Background Gallbladder cancer (GBC) is usually detected in advanced stages with a low 5-year survival rate. Delta-like ligand 4 (DLL4), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-2alpha (HIF2α) have been studied for their role in tumorigenesis and potential for therapeutic target, and multiple clinical trials of the agents targeting them are ongoing. We investigated the expression of these markers in surgically resected GBC and tried to reveal their association with the clinicopathologic features, mutual correlation of their expression, and prognosis of the GBC patients by their expression.
Methods We constructed the tissue microarray blocks of 99 surgically resected GBC specimens and performed immunohistochemistry of DLL4, VEGF, and HIF2α. We used the quantitative digital image analysis to evaluate DLL4 and VEGF expression, while the expression of HIF2α was scored manually.
Results The expression of VEGF and HIF2α showed a significant trend with tumor differentiation (p= .028 and p= .006, respectively). We found that the high DLL4 and VEGF expression were significantly correlated with lymph node metastasis (p= .047, both). The expression of VEGF and HIF2α were significantly correlated (p < .001). The GBC patients with low HIF2α expression showed shorter recurrence-free survival than those with high HIF2α expression.
Conclusions This study suggested the possibility of the usage of DLL4 and VEGF to predict the lymph node metastasis and the possibility of VEGF and HIF2α to predict the expression level mutually. Further studies may be needed to validate our study results and eventually accelerate the introduction of the targeted therapy in GBC.
Citations
Citations to this article as recorded by
Dedifferentiated Leiomyosarcoma of the Uterine Corpus with Heterologous Component: Clinicopathological Analysis of Five Consecutive Cases from a Single Institution and Comprehensive Literature Review Suyeon Kim, Hyunsik Bae, Hyun-Soo Kim Diagnostics.2024; 14(2): 160. CrossRef
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.
Citations
Citations to this article as recorded by
Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis Giorgio Frega, Fernando P. Cossio, Jesus M. Banales, Vincenzo Cardinale, Rocio I. R. Macias, Chiara Braconi, Angela Lamarca Cells.2023; 12(16): 2098. CrossRef
Gallbladder carcinomas: review and updates on morphology, immunohistochemistry, and staging Whayoung Lee, Vishal S. Chandan Human Pathology.2023; 132: 149. CrossRef
Prognostic Relevance of PDL1 and CA19-9 Expression in Gallbladder Cancer vs. Inflammatory Lesions Neetu Rawal, Supriya Awasthi, Nihar Ranjan Dash, Sunil Kumar, Prasenjit Das, Amar Ranjan, Anita Chopra, Maroof Ahmad Khan, Sundeep Saluja, Showket Hussain, Pranay Tanwar Current Oncology.2023; 30(2): 1571. CrossRef
Identification of genes associated with gall bladder cell carcinogenesis: Implications in targeted therapy of gall bladder cancer Ishita Ghosh, Ruma Dey Ghosh, Soma Mukhopadhyay World Journal of Gastrointestinal Oncology.2023; 15(12): 2053. CrossRef
CD73 and PD-L1 as Potential Therapeutic Targets in Gallbladder Cancer Lu Cao, Kim R. Bridle, Ritu Shrestha, Prashanth Prithviraj, Darrell H. G. Crawford, Aparna Jayachandran International Journal of Molecular Sciences.2022; 23(3): 1565. CrossRef
Evolving Role of Immunotherapy in Advanced Biliary Tract Cancers Sandra Kang, Bassel F. El-Rayes, Mehmet Akce Cancers.2022; 14(7): 1748. CrossRef
Novel immune scoring dynamic nomograms based on B7-H3, B7-H4, and HHLA2: Potential prediction in survival and immunotherapeutic efficacy for gallbladder cancer Chao Lv, Shukun Han, Baokang Wu, Zhiyun Liang, Yang Li, Yizhou Zhang, Qi Lang, Chongli Zhong, Lei Fu, Yang Yu, Feng Xu, Yu Tian Frontiers in Immunology.2022;[Epub] CrossRef
PD-1 inhibitors plus nab-paclitaxel-containing chemotherapy for advanced gallbladder cancer in a second-line setting: A retrospective analysis of a case series Sirui Tan, Jing Yu, Qiyue Huang, Nan Zhou, Hongfeng Gou Frontiers in Oncology.2022;[Epub] CrossRef
Expression of HER2 and Mismatch Repair Proteins in Surgically Resected Gallbladder Adenocarcinoma You-Na Sung, Sung Joo Kim, Sun-Young Jun, Changhoon Yoo, Kyu-Pyo Kim, Jae Hoon Lee, Dae Wook Hwang, Shin Hwang, Sang Soo Lee, Seung-Mo Hong Frontiers in Oncology.2021;[Epub] CrossRef
Programmed Death Ligand-1 (PD-L1) Is an Independent Negative Prognosticator in Western-World Gallbladder Cancer Thomas Albrecht, Fritz Brinkmann, Michael Albrecht, Anke S. Lonsdorf, Arianeb Mehrabi, Katrin Hoffmann, Yakup Kulu, Alphonse Charbel, Monika N. Vogel, Christian Rupp, Bruno Köhler, Christoph Springfeld, Peter Schirmacher, Stephanie Roessler, Benjamin Goep Cancers.2021; 13(7): 1682. CrossRef
Immune Microenvironment in Gallbladder Adenocarcinomas Pallavi A. Patil, Kara Lombardo, Weibiao Cao Applied Immunohistochemistry & Molecular Morphology.2021; 29(8): 557. CrossRef
Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer Matteo Canale, Manlio Monti, Ilario Giovanni Rapposelli, Paola Ulivi, Francesco Giulio Sullo, Giulia Bartolini, Elisa Tiberi, Giovanni Luca Frassineti Cancers.2021; 13(22): 5671. CrossRef
Overview of current targeted therapy in gallbladder cancer Xiaoling Song, Yunping Hu, Yongsheng Li, Rong Shao, Fatao Liu, Yingbin Liu Signal Transduction and Targeted Therapy.2020;[Epub] CrossRef
BACKGROUND Cyclooxygenase-2 (COX-2) is an enzyme that promotes proliferation of tumor cells. HuR is a member of the family of embryonic lethal abnormal vision-like proteins. Recent studies show that cytoplasmic HuR stabilizes the mRNA of COX-2 and regulates the expression of COX-2. Moreover, cytoplasmic HuR expression is associated with a poorer prognosis for patients with some cancers. The aim of this study was to investigate the expression patterns of and the relationship between COX-2 and HuR in gallbladder carcinoma. METHODS We analyzed COX-2 and HuR expression by immunohistochemical staining of 108 gallbladder carcinomas. RESULTS COX-2 expression and nuclear and cytoplasmic HuR expression were seen in, respectively, 61 (56.5%), 77 (71.3%), and 4 (3.7%) cases. COX-2 and nuclear HuR were simultaneously expressed in 44 of the 108 samples without any quantitative association between the levels of each.
COX-2 expression correlated with tumor stage, differentiation (based on histology), lymph node metastasis, perineural invasion, and survival. Nuclear and cytological expression of HuR did not correlate with any clinical parameters. CONCLUSIONS COX-2 expression but not HuR may play an important role in the prognosis of patients with gallbladder carcinoma.
Citations
Citations to this article as recorded by
Prognostic molecular markers in resected extrahepatic biliary tract cancers; a systematic review and meta-analysis of immunohistochemically detected biomarkers Robert P Jones, Nicholas TE Bird, Richard A Smith, Daniel H Palmer, Steven W Fenwick, Graeme J Poston, Hassan Z Malik Biomarkers in Medicine.2015; 9(8): 763. CrossRef
BACKGROUND Matrix metalloproteinase (MMP)-2 and MMP-9 degrade type IV collagen and are antagonized by the tissue inhibitors of metalloproteinase (TIMP)-2 and TIMP-1, respectively. METHODS We studied by immunohistochemistry the expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 in 72 cases of adenocarcinoma of the gallbladder. RESULTS The MMP-2, MMP-9 and TIMP-1 expressions were significantly higher in well/moderately differentiated adenocarcinomas than in poorly differentiated adenocarcinomas, in adenocarcinomas that had invaded the lamina propria/proper muscle than in those that had invaded the perimuscular connective tissue or beyond the serosa, and in adenocarcinomas with fungating growth than in those with infiltrative growth. The TIMP-2 expression showed a similar pattern without statistical significance. Regarding the status of lymph node metastasis, the MMP-2 expression was significantly higher in cases without lymph node metastasis.
The MMP-2 and MMP-9 expressions were significantly related to those of TIMP-2 and TIMP-1, respectively, with regard to depth of invasion, differentiation, and growth patterns of the adenocarcinomas. CONCLUSIONS MMP-2, MMP-9, TIMP-1 and TIMP-2 are suggested to play important roles in the progression to early invasion of adenocarcinomas, in which the function of MMP-2 is inhibited by TIMP-2.
BACKGROUND It has been well demonstrated that the overexpression of epidermal growth factor receptor (EGFR) is associated with numerous gastrointestinal malignancies, including gallbladder carcinoma. However, the cellular events that regulate EGFR in cancer cells have not been fully elucidated. A novel negative regulator of EGFR that is referred to as EGFR related protein (ERRP) has recently been identified. The aim of this study was to investigate the expression and localization of ERRP in gallbladder carcinoma and to examine a possible role for ERRP. METHODS We examined the immunohistochemical expressions of ERRP, p53 and proliferating cell nuclear antigen labeling index (PCNA-LI) in formalin-fixed, paraffinembedded specimens of 43 cases of gallbladder carcinoma, 7 cases of adenoma and 3 cases of dysplasia. RESULTS In the normal mucosa, ERRP immunoreactivity was positive in over 64% of specimens. In contrast, the ERRP staining was positive in only 46% of the cancer specimens.
The expression of ERRP in cancer cells was inversely correlated with tumor cell proliferation. The loss of ERRP expression correlated with the p53 overexpression. CONCLUSIONS Our data indicate that the down-regulation or loss of ERRP could play an important role in the progression of gallbladder carcinoma. The inverse relationship between the ERRP expression and PCNA-LI suggests that ERRP may play a role in the inhibition of tumor cell proliferation in gallbladder cancer.
BACKGROUND There are evidences that uPA and its inhibitor play a key role in tumor spread. We studied whether uPA and PAI-1 expressions could serve as prognostic parameters along with clinical, gross and microscopic findings in gallbladder carcinomas. METHODS We analyzed 42 cases of gallbladder carcinomas by immunohistochemical staining and clinicopathologic parameters. RESULTS uPA and PAI-1 were more frequently expressed in the adenocarcinoma than in the normal or benign gallbladder tissue. The uPA expression in the glands of low grade adenocarcinoma was significantly correlated with both distant and lymph node metastases. The uPA expression in the stroma around the low grade adenocarcinoma was significantly correlated with either distant or lymph node metastasis. The PAI-1 expression was significantly correlated with lymph node metastasis only for both distant and lymph node metastases. In multivariate analysis, the lymphatic invasion was significantly related to poor survival (p= 0.0115). In univariate analysis, the cases without lymphatic invasion had prolonged survival. Positive expression of uPA in the glands of low-grade adenocarcinoma was significantly correlated with poor survival (p=0.0391). CONCLUSION In conjunction with clinicopathologic findings, expressions of uPA and PAI-1 may be useful prognostic markers in gallbladder carcinomas.