Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma arising from the epithelium of the nasopharynx, most frequently in the fossa of Rosenmüller (the pharyngeal recess). It has a unique geographic distribution. The tumour is highly invasive, with early lymph node metastasis and a high rate of distant metastasis.

Epidemiology. NPC is endemic in southern China (Guangdong, 20 to 50 per 100,000 in men), Southeast Asia, North Africa (Maghreb), the Arctic (Inuit), and East Africa (Kenya). It is rare elsewhere (below 1 per 100,000).

The age peak is 40 to 60 years in endemic regions (with a bimodal curve, and a small peak in adolescents and young adults in low incidence regions). The male to female ratio is about 2 to 3:1.

Aetiology is multifactorial:

• Epstein-Barr virus (EBV) infection (present in virtually all non-keratinising tumours)
• genetic susceptibility (HLA-A2, HLA-B46, HLA-B58; familial clustering)
• dietary exposure to salted fish and preserved foods (nitrosamines)
• tobacco and alcohol
• wood dust and formaldehyde exposure

Histology:

• keratinising squamous cell carcinoma (type I, about 25 percent in low incidence areas, and not EBV-related in many)
• non-keratinising carcinoma (differentiated type IIa, and undifferentiated type IIb, 95 percent in endemic areas, strongly EBV-related)
• basaloid squamous cell carcinoma (rare)

Retropharyngeal and upper deep cervical nodes are involved in about 75 to 90 percent at diagnosis, and bilaterally in 50 percent. Distant metastases (bone, lung, liver) are frequent.

Staging is by the tumour-node-metastasis system (T1 to T4, N0 to N3, M0 to M1) with stage I to IVB groupings.

• Neck mass (the commonest presentation, in 60 to 90 percent): a painless, firm, enlarged upper cervical lymph node (level II, V), often bilateral, and persistent.
• Nasal symptoms: unilateral or bilateral nasal obstruction, blood stained nasal discharge, epistaxis, and postnasal drip.
• Otological symptoms: unilateral conductive hearing loss from serous otitis media (Eustachian tube obstruction by tumour), tinnitus, and aural fullness (the often missed presentation in adults with unilateral effusion, which warrants nasopharyngeal endoscopy).
• Cranial nerve involvement from the skull base extension (about 20 percent): headache, trigeminal neuralgia or facial numbness (V), diplopia (VI, III, IV), and lower cranial nerve palsies (IX to XII).
• Skull base syndromes: the petrosphenoidal syndrome of Jacod (cranial nerves II to VI) and the retropharyngeal syndrome of Villaret. Trismus indicates pterygoid involvement.
• Metastatic disease: bone pain (spine, ribs, pelvis), liver and lung symptoms; weight loss, and fatigue.
• Paraneoplastic dermatomyositis in some patients.

• Nasopharyngoscopy (rigid or flexible endoscopy): mass, ulcer or mucosal asymmetry in the nasopharynx (especially in the fossa of Rosenmüller), with biopsy (under direct vision) for histological confirmation; multiple biopsies. A negative biopsy with high suspicion warrants repeat endoscopy.
• Fine needle aspiration of the neck node for diagnosis, if the primary is not found; an open biopsy of the neck node is avoided (risk of tumour spread).
• MRI of the nasopharynx and skull base with gadolinium (the best for local staging: parapharyngeal space, skull base, cavernous sinus, intracranial, and perineural spread, and retropharyngeal nodes) and neck.
• Systemic staging: PET-CT (with FDG; sensitivity above 90 percent for nodal and distant metastases) or CT of the chest, abdomen, and bone scan.
• Plasma EBV DNA (quantitative PCR): a marker for diagnosis (in endemic areas), prognosis (high pretreatment levels above 4,000 copies/mL predict worse outcomes), and monitoring of response and detection of recurrence and metastases.
• EBV serology (IgA against viral capsid antigen and early antigen) for screening in endemic regions.
• Pretreatment assessment: audiometry, dental assessment, nutritional status, renal function, liver function and full blood count, thyroid function and swallowing assessment.

Treatment is by radiotherapy based therapy, because the tumour is anatomically difficult to remove and is radiosensitive.

• Stage I (T1N0M0): intensity modulated radiotherapy (IMRT) alone, 70 Gy in 33 to 35 fractions to the primary tumour (with prophylactic irradiation of 50 to 60 Gy to the lower risk regions), with 5-year survival above 90 percent.
• Stage II: concurrent chemoradiotherapy (IMRT 70 Gy with cisplatin 100 mg/m2 every 3 weeks for 2 to 3 cycles, or 40 mg/m2 weekly for 6 to 7 weeks), or IMRT alone for selected low risk tumours.
• Stages III to IVA (locoregionally advanced): concurrent chemoradiotherapy with or without induction chemotherapy. Induction options, followed by chemoradiotherapy:
  • gemcitabine 1,000 mg/m2 on days 1 and 8 with cisplatin 80 mg/m2 on day 1 every 3 weeks for 3 cycles
  • docetaxel 60 mg/m2, cisplatin 60 mg/m2 and 5-fluorouracil 600 mg/m2 on days 1 to 5 (TPF) for 3 cycles
• Adjuvant capecitabine 650 mg/m2 twice daily (metronomic, for 1 year) after chemoradiation in selected high risk patients improves survival.
• PD-1 inhibitors (toripalimab 240 mg or camrelizumab 200 mg every 3 weeks, in combination with chemotherapy) are included in standard regimens in the advanced stage.
• Supportive care during treatment: premedication with antiemetics (ondansetron 8 mg, dexamethasone 8 mg, aprepitant 125 mg on day 1 then 80 mg on days 2 and 3), hydration to prevent cisplatin nephrotoxicity, and audiometry.
• Mucositis care (benzydamine mouthwash, topical anaesthetics, analgesics), nutritional support with early gastrostomy for patients with severe dysphagia, and dental care (fluoride, extraction of poor teeth before radiotherapy).
• Recurrent or residual disease: nasopharyngectomy (endoscopic transnasal or open approaches) for rT1 to T3 localised recurrences, or re-irradiation (stereotactic body radiotherapy, brachytherapy, or IMRT, with significant late toxicity); salvage neck dissection (radical or modified) for persistent or recurrent nodal disease.
• Metastatic disease (stage IVB): systemic chemotherapy with gemcitabine and cisplatin (gemcitabine 1,000 mg/m2 on days 1 and 8 with cisplatin 80 mg/m2 on day 1 every 3 weeks for 4 to 6 cycles) plus a PD-1 inhibitor (toripalimab or tislelizumab, camrelizumab), with maintenance immunotherapy.
• Locoregional radiotherapy for oligometastatic disease improves survival. Palliative radiotherapy for bone metastases, with bisphosphonates (zoledronic acid 4 mg every 4 weeks).
• Second line therapy: capecitabine, docetaxel, or PD-1 inhibitors.
• Late toxicities and rehabilitation: xerostomia (pilocarpine 5 mg three times daily, saliva substitutes, amifostine), trismus (jaw exercises and stretching devices), hearing loss, and hypothyroidism (annual thyroid function tests).
• Also temporal lobe necrosis (corticosteroids and bevacizumab 5 mg/kg every 2 weeks), cranial neuropathies, osteoradionecrosis, and carotid stenosis (monitor). Provide speech and swallowing therapy.
• Follow up: clinical examination, nasopharyngoscopy and plasma EBV DNA every 3 months for 2 years, then every 6 months to 5 years, then yearly; MRI of the nasopharynx at 3 months after treatment and then as indicated, with PET-CT for rising EBV DNA.
• Prognosis: 5-year survival of 90 percent in stage I, 80 percent in stage II, 70 to 80 percent in stage III, 60 to 70 percent in stage IVA, and 20 to 40 percent in metastatic disease.
• Screening: in high incidence areas, EBV serology (IgA VCA and EBNA1) and plasma EBV DNA screening for high risk individuals and families allows detection at early stages and reduces mortality; avoid salted fish and tobacco.