Laryngeal Airway and Lesions

## **Chapter 4** Vocal Cord Paralysis

*Shaili Priyamvada*

### **Abstract**

Vocal cord paralysis can be due to neurogenic cause, trauma due to surgery, or mechanical fixation of the cords. Diagnosis of the underlying cause leading to paralysis of the vocal cords is important. Most commonly, there is paralysis of recurrent laryngeal nerve. Treatment depends on the cause and whether the cord paralysis is unilateral or bilateral. Unilateral paralysis patients usually present with change in voice, regurgitation, and difficulty in swallowing. One-third of them they show spontaneous recovery, due to compensatory movement of opposite healthy vocal cord. Speech therapy is useful during initial conservative management period. In rest of the cases, vocal cord medialization procedures are performed. As for bilateral vocal cord paralysis which is troublesome entity, patients present with severe symptoms of respiratory distress, stridor, and aspiration. Voice is usually normal in bilateral paralysis cases but change in pitch, poor intensity, and voice fatigue are the complaints. The primary objective is to relieve patients' dyspnea. There are different treatment options available for bilateral vocal cord paralysis such as tracheostomy, arytenoidectomy, cordectomy, botulinum toxin injection, re-innervation procedures. All these procedures have been applied in with varying success. Unilateral cord paralysis is more common and has better prognostic outcomes as compared to bilateral vocal cord paralysis.

**Keywords:** vocal cord paralysis, change in voice, stridor, tracheostomy, arytenoidectomy

### **1. Introduction**

Larynx plays role in phonation, respiration, airway protection, prevention of aspiration, and swallowing. The extrinsic muscles are associated with swallowing, while the prime function of intrinsic muscles is respiration and phonation.

Vocal cord refers to the immobility of vocal cord. It can be unilateral or bilateral. Both can be due to diseases affecting the vocal cord itself such as tumor or scarring; or due to paralysis of recurrent laryngeal nerve or superior laryngeal nerve.

The most common causes include laryngeal or extralaryngeal cancers, iatrogenic trauma during neck, thyroid gland, or chest surgery, and various neurogenic conditions (e.g., amyotrophic lateral sclerosis and closed head injury) [1–4].

Vocal cord paralysis is most commonly unilateral. The affected vocal cords do not adduct or abduct properly causing voice disorder. Along with that there might be difficulty in swallowing. As for bilateral paralysis, breathing difficulty, choking, and aspiration are there along with voice change. The incidence of the bilateral vocal cords paralysis comprises around one-third of all vocal cord paralysis cases [2].

It requires interprofessional team of otolaryngologists, radiologists, and speech therapists in the evaluation and management of vocal cord paralysis.

### **2. Positions of vocal cords**

Five positions of vocal cords are described traditionally (**Table 1**; **Figure 1**). The position of the vocal cords may not correlate with the severity and site of the lesion and, thus, is not a reliable indicator. As re-innervation occurs the position of the vocal cord often changes.

*Median position:* Vocal cord is in midline position such as in phonation. It may occur in recurrent laryngeal nerve (RLN) paralysis.

*Paramedian position:* Vocal cord is 1.5 mm away from midline. It occurs in strong whisper in a healthy person. It may occur in RLN palsy.

*Intermediate (cadaveric)*: This is the neutral position of vocal cords. Abduction and adduction occur from this point. Vocal cord lies 3.5 mm away from mildline. This occurs when there is combined paralysis of RLN and SLN.

*Slight abduction*: Vocal cord is 7 mm away from the midline. It occurs during quite respiration and paralysis of adductors.


#### **Table 1.**

*Position of vocal cords from midline in healthy and diseased individuals.*

#### **Figure 1.**

*Diagram showing different positions of vocal cords (FA—full abduction, SA—slight abduction, C—cadaveric, PM—paramedian, M—median).*

*Full abduction*: Vocal cord in 9 mm away from midline such as in deep respiration.

### **3. Etiology of vocal cord paralysis**

Causes of vocal cord paralysis include

	- 1.Jugular foramen (skull base): Fractures, nasopharyngeal cancer, Glomus tumor, skull base osteomyeltis.
	- 2.Parapharyngeal space: Penetrating injury, parapharyngeal tumor, metastatic nodes, lymphoma.



#### **Table 2.**

*Causes of recurrent laryngeal nerve paralysis (low vagal trunk or RLN).*


### **4. Unilateral vocal cord paralysis**

### **4.1 Epidemiology**

Studies on comparison of patient demographics show no statistically significant difference in age, gender, or duration of symptoms. About one-third of UVCP cases are neoplastic in origin, one-third are post traumatic and one-third are idiopathic. Viral neuronitis probably accounts for most idiopathic cases. Paralysis of the left vocal cord is reported to be 1.4–2.5 times more than right [5].

### **4.2 Pathophysiology**

RLN damage is the most common cause of vocal cord paralysis. Combined paralysis of RLN and SLN is also possible and is seen post-thyroidectomy surgeries due to iatrogenic trauma.

To understand the pathophysiology of vocal cord paralysis, it is of importance to know the origin and course of vagus nerve and its branches as they give rise to laryngeal sensory and motor supply.

Vagus nerve has two nuclei—nucleus ambiguous and dorsal nucleus of vagus. Nucleus ambiguous is situated in medulla and gives origin to motor efferent fibers to soft palate, pharynx, and larynx. Dorsal nucleus of vagus is an autonomic nucleus, which gives general efferent visceral fibers that supply smooth muscles and glands of trachea and bronchi, heart, and abdominal viscera.

The superior laryngeal nerve arises from inferior ganglion of vagus and descends behind internal carotid artery, and at the level of greater cornua of hyoid, it divides into internal and external branches. The internal branch travels medially along superior laryngeal branch of superior thyroid artery and pierces the thyrohyoid membrane about 1 cm anterior to greater cornu and about 1 cm above ala of thyroid cartilage. The nerve then runs submucosally in the lateral wall of pyriform fossa. It provides sensory innervation to the mucosa above the true vocal cords. The external branch runs along the posterior aspect of superior thyroid artery and proceeds inferiorly along oblique line of thyroid. As it reaches inferior constrictor muscle, it sends a branch and then passes deep to sternothyroid muscle to reach the cricothyroid muscle. It innervates the cricothyroid muscle (essential in changing the pitch of the voice). Isolated superior laryngeal nerve lesions are rare and it is usually part of combined paralysis. It results in loss of sensation above the level of true vocal cords and a husky voice.

On the right side, RLN arises from vagus in front of subclavian artery in lower part of neck, and it traversus below the subclavian artery after emerging from vagus nerve. RLN is derived from sixth arch and is displaced by arteries of previous arch, which necessitates change in direction and course of recurrent laryngeal nerve. The right recurrent laryngeal nerve stays lateral to the trachea-esophageal groove in the fat plane and comes closure to the groove as it crosses inferior thyroid artery. The left RLN has longer course and from its origin at the anterior surface of arch of aorta to the interspace

### *Vocal Cord Paralysis DOI: http://dx.doi.org/10.5772/intechopen.104406*

between origin of left common carotid artery and subclavian artery. The nerve loops around arch of aorta distal to ligamentum arteriosum and then enters the neck, and lies deeper in the trachea-esophageal groove. Rest of the course is in similar on both sides, as RLN reaches the suspensory ligament of thyroid gland and lies on either medial or lateral from within. Then, it divides to supply the intrinsic muscles of larynx. Left RLN is more prone for injury as it has a longer course and injury most commonly occurs in the region of trachea-esophageal groove during thyroid or any other neck surgery.

There are two theories to explain the position of vocal cord in cases of cord paralysis. Semon's law states that in the sequence of position of the vocal cords in slowly progressive organic central lesions, motor nerve fibers supplying the abductors of vocal cords become involved much earlier than adductors. Wegner and Grossman hypothesis explains the median and paramedian position of cords after RLN palsy, on the basis that cricothyroid muscle that receives supply from superior laryngeal nerve takes over & it has adductor and tensor function.

### **4.3 History and physical examination**

Patients with unilateral cord paralysis present with a sudden onset of change in voice, that is, dysphonia and/or transient aphonia. In addition to dysphonia, a significant proportion of patients present with swallowing difficulties, weak cough reflex, and regurgitation. Poor exercise tolerance with shortness of breath on minimal exertion is observed in many patients with UVCP in spite of normal lung function.

It is important to obtain elaborate history including the symptoms and signs pertaining to head and neck cancer. History of pain during swallowing, hemoptysis, neck nodes, referred ear pain, and significant weight loss should be asked. Past medical history including heart or lung disease, smoking, tobacco chewing, and alcohol consumption status are all important indicators of potential malignant disease. Clinical evaluation of the patient should include a complete otolaryngological examination, with particular attention to inspection and palpation of the neck. Flexible nasal endoscopy of the oropharynx and glottis helps forming the diagnosis. Assessment of voice quality can be graded with GRBAS scale (Grade, Roughness, Breathlessness, Aesthenia, Strain) [6], which has frequently shown the voice to be worse in such patients.

### **4.4 Evaluation**

### *4.4.1 Flexible videolaryngoscopy*

Flexible laryngoscopy of the glottis is the most useful method of evaluating appearance and movement of vocal cords. It is easily performed in the outpatient setting and can be combined with videostroboscopy to obtain a detailed overview of vocal cord movements (**Figure 2**).

#### *4.4.2 Videostroboscopy*

Videostrobscopy uses the same equipment as videolaryngoscopy combined with a microphone and flashing strobe light. During speech production, our vocal cords move at a very high speed, too fast to be perceived by naked human eyes. Stroboscopy is used to "slow down" the movement to study the detailed vocal cord movements such as amplitude, mucosal wave, vibratory pattern. It is a gold standard test in cases of voice disorders (**Figure 3**).

### *Updates on Laryngology*

#### **Figure 2.**

*Videolaryngoscopy showing left vocal cord paralysis post left hemithyroidectomy (a)abduction (b) adduction.*

**Figure 3.** *Videostroboscopy pictures showing right vocal cord paralysis.*

### *4.4.3 Imaging*

A *chest X-ray* can be useful in cases of mediastinal or lung lesions and to read features of aspiration pneumonia. *CT scanning* is the most favored investigation. CT from skull base to diaphragm is adviceable in order to study the complete course of RLN. MRI can be used an alternative to CT scan when exposure to ionizing radiation is a concern but it has high false-positive rates.

### *Vocal Cord Paralysis DOI: http://dx.doi.org/10.5772/intechopen.104406*

Neck and laryngeal ultrasound can be used to assess vocal cord movement and investigate surrounding pathologies. However, ultrasound does not yield the same anatomical definition as CT requires an experienced ultrasonographer and is less reliable in obese patients.

### *4.4.4 Lab tests*

Routine serological testing only aids in the diagnosis of a particular etiology. There is no strong evidence of them in helping form a diagnosis. Serum tests can be used in suspected inflammatory or infectious UVCP, with common tests including rheumatoid factor, antinuclear antibodies, serum ACE, lyme titer, and erythrocyte sedimentation rate (ESR).

#### *4.4.5 Laryngeal electromyography*

Laryngeal electromyography can be used as a prognostic tool. It is an office-based procedure. A percutaneous EMG needle is inserted through the anterior part of neck to the muscles of the larynx and their electrophysiological evaluation is done. Although growing in popularity, the test is not widely available.

#### **4.5 Treatment/management**

Patients with UVCP are initially treated with speech therapy. A "watchful waiting" period of 6 to 9 months is observed for spontaneous motion recovery by the opposite healthy vocal cord, as there is no definitive guidelines on how long a clinician should wait before surgical intervention.

The aim of surgery in cases of unilateral cord paralysis is cord medialization. The different surgical options are as follows:

*Intracordal injection or injection thyroplasty*—this involves injection of a substance to the affected vocal cord, moving it medially to make better contact with the opposite vocal cord. Different materials have been used in injection thyroplasty, for example, autologous fat, teflon, collagen, gelfoams, calcium hydroxy-apatite, methylcellulose, and hyaluronic acid; however, no high-quality evidence exists confirming the ideal material [7]. Teflon has previously been used, but this has fallen out of favor due to the formation of granulomas.

*Type 1 Isshiki thyroplasty* is a medialization procedure wherein a window is cut into the thyroid cartilage, and the vocal cord moved medially by the use of an implant such as silastic prosthesis. Like injection thyroplasty, there are numerous implant materials available. Arytenoid rotation procedures such as adduction and arytenopexy can be performed concurrently, and voice outcomes are reported to be good at 1 and 3 years post-operatively [8].

*Dynamic procedures* like nerve-muscle pedicle transfer with superior belly of omohyoid muscle along with its nerve(ansa hypoglossi) and vessels is implanted into thyroarytenoid muscle. Ansa cervicalis-recurrent laryngeal nerve anastomosis has also been used with good results on voice outcomes.

*Type 1 Isshiki thyroplasty* has a greater long-term benefit over injection techniques, and there is a growing body of evidence that long-acting injectable materials have comparable longitudinal outcomes [9]. Surgical intervention should be considered after a trial of conservative management, with the technique used based on surgeon experience and patient preference.

### **4.6 Prognosis**

Around one-third of patients of UVCP will experience motion recovery, due to the compensatory action of the opposite vocal cord [10]. Laryngeal electromyography is an useful tool to track prognosis in patients with persistent dysphonia [11].

### **4.7 Complications**

The adverse effect on voice and swallowing can have a significant detrimental impact on the patient's quality of life. Incomplete closure of the glottis can also lead to a risk of aspiration, and despite being rare, this can lead to life-threatening aspiration pneumonia. In particular, patients who rely on their voice for a living (teachers, singers, secretaries) may suffer significant psychological and financial difficulty as a result of UVCP.

### **4.8 Enhancing healthcare team outcomes**

The interprofessional team approach is better in diagnosing and managing cases of UVCP. Otolaryngologists can diagnose it with elaborate history, clinical examination, and flexible video laryngoscopy. Radiologists can aid in diagnosis through the study of the course of nerve involved or mediastinal lesion through CT /MRI imaging. Management can be done with speech therapy with the support of speech and language therapists and surgical treatment for those patients by otolaryngologists who do not respond to initial therapy.

### **5. Bilateral vocal cord paralysis**

The most common presentation of bilateral vocal cord paralysis is stridor [12]. These patients typically present with respiratory distress. In addition to considerable airway obstruction, bilateral vocal cord paralysis presents with symptoms common in unilateral vocal cord immobility such as ineffective cough, aspiration, recurrent pneumonia, reactive airway disease, and feeding difficulties [13, 14]. Voice and cry may be fairly normal in children with bilateral vocal cord paralysis [15].

### **5.1 Epidemiology**

As bilateral vocal cord paralysis occurs most commonly after iatrogenic trauma to recurrent laryngeal nerve, there is history of recent thyroid surgery in these patients. The incidence of the bilateral vocal cords paralysis comprises around one-third of all vocal cord paralysis cases. Bilateral cord paralysis is slightly more common in females, and it is attributed to the fact that thyroid diseases are more common in them as compared to males. Idiopathic bilateral paralysis cases show no gender preponderance and incidence is equal in both males and females.

### **5.2 Pathophysiology**

RLN damage is the most common cause of bilateral vocal cord paralysis. Combined paralysis of RLN and SLN is also possible and is seen post-thyroidectomy surgeries due to iatrogenic trauma.

### *Vocal Cord Paralysis DOI: http://dx.doi.org/10.5772/intechopen.104406*

Bilateral vocal cord paralysis can be caused by injury to the vagus nerve near its origin or anywhere along its course or injury to its branches RLN and SLN through neck, thorax, and abdomen. Injury to the RLN is most common, classically leaving the vocal cords in a median position in case of bilateral vocal cord paralysis. Injury to the SLN will lower the pitch of the voice and can lead to a bowing deformity of the vocal cords due to a loss of tone from the dennervated cricothyroid muscles. A high vagal injury can leave the cord in a nearly fully abducted position.

### **5.3 History and physical examination**

A bilateral vocal cord paralysis patient most commonly presents with breathing difficulties such as stridor, increased work of breathing, and aspiration. It can be lifethreatening and immediate measures that have to be taken to secure the airway. Voice in bilateral paralysis is usually of good quality but of limited intensity, changed pitch, and with voice fatigue. Any recent history of URI, any neck or mediastinal surgery or trauma, malignancy, radiation therapy, and a thorough past medical history should be obtained. A thorough physical examination is done, with an emphasis on the head and neck and lung examination.

Clinical diagnosis can be made based on flexible fiber-optic laryngoscopy, where the vocal cord position can be noted and are observed to be immobile. If the diagnosis is still uncertain, video stroboscopy and bronchoscopy can provide additional information about motion wave of the vocal cord vibrations and rule out subglottic and tracheal pathology, such as subglottic stenosis or tracheomalacia.

### **5.4 Evaluation**

The investigations that aid in diagnosis are as follows:

*Flexible videolaryngoscopy:* It is essential part of the initial physical examination and is performed with the patient awake in the office to assess vocal cord movement. Direct laryngoscopy and bronchoscopy are reserved for the patients when there is any doubt about the diagnosis and patients with lung pathology, to visualize the lower airway. This procedure also allows palpation of the arytenoid joints to rule out fixation of vocal cords (**Figure 4**).

*Laryngeal electromyography:* This is an office procedure performed to determine the innervation status of the laryngeal muscles after a neurogenic injury. It is also useful as a prognostic tool during the recovery period.

#### **Figure 4.** *Videolaryngoscopy pictures showing bilateral vocal cord paralysis.*

*Imaging of the recurrent laryngeal nerve* CT is the most commonly employed investigation, though MRI can also be used. The area from brainstem to mediastinum is imaged to study the origin and entire course of vagus nerve and its branches RLN and SLN and detect pathology.

*Lab tests:* Blood investigations depend upon history and overall medical scenario of the patient. Antineutrophil cytoplasmic antibody test, thyroid function tests, tubercular skin tests, uric acid levels, rheumatoid factor test, serum K+, Ca+, Na+, antinuclear antibody tests, and erythrocyte sedimentation rate can all be considered.

### **5.5 Treatment**

In bilateral cord paralysis, patient adequate airway must be re-established. Common surgical options for management include tracheostomy, arytenoidectomy, and cordotomy. Laryngeal re-innervation techniques and botulinum toxin (Botox) injections into the vocal fold adductors have also been used with varying success rates. More recently, there has been research on neuromodulation, laryngeal pacing, gene therapy, and stem cell therapy. These newer approaches have the potential to recover the vocal cord movement without any anatomical destruction. However, clinical data are limited for these new treatment options, and more interventional studies are needed. These areas of research are expected to provide dramatic improvements in the treatment of bilateral cord paralysis in future.

*Tracheostomy* is the most common procedure performed in patients with bilateral vocal cord to establish a secure airway. It is potentially reversible without long-term sequelae. Although tracheostomy remains the standard in bilateral cord paralysis cases, it is associated with reduced quality of life, chronic care burden, cost, psychosocial impairment, and increased mortality. Endoscopic techniques have been shown to be more cost effective as compared to tracheostomy in the management of permanent bilateral vocal cord paralysis [16]. Although several alternative procedures have been developed to manage bilateral vocal cord paralysis, they all have the ability to produce permanent changes of the larynx that may predispose patients to lifelong aspiration and dysphonia postoperatively. *Arytenoidectomy* is an irreversible procedure where there is an endoscopic removal of the arytenoid cartilage to expand the glottic chink transversely, for adequate airway. It is either performed on its own or in combination with vocal fold resection, referred to as arytenoid cordectomy. In current scenario, it is performed using *CO2 laser* or KTP-532 laser, which aids in precision, achieving better hemostasis and reducing postoperative edema. Arytenoidectomy has positive results in terms of augmenting ventilation but some patients may experience worsening dyspnea after the procedure, which can be permanent. Arytenoidectomy can also lead to scarring and granuloma formation. In such cases, multiple surgical revisions are needed. Endoscopic plasma *coblator* can also be used to perform arytenoidectomy. *Cordotomy* is another endoscopic surgical procedure to enlarge the glottic chink to attain adequate airway. An incision is made in the vocal cord, ligament, and the thyroarytenoid muscle posteriorly at the attachment to the arytenoid. Revision cordotomy can be required in up to 30% of patients secondary to reduced glottic diameter from scarring or granulation tissue formation [17]. The most common complication associated with cordotomy was altered voice quality due to vocal fold damage [18]. Laser endoscopic cordotomy is preferred now, as compared to an arytenoidectomy, in vocal cord paralysis cases as it is less invasive and reduces the incidence of aspiration. Also, overall voice outcomes are also better than arytenoidectomy.

Botulinum toxin injection to adductor muscles provides transient improvement in symptoms for approximately three to 6 months at a time, requiring repeated injections for longer-lasting relief.

Reinnervation techniques are technically challenging and require experienced surgeons in its use for the procedure to be a success. The goal here is to establish vocal cord abduction through the restoration of the activity of the posterior cricoarytenoid (PCA) muscle. While it enables the return of spontaneous vocal cord abduction, it does not affect adduction. Gene therapy and stem cell therapy are in preclinical stage but hold promising for treatment in future.

### **5.6 Prognosis**

In adults, spontaneous recovery of idiopathic vocal cord paralysis can occur as early as 12 months following the onset. It is expected in 55% of patients, but full recovery can be very protracted. The prognosis for complete spontaneous recovery is far worse in bilateral vocal cord paralysis than unilateral. Recovery depends upon the underlying etiology.

### **5.7 Complications**

Bilateral cord paralysis can lead to the following complications: Stridor, airway obstruction, dyspnea, poor cough reflex, aspiration, bronchopneumonia due to aspiration, difficulty in swallowing, feeding difficulties, and failure to thrive in children & voice fatigue. In addition to this, in the long-run arytenoid granuloma formation and chondritis may occur.

### **5.8 Enhancing healthcare team outcomes**

Bilateral vocal cord paralysis is a challenging and troublesome entity. Tracheostomy, cordotomy, and arytenoidectomy all have been applied with positive outcomes in bilateral cord paralysis cases. Management should be individualized based on the patient's clinical presentation and the surgeon's expertise.

### **6. Paralyzed versus fixed cord**

Vocal cord fixation is immobility of vocal cords due to scarring or due to mass effect, involvement of muscles, and joints or the nerve as in case of malignancy. Cord fixation can also be due to rheumatoid arthritis. There may be obvious swelling around cricoarytenoid joint, cord is immobile and fixed, its position does not correspond to any of the described anatomical positions of vocal cords, and aryepiglottic folds are normal. There is no change in position on applying pressure passively on arytenoids, which is in contrast to vocal cord paralysis. Also, in cases of fixation there is absence of any neurological symptoms and signs. In cases of vocal cord paralysis, aryepiglottic folds are paralyzed and pushed aside, cord is fixed to median or paramedian position, but there is no fixation of the joint and it is mobile on manipulating passively. Also, cord paralysis is purely a neurological condition in contrast to cord fixation.

### **7. Laryngeal paralysis in children**

Vocal cord paralysis presents more commonly as stridor in neonates and children. It can be unilateral or bilateral in children, unilateral being more common. Vocal cord paralysis is the second most common cause of stridor in pediatric population following laryngomalacia and accounts for 10% of all congenital anomalies of larynx. Murty et al. estimate the incidence of bilateral vocal cord paralysis to be 0.75 cases per million births per year. Congenital vocal cord paralysis should be part of the differential diagnosis for an infant with respiratory distress. In up to 48–62% of neonates and children with bilateral vocal cord paralysis, spontaneous recovery of vocal cord function can occur, but the prognosis rests with the overall health of the child and any concomitant medical problems [19].

### **7.1 Etiology**

Birth trauma due to vertex or breech delivery and the use of forceps can also lead to RLN injury, though less commonly a bilateral injury [20]. In infants, cardiovascular surgery, including patent ductus arteriosus ligation, and repair of a tracheoesophageal fistula are the common causes of bilateral vocal cord paralysis [21]. **Table 3** summarizes causes of congenital vocal cord paralysis.

### **7.2 History and physical examination**

A detailed family and perinatal histories, including prolonged or protracted or forceps-assisted delivery, concurrent congenital conditions and length of any NICU stay, should be inquired. Presenting symptoms in children include stridor, a weak cry, feeding difficulties, failure to thrive, and aspiration. Neonates and children with bilateral cord paralysis are likely to exhibit severe manifestation such as cyanosis and apnea. Bilateral cases usually have good voice because vocal cords are in median or paramedian position with abductor paralysis but can have marked inspiratory stridor and accessory muscles of respiration working.

Diagnosis can be made by awake fiber-optic laryngoscopy and careful evaluation of the larynx by an experienced pediatric otolaryngologist. Laryngomalacia should be considered as differential diagnosis and ruled out during laryngoscopy, which is far more common than bilateral vocal cord paralysis but can have similar presenting symptoms.

If the diagnosis is still uncertain, direct laryngoscopy and bronchoscopy can be performed under general anesthesia. This is done with the patient spontaneously


#### **Table 3.** *Causes of congenital vocal cord paralysis.*

### *Vocal Cord Paralysis DOI: http://dx.doi.org/10.5772/intechopen.104406*

breathing so the motion of the vocal cords can be assessed intraoperatively. This also allows lower airway examination to rule out concurrent or alternate pathology such as subglottic stenosis and trachea- or bronchomalacia.

#### **7.3 Treatment**

Before surgical treatment is considered, parents are advised to position the child so that he or she is sitting up and to thicken the food in order to manage feeding difficulties and milk regurgitation. If gastroesophageal reflux is suspected, then this should also be treated. In addition, all children with vocal cord paralysis should be seen by a speech pathologist. Greater than 50% of children will undergo spontaneous symptom resolution in the first 12 months of life, though the prognosis is much more guarded for bilateral vocal cord paralysis cases when compared with unilateral [22].

There are no definite guidelines on when to perform surgery and the decision is difficult since in children spontaneous recovery may occur anytime over the years. It should be guided according to the individual case. In general, for cases of bilateral palsy destructive procedures such as cordotomy or arytenoidectomy are advised to be deferred till adolescence.

Tracheostomy is needed and should be performed to improve the airway in bilateral vord paralysis cases, even if spontaneous recovery is expected. Patient can be decanulated once vocal cord recovery occurs.

### **8. Conclusion**

An integrated diagnostic and treatment program is necessary for patients with vocal cord paralysis. Otolaryngologists, speech therapist, and radiologists all play important role in evaluation and management. Treatment strategies should be individualized based on the patient's clinical presentation and the surgeon's expertise.

### **Acknowledgements**

I would like to express my gratitude to the faculty members of the department and the management for giving their valuable suggestions and inputs. Special mention and thanks to Dr. Hukam singh and Dr. Avinash goswami for their encouragement and support in making this chapter possible.

### **Conflict of interest**

The author declares no conflict of interest.

### **Abbreviations**



## **Author details**

Shaili Priyamvada Department of Otolaryngology, Rama Medical College, Hospital and Research Centre, Ghaziabad, India

\*Address all correspondence to: dr.shaili.priyamvada1@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### **Chapter 5**

## Laryngeal Leukoplakia: A Focus on Histology

*Giuseppe Leoncini*

### **Abstract**

Leukoplakia is a clinical term referring to a whitish plaque on the mucosal surfaces that cannot be scraped off. Otolaryngologists daily have to face such findings in both the oral cavity and the larynx. In the latter, several pathological conditions ranging from reactive to neoplastic lesions can underlie leukoplakia. Hence, a proper understanding of the histological spectrum of laryngeal diseases sharing leukoplakia as their main clinical presentation plays a critical role in the clinical management of patients. In that setting, the histological assessment of laryngeal dysplasia is known to have represented a matter of disagreement mostly about grading, and several grading systems have been proposed over time. Nonetheless, the histologic assessment of laryngeal leukoplakia is a mandatory requirement in clinical planning, leading to a proper treatment choice.

**Keywords:** leukoplakia, dysplasia, larynx, grading, differential diagnosis

### **1. Introduction**

Laryngeal leukoplakia (LL) is a clinical term referring to the presence of a whitish plaque on mucosal membranes that cannot be scraped off [1]. Leukoplakia is a descriptive term having not a single histological counterpart but, on the contrary, a broad spectrum of pathological pictures, ranging from benign (reactive-inflammatory) lesions to dysplastic and neoplastic conditions. Establishing a proper diagnosis represents a unique challenge since the optimal clinical management depends on the identification of the reactive or dysplastic nature of that lesion. LL can be found at any laryngeal site, mostly onto the true vocal folds. Regardless of the clinical presentation, LL should be histopathologically examined to rule out both dysplasia and invasive carcinoma, which should be properly treated. Further complexity in managing LL relies on the frequent location along the vibratory side of the vocal folds, where scarring could produce functional consequences and voice quality impairment. Mucosal biopsies performed with flexible laryngoscope represent to date the most widely used diagnostic technique to obtain an earlier diagnosis. Early detection is the strongest prognostic factor affecting the patients' survival. However, the biopsy technique has some limitations, as mucosal sampling could underestimate the severity of the lesion first because of the poor depth of biopsy, then because of the histological heterogeneity of broader lesions [2, 3].

### **2. Histopathological assessment**

### **2.1 Vocal folds' normal anatomy and histology**

The true vocal folds are laryngeal structures consisting of both vocalis muscle and vocal ligament, covered by stratified squamous epithelium. The free edge is formed by the vocal ligament and its epithelial lining, representing the mobile top of the vocal folds and contributing to phonation. The vocal ligament is in continuity with the cricovocal (cricothyroid) ligament, extending from the thyroid cartilage to the vocal process of the arytenoid cartilages. The vocalis muscle lies laterally to the vocal ligament, extending from the vocal process of the arytenoids to the vocal ligament [4]. The true vocal folds are lined by nonkeratinized stratified squamous epithelium, as seen in the superficial rim of the ary-epiglottic folds, in the anterior epiglottic surface (**Figure 1**). In contrast, ventricle, ventricular folds, saccule, and subglottis are covered by ciliated columnar epithelium, with scattered goblet cells. Seromucinous glands can be found in small clusters within the loose stroma of the false vocal fold, whereas they are scattered in the lamina propria of ventricle, saccule, posterior epiglottic surface, subglottis. Seromucinous glands are usually scanty or absent in the true vocal folds [5]. The false vocal fold has no contractile structures, is covered by respiratory-type epithelium, and represents the upper limit of the ventricle, whereas the true vocal fold is the lower limit.

### **2.2 Histopathology**

LL is an *umbrella clinical term* including several histological conditions. *Squamous cell hyperplasia* (or *keratosis*) is qualified by the thickening of a pre-existing squamous epithelium, usually involving basal and prickle cells. It can encompass the presence of conspicuous keratin layer, composed of a nuclear keratin scales (*orthokeratosis*) or by squamous cells with picnotic nuclei and dense cytoplasm (*parakerathosis*). A preserved cellular differentiation, based on both normal nuclear-to-cytoplasmic ratio and base-to-top epithelial maturation, qualifies epithelial hyperplasia excluding dysplasia. Squamous cell hyperplasia can show exuberant features, represented by prominent squamous tongues

#### **Figure 1.**

*Trans-sectional cut including both true and false (yellow mark) vocal folds. Arrow points to the laryngeal ventricle (hematoxylin–eosin, x2,5 magnification). Note that the true vocal fold's mucosa is covered by stratified squamous epithelium (insert, hematoxylin–eosin, x10 magnification).*

*Laryngeal Leukoplakia: A Focus on Histology DOI: http://dx.doi.org/10.5772/intechopen.105635*

simulating an infiltrative growth into the underlying stroma, thus mimicking welldifferentiated squamous carcinoma. Such lesion is referred to as *pseudo-epitheliomatous hyperplasia*, a reactive lesion that can associate with chronic conditions. Squamous cell hyperplasia should be distinguished by *squamous metaplasia*, referring to the replacement of the ciliated respiratory-type epithelium by stratified squamous epithelium. It is a reactive phenomenon involving, by definition, those anatomical sites covered by nonsquamous epithelium and can extend to the sero-mucinous glands. The term *diskeratosis* is sometimes used - but not widely accepted - to describe a focal abnormal maturation in the squamous lining, involving one or few cells displaying abnormal keratinization. It belongs to the spectrum of reactive squamous lesions.

### **3. Laryngeal leukoplakia in nonneoplastic diseases**

The main histological feature of LL is represented by the epithelial thickening (hyperplasia) with preserved epithelial maturation or cellular atypia. Conversely, the presence of abnormal epithelial maturation and cellular atypia should raise suspicion for dysplasia. Despite the clinical setting of LL, dysplasia should be always suspected and ruled out through a proper histological assessment of mucosal specimens. In this regard, biopsy interpretation represents a critical part of the patient's management.

#### **3.1 Phonotrauma**

LL represents the main clinical presentation of laryngeal dysplasia and carcinoma. Nonetheless, it can also be detected in inflammatory disease of the upper airways. The so-called *phonotrauma* is a common clinical condition deriving from the improper use of phonation and characterized by an altered quality of voice, manifesting with hoarseness, rough or scratchy voice, and vocal fatigue. During phonation, the vocal folds' vibration represents a major physical threat. Indeed, both the magnitude and directions of the vocal folds' collision determine mechanical stress and subsequently an injury. The stratified squamous epithelium represents the outermost layer lining the vocal folds, supported by loose stroma and muscle. In some instances, the epithelial damage can extend down to the basal cell layer. Because of impact, stretching, and shearing forces, both the epithelial and the underlying loose connective layers could be affected, the latter being characterized by vascular and fibrotic changes, leading to the vocal folds' tendency to prolapse toward polyps' formation. In the setting of phonotrauma, epithelial reactive alterations could be seen, with or without stromal changes. A structural compromission of the vocal folds' epithelial barrier after acute phonotrauma has been reported by some Authors [6–10]. At histology, the epithelial lining is usually thicker than normal, showing several degrees of dyskeratosis, ranging from apoptotic-like epithelial changes to cytoplasmic clearing and ballooning. Epithelial maturation is preserved, sometimes associated with mild orthokeratosis. Inflammatory cells are usually absent or scanty. At fiberoptic examination, lesions usually appear as a slightly raised white plaque with ill-defined margins. Stromal changes could associate, giving rise to a bulging area or nodular/polypoid lesions.

### **3.2 Chronic laryngitis**

Laryngeal inflammation for at least 3-weeks-long is usually referred to as *chronic laryngitis*. It can result from several etiologies, ranging from infectious (bacterial, viral,

### *Updates on Laryngology*

fungal) to chronic inflammatory (tobacco smoke-related and reflux-related) conditions. Both symptoms and laryngoscopy are usually nonspecific. The great majority of bacterial laryngitis has an acute clinical course, characterized by prominent exudates and crusting. Chronic laryngitis should be suspected in those patients with prolonged impairment of the quality of voice. Viral infection is mainly due to Herpes Simplex Virus, which usually causes acute laryngitis, whereas chronic infection is rare. It is characterized by laryngeal edema, mucosal ulceration, and exudates. Fungal infections could run asymptomatic in immune-competent hosts. Such infections are seldom found in the larynx, being more common in the oral cavity. Immune compromission, drugs, previous radiotherapy, intubation, and neoplasms are common predisposing conditions. The most complained symptoms are hoarseness, cough, and local pain. Histology is not routinely obtained in inflammatory laryngeal diseases. When biopsy is performed, the histological picture is characterized by epithelial hyperplasia, ortho- or parakeratosis, and mixed inflammatory cells. The detection of PAS-D positive rod-like structures on the mucosal surface is diagnostic for fungal infection (**Figure 2**). Particularly, they could be superficially located, with scanty intra-epithelial neutrophil infiltration. Pseudo-epitheliomatous features can be observed. Patients suffering from Gastro-Esophageal Reflux Disease (GERD) frequently complain about laryngeal symptoms over time, such as hoarseness and cough. During the past years, the role of gastric acid reflux in determining laryngeal inflammation has been debated. Though chronic acid gastric reflux can promote laryngo-pharyngeal inflammation, only a minority of patients with clinically diagnosed reflux laryngitis shows pharyngeal reflux, with a similar prevalence in both healthy and reflux-laryngitis patients. Nonetheless, occult laryngeal pathology is known to be common in the adult population and laryngo-pharyngeal reflux has been reported as one of the most prevalent conditions [11, 12]. Mirroring the histologic picture seen at the gastro-esophageal junction, the vocal folds' mucosa is characterized by a variable degree of epithelial thickening, basal intercellular space dilation (spongiosis), and few intra-epithelial lymphocytes and granulocytes. Mild sub-epithelial edema is not uncommon. Current smokers have a

#### **Figure 2.**

*Mucosal sample of true vocal fold in patient with laryngeal fungal infection. Note the rod-like structures (arrows) over the superficial epithelium (periodic acid-Schiff -diastase [PAS-D] x10 magnification).*

### *Laryngeal Leukoplakia: A Focus on Histology DOI: http://dx.doi.org/10.5772/intechopen.105635*

higher risk to develop LL compared to never-smoker patients [13], with or without dysplasia. Chronic laryngitis can frequently underlie LL in smokers. In such circumstances, vocal folds' inflammation is characterized by mild-to-moderate subepithelial infiltration composed of lymphocytes, plasma cells, and histiocytes. Squamous cell hyperplasia and variable ortho- and para-keratosis are not uncommon findings. Dysplastic foci or invasive squamous cell carcinoma could associate.

### **3.3 Laryngeal involvement in systemic non neoplastic diseases**

Larynx can be rarely involved in systemic diseases, such as autoimmune diseases that could mimic chronic laryngitis. Laryngeal lichen planus (LP) is a rare - and probably under-recognized - autoimmune disease affecting both skin and mucosal membranes. Although mucosal LP is more frequent in the oral cavity, where it should be distinguished from pemphigoid of the mucosal membranes, laryngeal involvement has been reported as well. As in chronic laryngitis, laryngeal LP harbors sub-epithelial inflammation, squamous hyperplasia, and superficial ortho- and para-keratosis without dysplasia but, in contrast, laryngeal LP usually presents at least focally, with a sub-epithelial "band-like" inflammation, cytoplasmic vacuolization in basal keratinocytes and basal apoptotic (*cytoid* or c*ivatte*) bodies, commonly unseen in chronic laryngitis. The hyperkeratotic appearance of laryngeal LP can also mimic squamous cell carcinoma, which should be always ruled out, since LP can be successfully treated with glucocorticoid-based therapy,

**Figure 3.**

*A. Amyloid deposition beneath the mucosal surface in the ventricular region (hematoxylin–eosin, x10 magnification); B. Congo red dye under white light microscopy (x10 magnification); C. note the diagnostic applegreen refraction under polarized light microscopy (x10 magnification).*

avoiding unnecessary surgical procedures [14]. Among systemic diseases potentially involving the larynx, amyloidosis should be also mentioned. It consists of a disease group characterized by extracellular deposition of insoluble protein in tissues, known as amyloid fibers. Larynx can be involved in both the system and localized amyloidosis. In the localized variant the laryngeal location is not uncommon, accounting for about 15% of cases, being the glottic region the most involved laryngeal site. At fiber-optic examination, a raised whitish plaque can be detected. Histological examination is useful to recognize the presence of amorphous material in the subepithelial connective tissue. Squamous hyperplasia is usually absent and, in contrast with other nonneoplastic causes of LL, the gross features of the lesions are related to the amyloid protein accumulation rather than to the epithelial thickening. The use of Congo Red dye is useful to highlight a green apple birefringence using polarized light microscopy (**Figure 3**) [15, 16].

### **4. Laryngeal leukoplakia and dysplasia**

Laryngeal dysplasia (LD) is defined by a spectrum of both maturation abnormalities and nuclear atypia involving the laryngeal epithelial lining, that may or may not precede an invasive squamous carcinoma. Even though dysplasia includes atypical cellular features, such a term should not be considered synonymous with atypia, as the latter indicates atypical nuclear features alone, excluding the maturation abnormalities. Thus, the two terms should not be used interchangeably. Dysplastic changes encompass crowded immature epithelial cells, loss of cellular polarity, nuclear pleomorphism and hyperchromasia, increased nucleus-to-cytoplasm ratio, and mitoses including atypical forms. Such cellular and architectural abnormalities can be found as either superimposed into pre-existing squamous hyperplasia or raised into non-hyperplastic laryngeal epithelium. Hence squamous hyperplasia should not be considered a prerequisite for developing LD. According to the dysplasia model applied for the uterine cervix, LD is defined as mild, moderate, and severe regarding the level of epithelial involvement. In situ carcinoma (CIS-non-keratinizing type) is defined by the full-thickness mucosal epithelial dysplastic change without infiltration of the basement membrane. Conversely to the uterine cervix, the larynx usually harbors keratinizing dysplasia, which exhibits by definition at least focal squamous maturation, making the concept of a full-thickness dysplastic involvement not suitable for laryngeal CIS. As a consequence, the use of the term *severe keratinizing dysplasia* (SKD) is likely a more appropriate designation. Abnormal supra-basal maturation with dyskeratotic features, mitoses and surface keratinization are needed to qualify the histologic picture of LD as severe. Nonetheless, histopathologic criteria for evaluating laryngeal keratinizing dysplasia are less defined [17–20].

### **4.1 Grading systems**

LD represents the earliest lesion manifesting, at both microscopic and molecular levels, neoplastic features [5]. Although the progression risk differs according to the grading, LD is widely considered the precursor lesion of squamous cell carcinoma (SCC). The LD grading has been a matter of disagreement among clinicians and pathologists, because of terminology was not uniform, grade designation seemed burdened by subjectivity and the risk stratification was often imprecise. The role of grading is mainly focused on the definition of the progression risk toward SCC. Squamous hyperplasia carries a very low risk of developing invasive SCC, whereas the presence of dysplasia increased such a risk [21]. In order to improve uniformity in diagnostic terminology,

#### **Figure 4.**

*Laryngeal dysplasia grading: A. mild laryngeal dysplasia, note that nuclear crowding, cellular atypia and abnormal maturation is limited to the lower third of the epithelial lining (, hematoxylin–eosin, x10 magnification); B. moderate laryngeal dysplasia, note that nuclear crowding, cellular atypia and abnormal maturation involve the lower half of the epithelial lining (hematoxylin–eosin, x20 magnification); C. severe laryngeal dysplasia, note that nuclear crowding, cellular atypia and abnormal maturation involve more than one half of the epithelial lining (hematoxylin–eosin, x20 magnification).*

several grading systems and classification schemes have been proposed. It was previously suggested that *squamous intra-epithelial neoplasia* (SIN) was the most suitable term to refer to these epithelial changes since they are regarded as a morphologic manifestation of the noninvasive neoplasia [22, 23]. The Ljubljana Classification improved the concordance degree of histopathologic assessment of LD [24], even though the SIN classification system and the Ljubljana Classification were conceptually different, beyond their terminology. Subsequently, the concept of laryngeal intraepithelial neoplasia (LIN) was introduced, including both dysplasia and CIS. In 2017, the World Health Organization (WHO) recommended a two-tier classification, consisting of low and high-grade dysplasia/intraepithelial neoplasia, based on the severity of both architectural changes and cytological atypia, in order to improve the diagnostic reproducibility (**Figure 4**) [25, 26]. The concept of laryngeal CIS was introduced in the previous WHO classification (2005) and subsequently removed from the SIN classification, which considered both severe dysplasia and CIS in the SIN3 category. A transient reappraisal of CIS was seen in the amended version of the Ljubljana Classification, distinguishing the high-grade squamous intra-epithelial lesions (SIL) from CIS. Actually, laryngeal CIS has been included in the high-grade dysplasia, according to the latest WHO classification (**Table 1**).


#### **Table 1.**

*Comparison of following grading systems for laryngeal dysplasia.*

### **4.2 Carcinogenic mechanisms**

Several causative agents and carcinogenic mechanisms have been suggested in SCC. The concept of *field cancerization* (FC) was introduced to describe pathologic atypia in epithelial cells surrounding oro-pharyngeal carcinomas. The role of multiple independent carcinogenic events involving different cells has been postulated, suggesting the role played by carcinogen activation on the whole exposed mucosa. Hence, mutant cellular clones can develop within that field giving rise to metachronous secondary tumors, that should be interpreted as secondary primary rather than recurrent tumors [27, 28]. The concept of FC was confirmed by further studies on head and neck SCC recurrences despite therapy [29, 30]. Alternatively, it has been proposed that neoplastic clones could spread laterally, running within the epithelial lining, from the site of the neoplastic primary toward adjacent normal mucosa [31–34]. Besides the oral cavity, FC has been described in the larynx, which can be exposed to tobacco smoke and other environmental carcinogens. Tobacco and alcohol consumption are the most important risk factors, implicated in 75% of all head and neck SCC [35, 36]. Recent molecular findings suggested that such a phenomenon could be promoted by the acquirement of genetic alteration in a cellular subset with stemness properties, giving rise to a clonal cellular progeny characterized by p53 mutation [37]. Moreover, some nutritional, environmental, and occupational factors were claimed to be implied in the development of head and neck malignancies [38].

The carcinogenic role of the *Human Papilloma Virus (HPV) infection* has been advocated as a causative agent in a subset of LD and SCC. More than 200 different HPV genotypes have been characterized and subclassified into low-, intermediate-, and high-risk types according to their carcinogenic potential. HPV infection was found to play a role in the earliest stage of carcinogenesis, but a direct causative effect lacked to be fully established in laryngeal SCC [39] Moreover, high-risk HPV (hr-HPV) DNA was also detected in healthy laryngeal tissue where it was considered a bystander [40]. The significance of HPV laryngeal infection lacks to be fully elucidated. The carcinogenetic role of HPV infection relies on the viral integration in the host genome

#### **Figure 5.**

*Laryngeal HPV-related invasive SCC. Note the immunohistochemical p16(red) and Ki67(DAB) co-staining (x 40 magnification).*

#### *Laryngeal Leukoplakia: A Focus on Histology DOI: http://dx.doi.org/10.5772/intechopen.105635*

and disruption of intracellular control pathways. Indeed, the interaction of the viral subunits E6 and E7 with cell-cycle regulatory proteins p53 and retinoblastoma respectively has been established for integrated and transcriptionally active hr-HPV and contributed to promoting carcinogenesis [41, 42]. Low-risk genotypes such as HPV-6 and HPV-11 are related to recurrent laryngeal papillomatosis [43]. Despite the carcinogenetic role of HPV infection being a controversial topic in the larynx, the causative involvement of hr-HPV (e.g., HPV-16) in the pathogenesis of peculiar SCC subtypes, such as the verrucous [44] and papillary [45] variants have been reported [46, 47]. HPV-related SCC of the larynx and hypo-pharynx are mostly non-keratinizing cancers. In papillary SCC the prevalence of HPV infection is variable, and its oncogenic role remains a matter of concern [48]. Non-keratinizing SCC is an emergent variant of HPV-related laryngeal SCC. It is the most frequent histologic pattern in HPV-related SCC of the head and neck (**Figure 5**) [49]. In contrast with laryngeal SCC, the potential role of HPV infection in lung cancer is actually not supported [50].

### **5. Laryngeal leukoplakia and squamous cell cancer**

Any neoplastic infiltration beyond the basement membrane into the underlying connective tissue should be referred to as invasive SCC.

The *micro-invasive* SCC is considered the earliest invasive lesion. It is defined by the presence of scattered malignant cells or discrete foci or tongues of neoplastic cells within the submucosa, just below the basement membrane. They are excluded from microinvasive laryngeal carcinomas both CIS, because non-invasive by definition, and those lesions show vascular invasion and muscle or cartilage involvement. Some authors established 1–2 mm as a cut-off to identify an SCC as microinvasive, others proposed the extension into the stroma by <0,5 mm, as measured from the basement membrane of the closest non-neoplastic epithelium [51–53]. The assessment of microinvasion on biopsy can be challenging because mucosal specimens could be superficial and not comprehensive of the invasive component. Thus, caution should be paid in excluding an invasive component when full-thickness malignant cells' replacement is seen on small biopsy specimens since it could lead to an underestimation of micro-invasive SCC. Furthermore, integrity gaps in the basement membrane alone do not stand for a micro-invasive carcinoma, as the evidence of neoplastic foci in the sub-epithelial connective tissue is a necessary diagnostic requirement. Once evaluated on biopsy, such findings should be accepted as noninvasive carcinoma with reservations, until the assessment of the full surgical excision [54]. Multiple sections of the whole surgical specimen should be examined to confidently rule out invasion. The colonization of seromucinous glands by dysplastic epithelial cells should not be misinterpreted as micro-invasion. Microinvasive SCC can be connected to the overlying dysplastic epithelium or not. The lack of such a morphologic continuum does not exclude the diagnosis of microinvasive SCC, as severe dysplasia is not a prerequisite for developing an invasive SCC, in the larynx as well as in the whole upper aerodigestive tract. The invasive nests must have unequivocable malignant cytological features and mitoses, including atypical forms.

The *superficially extending* SCC identifies a more advanced laryngeal lesion, invading beyond those histological limits introduced for defining microinvasion, without muscle or cartilage involvement [23]. The neoplastic invasion beyond the basement membrane makes the tumor capable of gaining access to the lymph-vascular channels, resulting in metastatic disease. A peculiar behavior is seen in glottic SCC, which

is usually not associated with metastatic spread in the early stage of disease compared to supra- and sub-glottis since this laryngeal compartment is characterized by a paucity of lymphatic drainage [55].

*Invasive* SCC is characterized by a spectrum of gross and histopathological features. Grossly, the larynx can harbor exophytic, flat, and ulcerated masses. From a histological perspective, both keratinizing and nonkeratinizing tumors can be found. Several growth patterns can be detected, ranging from conventional to papillary, verrucous, spindle cells, basaloid, and undifferentiated SCC. Neoplastic invasion can be characterized by both neoplastic cords or tongues attached to the superficial epithelium and scattered cells or dyscohesive neoplastic clusters in the lamina propria. Squamous differentiation can vary from well-differentiated to poorly differentiated forms. Association to CIS is not an uncommon finding.

### **5.1 Histological variants of laryngeal SCC**

### *5.1.1 Papillary SCC*

It affects men more than women. The larynx is the most common location, even though it can be seen in the oral cavity and hypopharynx. Papillary SCC usually occurs de novo since the occurrence of cancer at the site of previous papilloma has been rarely reported. The role of HPV infection has been established by in situ hybridization study in such cancer variants [56]. The tumor presented as an exophytic mass, histologically characterized by finger-like projections supported by fibrovascular cores or by a broad-based cauliflower-like growth pattern. Surface keratinization is usually scanty or absent, differentiating the papillary from the verrucous subtype of SCC. Cytologic malignant features are evident in the neoplastic epithelium of the papillary SCC, again differentiating it from verrucous SCC.

### *5.1.2 Verrucous SCC*

It is a highly differentiated variant of SCC affecting men more than women, mostly in the laryngeal glottis. Tumor growth is locally destructive, without metastatic potential. Tobacco smoking and viral induction have been suggested as etiologic factors. The tumor presented as an exophytic mass, histologically characterized by a benign-appearing proliferation composed of uniform squamous cells without significant atypia nor mitoses, prominent surface *warty-like* keratinization, and a broad base with pushing-type margins. A mixed chronic inflammatory cells infiltrate can be seen in the stroma. Hybrid tumors composed of conventional and verrucous SCC have been described in the head and neck [57].

### *5.1.3 Spindle cells SCC*

It is a highly aggressive biphasic tumor composed of both SCC (CIS or invasive) and spindle cells malignant neoplasm, affecting men more than women. In the larynx, both the glottis and the supra-glottic region can be involved. Previous irradiation has been involved as a risk factor, whilst there was no significant correlation with tobacco smoking, alcohol consumption, and occupational/environmental factors [58, 59]. Spindle cells SCC are not related to HPV infection [60]. Tumor mass usually presents as exophytic neoplasm consisting in a malignant undifferentiated spindle cells proliferation with SCC nests. The spindle cells' component

### *Laryngeal Leukoplakia: A Focus on Histology DOI: http://dx.doi.org/10.5772/intechopen.105635*

usually predominates, and it is characterized by prominent cytological atypia and frequent mitoses, often associated with necrotic foci. The growth pattern can vary from fascicular to storiform and palisading. Areas of stromal collagenization and myxomatous degeneration can be seen. Heterologous elements could be detected, mostly consisting of chondro- and osteo-sarcomatous foci. Epithelial derivation is supported by the intimate relationship with conventional SCC and by epithelial markers' expression. Spindle cells were found to express cytokeratins in the majority of cases, even though vimentin expression and myogenic differentiation have been reported [18, 60, 61]. Overall, spindle cells SCC usually behave malignantly, even though flat and ulcerating lesions have a worse prognosis if compared to exophytic variants [62]. Reactive myo-fibroblastic proliferations, mucosal malignant melanomas, and sarcomas should be considered in the differential [63–65].

### *5.1.4 Basaloid SCC*

It is a high-grade variant of SCC involving palatal tonsils, tongue, hypopharynx, and larynx, the latter being mostly affected in the supraglottic region. Known etiologic factors are tobacco smoking and alcohol consumption. Tumor grossly presents as a firm whitish mass, associated with central necrosis. Basaloid cells, characterized by atypical hyperchromatic nuclei and scanty cytoplasm, increased mitotic activity, and peripheral nuclear palisading, are intermingled with conventional SCC. Mucohyaline stromal deposition can be seen. Basaloid cells usually expressed epithelial markers, even though Vimentin could be expressed in a subset. Adenoid cystic and neuroendocrine carcinoma should be considered in the differential [66, 67].

### *5.1.5 Undifferentiated (lymphoepithelioma-like/nasopharygeal type) SCC*

Undifferentiated (lymphoepithelioma-like/nasopharygeal type) SCC can rarely affect larynx and hypopharynx. Such tumors resulted more prevalent in the Chinese population and related to EBV infection. At histology, keratinizing and nonkeratinizing forms have been described, being the latter further subdivided into differentiated and undifferentiated types [68].

### **5.2 Molecular prognostic markers**

The risk of progression is known to vary in dysplastic LL according to the grading of dysplasia [69, 70]. The use of biomarkers to highlight the cumulative effect of genetic mutations can aid in a more accurate establishment of progression in LL. Prognostic biomarkers can be subdivided into four categories: (1) proliferation; (2) cell cycle control; (3) cell adhesion and invasion; (4) immune checkpoints. Malignant cells are known to acquire a high proliferative rate, that can be monitored by using several markers. Ki67 is a nuclear protein widely studied as proliferative marker, even though it does not represent a reliable marker of malignant transformation in laryngeal dysplasia [71–74]. TP53 is a well-established tumor suppressor gene involved in head and neck SCC. The loss of wild-type p53 activity, as well as p16 and cyclin D1, were frequently detected in many cancer types and were found to be involved in tumor progression [75, 76]. A specific isoform of CD44 (CD44v6) was established to interact with Osteopontin, which is known to be elevated in many cancer types and correlates with laryngeal SCC progression in the larynx [73]. Beta-catenin protein is coded by CTNNB1 gene and is involved together with E-cadherin in intercellular adherence

and epithelial structure maintenance. Alteration in beta-catenin protein expression plays a role in cancer progression and invasiveness [77]. In the past few years, tumor inflammatory microenvironment has gained more attention. In that setting, both tumors devoid of immune infiltrates and others marked by abundant T cell infiltrates have been detected. Programmed cell death protein 1 (PD1/CD279) is a member of the CD28 family of T cell co-stimulatory proteins that includes CTLA-4, ICOS, and BTLA. It has two specific ligands PD-L1 (B1-H1/CD274) and PD-L2 (B7-H2/CD273) which down-regulate T cell activation on binding to PD1. The PD-1/PD-L1 interaction represents a critical immune checkpoint in the adaptive immune resistance of SCC. Immunohistochemical assays have been employed to evaluate the expression of immune checkpoints in the tumor microenvironment, but limitations have been outlined by many authors, including the use of different antibody clones (including 5H1, E1L3N, SP142, 28–8, 22C3, SP142, and SP263) and the lack of a standardized scoring system. [78–80].

## **6. Conclusions**

The clinical management of LL is a daily critical challenge for Otolaryngologists, who must be aware of the broad spectrum of pathological conditions that could underlie leukoplakia. An effective clinical-pathological correlation represents the basis for proper treatment planning in such patients.

## **Acknowledgements**

Funding information: GRANT: Fondazione IRCCS Istituto Nazionale dei Tumori.

## **Conflict of interest**

The author declares no conflict of interest.

## **Author details**

Giuseppe Leoncini First Division of Pathology, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

\*Address all correspondence to: giuseppe.leoncini@istitutotumori.mi.it

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Updates on Laryngology*

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### **Chapter 6**

## Laryngomalacia

*Vaishali Waindeskar, Pooja Thaware, Garima Chamania, Anuj Jain and Ashutosh Kaushal*

### **Abstract**

Laryngomalacia is the most common cause of stridor in neonates and infants. In laryngomalacia, there is a supraglottic collapse of the larynx during inspiration leading to obstruction and thus resulting in stridor. The exact etiology of laryngomalacia is still unknown. The neurological basis is one of the leading theories explaining the etiology. Laryngomalacia in most of the patients resolves with conservative management by two years of age. In severe cases of laryngomalacia or when symptoms are persistent beyond two years of age, such cases need surgical management in the form of supraglottoplasty. Flexible fibreoptic laryngoscopy is the gold standard for the diagnosis of laryngomalacia. Various classifications have been proposed to classify laryngomalacia, although considering dynamic airway changes might be the most acceptable basis for classification. Supraglottoplasty has higher success and a low complication rate.

**Keywords:** flexible fiberoptic laryngoscopy, Laryngomalacia, larynx, stridor, Supraglottoplasty

### **1. Introduction**

Laryngomalacia is the most common cause of stridor in neonates and infants. In fact, laryngomalacia is the common cause of stridor in 60–70% of newborns and infants which makes laryngomalacia the most common congenital laryngeal anomaly [1]. Supraglottic collapse produced by certain anatomic variants causes airway obstruction in Laryngomalacia, which is most severe during inspiration. Flexible fiberoptic laryngoscopy is used to diagnose laryngomalacia. The general course is benign, with stridor progressing for 6 months until gradually disappearing by 12–24 months of age. The majority of cases resolve with minimal or no treatment. Of all the laryngomalacia patients, only ten to fifteen percent patients will have significant upper airway obstruction symptoms, including increased breathing effort, feeding difficulties, and failure to thrive. Supraglottoplasty is recommended in such severe situations.

The larynx is subdivided into three parts supraglottis, glottis, and subglottis. The supraglottis is the part between the inferior boundary of the hyoid bone and the vestibular folds. Therefore, the structures present in the supraglottis area are the epiglottis, arytenoid cartilages, and aryepiglottic folds. Laryngomalacia affects these supraglottic structures.

The pediatric airway is different from that of adults in many ways. The relatively large tongue in relation to the oropharynx, therefore pediatric patients are more likely to sustain airway obstruction under anesthesia due to relatively large tongue. The larynx is located more cephalic in the neck in neonates and infants. This high cephalic position helps to facilitate spontaneous breathing right after birth and prevents aspiration. The epiglottis is short, stubby and omega-shaped, angled over the vocal cords. Also, the infantile laryngeal cartilage is more flexible than older children and adults, which is a probable cause of collapsible characteristics of the neonatal and infantile larynx.

### **2. Signs and symptoms**

The most common symptom in infants with laryngomalacia is positional stridor. Stridor commonly appears in the first few days of life, although children may not seek medical help until they are many months old. Stridor is usually worse in the supine position, particularly during crying or eating, because such activities necessitate increased respiratory efforts. The severity of symptoms increases during several months of infancy but usually resolves by two years of age and often earlier [2].

Although stridor is a common symptom of laryngomalacia, it is not often the cause of presentation to the medical facility. Sometimes patients with severe disease present with other respiratory complaints such as respiratory distress, use of accessory respiratory muscles and hypoxemia. Laryngomalacia can also present with atypical symptoms like snoring, obstructive sleep apnea and difficulty in swallowing. Although incidence and distribution of these atypical presentations are yet to be established [3]. Difficulty in swallowing causes decreased intake and respiratory distress increases metabolic demand thus can lead to failure to thrive in infants with laryngomalacia.

The natural history of laryngomalacia and that it resolves during the second year of life is supported by the low level of evidence and lacks endoscopic evidence. The time range within which laryngomalacia resolves and the proportion of patients in which laryngomalacia do get spontaneously resolved is yet to be answered. Atypical presentations are to be further explored. Therefore, prospective longitudinal trials are required to better understand the natural history of laryngomalacia [4].

Laryngomalacia in older children presents with obstructive sleep apnea syndrome. Other reasons in older children for seeking medical attention are exercise-induced stridor and dysphagia [5].

### **3. Etiology**

The exact etiology and pathophysiology of laryngomalacia are still unknown. Multiple causal theories of laryngomalacia have been proposed. The neurological basis is one of the leading theories, which states that the abnormal integration of the laryngeal nerves leads to altered laryngeal tone. This theory has been supported by a pathologic study that has shown increased diameter of supraglottic nerve in patients with severe laryngomalacia. Another theory proposes an imbalance of demand and supply during inspiration as a cause of congenital laryngomalacia. This theory of imbalance needs further study. Acid reflux disease has not been established as a cause of laryngomalacia, although almost 60% of infants who present with laryngomalacia

#### *Laryngomalacia DOI: http://dx.doi.org/10.5772/intechopen.103862*

also have accompanying acid reflux disease. Acid reflux disease causes irritation and thus edema of the upper airway which further worsens laryngeal obstruction.

In the scenario of debated etiologies of laryngomalacia, a neurological basis is considered as the most probable etiology of laryngomalacia among all the theories mentioned before. Another case report supporting the neurological basis is a unique case report where a child who was diagnosed case of moyamoya disease suffered acquired laryngomalacia following a neurologic insult. The child suffered a cerebrovascular accident following which she developed laryngomalacia presenting with severe stridor and chest retractions and a nocturnal oxygen requirement, and severe laryngomalacia being noted on laryngoscopy. Prior to the cerebrovascular accident, she had no symptoms of laryngomalacia and had undergone several laryngoscopies, both awake and anesthetized, which showed no evidence of laryngomalacia [6].

Children with laryngomalacia showed vitamin D deficiency and increased proinflammatory cytokine IL-6, which may result from dysregulation of the immune responses. Laryngomalacia could be an inflammatory disease secondary to maternal deficiency of 25(OH)-vitamin D with subsequent Vitamin D deficiency in exclusively breast-fed infants during neonatal and infantile periods [7].

### **4. Factors that influence disease severity**

The patient factors that influence disease severity are Apgar score at birth and during the first several minutes after birth, resting oxyhemoglobin saturation level at the time of presentation, and the presence of a secondary airway anomaly. Additional co-morbidities in children with laryngomalacia increases disease severity and also affect the prognosis of surgical outcome. Such co-morbidities can be gastroesophageal reflux disease, laryngopharyngeal reflux, neurologic disease, congenital heart disease, genetic syndrome, or anomaly.

Patients with severe laryngomalacia will require surgery. Patients who have gastroesophageal reflux disease or laryngopharyngeal reflux and one additional co-morbidity are more likely to require revision supraglottoplasty. Those with three medical co-morbidities are more likely to require tracheostomy [8].

### **5. Classification of laryngomalacia**

There are a number of classifications of laryngomalacia. A simple and well-detailed classification of laryngomalacia by Olney et al. describing type 1, type 2, and type 3 laryngomalacia as prolapsing arytenoids, shortened aryepiglottic folds, and prolapsing epiglottis [9]. The classification of Olney et al. is simple, but covers only about twothird of laryngomalacia cases and also mixes static and dynamic findings.

Van der Heijden et al. after studying various laryngomalacia classifications have proposed a Groningen Laryngomalacia Classification System (GLCS) which is based on the photo and video documentation of eighty five patients diagnosed in a tertiary referral centre combined with a review of the literature [10].

This simplified system is supposed to ease communication among professionals and provide a base for treatment algorithms. In laryngomalacia, there is a collapse of the supraglottic airway during inspiration causing obstruction. This is a dynamic change of the airway happening during inspiration. Some previous classifications

#### *Updates on Laryngology*

were based on static findings. Anatomical findings such as omega-shaped epiglottis, short aryepiglottic folds and acutely angled epiglottis over laryngeal inlet are static findings. In laryngomalacia obstruction is due to dynamic change in the airway, and static findings do not completely explain these dynamic changes and therefore are not the excellent choice for the classification of laryngomalacia. McSwiney et al. were the first to introduce a system in order to classify laryngomalacia and it was based on static findings [11]. McSwiney et al. further combined omega-shaped epiglottis and posterior displacement in one single type of laryngomalacia, suggesting omega shaped epiglottis is exclusively associated with posterior displacement of the epiglottis. Although, omega-shaped epiglottis can also present in conjunction with medial displacement of aryepiglottic folds during inspiration. Holinger et al. divided laryngomalacia into six different types, with static and dynamic findings described as separate entities. Shah et al. exclusively described dynamic changes but the definitions of the different types of laryngomalacia were insufficiently described [12]. Kay et al. use a system in which Type 1 is defined as static finding and Type 2 as a dynamic finding and type 3 is a collection of "all other etiologies" including neuromuscular disease, which renders the classification less reliable [13]. None of these systems discussed here are widely accepted. Classifications require simplification in such a way that they not only provide a genuine classification based on dynamic findings but also allow making a righteous decision for the intervention required.

The Groningen laryngomalacia classification system is a newly proposed classification system exclusively based on dynamic laryngeal changes. In Groningen's laryngomalacia classification, laryngomalacia is divided into three types; Type 1 is inward collapse of arytenoid cartilages, Type 2 is medial displacement of aryepiglottic folds, and Type 3 is posterocaudal displacement of epiglottis against the posterior pharyngeal wall.

The GLCS has also proposed the probable surgical intervention for each category required. They suggested that the decision between surgical management and conservative strategy should be based on the severity of laryngomalacia, and when surgical management is planned, the GLCS can suggest the surgical intervention required. The surgical intervention suggested for Type 1 laryngomalacia of GLCS is the removal of redundant mucosa over arytenoids with or without the removal of cuneiform or corniculate cartilage. In Type 2 laryngomalacia suggested intervention is incision or excision of a wedge of aryepiglottic folds. In Type 3, epiglottopexy would be the surgical intervention required. However, these treatment options should be clinically individualized for each patient.

Kay et al. also provided a classification-based treatment algorithm. They discerned three types in which type I is recommended to be treated by dissection of the aryepiglottic folds, type II by resection of redundant mucosa over arytenoid cartilage, but cases with "all other etiology" were supposed to receive tracheostomy.

### **6. Diagnosis**

A thorough physical examination of the infant should be performed, with special attention to the oral cavity, nose, and neck. A complete birth history is required, including any surgical history or intubations performed on the patient. Parents should inform about any breathing problems children may have at home, with a

#### *Laryngomalacia DOI: http://dx.doi.org/10.5772/intechopen.103862*

focus on noisy breathing or apnea episodes. Laryngomalacia is characterized by noisy breathing that worsens with meals or while lying supine. The clinician should investigate the patient's eating habits and keep track of any weight loss or failure to thrive.

It's important to ensure choanal patency and rule out piriform aperture stenosis. A complete oral cavity examination is required to rule out cleft lip or cleft palate, glossoptosis, Pierre-Robin sequence, or micrognathia, all of which can cause breathing and feeding difficulties. A thorough examination of the neck is also required to rule out any tumors or vascular abnormalities. Hemangiomas with a beard-like distribution should be given special attention, as these infants are more prone to have hemangiomas in the airway. In order to properly evaluate a patient with suspected laryngomalacia, a flexible laryngoscopy examination of the supraglottic airway in an awake newborn is required. The infant should be transferred to the operating room for a diagnostic bronchoscopy if the examiner notices serious symptoms.

Flexible fiberoptic laryngoscopy is the mainstay in the diagnosis of infant stridor. It permits the real-time visualization of the aerodigestive tract during spontaneous ventilation. It allows complete visualization of the oropharynx, hypopharynx, supraglottis, glottis and subglottis. Due to the simplicity and ability to thoroughly examine the dynamic collapse of the supraglottic airway during awake respiration, flexible fiberoptic laryngoscopy is presently the gold standard for the diagnosis of laryngomalacia.

Direct laryngoscopy and diagnostic bronchoscopy in the operation theater give the clinician a complete evaluation of the upper aerodigestive tract to the level of carina and the mainstem bronchi. It is a valuable procedure principally in patients with severe symptoms or in patients who have concomitant secondary airway anomalies. Surgical intervention is also possible with direct laryngoscopy when warranted.

Radiologic studies might be helpful in the diagnosis of swallowing difficulty. A modified barium swallow examination is preferred in infants with laryngomalacia since aspiration may be silent and not detectable clinically.

A polysomnogram is beneficial in determining the presence and severity of obstructive sleep apnea, particularly in older children. To improve the apneahypopnea index in such children surgical intervention like supraglottoplasty might be beneficial.

Airway fluoroscopy due to low sensitivity and exposure to ionizing radiation is not advocated in the assessment of infant stridor.

### **7. Management**

Most of the children of laryngomalacia can be managed conservatively as the symptoms usually disappear by the end of the second year of life. In the majority of cases, laryngomalacia is a self-limiting condition. Only 5–20% of children with severe laryngomalacia undergo surgical intervention. As mentioned before transoral supraglottoplasty has a low complication in otherwise healthy children [14]. To reduce inspiratory obstruction in laryngomalacia, redundant tissue in the upper airway is cut and/or the aryepiglottic folds are loosened in bilateral supraglottoplasty. While bilateral supraglottoplasty is generally well tolerated, about 10% of individuals experience side effects such as laryngeal edema, new-onset aspiration, or supraglottic stenosis. Supraglottic stenosis is a life-threatening condition that is difficult to treat surgically.

A few clinicians have reported performing unilateral supraglottoplasty to lessen the risk of problems associated with bilateral surgery.

For the treatment of severe laryngomalacia, Walner et al. advocated a staged approach to bilateral supraglottoplasty [15]. Staged supraglottoplasty implies a unilateral supraglottoplasty on the most affected side, followed by, if necessary, an opposite-side operation week to months later. For the surgery, they used cold steel instruments, with or without the use of a microdebrider.

In the staged approach first stage of surgery involves the removal of the redundant tissue on the most affected side using either straight or curved microscissors. Then to release the ipsilateral aryepiglottic fold a small wedge of tissue was removed. Microdebrider can also be used to remove redundant tissue overlying the arytenoid cartilage on the most affected side, and then a small wedge of tissue from the aryepiglottic fold on the same side can be removed after using microscissors. Afrin-soaked pledgets were used on the cut surfaces to reduce bleeding. Walner et al. further describe that after surgery all patients were extubated and monitored for 24 hours prior [15]. Patients were reevaluated for symptoms after 4 to 6 weeks. If the problems of breathing or feeding continued, the second step of surgery was employed to provide further relief. An opposite-side supraglottoplasty was performed, with redundant arytenoid mucosa excised and the aryepiglottic fold released on the side opposite to the original surgery. If aryepiglottic fold on the side previously operated appears to be too tight it was re-released. According to Walner et al., 73% of individuals who underwent the first stage of surgery had considerable improvement or resolution of stridor, while 100% of those who underwent the second stage had significant improvement or resolution of stridor. There were no complications in any of the patients.

Low-temperature plasma radiofrequency ablation (LTP-RFA) is another surgical therapy option. According to the severity of laryngomalacia, Hongming Xu et al. presented the first prospective four-arm randomized trial to compare the efficacy and short outcomes of patients with moderate and severe laryngomalacia who were randomly treated with LTP-RFA, traditional surgical supraglottoplasty, or waitand-see policy [16]. When compared to typical surgical supraglottoplasty, LTP-RFA treatment dramatically reduced operating time, length of hospital stay, and amount of intraoperative hemorrhage in children with severe laryngomalacia, but treatment efficacy was equivalent. In addition, when compared to the control group, LTP-RFA treatment dramatically alleviated laryngomalacia symptoms in children with moderate laryngomalacia. Post-operative pneumonia was the most common consequence, affecting 11% of patients.

### **8. Anesthesia**

Choice of ventilation strategy is the main concern for the anesthesia team in the case of laryngomalacia. The following are the ventilation strategy that can be utilized [17]:


### *Laryngomalacia DOI: http://dx.doi.org/10.5772/intechopen.103862*

c.Intermittent apnea technique is another choice for ventilation under anesthesia but surgery needs to be interrupted in between for manual ventilation when the patient desaturates and thus surgeon gets limited time duration in between two ventilations.

d.Jet ventilation can sometimes be used for this surgery.

### **9. Conclusions**

Laryngomalacia despite the fact that it is a self limiting disease, caregivers must recognize severe cases. A child's growth may be hindered in severe cases of laryngomalacia due to breathing and feeding difficulty. Laryngomalacia is resolved in more than 90% of cases after supraglottoplasty, which enhances the child's quality of life. Only in a few cases a second surgery is required to resolve residual symptoms.

### **Conflict of interest**

The authors declare there are no conflict of interest.

### **Acronyms and abbreviations**


### **Author details**

Vaishali Waindeskar, Pooja Thaware\*, Garima Chamania, Anuj Jain and Ashutosh Kaushal Department of Anaesthesiology and Critical Care, All India Institute of Medical Sciences, Bhopal, India

\*Address all correspondence to: pthaware20@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Dobbie AM, White DR. Laryngomalacia. Pediatric Clinics of North America. 2013;**60**(4):893-902. DOI: 10.1016/j.pcl.2013.04.013

[2] Hysinger EB. Laryngomalacia, tracheomalacia and bronchomalacia. Current Problems in Pediatric and Adolescent Health Care. 2018;**48**(4):113- 118. DOI: 10.1016/j.cppeds.2018.03.002

[3] Cooper T, Benoit M, Erickson B, El-Hakim H. Primary presentations of laryngomalacia. JAMA Otolaryngology. Head & Neck Surgery. 2014;**140**(6):521- 526. DOI: 10.1001/jamaoto.2014.626

[4] Isaac A, Zhang H, Soon SR, Campbell S, El-Hakim H. A systematic review of the evidence on spontaneous resolution of laryngomalacia and its symptoms. International Journal of Pediatric Otorhinolaryngology. 2016;**83**:78-83. DOI: 10.1016/j. ijporl.2016.01.028

[5] Digoy GP, Burge SD. Laryngomalacia in the older child: Clinical presentations and management. Current Opinion in Otolaryngology & Head and Neck Surgery. 2014;**22**(6):501-505. DOI: 10.1097/MOO.0000000000000111

[6] Born H, Wineland A, Rutter MJ. Neurologically acquired laryngomalacia in a pediatric patient with Moyamoya: A case report and literature review. International Journal of Pediatric Otorhinolaryngology. 2019;**116**:34-37. DOI: 10.1016/j.ijporl.2018.10.001

[7] Hassan MM, Emam AM, Mahmoud AM, Awad AH, Rezk I, Abou-Taleb A, et al. Congenital laryngomalacia: Is it an inflammatory disease? The role of vitamin D. Laryngoscope. 2020;**130**(2):448-453. DOI: 10.1002/lary.27997

[8] Thompson DM. Laryngomalacia: Factors that influence disease severity and outcomes of management. Current Opinion in Otolaryngology & Head and Neck Surgery. 2010;**18**(6):564-570. DOI: 10.1097/MOO.0b013e3283405e48

[9] Olney DR, Greinwald JH Jr, Smith RJ, Bauman NM. Laryngomalacia and its treatment. Laryngoscope. 1999;**109**(11):1770-1775. DOI: 10.1097/ 00005537-199911000-00009

[10] Van der Heijden M,

Dikkers FG, Halmos GB. The Groningen laryngomalacia classification system- -based on systematic review and dynamic airway changes: Groningen Laryngomalacia classification system. Pediatric Pulmonology. 2015;**50**(12): 1368-1373. DOI: 10.1002/ppul.23186

[11] McSwiney PF, Cavanagh NP, Languth P. Outcome in congenital stridor (laryngomalacia). Archives of Disease in Childhood. 1977;**52**(3):215-218. DOI: 10.1136/adc.52.3.215

[12] Shah UK, Wetmore RF. Laryngomalacia: A proposed classification form. International Journal of Pediatric Otorhinolaryngology. 1998;**46**(1-2):21- 26. DOI: 10.1016/s0165-5876(98)00111-6

[13] Kay DJ, Goldsmith AJ. Laryngomalacia: A classification system and surgical treatment strategy. Ear, Nose, & Throat Journal. 2006;**85**(5):328-336. DOI: 10.1177/ 014556130608500514

[14] Zhang YM, Wang ZN, Xia ZF. Research progress of laryngomalacia in children. Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2017;**31**(2):162-166. DOI: 10.13201/j. issn.1001-1781.2017.02.023

*Laryngomalacia DOI: http://dx.doi.org/10.5772/intechopen.103862*

[15] Walner DL, Neumann DB, Hamming KK, Miller RP. Supraglottoplasty in infants: A staged approach: A staged approach. The Annals of Otology, Rhinology, and Laryngology. 2015;**124**(10):803-807

[16] Xu H, Chen F, Zheng Y, Li X. Efficacy and toxicities of low-temperature plasma radiofrequency ablation for the treatment of laryngomalacia in neonates and infants: A prospective randomized controlled trial. Annals of Translational Medicine. 2020;**8**(21):1366

[17] Ayari S, Aubertin G, Girschig H, Van Den Abbeele T, Denoyelle F, Couloignier V, et al. Management of laryngomalacia. European Annals of Otorhinolaryngology, Head and Neck Diseases. 2013;**130**(1): 15-21. DOI: 10.1016/j.anorl.2012.04.003

### **Chapter 7**

## Approach to the Difficult Airway in Laryngeal Cancer

*Maria Elena Buenrostro Espinosa, Samantha Rivero Borrell, Jorge Francisco Piña Rubio, Maria Fernanda Ochoa Cortez, Lesle Hernandez Uvence and Liz Marlene Montes Sandoval*

### **Abstract**

The laryngeal cancer is the second most frequent neoplasm of the upper aerodigestive tract. In these patients, the incidence of difficult airway is very high, and sometimes the anatomy can be modified because of the previous treatments like radiotherapy, making difficult intubation and difficult mask ventilation. To prevent an emergency, it is a priority to make an approach plan, appropriate preoperative assessment, have the necessary tools, and work together with the surgical team.

**Keywords:** airway management, laryngeal neoplasms, laryngectomy, video laryngoscope, difficult airway

### **1. Introduction**

The incidence of difficult airway in patients with head and neck cancer is higher than in the general population. Particularly, cancer of the larynx, which is the second most frequent neoplasm of the aerodigestive tract, represents a real challenge for the anesthesiologist, since he deals with patients with tumors at any stage and in elective or emergency situations.

### **2. Laryngeal cancer**

Of head and neck tumors, laryngeal cancer accounts for 50% with a higher incidence in men than woman with a 4:1 ratio. The three major locations for laryngeal cancer are glottis (59%), followed by the supraglottic area (40%) and the subglottic area (1%) [1]. Laryngeal stenosis, fistula formation, local recurrence, and adjacent lymph node metastasis are some of the complications that the patient can develop in long term [2].

Laryngectomy is an effective cancer procedure and is associated with good functional outcomes. The current UK standard of care for locally advanced malignancy is aimed at organ preservation. This is for patients with T3 tumors on the tumornodes-metastases (TNM) scale. For patients with T4 disease invading the laryngeal

cartilages, total laryngectomy is recommended. Although laryngeal preservation may seem preferable, these cases require careful discussion at a regional head and neck cancer multidisciplinary team meeting, as evidence is emerging that patients who undergo primary surgery have improved survival rates. Long-term complications of oncological treatments may ultimately result in a "frozen larynx," where the patient requires a tracheostomy and gastrostomy, or even ultimately a laryngectomy to prevent aspiration. National guidelines recommend that laryngectomy is performed in specialist centers, as complication rates are lower in departments that perform this procedure frequently [3].

Organ preservation is recommended in patients with T3 tumors on TNM classification (tumor, nodule, metastasis), and total laryngectomy is indicated in T4 patients with invasive disease to laryngeal cartilages. Although preserving surgery may seem better, all cases require careful analysis to perform the procedure that improves survival rates. We can see complications of oncological treatments; for example, "frozen larynx," in these cases the patient requires tracheostomy and gastrostomy, or even a laryngectomy to prevent aspiration. National guidelines recommend that laryngectomy is performed in specialist centers, as complication rates are lower in departments that perform this procedure frequently [3].

The context in which the anesthesiologist can find the patient is in elective or emergency situations, as well as in early or advanced stages. The most challenging aspect would be the intubation of the post-radiotherapy patient. It is important to understand the disease process and the management of these cancers, because a proper anesthetic management plan will be decisive. There must be open lines of communication with surgeon and wider team for better results [3].

Based on the knowledge of the possible occurrence of difficult ventilation, all the associated necessary equipment should be ready for an instant application, and also, additional measures such as preparation of emergent tracheostomy, cardiopulmonary resuscitation, and airway management following ASA guideline may be implemented [2].

### **3. Difficult airway**

Difficult airway is defined as the clinical situation in which a conventionally trained anesthesiologist experiences difficulty with facemask ventilation, difficulty with tracheal intubation, or both. Situations of "cannot intubate and cannot ventilate (CICV)" may occur in 0.01–0.07% of patients undergoing surgery. This is a true emergency situation. This situation must be resolved as soon as possible, so that a harmful outcome does not occur like permanent brain damage or death. Spontaneous breathing must be restored, if is not possible then the surgical access of the airway must be done [4].

The anatomical modifications due to the disease as well as morphological changes by previous treatments (radiotherapy and chemotherapy in the head and neck cancer patients) are responsible for the difficulties in the airway. The incidence of difficult intubation ranges from 0.5 to 2% in the general population, from 8 to 10% in patients having ears, nose, and throat surgery, and rises to 28% in patients with tumors of the airway [1, 5]. Glottic cancers are the commonest (50–60%). These patients present difficulties due to the presence of mass, a receding jaw, restricted mouth opening, and neck movement or due to associated comorbidities. The size and location of tumor are the crucial factors in determining the appropriate approach to the airway [1].

### **4. Preoperative assessment**

The characteristics that are most often observed in the patient who has head and neck cancer are the following: elderly, chronic consumer of ethanol, and/or a smoker. broncho-pneumopathie chronique obstructive, pulmonary emphysema, ischemic coronary heart disease, high blood pressure, chronic hepatopathy with toxic etiology, coagulopathies are associated with the oncological status [6].

Some patients have nutritional disorders due to the difficulty in swallowing due to the presence of the tumor, which leads to weight loss, anemia, and dyselectrolytemia. All these alterations should be corrected as far as possible before undergoing surgery [6].

Preoperative evaluation should include full blood count, clotting screen, biochemical profile with urea and electrolytes, liver function test, blood sugar, and electrocardiography. Other studies that should be considered in some patients are chest X-ray, pulmonary function tests, arterial blood gases, and echocardiogram, because some may have chronic obstructive pulmonary disease or some cardiopathy associated with their risk factors [7].

It is common to find chronic obstructive pulmonary disease (COPD) in head and neck cancer patients so modification of bronchodilator therapy, steroids, and treatment of acute infection can optimize patient conditions [7].

Laryngeal cancer treatment includes surgery, chemotherapy, and radiotherapy, and these treatments may worsen airway management. Radiation therapy after the primary surgery may lead to immobility of the mandible and neck. A careful examination of the área between the hyoid bone and submentum is required, because we can detect risk factors for difficult airway. For some patients, even with normal mentohyoid distance, the larynx might be located much more anterior than normal, due to radiotherapy-induced fibrosis in the submandibular área, and this factor makes intubation difficult. Some side effects of radiation therapy, for example, dermatitis and oral mucositis, can make the tissue more susceptible to infection, and bleeding may occur during airway management. The patient may present local edema due to damage to the lymphatic ducts after radiotherapy. Preoperative tracheostomy sometimes becomes indicated when a difficult airway is evident before surgery or after previously performed laryngeal surgery [2].

We should evaluate the mouth opening, mallampati score, laryngoscopic view at previous operations, neck movement, and prominent teeth, and look for masses in neck, scarring from previous surgery, and immobility of the larynx from previous radiotherapy.

Cross-sectional imaging techniques are the most useful in confirming intrinsic compression of the airways, a feature that may not be appreciated on endoscopic analysis alone [8]. It is indicated to identify the extension of the tumor and the potential obstruction through imaging studies, radiological imaging with computed tomography or magnetic resonance imaging can help. In experienced hands, ultrasonography is useful in identifying the cricothyroid membrane before induction of anesthesia to have identified the surgical access in case of emergency (**Figure 1**) [7].

Awake nasal endoscopy can be carried out before induction of anesthesia and is especially useful when no other radiological investigations are available. It gives a real-time view of the upper airway and the larynx [7].

Preoperative nasoendoscopy can determine the airway diameter, detailed evaluation of the airway, location, size, nature and mobility of tumor (e.g., pedunculated), bleeding and edema, the epiglottis and glottis, vocal cord movement, pooling of secretions, it does not require more than a simple preparation of the nose with a local

#### **Figure 1.**

*A. Computed tomography with axial section showing maximum glottic narrowing caused by tumor. B. Subglottic region, with less compromise in the tracheal diameter.*

anesthetic and a vasoconstrictor, and it is very important to identify a potential airway obstruction [8] and is useful in identifying patients in whom an awake technique or conscious fibroscopic-assisted intubation is more appropriate [2, 7]. In short, it allows us to examine the condition of larynx and pharynx.

Before starting surgery, the following points should be defined:


When you should consider awake intubation? When difficulty in tracheal intubation and bag-mask ventilation is predicted or has been experienced previously. When performing a technique with an awake patient, you have an advantage because you maintain the permeable airway, gas exchange, and protection against aspiration during the intubation process. General anesthesia makes the airway more difficult with more obstruction, making identification of landmarks difficult on endoscopy [7].

It is essential for the anesthesiologist to prevent an emergency situation and make the right decision for the safety of the patient; therefore, a plan must be formulated.

### **5. Planning airway management**

Procedures performed on patients with laryngeal cancer ranges from panendoscopy and biopsy to laryngectomy and occasionally emergency tracheostomy [3]. And the planning of airway management should be performed for elective patient and elective surgery and for those who may present in extremis with stridor.

Evaluation of the airway includes history and bedside examination, review of imaging and nasendocopy findings as well as discussion with the surgical team.

It is essential to bear in mind other rescue oxygenation techniques, in case the primary plan fails. The rescue plans may include ventilation with face mask or supraglottic devices, and also a surgical airway. The team must consider that insertion and placement of supraglottic airway devices are difficult in patients with reduced opening of the jaw, oropharyngeal lesions, and after radiotherapy. In these cases, intubation using a supraglottic airway as a conduit is difficult or even impossible so we must consider these risk factors before performing the anesthetic induction.

Because of the high incidence of anticipated difficult airways in head and neck patients, it is prudent to seek video-assisted laryngoscopy as the primary technique, video laryngoscopes have emerged as a common first-line option for laryngoscopy, and the Difficult Airway Society (DAS) highlights its role in difficult intubation. A 93–96% first-attempt intubation success rate can be achieved with acute-angle video laryngoscopes such as the Glidescope or CMAC Storz systems, reducing the number of patients at risk of intubation failure.

Direct laryngoscopy (DL) exposes the laryngeal inlet under direct vision and requires a direct line of sight to align airway axes (oral-pharyngeal-laryngeal) for optimal glottic visualization. Oftentimes, manipulations to align these axes include head extension, neck flexion, laryngeal manipulation, and other stressful movements [9]. Videolaryngoscopy (VL) optimizes first-attempt success when compared to direct laryngoscopy, and utilizes indirect laryngoscopy *via* its camera; glottic visualization is better, and the need for a direct line of sight to visualize airway structures is eliminated. VL requires the application of less force to the base of the tongue, reduces time to intubate, and lessens hemodynamic response to intubation when compared with the traditional direct visualization technique [9].

Evidence has made it clearer that videolaryngoscopy eases intubation difficulty and increases first-attempt success rates in the airway predicted to be difficult to intubate by direct laryngscopy.

Awake fiber-optic intubation is the safest approach to managing difficult airways, and it can be extremely helpful in patients with supraglottic obstruction (e.g., epiglottis, tongue, basal obstructions, intraoral masses), but it is not the first-line option in patients with a narrow laryngeal inlet or with tumors that cause obstruction at the laryngeal level, which may fail due to the inability to displace the tumor or simply because the tube cannot be advanced and thus precipitates a total obstruction [7].

Active oxygenation strategies must be present throughout the difficult airway management process. One of them is apneic oxygenation.

Trans-nasal high-flow rapid insufflation ventilatory exchange or THRIVE is an oxygenation technique that provides heated and humidified oxygen using high-flow nasal cannula. This system has recently been shown to increase the apnea time in head and neck patients including those with stridor. Trans-nasal high-flow rapid insufflation ventilatory exchange combines apneic oxygenation, continuous positive airway pressure and flow-dependent dead space flushing, which overcomes airway obstruction and increases safety margin during sedation. THRIVE provides up to 70 L/min of oxygen and is well tolerated because of humidification. It changes the nature of difficult intubations from a hurried process to a more controlled event, with an extended apneic window and reduced iatrogenic trauma [3].

The mainstay method of increasing the apneic window is through pre-oxygenation, which entails spontaneous facemask ventilation with 100% oxygen [10]. Pre-oxygenation denitrogenises the lungs and creates an alveolar oxygen reservoir. The physiological phenomenon that occurs is called aventilatory mass flow (AVMF) or apneic oxygenation. A patent air passageway exists between the lungs and the exterior, and the difference between the alveolar rates of oxygen removal and carbon dioxide excretion generates a negative pressure gradient of up to 20 cmH2O that drives oxygen into the lungs. This could extend safe apnea time during prolonged laryngoscopy and intubation.

### **6. The obstructed airway**

Inspiratory stridor suggests a reduction in airway diameter at the supraglottic, periglottic, or glottic level of at least 50%. Expiratory stridor originates at or below the glottis level, which is characteristic of tracheal or tracheobronchial narrowing, while inspiratory-expiratory (biphasic) stridor generally points to obstructive subglottic disease [11].

We have to define the group of patients who are being considered with stridor at rest. In this group, the stridor is due to a reduction in airway diameter of at least 50%. Patients with slow-growing tumors often present late. So when we meet patients classified in this small group, we know that we will face a tumor of important measure.

Perilaryngeal tumors include supraglottic, pharyngeal, pyriform fossa, epiglottic, vocal cord, and subglottic lesions.

#### **Figure 2.**

*A. Videolaryngoscopy images show a narrowing at the level of the glottis. B. decreased diameter, and inability to pass a #5.5 DI orotracheal tube. C. Friable and bleeding tumor.*

*Approach to the Difficult Airway in Laryngeal Cancer DOI: http://dx.doi.org/10.5772/intechopen.104111*

**Figure 3.** *Total laryngectomy in laryngeal cancer.*

The patient should be asked whether, in addition to having noisy breathing, he has actually experienced difficulty in breathing; in particular, has he woken at night in a panic. The presence of nocturnal symptoms usually indicates that there is more advanced obstruction [11].

Patients with significant stridor at rest can be divided broadly into two groups: (1) those in whom intubation is considered possible and (2) those definitely requiring preliminary local anesthetic tracheosomy [11].

The patient, who comes to hospital for the first time as an emergency, is usually the one who will needs a local anesthetic tracheostomy. Severe disease will generally manifest with nocturnal respiratory difficulties and panic attacks [11]. The patient with less severe obstruction is referred to an outpatient clinic (**Figures 2** and **3**).

### **7. Other anesthetic considerations**

It is required to identify patient at risk of airway obstruction because intravenous or inhalational induction may precipitate airway obstruction due to tumor bulk. Even local anesthesia is not without risk because severe airway obstruction precipitated by laryngospasm has occurred [12].

Is polemical the use of muscle relaxant drugs sometimes facilitates laryngoscopy but in other cases is controversial because of the greater risk of airway obstruction. Current practice has also been influenced by new intubation devices such as video laryngoscopes [12].

If tracheal intubation is considered possible, the main options are an inhalational induction with direct laryngoscopy and tracheal intubation, or an awake fiber-optic intubation. Supraglottic tumors may cause obstruction when intravenous induction and muscle relaxation are used. Intravenous induction of anesthesia and the use of a muscle relaxant are not recommended in this situation [8].

The objective of an inhalational induction is to preserve spontaneous ventilation until adequate depth of anesthesia is obtained and direct laryngoscopy and visualization of the glottis is allowed [8]. Sevoflurane is used and allows rapid, smooth induction of anesthesia, and has the benefit of lack of airway irritation and low blood gas solubility. The disadvantages that can be presented are coughing and laryngospasm upon instrumentation, and sometimes respiratory obstruction when the patient loses consciousness to the beginning of the anesthesia.

When anesthetic depth is adequate, laryngoscopy is undertaken and a rapid decision is made as to whether intubation is possible. If a laryngoscope does not provide an adequate view of the glottis, a second attempt may be made with a different instrument or a different approach, for example, video-laryngoscope. A rigid bronchoscope may be used by an experienced person.

If after laryngoscopy and under direct vision, the anatomy is difficult to visualize or the glottic opening is very small, which is prudent to let the surgeon perform the tracheostomy without haste; but if it is decided to intubate, it must be made a maximum of two attempts. Repeated laryngoscopies have a risk of generating bleeding in necrotic and friable tumors, and this may lead to a total obstruction of the airway, and lead to a situation of "I cannot intubate" "I cannot oxygenate." If the laryngoscopy fails, the team must be informed and continue with the planned plan [7].

The prolonged manipulation of the upper respiratory tract can cause cardiovascular responses: bradycardia, tachycardia, hypertension, cardiac arrhythmias, and is important to consider.

The way to ensure the airway in the postoperative of head and neck cancer surgery is with a tracheostomy. When orotracheal or nasotracheal intubation is not possible or a major surgical intervention for oral cancer with reconstructive tissue transfer is planned, the better option is an elective tracheostomy in a conscious patient [6].

Tracheostomy as an approach method of the airways is obligated in patients with tumors located in the larynx or below the glottis with obstructive effect, and also in cases of laryngeal stenosis or significant supraglottic edema. Tracheostomy should not be made in pediatric patients because the trachea is small with a soft cartilage and difficult to palpate [6].

### **8. Postoperative**

A careful strategy should be planned for the extubation of those patients who do not require postoperative tracheostomy.

After prolonged surgery, we can find some issues, for example, swelling, bleeding, and airway debris. If tracheal intubation was difficult in the first place, reintubation is likely to be more. Other strategies may also be used: trans-tracheal catheters and airway exchange catheters. An airway exchange catheter is a long, small internal diameter, hollow, semi-rigid catheter that is inserted through an *in situ* endotracheal tube prior to extubation. The patient tolerates the catheter and facilitates rapid reintubation if needed [8].

It is essential that anesthetists are aware of human factors, maintain situational awareness, avoid task fixation, and do not resort to unfamiliar techniques. A coordinated team approach with clear communication is essential [6].

*Approach to the Difficult Airway in Laryngeal Cancer DOI: http://dx.doi.org/10.5772/intechopen.104111*

### **9. Conclusions**

Difficult airway can lead to serious complications in head and neck cancer surgical patients, specifically in cancer of the larynx.

The anesthesiologist should need a careful planning for intubation and extubation of difficult airway depending on surgery and conditions of the patient.

The use of appropriate airway equipment, oxygenation techniques, surgical airway access, all options must be available to rescue a difficult airway.

Intubation of the patient with laryngeal cancer is a challenge that must be addressed through a team approach. Management will depend on clinical presentation, individual experience, and equipment availability.

### **Acknowledgements**

I thank the "Instituto Nacional de Cancerología" in México, the institution where I did the Onco-Anesthesia care Fellowship, and to all the doctors who taught me with their experience with patients with difficult airways.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Maria Elena Buenrostro Espinosa1 \*, Samantha Rivero Borrell2 , Jorge Francisco Piña Rubio3 , Maria Fernanda Ochoa Cortez4 , Lesle Hernandez Uvence5 and Liz Marlene Montes Sandoval6

1 Oncological Anesthesia, IMSS Mexicali, México

2 Oncological Anesthesia, Hospital Angeles del Carmen, Jalisco, México

3 Neuroanesthesiologists, Hospital ISSSTECALI Mexicali, B.C, México

4 Anesthesiologists, Hospital ISSSTECALI Mexicali, B.C, México

5 Bioengineer, Resident of Anesthesiology, Hospital ISSSTE Mexicali, B.C, México

6 Resident of Anesthesiology, Hospital ISSSTE Mexicali, B.C, México

\*Address all correspondence to: buenrostro.espinosa@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

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[2] Zhang X, Cavus O, Zhou Y, Dusitkasem S. Airway management during Anesthetic induction of secondary laryngectomy for recurrent laryngeal cancer: Three cases of report and analysis. Frontiers in Medicine. 2018;**5**. DOI: 10.3389/fmed.2018.00264

[3] Stephens M, Montgomery J, Urquhart CS. Management of elective laryngectomy. BJA Education. 2017;**17**(9):306-311. DOI: 10.1093/bjaed/ mkx014

[4] Xu Z, Ma W, Hester DL, Jiang Y. Anticipated and unanticipated difficult airway management. Current Opinion in Anaesthesiology. 2017;**1**. DOI: 10.1097/ aco.0000000000000540

[5] Ayuso MA, Sala X, Luis M, Carbó JM. Predicting difficult orotracheal intubation in pharyngolaryngeal disease: Preliminary results of a composite index. Canadian Journal of Anesthesia/Journal Canadien D'anesthésie. 2003;**50**(1):81-85. DOI: 10.1007/bf03020193

[6] Stelea C, Pătrășcanu E, Cureniuc L, et al. Airway management in head and neck cancer surgery. Romanian Journal of Oral Rehabilitation. 2020;**12**(4)

[7] Ahmed-Nusrath A. Anaesthesia for head and neck cancer surgery. BJA Education. 2017;**17**(12):383-389. DOI: 10.1093/bjaed/mkx028

[8] Flory S, Appadurai IR. Special considerations in Anesthesia for laryngeal cancer surgery. Otorhinolaryngology Clinics: An International Journal, September-December. 2010;**2**(3):185-190

[9] Chemsian R, Bhananker S, Ramaiah R. Videolaryngoscopy. International Journal of Critical Illness and Injury Science. 2014;**4**(1):35. DOI: 10.4103/2229-5151. 128011

[10] Patel A, Nouraei SAR. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE): A physiological method of increasing apnoea time in patients with difficult airways. Anaesthesia. 2014;**70**(3):323-329. DOI: 10.1111/anae.12923

[11] Mason RA, Fielder CP. The obstructed airway in head and neck surgery. Anaesthesia. 1999;**54**(7):625- 628. DOI: 10.1046/j.1365-2044. 1999.01036.x

[12] Charters P, Ahmad I, Patel A, Russell S. Anaesthesia for head and neck surgery: United Kingdom National Multidisciplinary Guidelines. The Journal of Laryngology & Otology. 2016;**130**(S2):S23-S27. DOI: 10.1017/ s0022215116000384

### **Chapter 8**

## Adenoid Cystic Carcinoma of Larynx

*Tarang Patel and Garima Anandani*

### **Abstract**

Salivary gland tumours are rare tumours of larynx, hypopharynx and parapharyngeal space. Adenoid cystic carcinoma (AdCC) is the most common malignant salivary gland tumour of larynx. Subglottic region is the most common site followed by supraglottic region. AdCC usually involves elderly patients. Etiology of AdCC is mostly unknown. Clinically patient presents with dysphagia, cough, dyspnoea, hoarseness and rarely haemoptysis. Indirect laryngoscopy shows submucosal laryngeal mass. On CT scan, there is a submucosal mass, which may show extra-laryngeal extension. Histopathological examination shows epithelial and myoepithelial cells arranged in cribriform pattern, which may present with perineural invasion in the periphery of the lesion. Patients usually present in a later course of the disease. Tumour may present with pulmonary metastasis. The surgical approach depends on the tumour stage.

**Keywords:** adenoid cystic carcinoma, larynx, minor salivary gland tumour, cribriform pattern, perineural invasion, local recurrence

### **1. Introduction**

Adenoid cystic carcinoma (AdCC) was first described in 1853 and thereafter underwent multiple modifications of names before it was given the current name of AdCC in 1930 by Spies [1, 2]. AdCC is an epithelial malignant neoplasm predominantly involving minor and major salivary glands [3]. Malignant tumours involving minor salivary glands are rare and consists of 2–4% of all the head and neck malignancies [4]. Minor salivary gland tumours commonly occur in the oral cavity, peculiarly in the hard palate, with an occasional occurrence in the nasal cavity, paranasal sinuses, pharynx and larynx, correlating with the usual distribution of minor salivary glands in the head and neck region [4, 5]. AdCC is a rare tumour comprising of <1% of all cancers of head and neck. Out of all salivary gland tumours, AdCC accounts for 7.5–10% [6–10]. Minor salivary gland tumours of larynx are very rare, constituting less than 1% of laryngeal tumours [11].

Laryngeal AdCC accounts for 0.07–0.25% of all laryngeal tumours, and hypoglottis is the most common laryngeal site to be involved [5, 8, 12]. Laryngeal AdCC originates from subepithelial minor salivary glands [13]. There is usually no sexual predilection for laryngeal AdCC [10, 14]. Spread through perineural invasion is common [15].

Patients of laryngeal AdCC commonly present with a complaint of dyspnoea. Rarely do patients present with loco-regional metastasis. The average survival of patients is about eight years, and the evolution of prognosis depends on local recurrence and metastasis to lung, bones and brain [12, 16].

### **2. Discussion**

The most common laryngeal malignancy is squamous cell carcinoma; however, other epithelial, mesenchymal and neuroendocrine tumours are rare in this location [16, 17]. Laryngeal salivary gland carcinomas are rare because density of minor salivary glands in larynx is very low, about 23–47 glands per cm2 . Laryngeal salivary gland malignancies comprise less than 1% of all laryngeal malignancies, the most common being AdCC [18, 19]. No definite risk factors have been identified for laryngeal AdCC [20]. Smoking affects laryngeal AdCC in the same way as it affects squamous cell carcinoma [21]. Sub-glottis (64%) is the most common site to be affected, followed by supra-glottis (25%), trans-glottic (6%) and glottic (5%) regions [22].

### **2.1 Etiopathogenesis and genetic profile**

The definite aetiology of AdCC of larynx is not known to date. However, according to recent research, genomic changes are the cornerstone of aetiology for the development of malignant salivary gland tumours including AdCC. The most common genomic changes are a chromosomal translocation t(6;9) or very rarely a translocation t(8;9), which result in fusion of MYB or MYBL1 oncogenes with NFIB transcription factor gene [23]. Recent findings suggest that t(6;9) led to the fusion of MYB exon 14 to NFIB coding exon. This caused deletion of MYB exon 15, which contains many regulatory genes. The loss of MYB gene regulation leads to the overactivation of crucial MYB target genes involved in apoptosis, cell growth, cell cycle control and cell adhesion [24, 25]. West et al. suggested that MYB-NFIB translocation is specific for AdCC and it is not present in any other salivary gland tumour [26]. Cytogenetic studies have demonstrated that AdCC tumour is derived from various differentiated salivary gland tissues undergoing dedifferentiation and lead to early developmental gene profile [27, 28]. Microarray study found that AdCC is associated with genes of myoepithelial differentiation and high levels of SOX4 transcription factor along with overexpression of casein kinase-1 epsilon and frizzled-7 involved in the Wnt/βcatenin pathway [29–31].

### **2.2 Clinical features**

These tumours often occur in elderly patients usually in 6th or 7th decades. However, they can occur at any age ranging from 10 to 96 years [21, 32]. There is generally no gender predilection [10, 14]; however, according to a few researchers, there is a slight preponderance in females [21, 32]. It is clinically characterized by indolent and slow growth [1]. Mostly tumour goes undetected, until the involvement of local structures and local nerves, which may cause variable symptoms depending on the site involved [33]. Clinical features correlate with tumour size and location. Patients with glottic tumours present with dyspnoea or hoarseness, whereas supraglottic tumours present with dysphagia. Patients with glottic and supraglottic tumours are diagnosed at an early stage due to the early detection of

*Adenoid Cystic Carcinoma of Larynx DOI: http://dx.doi.org/10.5772/intechopen.104211*

symptoms [4, 5]. Subglottic tumours often present with difficulty in breathing, cough and stridor at a later stage. Due to the submucosal spread of laryngeal AdCC, it is often tough to diagnose AdCC at an early stage [5, 16, 21]. Hence, most of the patients are diagnosed at a later stage of the disease [20]. There is neurological involvement along with local infiltrative growth penetrating the nerve, lymphatics, blood vessels, muscle and bone [34]. AdCC metastasis to cervical lymph nodes is rare, seen only in about 10–15% of cases of head and neck AdCC [35]. Previous reports suggest that AdCC presents with distant metastasis in 35–50% of cases, lung being the most common site followed by bone and liver [4, 14, 36, 37].

### **2.3 Radiological findings**

If dyspnoea persists even after adequate therapy, radiological examination such as computerized tomography (CT) scan is necessary for an exact assessment of the tumour [16, 38]. CT scan is also of crucial importance in accurate pre-operative evaluation. It can assess the primary tumour site, extra-luminal spread, local spread and distant metastasis. However, sometimes AdCC may be difficult to be diagnosed on CT scan because of submucosal spread of laryngeal AdCC in absence of any apparent mass. CT scan with contrast medium can be used in difficult cases [21]. FDG-PET scan shows variable uptake in case of AdCC depending on the differentiation and grade as compared to squamous cell carcinoma, which usually shows high uptake [39]. FDG-PET scan expresses high sensitivity in cases of residual/recurrent tumour or local metastasis of AdCC (**Figure 1**) [40, 41].

### **2.4 Pathological findings**

### *2.4.1 Gross examination*

Grossly tumour is usually firm and poorly circumscribed. Tumour size ranges from 1 to 8 cm. Tumour size more than 3 cm is usually related to increased rate of distal metastasis [42]. Cut surface is grey-white, firm to soft, and very rarely haemorrhage and necrosis which may suggest high-grade variant of tumour or dedifferentiated AdCC (**Figure 2**) [1, 43].

#### **Figure 1.**

*CT scan of larynx showing a mass involving the left vocal cord along with infiltration of adjacent cartilage.*

**Figure 2.** *Specimen of total laryngectomy showing right-sided glottic mass on gross examination.*

### *2.4.2 Microscopic examination*

Microscopy shows basaloid malignant tumour encompassing a mixture of epithelial and myoepithelial cells. Histopathological classification is mainly divided into three types: solid, cribriform and tubular [44–46]. Cribriform pattern is the most common histological pattern characterized by islands or nests of basaloid cells interrupted by punched out spaces, which form 'sieve-like' or 'swiss-cheese' pattern [47, 48]. These cystic spaces are not true glandular lumina and they are continuous with the stroma surrounding them. The characteristic eosinophilic periodic-acidschiff (PAS) positive basement membrane material is present in the pseudocyst [1, 47, 48]. Some tumour cells show true glandular lumina along with pseudocysts. Tumour cytology shows relatively uniform basaloid appearing cells with hyperchromatic angulated nuclei and scant cytoplasm [1]. AdCC is notorious for increased tendency for perineural invasion (PNI). AdCC showing perineural invasion is so common that in absence of invasion of perineurial spaces, diagnosis of AdCC is doubtful [49].

Some AdCC show mainly tubular growth, some may have predominantly solid patterns, and very rarely sclerosing pattern may be seen [50–52]. Solid variant is characterized by tumour cells arranged in sheets without the formation of lumen or pseudocysts and may consist of admixture of epithelial and myoepithelial cells. A solid component may show increased mitosis and cytological atypia along with foci of necrosis [23, 53]. Dedifferentiated or high-grade transformation of AdCC may be rarely seen, which consists of conventional AdCC along with dedifferentiated components in the form of poorly differentiated adenocarcinoma or undifferentiated carcinoma. High-grade components lack any ductal or myoepithelial differentiation and show increased mitosis (>5/HPF), comedo-necrosis and focal squamoid growth (**Figure 3** and **4**) [43].

*Adenoid Cystic Carcinoma of Larynx DOI: http://dx.doi.org/10.5772/intechopen.104211*

#### **Figure 3.**

*H&E stained sections from the excision biopsy showing submucosal proliferation of tumour cells arranged predominantly in cribriform and tubular pattern (100×).*

#### **Figure 4.**

*H&E stained sections from the excision biopsy showing basaloid cells having angulated hyperchromatic nuclei with punched out spaces containing basement membrane material (400×).*

Immunohistochemistry (IHC) or electron microscopy study revealed that tumour cells of AdCC depict either myoepithelial or intercalated ductal differentiation [54]. Tumour cells in the region of ductal cells express markers of intercalated duct phenotype, showing positivity for CD117 (c-kit), CEA, keratin and lysosome. Tumour cells adjacent to cystic spaces show myoepithelial markers in form of immunopositivity for p63, S-100 and actin [54–56]. Cytogenetics studies demonstrate loss of heterozygosity at chromosome 6q23-35 [57]. TP53 mutations are very rare except in a few cases of dedifferentiated AdCC [58].

Major diagnostic entities need to be differentiated from AdCC, including polymorphous adenocarcinoma, pleomorphic adenoma and basal cell adenoma/ adenocarcinoma. Polymorphous adenocarcinoma is also common in minor salivary gland, but it is negative or only focal positive for c-KIT. Pleomorphic adenoma is a benign encapsulated tumour with frequent chondromyxoid stroma, whereas AdCC is invasive tumour with foci of PNI [56]. Basal cell adenoma and basal cell adenocarcinoma predominantly arise in major salivary glands [1].

AdCC is graded in accordance with the percentage of solid components seen microscopically. Grade I tumour is composed of predominantly tubular and cribriform patterns. Grade II tumour shows cribriform and tubular pattern with less than 30% solid component and Grade III tumour consists of more than 30% solid tumour area [59]. Solid component of AdCC usually acts as a predictor of poor prognosis [33, 60]. However, grading can be difficult as a single tumour may be composed of variable patterns of more than one subtype. According to few reports, staging using American Joint Committee on Cancer (AJCC) is more useful to predict prognosis and distant metastasis [32, 61]. During staging, documentation of PNI is crucial because infiltration of major nerve has been associated with a poorer prognosis compared to infiltration of minor nerve [62, 63].

### **2.5 Treatment**

Surgical excision in form of total laryngectomy is the preferred treatment for localized AdCC, which ultimately results in complete resection of the tumour with negative surgical margins, without compromising the function of the affected organ [64–66]. Modified radical neck dissection is performed only in cases of positive cervical lymph nodes [64]. Post-operative recurrence rates usually range from 30 to 75% [67].

To minimize the risk of relapse or recurrence, post-operative radiotherapy (PORT) may be administered [63, 68, 69]. Five-year and ten-year local control rates are higher in patients treated with surgery and PORT compared to those patients treated only with surgery [67, 70, 71]. After complete resection in T1 and T2 tumours, radiotherapy (RT) is recommended in intermediate or high-grade AdCC. Cases of T3 and T4 tumours in presence of clinically positive lymph nodes, PNI and positive surgical margins are treated with adjuvant RT. The dose recommended in PORT is >60 Gy in high-risk patients and >44 Gy in low- to intermediate-risk patients [72]. Primary definitive RT is recommended in patients with unresectable tumour mass [68, 72]. Chemotherapy is useful along with surgery in cases of highgrade tumours or to prevent metastasis. It is also recommended in advanced cases of distant metastasis [16, 21, 72].

It is hypothesized that vascular endothelial growth factor receptor (VEGFR) plays an important role in tumour angiogenesis and AdCC pathogenesis of AdCC. The expression of VEGF by the tumour cells correlates with tumour size, staging, invasion of blood vessels, risk of recurrence and distant metastasis. VEGF-A also acts as a downstream regulator of MYB expression. So VEGFR signal inhibition in the tumour may be useful in suppressing the tumour growth and blood flow [29, 73, 74]. Anlotinib, a tyrosine kinase inhibitor against VEGFR-1,-2,-3, and Lenvatinib, a multiple kinase inhibitor against VEGFR-1,-2,-3 kinases have shown effective results as a molecular target therapy for AdCC [72, 75, 76].

Definitive tumour grading and TNM staging along with reporting of perineural invasion and status of surgical margins are the principal prognostic factors. Ki-67 and p53 markers further add details regarding tumour grade and prognosis. Post-therapy close and long-term follow-up are required to ascertain any tumour relapse or distant metastasis [77].

### **3. Conclusions**

Laryngeal minor salivary gland carcinomas are very rare, comprising <1% of all the malignancies of larynx. Laryngeal AdCC should be kept in mind in cases of locally aggressive laryngeal tumours, particularly when a patient is not at risk for the development of squamous cell carcinoma. Most of the patients are diagnosed at a later stage of the disease. Pre-operative diagnosis is usually confirmed by microscopy. Surgical excision with clear margins with or without RT is recommended for management. Recurrence or distant metastasis of laryngeal AdCC can be detected by regular post-operative follow-up. Identification and study of new molecular markers underlying AdCC pathogenesis, such as c-KIT and VEGFR may help in the development of targeted therapy.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Abbreviations**


*Updates on Laryngology*

### **Author details**

Tarang Patel\* and Garima Anandani All India Institute of Medical Sciences (AIIMS), Rajkot, India

\*Address all correspondence to: tarangpatel\_86@yahoo.co.in

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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