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Laryngeal papillomatosis

BY SAM MAJUMDAR

Laryngeal papillomatosis remains one of the most frustrating conditions seen by laryngologists. Sam Majumdar gives us an overview of the current science and clinical practice.

uman is a small Transmission Diagnosis (> 8kb) double stranded DNA HPV infection in children is most commonly All patients need formal diagnostic virus with approximately 200 transmitted vertically at birth from laryngo-tracheo- to correct Hsubtypes [1]. It belongs to the HPV infected mothers. Transplacental assessment and staging of the disease. papova family of virus. The subtypes 6, transmission of HPV to the foetus Histopathological findings would confirm 11, cause approximately 90% of laryngeal happens in about 12% of cases. Presence diagnosis. HPV subtyping is highly papilloma. The other 10% is attributed to of anogenital papillomata in the mother recommended as good practice, as it helps HPV Type 16, 18. The Type 11 is the clinically can increase the risk of development of to find the aggressive variety (i.e. subtype aggressive type while Type 16 and 18 have RRP by 231 times. In adults, HPV virus is 11) and those with higher predispositions more malignant transformation potential. transmitted through sexual interactions. It for malignant transformation (i.e. subtypes HPV Types 6, 11, 16 and 18 together cause is estimated that over 80% of us will pick up 16, 18). most cervical which became the HPV during our lifetime. Unfortunately, vast central logic for the development of the numbers of high-risk HPV infections can Management quadrivalent vaccination. remain asymptomatic and go unnoticed, Many patients are quite overwhelmed The incidence of recurrent respiratory thereby adding risk of spread to the and distressed by the diagnosis of an STI papillomatosis (RRP) is 4.3 per 100,000 population and long-term risk of malignant (sexually transmitted infection) causing population in children and 1.8 per transformation in those infected by the damage and deformity to their . A 100,000 in adults. RRP has a bimodal age virus. thorough assessment of voice function and distribution in first presentation – it usually recording of VHI-10 score before and after affects teens and people in their fourth Clinical presentation surgical interventions are very useful for decades of life. Presentation of RRP before Persistent hoarseness of voice, shortness of reassurance and rehabilitation of patients. the age of 12 years is classed as juvenile breath at rest or during exertion, cough and All patients with dysphonia and glottic onset RRP (JORRP). All presentation after are some of the common presenting involvement with papilloma should have the age of 12 is classified into the adult onset symptoms of laryngeal papillomatosis. stroboscopy assessment and have photo- RRP (AORRP) group. Clinical presentation depends on the site documentation of the disease. Presentation of RRP before the and size of the lesion(s). Involvement of At present there is no curative treatment age of three years is often associated the anterior commissure, anterior two for laryngeal papillomatosis. Removal of with significantly higher chances thirds of the vocal cord or bulky disease epithelial tissue infected with HPV, which of dissemination and malignant preventing vocal cord apposition during present as visible exophytic swelling in the transformation in later life. Malignant voice generation tend to present early. larynx, leaving the Reinke’s space intact transformation rate of RRP in children is Supraglottic involvement may go unnoticed where possible, is the frequent practice. The 1-2% (2). for a long time (Figure 1). microdebrider skimmer blade can be used,

“Many patients are quite overwhelmed and distressed by the diagnosis of an STI (sexually transmitted infection) causing damage and

Figure 1. Laryngeal papilloma multi-site involvement. Figure 2. RRP of anterior commissure involvement six months deformity to their larynx.” post treatment

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and some surgeons combine this with CO2 endothelial growth factor and thus the laser in scanning mode to remove papilloma viral induced angiogenesis. The mode of “Although 85% of parents close to the vocal cord. The use of KTP and delivery is intralesional. has would like their male other angiolytic lasers as a primary tool been reported to have reduced recurrence of to remove the bulk of laryngeal papilloma HPV when used as an adjuvant therapy after children to be vaccinated is not widely practised in the UK. More debulking of papilloma with KTP laser. This this is still not offered on recently, coblation has been suggested as a drug has very few side-effects in small trials. treatment (Figure 2). the public health disease Pembrolizumab Adjuvant therapy This is a humanised monoclonal antibody prevention programme in The aim of such therapy is to prevent that activates T-lymphocytes by selectively the UK.” scarring, local spread and dissemination and blocking some receptors thus helping recurrence. To date no adjuvant therapy has immune cells to recognise and kill virally been shown to have significant advantage infected abnormal cells. Pembrolizumab is in management of laryngeal papillomatosis. known to inhibit Programmed Cell Death None of these therapies have been widely Protein 1 which is highly expressed by some accepted in clinical practice although some HPV associated head and neck tumours. have shown promise and await further An ongoing Phase II clinical trial evidence from research. (NCT02632344) is investigating the Vaccinating boys safety and immunomodulatory effect Vaccination against HPV infection is most of Pembrolizumab in the treatment of effective in children at the age before any Interferon was the very first adjuvant advanced RRP cases with tracheo-broncho- sexual exposure. In the UK HPV vaccination therapy used to control disseminated RRP. pulmonary involvement. for girls aged 12-13 started in 2008. stimulate antigen production Although 85% of parents would like their by lymphocytes. IFN-α2b has shown partial Mitomycin C male children to be vaccinated this is still response in some trials. Leukopenia, This is not an adjuvant therapy; although not offered on the public health disease thrombocytopenia and neurological used by some surgeons. Local application prevention programme in the UK. An anti- disorders are some of the troublesome of Mitomycin C has been used to prevent HPV vaccination programme for boys in side effects of Interferon therapy. Use of glottic scarring. Mitomycin C is, therefore, Australia started in 2013. The annual cost for Interferon is no longer favoured [2]. used by some laryngologists especially in running a vaccination programme for boys the management of papilloma involving the has been estimated at £22 million compared anterior commissure. to the significantly larger economic and Cidofovir inhibits viral DNA polymerase, human cost of this notoriously challenging thus inhibiting viral replication. Intralesional vaccination disease that defies eradication. A tentative Cidofovir is the preferred route of HPV vaccination raises serum antibody titre date for HPV vaccination for boys in the administration of this drug. Frequent in patients. Kin Cho Goon et al. [4], in a small UK has been the year 2020; which will recurrence of RRP and aggressive disease study, have shown a seven-fold decrease leave 400,000 boys annually at the risk of are the situations where Cidofovir has in the recurrence of laryngeal papilloma in exposure to HPV infection (Gender Neutral been used successfully by some authors. the post-vaccination group needing surgical Vaccination – www.HPVAction.org). Reported development of dysplastic intervention. changes in 2.5% of a series of 188 cases of Future directions and challenges RRP treated with intralesional Cidofovir Vaccination and prevention The biggest challenge in managing HPV was a significant cause for concern [3]. HPV is the commonest sexually transmitted disease is probably the relentless spread of However, considering the natural tendency infection in the UK. HPV infection is almost this virus across all populations. Vaccination of 2-3% dysplastic change rate of HPV it is non-existent in people who have never programmes can effectively protect those difficult to attribute this solely to the drug had sexual intercourse. Sexual encounter who have not already been infected by in question. Marked regression of papilloma at an early age and having multiple sexual it. There is also emerging evidence of the and complete remission of disease have partners are the two most important protective effect of vaccination as adjuvant been reported in small prospective trials determinants of HPV infections in adults. therapy and prevention of infection in where intralesional Cidofovir was used. The US Centers for Disease Control and adults. Other studies have reported 75% complete Prevention recommended the routine use remission with disease stabilisation for 33.4 of vaccination in girls aged 11-15 and use of months in juvenile onset RRP. One RRP task vaccination until the age of 26 as a catch up force survey of 74 laryngologists highlighted for those who have missed out to prevent the use of Cidofovir as adjuvant therapy in cervical . Gardasil, a quadrivalent patients needing frequent surgical debulking vaccination by Merck, was approved for this and cautioned that the dose should remain purpose by the US Department of Food and below the safe limit of 3m/kg and volume. Drug Administration in 2006. The FDA had “The biggest challenge in Large randomised controlled trials are also approved another bivalent vaccination, needed to support the use of Cidofovir and for immunisation against HPV managing HPV disease is reassure patients and surgeons alike. 16, 18 which has limited use for laryngeal papillomatosis. Both these vaccinations probably the relentless Bevacizumab have been proven to be highly efficacious in spread of this virus across This recombinant monoclonal antibody clinical trials. Gardasil-9 (a 9-valent has the ability to inhibit the vascular for HPV) has been recently approved. all populations.”

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Some of the HPV subtypes are potentially link between increased serum anti-HPB References oncogenic. HPV associated cancers of the antibody titre with remission of clinical 1. Fortes HR, von Ranke FM, Escuissato DL, et al. Recurrent Respiratory Papillomatosis: A State-of-the-Art Review. head and neck were first suspected in 1983 disease. Respiratory Medicine 2017;126:116-21. in a group of oropharyngeal cancers. Based The primary interventions and the 2. Ivancic R, Iqbal H, deSilva B, Pan Q, Matrka L. on molecular findings, it is now believed use of adjuvant therapy for laryngeal Current and Future Management of Recurrent that 80% of oropharyngeal squamous cell papillomatosis show some variations Respiratory Papillomatosis. Laryngoscope Investigative Otolaryngology. 2018;3(1):22-34. are HPV positive. HPV-16 is amongst practitioners in the UK and 3. Broekema F, Dikkers FG. Side-Effects of Cidofovir in the found in 80 of these tumours [5]. globally. The establishment and use of a Treatment of Recurrent Respiratory Papillomatosis. Eur The American Joint Committee on national database and guidelines hopefully Arch Otorhinolaryngol 2008;265:871-9. Cancer (AJCC) and Union for International will help patients through evidence- 4. Kin Cho Goon P, Scholtz L-U, Sudhoff H, FRCS FRCPath. Cancer Control (UICC) have included testing based standardisation of practice; along Recurrent Respiratory Papillomatosis (RRP) – Time for a Reckoning? Laryngoscope Investigative Otolaryngology for HPV in their guidelines as a standard with dissemination of knowledge of good 2017;2. pathological assessment for oropharyngeal practice. Ideally all patients with laryngeal 5. Spence T, Bruce J, Yip KW, Liu FF. HPV Associated Head cancer. papillomatosis would receive direct care and Neck Cancer. Cancers 2016;8(8). Making HPV vaccination gender neutral from a laryngologist with phonosurgical 6. Friedrich G, Remacle M, Birchall M, Marie JP, Arens C. Defining Phonosurgery: A Proposal for classification will make a significant contribution to skills and concurrent input from a and Nomenclature by the Phonosurgery Committee increasing herd immunity. The use of multidisciplinary team [6]. of the European Laryngological Society (ELS). Eur Arch vaccination in patients with RRP may have Otorhinolaryngol 2007;264:1191-200. adjuvant benefits. Studies have shown a

AUTHOR Sam Majumdar, BM BS, BMed Sci(Hon), FRCS Ed, FDS RCPS, MFST Ed, FRCSEd(ORL-HNS), Laryngologist, Consultant Ear, Nose and Throat Surgeon, Hon. Senior Lecturer, Ninewells Hospital and Medical School, Dundee, UK. BLA Council Member E: [email protected] @sammajumdar www.linkedin.com/in/sammajumdar/

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