**7.1 T1 NPC**

104 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

Box 1.

Stage T1 refers to disease that is localized to the nasopharynx, as well as disease that has extended inferiorly into the oropharynx or anteriorly into the nasal cavity (Lee,2004; Liu *et al.,* 2008; Yu *et al.,* 2010). Disease that is isolated to the NP is described as being superficial to the pharyngobasilar fascia (PBF). In this case, there is no evidence of tumour breaching or crossing the PBF barrier, which occasionally can be identified on T2-weighted studies as a thin dark curvilinear line running from the medial pterygoid plate laterally and following the contour of the longus musculature along the back wall of the NP (**Figure 3).** The tumour appears as a hypointense to isointense mass on T1-weighted imaging that enhances to a lesser degree than normal mucosa (Chin *et al.*, 2003).

Oropharyngeal extension is readily noted on coronal or sagittal MR imaging as tumour that has extended inferiorly past the plane of palate (**Figure 5)**. On axial sections, the oropharynx is considered involved when tumour is seen inferior to the C1/C2 junction.

Fig. 5. Axial image of a patient with NPC that shows disease that has extended down to the level of the right oropharynx.

In addition, stage T1 disease comprises anterior extension past the plane of the posterior choana into the nasal cavity (**Figure 6)**. From the nasal cavity, NPC can invade through the sphenopalatine foramen into the pterygopalatine fossa (stage T3 disease), resulting in obliteration of the normal fat content in this fossa (**Figure 7).** Direct extension from the nasal cavity is the most common route of NPC invasion into the pterygopalatine fossa, followed

Imaging of Nasopharyngeal Carcinoma 107

Disease that has spread beyond the PBF and infiltrated posterolaterally into the parapharyngeal space (PPS) is considered stage T2. This can lead to compression of the Eustachian tube, resulting in middle ear and mastoid effusion (King & Bhatia, 2010). PPS invasion is associated with worse disease control and survival rates, as well as increased rate of distant metastases compared to stage T1 (Cheng *et al*., 2005; Chua *et al.*, 1996; Ho *et al.*, 2008; Teo *et al*., 1996). On imaging, key components of the PPS include the tensor veli palatini and levator palatine muscles. PPS involvement is recognized as a disruption or attenuation of the PBF, infiltration of the tensor veli palatini, or breach of the

Infiltration of the fatty component of the PPS is visible on T1-weighted imaging as an intermediate signal mass invading into the hyperintense fat of the PPS (**Figure 8).** As the disease progresses, the full thickness of the intrapharyngeal portion of the levator veli muscle and the tensor veli palatini muscle (appearing as a thin strip of muscle just lateral to the levator veli palatini) may also become involved, followed by infiltration of the normally pristine fat of the prestyloid PPS, which is located deep to the tensor muscle. With further posterolateral spread, the poststyloid PPS structures, such as the carotid sheath, also become

Fig. 8. Axial T2 weighted images shows a carcinoma that has infiltrated lateral to the tensor and levator veli palatini. Solid arrow shows normal tensor veli palatini on the right. Dashed arrow shows the abnormal left levator muscle which is being displaced and the presence of

intrapharyngeal portion of the levator veli palatini muscle.

vulnerable to disease (**Figure 9**).

tumor lateral to it.

**7.2 T2 NPC** 

by extension from the ethmoid and/or sphenoid sinuses. The significance of pterygopalatine fossa involvement is described later (T3 NPC).

Fig. 6. NPC which has extended beyond the plane of the posterior choana (dashed line) into the nasal cavity.

Fig. 7. Axial T1 weighted image shows abnormal soft tissue filling the right and left pterygopalatine fossae (\*).

#### **7.2 T2 NPC**

106 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

by extension from the ethmoid and/or sphenoid sinuses. The significance of

Fig. 6. NPC which has extended beyond the plane of the posterior choana (dashed line) into

Fig. 7. Axial T1 weighted image shows abnormal soft tissue filling the right and left

pterygopalatine fossa involvement is described later (T3 NPC).

the nasal cavity.

pterygopalatine fossae (\*).

Disease that has spread beyond the PBF and infiltrated posterolaterally into the parapharyngeal space (PPS) is considered stage T2. This can lead to compression of the Eustachian tube, resulting in middle ear and mastoid effusion (King & Bhatia, 2010). PPS invasion is associated with worse disease control and survival rates, as well as increased rate of distant metastases compared to stage T1 (Cheng *et al*., 2005; Chua *et al.*, 1996; Ho *et al.*, 2008; Teo *et al*., 1996). On imaging, key components of the PPS include the tensor veli palatini and levator palatine muscles. PPS involvement is recognized as a disruption or attenuation of the PBF, infiltration of the tensor veli palatini, or breach of the intrapharyngeal portion of the levator veli palatini muscle.

Infiltration of the fatty component of the PPS is visible on T1-weighted imaging as an intermediate signal mass invading into the hyperintense fat of the PPS (**Figure 8).** As the disease progresses, the full thickness of the intrapharyngeal portion of the levator veli muscle and the tensor veli palatini muscle (appearing as a thin strip of muscle just lateral to the levator veli palatini) may also become involved, followed by infiltration of the normally pristine fat of the prestyloid PPS, which is located deep to the tensor muscle. With further posterolateral spread, the poststyloid PPS structures, such as the carotid sheath, also become vulnerable to disease (**Figure 9**).

Fig. 8. Axial T2 weighted images shows a carcinoma that has infiltrated lateral to the tensor and levator veli palatini. Solid arrow shows normal tensor veli palatini on the right. Dashed arrow shows the abnormal left levator muscle which is being displaced and the presence of tumor lateral to it.

Imaging of Nasopharyngeal Carcinoma 109

Fig. 10. 10A is a sagittal T1 image that shows NPC invasion into the clivus. There is a loss of the inferior cortical margin of the clivus. The clivus is also of uniform lower signal that reflects sclerotic change. 10B is as coronal T1 image in another patient that shows NPC

Fig. 11. Coronal T2 (left) and post gadolinium enhanced T1 (right) weighted images show

superior extension of NPC through the floor of the sphenoid sinus (arrows).

infiltration into the left aspect of the clivus (arrow).

Fig. 9. Axial T1 image shows a large right sided NPC that has extended to encase the right internal carotid artery (arrow).

#### **7.3 T3 NPC**

Stage T3 disease is characterized by involvement of the paranasal sinuses and/or the central skull-base structures. Skull base invasion is seen in up to 60% of NPC patients at diagnosis (King *et al*., 1999; Roh *et al.,* 2004), with the most common sites of involvement being the clivus, pterygoid bones, body of the sphenoid bone, and apices of the petrous temporal bones (King & Bhatia, 2010). In addition, the number of sites involved within the skull base may have prognostic significance (Lu *et al.*, 2004). Assessment of the skull base should focus on five key regions: clivus, right pterygoid base, left pterygoid base, right petrous apex, and left petrous apex (King & Bhatia, 2010). On axial T1-weighted MR sequences, bony skull base disease is detected as a loss of the hyperintense signal, which is characteristic of normal fatty yellow bone marrow. It is replaced with an intermediate signal indicative of either bony reaction or actual invasion. NPC commonly invades posteriorly into the clivus (**Figure 10).** Although normal clival marrow may appear heterogeneous on T1-weighted images, it should still appear more intense than the pons (Goh & Lim, 2009). In addition, up to 25% of patients have tumour spread superiorly into the floor of the sphenoid sinus, often extending up into the sphenoid sinus cavity (Chong & Fan, 1993; Goh & Lim, 2009) (**Figure 11).** The body of the sphenoid is more difficult to assess and may be best studied on coronal images (King & Bhatia, 2010). The sphenoid wings and upper cervical spine should also be assessed. CT scans may also have a role in detecting the presence of cortical erosion and bony sclerosis, which reflects reactive changes due to tumour invasion. It is important, however, to note that sclerosis is a non-specific sign that may arise from adjacent sinus disease, particularly in the sinus margins and the pterygoids.

Fig. 9. Axial T1 image shows a large right sided NPC that has extended to encase the right

Stage T3 disease is characterized by involvement of the paranasal sinuses and/or the central skull-base structures. Skull base invasion is seen in up to 60% of NPC patients at diagnosis (King *et al*., 1999; Roh *et al.,* 2004), with the most common sites of involvement being the clivus, pterygoid bones, body of the sphenoid bone, and apices of the petrous temporal bones (King & Bhatia, 2010). In addition, the number of sites involved within the skull base may have prognostic significance (Lu *et al.*, 2004). Assessment of the skull base should focus on five key regions: clivus, right pterygoid base, left pterygoid base, right petrous apex, and left petrous apex (King & Bhatia, 2010). On axial T1-weighted MR sequences, bony skull base disease is detected as a loss of the hyperintense signal, which is characteristic of normal fatty yellow bone marrow. It is replaced with an intermediate signal indicative of either bony reaction or actual invasion. NPC commonly invades posteriorly into the clivus (**Figure 10).** Although normal clival marrow may appear heterogeneous on T1-weighted images, it should still appear more intense than the pons (Goh & Lim, 2009). In addition, up to 25% of patients have tumour spread superiorly into the floor of the sphenoid sinus, often extending up into the sphenoid sinus cavity (Chong & Fan, 1993; Goh & Lim, 2009) (**Figure 11).** The body of the sphenoid is more difficult to assess and may be best studied on coronal images (King & Bhatia, 2010). The sphenoid wings and upper cervical spine should also be assessed. CT scans may also have a role in detecting the presence of cortical erosion and bony sclerosis, which reflects reactive changes due to tumour invasion. It is important, however, to note that sclerosis is a non-specific sign that may arise from adjacent sinus disease,

internal carotid artery (arrow).

particularly in the sinus margins and the pterygoids.

**7.3 T3 NPC** 

Fig. 10. 10A is a sagittal T1 image that shows NPC invasion into the clivus. There is a loss of the inferior cortical margin of the clivus. The clivus is also of uniform lower signal that reflects sclerotic change. 10B is as coronal T1 image in another patient that shows NPC infiltration into the left aspect of the clivus (arrow).

Fig. 11. Coronal T2 (left) and post gadolinium enhanced T1 (right) weighted images show superior extension of NPC through the floor of the sphenoid sinus (arrows).

Imaging of Nasopharyngeal Carcinoma 111

Fig. 12. Coronal postcontrast study shows a large NPC that has extended laterally into the right masticator space as well as superiorly to invade the cavernous sinus, sphenoid sinus

Fig. 13. Axial image shows asymmetric thickening and enhancement along the left V2 nerve

Orbital invasion, usually arising from the pterygopalatine fossa via the inferior orbital fissure or directly from the cavernous sinus, denotes the most extensive form of disease (King & Bhatia, 2010) (**Figure 15).** From the PPS, pterygoid base, or pterygomaxillary fissure, NPC can extend laterally to involve masticator space, which includes the medial and lateral pterygoid muscles, temporalis muscle, infratemporal fat, as well as the mandibular division (V3) of the trigeminal nerve **(Figure 14).** Disease involving the masticator space can give rise to trismus and weakness in mastication. In addition, the V3 nerve is vulnerable to tumour infiltration within the masticator space. Both antegrade and retrograde perineural spread along V3 is possible. From the masticator space, NPC can also extend superiorly through the floor of the middle cranial fossa and foramen ovale to gain access to the intracranial cavity

and cause mass effect upon the right temporal lobe.

(arrows).

and the cavernous sinus.

Next, the skull base foramina and fissures – which include the foramen rotundum (V2 nerve), the vidian canal (vidian nerve), the foramen ovale (V3 nerve), and foramen lacerum – should be examined. Nerve involvement signifies stage T4 disease (see section below). The foramen ovale and lacerum are common routes of tumour extension into the intracranial cavity (King & Bhatia, 2010). While the skull base foramina present an unobstructed route for tumor spread, direct invasion of the bone bordering these foramina is also a common finding. The skull base foramina are best assessed on coronal images. Less common findings include inferior spread of tumor to involve the hypoglossal nerve canal (XII nerve) and jugular foramen (IX-XI nerves) (King & Bhatia, 2010).

It is important to differentiate tumour spread into the paranasal sinuses – which include the ethmoid sinuses, sphenoid sinuses, and maxillary sinuses – from benign mucosal inflammatory changes, which are common in patients with NPC. On MRI, mucosal thickening can be distinguished from NPC by a greater uniform T2-weighted signal and a marked degree of contrast enhancement. With tumor invasion into the ethmoid sinuses, which usually occurs via direct spread from the sphenoid sinus or nasal cavity, there is a reduced chance of shielding the optic nerve from the radiation dose in RT. Involvement of the sphenoid sinus, which is separated from the nasopharynx by only a thin plate of bone, is a common finding (**Figure 11**). In contrast, anteroinferior tumour invasion into the maxillary sinuses is a rare event, except in late disease where there is usually extensive invasion throughout the nasal cavity, other paranasal sinuses, skull base, and brain (King *et al.*, 1999). Sinus involvement is seen on imaging as a loss of contiguity of the sinus walls.

#### **7.4 T4 NPC**

T4 disease is denoted by intracranial extension and/or involvement of the cranial nerves, hypopharynx, orbit, or masticator space. Unchecked, NPC can extend superiorly into the cavernous sinus and dura **(Figure 12)**, while direct invasion of the brain is rare at diagnosis (King & Bhatia, 2010). There are multiple routes into the cavernous sinus, including extension from tumour surrounding the horizontal portion of the internal carotid artery or cranial nerve V3, as well as extension from the orbital fissures or the skull base in the region of the foramen ovale or sphenoid sinus (King & Bhatia, 2010). Within the cavernous sinus, cranial nerves III, IV, V1, V2, and VI are vulnerable to tumour invasion. Their involvement is manifested clinically through an abnormal neurological examination, as well as by signs and symptoms of various cranial nerve palsies, including extraocular muscle dysfunction, facial pain, paresthesia and numbness. True perineural spread, however, is uncommon in the pre-treatment setting (King & Bhatia, 2010). Prognostically, cranial nerve involvement has been shown to be associated with a higher rate of distant metastases and decreased survival (Yu *et al*., 2010). Radiologically, postcontrast T1-weighted MR sequences with fat saturation are used to assess for cranial nerve involvement, especially for V2 along foramen rotundum (**Figure 13**) and V3 in the foramen ovale **(Figure 14).** Contrast-enhanced MRI shows perineural disease extension and cavernous sinus involvement as asymmetric nodular thickening and abnormal enhancement. Skip lesions may also be noted. A late sequelae is expansion of the bony canals in which these nerves travel.

Next, the skull base foramina and fissures – which include the foramen rotundum (V2 nerve), the vidian canal (vidian nerve), the foramen ovale (V3 nerve), and foramen lacerum – should be examined. Nerve involvement signifies stage T4 disease (see section below). The foramen ovale and lacerum are common routes of tumour extension into the intracranial cavity (King & Bhatia, 2010). While the skull base foramina present an unobstructed route for tumor spread, direct invasion of the bone bordering these foramina is also a common finding. The skull base foramina are best assessed on coronal images. Less common findings include inferior spread of tumor to involve the hypoglossal nerve canal (XII nerve) and

It is important to differentiate tumour spread into the paranasal sinuses – which include the ethmoid sinuses, sphenoid sinuses, and maxillary sinuses – from benign mucosal inflammatory changes, which are common in patients with NPC. On MRI, mucosal thickening can be distinguished from NPC by a greater uniform T2-weighted signal and a marked degree of contrast enhancement. With tumor invasion into the ethmoid sinuses, which usually occurs via direct spread from the sphenoid sinus or nasal cavity, there is a reduced chance of shielding the optic nerve from the radiation dose in RT. Involvement of the sphenoid sinus, which is separated from the nasopharynx by only a thin plate of bone, is a common finding (**Figure 11**). In contrast, anteroinferior tumour invasion into the maxillary sinuses is a rare event, except in late disease where there is usually extensive invasion throughout the nasal cavity, other paranasal sinuses, skull base, and brain (King *et al.*, 1999). Sinus involvement is seen on imaging as a loss of contiguity of the sinus

T4 disease is denoted by intracranial extension and/or involvement of the cranial nerves, hypopharynx, orbit, or masticator space. Unchecked, NPC can extend superiorly into the cavernous sinus and dura **(Figure 12)**, while direct invasion of the brain is rare at diagnosis (King & Bhatia, 2010). There are multiple routes into the cavernous sinus, including extension from tumour surrounding the horizontal portion of the internal carotid artery or cranial nerve V3, as well as extension from the orbital fissures or the skull base in the region of the foramen ovale or sphenoid sinus (King & Bhatia, 2010). Within the cavernous sinus, cranial nerves III, IV, V1, V2, and VI are vulnerable to tumour invasion. Their involvement is manifested clinically through an abnormal neurological examination, as well as by signs and symptoms of various cranial nerve palsies, including extraocular muscle dysfunction, facial pain, paresthesia and numbness. True perineural spread, however, is uncommon in the pre-treatment setting (King & Bhatia, 2010). Prognostically, cranial nerve involvement has been shown to be associated with a higher rate of distant metastases and decreased survival (Yu *et al*., 2010). Radiologically, postcontrast T1-weighted MR sequences with fat saturation are used to assess for cranial nerve involvement, especially for V2 along foramen rotundum (**Figure 13**) and V3 in the foramen ovale **(Figure 14).** Contrast-enhanced MRI shows perineural disease extension and cavernous sinus involvement as asymmetric nodular thickening and abnormal enhancement. Skip lesions may also be noted. A late sequelae is expansion of the bony

jugular foramen (IX-XI nerves) (King & Bhatia, 2010).

walls.

**7.4 T4 NPC** 

canals in which these nerves travel.

Fig. 12. Coronal postcontrast study shows a large NPC that has extended laterally into the right masticator space as well as superiorly to invade the cavernous sinus, sphenoid sinus and cause mass effect upon the right temporal lobe.

Orbital invasion, usually arising from the pterygopalatine fossa via the inferior orbital fissure or directly from the cavernous sinus, denotes the most extensive form of disease (King & Bhatia, 2010) (**Figure 15).** From the PPS, pterygoid base, or pterygomaxillary fissure, NPC can extend laterally to involve masticator space, which includes the medial and lateral pterygoid muscles, temporalis muscle, infratemporal fat, as well as the mandibular division (V3) of the trigeminal nerve **(Figure 14).** Disease involving the masticator space can give rise to trismus and weakness in mastication. In addition, the V3 nerve is vulnerable to tumour infiltration within the masticator space. Both antegrade and retrograde perineural spread along V3 is possible. From the masticator space, NPC can also extend superiorly through the floor of the middle cranial fossa and foramen ovale to gain access to the intracranial cavity and the cavernous sinus.

Imaging of Nasopharyngeal Carcinoma 113

without positive nodal disease (N0). Positive neck nodal disease in NPC is associated with an increased risk of local recurrence and distant metastases (Goh & Lim, 2009). Unlike other head and neck squamous cell carcinomas, nodal disease in NPC is more frequently

NPC generally follows a very orderly pathway of nodal spread, beginning with the (lateral) retropharyngeal lymph nodes (RPN) (**Figure 16**) – located medial to the carotid artery – before involving nodal groups along the internal jugular chain (level II to IV), spinal accessory chain (Va and Vb), as well as supraclavicular nodes (Glastonbury, 2007; King *et al.,* 2004). Level IIa or b nodes, located posterior to the jugular vein in the upper neck, are the most common site for non-retropharyngeal node involvement (Mao *et al.*, 2008) (**Figure 17).** 

bilateral.

Fig. 16. Cystic right retropharyngeal lymph node.

Fig. 17. Right sided level II adenopathy (\*).

Fig. 14. Coronal image shows NPC that has extended laterally into the left masticator space and subsequent perineural tumor tracking superiorly (dashed arrows) along V3 into the left cavernous sinus (\*). Solid arrow shows the normal contralateral V3 nerve.

Fig. 15. Axial T2 weighted scan shows intermediate signal tumor that has extended through the superior orbital fissure into the left orbit.

The hypopharynx, which is the most inferior site included in the TMN staging classification, is very rarely involved at diagnosis due to the tendency of NPC to extend superiorly rather than inferiorly (King & Bhatia, 2010).

#### **7.5 Nodal stage**

The NPC N classification system differs from other head and neck mucosal malignancies (see Box 1). Up to 60–90% of NPC patients will have nodal metastases at presentation (Glastonbury, 2007; Goh & Lim, 2009), suggesting that only 10-40% of cases present

Fig. 14. Coronal image shows NPC that has extended laterally into the left masticator space and subsequent perineural tumor tracking superiorly (dashed arrows) along V3 into the left

Fig. 15. Axial T2 weighted scan shows intermediate signal tumor that has extended through

The hypopharynx, which is the most inferior site included in the TMN staging classification, is very rarely involved at diagnosis due to the tendency of NPC to extend superiorly rather

The NPC N classification system differs from other head and neck mucosal malignancies (see Box 1). Up to 60–90% of NPC patients will have nodal metastases at presentation (Glastonbury, 2007; Goh & Lim, 2009), suggesting that only 10-40% of cases present

the superior orbital fissure into the left orbit.

than inferiorly (King & Bhatia, 2010).

**7.5 Nodal stage** 

cavernous sinus (\*). Solid arrow shows the normal contralateral V3 nerve.

without positive nodal disease (N0). Positive neck nodal disease in NPC is associated with an increased risk of local recurrence and distant metastases (Goh & Lim, 2009). Unlike other head and neck squamous cell carcinomas, nodal disease in NPC is more frequently bilateral.

NPC generally follows a very orderly pathway of nodal spread, beginning with the (lateral) retropharyngeal lymph nodes (RPN) (**Figure 16**) – located medial to the carotid artery – before involving nodal groups along the internal jugular chain (level II to IV), spinal accessory chain (Va and Vb), as well as supraclavicular nodes (Glastonbury, 2007; King *et al.,* 2004). Level IIa or b nodes, located posterior to the jugular vein in the upper neck, are the most common site for non-retropharyngeal node involvement (Mao *et al.*, 2008) (**Figure 17).** 

Fig. 16. Cystic right retropharyngeal lymph node.

Fig. 17. Right sided level II adenopathy (\*).

Imaging of Nasopharyngeal Carcinoma 115

as a loss or irregularity of the nodal margins, and/or streakiness of the adjacent fat (Yu *et al*., 2010). Patients with nodes showing necrosis and extranodal spread have a very poor

There are several features on imaging that are suggestive of metastatic nodal disease, including a large size (although there is no accepted size criterion, generally >1.5 cm for levels I and II, >1 cm for levels for levels IV-VII, and >5 mm for RPN using the shortest transaxial diameter is considered suspicious) (Goh & Lim, 2009; King & Bhatia, 2010), a group of 3 or more nodes borderline in size, rounded nodes with loss of the fatty hilum, and necrosis (King & Bhatia, 2010). If identified, necrosis is considered 100% specific. However, due to resolution restrictions, necrosis can only be reliability identified in tumour foci greater than 3 mm, of which approximately one-third reportedly have nodal necrosis (Goh & Lim, 2009; Som & Brandwein, 2003; Yousem *et al.,* 1992). Necrosis or cystic change is hypointense on T1-weighted images with rim enhancement with contrast, and hyperintense on T2-weighted images (**Figure 16)**. In CT images, necrosis is seen as a focal area of

Fig. 19. Bilateral level II adenopathy. Focal areas of lower attenuation on CT is compatible

The M stage of NPC is similar to that of other malignancies, whereby M0 signifies the absence of distant metastasis and M1 refers to the presence of such disease. NPC has the highest incidence of distant metastasis among head and neck cancers, with a rate as high as 11% at diagnosis (Kumar *et al.,* 2004; Teo *et al.*, 1996). The likelihood of metastasis increases

prognosis with a 50% decreased 5-year survival rate (Som *et al*., 1987).

hypoattenuation with or without rim enhancement (**Figure 19)**.

with the presence of necrotic change.

**7.6 Distant metastasis (M)** 

with increasing T and N stage.

Nodal disease in the submandibular and parotid/periparotid regions is a rare occurrence (Chong & Fan, 2000; King & Bhatia, 2010), but should be evaluated for radiotherapy planning purposes. Although the RPN are generally considered the first echelon of metastatic spread, studies have shown that this is not true in all cases (Liu *et al.*, 2006; Mao *et al.*, 2008; Ng *et al.*, 2004; Wang *et al*., 2009). While King *et al.* found that the RPN were bypassed in only 6% of cases to preferentially affect the level II distribution, Ng *et al.* found that 17 of 89 cases of NPC bypassed the RPN (King *et al.,* 2000; Ng *et al.*, 2004). In addition, Ng *et al.* also reported skip metastases in the lower neck lymph nodes and the supraclavicular fossa in 7.9% of cases, and distant metastases to thoracic and abdominal nodes in 3-5% of cases. After radiotherapy, level I nodes may also become involved (Ahuja *et al.,* 1999).

In the current N classification system, N1 disease consists of the presence of unilateral metastasis in cervical lymph node(s) that are 6 cm or less in their greatest dimension, and/or unilateral or bilateral RPN metastasis that are 6 cm or less in their greatest dimension. Nodes greater than 3 cm in size are generally considered "nodal masses" and are indicative of confluent nodes. N2 disease is defined by bilateral metastasis in the cervical lymph node(s) that are again 6 cm or less in greatest dimension**.** Unlike other carcinomas in the neck, N2 is not further divided into substages. In both N1 and N2 stages, disease is restricted to above the supraclavicular fossa. Once supraclavicular fossa nodal involvement is noted, the disease is upstaged to N3b. Supraclavicular nodes include all lymph nodes seen on the same axial cross-sectional slice as a portion of the clavicle, and include Level IV and Vb nodes. Stage N3a disease is defined by matted nodes greater than 6 cm in their greatest dimension, although this is a rare finding (King & Bhatia, 2010) (**Figure 18**).

Fig. 18. Massive conglomerate right sided neck adenopathy measuring over 6cm in dimension -N3a disease.

While distinguishing between the primary tumour mass and adjacent RPN is best assessed with MRI, cervical lymph nodes can be evaluated accurately with both MRI and CT (King *et al.,* 2004). T2-weighted imaging with fat saturation shows nodes as bright structures in the posterior cervical fat (**Figure 17).** The higher resolution of CT facilitates the visualization of neck adenopathy, as well as nodal necrosis and extracapsular extension. The latter manifests

Nodal disease in the submandibular and parotid/periparotid regions is a rare occurrence (Chong & Fan, 2000; King & Bhatia, 2010), but should be evaluated for radiotherapy planning purposes. Although the RPN are generally considered the first echelon of metastatic spread, studies have shown that this is not true in all cases (Liu *et al.*, 2006; Mao *et al.*, 2008; Ng *et al.*, 2004; Wang *et al*., 2009). While King *et al.* found that the RPN were bypassed in only 6% of cases to preferentially affect the level II distribution, Ng *et al.* found that 17 of 89 cases of NPC bypassed the RPN (King *et al.,* 2000; Ng *et al.*, 2004). In addition, Ng *et al.* also reported skip metastases in the lower neck lymph nodes and the supraclavicular fossa in 7.9% of cases, and distant metastases to thoracic and abdominal nodes in 3-5% of cases. After radiotherapy, level I nodes may also become involved (Ahuja

In the current N classification system, N1 disease consists of the presence of unilateral metastasis in cervical lymph node(s) that are 6 cm or less in their greatest dimension, and/or unilateral or bilateral RPN metastasis that are 6 cm or less in their greatest dimension. Nodes greater than 3 cm in size are generally considered "nodal masses" and are indicative of confluent nodes. N2 disease is defined by bilateral metastasis in the cervical lymph node(s) that are again 6 cm or less in greatest dimension**.** Unlike other carcinomas in the neck, N2 is not further divided into substages. In both N1 and N2 stages, disease is restricted to above the supraclavicular fossa. Once supraclavicular fossa nodal involvement is noted, the disease is upstaged to N3b. Supraclavicular nodes include all lymph nodes seen on the same axial cross-sectional slice as a portion of the clavicle, and include Level IV and Vb nodes. Stage N3a disease is defined by matted nodes greater than 6 cm in their greatest

dimension, although this is a rare finding (King & Bhatia, 2010) (**Figure 18**).

Fig. 18. Massive conglomerate right sided neck adenopathy measuring over 6cm in

While distinguishing between the primary tumour mass and adjacent RPN is best assessed with MRI, cervical lymph nodes can be evaluated accurately with both MRI and CT (King *et al.,* 2004). T2-weighted imaging with fat saturation shows nodes as bright structures in the posterior cervical fat (**Figure 17).** The higher resolution of CT facilitates the visualization of neck adenopathy, as well as nodal necrosis and extracapsular extension. The latter manifests

*et al.,* 1999).

dimension -N3a disease.

as a loss or irregularity of the nodal margins, and/or streakiness of the adjacent fat (Yu *et al*., 2010). Patients with nodes showing necrosis and extranodal spread have a very poor prognosis with a 50% decreased 5-year survival rate (Som *et al*., 1987).

There are several features on imaging that are suggestive of metastatic nodal disease, including a large size (although there is no accepted size criterion, generally >1.5 cm for levels I and II, >1 cm for levels for levels IV-VII, and >5 mm for RPN using the shortest transaxial diameter is considered suspicious) (Goh & Lim, 2009; King & Bhatia, 2010), a group of 3 or more nodes borderline in size, rounded nodes with loss of the fatty hilum, and necrosis (King & Bhatia, 2010). If identified, necrosis is considered 100% specific. However, due to resolution restrictions, necrosis can only be reliability identified in tumour foci greater than 3 mm, of which approximately one-third reportedly have nodal necrosis (Goh & Lim, 2009; Som & Brandwein, 2003; Yousem *et al.,* 1992). Necrosis or cystic change is hypointense on T1-weighted images with rim enhancement with contrast, and hyperintense on T2-weighted images (**Figure 16)**. In CT images, necrosis is seen as a focal area of hypoattenuation with or without rim enhancement (**Figure 19)**.

Fig. 19. Bilateral level II adenopathy. Focal areas of lower attenuation on CT is compatible with the presence of necrotic change.

#### **7.6 Distant metastasis (M)**

The M stage of NPC is similar to that of other malignancies, whereby M0 signifies the absence of distant metastasis and M1 refers to the presence of such disease. NPC has the highest incidence of distant metastasis among head and neck cancers, with a rate as high as 11% at diagnosis (Kumar *et al.,* 2004; Teo *et al.*, 1996). The likelihood of metastasis increases with increasing T and N stage.

Imaging of Nasopharyngeal Carcinoma 117

Tumour volume has also been reported to have significant prognostic relevance outside of the TNM classification system (Wei & Sham, 2005). There is an estimated 1% increase risk of local control failure with every 1 cm3 increase in tumour volume. The increased risk is attributed to factors such as increase number of tumour clonogens, tumor hypoxia and relative radioresistance, etc (Bentzen *et al.*, 1991; Johnston *et al.,* 1995; Lartigau *et al.*, 1993; Sze *et al.*, 2004). However, issues with standardized methods of volume measurement, the intraand interobserver reliability due to operator-dependent tracing, as well as the technical challenges associated with implementing this in the clinical setting – including the time it takes to perform this tedious task – have prevented it from being routinely used in daily

Nasopharyngeal carcinoma is a relatively rare neoplasm with a characteristic geographic and ethnic distribution. It most commonly arises in the lateral pharyngeal recess, and has a tendency to invade widely and metastasize. Cervical lymphadenopathy is very common at

Diagnosis of NPC can be made on endoscopically-guided biopsy, but effective treatment of NPC requires an accurate mapping of tumor volume and extent with imaging. Imaging allows for evaluation of tumour extent, including submucosal, osseous, and intracranial tumour spread which cannot be assessed clinically or endoscopically. Staging of NPC is based on the new 2010 AJCC guidelines. MRI is the best tool for assessing tumour extent under the current staging system, while high-resolution CT has value for assessing cortical bone erosion and PET/CT is emerging as the most accurate modality for assessing distant

A thorough understanding of the anatomy of the nasopharynx and surrounding structures, as well as the natural history of the disease and patterns of spread, allows for accurate

Ahuja AT, Leung SF, Teo P, Ying M, King W, Metreweli C (1999). Submental metastasis

Bentzen SM, Johansen LV, Overgaard J, Thames HD (1991). Clinical radiobiology of

Burt RD, Vaughan TL, McKnight B (1992). Descriptive epidemiology and survival analysis of nasopharyngeal carcinoma in the United States. *Int J Cancer*. 52:549 – 56. Caglar M, Ceylan E, Ozyar E (2003). Frequency of skeletal metastases in nasopharyngeal

Brennan B (2006). Nasopharyngeal carcinoma. *Orphanet Journal or Rare Diseases. 1:23.* 

squamous cell carcinoma of the oropharynx. *Int J Radiat Oncol Bio Phys.* 206:1197-

carcinoma after initiation of therapy: should bone scans be used for follow-up?

from nasopharyngeal carcinoma. *Clin Radiol*. 54:25-8.

**8. Tumour volume** 

practice.

**9. Summary** 

metastases and recurrence.

**10. References** 

1206.

tumour mapping and treatment planning.

*Nucl Med Commun*. 24(12):1231

presentation and is a common presenting complaint.

The most commonly affected regions are the bone, lung and liver (Chiesa & De Paoli, 2001) (**Figure 20)**. Thus, bones and lung apices should be evaluated for tumour involvement in head and neck MRI studies, especially in patients with risk factors such as metastatic cervical nodes which extend to the supraclavicular fossa (stage N3b).

Fig. 20. A and B 20A is a sagittal T1 weighted exam of the spine showing multiple areas of abnormal intermediate signal within vertebral bodies in the lower thoracic and lumbar spine -bony metastases. 20B is a contrast CT of the abdomen that shows the presence of multiple liver metastases.

The presence of M1 disease is associated with shorter survival rates (Teo *et al.*, 1996) and significantly alters patient management, as such patients are generally considered to be incurable. Median survival is under four months and approximately 90% of patients with distant metastases pass away within a year (Goh & Lim, 2009; Khor *et al.,* 1978). The goal of treatment in such instances will be palliation with therapy being applied for locoregional symptom control.

The exact method for the evaluation of distant metastasis will vary from institution to institution. Imaging options include bone scintigraphy, chest x-ray, CT of the thorax, abdomen and pelvis, and PET/CT. Studies have shown fluorodeoxyglucose PET/CT imaging to have a higher sensitivity and specificity in detecting distant metastases (Chen *et al.,* 2006; Chua *et al.*, 2009; Comoretto *et al.,* 2008; King *et al.,* 2008; Lin *et al.*, 2008; Liu *et al.*, 2007; Ng *et al.*, 2009; Wang *et al.*, 2007; Yu *et al.,* 2010).
