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6 "Gallbladder neoplasm"
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Original Articles
Clinicopathologic significance of the delta-like ligand 4, vascular endothelial growth factor, and hypoxia-inducible factor-2α in gallbladder cancer
Sujin Park, Junsik Kim, Woncheol Jang, Kyoung-Mee Kim, Kee-Taek Jang
J Pathol Transl Med. 2023;57(2):113-122.   Published online March 14, 2023
DOI: https://doi.org/10.4132/jptm.2023.02.01
  • 1,563 View
  • 61 Download
  • 1 Web of Science
  • 1 Crossref
AbstractAbstract PDF
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
Programmed death-ligand 1 expression and its correlation with clinicopathological parameters in gallbladder cancer
Ji Hye Kim, Kyungbin Kim, Misung Kim, Young Min Kim, Jae Hee Suh, Hee Jeong Cha, Hye Jeong Choi
J Pathol Transl Med. 2020;54(2):154-164.   Published online February 10, 2020
DOI: https://doi.org/10.4132/jptm.2019.11.13
  • 6,679 View
  • 153 Download
  • 14 Web of Science
  • 13 Crossref
AbstractAbstract PDF
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
Expression of Cyclooxygenase-2 and Embryonic Lethal Abnormal Vision-Like Protein HuR in Gallbladder Carcinoma.
Sung Im Do, Gou Young Kim, Sung Jig Lim, Youn Wha Kim
Korean J Pathol. 2010;44(1):42-47.
DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.1.42
  • 2,999 View
  • 17 Download
  • 1 Crossref
AbstractAbstract PDF
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
Expression of Matrix Metalloproteinase (MMP)-2, MMP-9, Tissue Inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2 in Adenocarcinomas of The Gallbladder.
Jong Yup Bae, Jinsub Choi, Hyun Cheol Chung, Chanil Park, Young Nyun Park
Korean J Pathol. 2003;37(1):1-9.
  • 1,697 View
  • 13 Download
AbstractAbstract PDF
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.
Expression of Epidermal Growth Factor Receptor Related Protein in Gallbladder Cancer: An Association with p53 Mutation.
Ho Sung Park, Kyu Yun Jang, Kyung Ryoul Kim, Hak Yong Lee, Andrzej S Tarnawski, Adhip P N Majumdar, Myoung Jae Kang, Dong Geun Lee, Woo Sung Moon
Korean J Pathol. 2005;39(6):385-390.
  • 1,788 View
  • 16 Download
AbstractAbstract PDF
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.
Expression of Urokinase-type Plasminogen Activator (uPA) and Plasminogen Activator Inhibitor-1 (PAI-1) in Gallbladder Carcinoma.
Kee Hyung Lee, Haeng Ji Kang, Seung Yeoun Lee, Moon Hyang Park
Korean J Pathol. 2003;37(6):384-392.
  • 1,400 View
  • 12 Download
AbstractAbstract PDF
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.

J Pathol Transl Med : Journal of Pathology and Translational Medicine