Larynx and Hypopharynx Cancer

Key Points

Incidence

Laryngeal and hypopharyngeal cancers account for about one-third of all head and neck neoplasms, affecting approximately 13,000 Americans per year.

Biological Characteristics

Prognosis for all tumors is primarily dependent on extent of disease, although it is also influenced by the anatomic site of origin. Glottic tumors have the lowest incidence of metastases because they more commonly present with earlier-stage lesions and the true cords do not have a rich lymphatic supply compared with supraglottic and hypopharyngeal neoplasms. Hypopharyngeal cancers have a relatively high metastatic rate among head and neck cancers.

Staging Evaluation

Staging includes history; complete head and neck examination, including indirect and direct laryngoscopy, contrast-enhanced computed tomography (CT), or magnetic resonance imaging (MRI) of the head and neck region; blood chemistry, and chest radiography.

Primary Therapy

Early-stage disease can be treated with a single modality, either surgery or radiotherapy (RT). Reported cure rates range from 65% to 95% and depend primarily on the bulk of disease.

Adjuvant Therapy

High cure rates have not justified adjuvant therapies for early-stage disease.

Locally Advanced Disease

The concept of larynx preservation has been validated as an option for patients with T3 disease. Concurrent chemoradiation has been demonstrated to improve the larynx preservation rate compared with irradiation alone or treatment with neoadjuvant chemotherapy; the latter has been shown to have comparable survival to laryngectomy. Approximate 5-year survival rates for these patients are 50% to 55%. For elderly patients in whom the toxicity of chemotherapy is a concern, irradiation alone is a valid alternative for patients desiring larynx preservation. Altered fractionation may be employed in these cases to improve locoregional control. Surgery remains the mainstay for advanced but resectable disease (category T4a), with adjuvant postoperative RT used for patients at high risk for locoregional failure. Concurrent chemoradiation is advocated for patients with inadequate margins or extranodal or soft-tissue disease extension. Local control rates for this group range from 60% to 90%, but 5-year survival rates are between 20% and 40%.

Palliation

Palliative therapies are dependent on prior therapies received and disease location and extent. RT, chemotherapy, and surgery are all used but are individualized.

Management of cancers of the larynx is a special challenge for head and neck oncologists. Laryngeal cancer, even in locally 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 oncological 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, radiotherapy (RT), or a combination of the two therapies was used and individualized to best meet these endpoints. Both modalities have improved in eradicating the disease and preserving function over the years. Newer, more technically sophisticated voice-conserving surgical procedures have been developed. Decades of clinical trials have advanced our understanding of the influences of radiation dose, treatment duration, and treatment volumes. This knowledge, combined with dramatic advances in radiation delivery and planning, has led to better outcomes for patients with these diseases. Important improvements in defining disease extent, by both physical examination with fiberoptic laryngoscopy and radiological 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 attempts 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 the physician's best guess as to 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 deglutition; thus, 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 13,000 Americans per year, accounting for approximately one-fourth to one-third of all head and neck cancer cases and less than 1% of all new cancer cases in the United States. Mortality resulting from cancers of the larynx is relatively low, accounting for approximately 3700 deaths per year in the United States.

The most recent data from the Surveillance, Epidemiology, and End Results (SEER) program (1975-2015) estimated an overall incidence of 2.6 cases per 100,000 people per year in 2015, nearly half the incidence of 1975. Comparisons reveal case incidences of 5.2 versus 1.1 (per 100,000 persons) in males and females, respectively. There is a higher incidence among blacks than among whites for both men and women.

The median age of patients presenting with larynx cancer is 65 years. Less than 4% of patients are younger than 45 years old.

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. More than 95% of patients with laryngeal cancer have a history of tobacco use. Cigar and pipe smoking have also been associated with cancer of the larynx, but studies on this issue have been more controversial. In the years between 1965 and 2004, rates of cigarette smoking by adults in the United States were halved (42% to 21%); from 2005 to 2010, there was a less dramatic decrease in the rates of smoking (20.9% to 19.3%). Given the correlation between smoking and the development of laryngeal cancer, these reductions would be expected to translate into a lower incidence of laryngeal cancer. Indeed, there have been statistically significant reductions in the age-adjusted incidence rates for glottic and supraglottic cancers, as measured from 1973 to 2003.

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. A history of heavy alcohol use is more strongly associated with supraglottic and hypopharyngeal cancers. Likewise, occupational exposures to asbestos, mustard gas, nickel, soot, and tars have been linked to laryngeal cancer, but generally, a tobacco use history is also present. 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.

Attention has been directed at the influence of gastroesophageal reflux disease (GERD) on laryngeal diseases, including carcinomas. Three separate studies have described cohorts of nonsmoking patients with GERD and laryngeal cancer. Bacciu et al. 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 significant.

Human papillomavirus (HPV) has been causally linked to multiple cancers, including head and neck cancers, 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.

Hypopharyngeal cancers are less common than laryngeal tumors. The estimated incidence in the United States is 2500 cases per year. Etiological risk factors are similar to those for laryngeal tumors, 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 by-product of these policies may be a decline in the incidence of laryngeal and hypopharyngeal carcinomas.

Although government policies have been directed at diminishing carcinogenic etiological 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, particularly patients who have smoking or alcohol use histories. 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.

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. Research in the role of chemoprevention was popular in the 1990s. However, in 2002, the Radiation Therapy Oncology Group (RTOG) completed accrual to a trial testing chemoprevention with 13- cis -retinoic acid in a multi-institutional setting. Nearly 1400 patients with stage I or II cancer were accrued. 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 that those who smoked were more likely to develop second cancers.

While new compounds for chemoprevention are currently being investigated, the enthusiasm for chemoprevention, particularly for a disease whose incidence is decreasing through active smoking-cessation programs, has been muted. Compounds still of interest include green tea extracts, curcumin analogs, soybeans, celecoxib, erlotinib, and rapamycin. These agents are being tested in coordination with efforts to identify molecular prognostic markers. However, large trials similar to the RTOG trial mentioned earlier are unlikely.

Early Detection

Similar to the issues surrounding prevention, early detection of laryngeal and hypopharyngeal cancers centers on targeting the population at highest risk for developing these carcinomas. Cancers of the larynx and hypopharynx affect roughly 13,000 Americans per year; therefore, this group of cancers is not considered a large enough health problem to warrant screening of the general population. Some investigators have studied the role of screening a more focused population, such as tobacco users who work in high-risk occupations, and question the value of screening even a more limited population. However, Prout et al. argue that a primary care practitioner can, as part of a general evaluation, inquire about hoarseness in a patient from an at-risk population. If a positive response is obtained, the patient can be referred to an otolaryngologist for appropriate evaluations. The laryngeal carcinoma detection rate in this situation ranges between 3% and 4%.

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 pathological tissue changes within the larynx, ranging from premalignant atypia or dysplasia to carcinoma in situ and superficially invasive carcinomas.

Carcinoma in situ is a pathological 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 lamina propria makes the diagnosis of invasive carcinoma. Invasive tumor may be missed if biopsy samples are too small or too superficial for proper histological 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. These 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 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. Molecular evidence suggests that the sarcomatoid cells evolve from the conventional epithelium-type component and the sarcomatoid component has a malignant nature. Grossly, they can often present as large polypoid lesions that sometimes act as ball valves in the larynx. Basaloid squamous cell carcinoma and lymphoepithelioma not of 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 tumors (including small cell carcinomas), sarcomas, and lymphomas have all been reported in the literature.

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 the inferior aspect of the glottis to the superior aspect of the trachea ( Fig. 41.1 ).

Primary glottic cancers are about three times more common than supraglottic carcinomas, whereas subglottic carcinomas are extremely rare (about 2% of laryngeal 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 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, to respiratory obstruction. Invasion into the intrinsic musculature and joints of the larynx decreases vocal cord mobility, ultimately causing 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 preepiglottic 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; hence, they 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. The frequency of occult nodal involvement is also low. Byers et al. 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 2), midjugular (level 3), and paratracheal groups (level 6).

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 preepiglottic space, 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 into 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 are often 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 2) and midjugular (level 3) lymph nodes. Lee et al. 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; nearly an additional third of patients had pathological nodal involvement.

Subglottis.

Subglottic tumors spread inferiorly to the trachea, extend through the cricothyroid membrane into the neck, or directly invade the cricoid cartilage. Superiorly, they almost always involve the undersurface of the true glottis. From a staging perspective, it is sometimes difficult to differentiate between a tumor truly originating from the subglottis and a glottic tumor with significant subglottic extension.

Primary subglottic tumors drain to the paratracheal nodes (levels 6 and 7). The jugular nodes (levels 2, 3, and 4) are a secondary echelon and are rarely involved in the absence of metastases to the paratracheal nodes. Because of the rarity of subglottic tumors, the true incidence of involvement of nodes is difficult to determine, with estimates varying from less than 5% to 25%.

Hypopharynx.

The hypopharynx is the inferior portion of the three divisions of the pharynx ( Fig. 41.2 ). It extends from the hyoid bone superiorly to the cricoid inferiorly. Valleculae, the pharyngoepiglottic fold, and the lateral projections of the aryepiglottic folds are considered the superior border separating the hypopharynx from the oropharynx. Inferiorly, the hypopharynx ends at the cervical esophageal inlet. The hypopharynx is subdivided into three components: the pharyngeal walls, piriform sinus, and 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, covering the posterior aspect of the cricoid cartilage. The posterior larynx makes its anterior border; posteriorly, it again is a continuation of the posterior pharyngeal wall.

Hypopharyngeal cancers also commonly present with nodal metastases. Lindberg reported a 75% incidence of nodal metastases in patients presenting to the M. D. Anderson Cancer Center (MDACC) with hypopharyngeal tumors. Levels 2 and 3 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.

Piriform sinus tumors.

Piriform sinus tumors account for 70% of cancers originating in the hypopharynx. Tumors originating from the medial wall of the piriform sinus behave similarly to supraglottic tumors arising from the aryepiglottic folds, and it is often difficult to know the true origin of some of these lesions. Posteriorly, there is little to impede tumor extension into the postcricoid space or crossing from the ipsilateral arytenoid to the contralateral arytenoid. Lateral wall tumors also have few barriers to growth. They can extend medially along the mucosa to involve the posterior hypopharyngeal wall or anteromedially to involve the other two walls of the piriform sinus. Inferiorly, they have quick access to the apex and usually extend deep to the sinus submucosally to involve other adjacent structures, including the thyroid and cricoid cartilages, or directly into the thyroid gland. It is not uncommon to see advanced tumors from this location that have direct soft-tissue extension into the neck. These tumors can also extend into the cervical esophagus, primarily through submucosal routes, making a true definition of disease extent extremely difficult. They can also behave similarly to more classical esophageal tumors, with extensive spread along lymphatic spaces and with skip lesions.

Hypopharyngeal wall tumors.

Tumors originating from the hypopharyngeal walls are less common. Because early presentations are infrequent, it is unusual to see a lesion confined to and clearly originating from the lateral or posterior hypopharyngeal wall. Hypopharyngeal wall tumors frequently spread along the walls to involve either the posterior or lateral oropharyngeal walls and can also spread inferiorly and invade the cervical esophagus. Posterior wall tumors can also invade the prevertebral tissues or invade even more deeply to the bones of the cervical spine.

Postcricoid tumors.

Postcricoid tumors are the least common hypopharyngeal tumors. They almost always present in advanced stages. They can extend laterally into one or both piriform sinuses, directly invade laryngeal structures, and can also spread inferiorly and invade the cervical esophagus.

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