The Role of the Human Papillomavirus in the Pathogenesis of Schneiderian Inverted Papillomas: An Analytic Overview of the Evidence

  • William Lawson
  • Nicolas F. Schlecht
  • Margaret Brandwein-Gensler
Original Paper


Background Evidence of an etiological role for human papillomavirus (HPV) in Schneiderian inverted papillomas IP arose in the late 1980’s; yet almost three decades later, the association between HPV and IP has yet to be universally accepted. This is probably due to the disparate HPV detection rates in IP reported in the literature. We analyzed the weight of published data in order to address the following questions: why do the HPV detection rates in IP vary so greatly? What is the relationship between low-risk (LR) and high-risk (HR) HPV types and HPV detection rates in IP? Is there a relationship between the presence and type of HPV in IP and recurrence and malignant progression? Materials and methods A search using the Pubmed search engine was performed to identify studies published in English from 01/87 through 12/06 using the MeSH terms ‘‘HPV’’ and ‘‘Inverted”, “Exophytic”, “Oncocytic Schneiderian” or “Fungiform papilloma’’. Data was abstracted from publications including histology, HPV target, HPV type, method of detection, etc. HPV results were stratified by histology and other variables. Tests for heterogeneity (between-study variability) were conducted, and weighted prevalence (WP) estimates and 95% confidence intervals (CI) were calculated using a random-effects inverse-variance model stratified on study. The association between HPV IP recurrence was estimated by random-effects inverse-variance weighted odds ratio (OR). Results Weighted estimates revealed similar detection rates across detection methods, 26.8% (95%CI 16.4–37.2%) by ISH, 25.2% (95%CI 14.7–35.6%) by consensus PCR, and 23.6% (95%CI 12.2–35.0%) by type-specific PCR. A preponderance of HPV 6/11 is found in IP as compared to HPV 16/18; the overall unadjusted ratio of LR to high-risk HR HPV types is 2.8:1 The HPV detection rates significantly increase (Wald t-test P < 0.02) in IPs with high-grade dysplasia (WP 55.8%, 95%CI 30.5-81.0%) and carcinoma (WP 55.1%, 95%CI 37.0–73.2%) as compared to IPs with no dysplasia or mild dysplasia (WP 22.3%, 95%CI 15.9–28.6%). Furthermore, the preponderance of LR HPV in benign IP (ratio LR/HR = 4.8:1) shifts in dysplastic and malignant IP. The LR/HR ratio is 1.1:1 for IPs with high-grade dysplasias, this ratio is inverted to favor HR HPV (1:2.4) for malignant IP. Recurrences developed in 44 of 236 patients; HPV was detected in 27 of 44 IPs (WP 57.9%, 95%CI 31.6–84.2%) that developed recurrences and in 24 of 192 IPs (WP 9.7%, 95%CI 4.4–15.0%) that did not develop recurrence. The presence of HPV was significantly associated with the likelihood of developing recurrence (weighted OR of 10.2, 95%CI 3.2–32.8). Conclusions We hypothesize that LR HPV may induce IP formation, and then are lost as infected cells are shed, as a “hit and run” phenomenon. HPV detection rates increase in dysplastic IP and SCC-ex-IP with increasing ratio of HR to LR HPV types, compared to nondysplastic IP. We believe that one explanation for the variation in HPV detection rates between different studies may be the actual histologic composition of the cohort. That is, if one series contains a higher frequency of dysplastic and malignant IP, it may have a higher detection rate than another series which contains only nondysplastic IP. We hypothesize that the higher rates of HPV detection in dysplastic and malignant IP may be related to HPV integration. The implication of this is that HPV sub-type testing may identify patients at risk for recurrence, or progression to dysplasia and malignancy, and thus may impact surveillance protocols.


Inverted papilloma HPV detection Dysplasia High-risk Recurrence 


Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


  1. 1.
    Ogura H, Fujiwara T, Hamaya K, Saito R. Detection of HPV type 57 in a case of inverted nasal papillomatosis in Japan. Eur Arch Otorhinolaryngol. 1995;252:513–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Siivonen L, Virolainen E. Transitional papilloma of the nasal cavity and paranasal sinuses. Clinical course, viral etiology and malignant transformation. ORL J Otorhinolaryngol Relat Spec. 1989;51:262–7.PubMedGoogle Scholar
  3. 3.
    Bryan RL, Bevan IS, Crocker J, Young LS. Detection of HPV 6 and 11 in tumours of the upper respiratory tract using the PCR. Clin Otolaryngol Allied Sci. 1990;15:177–80.PubMedCrossRefGoogle Scholar
  4. 4.
    Weber RS, Shillitoe EJ, Robbins KT, Luna MA, Batsakis JG, Donovan DT, Adler-Storthz K. Prevalence of HPV in inverted papillomas. Arch Otolaryngol Head Neck Surg. 1988;114:23–6.PubMedGoogle Scholar
  5. 5.
    Saegusa M, Nitta H, Hashimura M, Okayasu I. Down-regulation of p27Kip1 expression is correlated with increased cell proliferation but not expression of p21waf1 and p53, and HPV infection in benign and malignant tumours of sinonasal regions. Histopathology. 1999;35:55–64.PubMedCrossRefGoogle Scholar
  6. 6.
    Kassim SK, Ibrahim SA, Eissa S, Zaki SS, El-Begermy MA, Abdou MH, Hassan MI, Khalifa A. Epstein Barr virus, HPV, and flow cytometric cell cycle kinetics in nasopharyngeal carcinoma and inverted papilloma among Egyption patients. Dis Markers. 1998;14:13–20.Google Scholar
  7. 7.
    Respler DS, Jahn A, Pater MM. Isolation and characterization of papillomavirus DNA from nasal inverting (Schneiderian) papillomas. Ann Otol Rhinol Laryngol. 1987;96:170–3.PubMedGoogle Scholar
  8. 8.
    Wu TC, Trujillo JM, Kashima HK, Mounts P. Association of HPV with nasal neoplasia. Lancet. 1993;341:522–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Syrjänen S, Happonen RP, Virolainen E, Siivonen L, Syrjänen K. Detection of HPV structural antigens and DNA types in inverted papillomas and squamous cell carcinomas of nasal cavities and paranasal sinuses. Acta Otolaryngol (stockh). 1987;104:334–41.CrossRefGoogle Scholar
  10. 10.
    Strauss M, Jenson AB. HPV in various lesions of the head and neck. Otolaryngol Head Neck Surg. 1985;93:342–6.PubMedGoogle Scholar
  11. 11.
    Gaito RA, Gaylord WH, Hilding DA. Ultrastructure of a human nasal papilloma. Laryngoscope. 1965;75:144–52.PubMedCrossRefGoogle Scholar
  12. 12.
    McLachlin CM, Kandel RA, Colgan TJ, Swanson DB, Witterick IJ, Ngan BY. Prevalence of HPV in sinonasal papillomas: a study using PCR and in-situ hybridization. Mod Pathol. 1992;5:406–9.PubMedGoogle Scholar
  13. 13.
    Brandsma JL, Abramson AL, Scuibba J, Shah K, Barrezuela N. Papillomavirus infection of the nose. In: Steinberg BM, Brandsma JL, Taichman LP, editors. Cancer cells 5: papillomaviruses. Cold Spring Harbor, NY: Cold Spring harbor Press; 1987. p. 301.Google Scholar
  14. 14.
    Brandwein M, Steinberg B, Thung S, Biller H, Dilorenzo T, Galli R. HPV 6/11 and 16/18 in Schneiderian inverted papillomas. Cancer. 1989;63:1708–13.PubMedCrossRefGoogle Scholar
  15. 15.
    Ishibashi T, Tsunokawa Y, Matsushima S, Nomura Y, Sugimura T, Terada M. Presence of HPV type-6-related sequences in inverted nasal papillomas. Eur Arch Otorhinolaryngol. 1990;247:296–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Judd R, Zaki SR, Coffield LM, Evatt BL. Sinonasal papillomas and HPV: HPV 11 detected in fungiform Schneiderian papillomas by in-situ hybridization and PCR. Hum Pathol. 1991;22:550–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Furuta Y, Shinohara T, Sano K, Nagashima K, Inoue K, Tanaka K, Inuyama Y. Molecular pathologic study of HPV infection in inverted papilloma and squamous cell carcinoma of the nasal cavities and paranasal sinuses. Laryngoscope. 1991;101:79–85.PubMedCrossRefGoogle Scholar
  18. 18.
    Sarkar FH, Visscher DW, Kintanar EB, Zarbo RJ, Crissman JD. Sinonasal Schneiderian papillomas: HPV typing by PCR. Mod Pathol. 1992;5:329–32.PubMedGoogle Scholar
  19. 19.
    Kashima HK, Kessis T, Hruban RH, Wu TC, Zinreich SJ, Shah KV. HPV in sinonasal papillomas and squamous cell carcinoma. Laryngoscope. 1992;102:973–6.PubMedGoogle Scholar
  20. 20.
    Tang AC, Grignon DJ, MacRae DL. The association of HPV with Schneiderian papillomas: a DNA in situ hybridization study. J Otolaryngol. 1994;23:292–7.PubMedGoogle Scholar
  21. 21.
    Buchwald C, Franzmann MB, Jacobsen GK, Lindeberg H. HPV in sinonasal papillomas: a study of 78 cases using in situ hybridization and PCR. Laryngoscope. 1995;105:66–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Beck JC, McClatchey KD, Lesperance MM, Esclamado RM, Carey TE, Bradford CR. HPV types important in progression of inverted papilloma. Otolaryngol Head Neck Surg. 1995;113:558–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Macdonald MR, Le KT, Freeman J, Hui MF, Cheung RK, Dosch HM. A majority of inverted sinonasal papillomas carries Epstein-Barr virus genomes. Cancer. 1995;75:2307–12.PubMedCrossRefGoogle Scholar
  24. 24.
    Gaffey MJ, Frierson HF, Weiss LM, Barber CM, Baber GB, Stoler MH. HPV and Epstein-Barr virus in sinonasal Schneiderian papillomas. An in situ hybridization and PCR study. Am J Clin Pathol. 1996;106:475–82.PubMedGoogle Scholar
  25. 25.
    Shen J, Tate JE, Crum CP, Goodman ML. Prevalence of HPV in benign and malignant tumors of the upper respiratory tract. Mod Pathol. 1996;9:15–20.PubMedGoogle Scholar
  26. 26.
    Caruana SM, Zwiebel N, Cocker R, McCormick SA, Eberle RC, Lazarus P. p53 alteration and HPV infection in paranasal sinus cancer. Cancer. 1997;79:1320–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Bernauer HS, Welkoborsky HJ, Tilling A, Amedee RG, Mann WJ. Inverted papillomas of the paranasal sinuses and the nasal cavity: DNA indices and HPV infection. Am J Rhinol. 1997;11:155–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Hwang CS, Yang HS, Hong MK. Detection of HPV in sinonasal inverted papillomas using PCR. Am J Rhinol. 1998;12:363–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Mirza N, Montone K, Sato Y, Kroger H, Kennedy DW. Identification of p53 and HPV in Schneiderian papillomas. Laryngoscope. 1998;108:497–501.PubMedCrossRefGoogle Scholar
  30. 30.
    Weiner JS, Sherris D, Kasperbauer J, Lewis J, Li H, Persing D. Relationship of HPV to Schneiderian papillomas. Laryngoscope. 1999;109:21–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Kraft M, Simmen D, Casas R, Pfaltz M. Significance of HPV in sinonasal papillomas. J Laryngol Otol. 2001;115:709–14.PubMedGoogle Scholar
  32. 32.
    Fischer M. Investigation of a broad-spectrum PCR assay for HPV in screening benign lesions of the upper aerodigestive tract. ORL J Otorhinolaryngol Relat Spec. 2005;67:237–41.PubMedGoogle Scholar
  33. 33.
    McKay SP, Grégoire L, Lonardo F, Reidy P, Mathog RH, Lancaster WD. HPV transcripts in malignant inverted papilloma are from integrated HPV DNA. Laryngoscope. 2005;115:1428–31.PubMedCrossRefGoogle Scholar
  34. 34.
    Katori H, Nozawat A, Tsukuda M. Relationship between p21 and p53 expression, HPV infection and malignant transformation in sinonasal-inverted papilloma. Clin Oncol (R Coll Radiol). 2006;18:300–5.Google Scholar
  35. 35.
    Hoffman M, Klose N, Gottschlich S, Görögh T, Fazel A, Lohery C, et al. Detection of HPV DNA in benign and malignant sinonasal neoplasms. Cancer Lett. 2006;239:64–70.CrossRefGoogle Scholar
  36. 36.
    Breslow NE, Day NE. Statistical methods in cancer research. Vol I: the analysis of case-control data. Lyon: IARC; 1980.Google Scholar
  37. 37.
    Rothman JR Greenland S. Modern epidemiology. (2nd ed). Philadelphia: Lippincott-Raven; 1998.Google Scholar
  38. 38.
    Furuta Y, Takasu Y, Asai T, Shinohara T, Sawa H, Nagashima K, Inuyama Y. Detection of HPV DNA in carcinomas of the nasal cavities and paranasal sinuses by PCR. Cancer. 1992;69:353–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Judd R, Zaki S, Coffield LM, Evatt BL. HPV type 6 detected by the PCR in invasive sinonasal papillary squamous cell carcinoma. Arch Pathol Lab Med. 1991;115:1150–3.PubMedGoogle Scholar
  40. 40.
    Tyan YS, Liu ST, Ong WR, Chen ML, Shu CH, Chang YS. Detection of EBV and HPV in head and neck tumors. J Clin Microbiol. 1993;31:53–6.PubMedGoogle Scholar
  41. 41.
    Buchwald C, Lindeberg H, Pedersen BL, Franzmann MB. Human papilloma virus and p53 expression in carcinomas associated with sinonasal papillomas: a Danish epidemiological study 1980–1998. Laryngoscope. 2001;111:1104–10.PubMedCrossRefGoogle Scholar
  42. 42.
    El-Mofty S, Lu DW. Prevalence of high-risk HPV DNA in nonkeratinizing (cylindrical cell) carcinoma of the sinonasal tract. Am J Surg Pathol. 2005;29:1367–72.PubMedCrossRefGoogle Scholar
  43. 43.
    Mineta H, Ogino T, Amano HM, Ohkawa Y, Araki K, Takebayashi S, Miura K. Human papilloma virus (HPV) type 16 and 18 detected in head and neck squamous cell carcinoma. Anticancer Res. 1998;18:4765–8.PubMedGoogle Scholar
  44. 44.
    Beck JC, McClatchey KD, Lesperance MM, Esclamado RM, Carey TE, Bradford CR. Presence of HPV predicts recurrence of inverted papilloma. Otolaryngol Head Neck Surg. 1995;113:49–55.PubMedCrossRefGoogle Scholar
  45. 45.
    Tate JE, Yang YC, Shen J, McLachlin CM, Sheets EE, Crum CP. A comparison of early (E7) and late (L1) primer-mediated amplification of papillomaviral DNA in cervical neoplasia. Mol Cell Probes. 1996;10:347–51.PubMedCrossRefGoogle Scholar
  46. 46.
    Smith EM, Swarnavel S, Ritchie JM, Wang D, Haugen TH, Turek LP. Prevalence of human papillomavirus in the oral cavity/oropharynx in a large population of children and adolescents. Pediatr Infect Dis J. 2007;26:836–40.PubMedCrossRefGoogle Scholar
  47. 47.
    Medeiros LR, Ethur AB, Hilgert JB, Zanini RR, Berwanger O, Bozzetti MC, Mylius LC. Vertical transmission of the HPV a systematic quantitative review. Cad Saude Publica. 2005;21:1006–15.PubMedCrossRefGoogle Scholar
  48. 48.
    Sedlacek TV, Lindheim S, Eder C, Hasty L, Woodland M, Ludomirsky A, Rando RF. Mechanism for HPV transmission at birth. Am J Obstet Gynecol. 1989;161:55–9.PubMedGoogle Scholar
  49. 49.
    Buchwald C, Franzmann MB, Jacobsen GK, Lindeberg H. HPV and normal nasal mucosa: detection of HPV DNA in normal nasal mucosa biopsies by PCR and in situ hybridization. Laryngoscope. 1994;104:755–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Fukushima K, Ogura H, Watanabe S, Yabe Y, Masuda Y. HPV type 16 DNA detected by the PCR in non-cancer tissues of the head and neck. Eur Arch Otorhinolaryngol. 1994;251:109–12.PubMedCrossRefGoogle Scholar
  51. 51.
    Eike A, Buchwald C, Rolighed J, Lindeberg H. HPV is rarely present in normal oral and nasal mucosa. Clin Otolaryngol Allied Sci. 1995;20:171–3.PubMedCrossRefGoogle Scholar
  52. 52.
    Califano J, Koch W, Sidransky D, Westra WH. Inverted sinonasal papilloma: a molecular genetic appraisal of its putative status as a precursor to squamous cell carcinoma. Am J Pathol. 2000;156:333–7.PubMedGoogle Scholar
  53. 53.
    Iwasaka T, Hayashi Y, Yokoyama M, Hara K, Matsuo N, Sugimori H. “Hit and run” oncogenesis by HPV 18 DNA. Acta Obstet Gynecol Scand. 1992;71:219–23.PubMedCrossRefGoogle Scholar
  54. 54.
    Koskinen WJ, Chen RW, Leivo I, Mäkitie A, Bäck L, Kontio R et al. Prevalence and physical status of HPV in squamous cell carcinomas of the head and neck. Int J Canc. 2003;107:401–6.CrossRefGoogle Scholar
  55. 55.
    Kim SH, Koo BS, Kang S, Park K, Kim H, Lee KR, et al. HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation. Int J Cancer. 2007;120:1418–25.PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2008

Authors and Affiliations

  • William Lawson
    • 1
  • Nicolas F. Schlecht
    • 2
  • Margaret Brandwein-Gensler
    • 3
  1. 1.Department of OtolaryngologyMount Sinai School of MedicineNew YorkUSA
  2. 2.Departments of Epidemiology & Population Health and MedicineMontefiore Medical Center, Albert Einstein College of MedicineBronxUSA
  3. 3.Departments of Pathology and OtolaryngologyMontefiore Medical Center, Albert Einstein College of MedicineBronxUSA

Personalised recommendations