Glottic Cancer BMJ

Laryngeal cancer
The right clinical information, right where it's needed
Last updated: Feb 20, 2019

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 5
Prevention 8
Primary prevention 8
Screening 8
Secondary prevention 8
Diagnosis 9
Case history 9
Step-by-step diagnostic approach 10
Risk factors 13
History & examination factors 14
Diagnostic tests 16
Differential diagnosis 18
Diagnostic criteria 19
Treatment 23
Step-by-step treatment approach 23
Treatment details overview 25
Treatment options 27
Emerging 33
Follow up 35
Recommendations 35
Complications 35
Prognosis 37
Guidelines 38
Diagnostic guidelines 38
Treatment guidelines 38
Online resources 40
References 41
Images 49
Disclaimer 53
Summary
◊ Eleventh most common form of cancer and second most common malignancy of the upper
aerodigestive tract in men.
◊ Smoking and alcohol use frequently associated with development of the disease.
◊ Hoarseness, dysphonia, sore throat, difficulty swallowing, referred otalgia, vocal cord lesions on
indirect laryngoscopy, and neck mass/adenopathy that persists for >3 weeks are sentinel signs that
should be evaluated by an otolaryngologist.
◊ Treatment is dictated by TNM stage.
◊ Modalities include surgical resection, radiotherapy, chemotherapy, or any combination of these.
◊ Goals of therapy are eradication of cancer with organ preservation.
◊ Speech therapy is appropriate after surgery, radiotherapy, chemoradiotherapy, or any combination of

these modalities.
◊ Overall mortality has not changed in nearly 30 years, but rate of organ preservation has significantly
improved.
Laryngeal cancer Basics
Definition
Laryngeal cancer most often refers to squamous cell carcinoma of the larynx. Other malignant tumours
of the larynx (e.g., sarcoma, lymphoma, neuroendocrine tumours) are extremely rare in comparison. This
BASICS
disease consists of malignant tumours of mucosal origin that originate from the supraglottis, glottis, and
subglottis. Specifically, this encompasses the following structures: the epiglottis, the vocal cords (false or
true), and the area immediately below the vocal cords extending below the glottis.
Epidemiology
The American Cancer Society estimates that 13,430 new cases of laryngeal cancer are expected to be
diagnosed in the US in 2016, or 0.79% of all new cancers diagnosed (excluding basal cell and squamous cell
skin cancer and in situ carcinoma except urinary bladder).[4] Data from the UK and Puerto Rico suggest that
rates are declining.[5] [6] However, the prevalence seems to be increasing in central and eastern European
countries.[7] Data from Denmark suggest that the incidence of the cancer increases with decreasing socio-
economic position.[8]
Laryngeal cancers account for about one quarter of all head and neck cancers, most of which affect the true
vocal folds (vocal cords).[9] [10] Black men are affected more commonly than white men.[11] The male-to-
female incidence ratio is about 4:1.[11] However, in several countries there are increased numbers of women
presenting with laryngeal cancer, presumably as the number of women who smoke increases.[8] [12] [13]
[14] Rates of chromosomal aberration and fragile site expression were higher in patients with head and neck
cancer and their first-degree relatives than in a control group.[15] The relative risks of laryngeal cancer are
1.38 for people who consume the equivalent of two 12 fluid-ounce (350 mL) containers of beer daily and 3.95
for eight 12 fluid-ounce (350 mL) containers (95% CI).[16] The relative risk for laryngeal cancer is >10 for
smokers who have smoked for 40 years or more, and for smokers who smoke 20 or more cigarettes per day.
Combined alcohol consumption and cigarette smoking have multiplicative effects on the risk of developing
laryngeal cancer. Estimated relative risks have been reported to range from 8.0 to >100.[17] The incidence
of head and neck cancers is expected to increase by about 500 to 1000 cases per year in the UK due to an
increase in smoking and alcohol consumption in younger age groups.[18] Squamous cell carcinoma is the
most common histological type of laryngeal cancer, about 95% of cases.[19] Less common malignancies
include sarcoma, lymphoma, adenocarcinoma, and neuro-endocrine carcinoma.[3]
Aetiology
There is overwhelming evidence that the risk of laryngeal cancer increases with increasing amounts of
tobacco use.[3] Alcohol consumption has also been found to be an independent risk factor for laryngeal
cancer.[17] Concurrent tobacco smoking and consumption of alcohol may have a multiplicative effect on
the risk of laryngeal cancer.[20] GORD may be more prevalent in people with laryngeal cancer, as may be
alkaline bile reflux in achlorhydric patients who have undergone gastrectomy.[21] [22] Patients may have a
distant history of radiotherapy to the neck, and genetic links are possible.[15] [23] [24] Vocal cord dysplasia
also seems to be implicated in the development of laryngeal cancer.
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 20, 2019.
BMJ Best Practice topics are regularly updated and the most recent version
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Pathophysiology
Laryngeal cancer arises from progressive accumulation of genetic alterations that lead to selection of a
clonal population of transformed cells.[25] Head and neck cancers (including laryngeal cancer) may require
BASICS
more genetic alterations in their development than other solid tumours, thus explaining the often long (20-
to 25-year) period of latency after initial toxin exposure.[26] Carcinogenesis is induced by DNA damage,
mutations, and adducts.[25] Laryngeal squamous cell carcinoma may appear as a mucosal irregularity,
erythroplasia, or leukoplakia. Human papillomavirus (HPV) has been well described in the pathogenesis
of oropharyngeal cancer but its role in laryngeal cancer is still controversial. A small subset of laryngeal
cancers test positive for markers of HPV but the implications of this are as yet unknown.[27]
Classification
American Joint Commission on Cancer: cancer TNM staging[1]
Primary tumour (T)
• Tx: primary tumour cannot be assessed

• Tis: carcinoma in situ.
Supraglottis
• T1: tumour limited to 1 subsite of supraglottis with normal vocal cord mobility
• T2: tumour invades mucosa of >1 adjacent subsite of supraglottis or glottis or region outside of the
supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of
the larynx
• T3: tumour limited to larynx with vocal cord fixation and/or invades any of the following: post-cricoid
area, pre-epiglottic tissue, paraglottic space, and/or inner cortex of thyroid cartilage
• T4: moderately advanced or very advanced
• T4a: moderately advanced local disease. Tumour invades through the outer cortex of the thyroid
cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including
deep extrinsic muscle of the tongue, strap muscles, thyroid, or oesophagus)
• T4b: Very advanced local disease. Tumour invades prevertebral space, encases carotid artery,
or invades mediastinal structures.
Glottis
• T1: tumour limited to the vocal cord(s) (may involve posterior or anterior commissure) with normal
mobility
• T1a: limited to 1 vocal cord

• T1b: involves both vocal cords
• T2: tumour extends to supraglottis and/or glottis, and/or with impaired vocal cord mobility
• T3: tumour limited to larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner
cortex of the thyroid cartilage
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 20, 2019.
5
• T4a: moderately advanced local disease. Tumour invades through the outer cortex of the
thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, cricoid cartilage, soft
tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or
oesophagus).
BASICS
• T4b: very advanced local disease. Tumour invades prevertebral space, encases carotid artery,
Subglottis
• T1: tumour limited to the subglottis

• T2: tumour extends to vocal cord(s) with normal or impaired cord mobility
• T4a: moderately advanced local disease. Tumour invades cricoid or thyroid cartilage and/or
invades other tissues beyond the larynx (e.g., trachea, soft tissues of the neck, including deep
extrinsic muscle of the tongue, strap muscles, thyroid, or oesophagus).
Regional lymph nodes (N)
Clinical N
• NX: regional lymph nodes cannot be assessed

• N0: no regional lymph node metastasis
• N1: metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and extranodal
extension (ENE)(-)
• N2
• N2a: metastasis in a single ipsilateral lymph node, >3 cm but ≤6 cm in greatest dimension and
ENE(-)
• N2b: metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and
ENE(-)
• N2c: metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
and ENE(-)
• N3
• N3a: metastasis in a lymph node, >6 cm in greatest dimension and ENE(-)

• N3b: metastasis in any lymph node(s) with clinically overt ENE(+).
Pathological N

• N1: metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(-)
• N2
• N2a: metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+); or
metastasis in a single ipsilateral lymph node >3 cm but ≤6 cm in greatest dimension and ENE(-)
ENE(-)
BASICS
• N2c: metastases in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension
and ENE(-)
• N3

• N3b: metastasis in a single ipsilateral lymph node, >3 cm in greatest dimension and ENE(+);
or multiple ipsilateral, contralateral, or bilateral lymph nodes, any with ENE(+); or a single
contralateral node of any size and ENE(+).
Distant metastasis (M)
• cM0: no distant (i.e., non-head and neck) metastases

• cM1: distant metastases present.
• pM1: distant metastases, microscopically confirmed.
The pyriform sinuses and post-cricoid mucosa are considered to be a part of the hypopharynx and are not
included in this topic.
Clinical staging[1]
Stage 0: TisN0M0
Stage I: T1N0M0
Stage II: T2N0M0
Stage III: T3N0M0, T1N1M0, T2N1M0, T3N1M0
Stage IVA: T1N2M0, T2N2M0, T3N2M0, T4aN0M0, T4aN1M0, T4aN2M0
Stage IVB: any T N3M0, T4b any N M0
Stage IVC: any T, any N M1
7
Laryngeal cancer Prevention
Primary prevention
Stopping smoking and avoiding alcohol are paramount in the primary prevention of laryngeal cancer. Also,
limited data exist to support claims that prophylactic treatment of GORD with proton pump inhibitors prevents
laryngeal cancer.[44]
Screening
Given the low incidence of laryngeal cancer, no screening test has been shown to be effective.
Secondary prevention
Patients with 1 head and neck malignancy are at an increased risk for a second, particularly if they continue
to smoke. There is no effective prophylaxis for laryngeal cancer, but many studies have examined prevention
of subsequent malignancy of the upper aerodigestive tract and prevention of cancer recurrence after
cessation of smoking.
PREVENTION
Combination therapy with a derivative of vitamin E, vitamin A, and interferon may effectively prevent tumour
recurrence and secondary primary tumours of the upper aerodigestive tract in patients with advanced
disease.[96] Further investigation with randomised controlled studies is necessary. Clinical trials indicate that
high-dose vitamin A derivatives act as anti-tumour agents.[97] A trial examining lower doses of isotretinoin in
humans did not decrease the rate of second primary tumour, death, or smoking-related disease.[98] Green
tea extracts and COX-2 inhibitors slow tumour progression in vitro and in animal models.[99] [100]
Laryngeal cancer Diagnosis
Case history
Case history #1
A 57-year-old man presents with a 6-month history of hoarseness. He has a reactive airway disease
diagnosis and is treated for asthma. Over the past week he has noted progressive difficulty breathing.
He also has otalgia, dysphagia, odynophagia (painful swallowing), and a 9-kg weight loss. He has an
80-pack-year tobacco history and drinks 8 beers per day. On physical examination, oral cavity and
oropharynx are within normal limits. Neck examination demonstrates a right-sided mass that is firm
and fixed. Cranial nerve examination is normal. There is mild biphasic stridor with deep inspiration and
expiration, but the patient has no increased work of breathing at rest, and breath sounds are clear.
Flexible fibre-optic laryngoscopy demonstrates a necrotic, ulcerating mass involving the right true and
false vocal cords, and extension onto the epiglottis and aryepiglottic folds. The right true vocal cord is
immobile. The glottic airway is partially obstructed.
Case history #2
A 45-year-old man presents with a 3-month history of sore throat and painless, enlarging, left-sided neck
mass. Two courses of antibiotics and a trial of corticosteroids did not clear the sore throat and mass. He
also reports dysphagia with solids and worsening odynophagia (painful swallowing), and a 7-kg weight
loss over the last 2 months. His past medical history is significant for hypertension and COPD, both well
controlled with medication. He has a 50-pack-year smoking history. Physical examination finds a 2-cm,
firm, mobile, and non-tender mass anterior to the sternocleidomastoid muscle in the patient's mid left
cervical lymph node chain. There is no overlying erythema or induration. The oral cavity and oropharynx
are normal, as are the cranial nerves on examination. Breath sounds are clear without stridor or stertor.
Flexible fibre-optic laryngoscopy demonstrates a thickened epiglottis with an ulcerating and necrotic mass
on its laryngeal surface that extends to involve both aryepiglottic folds and the left true and false vocal
cords. The true vocal cords are mobile bilaterally and appear normal.
DIAGNOSIS
Other presentations
Subglottic cancer is rare and presents as progressive difficulty breathing. Many of these patients may
be mistakenly thought to have asthma, but pulmonary function testing shows a pattern consistent with
upper airway obstruction. A few patients, about 10% to 15%, present with distant metastases. The most
common sites of metastases are the lungs, liver, and skeletal system.[2] Patients with laryngeal cancer
are at high risk of a second primary malignancy, most commonly in the lungs. Immunocompromised
patients may present with aggressive tumours in the absence of significant tobacco or alcohol histories.
The number of women presenting with laryngeal cancer is increasing as the number of women who
smoke has increased.[3]
Patients may present with a voice change, if the lesion begins on the true vocal cords, or without
symptoms, if the lesion begins on the epiglottis or arytenoids. As the tumour grows, it may ulcerate or
become necrotic. Voice changes are usually evident in tumours of the true vocal cords, and patients
experience pain and haemoptysis. Dysphagia and odynophagia (painful swallowing) are more common
in tumours involving the supraglottic larynx (e.g., epiglottis) but may also occur with vocal cord tumours.
With severe dysphagia, patients may present with aspiration pneumonia. If not treated, the tumour will
9
cause deviation and obstruction of the airway. This occurs over a period of days, as opposed to hours,
and patients often have an insidious shortness of breath that ultimately becomes intolerable. Stridor and
dysphonia are common. Patients may also present in extreme respiratory distress, requiring immediate
intervention to secure the airway. Neck masses (metastases to the cervical lymph nodes) and weight loss
are typical findings of advanced disease.
Step-by-step diagnostic approach

A focused history and physical examination may identify laryngeal malignancy in patients with hoarseness,
sore throat, dysphagia, odynophagia (painful swallowing), otalgia, and neck mass. Although the evidence is
less marked than for some other malignancies, diagnostic delay moderately increases the risk of mortality
from head and neck cancers.[45]
History
Strong risk factors for laryngeal cancer include smoking and alcohol usage, GORD and bile reflux,
previous radiotherapy to the neck, history of vocal fold dysplasia, and family history of laryngeal cancer.
Patients often present with insidious onset of hoarseness, sore throat, dysphagia, odynophagia (painful
swallowing), otalgia, and neck mass. Most cases of laryngeal carcinoma present in men >40 years of
age, with a predilection in black men. There is almost always a history of tobacco and alcohol usage,
either currently or in the past. A history of pre-malignant lesions, such as vocal fold dysplasia, increases
the suspicion of a malignant laryngeal lesion. Previous exposure to asbestos, Agent Orange, or human
papillomavirus, and a history of immunocompromise or respiratory papillomatosis also confer a mild risk
of laryngeal cancer. Chronic laryngitis lasting >3 weeks should be referred to a specialist.
Patients with laryngeal cancer involving the true vocal cords (glottic cancer) may become symptomatic
with phonic changes and seek medical attention sooner than those with supraglottic cancer. This is
usually because of more obvious symptoms of voice change with even minor changes in vocal fold
morphology. Patients with supraglottic cancer often present first with a persistent sore throat and
DIAGNOSIS
odynophagia (painful swallowing). Neck metastases are more common in patients with supraglottic
cancer. They may seek medical attention for a (metastatic) neck mass before having hoarseness or
dysphagia.
Physical examination
A breathy, gravelly voice or aphonic condition suggests the presence of laryngeal cancer and may be
apparent on initial assessment of the patient. Cachexia, weight loss, and general distress are signs of
advanced disease. Black men are affected more commonly than white men.[38] The male-to-female
incidence ratio is about 4:1.[38]
The signs of laryngeal cancer include (by organ system):
• Ear: otalgia (e.g., middle ear effusion, otitis externa).

• Oral cavity and oropharynx: masses or leukoplakia of the posterior pharyngeal wall, tonsillar pillars,
tonsils and palate, surfaces of the oral tongue, floor of mouth, and base of the tongue.
• Laryngeal inlet: lesions of the vocal cords, aryepiglottic folds, and local extension of tumour. A
handheld mirror and headlight can provide an excellent view of the base of the tongue and larynx.
Indirect laryngoscopy also allows immediate evaluation for obvious lesions involving the glottis.
Examination of many people is limited by a strong gag reflex.
• Neck: cervical lymph nodes or masses (noting approximate size, location, mobility, and degree
of firmness), laryngeal crepitus (lack may indicate a more advanced stage of cancer), palpable
nodules or masses of parotid or thyroid.
• Lungs: stridor (biphasic, inspiratory, and expiratory), diminished breath sounds (suggests
pneumonia, especially in circumstances in which aspiration is suspected). The difficulty with
which the patient is breathing at rest, while speaking, and while supine should be noted. Patients
who may appear comfortable while upright may have significant dyspnoea while lying supine. In
advanced cases, the airway may be compromised.
• Heart: haemodynamic instability may be present (e.g., catastrophic vascular-aerodigestive fistula).
[Fig-1]
[Fig-2]
Laboratory
Fine needle aspiration is indicated in patients who present with a palpable neck mass. Cytological
analysis of the aspirate may often confirm the diagnosis of squamous cell carcinoma, as well as other
malignancies. A negative result does not rule out cancer. Biopsy of laryngeal findings from the initial
examination is generally deferred to the specialist and follows formal radiographic investigation. Direct
visualisation of a laryngeal lesion is highly suggestive of laryngeal cancer, but diagnosis must be
confirmed by tissue biopsy.
Imaging
Once laryngeal malignancy is suspected, a neck computed tomography (CT) with contrast is indicated.
Ideally this is performed before biopsies are taken, to limit the confounding factor of post-biopsy oedema.
Neck CT with contrast is essential in the complete staging of laryngeal cancer. Intravenous contrast
enables better distinction between normal and abnormal soft tissue planes. Cuts should be finer than 2.5
mm. Suspicious lymph nodes and cartilage invasion are more easily assessed on CT than by physical
DIAGNOSIS
examination or magnetic resonance imaging.
The resolution advantage of chest CT with contrast over traditional chest x-ray is unquestionable,
and many clinicians obtain a chest CT at the same time as neck CT if laryngeal cancer is suspected.
Traditionally, the literature has supported the assessment of the chest cavity with a 2-view chest x-ray.[46]
However, recent studies have shown that chest x-ray is an insensitive test for distant metastases from
Whole-body positron emission tomography (PET)/CT scans have gained popularity among some head
and neck oncologists. This method is more sensitive than others in detecting cervical lymph nodes,
distant metastases, and recurrent disease.[48] [49] It has become useful in the initial staging of head and
neck cancer, detecting an unknown primary, planning radiation, and evaluating response to treatment.[48]
Availability and physician choice both affect whether a patient receives a PET/ CT scan. A dual PET/ CT
scanner is not available at all centres and is usually reserved for advanced disease.
[Fig-3]
[Fig-4]
11
Specialised examinations
Flexible endoscopy allows simultaneous rapid assessment of laryngeal pathology and of the upper
airway. Flexible fibre-optic laryngoscopy (usually performed by the otolaryngologist) identifies areas of
leukoplakia, erythroplasia, ulceration, mass, necrosis, or bleeding. The degree of airway obstruction
may also be evaluated. Flexible endoscopy is also necessary for sufficient follow-up of laryngeal cancer
patients.
• Technique: the nasal cavity that is subjectively most patent is treated with topical decongestant and
anaesthetic spray. A flexible fibre-optic laryngoscope is passed through the nasal cavity to evaluate
the nasopharynx, oropharynx, base of the tongue, vallecula, both vallecular and laryngeal surfaces
of the epiglottis, aryepiglottic folds, arytenoid mucosa, pyriform sinuses, false vocal folds, true vocal
folds, and (if appropriately anaesthetised), the subglottis. The patient is asked to phonate, and
vocal fold mobility is assessed.
Rigid videostroboscopy of the larynx (usually performed by an otolaryngologist or a speech pathologist) is
preferred to evaluate the vibratory motion of the true vocal folds and identify smaller underlying vocal cord
pathology. It is less useful in evaluating bulky tumours.
• Technique: a rigid 70° telescope is advanced into the laryngeal inlet through the oral cavity while
the tongue is gently retracted anteriorly. The patient is asked to breathe through the mouth.
Rigid endoscopy and biopsy under general anaesthesia with relaxation remains the preferred method
for completely evaluating laryngeal findings and pathology. A rigid telescope with a magnifying lens may
be used to appreciate finer detail and subtle abnormalities. A cupped biopsy forceps is passed through
the laryngoscope to obtain biopsy specimens. Frozen section pathology during the procedure is useful to
ascertain that sufficient tissue has been obtained to yield a diagnosis. Straight-on (0°) and angled (70°)
telescopes are useful to ascertain the size and extent of a tumour, particularly in the case of subglottic
cancer.
• Technique: after the airway has been secured and general anaesthesia induced, the neck,
oral cavity, and oropharynx are carefully palpated. Examination is much more thorough under
DIAGNOSIS
anaesthesia. The maxillary dentition is protected with a tooth guard (or moist gauze in edentulous
patients). The rigid laryngoscope is advanced into the oral cavity to examine the oral cavity, tonsils,
posterior pharyngeal wall, base of the tongue, vallecula, epiglottis, aryepiglottic folds, arytenoid
mucosa, pyriform sinuses, post-cricoid mucosa, false vocal folds, true vocal folds, and subglottis.
Some centres are now making use of fluorescence endoscopy. In auto-fluorescence endoscopy (AFE),
the mucosa is examined under narrow-spectrum light from a xenon arc lamp. Under the lamp, normal
mucosa and benign lesions exhibit a typical green auto-fluorescence (greatest at 515 nm), while
cancerous and pre-cancerous lesions exhibit loss of auto-fluorescence, resulting in a red-violet colour. In
induced fluorescence endoscopy (IFE), exogenous aminolevulinic acid is applied to the tissues 2 hours
before endoscopy, and is preferentially taken up and metabolised by tumour cells, which exhibit a red-
orange fluorescence (by contrast with the blue of normal tissue, under filtered blue light). AFE may be
particularly useful for early diagnosis of laryngeal cancer and its precursor lesions. IFE may be more
suited for detection of recurrent disease after initial surgery.[50]
Laryngeal cancer presents significant concerns for securing the airway. In patients with concerns for
significant airway obstruction, an awake tracheostomy may be considered before any endoscopic
evaluation under general anaesthesia. The otolaryngologist must coordinate and work closely with the
anaesthesiologist in this circumstance.
[Fig-1]
[Fig-2]
Risk factors
Strong
tobacco use >40 pack-years
• Studies have consistently reported that tobacco smokers have a greater risk than non-smokers
of developing laryngeal cancer. This risk is directly proportional to the amount and duration of
smoking.[28]
• The relative risk for laryngeal cancer is >10 for smokers who have smoked for ≥40 years and for
smokers who smoke ≥20 cigarettes per day. This risk decreases after smoking cessation.[29]
• Tobacco smoke is known to contain >55 mutagenic compounds.[30]
alcohol use >8 units/day

• Alcohol has been identified as an individual risk factor for laryngeal cancer.[29] [31]
• The relative risk of laryngeal cancer is proportional to the amount of alcohol consumed. The relative
risks of laryngeal cancer are 1.38 for people who consume the equivalent of two 12 fluid-ounce (350
mL) containers of beer daily and 3.95 for eight 12 fluid-ounce (350 mL) containers (95% CI).[32]
• Combined alcohol consumption and cigarette smoking have multiplicative effects on the risk of
developing laryngeal cancer. Estimated relative risks range from 8.0 to >100.[29]
achlorhydria
• Alkaline bile reflux in achlorhydric patients who have undergone gastrectomy may cause chronic
irritation and increase the risk of pre-malignant or malignant lesions of the larynx.[34]
DIAGNOSIS
history of radiotherapy
• Many cases have been reported of patients developing laryngeal cancer many years after receiving
radiotherapy to the neck. However, histological variability is greater with sarcoma (rather than
squamous cell carcinoma, the predominant cell type).[35]
family history of laryngeal cancer

• Rates of chromosomal aberration and fragile site expression were higher in patients with head and
neck cancer and their first-degree relatives than in a control group.[36] A mutation in the p16 tumour
suppressor gene has been identified in a family with a high incidence of head and neck cancer.[37]
black ethnicity
• Black men are affected more commonly than white men.[38]
male sex
• The male-to-female incidence ratio is about 4:1.[38]
13
vocal fold dysplasia
• Previous diagnosis of vocal fold dysplasia increases the suspicion of a newly diagnosed laryngeal
lesion as malignant.
Weak
GORD
• May be more prevalent in people with laryngeal cancer. In a large case-control series, a multivariate
analysis demonstrated that GORD was an independent risk factor for laryngeal cancer.[33]
asbestos exposure
• Findings from several prospective and retrospective studies are controversial regarding the risk of
asbestos exposure and development of laryngeal cancer. As a whole, the evidence does not support
assertions that asbestos exposure increases the relative risk of laryngeal cancer.[39]
Agent Orange exposure

• Evidence does not consistently show an increased rate of laryngeal cancer in people (e.g., veterans)
who were exposed to Agent Orange.[40] Studies have been limited by small sample size and
confounding factors, such as concurrent smoking and alcohol consumption.
immunocompromised host
• Immunocompromised status, such as chronic immunosuppression secondary to AIDS or organ
transplantation, increases the risk of laryngeal malignancy.
human papillomavirus (HPV) exposure

• Has been identified in many types of head and neck cancer, most consistently in the oropharynx
(e.g., tonsils).[41] Case-control studies have demonstrated variable prevalence of HPV in laryngeal
cancer.[42]
• HPV has been well described in the pathogenesis of oropharyngeal cancer but its role in laryngeal
DIAGNOSIS
cancer is still controversial. A small subset of laryngeal cancers test positive for markers of HPV but
the implications of this are as yet unknown.[42]
history of respiratory papillomatosis

• History of human papillomavirus-mediated recurrent respiratory papillomatosis may be a risk factor for
History & examination factors

Key diagnostic factors
presence of risk factors (common)
• Strong risk factors include smoking and alcohol usage, GORD and bile reflux, previous radiotherapy
to the neck, history of vocal fold dysplasia, black ethnicity, male sex, and family history of laryngeal
cancer.
age >40 years (common)
• Laryngeal cancer most commonly affects people in the fifth decade of life, probably relating to the
cumulative effect of prolonged exposure to carcinogens (e.g., tobacco, alcohol).
hoarseness (common)
• Voice changes are common in patients with laryngeal cancer of the glottis (vocal folds). Breathy,
gravelly voice or aphonia for >3 weeks suggests laryngeal cancer.
• Fixation of the vocal cords, indicated by disruption of the true vocal fold mucosal wave and vocal fold
mechanics, may indicate local progression of disease.
• Patients with long smoking histories may have a baseline degree of dysphonia that makes it difficult to
note changes caused by laryngeal cancer.
dysphagia (common)
• More common in patients with supraglottic cancer, often the presenting symptom in these patients.
With larger glottic tumours, dysphagia may be present.
odynophagia (painful swallowing) (common)

• More common in patients with supraglottic cancer. Odynophagia may also be present with larger
glottic tumours.
cervical lymphadenopathy (common)

• Cervical metastases may present as painless, firm masses. More common in supraglottic cancer.
Glottic cancer has a much lower rate of cervical metastases. Size, location, mobility, and degree of
firmness indicate degree of progression of laryngeal malignancy.
supraglot tic or glot tic mass (common)

• Indirect laryngoscopy allows immediate evaluation for obvious lesions involving the larynx.
lesional erythroplasia, ulceration, necrosis, or bleeding (common)

• May begin as erythroplasia and evolve into ulcerated, necrotic, friable, and bulky lesions involving the
true vocal folds, false vocal folds, arytenoids, epiglottis, or subglottic larynx. Seen either with mirror
DIAGNOSIS
laryngoscopy or flexible fibre-optic laryngoscopy.
signs of airway obstruction (uncommon)

• Supraglottic laryngeal cancer presents significant concerns with regard to obstructed airway.
• As masses grow within or around the glottis, the airway may become obstructed and cause
progressive difficulty breathing. Dyspnoea may be exacerbated by speaking or while supine.
• Diminished breath sounds may also indicate airway obstruction.
haemodynamic instability (uncommon)

• May indicate catastrophic bleeding from fistula (e.g., pharyngocarotid or tracheo-innominate artery).
Other diagnostic factors

sore throat (common)
• Patients with laryngeal cancer often present with insidious onset of pharyngitis.
otalgia (common)
• Referred pain to the ears may be seen in laryngeal cancer, particularly in more advanced cases.
15
middle ear effusion (uncommon)
• May be seen in more advanced cases.
stridor (uncommon)
• Airway obstruction may be seen in advanced stages of all histological types of laryngeal cancer. In the
rare case of subglottic laryngeal cancer, stridor is often the first sign.
weight loss or cachexia (uncommon)

• Weight loss is more common in advanced supraglottic cancer. Dysphagia and odynophagia (painful
swallowing) may lead to significant weight loss.
• Cachexia is an ominous sign of advanced disease.
general distress (uncommon)

• Airway obstruction or disseminated disease may be apparent on initial assessment.
oral and pharyngeal masses or leukoplakia (uncommon)

• Signs of malignant involvement may extend to the posterior pharyngeal wall, tonsillar pillars, tonsils
and palate, surfaces of oral tongue, floor of mouth, and base of tongue.
loss of laryngeal crepitus (uncommon)

• When displacing the larynx from side to side there should be a degree of mobility and crepitus; if not,
cancer may be at a more advanced stage.
parotid and thyroid growths (uncommon)

• Palpable nodules or masses of glands of the head and neck may indicate regional metastases or
advanced disease.
diminished breath sounds (uncommon)

• May indicate airway obstruction or pneumonia, especially when aspiration is suspected.
DIAGNOSIS
Diagnostic tests
1st test to order
Test Result
neck CT with contrast laryngeal mass
may show cartilage
• Preferably done before biopsy as staging for suspected malignancy.
invasion; presence or
CT scans performed without contrast are not as useful because
absence of cervical
of the inability to differentiate between normal and abnormal
lymphadenopathy
enhancement.
[Fig-3]
• CT scans are better than physical examination for detecting cervical
lymph node metastasis but cannot accurately assess lymph nodes
<1 cm. The sensitivity of CT for detecting cervical lymph node
metastasis is much less than that for PET scan (78% versus
96%).[48]
• Small laryngeal lesions may also be missed on CT scan, but these
will be seen on flexible fibre-optic laryngoscopy.
Test Result
chest CT with contrast normal or
metastatic nodules,
• Typically accompanies neck CT, as most common site of metastasis
lymphadenopathy
of head and neck cancer is to the lungs.
• The resolution advantage of chest CT with contrast over traditional
chest x-ray is unquestionable, and many clinicians obtain a chest CT
at the same time as neck CT if laryngeal cancer is suspected.
• CT combined with PET/CT may be superior in the assessment for
distant metastases.[46]
fine needle aspiration of neck mass may show squamous cell
carcinoma
• Indicated if a neck mass is palpable. If a mass is not palpable but is
seen on CT scan, a CT-guided or ultrasound-guided biopsy may be
useful.
• Cytological analysis of the aspirate may often confirm the diagnosis
of squamous cell carcinoma, as well as other malignancies.
• A negative result does not rule out malignancy.
flexible fibre-optic laryngoscopy lesion involving
the vocal folds,
• Performed in any person with hoarseness, dysphagia, odynophagia
epiglot tis, arytenoids, or
(painful swallowing), or throat pain lasting >3 weeks. Also necessary
aryepiglot tic folds
for sufficient follow-up of laryngeal cancer patients.
• Simultaneously allows excellent visualisation of the larynx and
assessment of airway patency. In some cases biopsies can be
performed using a fibre-optic laryngoscope.
[Fig-1]
[Fig-2]
• Limitations include inability to completely assess extent of tumour in
some patients and inability to definitively diagnose cancer (e.g., does
not yield immediate histopathology results).
• If no lesions are seen and the index of suspicion is high, rigid
endoscopy is indicated.
Other tests to consider
DIAGNOSIS
Test Result
rigid videostroboscopy may demonstrate vocal
cord fixation
• Enables superior evaluation of the true vocal fold mucosal wave and
vocal fold mechanics, at times helping to determine sub-mucosal
extent of disease.
rigid direct laryngoscopy ulcerative, friable,
necrotic mass involving
• Strong suspicion of laryngeal cancer and complete tumour staging
the larynx
mandate direct laryngoscopy with biopsy.
• General anaesthesia is required and necessitates careful co-
ordination with the anaesthesiologist to secure and maintain the
airway.
17
Test Result
laryngeal biopsy superficial ulceration,
necrosis, cellular atypia,
• Indicated if laryngeal malignancy is suspected (e.g., at time of rigid
mitotic figures, and
endoscopy).
invasion of basement
• Multiple biopsies should be obtained of the lesion, as pathology is
limited by the quality of the specimen collected. If the specimen is membrane; in advanced
cases, perineural and
obtained from a necrotic portion of the tumour, pathology may not
angiolymphatic invasion
demonstrate features characteristic of squamous cell carcinoma.
• Frozen section pathology may be used to confirm that the biopsy
specimen is representative. Additional specimens may be obtained if
frozen section is negative, if index of suspicion is high.
whole-body PET/CT scan increased uptake in
areas of malignancy and
• PET scanning may be superior to assessing nodal status and
metastasis
presence of distant metastasis.[48]
• Increased uptake on PET imaging is not specific to malignancy.
Infection or inflammation may also increase uptake.
[Fig-4]
• Findings must be put into context with the patient's overall clinical
condition and may warrant additional studies to evaluate these areas.
• Availability and physician choice both affect whether a patient
receives a PET/ CT scan. A dual PET/ CT scanner is not available at
all centres and is usually reserved for advanced disease.
fluorescence endoscopy red-violet coloration (loss
of auto-fluorescence) in
• Auto-fluorescence endoscopy is available in some centres, typically
dysplastic lesions
using a xenon arc lamp with a narrow excitation spectrum ranging
from 375 to 440 nm. Remitted excitation light up to 440 nm is blocked
out by an integrated optic filter within the endoscope, enabling
switching from white-light endoscopy to fluorescence endoscopy.[50]
Differential diagnosis
DIAGNOSIS
Condition Differentiating signs / Differentiating tests

symptoms
Laryngitis • Symptoms <7 days, • Generally a clinical
preceded by upper diagnosis, although indirect
respiratory infection, and laryngoscopy may be
ordinarily self-limiting. May performed to rule out
present with airway distress laryngeal cancer. Chronic
and high fever. Exudative laryngitis lasting >3 weeks
tonsillopharyngitis with should be referred to a
fever and anterior cervical specialist.
lymphadenitis is highly
suggestive of a bacterial
origin.
Condition Differentiating signs / Differentiating tests

symptoms
Fungal laryngitis • There is often an associated • Biopsy and fungal culture
infection of the oral distinguish this disorder from
cavity and oropharynx malignancy.
demonstrating signs of
thrush.
• More common in patients
who have history of
immunosuppression or
who take corticosteroids
(in particular inhaled
corticosteroids).
• Neck masses are
uncommon.
Sarcoidosis • Often associated with nasal • Localised pale oedema,

congestion and obstruction, submucosal nodules
and dyspnoea on exertion. on laryngoscopy, non-
Patients may have a known caseating granulomas
diagnosis of sarcoidosis. on histopathology. Hilar
adenopathy on chest x-ray
and increased ACE levels.
Tuberculosis (TB) • History of known TB, • Laryngoscopy shows

PPD positive, known risk multiple nodular lesions
factors for TB infection (similar findings to laryngeal
(e.g., homelessness, cancer). Biopsy and culture
incarceration, HIV positive). of lesions distinguish TB.[51]
Granulomatosis with • Patients may present with • Laryngoscopy shows

polyangiitis (formerly nasal congestion, nasal acute, erythematous friable
known as Wegener's crusting, cough and difficulty mucosa and subglottic
granulomatosis) breathing, and haematuria. narrowing.[52] Biopsy of
May have a known history lesions is diagnostic; may
DIAGNOSIS
of granulomatosis with demonstrate vasculitis.
polyangiitis. Serum tests of cytoplasmic-
staining antineutrophil
cytoplasmic antibodies may
be diagnostic, but sensitivity
is only 65% to 75%.
Diagnostic criteria
American Joint Commission on Cancer: cancer TNM staging[1]
Primary tumour (T)
• Tx: primary tumour cannot be assessed

• Tis: carcinoma in situ.
Supraglottis
• T1: tumour limited to 1 subsite of supraglottis with normal vocal cord mobility
19
• T2: tumour invades mucosa of >1 adjacent subsite of supraglottis or glottis or region outside of the
supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of
the larynx
• T3: tumour limited to larynx with vocal cord fixation and/or invades any of the following: post-cricoid
area, pre-epiglottic tissue, paraglottic space, and/or inner cortex of thyroid cartilage
• T4a: moderately advanced local disease. Tumour invades through the outer cortex of the thyroid
cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including
deep extrinsic muscle of the tongue, strap muscles, thyroid, or oesophagus)
• T4b: Very advanced local disease. Tumour invades prevertebral space, encases carotid artery,
Glottis
• T1: tumour limited to the vocal cord(s) (may involve posterior or anterior commissure) with normal
mobility
• T1a: limited to 1 vocal cord

• T1b: involves both vocal cords
• T2: tumour extends to supraglottis and/or glottis, and/or with impaired vocal cord mobility
• T4a: moderately advanced local disease. Tumour invades through the outer cortex of the
thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, cricoid cartilage, soft
tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or
oesophagus).
DIAGNOSIS
Subglottis
• T1: tumour limited to the subglottis

• T2: tumour extends to vocal cord(s) with normal or impaired cord mobility
• T4a: moderately advanced local disease. tumour invades cricoid or thyroid cartilage and/or
invades other tissues beyond the larynx (e.g., trachea, soft tissues of the neck, including deep
extrinsic muscle of the tongue, strap muscles, thyroid, or oesophagus).
Regional lymph nodes (N)
Clinical N

• N1: metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and extranodal
extension (ENE)(-)
• N2
• N2a: metastasis in a single ipsilateral lymph node, >3 cm but ≤6 cm in greatest dimension and
ENE(-)
ENE(-)
• N2c: metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
and ENE(-)
• N3

• N3b: metastasis in any lymph node(s) with clinically overt ENE(+).
Pathological N

• N1: metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(-)
• N2
• N2a: metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+); or
metastasis in a single ipsilateral lymph node >3 cm but ≤6 cm in greatest dimension and ENE(-)
ENE(-)
• N2c: metastases in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension
DIAGNOSIS
and ENE(-)
• N3

• N3b: metastasis in a single ipsilateral lymph node, >3 cm in greatest dimension and ENE(+);
or multiple ipsilateral, contralateral, or bilateral lymph nodes, any with ENE(+); or a single
contralateral node of any size and ENE(+).
Distant metastasis (M)
• cM0: no distant (i.e., non-head and neck) metastases

• cM1: distant metastases present.
• pM1: distant metastases, microscopically confirmed.
The pyriform sinuses and post-cricoid mucosa are considered to be a part of the hypopharynx and are not
included in this topic.
Clinical staging[1]
21
Stage 0: TisN0M0
Stage I: T1N0M0
Stage II: T2N0M0
Stage III: T3N0M0, T1N1M0, T2N1M0, T3N1M0
Stage IVA: T1N2M0, T2N2M0, T3N2M0, T4aN0M0, T4aN1M0, T4aN2M0
Stage IVB: any T N3M0, T4b any N M0
Stage IVC: any T, any N M1

DIAGNOSIS
Laryngeal cancer Treatment
Step-by-step treatment approach

The treatment of laryngeal cancer is dictated by TNM stage. Modalities include surgical resection,
radiotherapy, chemotherapy, or any combination of these. Goals of therapy are eradication of cancer with
organ preservation. Speech therapy is appropriate after surgery, radiotherapy, chemoradiotherapy, or any
combination of these modalities.[53] [54]
Glot tic and supraglot tic tumours: T1 and T2

Treatment in T1 and T2 N0 M0 tumours involves single-modality treatment with surgery or radiotherapy.
Larynx-sparing surgery (e.g., endoscopic laser resection, laryngofissure, cordectomy, vertical partial
laryngectomy) or radiotherapy are equally effective in terms of tumour control and survival.
In glottic tumours, larynx-sparing surgery is reported to have local cancer control rates ranging from 86%
to 98% and a 5-year disease-specific survival rate of 92% to 97%.[55] [56] Although the data vary, larynx-
sparing surgery and radiotherapy for treatment of T1 and T2 laryngeal cancers show similar survival
rates.[46] [57] [58] In experienced hands, endoscopic resection of T1 lesions may yield better outcomes
than definitive radiotherapy.[58] Single-mode treatment of T1 laryngeal cancer with radiotherapy has a
similar survival rate to surgery.
In supraglottic tumours, open or endoscopic surgery is comparable to radiotherapy alone, although some
report that there is a higher local control rate with open surgery. [58] For patients with T1 and T2 cancers,
trans-oral microlaser surgery should be offered where possible as a treatment option in addition to open
surgery, other larynx-sparing surgeries, and radiotherapy.[59] At this time there is insufficient evidence
to determine whether the endoscopic surgical techniques are superior to radiotherapy,[60] [61] but the
vocal and quality of life outcomes for radiotherapy and transoral laser surgery have been found to be
equivalent.[62]
Neck dissection is recommended for patients undergoing laryngectomy prior to adjuvant radiotherapy
or chemoradiotherapy. A systematic review using a number-needed-to-treat cut-off of 5 has provided
recommendations on the appropriate lymph node level treatment in N0 and N+ patients with squamous
cell carcinomas of the head and neck.[63]
Glot tic and supraglot tic tumours: T3

Treatment in T3 tumours involves either concurrent chemotherapy and radiotherapy or surgery. Partial
laryngectomy[56] or total laryngectomy can be used; partial laryngectomy allows for preservation
of speech and swallowing function in highly selected cases. The choice between surgery and
concurrent chemoradiotherapy for patients with primary T3 tumours is a matter of debate.[64] [65]
Chemoradiotherapy has the advantage of allowing better preservation of speech and swallowing function
if the alternative option requires total laryngectomy. However, a retrospective observational cohort study
of over 7,000 patients from the National Cancer Database found that, in patients with T3 laryngeal cancer,
those treated with chemoradiotherapy had a significantly increased risk for death compared with those
treated with total laryngectomy (hazard ratio=1.18; P=0.03).[64] Radiation alone, however, has been
shown to be inferior to the above-mentioned therapies for T3 and T4 tumours.[64] [46] [66] [67]
TREATMENT
Cisplatin may be given with or without 5-fluorouracil. In cases of excessive toxicity, patients may be
treated with carboplatin or cetuximab. However, the addition of cetuximab to cisplatin in combination
with radiation does not improve outcome compared with radiation plus cisplatin only.[68] Similarly,
23
altered fractionated radiation plus cisplatin does not confer any advantage over standard cisplatin
chemoradiation.[69]
Neck dissection is recommended for persistent neck disease after chemoradiotherapy and in patients
undergoing laryngectomy with clinically positive neck disease.[63] The role of neck dissection following
chemoradiotherapy; however, remains controversial.[70]
Adjuvant chemotherapy may be used postoperatively for certain unfavourable tumour characteristics (e.g.,
positive margins, >4 lymph nodes, extracapsular spread).[71] See local specialist protocol for dosing
guidelines.
Locoregional control and larynx preservation were found to be significantly improved with concomitant
chemoradiation compared with induction chemotherapy followed by radiotherapy or compared with
radiotherapy alone.[72]
Glot tic and supraglot tic tumours: T4

Treatment involves either concurrent chemotherapy and radiotherapy or surgery. Neck dissection and
adjuvant (postoperative) radiotherapy may also be required. Patients for whom no treatment options have
been effective or who are not candidates for therapy should be offered palliative care, which can include
chemotherapy.
Chemoradiotherapy or surgery are equally effective if cartilage is not involved. Total laryngectomy
is recommended over concurrent chemotherapy and radiotherapy if cartilage is involved.[46] [73]
In cases of cartilage invasion, positive or close margins, multiple positive cervical lymph nodes, or
extracapsular extension of disease, adjuvant (postoperative) chemoradiotherapy is recommended. Neck
dissection after chemoradiotherapy is recommended for persistent neck disease after and in patients
undergoing laryngectomy with clinically positive neck disease.[63] The role of neck dissection following
chemoradiotherapy in an N0 neck; however, remains controversial.[70] Good local control has been
demonstrated after open partial laryngectomy in patients with radiorecurrent laryngeal cancer, although
the technique is not widely practised in this setting.[74]
The choice of chemotherapy agents is the same as for T3 tumours. Adjuvant chemoradiotherapy may be
used postoperatively for certain unfavourable tumour characteristics (e.g., angiolymphatic or perineural
invasion, extracapsular spread).[71]
Patients for whom no treatment options have been effective or who are not candidates for therapy should
be offered supportive care (e.g., pain control, counselling). Although chemotherapy alone has no role
in the treatment of laryngeal cancer, it has been used as a single-mode adjunct in palliative care.[75]
Cetuximab is a monoclonal antibody that binds specifically to the epidermal growth factor receptor
(EGFR) expressed on epithelial tissues and inhibits the growth of tumour cells that express EGFR. While
studies have shown combined radiotherapy with cetuximab to be superior to radiotherapy alone, no
randomised controlled studies have compared cetuximab with cisplatin.[76] [77]
Locoregional control and larynx preservation were found to be significantly improved with concomitant
chemoradiation compared with induction chemotherapy followed by radiotherapy or compared with
TREATMENT
radiotherapy alone.[72]
Subglot tic tumours
Subglottic tumours are treated by total laryngectomy and neck dissection surgery (including
thyroidectomy) followed by radiotherapy.
Recurrence
Physical examination including laryngoscopy is most important in detection of recurrence.
Imaging and physical examination are vital in the setting of suspected recurrence or persistence of
cancer. Various imaging modalities are available, but all require biopsy for a definitive result.[78] Surgical
salvage is the standard of care in patients with recurrent disease that is considered resectable and who
are medically fit for surgery. Postoperative re-irradiation may be considered. In patients re-irradiated with
curative intent, the addition of chemotherapy is typically used.[79]
Treatment details overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
glot tic or supraglot tic
T1 or T2: N0 M0 1st laryngeal-sparing surgery or radiotherapy
plus post-treatment speech rehabilitation
T1 or T2: N1-N2c M0 1st partial or total laryngectomy or

chemoradiotherapy
T3: N0-N2c M0 1st partial or total laryngectomy or

chemoradiotherapy
T4 or N3 or M1 1st total laryngectomy or chemoradiotherapy
adjunct postoperative chemoradiotherapy
subglot tic
1st total laryngectomy and radiotherapy

TREATMENT
Ongoing ( summary )
treatment not effective/appropriate
1st palliative care
25
Ongoing ( summary )
adjunct chemotherapy
1st surgical salvage ± postoperative re-

irradiation ± chemotherapy
TREATMENT
Treatment options
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute
glot tic or supraglot tic
T1 or T2: N0 M0 1st laryngeal-sparing surgery or radiotherapy
» Treatment in T1 and T2 N0 M0 tumours

involves single-modality treatment with surgery
or radiotherapy. Larynx-sparing surgery (e.g.,
endoscopic laser resection, laryngofissure,
cordectomy, vertical partial laryngectomy) or
radiotherapy are equally effective in terms of
tumour control and survival.
» In glottic tumours, larynx-sparing surgery

is reported to have local cancer control
rates ranging from 86% to 98% and a 5-
year disease-specific survival rate of 92%
to 97%.[55] Although the data vary, larynx-
sparing surgery and radiotherapy for treatment
of T1 and T2 laryngeal cancers show similar
survival rates.[46] [57] [58] In experienced
hands, endoscopic resection of T1 lesions
may yield better outcomes than definitive
radiotherapy.[58] Single-mode treatment of T1
laryngeal cancer with radiotherapy has a similar
survival rate to surgery.
» In supraglottic tumours, open or endoscopic

surgery is comparable to radiotherapy alone,
although some report that there is a higher local
control rate with surgery.[58] For patients with T1
and T2 cancers, trans-oral microlaser surgery
should be offered where possible as a treatment
option in addition to open surgery, other larynx-
sparing surgeries, and radiotherapy.[59] At this
time there is insufficient evidence to determine
whether the endoscopic surgical techniques are
superior to radiotherapy[60] [61] but the vocal
and quality of life outcomes for radiotherapy and
transoral laser surgery have been found to be
equivalent.[62]
Treatment recommended for ALL patients in
selected patient group
TREATMENT
» Speech therapy is appropriate after surgery,

radiotherapy, chemoradiotherapy, or any
combination of these modalities.
T1 or T2: N1-N2c M0 1st partial or total laryngectomy or
chemoradiotherapy
27
Acute
» Patients with N1-N2c M0 staging (N1M0,
N2aM0, N2bM0, or N2cM0) have more
deeply invasive lesions with regional lymph
node metastases ≤6cm in size but no distant
metastases.
» Laryngeal surgery (with partial or total

laryngectomy) or concurrent chemotherapy and
radiotherapy is recommended.
» Cisplatin may be given with or without 5-

fluorouracil. In cases of excessive toxicity,
patients may be treated with carboplatin or
cetuximab. Adjuvant chemotherapy may be
used postoperatively for certain unfavourable
tumour characteristics (e.g., angiolymphatic or
perineural invasion, extracapsular spread).[71]
See local specialist protocol for dosing
guidelines.
» Neck dissection is recommended for patients

undergoing laryngectomy prior to adjuvant
radiotherapy or chemoradiotherapy.[63]
T3: N0-N2c M0 1st partial or total laryngectomy or
chemoradiotherapy
» Patients with N0-N2c M0 staging have either

no regional or distant lymph node metastases
(N0M0) or regional lymph node metastases ≤6
cm in size but no distant metastases (N1M0,
N2aM0, N2bM0, or N2cM0).
» Treatment in T3 tumours involves either

concurrent chemotherapy and radiotherapy
or surgery. Partial or total laryngectomy can
be used; partial laryngectomy allows for
preservation of speech and swallowing function
in highly selected cases. The choice between
surgery and concurrent chemoradiotherapy for
patients with primary T3 tumours is a matter
of debate.[64] [65] Chemoradiotherapy has
the advantage of allowing better preservation
of speech and swallowing function if the
alternative option requires total laryngectomy.
TREATMENT
However, a retrospective observational cohort

study of over 7,000 patients from the National
Cancer Database found that, in patients
with T3 laryngeal cancer, those treated with
chemoradiotherapy had a significantly increased
risk for death compared with those treated
Acute
with total laryngectomy (hazard ratio=1.18;
P=0.03).[64] Radiation alone, however, has been
shown to be inferior to the above-mentioned
therapies for T3 and T4 tumours.[64] [46] [67]
[66]

patients may be treated with carboplatin or
cetuximab. However, the addition of cetuximab
to cisplatin in combination with radiation
does not improve outcome compared with
radiation plus cisplatin only.[68] Similarly, altered
fractionated radiation plus cisplatin does not
confer any advantage over standard cisplatin
chemoradiation.[69]
» Neck dissection is recommended for persistent

neck disease after chemoradiotherapy and
in patients undergoing laryngectomy with
clinically positive neck disease.[63] The role of
neck dissection following chemoradiotherapy;
however, remains controversial.[70]
» Adjuvant chemotherapy may be used

postoperatively for certain unfavourable tumour
characteristics (e.g., positive margins, >4 lymph
nodes, extracapsular spread).[71] See local
specialist protocol for dosing guidelines.
» Locoregional control and larynx preservation

were found to be significantly improved with
concomitant chemoradiation compared with
induction chemotherapy followed by radiotherapy
or compared with radiotherapy alone.[72]
T4 or N3 or M1 1st total laryngectomy or chemoradiotherapy
» Patients with N3 staging have regional lymph

node metastases >6cm. Patients with M1
staging have distant metastases.
» Treatment involves either concurrent

chemotherapy and radiotherapy or surgery.
Neck dissection and adjuvant (postoperative)
TREATMENT
radiotherapy may also be required, although

the role of neck dissection in a clinically
negative neck following chemoradiation
remains controversial.[70] Patients for whom no
treatment options have been effective or who
29
Acute
are not candidates for therapy should be offered
palliative care, which can include chemotherapy.
» Chemoradiotherapy or surgery are equally

effective if cartilage is not involved. Total
laryngectomy is recommended over concurrent
chemotherapy and radiotherapy if cartilage is
involved.[46] [73] Chemoradiotherapy is used
for unresectable tumours. In cases of cartilage
invasion, positive or close margins, multiple
positive cervical lymph nodes, or extracapsular
extension of disease, adjuvant (postoperative)
chemoradiotherapy is recommended.
» Neck dissection is recommended for persistent

neck disease after chemoradiotherapy and in
patients undergoing laryngectomy with clinically
positive neck disease.[63]
» Adjuvant chemoradiotherapy may be used

postoperatively for certain unfavourable
tumour characteristics (e.g., angiolymphatic or
perineural invasion, extracapsular spread).[71]

patients may be treated with carboplatin. See
local specialist protocol for dosing guidelines.
» Locoregional control and larynx preservation

were found to be significantly improved with
concomitant chemoradiation compared with
induction chemotherapy followed by radiotherapy
or compared with radiotherapy alone.[72]
adjunct postoperative chemoradiotherapy
Treatment recommended for SOME patients in
» In cases of cartilage invasion, positive or
close margins, multiple positive cervical lymph
nodes, or extracapsular extension of disease,
adjuvant (postoperative) chemoradiotherapy is
recommended. See local specialist protocol for
dosing guidelines.
TREATMENT
subglot tic
1st total laryngectomy and radiotherapy
Acute
» Subglottic tumours are treated by total
laryngectomy and neck dissection surgery
(including thyroidectomy) followed by
radiotherapy. See local specialist protocol for
dosing guidelines.
Ongoing
treatment not effective/appropriate
1st palliative care
» Patients for whom no treatment options have

been effective or who are not candidates for
therapy should be offered supportive care (e.g.,
pain control, counselling).
adjunct chemotherapy
Treatment recommended for SOME patients in
Primary options
» cetuximab: see local specialist protocol for

dosing guidelines
» Although chemotherapy alone has no role in

the treatment of localised laryngeal cancer, it has
been used as a single-mode adjunct in palliative
care.[75] Cetuximab is a monoclonal antibody
that binds specifically to the epidermal growth
factor receptor (EGFR) expressed on epithelial
tissues and inhibits the growth of tumour cells
that express EGFR. While studies have shown
combined radiotherapy with cetuximab to be
superior to radiotherapy alone, no randomised
controlled studies have compared cetuximab
with cisplatin.[76] [77]
1st surgical salvage ± postoperative re-
irradiation ± chemotherapy
» Surgical salvage is the standard of care in

patients with recurrent disease that is considered
TREATMENT
resectable and who are medically fit for surgery.
» Postoperative re-irradiation may be

considered. In patients re-irradiated with curative
intent, the addition of chemotherapy is typically
used.[79]
31
TREATMENT Laryngeal cancer Treatment
Emerging
Robotic surgery
Robotic surgery and robotic endoscopic surgery have emerged as novel ways to improve surgical precision.
Green tea
Some investigators are examining the anti-tumour properties of green tea. It acts synergistically with
epidermal growth factor receptor expressed on epithelial tissues and tyrosine kinase inhibitors to inhibit
tumour cell growth in xenograft models.[80]
Vitamin A, vitamin E, and interferon

Combination therapy in vitro with forms of vitamin A, vitamin E, and interferon may induce cell-cycle arrest
and apoptosis in squamous cell carcinoma cell lines.[81]
Paclitaxel and docetaxel

Paclitaxel and docetaxel are taxanes that inhibit cellular mitosis by disrupting microtubule function. Trials of
induction chemotherapy with either agent in combination with a platinum and 5-fluorouracil or cetuximab,
followed by concurrent chemoradiotherapy, are assessing organ preservation and survival in head and
neck cancers, including laryngeal cancer. Results have demonstrated low toxicity and high levels of organ
preservation and survival at 2 years for laryngeal cancer, and this has been adopted as a standard of care in
some institutions.[82]
Pembrolizumab
Pembrolizumab is a humanised monoclonal antibody that targets the programmed cell death 1 (PD-1)
receptor. The US Food and Drug Administration (FDA) has given accelerated approval to pembrolizumab for
the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma with disease
progression on or after platinum-based chemotherapy. This is based on results from the KEYNOTE-012
trial.[83] It is also approved for this indication in Europe. The FDA has also given accelerated approval
to pembrolizumab for the treatment of adult and paediatric patients with unresectable or metastatic solid
tumours that have progressed following prior treatment and who have no satisfactory alternative treatment
options, and where there is a biomarker known as microsatellite instability-high or mismatch repair deficient
present.
Nivolumab
Nivolumab is a humanised monoclonal antibody with anti-PD-1 activity. It has been approved by the FDA
and in Europe for the treatment of patients with recurrent or metastatic head and neck squamous cell
carcinoma with disease progression on or after platinum-based chemotherapy. This is based on results from
the CheckMate 141 trial.[84]
Bevacizumab
A phase III clinical trial is currently looking at the overall survival of patients with recurrent or metastatic
squamous cell carcinoma of the head and neck treated with standard cisplatin-based chemotherapy with or
without bevacizumab.[85]
TREATMENT
Addition of cetuximab to platinum-fluorouracil chemotherapy

Results of the EXTREME study suggest that the addition of cetuximab to cisplatin or carboplatin combined
with 5-fluorouracil improves overall survival for patients with M1 disease.[86] [87]
33
Radiosensitising agents
Carbogen and nicotinamide are being investigated as radiosensitising agents. The study is ongoing and
results are pending. [Patient selection for hypoxia modifying treatments in larynx carcinomas]
Photodynamic therapy
Photodynamic therapy may be effective in treating carcinoma in situ and early laryngeal cancer but is still
considered experimental.[88] [89]
TREATMENT
Laryngeal cancer Follow up
Recommendations
Monitoring
FOLLOW UP
Patients require regular surveillance for cancer recurrence for 5 years after treatment. Patients may
undergo clinical examination with flexible fibre-optic laryngoscopy every 1 to 2 months for the first year
after treatment, every 2 to 3 months for the second year, every 3 to 4 months for the third year, every 4 to
6 months for the fourth year, and every year thereafter. Continued surveillance may not be needed after 5
years of follow-up.
Physical examination is considered the best measure to assess for long-term recurrence. Patients with
suspicious lesions or neck masses undergo repeat CT imaging and biopsy. Many treatment centres
obtain post-treatment PET/CT scans to assess for response to therapy, but this is not considered
mandatory. Induced fluorescence endoscopy may be useful for the detection of recurrent disease.[95] No
surveillance imaging studies are consistently recommended for routine surveillance.
Patient instructions
It is essential that patients stop smoking and at a minimum reduce if not discontinue their intake of
alcohol. The risk of recurrence of laryngeal cancer is known to be much higher in patients who continue to
smoke. Alcohol consumption is an independent risk factor for laryngeal cancer, and alcohol consumption
combined with cigarette smoking has multiplicative effects in the carcinogenesis of this disease. It is
also important to work closely in the post-treatment period with a speech and language pathologist to
rehabilitate communication and swallowing abilities. Major centres offer head and neck cancer support
groups, which many patients find helpful.
Complications
Complications Timeframe Likelihood

chemotherapy-related immunosuppression short term high
Chemotherapy causes immunosuppression. Some practitioners may use cytoproliferative agents to

increase white blood cell counts to counter this effect.
tracheo-innominate artery fistula and pharyngocarotid short term low

artery fistula
Massive haemorrhage may result from tumour erosion into a vessel or the trachea. This may also occur as
a consequence of surgery and prior radiotherapy.
radiation-related fibrosis and scarring long term high
Radiotherapy causes widespread fibrosis of all tissues in the treatment field. This may cause long-term
problems with wound healing and tissue integrity. Predictors for severe acute toxicity are female sex, lower
performance status, higher BMI, and more advanced disease; predictors for late toxicity are female sex
and weight loss during radiotherapy.[93]
35

cisplatin-related hearing loss long term high
FOLLOW UP
Cisplatin may cause permanent damage to the inner ear hair cells.
cisplatin-related acute renal failure variable high
Cisplatin is known to cause renal failure and cystitis.
dysphagia variable high
Dysphagia can be a consequence of laryngeal cancer, persisting during and after treatment, or a
consequence of treatment. Surgery to remove all or part of the larynx may significantly alter the native
anatomy involved in swallowing. Radiotherapy causes scarring and fibrosis, and leads to similar problems
with swallowing.
voice change and aphonia variable high
By nature of the location of the cancer, voice changes or aphonia may occur as a consequence of the
disease or the treatment. Voice complications after treatment for laryngeal cancer are almost universal.
Both surgery and radiation may change the laryngeal architecture, causing voice changes of variable
duration. Total laryngectomy will lead to aphonia unless the patient undergoes an additional procedure to
enable tracheo-oesophageal speech.
Overall, studies have indicated that voice and speech degenerate during chemoradiotherapy, improve
again 1 to 2 months after treatment, and exceed pre-treatment levels after 1 year or longer. However, voice
and speech measures do not show normal values before or after treatment. Given the large time range of
post-treatment data, missing baseline assessments, and the inclusion of non-laryngeal sites of disease
and radiation in some studies, there is an urgent need for structured standardised multi-dimensional
speech and voice assessment protocols in patients with advanced head and neck cancer treated with
chemoradiotherapy.[94]
post-tracheostoma taste disorders variable high
Total laryngectomy leaves a patient with a tracheostoma as the definitive airway. Bypassing the upper
airway significantly decreases the patient's ability to smell. Consequently, the ability to appreciate
combined taste and olfactory sensations is also altered.
cisplatin-related peripheral neuropathy variable high
Cisplatin may cause peripheral nerve damage.
treatment-related oesophageal stricture variable medium
Radiotherapy is a risk factor for developing an oesophageal stricture. Total laryngectomy may lead to
stricture at the site of pharyngeal closure. This is exacerbated by postoperative radiotherapy. Manifests as
difficulty swallowing, and may be treated successfully in some patients with oesophageal dilation.

postoperative pharyngocutaneous fistula variable medium
FOLLOW UP
Patients undergoing partial or total laryngectomy are at risk of fistulous communication between the
pharynx and the soft tissues of the neck. Aggressive local wound care is sufficient in many, but some
require additional reconstructive surgery to correct the problem. The risk of fistula formation is much higher
in patients who have undergone radiation to the neck before surgery. Choice of surgical technique and
correction of malnutrition helps to prevent fistula formation.
radiation-related salivary and mucosal problems variable medium
Radiotherapy may have short- and long-term effects on mucosa and salivary glands, such as mucositis
and xerostomia. Predictors for severe acute toxicity are female sex, lower performance status, higher
BMI, and more advanced disease; predictors for late toxicity are female sex and weight loss during
radiotherapy.[93]
Prognosis
The natural course of laryngeal cancer depends on the treatment modality, but almost always the voice
changes or is lost to some degree. The overall survival for laryngeal cancer has remained unchanged for the
last 30 years. However, in the US, there is new evidence to suggest that overall 5-year survival rates in fact
have declined in spite of advances in early detection, treatment protocols, and prevention programmes. The
causes are not fully elucidated and this subject remains highly controversial in specific regard to laryngeal
cancer.[90] [91] Black men have significantly worse 5-year survival than white men: 51% versus 68%.[11]
Overall survival, disease-free survival, and larynx preservation is largely determined by initial tumour stage at
the time of diagnosis and treatment. Survival by stage of laryngeal cancer is as follows:[92]
• Stage I: 5-year overall survival is 90%

• Stage II: 5-year overall survival is 70%
• Stage III: 5-year overall survival is 60%
• Stage IV: 5-year overall survival is 25%.
Patients who survive 5 years without recurrence are considered cured. The risk of recurrence is higher in
patients who continue to smoke and in those whose cancer is at an advanced stage at the time of diagnosis.
37
Laryngeal cancer Guidelines
Diagnostic guidelines
Europe
Cancer of the upper aerodigestive tract: assessment and management in

people aged 16 and over
Published by: National Institute for Health and Care Excellence Last published: 2018
Suspected cancer: recognition and referral

North America
NCCN clinical practice guidelines in oncology: head and neck cancers

GUIDELINES
Published by: National Comprehensive Cancer Network (NCCN) Last published: 2018
Treatment guidelines
Europe
Cancer of the upper aerodigestive tract: assessment and management in

people aged 16 and over
Cetuximab for treating recurrent or metastatic squamous cell cancer of the

head and neck
Improving outcomes in head and neck cancers

Published by: National Institute for Health and Care Excellence Last published: 2004 (re-
affirmed in 2015)
North America
NCCN clinical practice guidelines in oncology: head and neck cancers

Published by: National Comprehensive Cancer Network (NCCN) Last published: 2018
Clinical practice guideline for the use of larynx-preservation strategies in the

treatment of laryngeal cancer
Published by: American Society of Clinical Oncology Last published: 2017
American Cancer Society head and neck cancer survivorship care guideline
Published by: American Cancer Society Last published: 2016
Laryngeal cancer Guidelines
North America
ACR Appropriateness Criteria: retreatment of recurrent head and neck cancer

after prior definitive radiation
Published by: American College of Radiology Last published: 2014
GUIDELINES
39
Laryngeal cancer Online resources
Online resources
1. Patient selection for hypoxia modifying treatments in larynx carcinomas (external link)
ONLINE RESOURCES
Laryngeal cancer References
Key articles
• Pelucchi C, Gallus S, Garavello W, et al. Cancer risk associated with alcohol and tobacco use: focus
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• Troell RJ, Terris DJ. Detection of metastases from head and neck cancers. Laryngoscope. 1995
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Abstract
• Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the
head and neck. N Engl J Med. 2006 Feb 9;354(6):567-78. Full text Abstract
• Brouwer J, Hooft L, Hoekstra OS, et al. Systematic review: accuracy of imaging tests in the diagnosis
of recurrent laryngeal carcinoma after radiotherapy. Head Neck. 2008 Jul;30(7):889-97. Abstract
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2006;98:441-450. Full text Abstract
99. Zhang X, Zhang H, Tighiouart M, et al. Synergistic inhibition of head and neck tumor growth
by green tea (-)-epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor. Int J Cancer.
2008;123:1005-1014. Abstract
100. Zhang X, Chen ZG, Choe MS, et al. Tumor growth inhibition by simultaneously blocking
epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model. Clin Cancer Res.
2005;11:6261-6269. Full text Abstract
Laryngeal cancer Images
Images
IMAGES
Figure 1: Irregular mass of left arytenoid and aryepiglottic folds, and the right arytenoid mucosa
From the collection of Dr Amy Chen, Emory University; used with permission
49
IMAGES Laryngeal cancer Images
Figure 2: Small whitish mass along anterior third of left true vocal fold
IMAGES
Figure 3: CT scan showing bulky tumour invading ala of thyroid cartilage

51
Figure 4: Large, bulky transglottic mass and increased uptake on PET (bright yellow/orange)
IMAGES
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53
Contributors:
// Authors:
Clarence Sasaki, MD
Professor of Surgery
Yale Cancer Center, Yale School of Medicine, New Haven, CT
DISCLOSURES: CS declares that he has no competing interests.
Mat thew Pierce, MD

Otolaryngologist
Otolaryngology, Head and Neck Division, MedStar Washington Hospital Center, Georgetown University,
Washington, DC
DISCLOSURES: MP declares that he has no competing interests.
// Acknowledgements:
Dr Clarence Sasaki, and Dr Matthew Pierce would like to gratefully acknowledge Dr Scott V. Larson, Dr Hari
Deshpande, Dr Elina Kari, and Dr Amy Chen, previous contributors to this topic.
DISCLOSURES: SVL, HD, EK, and AC declare that they have no competing interests.
// Peer Reviewers:
Alfio Ferlito, MD, DLO, DPath, FRCSEd

Director
Department of Surgical Sciences, Professor and Chairman, ENT Clinic, University of Udine, Udine, Italy
DISCLOSURES: AF declares that he has no competing interests.
Steven J. Charous, MD, FACS

Assistant Professor
Department of Otolaryngology, Rush University Medical Center, Chicago, IL
DISCLOSURES: SJC declares that he has no competing interests.

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Laryngeal cancer

The right clinical information, right where it's needed

Last updated: Feb 20, 2019

◊ Treatment is dictated by TNM stage.

◊ Modalities include surgical resection, radiotherapy, chemotherapy, or any combination of these.

◊ Goals of therapy are eradication of cancer with organ preservation.

◊ Speech therapy is appropriate after surgery, radiotherapy, chemoradiotherapy, or any combination of

• Tx: primary tumour cannot be assessed

• T1a: limited to 1 vocal cord

• T1: tumour limited to the subglottis

Regional lymph nodes (N)

• NX: regional lymph nodes cannot be assessed

• N3a: metastasis in a lymph node, >6 cm in greatest dimension and ENE(-)

• NX: regional lymph nodes cannot be assessed

• N3a: metastasis in a lymph node, >6 cm in greatest dimension and ENE(-)

Distant metastasis (M)

• cM0: no distant (i.e., non-head and neck) metastases

Stage II: T2N0M0

Stage III: T3N0M0, T1N1M0, T2N1M0, T3N1M0

Stage IVA: T1N2M0, T2N2M0, T3N2M0, T4aN0M0, T4aN1M0, T4aN2M0

Stage IVB: any T N3M0, T4b any N M0

Stage IVC: any T, any N M1

Step-by-step diagnostic approach

The signs of laryngeal cancer include (by organ system):

• Ear: otalgia (e.g., middle ear effusion, otitis externa).

alcohol use >8 units/day

family history of laryngeal cancer

Agent Orange exposure

human papillomavirus (HPV) exposure

history of respiratory papillomatosis

History & examination factors

age >40 years (common)

odynophagia (painful swallowing) (common)

cervical lymphadenopathy (common)

supraglot tic or glot tic mass (common)

lesional erythroplasia, ulceration, necrosis, or bleeding (common)

signs of airway obstruction (uncommon)

haemodynamic instability (uncommon)

Other diagnostic factors

weight loss or cachexia (uncommon)

general distress (uncommon)

oral and pharyngeal masses or leukoplakia (uncommon)

loss of laryngeal crepitus (uncommon)

parotid and thyroid growths (uncommon)

diminished breath sounds (uncommon)

Other tests to consider

Condition Differentiating signs / Differentiating tests

Condition Differentiating signs / Differentiating tests

Sarcoidosis • Often associated with nasal • Localised pale oedema,

Tuberculosis (TB) • History of known TB, • Laryngoscopy shows

Granulomatosis with • Patients may present with • Laryngoscopy shows

• Tx: primary tumour cannot be assessed

• T1a: limited to 1 vocal cord

or invades mediastinal structures.

• T1: tumour limited to the subglottis

Regional lymph nodes (N)

• NX: regional lymph nodes cannot be assessed

• N3a: metastasis in a lymph node, >6 cm in greatest dimension and ENE(-)

• NX: regional lymph nodes cannot be assessed

• N3a: metastasis in a lymph node, >6 cm in greatest dimension and ENE(-)

Distant metastasis (M)

• cM0: no distant (i.e., non-head and neck) metastases

Stage II: T2N0M0

Stage III: T3N0M0, T1N1M0, T2N1M0, T3N1M0