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Dash S, Anirvan P, Samantaray S, Swain PK, Parida PK, Rout N, Ranjit M. Human epidermal growth factor receptor-2/neu expression in gallbladder cancer is significantly associated with clinicopathological parameters and survival. Indian J Gastroenterol 2025:10.1007/s12664-024-01723-x. [PMID: 39899204 DOI: 10.1007/s12664-024-01723-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 12/06/2024] [Indexed: 02/04/2025]
Abstract
BACKGROUND Anti-human epidermal growth factor receptor-2 (Her-2/neu) target therapy has substantially improved the disease outcome of patients with breast and gastric/gastroesophageal cancers characterized by Her-2/neu overexpression and/or amplification. Consequently, evaluating Her-2/neu expression in other cancers to predict response to Her-2/neu targeting agents emerges as a crucial approach. We aimed at investigating the positivity rate of this receptor in gallbladder cancer (GBC) and assess the relationship between Her-2/neu status, clinicopathological parameters and survival to identify patients who would benefit most from anti-Her-2/neu-targeted therapy. The Her-2/neu expression was correlated with clinicopathological parameters and survival of GBC cases. METHODS Total 235 surgically resected and histopathologically proven primary GBC cases were collected over a five-year period from January 1, 2017, to December 31, 2020. Her-2/neu expression in these cases was analyzed using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS Employing testing algorithms (IHC scoring based on gastric cancer criteria, followed by FISH in equivocal cases), Her-2/neu positivity was identified in 43 (18.29%) GBC cases and was significantly associated with grade-I tumors, tumor stage > T2, perineural invasion, surgical margin positivity and advanced Tumor-Node-Metastasis (TNM) stage. The mean survival time for Her-2/neu-positive cases was 14 months (SE, 1.1; 95% CI, 11.7-16.06), while it was 20 months (SE, 0.69; 95%CI, 18.1-20.9) for Her-2-negative cases (p < 0.001). CONCLUSION Her-2/neu is expressed in about one-fifth of GBC patients and is significantly associated with tumor behavior and patient survival. Utilizing novel targeted agents may hold the key to improving the prognosis of these patients.
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Affiliation(s)
- Sashibhusan Dash
- Department of Pathology, Acharya Harihar Postgraduate Institute of Cancer, Cuttack 753 007, India
- Department of Molecular Epidemiology, ICMR-Regional Medical Research Centre, Bhubaneswar 751 023, India
| | - Prajna Anirvan
- Department of Translational Research, Kalinga Gastroenterology Foundation, Cuttack 753 001, India.
| | - Sagarika Samantaray
- Department of Pathology, Acharya Harihar Postgraduate Institute of Cancer, Cuttack 753 007, India
| | - Prafulla Kumar Swain
- Department of Statistics, Utkal University, Vanibihar, Bhubaneswar 751 004, India
| | - Prasant Kumar Parida
- Department of Medical Oncology, Acharya Harihar Postgraduate Institute of Cancer, Cuttack 753 007, India
| | - Niranjan Rout
- Patholab Healthcare Private Limited, Cuttack 753 001, India
| | - Manoranjan Ranjit
- Department of Molecular Epidemiology, ICMR-Regional Medical Research Centre, Bhubaneswar 751 023, India.
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Kapoor VK. How I Manage My Patients with Gall Bladder Cancer? Indian J Surg Oncol 2024; 15:652-660. [PMID: 39555366 PMCID: PMC11564548 DOI: 10.1007/s13193-024-02008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/23/2024] [Indexed: 11/19/2024] Open
Abstract
The author outlines his philosophy and practice of management of gall bladder cancer based on his more than three-decade experience at a large tertiary level super-specialty referral hospital attached to a university-status teaching institution at Lucknow in northern India where GBC is very common.
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Affiliation(s)
- Vinay K. Kapoor
- Surgical Gastroenterology, Mahatma Gandhi Medical College & Hospital (MGMCH), Jaipur, 302004 Rajasthan India
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3
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Verma P, Gupta P, Gupta N, Srinivasan R, Gupta P, Dutta U, Sharma S, Uppal R, Nada R, Lal A. HER2/ERBB2 overexpression in advanced gallbladder carcinoma: comprehensive evaluation by immunocytochemistry and fluorescence in situ hybridisation on fine-needle aspiration cytology samples. J Clin Pathol 2024; 77:614-621. [PMID: 37221046 DOI: 10.1136/jcp-2023-208940] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 05/12/2023] [Indexed: 05/25/2023]
Abstract
AIMS Advanced gallbladder carcinoma (AGBC) carries a poor prognosis with dismal survival. There are no data regarding HER2/ERBB2 expression in AGBC. This study evaluated the overexpression of HER2/ERBB2 in cytological aspirates from AGBCs to identify potential patients for whom anti-HER2 targeted therapies can benefit. METHODS This prospective, case-control study was performed on 50 primary AGBC cases. A detailed cytomorphological assessment, followed by immunocytochemistry (ICC) for HER2/ERBB2, was performed on AGBC cell blocks. A similar number of age-matched and gender-matched resected chronic cholecystitis specimens were included as controls. Fluorescence in situ hybridisation (FISH) was performed in equivocal cases. RESULTS A total of 10 (20%) cases showed positive (3+), 19 (38%) equivocal (2+) expression and 21 (42%) were negative on HER2/ERBB2 ICC. None of the equivocal cases demonstrated HER2 amplification by FISH. Among the controls, none showed positive (3+) immunoexpression, 23 (46%) demonstrated equivocal expression and 27 (54%) were negative. On statistical analysis, HER2/ERBB2 overexpression was significantly associated with AGBC compared with the controls. Of all the clinical, radiological and cytomorphological parameters, the predominant papillary or acinar arrangements of the tumour cells were significantly associated with HER2/ERBB2 overexpression. CONCLUSIONS This is the first study to evaluate the expression of HER2/ERBB2 on cytological aspirates in AGBC using ICC and FISH. HER2/ERBB2 overexpression(20%) was significantly associated with AGBC. Furthermore, predominant papillary or acinar arrangements of tumour cells in the cytological smears were significantly associated with HER2/ERBB2 overexpression. They can serve as potential predictors of HER2/ERBB2 overexpression to select AGBC patients for anti-HER2 targeted therapies.
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Affiliation(s)
- Pragya Verma
- Department of Pathology, PGIMER, Chandigarh, India
| | - Parikshaa Gupta
- Department of Cytology and Gynecologic Pathology, PGIMER, Chandigarh, India
| | - Nalini Gupta
- Department of Cytology and Gynecologic Pathology, PGIMER, Chandigarh, India
| | - Radhika Srinivasan
- Department of Cytology and Gynecologic Pathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pankaj Gupta
- Department of Radiodiagnosis, PGIMER, Chandigarh, India
| | - Usha Dutta
- Department of Gastroenterology, PGIMER, Chandigarh, India
| | - Shelly Sharma
- Department of Cytology and Gynecologic Pathology, PGIMER, Chandigarh, India
| | - Radha Uppal
- Department of Cytology and Gynecologic Pathology, PGIMER, Chandigarh, India
| | - Ritambhra Nada
- Histopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Anupam Lal
- Department of Radiodiagnosis, PGIMER, Chandigarh, India
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Kumar A, Sarangi Y, Gupta A, Sharma A. Gallbladder cancer: Progress in the Indian subcontinent. World J Clin Oncol 2024; 15:695-716. [PMID: 38946839 PMCID: PMC11212610 DOI: 10.5306/wjco.v15.i6.695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/25/2024] [Accepted: 05/15/2024] [Indexed: 06/24/2024] Open
Abstract
Gallbladder cancer (GBC) is one of the commonest biliary malignancies seen in India, Argentina, and Japan. The disease has dismal outcome as it is detected quite late due to nonspecific symptoms and signs. Early detection is the only way to improve the outcome. There have been several advances in basic as well as clinical research in the hepatobiliary and pancreatic diseases in the West and other developed countries but not enough has been done in GBC. Therefore, it is important and the responsibility of the countries with high burden of GBC to find solutions to the many unanswered questions like etiopathogenesis, early diagnosis, treatment, and prognostication. As India being one of the largest hubs for GBC in the world, it is important to know how the country has progressed on GBC. In this review, we will discuss the outcome of the publications from India highlighting the work and the developments taken place in past several decades both in basic and clinical research.
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Affiliation(s)
- Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Yajnadatta Sarangi
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Annapurna Gupta
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Aarti Sharma
- Division of Haematology, Mayo Clinic Arizona, Phoenix, AZ 85054, United States
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5
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Mani R, Gupta A, Gupta S, Goyal B, Mishra R, Tandon A, Sharma O, Rohilla KK, Kishore S, Dhar P. Expression of ER, PR, and HER-2 Neu and correlation with tumor markers in gall bladder carcinoma. J Cancer Res Ther 2023; 19:1279-1287. [PMID: 37787296 DOI: 10.4103/jcrt.jcrt_1754_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
Background Females having a large proportion of gallbladder carcinoma (GBC) and a higher incidence of gallstones pointed toward the role of sex hormones in GBC development. In this study, we evaluated the expression of Estrogen receptor (ER), Progesterone receptor (PR), and Her2/neu and their correlation with tumor markers and clinicopathological parameters in the GBC. Methods A total of 50 patients of GBC and 42 patients in control group undergoing surgery for other conditions were taken. The patient's biopsy sample's paraffin block was tested for ER, PR, and Her2/neu expression by immunohistochemistry. Results ER and PR had no significant expression in GBC and control group, but Her2/neu had 16% expression in GBC, significantly associated with the degree of differentiation with 62.5% (n-5) being well-differentiated; 75% of Her2/neu positive were in stages III and IV. Her2/neu did not correlate with tumor markers despite expression. Conclusions Her2/neu amplification is a small step in validating that option so it could be included in the treatment and prognostication of GBC.
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Affiliation(s)
- Rishit Mani
- Department of Surgery, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Amit Gupta
- Department of Surgery, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Sweety Gupta
- Department of Radiation Oncology, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Bela Goyal
- Department of Biochemistry, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Rahul Mishra
- Department of Surgery, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Amoli Tandon
- Department of Surgery, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Oshin Sharma
- Department of Surgery, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Kusum K Rohilla
- Department of Nursing, College of Nursing, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Sanjeev Kishore
- Department of Pathology, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
| | - Puneet Dhar
- Department of Surgical Gastroenterology, All India Institute of Medical Science, Rishikesh, Uttarakhand, India
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Kwon CH, Seo HI, Kim DU, Han SY, Kim S, Lee SJ, Jeon DY. HER2 status based on breast cancer guidelines as a useful prognostic marker of T2 gallbladder cancer. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:392-398. [PMID: 36369228 DOI: 10.1016/j.ejso.2022.10.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/23/2022] [Accepted: 10/28/2022] [Indexed: 11/05/2022]
Abstract
INTRODUCTION T2 gallbladder cancer (GBC) is the only stage showing a survival benefit after complete surgical resection, but recurrence rates remain high. Although human epidermal growth factor receptor 2 (HER2) has emerged as a therapeutic target, its role in T2 GBC remains unclear. This study investigated the status and prognostic impact of HER2 expression on T2 GBC. MATERIALS AND METHODS HER2 expression and amplification were detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively, in 90 patients with T2 GBC who underwent radical cholecystectomy. We evaluated HER2 status according to the breast and gastric cancer guidelines and analyzed the effect of relevant prognostic factors on survival. RESULTS HER2 positive status was observed in 11.11% (10/90) and 8.89% (8/90) of cases based on gastric and breast cancer guidelines, respectively. Poor differentiation and a higher level of perineural invasion were independent prognostic factors of disease-free survival (DFS). Old age, male sex, presence of lymph node metastasis, poor differentiation, high levels of perineural invasion, and HER2 positivity based on breast cancer guidelines were identified as independent prognostic factors of overall survival (OS). Patients with HER2-positive T2 GBC according to breast cancer guidelines had worse OS. CONCLUSIONS HER2 positivity based on breast- but not gastric-cancer guidelines was associated with poorer survival. These results provide a criterion for the evaluation of HER2 and a rationale for therapeutic strategies targeting HER2 in T2 GBC.
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Affiliation(s)
- Chae Hwa Kwon
- Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Hyung Il Seo
- Department of Surgery, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea.
| | - Dong Uk Kim
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Sung Yong Han
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Suk Kim
- Department of Radiology, Pusan National University School of Medicine, Busan, South Korea
| | - So Jeong Lee
- Department of Pathology, Seegene Medical Foundation, Busan, South Korea
| | - Da Ye Jeon
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
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Chen L, Xu L, Shen L, Luo R, Jiang D, Wang Y, Li W, Hou Y. HER2 Positivity Is Affected by the Papillary Structure and Has a Bidirectional Prognostic Value for Gallbladder Carcinoma. Front Genet 2022; 12:831318. [PMID: 35265100 PMCID: PMC8899850 DOI: 10.3389/fgene.2021.831318] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 12/27/2021] [Indexed: 11/15/2022] Open
Abstract
Gallbladder carcinoma (GBC) is responsible for 80%–95% of biliary tract malignancies and has a dismal prognosis. Human epidermal growth factor receptor 2 (HER2) is a promising therapeutic target of GBC. Through immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods, HER2 expression and gene amplification were identified on high-output tissue microarrays (TMAs) developed in 306 GBC cases to investigate its relationship with GBC and clinicopathological characteristics. Adenocarcinomas accounted for 223 (72.9%) of the cases, with 62 (27.8%) being papillary adenocarcinoma or having partial papillary structure. HER2 positivity was studied in 16.1% (36/223) of patients with adenocarcinoma and 41.9% (26/62) in adenocarcinoma with papillary structures. For 143 radically resected primary GBC cases with 24 HER2-positive tumors, survival data were valid; the median survival time was not reached, and the 5-year survival rate was 52.9%. All patients in stages 0–I survived, and the results of the HER2-positive group and the stage II HER2-negative group were similar (p = 0.354). However, in stage III, the mortality rate in the HER2-positive group was reduced (p = 0.005) and that in stage IV was higher (p = 0.005). In conclusion, HER2 positivity was significantly higher in patients with papillary GBC. The predictive value of HER2 varies by clinical stage, with no prediction in the early stages, better in stage III, and worse in stage IV.
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Affiliation(s)
- Lingli Chen
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lei Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Licheng Shen
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Rongkui Luo
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yueqi Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Li
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- *Correspondence: Yingyong Hou,
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Singh P, Jain SL, Sakhuja P, Agarwal A. Expression of VEGF-A, HER2/neu, and KRAS in gall bladder carcinoma and their correlation with clinico-pathological parameters. INDIAN J PATHOL MICR 2021; 64:687-692. [PMID: 34673587 DOI: 10.4103/ijpm.ijpm_248_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Gall bladder carcinoma (GBC) is a multi-factorial disease, involving multiple genetic alterations. The present pilot study aims to explore some of the molecular pathways, by studying immunohistochemical (IHC) expression of biomarkers (HER2/neu, KRAS, and VEGF) in GBC with their correlation with various clinicopathological parameters. AIM OF THE STUDY To study the expression of prognostic biomarkers (HER2/neu, KRAS and VEGF-A) in GBC and their correlation with clinico-morphological parameters. Materials and. METHODS This prospective study was conducted over a period of 2 years. The study group included tissue of GBC (29) reported as malignant on histopathology and cholecystitis as a control group (29) for histopathological evaluation and IHC expression of above markers. RESULTS HER2/neu was expressed in 27.5% cases, and KRAS in 51.6%; however, both showed no association with tumor type, stage and grade. No association was found in KRAS expression and dysplasia. Vascular Endothelial Growth Factor - A (VEGF-A) was expressed in 86.1% cases, of which strong positivity was seen in 48.27%; it showed significant association with tumor stage (P value-0.027, Fishers' exact test), hence possibly suggesting its role in tumor progression; though no association was found in VEGF expression with tumor type and grade. No significant association was seen with vascular and tumor invasion also. CONCLUSION The results suggest that the VEGF-A expression may be used as a potential prognostic biomarker in GBC.
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Affiliation(s)
- Pomilla Singh
- Bharati Vidyapeeth Deemed to be University Medical College, Pune, Maharashtra; Department of Pathology, Maulana Azad Medical College, New Delhi, India
| | - Shyam Lata Jain
- Department of Pathology, Maulana Azad Medical College, New Delhi, India
| | - Puja Sakhuja
- Department of Pathology, GB Pant Institute of Post Graduate Medical Education and Research, New Delhi, India
| | - Anil Agarwal
- Department of GI Surgery, GB Pant Institute of Post Graduate Medical Education and Research, New Delhi, India
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Sung YN, Kim SJ, Jun SY, Yoo C, Kim KP, Lee JH, Hwang DW, Hwang S, Lee SS, Hong SM. Expression of HER2 and Mismatch Repair Proteins in Surgically Resected Gallbladder Adenocarcinoma. Front Oncol 2021; 11:658564. [PMID: 34367955 PMCID: PMC8339709 DOI: 10.3389/fonc.2021.658564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 06/29/2021] [Indexed: 12/30/2022] Open
Abstract
Background Gallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs. Materials and Methods To determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively. Results Three of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status. Conclusion MMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.
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Affiliation(s)
- You-Na Sung
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sung Joo Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sun-Young Jun
- Department of Pathology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kyu-Pyo Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jae Hoon Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Dae Wook Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sang Soo Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Gupta A, Gupta S, Mani R, Durgapal P, Goyal B, Rajput D, Rao S, Dhar P, Gupta M, Kishore S, Kant R. Expression of Human epidermal growth factor receptor 2, Survivin, Enhancer of zeste homolog -2, Cyclooxygenase-2, p53 and p16 molecular markers in Gall bladder carcinoma. J Carcinog 2021; 20:7. [PMID: 34321957 PMCID: PMC8312376 DOI: 10.4103/jcar.jcar_4_21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 02/26/2021] [Accepted: 03/05/2021] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION: Gallbladder cancer exhibits striking variability in the global rates, reaching epidemic levels for some regions and ethnicities. The basis of its variability resides in differences in environmental exposure and intrinsic genetic predisposition to carcinogenesis. There is little information present regarding genetic and molecular alterations in gall bladder cancer (GBC). We, therefore, have evaluated the molecular marker expression in GBC and studied their correlation with clinicopathological staging. MATERIALS AND METHODS: This prospective observational study was conducted on newly diagnosed GBC patients from July 2017 to July 2020. After complete staging workup, the GBC biopsy samples paraffin block was tested for molecular markers estrogen receptor (ER), progesterone receptor (PR), p53, p16, Human epidermal growth factor receptor 2 (HER 2-neu), Survivin, Enhancer of zeste homolog-2 (EZH2), and Cyclooxygenase-2 (COX-2) expression by immunohistochemistry. RESULTS: Fifty newly diagnosed patients of carcinoma gall bladder were included in the present study. Age was ranged from 29 – 69 years (mean 53.42). p53 was the most common positive marker in 74% of patients, survivin in 58%, COX-2 in 44%, and p16 in 42% whereas Her 2 neu and EZH-2 were positive in 16% of patients each. None of the patients of GBC were ER or PR positive. There was a significant difference between the various groups in terms of the distribution of histological grade and Her 2 neu (χ2 = 9.886, P = 0.014) but not with other markers. Furthermore, there was a significant difference in terms of distribution of p16 and p53 with stage (χ2 = 7.017, P = 0.037 and χ2 = 5.861, P = 0.033) respectively. CONCLUSIONS: The present study shows the expression of molecular markers Her2 neu, p53, p16, survivin, COX-2, and EZH-2 in GBC. Now the time has come, and it is also the need of the day to establish early biomarkers of this highly lethal malignancy. It can be used in future for the detection of disease in the early phase and targeted therapy.
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Affiliation(s)
- Amit Gupta
- Department of Surgery, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Sweety Gupta
- Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Rishit Mani
- Department of Surgery, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Prashant Durgapal
- Department of Pathology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Bela Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Deepak Rajput
- Department of Surgery, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Shalinee Rao
- Department of Pathology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Puneet Dhar
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Manoj Gupta
- Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Sanjeev Kishore
- Department of Pathology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Ravi Kant
- Department of Surgery, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
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Jain P, Goyal S, Chauhan G, Majumdar K, Ali S, Sakhuja P, Agarwal AK. HER-2/neu over expression in gall bladder adenocarcinoma: A quest for potential therapeutic target. INDIAN J PATHOL MICR 2020; 63:214-220. [PMID: 32317518 DOI: 10.4103/ijpm.ijpm_664_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gall bladder carcinoma (GBC) is an aggressive malignancy with high mortality and aggressive course, with palliation as the only available option. OBJECTIVES To evaluate frequency of HER-2/neu overexpression in GBC and to seek its correlation, if any with conventional clinicopathological parameters and survival. METHODS Immunohistochemistry (IHC) was performed on 200 cases of GBC, 32 cases of dysplasia, and 100 cases of chronic cholecystitis. Fluorescent in situ hybridization (FISH) was performed on 30 randomly selected cases of GBC to validate IHC. HER-2/neu overexpression (IHC 3+/FISH amplification ≥2.2) was correlated with clinicopathological parameters by Chi-square test.P < 0.05 was considered significant. Survival analysis was done by log-rank test and Kaplan-Meier analysis. RESULTS HER-2/neu overexpression was seen in 14% (28/200) GBC cases but was not found in dysplasia and chronic cholecystitis. Majority of these cases were ≤grade 2 and in advanced stage, however this was not statistically significant. A lower mean survival in HER-2/neu positive group as compared to HER-2/neu negative group (17.1 ± 2.3 month versus 67.6 ± 8.5 month, respectively) was observed. Concordance between IHC and FISH was seen in 18/19 cases. CONCLUSION This study delineates a subset of GBC patients with HER-2/neu overexpression, in whom targeted therapy can offer a survival benefit.
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Affiliation(s)
- Pragya Jain
- Department of Pathology, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
| | - Surbhi Goyal
- Department of Pathology, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
| | - Geeta Chauhan
- Department of Pathology, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
| | - Kaushik Majumdar
- Department of Pathology, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
| | - Shahajad Ali
- Department of Pathology, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
| | - Puja Sakhuja
- Department of Pathology, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
| | - Anil K Agarwal
- Department of Gastro-Surgery, GIPMER, Jawaharlal Nehru Marg, 64 Khamba, New Delhi, India
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Albrecht T, Rausch M, Roessler S, Geissler V, Albrecht M, Halske C, Seifert C, Renner M, Singer S, Mehrabi A, Vogel MN, Pathil-Warth A, Busch E, Köhler B, Rupp C, Weiss KH, Springfeld C, Röcken C, Schirmacher P, Goeppert B. HER2 gene (ERBB2) amplification is a low-frequency driver with potential predictive value in gallbladder carcinoma. Virchows Arch 2019; 476:871-880. [PMID: 31838585 DOI: 10.1007/s00428-019-02706-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/16/2019] [Accepted: 10/22/2019] [Indexed: 12/19/2022]
Abstract
Gallbladder carcinoma (GBC) is an aggressive type of cancer with a dismal prognosis. Recent case reports have highlighted the human epidermal growth factor receptor 2 (HER2) as a promising target for individualized therapy in biliary tract cancer; however, current data on HER2 positivity in GBC is contradictory. This study aimed to assess the proportion of HER2 positivity and its clinical implications in a large and well-characterized European GBC cohort. HER2 status was determined in 186 cases of surgically resected gallbladder adenocarcinoma and a subset of coexistent high-grade biliary intraepithelial neoplasia (BilIN, n = 74) in accordance with the up-to-date consensus for HER2 testing in gastric cancer by immunohistochemistry and dual-color chromogenic in situ hybridization. Positivity for HER2 was observed in 5.4% of all cases (n = 10). In those patients with concomitant high-grade BilIN, two of four positive samples also showed amplification in the precursor lesion, while in the two remaining cases, positivity was either confined to invasive tumor or high-grade BilIN, exclusively. Equivocal staining found in eleven cases was not accompanied by gene amplification. Staging of the HER2-positive group was significantly different from the HER2-negative group with most cases presenting at stage IV, paralleled by a trend towards decreased survival. One patient who received dual HER2 inhibition almost went into full clinical remission despite treatment initiation in a metastasized state. Our results reveal a low prevalence of HER2 positivity and highlight HER2 gene amplification as an early, potentially driving event in gallbladder carcinogenesis. Prospective standardized HER2 testing and randomized control studies are needed to prove clinical efficacy of targeted HER2 inhibition in GBC.
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Affiliation(s)
- Thomas Albrecht
- Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.,Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany
| | - Melina Rausch
- Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Stephanie Roessler
- Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.,Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany
| | - Veronika Geissler
- Tissue Bank of the National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - Michael Albrecht
- European Center for Angioscience (ECAS), Medical Faculty of Mannheim, Heidelberg University, Heidelberg, Germany
| | - Christine Halske
- Institute of Pathology, Schleswig-Holstein University Hospital, Kiel, Germany
| | - Carolin Seifert
- Institute of Pathology, Schleswig-Holstein University Hospital, Kiel, Germany
| | - Marcus Renner
- Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Stephan Singer
- Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Arianeb Mehrabi
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Monika Nadja Vogel
- Diagnostic and Interventional Radiology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Anita Pathil-Warth
- Department of Internal Medicine IV, Gastroenterology and Hepatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Elena Busch
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - Bruno Köhler
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - Christian Rupp
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany.,Department of Internal Medicine IV, Gastroenterology and Hepatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Karl Heinz Weiss
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany.,Department of Internal Medicine IV, Gastroenterology and Hepatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Christoph Springfeld
- Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - Christoph Röcken
- Institute of Pathology, Schleswig-Holstein University Hospital, Kiel, Germany
| | - Peter Schirmacher
- Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.,Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany
| | - Benjamin Goeppert
- Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. .,Liver Cancer Center Heidelberg (LCCH), Heidelberg University Hospital, Heidelberg, Germany.
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HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev 2017; 36:141-157. [PMID: 27981460 PMCID: PMC5385197 DOI: 10.1007/s10555-016-9645-x] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9-34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8-27.1 %) vs. 4.8 % (95 % CI 0-14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2-99 %) vs. 17.9 % (95 % CI 0.1-35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7-46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.
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Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
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15
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Han S, Liu L, Xu F, Chen S, Yuan W, Fu Z, Li D, Li D. A case-control study about the association between vascular endothelial growth inhibitor gene polymorphisms and breast cancer risk in female patients in Northeast China. Chin J Cancer Res 2016; 28:435-43. [PMID: 27647972 PMCID: PMC5018539 DOI: 10.21147/j.issn.1000-9604.2016.04.07] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Objective The inhibition of the neovascularization in tumors is a potential therapeutic target of cancer. Vascular endothelial growth inhibitor (VEGI) is a member of the TNF superfamily which has the ability to suppress the formation of new vessels in tumors. In order to study the association between VEGI gene polymorphisms and breast cancer risk, a case-control study was conducted in Chinese Han women in Northeast China. Methods Our study involved 708 female breast cancer patients and 685 healthy volunteers. Four SNPs of VEGI gene were analyzed through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between VEGI gene polymorphisms and breast cancer risk was analyzed in our study. The relation between VEGI gene variants and clinical features of breast cancer including lymph node (LN) metastasis, estrogen receptor (ER), progestrogen receptor (PR), tumor protein 53 (p53), human epidermal growth factor receptor 2 (Her-2) and triple negative (ER-/PR-/Her-2-) status was analyzed as well. Results We found that the CT genotype and T allele of rs6478106 were more frequent in patients than in controls. There was also a statistical difference in the distribution of Crs6478106Grs4263839 haplotype between patients and controls. In addition, SNP rs6478106 and rs4979462 were related with the Her-2 status. Conclusions Our results suggest that VEGI gene variants may be related to the breast cancer risk and the clinical features of breast cancer in Chinese Han women in Northeast China.
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Affiliation(s)
| | - Lei Liu
- Department of Immunology; College of Bioinformatics Science and Technology
| | | | | | - Weiguang Yuan
- Department of Immunology; Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin 150081, China
| | | | - Dalin Li
- Department of Surgery, the Third Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Dianjun Li
- Department of Immunology; Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin 150081, China
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Yoshida H, Shimada K, Kosuge T, Hiraoka N. A significant subgroup of resectable gallbladder cancer patients has an HER2 positive status. Virchows Arch 2016; 468:431-9. [PMID: 26758058 DOI: 10.1007/s00428-015-1898-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 10/24/2015] [Accepted: 12/28/2015] [Indexed: 12/13/2022]
Abstract
Gallbladder cancer (GBC) has a poor prognosis, and new targeted therapeutic options are needed. We investigated the human epidermal growth factor receptor 2 (HER2) status and its clinicopathological significance in a large cohort of GBC patients. We assessed HER2 expression in a consecutive series of 211 GBC cases by immunohistochemistry (IHC), paying particular attention to intratumoral heterogeneity. HER2 gene amplification was analyzed by dual-color fluorescence in situ hybridization (FISH). An HER2 positive status was called when the IHC score was 3+ or when the IHC score was 2+, and FISH was positive. Correlations were analyzed between HER2 status and clinicopathological parameters including survival. The HER2 IHC score was 0 in 144 (68.2%), 1+ in 28 (13.3%), 2+ in 14 (6.6%), and 3+ in 25 cases (11.8%). In 20/39 (51%) of the IHC 2+ and 3+ cases, the staining pattern was heterogeneous. In HER2 IHC score 2+ and 3+ cases, HER2 FISH was positive in 83% (10/12) and 96% (24/25), respectively. Altogether, 35/211 cases (16.6%) were HER2 positive. There was no significant association between HER2 status and clinicopathological variables or survival. We identified a significant subgroup of HER2-positive GBC cases, for whom a clinical trial with anti-HER2 therapy might be considered.
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Affiliation(s)
- Hiroshi Yoshida
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kazuaki Shimada
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tomoo Kosuge
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Nobuyoshi Hiraoka
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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Mishra K, Behari A, Kapoor VK, Khan MS, Prakash S, Agrawal S. Platelet Derived Growth Factor-B and Human Epidermal Growth Factor Receptor-2 Polymorphisms in Gall Bladder Cancer. Asian Pac J Cancer Prev 2015; 16:5647-54. [PMID: 26320430 DOI: 10.7314/apjcp.2015.16.14.5647] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Gall bladder cancer (GBC) is a gastro-intestinal cancer with high prevalence among north Indian women. Platelet derived growth factor-B (PDGFB) and human epidermal growth factor receptor-2 (HER2) may play roles in the etiology of GBC through the inflammation-hyperplasia-dysplasia-carcinoma pathway. To study the association of PDGFB and HER2 polymorphisms with risk of GBC, 200 cases and 300 controls were considered. PDGFB +286A>G and +1135A>C polymorphisms were investigated with an amplification refractory mutation system and the HER2 Ile655Val polymorphism by restriction fragment length polymorphism. Significant risk associations for PDGFB +286 GG (OR=5.25) and PDGFB +1135 CC (OR=3.19) genotypes were observed for GBC. Gender wise stratification revealed susceptibility for recessive models of PDGFB +1135A>C (OR=3.00) and HER2 Ile655Val (OR=2.52) polymorphisms among female GBC cases. GBC cases with gall stones were predisposed to homozygous +286 GG and +1135 CC genotypes. Significant risk associations were found for ACIle (OR=1.48), GAVal (OR=1.70), GAIle (OR=2.00) haplotypes with GBC cases and GCIle haplotype with female GBC cases (OR=10.37, P=<0.0001). Pair-wise linkage disequilibrium revealed negative associations among variant alleles. On multi-dimensional reduction analysis, a three factor model revealed significant gene-gene interaction for PDGFB +286A>G, PDGFB +1135A>C and HER2 Ile165Val SNPs with GBC. Protein-protein interaction showed significant association of PDGFB and HER2 with the epidermal growth factor receptor signaling pathway.
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Affiliation(s)
- Kumudesh Mishra
- Department of Surgical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India E-mail : ,
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Gallbladder Cancer in the 21st Century. JOURNAL OF ONCOLOGY 2015; 2015:967472. [PMID: 26421012 PMCID: PMC4569807 DOI: 10.1155/2015/967472] [Citation(s) in RCA: 187] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 08/07/2015] [Accepted: 08/12/2015] [Indexed: 02/07/2023]
Abstract
Gallbladder cancer (GBC) is an uncommon disease in the majority of the world despite being the most common and aggressive malignancy of the biliary tree. Early diagnosis is essential for improved prognosis; however, indolent and nonspecific clinical presentations with a paucity of pathognomonic/predictive radiological features often preclude accurate identification of GBC at an early stage. As such, GBC remains a highly lethal disease, with only 10% of all patients presenting at a stage amenable to surgical resection. Among this select population, continued improvements in survival during the 21st century are attributable to aggressive radical surgery with improved surgical techniques. This paper reviews the current available literature of the 21st century on PubMed and Medline to provide a detailed summary of the epidemiology and risk factors, pathogenesis, clinical presentation, radiology, pathology, management, and prognosis of GBC.
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Kitamura T, Srivastava J, DiGiovanni J, Kiguchi K. Bile acid accelerates erbB2-induced pro-tumorigenic activities in biliary tract cancer. Mol Carcinog 2013; 54:459-72. [PMID: 24839254 DOI: 10.1002/mc.22118] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 10/31/2013] [Accepted: 11/05/2013] [Indexed: 12/16/2022]
Abstract
Although very few studies have addressed the molecular and cellular mechanisms underlying the development of biliary tract cancer (BTC), several lines of evidence suggest a role for the erbB receptor family. Overexpression and activation of erbB2 has been reported in a significant percentage of human BTC. Further, we previously reported that overexpression of erbB2 basal epithelial cells of the biliary tract (BK5.erbB2 mouse) led to the development of BTC. However, the mechanisms by which erbB2 overexpression led to the spontaneous development of tumors specifically in the biliary tract are not completely understood. The goals of the current study were to (1) determine whether a cooperative relationship between bile acid exposure and erbB2 activation exists during biliary tract carcinogenesis and (2) to characterize the mechanism(s) underlying bile acid-mediated biliary tract carcinogenesis in cells with activated erbB2. In this study, we demonstrated that the secondary conjugated bile acid, taurochenodeoxycholic acid (TCDC), increased proliferation of primary cultured gallbladder epithelial cells from BK5.erbB2 mice and human BTC cells. TCDC treatment activated EGFR/erbB2 and downstream signaling molecules in both primary cultured cells and human BTC cells. TCDC also increased the expression of epidermal growth factor receptor (EGFR) ligands and TACE activity in human BTC cells. Inhibition of src activation led to attenuation of bile-induced upregulation of TACE activity as well as signaling through the EGFR/erbB2, suggesting that during the development of BTC erbB2 overexpression/activation accelerates the bile acid-induced signaling cascade: bile acid → src → TACE → EGFR/erbB2 → downstream signaling. We also provide direct evidence that bile acids possess tumor promoting capacity in epithelial cells overexpressing erbB2 using the two-stage skin carcinogenesis model. Collectively these findings suggest cooperative roles for bile acid and erbB2 activation in epithelial cell proliferation; bile acid appears to accelerate erbB2-induced pro-tumorigenic activities in the biliary tract and skin.
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Affiliation(s)
- Takuya Kitamura
- Department of Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas
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