Advanced Laryngeal Cancer
Bridget C. Loehn
Melda Kunduk
Andrew J. McWhorter
Laryngeal cancer affects nearly 12,720 men and women, and approximately 3,600 people will die of laryngeal cancer in the United States per year (1). The overall incidence of developing laryngeal cancer is approximately 0.7% with a mortality of 0% to 0.3% (2). If detected early, it can be effectively treated; however, over 40% of laryngeal cancers present with advanced-stage disease (3). Advanced-stage laryngeal cancer is defined as Stage III or IV disease, which includes not only T3 and T4 tumors but also tumors with regional cervical metastasis (N1 to N3 disease) (4).
The larynx produces one of the most complex motor functions of the body. It provides airway protection for respiration and deglutition as well as phonation. Any malignancy that affects the larynx can alter one or more of these main functions. Effects on this complex mechanism must be taken into account when formulating a treatment plan. The ultimate goal is to cure the patient of disease but with secondary goals to preserve phonation and deglutition and maintain a safe airway. There are many different treatment options for laryngeal cancer, but the clinician must balance quality of life (QOL) issues with the survival advantage of therapy. The treatment of laryngeal cancer should be a multidisciplinary approach to provide the patient with every opportunity available and the best oncologic and functional outcome.
Treatment of laryngeal cancer has evolved as medical advances have created more treatment options. Total and partial laryngectomy surgeries were the initial treatment for laryngeal cancer and were developed in the 19th century. Billroth is credited with the first laryngectomy in 1873 (5). Surgical advances in technique and antisepsis were major accomplishments that standardized surgical treatments and created reliable and safe conservation laryngeal surgery. With advances in radiation and chemotherapy and the use of multicentered prospective randomized trials, organ preservation therapy evolved to replace many of the surgical treatments and became the most common treatment for advanced laryngeal cancer. This shift in treatment paradigm during the early 1990s, from surgical excision to organ preservation using concurrent chemoradiation therapy, has provided similar survival to the gold standard total laryngectomy with postoperative radiation therapy but with a 73% organ preservation rate (6). Disappointing functional outcomes and new developments in minimally invasive techniques have further changed the treatment of laryngeal cancer with the popularization of endoscopic laser surgical resections in the 21st century.
EPIDEMIOLOGY
The larynx is the second most common site of primary epithelial malignant tumors of the head and neck. Laryngeal cancer accounts for 0.3% of all cancer-related deaths (2). Unfortunately, the 5-year survival for all stages of laryngeal cancer has worsened over the past 30 years despite efforts to improve treatment protocols. In between 1975 and 1977, the 5-year survival was 67%, and between 1999 and 2005, the 5-year survival has statistically decreased to 63% (1,7). There is an ongoing debate as to the etiology of the decrease in survival as to whether using chemoradiation versus total laryngectomy for earlier stage disease is the cause.
Laryngeal malignancies can occur in all three subsites of the larynx. The glottis is the most common site for laryngeal malignancy (51%), followed by the supraglottis (32%) and the subglottis (2%) (8) (Fig. 124.1).
From 2003 to 2007, the median age of diagnosis was 65 years with the highest incidence in the sixth and seventh decades (7). Men are more commonly affected than women with a male to female ratio of 3.6:1. The ratio of male:female has decreased over the years likely secondary to the increased rate of tobacco use in females. There are also differences in the 5-year survival according to race. Caucasians have a higher 5-year survival (67%) than African Americans (53%).
Over 40% of laryngeal cancers present as advanced stage disease. The 5-year survival also varied according to clinical stage (Table 124.1). Stage III supraglottic and glottic cancer had a 5-year survival of 50% to 60%. Stage IV supraglottic cancer has a 5-year survival of less than 50%, and Stage IV glottic cancer has a 5-year survival of 30% to 57% (3).
Over 40% of laryngeal cancers present as advanced stage disease. The 5-year survival also varied according to clinical stage (Table 124.1). Stage III supraglottic and glottic cancer had a 5-year survival of 50% to 60%. Stage IV supraglottic cancer has a 5-year survival of less than 50%, and Stage IV glottic cancer has a 5-year survival of 30% to 57% (3).
 Figure 124.1 Incidence of laryngeal cancer by subsite. Compiled from the National Cancer Database and Hoffman et al. (8). Approval for use obtained. |
ANATOMY
The larynx is found in the anterior neck at the level of the C3 to C5 vertebrae and connects the hypopharynx with the trachea. The larynx functions in airway protection, phonation, and respiration. These functions are made possible by the three valves contained within the larynx. These valves include the true vocal cords, false vocal cords, and epiglottis to the arytenoids. Any dysfunction of these valves can lead to aspiration, airway obstruction, and changes in voice. The larynx is divided anatomically and clinically into the supraglottis, glottis, and subglottis.
The supraglottic larynx is composed of the epiglottis (lingual and laryngeal aspects), aryepiglottic folds, arytenoids, and bilateral false vocal cords. Clinically, the inferior border of the supraglottis, according to the American Joint Committee on Cancer (AJCC), is defined by a horizontal plane passing through the lateral margin of the ventricle at its junction with the superior surface of the vocal cord (4). Anatomically, the inferior border is defined by the arcuate line, which marks the change from respiratory to squamous epithelium and is not reliably located at the apex of the ventricle. For staging purposes, the epiglottis is divided into suprahyoid and infrahyoid portions by a plane at the level of the hyoid bone. Histologically, the supraglottis is lined with ciliated columnar epithelium.
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The glottic larynx is comprised of the superior and inferior surfaces of the true vocal cords, including both the anterior and posterior commissures. The inferior border is defined as the line 1 cm below the apex of the ventricle (4). Histologically, the glottis is lined with stratified squamous epithelium. The layers of the true vocal cord from outward to inside are the following: stratified squamous epithelium, lamina propria, and vocalis muscle. The lamina propria is composed of three layers: a superficial layer that is composed of loose fibrous tissue and creates Reinke space an intermediate layer and a deep layer composed of elastic and collagen fibers that create the vocal ligament.
The subglottic larynx is the region below the glottis down to the inferior rim of the cricoid cartilage (4). The subglottis has no subsites. It is rarely the primary site of laryngeal cancer but is commonly involved in the inferior extent of glottic tumors. Histologically, the subglottis is lined with ciliated columnar epithelium (Fig. 124.2).
PATTERNS OF SPREAD
The larynx contains several fibroelastic membranes and ligaments that divide the larynx into compartments, limit the spread of early cancers, and allow for partial resections with adequate margins. Tumors tend to grow in the path of least resistance into preexisting compartments including the preepiglottic space and paraglottic space. The preepiglottic space is bound by the thyroepiglottic ligament inferiorly, the hyoepiglottic ligament superiorly, and the epiglottis posteriorly. At this level, the thyroepiglottic ligament is an ineffective barrier and offers little resistance to tumor spread. Tumor may also spread directly into the
preepiglottic space by traveling through lacunae on the laryngeal surface of the epiglottis into the space. The paraglottic space is another potential space bound laterally by the perichondrium of the thyroid cartilage and cricothyroid membrane and posteriorly by the mucosa of the pyriform sinus. Medially, the paraglottic space is bound by the quadrangular membrane above the ventricle and the conus elasticus below the ventricle. The conus elasticus extends superiorly from the superior border of the cricoid cartilage to merge with the inferomedial border of the vocal ligament. This ligament resists the extralaryngeal spread of early glottic and subglottic tumors. The paraglottic space allows tumors to become transglottic (superior and inferior to the ventricle) tumors and also to impair the movement of the true vocal cord. The preepiglottic space and paraglottic space communicate with each other.
preepiglottic space by traveling through lacunae on the laryngeal surface of the epiglottis into the space. The paraglottic space is another potential space bound laterally by the perichondrium of the thyroid cartilage and cricothyroid membrane and posteriorly by the mucosa of the pyriform sinus. Medially, the paraglottic space is bound by the quadrangular membrane above the ventricle and the conus elasticus below the ventricle. The conus elasticus extends superiorly from the superior border of the cricoid cartilage to merge with the inferomedial border of the vocal ligament. This ligament resists the extralaryngeal spread of early glottic and subglottic tumors. The paraglottic space allows tumors to become transglottic (superior and inferior to the ventricle) tumors and also to impair the movement of the true vocal cord. The preepiglottic space and paraglottic space communicate with each other.
 Figure 124.2 Midline sagittal section of the larynx demonstrating the supraglottis, glottis and subglottis. |
At the level of the glottis, the vocalis tendon attaches to the thyroid cartilage through Broyles ligament, which is an ineffective barrier and will allow tumors to spread into the thyroid cartilage and preepiglottic space. This region where the tendon attaches to the thyroid cartilage has no perichondrium. The perichondrium is considered another barrier to the spread of early cancers. As previously discussed, the true vocal cords contain a lamina propria consisting of three layers. The superficial layer (Reinke’s space) contains loose fibrous tissue and is almost void of lymphatics and blood vessels creating a resistance to the spread of early glottic tumors.
Lymphatic spread of the tumor usually occurs in a predictable manor and follows the embryologic origins of the larynx. The supraglottis is derived from the midline buccopharyngeal primordium and branchial arches 3 and 4. The supraglottis has a rich lymphatic supply. The glottis is derived from the tracheobronchial primordium and branchial arches 4, 5, and 6. In contrast to the supraglottis, the glottis has a very low lymphatic supply. These differences account for the high incidence of lymphatic spread for supraglottic carcinomas and the low incidence of lymphatic spread in glottic carcinomas. As a result of the rich lymphatic supply to the supraglottis, there is also a greater incidence of bilateral lymph node metastasis as compared to the unilateral spread in glottic tumors (10).
Since the lymphatic drainage of these sites is predictable, this allows surgeons to limit neck dissections to the lymph node levels most at risk. In 1972, Lindberg mapped out affected lymph nodes based on the primary site of the tumor. This study demonstrated that laryngeal carcinoma has lymphatic drainage to Levels II to V and that supraglottic tumors have a greater incidence of bilateral neck involvement (11) (Fig. 124.3).
STAGING
The current staging system for laryngeal cancer is the Tumor-Node-Metastasis (TNM) staging system of the AJCC. This system is an anatomical staging system characterized by the extent of invasion of the primary tumor, cervical lymph node involvement, and distant metastasis. This information is obtained through physical examination, imaging, and endoscopic examination and finally confirmed by surgical pathology from the resected tumor. For purposes of this chapter, advanced laryngeal cancer will be defined as Stage III or IV on the AJCC staging system (4) (Table 124.2).
 Figure 124.3 Parasagittal view of larynx demonstrating laryngeal spaces and cartilages and ligaments that compose them. |
While this system stages tumors based on size and extent of the tumor, other important prognostic factors are not included. There are histologic factors that can indicate a poorer prognosis including perineural invasion, angiolymphatic spread, extracapsular spread of nodal metastasis, and histologic grade of the tumor. There are also studies showing that multiple chromosomal and molecular markers are indicative of a poor prognosis. Some of these markers include overexpression of mutant p53 protein (12), a high Ki67 or proliferating cell nuclear antigen score, and the expression of c-myc oncogene or int-2 gene (13,14). Bradford et al. (12) in 1997 found that high levels of mutant p53 are associated with decreased survival.
Other staging systems have been proposed for laryngeal cancer. Some propose using a high-resolution computed tomography (CT) to assess the volume of tumor. Others suggest that any tumor with any change in vocal cord mobility be considered a T3 or T4. There was also a five-part system devised that used the TNM system but separated it into clinical/diagnostic, surgical, pathologic, retreatment, and autopsy. Other research is including comorbidities into the staging system and is looking at how it relates to the overall outcome (15) (Table 124.2).
TABLE 124.2 STAGING LARYNGEAL CARCINOMA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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EVALUATION AND DIAGNOSIS
History and Physical Examination
The majority of the time, the diagnosis of laryngeal cancer can be made through a complete history and physical examination. Presenting complaints can be site specific. Patients may complain of hoarseness (glottic carcinoma), muffled/hot potato voice (supraglottic carcinoma), dyspnea, dysphagia, and otalgia (usually supraglottic). Patients may also present with a history of aspiration pneumonia, stridor, hemoptysis, or sore throat. Constitutional symptoms may include weight loss, fevers, chills, and night sweats. Often, the initial complaint is that of a cervical mass. Glottic tumors usually present earlier than supraglottic
cancers due to the early change in voice. Supraglottic tumors present with fewer symptoms in the early stage and therefore are usually diagnosed at a later stage. Patients with supraglottic tumors tend to present with pain, dysphagia, and cervical metastasis. Subglottic tumors typically present as advanced stage disease with airway obstruction.
cancers due to the early change in voice. Supraglottic tumors present with fewer symptoms in the early stage and therefore are usually diagnosed at a later stage. Patients with supraglottic tumors tend to present with pain, dysphagia, and cervical metastasis. Subglottic tumors typically present as advanced stage disease with airway obstruction.
Past medical history is also important in assessing patient comorbidities, history of cancer, and immunologic status. Social history is important in assessing patient risk factors. More than 95% of patients with laryngeal cancer have a significant history of tobacco abuse (3). There is a positive relationship between the quantity of cigarettes consumed and the increased risk of developing laryngeal cancer. There is also a synergistic effect when tobacco is combined with alcohol use leading to even higher rates of malignancy (16). However, alcohol may be a risk factor by itself, but its role is less defined. Treatment of tobacco and alcohol dependency must be considered in the postoperative period. Delirium tremens and tobacco withdrawal can lead to a complicated and prolonged postoperative course and impaired healing.
Other risk factors include human papillomavirus, especially subtypes 16 and 18 (17); gastroesophageal reflux disease; and occupational exposures as seen in patients who are metal workers, construction workers (asbestos), and textile processors.
A complete examination including a complete head and neck exam should be performed on all patients to determine staging, the presence of second primaries, and other findings/comorbidities that may influence recommended treatments. A complete head and neck examination includes examination of the skin, eyes, ears, oral cavity, and pharynx, including palpation of the floor of mouth, base of tongue, and tonsils in addition to the larynx, neck, and cranial nerves. Dentition should be assessed for caries and periodontal disease. A more detailed exam of the larynx and pharynx is performed using flexible fiberoptic laryngoscopy at which time. The extent of the lesion as well as the mobility and position of the vocal cords are assessed. This also allows for assessment of the airway. Videostroboscopy can also be used to detect subtle changes in vocal cord function and mobility but is more helpful in early-stage disease. Palpation of the neck should occur bilaterally noting the location, size, and relationship of the lymph nodes to adjacent structures (18,19) (Fig 124.4).
Imaging
Physical examination is often limited in the evaluation of tumor depth and nodal metastases, and radiographic imaging is helpful in determining the extent of the disease. Imaging can provide information regarding cartilage invasion, extension into the preepiglottic and paraglottic spaces, and extralaryngeal spread of tumor. Imaging studies can also be used to assess cervical nodal disease. Both CT and magnetic resonance imaging are useful tools for this assessment. The CT scan is more specific for cartilage invasion (20), and in most centers, CT is considered the standard imaging modality for advanced laryngeal cancers (Fig 124.5).
 Figure 124.4 Seventy-degree fiberoptic view of T3N0M0 SCCA supraglottis. Tumor extends from epiglottis onto left false fold. |
Chest radiograph (CXR) should be obtained on all patients in the preoperative evaluation and staging of laryngeal cancer. This allows for the diagnosis of acute/chronic pulmonary disease as well as a synchronous or metastatic lung mass/tumor. Patients with abnormalities on CXR will usually require additional imaging (chest CT) for further work-up.
Another imaging modality used in the staging of many cancers, including laryngeal cancer, is positron emission tomography (PET). PET is a nuclear medicine technique that produces a three-dimensional image of the functional processes of the body. It utilizes fluorescence-tagged glucose molecules and then measures the uptake within the tissues. The hypermetabolic state of most malignancies will lead to increased uptake (10). PET has evolved to be an essential imaging modality in the assessment of advanced laryngeal cancer. It has limited utility in determining the
extent of the primary tumor; however, it is becoming the standard in the assessment of regional cervical metastasis as well as distant metastasis (21). The sensitivity and specificity of PET in detecting cervical metastatic disease range from 74% to 94% and from 82% to 100%, respectively, compared with the sensitivity and specificity of CT, which ranged from 67% to 81% and from 47% to 81%, respectively (22,23,24,25,26,27). Kyzas et al. (28) found that the overall sensitivity of PET in detecting cervical nodal metastasis was 79%; however, in tumors with nodal status as N0, the sensitivity decreased to 50%. Yamazaki et al. (27) found that metastatic nodes measuring greater than 1cm were detected 100% of the time whereas nodes measuring less than 5 mm were not detected. In the posttreatment period, PET has become useful in the identification of residual and recurrent disease (21). In the assessment of distant metastasis, Gourin et al. (29) reported that the sensitivity and specificity of PET-CT detecting distant metastasis were 86% and 84%, respectively.
extent of the primary tumor; however, it is becoming the standard in the assessment of regional cervical metastasis as well as distant metastasis (21). The sensitivity and specificity of PET in detecting cervical metastatic disease range from 74% to 94% and from 82% to 100%, respectively, compared with the sensitivity and specificity of CT, which ranged from 67% to 81% and from 47% to 81%, respectively (22,23,24,25,26,27). Kyzas et al. (28) found that the overall sensitivity of PET in detecting cervical nodal metastasis was 79%; however, in tumors with nodal status as N0, the sensitivity decreased to 50%. Yamazaki et al. (27) found that metastatic nodes measuring greater than 1cm were detected 100% of the time whereas nodes measuring less than 5 mm were not detected. In the posttreatment period, PET has become useful in the identification of residual and recurrent disease (21). In the assessment of distant metastasis, Gourin et al. (29) reported that the sensitivity and specificity of PET-CT detecting distant metastasis were 86% and 84%, respectively.
 Figure 124.5 Axial contrast CT scan, T4N0M0 transglottic SCCA demonstrating paraglottic space involvement and thyroid cartilage invasion with extralaryngeal spread. |
Ultrasound is another useful imaging tool in the determination of nodal disease. This is most commonly used in Europe but is gaining prevalence in the United States. This tool is noninvasive, low cost, and is a good technique for lymph node assessment.
Laboratory Tests
Laboratory tests are ordered as part of the preoperative and metastatic workup, usually according to patient factors and institutional guidelines. These tests typically include complete blood count, complete metabolic panel, coagulation studies, as well as other tests. If abnormal liver function tests and calcium and alkaline phosphatase levels are noted, abdominal CT, bone scan, or PET can be utilized to further determine the etiology of these abnormalities.
Consultations
A multidisciplinary approach is used in the treatment of advanced laryngeal cancer. Prior to the start of treatment, other specialists, who will assist in the treatment, as well as posttreatment care, should evaluate the patient. The members of the multidisciplinary team usually include radiation oncology, hematology oncology, dental oncology, speech pathology, nutritional services, and spiritual care. The speech pathologist is critical in pretreatment assessment, counseling, education regarding changes in voice and swallowing including alaryngeal speech, and posttreatment rehabilitation.
Surgical Evaluation
Panendoscopy is a term used to describe the endoscopic evaluation of the entire upper aerodigestive tract. This includes direct laryngoscopy, tracheobronchoscopy, and esophagoscopy and is typically done under general anesthesia. With the advent of advanced flexible scopes and the advancements of in-office procedures, panendoscopy has been performed successfully in this setting (30
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