Larynx and Hypopharynx Cancer

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Chapter 33 Larynx and Hypopharynx Cancer

Management of cancers of the larynx is a special challenge for head and neck oncologists. Laryngeal cancer even in advanced stages has a relatively high cure rate if managed appropriately. Because of this factor, it has become the paradigm for the concept of organ preservation in oncologic patient management. Curing the patient is not the only consideration in the management of this disease. Voice preservation and avoidance of tracheal stoma are important priorities.

In previous decades, surgery, radiation therapy (RT), or a combination of the two therapies were used and individualized to best meet these endpoints. Both modalities have improved over the years in eradicating the disease and preserving function. Newer, more technically sophisticated voice-conserving surgical procedures have been developed. Similarly, radiation oncologists have grown in their understanding of the influences of dose, treatment duration, and field placement to improve the results in managing these diseases. Important improvements in defining disease extent, by both physical examination with fiberoptic laryngoscopy and radiologic images obtained with computed tomography (CT) and magnetic resonance imaging (MRI), have allowed for better selection of the appropriate therapy for an individual patient. Systemic therapies have been incorporated into the management of these diseases, thus increasing the options in trying to cure patients with this disease while maintaining function.

Carcinomas of the hypopharynx are often considered together with carcinomas of the larynx, because the anatomy of the hypopharynx is essentially created by the location of the voice box in the throat. Hypopharyngeal tumors frequently involve the larynx and vice versa. In these situations, it is one’s best guess whether the epicenter of a large tumor is laryngeal or hypopharyngeal. It is therefore not unexpected that the concept of voice preservation also applies to the management of cancers of the hypopharynx. The pharynx is also involved in glutition, and issues of preservation of swallowing are also important in the management of these tumors.

Although affecting the area immediately adjacent to the larynx and thus having similar management concerns to laryngeal carcinoma, hypopharyngeal cancers typically have different natural histories compared with cancers arising in the larynx. At diagnosis, hypopharyngeal tumors have much higher rates of spread beyond the primary tumor; thus, even with successful local treatment, survival rates tend to be worse than other cancers of the head and neck.

Primary tumors of the hypopharynx also tend to present in locally advanced stages. However, local therapies have improved in recent years. Surgical grafting techniques have been developed to replace the resected pharyngeal tissues and allow the patient a better swallowing mechanism. Without these techniques, larger hypopharyngeal lesions would be unresectable. Improved control with altered RT schedules may allow preservation of the larynx and pharynx for intermediate-stage lesions. Adding systemic agents may also allow for organ preservation and help with the problem of distant disease prevalent in cancers of this site.

Epidemiology and Etiology

Laryngeal cancer occurs in roughly 12,000 Americans per year, accounting for approximately one fourth to one third of all head and neck cancer cases. However, mortality due to cancers of the larynx is relatively low: about 4200 deaths per year in the United States.

The median age of patients presenting with larynx cancer is 65 years. Less than 4% of patients are younger than 45 years old. Laryngeal cancer remains predominantly a disease affecting men. The most recent data from the Surveillance, Epidemiology, and End Results (SEER) program (2003–2007)1 estimated an overall incidence of 3.4 cases per 100,000 people per year, a slight decrease of 0.4 cases per 100,000 compared with the previous 5 years of data.2 Comparisons reveal case incidences of 6.1 versus 1.3 in males and females, respectively. There is a higher incidence among blacks than among whites for both men and women.

Tobacco use is strongly associated with the development of cancer of the larynx, with the highest risk among active heavy smokers and an intermediate risk among ex-smokers.3,4 More than 95% of patients with laryngeal cancer have a history of tobacco use.5 Cigar and pipe smoking have also been associated with cancer of the larynx,4 but studies on this issue have been more controversial.3,6,7

Alcohol use is also associated with laryngeal cancer but is believed to act synergistically with tobacco rather than independently. It is unusual to see laryngeal cancer in nonsmoking patients with alcohol abuse histories.7 A history of heavy alcohol use is more strongly associated with supraglottic and hypopharyngeal cancers.4,8 Likewise, occupational exposures to asbestos,4,9,10 mustard gas, nickel, soot, and tars have been linked to laryngeal cancer, but generally a tobacco use history is also present.11 Several authors have evaluated the influence of diet on the development of larynx cancer and have found, while controlling for tobacco and alcohol use, a higher incidence among patients with vitamin- and nutrient-deficient diets.6,12,13

Attention has been directed at the influence of gastroesophageal reflux disease (GERD) on laryngeal diseases, including carcinomas. Three separate studies14,15,16 have described cohorts of nonsmoking patients with GERD and larynx cancer. Bacciu and colleagues17 compared 36 consecutive patients with no history of tobacco and alcohol consumption who developed laryngeal carcinoma to a group of 125 lifetime nonsmokers who were cancer free. They found a much higher prevalence of GERD among the patients with laryngeal cancer. It is believed that chronic irritation on the larynx from acid may predispose these patients to cancer. It is thought that if this cancer is seen in nonsmokers, the influence of GERD on the development of laryngeal cancer in smokers and alcohol users (who are at higher risk for GERD) may be very significant.

Human papillomavirus (HPV) has been causally linked to multiple cancers, including head and neck cancers,18,19 particularly cancers of the tonsil. HPV has also been demonstrated to be associated with laryngeal cancers, although studies are, in general, retrospective and the reported prevalence rates vary widely. The evidence for HPV having a role in laryngeal cancer is less obvious than in other malignancies, and its interaction with other carcinogens such as tobacco is unclear. As in cervical cancer in women and tonsillar cancer, HPV-16 is the most common type noted.

Hypopharyngeal cancers are less common than laryngeal tumors. The estimated incidence in the United States is 2500 cases per year. Etiologic risk factors are similar to those for laryngeal tumors,12 with a predominance among men and older individuals. This type of cancer is closely linked to tobacco and alcohol use, and the ties to heavy alcohol use seem stronger than those for laryngeal cancer.

Prevention and Early Detection

Prevention

The primary preventive methods taken to eliminate malignancies of the upper aerodigestive tract have come from public awareness that tobacco and alcohol are the major causative agents of these cancers. National public health measures have been directed at diminishing the prevalence of smoking and drinking. A byproduct of these policies may be a decline in the incidence of laryngeal and hypopharyngeal carcinomas. The most recent SEER data has identified a decrease in the incidence of larynx cancer over the past two decades (1988–2007).1 The annual percentage decrease over this time period is 2.6%.

Although government policies have been directed at diminishing carcinogenic etiologic agents for the general population, investigators have tried to identify high-risk groups in whom more direct measures can be taken. The major group identified consists of patients who have been cured of a cancer of the upper aerodigestive tract,20,2123 particularly patients who have smoking or alcohol use histories.24 The incidence of second primary cancers of the upper aerodigestive tract ranges from 10% to 30%. The locations of these second cancers are evenly divided between the lungs, esophagus, and head and neck mucosal sites, including the larynx and hypopharynx.24

The high incidence of new cancers in this patient population has led investigators to develop programs designed to diminish the occurrence of second primary tumors. Hong and associates25 studied 13-cis-retinoic acid as a possible agent to prevent new cancers in patients with a history of head and neck malignancy. A randomized trial showed a 14% versus 31% incidence of second primary tumors in patients who received a relatively high dose of 13-cis-retinoic acid versus placebo.26 The Radiation Therapy Oncology Group (RTOG), in 2002, completed accrual to a trial testing chemoprevention with 13-cis-retinoic acid in a multi-institutional setting.27 Nearly 1400 patients with stage I or II cancer were accrued. The dose of 13-cis-retinoic acid was lower than that used by Hong and associates to ensure more compliance and less side effects. Unfortunately, the RTOG trial was negative and did not show any benefit to low dose isotretinoin in the prevention of second primary cancers. The RTOG study did show that the continuation of smoking had adverse effects on outcome and those who smoked were more likely to develop second cancers.

Papadimitralopoulou and colleagues28,29 investigated α-tocopherol, interferon-alfa, and isotretinoin in patients with laryngeal dysplasia and reported a 50% complete response rate at 12 months. The current thinking is that these agents may delay or prevent subclinical cancer from manifesting as clinical disease but are less likely to prevent cellular transformation. This three-drug combination is being tested in a phase III trial, but accrual has not been robust.

New compounds for chemoprevention are currently being investigated. These include green tea extracts, curcumin analogues, soybeans, celecoxib, erlotinib, and rapamycin. These agents are being tested in coordination with efforts to identify molecular prognostic markers. Once these markers are identified, ideally they will be incorporated into randomized clinical trials by using these markers for risk stratification purposes.

Pathology and Pathways of Spread

Pathology

The majority of laryngeal and hypopharyngeal cancers are squamous cell carcinomas. Laryngeal carcinomas are usually well differentiated. Because patients with laryngeal tumors often present with early-stage disease, it is common to see a spectrum of pathologic tissue changes, ranging from premalignant atypia or dysplasia to carcinoma in situ and superficially invasive carcinomas, within the larynx.

Carcinoma in situ is a pathologic entity representing carcinomatous changes confined to the thickened epithelium without breaching the lamina propria. The clinical appearance of carcinoma in situ is a white or grayish white thickening of the mucosa. Penetration through the basement membrane makes the diagnosis of invasive carcinoma. Invasive tumor may be missed if biopsy samples are too small or too superficial for proper histologic evaluation.

Less frequently, the larynx and hypopharynx can give rise to variants of squamous cell carcinoma. The most common of these cancers is verrucous carcinoma, accounting for approximately 4% of all larynx cancers.33 They are classically slow-growing tumors with a gross warty appearance. A less common variant with numerous nomenclatures is squamous cell carcinoma with spindle cell features. As its name implies, along with typical squamous cells, carcinoma cells are spindle cells. The significance of these spindle cells is the subject of debate, because theories range from these cells being a benign reactionary process with little clinical significance to highly malignant elements with adverse outcome.34 Molecular evidence suggests the sarcomatoid carcinoma evolves from the conventional epithelium-type component and the sarcomatoid component has a malignant nature.35 Grossly, they can often present as large polypoid lesions that sometimes act as ball valves in the larynx. Basaloid squamous cell carcinoma and lymphoepithelioma of non-nasopharyngeal origin are rare tumors seen in numerous head and neck mucosal sites, including the larynx and hypopharynx.

The remaining 5% of larynx cancers are composed of neoplasms more commonly found in other locations. Salivary gland cancers, neuroendocrine tumors36 (including small cell carcinomas), sarcomas, and lymphomas have all been reported in the literature.37

Pathways of Spread

Primary Site and Regional Lymphatics

Larynx

The larynx is divided into three regions: the supraglottis, glottis, and subglottis. The supraglottic larynx lies above the level where the mucosa of the upper surface of the true vocal cords turns upward to form the lateral wall of the ventricle. It consists of the false vocal cords, arytenoids, aryepiglottic folds, and infrahyoid and suprahyoid epiglottis. The glottic region by definition includes the true vocal cords and extends 0.5 cm inferiorly, and the subglottic region extends from there to the superior aspect of the trachea (Fig. 33-1).

Primary glottic cancers are about three times more common than supraglottic carcinomas, whereas subglottic carcinomas are extremely rare (about 2% of larynx cancers). At diagnosis, nearly two thirds of patients with laryngeal cancer have their disease confined to the laryngeal structures and less than 10% present with distant metastases. The patterns of spread, presentations, and management of cancers arising from these three subsites are very different.

Glottis

Most glottic lesions arise on the free margin and upper surface of the anterior two thirds of the true cord. These tumors tend to grow slowly and remain confined to the mucosa of the true cords. Eventually they will spread superiorly or inferiorly onto the mucosa of the supraglottic or subglottic structures. Some tumors may grow outward, in an exophytic fashion, leading to voice changes and subsequently respiratory obstruction. Invasion into the intrinsic musculature and joints of the larynx decreases vocal cord mobility and ultimately causes vocal cord fixation. Noteworthy is that tumor bulk alone can cause impaired mobility. Less commonly, infiltration of the recurrent laryngeal nerve may also cause impairment of mobility.

Infiltrative tumors will breach into the paraglottic and pre-epiglottic spaces. These spaces lie between the external frame of the larynx (thyroid-cricoid cartilages and hyoid bone) and the internal components of the larynx (epiglottis, muscles, and ligaments) and are filled with fat and hence offer little resistance to infiltration. From these spaces, infiltrative tumors may break through ligaments above or below the thyroid cartilage into the neck or may invade the cartilage directly.

The mucosa of the true vocal cords has a sparse lymphatic supply. Thus, glottic carcinomas have a low propensity for lymphatic spread. The incidence of lymphadenopathy at diagnosis is approximately 5% for T1 and T2 lesions and approximately 20% for T3 and T4 tumors.38 The frequency of occult nodal involvement is also low. Byers and colleagues39 found microscopic nodal involvement in 9 of 57 patients who underwent elective nodal dissection for T3 or T4 vocal cord lesions; most frequently involved nodes were the upper jugular (level II), midjugular (level III), and paratracheal groups (level VI).

Supraglottis

There are some variations of growth patterns within subsites of the supraglottic larynx. Suprahyoid epiglottic tumors sometimes grow in an exophytic pattern off the tip of the epiglottis, causing no symptoms until they become quite large. At other times they spread inferiorly, infiltrating and eroding the epiglottis. These lesions can eventually autoamputate the tip of the epiglottis. Complete regression of these tumors after RT may leave only a small epiglottic stump. Such an anatomic aberration increases the risk for aspiration.

Infrahyoid epiglottic lesions tend to spread anteriorly or circumferentially They can invade directly through the base of the epiglottis into the pre-epiglottic space and spread onto the lingual epiglottis and subsequently invade the vallecula, pharyngoepiglottic folds, and tongue base. At other times they spread onto the aryepiglottic folds, usually spreading from their midline position in both directions to involve both folds, producing a horseshoe-like appearance. They then spread either inferiorly onto the false vocal cords or over the aryepiglottic folds onto the piriform sinuses.

Lesions originating on the aryepiglottic folds can spread in all directions, that is, anteromedially onto the epiglottis, posteriorly to the arytenoids, inferiorly to the false cords, or laterally into the piriform sinus. Similar to lesions of the false vocal cords, they have variable growth patterns but often are infiltrative with easy access to the paraglottic space. They can frequently involve the cricoarytenoid joints or the musculature of the larynx, impairing mobility.

The primary difference between supraglottic cancers and true glottic cancers is the likelihood of developing cervical nodal metastases. At diagnosis, 55% of patients with supraglottic cancers have clinically involved lymph nodes. Lymphatic vessels in the supraglottic larynx collect in channels that pass through the piriform sinuses to drain to nodes along the jugular chain, particularly the upper (level II) and midjugular (level III) lymph nodes. Lee and associates40 reported on the data of a subgroup of patients with intermediate-stage disease who underwent supraglottic laryngectomy with neck dissections. One third of patients had palpable nodes on presentation, and nearly an additional third of patients had pathologic nodal involvement.

Hypopharynx

The hypopharynx is the inferior portion of the three divisions of the pharynx (Fig. 33-2). It extends from the hyoid bone superiorly to the cricoid inferiorly. Valleculae, pharyngoepiglottic fold, and lateral projections of aryepiglottic folds are considered the superior border separating the hypopharynx from oropharynx. Inferiorly, the hypopharynx ends at the cervical esophageal inlet. The hypopharynx is subdivided into three components: the pharyngeal walls, the piriform sinus, and the postcricoid pharynx. The hypopharyngeal walls are a continuation of the lateral and posterior oropharyngeal walls. The pair of piriform sinuses is created by the invagination of the larynx into the hypopharynx. They are conical (more truly pear shaped, hence the derivation of its name). Each sinus (or recess) consists of three walls. The medial wall is essentially the lateral aspect of the larynx; superiorly, it becomes the aryepiglottic fold. The lateral wall is a continuation of the lateral wall of the oropharynx. Anteriorly, the medial and lateral walls converge to form the narrow anterior wall. Superior is the base or vestibule formed by the rim of the three walls. Inferiorly, the three walls merge to form the apex.

The postcricoid pharynx begins superiorly at the level of the arytenoids and ends inferiorly at the esophagus. The posterior larynx makes its anterior border, and posteriorly it again is a continuation of the posterior pharyngeal wall.

Hypopharyngeal cancers also commonly present as nodal metastases. Lindberg41 reported a 75% incidence of nodal metastases in patients presenting to the M.D. Anderson Cancer Center (MDACC) with hypopharyngeal tumors. Level II and III nodes were most frequently involved, and bilateral lymphadenopathy was seen in 15% of patients. These tumors also have access to deep jugular and retropharyngeal lymph nodes.

Distant Metastases

The incidence of distant metastases from cancers of the head and neck and specifically laryngeal and hypopharyngeal cancers is low and is generally thought to be less than 10%. An often-referenced study by Crile in 190642 reported an incidence of 1% distant metastases in 4500 patients with epidermoid cancers of the head and neck. In subsets of patients with head and neck squamous cell cancers, patients with glottic tumors usually have the lowest rates of distant metastases whereas patients with hypopharyngeal carcinomas often have the highest rates.

Merino and colleagues43 analyzed the incidence of distant disease in over 5000 patients with head and neck squamous cell carcinomas treated from 1948 through 1967. Among patients with control of disease above the clavicle, the incidence of distant failure was 1%, 13%, and 23% for patients with carcinomas of the true vocal cords, supraglottic larynx, and hypopharynx, respectively. Similarly, Marks and associates44 found that 23% of patients with piriform sinus cancers developed distant metastases, with a higher rate among patients who underwent total laryngectomies as part of their therapy. The incidence of metastases is associated with stage of disease, because the clinical incidence of metastases is approximately 20% in patients with stage IV disease.

The sites of presentation of distant metastases are similar for cancers of the larynx and hypopharynx.43 The lungs are the most common site and are the first site of presentation in nearly 60% of patients. Bones are the next most common site, because 20% of patients with distant disease develop osseous metastases. Liver metastases are common in autopsy studies, but clinical liver metastases develop in only 10% of patients with hematogenous spread of disease from the larynx and hypopharynx.45 Spread to mediastinal lymph nodes, the brain, or other organs is very uncommon.

Molecular Biology

The critical events of carcinogenesis and tumor progression occurring at a molecular level have been heavily studied over several decades. Paradoxically, as our knowledge of molecular tumor biology increases, the complexity of tumorigenesis at this level also appears to increase. This is in part due to the realization that laryngeal and hypopharyngeal tumors, while developing in a “single” site, represent a heterogeneous group of neoplasms. Investigators have found genotypic markers, either chromosomal rearrangements, or the presence of an oncogene, tumor suppressor gene, or other markers but have only found them in some varying percentage of laryngeal and hypopharyngeal tumors.

A general view is that tumorigenesis of head and neck malignancies occurs because of a combination of factors. Carcinogen exposure (primarily tobacco) results in genetic damage. However, not all smokers develop cancer. The genetic damage in individuals varies based on the degree of exposure of the offending agent as well as the individual’s inherent sensitivity to genetic damage. The latter can be tested indirectly in individuals using an assay quantifying chromosomal breakage induced by in-vitro exposure to bleomycin. Patients with upper aerodigestive tract malignancies were compared with healthy controls. Mutagen-sensitive individuals had a higher likelihood of having a cancer, and mutagen-sensitive smokers were at the highest risk.46

A field of mucosa is placed at risk for developing carcinoma by the exposure and sensitivity described earlier, but it requires a number of events to develop a frank cancer. The concept of field cancerization was first described in 1953 by Slaughter and associates.47 These researchers found widespread microscopic abnormalities in “normal” mucosa adjacent to tumor obtained from resected specimens. These abnormalities ranged from hyperplasia to areas of carcinoma both invasive and in situ away from the known resected cancer. Califano and colleagues48 proposed a genetic progression model in which the local clinical phenomenon of field cancerization involves the expansion and migration of clonally related preneoplastic cells.

The molecular events leading to the development of carcinomas are believed to occur by a multistep process and have been described for other cancers.49 This theory is applicable to head and neck cancers and appears consistent with the pathologic findings of field cancerization. Genotypic alterations in histologically normal epithelium adjacent to invasive carcinomas have been described. Voravud and associates50 found increased chromosomal polysomies in normal mucosa of smokers with invasive carcinomas but not in mucosa of healthy nonsmoking volunteers. The most frequent findings in premalignant tissue are deletions of one of the two alleles at chromosomes 3p and 9p21.51 These regions harbor tumor suppressor genes and thus may be involved with malignant transformation. It has also been observed that telomerase is activated in head and neck squamous carcinoma and dysplasia and may be an early event in the tumorigenic process.51

TP53 is a tumor suppressor gene. A mutation in TP53 is regarded as the most common related genetic change in human cancers.52 The normal TP53 protein has a short half-life, so its detection is thought to represent TP53 mutation. Shin and colleagues53 found TP53 expression in normal tissue and premalignant lesions adjacent to head and neck tumors but not in normal tissues from normal control patients. Numerous investigators have found overexpression of TP53 protein in laryngeal carcinomas, typically in approximately half the tumors studied.53,54 Alterations in TP53 are thought to be an important step early in the carcinogenic process but not a necessary step for all laryngeal and hypopharyngeal tumors. The finding of this protein in laryngeal specimens is also unclear, because, although there are diverging study results, most investigators have not found a prognostic value to the finding of TP53 protein in larynx tumor specimens.5457

Other cellular changes in laryngeal carcinogenesis involve epidermal growth factor receptor (EGFR), CCND1 (formerly cyclin D1), and CDKN2A. Weichselbaum and colleagues58 described elevations in EGFR expression in head and neck tumor cell lines. In an analysis of premalignant and malignant head and neck tumor specimens, EGFR levels correlated with increasing severity of dysplasia.59 Furthermore, Shin and colleagues60 found elevated EGFR levels in premalignant tissues but dramatic up-regulation in invasive carcinoma specimens. EGFR was amplified in DNA from 29% of sampled hypopharyngeal cancers, and it is overexpressed in at least 80% of head and neck cancers. This overexpression has been demonstrated to be an independent prognosticator in head and neck cancer.59

Clinical Manifestations, Patient Evaluation, and Staging

Patient Evaluation

Laryngeal Cancer

Clinical evaluation of laryngeal cancer includes indirect laryngoscopy with a mirror that is frequently supplemented by fiberoptic endoscopy (Table 33-1). Similar to other tumors in the head and neck, the examiner assesses the tumor size, morphology, infiltration (defect, distortion) of adjacent structures, and vocal cord mobility. It is important to palpate the base of the tongue to determine direct invasion from the supraglottic larynx and to look for indirect signs of pre-epiglottic space invasion such as fullness of the vallecula or ulceration of the infrahyoid epiglottis. A direct laryngoscopy is often the final step in evaluation. It is needed to further outline the disease extent and, in particular, to obtain biopsy specimens for tissue diagnosis.

TABLE 33-1 Evaluation of Patients with Suspected Laryngeal or Hypopharyngeal Cancer

* In patients with more advanced disease, these tests may augment the workup for metastatic disease; PET and barium studies may help better define the inferior extent of advanced hypopharyngeal cancers.

Examination of the neck is important to detect lymphadenopathy or direct tumor extension manifesting as tenderness of the thyroid cartilage or the presence of a subcutaneous mass. Firm fullness over the thyroid notch is suggestive for pre-epiglottic space involvement.

Radiologic studies are indicated when there is the suggestion of deep infiltration. CT (Fig. 33-3) or MRI is useful for the assessment of the pre-epiglottic space, tongue base, paraglottic region, and subglottis (which is sometimes difficult to evaluate from above with the mirror or fiberoptic scope). These images may help differentiate direct primary tumor extension to the soft tissue of the neck from nodal involvement. Anterior commissure lesions may have subtle thyroid cartilage invasion only detectable by CT.

Hypopharyngeal Cancer

Evaluation of hypopharyngeal tumors is similar to that of larynx cancers. Because these lesions are typically at an advanced stage, it is not uncommon to palpate disease in the neck by direct extension. The thyroid click may be lost owing to anterior displacement of the larynx by a posteriorly located (particularly postcricoid) lesion. Phonation may provide better visualization of the piriform sinus on indirect mirror and fiberoptic examination. If unsuccessful, a Valsalva maneuver may open the sinus. Deep infiltrative lesions in the apex may be hard to see but are suspected by either pooling of secretions or arytenoid edema. Assessment of laryngeal mobility is important in medial wall lesions because they can invade directly into the laryngeal framework. In addition to CT (Fig. 33-4), combined 18F-fluorodeoxyglucose-labeled positron emission tomography and CT (FDG-PET/CT) may be helpful in defining tumor extent, particularly the inferior border where subtle changes in the inferior hypopharynx and superior cervical esophagus may be hard to identify solely on anatomic images.

Staging

Larynx

Tumors are staged using the American Joint Committee for Cancer (AJCC) TNM system27 (Table 33-2). The system is currently in its seventh iteration, most recently revised in 2010. The system classifies/categorizes larynx cancer primary tumors (T) by sites of extension and cord mobility but not size. For glottic tumors, stage T1 is disease limited to the vocal cord(s). The AJCC staging system further divides T1 glottic tumors into T1a for tumors confined to one true vocal cord and T1b for tumors involving both vocal cords. In general, this subdivision is more useful for communication and may influence the treatment decision (i.e., limited surgery vs. RT) but does not have a strong impact on prognosis. T2 glottic tumors have either supraglottic or subglottic extension and/or impaired mobility. Although not defined by the AJCC, T2 glottic lesions can be subdivided into T2a for normal mobility and T2b for impaired mobility. This subdivision is not uniformly used, however, because there is no general agreement that treatment outcomes differ among the substages.

TABLE 33-2 American Joint Committee on Cancer Staging of Laryngeal and Hypopharyngeal Cancers

Glottis
Tis Carcinoma in situ
T1 Tumor limited to the vocal cord(s) with normal mobility
T2 Tumor extends to supraglottis and/or subglottis and/or with impaired cord mobility
T3 Tumor limited to the larynx with vocal cord fixation and/or invades paraglottic space and/or minor thyroid cartilage erosion
T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx
T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Supraglottis
Tis Carcinoma in situ
T1 Tumor limited to one subsite of the supraglottis with normal vocal cord mobility
T2 Tumor invades mucosa of more than one subsite of the supraglottis or glottis or adjacent site outside the glottis, without fixation of the larynx
T3 Tumor limited to the larynx with vocal cord fixation and/or invades any of the following: the pre-epiglottic space, the postcricoid area, and/or minor thyroid cartilage erosion
T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx
T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Hypopharynx
T1 Tumor limited to one subsite of hypopharynx and 2 cm or less in greatest dimension
T2 Tumor invades more than one subsite of hypopharynx or an adjacent site or measures between 2 and 4 cm in greatest dimension, without fixation of hemilarynx
T3 Tumor measures greater than 4 cm or with fixation of hemilarynx
T4a Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, or central compartment soft tissue
T4b Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures
Nodal Involvement (N)
Nx Nodes cannot be assessed
N0 No clinically positive node
N1 Single clinically positive ipsilateral node 3 cm or less in diameter
N2 Single clinically positive ipsilateral node more than 3 cm, but not more than 6 cm in diameter or multiple clinically positive ipsilateral or bilateral or contralateral nodes, none more than 6 cm in diameter
N2a Single clinically positive ipsilateral node more than 3 cm, but not more than 6 cm in diameter
N2b Multiple clinically positive ipsilateral nodes, none more than 6 cm in diameter
N2c Bilateral or contralateral lymph node, none more than 6 cm in greatest dimension
N3 Metastases in a lymph node more than 6 cm in greatest dimension
Stage Groupings
Stage I T1N0M0
Stage II T2N0M0
Stage III T3N0M0
T1-3N1
Stage IVA T4aN0-1M0
T1-4aN2M0
Stage IVB T4bN0-3M0
T1-4bN3M0
Stage IVC T1-4N0-3M1

From Edge SB, Byrd DR, Compton C, et al, editors: AJCC Cancer Staging Handbook, ed 7. New York, 2010, Springer, pp 33-57. Used with permission of the American Joint Committee on Cancer.

Two significant revisions were made to the sixth edition of the staging system.61 Historically, the definition of T3 glottic disease has been fixation of the vocal cord. The sixth edition expanded on this definition and included paraglottic space invasion or minor thyroid cartilage invasion. Previous editions had defined T4 disease as invasion through the thyroid cartilage, but a common misinterpretation was to include any thyroid cartilage invasion into the T4 category. The new definition was made to clarify this point. The significance of this distinction is in the era of larynx preservation (see later); many still think that the presentation of invasion through the cartilage into the extralaryngeal tissues precludes a nonsurgical approach, but patients presenting with minimal invasion into the inner cortex may have disease suitable for larynx preservation.

The second modification is the subdivision of T4 disease. For head and neck cancers in general, the sixth edition had subdivided stage T4 into resectable (T4a) and unresectable (T4b) categories. Thus glottic cancer T4a disease has been defined as tumor that invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus), and T4b is tumor invading prevertebral space, encasing carotid artery, or invading mediastinal structures. Subsequently, the only change made in the seventh edition was descriptive. Stage T4a now describes moderately advanced local disease, and T4b describes very advanced local disease.

The staging of supraglottic cancers requires the division of the supraglottis into five subsites: the suprahyoid epiglottis, infrahyoid epiglottis, aryepiglottic folds, arytenoids, and ventricular bands (false cords). T1 disease is disease confined to one subsite (with normal vocal cord mobility). T2 disease invades more than one adjacent subsite or region outside the supraglottis (mucosa of base of tongue, vallecula, or medial wall of the piriform sinus). T3 disease is similar to glottic carcinoma, although it also includes pre-epiglottic space invasion or postcricoid involvement. Last, in the newest edition, the definition of T4 supraglottic cancer is the same as that for glottic cancer with subdivisions into moderately advanced and very advanced (T4a and T4b) categories.

Hypopharynx

T category for hypopharyngeal tumors is also based on sites of involvement and larynx motion (an indirect measurement of disease extension). The fifth edition of this staging classification had a significant modification to also include the size of the tumor in staging.62 This change addressed a major deficiency in prior systems, because the older systems tended to understage hypopharynx tumors relative to other head and neck mucosal cancers. The hypopharyngeal T category still does not reflect morphology, which remains an important criterion for selection of local therapies, because exophytic tumors in this site are usually selected more frequently than infiltrative lesions for organ-preserving therapies. The sixth edition made one additional modification. As described for laryngeal cancers, resectable T4a and unresectable T4b categories were defined. T4a hypopharyngeal disease can invade thyroid or cricoid cartilages, hyoid bone, thyroid gland esophagus, or central compartment, while T4b disease invades prevertebral fascia, encases carotid artery, or involves mediastinal structures. The newest edition now defines T4a and T4b as moderately advanced and very advanced.

Primary Therapy

Early Carcinomas

T1 and T2 Glottic Tumors

The management of early glottic carcinomas is controversial and is often determined by the preferences and expertise of the attending physicians. Oncologists advocate either irradiation or voice-preserving partial laryngectomy. Large published series have for all practical purposes demonstrated equivalent control rates with surgery (excision, cordectomy, or hemilaryngectomy) and RT. There has not been a true comparative study between these two modalities, and it is highly unlikely that a prospective trial will be performed.

There are several difficulties in comparing the results of various treatment options. Nearly all series are retrospective single-institutional studies. It is thus difficult to ascertain if small differences in control rates between series are real. Mendenhall and colleagues63 address this issue by defining the surgical procedure that would have been recommended in their irradiated patients. They found that the surgical treatment option would have required total laryngectomy, rather than partial voice-conserving procedures, in 10% of patients with T1 disease and 55% of those with T2 disease. However, the supracricoid laryngectomy, a procedure that removes an entire circumferential portion of the larynx and subsequently reconstitutes the larynx, has largely been developed during the past decade.64 Many patients described by Mendenhall and colleagues in 1993 deemed suitable only for total laryngectomy may now be managed with this voice-preserving surgery. Olsen65 states that it is very unusual for disease that does not fix the arytenoids to require total laryngectomy. Although this is possibly true from a technical standpoint, many larynx cancer patients are older, have long histories of tobacco exposure, and medically may not be suitable for partial laryngeal surgery other than excisions of small T1 lesions on the midcord.

In general, T1 tumors can be treated effectively with laser excision,66 laryngofissure,67 partial laryngectomy,68,69 or irradiation. Table 33-3 summarizes the results of RT. Local control rates of RT range from 85% to 95%, and ultimate control rates after salvage surgery for recurrences are greater than 95%. Surgical salvage for the uncommon local relapse often requires a total laryngectomy, but an occasional patient can have a lesion amenable to a voice-conserving partial laryngectomy.7074

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