Skip to main content

Advertisement

SpringerLink
Log in

Programmed Death-Ligand 1 Expression, Microsatellite Instability, Epstein–Barr Virus, and Human Papillomavirus in Nasopharyngeal Carcinomas of Patients from the Philippines

  • Original Paper
  • Published:
Head and Neck Pathology Aims and scope Submit manuscript

Abstract

Most nasopharyngeal carcinomas (NPCs) in a high-incidence population are driven by Epstein–Barr virus (EBV) infection. EBV-associated malignancies have increased expression of the programmed death-ligand 1 (PD-L1). Immunotherapy agents targeting the PD-1/PD-L1 pathway have achieved durable treatment effects in patients with various cancer types including EBV-associated malignancies. In this study, we sought to investigate PD-L1 expression in a cohort of patients with NPCs from the Philippines. Fifty-six NPCs were studied for PD-L1, p16, and DNA mismatch repair (MMR) deficiency by immunohistochemistry. One case with MMR deficiency was also assessed for microsatellite instability (MSI) by polymerase chain reaction. EBV and human papillomavirus (HPV) status were tested by in situ hybridization. All NPCs were p16 negative. Three of the 56 NPCs (5%) were EBV negative (EBV−) and HPV negative, while one NPC (1/56, 2%) was EBV positive and showed MSI (EBV+/MSI). Positive PD-L1 expression (PD-L1+), defined as membranous staining in ≥1% tumor cells, was seen in 64% (36/56) of NPCs. All three EBV− NPCs were PD-L1+ as was the EBV+/MSI NPC. PD-L1+ was seen significantly more often in NPCs from non-smokers than those from smokers (23/28, 82% vs 9/18, 50%; P = 0.047). PD-L1+ was not associated with pT, pN, distant metastasis, or clinical stage (P > 0.05). PD-L1+ was not associated with overall survival (P = 0.473). In summary, our results show frequent PD-L1 expression in NPCs regardless of EBV status and a preferential PD-L1 expression in non-smokers. MSI and HPV positivity are exceedingly rare in NPCs.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol. 2002;12(6):421–9.

    Article  PubMed  Google Scholar 

  2. Andersson-Anvret M, Forsby N, Klein G, Henle W. Relationship between the Epstein–Barr virus and undifferentiated nasopharyngeal carcinoma: correlated nucleic acid hybridization and histopathological examination. Int J Cancer. 1977;20(4):486–94.

    Article  CAS  PubMed  Google Scholar 

  3. Jin Y, Shi YX, Cai XY, Xia XY, Cai YC, Cao Y, et al. Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol. 2012;138(10):1717–25. doi:10.1007/s00432-012-1219-x.

    Article  CAS  PubMed  Google Scholar 

  4. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ra37. doi:10.1126/scitranslmed.3003689.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74. doi:10.1158/1078-0432.ccr-13-3271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71. doi:10.1038/nature13954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. doi:10.1038/nrc3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7. doi:10.1038/nature14011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. doi:10.1056/NEJMoa1200690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9. doi:10.1056/NEJMoa1411087.

    Article  PubMed  Google Scholar 

  11. Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O’Donnell E, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18(6):1611–8. doi:10.1158/1078-0432.ccr-11-1942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ma C, Patel K, Singhi AD, Ren B, Zhu B, Shaikh F, et al. Programmed death-ligand 1 expression is common in gastric cancer associated with Epstein–Barr virus or microsatellite instability. Am J Surg Pathol. 2016;. doi:10.1097/pas.0000000000000698.

    PubMed  Google Scholar 

  13. Chang Y-L, Yang C-Y, Lin M-W, Wu C-T, Yang P-C. PD-L1 is highly expressed in lung lymphoepithelioma-like carcinoma: a potential rationale for immunotherapy. Lung Cancer. 2015;88(3):254–9.

    Article  PubMed  Google Scholar 

  14. Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19(13):3462–73. doi:10.1158/1078-0432.ccr-13-0855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hsu MC, Hsiao JR, Chang KC, Wu YH, Su IJ, Jin YT, et al. Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma. Mod Pathol. 2010;23(10):1393–403. doi:10.1038/modpathol.2010.130.

    Article  CAS  PubMed  Google Scholar 

  16. Fang W, Zhang J, Hong S, Zhan J, Chen N, Qin T, et al. EBV-driven LMP1 and IFN-gamma up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy. Oncotarget. 2014;5(23):12189–202. doi:10.18632/oncotarget.2608.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lee VH, Lo AW, Leung CY, Shek WH, Kwong DL, Lam KO, et al. Correlation of PD-L1 expression of tumor cells with survival outcomes after radical intensity-modulated radiation therapy for non-metastatic nasopharyngeal carcinoma. PLoS ONE. 2016;11(6):e0157969. doi:10.1371/journal.pone.0157969.

    Article  PubMed  PubMed Central  Google Scholar 

  18. The Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9. doi:10.1038/nature13480.

    Article  Google Scholar 

  19. Lin DC, Meng X, Hazawa M, Nagata Y, Varela AM, Xu L, et al. The genomic landscape of nasopharyngeal carcinoma. Nat Genet. 2014;46(8):866–71. doi:10.1038/ng.3006.

    Article  CAS  PubMed  Google Scholar 

  20. Trimeche M, Braham H, Ziadi S, Amara K, Hachana M, Korbi S. Investigation of allelic imbalances on chromosome 3p in nasopharyngeal carcinoma in Tunisia: high frequency of microsatellite instability in patients with early-onset of the disease. Oral Oncol. 2008;44(8):775–83. doi:10.1016/j.oraloncology.2007.10.001.

    Article  CAS  PubMed  Google Scholar 

  21. Lo KW, Teo PM, Hui AB, To KF, Tsang YS, Chan SY, et al. High resolution allelotype of microdissected primary nasopharyngeal carcinoma. Cancer Res. 2000;60(13):3348–53.

    CAS  PubMed  Google Scholar 

  22. Sckolnick J, Murphy J, Hunt JL. Microsatellite instability in nasopharyngeal and lymphoepithelial carcinomas of the head and neck. Am J Surg Pathol. 2006;30(10):1250–3. doi:10.1097/01.pas.0000209829.16607.cd.

    Article  PubMed  Google Scholar 

  23. Pilch B, Wenig B, Huang D, Lo K, Zeng Y, Jia W. Nasopharyngeal carcinoma. In: Barnes L, Eveson J, Reichart P, Sidransky D, editors. Pathology & genetics of head and neck tumors (IARC WHO classification of tumors). 1st ed. Lyon: World Health Organization; 2005. p. 85–97.

    Google Scholar 

  24. Hartman DJ, Nikiforova MN, Chang DT, Chu E, Bahary N, Brand RE, et al. Signet ring cell colorectal carcinoma: a distinct subset of mucin-poor microsatellite-stable signet ring cell carcinoma associated with dismal prognosis. Am J Surg Pathol. 2013;37(7):969–77. doi:10.1097/PAS.0b013e3182851e2b.

    Article  PubMed  Google Scholar 

  25. Dogan S, Hedberg ML, Ferris RL, Rath TJ, Assaad AM, Chiosea SI. Human papillomavirus and Epstein–Barr virus in nasopharyngeal carcinoma in a low-incidence population. Head Neck. 2014;36(4):511–6. doi:10.1002/hed.23318.

    Article  PubMed  Google Scholar 

  26. Lewis JS Jr. p16 Immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2012;6(Suppl 1):S75–82. doi:10.1007/s12105-012-0369-0.

    Article  PubMed  Google Scholar 

  27. Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, et al. Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFNgamma that induce PD-L1 expression in head and neck cancer. Cancer Res. 2016;76(5):1031–43. doi:10.1158/0008-5472.can-15-2001.

    Article  CAS  PubMed  Google Scholar 

  28. Yu MC, Garabrant DH, Huang TB, Henderson BE. Occupational and other non-dietary risk factors for nasopharyngeal carcinoma in Guangzhou, China. Int J Cancer. 1990;45(6):1033–9.

    Article  CAS  PubMed  Google Scholar 

  29. D’Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112(1):95–102. doi:10.1038/bjc.2014.555.

    Article  PubMed  Google Scholar 

  30. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28. doi:10.1056/NEJMoa1501824.

    Article  PubMed  Google Scholar 

  31. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21. doi:10.1038/nature12477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet (London, England). 2005;365(9476):2041–54. doi:10.1016/s0140-6736(05)66698-6.

    Article  Google Scholar 

  33. Gulley ML. Molecular diagnosis of Epstein–Barr virus-related diseases. J Mol Diagn: JMD. 2001;3(1):1–10. doi:10.1016/s1525-1578(10)60642-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wu C-C, Liu M-T, Chang Y-T, Fang C-Y, Chou S-P, Liao H-W, et al. Epstein–Barr virus DNase (BGLF5) induces genomic instability in human epithelial cells. Nucleic Acids Res. 2010;38(6):1932–49. doi:10.1093/nar/gkp1169.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank members of the Developmental Laboratory of the Department of Pathology, University of Pittsburgh and Histopathology Section of St. Luke’s Medical Center, Quezon City for excellent technical support.

Author information

Author notes

    Authors and Affiliations

    1. Institute of Pathology, St. Luke’s Medical Center, Quezon City, Philippines

      Ann Margaret V. Chang

    2. Department of Pathology, School of Medicine, University of Pittsburgh, 200 Lothrop Street, A610, Pittsburgh, PA, 15213, USA

      Simion I. Chiosea, Alexey Altman, Hester A. Pagdanganan & Changqing Ma

    Authors
    1. Ann Margaret V. Chang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Simion I. Chiosea
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Alexey Altman
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Hester A. Pagdanganan
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Changqing Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Simion I. Chiosea or Changqing Ma.

    Ethics declarations

    Conflict of interest

    The authors of this study have no conflicts of interest with respect to this manuscript to disclose.

    Additional information

    Ann Margaret V. Chang and Simion I. Chiosea have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 17 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Chang, A.M.V., Chiosea, S.I., Altman, A. et al. Programmed Death-Ligand 1 Expression, Microsatellite Instability, Epstein–Barr Virus, and Human Papillomavirus in Nasopharyngeal Carcinomas of Patients from the Philippines. Head and Neck Pathol 11, 203–211 (2017). https://doi.org/10.1007/s12105-016-0765-y

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12105-016-0765-y

    Keywords

    Search

    Navigation