Safra kesesi adenokarsinomunda tümör tomurcuklanması, tümör stroma oranı ve tümörü infiltre eden lenfositlerin prognostik önemi

Öz

Amaç: Tümör mikroçevresi kanserin başlangıcında ve ilerlemesinde önemli rol oynar. Tümör tomurcuklanması (TB), tümör stroması ve tümörü infiltre eden lenfositler, tümör mikroçevresinin bileşenleridir. Bu çalışmada safra kesesi adenokarsinomunda TB, tümör stroma oranı (TSR) ve tümörü infiltre eden lenfositlerin (TILs) klinikopatolojik prognostik parametrelerle ilişkisinin belirlenmesi amaçlandı. Gereç ve yöntem: 2010-2020 yılları arasında adenokarsinom tanısı alan, neoadjuvan tedavi almayan ve arşiv preparatlarına ulaşılabilen 30 kolesistektomi olgusu çalışmaya dahil edildi. TB, TSR ve TILs değerlendirildi. p<0.05 değeri istatistiksel olarak anlamlı kabul edildi. Bulgular: Yüksek TB skoru, daha yüksek histolojik derece (p=0,008), daha yüksek pT evresi, lenfovasküler invazyon (LVI) (p=0,038), lenf nodu metastazı (p=0,046) ve uzak metastaz (p=0,036) ile anlamlı ilişkiliydi. TB skoru yüksek olan hastaların genel sağkalım süreleri daha kısaydı (p<0,001). Yüksek TILs grubunda, daha düşük histolojik derece (p=0,004), daha az LVI (p=0,029), daha az uzak metastaz (p=0,021) ve daha düşük TSR (p=0,008) saptandı. Yüksek TSR, daha yüksek histolojik derece (p=0.015) ve artan uzak metastaz (p=0.013) ile ilişkilendirildi. TSR'nin genel sağkalım üzerinde anlamlı bir etkisi yoktu (p=0,239). Sonuç: TB, safra kesesi kanserli hastalarda yeni bir prognostik histolojik özellik olarak kullanılabilir. Safra kesesi kanserlerinde prognostik göstergeler olarak TILs ve TSR'yi önermek için erken olduğu kanaatindeyiz. Gelecekte, TILs ve TSR'nin prognostik değerini netleştirmek için çok merkez katılımlı daha fazla sayıda GBC vakası üzerinde çalışmalar yapılabilir.

Anahtar Kelimeler

• Safra kesesi kanseri
• Prognoz
• Stroma
• Tümör tomurcuklanması
• Tümörü infilte eden lenfosit

The prognostic significant of tumor budding, tumor stroma ratio and tumor-infiltrating lymphocytes in gallbladder adenocarcinoma

Öz

Aim: Tumor microenvironment plays an important role in onset and progression of the cancer. Tumor budding (TB), tumor stroma and tumor-infiltrating lymphocytes are component of the tumor microenvironment. It was aim to determine the relationship of TB, tumor stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs) with clinicopathological prognostic parameters in gallbladder adenocarcinoma. Materials and Methods: Thirty cholecystectomy cases that were diagnosed as adenocarcinoma between 2010 and 2020, that did not receive neoadjuvant therapy and of which archive slides could be accessed, were included in the study. TB, TSR and TILs were evaluated. A p<0.05 value was statistically significant. Results: High TB score was significantly associated with higher histological grade (p=0.008), higher pT stage, lymphovascular invasion (LVI) (p=0.038), lymph node metastasis (p=0.046) and distant metastasis (p=0.036) . Patients with high TB scores had a shorter overall survival (p<0.001). In the high TILs group, lower histological grade (p=0.004), less LVI (p=0.029), fewer distant metastases (p=0.021) and lower TSR (p=0.008) were detected. Increased TCR was associated with higher histological grade (p=0.015) and increased distant metastasis (p=0.013). There was no significant effect of TCR on overall survival (p=0.239). Conclusion: TB can be used as a novel prognostic histological characteristic in the gallbladder cancer patients. We have concluded that it is early to recommend TILs and TSR as the prognostic indicators in gallbladder cancers. In the future, further studies can be conducted on a larger number of GBC cases with a multicenter participation to clarify the prognostic value of TILs and TSR.

Anahtar Kelimeler

• Gallbladder cancer
• Prognosis
• Stroma
• Tumor budding
• Tumor-infiltrating lymphocyte

Kaynakça

1. 1. Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol 2008; 98(7):485-9. doi: 10.1002/jso.21141.
2. 2. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71(3):209-49. doi: 10.3322/caac.21660.
3. 3. Lugli A, Zlobec I, Berger MD, Kirsch R, Nagtegaal ID. Tumour budding in solid cancers. Nat Rev Clin Oncol 2021;18(2):101-115. doi: 10.1038/s41571-020-0422-y.
4. 4. Kim HN, Lee SY, Kim BH, Kim CY, Kim A, Kim H. Prognostic value of tumor budding in gallbladder cancer: application of the International Tumor Budding Consensus Conference scoring system. Virchows Arch 2021;478(6):1071-8. doi: 10.1007/s00428-020-03012-2. 5. Kai K, Kohya N, Kitahara K, et al. Tumor budding and dedifferentiation in gallbladder carcinoma: potential for the prognostic factors in T2 lesions. Virchows Arch 2011;459(4):449-56. doi: 10.1007/s00428-011-1131-9.
5. 6. Okubo S, Mitsunaga S, Kato Y, et al. The prognostic impact of differentiation at the invasive front of biliary tract cancer. J Surg Oncol 2018;117(6):1278-87. doi: 10.1002/jso.24946.
6. 7. Salgado R, Denkert C, Demaria S, et al.; International TILs Working Group 2014. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 2015;26(2):259-71. doi: 10.1093/annonc/mdu450.
7. 8. Lang-Schwarz C, Melcher B, Haumaier F, et al. Budding and tumor-infiltrating lymphocytes - combination of both parameters predicts survival in colorectal cancer and leads to new prognostic subgroups. Hum Pathol 2018;79:160-167. doi: 10.1016/j.humpath.2018.05.010.
8. 9. Lang-Schwarz C, Melcher B, Haumaier F,et al. Budding, tumor-infiltrating lymphocytes, gland formation: scoring leads to new prognostic groups in World Health Organization low-grade colorectal cancer with impact on survival. Hum Pathol 2019;89:81-89. doi: 10.1016/j.humpath.2019.04.006.

9. 10. Li J, Wang J, Chen R, Bai Y, Lu X. The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer. Oncotarget 2017;8(9):15621-31. doi: 10.18632/oncotarget.14919.
10. 11. Li H, Yuan SL, Han ZZ, et al. Prognostic significance of the tumor-stroma ratio in gallbladder cancer. Neoplasma 2017;64(4):588-93. doi: 10.4149/neo_2017_413.
11. 12. Patil PA, Lombardo K, Cao W. Immune Microenvironment in Gallbladder Adenocarcinomas. Appl Immunohistochem Mol Morphol 2021;29(8):557-563. doi: 10.1097/PAI.0000000000000922.
12. 13. Amin MB. Edge SB. Greene FL et al (eds) (2016) AJCC cancer staging manual. 8th ed. 2017. Corr. 3rd printing 2018 edition. Springer. Chicago
13. 14. Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol 2017;30(9):1299-311. doi:10.1038/modpathol.2017.46
14. 15. Te Boekhorst V, Friedl P. Plasticity of Cancer Cell Invasion-Mechanisms and Implications for Therapy. Adv Cancer Res 2016;132:209-64. doi: 10.1016/bs.acr.2016.07.005.
15. 16. Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 2011 Nov 23;147(5):992-1009. doi: 10.1016/j.cell.2011.11.016.
16. 17. Lu W, Kang Y. Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis. Dev Cell 2019;49(3):361-74. doi: 10.1016/j.devcel.2019.04.010.
17. 18. Grigore AD, Jolly MK, Jia D, Farach-Carson MC, Levine H. Tumor Budding: The Name is EMT. Partial EMT. J Clin Med 2016;5(5):51. doi: 10.3390/jcm5050051.
18. 19. Li H, Xu F, Li S, Zhong A, Meng X, Lai M. The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis. Cell Adh Migr 2016;10(4):434-46. doi: 10.1080/19336918.2015.1129481.
19. 20. Zlobec I, Dawson HE, Blank A, et al. Are tumour grade and tumour budding equivalent in colorectal cancer? A retrospective analysis of 771 patients. Eur J Cancer 2020;130:139-45. doi: 10.1016/j.ejca.2020.02.007.
20. 21. Zlobec I, Berger MD, Lugli A. Tumour budding and its clinical implications in gastrointestinal cancers. Br J Cancer 2020;123(5):700-708. doi: 10.1038/s41416-020-0954-z.
21. 22. Rieger G, Koelzer VH, Dawson HE, et al. Comprehensive assessment of tumour budding by cytokeratin staining in colorectal cancer. Histopathology 2017;70(7):1044-51. doi: 10.1111/his.13164.
22. 23. Fujiyoshi K, Väyrynen JP, Borowsky J, et al. Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer. EBioMedicine. 2020 Jul;57:102860. doi: 10.1016/j.ebiom.2020.102860.
23. 24. Dawson H, Galuppini F, Träger P, et al. Validation of the International Tumor Budding Consensus Conference 2016 recommendations on tumor budding in stage I-IV colorectal cancer. Hum Pathol 2019;85:145-51. doi: 10.1016/j.humpath.2018.10.023.
24. 25. Hendry S, Salgado R, Gevaert T, et al. Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors. Adv Anat Pathol 2017;24(6):311-35.
25. 26. Hwang C, Lee SJ, Lee JH, et al. Stromal tumor-infiltrating lymphocytes evaluated on H&E-stained slides are an independent prognostic factor in epithelial ovarian cancer and ovarian serous carcinoma. Oncol Lett 2019;17(5):4557-4565. doi: 10.3892/ol.2019.10095.
26. 27. Weiss SA, Han SW, Lui K, et al. Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma. Hum Pathol 2016;57:116-125. doi: 10.1016/j.humpath.2016.07.008.
27. 28. Rozek LS, Schmit SL, Greenson JK, et al. Tumor-Infiltrating Lymphocytes, Crohn's-Like Lymphoid Reaction, and Survival From Colorectal Cancer. J Natl Cancer Inst 2016;108(8):djw027. doi: 10.1093/jnci/djw027.
28. 29. 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(1):766. doi: 10.1186/s12885-018-4651-8.
29. 30. Mesker WE, Junggeburt JM, Szuhai K, et al. The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Cell Oncol. 2007;29(5):387-98. doi: 10.1155/2007/175276.
30. 31. Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CSD. The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol 2014;25(3):644-51. doi: 10.1093/annonc/mdt593.
31. 32. Dekker TJ, van de Velde CJ, van Pelt GW, et al. Prognostic significance of the tumor-stroma ratio: validation study in node-negative premenopausal breast cancer patients from the EORTC perioperative chemotherapy (POP) trial (10854). Breast Cancer Res Treat 2013;139(2):371-9. doi: 10.1007/s10549-013-2571-5.