- 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
Laryngeal cancers constitute approximately 1.2% of all new cancer diagnoses in the United States. Approximately 12,360 new cases are expected in 2012, and it is estimated that 3,650 men and women will die of the disease.
Anatomy and pathology
The laryngeal anatomy is complex and includes cartilages, membranes, and muscles. The three subsites of the larynx are the glottis, or true vocal cords; the supraglottis, which includes the false cords, epiglottis, and aryepiglottic folds; and the subglottis, which is the region below the glottis and within the cricoid cartilage. The TNM staging system for cancers of the larynx is outlined in Table 4.
Surgery. Surgical treatment for laryngeal cancer includes transoral or open approaches. Treatment is dictated by the site and extent of the lesion. All or part of the larynx may need to be removed to achieve surgical control of laryngeal cancer. Decision making for partial laryngectomy is complex and depends on the patient's overall health, the extent of local disease, the skill of the surgeon, and patient preference.
External-beam radiation therapy and chemoradiation therapy. With improvements in techniques and fractionation schedules, external-beam radiation therapy, which allows for laryngeal preservation, is an option for all but the most advanced tumors.
• Results—As in other head and neck sites, patients with early laryngeal cancer may be treated with surgery or radiation therapy, and those with advanced-stage disease require multimodal therapy, including surgery and postoperative radiation therapy or chemotherapy and radiation therapy. For T1 and T2 tumors of the glottic or supraglottic larynx, radiation therapy is associated with local tumor control rates of 75% to 95%. Open partial laryngectomy for early laryngeal cancer is associated with local tumor control rates of 84% to 98% but requires a temporary tracheotomy and may be associated with postoperative vocal and swallowing dysfunction. Transoral laser surgery for early laryngeal cancer has yielded local tumor control rates of 82% to 100%, without significant dysphagia or a need for a temporary tracheotomy. However, the technical expertise required to perform transoral laser surgery is limited to a small number of institutions.
Select patients with T3 or T4 laryngeal cancers may be candidates for larynx preservation surgery, but most require total laryngectomy as the surgical option. The VA Cooperative Laryngeal Cancer Study was the first trial to test the efficacy of chemotherapy and radiation therapy in the management of stages III and IV laryngeal cancer, assess the possibility for laryngeal preservation using such a regimen, and compare its efficacy against the historic standard of surgery and postoperative radiation therapy. The VA Cooperative Laryngeal Cancer Study randomized patients with resectable squamous cell carcinoma of the larynx to receive either total laryngectomy followed by radiation therapy or neoadjuvant therapy with cisplatin(Drug information on cisplatin) and 5-FU followed by radiation therapy for those achieving a good response to chemotherapy.
Approximately two-thirds of patients survived 2 years following the combination of either chemotherapy plus irradiation or resection plus irradiation. Of patients initially treated with chemotherapy and irradiation, one-third required total laryngectomy because of a lack of response to treatment and in the remaining two-thirds the larynx was successfully preserved. In this study, the increased local recurrence rate in the chemoradiation therapy group was offset by the decreased incidence of distant metastases and second primary tumors, and the 2-year survival rate was comparable between the groups. Advanced T stage was a risk factor for local failure in this study. Salvage total laryngectomy was required for 56% of T4 laryngeal cancers, suggesting that patients with bulky primary tumors may not be optimal candidates for organ-preservation therapy.
Data from the RTOG 91-11 trial demonstrated an improvement in locoregional tumor control using concurrent chemoradiation therapy relative to induction chemotherapy followed by radiotherapy or radiotherapy alone. There was no primarily surgical or altered fractionated arm in the study. This three-armed study randomized 517 patients with stages III and IV laryngeal cancer to receive one of the following regimens: induction chemotherapy (with cisplatin/5-FU) followed by radiation therapy or concurrent chemoradiotherapy (with cisplatin given on days 1, 22, and 43) or radiation therapy alone. Locoregional tumor control for the three arms was 61%, 78%, and 56%, respectively. The larynx preservation rate was 75%, 88%, and 70%, respectively. At 2 years, the proportion of patients in whom the larynx was preserved after irradiation and concurrent cisplatin (88%) differed significantly from the proportion in groups given induction chemotherapy followed by irradiation (75%; P = .005) or irradiation alone (70%; P < .001). The authors concluded that the combination of irradiation and concurrent cisplatin was superior to induction chemotherapy followed by irradiation or irradiation alone for laryngeal preservation and locoregional tumor control. Notably, patients with T4 laryngeal cancers accounted for only 10% of patients in this study, compared with 25% in the original VA Cooperative Laryngeal Cancer Study, accounting for the improved local tumor control with surgery. Follow-up studies revealed that local failure nevertheless remained the predominant initial site of failure, and the survival of patients who underwent salvage laryngectomy was somewhat diminished.
The cure rate for early cancers of the larynx approaches 80% or more. Half of patients with T3 cancer are cured, whereas more than two-thirds of patients with T4 cancer will die of the disease.
Supraglottic tumors occur less frequently than tumors of the true vocal cords. The epiglottis is the most common location for supraglottic cancers.
Tumors close to the glottis produce symptoms earlier than do tumors at other subsites, usually hoarseness. In contrast, nearly 60% of patients with supraglottic tumors have T3 or T4 primary tumors at presentation.
The supraglottis has a rich lymphatic network. There is an associated high incidence of lymph node metastases in early-stage tumors (40% for T1 tumors). The incidence of metastases in patients with clinically N0 neck cancer is about 15%. The incidence of bilateral cervical lymph node involvement is about 10%, and this rate increases to 60% for anterior tumors. The neck is a frequent site of recurrence in patients with supraglottic malignancies.
Treatment. Appropriate cancers may be treated with partial laryngectomy. Supraglottic laryngectomy removes the upper portion of the thyroid cartilage and its contents, including the false vocal cords, as well as the epiglottis and aryepiglottic folds. This approach preserves speech and swallowing, but more extensive resections are not well tolerated by patients with impaired lung function who are not able to tolerate the inevitable postoperative aspiration. Supracricoid partial laryngectomy is suitable for supraglottic tumors that cross the ventricle to involve the glottis. Select T3 tumors with limited pre-epiglottic space involvement may be approached with this procedure. Patients must have sufficient pulmonary reserve to be able to tolerate the chronic aspiration associated with this procedure. The local tumor control rates of transoral laser supraglottic laryngectomy are between 75% and 100% for T1 and T2 lesions in recent series and are associated with less postoperative dysphagia than open approaches. Significant technical expertise is needed, and patients must have the proper habitus to ensure adequate exposure.
The high incidence of cervical metastases makes treatment of the neck a necessity. About one-third of cases of clinically negative neck cancer contain involved nodes, and the incidence of recurrence in untreated patients is high. For patients undergoing surgical treatment of T1 or T2 primary tumors, bilateral selective neck dissection is advisable.
Supraglottic laryngectomy is seldom appropriate as salvage therapy following irradiation because of complications, including swelling, difficulty in swallowing, and poor wound healing. The usual salvage operation for persistent supraglottic cancer following radiation therapy is total laryngectomy. However, some patients remain candidates for larynx-preservation surgery.
Advanced-stage laryngeal cancer usually requires multinodal treatment, as noted previously. Laryngeal preservation frequently is not possible using primary surgical approaches. The use of primary radiation enables preservation of the larynx. The use of combined radiation concurrently with chemotherapy is the treatment of choice for many patients.
The glottis is the most common location of laryngeal cancer in the United States, accounting for more than half of all cases. The incidence of laryngeal cancers and other malignancies related to smoking has been declining.
The cure rate for tumors of the true vocal cords is high. These cancers produce symptoms early and, thus, most are small when detected. Approximately 60% are T1 and 20% are T2. Normal cord mobility implies invasion of disease limited to the submucosa. Deeper tumor invasion results in impaired vocal cord motion; this finding is most common in the anterior two-thirds of the vocal cord.
The true vocal cords have very little lymphatic drainage. Cervical metastases are infrequent with T1 (1%) and T2 tumors (3% to 7%).
Carcinoma in situ is highly curable and may be treated equally well with microexcision, laser vaporization, or radiation therapy. Treatment decisions should be based on the extent of local disease. Serial recurrences should heighten suspicion of an invasive component, and a more aggressive approach, such as partial or total laryngectomy or irradiation, should be employed. Hypofractionated (> 2 Gy/d) radiotherapy is preferred to conventional fractionation (1.8 to 2 Gy). Local tumor control for T1 using surgery or irradiation is comparable, usually greater than 90%. Local tumor control for T2 glottic lesions is reported to be between 70% and 85% with radiotherapy and 85% and 95% with open partial laryngectomy. Partial laryngectomy can be performed in select patients after irradiation failure of some T1 or T2 glottic cancers.
Advanced T4 disease is best treated with total laryngectomy. Most T3 lesions are now being treated with concomitant chemoradiotherapy, with salvage laryngectomy required in approximately 20% of patients for residual/recurrent disease or laryngeal dysfunction.
Results. Cure rates by tumor size alone are as follows: T1, 90%; T2, 80%; T3, 50%; and T4, 40%. Neck involvement worsens the prognosis dramatically.
Subglottic cancer is unusual, accounting for less than 10% of all laryngeal cancers.
These cancers tend to be poorly differentiated and, because the region is clinically "silent," most present as advanced lesions (~70% are T3–T4). The subglottis also has rich lymphatic drainage, and the incidence of cervical metastases is 20% to 30%.
Partial laryngectomy is not practical for the treatment of tumors in the subglottis and, thus, therapy usually includes total laryngectomy plus neck dissection. Combination therapy (surgery plus radiation therapy [60 to 65 Gy in 6 to 7 weeks]) is recommended for patients with more advanced disease.
Results. The cure rate for the uncommon T1 and T2 tumors is approximately 70%. Most failures occur in the neck. The cure rate for more advanced lesions is approximately 40%.
The cervical lymph nodes are the most common metastatic site at which squamous cell carcinoma is found.
Most patients who present with squamous cell carcinoma involving cervical lymph nodes, especially in the upper or middle portion of the cervical chain, will have a primary site within the head and neck. When the lower cervical or supraclavicular lymph nodes are involved, a primary lung cancer should be suspected.
In the overwhelming majority of these cases, the primary lesion will be discovered on the basis of the history; physical examination; proper radiographic evaluation (CT and/or MRI); and examination with the patient under anesthesia, with endoscopy (direct laryngoscopy and nasopharyngoscopy), targeted biopsies, and tonsillectomy. Esophagoscopy and bronchoscopy seldom yield a diagnosis in patients with upper cervical lymph node involvement. "Silent" primary tumors are most often discovered in the base of the tongue or within tonsillar crypts. Tonsillectomy and/or base of tongue mucosectomy may identify the primary site, obviating the need for wide-field mucosal irradiation which otherwise includes the nasopharynx, oropharynx, and hypopharynx. Lymph node metastases should be tested for the presence of HPV/p16 and EBV.
A substantial percentage of patients achieve long-term disease-free survival after treatment of the involved side of the neck. Locoregional control and survival are diminished by multiple lymph nodes and the presence of extracapsular extension of disease in the involved neck.
Irradiation alone. Patients with early-stage neck disease (N1 disease) can be treated with surgery alone if an open biopsy has not been performed. Recurrences in mucosal sites occur in 20% to 30% of cases, and radiotherapy is used to lower the risk of recurrence in the neck, not the primary. Radiation therapy dosages and techniques should be similar to those used in patients with early-stage (ie, T1) primary head and neck cancer. Dosages ranging from 5,760 to 6,480 cGy are acceptable. The nasopharynx and oropharynx, with or without the hypopharynx, should be included in the irradiated field.
Surgery alone. When neck dissection is used at the initial treatment, a primary tumor in the head and neck subsequently becomes obvious in about 20% of patients when radiation therapy is not employed.
Irradiation alone or combined with surgery. Combination therapy (surgery plus radiation therapy [60 to 65 Gy in 6 to 7 weeks]) is recommended for patients found at surgery to have multiple involved nodes or extracapsular extension or for those who have suspected residual microscopic disease in the neck without a clinically detectable tumor. Open nodal biopsy does not appear to compromise outcome as long as adequate radiotherapy is delivered subsequently.
In most modern series utilizing predominantly combination therapy, 5-year survival rates exceed 50%. The volume of tumor in the involved neck influences outcome, with N1 and N2 disease having a significantly higher cure rate than N3 disease or massive neck involvement. Regional relapse is usually predicted by extranodal disease.
Chemotherapy. The role of chemotherapy in treating patients with an unknown primary metastatic squamous cell carcinoma in cervical lymph nodes remains undefined. The benefit of concurrent chemoradiation therapy for these patients is uncertain (because their primary sites are small or absent), and neck control after resection followed by irradiation, or after irradiation alone, is excellent in patients with cancers of an unknown primary site.
Nasopharyngeal carcinoma is uncommon in most of the world. Endemic areas include southern China, northern Africa, and regions of the far Northern Hemisphere. The incidence (per 1,000 population) ranges from 25.6 in men and 10.2 in women in Hong Kong to 0.6 in men and 0.1 in women in Connecticut.
Epidemiology and risk factors
Gender and age. The incidence of nasopharyngeal cancer peaks in the fourth to fifth decades of life, and the male-female ratio is 2.2:1. Both patient age at disease onset and male-female ratio are lower for nasopharyngeal cancer than for other head and neck malignancies.
Risk factors. Nasopharyngeal carcinoma World Health Organization (WHO) types 2 and 3 (see section on "Anatomy and pathology") appears to have different determinants than do other head and neck cancers. They include diet, viral agents, and genetic susceptibility. Populations of endemic areas have a diet characterized by high consumption of salt-cured fish and meat. Studies reveal an association between EBV and nasopharyngeal carcinoma. Anti-EBV antibodies have been found in the sera and saliva of patients with this type of carcinoma. Major histocompatibility (MHC) profiles associated with an increased relative risk include H2, BW46, and B17 locus antigens.
Anatomy and pathology
The nasopharynx communicates anteriorly with the nasal cavity and inferiorly with the oropharynx. The superior border is the base of the skull. The lateral and posterior pharyngeal walls are composed of muscular constrictors. Posteriorly, the nasopharynx overlies the first and second cervical vertebrae. The eustachian tubes open into the lateral walls. The soft palate divides the nasopharynx from the oropharynx.
Cancers arising in the nasopharynx are classified using WHO criteria: type 1 denotes differentiated squamous cell carcinoma; type 2, nonkeratinizing carcinoma; and type 3, undifferentiated carcinoma. The TNM staging system for cancers of the pharynx is outlined in Table 5.
A mass in the neck is the presenting complaint in 90% of patients. Other presenting symptoms include a change in hearing, sensation of ear stuffiness, tinnitus, nasal obstruction, and pain.
Cranial nerve involvement. Invasion of disease into the base of the skull is seen in approximately 25% of cases and may lead to cranial nerve involvement. CN VI is the first cranial nerve to be affected, followed by CN III and CN IV. Deficits are manifested by changes in ocular motion. Involvement of CN V may also occur; this is manifested by pain or paresthesia high in the neck or face.
Level V metastases. Unlike malignancies of the oral cavity and oropharynx, nasopharyngeal cancers often metastasize to level V lymph nodes. Bilateral metastases are common.
Treatment of nasopharyngeal cancer usually involves radiation therapy for the primary tumor and draining lymph nodes. Overall survival is 50% at 5 years. Surgical resection has high morbidity and is seldom entertained.
Nasopharyngeal cancer is distinguished from other sites of head and neck cancer by its radiosensitivity and chemosensitivity. Advanced nodal disease can be controlled by irradiation alone in approximately 50% of patients, but eventual distant metastasis remains a problem.
The final report of the Intergroup trial 0099 confirmed that for patients with locally advanced nasopharyngeal cancer, concurrent cisplatin chemotherapy with radiation therapy (followed by systemic chemotherapy) provided a clear survival benefit when compared with treatment with irradiation alone. At 5 years, patients who received combined-modality therapy had an overall survival rate of 67%, compared with 37% with radiation therapy alone (P = .001). Disease-free survival at 5 years was 74% for the chemoradiation therapy arm vs 46% for the arm that received radiation therapy alone. Treatment of metastatic disease involves cytotoxic therapy, often with a platinum doublet. For tumors associated with EBV, approaches with immunotherapy are an active area of research.