Description
Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumour originating from the nasopharynx, specifically the lateral nasopharyngeal recess or Rosenmüller’s fossa, which is the most common site of origin. It is closely associated with Epstein-Barr virus (EBV) infection and is unique amongst head and neck cancers due to its high degree of local invasiveness and high incidence of cervical lymph node and distant metastases. It is the most common cancer arising from the nasopharynx.
What are the anatomical boundaries of the nasopharynx?
- Superior Boundary: The nasopharynx extends from the base of the skull, specifically the sphenoid and occipital bones.
- Inferior Boundary: It is continuous with the oropharynx at the level of the soft palate.
- Anterior Boundary: Posterior choanae of the nasal cavity.
- Posterior Boundary: Oharyngeal constrictor muscles and the cervical vertebrae.
- Lateral Boundaries: The lateral walls contain the pharyngeal ostia of the Eustachian tubes, the torus tubarius and importantly the fossa of Rosenmüller.
Pathogenesis
The development of NPC is influenced by a combination of factors, including Epstein-Barr virus (EBV) infection, genetic predisposition, and environmental influences, such as consumption of certain types of preserved foods high in nitrosamines. EBV infection leads to the expression of viral oncoproteins, which interact with host cell proteins to drive malignant transformation and proliferation.
What is Epstein-Barr Virus?
Epstein-Barr Virus (EBV) is a herpesvirus (human herpesvirus 4) that is widespread globally, infecting more than 90% of the adult population. EBV is primarily transmitted through saliva and is the causative agent of infectious mononucleosis (glandular fever). It has a strong association with several malignancies, including nasopharyngeal carcinoma, Burkitt lymphoma, and Hodgkin lymphoma. The virus infects B-lymphocytes and epithelial cells, establishing a latent infection that can reactivate. EBV’s oncogenic potential is linked to its ability to drive uncontrolled cell proliferation and inhibit apoptosis through the expression of viral oncogenes like LMP1 and EBNA2. Environmental and genetic factors also influence the pathogenicity and clinical outcomes of EBV infection.
Subtypes
NPC is categorised based on the World Health Organisation (WHO) histological classification:
- Keratinising squamous cell carcinoma (WHO Type I) (25%): Least common and least associated with EBV.
- Non-keratinising carcinoma (WHO Type II):
- Differentiated: Moderately associated with EBV. Shows features between keratinising and undifferentiated types.
- Undifferentiated: Most common and most strongly associated with EBV.
- Basaloid Squamous Cell Carcinoma (BSCC) (WHO Type III): Rare, aggressive and has a poor prognosis
Epidemiology, Risk Factors & Associations
- More common in males than females (ratio 2-3:1)
- Higher incidence in Southern China, Southeast Asia, North Africa, and the Arctic (Inuit population)
- EBV infection (nearly all undifferentiated type NPCs show evidence of EBV infection)
- Dietary risk factors include consumption of salt-preserved fish and other preserved foods high in nitrosamines
- Genetic predisposition has been noted, with a higher incidence in individuals with affected first-degree relatives
Clinical Features
NPC typically presents with non-specific symptoms such as nasal obstruction, hearing loss, or recurrent serous otitis media. Neck mass (due to cervical lymphadenopathy) is common (80-90%) and often the first noticed sign. Cranial nerve palsies may occur in advanced disease due to skull base invasion.
Complications
- Metastasis to cervical lymph nodes, lungs, liver, and bones
- Cranial nerve palsies
- Nasopharyngeal stenosis
- Post-radiation trismus, xerostomia, temporal lobe radiation necrosis, cranial nerve dysfunction, atrophy and fibrosis of muscles of mastication and salivary glands.
Pathological Features
Histopathology
- Macroscopic: Tumour typically forms an ulcerative and infiltrative mass in the nasopharynx
- Microscopic: Depending on the subtype, it can range from keratinising squamous cell carcinoma with obvious squamous differentiation (Type I) to non-keratinising carcinoma with little to no squamous differentiation (Type II). BSCC consists of small, basaloid cells and often has foci of squamous differentiation.
Radiological Features
General Features
- Characteristically demonstrates a soft tissue mass arising near the eustachian tube in the region of Rosenmüller’s fossa
- In early stages, NPC may appear as an asymmetrical thickening of the mucosal layer in the nasopharynx, usually confined by the pharyngobasilar fascia and may be indistinguishable from prominent adenoid tissue.
- However, in advanced cases, it may present as a large mass and;
- May extend to adjacent structures such as the nasal cavity, oropharynx, skull base, and cervical lymph nodes
- May invades the prevertebral muscles and spreads along the neural foramina
- The cervical lymph nodes are often involved, with nodal metastases being a common feature.
- Retropharyngeal nodes are typically affected first, although metastases may skip to the level II nodes in some cases.
CT
- Non-contrast: NPC may be seen as a mass causing asymmetrical thickening of the nasopharyngeal wall, particularly arising from the Fossa of Rosenmüller. Erosion or destruction of the base of the skull may be evident in advanced disease.
- Contrast-enhanced: Heterogenously enhancing soft tissue mass. Lymphadenopathy with central necrosis, if present, may show rim enhancement.
MRI
- T1: Typically isointense to muscle
- T2: Typically iso- to hyperintense to muscle. Better appreciate tumour extension. Mastoid effusion may be seen.
- T1 FS Gd+: Prominent heterogenous enhancement and associated lymphadenopathy. Evaluate for perineural extension (nerve enlargement and enhancement).
- DWI/ADC: Restricted diffusion due to high cellularity.
NM
- PET FDG: Marked uptake in the primary tumour and any metastatic lymph nodes. Highly sensitive. Modality of choice for detection of recurrence.
Grading and Staging
The grading of nasopharyngeal carcinoma is based on histopathological findings from biopsy, and these grades inform prognosis and treatment planning.
Histological grading of nasopharyngeal carcinoma (NPC) is determined by the World Health Organisation (WHO), which classifies NPC into three types:
- Type 1 – Keratinising Squamous Cell Carcinoma (KSCC): This type is the least common, accounting for around 25% of all NPCs, and has the worst prognosis. KSCC is associated with differentiated squamous epithelial cells that form keratin. It tends to occur in older adults and is less associated with Epstein-Barr virus (EBV).
- Type 2 – Non-keratinising Carcinoma (NKC): This type is further divided into differentiated and undifferentiated types. The differentiated type is less common than the undifferentiated type, but both are highly associated with EBV infection. The undifferentiated type is the most common subtype globally, particularly in endemic regions, and has a better prognosis than the KSCC.
- Type 3 – Basaloid Squamous Cell Carcinoma (BSCC): This is a rare type of NPC, which is aggressive and has a poor prognosis. BSCC consists of small, basaloid cells and often has foci of squamous differentiation.
The staging of NPC is carried out using the TNM staging system developed by the American Joint Committee on Cancer (AJCC).
T Stage:
- T1: Tumour confined to the nasopharynx
- T2: Tumour extends to soft tissues of oropharynx and/or nasal cavity
- T2a: Without parapharyngeal extension
- T2b: With parapharyngeal extension
- T3: Tumour invades bony structures and/or paranasal sinuses
- T4: Tumour with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, or orbit
N Stage:
- N0: No regional lymph node metastasis
- N1: Unilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa, and/or unilateral or bilateral retropharyngeal lymph nodes, ≤6 cm in greatest dimension
- N2: Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa
- N3: Metastasis in a lymph node(s)
- N3a: >6 cm in dimension and above the supraclavicular fossa
- N3b: Extension to the supraclavicular fossa
M Stage:
- M0: No distant metastasis
- M1: Distant metastasis present
Diagnosis
Diagnosis typically requires a combination of clinical presentation, imaging findings, and confirmatory biopsy demonstrating carcinoma and often EBV positivity.
Differential Diagnosis
- Lymphoma: A lymphoma might present as a nasopharyngeal mass, typically in younger patients. It generally shows homogeneous enhancement, without the necrosis seen in nasopharyngeal carcinoma. Lymphoma would also typically present with bilateral, symmetrical lymphadenopathy, as opposed to the unilateral or asymmetrical lymphadenopathy seen in nasopharyngeal carcinoma.
- Juvenile Nasopharyngeal Angiofibroma (JNA): JNA is a benign, highly vascular tumour that occurs in adolescent males. Unlike NPC, JNA is usually associated with nasal obstruction and recurrent epistaxis. On imaging, it demonstrates a characteristic ‘holly leaf’ pattern of enhancement.
- Metastasis to the nasopharynx: Metastasis to the nasopharynx is rare but should be considered, particularly in a known malignancy patient. These tend to occur in patients with a known primary malignancy and may present with multiple other sites of metastasis.
- Inflammatory Conditions (like nasopharyngitis): Chronic inflammatory conditions may cause thickening of the nasopharyngeal mucosa that could mimic NPC. However, these conditions are usually symmetrical and are associated with clinical signs of inflammation, such as fever and elevated inflammatory markers.
Management
Management of NPC typically involves external beam radiotherapy as the mainstay of treatment, often combined with chemotherapy for advanced disease. Surgery is typically reserved for recurrent or residual disease.