Published: August 2010
This chapter reviews squamous cell carcinomas of the head and neck. These are the malignancies arising from the mucosal lining of the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx. Although there are also a diverse group of tumors that arise from other structures of the head and neck, including the salivary glands, sinuses, thyroid and skin, these primary cancers do not share a similar natural history and should be considered separately.
In 2008 in the United States head and neck cancer was diagnosed in an estimated 35,000 persons, accounting for 3% of all new malignancies. Worldwide, approximately 500,000 new cases are diagnosed annually. Males are at higher risk for developing this disease. In the United States, there are significant racial and socioeconomic disparities in disease incidence. In particular, African Americans have a higher incidence, more-advanced disease at presentation, and greater mortality when compared to whites. Tobacco and alcohol are the most strongly implicated etiologic agents. Occupational exposures to inhaled organic dusts, gases, and asbestos in the construction and mining industries are additional risk factors.
Primary cancers of the nasopharynx are distinct among head and neck cancers in etiology and in racial and geographic distribution. This cancer is endemic to southern China, Southeast Asia and northern Africa, and its association with tobacco and alcohol is weak. Its pathogenesis is thought to involve exposure to unrelated carcinogens, such as nitrosamines from consumption of salted fish in endemic areas. However, there is increasing evidence supporting the oncogenic role of viruses infecting the upper aerodigestive tract. A very strong association between Epstein-Barr virus (EBV) infection and endemic nasopharyngeal cancer has been established. Malignant cells harbor clonal EBV DNA, and antibody titers to EBV are directly related to tumor bulk, stage at presentation, and risk of recurrence.
Since the 1980s, an overall decline in diagnoses of new head and neck cancers has been observed and attributed to public health efforts against tobacco use. The exception to this is oropharyngeal squamous cell carcinoma, which has risen in incidence in the same time frame and has appeared in a younger, nonsmoking population. High-risk human papillomavirus (HPV) subtypes have been identified in a significant fraction of these tumors, including HPV 16, 18, 31, and 33. Greater numbers of sexual partners, early age of first sexual intercourse, and high-risk sexual behavior are emerging as risk factors for HPV-related disease independent of tobacco and alcohol abuse.
Malignant transformation of the involved epithelium is a culmination of constant exposure to carcinogens and an accumulation of genetic alterations. Molecular aberrations have been identified in premalignant lesions of the oral mucosa, which increase in number as lesions progress toward malignancy. Loss of heterozygosity at 9p21 is thought to be an early event, identified in hyperplastic lesions. Mutations in the tumor-suppressor genes p53 and Rb are common in tobacco-related premalignant and malignant lesions. Most HPV-related oropharyngeal head and neck cancers carry wild-type Rb and p53. Evidence now supports the role of the viral oncoproteins E6 and E7 in the development of malignancy through inactivation of p53 and Rb gene products.
Head and neck squamous cell carcinomas are classified as well, moderately well, or poorly differentiated according to the degree by which their histologic appearance deviates from the normal squamous epithelium. Poorly differentiated carcinomas have little evidence of keratinization, have a more-aggressive clinical behavior, and carry a poorer prognosis. The World Health Organization (WHO) classifies nasopharyngeal carcinomas using a similar principle. Undifferentiated tumors (WHO III) are almost always of the endemic variety and EBV DNA positive. This type is often characterized by a dense lymphocytic infiltrate, hence the term lymphoepithelioma previously used to refer to this subtype. The differentiated tumors are divided into keratinizing (WHO I) and nonkeratinizing (WHO II) types. These are less commonly EBV positive and are more prevalent in nonendemic regions.
Head and neck cancer spreads from the primary sites to the draining lymph nodes followed, only late in its natural history, by hematogenous dissemination. Among the different subsites, nasopharyngeal cancer has a more aggressive clinical course and carries the highest risk of systemic involvement at presentation. TNM (tumor, node, metastasis) staging using the 2002 AJCC system correlates with survival outcomes. Approximately 30% of patients present with stage I or II disease, considered early-stage resectable disease. These patients have small primary site lesions and no lymph node disease (T1-2, N0). Another 60% have stage III to IVB cancers, characterized by advanced primary site tumors (T3-4), early or by advanced nodal spread (N1-3) but no with distant hematogenous metastases. Although these cancers are locoregionally advanced, and sometimes unresectable, they are still curable in a significant percentage of patients. Metastatic disease (stage IVC) at presentation is uncommon and incurable. Less than 10% of patients have disseminated disease when it is newly diagnosed.
The association of head and neck cancers with tobacco and alcohol has several implications and has led to the concept of field cancerization, wherein the entire exposed aerodigestive tract epithelium is at risk for developing malignancy. Synchronous and metachronous primary cancers of the head and neck and of the lung and esophagus are common. Patients with a prior history of head and neck cancer have a 5% to 7% annual risk of developing a second primary cancer. In addition, tobacco-related cardiac, pulmonary, and vascular comorbidities are significant issues influencing management and mortality.
The presenting symptoms of head and neck cancer can relate to local effects of the primary tumor, regional spread, metastatic disease, or paraneoplastic phenomena.
Symptoms resulting from local disease vary according to the primary tumor site. Oral cavity, oropharynx, or hypopharynx tumors can result in painful oral mucosal tumors or ulcerations, dysphagia, or odynophagia. Cancers arising from the larynx often cause hoarseness or voice changes. Nasopharyngeal cancer usually arises in the fossae of Rosenmüller, adjacent to the eustachian tube orifices and the base of the skull. Epistaxis, recurrent middle ear effusions, or cranial nerve palsies are common presenting symptoms.
A painless enlarged cervical lymph node may be the only presenting symptom. HPV-related oropharyngeal lesions have been associated with cystic lymph node involvement. The location of lymph node involvement may be helpful in identifying the primary site. Nasopharyngeal primaries are the most common subtype to involve the posterior cervical lymph node chain. The palatine tonsils, nasopharynx, and supraglottis are embedded in a rich lymphatic plexus that drains to both sides of the neck, and these cancers often involve the anterior upper cervical lymph nodes (levels II and III). Oral cavity lesions often spread to the submental and submandibular nodes.
Metastatic head and neck cancer most often involves the lung. Bone and liver involvement is much less common. The squamous cell histology of this disease is also associated with certain paraneoplastic phenomena. These can become evident in advanced disease stages, most commonly hypercalcemia resulting from elaboration of a parathyroid hormone–like peptide. Nasopharyngeal cancer has been associated with leukemoid reactions and paraneoplastic motor neuropathies.
The diagnosis is often arrived at by a biopsy from the primary site. Evaluation must include a thorough examination of the upper aerodigestive tract, usually under anesthesia, to identify synchronous primary lesions, carefully delineate the extent of the primary tumor, and palpate for cervical lymph nodes. The positron emission tomography (PET) scan, when combined with computed tomography (CT) imaging, may be useful in detecting occult lymph node involvement and metastatic disease.
In the situation where a cervical lymph node is positive without an apparent primary site, a meticulous examination under anesthesia might reveal the primary tumor. If a primary site is not evident by visual inspection or palpation, random biopsies of the nasopharynx, base of tongue, hypopharynx, and an ipsilateral tonsillectomy are often performed. These areas are the most common occult primary sites.
The treatment of head and neck cancer requires a multispecialty approach coordinated among surgeons, radiation oncologists, and medical oncologists. Surgery and radiation are the only definitive treatment modalities for both early and locally advanced disease. Adequate oncologic surgical resection, wherein the tumor is completely removed with uninvolved resection margins, is often challenging in the head and neck and can involve sacrificing critical structures including the larynx, eye, or mandible. Radiation, when used as definitive therapy, circumvents this difficulty, but it results in significant acute and late toxicity. Chemotherapy alone is not a curative therapeutic modality, but it has been shown to improve outcomes when used in conjunction with radiation for locally advanced disease.
Single-modality surgery or radiation are options for curative-intent treatment in early stage head and neck cancers. Cure rates using either intervention for stage I disease often exceed 90%, but this decreases to approximately 70% for stage II disease. The choice between surgery or radiation is influenced by the location of the primary site, side-effect profile, comorbidity, and institutional experience. Oral cavity lesions of the mobile tongue or floor of mouth, for example, are amenable to surgical resection and reconstruction with acceptable cosmetic and functional results. Radiation therapy, on the other hand, produces a long-term risk of xerostomia and mandibular osteonecrosis. More-limited surgical techniques have been developed and have produced excellent oncologic and functional outcomes in appropriately selected patients with limited primary tumors. The partial laryngectomy and the endoscopic laser resections for T1 or T2 glottic tumors are good examples.
The decision to treat clinically uninvolved cervical lymph nodes with either surgery or radiation is controversial. The rates of occult lymph node metastases in node-negative T1 and T2 tumors varies according to the location of the primary tumor and ranges between 6% and 46%. The estimated risk of occult neck node involvement is used to guide this decision. Early glottic primary tumors have a low rate of occult lymph node involvement due to the paucity of lymphatics in the vocal cords, making it a subsite ideal for local treatment alone. In contrast, at least 20% of clinically N0 supraglottic cancers and a majority of nasopharyngeal primaries have occult lymph node metastases. Treatment of the neck is considered standard for these subsites. Promising reports have emerged about the role of sentinel cervical lymph node biopsy, a procedure under continued investigation.
For patients with locoregionally advanced stage III to IV lesions, the historical results with surgery and postoperative radiation have been suboptimal, with reported cure rates ranging from 10% to 50% and with locoregional failure predominating. Early chemotherapy experience using drugs such as methotrexate, 5-fluorouracil, and the platins (cisplatin and carboplatin) suggested significant antitumor efficacy. Response rates as high as 90%, with complete responses in up to 30% of patients, were reported in patients with previously untreated tumors, suggesting that chemotherapy might have a role in the definitive management of this disease. The landmark Veterans Administration Laryngeal Cancer Study Group (VALCSG) trial, reported in 1991, randomized patients with locally advanced larynx cancer to standard treatment with a laryngectomy followed by radiation or to induction chemotherapy using cisplatin and 5-fluorouracil followed by radiation in chemotherapy responders. Survival proved equivalent in both arms, and 64% of patients randomized to induction chemotherapy arm did not require laryngectomy.
The second-generation larynx preservation trial, Radiation Therapy Oncology Group (RTOG) 91-11, sought to determine whether chemotherapy worked in conjunction with radiation to effect organ preservation or if it merely selected patients with better-prognosis disease for nonoperative management. Patients with locally advanced laryngeal cancer were randomized to radiation alone, induction chemotherapy followed by radiation (as in the VALCSG trial), and chemotherapy with single-agent cisplatin given concurrently with radiation. Overall survival was similar in all three groups, and distant metastases were significantly reduced in patients receiving chemotherapy. Organ preservation and locoregional control rates were superior in the concurrent chemotherapy and radiation arm. Disease-free survival and laryngectomy-free survival were improved in the induction and concurrent chemotherapy arms when compared to radiation alone, and no differences in these outcomes were noted between the two chemotherapy-containing arms.
Similar results emerged from a cooperative group study of 295 patients with unresectable stage III and IV head and neck cancer randomized among three arms: radiation alone, radiation with concurrent cisplatin, and split-course radiation concurrent with cisplatin and 5-fluorouracil. Overall and disease-free survival were improved in the radiation and concurrent cisplatin arm, establishing this treatment regimen as the standard of care for locally advanced unresectable head and neck cancer.
The success of concurrent chemotherapy and radiation has also been demonstrated in nasopharyngeal cancer, a disease subsite rarely amenable to surgical resection. The Intergroup 00-99 study randomized 147 patients with locally advanced nasopharyngeal cancer (both endemic and nonendemic), to radiation alone, or to radiation concurrent with cisplatin chemotherapy followed by three cycles of adjuvant chemotherapy with cisplatin and 5-fluroruracil. A significant overall survival advantage was noted in the experimental arm, leading to the study’s early termination and the adoption of this regimen as the treatment standard for locally advanced nasopharyngeal carcinoma in the United States. The benefit of adding adjuvant chemotherapy has been questioned by many in the Asian oncology community, who have demonstrated similar survival outcomes in patients with endemic nasopharyngeal cancer treated with concurrent chemoradiotherapy alone without additional chemotherapy.
Although concurrent chemoradiotherapy approaches significantly improved survival endpoints, the toxicity resulting from this treatment is quite significant. In the RTOG 91-11 trial, Grade 3 and 4 toxicity was experienced by 77% of the patients on the concurrent treatment arm, compared to 47% of those treated with radiation alone. Twenty-three percent of the concurrently treated patients continued to experience difficulty in swallowing 1 year after treatment was completed. Given the significant comorbidity found in the population affected by this disease, concurrent chemotherapy and radiation might not be feasible for all, underscoring the need to tailor treatment options to the individual patient.
Head and neck cancers often overexpress the epidermal growth factor receptor (EGFr). Cetuximab is a monoclonal antibody that competitively inhibits ligand binding to the EGFr receptor. In a randomized trial of 424 stage III and IV head and neck cancer patients comparing radiation alone to radiation with concurrent cetuximab, a significant difference in overall survival and locoregional control favoring the cetuximab and radiation arm was observed. The subgroup that seemed to benefit most from this treatment were patients with oropharyngeal primary tumors. More importantly, the only toxicity found to be significantly worse in the cetuximab and radiation arm was an acneiform rash.
The detrimental impact of smoking among patients with this disease extends beyond its role as an etiologic agent. Continued smoking during treatment has been associated with adverse treatment outcomes. A study of 115 patients undergoing radiation or radiation with chemotherapy for head and neck cancer found inferior complete response and 2-year overall survival rates in patients who reported that they continued smoking during treatment. This has been attributed to various factors, including nicotine-drug interactions, which might diminish the efficacy of chemotherapy; hypoxemia leading to reduced radiation-induced formation of free radicals; and patient comorbidity, which might limit the patient’s ability to complete radiation therapy.
With the improvement in locoregional control and survival from the adoption of concurrent chemotherapy and radiation for locally advanced disease, the pattern of disease failure appears to have changed, and distant metastasis is now emerging as the most common reason for failure. The use of induction chemotherapy before concurrent chemoradiation to decrease the rate of distant metastasis is now under active study.
No curative options exist for metastatic head and neck cancer. Median survival ranges from 5 to 9 months. In patients with distant metastasis, the goal of therapy is palliation of symptoms. A multitude of chemotherapeutic agents and targeted treatments have produced responses. These increase with the use of combination chemotherapy but at the cost of incremental toxicity. Randomized data suggesting the superiority of a particular regimen are scarce. EGFr inhibitors, when used alone, result in response rates of up to 10%, with disease stability in almost half of the patients treated. A study has compared cisplatin and 5-fluorouracil to the same regimen with cetuximab in 442 patients with metastatic disease or locally advanced disease not amenable to local therapy. A modest but significant overall survival advantage was noted in the chemotherapy and cetuximab group, which had a median survival of 10 months, compared to 7 months in the chemotherapy alone group.