Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

The presence of high-risk human papillomavirus (HPV) E6/E7 mRNA transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis

Abstract

The aim of the study was to investigate prevalence of high-risk human papillomavirus (HR-HPV) infection in sinonasal carcinomas by immunohistochemistry, in situ hybridization, and polymerase chain reaction, detecting p16INK4a protein (p16) expression and presence of both HPV DNA and HPV E6/E7 messenger RNA (mRNA). The study comprised 47 males and 26 females, aged 23–83 years (median 62 years), mostly (67 %) with a squamous cell carcinoma (SCC). Of the tumors, 53 % arose in the nasal cavity, 42 % in the maxillary sinus, and 5 % in the ethmoid complex. The follow-up period ranged 1–241 months (median 19 months). HPV16, HPV18, or HPV35 were detected in 18/73 (25 %) tumors, 17 SCCs, and 1 small cell neuroendocrine carcinoma. There was a strong correlation between results of HPV detection methods and p16 expression (p < 0.005). HPV-positive SCCs occurred more frequently in smokers (p = 0.04) and were more frequently p16-positive (p < 0.0001) and nonkeratinizing (p = 0.02), the latter occurring more commonly in nasal cavity (p = 0.025). Median survival for HPV-positive SCC patients was 30 months, while for HPV-negative SCC patients was 14 months (p = 0.23). In summary, we confirm that HR-HPV is actively involved in the etiopathogenesis of a significant subset of sinonasal SCCs. p16 may be used as a reliable surrogate marker for determination of HPV status also in sinonasal SCCs. Although we observed a trend toward better overall survival in HPV-positive SCCs, the prognostic impact of HPV status in sinonasal carcinomas needs to be elucidated by further studies.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Zvolsky M (2014) Incidence of malignant neoplasms in the Czech Republic in 2011. http://www.uzis.cz/rychle-informace/zhoubne-nadory-roce-2011. Accessed 1 March 2015

  2. 2.

    Syrjänen K, Syrjänen S (2013) Detection of human papillomavirus in sinonasal carcinoma: systematic review and meta-analysis. Hum Pathol 44:983–991. doi:10.1016/j.humpath.2012.08.017

  3. 3.

    Turner JH, Reh DD (2012) Incidence and survival in patients with sinonasal cancer: a historical analysis of population-based data. Head Neck 34:877–885. doi:10.1002/hed.21830

  4. 4.

    Barnes L, Eveson JW, Reichart P, Sidransky S, World Health Organization (2005) Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. IARC Press, Lyon, pp 9–80

  5. 5.

    ’t Mannetje A, Kogevinas M, Luce D, Demers PA, Bégin D, Bolm-Audorff U et al (1999) Sinonasal cancer, occupation, and tobacco smoking in European women and men. Am J Ind Med 36:101-107

  6. 6.

    de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B et al (2010) Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 11:1048–1056. doi:10.1016/S1470-2045(10)70230-8

  7. 7.

    de Sanjosé S, Alemany L, Ordi J, Tous S, Alejo M, Bigby SM et al (2013) Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer 49:3450–3461. doi:10.1016/j.ejca.2013.06.033

  8. 8.

    Alemany L, de Sanjosé S, Tous S, Quint W, Vallejos C, Shin HR et al (2014) Time trends of human papillomavirus types in invasive cervical cancer, from 1940 to 2007. Int J Cancer 135:88–95. doi:10.1002/ijc.28636

  9. 9.

    Alemany L, Saunier M, Tinoco L, Quirós B, Alvarado-Cabrero I, Alejo M et al (2014) Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples. Eur J Cancer 50:2846–2854. doi:10.1016/j.ejca.2014.07.018

  10. 10.

    Alemany L, Saunier M, Alvarado-Cabrero I, Quirós B, Salmeron J, Shin HR et al (2015) Human papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. Int J Cancer 136:98–107. doi:10.1002/ijc.28963

  11. 11.

    Nováková V, Laco J (2008) Role of human papillomavirus in carcinogenesis of head and neck cancer. Klin Onkol 21:141–148

  12. 12.

    Laco J, Vosmikova H, Novakova V, Celakovsky P, Dolezalova H, Tucek L et al (2011) The role of high risk human papillomavirus infection in oral and oropharyngeal squamous cell carcinoma in non-smoking and non-drinking patients: a clinicopathological and molecular study of 46 cases. Virchows Arch 458:179–187. doi:10.1007/s00428-010-1037-y

  13. 13.

    Laco J, Nekvindova J, Novakova V, Celakovsky P, Dolezalova H, Tucek L et al (2012) Biologic importance and prognostic significance of selected clinicopathological parameters in patients with oral and oropharyngeal squamous cell carcinoma, with emphasis on smoking, protein p16INK4a expression, and HPV status. Neoplasma 59:398–408. doi:10.4149/neo_2012_052

  14. 14.

    Buchwald C, Lindeberg H, Pedersen BL, Franzmann MB (2001) Human papilloma virus and p53 expression in carcinomas associated with sinonasal papillomas: a Danish Epidemiological study 1980-1998. Laryngoscope 111:1104–1110

  15. 15.

    Syrjänen KJ (2003) HPV infections in benign and malignant sinonasal lesions. J Clin Pathol 56:174–181

  16. 16.

    El-Mofty SK, Lu DW (2005) Prevalence of high-risk human papillomavirus DNA in nonkeratinizing (cylindrical cell) carcinoma of the sinonasal tract: a distinct clinicopathologic and molecular disease entity. Am J Surg Pathol 29:1367–1372

  17. 17.

    McKay SP, Grégoire L, Lonardo F, Reidy P, Mathog RH, Lancaster WD (2005) Human papillomavirus (HPV) transcripts in malignant inverted papilloma are from integrated HPV DNA. Laryngoscope 115:1428–1431

  18. 18.

    Alos L, Moyano S, Nadal A, Alobid I, Blanch JL, Ayala E et al (2009) Human papillomaviruses are identified in a subgroup of sinonasal squamous cell carcinomas with favourable outcome. Cancer 115:2701–2709. doi:10.1002/cncr.24309

  19. 19.

    Jo VY, Mills SE, Stoler MH, Stelow EB (2009) Papillary squamous cell carcinoma of the head and neck: frequent association with human papillomavirus infection and invasive carcinoma. Am J Surg Pathol 33:1720–1724. doi:10.1097/PAS.0b013e3181b6d8e6

  20. 20.

    Cheung FM, Lau TW, Cheung LK, Li AS, Chow SK, Lo AW (2010) Schneiderian papillomas and carcinomas: a retrospective study with special reference to p53 and p16 tumor suppressor gene expression and association with HPV. Ear Nose Throat J 89:E5–E12

  21. 21.

    Bishop JA, Guo TW, Smith DF, Wang H, Ogawa T, Pai SI et al (2013) Human papillomavirus-related carcinomas of the sinonasal tract. Am J Surg Pathol 37:185–192. doi:10.1097/PAS.0b013e3182698673

  22. 22.

    Larque AB, Hakim S, Ordi J, Nadal A, Diaz A, del Pino M et al (2014) High-risk human papillomavirus is transcriptionally active in a subset of sinonasal squamous cell carcinomas. Mod Pathol 27:343–351. doi:10.1038/modpathol.2013.155

  23. 23.

    Takahashi Y, Bell D, Agarwal G, Roberts D, Xie TX, El-Naggar A et al (2014) Comprehensive assessment of prognostic markers for sinonasal squamous cell carcinoma. Head Neck 36:1094–1102. doi:10.1002/hed.23423

  24. 24.

    Lewis JS Jr, Westra WH, Thompson LD, Barnes L, Cardesa A, Hunt JL et al (2014) The sinonasal tract: another potential “hot spot“ for carcinomas with transcriptionally-active human papillomavirus. Head Neck Pathol 8:241–249. doi:10.1007/s12105-013-0514-4

  25. 25.

    Sobin LH, Gospodarowicz MK, Wittekind C (eds). TNM Classification of Malignant Tumours, 7th ed. Wiley-Blackwell, 2009, pp. 47-50 (Czech ed. 2011)

  26. 26.

    Cordes B, Williams MD, Tirado Y, Bell D, Rosenthal DI, Al-Dhahri SF et al (2009) Molecular and phenotypic analysis of poorly differentiated sinonasal neoplasms: an integrated approach for early diagnosis and classification. Hum Pathol 40:283–292. doi:10.1016/j.humpath.2008.07.019

  27. 27.

    Franchi A, Palomba A, Cardesa A (2011) Current diagnostic strategies for undifferentiated tumours of the nasal cavities and paranasal sinuses. Histopathology 59:1034–1045. doi:10.1111/j.1365-2559.2011.03813.x

  28. 28.

    Chernock RD, El-Mofty SK, Thorstad WL, Parvin CA, Lewis JS Jr (2009) HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome. Head Neck Pathol 3:186–194. doi:10.1007/s12105-009-0126-1

  29. 29.

    Lewis JS Jr, Khan RA, Masand RP, Chernock RD, Zhang Q, Al-Naief NS et al (2012) Recognition of nonkeratinizing morphology in oropharyngeal squamous cell carcinoma – a prospective cohort and interobserver variability study. Histopathology 60:427–436. doi:10.1111/j.1365-2559.2011.04092.x

  30. 30.

    Lewis JS Jr, Chernock RD (2014) Human papillomavirus and Epstein-Barr virus in head and neck carcinomas: suggestions for the new WHO classification. Head Neck Pathol 8:50–58. doi:10.1007/s12105-014-0528-6

  31. 31.

    Singhi AD, Westra WH (2010) Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer 116:2166–2173. doi:10.1002/cncr.25033

  32. 32.

    Lewis JS Jr (2012) p16 immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol 6:S75–S82. doi:10.1007/s12105-012-0369-0

  33. 33.

    Lewis JS Jr, Chernock RD, Ma XJ, Flanagan JJ, Luo Y, Gao G et al (2012) Partial p16 staining in oropharyngeal squamous cell carcinoma: extent and pattern correlate with human papillomavirus RNA status. Mod Pathol 25:1212–1220. doi:10.1038/modpathol.2012.79

  34. 34.

    Dreyer JH, Hauck F, Oliveira-Silva M, Barros MH, Niedobitek G (2013) Detection of HPV infection in head and neck squamous cell carcinoma: a practical proposal. Virchows Arch 462:381–389. doi:10.1007/s00428-013-1393-5

  35. 35.

    Seethala RR, Weinreb I, Carlson DL, McHugh JB, Harrison LB, Richardson MS et al (2013) Protocol for the examination of specimens from patients with carcinomas of the pharynx. http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/pdf/pharynx-13protocol-3300.pdf .Accessed 1 March 2015

  36. 36.

    Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A et al (2012) RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin embedded tissues. J Mol Diagn 14:22–29. doi:10.1016/j.jmoldx.2011.08.002

  37. 37.

    Sato Y, Sugie R, Tsuchiya B, Kameya T, Natori M, Mukai K (2001) Comparison of the DNA extraction methods for polymerase chain reaction amplification from formalin-fixed and paraffin-embedded tissues. Diagn Mol Pathol 10:265–271

  38. 38.

    Gao G, Chernock RD, Gay HA, Thorstad WL, Zhang TR, Wang H et al (2013) A novel RT-PCR method for quantification of human papillomavirus transcripts in archived tissues and its application in oropharyngeal cancer prognosis. Int J Cancer 132:882–890

  39. 39.

    Lewis JS Jr, Thorstad WL, Chernock RD, Haughey BH, Yip JH, Zhang Q et al (2010) p16 positive oropharyngeal squamous cell carcinoma: an entity with a favourable prognosis regardless of tumor HPV status. Am J Surg Pathol 34:1088–1096. doi:10.1097/PAS.0b013e3181e84652

  40. 40.

    Ukpo OC, Flanagan JJ, Ma XJ, Luo Y, Thorstad WL, Lewis JS Jr (2011) High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma. Am J Surg Pathol 35:1343–1350. doi:10.1097/PAS.0b013e318220e59d

  41. 41.

    Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF et al (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24–35. doi:10.1056/NEJMoa0912217

  42. 42.

    Laco J, Slaninka I, Jirasek M, Celakovsky P, Vosmikova H, Ryska A (2008) High-risk human papillomavirus infection and p16INK4a protein expression in laryngeal lesions. Pathol Res Pract 204:545–552. doi:10.1016/j.prp.2008.03.001

  43. 43.

    Isayeva T, Li Y, Maswahu D, Brandwein-Gensler M (2012) Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol 6(Suppl 1):S104–S120. doi:10.1007/s12105-012-0368-1

  44. 44.

    Lewis JS Jr, Ukpo OC, Ma XJ, Flanagan JJ, Luo Y, Thorstad WL et al (2012) Transcriptionally-active high-risk human papillomavirus is rare in oral cavity and laryngeal/hypopharyngeal squamous cell carcinomas – a tissue microarray study utilizing E6/E7 mRNA in situ hybridization. Histopathology 60:982–991. doi:10.1111/j.1365-2559.2011.04169.x

  45. 45.

    Combes JD, Franceschi S (2014) Role of human papillomavirus in non-oropharyngeal head and neck cancers. Oral Oncol 50:370–379. doi:10.1016/j.oraloncology.2013.11.004

  46. 46.

    Barnes L (2002) Schneiderian papillomas and nonsalivary glandular neoplasms of the head and neck. Mod Pathol 15:279–297

  47. 47.

    Syrjänen K, Syrjänen S (2013) Detection of human papillomavirus in sinonasal papillomas: systematic review and meta-analysis. Laryngoscope 123:181–192. doi:10.1002/lary.23688

  48. 48.

    Lawson W, Schlecht NF, Brandwein-Gensler M (2008) The role of the human papillomavirus in the pathogenesis of Schneiderian inverted papillomas: an analytic overview of the evidence. Head Neck Pathol 2:49–59. doi:10.1007/s12105-008-0048-3

  49. 49.

    Jenko K, Kocjan B, Zidar N, Poljak M, Strojan P, Žargi M et al (2011) In inverted papillomas HPV more likely represents incidental colonization than an etiological factor. Virchows Arch 459:529–538. doi:10.1007/s00428-011-1139-1

  50. 50.

    Shah AA, Evans MF, Adamson CS, Peng Z, Rajendran V, Cooper K (2010) HPV DNA is associated with a subset of Schneiderian papillomas but does not correlate with p16INK4a immunoreactivity. Head Neck Pathol 4:106–112. doi:10.1007/s12105-010-0176-4

  51. 51.

    Skalova A, Kaspirkova J, Andrle P, Hosticka L, Vanecek T (2013) Human papillomaviruses are not involved in the etiopathogenesis of salivary gland tumors. Cesk Patol 49:72–75

  52. 52.

    Bishop JA, Ogawa T, Stelow EB, Moskaluk CA, Koch WM, Pai SI et al (2013) Human papillomavirus-related carcinoma with adenoid cystic-like features: a peculiar variant of head and neck cancer restricted to the sinonasal tract. Am J Surg Pathol 37:836–844. doi:10.1097/PAS.0b013e31827b1cd6

Download references

Acknowledgments

The authors are very grateful to Professor Ivo Šteiner, MD, PhD, and to Folakemi A. Sobande, MD, PhD, for English language correction.

The experiments carried out in this study comply with the current laws of the Czech Republic.

This study is based on the experiments conducted by one of the co-authors, Kateřina Sieglová, during her undergraduate studies for Master degree at the Charles University in Prague, Faculty of Pharmacy in Hradec Kralove. The study was supported by the programs PRVOUK P37/11 and PRVOUK P27/LF1/1 and by the project BBMRI LM2010004. The funding sources had no involvement on the study design, collection, analysis, and interpretation of data, on the writing of the report, and on the decision to submit the article for publication.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Correspondence to Jan Laco.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 17 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Laco, J., Sieglová, K., Vošmiková, H. et al. The presence of high-risk human papillomavirus (HPV) E6/E7 mRNA transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis. Virchows Arch 467, 405–415 (2015). https://doi.org/10.1007/s00428-015-1812-x

Download citation

Keywords

  • Sinonasal carcinoma
  • Squamous cell carcinoma
  • Nonkeratinizing
  • Human papillomavirus (HPV)
  • p16 protein
  • RNA