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Evaluation of high-risk human papillomavirus in sinonasal papillomas and squamous cell carcinomas

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Abstract

The sinonasal tract is considered a second hotspot for human papillomavirus (HPV)-related tumors in the head and neck, with HPV being identified in up to 62% of squamous cell carcinomas (SCCs) and 38% of papillomas. There is limited data from geographical regions with low prevalence of high-risk (HR)-HPV on the association of HR-HPV in sinonasal neoplasms and on utility of p16 as a surrogate marker. p16 immunohistochemistry, HR-HPV mRNA ISH and quantitative real-time PCR (qPCR) were performed on a retrospective cohort of sinonasal papillomas and SCCs. KRAS mutation analysis was done in oncocytic papillomas. p16 positivity was present in 22/142 cases (15.5%) including eight inverted papillomas, one oncocytic papilloma (OP), and 13 SCC. Among these, mRNA ISH showed HR-HPV in the OP and two SCC, while another SCC was found to harbour HPV18 by qPCR. Two HPV-associated SCCs had foci of OP. mRNA ISH was negative in all p16 negative cases. p16 immunohistochemistry showed 68% concordance with mRNA ISH, and had sensitivity and negative predictive value of 100%; specificity was 67%, and positive predictive value was 14.3%. Association with HR-HPV in sinonasal papillomas and SCC is rare, and may be seen in cases demonstrating oncocytic morphology. p16 immunohistochemistry has low specificity and positive predictive value in low-prevalence populations; thus, reflex direct HR-HPV testing should be performed in p16 immunopositive cases. This two-step approach is viable in resource-limited settings, as the proportion of p16 positive cases is small.

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References

  1. 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

    PubMed  PubMed Central  Google Scholar 

  2. Lewis JS Jr, Westra WH, Thompson LD et al (2014) The sinonasal tract: another potential "hot spot" for carcinomas with transcriptionally-active human papillomavirus. Head Neck Pathol 8:241–249

    PubMed  Google Scholar 

  3. Elgart K, Faden DL (2020) Sinonasal Squamous Cell Carcinoma: Etiology, Pathogenesis, and the Role of Human Papilloma Virus. Curr Otorhinolaryngol Rep 8:111–119

    PubMed  PubMed Central  Google Scholar 

  4. Allen CT, Lewis JS Jr, El-Mofty SK, Haughey BH, Nussenbaum B (2010) Human papillomavirus and oropharynx cancer: biology, detection and clinical implications. Laryngoscope 120:1756–1772

    PubMed  Google Scholar 

  5. Adelstein DJ, Ridge JA, Gillison ML et al (2008) Head and neck squamous cell cancer and the human papilloma- virus: summary of a National Cancer Institute State of the Science Meeting, November 9-10, 2008, Washington D.C. Head Neck 31:1393–1422

    Google Scholar 

  6. 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

    PubMed  Google Scholar 

  7. Bishop JA, Guo TW, Smith DF et al (2013) Human papillomavirus-related carcinomas of the sinonasal tract. Am J Surg Pathol 37:185–192

    PubMed  PubMed Central  Google Scholar 

  8. Larque AB, Hakim S, Ordi J et al (2014) High-risk human papillomavirus is transcriptionally active in a subset of sinonasal squamous cell carcinomas. Mod Pathol 27:343–351

    CAS  PubMed  Google Scholar 

  9. Rooper LM, Bishop JA, Westra WH (2017) Transcriptionally Active High-Risk Human Papillomavirus is Not a Common Etiologic Agent in the Malignant Transformation of Inverted Schneiderian Papillomas. Head Neck Pathol 11:346–353

    PubMed  PubMed Central  Google Scholar 

  10. Chowdhury N, Alvi S, Kimura K et al (2017) Outcomes of HPV-related nasal squamous cell carcinoma. Laryngoscope 127:1600–1603

    CAS  PubMed  Google Scholar 

  11. Jiromaru R, Yamamoto H, Yasumatsu R et al (2020) HPV-related Sinonasal Carcinoma: Clinicopathologic Features, Diagnostic Utility of p16 and Rb Immunohistochemistry, and EGFR Copy Number Alteration. Am J Surg Pathol 44:305–315

    PubMed  Google Scholar 

  12. Syrjänen KJ (2003) HPV infections in benign and malignant sinonasal lesions. J Clin Pathol 56:174–181. https://doi.org/10.1136/jcp.56.3.174

    Article  PubMed  PubMed Central  Google Scholar 

  13. Syrjanen S, Happonen RP, Virolainen E et al (1987) Detection of human papillomavirus (HPV) structural antigens and DNA types in inverted papillomas and squamous cell carcinomas of the nasal cavities and paranasal sinuses. Acta Otolaryngol 104:334–341

    CAS  PubMed  Google Scholar 

  14. Lewis JS Jr, Beadle B, Bishop JA et al (2018) Human papillomavirus testing in head and neck carcinomas: guideline from the College of American Pathologists. Arch Pathol Lab Med 142:559–597

    PubMed  Google Scholar 

  15. Bahl A, Kumar P, Dar L et al (2014) Prevalence and trends of human papillomavirus in oropharyngeal cancer in a predominantly north Indian population. Head Neck 36:505–510

    PubMed  Google Scholar 

  16. Lewis JS Jr (2016) Sinonasal Squamous Cell Carcinoma: A Review with Emphasis on Emerging Histologic Subtypes and the Role of Human Papillomavirus. Head Neck Pathol 10:60–67

    PubMed  PubMed Central  Google Scholar 

  17. Antony VM, Kakkar A, Sikka K et al (2020) p16 Immunoexpression in sinonasal and nasopharyngeal adenoid cystic carcinomas: a potential pitfall in ruling out HPV-related multiphenotypic sinonasal carcinoma. Histopathol 77:989–993

    Google Scholar 

  18. Kim KY, Lewis JS Jr, Chen Z (2018) Current status of clinical testing for human papillomavirus in oropharyngeal squamous cell carcinoma. J Pathol Clin Res 4:213–226

    PubMed  PubMed Central  Google Scholar 

  19. Avasthi A, Kaur R, Prakash O, Banerjee A, Kumar L, Kulhara P (2008) Sexual behavior of married young women: a preliminary study from north India. Indian J Community Med 33:163–167. https://doi.org/10.4103/0970-0218.39677

    Article  PubMed  PubMed Central  Google Scholar 

  20. Alos L, Moyano S, Nadal A et al (2009) Human papillomaviruses are identified in a subgroup of sinonasal squamous cell carcinomas with favorable outcome. Cancer 115:2701–2709. https://doi.org/10.1002/cncr.24309

    Article  PubMed  Google Scholar 

  21. Kilic S, Kilic SS, Kim ES et al (2017) Significance of human papillomavirus positivity in sinonasal squamous cell carcinoma. Int Forum Allergy Rhinol 7:980–989. https://doi.org/10.1002/alr.21996

    Article  PubMed  Google Scholar 

  22. Oliver JR, Lieberman SM, Tam MM et al (2020) Human papillomavirus and survival of patients with sinonasal squamous cell carcinoma. Cancer 126:1413–1423. https://doi.org/10.1002/cncr.32679

    Article  PubMed  Google Scholar 

  23. Markovic ES, Marqueen KE, Sindhu KK et al (2020) The prognostic significance of human papilloma virus in sinonasal squamous cell carcinoma. Laryngoscope Investig Otolaryngol 5:1070–1078

    Google Scholar 

  24. Thavaraj S (2016) Human papillomavirus-associated neoplasms of the sinonasal tract and nasopharynx. Semin Diagn Pathol 33:104–111

    PubMed  Google Scholar 

  25. Lewis JS Jr (2020) Human Papillomavirus Testing in Head and Neck Squamous Cell Carcinoma in 2020: Where Are We Now and Where Are We Going? Head Neck Pathol 14:321–329

    PubMed  PubMed Central  Google Scholar 

  26. Kapadia SB, Barnes L, Pelzman K, Mirani N, Heffner DK, Bedetti C (1993) Carcinoma ex oncocytic Schneiderian (cylindrical cell) papilloma. Am J Otolaryngol 14:332–338

    CAS  PubMed  Google Scholar 

  27. Kaufman MR, Brandwein MS, Lawson W (2002) Sinonasal papillomas: clinicopathologic review of 40 patients with inverted and oncocytic schneiderian papillomas. Laryngoscope 112:1372–1377

    PubMed  Google Scholar 

  28. Stoddard DG Jr, Keeney MG, Gao G, Smith DI, García JJ, O'Brien EK (2015) Transcriptional activity of HPV in inverted papilloma demonstrated by in situ hybridization for E6/E7 mRNA. Otolaryngol Head Neck Surg 152:752–758

    PubMed  Google Scholar 

  29. Syrjänen K, Syrjänen S (2013) Detection of human papillomavirus in sinonasal carcinoma: Systematic review and meta-analysis. Hum Pathol 44:983–991

    PubMed  Google Scholar 

  30. Laco J, Sieglová K, Vošmiková H et al (2015) 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

    CAS  PubMed  Google Scholar 

  31. Udager AM, McHugh JB, Goudsmit CM et al (2018) Human papillomavirus (HPV) and somatic EGFR mutations are essential, mutually exclusive oncogenic mechanisms for inverted sinonasal papillomas and associated sinonasal squamous cell carcinomas. Ann Oncol 29:466–471

    CAS  PubMed  Google Scholar 

  32. Sahnane N, Ottini G, Turri-Zanoni M et al (2019) Comprehensive analysis of HPV infection, EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal-inverted papilloma to squamous cell carcinoma. Int J Cancer 144:1313–1320

    CAS  PubMed  Google Scholar 

  33. Brown NA, Plouffe KR, Yilmaz O, Weindorf SC, Betz BL, Carey TE et al (2021) TP53 mutations and CDKN2A mutations/deletions are highly recurrent molecular alterations in the malignant progression of sinonasal papillomas. Mod Pathol 34:1133–1142

    CAS  PubMed  Google Scholar 

  34. Gheit T, Vaccarella S, Schmitt M et al (2009) Prevalence of human papillomavirus types in cervical and oral cancers in central India. Vaccine 27:636–639. https://doi.org/10.1016/j.vaccine.2008.11.041

    Article  CAS  PubMed  Google Scholar 

  35. Shah A, Malik A, Garg A, Mair M, Nair S, Chaturvedi P (2017) Oral sex and human papilloma virus-related head and neck squamous cell cancer: a review of the literature. Postgrad Med J 93:704–709

    PubMed  Google Scholar 

  36. Hongo T, Yamamoto H, Tanabe M et al (2022) High-risk HPV-related Squamous Cell Carcinoma in the Conjunctiva and Lacrimal sac: Clinicopathologic Characteristics and Diagnostic Utility of p16 and Rb Immunohistochemistry. Am J Surg Pathol 46:977–987

    PubMed  Google Scholar 

  37. Vor der Holte AP, Fangk I, Glombitza S, Wilkens L, Welkoborsky HJ (2020) Identification of Rare and Common HPV Genotypes in Sinonasal Papillomas. Head Neck Pathol 14:936–943

    PubMed  PubMed Central  Google Scholar 

  38. Vor der Holte AP, Fangk I, Glombitza S, Wilkens L, Welkoborsky HJ (2020) Prognostic factors and risk factors for development and recurrence of sinonasal papillomas: potential role of different HPV subtypes. Eur Arch Otorhinolaryngol 277:767–775

    Google Scholar 

  39. Udager AM, McHugh JB, Betz BL et al (2016) Activating KRAS mutations are characteristic of oncocytic sinonasal papilloma and associated sinonasal squamous cell carcinoma. J Pathol 239:394–398

    CAS  PubMed  Google Scholar 

  40. Wang H, Zhai C, Liu J et al (2020) Low prevalence of human papillomavirus infection in sinonasal inverted papilloma and oncocytic papilloma. Virchows Arch 476:577–583

    CAS  PubMed  Google Scholar 

  41. Hyams VJ (1971) Papillomas of the nasal cavity and paranasal sinuses. A clinicopathological study of 315 cases. Ann Otol Rhinol Laryngol 80:192–206

    CAS  PubMed  Google Scholar 

  42. Barnes L, Bedetti C (1984) Oncocytic Schneiderian papilloma: a reappraisal of cylindrical cell papilloma of the sinonasal tract. Hum Pathol 15:344–351

    CAS  PubMed  Google Scholar 

  43. Ward BE, Fechner RE, Mills SE (1990) Carcinoma arising in oncocytic Schneiderian papilloma. Am J Surg Pathol 14:364–369

    CAS  PubMed  Google Scholar 

  44. Yang YJ, Abraham JL (1997) Undifferentiated carcinoma arising in oncocytic Schneiderian (cylindrical cell) papilloma. J Oral Maxillofac Surg 55:289–294

    CAS  PubMed  Google Scholar 

  45. Maitra A, Baskin LB, Lee EL (2001) Malignancies arising in oncocytic schneiderian papillomas: a report of 2 cases and review of the literature. Arch Pathol Lab Med 125:1365–1367

    CAS  PubMed  Google Scholar 

  46. Karligkiotis A, Bignami M, Terranova P et al (2014) Oncocytic Schneiderian papillomas: Clinical behavior and outcomes of the endoscopic endonasal approach in 33 cases. Head Neck 36:624–630

    PubMed  Google Scholar 

  47. Zhang L, Hu C, Zheng X et al (2018) Oncocytic Schneiderian papilloma-associated adenocarcinoma and KRAS mutation: A case report. Med 97:e11025

    Google Scholar 

  48. Nudell J, Chiosea S, Thompson LD (2014) Carcinoma ex-Schneiderian papilloma (malignant transformation): a clinicopathologic and immunophenotypic study of 20 cases combined with a comprehensive review of the literature. Head Neck Pathol 8:269–286

    PubMed  PubMed Central  Google Scholar 

  49. Bishop JA, Lewis JS Jr, Rocco JW, Faquin WC (2015) HPV-related squamous cell carcinoma of the head and neck: An update on testing in routine pathology practice. Semin Diagn Pathol 32:344–351

    PubMed  Google Scholar 

  50. Doxtader EE, Katzenstein AL (2012) The relationship between p16 expression and high-risk human papillomavirus infection in squamous cell carcinomas from sites other than uterine cervix: a study of 137 cases. Hum Pathol 43:327–332

    CAS  PubMed  Google Scholar 

  51. Shinn JR, Davis SJ, Lang-Kuhs KA et al (2021) Oropharyngeal Squamous Cell Carcinoma With Discordant p16 and HPV mRNA Results: Incidence and Characterization in a Large, Contemporary United States Cohort. Am J Surg Pathol 45:951–961

    PubMed  PubMed Central  Google Scholar 

  52. Nauta IH, Rietbergen MM, van Bokhoven AAJD et al (2018) Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing. Ann Oncol 29:1273–1279

    CAS  PubMed  Google Scholar 

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Funding

This study received funds from Collaborative intramural grant (AC-005), Research Section, All India Institute of Medical Sciences, New Delhi.

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Authors and Affiliations

  1. Department of Pathology, All India Institute of Medical Sciences, 110029, New Delhi, India

    Aanchal Kakkar, Shraddhanjali Satapathy & Deepali Jain

  2. Department of Otorhinolaryngology and Head-Neck Surgery, All India Institute of Medical Sciences, 110029, New Delhi, India

    Kapil Sikka

  3. Department of Laboratory Oncology, All India Institute of Medical Sciences, 110029, New Delhi, India

    Pranay Tanwar

  4. Department of Surgical Oncology, All India Institute of Medical Sciences, 110029, New Delhi, India

    SVS Deo

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  1. Aanchal Kakkar
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  2. Shraddhanjali Satapathy
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  3. Kapil Sikka
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  4. Pranay Tanwar
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  5. SVS Deo
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  6. Deepali Jain
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Contributions

AK: Data acquisition, analysis and interpretation of results, drafting the manuscript; SS, KS, PT, SVS: Data acquisition and analysis; DJ: Conception and design, data acquisition and analysis, final interpretation of results, overall supervision, and critical revision of the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Deepali Jain.

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Ethics approval was obtained from the Institute Ethics committee for conducting this study (IEC-608/03.11.2017)

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Kakkar, A., Satapathy, S., Sikka, K. et al. Evaluation of high-risk human papillomavirus in sinonasal papillomas and squamous cell carcinomas. Virchows Arch 483, 381–392 (2023). https://doi.org/10.1007/s00428-023-03601-x

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