GENERAL PRINCIPLES
Squamous cell carcinoma of the head and neck (SCCHN) represents 5% of newly diagnosed cancers in adult patients in the United States. There are more than 500,000 new cases that are diagnosed annually worldwide.1 While there are many similarities between head and neck cancers arising from different sites, there are particular differences in anatomy, natural history, and functional consequence that present unique treatment challenges for each site.
Classification
Malignancies of the head and neck are classified by their anatomic location, which is divided into (a) lip and oral cavity, (b) oropharynx, (c) larynx and hypopharynx, (d) nasopharynx, (e) nasal cavity and sinuses, and (f) salivary glands. With the exception of salivary gland tumors, squamous cell carcinoma accounts for >90% of head and neck tumors. As nasopharyngeal cancer and neck masses with unknown primary have different epidemiology and/or management, they are discussed separately.
SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
GENERAL PRINCIPLES
Epidemiology
Head and neck cancers have a significant male predominance, with a male-to-female ratio of 3:1. These tumors are estimated to account for ~45,000 new cases per year, with an estimated 11,000 deaths per year. Incidence and mortality are higher in African-Americans.
Pathophysiology
SCCHN is an example of the multistep process of carcinogenesis with accumulated genetic mutations that result in changes ranging from hyperplasia to dysplasia to carcinoma in situ to invasive cancer. Statistical analysis based on the age-specific incidence of head and neck cancer suggests that HNSCC tumors arise after the accumulation of 6 to 10 independent genetic events. These studies demonstrated consistent chromosomal abnormalities and the presence of important alterations. Loss of chromosomes 3p, 5q, 8p, 9p, 18q, and 21q were commonly identified, and data also suggest that loss of 18q may indicate the presence of a tumor with a poor prognosis.2 Moderateincreases in epidermal growth factor receptor (EGFR) copy number are observed in SCCHN, and EGFR signaling is a key pathway in HNSCC tumorigenesis.3 In some tumors, an alternately translated EGFR variant (EGFRvIII) contributes to head and neck growth and resistance to EGFR targeting.
Risk Factors
The main risk factors for development of these malignancies are tobacco in any form and alcohol use. Tobacco and alcohol are sources of carcinogens that increase the risk of cancer in a dose-dependent fashion and are synergistic in their effects. Field cancerization is a key concept in the natural history of head and neck cancer. Exposure of the mucosa to carcinogens in tobacco is diffuse across the aerodigestive tract. Consequently, tumors may be surrounded by areas of dysplasia or carcinoma in situ. Patients diagnosed with a head and neck cancer are at an increased risk of developing new primary tumors in the head and neck, lung, and esophagus. The risk is estimated to be 3% to 4% per year. Sun exposure has been associated with an increased risk of carcinoma of the lip.
Approximately 20% of head and neck cancers, however, occur in people without these established risk factors. A subset of these cancers includes human papilloma virus (HPV)-associated tumors of the oropharynx.4 Risk factors for HPV-associated tumors of the oropharynx include an increasing number of sexual partners, the practice of oral sex, a history of genital warts, and a younger age at first sexual intercourse. As in cervical cancer, HPV-16 and HPV-18 are thought to play an important role. These HPV-positive oropharyngeal cancers were less likely to occur among heavy smokers and drinkers, less likely to harbor a p53 mutation, and had an improved disease-specific survival. Another group suggested that HPV-positive tumors may also inactivate Rb and harbor a better prognosis.
DIAGNOSIS
Clinical Presentation
The clinical presentation of these malignancies varies depending on the anatomic location of the tumor. Cancers of the lip and oral cavity often present with nonhealing lesions in the mouth, pain in the mouth or ear, trismus, weight loss, and “hot potato speech.” Leukoplakia and erythroplakia are pre-malignant lesions of the mucosa and are frequently seen in conjunction with dysplastic changes or invasive carcinoma.
Cancers of the nasal cavity can present with epistaxis, nonhealing ulcers, or obstruction.
Cancers of the oropharynx present with many of the features associated with cancers of the lip and oral cavity. Bleeding from the mouth, alterations in speech, dysphagia, odynophagia, otalgia, and weight loss can be symptoms of oropharyngeal cancers.
Cancers of the larynx and hypopharynx can present challenges in management, as these anatomic structures are intricately associated with the key functions of speech and swallowing. Symptoms include dysphagia, odynophagia, weight loss, dyspnea (including dyspnea with speech), and hoarseness. Symptoms of aspiration should also be elucidated in the history. However, the time of presentation of these cancers varies greatly with their primary site. Supraglottic tumors or tumors in the pyriform sinus may be diagnosed only after cervical metastases occur because symptoms of dysphagia may not become significant until the tumors are quite advanced. On the other hand, glottic carcinomas are associated with symptoms of hoarseness even when they are small, which may lead to earlier detection.
Diagnostic Testing
The initial workup of suspected head and neck cancers includes a detailed history and physical examination. Assessment should include a cranial nerve exam, assessment of status of dentition, and examination of tongue movement and atrophy. Lymph nodes in the neck should be palpated, and measurements taken of palpable nodes. Suspicious lesions should be biopsied for histologic confirmation and grading.
Imaging studies should include a chest radiograph, Panorex x-ray for mandibular bony involvement for cancers that abut the mandible, and computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck to help further delineate disease extent at presentation. Panendoscopy, including esophagoscopy with direct laryngoscopy, helps characterize the primary lesion and evaluates for possible second tumors, as there is a 10% to 15% incidence of synchronous primary tumors. A CT scan of the chest should also be performed to rule out pulmonary metastases. Positron emission tomography (PET) or CT may also be helpful in the staging of head and neck cancers and are used at some centers. The staging for head and neck cancer is according to the American Joint Committee on Cancer TNM system, with different staging for SCCHN (Tables 23-1 through 23-6).
TREATMENT
Management of patients requires a multidisciplinary approach, including head and neck surgeons and radiation and medical oncologists, along with allied health professionals including speech language pathologists and nutritionists. Radiation and surgery are the mainstays of treatment with head and neck cancers. Chemotherapy is reserved for patients with regionally advanced disease or metastatic disease.
Patientswith stage I and stage II SCCHN as a group have survival rate of 70% to 80% with standard therapy, which includes either surgery or radiotherapy alone. Surgery is generally the preferred approach in operable patients, because it is typically associated with less morbidity than RT. Definitive RT is reserved for patients who cannot tolerate surgery or for whom surgical resection would result in particularly significant functional loss. Chemotherapy is unproven as first-line curative treatment for early SCCHN and should not be used outside the setting of a clinical trial. Although outcomes with primary surgery and definitive RT are comparable, neither surgery nor RT has been compared in a randomized trial. Thus, outcomes are based upon retrospective reviews or uncontrolled case series.
Unfortunately, patients often present with advanced locoregional disease and carry poor prognosis with survival rate of 50% to 60% at 2 years with standard therapy.5 Failure to control the tumor occurs via two biologically distinct pathways: local recurrence and/or metastatic spread. This makes the treatment of locoregionally advanced SCCHN complex as it continues to evolve. Patients with tumors amenable to surgical resection undergo surgery followed by adjuvant therapy with postoperative radiation or concurrent chemoradiation. For patients with locally advanced, unresectable disease, the standard of care is definitive concurrent chemoradiation for patients who can tolerate such therapy because an 8% survival advantage for concurrent chemoradiation compared to radiation alone, particularly with the use of platinum chemotherapy, was shown by meta-analyses of more than 10,000 patients from 63 randomized trials. Usually this entails the use of cisplatin, 100 mg/m2, on days 1, 22, and 43 of a 7-week course of 70 Gy of radiation. More recently, an epidermal growth factor receptor (EGFR) inhibitor, cetuximab (Erbitux), has demonstrated benefits when used concurrently with radiation. In patients who do not achieve a complete tumor response after definitive chemoradiation, surgical resection of residual tumor may improve survival.
In patientswith distant metastases, several standard chemotherapeutic agents have significant activity against SCCHN and can provide palliation of symptoms. These include cisplatin, carboplatin, 5-fluorouracil (5-FU), paclitaxel, docetaxel, pemetrexed, methotrexate, ifosfamide, and gemcitabine. The most commonly used first-line therapy is a platinum compound combined with a second agent, usually a taxane or 5-FU. First-line therapy typically has a tumor response rate of ~20% to 30%. Targeted therapy also has a significant role in the management of SCCHN. Cetuximab has recently been found to extend survival in recurrent and/or metastatic SCCHN when added to chemotherapy. Cetuximab is also a reasonable option for platinum-resistant disease.
COMPLICATIONS
A multidisciplinary approach is essential to minimize the complications of the malignancy and treatment. Complications of disease include weight loss, aspiration, and airway compromise. Nutritional support in the form of oral supplements or enteral feedings may be needed when caloric intake is inadequate. Tracheostomy may be needed in cases of airway compromise. Head and neck tumors may also invade into key structures, such as the carotid artery, leading to major bleeding, which may be a terminal event. Invasion into neural structures may lead to neuropathic pain syndromes. Amitriptyline or gabapentin may be helpful in such cases. The limitation to swallowing imposed by some head and neck cancers can make pain management difficult. In such cases, transdermal fentanyl patches or methadone elixir can be used in conjunction with concentrated opiate elixirs (breakthrough) for pain relief.
Complications of treatment include complications of surgery, acute radiation toxicity, late radiation effects, and complications of chemotherapy. Acute radiation toxicity may include severe mucositis, with resulting pain and difficulties with swallowing. Concurrent chemoradiation increases the risk of severe mucositis beyond radiation alone. Oral candidiasis complicating mucositis may be treated with topical or systemic antifungal agents. Many patients find a cocktail of equal volume of diphenhydramine suspension, nystatin, viscous lidocaine, and aluminum hydroxide/magnesium hydroxide (“magic mouthwash”) as a topical oral swish-and-swallow solution to be helpful. Opiates can also help in pain management, especially in severe cases. Skin toxicity should be treated with emollients. Late radiation effects include xerostomia, dental caries, osteoradionecrosis, and fibrosis of neck tissues resulting in trismus, lymphedema, and loss of range of motion. Xerostomia can be treated with cholinergic stimulants such as pilocarpine to improve salivary flow. Other measures, including topical lubricants, lozenges, coating agents, and artificial saliva, may provide some transient relief. The risk of dental caries should be minimized with good dental care. Osteoradionecrosis may be treated conservatively with antibiotics, hyperbaric oxygen therapy, or surgical debridement. Exercises may help in prevention of trismus associated with radiation therapy. With neck irradiation, hypothyroidism may occur, which can be treated with thyroid replacement therapy.
The complications of chemotherapy are dependent on the agents used. Platinum compounds, a mainstay of chemotherapy in head and neck cancer, are known to cause significant nausea, nephrotoxicity, ototoxicity, myelosuppression, and peripheral neuropathy. 5-FU, another commonly used agent, is associated with mucositis and myelosuppression. Cetuximab, a newer agent, is associated with rash, diarrhea, hypomagnesemia, paronychial inflammation, andhypersensitivityinfusionreactions.
MONITORING/FOLLOW-UP
Patients should have close follow-up for evaluation of local recurrence and distant metastases, as well as physical therapy and speech pathology follow-up if needed. In addition, patients should be advised on tobacco and alcohol cessation.
PROGNOSIS
Patients with recurrent or metastatic squamous cell carcinomas of the head and neck have a median survival of 6 to 9 months, and a 1-year survival rate of 20% to 40% when treated with chemotherapy alone.6 Common sites of distant metastases include the bone, lung, and liver.
NASOPHARYNGEAL CARCINOMA
GENERAL PRINCIPLES
Epidemiology
Nasopharyngeal carcinoma has a different epidemiology and a separate set of risk factors from the other head and neck cancers. Although rare in the United States, it is endemic in the Far and Middle East and in Africa, especially in Southern China and Southeast Asia. It accounts for 18% of newly diagnosed malignancies in Southeast China.
Risk Factors
In Southeast Asia, nasopharyngeal cancer is associated with Epstein–Barr virus infection in genetically predisposed individuals. Other risk factors have been implicated, including diet (consumption of salted fish and low intake of fresh fruits and vegetables) and smoking.
DIAGNOSIS
Clinical Presentation
Nasopharyngeal cancer can present with a painless neck mass, but other symptoms include nasal obstruction, epistaxis, dysphagia, odynophagia, and Eustachian tube obstruction with otitis media. Tumors may extend through the foramen ovale to access the middle cranial fossa and the cavernous sinus to involve the oculomotor, trochlear, trigeminal, and abducens nerves leading to cranial neuropathy. In advanced cases, the optic nerve and orbital invasion can occur. Headaches, weight loss, trismus, and referred pain to the ear and neck can also be symptoms. Physical examination should include a thorough examination of the nares and oral cavity and the cranial nerves. Proptosis suggests orbital invasion by the tumor.
Diagnostic Testing
Workup of patients with nasopharyngeal cancer should include a thorough physical evaluation and diagnostic imaging with CT or MRI from the skull down to the clavicles. Endoscopy should also be performed. A chest x-rayor CT scan should be done to assess for pulmonary metastases. The staging for nasopharynx is according to the American Joint Committee on Cancer TNM system (Tables 23-7 and 23-8).
TREATMENT
Nasopharyngeal carcinoma is very sensitive to chemoradiation. Early-stage disease (stages I and II) is typically treated with radiation therapy alone. For local recurrences, surgical resection or repeat irradiation are options for treatment. For advanced disease (stages III and IV), concurrent chemoradiation followed by adjuvant cisplatin and 5-FU has demonstrated benefit in terms of overall survival, progression-free survival, and control of local disease and distant metastases.7Metastatic disease is managed with chemotherapeutic agents such as cisplatin, carboplatin, and 5-FU.
SALIVARY GLAND TUMORS
GENERAL PRINCIPLES
Salivary gland tumors may arise either in the major glands, namely, the parotid, submandibular, and sublingual glands, or in the minor glands located in the oral mucosa, palate, uvula, floor of the mouth, posterior tongue, retromolar area and peritonsillar area, pharynx, larynx, and paranasal sinuses. Salivary gland tumors account for ~5% of all head and neck cancers and are varied in their histologic patterns as low- or high-grade malignancies. Approximately 80% arise from the parotid gland, but of those, 80% are benign. In contrast, 95% to 100% of tumors arising from the sublingual gland are malignant.
TREATMENT
Treatment usually involves surgical resection of the gland. Prognosis is more favorable for low-grade tumors and those located in major glands, especially in the parotid. For aggressive or bulky tumors, resection is often combined with postoperative radiation.
NECK MASS WITH AN UNKNOWN PRIMARY
DIAGNOSIS
Differential Diagnosis
The differential diagnosis for a malignant neck mass includes squamous cell carcinoma, adenocarcinoma, lymphoma, thyroid neoplasms, and melanoma.
Diagnostic Testing
As cancers that originate elsewhere in the body can also present with a neck mass, a thorough history and physical should be performed, along with evaluation for potential primary sites. A fine-needle biopsy for cytology may be pursued as the initial step for evaluation of a neck mass without a clear primary. Open biopsy may be helpful if the suspicion for lymphoma is high. If the cytology shows squamous cell carcinoma, then endoscopy with blind biopsy of potential sites in the nasopharynx, tonsils, base of tongue, and pyriform sinus should be performed.
TREATMENT
If no primary site is found and the tumor is amenable to resection, surgical resection may be the primary therapy. If the surgical pathology shows extracapsular extension or involvement of multiple nodes, postoperative radiation may be given. If the tumor is not amenable to surgical resection, radiation therapy is the primary treatment modality.
REFERENCES
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2. Van Dyke DL, Worsham MJ, Benninger MS, et al. Recurrent cytogenetic abnormalities in squamous cell carcinomas of the head and neck region. Genes Chromosomes Cancer. 1994;9(3):192–206.
3. Chung CH, Ely K, McGavran L, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. Clin Oncol. 2006;24(25):4170–4176.
4. D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944–1956.
5. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091–2098.
6. Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2006;24:2644–2652.
7. Al-Sarraf M, LeBlanc M, Shanker Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Oncol. 1998;16:1310–1317.