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Oral cancer 

Oral cancer
Oral cancer

Crispian Scully

and Jose Bagan

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date: 04 July 2020


Oral cancer is a major public health problem throughout the world. In most cases (90%), the tumour is an oral squamous cell carcinoma (OSCC), although a variety of other types of tumour can be found within the oral cavity. This chapter will focus on OSCC, whilst Chapter 8 will focus on the other types of tumour found within (and around) the oral cavity.


Worldwide, OSCC is the sixth most common cancer for both sexes[1], with 350–400 000 new cases identified each year.

Geographical factors

The incidence varies widely between countries and geographical areas[1], but is generally more common in ‘developing’ countries. These variations have traditionally been explained by the exposure of these groups of people to specific risk factors (e.g. tobacco, alcohol, betel use), although other factors such as genetics, environmental factors (especially infective agents) and socioeconomic factors may also be at play[2].

Two out of three cases in males, and three out of four cases in females, are in the developing world. OSCC is the third most common cancer in developing nations, and it is particularly common in south-central Asia, where approximately 58% of the cases are concentrated[3]. In most regions of India, oral cancer is the most common cancer in men, and the third most common cancer in women. In Karachi (Pakistan), which has one of the highest reported incidences in the world, oral cancer is the second commonest malignancy amongst both males and females[4].

In the United States, OSCC is the tenth most common cancer amongst males[5]. Central and East European countries (Croatia, Hungary, Lithuania, Russia, Slovenia, and Ukraine) have high rates at over seven cases per 100 000 of the population; intermediate rates at 6–7 cases per 100 000 are seen in Germany, Italy, Poland, Spain, and Switzerland; and low rates at less than four cases per 100 000 are found in England and Wales, Greece, the Netherlands, and some Nordic countries[6]. However, the highest recorded incidence worldwide of OSCC has been reported in parts of France, such as Bas-Rhin (up to 55 cases per 100 000)[6,7].

Other factors

The incidence of OSCC increases with age, with a steep increase beginning in the 60–64-year age group[8]. However, there have been increases in OSCC in the younger generations, which appear to be mainly related to lifestyle habits (i.e. tobacco, alcohol, and betel use).

The male-to-female ratio is greater than 2:1 for OSCC[9]. The gender difference in OSCC rates has been decreasing over time, presumably due to the equalizing in tobacco and alcohol consumption[10].


OSCCs are routinely discovered late, and have one of the lowest 5-year survival rates of any major cancer site (i.e. 53%). The 5-year survival rate has not changed in the past 30 years[11]. Not surprisingly, localized cancers have the highest 5-year survival rates (79%), those with regional disease have intermediate figures (42%), and those with distant metastases have the lowest 5-year survival rates (19%)[12].

A recent review of the SEER (The Surveillance Epidemiology and End Results Program of the National Cancer Institute) database showed that disease specific mortality from cancer of the tongue increases with age[13], which may be a reflection of increasing co-morbidities with increasing age. OSCC is also associated with the potentially lethal development of second primary tumours (up to a 20 times higher risk than controls)[14].


Carcinogenesis is the result of disturbed growth control arising from DNA damage (mutation), which can arise spontaneously, but may also be precipitated by a range of mutagens[15]. OSCC arises as a consequence of multiple DNA mutations, and seems to gradually evolve from normal epithelium through precursor lesions to full-blown malignancy.

Tobacco, alcohol, and betel are the main risk factors for OSCC. The results of many studies of lifestyle factors have been summarized by the International Agency for Research on Cancer (IARC)[16–18]. However, significant numbers of younger patients with OSCC deny any of the known risk factors[19–21].


Tobacco contains addictive components (e.g. nicotine), and releases many carcinogens including polycyclic aromatic hydrocarbons (e.g. benzopyrene), nitrosamines (e.g. nitrosonornicotine), and aldehydes (e.g. formaldehyde).

Cigarette smokers appear to be about 5 times more likely to develop OSCC than are non-smokers. Compared to non-smokers, the risk of oral cancer to low/medium-tar cigarette-smokers was 8.5 times, and for high tar cigarette mokers the risk was significantly greater at 16.4 times in one European study[22].

Other types of tobacco usage/smoking are also associated with an increased risk of OSCC, including:

  • Bidi smoking (South Asia) [23] – these unfiltered cigarettes contain a small amount of flaked tobacco.

  • Cigar smoking [24]

  • Pipe smoking [25]

  • Reverse smoking (India, Philippines, Taiwan, and South America) [24] – reverse smoking involves holding the burning end of cigarettes or cigars within the mouth. Reverse smoking is strongly associated with OSCC.

  • Use of smokeless tobacco products [24] – these diverse products contain tobacco and a variety of other constituents (dependent on the geographical region).

  • Snuff [25] – these finely powdered materials principally contain tobacco (and are used orally or nasally). The risks are mainly in snuff users, who also use other tobacco products[26].

It should be noted that oral cancer risk shows a clear decline after stopping tobacco use[27].

A review of two cohort studies, and 14 case-control studies, showed a possible association between marijuana use and cancer risk[28], although users of marijuana are often also heavy cigarette smokers.


Increased consumption of alcohol-containing beverages is associated with an increased risk of OSCC[29,30]. The risk decreases after stopping alcohol use, but the effects appear to persist for several years[31]. The risk is greatest amongst the heaviest drinkers of alcohol[32,33]. The type of alcoholic beverage appears to influence the risk, with hard liquors (‘spirits’) conferring a higher risk[32,33]. Epidemiological studies suggest that the impact of alcohol on OSCC has increased in recent years[33,34].

The combined effect of alcohol and tobacco is far greater than the sum of the two effects (Tables 7.1 and 7.2)[35–38].

Table 7.1 Effects of cigarette smoking and alcohol use on risk of cancer of the upper GI tract [35]

Consumption tobacco (number cigarettes/day)

Relative risk of cancer

Never smoked








Consumption alcohol (g alcohol/day)*

Relative risk of cancer



˃0 – 30


˃30 – 60




* Mean lifelong consumption of alcohol

Table 7.2 Effects of combined cigarette smoking and alcohol use on risk of cancer of the upper GI tract [35]

Consumption tobacco (number cigarettes/day)

Non smoker



Consumption alcohol (g alcohol/day)

˃0 – 30

RR – 1

RR – 2

RR – 6.8

˃30 – 60

RR – 2.6

RR – 5.1

RR – 20.7


RR – 6.9

RR – 22

RR – 48.7

RR = relative risk

The risk of OSCC amongst users of mouthwashes with high alcohol content (≥25%) is increased by 40% in men, and by 60% in women[39]. However, it appears as if the effect of alcohol from mouthwash could be similar to that of alcohol used for drinking, although in terms of attributable risk, the contribution of mouthwash use to OSCC must be very small[40].

Betel leaves and areca nut

Areca nut wrapped in betel leaves (‘betel nut’) is chewed in many cultures, and produces a mild stimulant effect (cf. drinking coffee). Betel nut is probably used by 20% of the world population. Chewing betel nut is associated with OSCC[41,42], and this may be exacerbated by the addition of tobacco to the combination.

Genetic factors

A case-control study in Brazil showed the risk for cancer in the head and neck to be raised for those who reported cancer at any site in a first-degree relative, with a greater risk if the relative had cancer in the head and neck[43]. It has been suggested that such familial clustering of cancer points to a possible genetic component in the development of OSCC.

Socioeconomic status

Socioeconomic status plays an important role, with most OSCC being seen in people of low socioeconomic status[44,45]. In addition, a number of different manual occupations have been found to be associated with increased risk of oral cancer.


Fried foods and charcoal-grilled red meat have been implicated as risk factors for OSCC[46]. However, an increased consumption of fruits and vegetables is associated with a lower risk of OSCC[47].


Microorganisms have been implicated in the aetiology of OSCC[48]. Thus, Treponema pallidum[49], Candida albicans[50], herpesviruses, and human papillomaviruses (HPV) [51] may be implicated in at least some cases of oral cancer.

Candidal leukoplakia are potentially malignant[50], and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), an autosomal recessive disease associated with a limited T-lymphocyte defect, seems to favour the growth of Candida albicans and predisposes to chronic stomatitis and OSCC[52].

Viral infections, particularly with oncogenic HPV subtypes, can have a tumourigenic effect[53]. Oropharyngeal cancer is significantly associated with oral HPV type 16, and also associated with a high lifetime number of vaginal-sex partners (˃26), and oral-sex partners (≥6). In one study, HPV-16 DNA was detected in 72% tumour samples[54].

Oral health

Table 7.3 shows some oral lesions which can progress to OSCC.

Table 7.3 Potentially pre-malignant oral lesions and conditions

Malignant potential


Known aetiological factors

Main clinical features

Very high (≥ 85%)




Velvety red plaque

High (≥ 30%)

Actinic cheilitis


White plaque/erosions

Candidal leukoplakia

Candida albicans

White or speckled white and red plaque

Dyskeratosis congenital


White plaques




Speckled white and red plaque or nodular plaque

Proliferative verrucous leukoplakia

Tobacco/alcohol/human papillomavirus (HPV)

White or speckled white and red or nodular plaque

Sublingual leukoplakia

(sublingual keratosis)


White plaque

Submucous fibrosis

Areca nut

Immobile pale mucosa

Syphilitic leukoplakia


White plaque

Low (˂ 5%)

Atypia in immunocompromised patients

? Human papillomavirus (HPV)

White or speckled white and red plaque




White plaque

Discoid lupus erythematosus


White plaque/erosions

Lichen planus


White plaque/erosions

Paterson-Kelly-Brown syndrome

Iron deficiency

Post-cricoid web

Poor oral hygiene may be associated with an increased risk of OSCC, although not all workers agree about this association (and so further studies are required).

Systemic health

There is an increase in the incidence of OSCC in transplant recipients[55], and of tongue tumours in patients with systemic sclerosis[56]. Epidemiological studies also suggest an association between diabetes mellitus and oral cancer[57].


Lip cancer is seen in people with chronic sun exposure [58]. (Ionizing radiation exposure is a possible risk factor for second primary cancers[59]).

Clinical features

Many OSCCs can be detected visually[60], although early OSCCs may be asymptomatic, and can be overlooked if the examination is not thorough enough[61]. Cancer must be suspected when there is a single oral lesion persisting for more than 3 weeks.

In the developed world, some 42% of OSCC affect the lip, with the majority of intraoral OSCC involving the floor of the mouth or lateral border of the tongue (22% the tongue and 17% the floor of mouth)[62]. However, in the developing world, tongue and buccal mucosal cancers are the most common[63].

OSCC may present variously as[64,65]:

  • A lump – may be indurated and/or fixed (to mucosa, deeper tissues, or overlying skin); may have abnormal supplying blood vessels.

  • An ulcer – may be indurated and/or fixed (to mucosa, deeper tissues, or overlying skin); may have fissured/raised exophytic margins.

  • A red lesion (erythroplasia).

  • A white or mixed white-and-red lesion.

  • Loose teeth.

  • A non-healing extraction socket.

  • Pain.

  • Sensory changes (e.g. numbness).

  • Other local symptoms.

  • Systemic symptoms.

  • Cervical lymph node enlargement – especially if there is hardness or fixation. Enlarged nodes in a patient with oral carcinoma may be caused by infection, reactive hyperplasia, or metastatic disease. Occasionally (∼5% cases) cervical lymph node enlargement is detected in the absence of any obvious primary tumour – the most likely site for the primary in order of predilection is the tongue base, tonsil, or nasopharynx (Figures 7.1 and 7.2).

              Figure 7.1 Squamous cell carcinoma of lip.

Figure 7.1
Squamous cell carcinoma of lip.

              Figure 7.2 Squamous cell carcinoma of tongue.

Figure 7.2
Squamous cell carcinoma of tongue.

It should be noted that many of the classic features of OSCC such as ulceration, induration, bleeding, and cervical lymphadenopathy are features of advanced, not early stage, disease[66].

OSCC should be staged according to the TNM (tumour, node, metastasis) classification of the International Union against Cancer. This classification relates well to overall survival rate, i.e. the earlier the tumour, the better the prognosis (and the less complicated is the treatment)[67,68]. Prognosis is also influenced by the degree of differentiation of the tumour (i.e. the more differentiated the tumour the better the prognosis; see Table 7.4).

Table 7.4 Stage versus prognosis of intraoral carcinoma [67,68]

Tnm stage

5 year survival (%)

T1 N0 M0


T2 N0 M0


T1-3 N1 M0

T3 N0 M0


Any T4

Any N2-3

Any M1


Oral cancers may have a multicentric origin[69]. Furthermore, dysplastic or malignant changes may be detectable in clinically normal mucosa at sites far removed from an OSCC (‘field change’)[70,71]. It is, therefore, hardly surprising that second primary tumours are seen in up to about one-third of patients within a five-year period (and are a crucial factor in treatment failure)[72].


The reliable differentiation of benign lesions from malignant lesions is not possible by clinical inspection alone[64]. The only method currently available to reliably determine the diagnosis is a histopathological examination of a biopsy tissue sample[73]. Indeed, the golden rule is to biopsy any persistent mucosal lesion where there is not absolute confidence that the diagnosis is of a benign lesion. Thus, a biopsy is invariably indicated for a solitary lesion present for over 3 weeks. The early diagnosis (and treatment) of OSCC are the goals of such a strategy[67,68].

An incisional biopsy is invariably indicated and should be sufficiently large to include enough suspect and apparently normal tissue to give the pathologist a chance to make a diagnosis (and not to have to request a further specimen). Some authorities take several biopsies at the first visit in order to avoid a false-negative pathology report. An excisional biopsy should be avoided, since this is unlikely to have excised an adequately wide margin of tissue if the lesion is malignant. If the pathology report denies malignancy, and yet clinically this is suspected, then a re-biopsy is invariably indicated.

Toluidine blue staining is a simple diagnostic tool that uses a blue dye to highlight abnormal areas of mucosa. The reported sensitivity of positive staining in one meta-analytical study ranged from 93.5% to 97.8%, and the specificity ranged from 73.3% to 92.9%, in patients at high risk for OSCC[74]. In the highest risk population (i.e. patients with prior upper autodigestive tract cancer), toluidine blue staining has a higher sensitivity to detect carcinoma in situ and OSCC when compared to clinical examination (96.7% and 40%, respectively)[75]. False-positive staining (when lesions stain blue, but no carcinoma is identified) occurred in 8–10% of cases associated with keratotic lesions and the regenerating edges of ulcers and erosions[75].

In cases of confirmed OSCC, a variety of other investigations are invariably required, including specific staging investigations (e.g. radiological imaging) and non-specific pretreatment investigations (see Chapter 5). Many patients with OSCC have significant co-morbidities, and assessment of these co-morbidities is also required prior to initiation of cancer treatment.


A variety of different modalities is used in the management of OSCC, including surgery, laser therapy, radiotherapy, chemotherapy, and biological therapy. Furthermore, in many cases, more than one modality is used to try and improve the control of the disease[76]. The choice of treatment is determined by a number of factors, including stage of the disease, performance status of the patient, preference of the patient, and availability of specific interventions. Unfortunately, developments in the treatment of oral cancer have not led to significant improvements in 5-year disease-specific survival over the decades.


Surgery is the oldest form of treatment for oral cancer, and current surgical treatment has recently been reviewed[77,78]. Surgery may be used in a number of different ways:

  • Diagnostic surgery.

  • Staging surgery.

  • Preventive (or prophylactic) surgery.

  • ‘Curative’ surgery – is used to treat early-stage disease. It may be used along with radiotherapy and/or chemotherapy, which can be given prior to or following the operation. In some cases, radiotherapy is actually used during an operation (intraoperative radiotherapy).

  • Debulking (or cytoreductive) surgery – is done in some cases when removing a tumour entirely would cause too much damage to an organ or surrounding area. Radiotherapy and/or chemotherapy are also typically used in such circumstances.

  • ‘Palliative’ surgery – is used to treat the complications of advanced disease.

  • Supportive surgery – is used to help with other types of treatment. For example, a vascular-access device, such as a catheter port, can be placed into a large vein to facilitate chemotherapy.

  • Restorative (or reconstructive) surgery – is used to restore a person's appearance or the function of an organ or body part following primary surgery. Examples include the use of tissue flaps, bone grafts, or prosthetic materials. Dental and prosthetic rehabilitation are enhanced by successful surgical reconstruction[77].

Perioperative surgical complications are common, and occurred in 47% of patients with mouth cancer in one report from the UK (with an operative death rate of 3.2%)[79]. Factors predicting complications included the stage and differentiation of tumour; the nature, scale, and duration of surgery; pre-existing cardiovascular disease, respiratory disease, and alcohol consumption. The overall 30-day mortality rate was 3.83% in another European centre[80]. The risk factors for mortality in that study were old age (≥70 year), female gender, and current alcohol addiction (and laryngeal location). The postoperative mortality was 1.63% for patients without risk factors, and was 6.41% for those with one or two risk factors.

Transoral laser microsurgery is a new trend for resection of tumours, and is associated with good preservation of function.


Radiotherapy is commonly used to treat oral cancer (and other tumours of the head and neck region), and may also be used in a number of different ways[81]:

  • ‘Radical’ radiotherapy

    1. 1. Primary treatment – radiotherapy may be used in isolation to treat patients with early (‘curable’) disease.

    2. 2. Adjuvant treatment – radiotherapy may be used following surgery to treat patients at high risk of recurrence (e.g. patients with positive surgical margins or positive lymph nodes)[82]. In some cases, chemotherapy is given in conjunction with the radiotherapy.

    3. 3. Neo-adjuvant treatment – radiotherapy may be used prior to surgery to ‘down-size’ the tumour. Again, in some cases, chemotherapy is given in conjunction with the radiotherapy.

  • ‘Palliative’ radiotherapy

    1. 1. Primary treatment – radiotherapy may be used in isolation (or with chemotherapy) to treat patients with advanced (‘incurable’) disease.

    2. 2. Symptomatic treatment.

A variety of different modalities, techniques, and schedules may be employed in the management of OSCC. A detailed discussion of the various options is beyond the scope of this chapter, although these options are discussed in some detail in Chapter 10.


Chemotherapy is increasingly used to treat oral cancer (and other tumours of the head and neck region)[80]. Chemotherapy may be used in isolation (e.g. intra-arterial methotrexate for early SCC of lip)[81], or more commonly in combination with radiotherapy (chemoradiotherapy). In the latter instance, the chemotherapy may act as both an anti-neoplastic agent and a radiosensitizing agent.

Biological therapy

There is considerable interest in a range of so-called targeted therapies (biological therapies). One of the growth factors linked to oral cancers is epidermal growth factor. Cetuximab blocks epidermal growth factor receptors (EGFR), and has been approved by the Food and Drug Administration in the United States of America to use along with radiotherapy in people with advanced oral cancer[82]. Erlotinib also blocks EGFR, and also seems to help some patients with oral cancer.

A study of QOL changes from baseline to 6 and 12 months following treatment of patients with advanced OSCC treated with reconstructive surgery and adjuvant radiotherapy showed that most general quality-of-life issues (pain, constipation, insomnia, emotional functioning, etc.) did not to improve/change after treatment, and that head-and-neck-specific quality-of-life issues deteriorated immediately after treatment but returned to pretreatment levels at 12 months. The only exceptions were senses, opening mouth, sticky saliva, and coughing, which remained impaired in the long term. Tumour site and stage, extensive resections, and co-morbidity were significantly associated with adverse quality-of-life outcomes (as were age and marital status)[83].


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