ORIGINAL ARTICLE
Risk factors for the development of high-grade dysplasia and carcinoma in patients with laryngeal squamous cell papillomas: Large retrospective cohort study
Daša Gluvajić MD,
Lea Hošnjak PhD,
Vida Stegel PhD,
Srdjan Novaković PhD,
Nina Gale MD, PhD,
Mario Poljak MD, PhD,
Irena Hočevar Boltežar MD, PhD,
Corresponding Author
Daša Gluvajić MD
Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre, Ljubljana, Slovenia
Correspondence
Daša Gluvajić, Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre, Zaloška Street 2, 1000 Ljubljana, Slovenia.
Email: [email protected]
Search for more papers by this authorLea Hošnjak PhD
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia
Search for more papers by this authorVida Stegel PhD
Department of Molecular Diagnostics, Institute of Oncology, Ljubljana, Slovenia
Search for more papers by this authorSrdjan Novaković PhD
Department of Molecular Diagnostics, Institute of Oncology, Ljubljana, Slovenia
Search for more papers by this authorNina Gale MD, PhD
Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia
Search for more papers by this authorMario Poljak MD, PhD
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia
Search for more papers by this authorIrena Hočevar Boltežar MD, PhD
Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre, Ljubljana, Slovenia
Search for more papers by this authorDaša Gluvajić MD,
Lea Hošnjak PhD,
Vida Stegel PhD,
Srdjan Novaković PhD,
Nina Gale MD, PhD,
Mario Poljak MD, PhD,
Irena Hočevar Boltežar MD, PhD,
Corresponding Author
Daša Gluvajić MD
Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre, Ljubljana, Slovenia
Correspondence
Daša Gluvajić, Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre, Zaloška Street 2, 1000 Ljubljana, Slovenia.
Email: [email protected]
Search for more papers by this authorLea Hošnjak PhD
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia
Search for more papers by this authorVida Stegel PhD
Department of Molecular Diagnostics, Institute of Oncology, Ljubljana, Slovenia
Search for more papers by this authorSrdjan Novaković PhD
Department of Molecular Diagnostics, Institute of Oncology, Ljubljana, Slovenia
Search for more papers by this authorNina Gale MD, PhD
Institute of Pathology, Faculty of Medicine, University of Ljubljana, Slovenia
Search for more papers by this authorMario Poljak MD, PhD
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia
Search for more papers by this authorIrena Hočevar Boltežar MD, PhD
Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre, Ljubljana, Slovenia
Search for more papers by this authorSection Editor: Eben Rosenthal
Funding information: Javna Agencija za Raziskovalno Dejavnost RS, Grant/Award Number: P3-0083; University Medical Centre, Ljubljana, Slovenia, Grant/Award Number: 20150093
Abstract
Background
The incidence and risk factors for the development of high-grade dysplasia (HG-D) and laryngeal squamous cell carcinoma (LSCC) were assessed in patients with laryngeal squamous cell papillomas (LSP).
Methods
Clinical data, human papillomaviruses (HPV) typing, HPV E6/E7 mRNA in situ hybridization, and sequencing of host genes in LSP biopsies of 163 patients were analyzed.
Results
Progression to HG-D and LSCC was identified in 21.5% and 4.3% of LSP patients, respectively. A more advanced age at LSP onset and lack of HPV infection were detected as risk factors for the development of HG-D and LSCC (P < .05). The identification of HG-D was associated with its progression to LSCC (P < .05). Host gene mutations were identified in 3 of 7 patients with LSCC.
Conclusions
The histological monitoring of LSP and HPV typing are necessary for early detection of epithelial changes. Further research is needed to elucidate the role of host gene mutations in LSCC transformation.
CONFLICT OF INTEREST
The authors reported no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1Gissmann L, Diehl V, Schultz-Coulon HJ, zur Hausen H. Molecular cloning and characterization of human papilloma virus DNA derived from a laryngeal papilloma. J Virol. 1982; 44(1): 393-400.
- 2Gale N, Poljak M, Zidar N. Update from the 4th edition of the World Health Organization Classification of Head and Neck Tumours: what is new in the 2017 WHO Blue Book for Tumours of the Hypopharynx, Larynx, Trachea and Parapharyngeal Space. Head Neck Pathol. 2017; 11(1): 23-32.
- 3Doyle DJ, Gianoli GJ, Espinola T, Miller RH. Recurrent respiratory papillomatosis: juvenile versus adult forms. Laryngoscope. 1994; 104(5 Pt 1): 523-527.
- 4Lindeberg H, Oster S, Oxlund I, Elbrønd O. Laryngeal papillomas: classification and course. Clin Otolaryngol Allied Sci. 1986; 11(6): 423-429.
- 5Richardson M, Gale N, Hille J, Zidar N. Squamous cell papilloma and squamous cell papillomatosis. In: AK El-Naggar, JKC Chan, JR Grandis, T Takata, PJ Slootweg, eds. WHO Classification of Head and Neck Tumours. 4th ed. Lyon: IARC Press; 2017: 93-95.
- 6San Giorgi MR, van den Heuvel ER, Tjon Pian Gi RE, et al. Age of onset of recurrent respiratory papillomatosis: a distribution analysis. Clin Otolaryngol. 2016; 41(5): 448-453.
- 7Morshed K, Polz-Dacewicz M, Szymański M, Polz D. Short-fragment PCR assay for highly sensitive broad-spectrum detection of human papillomaviruses in laryngeal squamous cell carcinoma and normal mucosa: clinico-pathological evaluation. Eur Arch Otorhinolaryngol. 2008; 265(Suppl 1): S89-S96.
- 8Duray A, Descamps G, Arafa M, et al. High incidence of high-risk HPV in benign and malignant lesions of the larynx. Int J Oncol. 2011; 39(1): 51-59.
- 9Aaltonen LM, Peltomaa J, Rihkanen H. Prognostic value of clinical findings in histologically verified adult-onset laryngeal papillomas. Eur Arch Otorhinolaryngol. 1997; 254(5): 219-222.
- 10Aaltonen LM, Rihkanen H, Vaheri A. Human papillomavirus in larynx. Laryngoscope. 2002; 112(4): 700-707.
- 11Halec G, Holzinger D, Schmitt M, et al. Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma. Br J Cancer. 2013; 109(1): 172-183.
- 12Ndiaye C, Mena M, Alemany L, et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. Lancet Oncol. 2014; 15(12): 1319-1331.
- 13Fusconi M, Campo F, Gallo A, et al. Laryngeal cancer, HPV DNA vs E6/E7 mRNA test: a systematic review. J Voice. 2017; 31(2): 248.e1-248.e5.
- 14zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002; 2(5): 342-350.
- 15Pim D, Banks L. Interaction of viral oncoproteins with cellular target molecules: infection with high-risk vs low-risk human papillomaviruses. APMIS. 2010; 118(6–7): 471-493.
- 16Karatayli-Ozgursoy S, Bishop JA, Hillel A, Akst L, Best SR. Risk factors for dysplasia in recurrent respiratory papillomatosis in an adult and pediatric population. Ann Otol Rhinol Laryngol. 2016; 125(3): 235-241.
- 17Davids T, Muller S, Wise JC, Johns MM, Klein A. Laryngeal papillomatosis associated dysplasia in the adult population: an update on prevalence and HPV subtyping. Ann Otol Rhinol Laryngol. 2014; 123(6): 402-408.
- 18Omland T, Lie KA, Akre H, et al. Recurrent respiratory papillomatosis: HPV genotypes and risk of high-grade laryngeal neoplasia. PLoS One. 2014; 9(6):e99114.
- 19Donne AJ, Hampson L, Homer JJ, Hampson IN. The role of HPV type in recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol. 2010; 74(1): 7-14.
- 20Papaioannou VA, Lux A, Voigt-Zimmermann S, Arens C. Treatment outcomes of recurrent respiratory papillomatosis: retrospective analysis of juvenile and adult cases. HNO. 2018; 66(Suppl 1): 7-15.
- 21Tjon Pian Gi RE, San Giorgi MR, Slagter-Menkema L, et al. Clinical course of recurrent respiratory papillomatosis: comparison between aggressiveness of human papillomavirus-6 and human papillomavirus-11. Head Neck. 2015; 37(11): 1625-1632.
- 22Ilmarinen T, Hagström J, Haglund C, et al. Low expression of nuclear Toll-like receptor 4 in laryngeal papillomas transforming into squamous cell carcinoma. Otolaryngol Head Neck Surg. 2014; 151(5): 785-790.
- 23Sanchez GI, Jaramillo R, Cuello G, et al. Human papillomavirus genotype detection in recurrent respiratory papillomatosis (RRP) in Colombia. Head Neck. 2013; 35(2): 229-234.
- 24Hall JE, Chen K, Yoo MJ, Fletcher KC, Ossoff RH, Garrett CG. Natural progression of dysplasia in adult recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg. 2011; 144(2): 252-256.
- 25Blumin JH, Handler EB, Simpson CB, Osipov V, Merati AL. Dysplasia in adults with recurrent respiratory papillomatosis: incidence and risk factors. Ann Otol Rhinol Laryngol. 2009; 118(7): 481-485.
- 26Jeong WJ, Park SW, Shin M, et al. Presence of HPV type 6 in dysplasia and carcinoma arising from recurrent respiratory papillomatosis. Head Neck. 2009; 31(8): 1095-1101.
- 27Pinter B, Čeh F, Verdenik I, et al. Spolno vedenje slovenskih srednješolcev v letu 2004. Zdrav Vestn. 2006; 75: 615-619.
- 28Komloš KF, Kocjan BJ, Košorok P, et al. Tumor-specific and gender-specific pre-vaccination distribution of human papillomavirus types 6 and 11 in anogenital warts and laryngeal papillomas: a study on 574 tissue specimens. J Med Virol. 2012; 84(8): 1233-1241.
- 29Kocjan BJ, Hošnjak L, Poljak M. Detection of alpha human papillomaviruses in archival formalin-fixed, paraffin-embedded (FFPE) tissue specimens. J Clin Virol. 2016; 76(Suppl 1): S88-S97.
- 30Hošnjak L, Kocjan BJ, Pirš B, Seme K, Poljak M. Characterization of two novel gammapapillomaviruses, HPV179 and HPV184, isolated from common warts of a renal-transplant recipient. PLoS One. 2015; 10(3):e0119154.
- 31Kocjan BJ, Seme K, Poljak M. Detection and differentiation of human papillomavirus genotypes HPV-6 and HPV-11 by FRET-based real-time PCR. J Virol Methods. 2008; 153(2): 245-249.
- 32Evans MF, Adamson CS, Simmons-Arnold L, Cooper K. Touchdown general primer (GP5+/GP6+) PCR and optimized sample DNA concentration support the sensitive detection of human papillomavirus. BMC Clin Pathol. 2005; 5: 10.
- 33Nazarenko I, Kobayashi L, Giles J, Fishman C, Chen G, Lorincz A. A novel method of HPV genotyping using hybrid capture sample preparation method combined with GP5+/6+ PCR and multiplex detection on Luminex XMAP. J Virol Methods. 2008; 154(1–2): 76-81.
- 34Mlakar J, Kocjan BJ, Hošnjak L, et al. Morphological characteristics of conjunctival squamous papillomas in relation to human papillomavirus infection. Br J Ophthalmol. 2015; 99(3): 431-436.
- 35Hošnjak L, Fujs Komloš K, Kocjan BJ, Seme K, Poljak M. Development of a novel multiplex type-specific quantitative real-time PCR for detection and differentiation of infections with human papillomavirus types HPV2, HPV27, and HPV57. Acta Dermatovenerol Alp Pannonica Adriat. 2016; 25(4): 65-71.
- 36Castellsagué X, Alemany L, Quer M, et al. HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 patients. J Natl Cancer Inst. 2016; 108(6):djv403.
- 37Go C, Schwartz MR, Donovan DT. Molecular transformation of recurrent respiratory papillomatosis: viral typing and p53 overexpression. Ann Otol Rhinol Laryngol. 2003; 112(4): 298-302.
- 38Gale N, Gnepp DR, Poljak M, et al. Laryngeal squamous intraepithelial lesions: an updated review on etiology, classification, molecular changes, and treatment. Adv Anat Pathol. 2016; 23(2): 84-91.
- 39Gale N, Blagus R, El-Mofty SK, et al. Evaluation of a new grading system for laryngeal squamous intraepithelial lesions—a proposed unified classification. Histopathology. 2014; 65(4): 456-464.
- 40Lee LA, Cheng AJ, Fang TJ, et al. High incidence of malignant transformation of laryngeal papilloma in Taiwan. Laryngoscope. 2008; 118(1): 50-55.
- 41Sajan JA, Kerschner JE, Merati AL, Osipov V, Szabo S, Blumin JH. Prevalence of dysplasia in juvenile-onset recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg. 2010; 136(1): 7-11.
- 42 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum. 2004; 83: 1-1438.
- 43Moore JE, Garcia A, Sanyal S, et al. Degrees of dysplasia based on viral typing in patients with cidofovir use and recurrent respiratory papillomatosis. J Voice. 2013; 27(6): 765-768.
- 44Tjon Pian Gi RE, Ilmarinen T, van den Heuvel ER, et al. Safety of intralesional cidofovir in patients with recurrent respiratory papillomatosis: an international retrospective study on 635 RRP patients. Eur Arch Otorhinolaryngol. 2013; 270(5): 1679-1687.
- 45Kashima H, Mounts P, Leventhal B, Hruban RH. Sites of predilection in recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 1993; 102(8 Pt 1): 580-583.
- 46Torrente MC, Rodrigo JP, Haigentz M, et al. Human papillomavirus infections in laryngeal cancer. Head Neck. 2011; 33(4): 581-586.
- 47Guillou L, Sahli R, Chaubert P, Monnier P, Cuttat JF, Costa J. Squamous cell carcinoma of the lung in a nonsmoking, nonirradiated patient with juvenile laryngotracheal papillomatosis. Evidence of human papillomavirus-11 DNA in both carcinoma and papillomas. Am J Surg Pathol. 1991; 15(9): 891-898.
- 48Lindeberg H, Syrjänen S, Kärjä J, Syrjänen K. Human papillomavirus type 11 DNA in squamous cell carcinomas and pre-existing multiple laryngeal papillomas. Acta Otolaryngol. 1989; 107(1–2): 141-149.
- 49Rady PL, Schnadig VJ, Weiss RL, Hughes TK, Tyring SK. Malignant transformation of recurrent respiratory papillomatosis associated with integrated human papillomavirus type 11 DNA and mutation of p53. Laryngoscope. 1998; 108(5): 735-740.
- 50Byrne JC, Tsao MS, Fraser RS, Howley PM. Human papillomavirus-11 DNA in a patient with chronic laryngotracheobronchial papillomatosis and metastatic squamous-cell carcinoma of the lung. N Engl J Med. 1987; 317(14): 873-878.
- 51Cook JR, Hill DA, Humphrey PA, Pfeifer JD, El-Mofty SK. Squamous cell carcinoma arising in recurrent respiratory papillomatosis with pulmonary involvement: emerging common pattern of clinical features and human papillomavirus serotype association. Mod Pathol. 2000; 13(8): 914-918.
- 52Boudjemaa S, Leboulanger N, Daınese L, Cremoux PD, Pointe HD, Coulomb A. Metastatic squamous-cell carcinoma of the lung arising in a 12-year-old boy with juvenile recurrent respiratory papillomatosis of neonatal onset. Turk Patoloji Derg. 2014; 30(2): 133-136.
- 53Gerein V, Rastorguev E, Gerein J, Draf W, Schirren J. Incidence, age at onset, and potential reasons of malignant transformation in recurrent respiratory papillomatosis patients: 20 years experience. Otolaryngol Head Neck Surg. 2005; 132(3): 392-394.
- 54Can NT, Tretiakova MS, Taxy JB. Natural history and malignant transformation in recurrent respiratory papillomatosis: human papillomavirus (HPV), dysplasia and an autopsy review. Fetal Pediatr Pathol. 2015; 34(2): 80-90.
- 55Duensing S, Münger K. Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer. 2004; 109(2): 157-162.
- 56van Houten VM, Snijders PJ, van den Brekel MW, et al. Biological evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell carcinomas. Int J Cancer. 2001; 93(2): 232-235.
- 57Braakhuis BJ, Snijders PJ, Keune WJ, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst. 2004; 96(13): 998-1006.
- 58Braakhuis BJ, Brakenhoff RH, Meijer CJ, Snijders PJ, Leemans CR. Human papilloma virus in head and neck cancer: the need for a standardised assay to assess the full clinical importance. Eur J Cancer. 2009; 45(17): 2935-2939.
- 59Westra WH, Taube JM, Poeta ML, Begum S, Sidransky D, Koch WM. Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2008; 14(2): 366-369.
- 60Gillison ML, Alemany L, Snijders PJ, et al. Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis. Vaccine. 2012; 30(Suppl 5): F34-F54.
- 61Huebbers CU, Preuss SF, Kolligs J, et al. Integration of HPV6 and downregulation of AKR1C3 expression mark malignant transformation in a patient with juvenile-onset laryngeal papillomatosis. PLoS One. 2013; 8(2):e57207.
- 62Reidy PM, Dedo HH, Rabah R, et al. Integration of human papillomavirus type 11 in recurrent respiratory papilloma-associated cancer. Laryngoscope. 2004; 114(11): 1906-1909.
Citing Literature
