12 Diseases of Oral Cavity and Oropharynx

Question 1

Describe the anatomy of the oral cavity and name the eight subsites within it.

Answer 1

The oral cavity extends from the vermilion border of the lip (mucocutaneous junction) to the circumvallate papillae of the tongue inferorly and the junction of the hard and soft palate superiorly. The eight subsites are:

1. Lips
2. Buccal mucosa
3. Lower (mandibular) alveolar ridge/gingiva
4. Upper (maxillary) alveolar ridge/gingiva
5. Retromolar trigone
6. Hard palate
7. Floor of mouth
8. Oral tongue (anterior two thirds)

Question 2

What is the most common type of malignancy within the oral cavity?

Answer 2

Squamous cell carcinoma. As in all head and neck sites, squamous cell carcinoma (SCC) is by far the most common type of tumor seen. More than 90% of oral cavity cancers are SCC. Other malignant tumors include minor salivary gland malignancies, Kaposi’s sarcoma, other sarcomas, melanoma, and rarely lymphoma.

Question 3

Where in the oral cavity are minor salivary gland malignancies most commonly seen? What is the most common type?

Answer 3

Within the oral cavity, minor salivary gland malignancies most commonly occur on the hard palate.

Adenoid cystic carcinoma is the most common tumor of the minor salivary glands in the oral cavity.

Question 4

What are the most common subsites for oral cavity squamous cell carcinoma?

Answer 4

1. Lips: Incidence varies by geographic location, but overall 15% to 30% of oral cavity cancers occur on the lips. The lower lip is much more common than the upper lip (>90% arise in lower lip). Though still considered oral cavity SCC by the American Joint Committee on Cancer (AJCC), lip cancer can be considered separately because the vermilion of the lip is exposed to external environmental factors (such as UV radiation from the sun) and sometimes behaves more like cutaneous SCC.
2. Oral tongue: 20% to 30% of oral cavity cancers. Lateral tongue is more common than dorsal tongue.

Question 5

Discuss three premalignant clinical lesions or conditions of the oral cavity.

Answer 5

1. Leukoplakia: White keratotic plaque or patch* that cannot be rubbed off. Often seen due to chronic trauma or irritation of oral mucosa. Most are benign, but malignant potential/transformation rate is very difficult to predict. *Baseline biopsy and follow-up or excision is recommended depending on pathologic findings.
2. Erythroplakia: Red mucosal plaque not arising from an obvious mechanical or inflammatory cause. This lesion has a much higher malignant potential than leukoplakia (estimated to be 7 times more malignant potential), and can be seen in conjunction with leukoplakia. More aggressive therapy is recommended than that for leukoplakia, including complete excision with adequate margins.
3. Oral lichen planus: Lacy white lines primarily noted on buccal mucosa (but changes can be seen throughout the oral cavity). Exact cause is unknown but thought to be immune mediated (lymphocytic infiltration of epithelial layers seen). Associated with pain and burning and clinical course waxes and wanes. Treated with topical steroids, systemic steroids, and sometimes other immunosuppressants. Lifetime malignant transformation risk is 5% to 10%.

Note: The above are clinical, rather than pathologic, descriptions of premalignant conditions. Dysplasia, which can be seen in any of these lesions, is the pathologic description of premalignant change describing degrees of cellular change. Dysplasia can be described as mild, moderate, and severe. Severe dysplasia and carcinoma in situ are often utilized interchangeably by pathologists.

Question 6

Are oral cavity SCCs commonly caused by human papilloma virus (HPV)?

Answer 6

No. Whereas oropharynx SCC is very commonly driven by the HPV virus (some reports >80%), only a small percentage (<3%) of oral cavity cancers are truly HPV driven.

Question 7

Where in the neck do regional metastases of oral cavity SCC most commonly appear and how is this clinically significant?

Answer 7

Regional nodal disease from oral cavity SCC most commonly presents in the upper cervical lymph nodes: level I (submental and submandibular), level II, and level III (upper and middle jugular nodes). This relatively predictable nodal drainage of oral cavity subsites has led to the use of what is termed the supraomohyoid neck dissection (includes levels I, II, and III) for elective nodal dissection in oral cavity cancers. The finding of microscopic nodal disease in levels III and IV without level I and II disease in greater than 15% of oral tongue cancer patients has led to some recommending inclusion of level IV in elective neck dissections for oral tongue cancer.

Question 8

How is cancer of the oral cavity staged?

Answer 8

SCC of the oral cavity is staged according to the tumor, node, metastasis (TNM) sytem by the American Joint Committee for Cancer (AJCC), currently in its seventh iteration. Within the oral cavity, size of the tumor is the major factor determining T-stage.

• Tx: No information available on primary tumor
• T0: No evidence of primary tumor
• Tis: Carcinoma in situ
• T1: Tumor <2 cm
• T2: Tumor size 2 to 4 cm
• T3: Tumor size >4 cm
• T4a: Moderately advanced local disease.
  
  • Lip: Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face
  • Oral cavity: Tumor invades adjacent structures only (e.g., through cortical bone [mandible or maxilla], into deep [extrinsic] muscle of tongue [genioglossus, hyoglossus, palatoglossus, styloglossus], maxillary sinus, skin of face) Note: superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as T4.
• T4b: Very advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base, and/or encases internal carotid artery

Nodal staging is the same for most head and neck squamous cell cancers.

• Nx: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
• N2a: Metastasis in single ipsilateral lymph node more than 3 cm-6 cm
• N2b: Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension
• N2c: Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension
• N3: Metastasis in a lymph node more than 6 cm in greatest dimension

Question 9

How is depth of invasion utilized in treatment of early oral tongue cancers?

Answer 9

Depth of tumor invasion is correlated with risk of nodal metastasis (and also correlates with prognosis and risk of recurrence). Depth of invasion refers to the depth below the surface epithelium into which the tumor extends. Depth of invasion and tumor thickness are not technically synonymous, as exophytic tumors can be very thick but have shallow depth of invasion into underlying structures.

In oral tongue cancer, depth of invasion has been studied as a deciding factor regarding elective treatment of a clinically node-negative neck. Multiple trials have supported tumor depth of invasion of 4 mm as the cutoff point regarding elective treatment of the neck. Tumors with depth of invasion of 4 mm or greater are associated with greater than 20% incidence of microscopic nodal metastasis and thus elective neck treatment is indicated.

Question 10

What does the initial workup for patients with oral cavity or oropharynx cancer typically include?

Answer 10

1. Complete history and physical examination,
2. Imaging (most commonly CT neck with contrast; MRI with gadolinium can be useful, especially if dental artifact on CT scan obscures view of tumor)
3. Dental evaluation
4. Tissue biopsy
5. Chest radiograph. Chest radiograph is still considered acceptable evaluation for distant metastasis or second primary malignancy, though CT chest and PET/CT are being utilized more recently. However, use of PET/CT as the primary staging imaging modality for all head and neck cancer patients is controversial and is the subject of ongoing debate.
6. Generally, most patients will have laboratory evaluation including liver function tests (though abnormal liver function tests leading to the finding of liver metastases at initial presentation is a rare scenario).

Question 11

What is the recommended treatment for oral cavity cancer?

Answer 11

Primary surgery is accepted as first-line therapy for all oral cavity sites. Surgical excision of all involved structures including a margin of normal tissue is performed. The generally accepted pathologically negative margin is 5 mm, but due to tissue shrinkage, clinical margins measured and excised by the surgeon intraoperatively are 1 to 1.5 cm.

Question 12

What factors are indications to consider giving postoperative adjuvant therapy after resection of oral cavity SCC to minimize risk of locoregional recurrence?

Answer 12

Tumor Factors

1. Locally advanced T3 or T4 lesions
2. High-grade histology
3. Presence of perineural invasion or lymphovascular invasion on pathology
4. Infiltrating rather than pushing borders of tumor
5. Positive or close (<5 mm on pathologic specimen) margins of surgical resection
6. Surgeon concern regarding adequacy of resection regardless of histologic surgical margins

Nodal Factors

1. N stage higher than N1
2. Surgical contamination (excisional or incisional nodal biopsy prior to definitive surgery)
3. Presence of extracapsular extension

Note: Positive margins and presence of extracapsular extension are even higher risk features for recurrence and are used as indications to give chemotherapy with radiation postoperatively.

Question 13

What are the subsites within the oropharynx?

Answer 13

The oropharynx is bounded by the junction of the hard and soft palate and circumvallate papillae anteriorly, superior surface of the soft palate superiorly, and pharyngoepiglottic fold inferiorly. Subsites include:

1. Tonsils
2. Base of tongue and vallecula
3. Soft palate
4. Tonsillar pillars (palatoglossus and palatopharyngeus muscles)
5. Pharyngeal walls

Question 14

What is the primary lymphatic drainage of the oropharynx?

Answer 14

What is the primary lymphatic drainage of the oropharynx?

Lymphatic drainage is primarily to the jugular lymphatics in level II, III, and IV. Nodal metastases are most commonly seen in level II. Isolated nodal metastasis to levels I and V is rare from oropharynx tumors.

Subsites within the oropharynx known specifically to have rich bilateral lymphatic drainage are the base of tongue and soft palate (as well as posterior pharyngeal well, which is generally a much less common primary site for SCC). Oropharyngeal structures also drain to retropharyngeal and parapharyngeal lymph nodes.

Question 15

Which more commonly presents as an isolated neck mass, oral cavity or oropharyngeal SCC?

Answer 15

Which more commonly presents as an isolated neck mass, oral cavity or oropharyngeal SCC?

Oropharyngeal cancer may commonly present as an isolated neck mass without other symptoms.

Oral cancer more commonly presents with oral cavity symptoms such as pain, bleeding, ulcer/visible lesion, change in speech, ear pain.

Question 16

List common symptoms of oropharynx cancer.

Answer 16

List common symptoms of oropharynx cancer.

Oropharyngeal cancer commonly presents with throat pain or fullness, dysphagia, odynophagia, referred ear pain, neck mass, change in voice (muffled voice), foul breath or foul taste, expectorating bloody secretions. With more advanced disease, patients may have trismus, difficulty with tongue mobility due to deep infiltration, or airway obstruction.

Question 17

How do oral and pharyngeal neoplasms refer pain to the ipsilateral ear?

Answer 17

How do oral and pharyngeal neoplasms refer pain to the ipsilateral ear?

Otalgia is referred from the pharynx by way of the pharyngeal cranial nerves IX and X, which also supply sensory innervation to the ear.

The tongue and floor of mouth are supplied by the lingual branch of V3. V3 also provides sensation to the external auditory canal, tympanic membrane, and temporomandibular joint through the auriculotemporal nerve.

In some patients, the sensation of otalgia is much more prominent than oral or throat pain.

Question 18

Why should one be wary of the diagnosis of “branchial cleft cyst” in a 55-year-old former smoker?

Answer 18

Why should one be wary of the diagnosis of “branchial cleft cyst” in a 55-year-old former smoker?

Oropharynx subsites very commonly present with cystic nodal metastases. Since the most common cervical location of these is level II of the neck, these metastases are located in the presenting location of a second branchial cleft cyst. These cystic metastases can have a thin wall and be full of clear/serous appearing fluid just like the branchial cleft cyst. We often cannot rely on fine needle aspiration (FNA) for diagnosis because the fluid obtained from either type of neck mass may look similar under the microscope—degenerated squamous cells and debris can be seen in the fluid of both a malignant metastasis or a branchial cleft cyst. Though it is possible for older persons to have their congenital branchial anomaly present later in life, this is an uncommon scenario and one must think of a cystic neck mass in an adult as cancer until proven otherwise.

Question 19

The incidence of many head and neck malignancies in the United States has been declining slowly in the recent past (likely due to decreased rates of smoking); however, the rate of oropharynx cancer is increasing significantly. To what factor is this attributed?

Answer 19

To what factor is this attributed?

Human papilloma virus (HPV)-associated oropharynx cancer is increasing dramatically in the United States and some European countries. Since the late 1990s and early 2000s, HPV has risen to the forefront of discussion in oropharynx SCC. Primary sites most associated with HPV are the tonsil and the base of tongue. Overall prognosis associated with HPV-positive SCC is significantly better than that of HPV-negative SCC, and research is ongoing to determine causes of this difference.

Question 20

Which subtype of HPV is considered to be highest risk for association with oropharyngeal malignancy?

Answer 20

Which subtype of HPV is considered to be highest risk for association with oropharyngeal malignancy?

HPV 16 is by far the most common subtype of HPV associated with oropharynx SCC. Types 18, 31, and 33 are also considered high-risk subtypes, but are actually not that commonly seen in oropharyngeal cancer. Overexpression of the p16 protein can be evaluated by immunohistochemistry on pathologic specimens and is commonly utilized as a surrogate marker for HPV-positive tumors.

Question 21

How does HPV cause oropharyngeal cancer?

Answer 21

How does HPV cause oropharyngeal cancer?

Viral proteins E6 and E7 cause inactivation/degradation of p53 tumor suppressor gene allowing malignant cells to proceed through normal cell cycle check points and continue to replicate.

Question 22

How do oropharyngeal cancer patients diagnosed today differ from those seen 30 years ago?

Answer 22

How do oropharyngeal cancer patients diagnosed today differ from those seen 30 years ago?

We are more commonly seeing oropharyngeal cancer in younger (40s to 50s) patients with little to no smoking history. Specifically, incidence is expanding in the white male population (though female incidence is expanding as well). These are classic HPV-associated oropharyngeal cancer patients. HPV-associated tumors present with early cervical nodal metastases, but these patients are noted to have overall better prognosis than their HPV-negative counterparts, suggesting a need to include HPV status in staging information and perhaps revise the future staging schema.

Question 23

How does primary treatment of oropharynx SCC differ from oral cavity SCC?

Answer 23

How does primary treatment of oropharynx SCC differ from oral cavity SCC?

Whereas recommendation for primary treatment of oral cavity cancer is surgical excision, oropharyngeal cancer is very commonly treated primarily with radiation with or without chemotherapy. Based initially on studies from the 1990s and 2000s regarding “organ preservation” therapy for laryngeal cancer that showed similar oncologic outcomes between nonsurgical therapy and laryngectomy for laryngeal cancer, further evidence has amassed for nonsurgical treatment of oropharyngeal cancer providing similar oncologic outcomes to surgery with postoperative radiation and significantly less morbidity. Thus, radiation-based therapy became standard of care for treatment of most oropharyngeal SCC over the last 30 years. With improved technology to allow for less invasive access to the oropharynx (TLM and TORS), surgical therapy for oropharyngeal cancer is being revisited and is the subject of much ongoing research.

Question 24

Describe two techniques for a minimally invasive approach to the oropharynx.

Answer 24

With the following techniques, surgeons can have access to the oropharynx for resection of tumors via the transoral route.

1. Transoral Laser CO2 Microsurgery (TLM): Initially described in the 1970s, this is a technique utilized initially for laryngeal surgery and subsequently applied to tumors of the oropharynx and hypopharynx. It utilizes laryngoscopes of various types to provide access to the pharynx and a microscope for magnified view of the tumor. A CO2 laser is used as a cutting and coagulating instrument. This technique is traditionally limited by line of sight—the structures being visualized are in a straight line with the laryngoscope used and the CO2 laser travels in a straight line from the microscope (though use of a CO2 laser fiber has allowed for some angled use of the CO2 laser).
2. Transoral Robotic Surgery (TORS): In this technique, described in 2005, a surgeon seated at a distant console utilizes robotic arms inserted into the mouth to perform the dissection. Zero-degree or 30-degree angled, high-definition binocular endoscopy is utilized for enhanced visualization, and the robotic arms can be fitted with various grasping, cautery, or cutting instruments (including the laser fiber). This technique has become much more widely utilized than TLM for access to the oropharynx.

Question 25

How does presence of cervical nodal metastasis affect overall prognosis for oral cavity and oropharynx cancer?

Answer 25

How does presence of cervical nodal metastasis affect overall prognosis for oral cavity and oropharynx cancer?

Cervical nodal metastasis is associated with worse prognosis, with survival rates diminished by up to 50% compared with patients lacking cervical nodal disease.