Laryngeal Papillomas

Etiology

Laryngeal papillomatosis is a disease that is caused by a viral etiology. The virus that has been associated with LP is the human papilloma virus (HPV). HPV is a small deoxyribonucleic acid (DNA) nonenveloped capsid virus of the Papovaviridae family, which has a predilection of infecting epithelial cells. Even though many subtypes have been identified, immunochemistry has found HPV 6 and HPV 11, also associated with condyloma lata, to be the most related. On the contrary to HPV 16 and HPV 18, LP has a low malignant potential.

The mode of transmission in juvenile-onset has been closely associated with vertical transmission during childbirth. However, the exact mode of transmission is still unknown. Risk factors are prima-gravid women, firstborn child, and recently acquired genital warts. A mother's first birth usually has a longer stage of labor, leading to a longer time of exposure to the neonate. In addition, recently acquired genital warts have a higher virulence. In adult-onset LP, the mode of transmission is speculated to be oral sex. Yet, research has demonstrated that other factors have to be implemented in the infection since the presence of HPV alone on the mucosa does not necessarily cause the condition.[1] 

Another mode of transmission that has been studied is through exposure to laser smoke on laser surgeons. Kashima et al. demonstrated high amounts of HPV 6 and 11 on gel foams that were soaked in the surgical area of LP. They concluded that the amount of active viral load in smoke is too small to cause transmission of the virus.[2] Yet, precautions are still advised to be used in the operating room when dealing with laryngeal papilloma.

Epidemiology

It is estimated that the incidence of laryngeal papillomatosis is 4.3 per 100,000 children and 1.8 per 100,000 adults.[3] LP is the second most common benign neoplasm of the larynx among children and the second most frequent cause of childhood hoarseness.[4] LP can be divided into two subtypes, which have a strong correlation with how aggressive the disease acts. The juvenile or childhood-onset is the most aggressive form. It has a higher chance to cause airway obstruction, spread to more than one site of the aerodigestive tract, recur faster, and lead to more frequent surgical interventions. The other type is the adult-onset form, which tends to be less aggressive. Yet, some adult-onset LP may have aggressive characteristics mostly based on the HPV subtype.

Pathophysiology

Laryngeal papilloma is a condition that has been studied thoroughly but is still being constantly researched since no cure has yet been found. The pathophysiology behind LP is thought to be an infection of the stem cells within the basal layer of the aerodigestive tract squamous mucosa that may lead to either activation expression or latent expression of the genes. HPV has also been associated with activating the epidermal growth factor (EGF) receptor pathway.[5] Furthermore, research has demonstrated an immunologic suppression of the T cells to recognize and respond to HPV antigen exposure.[6]

Histopathology

In a microscopic view, laryngeal papillomas are characterized by multiple proliferations of hyperplastic stratified squamous epithelium with a central fibrovascular core. There is also basal and parabasal cell hyperplasia in a perpendicular orientation with koilocytosis atypia.[7]

History and Physical

A careful history should be obtained with an initial focus on respiratory symptoms and patient stability. During the evaluation, it is important to ask about previous intubations, perinatal history, onset and progression of symptoms, any trauma, or voice changes. Associated symptoms like feeding difficulties, allergic rhinitis, vocal abuse, and reflux irritation are key questions since it may distinguish from alternative diagnoses. Afterward, clinicians should observe the patient for tachypnea, stridor, use of accessory muscles, speech, cry or change of stridor with position.

The flexible fiberoptic nasopharyngoscope provides a precise preoperative diagnosis and the ability to rule out some differential diagnoses. Laryngeal papilloma is observed as pinkish to white “grape-like” projections that can be sessile or pedunculate with a visible central vascular core. It appears as a clear grape with visible seed. Furthermore, when stroboscopy is available, the use of novel technology known as narrow-band imaging (NBI) is extremely helpful. NBI is a short wavelength blue light absorbed mostly by hemoglobin. Therefore, since laryngeal papilloma has a vascular core, it will be depicted as a soft tissue surrounding blue foci.[8] 

The condition has a predilection to respiratory tract transition zones. The true vocal cords transition from pseudostratified epithelium to stratified squamous epithelium. Therefore, they are a common location for papilloma lesions to occur. Nevertheless, LP may be seen in other regions of the respiratory tract.

Evaluation

The definitive diagnosis of laryngeal papilloma is a biopsy of the lesion with HPV typing. The malignant transformation of laryngeal papilloma into squamous cell carcinoma can occur in up to 1% to 4% of the cases and depends mostly on the HPV typing and is more common in adults. Even though low-risk HPV 6 and 11 are most commonly related to the condition, high-risk HPV 16 and 18 can be present.[9] 

Due to the benign course of the disease, imaging modalities are normally not required. Yet, a computed tomography (CT) scan can be useful in evaluating pulmonary papillomatosis or any other respiratory lesion preoperatively.

Treatment / Management

Surgical Management

Currently, there is no “cure” for LP. The standard of care consists of surgical removal of the papillomas with preservation of normal mucosa. Clinicians should be prudent to accept some residual papillomas rather than damage normal tissue since adjacent tissue may have latent virus not clinically visible. Suspension microlaryngoscopy with laser removal is the gold standard, preferably with a CO2 laser (10,600 nm), but a potassium titanium phosphate (KTP) laser, a 585-nm pulsed-dye laser or an argon laser can also be used. Other modalities, such as microdebriders, cold instruments, and phonomicrosurgery, may be implemented as well. The operating room has been the standard of care until the emergence of the flexible laryngoscope, which has been improved with high-definition distal chip endoscopes. Nowadays, office-based laser surgery has helped with the control of the disease and decreased the need for general anesthesia.

During the procedure, care must be taken to minimize damage to normal tissue since it may lead to an iatrogenic squamociliary junction, creating additional foci of possible papillomatous growth. Airway compromise is a serious concern when dealing with distant or large clusters of laryngeal papilloma. Nevertheless, during situations of airway compromise, endotracheal intubation with flexible bronchoscope or video laryngoscope should be attempted first to try and avoiding tracheostomy. Most laryngeal papillomas are easily displaced and manipulated since they do not invade deep tissues. Tracheostomy should be avoided unless completely necessary to secure the airway since it creates a transition zone and predisposes further spread of the disease.

Adjuvant Management

The gold standard for therapy is still surgical intervention. Nevertheless, the criteria for implementing adjuvant therapy consists of more than 4 surgical procedures in 1 year, rapid regrowth of papilloma, airway compromise, and/or distal multisite spread of disease. The options include the use of cidofovir, photodynamic therapy, bevacizumab, interferon, indole-3 carbinol, and proton pump inhibitors. Many of these adjuvant therapies are mostly off label use and have a wide range of responses to therapy. The most commonly utilized interferon was peginterferon alpha 2a, but it has been replaced due to its high side-effects and emergence of cidofovir. Intralesional injection of cidofovir is a prodrug that becomes incorporated into the DNA and leads to toxicity against the virus. Many case series and case reports have demonstrated excellent response to cidofovir, but no clinical trial has been developed about the efficacy of cidofovir. The RRP task force recommends the use of cidofovir for patients with extra-laryngeal spread or those with more than six surgeries per year.[3] 

Even though it is a preventive therapy, the human papillomavirus 9-valent vaccine has been studied as adjuvant therapy. Yin Yiu et al. reported a retrospective study of patients with existent laryngeal papilloma who had a significant decrease in surgical intervals, the number of procedures per year, and disease burden.[10] Apart from the previously mentioned adjuvant therapies, it is also important to partake in preventive measures such as the use of proton pump inhibitors. Controlling chronic exposure of gastric acid with proton pump inhibitors can help avoid metaplastic changes in the epithelium that could lead to the propagation of the papillomas.[11][12](B3)

Differential Diagnosis

Laryngeal papilloma may be confused with other laryngeal lesions. Even though laryngeal papilloma has a risk of malignancy, vocal cord leukoplakia, squamous cell carcinoma, and verrucous carcinoma need to be ruled out. These can be easily differentiated with a biopsy of the lesion. LP can be confused with other benign lesions such as vocal cord granulomas, vocal cord nodules, and polypoid corditis, known as Reinke edema. These lesions, contrary to malignant lesions, are mostly differentiated with a detailed stroboscopic examination.

Prognosis

The prognosis of these patients is excellent since laryngeal papilloma is a benign lesion.  Nevertheless, it has potentially fatal consequences if airway obstruction is the presenting symptom as well as the low risk of malignant transformation. Also, due to the high recurrence rate of the condition, most patients require multiple interventions, which increases the risk of postoperative complications.

Complications

The high incidence of laryngeal airway surgery may lead to several complications. The first and most common complication is the recurrence of the lesion or spread of the disease to adjacent tissues due to iatrogenic squamous metaplasia. Furthermore, aggressive removal may lead to vocal cord scarring or glottic webs. These complications would affect the phonatory qualities of the vocal cords. Another complication in the use of laser surgery is airway fire.