Amber Luong, MD, PhD
Benign laryngeal tumors encompass a large number of lesions. They often present with hoarseness, change in voice quality, stridor, globus and dysphagia. This review will begin with a discussion of the pertinent anatomy, embryology and development of the larynx. In addition, given that hoarseness is a frequent symptom, speech physiology will be covered. Finally, several of the most common benign laryngeal lesions will be highlighted in detail including vocal cord nodules, cystic laryngeal lesion, and recurrent respiratory papillomatosis.
Embryology and Development of the Larynx
The larynx is derived from endodermal lining and adjacent mesenchyme between the fourth and sixth branchial arches. The laryngotracheal groove deepens forming a tube from which the esophagus separates from the remaining trachea. At 32 days of gestation, the lateral mesenchyme swelling approximates the developing larynx, which will later become the arytenoids, corniculate cartilage and the aryepiglottic folds. The hypobranchial eminence gives rise to the epiglottic and cuneiform cartilages. The thyroid cartilage develops from bilateral chondrification centers of the fourth branchial arch. This arch also gives rise to the superior laryngeal nerve. The cricoid and tracheal cartilages develop from the sixth branchial arch. Also emenating from this arch is the recurrent laryngeal nerve. From the third month of gestation onward, the larynx continues to mature.
At birth, the larynx is positioned high in the neck between vertebrae C1 and C4. The epiglottis in the neonate is able to approximate the soft palate separating the functions of respiration from deglutination. By 18 to 24 months, the larynx begins to descend inferiorly such that by age 6 the larynx is located between vertebrae C4 and C7. This allows improved range of phonation at the expense of separating the functions of respiration and deglutition.
Anatomy of the True Vocal Folds
The physical properties of the vocal folds are crucial in determining vocal function.
Hirano described the histology of the vocal folds, which explained the mobile nature of the superficial layer and the underlying static nature of the vocal cords. The cords are covered with a layer of unciliated epithelial cells. Just below the epithelial cells lies a specialized layer of connective tissue. The most superficial layer consists of loosely connected collagen and elastin fibers called Reinke’s space. The intermediate and deep layer of this connective tissue is composed primarily of elastin and densely arranged collagen, respectively. It is the intermediate and deep layers that form the vocal ligament. Just deep to this connective tissue layer lies the thyroarytenoid muscle.
Physiology of Speech
There are three necessary components of human speech: phonation, resonance and articulation. Phonation involves the generation of sound by the movement of the vocal folds. Resonance is the reverberation of the sound. Articulation is the formulation of this sound to words.
The key structures involved in phonation are the lungs and the true vocal folds. Adequate breath from the lungs generates air that passes thru the vocal folds. Van de Berg in 1958 proposed the myoelastic-aerodynamic theory to explain the forces in play in the movement of the vocal folds and the generation of the mucosal wave.
Starting the cycle at the point where the vocal folds are medialized, the generation of a breath creates an increase in subglottic pressure. This increased pressure ultimately forces the vocal fold apart from an inferior to superior direction. This cycle of vocal movement also initiates the mucosal wave. As the air column continues superiorly, the Bernouli effect pulls the inferior edges of the vocal fold medially, reapproximating the cords. The mucosal wave initiates on the medial vertical surface of the vocal folds and is observed as it travels from the medial to lateral edge. The fundamental frequency is the number of vibratory cycles completed in one second. The average speaking fundamental frequency for men falls between 100 and 150 Hz, while that of women is between 188 to 221 Hz.
The isolated sound generated from the vocal folds is not recognizable human voice. Rather, this sound resonates within the chest, skull and upper airway where it is modified to a sound recognized as a human voice. The vocal frequencies that are enhanced by resonance are termed formants. Resonance is controlled by altering the position and shape of the pharynx and the larynx as well as by varying the amount of sound transmitted through the nasopharynx.
Finally, the last component of speech is articulation. The tongue, lips and palate are the primary structures important in articulation.
Vocal cord nodules
Vocal cord nodules (VCN) are benign superficial growths usually on the medial aspects of the vocal cords. They are most often bilateral and located on the anterior 2/3 of the cords. As a result of their location and size, vocal cord nodules can prevent proper medialization of the vocal folds causing hoarseness or change in voice quality. These benign lesions affect primarily women between the ages of 20 to 40 years and children.
Vocal abuse and misuse are thought to be the primary cause for the formation of vocal cord nodules. In support of this clinical belief, a retrospective study of 254 pediatric patients with vocal cord nodules found that 75% of these patients had a history of vocal overuse and the size of the nodule was correlated with the degree of hyperfunctional behaviors (Shah et al, 2005). In this study, gastro-esophageal reflux disease was not associated with the presence of vocal cord nodules. However, a study by Kuhn et al (1998) found that pharyngeal acid reflux events were more often present in patients with vocal cord nodules as compared to patient without nodules. This study was a small study based on 11 patients with nodules. Despite the lack of clear data, many feel that laryngopharyngeal reflux contributes to phonotrauma leading to the formation of vocal cord nodules.
Diagnosis of vocal cord nodules is based on history of persistent hoarsesness, change if voice quality or increased phonation effort and visualization of the nodules. Often, nodules are noted on fiberoptic exam; however, videostrobolaryngoscopy is a more sensitive study detecting smaller lesions. Vocal cord nodules do not significantly disturb the propagation of the mucosal wave on stroboscopy, but the larger nodules can prevent they complete closure during the glottic cycle. Histologically, VCNs have a thickened basement membrane zone (BMZ) and dense fibronectin arrangement within the superficial lamina propria.
Both medical and surgical therapy options are available for the treatment of VCNs. Given the suspected etiology of VCN, the first line therapy is voice therapy and education. This entails educating patients on voice hygiene and the importance of hydration and the effects of voice abuse, misuse and overuse. Voice therapy over a 4- to 6-month period results in perceptual improvements in voice and reduction in nodule in a majority of VCNs, although the nodules do not necessarily disappear completely (Holmberg et al, 2000). In a small percentage of patients for which symptoms and the nodules persist despite medical therapy, surgical excision represents another treatment option.
The goal of surgical therapy is to minimize trauma to normal vocal cord tissue leaving a flat surface on the medial surface of the vocal cord. A number of surgical options are available including cold steel excision with microflap technique and microspot CO2 laser resection. Several studies have compared cold steel excision and laser resection without noting a significant difference in terms of stroboscopy exam and quality of voice.
In a recent Cochrane Review of the literature evaluating surgical and non-surgical treatment of VCNs, no definitive conclusion could be made because of the lack of randomized controlled studies. The review showed poor correlation between objective and subjective measures of treatment. In addition, it was unclear how long a trial of voice therapy should be attempted. Also, no differentiating characteristics and/or findings could be identified to determine which patients would fail voice therapy and require surgical intervention. The standard treatment involves an exhaustive trial of voice therapy. For those who fail voice therapy, surgical resection with either cold steel or laser is pursued. Voice rest is recommended for 4 to 14 days post-operative and speech therapy re-initiated, although no randomized studies are available for these recommendations (Johns, 2003). In addition, other comorbidities that can affect voice such as allergic rhinitis and laryngopharyngeal reflux need to be managed.
Cystic lesions
A cyst is an epithelial lined structure. There are two types of cyst that can be found within the vocal cords: mucus retention cyst and epidermoid cyst. They are found within Reinke’s space within the cords. Like cyst located in other anatomical sites, mucus retention cysts contain mucus and arise from a blocked mucus-producing gland while epidermoid cysts are filled with keratin debris. The epidermoid cysts are thought to form from trapped epithelial cells within the lamina propria from phonotrauma.
Similar to other vocal cord lesions, vocal cord cyst can present with hoarseness, changes in voice quality and vocal strain. Occasionally, vocal cyst can cause abnormalities only on the singing with little or no effect on the speaking voice.
Vocal cord cysts are commonly diagnosed by fiberoptic laryngoscopy. Video stroboscopy is also an important diagnostic tool for vocal cord cyst. The overlying mucosa will present with an absent or decreased mucosal wave.
Treatment, similar to VCN, is primarily medical and voice therapy. The goal of medical treatment is to minimize local edema and inflammation. Towards such goal, management of other conditions that can result in vocal cord edema such as LPR is critical for the successful treatment of vocal cord cyst. Voice therapy again plays a key role in the treatment of vocal cord cyst. The voice therapy is based on educating patients voice hygiene and good speech habits. Medically, patients are placed on a 2-week taper of steroids to minimize local edema and inflammation.
For patients who do not respond to medical and voice therapy, surgery remains the final treatment option. Laryngeal microsurgery raising a submucosal flap represents the best technique for excision of the cyst with minimum alteration to voice. In an outcomes study evaluating microflap surgical resection followed by voice therapy, Johns (2003) showed a significant improvement 3 months after treatment by video stroboscopy parameters (shimmer, jitter, and upper pitch limit).
In addition to cysts on the vocal cords, cyst can be found elsewhere in the larynx. Other noteworthy laryngeal cystic lesions are laryngoceles and saccular cysts. Laryngoceles are disorders of the saccule and categorized as internal or combined, which refers to the extension of the cyst. If the cyst is entirely contained within the thyroid cartilage, it is referred to as internal. Once the cyst extends through the thyrohyoid membrane, it is called a combined laryngocele with an internal and external component.
Clinically, internal laryngoceles often present with hoarseness while neck swelling is a common chief complaint of external laryngoceles. The diagnosis is based on laryngoscopy and a computed tomography or radiography revealing a fluid- or air-filled sac extending from the larynx.
The etiology of laryngoceles is unknown. An association between laryngoceles and activities causing high transglottic pressures has been hypothesized. However, the presence of these activities in patients with laryngoceles is not common (Stell and Maran, 1975). Although not a common cause, laryngeal carcinoma obstructing the saccule orifice can lead to saccular cyst.
Treatment is surgical. Depending on the size of the cyst, surgery entails either excision of the cyst via an external approach versus marsupilization of the cyst via an endoscopic approach. Some newer techniques are being tried for complete endoscopic resection. The method of surgical treatment will be dependent on a number of factors including size of the cyst, location, and surgeon’s experience.
Recurrent respiratory papillomatosis
Recurrent respiratory papillomatosis (RRP) represents the most common benign laryngeal tumors and the second most common cause of hoarseness. Multiple exophytic lesions lining the airway characterize this disease.
Clinically, there are 2 forms: adult onset RRP (AORRP) and juvenile onset RRP (JORRP). Adult onset RRP has a slight male predominance presenting commonly between 20 and 40 years of age. On the other hand, juvenile onset RRP has no gender predominance and the peak age of diagnosis is 2 to 4 years of age. The incidence in adults is 3.9 in 100,000 and similarly in children the incidence is 3.6 in 100,000. Disease aggressiveness in JORRP has been associated with children diagnosed before the age of 3. This subset of patients is more likely to have more than 4 procedures a year (the average is 4 procedures per year) and 2.1 times more likely to have multiple laryngeal subsite involvement. Extralaryngeal spread occurs in 13 – 30% of JORRP and in 16% of AORRP. The most common site of spread is the oral cavity followed by the trachea and bronchus.
Juvenile onset RRP has an interesting disease progression. The disease will commonly and spontaneously resolve by puberty. From this clinical observation, it is suspected that RRP is hormonally regulated. No clear data is currently available to relate an endocrine component in the regulation of RRP disease expression. In AORRP unlike JORRP, the disease is often resolved with only few number surgical procedures.
Recurrent respiratory papillomatosis is associated with the human papilloma virus (HPV) serotypes 6 and 11. HPV is a nonenveloped capsid virus with double-stranded DNA. The DNA virus attacks the basal layer of mucosa and is either expressed or exists as a latent infection in mucosa.
Histologically, RPP lesions have a fingerlike projection with a center core consisting of connective tissue stroma lined with nonkeratinizing squamous epithelium. Junctions between squamous and ciliated epithelium are susceptible to HPV infections.
The primary treatment for RRP is surgical resection. Given the recurrent nature of the disease, the goals of surgery are to establish a safe airway, to reduce tumor burden, to improve voice quality, to minimize disease spread and to extend the interval between surgical procedures. The two most common modalities for removal of the papillomas are carbon dioxide ablation versus microdebrider. The advantage of using the carbon dioxide laser is the ability to provide hemostasis as well as ablation. The disadvantage is the possible thermal injury to normal tissue. The extent of thermal injury can be minimized with use of the microspot CO2 laser. A recent survey of ASPO members showed that the majority favored the microdebrider. Prospective studies by Patel et al. (2003) showed that use of the microdebrider resulted in shorter OR time, less pain, and less OR expense as compared to the CO2 laser. Other modalities, specifically different types of lasers, are available, but have yet to enjoy popular use.
In some severe cases, airway obstruction is a major concern. In only those situations, a tracheostomy may be necessary. Decannulation is recommended as soon as possible. Some ancedetotal evidence has suggested a risk of tracheal spread with placement of tracheostomy. However, no clear data can support this association. Therefore, tracheostomy is performed as needed.
Given the recurrent nature of the disease, a number of adjuvant treatments are under active investigation. One of the most popular is intralesional injection of cidofovir. Cidofovir is a nucleoside analog with antiviral activity that has FDA approval for use in CMV retinitis in HIV patients. Because of its antiviral effects, cidofovir was tested as an adjunvant therapy for RRP. Snoeck et al performed intralesional cidofovir injections after a surgical procedure in 17 patients. They found that 14 of the 17 patients had an initial clinical response (Snoeck et al, 1998). In addition, 10 of the 14 who had a response were disease-free at the 2 yr follow-up. Although cidofovir has enjoyed enthusiasm in the RRP community, there is a lack of controlled studies evaluating the effects of cidofovir on the natural course of the disease. There has been no controlled study showing a benefit of cidofovir as the treatment of RRP.
Interferon is a cytokine that can activate the immune system in response to an infection. The immune response makes cells less susceptible to additional viral infections. It is delivered as subcutaneous injection daily for 28 days, followed by 3 days per week for 6 months. The initial success of this therapy was tempered by the side effects of the medication and resumption of pretherapy growth rate with the cessation of interferon (Lee et al, 2005)
Another adjunvant therapy is phototherapy using dihematoporphyrin ether (DHE) as the photosensitive drug. Delivered intravenously, DHE tends to concentrate in the papillomas relative to the surrounding normal tissue. An argon dye laser is then used to activate the DHE. In a small study at Long Island Jewish Hospital, DHE phototherapy caused significant decrease in RRP growth. Other studies have shown poor benefit and long-term follow-up showed recurrence in many of the initial responders.
Another antiviral that has been tried is ribavirin. It is usually used against respiratory syncytial virus. As a supplement, ribavirin showed an increase in time interval between surgical procedures primarily in patients with aggressive forms of RRP. Again, ribavirin has only been tried in a small number of patients. Larger studies will be necessary to determine the true effectiveness of ribavirin against RRP.
An exciting new prospective therapy against general HPV diseases utilizes a recombinant fusion protein of heat shock protein 65 and the E7 protein from HPV 16. Initial data suggests that subcutaneous injections of this fusion protein can increase the interval between surgical procedures and reduce the number of total surgical procedures. Additional studies are still pending.
Finally, a last note on treatment, a couple of HPV vaccines have become available, primarily for the prevention of cervical cancer. One is called Gardasil and is available from Merck as a quadravalent vaccine primarily against HPV 16,18, 6 and 11. The other vaccine called Cevarix is from GalaxoSmithKlein. Cervarix contains virus-like particles that stimulate a response to HPV 16 and 18. Studies on these vaccines and the effect of the incidence of RRP will be interesting. It is anticipated that these vaccines will ultimately reduce the incidence of JORRP.
Conclusion
Only a few of the most common benign laryngeal lesions were presented in this review. For a complete differential of benign laryngeal lesions, it is important to recall all the possible tissue types within the larynx. Other common benign laryngeal lesions not discussed in this review include chondromas, neurofibromas, hemangiomas, granular cell tumors, fibromas, and myxomas. This review presents an update on understanding of the pathophysiology and treatment options for several of the most common benign larygneal tumors.
References
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