T1	Tumour confined to the nasopharynx
T2A	Tumour extends to the oropharynx and/or nasal cavity without parapharyngeal extension
T2B	Tumour with parapharyngeal extension, i.e. infiltrates beyond the pharyngobasilar fascia
T3	Tumour that invades bony structures and/or paranasal sinuses
T4	Tumour with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit or masticator space
N1	Unilateral (including midline) lymph node(s) ≤6 cm above the supraclavicular fossa
N2	Bilateral lymph node(s) ≤ 6 cm above the supraclavicular fossa
N3A	Any lymph node >6 cm
N3B	Any node that involves the supraclavicular fossa

Aetiology, pathology and lymphatic spread

Squamous cell carcinomas comprise the commonest histological type. They may be subdivided into well to poorly differentiated types, those with a heavy lymphatic infiltrate (‘lymphoepithelioma’), transitional cell tumours and keratinizing and non-keratinizing types. The WHO usefully classifies nasopharyngeal tumours as follows:

Type 1	Well-differentiated keratinizing type
Type 2	Moderately-differentiated non-keratinizing type
Type 3	Undifferentiated type typically with an extensive lymphocytic infiltrate.

The presence of keratin (i.e. type 1) is associated with local infiltration while type 3 tumours tend to disseminate widely.

NPC is associated with infection with the Epstein-Barr virus (EBV). EBV DNA is incorporated into the tumour genome. Antibodies to EBV (IgG and IgA) precede tumour development by several years and the antibody titer is correlated with tumour burden, remission and recurrence. A practical point is the detection of EBV genomic material in the biopsies from neck lymph node metastases from an apparent unknown primary may point to the origin in the nasopharynx. Infection with EBV is common and is the cause of glandular fever. In Hong Kong, almost all children aged 10 years have been infected by the virus. Even in Hong Kong, only a small minority develop NPC. Genetic and dietary factors seem important in tumour development. Searches for genes conferring susceptibility to NPC have focused on human leukocytes antigen (HLA) genes. The genes encode proteins required for viral lysis.

Three HLA alleles have a consistent association with an increased risk of NPC in South Chinese and other Asian populations. They are HLA-A2, B46 and B17. Dietary factors are also important, including eating salt dried fish (containing carcinogenic nitrosamines) and lack of fresh fruit and vegetables (lack of antioxidants).

While squamous cell carcinomas form the majority of nasopharyngeal cancers, other pathologies are recognized in this region. These include adenocarcinoma, adenoid cystic carcinoma and lymphoma. Treatment may vary according to the tumour type according to the propensity for nodal spread and response to radiation, though the principles of technique as described here can still broadly be applied.

It is because of the rich lymphatic supply that these tumours commonly spread and, indeed, present with neck nodes. This spread may be bilateral but the distribution is dissimilar to other head and neck squamous cell carcinomas and is reflected in the TNM classification outlined earlier. Seventy to 90% of cases have nodes at some point. Levels 1A/B are rarely involved while levels 2 and 5 (the post-cervical chain) can be considered the first echelon nodes for this tumour site.

Nasopharyngeal cancers have a high propensity for distal haematogenous spread and, as a consequence, distal failure. This is generally unlike other head and neck squamous cell carcinomas where locoregional control is the barrier to success (though the more aggressive treatments are starting to alter this pattern).

Signs and symptoms

The first presenting symptom is often painless node enlargement confirmed on examination. These are often bilateral in their distribution and, as mentioned earlier, typically involve the posterior cervical chain.

Other common symptoms include nasal obstruction and epistaxis through expansion into the nasal cavity and auditory disturbances, especially unilateral deafness and recurrent otitis media. Examination findings may confirm a mass in the post-nasal space and cranial nerve palsies especially of II–VI through direct expansion through bone and via nerve foramina and IX–XII through compression from Rouviere’s node. Rouviere’s node is the most superior node of the retropharyngeal node chain and overlies the transverse process of C1.

Patients may report headaches though other symptoms or signs will usually be readily apparent.

Diagnosis and staging

The diagnosis may be strongly suspected on clinical grounds alone from the above findings especially on nasendoscopic examination, but histological confirmation of any nasopharyngeal mass will be required. A formal examination under anaesthesia will often be helpful in delineating the extent but further locoregional staging, best with magnetic resonance imaging (MRI), is mandatory. A computed tomography (CT) scan, while adequate, does not afford the same degree of information, particularly in the base of skull region.

In the context of neck nodes where a primary is not readily apparent, especially when they lie posteriorly in the upper neck, the finding of EBV genomic material using DNA amplification techniques (PCR) is usually indicative of a clinically inapparent nasopharyngeal primary and treatment should be along the lines of such tumours.

Since nasopharyngeal cancers have a high propensity for systemic spread, a work-up for distal disease is essential. As such, haematological and biochemical screens and a chest x-ray are an absolute minimum. More detailed imaging of the viscera (CT scan of chest and abdomen) and bones (isotope scan) are essential for more advanced disease and if basic screening tools are in any way suspicious. A positron emission tomography (PET)-CT may be useful in that regard.

Treatment

The relative inaccessible nature of the primary tumour and frequent involvement of Rouviere’s node dictates that radiation therapy is the main modality for treatment. In addition and unlike other head and neck squamous cell carcinomas, the presence of substantial neck nodes should not lead to initial surgical excision as they generally respond well to radiation therapy. Any nodes that have failed to respond adequately or at recurrence can, provided the primary disease is controlled, then be managed by an appropriate neck dissection.

Prior to radiation therapy, a thorough dental assessment is mandatory with essential treatment performed as necessary.

Small tumours of the nasopharynx can be adequately treated with radiation alone. However, the majority should, co-morbidity permitting, be managed with concurrent chemoradiation. The nasopharynx is the one head and neck site where concurrent chemoradiation has been more readily adopted internationally due in part to the intergroup 0099 study. This study compared concurrent chemoradiation and adjuvant chemotherapy with radiotherapy alone and showed a significant advantage in survival with the combined modality approach. The control arm was particularly inferior, however, when compared with other studies. Further studies and a recent meta-analysis specifically of nasopharyngeal cancers have, however, supported the concurrent chemoradiation approach. Neoadjuvant chemotherapy may result in useful reduction of the primary and/or nodal disease. A major problem in delivering adjuvant chemotherapy is the poor compliance following definitive therapy. Research from Taiwan suggests that adjuvant treatment after concomitant chemoradiotherapy may only be necessary for patients with a high chance of developing metastatic disease. This includes patients with a single lymph node >6 cm, multiple nodes over >4 cm or supraclavicular nodes. The most frequently used regimen is cisplatin (100 mg/m² or 20 mg/m² for 5 days) plus 5-fluorouracil (400–100 mg/m² daily by infusion for up to 4 days). This is repeated at 3–4 weekly intervals during radiotherapy.

Radiation technique (Figures evolve 22.3–22.8 for NPC section)

The technique of Ho forms the basis of the 2-dimensional approach to treating nasopharyngeal carcinoma. Treatment fields are precisely defined according to local staging. Determination of the primary clinical target volume is now very much individualized based on all clinical information available allowing for a more conformal 3-dimensional approach. The pattern of spread outlined earlier dictates that the whole cervical lymphatic chain should be outlined and treated as routine, though doses prescribed will be determined by whether they are overtly involved and proximal to the primary site or more distal and clinically uninvolved. In other words, even in early cases, at least prophylactic doses of radiation should be given to the nodes.

A full head and neck immobilization device is mandatory with the shoulders kept well down. A tongue depressor is frequently utilized but a drop in jaw position might negate the perceived benefits of this technique in sparing the oral cavity. A single shell is preferred throughout the treatment with the degree of neck extension optimized at the outset.

Except in the case of intensity modulated radiotherapy techniques, a multiple phase technique will be utilized to treat the primary disease and involved nodes using parallel-opposed fields. The lower cervical nodes will be treated by an anterior (or anterior-posterior (AP) depending on the location of nodes in the AP plane) field matched on preferably by the mono-isocentric technique. As a general rule, matching of fields should not occur at sites of gross disease but this may not be practical in nasopharyngeal cancers.

Where the primary tumour is relatively small (T1, T2), it might be practical to irradiate it as a final phase with a three-field technique thereby sparing some of the laterally placed normal structures from the maximum intended dose. Alternatively, and according to available expertise, intracavity, stereotactic radiosurgery or intensity modulated radiotherapy (IMRT) may facilitate dose escalation at the site of gross disease with improved local control.

Complications

The significant volumes of normal tissue ordinarily irradiated can give rise to a range of long-term sequelae.

Irradiation of major aspects of the salivary tissue will lead to chronic xerostomia. The technique of IMRT may facilitate less of an impact here, though care will need to be taken in underdosing any adjacent diseased lymph nodes. In practice, it may be prudent to spare only the superficial parotid glands bilaterally even using IMRT.

High doses of radiation may be delivered to a substantial component of the mandible, particularly when using the parallel-opposed technique and where there are involved nodes. As a consequence, treatment risks osteoradionecrosis (ORN) and preventive measures beyond meticulous radiation technique should be adopted. Moreover, the proximity of the pterygoid muscles to the primary target volume will give rise to trismus and jaw exercises should be encouraged to minimize this.

Endocrine failure due to irradiation of the pituitary and thyroid glands, though relatively easy to treat, is a not uncommon outcome in long-term survivors and should be actively sought through routine testing in the follow up of these patients.

Advanced tumours with extension into the skull base introduce additional tissues exposed to the high doses of radiation that will be necessary to achieve local control. Aspects of the temporal lobes, optic nerves and chiasm, middle and inner ear will be irradiated and, as a consequence, are at risk of late neurological damage. The addition of chemotherapy may add to this toxicity. In all cases, the brainstem and spinal cord are organs of risk and prescribed doses should not exceed an agreed tolerance dose. The complex interrelationship with such a range of normal tissues mandates a meticulous radiation technique to minimize these complications. The technique of IMRT lends itself to such a site but does not obviate the need for precise target volume delineation. Results using IMRT demonstrate superior coverage of advanced tumours and an improvement in disease control.

The undifferentiated type of nasopharyngeal cancer is rather more radiosensitive and, as such, slightly lower doses may be delivered with a consequent lessening effect on late sequelae.

Results

Small tumours of the nasopharynx are successfully treated in about 80–90% cases. More advanced tumours, when treated optimally, will result in 5-year survival rates of the order of 50–70%. Those patients with extensive nodes and/or involvement of the skull base with cranial nerve palsies fare particularly badly with 5-year survival rates ranging from 0 to 20%, often succumbing to distal failure. Late recurrences are recognized suggesting that follow up beyond 5 years might be prudent and/or advising patients and primary care practitioners of this so that they can re-referred without delay. Recurrent disease may, on occasions, be amenable to re-irradiation as long as volumes to be treated are relatively small and the patient is prepared to accept the additional risks associated with such an approach.

Nose and nasal cavity

Anatomy

The external nose is like the tip of an iceberg with a complex array of passageways and air cavities within it that form the nasal cavity and paranasal sinuses. The hair-bearing entrance that forms the vestibule and the mucociliary escalator provides an important initial defence against the inhalation of germs (Figure 22.9).

Figure 22.9 Nose and nasal cavity anatomy.

The nasal vestibule lies within the aperture of the nostril. It is bounded laterally by cartilage that forms the nasal ala, medially by cartilage that forms the columella and inferiorly by the most anterior portion of the floor of the nose. Importantly, this area is lined by squamous epithelium as an extension from the outside skin.

The nasal cavity or nasal fossa proper lies between the maxillary sinus inferiorly and the eyes and ethmoidal sinus superiorly. It is divided into two by a midline cartilaginous septum.

Superior wall

This is comprised of the cribriform plate of the ethmoidal sinus. The olfactory apparatus which lies here provides us with our sense of smell.

Inferior wall

Broader than the superior wall, this is formed from the hard palate.

Anterior wall

The nasal bones and cartilage that form the external nose give rise to the anterior wall.

Posterior wall

The posterior border of the hard palate and maxillary sinus gives an open passage into the nasopharynx.

Lateral wall

Three turbinates overlie the lateral wall which itself is formed from the medial walls of the maxillary sinus inferiorly and the ethmoid sinus superiorly.

Incidence

Many cancer registries combine nasal, paranasal and middle ear tumours together when reporting incidence, as all three types are rare. The incidence of all three types combined is 1:100 000 per annum. About two-thirds of all cases arise in the sinuses giving a true incidence of nasal cancer of about 0.3:100 000. The nasal vestibule is the most common site of origin. Men who have worked in the chromium industry (Glasgow/Teeside) or nickel refining (South Wales) are at increased risk of developing this rare cancer. Chromate-induced cancers are often accompanied by a septal perforation.

Staging system

The system used for the nasal cavity is identical to that for ethmoidal sinus tumours in view of the anatomical relationship of these two structures. The reader is referred to the later section on paranasal sinus tumours for fuller details, but the following summarizes the T classification as applicable here.

T1	Tumour restricted to one subsite of the nasal cavity
T2	Tumour involves two subsites in a single site or extends to involve an adjacent site within the nasoethmoidal complex
T3	As ethmoid sinus
T4A	As ethmoid sinus
T4B	As ethmoid sinus

Aetiology, pathology and lymphatic spread

The normal lining of the nasal cavity is pseudostratified columnar ciliated epithelium except for the vestibule, as mentioned earlier, that comprises squamous epithelium with sweat and sebaceous glands.

The aetiology of true nasal cavity tumours is not dissimilar to that of the paranasal sinuses with many environmental factors being implicated. Smoking is associated with the commonest histological subtype seen. Such squamous cell carcinomas arise most commonly at the lateral wall.

Other histologies comprise the remaining 20% and include adenocarcinoma, adenoid cystic carcinoma, melanoma, lymphoma, plasmacytoma and sarcoma. Inverted papillomas, themselves rare, can transform or coexist with squamous cell carcinoma. Olfactory neuroblastomas (aesthesioblastomas) arise from the olfactory tissue at the level of the cribriform plate. Basal cell carcinomas can arise in the vestibule.

The lymphatic drainage of the nasal cavity can be usefully divided into two. The main part of the nasal cavity drains via the nasopharynx to the retropharyngeal nodes and upper deep cervical nodes (levels 2A and 2B). The lower anterior portion drains to the submandibular (level 1B), parotid (preauricular) and jugulodigastric (level 2A) nodes. The nasal vestibule itself includes, additionally, the buccinator node as part of the facial lymphatic complex.

Signs and symptoms

Unlike paranasal sinus tumours, these tumours tend to present comparatively early with obstructive symptoms and epistaxis. However, symptoms of benign disease can blur the presence of malignancy and squamous cell carcinomas of the lateral wall may, on further investigation, be a late manifestation of maxillary sinus disease. Inspection of the nasal cavity will typically reveal a fleshy outgrowth.

Diagnosis and staging

Biopsy of the suspected lesion is required. A polypoidal lesion may be snared off and may give rise to an unsuspected tumour when examined pathologically. It may be necessary to perform a lateral rhinotomy to obtain adequate exposure and surgical evaluation of lesions within the nasal cavity.

Except for the small tumour of vestibule, which can usually be demarcated in the clinic, tumours of the nasal fossa proper require thorough staging with CT and/or MRI. Care must be taken in interpreting benign secretions from malignant infiltration of soft tissue and bone invasion as this may impact on the degree of surgery.

Certain tumour types, for example adenoid cystic as well as lymphoma, will require exclusion of distal involvement as this may dictate local management.

Treatment (see Figures evolve 22.10–22.14 )

Small tumours of the vestibule can be managed by either surgery or radiotherapy. The choice will in part be based on the expected cosmetic outcome.

More advanced tumours of the vestibule or those of the nasal fossa proper will usually require surgical clearance often followed by radiotherapy, especially if it is a squamous cell carcinoma in view of the propensity for bone invasion. Lymphomas and plasmacytomas can be managed by primary radiotherapy at appropriate doses with or without the addition of chemotherapy.

Inoperable nasal cavity tumours should be managed by combined chemoradiation according to the co-morbidity of the patient.

Tumours of the vestibule and low anterior nasal fossa tumours may be treated by a direct anterior appositional electron beam, implantation with iridium wires, direct lateral photons or an anterior oblique wedged pair field arrangement (Figure evolve 22.15 ). The choice will be dictated by the extent of the clinical target volume (CTV) and the physical constraints of the particular modality as well as local expertise. The relatively superficial nature of these tumours and the shape that presents dosimetry problems usually dictates the need for some bolus material on the skin surface when using external beam treatment. The facial lymphatics may be included as a separate target volume and treated prophylactically using separate electron fields.

More advanced tumours and those within the nasal fossa proper frequently require an approach similar to that used for maxillary sinus tumours. Here, a midline anterior and two lateral photons are used to cover adequately the defined target volume or ideally IMRT. The reader is referred to this later section for more details.

CT planning for all but the most superficial tumours facilitates accurate tumour definition and normal tissue avoidance. The true CTV may extend much more posteriorly than initially envisaged and therefore needs to be delineated with precision.

As with all head and neck tumours, good immobilization is required. A mouthbite is used to move the tongue away from the treatment volume. For superficial tumours treated by electrons, this may also facilitate the placement of lead material for shielding and wax bolus for the anterior wedge photon technique.

Complications

Superficial tumours will inevitably manifest acute skin reactions that usually heal promptly. In the longer term, atrophy of the nasal cartilage may result in some loss of the original nasal profile.

Deeper tumours managed with techniques similar to that used for paranasal sinus tumours may be complicated by damage to the normal tissues in the vicinity. Atrophy of the nasal lining will result in dryness and a tendency towards the development of crusts. Regular use of a saline spray helps to address this. Epiphora will result if there is stenosis of the nasolacrimal duct.

Results

The diversity of pathologies at this site and the relative rarity even of squamous cell carcinoma of the nasal cavity give rise to only limited outcome data. Nonetheless, early squamous cell carcinoma of the vestibule can be expected to result in cure rates of the order of 80–90% at 5 years. More advanced tumours of the vestibule and fossa proper will give rise to cure rates of the order of 40–60%. Olfactory neuroblastomas carry a better prognosis, while patients with mucosal melanomas generally fare badly.

Paranasal sinus tumours

Anatomy (Figure 22.16)

The paranasal sinuses comprise four pairs of linked hollow cavities within the anterior and mid-portions of the skull that link to the nasal cavity. They are named according to the bone within which they lie. The purpose of the paranasal sinuses is to lighten the bone and give resonance to the voice.

Figure 22.16 Paranasal sinus anatomy.

Maxillary sinuses

Lying under the eyes, these sinuses are pyramidal in shape. The base of the pyramid forms the lateral wall of the nasal cavity with the apex extending towards the zygomatic process. The superior aspect comprises the floor of the orbit and the ethmoidal sinus while the inferior extent is that of the alveolar process and typically lies just below the floor of the nasal cavity. The infraorbital nerve traverses the roof of the sinus while the first and second molar teeth typically project into the sinus floor. The posterior wall abuts the infratemporal and pterygopalatine fossae. The maxillary sinus drains via the ostium maxillare beneath the middle concha.

Frontal sinus

Lying over the eyes in the frontal bones, these sinuses only reach full size after puberty. They drain into the nasal cavity through the middle meatus beneath the middle concha via the frontonasal duct.

Ethmoid sinus

Lying either side of the upper part of the nasal cavity and between the orbits, these sinuses are grouped into three portions: the anterior and middle drain into the nasal cavity via the middle meatus, the posterior via the superior meatus beneath the superior concha. A thin bony lamina (the lamina papyracea) separates the sinus from the orbital and nasal cavities. The optic nerve lies posterior to the sinus and the anterior cranial fossa superiorly.

Sphenoid sinus

Lying deep in the skull base beneath the pituitary gland, this sinus, which also develops mainly after puberty, drains into the nasal cavity via the sphenoethmoidal recess above the superior concha of the nasal cavity. The nasopharynx lies inferiorly and the nasal cavity anteriorly to the sinus while the optic nerve and cavernous sinuses lie laterally.

Incidence of paranasal sinus tumours

These tumours are rare with a crude incidence of <0.5/100 000. Most tumours arise in the maxillary sinus, less commonly the ethmoid sinus. Tumours arising de novo in the frontal and sphenoidal sinuses are especially rare. Frequently, multiple sinuses are involved at presentation.

Staging system for paranasal sinus tumours

The TNM system as described here is only applicable to maxillary sinus tumours. The ethmoidal sinuses are classified separately. There is no formal system that applies to tumours of the sphenoidal and frontal sinuses. The N component is as elsewhere for head and neck squamous cell carcinomas.

	Maxillary sinus	Ethmoidal sinus
T1	Mucosa only	One subsite
T2	Bone erosion/destruction (not posteriorly)	Two subsites
T3	Bone erosion/destruction (if posteriorly), involvement of the subcutaneous tissues floor and medial wall of the orbit, pterygoid fossa and ethmoid sinus	Involvement of the medial wall and floor of the orbit, maxillary sinus, cribriform plate
T4A	Involvement of the anterior orbital contents, skin of the cheek, pterygoid plates, infra-temporal fossa, cribriform plate, sphenoidal or frontal sinuses	As maxillary sinus
T4B	Involvement of the orbital apex, dura, brain, middle cranial fossa, cranial nerves (excluding the second division of the Vth cranial nerve), nasopharynx or clivus	As maxillary sinus