a favourable impact on outcome.
The approach with induction chemotherapy aims to reduce the local burden of disease, with the two objectives of promoting a better approach with radical surgery or radiotherapy, and to reduce the risk of distant spread, for the most aggressive forms.
There is no evidence to suggest that the choice of the type of surgery, as well as the doses of radiation to be delivered with radical intent, should be re-evaluated on the basis of the response to initial chemotherapy.
On one hand, the future of chemotherapy within the multimodal treatment of paranasal sinus carcinomas is linked to the use of new chemotherapy regimens; on the other hand the definition of predictive and prognostic factors will influence the choice of treatment, in order to select more responsive patients and more aggressive diseases potentially benefiting from medical treatment.

6.3 Surgery for sinonasal malignancies

The optimal treatment strategy for patients with sinonasal malignancies is currently defined by a multidisciplinary team, based on a careful assessment of the patient’s profile (comorbidities and impact on the feasibility of treatment alternatives) and adequate evaluation of the tumour (histology, local extension, involvement of critical structures, possible regional and distant spread). Patient willingness is another key factor that needs to be taken into account.

6.3.1 Surgical treatment for naso-ethmoidal malignancies

Surgical treatment for naso-ethmoidal malignancies has dramatically evolved over the last two decades due to the progressive application of transnasal endoscopic techniques and the concomitant decrease in indications for external approaches, such as anterior craniofacial resection. This paradigm shift has been favoured not only by the increase in surgical expertise, but also by advances in imaging techniques and surgical instrumentation. It is worth remembering that, due to the rarity of sinonasal malignant neoplasms and the absence of comparative randomized studies, the level of available evidence is generally 3 or 4 and treatment recommendations reach level C or D.
The first reports on endoscopic resection of naso-ethmoidal malignancies included only patients with lesions limited to the area of origin, without involvement of the adjacent skull base. In the following years, due to increased experience in CSF-leak repair, lesions with involvement of the skull base were also deemed amenable to a purely endoscopic excision. Recent experience, reporting good results in terms of local control and disease-free survival in the management not only of lesions in contact with but also crossing the anterior skull base, reinforced the idea that transnasal endoscopic surgery has acquired an indisputable role in the therapeutic armamentarium for naso-ethmoidal malignancies.
Endoscopic surgery for the treatment of sinonasal malignancies encompasses different techniques that may be summarised, with specific indications, as follows:

Purely endoscopic excision without resection of the anterior skull base and dura: tumours limited to the naso-ethmoidal box, in the absence of any relationship with the orbital content and anterior-skull base, and no propensity of the lesion to spread along olfactory nerve (i.e., olfactory neuroblastoma, adenoid cystic carcinoma).
Lesions: T1, T2
Level of evidence: 3
Treatment recommendation: C

Endoscopic resection extending to the anterior skull base and dura, on one or both sides (unilateral or bilateral endoscopic craniectomy): lesions abutting or invading the anterior skull base or dura, even with limited brain infiltration and tumours with propensity to spread along olfactory phyla are ideal for this approach. Dural involvement far laterally over the orbital roof and massive brain infiltration are the main contraindications.
Lesions: T3 and selected T4a-T4b
Level of evidence: 3
Treatment recommendation: C

Endoscopic resection combined with subfrontal craniotomy (so-called cranioendoscopic approach): whenever the tumour involves the dura laterally over the orbital roof, and/or there is extensive brain infiltration and/or a diffuse involvement of the frontal sinus.
Lesions: T3 and selected T4a-T4b
Level of evidence: 3
Treatment recommendation: C

Endoscopic-assisted external transfacial approach when there is extension to the maxillary sinus (with the exception of its medial wall), the nasal fossa bony floor, premaxillary and/or orbital soft tissues, lacrimal pathway and/or infratemporal fossa.
Lesions: selected T3, T4a-T4b
Level of evidence: 3
Treatment recommendation: C

The description of the most relevant steps of each surgical procedure has already been published (Nicolai 2011; Bolzoni Villaret 2010; Nicolai 2008) and is beyond the scope of the present paper.

Anterior skull base reconstruction is required whenever the dura is excised; while different materials and techniques are available, the preference is in favour of autologous tissues.
The absolute contraindications for surgery, at least with radical intent,
are massive brain infiltration associated with extensive surrounding oedema, involvement of the internal carotid artery, cavernous sinus or optic chiasm, bilateral intraorbital extension, massive optical apex and superior orbital fissure involvement, and the presence of distant metastases (other than adenoid cystic carcinoma).
Level of evidence: 3
Treatment recommendation: C Outcomes of surgery for naso-ethmoidal malignancies

It is difficult to draw meaningful conclusions about the outcome of patients treated by surgery (± adjuvant treatment) for naso-ethmoidal malignancies due to the rarity of these tumours, their high degree of histological variability, and the short follow-up often reported. Moreover, comparison of endoscopic with “classic” craniofacial resection, which for many decades has been considered the gold standard in the treatment of tumours at the sinonasal-anterior skull base interface, is hampered by relevant differences in inclusion criteria and composition of case series in terms of histology, stage, adjuvant protocols, and follow-up strategy. In spite of these limitations, some speculations can be offered. The reference paper for anterior craniofacial resection (Patel 2003) summarises data on 1,317 patients treated at 17 centres worldwide. After a median follow-up of 25 months, 5-year overall, disease-specific and recurrence-free survival were 54%, 60%, and 53%, respectively. This paper, due to the large patient cohort and the value of the analysis, serves as benchmark for later investigations focusing on purely endoscopic or combined approaches. Two important series, one from the US (Hanna 2009) and one from Italy (Nicolai 2008), obtained a 5-year disease-specific survival of 87% and 81.9%, respectively, after a reasonable follow-up period (37 and 34.1 months, respectively). Eloy et al. (Eloy 2009) deserve credit for the attempt, even though retrospective, to compare patients treated by either endoscopic or craniofacial resection. They found no statistical difference in terms of overall survival between the two groups.

6.3.2 Surgical treatment for malignancies of the maxillary sinus

The last decades have seen a remarkable progress in reconstructive techniques after resection of cancers of the maxillary sinus more than a refinement in the ablative procedures. In fact, the indications for a purely endoscopic approach are limited to those rare neoplasms confined to the medial wall, while for all remaining cases transoral or transfacial approaches are still mandatory. These include inferior maxillectomy, subtotal maxillectomy, radical maxillectomy, and subtotal or radical maxillectomy extended to adjacent sites (ethmoid, frontal sinus, anterior cranial fossa, orbital content, pterygoid process, infratemporal fossa, nasopharynx, middle cranial fossa, and/or pre-maxillary soft tissues). The aims of reconstruction, which are strictly related to the extent of the resection, are the following: separation of the maxillary-nasal complex from the oral cavity, restoration of the maxillary contour, support of the orbital content, management of the orbital cavity in case of orbital clearance, closure of a dural defect.
These goals can be achieved either by prosthetic obturators or epithesis, pedicled flaps (e.g., temporalis muscle, pericranium), microvascular transfer of bone and soft tissues (Browne 2011), or a combination of these. The development and widespread expertise in harvesting a variety of free flaps have certainly encouraged surgeons to perform more extensive resections. Management of the neck is not a major issue in maxillary cancer. The indications are limited to N+ cases and to N0 cases, which – due to a specific histology (e.g., undifferentiated carcinoma) and/or local extension (e.g., involvement of the hard palate) – have a non-negligible likelihood to harbour occult nodal metastases (Cantù 2008).
The surgical options include:

Medial maxillectomy by a purely endoscopic approach: only small lesions limited to the medial wall, with or without bony involvement, are amenable to a purely endoscopic excision.
Lesions: selected T1-T2
Level of evidence: 3
Treatment recommendation: C

Medial maxillectomy by a lateral rhinotomic approach: this procedure has the same indications as a purely endoscopic approach and, intuitively, is losing popularity since endoscopy is associated with lower morbidity and better cosmetic outcomes.
Lesions: selected T1-T2
Level of evidence: 3
Treatment recommendation: C

Inferior maxillectomy by a purely transoral approach: lesions of the alveolar process, hard palate, or alveolar recess without extension to the upper part of the maxillary sinus can be treated with this approach.
Lesions: selected T1-T2
Level of evidence: 3
Treatment recommendation: C

Midfacial degloving: small median-paramedian lesions with limited lateral extension and no critical relationship with the orbit may be removed by this combined oro-nasal approach.
Lesions: T1-T2
Level of evidence: 3
Treatment recommendation: C

Subtotal or radical maxillectomy via a lateral rhinotomic approach: lateral rhinotomy with superior labial split and possible lateral prolongation at the subciliary level allows the exposure and removal of the entire maxillary sinus. All lesions originating within the sinus and involving its bony walls may be treated by this approach. In the presence of orbital content involvement, orbital clearance is associated. Involvement of the anterior and/or middle skull base requires skull base resection and reconstruction (Cantù 2010). This rhinotomic approach may also allow the contemporary removal of the masticatory space, pterygopalatine, and infratemporal fossa content whenever extension beyond the posterior maxillary wall is detected.
Lesions: T2-T3-T4a and selected T4b
Level of evidence: 3
Treatment recommendation: C Outcomes of surgery for maxillary sinus malignancies

The rarity of the disease, histologic heterogeneity, and the use of different treatment protocols have all contributed to the paucity of reports with meaningful data on survival and prognostic factors. Nevertheless, many studies concur in showing that during the last three decades there has been no significant changes in 5-year overall survival, which is in the range of 35-60%. Factors affecting survival are T stage, histology, and the presence of positive lymph nodes. Local recurrence remains the most frequent reason for treatment failure.
As a general rule, exclusive surgery is limited to selected cases of pT1-T2 lesions without any adverse histologic features (positive margins, high grade, perineural spread). Extensive surgery for advanced cancer, at least in the past, was associated with substantial risk of permanent deformity and loss of function, especially when palatal and/or orbital content removal was required. With the advent of a vast array of revascularised free flaps that transfer soft tissues and even bone, the reconstructive surgeon has the opportunity of limiting functional and aesthetic sequelae, thus improving the quality of life. This is the reason why in recent years there has been a trend favouring the use of primary surgery, followed in most cases by radiation with or without chemotherapy.


7.1 Radiotherapy

Side effects can be quite significant and are related to the anatomical proximity of adjacent structures. Almost all published studies analysing postoperative conventional or conformal radiotherapy have reported high rates of severe acute toxicities that did not occur with IMRT (Karim 1990; Jiang 1991; Roa 1994; Wiegner 2012; Duprez 2012).
A significant correlation between lacrimal gland and cornea dose and the incidence of acute visual toxicity have been reported (Wiegner 2012). Patients with a mean cornea dose of 30 Gy had a 78% risk of acute toxicity. Likewise, a median dose lacrimal gland of 25.6 Gy had an 86% incidence of toxicity (Wiegner 2012). Older studies using conventional radiotherapy reported excessive radiation-induced ocular toxicity such as blindness, retinopathy, and optic neuropathy in up to 37% 40% and 47% of patients, respectively (Katz 2002; Parsons 1994). The primary goal of implementing IMRT for sinonasal tumours is to minimize radiation-induced injury to the retinas, optic nerves, and chiasm. Numerous dosimetric studies reported a dose reduction to critical normal structures including the optic pathways and brainstem with increased target volume coverage. Optic neuropathy usually develops 2 to 4 years after treatment, but can occur as late as 14 years after treatment. Radiation-induced retinopathy develops earlier within a period of 1.5 to 5 years after RT (Dirix 2010). Most IMRT series did not observe any Grade 3 visual impairment (Dirix 2010; Daly 2007; Combs 2006; Duthoy 2005; Hoppe 2008). Chen et al. (Chen 2007) found that IMRT significantly preserved vision as compared with conformal and conventional radiotherapy (Grade 3 late ocular toxicity in 0%, 9% and 20% respectively).
Other reported severe late radiation-induced toxicity includes xerophthalmia, lacrimal canal stenosis and corneal ulceration. With regard to dry-eye syndrome, IMRT has proven able to prevent this effect, which usually starts during the first year after RT. (Claus 2002). Finally, the incidence of brain necrosis and osteoradionecrosis was low with IMRT compared with earlier studies on non-IMRT, where brain necrosis and osteoradionecrosis were reported in up to 11% of patients (Hawkins 1988). There was only one report by Daly et al describing IMRT induced brain necrosis in 1 patient (3%) (Daly 2007).

7.2 Early complications and sequelae after surgery for naso-ethmoidal lesions

When complications of endoscopic and craniotomic approaches are compared, the difference between the two groups is striking. The rate of post-surgical complications in patients who underwent endoscopic excision of naso-ethmoidal malignancies (either endoscopic or cranioendoscopic resection) is generally about 10% (Nicolai 2008). Notably, postoperative fatalities occurred in only two patients treated by cranioendoscopic resection in the Italian series, whereas no perioperative deaths were reported by the MD Anderson group. Intuitively, the rate and type of complications are strictly related not only to the expertise of the surgical team, but also to the extent of disease and, therefore, to the type of procedure performed. In endoscopic resections without craniectomy or dural resection, the most frequent early complications are epistaxis and adhesions. Whenever the periorbita is removed for oncological reasons, eyelid ecchymosis or oedema must be expected. When the endoscopic approach includes dural resection (i.e. endoscopic craniectomy) postoperative complications may encompass CSF-leak (which is by far the most frequent) hypertensive pneumocephalus, and meningitis. Commonly, all patients complain of nasal crusting associated with a foul odour, which tends to decrease within around six months after treatment, but can be more cumbersome in patients receiving adjuvant radiotherapy.
In the aforementioned multicentric international study group, the complication rates of “classic” anterior craniofacial resection were higher (33%), with wound infection the most common (18%), but with a non-negligible postoperative mortality rate of 4%.
Late sequelae of endoscopic resection of sinonasal malignancies generally include sinusitis due to shrinkage of sinus ostium; in rare cases, in the presence of complete closure of the ostium, a mucocele, especially in the frontal and sphenoid sinus, may occur. Epiphora secondary to scar occlusion of the lacrimal pathway may be expected in patients who underwent resection of the naso-lacrimal duct, especially after adjuvant radiotherapy.

7.3 Early complications and sequelae after surgery for maxillary lesions

7.3.1 Subtotal/radical maxillectomy by lateral rhinotomy

Early complications include haemorrhage, most frequently from the spheno-palatine or maxillary artery, blindness due to optic nerve injury, CSF-leak and possible meningitis from inadvertent anterior skull base penetration, diplopia from damage to the trochlea of the superior oblique muscle or loss of orbital support (when the floor of the orbit is removed), and nasal collapse (whenever the ascending process of the maxillary bone is resected). Conversely, the most frequent late sequelae are nasal crusting, unaesthetic scarring of the skin incision, epiphora due to stenosis of the lacrimal pathway, and frontal mucocele.

7.3.2 Midfacial degloving

The most frequent early complications are epistaxis and infraorbital nerve paresthesia. Late sequelae encompass nasal crusting and stenosis of the nasal vestibule due to extensive retraction of intranasal incisions.


Follow-up of patients treated for sinonasal malignancies includes a combination of clinical and imaging evaluations that must be performed for a minimum of five years. Notably, according to the European Position Paper on endoscopic management of tumours of the nose, paranasal sinuses, and skull base, follow-up for these patients should be for life (Lund 2010). According to this protocol, endoscopy and MR should be performed every four months in the first postoperative year, every six months for the following four years, and then yearly.
A combination of endoscopy and imaging is essential to maximize the possibility of early detection not only of recurrences, but also treatment complications and sequelae. At endoscopic evaluation, small mucosal surface lesions, suggestive of recurrence, may be easily identified and biopsied. Endoscopy may also ease diagnosis of post-treatment sequelae such as adhesions, sinus ostium stenosis, or closure leading to symptomatic sinusitis. MRI is crucial to detect submucosal recurrences, such as those arising within bone, but it may also be helpful in differentiation of inflammatory tissue, especially in irradiated patients, from local recurrence. Moreover, some late complications, such as asymptomatic mucoceles, can be identified. The role of PET-CT in the follow-up of patients with sinonasal malignancies remains unclear; early detection of distant metastases is not generally associated with significant alterations in the clinical course.


Airoldi M, Garzaro M, Valente G, Mamo C, Bena A, Giordano C et al. Clinical and biological prognostic factors in 179 cases with sinonasal carcinoma treated in the Italian Piedmont region. Oncology 2009; 76(4): 262-9. [Medline]

AIRTUM Working Group. Italian cancer figures – report 2007. 1. Survival. Epidemiol Prev 2007; 31(1 Suppl 1): 1-96.

Alos L, Moyano S, Nadal A, Alobid I, Blanch JL, Ayala E et al. Human papillomaviruses are identified in a subgroup of sinonasal squamous cell carcinomas with favorable outcome. Cancer 2009; 115(12): 2701-9. [Medline]

Bachar G, Goldstein DP, Shah M, Tandon A, Ringash J, Pond G et al. Esthesioneuroblastoma: The Princess Margaret Hospital experience. Head Neck 2008; 30(12): 1607-14. [Medline]

Bacskulin A, Guthoff R. Neuromyotonia of the abducens nerve after hypophysectomy and radiation. Strabismus 1999; 7(1): 37-40. [Medline]

Barnes L, Eveson JW, Reichart P, Sidransky D (eds). World Health Organization classification of tumours. Pathology and Genetics. Head and Neck Tumours. Lyon, IARC Press, 2005.

Bell D, Saade R, Roberts Dianna, Ow TJ, Kupferman M, Demonte F et al. Prognostic utility of Hyams Histological Grading and Kadish-Morita Staging Systems for esthesioneuroblastoma outcomes. Head Neck Pathol 2014. [Epub ahead of print] [Medline]

Bhattacharyya N. Cancer of the nasal cavity: survival and factors influencing prognosis. Arch Otolaryngol Head Neck Surg 2002a; 128(9): 1079-83. [Medline]

Bhattacharyya N. Factors predicting survival for cancer of the ethmoid sinus. Am J Rhinol 2002b; 16(5): 281-6. [Medline]

Bimbi G, Saraceno MS, Riccio S, Gatta G, Licitra L, Cantù G. Adenocarcinoma of ethmoid sinus: an occupational disease. Acta Otorhinolaryngol Ital 2004; 24(4): 199-203. [Medline]

Björk-Eriksson T, Mercke C, Petruson B, Ekholm S. Potential impact on tumor control and organ preservation with cisplatin and 5-fluorouracil for patients with advanced tumors of the paranasal sinuses and nasal fossa. A prospective pilot study. Cancer 1992; 70(11): 2615-20. [Medline]

Blanch JL, Ruiz AM, Alos L, Traserra-Coderch J, Bernal-Sprekelsen M. Treatment of 125 sinonasal tumors: prognostic factors, outcome, and follow-up. Otolaryngol Head Neck Surg 2004; 131(6): 973-6. [Medline]

Bolzoni Villaret A, Yakirevitch A, Bizzoni A, Bosio R, Bignami M, Pistochini A et al. Endoscopic transnasal craniectomy in the management of selected sinonasal malignancies. Am J Rhinol Allergy 2010; 24(1): 60-5. [Medline]

Bornholdt J, Saber AT, Sharma AK, Savolainen K, Vogel U, Wallin H. Inflammatory response and genotoxicity of seven wood dusts in the human epithelial cell line A549. Mutat Res 2007; 632(1-2): 78-88. [Medline]

Bornholdt J, Hansen J, Steiniche T, Dictor M, Antonsen A, Wolff H et al. K-ras mutations in sinonasal cancers in relation to wood dust exposure. BMC Cancer 2008; 8: 53. [Medline]

Bossi P, Perrone F, Miceli R, Cantù G, Mariani L, Orlandi E et al. Tp53 status as guide for the management of ethmoid sinus intestinal-type adenocarcinoma. Oral Oncol 2013; 49(5): 413-9. [Medline]

Browne JD, Butler S, Rees C. Functional outcomes and suitability of the temporalis myofascial flap for palatal and maxillary reconstruction after oncologic resection. Laryngoscope 2011; 121(6): 1149-59. [Medline]

Cantù G, Solero CL, Mariani L, Mattavelli F, Pizzi N, Licitra L. A new classification for malignant tumors involving the anterior skull base. Arch Otolaryngol Head Neck Surg 1999; 125(11): 1252-7. [Medline]

Cantù G, Bimbi G, Miceli R, Mariani L, Colombo S, Riccio S et al. Lymph node metastases in malignant tumors of the paranasal sinuses: prognostic value and treatment. Arch Otolaryngol Head Neck Surg 2008; 134(2): 170-7. [Medline]

Cantù G, Solero CL, Riccio S, Colombo S, Pompilio M et al. Surgery for malignant maxillary tumors involving the middle cranial fossa. Skull Base 2010; 20(2): 55-60. [Medline]

Carnes BA, Groer PG, Kotek TJ. Radium dial workers: issues concerning dose response and modeling. Radiat Res 1997; 147(6): 707-14. [Medline]

Charbotel B, Fervers B, Droz JP. Occupational exposures in rare cancers: A critical review of the literature. Crit Rev Oncol Hematol 2014; 90(2): 99-134. [Medline]

Chargari C, Bauduceau O, Védrine L, Haen P, Fayolle M, Ceccaldi B et al. Radiotherapy of maxillary sinus carcinoma: state of art. Cancer Radiother 2009; 13(3): 195-204. [Medline]

Chen AM, Daly ME, Bucci MK, Xia P, Akazawa C, Quivey JM et al. Carcinoma of the paranasal sinuses and nasal cavity treated with radiotherapy at a single institution over five decades: are we making improvement? Int J Radiat Oncol Biol Phys 2007; 69(1): 141-7. [Medline]

Chernock RD, Perry A, Pfeifer JD, Holden JA, Lewis JS Jr. Receptor tyrosine kinases in sinonasal undifferentiated carcinomas – evaluation for EGFR, c-KIT, and HER2/neu expression. Head and Neck 2009; 31(7): 919-27. [Medline]

Claus F, De Gersem W, De Wagter C, Van Severen R, Vanhoutte I, Duthoy W et al. An implementation strategy for IMRT of ethmoid sinus cancer with bilateral sparing of the optic pathways. Int J Radiat Oncol Biol Phys 2001; 51(2): 318-31. [Medline]

Claus F, Boterberg T, Ost P, De Neve W. Short term toxicity profile for 32 sinonasal cancer patients treated with IMRT. Can we avoid dry eye syndrome? Radiother Oncol 2002; 64(2): 205-8. [Medline]

Combs SE, Konkel S, Schulz-Ertner D, Münter MW, Debus J, Huber PE et al. Intensity modulated radiotherapy (IMRT) in patients with carcinomas of the paranasal sinuses: clinical benefit for complex shaped target volumes. Radiat Oncol 2006; 1: 23. [Medline]

Curtin HD, Hirsch WL. Base of the skull. In: Atlas SW (ed). Magnetic resonance imaging of the brain and spine. New York, Raven Press; 1991, p. 668-706.

d’Errico A, Pasian S, Baratti A, Zanelli R, Alfonzo S, Gilardi L et al. A case-control study on occupational risk factors for sino-nasal cancer. Occup Environ Med 2009; 66(7): 448-55. [Medline]

Daffner RH, Lupetin AR, Dash N, Deeb ZL, Sefczek RJ, Schapiro RL. MRI in the detection of malignant infiltration of bone marrow. AJR Am J Roentgenol 1986; 146(2): 353-8. [Medline]

Daly ME, Chen AM, Bucci MK, El-Sayed I, Xia P, Kaplan MJ et al. Intensity-modulated radiation therapy for malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys 2007; 67(1): 151-7. [Medline]

Demers PA, Kogevinas M, Boffetta P, Leclerc A, Luce D, Gérin M et al. Wood dust and sino-nasal cancer: pooled reanalysis of twelve case-control studies. Am J Ind Med 1995; 28(2): 151-66. [Medline]

Demiroz C, Gutfeld O, Aboziada M, Brown D, Marentette LJ, Eisbruch A. Esthesioneuroblastoma: is there a need for elective neck treatment? Int J Radiat Oncol Biol Phys 2011; 81(4): e255-61. [Medline]

Dirix P, Vanstraelen B, Jorissen M, Vander Poorten V, Nuyts S. Intensity-modulated radiotherapy for sinonasal cancer: improved outcome compared to conventional radiotherapy. Int J Radiat Oncol Biol Phys 2010; 78(4): 998-1004. [Medline]

Dulguerov P, Calcaterra T. Esthesioneuroblastoma: the UCLA experience 1970-1990. Laryngoscope 1992; 102(8): 843-9. [Medline]

Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer 2001; 92(12): 3012-29. [Medline]

Dulguerov P, Allal AS. Nasal and paranasal sinus carcinoma: how can we continue to make progress? Curr Opin Otolaryngol Head Neck Surg 2006; 14(2): 67-72. [Medline]

Duprez F, Madani I, Morbée L, Bonte K, Deron P, Domján V et al. IMRT for sinonasal tumors minimizes severe late ocular toxicity and preserves disease control and survival. Int J Radiat Oncol Biol Phys 2012; 83(1): 252-9. [Medline]

Duthoy W, Boterberg T, Claus F, Ost P, Vakaet L, Bral S et al. Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: clinical results in 39 patients. Cancer 2005; 104(1): 71-82. [Medline]

Ebner R, Slamovits TL, Friedland S, Pearlman JL, Fowble B. Visual loss following treatment of sphenoid sinus carcinoma. Surv Ophthalmol 1995; 40(1): 62-8. [Medline]

Eggesbø HB. Imaging of sinonasal tumours. Cancer Imaging 2012; 12: 136-52. [Medline]

Eisen MD, Yousem DM, Montone KT, Kotapka MJ, Bigelow DC, Bilker WB et al. Use of preoperative MR to predict dural, perineural, and venous sinus invasion of skull base tumors. AJNR Am J Neuroradiol 1996; 17(10): 1937-45. [Medline]

Ejaz A, Wenig BM. Sinonasal undifferentiated carcinoma: clinical and pathologic features and a discussion on classification, cellular differentiation, and differential diagnosis. Adv Anat Pathol 2005; 12(3): 134-43. [Medline]

Elkon D, Hightower SI, Lim ML, Cantrell RW, Constable WC. Esthesioneuroblastoma. Cancer 1979; 44(3): 1087-94. [Medline]

Eloy JA, Vivero RJ, Hoang K, Civantos FJ, Weed DT, Morcos JJ et al. Comparison of transnasal endoscopic and open craniofacial resection for malignant tumors of the anterior skull base. Laryngoscope 2009; 119(5): 834-40. [Medline]

Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991; 21(1): 109-22. [Medline]

Farina D, Borghesi A, Botturi E, Ravanelli M, Maroldi R. Treatment monitoring of paranasal sinus tumors by magnetic resonance imaging. Cancer Imaging 2010; 10: 183-93. [Medline]

Fitzek MM, Thornton AF, Varvares M, Ancukiewicz M, Mcintyre J, Adams J et al. Neuroendocrine tumors of the sinonasal tract. Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy. Cancer 2002 ;94(10): 2623-34. [Medline]

Foote RL, Morita A, Ebersold MJ, Olse KD, Lewis JE, Quast LM et al. Esthesioneuroblastoma: the role of adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 1993; 27(4): 835-42. [Medline]

Franchi A, Fondi C, Paglierani M, Pepi M, Gallo O, Santucci M. Epidermal growth factor receptor expression and gene copy number in sinonasal intestinal type adenocarcinoma. Oral Oncology 2009; 45(9): 835-8. [Medline]

Gabriele AM, Airoldi M, Garzaro M, Zeverino M, Amerio S, Condello C et al. Stage III-IV sinonasal and nasal cavity carcinoma treated with three-dimensional conformal radiotherapy. Tumori 2008; 94(3): 320-6. [Medline]

Gandini S, Botteri E, Iodice S, Boniol M, Lowenfels AB, Maisonneuve P et al. Tobacco smoking and cancer: a meta-analysis. Int J Cancer 2008; 122(1): 155-64. [Medline]

Ganly I, Patel SG, Singh B, Kraus DH, Bridger PG, Cantù G et al. Complications of craniofacial resection for malignant tumors of the skull base: report of an International Collaborative Study. Head Neck 2005; 27(6): 445-51. [Medline]

Garden AS, Weber RS, Morrison WH, Ang KK, Peters LJ. The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation. Int J Radiat Oncol Biol Phys 1995; 32(3): 619-26. [Medline]

Gelbard A, Hale KS, Takahashi Y, Davies M, Kupferman ME, El-Naggar AK et al. Molecular profiling of sinonasal undifferentiated carcinoma. Head and Neck 2014; 36(1): 15-21. [Medline]

Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005; 23(1): 3562-7. [Medline]

Gil Z, Carlson DL, Gupta A, Lee N, Hoppe B, Shah JP et al. Patterns and incidence of neural invasion in patients with cancers of the paranasal sinuses. Arch Otolaryngol Head Neck Surg 2009; 135(2): 173-9. [Medline]

Gordon I, Boffetta P, Demers PA. A case study comparing a meta-analysis and a pooled analysis of studies of sinonasal cancer among wood workers. Epidemiology 1998; 9(5): 518-24. [Medline]

Gray ST, Herr MW, Sethi RK, Diercks G, Lee L, Curry W et al. Treatment outcomes and prognostic factors, including human papillomavirus, for sinonasal undifferentiated carcinoma: a retrospective review. Head Neck 2015; 37(3): 366-74. [Medline]

Grimsrud TK, Peto J. Persisting risk of nickel related lung cancer and nasal cancer among Clydach refiners. Occup Environ Med 2006; 63(5): 365-6. [Medline]

Guan X, Wang X, Liu Y, Hu C, Zhu G. Lymph node metastasis in sinonasal squamous cell carcinoma treated with IMRT/3D-CRT. Oral Oncol 2013; 49(1): 60-5. [Medline]

Guntinas-Lichius O, Kreppel MP, Stuetzer H, Semrau R, Eckel HE, Mueller RP. Single modality and multimodality treatment of nasal and paranasal sinuses cancer: a single institution experience of 229 patients. Eur J Surg Oncol 2007; 33(2): 222-8. [Medline]

Hähnel S, Ertl-Wagner B, Tasman AJ, Forsting M, Jansen O. Relative value of MR imaging as compared with CT in the diagnosis of inflammatory paranasal sinus disease. Radiology 1999; 210(1): 171-6. [Medline]

Hanna E, DeMonte F, Ibrahim S, Roberts D, Levine N, Kupferman M. Endoscopic resection of sinonasal cancers with and without craniotomy: oncologic results. Arch Otolaryngol Head Neck Surg 2009;135(12):1219-24. [Medline]

Hanna EY, Cardenas AD, DeMonte F, Roberts D, Kupferman M, Weber R et al. Induction chemotherapy for advanced squamous cell carcinoma of the paranasal sinuses. Arch Otolaryngol Head Neck Surg 2011; 137(1): 78-81. [Medline]

Hawkins RB, Wynstra JH, Pilepich MV, Fields JN. Carcinoma of the nasal cavity – results of primary and adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 1988; 15(5): 1129-33. [Medline]

Hayes RB, Gerin M, Raatgever JW, de Bruyn A. Wood-related occupations, wood dust exposure, and sinonasal cancer. Am J Epidemiol 1986; 124(4): 569-77. [Medline]

Hermans R, De Vuysere S, Marchal G. Squamous cell carcinoma of the sinonasal cavities. Semin Ultrasound CT MR 1999; 20(3): 150-61. [Medline]

Higo R, Takahashi T, Nakata H, Harada H, Sugasawa M. Salivary duct carcinoma in the sinonasal tract. Eur Arch Otorhinolaryngol 2007; 264(5): 561-3. [Medline]

Holmila R, Bornholdt J, Heikkilä P, Suitiala T, Févotte J, Cyr D et al. Mutations in TP53 tumor suppressor gene in wood dust-related sinonasal cancer. Int J Cancer 2010; 127(3): 578-88. [Medline]

Homma A, Oridate N, Suzuki F, Taki S, Asano T, Yoshida D et al. Superselective high-dose cisplatin infusion with concomitant radiotherapy in patients with advanced cancer of the nasal cavity and paranasal sinuses: a single institution experience. Cancer 2009; 115(20): 4705-14. [Medline]

Hoppe BS, Stegman LD, Zelefsky MJ, Rosenzweig KE, Wolden SL, Patel SG et al. Treatment of nasal cavity and paranasal sinus cancer with modern radiotherapy techniques in the postoperative setting – the MSKCC experience. Int J Radiat Oncol Biol Phys 2007; 67(3): 691-702. [Medline]

Hoppe BS, Nelson CJ, Gomez DR, Stegman LD, Wu AJ, Wolden SL et al. Unresectable carcinoma of the paranasal sinuses: outcomes and toxicities. Int J Radiat Oncol Biol Phys 2008; 72(3): 763-9. [Medline]

Hu YH, Tu GY, Qi YQ, Xu GS, Wu XL, Cai WM et al. Comparison of pre- and postoperative radiation in the combined treatment of carcinoma of maxillary sinus. Int J Radiat Oncol Biol Phys 1982; 8(6): 1045-9. [Medline]

IARC. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans – Tobacco Smoking. Volume 38. Lyon, IARC, 1986.

IARC. IARC Monographs on the evaluation of the carcinogenic risk to humans – Tobacco Smoke and Involuntary Smoking. Volume 83. Lyon, IARC, 2004.

IARC. List of Classifications by cancer sites with sufficient or limited evidence in humans. Volumes 1 to 108. Lyon, IARC, 2013.

Iwata H, Tatewaki K, Inoue M, Yokota N, Sato K, Shibamoto Y. Salvage stereotactic reirradiation using the CyberKnife for the local recurrence of nasal or paranasal carcinoma. Radiother Oncol 2012; 104(3): 355-60. [Medline]

Jaspers HC, Verbist BM, Schoffelen R, Mattijssen V, Slootweg PJ, van der Graaf WT et al. Androgen receptor-positive salivary duct carcinoma: a disease entity with promising new treatment options. J Clin Oncol 2011; 29(16): e473-6. [Medline]

Jégoux F, Métreau A, Louvel G, Bedfert C. Paranasal sinus cancer. Eur Ann Otorhinolaryngol Head Neck Dis 2013; 130(6): 327-35. [Medline]

Jensen AD, Nikoghosyan AV, Ecker S, Ellerbrock M, Debus J, Münter MW. Carbon ion therapy for advanced sinonasal malignancies: feasibility and acute toxicity. Radiat Oncol 2011; 6: 30. [Medline]

Jiang GL, Ang KK, Peters LJ, Wendt CD, Oswald MJ, Goepfert H. Maxillary sinus carcinomas: natural history and results of postoperative radiotherapy. Radiother Oncol 1991; 21(3): 193-200. [Medline]

Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases Cancer 1976; 37(3): 1571-6. [Medline]

Karim AB, Kralendonk JH, Njo KH, Tabak JM, Elsenaar WH, van Balen AT. Ethmoid and upper nasal cavity carcinoma: treatment, results and complications. Radiother Oncol 1990; 19(2): 109-20. [Medline]

Kasperts N, Slotman BJ, Leemans CR, de Bree R, Doornaert P, Langendijk JA. Results of postoperative reirradiation for recurrent or second primary head and neck carcinoma. Cancer 2006; 106(7): 1536-47. [Medline]

Katz TS, Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Villaret DB. Malignant tumors of the nasal cavity and paranasal sinuses. Head Neck 2002; 24(9): 821-9. [Medline]

Kauppinen T, Vincent R, Liukkonen T, Grzebyk M, Kauppinen A, Welling I et al. Occupational exposure to inhalable wood dust in the member states of the European Union. Ann Occup Hyg 2006; 50(6): 549-61. [Medline]

Kawashima M, Ogino T, Hayashi R, Ishikura S, Nihei K, Ito Y et al. Influence of postsurgical residual tumor volume on local control in radiotherapy for maxillary sinus cancer. Jpn J Clin Oncol 2001; 31(5): 195-202. [Medline]

Khademi B, Moradi A, Hoseini S, Mohammadianpanah M. Malignant neoplasm of the sinonasal tract: report of 71 patients and literature review and analysis. Oral Maxillofac Surg 2009; 13(4): 191-9. [Medline]

Kim GE, Chung EJ, Lim JJ, Keum KC, Lee SW, Cho JH et al. Clinical significance of neck node metastasis in squamous cell carcinoma of the maxillary antrum. Am J Otolaryngol 1999; 20(6): 383-390. [Medline]

King AD, Leung SF, Teo P, Lam WW, Chan YL, Metreweli C. Hypoglossal nerve palsy in nasopharyngeal carcinoma. Head Neck 1999; 21(7): 614-9. [Medline]

Koivunen P, Mäkitie AA, Bäck L, Pukkila M, Laranne J, Kinnunen I et al. A national series of 244 sinonasal cancers in Finland in 1990-2004. Eur Arch Otorhinolaryngol 2012; 269(2): 615-21. [Medline]

Kraus DH, Lanzieri CF, Wanamaker JR, Little JR, Lavertu P. Complementary use of computed tomography and magnetic resonance imaging in assessing skull base lesions. Laryngoscope 1992; 102(6): 623-9. [Medline]

Kreppel M, Scheer M, Beutner D, Drebber U, Semrau R, Zöller JE et al. Stage grouping in tumors of the ethmoid sinuses and the nasal cavity using the sixth edition of the UICC classification of malignant tumors. Head Neck 2013; 35(2): 257-64. [Medline]

Lamarre ED, Batra PS, Lorenz RR, Citardi MJ, Adelstein DJ, Srinivas SM et al. Role of positron emission tomography in management of sinonasal neoplasms – a single institution’s experience. Am J Otolaryngol 2012; 33(3): 289-95. [Medline]

Langer CJ, Harris J, Horwitz EM, Nicolaou N, Kies M, Curran W et al. Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Protocol 9911. J Clin Oncol 2007; 25(30): 4800-5. [Medline]

Langendijk JA, Kasperts N, Leemans CR, Doornaert P, Slotman BJ. A phase II study of primary reirradiation in squamous cell carcinoma of head and neck. Radiother Oncol 2006; 78(3): 306-12. [Medline]

Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol 2006; 24(17): 2673-8. [Medline]

Le QT, Fu KK, Kaplan MJ, Terris DJ, Fee WE, Goffinet DR. Lymph node metastasis in maxillary sinus carcinoma. Int J Radiat Oncol Biol Phys 2000; 46(3): 541-9. [Medline]

Lee MM, Vokes EE, Rosen A, Witt ME, Weichselbaum RR, Haraf DJ. Multimodality therapy in advanced paranasal sinus carcinoma: superior long-term results. Cancer J Sci Am 1999; 5(4): 219-23. [Medline]

Licitra L, Locati LD, Cavina R, Garassino I, Mattavelli F, Pizzi N et al. Primary chemotherapy followed by anterior craniofacial resection and radiotherapy for paranasal cancer. Ann Oncol 2003; 14(3): 367-72. [Medline]

Licitra L, Suardi S, Bossi P, Locati LD, Mariani L, Quattrone P et al. Prediction of TP53 status for primary cisplatin, fluorouracil, and leucovorin chemotherapy in ethmoid sinus intestinal-type adenocarcinoma. J Clin Oncol 2004; 22(24): 4901-6. [Medline]

Lindeman P, Eklund U, Petruson B. Survival after surgical treatment in maxillary neoplasms of epithelial origin. J Laryngol Otol 1987; 101(6): 564-8. [Medline]

Lloyd G, Lund VJ, Howard D, Savy L. Optimum imaging for sinonasal malignancy. J Laryngol Otol 2000; 114(7): 557-62. [Medline]

Locati LD, Perrone F, Cortelazzi B, Lo vullo S, Bossi P, Dagrada G et al Clinical activity of androgen deprivation therapy in patients with metastatic/relapsed AR-positive salivary gland cancers. Head Neck 2014. [Epub ahead of print] [Medline]

Loevner LA, Sonners AI. Imaging of neoplasms of the paranasal sinuses. Neuroimaging Clin N Am 2004; 14(4): 625-46. [Medline]

Lopez F, García Inclán C, Pérez-Escuredo J, Alvarez Marcos C, Scola B, Suárez C et al. KRAS and BRAF mutations in sinonasal cancer. Oral Oncology 2012a; 48(8): 692-7. [Medline]

Lopez F, Llorente JL, Oviedo CM, Vivanco B, Marcos CÁ, García-Inclán C et al. Gene amplification and protein overexpression of EGFR and ERBB2 in sinonasal squamous cell carcinoma. Cancer 2012b; 118(7): 1818-26. [Medline]

LoRusso P, Tapazoglou E, Kish JA, Ensley JF, Cummings G, Kelly J et al. Chemotherapy for paranasal sinus carcinoma. A 10-year experience at Wayne State University. Cancer 1988; 62(1): 1-5. [Medline]

Luce D, Leclerc A, Bégin D, Demers PA, Gérin M, Orlowski E et al. Sinonasal cancer and occupational exposures: a pooled analysis of 12 case-control studies. Cancer Causes Control 2002; 13(2): 147-57. [Medline]

Lund VJ, Stammberger H, Nicolai P, Castelnuovo P, Beal T, Beham A et al. European position paper on endoscopic management of tumours of the nose, paranasal sinuses and skull base. Rhinol Suppl 2010; (22): 1-143. [Medline]

Määttä J, Luukkonen R, Husgafvel-Pursiainen K, Alenius H, Savolainen K. Comparison of hardwood and softwood dust-induced expression of cytokines and chemokines in mouse macrophage RAW 264.7 cells. Toxicology 2006; 218(1): 13-21. [Medline]

Mabanta SR, Mendenhall WM, Stringer SP, Cassisi NJ. Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes. Head Neck 1999; 21(7): 591-4. [Medline]

Mafee MF. Nonepithelial tumors of the paranasal sinuses and nasal cavity. Role of CT and MR imaging. Radiol Clin North Am 1993; 31(1): 75-90. [Medline]

Maghami E, Kraus DH. Cancer of the nasal cavity and paranasal sinuses. Expert Rev Anticancer Ther 2004; 4(3): 411-24. [Medline]

Maroldi R, Farina D, Battaglia G, Maculotti P, Nicolai P, Chiesa A. MR of malignant nasosinusal neoplasms. Frequently asked questions. Eur J Radiol 1997; 24(3): 181-90. [Medline]

McElroy EA Jr, Buckner JC, Lewis JE. Chemotherapy for advanced esthesioneuroblastoma: the Mayo Clinic experience. Neurosurgery 1998; 42(5): 1023-7; discussion 1027-8. [Medline]

McKay SP, Shibuya TY, Armstrong WB, Wong HS, Panossian AM, Ager J et al. Cell carcinoma of the paranasal sinuses and skull base. Am J Otolaryngol 2007; 28(5): 294-301. [Medline]

Mendenhall WM, Amdur RJ, Morris CG, Kirwan J, Malyapa RS, Vaysberg M et al. Carcinoma of the nasal cavity and paranasal sinuses. Laryngoscope 2009; 119(5): 899-906. [Medline]

Mhawech P, Berczy M, Assaly M, Herrmann F, Bouzourene H, Allal AS et al. Human achaete-scute homologue (hASH1) mRNA level as a diagnostic marker to distinguish esthesioneuroblastoma from poorly differentiated tumors arising in the sinonasal tract. Am J Clin Pathol 2004; 122(1): 100-5. [Medline]

Mirghani H, Mortuaire G, Armas GL, Hartl D, Aupérin A, El Bedoui S et al. Sinonasal cancer: Analysis of oncological failures in 156 consecutive cases. Head Neck 2014; 36(5): 667-74. [Medline]

Miyamoto RC, Gleich LL, Biddinger PW, Gluckman JL. Esthesioneuroblastoma and sinonasal undifferentiated carcinoma: impact of histological grading and clinical staging on survival and prognosis. Laryngoscope 2000; 110(8): 1262-5. [Medline]

Monroe AT, Hinerman RW, Amdur RJ, Morris CG, Mendenhall WM. Radiation therapy for esthesioneuroblastoma: rationale for elective neck irradiation. Head Neck 2003; 25(7): 529-34. [Medline]

Moonis G, Cunnane MB, Emerick K, Curtin H. Patterns of perineural tumor spread in head and neck cancer. Magn Reson Imaging Clin N Am 2012; 20(3): 435-46. [Medline]

Mourad WF, Hauerstock D, Shourbaji RA, Hu KS, Culliney B, Li Z et al. Trimodality management of sinonasal undifferentiated carcinoma and review of the literature. Am J Clin Oncol 2013; 36(6): 584-8. [Medline]

Musy PY, Reibel JF, Levine PA. Sinonasal undifferentiated carcinoma: the search for a better outcome. Laryngoscope 2002; 112(8 Pt 1): 1450-5. [Medline]

Nicolai P, Castelnuovo P, Lombardi D, Battaglia P, Bignami M, Pianta L et al. Role of endoscopic surgery in the management of selected malignant epithelial neoplasms of the naso-ethmoidal complex. Head Neck 2007; 29(12): 1075-82. [Medline]

Nicolai P, Battaglia P, Bignami M, Bolzoni Villaret A, Delù G, Khrais T et al. Endoscopic surgery for malignant tumors of the sinonasal tract and adjacent skull base: a 10-year experience. Am J Rhinol 2008; 22(3): 308-16. [Medline]

Nicolai P, Castelnuovo P, Bolzoni Villaret A. Endoscopic resection of sinonasal malignancies. Curr Oncol Rep 2011; 13(2): 138-44. [Medline]

Orlandi E, Giandini T, Iannacone E, De Ponti E, Carrara M, Mongioj V et al. Radiotherapy for unresectable sinonasal cancers: Dosimetric comparison of intensity modulated radiation therapy with coplanar and non-coplanar volumetric modulated arc therapy. Radiother Oncol 2014; 113(2): 260-6. [Medline]

Papadimitrakopoulou VA, Ginsberg LE, Garden AS, Kies MS, Glisson BS, Diaz EM Jr et al. Intraarterial cisplatin with intravenous paclitaxel and ifosfamide as an organ-preservation approach in patients with paranasal sinus carcinoma. Cancer 2003; 98(10): 2214-23. [Medline]

Parsons JT, Bova FJ, Fitzgerald CR, Mendenhall WM, Million RR. Severe dry-eye syndrome following external beam irradiation. Int J Radiat Oncol Biol Phys 1994; 30(4): 775-80. [Medline]

Patel SG, Singh B, Polluri A, Bridger PG, Cantù G, Cheesman AD et al. Craniofacial surgery for malignant skull base tumors: report of an international collaborative study. Cancer 2003; 98(6): 1179-87. [Medline]

Patel S, Shah JP. Part II: Head and neck sites. In: Edge SB, Byrd DR, Carducci MA, Compton CA (eds). AJCC Cancer Staging Manual. 7th ed. New York, Springer, 2009.

Patel SH, Wang Z, Wong WW, Murad MH, Buckey CR, Mohammed K et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2014; 15(9): 1027-38. [Medline]

Paulino AC, Fisher SG, Marks JE. Is prophylactic neck irradiation indicated in patients with squamous cell carcinoma of the maxillary sinus? Int J Radiat Oncol Biol Phys 1997; 39(2): 283-9. [Medline]

Pérez P, Dominguez O, González S, González S, Triviño A, Suárez C. ras gene mutations in ethmoid sinus adenocarcinoma: prognostic implications. Cancer 1999; 86(2): 255-64. [Medline]

Perrone F, Oggionni M, Birindelli S, Suardi S, Tabano S, Romano R et al. TP53, p14ARF, p16INK4a and H-ras gene molecular analysis in intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses. Int J Cancer 2003; 105(2): 196-203. [Medline]

Pommier P, Ginestet C, Sunyach M, Zrounba P, Poupart M, Céruse P et al. Conformal radiotherapy for paranasal sinus and nasal cavity tumors: three-dimensional treatment planning and preliminary results in 40 patients. Int J Radiat Oncol Biol Phys 2000; 48(2): 485-93. [Medline]

Porter AB, Bernold DM, Giannini C, Foote RL, Link MJ, Olsen KD et al. Retrospective review of adjuvant chemotherapy for esthesioneuroblastoma. J Neurooncol 2008; 90(2): 201-4. [Medline]

Ramaekers BL, Pijls-Johannesma M, Joore MA, van den Ende P, Langendijk JA, Lambin P et al. Systematic review and meta-analysis of radiotherapy in various head and neck cancers: comparing photons, carbon-ions and protons. Cancer Treat Rev 2011; 37(3): 185-201. [Medline]

Rao VM, Sharma D, Madan A. Imaging of frontal sinus disease: concepts, interpretation, and technology. Otolaryngol Clin North Am 2001; 34(1): 23-39. [Medline]

RARECAREnet – Information Network on Rare Cancers.

Reiersen DA, Pahilan ME, Devaiah AK. Meta-analysis of treatment outcomes for sinonasal undifferentiated carcinoma. Otolaryngology Head Neck Surg 2012; 147(1): 7-14. [Medline]

Rischin D, Porceddu S, Peters L, Martin J, Corry J, Weih L. Promising results with chemoradiation in patients with sinonasal undifferentiated carcinoma. Head Neck 2004; 26(5): 435-41. [Medline]

Roa WH, Hazuka MB, Sandler HM, Martel MK, Thornton AF, Turrisi AT et al. Results of primary and adjuvant CT-based 3-dimensional radiotherapy for malignant tumors of the paranasal sinuses. Int J Radiat Oncol Biol Phys 1994; 28(4): 857-65. [Medline]

Roh KW, Jang JS, Kim MS, Sun DI, Kim BS, Jung SL et al. Fractionated stereotactic radiotherapy as reirradiation for locally recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2009; 74(5): 1348-55. [Medline]

Rosen A, Vokes EE, Scher N, Haraf D, Weichselbaum RR, Panje WR. Locoregionally advanced paranasal sinus carcinoma. Favorable survival with multimodality therapy. Arch Otolaryngol Head Neck Surg 1993; 119(7): 743-6. [Medline]

Rosenthal DI, Barker JL Jr, El-Naggar AK, Glissoon BS, Kies MS, Diaz EM Jr et al. Sinonasal malignancies with neuroendocrine differentiation: patterns of failure according to histologic phenotupe. Cancer 2004; 101(11): 2567-73. [Medline]

Roux FX, Brasnu D, Devaux B, Chabardes E, Schwaab G, Laccourreye O et al. Ethmoid sinus carcinomas: results and prognosis after neoadjuvant chemotherapy and combined surgery – a 10-year experience. Surg Neurol 1994; 42(2): 98-104. [Medline]

Saber AT, Nielsen LR, Dictor M, Hagmar L, Mikoczy Z, Wallin H. K-ras mutations in sinonasal adenocarcinomas in patients occupationally exposed to wood or leather dust. Cancer Lett 1998; 126(1): 59-65. [Medline]

Samant S, Robbins KT, Vang M, Wan J, Robertson J. Intra-arterial cisplatin and concomitant radiation therapy followed by surgery for advanced paranasal sinus cancer. Arch Otolaryngol Head Neck Surg 2004; 130(8): 948-55. [Medline]

Schröck A, Göke F, Wagner P, Bode M, Franzen A, Huss S et al. Fibroblast growth factor receptor-1 as a potential therapeutic target in sinonasal cancer. Head Neck 2014; 36(9):1253-7. [Medline]

Seong SY, Hyun DW, Kim YS, Cho HJ, Lee JG, Yoon JH et al. Treatment outcomes of sinonasal adenoid cystic carcinoma: 30 cases from a single institution. J Craniomaxillofac Surg 2014; 42(5): e171-5. [Medline]

Sisson GA Sr, Toriumi DM, Atiyah RA. Paranasal sinus malignancy: a comprehensive update. Laryngoscope 1989; 99(2): 143-50. [Medline]

Snyers A, Janssens GO, Twickler MB, Hermus AR, Takes RP, Kappelle AC et al. Malignant tumors of the nasal cavity and paranasal sinuses: long-term outcome and morbidity with emphasis on hypothalamic-pituitary deficiency. Int J Radiat Oncol Biol Phys 2009; 73(5): 1343-51. [Medline]

Som PM, Shapiro MD, Biller HF, Sasaki C, Lawson W. Sinonasal tumors and inflammatory tissues: differentiation with MR imaging. Radiology 1988; 167(3): 803-8. [Medline]

Spencer SA, Harris J, Wheeler RH, Machtay M, Schultz C, Spanos W et al. Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. Head Neck 2008; 30(3): 281-8. [Medline]

Syrjänen S, Happonen RP, Virolainen E, Siivonen L, Syrjänen K. Detection of human papillomavirus (HPV) structural antigens and DNA types in inverted papillomas and squamous cell carcinomas of the nasal cavities and paranasal sinuses. Acta Otolaryngol 1987; 104(3-4): 334-41. [Medline]

Syrjänen KJ. HPV infections in benign and malignant sinonasal lesions. J Clin Pathol 2003; 56(3): 174-81. [Medline]

Syrjänen K, Syrjänen S. Detection of human papillomavirus in sinonasal carcinoma: systematic review and meta-analysis. Human Pathol 2013; 44(6): 983-91. [Medline]

Takeda A, Shigematsu N, Suzuki S, Fujii M, Kawata T, Kawaguchi O et al. Late retinal complications of radiation therapy for nasal and paranasal malignancies: relationship between irradiated-dose area and severity. Int J Radiat Oncol Biol Phys 1999; 44(3): 599-605. [Medline]

Tanzler ED, Morris CG, Orlando CA, Werning JW, Mendenhall WM. Management of sinonasal undifferentiated carcinoma. Head Neck 2008; 30(5): 595-9. [Medline]

Takahashi Y, Bell D, Agarwal G, Roberts D, Xie TX, El-Naggar A et al. Comprehensive assessment of prognostic markers for sinonasal squamous cell carcinoma. Head Neck 2014; 36(8): 1094-102. [Medline]

Thiagarajan A, Mechalakos J, Lee N. Feasibility of reirradiation of recurrent sinonasal carcinoma in the periorbital region using hypofractionated image-guided intensity-modulated radiation therapy. Head Neck 2011; 33(9): 1372-8. [Medline]

Thorup C, Sebbesen L, Danø H, Leetmaa M, Andersen M, Buchwald C et al. Carcinoma of the nasal cavity and paranasal sinuses in Denmark 1995-2004. Acta Oncol 2010; 49(3): 389-94. [Medline]

U.S. Cancer Statistics Working Group. United States Cancer Statistics: 2004 Incidence and Mortality. Atlanta, U.S. Department of Health and Human Services, Centres for Disease Control and Prevention and National Cancer Institute; 2007.

Van Dijk BA, Gatta G, Capocaccia R, Pierannunzio D, Strojan P, Licitra L, RARECARE Working Group. Rare cancers of the head and neck area in Europe. Eur J Cancer 2012; 48(6): 783-96. [Medline]

Waldron J, Witterick I. Paranasal sinus cancer: caveats and controversies. World J Surg 2003; 27(7): 849-55. [Medline]

Wiegner EA, Daly ME, Murphy JD, Abelson J, Chapman CH, Chung M et al. Intensity-modulated radiotherapy for tumors of the nasal cavity and paranasal sinuses: clinical outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2012; 83(1): 243-51. [Medline]

Wild D, Eyrich GK, Ciernik IF, Stoeckli SJ, Schuknecht B, Goerres GW. In-line (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (PET/CT) in patients with carcinoma of the sinus/nasal area and orbit. J Craniomaxillofac Surg 2006; 34(1): 9-16. [Medline]

Wu TT, Barnes L, Bakker A, Swalsky PA, Finkelstein SD. K-ras-2 and p53 genotyping of intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses. Mod Pathol 1996; 9(3): 199-204. [Medline]

Youlden DR, Cramb SM, Peters S, Porceddu SV, Møller H, Fritschi L et al. International comparisons of the incidence and mortality of sinonasal cancer. Cancer Epidemiol 2013; 3786: 770-9. [Medline]

Yousem DM, Gad K, Tufano RP. Resectability issues with head and neck cancer. AJNR Am J Neuroradiol 2006; 27(10): 2024-36. [Medline]

Zenda S, Kohno R, Kawashima M, Arahira S, Nishio T, Tahara M et al. Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys 2011; 81(5): 1473-8. [Medline]

Dr. Paolo Bossi (Editor)
Head and Neck Medical Oncology, IRCCS Foundation, Italian National Cancer Institute – Milan, Italy

Dr. Davide Farina (Author)
Department of Radiology, University of Brescia – Brescia, Italy

Dr. Gemma Gatta (Consultant)
Italian National Cancer Institute – Milan, Italy

Dr. Davide Lombardi (Author)
Department of Otorhinolaryngology, University of Brescia – Brescia, Italy

Dr. Piero Nicolai (Reviewer)
Director and Chief of the Department of Otorhinolaryngology, University of Brescia – Brescia, Italy

Dr. Ester Orlandi (Author)
Radiotherapy 2 Unit, IRCCS Foundation, Italian National Cancer Institute – Milan, Italy