Skip to main content

The relationship between the PD-L1 expression of surgically resected and fine-needle aspiration specimens for patients with pancreatic cancer

Abstract

Background

Recently, therapeutic antibodies against programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) have shown promising clinical results for several solid tumors, including pancreatic cancer. In this study, we evaluated the relationship between the PD-L1 expression of surgical resected and fine-needle aspiration (FNA) specimens for patients with pancreatic cancer.

Methods

Of 121 patients who underwent endoscopic ultrasound-guided (EUS)–FNA before surgery for pancreatic cancer in an academic center, the 94 (78%) with adequate FNA specimens for a histological evaluation were retrospectively analyzed. All the patients had undergone upfront surgery without any chemotherapy or radiotherapy. We performed immunohistochemistry (IHC) staining to investigate the PD-L1 expression in both resected and FNA specimens. The positive-stained cells were counted, and their percentage was used for the investigation.

Results

Of the 94 patients, 16 (17%) and 11 (10%) were defined as positive on resected cancer specimens using cutoff points of 5% and 10% positively stained cancer cell counts, respectively. The concordance rates for the positive frequency of PD-L1 expression between resected and FNA specimens were 44% (7/16) and 55% (6/11) when the positivity was set to ≥ 5% and ≥ 10%, respectively. The concordance rates for the negative frequency of PD-L1 expression between two specimens were 97% (76/78) and 99% (82/83) when the positivity was set to ≥ 5% and ≥ 10%, respectively.

Conclusions

Approximately, half of the patients with PD-L1 expression positive and almost all the patients with PD-L1 expression negative could be diagnosed on FNA specimens.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

PD-1:

Programmed death-1

PD-L1:

Programmed death-ligand 1

MMR:

Mismatch repair

MSI-H:

High-frequency microsatellite instability

IHC:

Immunohistochemistry

EUS:

Endoscopic ultrasound

FNA:

Fine-needle aspiration

ROSE:

Rapid on-site evaluation

PBS:

Phosphate-buffered saline

IQR:

Interquartile range

CEA:

Carcinoembryonic antigen

CA19-9:

Carbohydrate antigen 19-9

DUPAN-2:

Duke pancreatic monoclonal antigen type 2

Span-1:

Serum pancreas antigen type 1

hENT1:

Human equilibrative nucleoside transporter 1

References

  1. 1.

    Seigel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin. 2012;62:10–29.

    Article  Google Scholar 

  2. 2.

    Benassai G, Mastrorilli M, Quarto G, et al. Factors influencing survival after resection for ductal adenocarcinoma of the head of the pancreas. J Surg Oncol. 2000;73:212–8.

    CAS  Article  Google Scholar 

  3. 3.

    Traverso LW. Pancreatic cancer: surgery alone is not sufficient. Surg Endosc. 2006;20:S446–S44949.

    Article  Google Scholar 

  4. 4.

    Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363:1049–57.

    CAS  Article  Google Scholar 

  5. 5.

    Laheru D, Jaffee EM. Immunotherapy for pancreatic cancer-science driving clinical progress. Nat Rev Cancer. 2005;5:459–67.

    CAS  Article  Google Scholar 

  6. 6.

    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    CAS  Article  Google Scholar 

  7. 7.

    Dong H, Zhu G, Tamada K, et al. B7-H, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365–9.

    CAS  Article  Google Scholar 

  8. 8.

    Dong H, Strome SE, Saloma DR, et al. Tumor-associated B7–H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

    CAS  Article  Google Scholar 

  9. 9.

    Carter L, Fouser LA, Jussif J, et al. PD-1: PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol. 2002;32:634–43.

    CAS  Article  Google Scholar 

  10. 10.

    Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.

    CAS  Article  Google Scholar 

  11. 11.

    Wang X, Bao Z, Zhang X, et al. Effectiveness and safety of PD-1/PD-L1 inhibitors in the treatment of solid tumors: a systematic review and meta-analysis. Oncotarget. 2017;8:59901–14.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 Blockade. Science. 2017;357:409–13.

    CAS  Article  Google Scholar 

  13. 13.

    Vanderwalde A, Spetzier D, Xiao N, et al. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 2018;7:746–58.

    CAS  Article  Google Scholar 

  14. 14.

    Hu ZL, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res. 2018;24:1326–36.

    CAS  Article  Google Scholar 

  15. 15.

    Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet. 2016;387:1540–50.

    CAS  Article  Google Scholar 

  16. 16.

    Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7.

    CAS  Article  Google Scholar 

  17. 17.

    Banafea O, Mghanga FP, Zhao J, Zhao R, Zhu L. Endoscopic ultrasonography with fine-needle aspiration for histological diagnosis of solid pancreatic masses: a meta-analysis of diagnostic accuracy studies. BMC Gastroenterol. 2016;16:108.

    Article  Google Scholar 

  18. 18.

    Sakamoto H, Kitano M, Komaki T, et al. Prospective comparative study of the EUS guided 25-gauge FNA needle with solid pancreatic masses. J Gastroenterol Hepatol. 2009;24:384–90.

    Article  Google Scholar 

  19. 19.

    Park JK, Kang KJ, Oh CR, et al. Evaluating the minimal specimens from endoscopic ultrasound-guided fine-needle aspiration in pancreatic masses. Medicine. 2016;95:e3740.

    Article  Google Scholar 

  20. 20.

    Yoshizawa N, Yamada R, Sakuno T, et al. Comparison of endoscopic ultrasound-guided fine-needle aspiration and biopsy with 22-gauge and 25-gauge needles for the “precision medicine” of pancreatic cancer: a retrospective study. Med (Baltim). 2018;97:e11096.

    Article  Google Scholar 

  21. 21.

    Boone BA, Sabbaghian S, Zenati M, et al. Loss of SMAD4 staining in preoperative cell blocks is associated with distant metastases following pancreaticoduodenectomy with venous resection for pancreatic cancer. J Surg Oncol. 2014;110:171–5.

    Article  Google Scholar 

  22. 22.

    Gleeson FC, Levy MJ, Roden AC, et al. EUS fine-needle pancreatic core biopsy can determine eligibility for tumor-agnostic immunotherapy. Endosc Int Open. 2018;6:E1278–1282.

    Article  Google Scholar 

  23. 23.

    Zuhan-Sun Y, Huang F, Feng M, et al. Prognostic value of PD-L1 overexpression for pancreatic cancer: evidence from a meta-analysis. Onco Targets Ther. 2017;10:5005–122.

    Article  Google Scholar 

  24. 24.

    Chen Y, Sun J, Zhao H, et al. The coexpression and clinical significance of costimulatory molecules B7–H1, B7–H3, and B7–H4 in human pancreatic cancer. Onco Targets Ther. 2014;7:1465–72.

    Article  Google Scholar 

  25. 25.

    Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13:2151–7.

    CAS  Article  Google Scholar 

  26. 26.

    Wang Y, Lin J, Cui J, et al. Prognostic value and clinicopathological features of PD-1/PD-L1 expression with mismatch repair status and desmoplastic stroma in Chinese patients with pancreatic cancer. Oncotarget. 2017;8:9354–65.

    PubMed  Google Scholar 

  27. 27.

    Yamaki S, Yanagimoto H, Tsuta K, et al. PD-L1 expression in pancreatic ductal adenocarcinoma is a poor prognostic factor in patients with high CD8+ tumor-infiltrating lymphocytes: highly sensitive detection using phosphor-integrated dot staining. Int J Clin Oncol. 2017;22:726–33.

    CAS  Article  Google Scholar 

  28. 28.

    Lie JW, Lu Y, Shen GJ, et al. The relationship of B7–H1 with clinicopathologic characteristics and prognosis of pancreatic carcinoma. Chin J Gen Pract. 2016;14:571–4.

    Google Scholar 

  29. 29.

    Wang L, Ma Q, Chen X, et al. Clinical significance of B7–H1 and B7–1 expressions in pancreatic carcinoma. World J Surg. 2010;34:1059–65.

    Article  Google Scholar 

  30. 30.

    Navina S, McGrath K, Chennat J, et al. Adequacy assessment of endoscopic ultrasound-guided, fine-needle aspirations of pancreatic masses for theranostic studies: optimization of current practices is warranted. Arch Pathol Lab Med. 2014;138:923–8.

    Article  Google Scholar 

  31. 31.

    Liang X, Sun J, Wu H, et al. PD-L1 in pancreatic ductal adenocarcinoma: a retrospective analysis of 373 Chinese patients using an in vitro diagnostic assay. Diagn Pathol. 2018;13:5.

    Article  Google Scholar 

  32. 32.

    Diana A, Wang LM, D’Costa Z, et al. Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget. 2016;7:40992–1004.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Dill EA, Gru AA, Atkins KA, et al. PD-L1 expression and intratumoral heterogeneity across breast cancer subtypes and stages: an assessment of 245 primary and 40 metastatic tumors. Am J Surg Pathol. 2017;41:334–42.

    Article  Google Scholar 

  34. 34.

    Casadevall D, Clave S, Taus A, et al. Heterogeneity of tumor and immune cell PD-L1 expression and lymphocyte counts in surgical NSCLC samples. Clin Lung Cancer. 2017;18:682–91.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The author are indebted to Dr. Toshiharu Mitsuhashi, Assistant Professor of the Center for Innovative Clinical Medicine of Okayama University Hospital for statistical analyses.

Funding

This work was supported by JSPS KAKENHI Grant no. 17K09462.

Author information

Affiliations

Authors

Contributions

KM, TO and AK: conception and design of the research and writing the paper. FM, MT and NT: analysis and interpretation of data. HK and SH: critical revision of the article for important intellectual content. RY, YU and TY: collection of the surgical specimens. SF: performing the external validation for pathological evaluation. MA and HO: final approval of the article. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Kazuyuki Matsumoto.

Ethics declarations

Conflict of interest

All the authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

535_2019_1586_MOESM1_ESM.jpg

Supplemental figure 1 PD-L1 and HE staining of a resected specimen. The PD-L1 positive cells distributed patchy in the resected whole cancer area. HE (low magnification): A, PD-L1: B, HE (mild magnification): C, PD-L1: D (JPEG 638 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Matsumoto, K., Ohara, T., Fujisawa, M. et al. The relationship between the PD-L1 expression of surgically resected and fine-needle aspiration specimens for patients with pancreatic cancer. J Gastroenterol 54, 1019–1028 (2019). https://doi.org/10.1007/s00535-019-01586-6

Download citation

Keywords

  • PD-L1
  • Pancreatic cancer
  • EUS–FNA
  • Immunohistochemistry