J Pathol Transl Med.  2020 Mar;54(2):154-164. 10.4132/jptm.2019.11.13.

Programmed death-ligand 1 expression and its correlation with clinicopathological parameters in gallbladder cancer

• Kim JH
• Kim K
• Kim M
• Kim YM
• Suh JH
• Cha HJ
• Choi HJ

• KMID: 2501605
• DOI: http://doi.org/10.4132/jptm.2019.11.13

Abstract

Background
Immunomodulatory therapies targeting the interaction between programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) have become increasingly important in anticancer treatment. Previous research on the subject of this immune response has established an association with tumor aggressiveness and a poor prognosis in certain cancers. Currently, scant information is available on the relationship between PD-L1 expression and gallbladder cancer (GBC).
Methods
We investigated the expression of PD-L1 in 101 primary GBC cases to determine the potential association with prognostic impact. PD-L1 expression was immunohistochemically assessed using a single PD-L1 antibody (clone SP263). Correlations with clinicopathological parameters, overall survival (OS), or progression- free survival (PFS) were analyzed.
Results
PD-L1 expression in tumor cells at cutoff levels of 1%, 10%, and 50% was present in 18.8%, 13.8%, and 7.9% of cases. Our study showed that positive PD-L1 expression at any cutoff was significantly correlated with poorly differentiated histologic grade and the presence of lymphovascular invasion (p < .05). PD-L1 expression at cutoff levels of 10% and 50% was significantly positive in patients with perineural invasion, higher T categories, and higher pathologic stages (p < .05). Additionally, there was a significant association noted between PD-L1 expression at a cutoff level of 50% and worse OS or PFS (p = .049 for OS, p = .028 for PFS). Other poor prognostic factors included histologic grade, T category, N category, pathologic stage, lymphovascular invasion, perineural invasion, growth pattern, and margin of resection (p < .05).
Conclusions
The expression of PD-L1 in GBC varies according to cutoff level but is valuably associated with poor prognostic parameters and survival. Our study indicates that the overexpression of PD-L1 in GBC had a negative prognostic impact.

Keyword

Gallbladder neoplasm; Programmed death-ligand 1; Prognosis

Figure

• 

  Fig. 1. Programmed death-ligand 1 (PD-L1) expression in the tumor cells of gallbladder cancer (GBC). (A) ≥ 50% positive staining of PDL1 in tumor cells. (B) 10% to 49% positive staining of PD-L1 in tumor cells. (C) 1% to 9% staining of PD-L1 in tumor cells. (D) Positive staining of PD-L1 in tumor cells of lymphovascular invasion. (E) Positive staining of PD-L1 in tumor cells of perineural invasion.

• 

  Fig. 2. Kaplan-Meier plots for overall survival or progression-free survival of gallbladder cancer according to programmed death-ligand 1 (PD-L1) expression (A, 1% cutoff; B, 10% cutoff; C, 50% cutoff; D, 1% cutoff; E, 10% cutoff; F, 50% cutoff).

Reference

1. Shaffer EA. Gallbladder cancer: the basics. Gastroenterol Hepatol (N Y). 2008; 4:737–41.

2. Goldin RD, Roa JC. Gallbladder cancer: a morphological and molecular update. Histopathology. 2009; 55:218–29.

3. Albores-Saavedra J, Kloppel G, Adsay NV, et al. Carcinoma of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO classification of tumours of the digestive system. Lyon: IARC Press;2010. p. 266–73. 4th.

4. Aloia TA, Jarufe N, Javle M, et al. Gallbladder cancer: expert consensus statement. HPB (Oxford). 2015; 17:681–90.

5. Wi Y, Woo H, Won YJ, Jang JY, Shin A. Trends in gallbladder cancer incidence and survival in Korea. Cancer Res Treat. 2018; 50:1444–51.

6. Kim BW, Oh CM, Choi HY, Park JW, Cho H, Ki M. Incidence and overall survival of biliary tract cancers in South Korea from 2006 to 2015: using the National Health Information Database. Gut Liver. 2019; 13:104–13.

7. Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013; 45:1470–3.

8. Javle MM, Rashid A, Kar SP, et al. Identification of unique somatic mutations with functional relevance through genetic characterization of gallbladder cancer (GB ca). J Clin Oncol. 2013; 31(4 Suppl):214.

9. Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and survival in solid tumors: a meta-analysis. PLoS One. 2015; 10:e0131403.

10. Pyo JS, Kang G, Kim JY. Prognostic role of PD-L1 in malignant solid tumors: a meta-analysis. Int J Biol Markers. 2017; 32:e68–74.

11. Neyaz A, Husain N, Kumari S, et al. Clinical relevance of PD-L1 expression in gallbladder cancer: a potential target for therapy. Histopathology. 2018; 73:622–33.

12. Lin J, Long J, Wan X, et al. Classification of gallbladder cancer by assessment of CD8(+) TIL and PD-L1 expression. BMC Cancer. 2018; 18:766.

13. Takahashi R, Yoshitomi M, Yutani S, et al. Current status of immunotherapy for the treatment of biliary tract cancer. Hum Vaccin Immunother. 2013; 9:1069–72.

14. Bang YJ, Ueno M, Malka D, et al. Pembrolizumab (pembro) for advanced biliary adenocarcinoma: results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies. J Clin Oncol. 2019; 37(15 Suppl):4079.

15. Amin MB, Edge S, Greene F, et al. AJCC cancer staging manual. New York: Springer;2017.

16. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018; 379:2108–21.

17. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019; 380:1103–15.

18. Giroux Leprieur E, Dumenil C, Julie C, et al. Immunotherapy revolutionises non-small-cell lung cancer therapy: results, perspectives and new challenges. Eur J Cancer. 2017; 78:16–23.

19. Carretero-González A, Lora D, Ghanem I, et al. Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials. Oncotarget. 2018; 9:8706–15.

20. Zhao B, Zhang W, Yu D, Xu J, Wei Y. The benefit and risk of nivolumab in non-small-cell lung cancer: a single-arm meta-analysis of noncomparative clinical studies and randomized controlled trials. Cancer Med. 2018; 7:1642–59.

21. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016; 375:1823–33.

22. Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016; 9:5023–39.

23. Fang W, Chen Y, Sheng J, et al. Association between PD-L1 expression on tumour-infiltrating lymphocytes and overall survival in patients with gastric cancer. J Cancer. 2017; 8:1579–85.

24. Qing Y, Li Q, Ren T, et al. Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Devel Ther. 2015; 9:901–9.

25. Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005; 11:2947–53.

26. Shi SJ, Wang LJ, Wang GD, et al. B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS One. 2013; 8:e76012.

27. Yang CY, Lin MW, Chang YL, Wu CT, Yang PC. Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. Eur J Cancer. 2014; 50:1361–9.

28. Skov BG, Rorvig SB, Jensen TH, Skov T. The prevalence of programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer in an unselected, consecutive population. Mod Pathol. 2020; 33:109–17.

29. Walter D, Herrmann E, Schnitzbauer AA, et al. PD-L1 expression in extrahepatic cholangiocarcinoma. Histopathology. 2017; 71:383–92.

30. Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009; 15:971–9.

31. Chen CL, Pan QZ, Zhao JJ, et al. PD-L1 expression as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma. Oncoimmunology. 2016; 5:e1176653.

32. Zoroquiain P, Esposito E, Logan P, et al. Programmed cell death ligand-1 expression in tumor and immune cells is associated with better patient outcome and decreased tumor-infiltrating lymphocytes in uveal melanoma. Mod Pathol. 2018; 31:1201–10.

33. Ha H, Nam AR, Bang JH, et al. Soluble programmed death-ligand 1 (sPD-L1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy. Oncotarget. 2016; 7:76604–12.

34. Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response. Biomark Res. 2017; 5:12.

35. Festino L, Botti G, Lorigan P, et al. Cancer treatment with anti-PD-1/PD-L1 agents: is PD-L1 expression a biomarker for patient selection? Drugs. 2016; 76:925–45.

36. O’Malley DP, Yang Y, Boisot S, et al. Immunohistochemical detection of PD-L1 among diverse human neoplasms in a reference laboratory: observations based upon 62,896 cases. Mod Pathol. 2019; 32:929–42.