Laryngeal papillomatosis (LP), also known as recurrent respiratory papillomatosis (RRP), is the most common benign mesenchymal neoplasm of the larynx in children. RRP is characterized by an over-proliferation of benign squamous papillomas in the aerodigestive tract. The condition has a childhood-onset type and an adult-onset type. It is one of the most difficult benign histologic conditions to treat due to its high tendency to recur and spread to the adjacent respiratory tract. This chapter will briefly discuss the etiology, clinical findings, diagnostic modalities, and the different surgical and nonsurgical management options, as well as recent preventive measures.
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.
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. Yet, precautions are still advised to be used in the operating room when dealing with laryngeal papilloma.
It is estimated that the incidence of laryngeal papillomatosis is 4.3 per 100,000 children and 1.8 per 100,000 adults. LP is the second most common benign neoplasm of the larynx among children and the second most frequent cause of childhood hoarseness. 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.
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. Furthermore, research has demonstrated an immunologic suppression of the T cells to recognize and respond to HPV antigen exposure.
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.
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.
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.
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.
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.
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.
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.
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. 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.
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.
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.
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.
Patients and family members should be educated about the natural cause of the condition and the chronicity of it. They need to be aware that there is no cure for laryngeal papilloma and understand the need for multiple surgical interventions in their lifetime. Adjuvant therapy is not effective in all patients, and most modulators are not FDA approved. However, they are a continuous topic of research. Additionally, preventive measures need to be exercised by explaining to patients about the 9-valent HPV vaccine to treat or limit the spread of laryngeal papilloma.
Laryngeal papillomatosis is a chronic condition of the respiratory tract that can affect both adults and children. It is best managed by an interprofessional team that includes primary clinicians, emergency department clinicians, and otolaryngologists. Attempts at treating or eradicating the condition through multiple management options, surgical and adjuvant have been implemented without a consistent outcome. A hypothesis of a multigene-disease theory has been proposed. This consists of innate and adaptive immunity disruption, as well as HLA alleles absence. Nevertheless, the condition could be eradicated initially by implementing a preventive method.
The HPV vaccine, which has been historically used to prevent cervical cancer and genital warts associated with HPV 6, 11, 16, and 18, has been approved for recurrent respiratory papillomatosis. The CDC has recommended that all boys and girls between the ages of 11 to 26 years be vaccinated. Recently the quadrivalent HPV vaccine has been replaced with the 9-valent HPV vaccine for prevention. Often overlooked, the role that primary clinicians and obstetric and gynecologists play in eradicating LP is fundamental. These subspecialties have the highest contact with the most evident mode of transmission and can recommend the use of the vaccine. Additionally, concurrent research has been focusing on further developing genetic and immunologic tools for the treatment of patients with the condition through gene mutations or through T-cell restoration.
|||Carifi M,Napolitano D,Morandi M,Dall'Olio D, Recurrent respiratory papillomatosis: current and future perspectives. Therapeutics and clinical risk management. 2015; [PubMed PMID: 25999724]|
|||Kashima HK,Kessis T,Mounts P,Shah K, Polymerase chain reaction identification of human papillomavirus DNA in CO2 laser plume from recurrent respiratory papillomatosis. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 1991 Feb; [PubMed PMID: 1848926]|
|||Derkay CS, Recurrent respiratory papillomatosis. The Laryngoscope. 2001 Jan; [PubMed PMID: 11192901]|
|||Larson DA,Derkay CS, Epidemiology of recurrent respiratory papillomatosis. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2010 Jun; [PubMed PMID: 20553527]|
|||Vambutas A,Di Lorenzo TP,Steinberg BM, Laryngeal papilloma cells have high levels of epidermal growth factor receptor and respond to epidermal growth factor by a decrease in epithelial differentiation. Cancer research. 1993 Feb 15; [PubMed PMID: 7679053]|
|||Hatam LJ,Devoti JA,Rosenthal DW,Lam F,Abramson AL,Steinberg BM,Bonagura VR, Immune suppression in premalignant respiratory papillomas: enriched functional CD4 Foxp3 regulatory T cells and PD-1/PD-L1/L2 expression. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012 Apr 1; [PubMed PMID: 22322668]|
|||Abramson AL,Steinberg BM,Winkler B, Laryngeal papillomatosis: clinical, histopathologic and molecular studies. The Laryngoscope. 1987 Jun; [PubMed PMID: 3035299]|
|||Jackowska J,Klimza H,Winiarski P,Piersiala K,Wierzbicka M, The usefulness of narrow band imaging in the assessment of laryngeal papillomatosis. PloS one. 2018; [PubMed PMID: 30300415]|
|||Ribeiro El-Achkar VN,Duarte A,Pinto Saggioro F,De Mello Filho FV,León JE,Ribeiro-Silva A,Kaminagakura E, Squamous Cell Carcinoma Originating from Adult Laryngeal Papillomatosis: Case Report and Review of the Literature. Case reports in otolaryngology. 2018; [PubMed PMID: 30662782]|
|||Yiu Y,Fayson S,Smith H,Matrka L, Implementation of Routine HPV Vaccination in the Management of Recurrent Respiratory Papillomatosis. The Annals of otology, rhinology, and laryngology. 2019 Apr; [PubMed PMID: 30595025]|
|||Borkowski G,Sommer P,Stark T,Sudhoff H,Luckhaupt H, Recurrent respiratory papillomatosis associated with gastroesophageal reflux disease in children. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 1999; [PubMed PMID: 10473833]|
|||Formánek M,Komínek P,Jančatová D,Staníková L,Tomanová R,Vaculová J,Urík M,Šlapák I,Zeleník K, Laryngopharyngeal Reflux Is a Potential Risk Factor for Juvenile-Onset Recurrent Respiratory Papillomatosis. BioMed research international. 2019; [PubMed PMID: 30881982]|
|||Ivancic R,Iqbal H,deSilva B,Pan Q,Matrka L, Current and future management of recurrent respiratory papillomatosis. Laryngoscope investigative otolaryngology. 2018 Feb; [PubMed PMID: 29492465]|