Head and Neck Squamous Cell Carcinoma

Malignant epithelial tumour arising from the mucosal surfaces of the oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, nasal cavity and paranasal sinuses. It represents around 90 percent of all head and neck malignancy and is the sixth commonest cancer worldwide.

Two distinct diseases with the same histology

The most important development in this field is the recognition that human papillomavirus associated oropharyngeal carcinoma is a biologically and prognostically distinct entity from carcinoma driven by tobacco and alcohol.

• Human papillomavirus negative disease: driven by tobacco and alcohol, with widespread field cancerisation, frequent TP53 mutation, older patients, poorer performance status, more comorbidity, higher rates of second primary tumours at around 3 to 5 percent per year, and substantially worse survival.
• Human papillomavirus positive oropharyngeal disease is driven by high risk human papillomavirus, principally type 16.
• Viral E6 and E7 oncoproteins inactivate p53 and retinoblastoma protein respectively. This produces p16 overexpression, which is used as a surrogate marker.
• Patients are younger, often non smokers, with a history of multiple sexual partners and oral sex. They present with small primaries and large cystic nodal metastases.
• Radiosensitivity and chemosensitivity are markedly greater. 3 year survival exceeds 80 percent compared with around 50 to 60 percent for human papillomavirus negative disease.
• Staging is therefore different. The eighth edition staging system has an entirely separate classification for p16 positive oropharyngeal carcinoma.
• In that classification, nodal staging is based on the number and laterality of nodes rather than extranodal extension, and stage IV is reserved for distant metastasis.

Risk factors

• Tobacco in all forms, with a dose dependent relationship. Smokeless tobacco, snuff and reverse smoking produce site specific tumours.
• Alcohol, which acts synergistically with tobacco rather than additively, with combined heavy use conferring a risk 30 fold or more above baseline.
• Areca nut and betel quid, which is a major driver of oral cavity carcinoma in South and Southeast Asia and which causes oral submucous fibrosis as a precursor.
• High risk human papillomavirus for the oropharynx.
• Epstein Barr virus for nasopharyngeal carcinoma, particularly the undifferentiated non keratinising type, with a marked geographical distribution in southern China, Southeast Asia, North Africa and East Africa, and dietary salted fish as a cofactor.
• Poor oral hygiene and chronic dental trauma.
• Occupational exposure: hardwood dust and leather dust for sinonasal adenocarcinoma, nickel and chromium for sinonasal carcinoma, and asbestos.
• Immunosuppression, including transplantation and HIV.
• Fanconi anaemia and dyskeratosis congenita, which produce early aggressive disease in young non smokers.
• Previous radiotherapy.
• Gastro oesophageal reflux, as a weaker association.
• Iron deficiency with Plummer Vinson syndrome for postcricoid carcinoma.

Field cancerisation

The entire mucosa exposed to carcinogens undergoes molecular change, so multiple independent primaries arise across the upper aerodigestive tract. This explains synchronous tumours in 3 to 5 percent, metachronous second primaries at 3 to 5 percent per year in human papillomavirus negative disease, and the requirement for panendoscopy at staging and lifelong surveillance.

Symptoms depend on subsite, but the following demand urgent referral in any adult, particularly a smoker or drinker.

• An ulcer in the oral cavity persisting beyond 3 weeks. This is the single most important rule in oral cancer detection.
• Hoarseness persisting beyond 3 weeks, which is the corresponding rule for the larynx.
• A neck lump persisting beyond 3 weeks in an adult, which in a patient over 40 is metastatic squamous cell carcinoma until proven otherwise.
• Unilateral referred otalgia with a normal ear examination, which reflects referred pain through cranial nerves IX and X from the oropharynx, hypopharynx or larynx and which is a classically overlooked symptom.
• Persistent unilateral sore throat.
• Dysphagia, odynophagia and a sensation of food sticking.
• Unexplained weight loss.
• Trismus, which indicates pterygoid muscle invasion and locally advanced disease.
• Loosening of teeth without dental cause.
• Oral bleeding.
• A persistent red or mixed red and white patch.
• Unilateral nasal obstruction with epistaxis.
• Unilateral serous otitis media in an adult, which is nasopharyngeal carcinoma until proven otherwise and which mandates nasoendoscopy.
• Cranial neuropathies, particularly in nasopharyngeal and skull base disease.
• Numbness of the lower lip or chin, indicating inferior alveolar nerve involvement.
• Stridor, indicating advanced laryngeal obstruction.

Examination

• Systematic examination of the whole oral cavity with a good light, gloves and gauze, including the lateral and ventral tongue lifted with gauze, the floor of mouth, the retromolar trigone, the buccal mucosa stretched flat, the gingivae and the hard and soft palate. Palpate every lesion for induration, which is the cardinal sign of invasion.
• Flexible nasoendoscopy in every patient, examining the nasopharynx including the fossa of Rosenmüller, the oropharynx including the tongue base and vallecula, the hypopharynx including the pyriform sinuses and postcricoid region, and the larynx with assessment of vocal fold mobility.
• Bimanual palpation of the tongue base and floor of mouth.
• Systematic palpation of all neck levels, recording the level, size, number, consistency, mobility and laterality of any node.
• Assess cranial nerves, trismus and dental status.
• Assess nutrition, weight, performance status and comorbidity, which determine treatment tolerance.

• Biopsy of the primary lesion for histology, which is mandatory. Incisional biopsy from the edge including adjacent normal tissue, avoiding necrotic centre.
• p16 immunohistochemistry on all oropharyngeal tumours, with p16 positivity defined as strong nuclear and cytoplasmic staining in more than 70 percent of tumour cells, and confirmatory human papillomavirus DNA or RNA testing where p16 alone is insufficient.
• Epstein Barr virus encoded RNA in situ hybridisation for nasopharyngeal carcinoma, and plasma Epstein Barr virus DNA for screening, prognostication and surveillance.
• Ultrasound guided fine needle aspiration cytology of any neck node, which is the first line nodal investigation. Core biopsy where cytology is inconclusive or where lymphoma is a possibility. Open neck biopsy should be avoided before a primary has been sought, since it violates tissue planes, may compromise subsequent neck dissection and is associated with worse outcomes.
• Contrast enhanced computed tomography of the head, neck and chest, which stages the primary, the neck and the chest for metastases and second primaries.
• Magnetic resonance imaging for the primary, which is superior for soft tissue extent, tongue base and oral cavity involvement, perineural spread, skull base and intracranial extension, and marrow invasion of the mandible.
• Positron emission tomography with computed tomography for stage III and IV disease, for identification of an unknown primary in a patient presenting with nodal disease, for detection of distant metastases and synchronous second primaries, and for post treatment response assessment at 12 weeks.
• Panendoscopy under general anaesthesia with examination of the nasopharynx, oropharynx, hypopharynx, larynx, oesophagus and tracheobronchial tree, with mapping of the tumour, biopsy, and directed biopsies of the tongue base and tonsillectomy where the primary is unknown.
• Orthopantomogram and dental assessment before radiotherapy, since extraction of unrestorable teeth must be completed before treatment to reduce the risk of osteoradionecrosis.
• Full blood count, renal and liver function, calcium, albumin, thyroid function as a baseline before neck irradiation, and nutritional assessment.
• Audiometry before platinum chemotherapy.
• Human immunodeficiency virus testing where relevant.

Staging

TNM staging with the eighth edition. The important changes are as follows.

• Depth of invasion is incorporated into T staging for oral cavity carcinoma, with thresholds at 5 mm and 10 mm.
• Extranodal extension is incorporated into N staging for human papillomavirus negative disease as N3b.
• There is a separate staging system for p16 positive oropharyngeal carcinoma.

Differential diagnosis

Traumatic ulcer, aphthous ulceration, tuberculosis, syphilis, deep fungal infection, necrotising sialometaplasia, lymphoma, minor salivary gland malignancy, melanoma, sarcoma and metastasis.

All patients must be discussed at a head and neck multidisciplinary team meeting before treatment begins. The team includes surgeons, oncologists, radiologists, pathologists, specialist nurses, dietitians, speech and language therapists, dentists and restorative dentistry.

Pretreatment preparation

• Dental assessment and extraction of unrestorable teeth at least 10 to 14 days before radiotherapy, with fluoride trays and lifelong high fluoride toothpaste.
• Nutritional assessment with dietitian involvement, and prophylactic gastrostomy in patients undergoing chemoradiotherapy to the oropharynx and hypopharynx, or in those with existing dysphagia and weight loss.
• Speech and language therapy baseline assessment with pretreatment swallowing exercises, which reduce long term dysphagia.
• Smoking and alcohol cessation, which improves treatment tolerance, reduces complications and improves survival. Continued smoking during radiotherapy reduces its efficacy and this should be stated plainly.
• Thyroid function baseline.
• Audiometry before cisplatin.
• Fertility discussion where relevant.

Early stage disease, that is stage I and II

Single modality treatment with either surgery or radiotherapy, chosen on the basis of the functional outcome, patient preference and local expertise.

• Oral cavity: surgery is preferred, with transoral resection and a margin of 1 cm, or open resection with reconstruction for larger tumours.
• Elective neck dissection of levels I to III for oral cavity tumours with a depth of invasion above 3 to 4 mm. Occult nodal metastasis exceeds 20 percent above this threshold, and elective neck dissection improves survival compared with observation.
• Larynx: transoral laser microsurgery or radiotherapy for early glottic carcinoma, both giving local control above 90 percent for T1 disease. The choice is determined by voice outcome, tumour extent, exposure at endoscopy and patient factors.
• Anterior commissure involvement reduces the success of transoral surgery.
• Oropharynx: transoral robotic surgery or transoral laser microsurgery with neck dissection, or radiotherapy.
• In human papillomavirus positive disease, treatment de intensification is an active area, with reduced radiotherapy dose and omission of chemotherapy under investigation. It should be delivered within a trial rather than adopted informally.

Locally advanced disease, that is stage III and IV

Multimodality treatment.

• Surgery with adjuvant radiotherapy or chemoradiotherapy: resection of the primary with reconstruction, and neck dissection.
• Definitive concurrent chemoradiotherapy for organ preservation, particularly in the larynx and hypopharynx. Use radiotherapy at 70 Gy in 35 fractions with concurrent cisplatin 100 mg/m squared on days 1, 22 and 43, or weekly cisplatin 40 mg/m squared.
• Cisplatin requires adequate renal function, hydration, antiemetic prophylaxis and audiometric monitoring. Carboplatin or cetuximab are alternatives in renal impairment or intolerance.
• Cetuximab is inferior to cisplatin in human papillomavirus positive disease and should not be substituted for convenience.
• Induction chemotherapy with docetaxel, cisplatin and fluorouracil is used selectively for organ preservation selection and for bulky disease.
• Indications for adjuvant radiotherapy after surgery: T3 or T4 primary, N2 or N3 nodal disease, perineural invasion, lymphovascular invasion, close margins under 5 mm, and level IV or V nodal involvement.
• Indications for adjuvant concurrent chemoradiotherapy rather than radiotherapy alone: positive margins and extranodal extension, both of which are high risk features that mandate the addition of cisplatin.
• Adjuvant treatment should commence within 6 weeks of surgery, with the total package of surgery plus radiotherapy completed within 100 days, since delay compromises outcome.

Neck management

• Therapeutic neck dissection for clinically or radiologically positive nodes, usually a modified radical or selective dissection preserving the accessory nerve, internal jugular vein and sternocleidomastoid where oncologically safe.
• Elective neck dissection or elective neck irradiation where the risk of occult metastasis exceeds 20 percent.
• Sentinel lymph node biopsy for early oral cavity carcinoma, which is an accepted alternative to elective neck dissection in T1 and T2 node negative disease and which reduces morbidity.
• Level selection by subsite: levels I to III for oral cavity, levels II to IV for oropharynx, hypopharynx and larynx, with level IIb and V included as indicated.

Reconstruction

• Primary closure, local flaps and skin grafts for small defects.
• Regional pedicled flaps including pectoralis major and supraclavicular artery island flaps.
• Free tissue transfer for major defects.
• Radial forearm free flap for soft tissue and thin pliable coverage of oral cavity and oropharyngeal defects, and anterolateral thigh flap for bulkier defects.
• Fibula free flap for mandibular reconstruction with the potential for dental implantation, and scapular and iliac crest flaps for composite defects.
• Reconstruction aims to restore speech, swallowing, mastication, airway and appearance. Functional outcomes should be a primary consideration in the treatment decision rather than an afterthought.

Recurrent and metastatic disease

• Salvage surgery for resectable local or regional recurrence, which offers the only realistic prospect of cure.
• Re irradiation in selected cases with stereotactic techniques, accepting substantial toxicity.
• Systemic therapy for unresectable or metastatic disease: immune checkpoint inhibition with pembrolizumab as first line, alone in tumours with a combined positive score of 1 or above, or with platinum and fluorouracil. This has improved outcomes substantially. Nivolumab for platinum refractory disease.
• Platinum, taxane, fluorouracil, methotrexate and cetuximab regimens.
• Palliative radiotherapy for bleeding, pain and obstruction.

Toxicity management

• Acute: mucositis, managed with analgesia including opioids, mouth care, and nutritional support; dermatitis; xerostomia; taste loss; dysphagia; candidiasis; and cytopenias.
• Late xerostomia is reduced by intensity modulated radiotherapy sparing the contralateral parotid and by submandibular gland transfer.
• Late dental caries and osteoradionecrosis are prevented by pretreatment dental clearance and lifelong fluoride.
• Osteoradionecrosis is treated with conservative measures, pentoxifylline with tocopherol, hyperbaric oxygen in selected cases, and resection with free flap reconstruction for established disease.
• Late dysphagia and aspiration require long term gastrostomy in a proportion of patients.
• Hypothyroidism affects up to 50 percent after neck irradiation and requires annual thyroid function testing.
• Other late toxicity: carotid stenosis and stroke; trismus; lymphoedema; and second malignancy.
• Shoulder dysfunction after neck dissection, requiring physiotherapy.

Supportive and survivorship care

• Clinical nurse specialist as key worker throughout.
• Dietitian, speech and language therapy, physiotherapy, restorative dentistry, psychology and smoking cessation services.
• Voice and swallowing rehabilitation, including surgical voice restoration with a tracheoesophageal puncture and voice prosthesis after laryngectomy.
• Psychological support, given high rates of depression, anxiety and, notably, suicide, which is higher in head and neck cancer than in most other malignancies. Screen actively.
• Palliative care involvement early in advanced disease rather than only at the end.

Follow up

Clinical review every 1 to 2 months in year 1, 2 to 4 monthly in year 2, 4 to 6 monthly in years 3 to 5, and annually thereafter, with lifelong surveillance given the risk of second primaries. Positron emission tomography with computed tomography at 12 weeks after chemoradiotherapy to assess response and to guide the need for salvage neck dissection. Annual thyroid function. Lifelong reinforcement of smoking and alcohol cessation, which reduces second primary risk substantially.