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1
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Park JH, Shin JI, Lim BJ. Prognostic significance of tumour budding in noncolorectal gastrointestinal tract and pancreatobiliary tract: a systematic review and meta-analysis. Histopathology 2024; 84:1079-1091. [PMID: 38362762 DOI: 10.1111/his.15154] [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] [Received: 12/07/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/17/2024]
Abstract
Tumour budding shows promise as a prognostic factor in various cancers, but its widespread application is hindered by the lack of large, validated studies and standardized criteria. This meta-analysis aims to review and examine the prognostic role of tumour budding specifically in noncolorectal gastrointestinal and pancreatobiliary tract cancers, broadening our perspective on its clinical relevance. The literature review was conducted through PubMed, Embase, and Web of Science from inception till 20 February 2023. Pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) were calculated to assess the relation between tumour budding and clinicopathologic features, as well as overall survival. Each study was evaluated using the Newcastle-Ottawa Scale and both heterogeneity and publication bias were analysed. In this meta-analysis of 57 studies across various cancer types, multivariate HR revealed worse overall survival in oesophageal squamous cell carcinoma (HR 3.34 [95% CI 2.21-5.04]), gastric adenocarcinoma (2.03 [1.38-2.99]), pancreatic ductal adenocarcinoma (2.56 [2.02-3.25]), and biliary tract adenocarcinoma (3.11 [2.46-3.93]) with high-grade tumour budding. Additionally, high-grade tumour budding consistently correlated with adverse clinicopathological features, including lymph node metastasis, lymphovascular invasion, and distant metastasis without any observed inverse association. High heterogeneity was noted. Our study suggests that tumour budding is a valuable prognostic marker in various cancers. Nonetheless, standardized criteria tailored to specific organ types are necessary to enhance its clinical utility.
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Affiliation(s)
- Ji Hyun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Beom Jin Lim
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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Liu H, Lan T, Cai YS, Lyu YH, Zhu J, Xie SN, Hu FJ, Liu C, Wu H. Predicting prognosis in intrahepatic cholangiocarcinoma by the histopathological features. Asian J Surg 2024; 47:2589-2597. [PMID: 38604849 DOI: 10.1016/j.asjsur.2024.03.085] [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] [Received: 09/12/2023] [Revised: 12/23/2023] [Accepted: 03/06/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous liver tumor. The associations between histopathological feature and prognosis of ICC are limited. The present study aimed to investigate the prognostic significance of glandular structure and tumor budding in ICC. METHODS Patients received radical hepatectomy for ICC were included. Glandular structure and tumor budding were detected by Hematoxylin-eosin staining. The Kaplan-Meier method and the Cox proportional hazards regression model were used to calculate the survival and hazard ratio. Based on the results of multivariate analysis, nomograms of OS and DFS were constructed. C-index and Akaike information criterion (AIC) were used to assess accuracy of models. RESULTS A total of 323 ICC patients who underwent surgery were included in our study. Glandular structure was associated with worse overall survival (OS) [hazard ratio (HR): 2.033, 95% confidence interval (CI): 1.047 to 3.945] and disease-free survival (DFS) [HR: 1.854, 95% CI: 1.082 to 3.176]. High tumor budding was associated with worse DFS [HR: 1.636, 95%CI: 1.060 to 2.525]. Multivariate analysis suggested that glandular structure, tumor number, lymph node metastasis, and CA19-9 were independent risk factors for OS. Independent predictor factors for DFS were tumor budding, glandular structure, tumor number, and lymph node metastasis. The c-index (0.641 and 0.642) and AIC (957.69 and 1188.52) showed that nomograms of OS and DFS have good accuracy. CONCLUSION High tumor budding and glandular structure are two important histopathological features that serve as prognostic factors for ICC patients undergoing hepatectomy.
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Affiliation(s)
- Hu Liu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tian Lan
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yun-Shi Cai
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ying-Hao Lyu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiang Zhu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Si-Nan Xie
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Feng-Juan Hu
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chang Liu
- Division of Liver, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Minimal Invasive Surgery, Shangjin Nanfu Hospital, Chengdu, 610037, China.
| | - Hong Wu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Yoshida Y, Nakanishi Y, Mitsuhashi T, Yamamoto H, Hayashi MO, Oba M, Nitta T, Ueno T, Yamada T, Ono M, Kuwabara S, Hatanaka Y, Hirano S. Postoperative Prognosis According to Pathologic Categorization of Desmoplastic Reaction in Patients with Extrahepatic Cholangiocarcinoma. Ann Surg Oncol 2023; 30:7348-7357. [PMID: 37528304 DOI: 10.1245/s10434-023-13867-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 06/19/2023] [Indexed: 08/03/2023]
Abstract
BACKGROUND Recent studies have demonstrated the importance of desmoplastic reaction (DR) in predicting postoperative prognosis for patients with colorectal carcinoma. However, the impact of DR on the prognosis of extrahepatic cholangiocarcinomas (EHCCs) is not established. This study aimed to clarify the associations of pathologic DR categories with clinicopathologic factors and postoperative prognosis of perihilar cholangiocarcinoma (PHCC) and distal cholangiocarcinoma (DCC). METHODS A pathologic review of 174 patients with PHCC and 109 patients with DCC who underwent surgical resection was performed. The patients were classified into three DR categories (immature, intermediate, and mature) based on the histologic features within the fibrotic stroma in the invasive front. The association between DR categories and the distribution of fibroblasts with anti-α-smooth muscle actin (SMA) expression, seeming to be tumor-promoting cancer-associated fibroblasts (CAFs), was evaluated in 191 tissue microarray specimens of EHCCs. RESULTS Intermediate/immature DR categories were significantly associated with a more invasive nature, including higher pT and pN stages and more tumor buds than the mature category in both PHCC and DCC. The DR categories could stratify overall survival (OS) and relapse-free survival (RFS) in both PHCC and DCC patients. In the multivariate analysis, the DR category was an independent prognostic factor for OS and RFS in both PHCC and DCC (p < 0.001). The mature and immature DR categories were significantly associated respectively with the confined and pervasive distribution of fibroblasts with α-SMA expression. CONCLUSION In patients with EHCCs, DR categorization was an independent prognostic factor reflecting the distribution of tumor-promoting CAFs in the invasive front.
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Affiliation(s)
- Yusuke Yoshida
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Yoshitsugu Nakanishi
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Hiroyuki Yamamoto
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Mariko O Hayashi
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Mitsunobu Oba
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Takeo Nitta
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takashi Ueno
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Toru Yamada
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masato Ono
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Shota Kuwabara
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yutaka Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, N-15, W-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
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Unal B, Celik MY, Gedik EO, Bassorgun CI, Elpek GO. Tumor budding as a potential prognostic marker in determining the behavior of primary liver cancers. World J Hepatol 2023; 15:775-785. [PMID: 37397937 PMCID: PMC10308291 DOI: 10.4254/wjh.v15.i6.775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/22/2023] [Accepted: 04/18/2023] [Indexed: 06/25/2023] Open
Abstract
Hepatocellular (HCC) and intrahepatic cholangiocarcinoma (ICC), the most common primary tumors of the liver, are among the most important causes of cancer deaths worldwide. Because patients with primary liver tumors are frequently diagnosed at an advanced stage and have high mortality, many efforts have been made to identify new markers to determine their behavior and treatment, similar to those in other solid organ tumors. Recently, morphological assessment of tumor budding (TB) has been revealed as a promising prognostic finding to predict tumor behavior and survival across several different tumor types. Currently, the TB score in colorectal cancer has been revealed as an important parameter in pathology report protocols to determine the course of the disease. Regarding the liver, despite enormous data showing that many mechanisms involved in TB are associated with tumor behavior in both HCC and ICC, studies focusing on the role of TB in predicting the behavior and prognosis of these tumors have started to be investigated very recently. The purpose of this review is to present data about TB in primary tumors of the liver, pointing out the potential role of this parameter in determining the course of the disease, and emphasize the need to increase the number of further studies focusing on the evaluation of this parameter with an overview of the mechanisms involved in TB.
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Affiliation(s)
- Betul Unal
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
| | | | - Elif Ocak Gedik
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
| | | | - Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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Kim KB, Ahn JH, Kwon SW, Lee SJ, Lee Y, Park SY, Kim A, Choi KU, Lee CH, Huh GY. Tumor budding as a predictor of disease-free survival in patients with cholangiocarcinoma. Pathol Oncol Res 2023; 29:1611216. [PMID: 37274771 PMCID: PMC10232744 DOI: 10.3389/pore.2023.1611216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/08/2023] [Indexed: 06/07/2023]
Abstract
Background: Tumor budding is considered a prognostic factor in several solid cancer types. However, we lack comprehensive information on the importance of tumor budding in cholangiocarcinoma. Therefore, we aimed to assess the prognostic value of tumor budding in intrahepatic and extrahepatic cholangiocarcinomas and to evaluate its correlations with other clinicopathological parameters. Methods: We monitored 219 patients who underwent surgery for intrahepatic or extrahepatic cholangiocarcinoma at the Pusan National University Hospital between 2012 and 2021. Tumor budding was evaluated using the International Tumor Budding Consensus Conference scoring system. Tumor budding was classified into low (0-4), intermediate (5-9), and high (≥10). For statistical analysis, tumor budding was divided into two groups based on the cut-off value of 10 (lower: 0-9 vs. higher: ≥10). The correlations between clinicopathological parameters were examined using the chi-square and Fisher's exact test. The prognostic values of the variables were analyzed using the log-rank test and Cox regression analysis. Results: Low, intermediate, and high tumor buddings were identified in 135 (61.6%), 63 (28.8), and 21 (9.6%), patients, respectively. Higher tumor budding was related to the presence of lymphatic invasion (p = 0.017), higher tumor grade (p = 0.001), higher N category (p = 0.034). In the univariable and multivariable analyses, higher tumor budding was associated with shorter disease-free survival in 97 (44.3%) patients who underwent R0 resection (p < 0.001 and p = 0.011). Tumor budding did not significantly correlate with disease-specific survival in entire patients. Conclusion: Tumor budding may serve as a prognostic factor for intrahepatic and extrahepatic cholangiocarcinomas treated with R0 resection.
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Affiliation(s)
- Kyung Bin Kim
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
| | - Ji Hyun Ahn
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
| | - Soon Wook Kwon
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
| | - Su Ji Lee
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
| | - Yury Lee
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
| | - Seo Young Park
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
| | - Ahrong Kim
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
- Department of Pathology, Pusan National University School of Medicine, Yangsan-si, Gyeongsangnamdo, Republic of Korea
| | - Kyung Un Choi
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
- Department of Pathology, Pusan National University School of Medicine, Yangsan-si, Gyeongsangnamdo, Republic of Korea
| | - Chang Hun Lee
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
- Department of Pathology, Pusan National University School of Medicine, Yangsan-si, Gyeongsangnamdo, Republic of Korea
| | - Gi Yeong Huh
- Department of Pathology, Pusan National University Hospital, Busan, Republic of Korea
- Department of Pathology, Pusan National University School of Medicine, Yangsan-si, Gyeongsangnamdo, Republic of Korea
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Oba M, Nakanishi Y, Mitsuhashi T, Sasaki K, Hatanaka KC, Sasaki M, Nange A, Okumura A, Hayashi M, Yoshida Y, Nitta T, Ueno T, Yamada T, Ono M, Kuwabara S, Okamura K, Tsuchikawa T, Nakamura T, Noji T, Asano T, Tanaka K, Takayama K, Hatanaka Y, Hirano S. CCR7 Mediates Cell Invasion and Migration in Extrahepatic Cholangiocarcinoma by Inducing Epithelial-Mesenchymal Transition. Cancers (Basel) 2023; 15:cancers15061878. [PMID: 36980764 PMCID: PMC10047000 DOI: 10.3390/cancers15061878] [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: 02/10/2023] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) contributes to the metastatic cascade in various tumors. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine (C-C motif) ligand 19 (CCL19), to promote EMT. However, the association between EMT and CCR7 in extrahepatic cholangiocarcinoma (EHCC) remains unknown. This study aimed to elucidate the prognostic impact of CCR7 expression and its association with clinicopathological features and EMT in EHCC. The association between CCR7 expression and clinicopathological features and EMT status was examined via the immunohistochemical staining of tumor sections from 181 patients with perihilar cholangiocarcinoma. This association was then investigated in TFK-1 and EGI-1 EHCC cell lines. High-grade CCR7 expression was significantly associated with a large number of tumor buds, low E-cadherin expression, and poor overall survival. TFK-1 showed CCR7 expression, and Western blotting revealed E-cadherin downregulation and vimentin upregulation in response to CCL19 treatment. The wound healing and Transwell invasion assays revealed that the activation of CCR7 by CCL19 enhanced the migration and invasion of TFK-1 cells, which were abrogated by a CCR7 antagonist. These results suggest that a high CCR7 expression is associated with an adverse postoperative prognosis via EMT induction and that CCR7 may be a potential target for adjuvant therapy in EHCC.
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Affiliation(s)
- Mitsunobu Oba
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Yoshitsugu Nakanishi
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Katsunori Sasaki
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Kanako C Hatanaka
- Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo 060-8648, Japan
- Center for Development of Advanced Diagnostics (C-DAD), Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Masako Sasaki
- NB Health Laboratory Co. Ltd., Sapporo 001-0021, Japan
| | - Ayae Nange
- Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Asami Okumura
- Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Mariko Hayashi
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Yusuke Yoshida
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Takeo Nitta
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Takashi Ueno
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Toru Yamada
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Masato Ono
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Shota Kuwabara
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Keisuke Okamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Takehiro Noji
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Toshimichi Asano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Kimitaka Tanaka
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | | | - Yutaka Hatanaka
- Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo 060-8648, Japan
- Center for Development of Advanced Diagnostics (C-DAD), Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
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Yang Y, Zhang X. An overview of extrahepatic cholangiocarcinoma: from here to where? Front Oncol 2023; 13:1171098. [PMID: 37197436 PMCID: PMC10183586 DOI: 10.3389/fonc.2023.1171098] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/11/2023] [Indexed: 05/19/2023] Open
Abstract
Extrahepatic cholangiocarcinoma (eCCA) contains perihilar cholangiocarcinoma and distal cholangiocarcinoma both of which can arise at any point of the biliary tree and originate from disparate anatomical sites. Generally, the incidence of eCCA is increasing globally. Though surgical resection is the principal treatment of choice for the early stages of eCCA, optimal survival remains restricted by the high risk of recurrence when most patients are present with unresectable disease or distant metastasis. Furthermore, both intra- and intertumoral heterogeneity make it laborious to determine molecularly targeted therapies. In this review, we mainly focused on current findings in the field of eCCA, mostly including epidemiology, genomic abnormalities, molecular pathogenesis, tumor microenvironment, and other details while a summary of the biological mechanisms driving eCCA may shed light on intricate tumorigenesis and feasible treatment strategies.
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Tumour invasion and dissemination. Biochem Soc Trans 2022; 50:1245-1257. [PMID: 35713387 PMCID: PMC9246329 DOI: 10.1042/bst20220452] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/16/2022] [Accepted: 05/30/2022] [Indexed: 11/17/2022]
Abstract
Activating invasion and metastasis are one of the primary hallmarks of cancer, the latter representing the leading cause of death in cancer patients. Whilst many advances in this area have been made in recent years, the process of cancer dissemination and the underlying mechanisms governing invasion are still poorly understood. Cancer cells exhibit multiple invasion strategies, including switching between modes of invasion and plasticity in response to therapies, surgical interventions and environmental stimuli. The ability of cancer cells to switch migratory modes and their inherent plasticity highlights the critical challenge preventing the successful design of cancer and anti-metastatic therapies. This mini-review presents current knowledge on the critical models of tumour invasion and dissemination. We also discuss the current issues surrounding current treatments and arising therapeutic opportunities. We propose that the establishment of novel approaches to study the key biological mechanisms underlying the metastatic cascade is critical in finding novel targets that could ultimately lead to complete inhibition of cancer cell invasion and dissemination.
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Sakaguchi T, Satoi S, Hashimoto D, Yamamoto T, Yamaki S, Hirooka S, Ishida M, Ikeura T, Inoue K, Naganuma M, Ishikawa H, Sekimoto M. High tumor budding predicts a poor prognosis in resected duodenal adenocarcinoma. Surg Today 2022; 52:931-940. [PMID: 34988677 DOI: 10.1007/s00595-021-02433-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/28/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE Tumor budding is a histological characteristic defined as the presence of small clusters of cancer cells at the invasion front. Its significance in duodenal adenocarcinoma (DA) has not been fully described. METHODS A single-center, retrospective study was conducted. Patients who underwent curative surgery for histologically diagnosed DA from January 2006 to December 2018 at Kansai Medical University Hospital were included. Tumor budding was counted per 0.785 mm2 and classified as low (0-4 buds), intermediate (5-9 buds), or high (≥ 10 buds). RESULTS In total, 47 patients were included. The 5-year overall survival and relapse-free survival rates were 77% and 72%, respectively. High tumor budding was seen in 15 patients (32%). Excluding patients with superficial type (pT1) DA (n = 22), high tumor budding [hazard ratio (HR) 13.4, p = 0.028], regional lymph node metastasis (HR 19.9, p = 0.039), and adjuvant chemotherapy (HR 0.056, p = 0.036) were independent factors related to the overall survival in multivariate analyses. Distant metastases occurred significantly more often in patients who had high tumor budding than in others (p = 0.039). CONCLUSION The data suggest that high tumor budding is a predictor of a poor prognosis in resected DA.
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Affiliation(s)
- Tatsuma Sakaguchi
- Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-city, Osaka, 573-1010, Japan
| | - Sohei Satoi
- Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-city, Osaka, 573-1010, Japan.
| | - Daisuke Hashimoto
- Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-city, Osaka, 573-1010, Japan
| | - Tomohisa Yamamoto
- Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-city, Osaka, 573-1010, Japan
| | - So Yamaki
- Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-city, Osaka, 573-1010, Japan
| | - Satoshi Hirooka
- Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-city, Osaka, 573-1010, Japan
| | - Mitsuaki Ishida
- Department of Pathology and Clinical Laboratory, Kansai Medical University, Osaka, Japan
| | - Tsukasa Ikeura
- The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Kentaro Inoue
- Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-city, Osaka, 573-1010, Japan
| | - Makoto Naganuma
- The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mitsugu Sekimoto
- Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-city, Osaka, 573-1010, Japan
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Goyal S, Banga P, Meena N, Chauhan G, Sakhuja P, Agarwal AK. Prognostic significance of tumour budding, tumour-stroma ratio and desmoplastic stromal reaction in gall bladder carcinoma. J Clin Pathol 2021; 76:308-314. [PMID: 34853164 DOI: 10.1136/jclinpath-2021-207957] [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: 09/21/2021] [Accepted: 11/03/2021] [Indexed: 11/04/2022]
Abstract
AIMS AND METHODS The prognostic role of tumour budding (TBd) and its interaction with the stromal microenvironment has gained a lot of attention recently, but remains unexplored in gall bladder cancer (GBC). We aimed to study the interrelationship of TBd by International Tumour Budding Consensus Conference scoring system, tumour-stroma ratio (TSR) and desmoplastic stromal reaction (DSR) with the conventional clinicopathological prognostic factors, mortality and overall survival (OS) in 96 patients of operated GBC. RESULTS Higher age, high TNM stage, lymphovascular and perineural invasion, positive resection margins, higher TBd score, low TSR and immature DSR were significantly associated with worse OS. However, on multivariate analysis, only metastases, positive resection margins and TSR <50% proved to be independent prognostic factors. The TBd score of stroma-rich tumour group (6.40±4.69) was significantly higher than that of stroma-poor group (2.77±3.79, p≤0.001). The TBd score of immature and intermediate DSR groups was significantly higher than that of mature group (p≤0.001 and p=0.002, respectively). There was a strong interobserver agreement for TBd score, TSR and type of DSR (Cohen's Kappa=0.726 to 0.864, p≤0.001). Stroma-rich tumours were significantly associated with immature DSR and fibrotic DSR with high TSR (p≤0.001). CONCLUSION A high TBd, low TSR and immature DSR were significantly associated with several high-risk clinicopathological parameters and poor OS in GBC. These novel, simple, reproducible and cost-effective parameters may be included in the routine reporting checklist for GBC as additional prognostic parameters that can substratify the high-risk patients.
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Affiliation(s)
- Surbhi Goyal
- Pathology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, Delhi, India
| | - Priyanka Banga
- Pathology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, Delhi, India
| | - Nisha Meena
- Pathology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, Delhi, India
| | - Geeta Chauhan
- Pathology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, Delhi, India
| | - Puja Sakhuja
- Pathology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, Delhi, India
| | - Anil Kumar Agarwal
- Gastrointestinal Surgery, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, Delhi, India
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11
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Regmi P, Paudyal A, Paudyal P, Hu HJ, Liu F, Ma WJ, Jin YW, Li FY. Prognostic significance of tumor budding in biliary tract cancer. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2021; 48:160-168. [PMID: 34412954 DOI: 10.1016/j.ejso.2021.08.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/05/2021] [Accepted: 08/09/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Tumor budding is a significant prognostic indicator for poor survival of several solid tumors. However, due to the lack of a standard scoring system, its clinical application for biliary tract cancer (BTC) is limited. OBJECTIVE To identify the prognostic significance of tumor budding in BTC. RESULTS Tumor budding was associated with poor histologic differentiation, lymphovascular invasion, perineural invasion, lymph node metastasis, positive surgical margin, etc. Tumor budding was a predictor of poor OS in univariate (HR: 4.36; 95% CI 3.15 to 6.02; P < 0.001) and multivariate (HR: 2.95; 95% CI 2.28 to 3.80; P < 0.001) analysis. Similarly, it was also a predictor of poor DFS in univariate (HR: 3.26; 95% CI 2.12 to 4.99; P < 0.001) and multivariate (HR: 3.21; 95% CI 1.90 to 5.40; P < 0.001) analysis. In addition, tumor budding was also associated with advanced T-stage, poor histologic differentiation, lymph node metastasis, positive resection margin, lymphatic invasion, vascular invasion, and perineural invasion. CONCLUSION Results of our study have shown that tumor budding is a strong predictor of poor survival for BTC. The clinical utility of tumor budding as a prognostic marker for BTC should be considered after developing a standard international consensus based on the current evidence.
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Affiliation(s)
- Parbatraj Regmi
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Aliza Paudyal
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Pranita Paudyal
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Hai-Jie Hu
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
| | - Fei Liu
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Wen-Jie Ma
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Yan-Wen Jin
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Fu-Yu Li
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
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12
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Liao X, Zhang D. The 8th Edition American Joint Committee on Cancer Staging for Hepato-pancreato-biliary Cancer: A Review and Update. Arch Pathol Lab Med 2021; 145:543-553. [PMID: 32223559 DOI: 10.5858/arpa.2020-0032-ra] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2020] [Indexed: 02/06/2023]
Abstract
CONTEXT.— Cancer staging provides critical information for patients and treating physicians to battle against cancer, predict prognosis, and guide treatment decisions. The American Joint Committee on Cancer (AJCC) staging system uses a tumor, node, metastasis (TNM) scoring algorithm and is the foremost classification system for adult cancers. This system is updated every 6 to 8 years to allow sufficient time for implementation of changes and for relevant examination and discussion of data validating those changes in staging. OBJECTIVE.— To review the updates in the 8th edition American Joint Committee on Cancer staging system on hepato-pancreato-biliary cancer. DATA SOURCES.— Literature review. CONCLUSIONS.— The 8th edition, published in 2016 and implemented on January 1, 2018, has been in use for approximately 3 years. Compared with the 7th edition, some of the changes are quite radical. This review aims to provide a summary of the changes/updates of the 8th edition with focus on hepato-pancreato-biliary cancers, and evaluate its performance through literature review.
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Affiliation(s)
- Xiaoyan Liao
- From the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
| | - Dongwei Zhang
- From the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
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13
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Agostini-Vulaj D, Cates JMM, Bratton LE, Gonzalez RS. Increasing tumor budding in cholangiocarcinoma is associated with decreased disease-specific survival. Hum Pathol 2021; 111:75-83. [PMID: 33727168 DOI: 10.1016/j.humpath.2021.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/16/2021] [Accepted: 03/02/2021] [Indexed: 12/16/2022]
Abstract
Tumor budding (TB) has been shown to be an adverse prognostic factor in several gastrointestinal malignancies, most notably colorectal carcinoma (CRC). TB has undergone some evaluation in Eastern cohorts of cholangiocarcinoma (CC), and we undertook this study to evaluate whether TB in CC was linked to other clinicopathologic factors or to outcome in a Western cohort. We evaluated 112 cases of CC for age, sex, margin status, location, size, grade, lymphovascular invasion (LVI), perineural invasion (PNI), subtype (large or small duct), staging parameters, recurrence-free survival, disease-specific survival (DSS), and TB. Budding was scored using International Tumor Budding Consensus Conference recommendations for CRC: The highest tumor bud count at the invasive tumor front in a 0.785 mm2 area was recorded and stratified into Bd1 (0-4 buds), Bd2 (5-9 buds), and Bd3 (≥10 buds). Our cohort included 54 (48%) extrahepatic CCs and 58 (52%) intrahepatic CCs. TB was more commonly seen in the settings of higher-grade lesions, males, extrahepatic CC, PNI, LVI, and positive resection margin (all P ≤ 0.021). In multivariate analysis, worse DSS was correlated with budding score Bd2/Bd3 (hazard ratio [HR] 2.6687, 95% confidence interval [CI] 1.585-5.217, P = 0.001) and with nodal disease (HR 2.876, 95% CI 1.585-5.217, P = 0.001). TB is associated with higher-grade disease in CC, and increased TB is associated with poor disease-specific survival. Our findings support the notion that TB may serve as useful information for clinicians with respect to patient prognosis in CC, as in CRC.
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Affiliation(s)
- Diana Agostini-Vulaj
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Justin M M Cates
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | | | - Raul S Gonzalez
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
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Abstract
Tumour budding is an emerging prognostic biomarker in colorectal cancer (CRC) and other solid cancers. Tumour buds are usually defined as isolated single cancer cells or clusters of up to four cancer cells located at the invasive tumour front. The prognostic value of tumour budding is now supported by a large body of evidence, whereas the utility of this phenotype as a predictive biomarker remains under investigation. The application of tumour budding indices in clinical practice requires a standardized scoring system that can be tailored to specific tumour types and clinical scenarios. In the context of CRC, tumour budding can be assessed according to the method agreed at the International Tumour Budding Consensus Conference (ITBCC) in 2016. Using the ITBCC scoring system, tumour budding is an independent predictor of lymph node metastasis in patients with pT1 CRC and of unfavourable survival in patients with stage II colon cancer. Regardless of the clinical scenario or tumour type, the assertion that 'the more tumour buds, the worse the clinical outcome' applies. In this Review, we provide an overview of tumour budding in solid cancers, highlighting the molecular and biological aspects of this phenomenon, including its associations with epithelial-mesenchymal transition and features of the tumour microenvironment. We also describe the available evidence demonstrating the value of tumour budding as a biomarker across various solid cancers.
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15
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Lohneis P, Hieggelke L, Gebauer F, Ball M, Bruns C, Büttner R, Löser H, Quaas A. Tumor budding assessed according to the criteria of the International Tumor Budding Consensus Conference determines prognosis in resected esophageal adenocarcinoma. Virchows Arch 2020; 478:393-400. [PMID: 32761393 DOI: 10.1007/s00428-020-02897-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/10/2020] [Accepted: 07/22/2020] [Indexed: 12/14/2022]
Abstract
Only few studies examined the prognostic effect of tumor budding in esophageal adenocarcinomas so far. However, different quantification approaches were used, so results cannot be directly compared. Recently, the International Tumor Budding Consensus Conference (ITBCC) published consensus criteria for the evaluation of tumor budding in colorectal cancer, which we applied in our study. Hematoxylin and eosin (H&E) and cytokeratin (AE1/AE3) stained whole tissue slides of 104 resected esophageal adenocarcinomas were evaluated. The mean count of tumor buds was analyzed in one high power field according to the ITBCC criteria and assigned to budding groups Bd1-3. Tumor budding was significantly associated with a worse overall survival. Regardless of the quantification approach, an increased number of tumor buds was significantly associated with reduced overall survival (OS) (H&E: HR = 1.05 (95% CI 1.029-1.073), p < 0.001; cytokeratin: HR = 1.073 (95% CI 1.045-1.101), p < 0.001). In multivariable analysis tumor budding according to ITBCC criteria on H&E stained slides was an independent prognostic factor. Tumor budding, according to ITBCC criteria, is an independent prognostic factor in resected esophageal adenocarcinoma. Prospective studies using ITBCC criteria are useful in the near future to validate our results.
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Affiliation(s)
- Philipp Lohneis
- Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.
| | - Lena Hieggelke
- Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany
| | - Florian Gebauer
- Faculty of Medicine and University Hospital Cologne, Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany
| | - Markus Ball
- Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany
| | - Christiane Bruns
- Faculty of Medicine and University Hospital Cologne, Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany
| | - Reinhard Büttner
- Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany
| | - Heike Löser
- Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany
| | - Alexander Quaas
- Faculty of Medicine and University Hospital Cologne, Institute of Pathology, University of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany
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16
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Yoshizawa T, Hong SM, Jung D, Noë M, Kiemen A, Wu PH, Wirtz D, Hruban RH, Wood LD, Oshima K. Three-dimensional analysis of extrahepatic cholangiocarcinoma and tumor budding. J Pathol 2020; 251:400-410. [PMID: 32476131 PMCID: PMC9920311 DOI: 10.1002/path.5474] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/27/2020] [Accepted: 05/19/2020] [Indexed: 01/04/2023]
Abstract
Advances in tissue clearing and microscopy make it possible to study human diseases in three dimensions (3D). High-grade tumor budding is known to be associated with poor prognosis in various cancers; however, little is known about the 3D architecture of tumor budding. Using tissue clearing, we analyzed the 3D structure of tumor budding and E-cadherin expression in 31 extrahepatic cholangiocarcinomas. A total of 31 thick slabs (up to 5 mm) were harvested from surgically resected tumor tissue, including 27 hilar and 4 distal cholangiocarcinomas. Twenty-eight cases were adenocarcinoma, and three were undifferentiated carcinoma. After clearing, the tissues were immunolabeled with antibodies to cytokeratin 19 and to E-cadherin, and then visualized using light-sheet and confocal laser scanning microscopy. Tumor budding was evaluated in hematoxylin and eosin-stained sections (2D) using standard pathological criteria. Of the 31 cancers, 13 showed low-grade tumor budding and 18 showed high-grade tumor budding. First, 3D analysis revealed that the neoplastic cells in tumor buds of adenocarcinoma were typically not individual islands of cells, but rather tips of attenuated protrusions connected to the main tumor. Second, adenocarcinomas with low-grade tumor budding were composed predominantly of tubules that only focally form cords at the periphery. By contrast, adenocarcinomas with high-grade tumor budding predominantly formed cords in both centers and peripheries of the tumors. Third, adenocarcinoma with low-grade tumor budding was characterized by a few short protrusions with few branches, whereas adenocarcinoma with high-grade tumor budding was characterized by longer protrusions with more branching. Finally, immunolabeling of E-cadherin was stronger in the center of the adenocarcinoma but decreased at the tips of protrusions. E-cadherin loss was more extensive in the protrusions of high-grade tumor budding than in the protrusions of low-grade tumor budding. Our findings suggest that tumor buds as seen in 2D are, in fact, cross-sections of attenuated but contiguous protrusions extending from the main tumor. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Tadashi Yoshizawa
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA,Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - DongJun Jung
- Department of Medicine, Graduate school, University of Ulsan, Seoul, Republic of Korea
| | - Michaël Noë
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Ashley Kiemen
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Pei-Hsun Wu
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Denis Wirtz
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA,Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ralph H Hruban
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA,Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA,Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Kiyoko Oshima
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA,Correspondence to: K Oshima, Department of Pathology, Johns Hopkins Medical Institutions, Weinberg Building Room 2333, 401 N. Broadway, Baltimore, MD 21231, USA.
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17
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Tumour budding and its clinical implications in gastrointestinal cancers. Br J Cancer 2020; 123:700-708. [PMID: 32601463 PMCID: PMC7462864 DOI: 10.1038/s41416-020-0954-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 04/17/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023] Open
Abstract
Tumour budding in colorectal cancer has become an important prognostic factor. Represented by single cells or small tumour cell clusters at the invasion front of the tumour mass, these tumour buds seem to reflect cells in a ‘hybrid’ state of epithelial–mesenchymal transition, and evidence indicates that the presence of these entities is associated with lymph node metastasis, local recurrence and distant metastatic disease. The International Tumour Budding Consensus Conference (ITBCC) has highlighted a scoring system for the reporting of tumour budding in colorectal cancer, as well as different clinical scenarios that could affect patient management. Other organs are not spared: tumour budding has been described in numerous gastrointestinal and non-gastrointestinal cancers. Here, we give an update on ITBCC validation studies in the context of colorectal cancer and the clinical implications of tumour budding throughout the upper gastrointestinal and pancreatico-biliary tract.
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18
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Ito T, Kuriyama N, Kozuka Y, Komatsubara H, Ichikawa K, Noguchi D, Hayasaki A, Fujii T, Iizawa Y, Kato H, Tanemura A, Murata Y, Kishiwada M, Mizuno S, Usui M, Sakurai H, Isaji S. High tumor budding is a strong predictor of poor prognosis in the resected perihilar cholangiocarcinoma patients regardless of neoadjuvant therapy, showing survival similar to those without resection. BMC Cancer 2020; 20:209. [PMID: 32164621 PMCID: PMC7069056 DOI: 10.1186/s12885-020-6695-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023] Open
Abstract
Background Tumor budding (TB) is used as an indicator of poor prognosis in various cancers. However, studies on TB in perihilar cholangiocarcinoma are still limited. We examined the significance of TB in resected perihilar cholangiocarcinoma with or without neoadjuvant therapy. Methods Seventy-eight patients who underwent surgical resection at our institution for perihilar cholangiocarcinoma from 2004 to 2017, (36 with neoadjuvant therapy), were enrolled in this study. TB was defined as an isolated cancer cell or clusters (< 5 cells) at the invasive front and the number of TB was counted using a 20 times objective lens. Patients were classified into two groups according to TB counts: low TB (TB < 5) and high TB (TB ≥5). Results In this 78 patient cohort, high TB was significantly associated with advanced tumor status (pT4: 50.0% vs 22.2%, p = 0.007, pN1/2: 70.8% vs 39.6%, p = 0.011, M1: 20.8% vs 1.9%) and higher histological grade (G3: 25.0% vs 5.7%, p = 0.014). Disease specific survival (DSS) in high TB was significantly inferior compared to that in low TB group (3-y DSS 14.5% vs 67.7%, p < 0.001). Interestingly, DSS in high TB showed similar to survival in unresected patients. In addition, high TB was also associated with advanced tumor status and poor prognosis in patients with neoadjuvant therapy. Multivariate analysis identified high TB as an independent poor prognostic factors for DSS (HR: 5.206, p = 0.001). Conclusion This study demonstrated that high TB was strongly associated with advanced tumor status and poor prognosis in resected perihilar cholangiocarcinoma patients. High TB can be a novel poor prognostic factor in resected perihilar cholangiocarcinoma regardless of neoadjuvant therapy.
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Affiliation(s)
- Takahiro Ito
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Naohisa Kuriyama
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
| | - Yuji Kozuka
- Pathology Division, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Haruna Komatsubara
- Pathology Division, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Ken Ichikawa
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Daisuke Noguchi
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Aoi Hayasaki
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Tekehiro Fujii
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Yusuke Iizawa
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Hiroyuki Kato
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Akihiro Tanemura
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Yasuhiro Murata
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Masashi Kishiwada
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Shugo Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Masanobu Usui
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Hiroyuki Sakurai
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Shuji Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
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19
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Ulase D, Heckl S, Behrens HM, Krüger S, Röcken C. Prognostic significance of tumour budding assessed in gastric carcinoma according to the criteria of the International Tumour Budding Consensus Conference. Histopathology 2019; 76:433-446. [PMID: 31538348 DOI: 10.1111/his.13997] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 09/16/2019] [Indexed: 12/24/2022]
Abstract
AIMS In this study, we aimed to independently evaluate the utility and prognostic value of tumour budding (TB) according to the International Tumour Budding Consensus Conference (ITBCC) criteria in a large and a well-characterised European gastric cancer (GC) cohort. METHODS AND RESULTS In 456 consecutive, surgically treated GCs, TB was assessed according to the ITBCC criteria and scored as Bd0 (no buds), Bd1 (one to four buds), Bd2 (five to nine buds) or Bd3 (≥10 buds). Cases with TB present were divided into low- (Bd1/Bd2) and high-budding (Bd3) groups. The TB score was analysed in relation to the clinicopathological parameters, overall survival (OS) and tumour-specific survival (TSS); 115 (25.2%) cases had no, 104 (22.8%) had low and 237 (52.0%) had high TB. The TB score correlated significantly with sex, Laurén phenotype, pT-, pN- and M categories, histological grade, R status; and lymph node ratio, lymphatic invasion, perineural invasion and HER2-, MET- and MSI status. In both total and intestinal-type early invasive GC (n = 57 and n = 41, respectively), significant associations between the presence and extent of TB and presence of lymph node metastasis were detected. Significant differences in OS and TSS between the TB groups were found; however, TB did not retain significance in multivariate models. CONCLUSIONS Our data show that the ITBCC criteria can be applied to GC. The data correlated significantly with the diverse clinicopathological characteristics, including patient outcome, and can help to standardise diagnostics and research into special histological features of malignant tumours in general and GC in particular.
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Affiliation(s)
- Dita Ulase
- Department of Pathology, Riga Stradins University, Riga, Latvia.,Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Steffen Heckl
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.,Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | | | - Sandra Krüger
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
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21
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Gerashchenko TS, Novikov NM, Krakhmal NV, Zolotaryova SY, Zavyalova MV, Cherdyntseva NV, Denisov EV, Perelmuter VM. Markers of Cancer Cell Invasion: Are They Good Enough? J Clin Med 2019; 8:E1092. [PMID: 31344926 PMCID: PMC6723901 DOI: 10.3390/jcm8081092] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/20/2019] [Accepted: 07/22/2019] [Indexed: 12/12/2022] Open
Abstract
Invasion, or directed migration of tumor cells into adjacent tissues, is one of the hallmarks of cancer and the first step towards metastasis. Penetrating to adjacent tissues, tumor cells form the so-called invasive front/edge. The cellular plasticity afforded by different kinds of phenotypic transitions (epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and vice versa) significantly contributes to the diversity of cancer cell invasion patterns and mechanisms. Nevertheless, despite the advances in the understanding of invasion, it is problematic to identify tumor cells with the motile phenotype in cancer tissue specimens due to the absence of reliable and acceptable molecular markers. In this review, we summarize the current information about molecules such as extracellular matrix components, factors of epithelial-mesenchymal transition, proteases, cell adhesion, and actin cytoskeleton proteins involved in cell migration and invasion that could be used as invasive markers and discuss their advantages and limitations. Based on the reviewed data, we conclude that future studies focused on the identification of specific invasive markers should use new models one of which may be the intratumor morphological heterogeneity in breast cancer reflecting different patterns of cancer cell invasion.
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Affiliation(s)
- Tatiana S Gerashchenko
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, 634009 Tomsk, Russia.
| | - Nikita M Novikov
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, 634009 Tomsk, Russia
- Department of Cytology and Genetics, Tomsk State University, 634050 Tomsk, Russia
| | - Nadezhda V Krakhmal
- Department of Pathological Anatomy, Siberian State Medical University, 634050 Tomsk, Russia
| | - Sofia Y Zolotaryova
- Department of Cytology and Genetics, Tomsk State University, 634050 Tomsk, Russia
| | - Marina V Zavyalova
- Department of Pathological Anatomy, Siberian State Medical University, 634050 Tomsk, Russia
- Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, 634009 Tomsk, Russia
| | - Nadezhda V Cherdyntseva
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, 634009 Tomsk, Russia
- Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, 634050 Tomsk, Russia
| | - Evgeny V Denisov
- Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, 634009 Tomsk, Russia
- Department of Organic Chemistry, Tomsk State University, 634050 Tomsk, Russia
| | - Vladimir M Perelmuter
- Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, 634009 Tomsk, Russia
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