Cancer of the Larynx
Richard O. Wein
Kathryn A. Gold
G. Brandon Gunn
Randal S. Weber
The incidence of cancer of the larynx has stabilized at ˜10,000 cases reported in the United States per year. The larynx is composed of three subsites that are unique in their predilection for regional spread, response to therapy, and capacity for laryngeal preservation with treatment. The major goals of therapy are to offer cure while preserving quality of life (QOL) and function. Posttreatment speech and swallowing capacity weigh heavily on a patient’s selection from the variety of treatment options. With early-stage cancers, the monomodality treatment options of surgery or radiation offer the possibility of good locoregional control and maintenance of function. For advanced-stage lesions, the collaborative multimodality options of surgery with adjuvant radiation or primary chemoradiation (induction vs. concomitant) offer more aggressive approaches with associated toxicity and side effects while attempting organ preservation. As with all sites in the head and neck, recurrence has a poor associated overall prognosis and, when feasible, salvage options typically require radical surgical approaches with special techniques to facilitate functional rehabilitation.
EPIDEMIOLOGY
Approximately 0.7% of all new cancer cases and 0.6% of all cancer-related deaths are due to laryngeal cancer. It is the 21st most common cancer in the United States. The estimated 5-year relative survival for cancer of the larynx by stage at diagnosis, all stages included, was reported as 61% (for the years 2001-2007). The relative survival rate by race (all races included) for laryngeal cancer has remained stable over time with only a slight decline from 66% for 1975-1989 to 63% for 2001-2007.1,2 In 2012, the American Cancer Society reported 12,360 newly diagnosed cases of cancer of the larynx (male 9,840, female 2,520) and 3,650 deaths attributable to the disease.1 In 2013, The SEER database estimated that 12,260 new cases of laryngeal cancer were diagnosed, representing 0.7% of all new cancer cases, with 3,630 attributable deaths.2
Statistics for patients with cancer of the larynx demonstrated a decrease in survival from the mid-1980s to the mid-1990s in a review performed by the National Cancer Data Base by Hoffman et al. It was noted that during this time frame, there was also an increase in nonsurgical approaches (chemoradiation or radiation alone) for the primary management of cancer of the larynx. This statistical decline in relative survival was most significant for patients with T1-T3 N0M0 supraglottic cancer.3
The male-to-female ratio is greater for glottic (9.2:1 among whites and 11.8:1 among blacks) than for supraglottic cancer (3-5:1 for both races).4 Women are more likely to develop supraglottic cancer than glottic.5 Cancer of the larynx has a peak incidence in the sixth and seventh decades with the median age at diagnosis of 65.1 Less than 1% of cases occur in patients younger than 30 years of age, although it has been reported in children with no risk factors.6,7
RISK FACTORS
Multiple factors contribute to the development of cancer of the larynx. Foremost among them is the use of tobacco. Possible effects of secondhand smoking have not yet been carefully investigated for cancer of the larynx. The relationship of alcohol consumption to the relative risk is not clear; most studies show that it has a synergistic effect when combined with smoking. After controlling for factors such as tobacco exposure and average alcohol consumption, a case-control study using scoring with Michigan alcoholism and screening test (MAST) demonstrated an association between alcohol and the risk for development of glottic (OR = 1.9), supraglottic (OR = 2.3), and subglottic carcinoma (OR = 1.9). The highest risk was seen in patients consuming 42 or greater alcohol-based beverages per week (OR = 3.1).8
A review by the British Occupational Cancer Burden Study Group in 2012 attempted to summarize the occupational risk factors identified in Health and Safety Executive technical reports related to cancer of the larynx. Asbestos exposure and working within the rubber industry were considered to have a weak association with the development of cancer of the larynx. Contrary to this, occupational exposure to strong inorganic acids containing sulfuric acid was found to have a strong association (odds ratio = 2.90, 95% CI = 1.62 to 5.20) with cancer of the larynx and demonstrated an exposure-response relationship. The attributable fraction (AF) for all exposures combined for laryngeal carcinoma was 2.61% (95% CI = 0.83 to 4.32), largely due to the impact of strong inorganic acids, which equated to 20 attributable deaths.9
Dietary factors have also been postulated to have a significant influence on the development of laryngeal cancer. The International Head and Neck Cancer Epidemiology consortium investigated the impact of vitamin and mineral supplementation on the incidence of cancer of the head and neck by reviewing 12 case-control studies on the topic. The study included 1,329 patients with cancer of the larynx. Although supplementation with vitamin C (OR 0.76, 95% CI 0.59 to 0.96) and calcium (OR = 0.64, 95% CI 0.42 to 0.97) was associated with a reduced risk in the development of head and neck cancer (yet lacked a dose-response relationship), the authors ultimately failed to discern a strong association between the vitamin and/or mineral intake and risk reduction in the development of cancer.10
Reviews of the literature have failed to demonstrate a causal role of gastroesophageal reflux disease (GERD) as an independent risk factor in the development of cancer of the larynx. Cited confounding factors limiting the ability to confirm a statistical association include a coexisting history of habitual tobacco and alcohol use and the inherent inaccuracies in establishing the clinical diagnosis of GERD and laryngopharyngeal reflux (LPR).11 Given that lower esophageal reflux is associated with the development esophageal adenocarcinoma and not esophageal squamous cell carcinoma, skepticism in the relationship of GERD and LPR to cancer of the larynx would appear reasonable.12
Given that chronic inflammation has been implicated as a potential etiology for the development of neoplasia, the question of whether anti-inflammatory therapy could be associated with a reduction in the risk of future development of specific cancers has provoked investigation. In a nested case-control study, performed through the Seoul National University College of Medicine, the association between the use of inhaled corticosteroids and cancer of the lung and larynx was examined. Patients with a documented history of cancer of the larynx (n = 408) were matched with 1,651 controls. Although the authors noted a statistically significant reduction in the risk of developing lung cancer with the use of inhaled corticosteroids, there was no effect noted on the incidence of cancer of the larynx (positive or negative) with habitual use.13
The ARCAGE (alcohol-related cancers and genetic susceptibility) project was a multicenter case-control study performed in 10 European countries. As part of the study, investigators examined type-specific human papillomavirus (HPV) antibodies in 1,496 patients with an upper aerodigestive tract (UADT) cancer. The results of the study revealed only a marginal role for HPV6 (OR = 3.25, 95% CI+1.46 to 7.24 for HPV6 E7 seropositivity) in laryngeal cancer.14
A separate aspect of the ARCAGE study, examining the effect of medication and medical history on the development of UADT carcinomas demonstrated that the regular use of aspirin was associated with a reduced risk in the future development of cancer of the larynx (OR 0.74, 95% CI 0.54 to 1.01).15
ANATOMY AND EMBRYOLOGY
The larynx is divided into three anatomical subsites. Beyond the embryologic differences, the supraglottis, glottis, and subglottis have different lymphatic drainage pathways and therefore varied risk for regional metastasis in the setting of carcinoma. Clinically, neoplastic lesions in each of these subsites tend to present with a characteristic set of symptoms unique to the anatomic location of involvement.
Supraglottic Larynx
The supraglottis subunit includes the lingual and laryngeal surfaces of the epiglottis, the aryepiglottic folds, the arytenoid cartilages, the false vocal folds, and the ventricle. During embryologic development, these structures are derived from the buccopharyngeal anlagen of branchial arches three and four. The glottic and subglottic subunits develop from the tracheobronchial anlagen of the fifth and sixth branchial arches. The embryonic fusion plane between the supraglottic subunit and the glottic and subglottic subunits is represented by a horizontal line drawn through the ventricle. This horizontal plane provides the anatomic and oncologic basis of supraglottic laryngectomy.
The supraglottic larynx is comprised of the suprahyoid epiglottis (both lingual and laryngeal surfaces), the infrahyoid epiglottis, the preepiglottic space, the laryngeal aspects of the aryepiglottic folds, the two arytenoids, and the ventricular bands (false cords). The inferior portion of the epiglottic cartilage is the petiole (Fig. 15.1). The inferior boundary of the supraglottis is a horizontal plane passing through the apex of the ventricle of the larynx. The supraglottis is intimately associated with the preepiglottic and paraglottic spaces, which can provide a pathway for transglottic spread (Figs. 15.2 and 15.3). The anatomic division is located at the arcuate line, which marks the change from respiratory to squamous epithelium and is reliably located at the apex of the ventricle. Thus, the roof of the ventricle is included in the supraglottis, and the floor belongs to the glottis.16
Histologically, the supraglottis is lined by ciliated columnar epithelium, as is the majority of the upper respiratory tract. Exceptions are the free edges of the epiglottis and the aryepiglottic folds, which are lined with stratified squamous mucosa. Mucous glands are abundant and are of greatest density in the saccule and the periarytenoid areas. The predilection for lymphatic spread of supraglottic cancer is explained by the rich vascularity and lymphatics associated with this anatomic region.
Glottis
The glottic larynx includes the true vocal cords and the anterior and posterior commissures. The inferior border is the horizontal plane passing 1 cm below the apex of the ventricle. Histologically, the vocal cords are covered by stratified squamous epithelium around the edges and pseudostratified ciliated epithelium at the superior and inferior aspects, where the glottis merges with the supraglottis and the subglottis, respectively. The lamina propria has (1) a superficial layer composed of loose fibrous tissues that makes Reinke space
and (2) intermediate and deep layers of elastic and collagenous fibers that form the vocal ligament. Blood vessels and lymphatics are almost absent in Reinke space, creating a resistance to the spread of early cancer of the glottis. No mucous glands are found on the free edge of the vocal cord, and only sparse glands are noted on the superior aspect. The conus elasticus extends upward from the superior border of the cricoid cartilage to merge with the inferior surface of the vocal ligament; it has the capacity to resist the extralaryngeal spread of glottic and subglottic cancer.
and (2) intermediate and deep layers of elastic and collagenous fibers that form the vocal ligament. Blood vessels and lymphatics are almost absent in Reinke space, creating a resistance to the spread of early cancer of the glottis. No mucous glands are found on the free edge of the vocal cord, and only sparse glands are noted on the superior aspect. The conus elasticus extends upward from the superior border of the cricoid cartilage to merge with the inferior surface of the vocal ligament; it has the capacity to resist the extralaryngeal spread of glottic and subglottic cancer.
 Figure 15.1. The three portions of the epiglottis. |
 Figure 15.2. Sagittal cut of the larynx demonstrating the relative anatomy, highlighting the preepiglottic space. |
Subglottis
The subglottic larynx has no subsites and is the area of the larynx inferior to the glottis down to the inferior rim of the cricoid cartilage. It is a rare site of origin but is commonly involved by extension of glottic and supraglottic cancers. Cancer arising in the subglottis has a higher incidence of extralaryngeal spread owing to the proximity of the cricothyroid membrane and the rich postcricoid lymphatics.
DIAGNOSIS
History, Physical Examination, and Laboratory Tests
Common presenting symptoms can include progressive hoarseness, chronic sore throat, referred otalgia, odynophagia, dysphagia, dyspnea, chronic cough, hemoptysis, and unexplained weight loss. Cancer in the glottis is seen in an earlier stage more frequently because of the notable finding of change in vocal quality not seen immediately with the other subsites. Patients with cancer of the supraglottis are more likely to present with advanced-stage cancer secondary to palpable regional metastases to the lymph nodes and a history of an ill-defined discomfort in the throat. The history should also assess for the current and prior use of tobacco products, average alcohol consumption, medical comorbidities (in particular chronic cardiovascular or pulmonary diagnoses), and potential occupational exposures.
A complete examination of the head and neck including detailed examination of the oral cavity, oropharynx, larynx,
hypopharynx, and neck is critical. Indirect laryngoscopy (mirror examination) should be performed and supplements the findings of fiberoptic examination. Flexible fiberoptic laryngoscopy and/or videostroboscopy provide superior information about the anatomical and functional findings within the larynx and pharynx, which assist in treatment planning and staging. Careful palpation of the neck bilaterally is important with documentation of the location (group or level I to VI), size, mobility, and relationship of the node(s) to adjacent structures. Staging of the primary and the cervical lymph nodes is necessary prior to considering a patient’s treatment options.
hypopharynx, and neck is critical. Indirect laryngoscopy (mirror examination) should be performed and supplements the findings of fiberoptic examination. Flexible fiberoptic laryngoscopy and/or videostroboscopy provide superior information about the anatomical and functional findings within the larynx and pharynx, which assist in treatment planning and staging. Careful palpation of the neck bilaterally is important with documentation of the location (group or level I to VI), size, mobility, and relationship of the node(s) to adjacent structures. Staging of the primary and the cervical lymph nodes is necessary prior to considering a patient’s treatment options.
 Figure 15.3. Sagittal cut of the larynx demonstrating the relative anatomy, highlighting the paraglottic space. |
The diagnosis of a cancer of the larynx usually requires direct laryngoscopy and biopsy with the patient under general anesthesia. Direct laryngoscopy not only helps the clinician in making a diagnosis; it is also an important tool in proper mapping of the cancer for further management planning. Some authors advocate additional bronchoscopy and esophagoscopy in all patients with cancer of larynx for full pretreatment assessment and in evaluating for concurrent second cancers. Although the empiric performance of “panendoscopy” remains controversial, it is indicated when symptoms mandate additional evaluation. A typical example warranting this approach would be a patient who complains of dysphagia/odynophagia with supraglottic cancer spreading to the hypopharynx. Esophagoscopy would be performed to rule out extension to the cervical esophagus. For patients with enlarged lymph nodes in the setting of a laryngeal cancer, fine-needle aspiration biopsy (preferably with ultrasound guidance) should be considered and can have a significant impact on staging and treatment.
Office-based transnasal flexible fiberoptic biopsy of laryngeal pathology has represented an alternative to conventional operative direct laryngoscopy with biopsy. Cohen et al. reported a low sensitivity of 69.2% with a specificity of 96.1% for officebased flexible fiberoptic laryngeal biopsy. Adequate tissue to establish the diagnosis of carcinoma was obtained in 35.4% of the 102 patients and allowed for early referral for treatment. The study’s algorithm included follow-up operative biopsies for patients with initial benign or carcinoma in situ (CIS) biopsy results found with office-based biopsy. The authors expressed concern that pathologists were more reluctant to confirm a diagnosis of cancer with small tissue samples typically resulting from flexible fiberoptic office-based laryngeal biopsy.17
Laboratory testing at the time of initial assessment can be directed by the findings from the patient’s history and physical
examination. Preoperative pulmonary function testing should be considered along with history of activity level and exercise tolerance when making decisions about the suitability of a patient for partial laryngectomy. Consultations with other services, including radiation therapy, medical oncology, dentistry, speech pathology, psychiatry, and general medical services, are obtained as indicated.
examination. Preoperative pulmonary function testing should be considered along with history of activity level and exercise tolerance when making decisions about the suitability of a patient for partial laryngectomy. Consultations with other services, including radiation therapy, medical oncology, dentistry, speech pathology, psychiatry, and general medical services, are obtained as indicated.
Radiographic Examination
Clinical/endoscopic examination alone can fail to reveal extension of the cancer into the laryngeal cartilages and the extralaryngeal soft tissues. The combination of clinical/endoscopic and radiologic examination, by either computed tomography (CT) or magnetic resonance imaging (MRI), results in significantly improved staging accuracy (CT scan improves imaging in 80% of patients, and MRI in 87.5%). MRI is significantly more sensitive but is less specific than CT in detecting cartilage invasion. MRI can overestimate cartilage invasion and lead to overtreatment, whereas CT tends to underestimate cartilage invasion and may result in inadequate therapy.18 A chest radiograph should be obtained to rule out concurrent cancer of the lung or metastatic disease.
Park et al. demonstrated that pretreatment Mean Tumor Volume (MTV) assessed by PET-CT correlated with 3-year LRC and OS for patients with locoregionally advanced laryngeal and hypopharyngeal carcinoma. The median SUVmax for patients was 10.3 and the MTV was 15 mL. MTV of >18 mL was seen to be a cutoff value that correlated with prognosis. The 3-year LRC and OS for patients with MTV ≤ 18 was 85.3 % and 91.4%, whereas for a MTV > 18, these values fell to 50.8% and 60.6%, respectively.19
The recommended timing of posttreatment PET-CT varies; however, most authors advocate that an accurate reading can be achieved at 10 to 12 weeks after CRT. However, it should be noted that a mild to moderate intensity of tracer uptake may persist for several months as a result of inflammation or radionecrosis and is typically diffuse and nonfocal. In addition, standardized uptake values (SUVs) cannot differentiate reliably between residual cancer and inflammation. Although SUV cutoffs have been reported to correlate with malignancy in a single institutional experience, these values have not been validated as reproducible at other institutions. The high NPV associated with PET-CT in the posttreatment setting is considered to be the most significant impact of this imaging modality on care.20
STAGING
Primary Site
The specifics of the primary staging system for the supraglottic, glottic, and subglottic larynx are listed later in the discussion of the TNM staging system.
Metastases to Regional Lymph Nodes
The incidence and distribution of metastases to the cervical nodes from cancer of the larynx vary with the specific site of origin of the primary cancer and the stage of the primary cancer. The true vocal cords are nearly devoid of lymphatics so that early-stage glottic cancer rarely spreads to regional nodes. In contrast, the supraglottis has a rich and bilaterally interconnected lymphatic network. Advanced-stage glottic cancer may spread to adjacent soft tissues and to prelaryngeal, pretracheal, paralaryngeal, and paratracheal nodes, in addition to upper, middle, and lower jugular nodes. Supraglottic cancer commonly spreads to upper and middle jugular nodes and only occasionally metastasizes to retropharyngeal nodes. Primary cancer of the subglottic spread initially to adjacent soft tissues and prelaryngeal, pretracheal, paralaryngeal, and paratracheal nodes and may metastasize to the middle and lower jugular nodes.
In clinical evaluation, the size of a mass in the neck should be measured and recorded in the medical record. It is recognized that most masses larger than 3 cm in diameter are not single nodes but multiple, confluent nodes with extracapsular spread. Clinically positive nodes are classified into three categories: N1, N2, and N3. In an N1 neck, the single enlarged lymph node is <3 cm in size. N2a represents a neck with a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in greatest dimension; N2b represents multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension; N2c represents bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension. Midline nodes are considered ipsilateral nodes. An N3 neck has a lymph node >6 cm in size and often represents unresectable cancer.
In addition to the components used to describe the N category, regional lymph nodes should be described according to the level of the neck involved. Imaging studies showing amorphous margins of involved nodes or involvement of internodal adipose tissue strongly suggest extracapsular (extranodal) spread of the cancer. No imaging study can yet identify microscopic foci in regional nodes. In addition, a distinction cannot be made between small reactive nodes and small malignant nodes unless central radiographic inhomogeneity is present.
Metastatic Sites
Distant metastases are more common among patients who have bulky (N2b, N2c, N3) lymph node metastases. Distant spread to the lungs is most common, whereas metastasis to the bone and/or liver occurs less often. Patients with extracapsular spread have a higher rate of metastasis to distant sites than those without extracapsular spread. Mediastinal lymph node metastases are considered distant metastases for the purposes of staging.
STAGING
Clinical Staging
The larynx is assessed primarily by inspection, with the use of indirect mirror and direct endoscopic examinations. The cancer must be confirmed histologically, and any other data obtained by biopsy may be included. Cross-sectional imaging in laryngeal carcinoma is particularly recommended when the extent of the primary cancer is in question based on clinical examination. This may be accomplished with a high-resolution/fine-cut CT scan with contrast, through the larynx. In addition, it can help to distinguish between a coalescence of several lymph nodes and a single larger node, thereby making staging of the neck more precise. Endoscopic examination with the patient under general anesthesia is generally performed after completion of other diagnostic studies that accurately assess, document, and biopsy the cancer.
Pathologic Staging
All information used in clinical staging and in histologic study of the surgically resected specimen is also used for pathologic
staging (Table 15.1). The pathologic description of any neck dissection should describe the size, number, and level of involved lymph nodes, as well as whether extracapsular spread is present. Specimens should also be examined for the presence of lymphovascular and/or perineural invasion in the primary cancer resection.
staging (Table 15.1). The pathologic description of any neck dissection should describe the size, number, and level of involved lymph nodes, as well as whether extracapsular spread is present. Specimens should also be examined for the presence of lymphovascular and/or perineural invasion in the primary cancer resection.
Table 15.1 Stage Grouping | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Table 15.2 Definition of TNM | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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In a trial to assess for tumor biomarkers predictive of outcome in laryngeal carcinoma, Bradford et al. analyzed 58 pretreatment specimens as tissue microarrays with a panel of various biomarkers. Expression of Bcl-xL, a member of the antiapoptotic Bcl-2 family of proteins, was increased in patients with recurrent/persistent tumors. Overexpression of EGFR was correlated with an increase in risk of death from laryngeal carcinoma. When BAK (a proapoptotic protein) was expressed in low levels, cancers were more likely to respond to neoadjuvant chemotherapy. Lack of cyclin D1 expression and elevated cytoplasmic expression of CD24 were the best predictors of overall survival (p ≤ 0.05) within the tested panel.21
In patients with advanced cancer of the larynx, individuals with high circulating levels of CD4-positive T lymphocytes (both absolute count [p = 0.006] and percentage [p = 0.04]) demonstrated a better response to induction chemotherapy and experienced an improved survival. The results of these studies suggest that a peripheral blood draw could someday be used to identify patients with advanced-stage cancer that may be more likely to respond to an organ preservation protocol that uses induction chemotherapy (Table 15.2).22
NATURAL COURSE OF DISEASE
Nodal Metastases
Most lymph node metastases are found within levels II, III, and IV (Fig. 15.4). Levels I and V are rarely involved unless lymph node metastasis is extensive. Occult cervical lymph node
metastases are often associated with cancer of the supraglottic larynx. Esposito et al. reported a rate of occult regional spread of 27% in 97 N0 patients with previously untreated supraglottic carcinoma undergoing neck dissection at the time of horizontal laryngectomy. In this group, based on the preoperative staging of the cancer, 14% of cases had occult metastases involving lymph nodes in T1 cancer, 21% in T2 cancer, 35% in T3 cancer, and 75% in T4 cancer. The incidence of occult metastases was higher for the less differentiated cancer and for primary cancer with a higher T stage. In a subset of patients with lateralized supraglottic primary tumors, contralateral occult regional spread occurs in 37% of patients. The authors stressed the importance of bilateral regional nodal treatment with supraglottic tumors even in the N0 setting.23
metastases are often associated with cancer of the supraglottic larynx. Esposito et al. reported a rate of occult regional spread of 27% in 97 N0 patients with previously untreated supraglottic carcinoma undergoing neck dissection at the time of horizontal laryngectomy. In this group, based on the preoperative staging of the cancer, 14% of cases had occult metastases involving lymph nodes in T1 cancer, 21% in T2 cancer, 35% in T3 cancer, and 75% in T4 cancer. The incidence of occult metastases was higher for the less differentiated cancer and for primary cancer with a higher T stage. In a subset of patients with lateralized supraglottic primary tumors, contralateral occult regional spread occurs in 37% of patients. The authors stressed the importance of bilateral regional nodal treatment with supraglottic tumors even in the N0 setting.23
In a study from Washington University of 2,550 patients with cancer of the larynx and hypopharynx, the overall incidence of delayed regional metastases was 12.4% (317/2,550 patients); distant metastases, 8.5% (217/2,550); and second primary cancer, 8.9% (228/2,550). Delayed regional metastases and distant metastases were related to advanced primary cancer (T4 stage), lymph node metastases (node positive [N+]), the cancer arising in the hypopharynx as the
primary site, and locoregional cancer recurrence (p = 0.028). Advanced regional metastases at initial diagnosis (N2 and N3 disease) increased the incidence of delayed and distant metastases threefold (p = 0.017). Incidences of delayed regional metastases by anatomic location of the primary cancer were glottic, 4.4%; supraglottic, 16%; subglottic, 11.5%; aryepiglottic fold, 21.9%; pyriform sinus, 31.1%; and posterior wall of the hypopharynx, 18.5%. Delayed regional metastases to the ipsilateral-treated neck had a significantly worse survival prognosis than did delayed metastases to the contralateral untreated neck.24
primary site, and locoregional cancer recurrence (p = 0.028). Advanced regional metastases at initial diagnosis (N2 and N3 disease) increased the incidence of delayed and distant metastases threefold (p = 0.017). Incidences of delayed regional metastases by anatomic location of the primary cancer were glottic, 4.4%; supraglottic, 16%; subglottic, 11.5%; aryepiglottic fold, 21.9%; pyriform sinus, 31.1%; and posterior wall of the hypopharynx, 18.5%. Delayed regional metastases to the ipsilateral-treated neck had a significantly worse survival prognosis than did delayed metastases to the contralateral untreated neck.24
 Figure 15.4. The lymph node levels of the neck. |
Distant Metastases
Distant metastases are associated with a poor prognosis. Among patients with cancers of the head and neck region, ˜8% eventually develop distant metastases.25 The lung is the most common site of distant metastases in primary cancer of the larynx. Staging has been helpful in predicting the likelihood of distant metastases with the highest frequency seen in patients in stages III and IV (85%). A supraglottic primary cancer is the most common subsite associated with the development of distant metastases.
The overall 5-year disease-specific survival after patients developed distant metastases was 6.4%. Distant metastases were related to advanced local cancer (T3 + T4), lymph node metastases at presentation (N+), and locoregional cancer recurrence (p = 0.028). A meta-analysis of variables that predispose to a higher incidence of distant metastasis identified tumor location (hypopharynx > larynx), advanced primary disease (T3 + T4), regional metastasis (N+), locoregional cancer recurrence, and advanced regional metastasis (N2 + N3).26
Second Primary Cancers
In a retrospective study from France including 410 patients, the incidence of second primary cancer was 23.9% (98/410). Cancer of the lung was the most common second primary and two-thirds of patients who developed a second primary cancer died of disease.27
In another retrospective review of 240 patients from Oregon with T1-T2 SCC of the larynx, 72% had glottic primaries, 27% had supraglottic cancer, and 1% had subglottic cancer. With a median follow-up of 68 months, 68 patients (28%) have developed 72 additional cancers. 15% were diagnosed with synchronous primaries.28
PATHOLOGY
Keratosis/Leukoplakia
Leukoplakia, also described as keratosis, of the larynx most commonly involves the true vocal cords and the interarytenoid area. It often occurs in smokers, singers, and professional voice users. Keratosis is grossly characterized as a white, thickened plaques. Microscopically, keratotic lesions are characterized by increased thickness of the normally present keratin layer of the epithelium. Hyperkeratosis is defined as the presence of a keratin layer in a normally nonkeratinized epithelium and may represent an early response to mucosal trauma.
Bartlett and colleagues performed real-time polymerase chain reaction analysis on the RNA of 17 specimens, originally classified clinically as glottic leukoplakia, yet subsequently diagnosed with nondysplastic keratosis, dysplasia, and invasive carcinoma on final pathology. Differential gene up-regulation and matrix metalloproteinase (MMP-1, MMP-2, MMP-9) expression was noted among the specimens suggesting a correlation between genetic changes and the progression of cancer. As a result of their findings, the authors suggest that the development of cDNA microarray genomic expression profiles could increase the sensitivity of assessment for patients with glottic leukoplakia by identifying disease progression reflected in markers of extracellular matrix degradation and the promotion of angiogenesis.29
Dysplasia
Dysplasia refers to a microscopic change that is characterized by cellular atypia, loss of maturity, and loss of stratification. Three grades of dysplasia are defined by the World Health Organization (WHO) classification30:
Mild—Changes are limited to the lower third of the epithelial thickness.
Moderate—Changes are limited to the lower two-thirds of the epithelial thickness.
Severe—Changes involve more than the lower two-thirds of the epithelial thickness. Cells are less crowded than with CIS and usually reveal greater differentiation.
Carcinoma in Situ
CIS may be present as the only lesion, or it may occur at the periphery of an invasive carcinoma. The standard criterion for diagnosis is the presence of atypical changes throughout the epithelium without evidence of surface maturation or invasion through the basement membrane.
Papillary CIS is a form of CIS characterized by papillary fronds with cytologic features of the classic CIS. The actual rate of malignant progression for untreated cases of laryngeal is unknown; however, some estimates have been reported to be as high as 40%. CIS of the larynx can be treated by means of biopsy, local excision, laryngofissure, stripping, or radiation.
Invasive Squamous Cell Carcinoma
Microscopically, more than 90% of cancers of the larynx are SCCs. They are graded into well-, moderately, and poorly differentiated cancers based on the degree of differentiation, cellular pleomorphism, and mitotic activity.
Persistence of SCC after radiation can be difficult to distinguish from postradiation atypia because of the similar histologic appearance. Immunoreactivity for keratin is universally present and cells also express epidermal growth factor receptors.
Various prognostic factors have been reported in the literature for invasive SCC and include clinical stage and site, histopathologic grade, lymphovascular invasion, perineural spread, lymph node spread (+/- extracapsular spread), HPV, tumor thickness/depth of invasion, and DNA ploidy.
Basaloid Squamous Cell Carcinoma
Basaloid SCC is characterized by a predominance of basaloid features in the epithelium and is considered an aggressive variant of squamous cell carcinoma that can present in the larynx.
An association with HPV positivity and basaloid carcinoma has been seen with cancer of the oropharynx, yet similar findings have not been reported with laryngeal carcinoma.31 Patients with laryngeal basaloid carcinoma typically present with a more advanced overall stage at diagnosis and have a worse disease-specific survival than individuals with conventional squamous cell carcinoma of the larynx. In a review of 145 cases of basaloid carcinoma of the larynx, 11.6% were found to harbor distant metastases at the time of initial presentation (vs. 2.7% for conventional squamous cell carcinoma of the larynx). The majority of basaloid carcinomas of the larynx present as supraglottic primaries (64.8%) and ˜50% develop regional lymph node spread of metastases.32
Verrucous Carcinoma
Clinically, verrucous carcinoma is a slow-growing, locally aggressive cancer with an exophytic, fungating, warty, graywhite appearance and well-defined margins. Because it produces few early symptoms, patients often present with a bulky cancer. Histologically, this cancer is composed of elongated papillary fronds of well-differentiated squamous epithelium with extensive keratinization. Cytologic abnormalities are absent. The margins of the cancer have “pushing” rather than infiltrative growth that is usually accompanied by an exuberant host response of inflammatory cells. Regional lymph nodes may be enlarged and raise suspicion for occult malignancy, but this cancer does not metastasize, and nodal enlargement is invariably part of the host inflammatory response. The combination of the gross appearance of the cancer and the suggestive histologic findings is usually sufficient to establish the diagnosis.
Verrucous carcinoma constitutes from 1% to 3% of all cancers of the larynx. Within the larynx, a majority of these cancers arise from the glottis with the remainder diagnosed in the supraglottis. The typical patient is a male in his fifties or sixties who have been hoarse for at least a year before presentation. Smoking is a known risk factor. Overall prognosis is excellent with proper treatment, even among patients with locally advanced cancer. Fliss et al.33 found 45% of patients with verrucous carcinoma of the larynx to have HPV detectable in their cancer by the polymerase chain reaction, all of which cases of HPV were either type 16 or 18.
Huang et al. reviewed the experience of 62 patients with verrucous carcinoma of the larynx treated with primary
radiation over a 43-year period. In the series, there were no reported episodes of posttreatment anaplastic transformation. Disease-specific survival was also noted to be comparable to those from series reporting on surgical management; however, local control (66% at 5 years) was noted to be inferior in comparison to surgery. Individuals who experienced a local recurrence (21/62) were capable of undergoing successful salvage resection of persistent cancer.34
radiation over a 43-year period. In the series, there were no reported episodes of posttreatment anaplastic transformation. Disease-specific survival was also noted to be comparable to those from series reporting on surgical management; however, local control (66% at 5 years) was noted to be inferior in comparison to surgery. Individuals who experienced a local recurrence (21/62) were capable of undergoing successful salvage resection of persistent cancer.34
Verrucous carcinoma of the larynx can be difficult to differentiate from benign papillary hyperplasia on biopsy if a limited quantity of tissue is available for histopathologic examination. Increased mean levels of expression of survivin, a member of the inhibitor of apoptosis protein family, in regions of parakeratosis have been shown to have the capacity to differentiate verrucous carcinoma from laryngeal papillary hyperplasia.35
Nonsquamous Tumors
Nonsquamous cancers account for <5% of all laryngeal malignancies. Among these, salivary gland tumors, cartilaginous neoplasms, sarcomas, and neuroendocrine carcinomas have been the types most commonly reported.
Adenocarcinoma
Adenocarcinomas of the larynx follow the distribution of the laryngeal mucous glands and are primarily supraglottic and subglottic in origin. Male predominance has been reported. Clinically, the cancers appear as submucosal, nonulcerated masses and symptoms are the same as for carcinomas of the larynx.
Most adenocarcinomas of the larynx present with advanced primary cancer and cervical lymph node metastases. Distant metastases to the liver and lung account for the dismal 5-year survival under 20%.36 Secondary to the aggressive behavior of this primary, most authors have recommended radical surgery with total laryngectomy and bilateral neck dissections. Postoperative radiotherapy is usually advocated, although the numbers of reported cases are too small to know if this confers a survival benefit. Patients succumb to both locoregional failure and distant metastases.
Adenosquamous carcinoma is an uncommon but aggressive variant of head and neck squamous cell carcinoma with a propensity for regional and distant metastases with ˜50% of cases presenting with a laryngeal primary. Very little has been reported concerning the risk factors or etiology of this variant. In a review by Masand et al. of 18 cases, 7 cases of primary laryngeal presentation were reported. The average age of patients was 58, all cases were male, and none of the cancers were positive for high-risk HPV.37
Adenoid Cystic Carcinoma
Although not exceedingly rare, a limited number of cases of adenoid cystic carcinoma have been reported and they are estimated to represent only 0.6% of all cancer of the larynx. The most common site of origin is the subglottis, followed by supraglottic primaries. These cancers produce only vague symptoms while they spread in a perineural and infiltrative growth pattern. When the primary originates from the subglottis, patients typically present with involvement of the laryngeal framework, trachea, thyroid gland, and esophagus. Metastases to the lung are common with this entity.
Adenoid cystic carcinoma of the larynx can be difficult to treat because of the predilection for perineural spread and pulmonary metastases. The mainstay of treatment, dependent upon stage and presentation, has typically been surgery (open vs. endoscopic approach) with potential adjuvant radiation therapy. Misiukiewicz et al. reported on the use of primary concomitant chemoradiation (CRT), using carboplatin and paclitaxel, as a means of organ-sparing therapy for patients who otherwise would have required laryngectomy and radiation. Locoregional control with functional laryngeal preservation was obtained with a follow-up of at least 5 years in two patients. The authors suggested that this regimen represented an alternative for selected patients with this diagnosis when laryngeal preservation is desired and salvage laryngectomy would be used for nonresponders.38
Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma of the larynx is an uncommon cancer that typically presents in older males with the supraglottis as the most common primary site. The worst prognosis is seen with patients with high-grade cancer. Low-grade cancers rarely spread beyond the confines of the larynx and conservation surgical approaches without neck dissection may be curative. Radiation has not been shown to be effective when used as a single modality.
The management of high-grade mucoepidermoid carcinoma is similar to that of SCC. The extent of surgery is dictated by the extent of the cancer and elective neck dissection is recommended, even for smaller cancers, because of the risk of occult neck metastases. Radiation therapy is usually administered in the adjuvant setting.39
The management of intermediate-grade cancer is controversial, and many authors tend to follow a more aggressive approach. Surgery is the mainstay of therapy. The use of postoperative radiation therapy varies according to the surgical margins and other factors, such as the patient’s age and the presence of regional metastases.40
Chondrosarcoma
Chondrosarcoma is the most common sarcoma of the larynx. Its incidence is difficult to know because the low-grade form of this tumor is often confused with a benign chondroma. It predominantly affects men (3:1 male-to-female ratio) between the ages of 50 and 70 years and arises from the hyaline cartilages of the larynx.39 The most common of these sites are the cricoid (especially the posterior lamina) (70%), the thyroid (20%), and the body of the arytenoid cartilage (10%).
Chondrosarcoma arising from the cricoid cartilage tends to grow into the airway and cause progressive obstruction, whereas chondrosarcoma arising from the thyroid cartilage typically protrudes laterally and presents as a firm mass in the neck. Endoscopically, the tumor appears as a firm, submucosal mass that is difficult to biopsy because it is so dense. On imaging, these lesions are typically hypodense, well-circumscribed masses containing mottled calcifications with smooth walls centered within the cartilage.41
The management of chondrosarcoma varies with the grade and extent of the tumor. The primary modality of treatment is surgery. For low-grade and some medium-grade tumors, local control is the goal. Partial laryngectomy with voice preservation and reoperation if the tumor recurs is an option in selected patients. Challenges arise with tumors arising in
the cricoid, and a variety of techniques have been described to reconstruct the larynx following partial resection with reconstruction of the cricoid, using hyoid bone, rib, and strap muscle. High-grade chondrosarcomas usually require a total laryngectomy, with neck dissection reserved for clinical or radiographic evidence of metastasis.
the cricoid, and a variety of techniques have been described to reconstruct the larynx following partial resection with reconstruction of the cricoid, using hyoid bone, rib, and strap muscle. High-grade chondrosarcomas usually require a total laryngectomy, with neck dissection reserved for clinical or radiographic evidence of metastasis.
Five-year survival rates are not useful data for chondrosarcomas of the larynx, especially with low-grade tumors, because recurrences and subsequent mortality may occur well beyond this time point.42
Neuroendocrine Tumors
The second most common tumor type in the larynx takes rise from neuroendocrine family of neoplasms, which include carcinoid tumors (6.6%), atypical carcinoid tumors (53.7%), small cell neuroendocrine carcinomas (27.6%), and paragangliomas (12.1%).
Laryngeal carcinoid tumors can be mistaken as being an indolent pathology yet has reported rate of regional and distant metastasis of 33%. It typically presents in the supraglottic or transglottic lesion. Conservative surgical resection with therapeutic neck dissection (in N+ patients) has been advocated. Elective neck dissection is considered unnecessary because of the low rate of associated occult spread. Radiation is considered to be ineffective in the management of this pathology.
Atypical carcinoid tumors are aggressive lesions with regional and distant metastatic rates ranging from 43% to 67%. The reported 5-year survival is <50%. Histopathologic misclassification of atypical carcinoid as carcinoid tumor can occur and may prompt re-evaluation of tissue specimens if the clinical behavior of the tumor is uncharacteristic for a specific patient’s presentation. Surgical resection is considered the treatment standard with bilateral elective neck dissection being advocated for supraglottic presentations. One series from MD Anderson reported on the use of radiation and chemotherapy (primary therapy and as an adjuvant) in the care of selected patients with mixed results.
Small cell neuroendocrine carcinoma has a poor associated prognosis with 90% of patients experiencing regional and/or distant metastasis. The 5-year survival is typically <10%. Paraneoplastic syndromes can occur in association with this diagnosis. Nonsurgical treatment is advocated for this diagnosis and frequently requires a multidrug chemoradiation regimen.
Paraganglioma of the larynx is a benign tumor with a female predominance. Surgery is the treatment of choice for this lesion with both open and endoscopic CO2 lesion resections described.43
Liposarcoma
Liposarcoma of the larynx is a rare entity that typically presents as a supraglottic lesion in males in the fourth to seventh decade of life. The tumors tend to be low grade and are rarely associated with regional or distant spread. The four most commonly described histologic variants are pleomorphic, round cell, myxoid, and well-differentiated liposarcoma. Welldifferentiated liposarcoma represents ˜65% of cases and can be easily confused with a basic lipoma both macroscopically and microscopically. Wide surgical excision is advocated for this tumor with little evidence of a role for radiation in this setting. Recurrence is common and occurs in over 50% of reported cases.44
Composite Tumors
Synchronous presentation of small cell carcinoma and squamous cell carcinoma of the larynx, also known as “composite tumor of the larynx,” is rare and represents a clinical quandary and requires a collaborative approach to management.45 Additional reports of synchronous “double-tumor” presentations, such as with squamous cell carcinoma in the setting of laryngeal chondrosarcoma, have also been reported.46
TREATMENT OF CANCER OF THE LARYNX
Early-stage laryngeal carcinoma (stage I or II) is usually treated with a single-modality regimen involving surgery or radiation therapy. Although controversy exists regarding the relative merits of either treatment modality, the rates of cancer control are similar, and patients should be made aware of the options available. Surgical options include endoscopic laser resection, open partial laryngectomy, and total laryngectomy.
In contrast, advanced-stage cancers of the larynx typically require combined multimodality therapy to treat the primary site and regional lymphatics. Primary surgical management and adjuvant radiation therapy (with or without chemotherapy) versus chemoradiation with surgery reserved for salvage are typically the options employed in this setting.
SURGICAL TREATMENT
The options of conventional (open) conservation surgery (CCS), transoral endoscopic laser microsurgery (TLM), and supracricoid partial laryngectomy (SCPL) provide a variety of treatments that can offer the goal of cure with preservation of laryngeal function and integrity of the airway.
Although CCS has been supplanted for many early-stage lesions by TLM, centers throughout the world have reported favorable results with CCS, which may be modified to allow resection of more extensive tumors. A number of extended CCS procedures exist for the management of glottic cancer involving both vocal cords and the anterior commissure (AC), for cancer in the paraglottic space with vocal cord fixation, and for supraglottic tumors involving the glottis or hypopharynx.
TLM has proved to be an effective, minimally invasive, and functionally satisfactory procedure for management of selected T1 and T2 glottic cancers, as well as for T1-T3 supraglottic cancers (Figs. 15.5 and 15.6). The procedure may be effectively employed in combination with neck dissection and postoperative radiotherapy when necessary, particularly for moderately advanced supraglottic carcinomas.
SCPL has proved effective in the management of glottic and supraglottic cancers, even when involvement of the paraglottic space and the thyroid cartilage exists, provided at least one arytenoid unit could be preserved with clear margins. Invasion of the cricoid cartilage is the most significant limitation of this procedure. Voice quality results are variable.
All three surgical approaches have been employed for radiation failure but with increased failure and complication rates compared with primary surgical treatment. A decision to treat a cancer of the larynx initially with radiation may complicate
the potential for a satisfactory result with salvage partial laryngectomy. The treatment of cancer of the larynx should be individualized with various treatment modalities and surgical procedures according to the size and extent of the cancer, the age and physical condition of the patient, and the skill and experience of the treating physicians.
the potential for a satisfactory result with salvage partial laryngectomy. The treatment of cancer of the larynx should be individualized with various treatment modalities and surgical procedures according to the size and extent of the cancer, the age and physical condition of the patient, and the skill and experience of the treating physicians.
 Figure 15.5. T1a glottic carcinoma prior to resection. |
 Figure 15.6. T1a glottic carcinoma after TLM (using CO2 laser) resection of tumor potential paths of spread of tumor within the laryngeal ventricle. |
In 1866, Patrick Watson of Edinburgh performed the first laryngectomy. The patient was a 36-year-old man whose larynx was being destroyed by syphilis. He survived the operation but died several weeks later from pneumonia; after his death, the procedure was condemned. In 1873, Billroth of Vienna performed what is considered to be the first successful laryngectomy. Since then, surgery for cancer of the larynx has seen significant advances that have made the surgery both safe and reliable.47
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