MOUTH AND OESOPHAGUS

Squamous cell carcinoma of What’s new?

the oral cavity, oropharynx C Increased recognition of the role of human papilloma virus as a

and upper oesophagus causative agent in carcinomas of the oropharynx. Research is

ongoing to ascertain whether these cancers could be managed
Isabella Maund less aggressively
C The growth of intensity-modulated radiotherapy for delivering
Sarah Jefferies radiotherapy, especially to tumours in the head and neck, to
spare normal tissues and reduce long-term toxicity
C Continued expansion of specialist multi-disciplinary teams to
Abstract
Squamous cell carcinomas of the oral cavity, oropharynx and oesophagus deliver high-quality care to patients who often have complex
are relatively common cancers frequently associated with heavy alcohol needs
and tobacco use. The dramatic increase in the incidence of oropharyngeal
cancers over the past three decades is attributed to human papilloma
virus infection. Early detection of cancers is associated with improved histological subtype, whereas in the lower oesophagus adenocar-
outcome; unfortunately, many cancers remain clinically silent until they cinomas dominate. In contrast with adenocarcinomas, the inci-
are locally advanced, leading to poor overall survival figures. Surgery is dence of oesophageal SCC has stabilized, or even decreased, since
often preferred in early stage disease in patients fit to undergo treatment. the 1970s, reflecting changing exposure to risk factors.5 The inci-
For advanced disease, combined use of chemotherapy and radiotherapy, dence of oesophageal cancer is strongly associated with increasing
with or without surgery, is often required. Treatment is associated with age and is more prevalent among men (Table 1).
significant morbidity, which requires intensive support from a multi-
disciplinary team. Clinical anatomy
Keywords Human papilloma virus; oesophagus; oral cavity; oropharynx; The oral cavity includes the lips (sometimes classified separately
squamous cell carcinoma as skin), anterior two-thirds of tongue, hard palate, floor of
mouth, buccal mucosa, upper and lower alveoli and gingiva, and
the retromolar trigones (mucosal fold extending posteriorly from
the last molar).
Incidence and trends The oropharynx is the posterior continuation of the oral cavity
Worldwide, cancers of the head and neck represent the sixth extending from the palate superiorly to the level of hyoid infe-
most common malignancy, accounting for 6% of all cancer di- riorly. It is subdivided into the:
agnoses.1 There is substantial geographical variation, with an  lateral wall: palatine tonsil, tonsillar fossae and pillars
excess of cases from developing countries. Over 90% of cancers  anterior wall: base of tongue and vallecula
arising from the mouth and oropharynx are squamous cell car-  superior wall: soft palate and uvula
cinomas (SCC).  posterior pharyngeal wall
Over the past three decades, the incidence of oropharyngeal The oesophagus extends from 15 to 40 cm from the central
cancers has changed dramatically, increasing twofold since incisors. It is subdivided into the cervical oesophagus (15e18 cm),
1990.2 The epidemiological profile has also changed, from what thoracic oesophagus (18e40 cm) and gastro-oesophageal junc-
was historically a male-dominated cancer, with a peak incidence tion. The majority of SCCs are found in the upper two-thirds of the
in the fifth and sixth decades of life, to include increasing oesophagus.
numbers of women and patients aged under 45.
Oesophageal cancer is the 13th most common cancer in the UK.3 Aetiology
Worldwide, an estimated 456,000 new cases were identified in Smoking and alcohol consumption are the most significant risk
2012 (3.2% of the total), 80% of which occurred in less developed factors in the development of SCC of the head and neck. These
regions.4 In the upper oesophagus, SCC is the most common

UK incidence of oral, oropharyngeal and oesophageal

Isabella Maund FRCR MBBS MSc is a Specialist Registrar Clinical Oncology
cancers (any histology) by sex and subsite3
at Oncology Centre, Addenbrooke’s Hospital, Cambridge University
Hospitals NHS Foundation Trust, Cambridge, UK. Competing interests: Site Males Females Persons M:F ratio
none declared.
Lip 248 133 381 1.9:1
Sarah Jefferies PhD FRCR FRCP MBBS BSc is Consultant Clinical Oncologist Tongue 1336 590 2028 1.9:1
and Associate Lecturer at Oncology Centre, Addenbrooke’s Hospital, Mouth 1101 819 1920 1.3:1
Cambridge University Hospitals NHS Foundation Trust, Cambridge. Oropharynx 1065 391 1456 2.7:1
University of Cambridge Department of Oncology, Cambridge Biomed- Oesophagus 5582 2750 8332 1.5:1
ical Campus, Addenbrooke’s Hospital, Cambridge, UK. Competing
interests: none declared. Table 1

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Please cite this article in press as: Maund I, Jefferies S, Squamous cell carcinoma of the oral cavity, oropharynx and upper oesophagus, Medicine
(2015), http://dx.doi.org/10.1016/j.mpmed.2015.01.004
 MOUTH AND OESOPHAGUS

causative agents are implicated in the development of 75% of  age and performance status
oral and pharyngeal cancers, acting synergistically to promote  smoking and alcohol use
tumour development.6  other co-morbid conditions including smoking-related
In certain populations, betel-quid and oral tobacco chewing are diseases
important risk factors for oral cancer. Poor dentition acts as an  previous carcinomas and their treatment.
independent risk factor, whereas diets rich in b-carotene-con-
taining vegetables and citric fruits may have a protective effect. Examination
The use of either tobacco or alcohol alone increases the risk of This should include:
oesophageal SCC by 20e30%; combined use results in a sub-  general inspection for signs such as cachexia and anaemia
stantial threefold increase, demonstrating a significant synergis-  inspection of the oral cavity (after removal of any dentures)
tic effect.7 Consumption of scalding hot tea has also been  assessment of tongue and palatal movement
associated with an increased risk of oesophageal SCC.8 Other  bimanual palpation of any accessible lesions
risks include dietary factors and conditions such as achalasia,  indirect laryngoscopy or flexible nasendoscopy
tylosis and PlummereVinson syndrome.  examination for trismus (restricted mouth opening)
 palpation of the cervical and supraclavicular nodes
Human papilloma virus (HPV)  examination of the chest (and abdomen in oesophageal
In 2007, the International Agency for Research on Cancer (IARC) carcinoma).
concluded that HPV is a causative factor in the development of
oropharyngeal cancer. Retrospective analysis has demonstrated a Investigations
dramatic increase in the incidence of oropharyngeal cancer Investigations will depend upon the primary site of disease and
associated with HPV16.9 The factors responsible for this phe- may include:
nomenon have yet to be fully established, although changing  full blood count, biochemistry and liver function tests
sexual behaviour has been strongly implicated.10  CT and/or MR scans of the head and neck (Figure 1)
HPV16-related tumours represent an entity that is distinct  US neck with fine needle aspiration cytology (FNAC) of
from alcohol- and tobacco-related disease. Typically, patients are suspicious lymph nodes
younger, presenting in their 40s and early 50s, non-smokers,  biopsy of the primary cancer either in the clinic or during
without a history of heavy alcohol consumption. Although pre- examination under anaesthesia (EUA). Staging procedures
sentation with advanced stage disease is more common, this such as panendoscopy, oesophagoscopy or bronchoscopy
does not translate to poorer outcomes. Patients with HPV- may also be performed
positive cancers have higher overall survival compared with  CT scan of the thorax to assess for pulmonary metastases
their HPV-negative counterparts, with enhanced responsiveness and synchronous primary tumours. For oesophageal tu-
to chemotherapy and radiotherapy (RT).11 However, there is mours, or suspicious findings such as deranged liver
insufficient evidence at present to suggest that treatment can be function tests, the abdomen should also be imaged.
modified or de-escalated on the basis of HPV status. Histological reporting of biopsy specimens should follow
published UK guidelines.12 HPV testing is desirable for oropha-
Presentation and diagnosis ryngeal SCC as it provides prognostic information, although it is
not currently mandated. Immunocytochemical identification of
The most common presentation of carcinomas of the oral cavity
is a non-healing ulcer. Other presentations include a flat, red or
white lesion, or a mass. Carcinomas may arise de novo or from a
pre-malignant dysplastic lesion.
The rich lymphatic supply of the oropharynx means that
carcinomas originating here most commonly present as a pain-
less neck lump secondary to involvement of the cervical lymph
nodes, often with few other symptoms. Other presentations
include pain in the tongue or throat, referred ear pain (otalgia),
dysphagia or change in voice quality (‘hot potato’ speech).
Carcinomas of the oesophagus tend to present late, with
dysphagia, progressing from liquids to solids, being the most
common symptom. Other presentations include weight loss,
pain, bleeding or symptoms secondary to metastatic spread, for
example to the supraclavicular nodes or liver.

History
When taking a history from a patient with suspected SCC of the
oral cavity, oropharynx or upper oesophagus, important features
to assess include:
Figure 1 T1-weighted MRI with contrast demonstrating large conglom-
 the presence and duration of symptoms and signs, erate cystic nodal mass in the right neck (blue arrow) with adjacent
including pain, mucosal ulceration, cervical node enlarge- tonsillar mass (red arrow) invading tongue base and oral tongue (stage
ment, dysphagia or odynophagia and weight loss T4a N2b).

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Please cite this article in press as: Maund I, Jefferies S, Squamous cell carcinoma of the oral cavity, oropharynx and upper oesophagus, Medicine
(2015), http://dx.doi.org/10.1016/j.mpmed.2015.01.004
 MOUTH AND OESOPHAGUS

p16 protein over-expression is a commonly used surrogate extracapsular spread of lymph node metastases, postoperative
marker for HPV infection, which, if positive, should be confirmed chemoradiotherapy with platinum-based chemotherapy given as
by in situ hybridization if possible.12 a radio-sensitizing agent has been shown to improve outcomes.14
The role of PET-CT in head and neck cancer is mainly
Oropharynx overview
reserved for the investigation of suspected recurrence and for the
detection of occult primary disease in patients presenting with Early stage SCC may be treated equally effectively with surgery
isolated cervical nodal metastases. In patients with carcinoma of or RT, although the latter is often preferred due to the morbidity
the oesophagus, PET-CT is now considered part of the routine associated with surgery at this site.
investigation of patients being considered for radical treatment. For advanced tumours, an ‘organ-preserving’ strategy using
primary chemoradiotherapy is generally advocated. The addition
Management of chemotherapy to locoregional RT for SCC of the head and neck
is associated with an absolute survival benefit of 4% at both 2
The formulation of an appropriate management plan is depen-
years (from 50 to 54%) and 5 years (from 32% to 36%), which is
dent upon a number of factors including:
statistically significant.15 However, concurrent treatment is
 tumour: pathology, site and stage (TNM system)13
associated with significantly increased toxicity compared with
 patient: performance status, smoking history, co-
RT alone and careful pre-treatment patient selection is crucial to
morbidity and preference
exclude patients unfit for intensive treatment.
 treatment: functional and cosmetic outcome, cure rate
Cisplatin given concurrently with RT is the standard chemo-
 centre: skill mix, resources.
therapeutic agent in most UK centres, given as a weekly (40 mg/
A multidisciplinary approach is vital and should include sur-
m2) or 3-weekly (100 mg/m2) regimen. Cetuximab is a mono-
geons, oncologists, radiologists, histopathologists, restorative
clonal antibody targeting the epidermal growth factor receptor
dentists, specialist nurses and radiographers, dieticians, speech
(EGFR), which is frequently amplified in SCC of the head and
and language therapists.
neck. Cetuximab combined with radiotherapy has been shown to
provide a survival advantage over radiotherapy alone (49.0
Oral cavity overview
months for combined therapy versus 29.3 months for radiation
Surgery is the mainstay of management for SCCs of the oral alone16) and is currently approved by the National Institute for
cavity. This is often possible via a trans-oral route but larger and Health and Care Excellence (NICE) for treatment of patients with
more posteriorly placed lesions may require more extensive a Karnofsky performance status of 90% or greater, where all
surgery. For advanced stage disease, management includes sur- forms of platinum agents are contra-indicated.17
gical resection of the primary tumour, neck dissection, recon- RT is delivered at doses of 70 Gray in 35 fractions over 7
struction and postoperative RT. This is commonly delivered at a weeks or equivalent. A growing number of centres are employing
dose of 60 Gray in 30 fractions over 6 weeks commenced within 6 intensity-modulated radiotherapy (IMRT), which uses multiple
weeks of surgery, with the aim of improving local control. For radiation beams of varying intensity to sculpt the radiotherapy to
patients fit for treatment with positive surgical margins and/or the intended target more precisely (Figure 2). Whereas IMRT has

Figure 2 IMRT plan for a patient with SCC left tonsil (T3 N2b). Note different dose levels: red-high dose to primary and involved nodes,
orange-intermediate dose to left neck, yellow-prophylactic dose to right (uninvolved) neck.

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Please cite this article in press as: Maund I, Jefferies S, Squamous cell carcinoma of the oral cavity, oropharynx and upper oesophagus, Medicine
(2015), http://dx.doi.org/10.1016/j.mpmed.2015.01.004
 MOUTH AND OESOPHAGUS

been shown to improve toxicity in the form of dry mouth by and endoscopy if needed. A PET-CT scan is usually performed at 3
sparing the parotid gland,18 there is no evidence as yet from months following chemoradiation. CT scanning is usually under-
randomized trials to support improvements in other outcomes, taken at 3 months and then at regular intervals. Patients are fol-
including survival. lowed up for 5 years after treatment at increasing intervals.

Management of the neck Prevention

The lymphatic drainage of the oral cavity and pharynx is to the Reducing environmental risk factors, including smoking cessa-
neck nodes. Where histology confirms that neck nodes are tion and avoiding excess alcohol, are important in both primary
infiltrated, they are managed either by surgical neck dissection or and secondary prevention. Female-only HPV vaccination pro-
by radical chemoradiotherapy/RT. grammes for cervical cancer prevention may affect rates of HPV-
The propensity for tumours to spread to lymph nodes depends related oropharyngeal carcinoma but at present there are no
on the site, stage and depth of invasion of the primary tumour. plans for vaccination to be extended to men in the UK. A
This is used to guide prophylactic treatment of the clinically
node-negative neck, with surgery or RT, which is advocated if
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(2015), http://dx.doi.org/10.1016/j.mpmed.2015.01.004
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Please cite this article in press as: Maund I, Jefferies S, Squamous cell carcinoma of the oral cavity, oropharynx and upper oesophagus, Medicine
(2015), http://dx.doi.org/10.1016/j.mpmed.2015.01.004