- TABLE OF CONTENTS
- Etiology and Risk Factors
- Signs and Symptoms
- Screening and Diagnosis
- Staging and Prognosis
- Treatment Approaches
- Tumor Regions
- Oral cavity
- Unknown Primary Site
- Recurrent Cancer
- Suggested Reading
As mentioned previously, tumors occurring at different anatomic sites and subsites of the head and neck vary considerably with regard to epidemiology, risk factors, anatomy, natural history, staging of the primary tumor, and therapy. The following sections highlight these differences.
Sites of the oral cavity include the lips, hard palate, floor of the mouth, buccal mucosa, and tongue. Cancers at these sites account for less than 5% of all malignancies in the United States.
The oral cavity extends from the cutaneous vermilion junction of the lips to the junction of the hard and soft palates above and to the line of the circumvallate papillae below. It includes the lips, buccal mucosa, upper and lower alveolar ridges, retromolar trigone, floor of the mouth, hard palate, and anterior two-thirds of the tongue (the "oral" tongue). The primary lymphatic drainage is to the submental triangle, submandibular nodes, and upper deep jugular nodes.
The most common presenting complaint is a sore in the mouth or on the lips. One-third of patients present with a neck mass.
The differential diagnosis includes other malignancies and benign diseases or lesions. Other malignancies to be considered include salivary gland tumors, sarcoma, lymphoma, and melanoma. Benign diseases include pyogenic granuloma, tuberculous disease, aphthous ulcers, and chancres.
Benign mucosal lesions include papillomas and keratoacanthomas, which may be exophytic or infiltrative. The exophytic lesions are less aggressive. The infiltrative papillomas and keratoacanthomas are more often associated with destruction of surrounding tissues and structures. These lesions may progress to malignancy. The TNM staging system for cancers of the lips and oral cavity is outlined in Table 3. T4 lesions have been divided into T4a (resectable) and T4b (unresectable) in the seventh edition of the AJCC Cancer Staging Manual.
Management of cancers of the oral cavity involves surgery or radiotherapy for T1 or T2 lesions or combined-modality treatment that includes surgical resection and postoperative radiation therapy (60 to 70 Gy in 6 to 7 weeks) for advanced disease. For early-stage disease, surgery and radiotherapy are considered to have equivalent efficacy, although surgery is associated with less morbidity. Supraomohyoid neck dissection is performed in surgically treated patients with N0 necks. Bilateral neck dissection is performed if the tumor approaches the midline. Neck dissection is recommended for tumor thickness that is at least 4 mm, although some investigators believe that tumor thickness of 2 to 3 mm would be a more appropriate cutoff.
The lips are the most common site of oral cavity cancer. There are approximately 4,000 new cases of oral cavity cancer per year in the United States. The lower lip is affected most often. The vast majority of patients (90%) with lip cancer are men, and 33% have outdoor occupations.
Natural history. The most frequent presentation is a slow-growing tumor of the lower lip that may bleed and hurt. Physical examination must include assessment of hypoesthesia in the distribution of the mental nerve (cutaneous sensation of the chin area). Currently, less than 10% of American patients with squamous cell carcinoma of the lower lip have cervical metastases.
Treatment of primary tumor. Patients with early-stage lip cancers are usually treated with surgery. Radiation therapy may be used in patients who are medically unsuited for surgery or who refuse surgical resection.
Resection involves excision with at least 0.5 cm of normal tissue circumferentially beyond the recognized border of the tumor. After the resection of larger lesions, reconstruction may pose a major challenge. Small tumors are excised with a V incision.
Patients with advanced disease (stage III or IV) are usually managed with a combination of surgery and postoperative radiation therapy.
• The neck—Elective treatment of the neck is seldom recommended for patients with squamous cell carcinoma of the lower lip and a clinically negative neck, because few of these patients have cervical metastases. Neck dissection is recommended only in patients with palpable cervical metastases. Neck dissection is followed by postoperative radiation therapy.
• Results—The cure rate for T1–T3 tumors is 90% with surgical excision alone. Smaller lesions (T1–T2) may be treated equally well with radiation therapy. Survival rates for patients with T1 and T2 lesions are 90% and 80%, respectively. Overall, younger patients have a poorer prognosis, as do those with involvement of the mandible and extension of the tumor within the oral cavity.
The oral tongue (anterior two-thirds) is the site of 75% of all tongue cancers. In 2012, approximately 12,770 men and women (9,040 men and 3,730 women) will be diagnosed with cancer of the tongue, and 2,050 will succumb to the disease.
Natural history. The most common presenting symptom in patients with cancer of the tongue is a persistent, nonhealing ulcer with or without associated pain. Other symptoms include difficulty with deglutition and speech. There may be a history of leukoplakia, especially in younger women.
• Rate of growth—Cancer of the tongue seems to grow more rapidly than other oral cavity cancers. Tongue cancers may grow in an infiltrative or exophytic fashion. The infiltrative tumors may be quite large at presentation.
• Lesion thickness—Thicker lesions have a worse prognosis than thin cancers, and lesion thickness is a more important prognostic factor than simple tumor stage. The incidence of clinically occult cervical metastases to the neck is significantly higher when the tumor thickness exceeds 4 mm. Nevertheless, tumor thickness has not been incorporated into the TNM staging system.
• Cervical metastases—Cervical metastases occur more frequently from tongue cancer than from any other tumor of the oral cavity. At initial evaluation, 40% of patients have node metastases.
Treatment of early-stage disease. Treatment usually entails partial glossectomy. Margins should be assessed at the time of resection, because the disease spreads along muscle bundles, leading to more extensive tumor than is appreciated grossly.
Radiation therapy using external-beam radiation or an interstitial implant is a suitable option for small or minimally infiltrating tumors. In general, morbidity appears to be less with surgery. Small cancers are resected without reconstruction. Following larger resections, reconstruction with a skin graft or with free tissue transfer produces good function.
Large, infiltrative lesions should be treated with combined-modality therapy (radiation therapy and surgical resection).
Treatment of advanced disease. More advanced tumors with mandibular involvement require composite resection, including a partial glossectomy, mouth floor resection, and mandibulectomy.
• The neck—A selective neck dissection is often recommended for clinically N0 neck cancer. Comprehensive neck dissection is required in the presence of palpable cervical metastases.
• Results—Control of disease closely correlates with the extent of the primary tumor and the presence of metastases. Rates of local tumor control using radiation therapy or surgery are similar for T1 (~85%) and T2 (~80%) tumors. T3 tumors should be treated using surgery and radiation therapy. Only 10% to 15% of local recurrences are amenable to repeated resection.
Overall survival is approximately 50%. Rates of survival at 5 years by stage are the following: stage I, 80%; stage II, 60%; and stages III and IV, 15% to 35%. For equivalent primary cancers, the presence of lymph node metastases decreases the survival rate by 50%.
The floor of the mouth
There are approximately 4,000 cases of floor of the mouth cancer in the United States annually. Mouth floor cancer accounts for 10% of head and neck cancer.
Pathology. Most lesions are moderately differentiated to well-differentiated squamous cell cancers and are exophytic.
Natural history. Patients usually present with a painful mass located near the oral tongue. Because these lesions do not cause pain until they are deep, they are frequently advanced at presentation.
Extension of disease into the soft tissues of the submandibular triangle is not uncommon. Fixation of the tumor to bone suggests possible mandibular involvement, which may be evaluated further with CT imaging. Changes in the mental foramen can be distinct or demonstrate slight asymmetry when compared with the contralateral anatomy. Restricted tongue mobility reflects invasion into the root of the tongue. Palpation demonstrates the depth of infiltration much better than does inspection alone.
Tumors near the midline may obstruct the duct of the submandibular gland, leading to swelling and induration in the neck, which may be difficult to distinguish from lymph node metastases. Level I nodes are the first-echelon metastatic sites.
• Multifocality—Multifocal cancers are more common in the floor of the mouth than in other oral cavity sites. Approximately 20% of patients with mouth floor tumors have second primary tumors, half of which are in the head and neck.
Treatment of early invasive lesions. Lesions (T1–T2) involving the mucosa alone may be treated with either surgery or irradiation alone with comparable results. Primary tumors with mandibular involvement should be surgically resected.
Cancer invades the mandible through tooth sockets. Hence, if the tumor merely abuts the mandible, a marginal mandibulectomy (which removes the bone margin but preserves continuity) may be performed. Otherwise, a segmental resection is needed. Selective neck dissection for treatment planning is advisable for thick stage I or II cancers.
Treatment of advanced disease. The treatment of choice for advanced disease is combined-modality therapy with surgery and radiation therapy. Complete surgical resection may require a composite resection of the mandible, including a partial glossectomy and neck dissection for advanced primary cancers. Lesions near the midline with a clinically positive lymph node require ipsilateral comprehensive neck dissection with a contralateral selective (supraomohyoid) neck dissection.
• Results—Overall, approximately 40% of patients are cured of their disease; 80% of recurrences appear within the first 2 years. Survival rates at 5 years by stage are the following: stage I, 85%; stage II, 75%; stage III, 66%; and stage IV, 30%. Signs of poor prognosis include involvement of both the tongue and mandible and extension of the tumor beyond the oral cavity.
Carcinoma of the oropharynx affects approximately 8,000 patients in the United States annually. The incidence of oropharyngeal cancer is increasing. In the United States, over 60% of newly diagnosed oropharyngeal cancers are now attributable to HPV.
In ECOG 2399, a phase II trial, patients with locally advanced oropharyngeal and laryngeal cancers were treated with neoadjuvant paclitaxel(Drug information on paclitaxel) and carboplatin(Drug information on carboplatin) followed by radiation with weekly paclitaxel. In 2008, Fakhry et al reported that patients who were HPV-positive had a higher response rate to both neoadjuvant chemotherapy and chemoradiation and had improved survival. For patients with HPV-positive tumors, HRs for progression and death were 0.27 and 0.36, respectively. These preliminary prospective data strongly confirmed previous retrospective analyses identifying HPV association as a favorable prognostic indicator, especially for oropharyngeal primary tumors.
Recursive partitioning analysis of RTOG 0129 revealed HPV status was the most important predictor of overall and progression-free survival. Patients with a history of smoking and high nodal burden had intermediate survival outcomes: not as favorable as those of HPV-positive non-smokers, but better than those of HPV-negative patients, according to a 2010 study by Ang et al. In addition, unlike smoking-related oropharyngeal cancer, HPV-related disease is not associated with a high incidence of second primary cancers. Future clinical trials will stratify oropharyngeal cancer patients based on this important risk factor.
Anatomy and pathology
The opening to the oropharynx is a ring bounded by the anterior tonsillar pillars (faucial arch), extending upward to blend with the uvula and inferiorly across the base of the tongue (behind the circumvallate papillae). The walls of the oropharynx are formed by the pharyngeal constrictor muscles, which overlie the cervical spine posteriorly. The superior boundary is the soft palate, which separates the oropharynx from the nasopharynx.
Subsites of the oropharynx include the base of the tongue, soft palate, tonsillar area, and posterior pharyngeal wall. The extent of a primary tumor may be difficult to assess because of its location.
The jugulodigastric nodes (levels II and III) constitute the first echelon of lymphatic drainage. Metastases may also appear in the parapharyngeal and retropharyngeal nodes and may be detected only through imaging studies.
Premalignant lesions occur in the oropharynx but are less common than in the oral cavity.
Radiation therapy. External-beam radiation therapy (65 to 70 Gy over 7 weeks) and interstitial irradiation have been used in the curative treatment of oropharyngeal carcinomas for over 70 years. Radiation therapy represents a reasonable alternative to surgery and may also be required following radical resection of tumors with poor pathologic features to reduce the likelihood of local recurrence.
Altered fractionation schedules (accelerated and/or hyperfractionated) have gained interest in the past several decades based on both theoretical grounds and the results of mainly retrospective data. One prospective, randomized trial in patients with oropharyngeal cancer (excluding base of the tongue cancer) documented a 20% increase in locoregional tumor control and a 14% survival benefit at 5 years in patients who received a total dose of 8,160 cGy using 120 cGy bid 5 days per week in a hyperfractionated schedule, as opposed to 7,000 cGy in a conventionally fractionated schedule, specifically for intermediate-risk patients with T2 or T3 N0 or N1 squamous cell carcinomas. This improvement in outcome was not offset by any significant increase in acute or late tissue toxicity.
Local tumor control rates with radiation therapy alone for all primary sites (including the tonsils, soft palate, base of the tongue, and posterior oropharyngeal wall) are as follows: T1, 90%; T2, 80%; T3, 65%; and T4, 55%. Cancers of the tonsillar fossa are better controlled with irradiation than are cancers arising in other subsites of the oropharynx; this phenomenon may be related to tumors linked to HPV.
Chemoradiation therapy. A number of studies have been published supporting the use of multimodality therapy with radiation therapy and chemotherapy as an alternative to surgery with postoperative irradiation or irradiation alone. In an Intergroup trial by Adelstein et al, cisplatin(Drug information on cisplatin) (100 mg/m2) given every 3 weeks with standard irradiation was found to be safe and effective. Induction therapy followed by concurrent chemoradiation regimens has the potential for diminishing distant failure while maintaining the local tumor control achieved via concurrent regimens. Such regimens are currently under active investigation.
Surgery. Surgical extirpation of relatively inaccessible tumors in the oropharynx traditionally required radical surgery, including mandibulotomy or mandibulectomy, and occasionally laryngectomy. These surgical procedures were associated with worse functional outcomes relative to nonsurgical approaches. Radical surgery, however, has been supplanted by minimally invasive approaches. Using bivalved laryngoscopes for tumor exposure, surgical resection using the carbon dioxide (CO2) laser coupled to a microscope has led to complete pathologic resections and high local control rates for oropharyngeal cancer. The reported functional results have been good, with few patients requiring placement of a feeding tube or tracheotomies.
The use of the line-of-sight CO2 laser beam has been limited by inadequate exposure of the pathologic lesion in patients with short or stiff necks, retrognathia, full dentition, trismus, or obesity. Limited access to pathology has precluded use of transoral CO2 laser surgery in many patients. A flexible, photonic, band-gap fiber for the delivery of CO2 laser energy, developed by OmniGuide Inc, allows video-assisted visualization and extirpation of previously poorly accessible pathology. Limited access has also been surmounted by adaptation of the surgical robot for transoral applications. The daVinci Surgical System (Intuitive Surgical; Sunnyvale, California), originally designed as a three-armed robotic device controlling "wristed" surgical microinstruments and angled telescopes, has now been FDA-approved for a variety of general, cardiac, gynecologic, and urologic procedures. Improved surgical exposure to tumors in the upper aerodigestive tract has been reported relative to that obtained with more traditional transoral approaches. In 2009, transoral robotic surgery received FDA approval for T1 and T2 oropharyngeal lesions. Minimally invasive surgery is safe and effective for early-stage disease (stages I and II) and is under active investigation for advanced-stage disease. In 2011, Cohen et al published their experience using transoral robotic surgery in the treatment of 37 HPV-positive and 13 HPV-negative oropharyngeal cancer patients. Negative surgical resection margins were achieved in over 90% of patients. Extracapsular extension was identified in 44% of patients with HPV-positive cancers, and 25% of HPV-negative cancers. Two-year disease-specific and overall survival was 89.5% and 100%, and 81% and 80% for HPV-positive and HPV-negative patients, respectively. In this cohort, the most common cause of disease failure was distant metastases. One year after transoral resections, patient speech and swallowing scores approached pretreatment values.
The base of the tongue
Cancer of the base of the tongue is far less common than that of the oral tongue, but its incidence is increasing.
Anatomy. The base of the tongue is bordered anteriorly by the circumvallate papillae and posteriorly by the epiglottis. There is a rich lymphatic network, with metastases frequently seen in levels II to V.
Natural history. The base of the tongue is notorious for lesions that infiltrate deeply into muscle and are advanced at diagnosis. This finding is probably due to the relatively asymptomatic anatomic location. Thus, bimanual oral examination with digital palpation is a critical part of the physical examination.
Most patients present with pain and dysphagia. Other symptoms include a neck mass, weight loss, otalgia, and trismus.
All oropharyngeal cancers have a strong propensity to spread to the lymph nodes, and tumors arising at the base of the tongue are no exception. Approximately 70% of patients with T1 primary base of the tongue tumors have clinically palpable disease in the neck, and 20% to 30% have palpable, bilateral lymph node metastases. The risk of nodal metastases increases with increasing T stage and approaches 85% for T4 lesions.
Treatment of early-stage disease. Stage I or II cancers may be treated equally effectively with either surgical resection or radiation therapy alone. If irradiation of the primary tumor is employed, both sides of the neck should be treated, even if the nodes do not seem to be involved. Surgical management of an oropharyngeal malignancy includes lymphadenectomy. For patients clinically staged N0, selective neck dissection encompassing levels II–IV is sufficient. For patients with cancers at the base of the tongue, bilateral neck dissection is required.
Treatment of advanced disease. More advanced disease may require total resection of the tongue base with or without laryngectomy to ensure complete removal of disease. Total resection of the tongue base is associated with severe oropharyngeal dysphagia with aspiration, but even subtotal resection of the base of the tongue may result in significant aspiration, which is exacerbated by postoperative radiotherapy. Total laryngectomy may be the only way to isolate the airway from oral secretions and eliminate the risk of aspiration. Chemoradiation therapy via external-beam irradiation or irradiation alone combined with an implant can be curative for patients with advanced tumors of the tongue base.
• Results—In general, the prognosis of cancers of the tongue base is poor because of their advanced stage at presentation. The extent of nodal disease predicts survival. For T1 and T2 cancers, local tumor control rates approach 85%. The major determinant of treatment failure is the tumor's growth pattern, with a high local tumor control rate for exophytic lesions and a far worse rate for infiltrative tumors.
Tonsils and tonsillar pillar
The tonsils and tonsillar pillar are the most common locations for tumors of the oropharynx.
Natural history. Tonsillar fossa tumors tend to be more advanced and more frequently metastasize to the neck than do tonsillar pillar cancers. At presentation, 55% of patients with fossa tumors have N2 or N3 disease, and contralateral metastases are common. Symptoms include pain, dysphagia, weight loss, a mass in the neck, and trismus.
Treatment. Single-modality therapy (irradiation or surgery alone) is acceptable for T1 and T2 tumors. Irradiation alone may be curative for more advanced tumors, although chemotherapy is often added in a concurrent fashion for T3 or T4 disease or in the setting of N2 or N3 disease. The neck should always be included in treatment planning. More advanced disease usually requires surgery combined with irradiation. Well-lateralized cancers of the tonsillar fossa (minimal to no involvement of the soft palate or base of the tongue) may be treated with unilateral irradiation, since contralateral neck failure is rare (< 10%).
Hypopharyngeal cancers are approximately one-third as common as laryngeal cancers.
The hypopharynx (or laryngopharynx) is the entrance to the esophagus. The superior aspect (above the plane of the hyoid bone) communicates with the oropharynx, and the inferior border is situated in the plane of the lowest part of the cricoid cartilage (the esophageal inlet). The anterior surface (postcricoid area) is contiguous with the posterior surface of the larynx, adjacent to the lamina of the cricoid cartilage. The pharyngeal musculature forms the lateral and posterior walls. The piriform sinuses are within the hypopharynx on each side of the larynx.
The hypopharynx contains three subsites: the paired piriform sinuses (lateral, pear-shaped funnels); the posterior pharyngeal wall, from the level of the vallecula to the level of the cricoarytenoid joints; and the postcricoid area (pharyngoesophageal junction), which begins just below the arytenoids and extends to the inferior border of the cricoid cartilage. The piriform sinuses are composed of a medial wall, which abuts the aryepiglottic fold, and a lateral wall. Seventy percent of hypopharyngeal cancers occur in the piriform sinuses.
Hypopharyngeal tumors produce few symptoms until they are advanced (> 70% are stage III or IV at presentation). They may cause a sore throat, otalgia, a change in voice, odynophagia, or an isolated neck mass. Subtle changes on physical examination, including pooling of secretions, should be regarded with concern.
Nodal metastases. Diffuse local spread is common and is due to tumor extension within the submucosa. Abundant lymphatic drainage results in a higher incidence of lymph node metastases than with other head and neck tumors. At presentation, 70% to 80% of patients with hypopharyngeal tumors have palpable cervical lymph node metastases; in half of these patients, palpable cervical nodes are the presenting complaint. Levels II and III are most commonly involved. Bilateral metastases are seen in only 10% of patients with piriform sinus cancers but in 60% of those with postcricoid tumors.
Synchronous lesions. These are common. Overall, 20% to 25% of patients with hypopharyngeal cancer develop a second primary tumor within 5 years, usually in the head and neck.
Chemotherapy and external-beam radiotherapy. Similar in design to the VA Cooperative Laryngeal Cancer Study, a randomized EORTC trial has shown that initial therapy with cisplatin and 5-FU, followed by definitive irradiation in patients with complete remissions (or, alternatively, surgical salvage), results in at least equivalent survival relative to immediate pharyngolaryngectomy. Of patients treated with initial chemotherapy, 28% retained a functional larynx at 3 years (approximately two-thirds of survivors).
Though directed to laryngeal cancers (rather than hypopharyngeal cancers), the RTOG 91-11 trial results have been widely interpreted as applying to hypopharyngeal cancer, increasing enthusiasm for concomitant chemoradiation therapy for patients with advanced cancers of the hypopharynx.
Transoral laser surgery for piriform sinus carcinoma. Organ-sparing approaches such as transoral laser microsurgery for piriform sinus carcinomas have been used in several institutions for the past 25 years. Long-term follow-up in a retrospective review of 129 previously untreated patients has been published. In this series, which included mostly patients with advanced-stage disease, the reported 5-year local control rate was 82% for patients with stages I and II cancers and 69% for those with stages III and IV cancers. Radiation therapy was administered after surgery. Laryngeal preservation rates were comparable to the local tumor control rates. The 2-year overall survival rates were 91% for patients with stages I and II cancer and 75% for patients with stages III and IV cancer. These oncologic and functional results compare favorably with those obtained with either nonsurgical or surgical approaches requiring opening the neck and pharynx.