Etiology

Squamous cell carcinoma of the larynx is strongly associated with the use of tobacco and alcohol. An increase in the prevalence of cigarette use among females in the past has been linked to a proportionate increase in the number of female patients with laryngeal cancer. Other factors implicated in the development of laryngeal cancer include passive smoking, chronic laryngeal irritation from gastroesophageal reflux, and viral infection.^5–9

Since 1979 gastric acid reflux has been identified as a risk factor for laryngeal and pharyngeal cancer.^10,11 Alkaline reflux has more recently been identified as a laryngeal carcinogen by Galli and colleagues.¹² These investigators identified a higher than expected number of patients with pharyngolaryngeal cancer associated with achlorhydria and presumed alkaline reflux after gastric resection. They concluded that periodic endoscopy of the upper aerodigestive tract should be performed on gastrectomized patients because of their higher risk for pharyngolaryngeal disorders in general and cancer in particular. These investigators also identified that, among patients with laryngeal squamous cell carcinoma with an intact gastric acid secreting mechanism, 81% showed abnormal acid reflux on 24-hour pH testing.

Human papillomavirus (most notably the oncogenic type 16) has been associated with head and neck cancer.^13–15 The role for human papillomavirus (HPV) infection in laryngeal oncogenesis has been supported by previous study but does not have as strong an association as has been identified with cancer of the oropharynx and oral cavity.^16,17 Initial study suggests that a difference exists in behavior between HPV and non–HPV-related squamous cell carcinoma of the upper aerodigestive tract, with a better prognosis afforded the HPV-positive cases.¹⁸

Differences in exposure to carcinogens or genetic susceptibility may explain the differences in the predominant types of laryngeal cancer throughout the world. Glottic cancers predominate over supraglottic cancers in the United States at a ratio of 2 : 1. In France the opposite occurs, where the number of supraglottic cancers exceeds that of glottic cancers at a ratio of 2 : 1.¹⁹ In Finland the incidence of supraglottic cancer decreased and the incidence of glottic cancers increased between the decades 1976 to 1985 and 1986 to 1995.²⁰ Supraglottic cancers were more common than glottic cancers in the earlier decade (ratio of 1.4 : 1). Glottic cancers predominated in the later decade at a ratio of 2 : 1. The reason for this change in distribution of laryngeal cancers in Finland is not clear. A low exposure to alcohol and a high availability of medical services were factors Brenner and colleagues identified as important determinants to the characteristics of laryngeal cancer in Israel. These investigators linked these factors to the high proportion of laryngeal cancers treated at an early stage with an overall better outcome when compared with other countries.²¹

Staging

The most widely accepted system for classifying cancer in the United States, as is currently promoted by the American Joint Committee on Cancer (AJCC), had its beginning in 1959 with the organization of the American Joint Committee for Cancer Staging and End-Results Reporting (AJC).²² This staging system was first published in 1977 in the Manual for Staging of Cancer.²³ The staging system has evolved to its current form as it is codified in the AJCC Staging Manual, Sixth Edition published in May of 2002 and implemented as of January 1, 2003.²⁴ Major revisions made to the fifth edition in the head and neck section were directed primarily to the advanced-stage cases. Although the definitions for stages 0, I, and II laryngeal cancers remained unchanged, alterations to the T₃ definitions in the sixth edition have impacted on the interpretation of T₁ and T₂ classification.

The anatomic definitions and boundaries between sites, as published in the AJCC Staging Manual, have remained constant across the multiple editions. The glottis has been defined as the true vocal cords including the anterior and posterior commissures. Unfortunately, the definition of the posterior commissure remains vague. It is difficult to discriminate among the glottis, the adjacent supraglottis (arytenoids), and the hypopharynx (postcricoid region) in the region of the posterior commissure.²⁵ The superior border of the glottis is more clearly defined by a horizontal plane passing through the apex of the ventricle. The inferior limit of the glottis is defined by a line parallel to and 1 cm inferior to this plane.

Glottic cancers are staged primarily by clinical assessment of degree of vocal cord mobility (Table 108-1).²⁴ Cancers confined to the glottis with normal mobility are staged T₁. Subdivision of T₁ vocal cord cancers is based on extension to involve the opposite cord. A tumor limited to one vocal cord is T_1a. A horseshoe lesion that extends around the anterior commissure to involve both vocal cords without impairing mobility is T_1b. Despite consistency across all previous editions of AJCC staging manuals indicating that T₄ status is based on “tumor invasion through the thyroid cartilage …, ” it has been common clinical practice to consider any extent of thyroid cartilage invasion from a glottic cancer to be cause for T₄ classification. Clinically apparent stage I glottic cancers (T₁N₀M₀) were reassigned stage IV status (T₄N₀M₀) when “microscopic invasion of adjacent cartilage” was identified.²⁶ Revision to the AJCC Staging Manual, Sixth Edition identifies that minor cartilage erosion (e.g., inner cortex) should be classified as T₃ rather than T₄.

Table 108-1 Primary Tumor (T) Classification of Glottic Cancer

From Greene F, Page D, Fleming I, et al. AJCC Cancer Staging Manual. 6th ed. New York: Springer Verlag; 2002.

Glottic cancers continue to be classified T₂ on the basis of two separate criteria: impaired vocal cord motion or transglottic spread beyond the glottis to involve either the supraglottis or subglottis. Although the AJCC does not discriminate between these two criteria, some investigators distinguish T_2a from T_2b cancers. T_2a vocal cord cancers do not impair mobility but are a higher stage than T₁ cancers by virtue of transglottic spread to involve the supraglottis or subglottis. T_2b cancers are sufficiently invasive to impair vocal cord mobility without causing complete fixation. Revision to the sixth edition identifies that T₃ classification results from vocal cord fixation or invasion of the paraglottic space. This clarification is helpful to resolve controversy in the interpretation of subtle differences between impaired vocal cord motion and fixation. If the arytenoid remains mobile but the membranous vocal cord is tethered by deep infiltration to the paraglottic space, the cancer is considered a T₃.

Still further clarification is necessary to address inconsistencies that persist among publications describing the paraglottic space.^12,27–29 Berman defined the borders of the paraglottic space as they have been commonly reported by others:

This definition fails to address the controversy as to whether all, part, or none of the thyroarytenoid muscle is part of the paraglottic space.³⁰ An assessment by Weinstein and colleagues³¹ defines the medial border of the paraglottic space as the tissue lateral to the conus elasticus at the glottic level and lateral to the quadrangular membrane at the supraglottic level. By this convention, the thyroarytenoid muscle is considered part of the paraglottic space. Others define the glottic portion of the paraglottic space as the fat deep to the intrinsic laryngeal musculature. For the purposes of T classification according to the revised AJCC criteria, it is reasonable to consider that paraglottic space invasion (T₃) occurs when the fat compartment deep to the intrinsic laryngeal musculature is involved with tumor. Impaired vocal cord mobility (T₂) (without paraglottic space involvement) may be considered when the thyroarytenoid or lateral cricoarytenoid muscles are infiltrated but not fully transgressed.

Carcinoma in situ is classified as T_is. Accuracy in classifying premalignant changes affecting the laryngeal epithelium is compromised by the subjective nature of the assessment and by a lack of uniformity in terminology. Some pathologists discriminate between severe dysplasia and carcinoma in situ, whereas others group them together as type III intraepithelial neoplasia.^32–34 The grading of laryngeal dysplasia as mild, moderate, and severe or as carcinoma in situ originated from a similar classification of preneoplastic diseases of the uterine cervix. Keratinizing dysplastic lesions of the upper airway are more common than in the cervix and are also more difficult to categorize. The differences that exist in the behavior of carcinoma in situ originating at these two distinctly different anatomic sites has also undermined the transfer of concepts governing uterine cervical carcinoma in situ to laryngeal carcinoma in situ.³⁵ Despite the clearly stated pathologic principle that high-grade dysplasia and carcinoma in situ are equivalent terms in describing abnormal laryngeal squamous epithelium, clinical management is generally less aggressive for high-grade dysplasia than for carcinoma in situ.

The stage grouping of primary tumor, regional lymph nodes, distant metastatic (TNM) classifications for laryngeal cancer is the same as for other head and neck mucosal sites (Table 108-2). Although the stage groupings have been revised—with the sixth edition introducing the division of stage IV into IV a, IV b, and IV c—the staging of early glottic cancer has remained constant (stages 0, I, and II).

Definitions: Early Glottic Cancer

The appropriate definition of the term early as it applies to laryngeal cancer has been debated. Some investigators have loosely used the term to describe laryngeal cancer in the context of management options. By this convention, a laryngeal cancer is considered early if it can be treated by partial laryngeal (conservative) surgery without a neck dissection, by endoscopic excision, or by radiotherapy alone.³⁶ Others apply the term early to stage 0, I, or II tumors and late to stage III or IV tumors. This definition of early may be inappropriate. Because the extent of disease—not the rate of growth—determines staging, the term localized is more accurate than the term early.³⁷ Similarly, the term advanced may be more appropriate than the term late.³⁸ The most accurate grouping uses the terms localized for any-TN₀M₀ disease, regionally spread or vicinally spread for any-TN+M₀ disease, and widely disseminated for any-T-any-NM₁ disease.³⁹ Convention and tradition dictate that this chapter continue to use the terms early to refer to lower stage (0, I, and II) and late to refer to higher stage (III and IV).

Endoscopic Imaging

The initial evaluation of a patient with an early glottic lesion requires inspection of the larynx. The common use of flexible fiberoptic laryngoscopy to supplement indirect mirror examination now permits visualization of the majority of laryngeal cancers in a clinical setting. Videoendoscopy and videostroboscopy offer further refinement in assessing glottic lesions. It has become standard practice in many institutions to permanently record the appearance of all laryngeal cancers through video recording, using rigid or fiberoptic endoscopy. The capacity to refer to these permanent records documenting the extent of the original lesion often improves long-term patient care.

The development of flexible fiberoptic endoscopes designed for transnasal endoscopy has also permitted use of these instruments to evaluate the larynx and trachea.^40–43 The improved optics of these instruments—coupled with the presence of a side port that permits the use of suction, placement of biopsy instruments, and instillation of topical anesthetics—has expanded the capacity to perform in-office laryngeal evaluations (Fig. 108-5A). Although direct laryngoscopy remains the most appropriate approach to evaluate and biopsy the majority of lesions suspected of being malignant, in selected cases biopsy can be effected in the clinic (see Fig. 108-5B and C).

Figure 108-5. A, Transnasal esophagoscope (TNE) (Pentax). B, View of oropharynx and hypopharynx through TNE. C, Biopsy forceps prepared to remove posterior pharyngeal wall lesion.

When videostroboscopy was introduced as a common clinical tool, enthusiasm was high for its potential to help discriminate invasive cancer from epithelial atypia on the basis of the stroboscopic appearance of the vocal fold epithelial pliability.^44,45 Subsequent experience of Colden and colleagues⁴⁶ has identified that laryngeal stroboscopy is neither reliable in distinguishing vocal fold atypia from invasive cancer nor useful in determining the depth of invasion of vocal fold cancer. These investigators did suggest that the stroboscopic appearance of a relatively normal mucosal wave indicates that a lesion is superficial and does not extensively involve the underlying vocal ligament.

Advances in technology, coupling physical and biologic analysis to endoscopy, have identified several adjuncts to complement standard imaging of the larynx at the time of direct laryngoscopy. Lugol’s solution, as well as toluidine blue, have been used to stain laryngeal tissue in an effort to discriminate normal tissue from tumor.^47,48 These approaches have not met with uniform success and therefore have not been widely adopted. Fluorescent tumor markers such as tetracyclines and hematoporphyrin derivatives are preferentially absorbed by tumor cells and can be used to discriminate tumor from adjacent normal tissue by the red fluorescence they emit when exposed to ultraviolet light.⁴⁹ Additional cost and operating time, as well as problems with skin photosensitivity, have limited the usefulness of this technique. A more promising approach employing autofluorescence laryngoscopy has been reported. Zargi and colleagues⁵⁰ have employed the lung imaging fluorescence endoscope (LIFE) system to evaluate laryngeal lesions. Their preliminary work identified differences in the intensity of autofluorescence between normal and tumor tissue when exposed to blue or violet light. They also identified shortcomings in the use of the LIFE system for this purpose, noting that further technical advances are necessary to make this endeavor a useful clinical tool.

Stone and colleagues⁵¹ reported that the fluorescence of biologic tissue actually may impede the use of Raman spectroscopic analysis to discriminate normal from malignant laryngeal lesions. These investigators have developed strategies that negate the impact of the natural biologic fluorescence to permit evaluation of the distinctive spectral signatures of tissues elicited when exposed to monochromatic laser excitation. This strategy may develop into a noninvasive tool in the early detection of cancerous and precancerous lesions.

Radiology

Surgery

Physicians’ views vary on the indications for use of a specific procedure or radiotherapy technique. General guidelines for selection of an approach based on the extent of a lesion are listed in Table 108-3 and depicted in Fig. 108-6. The choice of therapeutic approach for a patient requires consideration of many other variables in addition to the anatomic extent of the cancer. Overall cure rates and laryngeal preservation figures are high for the surgical management of early glottic squamous cell carcinoma (Table 108-4).

Table 108-3 Selected Surgical Procedures for Glottic Cancer