Oral Cancer

Oral cancer includes neoplasms arising from the oral mucosa, tonsils, and salivary glands. More than 90% of oral cancers are squamous cell carcinoma (SCC). Risk factors include premalignant lesions, tobacco chewing/smoking, alcohol consumption, and HPV infection. The patient typically presents with a nonhealing, oral mucosa ulcer, oral pain, mass, or a red/white lesion. Lesions persisting beyond 3 weeks warrant further evaluation with a biopsy. Additional evaluation of the extent of the disease is made with imaging studies. Depending on the stage of the disease, management options include surgical resection, radiation therapy, and chemotherapy. The involvement of lymph nodes is the most important prognostic factor.

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Epidemiology and Etiology

Epidemiology

  • Oral (mouth) cancer accounts for most head and neck cancers.
  • The majority is squamous cell carcinoma (SCC).
  • Peak incidence is in the 6th decade of life.
  • Men > women by a 2:1 ratio
  • Common in certain countries: Bangladesh, Sri Lanka, India, and Pakistan

Etiology

  • Tobacco chewing/smoking
  • Alcohol
  • HPV infection
  • Chronic mechanical irritation (badly positioned dentures)
  • Low intake of fruits and vegetables
  • Betel quid chewing (contains areca nut)
  • Presence of precancerous lesions:
    • Erythroplakia (red plaque)
    • Leukoplakia (white plaque)
    • Leukoerythroplakia (speckled plaque)
    • Oral lichen planus
    • Oral submucous fibrosis
    • Actinic or solar cheilitis
    • Oral discoid lupus erythematosus
    • Chronic oral graft-versus-host disease (GVHD)
  • Risk for malignant transformation:
    • ↑ With age
    • ↑ With the age of the lesion
    • Smoking
    • ↑ With alcohol consumption
    • Depends on the anatomical site of the premalignant lesion

Pathophysiology

  • Histopathology:
    • Over 90% of head and neck cancer is SCC. 
    • The remainder is adenocarcinoma of the salivary gland with tumors mainly arising from the mucosal epithelium.
  • SCC development:
    • Mutations and epigenetic changes accumulate, which affect the expression of oncogenes and tumor suppressor genes.
    • Major pathways:
      • Tobacco and alcohol: overexpressed p53 gene
      • HPV: inactivated Rb gene, leading to overexpressed p16 gene
    • Progression of squamous epithelium in response to toxin/HPV exposure → hyperkeratosis → dysplasia → carcinoma in situ → cancer
  • Anatomical sites frequently involved: 
    • Lateral and ventrolateral tongue 
    • The floor of the mouth
    • Buccal mucosa
    • Retromolar trigone: attached mucosa overlying the ascending ramus of the mandible (posterior to the last molar tooth) and extending superiorly to the maxillary tuberosity
Oral cavity

Oral cavity:
Common areas for oral cancer include the tongue, the floor of the mouth, and the retromolar trigone (the area posterior to the molars).

Image: “The mouth includes the lips, tongue, palate, gums, and teeth” by Phil Schatz. License: CC BY 4.0

Clinical Presentation

  • Oral features:
    • Red or red-white lesion(s)
    • Persistent oral swelling 
    • Mouth ulceration
    • Sore tongue
    • Unexplained tooth mobility 
    • Unusual bleeding in the mouth
  • Other related signs and symptoms:
    • Trismus
    • Difficulty swallowing 
    • Halitosis
    • Jaw or facial swelling
    • Painless neck lump (lymphadenopathy)

Mnemonic

Biopsy is recommended for suspicious oral lesions lasting 3 or more weeks:

  • Red
  • Ulcer
  • Lump
  • Especially indurated (firm on palpation) lesion(s) or a combination of lesions

Diagnosis

Diagnostic approach

  • Established by lesion biopsy
  • Panendoscopy (to determine tumor extent)
  • Imaging (to locate metastasis):
    • Chest X-ray
    • CT and MRI
    • PET-CT scans

Staging

  • TNM staging for oropharyngeal cancers: 
    • Primary tumor (T):
      • TX: Primary tumor cannot be assessed.
      • T0: no evidence of primary tumor
      • Tis: carcinoma in situ
      • T1: tumor ≤ 2 cm in greatest dimension
      • T2: tumor > 2 cm but ≤ 4 cm
      • T3: tumor > 4 cm 
      • T4: Tumor invades adjacent structures (e.g., mandible, skin, muscle).
    • Regional lymph nodes (N):
      • NX: Regional lymph nodes cannot be assessed.
      • N0: no regional lymph node metastasis
      • N1: metastasis in a single, ipsilateral lymph node ≤ 3 cm 
      • N2a: metastasis in a single, ipsilateral lymph node > 3 cm but < than 6 cm
      • N2b: metastasis in multiple, ipsilateral lymph nodes all < 6 cm in greatest dimension
      • N2c: metastasis in bilateral or contralateral lymph nodes all < 6 cm in greatest dimension
      • N3: metastasis in any lymph node > 6 cm
    • Distant metastasis (M):
      • M0: no evidence of distant metastasis
      • M1: distant metastasis
  • Spreading of the tumor to a contralateral lymph node is prognostically worse than spreading into multiple, ipsilateral lymph nodes.
Table: Staging of oral cancer
StageDescription
0TisN0M0 (in situ or cancer limited to epithelium)
IT1N0M0 (lesion ≤ 2 cm and without node involvement or distant spread)
IIT2N0M0 (lesion > 2 cm but < 4 cm without node involvement or distant metastasis)
III
  • T3N0M0 (lesion > 4 cm without node involvement or distant metastasis)
  • T1–3N1M0 (lesion of any size with ipsilateral node of < 3 cm, but no distant metastasis)
IVInvasion of adjacent structures or distant metastasis

Management and Prognosis

Management

  • Early cancer (stages I and II):
    • Surgical resection: > 3 mm tumor invasion for stage I lesions; neck dissection for stage II lesions
    • Radiotherapy if surgery is not feasible
  • Locoregionally advanced cancer (stage III and IV): aggressive lesions, with a high rate of recurrence even with surgery or radiotherapy:
    • Surgery + neck dissection:
      • Maxillectomy/mandibulectomy: bone involvement 
      • Glossectomy: tongue involvement
      • Laryngectomy: larynx involvement
    • Followed by radiotherapy with or without chemotherapy
  • Inoperable tumors: radiotherapy or radiotherapy + chemotherapy
  • Additional management:
    • Cancer surveillance
    • Functional rehabilitation
    • Educate on tobacco cessation, alcohol cessation, and other high-risk factors.

Prognosis

  • Five-year survival: 
    • Early oral cancer: 82.5%
    • Locally advanced oral cancer: 54.7%
  • Recurrence and 2nd primary malignancy risk:
    • > 80% of stage III and IV cancers recur within 4-years posttreatment.
    • Frequent surveillance needed:
      • In the 1st 4 years
      • For patients with continued high-risk behavior (i.e. smoking, alcohol consumption)
  • Most important factor in prognosis: involvement of lymph node(s)

Differential Diagnosis

  • Aphthous stomatitis: round-to-oval, painful ulcers with a crater-like appearance on a yellow-gray base with erythematous margins. Mucosal ulcers are on nonkeratinized mucosal surfaces only. Recurrence of ulcers is common and does not involve systemic symptoms. Aphthous stomatitis commonly occurs after minimal trauma (e.g., tongue biting). Management is supportive. 
  • Oral candidiasis: presents as white plaques on the oral mucosa, which can be scraped off with a tongue depressor. 90% of cases are due to Candida. Predisposing conditions include ill-fitting dentures, immunosuppression, and corticosteroid inhaler use. Oral candidiasis is common in pediatrics, particularly in small children. Management is with antifungal mouthwash. 
  • Herpetic gingivostomatitis: presents as painful, perioral vesicular lesions in clusters. The condition is contagious and caused by herpes simplex virus type 1. Herpetic gingivostomatitis is more common in children and at 1st exposure to the herpes virus, which is also responsible for cold sores and fever blisters. Management is supportive, but antivirals can be used.
  • Herpangina: a common childhood illness often caused by group A coxsackieviruses. The presentation includes oral lesions (usually with a white base and a red border) and a prodrome of fever, anorexia, irritability, malaise, sleeplessness, and headache. The lesions typically involve the posterior pharynx and may be very painful. Management is supportive.

References

  1. Gross, N., Lee, N., Okuno, S., Rao, S. (2021). Treatment of stage I and II (early) head and neck cancer: The oral cavity. UpToDate. Retrieved June 7, 2021, from https://www.uptodate.com/contents/treatment-of-stage-i-and-ii-early-head-and-neck-cancer-the-oral-cavity
  2. Lee, N., Gross, N., Okuno, S., Rao, S. (2021). Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The oral cavity. UpToDate. Retrieved June 7, 2021, from https://www.uptodate.com/contents/treatment-of-locoregionally-advanced-stage-iii-and-iv-head-and-neck-cancer-the-oral-cavity
  3. Lodi, G. (2021). Oral lesions. UpToDate. Retrieved April 19, 2021, from https://www.uptodate.com/contents/oral-lesions
  4. Montero, P.H., Patel, S.G. (2015). Cancer of the oral cavity. Surg Oncol Clin N Am. 24(3), 491–508. https://pubmed.ncbi.nlm.nih.gov/25979396/
  5. Sim, C.Q. (2021). Cancers of the Oral Mucosa. Emedicine. Retrieved April 19, 2021, from http://emedicine.medscape.com/article/1075729
  6. American Cancer Society. (2021). Key Statistics For Oral Cavity and Oropharyngeal Cancers. Retrieved April 19, 2021, from https://www.cancer.org/cancer/oral-cavity-and-oropharyngeal-cancer/about/key-statistics.html
  7. Stenson, K. (2021). Epidemiology and risk factors for head and neck cancer. UpToDate. Retrieved June 7, 2021, from https://www.uptodate.com/contents/epidemiology-and-risk-factors-for-head-and-neck-cancer
  8. Taxy, J. (2021). Pathology of head and neck neoplasms. UpToDate. Retrieved June 7, 2021, from https://www.uptodate.com/contents/pathology-of-head-and-neck-neoplasms

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