OncologyTier 2Disease (DEADMAN)

Cancer - pharyngeal

Description

	HPV-positive oropharyngeal	HPV-negative (tobacco/alcohol)
Site	Tonsil, base of tongue	Any; hypopharynx, larynx, oral cavity
Patient	Younger (50s), non-smoker, higher SES, M>F	Older, heavy smoker + drinker
Genetics	Wild-type TP53 (E6 degrades p53)	TP53 mutated, CDKN2A loss
Presentation	Small primary, bulky cystic neck node	Larger primary, field change
Radio/chemosensitivity	High	Lower
5-yr survival	~80-90%	~45-50%
Second primaries	Uncommon	Common (field cancerisation)

Subsites

Nasopharynx - EBV-driven, distinct: Southern Chinese and Southeast Asian, Inuit; presents with neck node, epistaxis, unilateral serous otitis media, cranial nerve palsies; treated with chemoradiation (never surgery)
Oropharynx - tonsil, base of tongue, soft palate; HPV-driven
Hypopharynx - pyriform sinus, postcricoid; worst prognosis of all head and neck sites, presents late with dysphagia and referred otalgia

Head and neck cancer ~4,000/yr AU; M:F ~3:1
HPV-positive oropharyngeal cancer is rising steeply while smoking-related sites fall - now the majority of oropharyngeal cancer in Australia
HPV vaccination is expected to reverse this, with a long lag
Nasopharyngeal carcinoma: strong ethnic and geographic clustering; also Plummer-Vinson syndrome for postcricoid carcinoma (iron deficiency, F>M)

Tobacco and alcohol - synergistic (multiplicative); also betel quid/areca nut
HPV-16 (~90% of HPV-positive cases)
- E6 -> degrades p53; E7 -> inactivates Rb -> p16 overexpressed (the IHC surrogate)
EBV - nasopharyngeal carcinoma (plus salted fish/nitrosamines, genetic susceptibility)
Iron deficiency - Plummer-Vinson/Paterson-Brown-Kelly (postcricoid)
GORD, poor dentition, immunosuppression, prior radiotherapy
Fanconi anaemia, dyskeratosis congenita - young patients with head and neck SCC

Presentation

Persistent unilateral sore throat, otalgia (referred via CN IX/X), dysphagia, hoarseness
A neck lump is the commonest presentation of HPV-positive disease - often cystic, mistaken for a branchial cyst
*Any adult with a neck mass persisting >3 weeks, or any unilateral throat/ear symptom >3 weeks, needs ENT referral*
Trismus, cranial nerve palsy, weight loss, haemoptysis

Workup

Flexible nasendoscopy + examination under anaesthesia with panendoscopy and biopsy
*Never do an open excisional neck node biopsy for a suspected SCC node - compromises subsequent neck dissection and seeds the field; FNA/core biopsy* instead
p16 immunohistochemistry on every oropharyngeal SCC - the surrogate for HPV; confirm with HPV DNA/RNA if equivocal
EBV DNA (plasma) for nasopharyngeal carcinoma - diagnosis, prognosis and surveillance
MRI (soft tissue, perineural spread, skull base) + CT neck; PET-CT for staging and for unknown primary
OPG and dental assessment; nutrition and speech pathology assessment; audiogram if cisplatin planned

Staging - HPV changed it

AJCC 8 has separate staging for p16-positive oropharyngeal cancer - the same anatomical extent is a lower stage because the prognosis is so much better

Multidisciplinary: ENT/head and neck surgery, radiation and medical oncology, dentistry, speech pathology, dietitian.

A. Early stage (I-II)

Single modality: surgery OR radiotherapy - equivalent outcomes, choose by morbidity
Transoral robotic surgery (TORS) increasingly used for oropharyngeal primaries
Neck dissection for nodal disease

B. Locally advanced (III-IVB)

Concurrent chemoradiotherapy: high-dose cisplatin 100 mg/m2 on days 1, 22, 43 + 70 Gy IMRT
- Cetuximab is inferior to cisplatin in HPV-positive disease (De-ESCALaTE, RTOG 1016) - reserve it for genuinely cisplatin-ineligible patients, do not "de-escalate" with it
- Carboplatin/weekly cisplatin if renal impairment or hearing loss
Or surgery + adjuvant (chemo)radiotherapy
- Add chemotherapy to adjuvant RT if positive margins or extranodal extension
Nasopharyngeal carcinoma - induction chemotherapy (gemcitabine/cisplatin) then chemoradiation; never primary surgery
De-escalation of therapy in HPV-positive disease remains a trial question - do not do it off protocol

C. Recurrent/metastatic

D. Supportive care - determines whether treatment is completed

Dental extraction of unsalvageable teeth BEFORE radiotherapy (osteoradionecrosis risk after)
Prophylactic PEG or NG feeding - almost all develop severe mucositis
Mucositis, xerostomia, dysgeusia, candidiasis, trismus, aspiration
Smoking and alcohol cessation - continued smoking during radiotherapy reduces its efficacy
Thyroid function annually after neck irradiation (hypothyroidism in ~30-40%)
Speech and swallow rehabilitation, lymphoedema therapy

E. Prevention

HPV vaccination - Australian school program at 12-13, single dose since 2023, boys and girls
Tobacco and alcohol reduction

Tobacco, alcohol, betel quid
HPV-16 - also cervical, anal, vulval, penile cancer
EBV - nasopharyngeal carcinoma, also Burkitt, Hodgkin, PTLD
Plummer-Vinson syndrome - iron deficiency, dysphagia, oesophageal web, postcricoid carcinoma
Fanconi anaemia, dyskeratosis congenita
Field cancerisation -> synchronous/metachronous lung and oesophageal SCC
Hypercalcaemia via PTHrP
Osteoradionecrosis, carotid blowout, radiation-induced second malignancy
Paraneoplastic: dermatomyositis (nasopharyngeal carcinoma is a classic association)

*HPV/p16 status is the single most important prognostic factor* - HPV-positive oropharyngeal cancer has ~50-60% lower risk of death
5-yr survival: HPV-positive oropharyngeal ~80-90%; HPV-negative ~45-50%; hypopharyngeal ~30-35%
Nasopharyngeal carcinoma 5-yr survival ~70-80% with chemoradiation; monitored with plasma EBV DNA
Most recurrences within 2 years - intensive early follow-up, then annual
HPV-negative disease: field cancerisation -> 2-3%/yr risk of a second primary in the aerodigestive tract, lifelong
HPV-positive disease relapses later and more often distantly (lung, bone) - and can still be salvaged

Long-term treatment morbidity

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