History
Some oral squamous cell carcinomas (SCCs) arise in apparently normal mucosa, but many are preceded by clinically obvious potentially malignant disorders, especially erythroplakia (red patch), leukoplakia (white patch), erythroleukoplakia (red and white patch), or verrucous leukoplakia, and lichenoid lesions. [23, 28] Many others are associated with such lesions (especially in Southeast Asia). The challenges in predicting which oral mucosal potentially malignant disorder will progress to neoplasia are discussed more fully elsewhere. [29]
Erythroplastic lesions are velvety red plaques, with a prevalence ranging from 0.01-0.21%, [5, 30] which, in at least 90% of cases, show severe dysplasia or frank malignancy. In contrast, most white lesions are not malignant or premalignant. Speckled or verrucous leukoplakias are more likely to be premalignant. The prevalence of leukoplakias as compared with erythroplakia is higher, and severe dysplasia or carcinomatous change is more common in erythroplakia. Homogeneous leukoplakias are only very occasionally premalignant, but speckled or verrucous leukoplakias are more likely to be premalignant. In a study of 257 patients with oral leukoplakia, Silverman et al followed these patients over a mean period of 7.2 years. Of these patients, 17.5% developed carcinoma. The time from initial diagnosis of either epithelial dysplasia or hyperkeratosis to carcinoma ranged from 6 months to 39 years. [28]
In most cases, a biopsy with histologic examination is required because dysplasia may precede malignant changes. The rate of malignant changes can be as high as 36% when moderate or severe dysplasia is present. Be aware that single ulcers, lumps, red patches, or white patches (particularly if they persist >3 wk) may be manifestations of malignancy.
Oral SCC may manifest as the following:
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A red lesion (erythroplakia)
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A granular ulcer with fissuring or raised exophytic margins
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A white or mixed white and red lesion (erythroleukoplakia)
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A white (raylike) and red, unilateral lesion on lateral border of the tongue or buccal mucosa.
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An indurated lump/ulcer (ie, a firm infiltration beneath the mucosa)
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A nonhealing extraction socket
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An ulcer or crust on the vermilion border of the lip lasting for over 3 weeks (rule out herpes simplex)
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A lesion fixed to deeper tissues or to overlying skin or mucosa
Cervical lymph node enlargement, especially if hardness is present in a lymph node or fixation: Enlarged nodes in a patient with oral carcinoma may be caused by infection, reactive hyperplasia secondary to the tumor, or metastatic disease. Occasionally, a lymph node is detected in the absence of any obvious primary tumor. Nodal enlargement is a feature particularly in oropharyngeal cancers.
These potentially malignant disorders and oral SCC should be detected at an early stage; however, many oral SCCs still are seen only when advanced. Diagnosis is often delayed by up to 6-7 months, even in developed countries, despite exhortations over the past 25 years to increase the index of suspicion. Early detection and treatment is the short-term goal because this results in considerably better survival rates. Early carcinomas may not be painful and can mimic other inflammatory conditions that occur in the mouth such as lichenoid lesions and oral lichen planus [23] ; however, as they progress, they can cause pain and difficulty with speech and swallowing.
Oral medicine specialists and dental care professionals should remain vigilant for signs of potentially malignant disorders and oral cancer while performing routine oral examinations. [31]
Physical Examination
A systematic and thorough examination of the mouth, lips, fauces, and cervical lymph nodes should be performed by a clinician trained in the diagnosis of oral diseases, and a general physical examination is indicated. Oral health professionals are trained in the examination of the mouth. Examine the teeth, periodontium, and entire mucosa in good lighting.
In those with oral SCC, advanced caries, periodontal disease, or periapical lesions may need early attention, especially if radiotherapy is to be used in the management of oral SCC to avoid complications that may interrupt therapy.
The most common sites of oral SCC include the tongue, mainly the lateral and ventrolateral aspects, and the floor of the mouth; however, all areas should be scrutinized. A common site for oral SCC is the posterior portion of the tongue, which may be missed on cursory inspection; hence, special care is needed to ensure close examination.
The clinical appearance of oral cancer is highly variable and includes ulcers, red or white areas, lumps, or fissures. Lesions must always be palpated after inspection to detect induration and fixation to deeper tissues.
Erythroplakia is a red and often velvety lesion, which, unlike leukoplakias, may not form a plaque but is level with or depressed below the surrounding mucosa. Of these lesions, 75-90% may show severe epithelial dysplasia, carcinoma in situ, or invasive changes. Erythroplakia can affect patients of either sex in their sixth and seventh decades and typically involves the floor of the mouth, the ventral surface of the tongue, or the soft palate. Erythroplakias (red) oral lesions usually are more dangerous than white oral lesions.
Oral mucosal white patches usually result from increased keratinization or candidosis. Leukoplakia is restricted to white patches for which a cause cannot be established; therefore, the term implies a diagnosis by exclusion (eg, lichen planus, candidiasis). The term leukoplakia is also used irrespective of the presence or absence of epithelial dysplasia. Leukoplakia is a clinical term for a persistent adherent white patch with no histologic connotation and no implied premalignant potential. Some oral SCC can also appear as a white patch.
Late oral SCC may manifest as an exophytic lesion or an area of ulceration with induration.
A typical malignant ulcer is hard with heaped-up and often everted or rolled edges and a granular floor, as shown in the image below.
Advanced oral squamous cell carcinoma presenting as a large, ulcerated lump on the left anterior and midlateral border of the tongue.
The floor of the mouth is the second most common intraoral site for cancer and is more commonly associated with leukoplakia. Most cancer arises in the anterior floor of the mouth as a red patch progressing into ulceration and induration, resulting in slurring of speech. Floor-of-the-mouth cancer is often found in heavy drinkers.
Carcinomas of the alveolus or gingiva can present as an exophytic mass or a persistent ulcer. The underlying alveolar bone is invaded in 50% of cases, even in the absence of radiographic changes, and adjacent teeth may be loose.
Carcinomas of the buccal mucosa are mostly seen at the commissure or in the retromolar area. Most start as lumps, and some may arise in candidal-associated leukoplakia.
Any single lesion that persists more than 3 weeks, especially if red, ulcerated, or a lump with or without induration (ie, the RULE mnemonic), should be regarded with suspicion and a histopathological diagnosis established. [2]
Second primary tumors are additional primary carcinomas (synchronous tumors) present in as many as 10-15% of persons with oral carcinoma and are most commonly seen in the mouth in patients with gingival, floor of mouth, lingual, or buccal carcinoma. Second primary tumors may also be present elsewhere in the upper aerodigestive tract.
Lymph node examination is of paramount importance, and general examination and, possibly, endoscopy, may be indicated to detect metastases or second primary tumors. From 30-80% of patients with oral cancer have metastases in the cervical lymph nodes at presentation. Oral cancer predominantly metastasizes locally and to regional lymph nodes, primarily in the anterior neck. Later, dissemination to the lungs, liver, or bones may occur.
Any chronic oral lesion, over 2-3 weeks, should be regarded with suspicion when found in an older or young patient, when lesions appear (see History) with induration, with fixation to underlying tissues, with any recent changes in appearance, with associated lymphadenopathy, and without obvious explanation for the lesion. Examine the entire mucosa because widespread dysplastic mucosa (field change) or a second neoplasm (see Staging) may be present. Carefully record the location of suspicious lesions, preferably on a standard topographic diagram.
Table 1. Practical Clinical Tool for Evaluating Oral Mucosal Lesions (Open Table in a new window)
Issue |
|
No Serious Concern |
Concern: Consider Referral to Specialist if Clinician or Patient Concerned, Especially if Multiple Issues Apply |
Serious Concern: Referral to a Specialist |
Historical Features |
Size |
No change |
No reduction in size, even after eliminating trauma to lesion after 10-14 days |
Increasing size, even after eliminating trauma to lesion after 10-14 days |
|
Chronology |
Lesion heals |
No resolution over brief observation period |
Rapid symptom onset Solitary lesion or change in one area of lesion Lesion persisting 2-3 weeks or longer Persistent ulceration Persistent swelling Loosening of a tooth Nonhealing tooth extraction socket |
|
Neurological |
None |
Lack of pain |
Pain Dysphagia Odynophagia Otalgia Numbness/paresthesia Speech or voice change |
|
Weight |
Normal |
No weight loss |
Weight loss |
History |
Lifestyle Habits |
None |
Tobacco consumption mild/moderate Betel quid or khat consumption mild/moderate UV light exposure mild/moderate (lip surface exposure) Late-onset sexual debut (oral sex) Moderate number of lifetime sexual partners |
Tobacco consumption high Betel quid or khat consumption high Alcohol consumption high UV light exposure high Early sexual debut Numerous lifetime sexual partners |
|
Medical History |
Clear |
Deficiencies of iron or vitamins A, C, or E Fanconi anemia High-risk human papillomavirus (HPV) infection Immune defects, including HIV/AIDS or chronic candidosis Medications: Immunosuppressants, antihypertensives Periodontitis, poor hygiene Plummer-Vinson syndrome Scleroderma Xeroderma pigmentosum |
Deficiencies of iron or vitamins A, C, or E Fanconi anemia High-risk HPV infection Immune defects, including HIV/AIDS or chronic candidosis Medications: Immunosuppressants, antihypertensives Periodontitis, poor hygiene Plummer-Vinson syndrome Scleroderma Xeroderma pigmentosum |
Examination and Imaging |
Potentially Malignant Disorder |
None |
Leukoplakia Lichenoid mucositis (unilateral); Oral lichen planus Oral submucous fibrosis |
Erythroplakia Leukoplakia (speckled or verrucous) lichenoid mucositis(unilateral) Oral lichen planus |
|
Lesion Features |
Equivocal |
White patch (leukoplakia) Lichenoid mucositis (unilateral) Oral submucous fibrosis |
Red patch (erythroplakia) Mixed red and white patch (erythroleukoplakia/speckled leukoplakia) Granular surface Rolled, elevated margins Ulceration Induration |
|
Cervical Lymph Nodes |
No enlargement |
Possible enlargement |
Enlarged, firm, fixed, nontender, asymmetric |
|
Imaging |
No abnormality |
Any bone density change |
Poorly defined, uncorticated, irregular radiolucency Lamina dura loss Teeth displaced and/or resorbed Pathological fracture |
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Oral squamous cell carcinoma in the most common intraoral site, lateral tongue, initially reported as a chronic leukoplakia, which had become ulcerated and indurated at the time diagnosis was confirmed.
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Oral squamous cell carcinoma in the anterior buccal mucosa arising from a chronic candidal-associated leukoplakia. The lesion slowly developed into an indurated lump in a patient with a history of smoking, who thought it was a traumatic lesion.
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Cancer developing on the gingiva, misdiagnosed as a pyogenic granuloma.
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Cervical lymph node metastasis from oral cancer.
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Oral squamous cell carcinoma on the midlateral border of the tongue. Soft to palpation, it serves to illustrate the importance of the differential diagnosis. It was initially misdiagnosed as an allergic reaction (lichenoid lesion) to amalgam
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This photo illustrates the importance of a thorough oral examination. Oral squamous cell carcinoma on lateral posterior border of tongue. Notice the ulcer, tender at the time of diagnosis, but not indurated, which was missed by the referral doctor. Oral cancer on the posterior border of the tongue is difficult to see unless the tongue is pulled forward.
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Advanced oral squamous cell carcinoma presenting as a large, ulcerated lump on the left anterior and midlateral border of the tongue.
Tables
Issue |
|
No Serious Concern |
Concern: Consider Referral to Specialist if Clinician or Patient Concerned, Especially if Multiple Issues Apply |
Serious Concern: Referral to a Specialist |
Historical Features |
Size |
No change |
No reduction in size, even after eliminating trauma to lesion after 10-14 days |
Increasing size, even after eliminating trauma to lesion after 10-14 days |
|
Chronology |
Lesion heals |
No resolution over brief observation period |
Rapid symptom onset Solitary lesion or change in one area of lesion Lesion persisting 2-3 weeks or longer Persistent ulceration Persistent swelling Loosening of a tooth Nonhealing tooth extraction socket |
|
Neurological |
None |
Lack of pain |
Pain Dysphagia Odynophagia Otalgia Numbness/paresthesia Speech or voice change |
|
Weight |
Normal |
No weight loss |
Weight loss |
History |
Lifestyle Habits |
None |
Tobacco consumption mild/moderate Betel quid or khat consumption mild/moderate UV light exposure mild/moderate (lip surface exposure) Late-onset sexual debut (oral sex) Moderate number of lifetime sexual partners |
Tobacco consumption high Betel quid or khat consumption high Alcohol consumption high UV light exposure high Early sexual debut Numerous lifetime sexual partners |
|
Medical History |
Clear |
Deficiencies of iron or vitamins A, C, or E Fanconi anemia High-risk human papillomavirus (HPV) infection Immune defects, including HIV/AIDS or chronic candidosis Medications: Immunosuppressants, antihypertensives Periodontitis, poor hygiene Plummer-Vinson syndrome Scleroderma Xeroderma pigmentosum |
Deficiencies of iron or vitamins A, C, or E Fanconi anemia High-risk HPV infection Immune defects, including HIV/AIDS or chronic candidosis Medications: Immunosuppressants, antihypertensives Periodontitis, poor hygiene Plummer-Vinson syndrome Scleroderma Xeroderma pigmentosum |
Examination and Imaging |
Potentially Malignant Disorder |
None |
Leukoplakia Lichenoid mucositis (unilateral); Oral lichen planus Oral submucous fibrosis |
Erythroplakia Leukoplakia (speckled or verrucous) lichenoid mucositis(unilateral) Oral lichen planus |
|
Lesion Features |
Equivocal |
White patch (leukoplakia) Lichenoid mucositis (unilateral) Oral submucous fibrosis |
Red patch (erythroplakia) Mixed red and white patch (erythroleukoplakia/speckled leukoplakia) Granular surface Rolled, elevated margins Ulceration Induration |
|
Cervical Lymph Nodes |
No enlargement |
Possible enlargement |
Enlarged, firm, fixed, nontender, asymmetric |
|
Imaging |
No abnormality |
Any bone density change |
Poorly defined, uncorticated, irregular radiolucency Lamina dura loss Teeth displaced and/or resorbed Pathological fracture |
Therapies |
Examples |
Adverse effects |
Epidermal growth factor receptor (EGFR) inhibitors (FDA approved) |
Cetuximab |
Ulcers |
EGFR inhibitors |
Panitumumab, erlotinib in combination with gemcitabine |
Ulcers |
Mammalian target of rapamycin (mTOR) inhibitors |
Deforolimus, rapamycin (sirolimus) and temsirolimus |
Ulcers |
Tyrosine kinase inhibitors (TKIs) of platelet-derived growth factor (PDGF) |
Imatinib |
Ulcers, dysgeusia |
TKIs of PDGF and vascular endothelial growth factor (VEGF) |
Sunitinib |
Ulcers, dry mouth, dysgeusia |
Raf multi-kinase inhibitors |
Sorafenib |
Dysgeusia |
