PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
To understand the malignant gradient of the nasopharynx in terms of the oncoanatomy of the head and face, it is essential to understand both its superior aspect and its relationship to the cavernous sinus in the skull.
PERSPECTIVE AND PATTERNS OF SPREAD
Nasopharyngeal cancer is uncommon in white populations and accounts for only 2% of all head and neck cancers in the United States. The nasopharynx can be a harbinger of malignant disease, particularly common among the Chinese population. This is true for specific provinces and subpopulations; the risk is maintained even after migrating to the United States and applies to second-generation Chinese. Its etiology is being investigated from the point of view of viral induction, immunologic response, environmental pollutants, and ingestion of nitrates in food. The Epstein-Barr virus is commonly identified in elevated antibody titers, but it also has been associated with other malignances and is not truly specific for this site.
Cancer of the nasopharynx has two major spread patterns, depending on whether the primary tumor extends locally or metastasizes to parapharyngeal nodes (Fig. 4.2A). The juxtaposition of the mucosa to the base of the skull allows for immediate access to the cranial fossa. The foramen lacerum is accessible and is the only foramen medial to the pharyngeal tube and its fascia. Once the base of the skull is invaded, the tumor enters into the cavernous sinus and can involve a number of cranial nerves. There are numerous clinical syndromes, depending on which combination of nerves is involved. Invasion of cranial nerves, inferiorly to superiorly, are cranial nerves III, IV, and VI, which can cause diplopia or ophthalmoplegia because of the resultant partial paralysis of one eye (Fig. 4.2B). Deafness is caused by local obstruction of the eustachian tube leading to tympanic membrane fixation, and not caused by involvement of cranial nerve VIII. The acoustic nerve is well encased in the mastoid bone of the inner ear with its meatus in the posterior fossa. Despite the fact that the eustachian tube is open, cancer rarely invades along this pathway into the middle ear, probably because of the cartilaginous wall of the tube and the absence of a good vascular bed. Proptosis, periorbital edema, and orbital invasion are a result of extensive invasion along the base of the skull and/or thrombosis of the cavernous sinuses. Patterns of Spread are presented as a cancer crab that can invade in six basic directions Superior-Inferior, Medial-Lateral, Anterior-Posterior (SIMLAP) of adjacent anatomic sites (Fig. 4.2 and Table 4.2).
PATHOLOGY
The epithelium of the nasopharynx varies from a stratified squamous in its lower part to a pseudostratified ciliated columnar epithelium along its walls and roof. Because of Waldeyer's lymphatic ring, many different tumors can arise in this site—lymphoepitheliomas and lymphosarcomas in addition to carcinomas (Table 4.1). The most common, however, are carcinomas, which are locally invasive and destructive to the bony structures of the skull (Fig. 4.1). Lymphoepitheliomas tend to spread bilaterally to nodes in the neck and may present in this fashion. Lymphosarcomas are bulky lesions that tend to interfere with breathing but tend to be less destructive.
Figure 4.1 | Nasopharyngeal nonkeratinizing carcinoma, undifferentiated type. The cells have large nuclei and prominent eosinophilic nucleoli. The cells are cytokeratin-positive (by immunohistochemistry; inset) indicating an epithelial cell proliferation.
Figure 4.2 | Patterns of spread. A. Sagittal view notes extensions into Oropharynx and parapharyngeal invasion. B. Coronal view notes invasion of skull base, cavernous sinus and cranial nerves. The primary cancer (nasopharynx) invades in various directions which are color-coded vectors (arrows) representing stage of progression: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red; and T4, black. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six directional pattern i.e. SIMLAP Table 4.2.
TMN STAGING CRITERIA
TNM STAGING CRITERIA
The classification and staging of nasopharyngeal cancers, both for primary (T) and nodes (N) criteria, are unique to this site and do not follow the majority of head and neck cancer sites. The major variable has been assessment of the suprastructure involvement of the base of the skull and contents of cavernous sinus, cranial nerves III, IV, and VI. Essentially, the T progression is into subsites of the nasopharyngeal region; however, T4 has been, since the first edition of American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC), an invasion of suprastructure bone and cranial nerves. Nodal progression was similar to other head and neck sites until the fifth and sixth editions of AJCC/UICC.
Nasopharyngeal cancer is different from other cancers of the head and neck, but has remained relatively unchanged since its introduction in the third edition of the AJCC/UICC classifications (1988). The vectors of invasion vary with the biologic behavior of these different malignancies.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
The TNM stages according to the 7th Edition of AJCC are illustrated in color code of advancement (Fig. 4.3). For Nasopharynx, T2a lesions will now be designated T1. Stage IIA will therefore be Stage I. Lesions previously staged T2b will be T2 and therefore Stage IIB will now be designated Stage II. Retropharyngeal lymph node(s), regardless of unilateral or bilateral location, is considered N1. T2a lesions are T1 confined to nasopharynx with extension to oropharynx or nasal cavity. T2b lesions are T2 parapharyngeal extension. The TNM Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 4.3).
NASOPHARYNX
Figure 4.3 | TNM stage grouping. Nasopharyngeal cancers are not resectable and staging categories differ from other head and neck sites as to T/N definitions. Vertical presentations of stage groupings, which follow the same color code for cancer stage advancement, are organized in horizontal lanes: Stage 0, yellow; I, green; II, blue; III, purple; IVA, red; and IVB, black. Definitions of TN on left and stage grouping on right.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
For the nasopharynx, the anatomic isocenter is at the level of C1, the atlas. The anterior surface bullet enters through the tip of the nose (Fig. 4.4A) and the lateral bullet is at the temporal mandibular joint, just below the level of the external auditory canal (Fig. 4.4B).
T-oncoanatomy
The nasopharynx is a small, box-like space in the center of the head, posterior to the nasal cavity and superior to the pharyngeal tube. The anterior limit of the nasopharynx is the chona, through which it is continuous with the nasal cavity. Its roof is attached to the base of the skull, and slopes downward to become continuous with the posterior pharyngeal wall. The lateral wall is composed of the torus tubarius, the eustachian tube orifice, and that posterior portion of the mucosa, the fossa of Rosenmüller, extending up to its apex and junction with the roof. The inferior limit of the nasopharynx is level with the plane of the hard palate.
To understand the importance of the nasopharynx in terms of the anatomy of the head and face, it is essential to understand both its superior aspect and its relationship to the skull and lateral walls. The pharyngeal fascia is attached to the base of the skull. This can be diagrammed in relationship to those foramina, which may be invaded and destroyed by carcinomas. The superior attachment of the pharyngobasilar fascia starts from the midline pharyngeal tubercle on the basiocciput, extending across the petrous portion of the temporal bone to a point in front of the carotid canal. From there, it passes posteromedially to the petrotympanic fissure in the region where the eustachian tube attaches and the levator palati originates, and then attaches to the medial pterygoid lamina. The fascia inferiorly is continuous over the superior pharyngeal constrictor muscle.
• Coronal section (Fig. 4.5A) provides a view from the retropharyngeal space. The roof of the nasopharynx is occupied by the sphenoid sinus, alongside of which are the cavernous sinuses. Within its contents are three cranial nerves responsible for extraocular motion (III, IV, and VI), laterally lies the Gasserian (trigeminal) ganglion (cranial nerve V) and its major branches as they exit through different foramina along the base of the skull into the parapharyngeal space, paranasal sinuses, and orbit.
• Sagittal plane (Fig. 4.5B) shows the lateral walls of the nasopharynx, which consist of the eustachian tube and its two related muscles, the tensor veli palatini and the levator veli palati, the latter of which is more important functionally for tubal patency. The muscles are continuous with the palatopharyngeus muscles and superior constrictor, forming the pharyngeal muscular tube.
• Transverse plane (Fig. 4.5C) shows the parapharyngeal space divided into three compartments by the styloid process, its muscles, and the related fascial expansions from the carotid sheath and prevertebral fascia. A neoplastic process may extend into and follow these preformed spaces but, unlike an inflammatory process, also may extend through these barriers and invade nerves.
The retropharyngeal compartment houses Rouviere's node, which is a major focus of metastatic spread. As these parapharyngeal nodes enlarge, they compress the neurovascular bundle in the carotid sheath. The retrostyloid compartment contains the internal carotid artery, the last four cranial nerves, and cervical sympathetics. The prestyloid is formed by the tensor palatini muscle and the pterygoid muscles. It contains the maxillary artery and important nerves. Once this latter space is invaded, access is gained laterally into the deep portion of the parotid gland and inferiorly to the submaxillary gland.
Figure 4.4 | Orientation of three-planar T-oncoanatomy. The anatomic isocenter is at the axial level at clivus/C1. A. Coronal. B. Sagittal.
Figure 4.5 | T-oncoanatomy. The Color Code for the anatomic sites correlates with the color code for the stage group (Fig. 4.3) and patterns of spread (Fig. 4.2) and SIMLAP table (Table 4.2). Connecting the dots in similar colors will provide an appreciation for the 3D Oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
With nodal dissemination, the high parapharyngeal nodes along the carotid sheath are involved and extend into the retrostyloid compartment (Fig. 4.6). This leads to entrapment of the cranial nerves emerging alongside the jugular foramen. The nodes in this region are named after Rouviere—famous for his treatise on lymphoid anatomy. Again, numerous neurologic syndromes can occur. The retroparotidian syndrome, or the jugular foramen syndrome, is characterized by loss of the gag reflex (cranial nerve IX), vocal cord paralysis (cranial nerve X), atrophy of the trapezius muscle (cranial nerve XI), and deviation of the uvula (cranial nerve X) and tongue on protrusion (cranial nerve XII).
In addition to retropharyngeal and parapharyngeal nodes, the main routes of lymphatic spread of the nasopharynx are into the first station nodes, that is, the jugulodigastric, juguloomohyoid, upper deep cervical, lower deep cervical, and submaxillary and submental lymph nodes. Bilateral node spread is common (Table 4.4). Mediastinal lymph node metastases are considered distant metastases. Distant spread to the lungs is common in this type of cancer. Incidence and distribution of neck node metastases in a clinically negative (N0) neck are presented in Figure 4.7A.
Figure 4.6 | N-oncoanatomy. The red node highlights the sentinel node, which is the retropharyngeal node (Rouviere's Node). A. Anterior view. B. Lateral view. M-oncoanatomy is determined by the jugular vein, which joins with the subclavian vein to form the superior vena cava on the right, and the innominate vein, which drains into the right side of the heart and then into lung.
Figure 4.7 | A. Percent of neck nodes () on presentation by MRI according to AJCC levels. B. The Incidence and Distribution of Distant Metastases. The Oropharyngeal Cancers can serve as a prototype for head and neck cancers. Lung (58%) is the target organ with liver metastases next (29%) and bone metastases third (22%) followed by distant lymph nodes (17%), mediastinum (14%). The remainder of sites are 11% (kidney) or less than 10%.
M-ONCOANATOMY
The cavernous sinus and lateral pterygoid buccal venous plexus drains into the jugular vein, brachiocephalic vein, and then into the subclavian vein and right superior vena cava. Hematogenous spread, although uncommon, can include lung and bone as favored sites of involvement. Skeletal and other distant metastases occur infrequently (see Fig. 4.7B; Table 4.5).
CRANIAL NERVES AND NEUROVASCULAR BUNDLE
Nasopharynx cancers first invade parapharyngeal space and then invade through the foramen, lacerum, and then enter the cavernous sinus and pack off CN VI, IV, and III in that order causing diplopia. As it extends laterally, the Gasserian ganglion is encountered and as each branch of cranial nerve veins become involved, each produces a specific neurologic defect: V1 eyelid anesthesia, V2 upper lip and nasal anesthesia, and V3 lower face anesthesia. Retropharyngeal (Rouviere's) Node compresses the neurovascular bundle of CN IX, X, XI, XII exiting the skull along side the carotid artery and jugular vein (Table 4.5).
The importance of appreciating the complex anatomy of cranial nerves lies in the patterns of cancer spread at the primary cancer site as well as nodal spread patterns. Perineural invasion or compression by metastatic lymph nodes often is manifested by specific neurologic symptoms and signs. The overview of cranial nerves provides an intricate roadmap as to points of vulnerability.
Cranial nerve invasion can produce specific syndromes and neurologic evaluation is a vital part of physical diagnosis in all head and neck cancers.
A tabulation of potential neurologic syndromes either due to perineural invasion at the primary site or nodal compression will alert the astute clinician to extent of cancer advancement anatomically.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
For nasopharyngeal cancers, careful history taking and inspection and palpations of the face and neck are essential. Testing all cranial nerves is critical. Both direct and indirect endoscopy are useful. Despite patient cooperation, pharyngeal cancers are inaccessible and imaging is important. To determine the true extent of primary nasopharyngeal cancers, imaging is essential. Magnetic resonance imaging (MRI) is superior to computed tomography (CT) in demonstrating soft tissue extension, skull base bone changes, and perineural invasion (see Table 4.6 and Figure 4.8).
Pathologic Staging
Histopathologic verification of primary and nodes is performed by needle aspiration or biopsy. Nasopharyngeal cancers are not resectable.
Oncoimaging Annotations
• Most nasopharyngeal tumors arise in the fossa of Rosenmüller and tend to spread deeply, often obstructing the eustachian tube.
• The vast majority (75%) of nasopharyngeal cancer patients have cervical node metastases at presentation. Bilateral involvement occurs in up to 80%.
• MRI is superior to CT in demonstrating the soft tissue extent of the tumor and skull base changes. CT often underestimates the frequency and extent of skull base involvement.
• After successful radiation therapy, there is usually complete tumor resolution on images within 3 months. A baseline, posttreatment scan should be obtained at approximately 6 months. Differentiating tumor recurrence from fibrosis can be a formidable task.
• Positron emission tomography (PET) with fluorine-18–labeled deoxy-D-glucose (FDG) enhancement may be useful in evaluating tumor recurrence. Both PET and thallium 201 single-photon emission computed tomography (SPECT) may be used to differentiate tumor from radiation-induced necrosis.
• CT and MRI can identify Rouviere's node opposite C1 transverse process.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSTIC FACTORS
The seventh edition of the AJCC Cancer Staging Manual lists the following prognostic factors for nasal ethmoid sinus cancers:
• Size of lymph nodes
• Extracapsular extension from lymph nodes for head and neck
• Head and neck lymph nodes levels I-III
• Head and neck lymph nodes levels IV-V
• Head and neck lymph nodes levels VI-VII
• Other lymph node group
• Clinical location of cervical nodes
• Extracapsular spread (ECS) clinical
• Extracapsular spread (ECS) pathologic
• Human papillomavirus (HPV) status
• Tumor thickness*
*The foregoing passage is from Edge SB, Byrd DR, and Compton CC, et al, AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 99.
CANCER STATISTICS AND SURVIVAL
Generally, cancers of the oral cavity and pharynx, the upper digestive passage, account for 36,540 new cases per year. In addition, cancer of the larynx affects another 12,720 patients and thyroid cancers, 44,670. Approximately 25% of head and neck cancer patients die annually, often due to other causes. Long-term survival in thyroid cancer is the exception, with only 1,500 deaths (5%). The improvement in oral cavity and pharyngeal tumors from 1950 to 2000 was modest at 14% and matches larynx at 15%. A multidisciplinary approach is vital.
Specifically, nasopharyngeal cancers are difficult to detect and metastasize to bilateral neck nodes with generally poor overall survival for all stages. When encountered in early stages in high-risk Chinese populations, 5-year survival is at the 90% level. Combined chemoradiation regimens (Cis-platinum and 5-fluoracil with radiation) have dramatically improved response rates and survival. Recent AJCC survival data indicated improved survival rates for all stages as compared to other head and neck sites (Fig. 4.9).
Figure 4.8 | MRI of nasal cavity and nasopharynx—Transverse (axial) inferior view. Normal anatomy of the nasopharynx. A: Sagittal contrast-enhanced magnetic resonance (MR) image shows the nasopharynx (asterick), sphenoid sinus (large star), clivus (C), and soft palate (small star). B: Axial T1-weighted MR image shows the right Eustachian tube opening (small arrow), torus tubarius (small arrow), torus tubaris (small white asterisk), fossa of Rosenmuller (large white arrow), parapharyngeal space (black asterick), masticator space (star), left carotid space (black arrow), and left longus colli muscle (L). C: Coronal CT shows the sphenoid sinus (star), left torus tubarius (asterick), fossa of Rosenmüller (thick white arrow), eustachian tube opening (thin white arrow), and foramen ovale (black arrow). The CT/MRI transverse section can be correlated with the anatomy in Fig. 4.5C. (Bragg DG, Rubin P, Hricak H. Oncologic Imaging, 2nd edition. Philadelphia, W. B. Saunders, 2002.)
Figure 4.9 | Five-year survival rates by stage at diagnosis. (Data from Edge SB, Byrd DR, and Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.)