Epithelial carcinomas of the head and neck arise from the mucosal surfaces in the head and neck and typically are squamous cell in origin. This category includes tumors of the paranasal sinuses, the oral cavity, and the nasopharynx, oropharynx, hypopharynx, and larynx. Tumors of the salivary glands differ from the more common carcinomas of the head and neck in etiology, histopathology, clinical presentation, and therapy. They are rare and histologically highly heterogeneous. Thyroid malignancies are described in Chap. 405.
INCIDENCE AND EPIDEMIOLOGY
The number of new cases of head and neck cancers (oral cavity, pharynx, and larynx) in the United States was 53,640 in 2013, accounting for about 3% of adult malignancies; 11,520 people died from the disease. The worldwide incidence exceeds half a million cases annually. In North America and Europe, the tumors usually arise from the oral cavity, oropharynx, or larynx. The incidence of oropharyngeal cancers is increasing in recent years. Nasopharyngeal cancer is more commonly seen in the Mediterranean countries and in the Far East, where it is endemic in some areas.
Alcohol and tobacco use are the most significant risk factors for head and neck cancer, and when used together, they act synergistically. Smokeless tobacco is an etiologic agent for oral cancers. Other potential carcinogens include marijuana and occupational exposures such as nickel refining, exposure to textile fibers, and woodworking.
Some head and neck cancers have a viral etiology. Epstein-Barr virus (EBV) infection is frequently associated with nasopharyngeal cancer, especially in endemic areas of the Mediterranean and Far East. EBV antibody titers can be measured to screen high-risk populations. Nasopharyngeal cancer has also been associated with consumption of salted fish and in-door pollution.
In Western countries, the human papilloma virus (HPV) is associated with a rising incidence of tumors arising from the oropharynx, i.e., the tonsillar bed and base of tongue. Over 50% of oropharyngeal tumors are caused by HPV in the United States. HPV 16 is the dominant viral subtype, although HPV 18 and other oncogenic subtypes are seen as well. Alcohol- and tobacco-related cancers, on the other hand, have decreased in incidence. HPV-related oropharyngeal cancer occurs in a younger patient population and is associated with increased numbers of sexual partners and oral sexual practices. It is associated with a better prognosis, especially for nonsmokers.
Dietary factors may contribute. The incidence of head and neck cancer is higher in people with the lowest consumption of fruits and vegetables. Certain vitamins, including carotenoids, may be protective if included in a balanced diet. Supplements of retinoids, such as cis-retinoic acid, have not been shown to prevent head and neck cancers (or lung cancer) and may increase the risk in active smokers. No specific risk factors or environmental carcinogens have been identified for salivary gland tumors.
HISTOPATHOLOGY, CARCINOGENESIS, AND MOLECULAR BIOLOGY
Squamous cell head and neck cancers are divided into well-differentiated, moderately well-differentiated, and poorly differentiated categories. Poorly differentiated tumors have a worse prognosis than well-differentiated tumors. For nasopharyngeal cancers, the less common differentiated squamous cell carcinoma is distinguished from nonker-atinizing and undifferentiated carcinoma (lymphoepithelioma) that contains infiltrating lymphocytes and is commonly associated with EBV.
Salivary gland tumors can arise from the major (parotid, submandibular, sublingual) or minor salivary glands (located in the submucosa of the upper aerodigestive tract). Most parotid tumors are benign, but half of submandibular and sublingual gland tumors and most minor salivary gland tumors are malignant. Malignant tumors include mucoepidermoid and adenoid cystic carcinomas and adenocarcinomas.
The mucosal surface of the entire pharynx is exposed to alcohol- and tobacco-related carcinogens and is at risk for the development of a premalignant or malignant lesion. Erythroplakia (a red patch) or leukoplakia (a white patch) can be histopathologically classified as hyperplasia, dysplasia, carcinoma in situ, or carcinoma. However, most head and neck cancer patients do not present with a history of premalignant lesions. Multiple synchronous or metachronous cancers can also be observed. In fact, over time, patients with early-stage head and neck cancer are at greater risk of dying from a second malignancy than from a recurrence of the primary disease.
Second head and neck malignancies are usually not therapy-induced; they reflect the exposure of the upper aerodigestive mucosa to the same carcinogens that caused the first cancer. These second primaries develop in the head and neck area, the lung, or the esophagus. Thus, computed tomography (CT) screening for lung cancer in heavy smokers who have already developed a head and neck cancer should be considered. Rarely, patients can develop a radiation therapy–induced sarcoma after having undergone prior radiotherapy for a head and neck cancer.
Much progress has been made in describing the molecular features of head and neck cancer. These features have allowed investigators to describe the genetic and epigenetic alterations and the mutational spectrum of these tumors. Early reports demonstrated frequent overexpression of the epidermal growth factor receptor (EGFR). Overexpression was shown to correlate with poor prognosis. However, it has not proved to be a good predictor of tumor response to EGFR inhibitors, which are successful in only about 10–15% of patients. p53 mutations are also found frequently with other major affected oncogenic driver pathways including the mitotic signaling and Notch pathways and cell cycle regulation. The PI3K pathway is frequently altered, especially in HPV-positive tumors, where it is the only mutated cancer gene identified to date. Overall, these alterations affect mitogenic signaling, genetic stability, cellular proliferation, and differentiation. HPV is known to act through inhibition of the p53 and RB tumor-suppressor genes, thereby initiating the carcinogenic process, and has a mutational spectrum distinct from alcohol- and tobacco-related tumors.
CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS
Most tobacco-related head and neck cancers occur in patients older than age 60 years. HPV-related malignancies are frequently diagnosed in younger patients, usually in their forties or fifties, whereas EBV-related nasopharyngeal cancer can occur in all ages, including teenagers. The manifestations vary according to the stage and primary site of the tumor. Patients with nonspecific signs and symptoms in the head and neck area should be evaluated with a thorough otolaryngologic exam, particularly if symptoms persist longer than 2–4 weeks. Males are more frequently affected than women by head and neck cancers, including HPV-positive tumors.
Cancer of the nasopharynx typically does not cause early symptoms. However, it may cause unilateral serous otitis media due to obstruction of the eustachian tube, unilateral or bilateral nasal obstruction, or epistaxis. Advanced nasopharyngeal carcinoma causes neuropathies of the cranial nerves due to skull base involvement.
Carcinomas of the oral cavity present as nonhealing ulcers, changes in the fit of dentures, or painful lesions. Tumors of the tongue base or oropharynx can cause decreased tongue mobility and alterations in speech. Cancers of the oropharynx or hypopharynx rarely cause early symptoms, but they may cause sore throat and/or otalgia. HPV-related tumors frequently present with neck lymphadenopathy as the first sign.
Hoarseness may be an early symptom of laryngeal cancer, and persistent hoarseness requires referral to a specialist for indirect laryngoscopy and/or radiographic studies. If a head and neck lesion treated initially with antibiotics does not resolve in a short period, further workup is indicated; to simply continue the antibiotic treatment may be to lose the chance of early diagnosis of a malignancy.
Advanced head and neck cancers in any location can cause severe pain, otalgia, airway obstruction, cranial neuropathies, trismus, odynophagia, dysphagia, decreased tongue mobility, fistulas, skin involvement, and massive cervical lymphadenopathy, which may be unilateral or bilateral. Some patients have enlarged lymph nodes even though no primary lesion can be detected by endoscopy or biopsy; these patients are considered to have carcinoma of unknown primary (Fig. 106-1). If the enlarged nodes are located in the upper neck and the tumor cells are of squamous cell histology, the malignancy probably arose from a mucosal surface in the head or neck. Tumor cells in supraclavicular lymph nodes may also arise from a primary site in the chest or abdomen.
Evaluation of a patient with cervical adenopathy
without a primary mucosal lesion; a diagnostic workup. FNA, fine-needle aspiration.
The physical examination should include inspection of all visible mucosal surfaces and palpation of the floor of the mouth and of the tongue and neck. In addition to tumors themselves, leukoplakia (a white mucosal patch) or erythroplakia (a red mucosal patch) may be observed; these “premalignant” lesions can represent hyperplasia, dysplasia, or carcinoma in situ and require biopsy. Further examination should be performed by a specialist. Additional staging procedures include CT of the head and neck to identify the extent of the disease. Patients with lymph node involvement should have CT scan of the chest and upper abdomen to screen for distant metastases. In heavy smokers, the CT scan of the chest can also serve as a screening tool to rule out a second lung primary tumor. A positron emission tomography (PET) scan may also be administered and can help to identify or exclude distant metastases. The definitive staging procedure is an endoscopic examination under anesthesia, which may include laryngoscopy, esophagoscopy, and bronchoscopy; during this procedure, multiple biopsy samples are obtained to establish a primary diagnosis, define the extent of primary disease, and identify any additional premalignant lesions or second primaries.
Head and neck tumors are classified according to the tumor-node-metastasis (TNM) system of the American Joint Committee on Cancer (Fig. 106-2). This classification varies according to the specific anatomic subsite. In general, primary tumors are classified as T1 to T3 by increasing size, whereas T4 usually represents invasion of another structure such as bone, muscle, or root of tongue. Lymph nodes are staged by size, number, and location (ipsilateral vs contralateral to the primary). Distant metastases are found in <10% of patients at initial diagnosis and are more common in patients with advanced lymph node stage; microscopic involvement of the lungs, bones, or liver is more common, particularly in patients with advanced neck lymph node disease. Modern imaging techniques may increase the number of patients with clinically detectable distant metastases in the future.
Tumor-node-metastasis (TNM) staging system.
In patients with lymph node involvement and no visible primary, the diagnosis should be made by lymph node excision (Fig. 106-1). If the results indicate squamous cell carcinoma, a panendoscopy should be performed, with biopsy of all suspicious-appearing areas and directed biopsies of common primary sites, such as the nasopharynx, tonsil, tongue base, and pyriform sinus. HPV-positive tumors especially can have small primary tumors that spread early to locoregional lymph nodes.
TREATMENT Head and Neck Cancer
Patients with head and neck cancer can be grossly categorized into three clinical groups: those with localized disease, those with locally or regionally advanced disease (lymph node positive), and those with recurrent and/or metastatic disease. Comorbidities associated with tobacco and alcohol abuse can affect treatment outcome and define long-term risks for patients who are cured of their disease. LOCALIZED DISEASE
Nearly one-third of patients have localized disease, that is, T1 or T2 (stage I or stage II) lesions without detectable lymph node involvement or distant metastases. These patients are treated with curative intent by either surgery or radiation therapy. The choice of modality differs according to anatomic location and institutional expertise. Radiation therapy is often preferred for laryngeal cancer to preserve voice function, and surgery is preferred for small lesions in the oral cavity to avoid the long-term complications of radiation, such as xerostomia and dental decay. Overall 5-year survival is 60–90%. Most recurrences occur within the first 2 years following diagnosis and are usually local. LOCALLY OR REGIONALLY ADVANCED DISEASE
Locally or regionally advanced disease—disease with a large primary tumor and/or lymph node metastases—is the stage of presentation for >50% of patients. Such patients can also be treated with curative intent, but not with surgery or radiation therapy alone. Combined-modality therapy including surgery, radiation therapy, and chemotherapy is most successful. It can be administered as induction chemotherapy (chemotherapy before surgery and/or radiotherapy) or as concomitant (simultaneous) chemotherapy and radiation therapy. The latter is currently most commonly used and supported by the best evidence. Five-year survival rates exceed 50% in many trials, but part of this increased survival may be due to an increasing fraction of study populations with HPV-related tumors who carry a better prognosis. HPV testing of newly diagnosed tumors is now performed for most patients at the time of diagnosis, and clinical trials for HPV-related tumors are focused on exploring reductions in treatment intensity, especially radiation dose, in order to ameliorate long-term toxicities (fibrosis, swallowing dysfunction).
In patients with intermediate-stage tumors (stage III and early stage IV), concomitant chemoradiotherapy can be administered either as a primary treatment for patients with unresectable disease, to pursue an organ-preserving approach, or in the postoperative setting for intermediate-stage resectable tumors. Induction Chemotherapy
In this strategy, patients receive chemotherapy (current standard is a three-drug regimen of docetaxel, cisplatin, and fluorouracil [5-FU]) before surgery and radiation therapy. Most patients who receive three cycles show tumor reduction, and the response is clinically “complete” in up to half of patients. This “sequential” multimodality therapy allows for organ preservation (omission of surgery) in patients with laryngeal and hypopharyngeal cancer, and it has been shown to result in higher cure rates compared with radiotherapy alone. Concomitant Chemoradiotherapy
With the concomitant strategy, chemotherapy and radiation therapy are given simultaneously rather than in sequence. Tumor recurrences from head and neck cancer develop most commonly locoregionally (in the head and neck area of the primary and draining lymph nodes). The concomitant approach is aimed at enhancing tumor cell killing by radiation therapy in the presence of chemotherapy (radiation enhancement) and is a conceptually attractive approach for bulky tumors. Toxicity (especially mucositis, grade 3 or 4 in 70–80%) is increased with concomitant chemoradiotherapy. However, meta-analyses of randomized trials document an improvement in 5-year survival of 8% with concomitant chemotherapy and radiation therapy. Results seem more favorable in recent trials as more active drugs or more intensive radiotherapy schedules are used. In addition, concomitant chemoradiotherapy produces better laryngectomy-free survival (organ preservation) than radiation therapy alone in patients with advanced larynx cancer. The use of radiation therapy together with cisplatin has also produced improved survival in patients with advanced nasopharyngeal cancer. The outcome of HPV-related cancers seems to be especially favorable following cisplatin-based chemoradiotherapy.
The success of concomitant chemoradiotherapy in patients with unresectable disease has led to the testing of a similar approach in patients with resected intermediate-stage disease as a postoperative therapy. Concomitant chemoradiotherapy produces a significant improvement over postoperative radiation therapy alone for patients whose tumors demonstrate higher risk features, such as extracapsular spread beyond involved lymph nodes, involvement of multiple lymph nodes, or positive margins at the primary site following surgery.
A monoclonal antibody to EGFR (cetuximab) increases survival rates when administered during radiotherapy. EGFR blockade results in radiation sensitization and has milder systemic side effects than traditional chemotherapy agents, although an acneiform skin rash is commonly observed. Nevertheless, the integration of cetuximab into current standard chemoradiotherapy regimens has failed to show additional improvement in survival and is not recommended. RECURRENT AND/OR METASTATIC DISEASE
Five to ten percent of patients present with metastatic disease, and 30–50% of patients with locoregionally advanced disease experience recurrence, frequently outside the head and neck region. Patients with recurrent and/or metastatic disease are, with few exceptions, treated with palliative intent. Some patients may require local or regional radiation therapy for pain control, but most are given chemotherapy. Response rates to chemotherapy average only 30–50%; the durations of response are short, and the median survival time is 8–10 months. Therefore, chemotherapy provides transient symptomatic benefit. Drugs with single-agent activity in this setting include methotrexate, 5-FU, cisplatin, paclitaxel, and docetaxel. Combinations of cisplatin with 5-FU, carboplatin with 5-FU, and cisplatin or carboplatin with paclitaxel or docetaxel are frequently used.
EGFR-directed therapies, including monoclonal antibodies (e.g., cetuximab) and tyrosine kinase inhibitors (TKIs) of the EGFR signaling pathway (e.g., erlotinib or gefitinib), have single-agent activity of approximately 10%. Side effects are usually limited to an acneiform rash and diarrhea (for the TKIs). The addition of cetuximab to standard combination chemotherapy with cisplatin or carboplatin and 5-FU was shown to result in a significant increase in median survival. Drugs targeting specific mutations are under investigation, but no such strategy has yet been shown to be feasible in head and neck cancer. COMPLICATIONS
Complications from treatment of head and neck cancer are usually correlated to the extent of surgery and exposure of normal tissue structures to radiation. Currently, the extent of surgery has been limited or completely replaced by chemotherapy and radiation therapy as the primary approach. Acute complications of radiation include mucositis and dysphagia. Long-term complications include xerostomia, loss of taste, decreased tongue mobility, second malignancies, dysphagia, and neck fibrosis. The complications of chemotherapy vary with the regimen used but usually include myelosuppression, mucositis, nausea and vomiting, and nephrotoxicity (with cisplatin).
The mucosal side effects of therapy can lead to malnutrition and dehydration. Many centers address issues of dentition before starting treatment, and some place feeding tubes to ensure control of hydration and nutrition intake. About 50% of patients develop hypothyroidism from the treatment; thus, thyroid function should be monitored.
Most benign salivary gland tumors are treated with surgical excision, and patients with invasive salivary gland tumors are treated with surgery and radiation therapy. These tumors may recur regionally; adenoid cystic carcinoma has a tendency to recur along the nerve tracks. Distant metastases may occur as late as 10–20 years after the initial diagnosis. For metastatic disease, therapy is given with palliative intent, usually chemotherapy with doxorubicin and/or cisplatin. Identification of novel agents with activity in these tumors is a high priority.