Pharyngeal Cancer

Pharyngeal cancer is malignancy of the pharyngeal mucosa. It is divided anatomically into nasopharyngeal, oropharyngeal and hypopharyngeal carcinoma, each with distinct epidemiology, aetiological associations and clinical presentation. Squamous cell carcinoma is the predominant histological subtype at all three subsites.

A fundamental distinction in contemporary practice is between human papillomavirus associated oropharyngeal carcinoma and the more traditional, smoking and alcohol related pharyngeal cancer. The human papillomavirus associated form is increasingly common, generally affects younger, often non-smoking patients, and carries a substantially more favourable prognosis.

Nasopharyngeal carcinoma has a distinct, geographically clustered epidemiology and an Epstein-Barr virus association.

Accurate anatomical and aetiological classification guides tailored staging, treatment and prognostic counselling.

Classification and aetiology

• Nasopharyngeal carcinoma shows striking geographic clustering. Incidence is substantially higher in Southern Chinese and Southeast Asian populations, and in certain North African and Arctic populations.
• Contributors are genetic susceptibility and environmental and dietary factors. These include a historically recognised association with consumption of salt-preserved fish, particularly during critical periods of early childhood.
• The endemic, undifferentiated subtype of these high incidence populations has an almost universal association with Epstein-Barr virus infection.
• Oropharyngeal carcinoma affects the tonsils, base of tongue, soft palate and posterior pharyngeal wall. It has undergone a substantial epidemiological shift in recent decades.
• Human papillomavirus (predominantly type 16) associated disease is now a substantial proportion of cases and, in many high income settings, the predominant one. These patients are younger, with lower rates of smoking and alcohol related risk factors.
• Human papillomavirus associated disease carries a substantially more favourable prognosis and treatment response than human papillomavirus negative disease. This distinction is well established for prognosis and increasingly stratifies treatment.
• Hypopharyngeal carcinoma affects the pyriform sinus, postcricoid region and posterior pharyngeal wall below the level of the hyoid bone. It remains most strongly associated with significant tobacco and alcohol use.
• It carries a generally less favourable prognosis than the other pharyngeal subsites. Reasons are later stage presentation, because early symptoms are less specific and easily overlooked, and a generally more aggressive tumour biology.

• Nasopharyngeal carcinoma frequently presents with a neck mass from cervical lymph node metastasis, given the rich lymphatic drainage of the nasopharynx and the tendency for early, sometimes bilateral nodal spread. Other features are nasal obstruction and epistaxis.
• Because the nasopharynx lies close to the skull base and cranial nerves, cranial nerve palsies occur, particularly of the trigeminal and abducens nerves, from direct tumour extension toward the skull base.
• Unilateral middle ear effusion with conductive hearing loss is characteristic, from eustachian tube obstruction by the primary tumour. Examine the nasopharynx in any adult with new, unexplained unilateral middle ear effusion.
• Oropharyngeal carcinoma presents with sore throat, odynophagia, referred otalgia (from shared cranial nerve sensory innervation of the oropharynx and ear), and a visible or palpable mass or ulcer.
• A neck mass from cervical lymph node metastasis is frequently the presenting feature, particularly in human papillomavirus associated disease. The mass is sometimes disproportionately large relative to a small, sometimes clinically inapparent primary tumour.
• Hypopharyngeal carcinoma presents with dysphagia, odynophagia, hoarseness (from laryngeal involvement or recurrent laryngeal nerve compromise), referred otalgia and weight loss.
• Presentation is frequently at a relatively advanced stage, because early symptoms are less specific and readily overlooked. This contributes to the less favourable prognosis of this subsite.
• Persistent (beyond three weeks) unexplained sore throat, dysphagia, odynophagia, hoarseness, otalgia or neck mass in an adult warrants prompt assessment. This applies particularly with risk factors: significant smoking or alcohol history, or sexual history factors associated with human papillomavirus exposure.
• Keep a low threshold for specialist head and neck examination and, where indicated, further investigation.

• Head and neck examination, including flexible nasendoscopy to visualise the nasopharynx, oropharynx and hypopharynx, is the essential initial investigation.
• Biopsy any suspicious lesion for definitive histological confirmation. This is generally done under general anaesthesia as part of a formal panendoscopy, which examines the entire upper aerodigestive tract. This matters because of the risk of synchronous second primary malignancy elsewhere in the tract, particularly in patients with smoking and alcohol related risk factors.
• Human papillomavirus testing is essential for confirmed oropharyngeal carcinoma. Use p16 immunohistochemistry as a surrogate marker, with confirmatory direct human papillomavirus testing where available. The result bears directly on prognosis and, increasingly, on treatment stratification and de-escalation for appropriately selected human papillomavirus positive patients.
• Epstein-Barr virus testing supports confirmation of nasopharyngeal carcinoma, particularly the endemic, undifferentiated subtype. It includes serology and, on tumour tissue, in situ hybridisation for Epstein-Barr virus encoded RNA.
• Plasma Epstein-Barr virus DNA is additionally useful as a circulating biomarker for monitoring and surveillance after treatment.
• Magnetic resonance imaging is generally preferred for its superior soft tissue delineation. This matters for nasopharyngeal carcinoma, where accurate assessment of skull base and perineural extension is important.
• Computed tomography of the neck and chest, and where clinically indicated by stage and risk profile further staging investigation including positron emission tomography, complete tumour, nodal and distant metastatic staging and inform treatment planning.

• Nasopharyngeal carcinoma is characteristically radiosensitive. The primary tumour is frequently advanced and involves the skull base at presentation, generally precluding surgical resection as primary treatment.
• It is therefore managed with radiotherapy, generally combined with concurrent chemotherapy for locally advanced disease. This is the standard primary treatment, in contrast to the more prominent role of surgery at the other pharyngeal subsites.
• Human papillomavirus positive oropharyngeal carcinoma has a generally more favourable prognosis and treatment responsiveness. Options are primary surgical resection followed by adjuvant treatment according to pathological risk factors, or primary radiotherapy, generally with concurrent chemotherapy for more advanced disease.
• Surgery is increasingly performed with transoral robotic or laser microsurgical techniques, which offer reduced morbidity compared with traditional open approaches.
• Treatment de-escalation is an area of active clinical research and evolving practice. It reduces the intensity of adjuvant or concurrent treatment for appropriately selected, favourable risk human papillomavirus positive patients. The aim is to reduce long term treatment related morbidity while maintaining the excellent oncological outcomes of this subtype.
• Human papillomavirus negative oropharyngeal carcinoma and hypopharyngeal carcinoma are generally managed with a combination of surgery, radiotherapy and chemotherapy according to stage and location. Sequencing and combination are individualised through multidisciplinary team discussion.
• The overall approach is generally somewhat more aggressive, given the less favourable tumour biology and prognosis compared with human papillomavirus positive disease.
• Managing treatment related morbidity is an integral part of multidisciplinary care. Swallowing dysfunction needs speech and language therapy input and, in some cases, temporary or, in severe cases, longer term feeding tube support.
• Xerostomia (dry mouth) is a common consequence of radiotherapy to the salivary glands, often with significant impact on quality of life. It is managed with saliva substitutes and other supportive measures.
• Dental complications need full dental assessment. Where indicated, extract at risk teeth before radiotherapy starts, because extraction in previously irradiated tissue carries a substantially increased risk of osteoradionecrosis.
• After treatment, offer regular, structured, long term surveillance. It incorporates clinical examination and, where relevant, imaging, and for nasopharyngeal carcinoma plasma Epstein-Barr virus DNA monitoring, to identify recurrence early.
• Provide ongoing rehabilitation support for the potentially substantial, long term functional and quality of life impact of both the malignancy and its treatment.