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A Case of HPV-Associated Oropharyngeal Squamous Cell Carcinoma with Block-Like, Partial Loss of p16 Expression

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Abstract

Background

Oropharyngeal squamous cell carcinoma is frequently associated with high-risk HPV infection, which confers a good prognosis. Immunohistochemistry for p16 is used as a surrogate for HPV status, but discrepant results are occasionally seen. Here, we report a case with a unique pattern of partial loss of p16.

Methods

A 63 year old male presented with a base of tongue nonkeratinizing squamous cell carcinoma and a large metastatic neck mass. The primary lesion and multiple regions of the metastatic mass were assessed with p16 immunohistochemistry, RNA in situ hybridization for high-risk HPV, and HPV16 genome sequencing.

Results

The primary lesion was p16 negative, and the metastatic neck mass had large, confluent regions that were either strongly p16 positive or entirely p16 negative. All of these regions were positive for high-risk HPV with identical HPV16 genomes.

Conclusion

This unusual case illustrates a potential diagnostic pitfall, and it raises important questions regarding molecular mechanisms and prognostic implications of p16 staining in oropharyngeal squamous cell carcinoma.

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Data Availability

Not applicable.

Code Availability

https://github.com/NCI-CGR/cgrHPV16.

References

  1. Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of human papillomavirus–positive head and neck squamous cell carcinoma. J Clin Oncol. 2015;33(29):3235–43.

    Article  CAS  Google Scholar 

  2. Näsman A, Du J, Dalianis T. A global epidemic increase of an HPV-induced tonsil and tongue base cancer–potential benefit from a pan-gender use of HPV vaccine. J Intern Med. 2020;287(2):134–52.

    Article  Google Scholar 

  3. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.

    Article  CAS  Google Scholar 

  4. Lewis JS Jr, Beadle B, Bishop JA, Chernock RD, Colasacco C, Lacchetti C, Moncur JT, Rocco JW, Schwartz MR, Seethala RR, Thomas NE. Human papillomavirus testing in head and neck carcinomas: guideline from the College of American Pathologists. Arch Pathol Lab Med. 2018;142(5):559–97.

    Article  Google Scholar 

  5. Lewis JS Jr, Thorstad WL, Chernock RD, Haughey BH, Yip JH, Zhang Q, El-Mofty SK. p16 positive oropharyngeal squamous cell carcinoma: an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol. 2010;34(8):1088–96.

    Article  Google Scholar 

  6. Larsen CG, Gyldenløve M, Jensen DH, Therkildsen MH, Kiss K, Norrild B, Konge L, Von Buchwald C. Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: a systematic review. Br J Cancer. 2014;110(6):1587–94.

    Article  Google Scholar 

  7. Shinn JR, Davis SJ, Lang-Kuhs KA, Rohde S, Wang X, Liu P, Dupont WD, Plummer D Jr, Thorstad WL, Chernock RD, Mehrad M. 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. 2021;45(7):951–61.

    Google Scholar 

  8. Nauta IH, Rietbergen MM, Van Bokhoven AA, Bloemena E, Lissenberg-Witte BI, Heideman DA, de Jong RB, Brakenhoff RH, Leemans CR. 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. 2018;29(5):1273–9.

    Article  CAS  Google Scholar 

  9. Wagner S, Prigge ES, Wuerdemann N, Reder H, Bushnak A, Sharma SJ, Obermueller T, von Knebel DM, Dreyer T, Gattenlöhner S, Wolf G. Evaluation of p16INK4a expression as a single marker to select patients with HPV-driven oropharyngeal cancers for treatment de-escalation. Br J Cancer. 2020;123(7):1114–22.

    Article  CAS  Google Scholar 

  10. Lewis JS, Chernock RD, Ma XJ, Flanagan JJ, Luo Y, Gao G, Wang X, El-Mofty SK. Partial p16 staining in oropharyngeal squamous cell carcinoma: Extent and pattern correlate with human papillomavirus RNA status. Mod Pathol. 2012;25(9):1212–20.

    Article  CAS  Google Scholar 

  11. Schlecht NF, Brandwein-Gensler M, Nuovo GJ, Li M, Dunne A, Kawachi N, Smith RV, Burk RD, Prystowsky MB. A comparison of clinically utilized human papillomavirus detection methods in head and neck cancer. Mod Pathol. 2011;24(10):1295–305.

    Article  CAS  Google Scholar 

  12. Cullen M, Boland JF, Schiffman M, Zhang X, Wentzensen N, Yang Q, Chen Z, Yu K, Mitchell J, Roberson D, Bass S. Deep sequencing of HPV16 genomes: A new high-throughput tool for exploring the carcinogenicity and natural history of HPV16 infection. Papillomavirus Res. 2015;1:3–11.

    Article  Google Scholar 

  13. Mirabello L, Yeager M, Yu K, Clifford GM, Xiao Y, Zhu B, Cullen M, Boland JF, Wentzensen N, Nelson CW, Raine-Bennett T. HPV16 E7 genetic conservation is critical to carcinogenesis. Cell. 2017;170:1164–74.

    Article  CAS  Google Scholar 

  14. Zhu B, Xiao Y, Yeager M, Clifford G, Wentzensen N, Cullen M, Boland JF, Bass S, Steinberg MK, Raine-Bennett T, Lee D. Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance. Nat Commun. 2020;11:886.

    Article  CAS  Google Scholar 

  15. Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, Wang L, Land SJ, Lu X, Ruden DM. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly. 2012;6:80–92.

    Article  CAS  Google Scholar 

  16. Robinson JT, Thorvaldsdottir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.

    Article  CAS  Google Scholar 

  17. Hayes DN, Van Waes C, Seiwert TY. Genetic landscape of human papillomavirus–associated head and neck cancer and comparison to tobacco-related tumors. J Clin Oncol. 2015;33(29):3227–34.

    Article  CAS  Google Scholar 

  18. Larque AB, Conde L, Hakim S, Alos L, Jares P, Vilaseca I, Cardesa A, Nadal A. p16 (INK4a) overexpression is associated with CDKN2A mutation and worse prognosis in HPV-negative laryngeal squamous cell carcinomas. Virchows Arch. 2015;466(4):375–82.

    Article  CAS  Google Scholar 

  19. Berdugo J, Rooper LM, Chiosea SI. RB1, p16, and human papillomavirus in oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2021;15:1109–18.

    Article  Google Scholar 

  20. Ai L, Stephenson KK, Ling W, Zuo C, Mukunyadzi P, Suen JY, Hanna E, Fan CY. The p16 (CDKN2a/INK4a) tumor-suppressor gene in head and neck squamous cell carcinoma: a promoter methylation and protein expression study in 100 cases. Mod Pathol. 2003;16(9):944–50.

    Article  Google Scholar 

  21. O’Regan EM, Toner ME, Finn SP, Fan CY, Ring M, Hagmar B, Timon C, Smyth P, Cahill S, Flavin R, Sheils OM. p16(INK4A) genetic and epigenetic profiles differ in relation to age and site in head and neck squamous cell carcinomas. Hum Pathol. 2008;39(3):452–8.

    Article  CAS  Google Scholar 

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Funding

This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH.

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Authors and Affiliations

Authors

Contributions

Surgical care was provided by MJC. Pathology investigation was performed by MJB, JSL Jr., and SAR. Genome sequencing and interpretation were performed by LM, SB, and MY. The first draft of the manuscript was written by SAR. All authors contributed to subsequent revision of the manuscript.

Corresponding author

Correspondence to S. A. Rasmussen.

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The authors have no conflicts of interest to declare.

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Data was collected in accordance with guidelines from the institutional Research Ethics Board.

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Written informed consent was obtained from the patient for data collection and publication of this case report and accompanying images.

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Rasmussen, S.A., Lewis, J.S., Mirabello, L. et al. A Case of HPV-Associated Oropharyngeal Squamous Cell Carcinoma with Block-Like, Partial Loss of p16 Expression. Head and Neck Pathol 16, 1251–1256 (2022). https://doi.org/10.1007/s12105-022-01463-4

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