Laboratory Studies
To confirm the diagnosis of oral squamous cell carcinoma (oral SCC), a tissue biopsy must be performed to allow histopathologic examination of the lesional tissue. In addition, to determine whether malignant disease is present elsewhere after the initial diagnosis of oral SCC is rendered, further investigations can be performed to look for the following:
-
Bone, muscle, or primary tumors: Other primary tumors are typically located in the upper aerodigestive tract (eg, mouth, nares, pharynx, larynx, esophagus). Whether endoscopy is warranted to detect such tumors in all cases remains controversial.
-
Metastases: This initially occurs to regional lymph nodes and later to the lungs, liver, bones, and brain. Imaging studies may help detect abnormalities missed during the clinical examination.
Blood tests include the following:
-
Liver function tests: Results may reveal metastases in persons with advanced disease.
-
Complete blood cell count and hemoglobin value
-
Urea and electrolyte measurements
-
Blood group testing and cross-matching
-
Calcium level: As many as 4% of patients with cancer in the head and neck may have elevated serum calcium levels. This is a poor prognostic indicator primarily found in persons with advanced disease.
-
Serum ferritin, alpha-antitrypsin, and alpha-antiglycoprotein levels: Persons with high-stage cancer of the head and neck also have increased levels of serum ferritin, alpha-antitrypsin, and alpha-antiglycoprotein, while those at any stage of disease have increased haptoglobin levels (although not known if this is true specifically for oral cancer). Additionally, prealbumin levels are decreased slightly in persons at any stage. Results from assays of these serum constituents cannot be regarded as sufficiently specific or sensitive to be of reliable clinical value, and this, unfortunately, is also true of the many tissue markers thus far described.
Imaging Studies
Photography to create a photographic record is especially useful for monitoring the clinical state and site of premalignant lesions.
Chest radiography and endoscopy are valuable procedures for excluding synchronous second primary tumors. Chest radiography may be indicated because the lungs are the most common site for metastases and a site for second primary carcinomas. Radiography, including CT scanning to map the tumor in 3 dimensions, and/or other imaging techniques, such as positron-emission tomography and magnetic resonance imaging, can be used to generate an outline of the tumor, particularly to exclude bone invasion and lymph node involvement. Chest radiography is important as a preanesthetic check, especially in patients with known pulmonary or airway disease and to demonstrate metastasis to the lungs or hilar lymph nodes, ribs, or vertebrae. Jaw radiography (often rotating pantomography) is used to evaluate dental status.
Radionuclide scanning occasionally is useful. Bone scanning is of little value in screening because findings are positive only where bone involvement is symptomatic. Bone scanning is primarily used to determine the extent of tumor spread. Liver radionuclide scanning shows abnormal findings in as many as 6% of patients with cancer in the head and neck, but two thirds are false-positive findings; therefore, liver scanning normally is not indicated.
Routine panendoscopy helps identify simultaneous second primary carcinomas in the esophagus, larynx, or lungs in as many as 14% of patients. Endoscopy is widely recommended, although it is not performed in all centers. More than one third of second primary tumors are detectable by endoscopy at or within 1 year of diagnosis of the index tumor.
Procedures
Incisional biopsy, guided when appropriate by vital staining, is essential to confirm the diagnosis. A biopsy must be performed on any oral mucosal lesion suggestive of possible malignant changes, such as an ulcer that does not heal within 2-3 weeks. Lesional tissue must be obtained to allow histopathologic examination of the tissue. It is a good rule to obtain the tissue specimen from the worst-looking area. Always take a biopsy specimen of the red lesions if both red and white lesions are present because red, rather than white, areas are more likely to show dysplasia, or from the ulcer if the lesion is ulcerated.
Vital staining maybe helpful if difficulty arises when deciding which area is most appropriate for the biopsy, particularly if widespread lesions are present. Staining with toluidine blue followed by a rinse with 1% acetic acid and then saline may stain the areas most suggestive of findings and indicate which need a biopsy. [32] Oral carcinoma in situ and early invasive carcinoma have an affinity for toluidine blue dye, and although false-positive results may be encountered, these can be minimized by having the proper differential diagnosis. Toluidine blue clearly is more effective in experienced hands and when used with appropriate clinical judgment.
Various light sources are becoming available to help delineate areas for biopsy, but it is most crucial to perform a direct oral examination under good light. When taking a biopsy specimen, ensure that sufficient tissue is obtained to avoid the need for a rebiopsy. Fix tissue biopsies in 10% formalin as soon as possible after the procedure.
Excisional biopsies are always contraindicated, specially of small lesions because the procedure is unlikely to have achieved excision of an adequately wide margin of tissue if the lesion is malignant and will have destroyed clinical evidence of the site and the character of the lesion for the surgeon or radiotherapist. It is good practice to take a good-quality photograph prior to biopsy that can be presented at the local tumor board with the final diagnosis.
Lymph node biopsy is generally performed by an interventional radiologist should there be suspicion for involvement of regional lymph nodes. This is done using a fine-bore needle to aspirate cells for cytologic examination. Ultrasound-guided fine-needle aspiration cytology is now favored. False-negative results are possible, but the primary danger of a fine-needle aspiration biopsy is that it may seed malignant cells. In practical terms, ipsilateral, firm or hard, enlarged regional lymph nodes in a patient with an obvious oral carcinoma are likely to include metastases.
Histologic Findings
Microscopic examination of oral SCC reveals nests and islands of squamous cells invading the underlying connective tissue. In some of these tumor islands, there is aberrant keratinization, forming whorls of keratin within. The presence of aberrant keratinization is a feature of well-differentiated carcinoma. Occasionally, an endogenous foreign body giant cell reaction to the keratin from ruptured pearls occurs.
Poorly differentiated oral SCC consists of sheets of cells showing extreme pleomorphism, giant nuclei, and multiple and bizarre mitoses and often is difficult to distinguish from other malignancies, particularly poorly differentiated lymphoma or melanoma. In this instance, immunocytochemical markers such as keratins, common leukocyte antigen, and melanoma-specific antibodies are indicated.
Generally, oral SCC are rarely positive for human papillomavirus (HPV), unlike the oropharyngeal SCCs that involve the tonsillar tissue at the posterior/base of the tongue.
Staging
In 2018 the American Joint Committee on Cancer tumor (AJCC) upgraded the tumor, node, metastasis (TNM) classification and staging of oral cancer as follows [33, 34] :
Classification
Primary tumor, as follows:
-
Tis - Carcinoma in situ
-
T1 - Tumor 2 cm or smaller
-
T2 - Tumor 4 cm or smaller
-
T3 - Tumor larger than 4 cm
-
T4 - Tumor larger than 4 cm and deep invasion to muscle, bone, or deep structures (eg, antrum)
Lymphatic node involvement, as follows:
-
N0 - No nodes
-
N1 - Single ipsilateral node smaller than 3 cm
-
N2 - Nodes(s) ipsilateral smaller than 6 cm
-
N3 - Nodes(s) larger than 6 cm and/or bilateral
Tumor metastasis, as follows:
-
M0 - No metastasis
-
M1 - Metastasis noted
Staging
Stage I is T1, N0, M0.
Stage II is T2, N0, M0.
Stage III is as follows:
-
T3, N0, M0
-
T1-T3, N1, M0
Or
Stage IVa is as follows:
-
T4a, N0-N1, M0 or
-
T1-T4a, N2, M0
Stage IVb is as follows:
-
Any T, N3, M0 or
-
T4b, N0-N1, M0
Stage IVc is as follows:
-
Any T, Any N, M1
-
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.
-
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.
-
Cancer developing on the gingiva, misdiagnosed as a pyogenic granuloma.
-
Cervical lymph node metastasis from oral cancer.
-
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
-
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.
-
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 |
