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Li H, Zheng L, Zhang X, Yu X, Zhong G, Chen X, Chen X, Chen L. SH3 domain‑binding glutamic acid‑rich protein‑like 3 is associated with hyperglycemia and a poor outcome in Epstein‑Barr virus‑negative gastric carcinoma. Oncol Lett 2025; 29:8. [PMID: 39492939 PMCID: PMC11526421 DOI: 10.3892/ol.2024.14754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 09/03/2024] [Indexed: 11/05/2024] Open
Abstract
SH3 domain-binding glutamic acid-rich protein-like 3 (SH3BGRL3) is involved in several human cancers. However, its relationship with gastric cancer (GC) remains elusive. Multiple online bioinformatic tools were used to evaluate the messenger (m)RNA expression levels of SH3BGRL3 in GC using data from The Cancer Genome Atlas and Gene Expression Omnibus databases. Reverse transcription-quantitative PCR and tissue microarray-based immunohistochemistry were performed to assess SH3BGRL3 expression in relation to clinicopathological parameters and outcomes in patients with GC. Significant differentially expressed genes (DEGs) of SH3BGRL3 were enriched and visualized. Furthermore, associations between the expression of SH3BGRL3 and the infiltration of immune cells were explored. SH3BGRL3 exhibited aberrant expression in tumor tissues compared with adjacent normal tissues at the mRNA and protein expression levels, especially in Epstein-Barr virus-negative GC (EBVnGC). Higher SH3BGRL3 expression was significantly associated with increasing tumor-node-metastasis staging, tumor budding, perineural invasion, EGFR expression, and a notably higher preoperative blood glucose concentration in clinical specimens. Multivariate analysis revealed that higher SH3BGRL3 expression was an independent adverse prognostic factor for the overall survival of patients with EBVnGC (hazard ratio, 1.666; P=0.018). Furthermore, the stratified analysis revealed that the SH3BGRL3 phenotype could help to refine prognosis in patients. The C-index of the nomogram was 0.740 when combining SH3BGRL3 with other clinicopathological parameters, which indicated a good model for clinical follow-up decisions. Gene functional enrichment analysis also revealed that the DEGs of SH3BGRL3 were mainly enriched in regulating ATP metabolism, ATP synthesis, oxidative phosphorylation and the electron transport chain in GC. Moreover, a higher SH3BGRL3 expression was significantly positively correlated with the infiltrating macrophages in GC. In conclusion, SH3BGRL3 is upregulated in GC, particularly in EBVnGC. Higher SH3BGRL3 expression is closely associated with hyperglycemia and poor outcomes in patients with EBVnGC, suggesting its potential as a biomarker and prognostic predictor.
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Affiliation(s)
- Houqiang Li
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Lanqing Zheng
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Nursing Department, Fujian Provincial Hospital, Fuzhou, Fujian 35001, P.R. China
| | - Xia Zhang
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Xunbin Yu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Guodong Zhong
- Department of Pathology, The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fuzhou, Fujian 350003, P.R. China
| | - Xiaoyan Chen
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Xin Chen
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Linying Chen
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
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Tian CF, Jing HY, Sinicrope FA, Wang JS, Gao BB, Sun XG, Yao ZG, Li LP, Saberzadeh-Ardestani B, Song W, Sha D. Tumor microenvironment characteristics association with clinical outcome in patients with resected intestinal-type gastric cancer. Oncologist 2024; 29:e1280-e1290. [PMID: 38907674 PMCID: PMC11448893 DOI: 10.1093/oncolo/oyae124] [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: 01/22/2024] [Accepted: 05/04/2024] [Indexed: 06/24/2024] Open
Abstract
BACKGROUND Tumor microenvironment (TME) characteristics including tumor stroma ratio (TSR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs) were examined in resected gastric cancer. These TME features have been shown to indicate metastatic potential in colon cancer, and intestinal-type gastric cancer (IGC) has pathological similarities with that malignancy. METHODS TSR, TB, and TILs were quantified in routine histological sections from 493 patients with IGC who underwent radical resection at 2 university hospitals in China from 2010 to 2016. TME variables were dichotomized as follows: TSR (50%), TILs (median), TB per international guidelines (4 buds/0.785mm2), and platelet-lymphocyte ratio (PLR) per survival ROC. Association of TME features with patient clinicopathological characteristics, time-to-recurrence (TTR), and cancer-specific-survival (CSS) were examined using univariate and multivariate analysis, including a relative contribution analysis by Cox regression. RESULTS Patients whose tumors showed high TSR or high TB or low TILs were each significantly associated with increased T and N stage, higher histological grade, and poorer TTR and CSS at 5 years. Only TSR and N stage were independently associated with TTR and CSS after adjustment for covariates. PLR was only independently associated with TTR after adjustment for covariates. Among the variables examined, only TSR was significantly associated with both TTR (HR 1.72, 95% CI, 1.14-2.60, P = .01) and CSS (HR 1.62, 95% CI, 1.05-2.51, P = .03) multivariately. Relative contribution to TTR revealed that the top 3 contributors were N stage (45.1%), TSR (22.5%), and PLR (12.9%), while the top 3 contributors to CSS were N stage (59.9%), TSR (14.7%), and PLR (10.9%). CONCLUSIONS Among the examined TME features, TSR was the most robust for prognostication and was significantly associated with both TTR and CSS. Furthermore, the relative contribution of TSR to patient TTR and CSS was second only to nodal status.
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Affiliation(s)
- Chun-Fang Tian
- Department of Minimally Invasive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
| | - Hai-Yan Jing
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
| | - Frank A Sinicrope
- Department of Oncology, Mayo Clinic, Rochester, 55905, United States
| | - Jin-Shen Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
| | - Bin-Bin Gao
- Department of Minimally Invasive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
| | - Xiao-Gang Sun
- Department of Minimally Invasive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
| | - Zhi-Gang Yao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
| | - Le-Ping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
| | | | - Wei Song
- Department of Minimally Invasive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
| | - Dan Sha
- Department of Minimally Invasive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People's Republic of China
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Ulase D, Behrens HM, Röcken C. Stroma AReactive Invasion Front Areas (SARIFA) predict poor survival in adenocarcinomas of the stomach and gastrooesophageal junction: a validation study. Virchows Arch 2024; 485:527-534. [PMID: 38748262 DOI: 10.1007/s00428-024-03826-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/03/2024] [Accepted: 05/09/2024] [Indexed: 09/21/2024]
Abstract
Recently, the presence of "Stroma AReactive Invasion Front Areas" (SARIFA) has been described as a promising adverse prognostic factor in gastric cancer. However, the validity of this approach still needs to be tested. The aim of this study was to independently assess the utility of the proposed method in a well-characterised cohort of primary resected adenocarcinomas of stomach and gastrooesophageal junction (n = 392). SARIFA status was analysed on routine slides of resection specimens. Cases were divided into SARIFA-positive and negative groups and analysed in relation to clinicopathological and survival data. SARIFA positivity was found in 15.1% (n = 59) cases and was significantly associated with Lauren phenotype (p < 0.001), pT (p = 0.001), pN (p = 0.018), UICC stage (p = 0.031), tumour budding (p = 0.002), overall survival (p < 0.001) and cancer-specific survival (p < 0.001). SARIFA-positive tumours had a worse prognosis in the multivariate setting (HR = 1.847, 95% CI: 1.300-2.624, p = 0.001). SARIFA status is an independent prognostic factor in gastric cancer, in particular in locally advanced tumours.
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Affiliation(s)
- Dita Ulase
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany.
| | - Hans-Michael Behrens
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
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Wang X, Yang X, Cai F, Cai M, Liu Y, Zhang L, Zhang R, Xue F, Sun Y, Deng J. The Key Role of Tumor Budding in Predicting the Status of Lymph Node Involvement in Early Gastric Cancer Patients: A Clinical Multicenter Validation in China. Ann Surg Oncol 2024; 31:4224-4235. [PMID: 38536585 DOI: 10.1245/s10434-024-15229-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 03/12/2024] [Indexed: 06/14/2024]
Abstract
BACKGROUND Accurate preoperative prediction of lymph node (LN) involvement is essential for the management of early gastric cancer (EGC). Our objective was to formulate a potent nomogram for predicting LN involvement in EGC by leveraging an innovative predictor of tumor budding. METHODS We assembled a cohort of EGC patients who underwent radical surgery at two tertiary cancer centers. Tumor budding was stratified by using an optimal cutoff value and integrated with other clinicopathological variables to ascertain the risk factors associated with LN involvement. A nomogram was developed and its predictive performance was assessed by using receiver operating characteristic (ROC) curves and calibration plots. In addition, we conducted decision curve analysis to evaluate its clinical utility. Finally, an external validation was conducted by using an independent cohort. RESULTS Finally, 307 eligible patients (215 in the primary cohort and 92 in the validation cohort) were included. Tumor budding, categorized by a count of two, exhibited a robust association with LN involvement (OR 14.12, p = 0.012). Other significant risk factors include lymphovascular invasion, depth of tumor invasion, ulceration, and tumor differentiation. Notably, the nomogram demonstrated exceptional discriminative power (area under the ROC curve, 0.872 in the primary cohort and 0.885 in the validation cohort) and precise predictive capabilities. Furthermore, the nomogram showed notable clinical applicability through decision curve analysis, particularly in endoscopic curability C-2, by mitigating the risk of overtreatment. CONCLUSIONS Tumor budding is a robust predictor of LN involvement in EGC. The incorporation of tumor budding into a nomogram is an effective strategy, thereby informing and enhancing clinical decision-making.
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Affiliation(s)
- Xiangyu Wang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China
- Department of Gastrointestinal Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, People's Republic of China
| | - Xiuding Yang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Fenglin Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Mingzhi Cai
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Yong Liu
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Li Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Rupeng Zhang
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Fangqin Xue
- Department of Gastrointestinal Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, People's Republic of China.
| | - Yan Sun
- Department of Pathology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China.
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China.
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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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Yavuz A, Simsek K, Alpsoy A, Altunay B, Gedik EO, Unal B, Bassorgun CI, Tatli AM, Elpek GO. Prognostic significance of tumor budding, desmoplastic reaction, and lymphocytic infiltration in patients with gastric adenocarcinoma. World J Gastrointest Pathophysiol 2024; 15:91237. [PMID: 38682027 PMCID: PMC11045359 DOI: 10.4291/wjgp.v15.i1.91237] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 03/08/2024] [Accepted: 03/22/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Recent studies have shown that the tumor microenvironment significantly influences the behavior of solid tumors. In this context, Accumulated data suggests that pathological evaluation of tumor budding (TB), desmoplastic reaction (DR), and tumor-infiltrating lymphocytes (TILs) may be crucial in determining tumor behavior in the gastrointestinal tract. Regarding gastric adenocarcinoma (GAC), although some results suggest that TB and TILs may be effective in determining the course of the disease, the data do not agree. Moreover, very few studies have investigated the relationship between DR and survival. At present, the associations between tumor TB, DR and TILs in GAC patients have not been determined. AIM To establish the relationships between TB, DR, and TILs in patients with GAC and to assess their influence on prognosis. METHODS Our study group comprised 130 patients diagnosed with GAC. The definition of TB was established based on the International TB Consensus Conference. The DR was categorized into three groups according to the level of tumor stroma maturation. The assessment of TILs was conducted using a semiquantitative approach, employing a cutoff value of 5%. The statistical analysis of the whole group and 100 patients with an intestinal subtype of GAC was performed using SPSS version 27. RESULTS A significant correlation between peritumoral budding (PTB) and intratumoral budding (ITB) was noted (r = 0.943). Tumors with high PTBs and ITBs had a greater incidence of immature DRs and low TILs (P < 0.01). PTB and ITB were associated with histological subtype, lymph node metastasis (LNM), and stage (P < 0.01). ITB, PTB, LNM, DR, and stage were significant risk factors associated with poor prognosis. The multivariate Cox regression analysis identified ITB, PTB, and LNM as independent prognostic variables (P < 0.05). In intestinal-type adenocarcinomas, a positive correlation between PTB and ITB was noted (r = 0.972). While univariate analysis revealed that LNM, stage, PTB, ITB, and DR were strong parameters for predicting survival (P < 0.05), only PTB and ITB were found to be independent prognostic factors (P < 0.001). CONCLUSION TB may be a potential prognostic marker in GAC. However, further studies are needed to delineate its role in pathology reporting protocols and the predictive effects of DR and TILs.
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Affiliation(s)
- Aysen Yavuz
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Kubra Simsek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Anil Alpsoy
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Busra Altunay
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Elif Ocak Gedik
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Betul Unal
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | | | - Ali Murat Tatli
- Department of Medical Oncology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
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Xiang YC, Zhang XL, Wang ZW. The effect of tumor budding on patients with gastric cancer. Asian J Surg 2024; 47:1157-1158. [PMID: 37977925 DOI: 10.1016/j.asjsur.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/03/2023] [Indexed: 11/19/2023] Open
Affiliation(s)
- Ying-Chun Xiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xiao-Long Zhang
- Department of Thoracic and Mastothyroid Surgery, People's Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing, 404000, China
| | - Zi-Wei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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El Mashad SN, Kandil MAEH, Talab TAEH, Saied Abd El Naby AEN, Sultan MM, Sohaib A, Hemida AS. Gastric Carcinoma with low ROR alpha, low E- Cadherin and High LAPTM4B Immunohistochemical Profile; is associated with unfavorable prognosis in Egyptian patients. J Immunoassay Immunochem 2024; 45:50-72. [PMID: 38031398 DOI: 10.1080/15321819.2023.2279639] [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: 12/01/2023]
Abstract
In view of multiplicity of carcinogenic pathways of gastric carcinoma (GC), poor survival and chemotherapy resistance, more analysis of these pathways is required for prediction of prognosis and developing new therapeutic targets. Knocking down of RORα; induces tumor cell proliferation and epithelial-mesenchymal transition (EMT). LAPTM4B has been suggested to be associated with EMT which promote tumor invasion. This work aimed to investigate prognostic role of RORα, LAPTM4B, and E-Cadherin expression in GC. This retrospective immunohistochemical study assesses the expression of RORα, LAPTM4B, and E-Cadherin in 73 primary gastric carcinomas. Low RORα and high LAPTM4B expression in GC cases were associated with unfavorable prognostic factors such as positive lymph nodes, and high tumor budding. E-Cadherin heterogeneous staining was associated with poor prognostic criteria, such as diffuse type GC and high tumor budding. Low RORα, high LAPTM4B, and heterogeneous E-Cadherin were the most common immunohistochemical profile in GC cases. Low RORα expression showed poor prognostic impact on overall patient survival. In conclusion, RORα and LAPTM4B may have crucial role in GC aggressiveness. The predominance of low RORα, high LAPTM4B, and heterogeneous or negative E-Cadherin immunohistochemical profile in GC cases with unfavorable pathological parameters suggested that this profile may predict tumor behavior.
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Affiliation(s)
| | | | | | | | - Mervat Mahmoud Sultan
- Pathology Department, National Liver Institute, Menoufia University, Shebin El Kom, Egypt
| | - Ahmed Sohaib
- Clinical Oncology& Nuclear medicine Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | - Aiat Shaban Hemida
- Pathology Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
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Lee YS, Chong Y, Seo KJ, Yim K. Two Cases of Lymph Node Metastasis Found in Differentiated, Small-Sized Gastric Adenocarcinomas: Did Tumor Budding Play a Critical Role? MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2126. [PMID: 38138228 PMCID: PMC10745076 DOI: 10.3390/medicina59122126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/27/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023]
Abstract
Background: Endoscopic resection (ER) is a minimally invasive therapeutic approach for early gastric cancer (EGC), particularly for cases with a low risk of lymph node metastasis (LNM). Tumor budding (TB) has gained attention as a potential prognostic indicator for LNM in EGC. Case Presentation: We report two cases-a 73-year-old and an 81-year-old male patient-who presented with gastric adenocarcinoma. Both patients had small-sized, differentiated, and intramucosal adenocarcinomas. However, high-grade TBs per high-power field under ×200 magnification at the invasive front and LNMs were found in both cases. Conclusions: These cases conformed to the post-ER observation guidelines of the current treatment protocol, yet demonstrated LNMs. We found that TB could serve as an effective prognostic marker for LNM compared to traditional risk factors. The aim of this study is to re-examine the ability of TB to predict LNM in EGC, thereby providing an impetus for reconsideration and potential revision of the current treatment guidelines for EGC.
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Affiliation(s)
- Young Sub Lee
- Department of Hospital Pathology, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea;
| | - Yosep Chong
- Department of Hospital Pathology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.C.); (K.J.S.)
| | - Kyung Jin Seo
- Department of Hospital Pathology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.C.); (K.J.S.)
| | - Kwangil Yim
- Department of Hospital Pathology, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.C.); (K.J.S.)
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10
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Muti HS, Röcken C, Behrens HM, Löffler CML, Reitsam NG, Grosser B, Märkl B, Stange DE, Jiang X, Velduizen GP, Truhn D, Ebert MP, Grabsch HI, Kather JN. Deep learning trained on lymph node status predicts outcome from gastric cancer histopathology: a retrospective multicentric study. Eur J Cancer 2023; 194:113335. [PMID: 37862795 DOI: 10.1016/j.ejca.2023.113335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 08/15/2023] [Accepted: 09/03/2023] [Indexed: 10/22/2023]
Abstract
AIM Gastric cancer (GC) is a tumour entity with highly variant outcomes. Lymph node metastasis is a prognostically adverse biomarker. We hypothesised that GC primary tissue contains information that is predictive of lymph node status and patient prognosis and that this information can be extracted using deep learning (DL). METHODS Using three patient cohorts comprising 1146 patients, we trained and validated a DL system to predict lymph node status directly from haematoxylin and eosin-stained GC tissue sections. We investigated the concordance between the DL-based prediction from the primary tumour slides (aiN score) and the histopathological lymph node status (pN). Furthermore, we assessed the prognostic value of the aiN score alone and when combined with the pN status. RESULTS The aiN score predicted the pN status reaching area under the receiver operating characteristic curves of 0.71 in the training cohort and 0.69 and 0.65 in the two test cohorts. In a multivariate Cox analysis, the aiN score was an independent predictor of patient survival with hazard ratios of 1.5 in the training cohort and of 1.3 and 2.2 in the two test cohorts. A combination of the aiN score and the pN status prognostically stratified patients by survival with p-values <0.05 in logrank tests. CONCLUSION GC primary tumour tissue contains additional prognostic information that is accessible using the aiN score. In combination with the pN status, this can be used for personalised management of GC patients after prospective validation.
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Affiliation(s)
- Hannah S Muti
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Christoph Röcken
- Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | | | - Chiara M L Löffler
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany; Department of Medicine I, University Hospital Dresden, Dresden, Germany
| | - Nic G Reitsam
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Bianca Grosser
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Bruno Märkl
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Daniel E Stange
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Xiaofeng Jiang
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
| | - Gregory P Velduizen
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
| | - Daniel Truhn
- Department of Diagnostic and Interventional Radiology, University Hospital Aachen, Germany
| | - Matthias P Ebert
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DKFZ-Hector Cancer Institute at the University Medical Center, Mannheim, Germany; Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Heike I Grabsch
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Jakob N Kather
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany; Department of Medicine I, University Hospital Dresden, Dresden, Germany; Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
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11
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Pun C, Luu S, Swallow C, Kirsch R, Conner JR. Prognostic Significance of Tumour Budding and Desmoplastic Reaction in Intestinal-Type Gastric Adenocarcinoma. Int J Surg Pathol 2023; 31:957-966. [PMID: 35726174 PMCID: PMC10492422 DOI: 10.1177/10668969221105617] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/13/2022] [Accepted: 05/19/2022] [Indexed: 12/24/2022]
Abstract
Objective. Tumour budding and desmoplastic reactions in peritumoural stroma are features of the tumour microenvironment that are associated with colorectal cancer prognosis but have not been as thoroughly examined in gastric cancer. We aimed to further characterize the prognostic role of tumour budding and desmoplastic reaction in gastric adenocarcinoma with intestinal differentiation. Methods. 76 curative gastrectomy specimens were identified, excluding post-neoadjuvant cases or cases with >50% diffuse-type histology. Tumour budding was defined and graded according to the International Tumor Budding Consensus Conference recommendations and desmoplastic reaction was classified as described by Ueno et al 2017. Tumour budding and desmoplastic reaction were analyzed for associations with pathologic features and clinical outcomes. Results. Tumour budding was associated with pT (P < .001), pN (P < .004), overall stage (P < .001), LVI (P < .001) and PNI (P = .002). Desmoplastic reaction was associated with pT (P < .001), pN (P = .005), overall stage (P = .031) and PNI (P < .001), but not LVI. Survival analysis showed decreased overall survival (OS) and recurrence-free survival (RFS) for intermediate and high grade tumour budding (P = .031, .014 respectively). Immature stroma was significantly associated with RFS but not OS. Neither tumour budding nor desmoplastic reaction were independent predictors of OS or RFS on multivariate analysis in this cohort. Conclusion. Tumour budding and desmoplastic reaction were associated with known pathologic risk factors. Prognostically, tumour budding was associated with OS and RFS while desmoplastic reaction was associated with RFS only. Our data suggest that tumour budding and desmoplastic reaction have prognostic value in intestinal-type gastric adenocarcinoma.
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Affiliation(s)
- Cherry Pun
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Shelly Luu
- Department of Surgery, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Carol Swallow
- Department of Surgery, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Richard Kirsch
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Department of Pathology and Laboratory Medicine, Sinai Health System, Toronto, Ontario, Canada
| | - James R. Conner
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Department of Pathology and Laboratory Medicine, Sinai Health System, Toronto, Ontario, Canada
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12
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Veldhuizen GP, Röcken C, Behrens HM, Cifci D, Muti HS, Yoshikawa T, Arai T, Oshima T, Tan P, Ebert MP, Pearson AT, Calderaro J, Grabsch HI, Kather JN. Deep learning-based subtyping of gastric cancer histology predicts clinical outcome: a multi-institutional retrospective study. Gastric Cancer 2023; 26:708-720. [PMID: 37269416 PMCID: PMC10361890 DOI: 10.1007/s10120-023-01398-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/09/2023] [Indexed: 06/05/2023]
Abstract
INTRODUCTION The Laurén classification is widely used for Gastric Cancer (GC) histology subtyping. However, this classification is prone to interobserver variability and its prognostic value remains controversial. Deep Learning (DL)-based assessment of hematoxylin and eosin (H&E) stained slides is a potentially useful tool to provide an additional layer of clinically relevant information, but has not been systematically assessed in GC. OBJECTIVE We aimed to train, test and externally validate a deep learning-based classifier for GC histology subtyping using routine H&E stained tissue sections from gastric adenocarcinomas and to assess its potential prognostic utility. METHODS We trained a binary classifier on intestinal and diffuse type GC whole slide images for a subset of the TCGA cohort (N = 166) using attention-based multiple instance learning. The ground truth of 166 GC was obtained by two expert pathologists. We deployed the model on two external GC patient cohorts, one from Europe (N = 322) and one from Japan (N = 243). We assessed classification performance using the Area Under the Receiver Operating Characteristic Curve (AUROC) and prognostic value (overall, cancer specific and disease free survival) of the DL-based classifier with uni- and multivariate Cox proportional hazard models and Kaplan-Meier curves with log-rank test statistics. RESULTS Internal validation using the TCGA GC cohort using five-fold cross-validation achieved a mean AUROC of 0.93 ± 0.07. External validation showed that the DL-based classifier can better stratify GC patients' 5-year survival compared to pathologist-based Laurén classification for all survival endpoints, despite frequently divergent model-pathologist classifications. Univariate overall survival Hazard Ratios (HRs) of pathologist-based Laurén classification (diffuse type versus intestinal type) were 1.14 (95% Confidence Interval (CI) 0.66-1.44, p-value = 0.51) and 1.23 (95% CI 0.96-1.43, p-value = 0.09) in the Japanese and European cohorts, respectively. DL-based histology classification resulted in HR of 1.46 (95% CI 1.18-1.65, p-value < 0.005) and 1.41 (95% CI 1.20-1.57, p-value < 0.005), in the Japanese and European cohorts, respectively. In diffuse type GC (as defined by the pathologist), classifying patients using the DL diffuse and intestinal classifications provided a superior survival stratification, and demonstrated statistically significant survival stratification when combined with pathologist classification for both the Asian (overall survival log-rank test p-value < 0.005, HR 1.43 (95% CI 1.05-1.66, p-value = 0.03) and European cohorts (overall survival log-rank test p-value < 0.005, HR 1.56 (95% CI 1.16-1.76, p-value < 0.005)). CONCLUSION Our study shows that gastric adenocarcinoma subtyping using pathologist's Laurén classification as ground truth can be performed using current state of the art DL techniques. Patient survival stratification seems to be better by DL-based histology typing compared with expert pathologist histology typing. DL-based GC histology typing has potential as an aid in subtyping. Further investigations are warranted to fully understand the underlying biological mechanisms for the improved survival stratification despite apparent imperfect classification by the DL algorithm.
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Affiliation(s)
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts University, Kiel, Germany
| | | | - Didem Cifci
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Hannah Sophie Muti
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
- Department of Visceral, Thoracic and Vascular Surgery, Technical University Dresden, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
| | - Takashi Oshima
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Patrick Tan
- Duke-NUS Medical School, Singapore, Singapore
| | - Matthias P Ebert
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center, Mannheim, Germany
- Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Alexander T Pearson
- Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA
| | - Julien Calderaro
- Université Paris Est Créteil, INSERM, IMRB, Créteil, France
- Department of Pathology, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France
| | - Heike I Grabsch
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Jakob Nikolas Kather
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany.
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
- Department of Medicine I, University Hospital Dresden, Dresden, Germany.
- Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
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Xiao SM, Li J. Tumor budding in gastric cancer. World J Gastrointest Surg 2023; 15:578-591. [PMID: 37206064 PMCID: PMC10190737 DOI: 10.4240/wjgs.v15.i4.578] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/04/2023] [Accepted: 03/21/2023] [Indexed: 04/22/2023] Open
Abstract
The tumor, nodes, metastasis (TNM) staging system has long been the gold standard for the classification and prognosis of solid tumors. However, the TNM staging system is not without limitations. Prognostic heterogeneity exists within patients at the same stage. Therefore, the pursuit of other biomarkers with the potential to classify patients with cancer has never stopped. One of them, tumor budding (TB), has gained much success in colorectal cancer. In recent years, TB in gastric cancer has attracted much attention from researchers, beginning to reveal the molecular and biological aspects of this phenomenon in gastric cancer, and has emerged as a promising prognostic biomarker in gastric cancer, predicting disease progression and unfavorable survival. Therefore, it is time and essential to provide a holistic overview of TB in gastric cancer, which has not been achieved and is the aim of this review.
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Affiliation(s)
- Shuo-Meng Xiao
- Department of Gastric Surgery, Sichuan Cancer Hospital, Chengdu 610041, Sichuan Province, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang 621000, Sichuan Province, China
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14
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Xue C, Du Y, Li Y, Xu H, Zhu Z. Tumor budding as a predictor for prognosis and therapeutic response in gastric cancer: A mini review. Front Oncol 2023; 12:1003959. [PMID: 36755859 PMCID: PMC9900096 DOI: 10.3389/fonc.2022.1003959] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 12/30/2022] [Indexed: 01/24/2023] Open
Abstract
In recent years, the role of tumor budding in gastric cancer has received increased attention across a number of disciplines. Several studies have found associations between tumor budding and the prediction of lymph node metastasis in early gastric cancer, prognosis of advanced gastric cancer, predictors of therapeutic response to immune checkpoint inhibitors, such as microsatellite instability (MSI), and therapeutic targets of molecular targeted therapy, such as human epidermal growth factor receptor 2 (HER-2). Therefore, tumor budding is a major element in the formulation of risk stratification and precision medicine strategies for patients with gastric cancer.
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15
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El Yaagoubi S, Zaryouhi M, Benmaamar S, El Agy F, Tahiri El Ousrouti L, Hammas N, El Bouhaddouti H, Benbrahim Z, Lahmidani N, Chbani L. Prognostic Impact of Tumor Budding on Moroccan Gastric Cancer Patients. CLINICAL PATHOLOGY (THOUSAND OAKS, VENTURA COUNTY, CALIF.) 2023; 16:2632010X231184329. [PMID: 37426068 PMCID: PMC10326459 DOI: 10.1177/2632010x231184329] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 06/08/2023] [Indexed: 07/11/2023]
Abstract
Background Tumor budding (TB) has been defined as an independent prognostic factor in many carcinomas like colon adenocarcinoma, but its prognostic impact on gastric cancer patients remains not well established. In the present study, we aimed to highlight the correlation of tumor budding with clinicopathological features and predict its survival outcomes in gastric cancer patients for the first time in the Moroccan population. Methods This study was conducted on 83 patients who underwent surgery for gastric adenocarcinoma from 2014 to 2020. The patient's clinico-pathological characteristics were obtained from the pathological and clinical records of each patient. Tumor budding was assessed on HES slides, according to the 2016 International Tumor Budding Consensus Conference criteria. The association of tumor budding grades with categorical and continuous variables were respectively assessed by the χ2-test and the unpaired t-test. Survival analysis was performed by the Kaplan-Meier method, the log-rank test. Results Patients consisted of 65.1% of men and 34.9% of women with a median age of 61.2 years. Histologically, the majority of the tumors were adenocarcinoma (65.1%). Among all cases, 18.1% were classified as Bud1 (15/83), (27/83) 32.5% as Bud 2, and 49.4% (41/83) as Bud 3 grades. High-grade tumor budding (BUD 3) was found to be significantly associated with special clinicopathological features including older age (P = .02), unradical resection (R1/R2) (P = .03), and the presence of vascular invasion (P = .05), and perineural invasion (P = .04). Furthermore, tumors with high-grade tumor budding were significantly associated with a low rate of resected lymph nodes (P = .04) and advanced TNM stage (P = .02). Among all stages, high-grade tumor budding was correlated with shorter overall survival in univariate and multivariate analysis (P = .04). Patients with high-tumor budding had worse relapse-free survival compared with patients with low-tumor budding grade (P = .01). Conclusion According to our study, the high-tumor budding grade was correlated with unfavorable clinicopathological features and poorer survival. The present study findings suggest that tumor budding should be considered in the treatment and prognosis of gastric cancer patients.
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Affiliation(s)
- Souhaila El Yaagoubi
- Department of Pathology, Hassan II
University Hospital, Fez, Morocco
- Faculty of Medicine, Pharmacy, and
Dental Medicine of Fez, University Sidi Mohamed Ben Abdellah, Fez, Morocco
| | - Meryem Zaryouhi
- Department of Pathology, Hassan II
University Hospital, Fez, Morocco
- Faculty of Medicine, Pharmacy, and
Dental Medicine of Fez, University Sidi Mohamed Ben Abdellah, Fez, Morocco
| | - Soumaya Benmaamar
- Faculty of Medicine, Pharmacy, and
Dental Medicine of Fez, University Sidi Mohamed Ben Abdellah, Fez, Morocco
- Department of Epidemiology, Hassan II
University Hospital, Fez, Morocco
| | - Fatima El Agy
- Department of Pathology, Hassan II
University Hospital, Fez, Morocco
| | - Layla Tahiri El Ousrouti
- Department of Pathology, Hassan II
University Hospital, Fez, Morocco
- Faculty of Medicine, Pharmacy, and
Dental Medicine of Fez, University Sidi Mohamed Ben Abdellah, Fez, Morocco
| | - Nawal Hammas
- Department of Pathology, Hassan II
University Hospital, Fez, Morocco
- Faculty of Medicine, Pharmacy, and
Dental Medicine of Fez, University Sidi Mohamed Ben Abdellah, Fez, Morocco
- Biomedical and Translational Research
Laboratory, Fez, Morocco
| | | | - Zineb Benbrahim
- Department of Oncology, Hassan II
University Hospital, Fez, Morocco
| | - Nada Lahmidani
- Department of Gastrology, Hassan II
University Hospital, Fez, Morocco
| | - Laila Chbani
- Department of Pathology, Hassan II
University Hospital, Fez, Morocco
- Faculty of Medicine, Pharmacy, and
Dental Medicine of Fez, University Sidi Mohamed Ben Abdellah, Fez, Morocco
- Biomedical and Translational Research
Laboratory, Fez, Morocco
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Li F, Li S, Wang X, Liu C, Li X, Li Y, Liu Y. To investigate the prognostic factors of stage Ⅰ-Ⅱ gastric cancer based on P53 mutation and tumor budding. Pathol Res Pract 2022; 240:154195. [PMID: 36356333 DOI: 10.1016/j.prp.2022.154195] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/27/2022] [Accepted: 10/29/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND P53 is a tumor suppressor and genome guardian factor, and tumor budding is a key link in tumor metastasis. The purpose of this study was to investigate P53 mutation and tumor budding in stage Ⅰ-Ⅱ gastric cancer, to explore the correlation with clinicopathological features, and to reveal the independent prognostic factors of gastric cancer. METHODS The data of 588 patients with stage Ⅰ-Ⅱ gastric cancer who underwent radical surgical resection from April 2015 to December 2016 in the Fourth Hospital of Hebei Medical University were retrospectively analyzed and followed up. Immunohistochemistry Envision method was used to conduct P53 staining for paraffin-embedded gastric cancer tissues, and ITBCC recommended tumor budding evaluation method was used to count tumor budding in gastric cancer tissues. The factors affecting the prognosis of gastric cancer were analyzed. RESULTS There were 209 cases (35.54%) of P53 wild-type and 379 cases (64.46 %) of P53 mutant in 588 patients with stage Ⅰ-Ⅱ gastric cancer. P53 mutation rate were closely correlated with Lauren classification (χ2 =8.152, p = 0.017), degree of differentiation (χ2 =10.495, p = 0.004), number of lymph node metastasis (χ2 =25.550, p < 0.001), and clinical stage (χ2 =7.617, p = 0.016). Tumor budding were closely correlated with Lauren classification (χ2 =194.533, p < 0.001), degree of tissue differentiation (χ2 =22.719, p < 0.001), depth of tumor invasion (χ2 =19.204, p = 0.004), number of lymph node metastasis (χ2 =22.555, p = 0.001), clinical stage (χ2 =10.769, p = 0.005), and vascular tumors bolt (χ2 =12.478, p = 0.002). The higher the tumor budding grade was, the higher the P53 mutation rate was (χ2 =12.933, p = 0.002). Lauren classification (p < 0.001), degree of tissue differentiation (p = 0.005), vascular tumors bolt (p < 0.001) and P53 mutation (p = 0.006) were independent influencing factors for 5-year survival of patients with stage Ⅰ-Ⅱ gastric cancer. CONCLUSION P53 mutation status is an independent prognostic factor for gastric cancer patients and a promising cancer treatment target. Tumor budding is a very reliable independent prognostic parameter with important clinical value and should be routinely reported as a biomarker.
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Affiliation(s)
- Fang Li
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shi Li
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xinran Wang
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chang Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoya Li
- Department of Scientific Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yong Li
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yueping Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
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Szalai L, Jakab Á, Kocsmár I, Szirtes I, Kenessey I, Szijártó A, Schaff Z, Kiss A, Lotz G, Kocsmár É. Prognostic Ability of Tumor Budding Outperforms Poorly Differentiated Clusters in Gastric Cancer. Cancers (Basel) 2022; 14:4731. [PMID: 36230653 PMCID: PMC9563769 DOI: 10.3390/cancers14194731] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/25/2022] [Accepted: 09/26/2022] [Indexed: 11/24/2022] Open
Abstract
The prognostic value of histological phenomena tumor budding (TB) and poorly differentiated clusters (PDCs) have been less studied in gastric cancer (GAC) and the data provided so far are controversial. In our study, 290 surgically resected GAC cases were evaluated for TB according to the criteria of International Tumor Budding Consensus Conference (ITBCC) and PDC, and both parameters were scored on a three-grade scale as described for colorectal cancer previously (0: Grade0, 1-4: Grade1, 5-9: Grade2 and ≥10: Grade3) and classified as low (Grade0-2) and high (Grade3) TB/PDC. High TB/PDC was associated with diffuse-type morphology, higher pT status, incomplete surgical resection, poor tumor differentiation and perineural and lymphovascular invasion. Multivariable survival analyses have shown an independent prognostic role of high TB with poorer overall survival in the total cohort (p = 0.014) and in intestinal-type adenocarcinomas (p = 0.005). Multivariable model revealed high TB as an independent predictor for lymph node metastasis in both the total cohort (p = 0.019) and in the intestinal type adenocarcinomas (p = 0.038). In contrast to tumor budding, no significant association was found between PDC and the occurrence of lymph node metastasis and tumor stage and even survival. In conclusion, tumor budding is an independent prognostic factor of survival in gastric cancer, especially in intestinal-type adenocarcinomas.
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Affiliation(s)
- Luca Szalai
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
- Department of Pathology, National Institute of Oncology, Ráth György Str. 7-9, H-1122 Budapest, Hungary
| | - Ákos Jakab
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
| | - Ildikó Kocsmár
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
- Department of Urology, Semmelweis University, Üllői Str. 78b, H-1082 Budapest, Hungary
| | - Ildikó Szirtes
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
| | - István Kenessey
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
- National Cancer Registry, National Institute of Oncology, Ráth György Str. 7-9, H-1122 Budapest, Hungary
| | - Attila Szijártó
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Üllői Str. 78, H-1091 Budapest, Hungary
| | - Zsuzsa Schaff
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
| | - András Kiss
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
| | - Gábor Lotz
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
| | - Éva Kocsmár
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Üllői Str. 93, H-1091 Budapest, Hungary
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Thakur N, Ailia MJ, Chong Y, Shin OR, Yim K. Tumor Budding as a Marker for Poor Prognosis and Epithelial-Mesenchymal Transition in Lung Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2022; 12:828999. [PMID: 35719992 PMCID: PMC9201279 DOI: 10.3389/fonc.2022.828999] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 05/05/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction Currently, tumor budding (TB) is considered to predict the prognosis of patients. The prognostic significance of TB has also been explored in patients with lung cancer, but has not been fully clarified. In the present meta-analysis, we evaluated the prognostic significance, clinicopathological value, and relationship with epithelial–mesenchymal transition (EMT) of TB in lung cancer. Methods The MEDLINE, EMBASE, and Cochrane databases were searched up to July 7, 2021, for the relevant articles that showed the relationship between TB and prognosis in patients with lung cancer. For statistical analysis, we used pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) to assess the correlation between high-grade TB expression and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), clinicopathological factors, and EMT markers. Results A total of 3,784 patients from 10 independent studies were included in the statistical analysis. Our results indicated that high-grade TB was significantly associated with poor OS [HR 1.64 (95% CI, 1.43–1.87)] and DFS [HR 1.65 (95% CI, 1.22–2.25)]. In terms of clinicopathological characteristics, high-grade TB was associated with larger tumor size, higher T and N stage, pleural invasion, vascular invasion, lymphatic invasion, and severe nuclear atypia. Interestingly, smoking showed significant association with high-grade TB, despite the fact that previous studies could not show a significant relationship between them. Furthermore, through our systematic analysis, high-grade TB showed a significant relationship with EMT markers. Conclusion Our findings indicate that high-grade TB is associated with a worse prognosis in patients with lung cancer. TB evaluation should be implemented in routine pathological diagnosis, which may guide the patient’s treatment.
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Affiliation(s)
- Nishant Thakur
- Department of Hospital Pathology, The Catholic University of Korea, Seoul, South Korea
| | - Muhammad Joan Ailia
- Department of Hospital Pathology, The Catholic University of Korea, Seoul, South Korea
| | - Yosep Chong
- Department of Hospital Pathology, The Catholic University of Korea, Seoul, South Korea
| | - Ok Ran Shin
- Department of Hospital Pathology, The Catholic University of Korea, Seoul, South Korea
| | - Kwangil Yim
- Department of Hospital Pathology, The Catholic University of Korea, Seoul, South Korea
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Jesinghaus M, Herz AL, Kohlruss M, Silva M, Grass A, Lange S, Novotny A, Ott K, Schmidt T, Gaida M, Hapfelmeier A, Denkert C, Weichert W, Keller G. Post-neoadjuvant assessment of tumour budding according to ITBCC subgroups delivers stage- and regression-grade independent prognostic information in intestinal-type gastric adenocarcinoma. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2022; 8:448-457. [PMID: 35715937 PMCID: PMC9353660 DOI: 10.1002/cjp2.284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/20/2022] [Accepted: 06/02/2022] [Indexed: 11/09/2022]
Abstract
Tumour budding (TB) has been associated with adverse clinicopathological factors and poor survival in a plethora of therapy‐naïve carcinoma entities including gastric adenocarcinoma (GC). As conventional histopathological grading is usually omitted in the post‐neoadjuvant setting of GC, our study aimed to investigate the prognostic impact of TB in GCs resected after neoadjuvant therapy. We evaluated TB according to the criteria from the International Tumour Budding Consensus Conference (ITBCC) in 167 post‐neoadjuvant resections of intestinal‐type GC and correlated the results with overall survival (OS) and clinicopathological parameters. GCs were categorised into Bd1 (0–4 buds, low TB), Bd2 (5–9 buds, intermediate TB), and Bd3 (≥10 buds, high TB). Carcinomas with intermediate and high TB were significantly enriched in higher ypTNM stages and strongly associated with reduced 5‐year OS in univariable analyses (p < 0.001). In multivariable analyses including sex, age, resection status, UICC stage, and tumour regression grading, TB remained a stage‐independent predictor of survival (p < 0.001, hazard ratio Bd2: 2.60, Bd3: 4.74). The assessment of TB according to the ITBCC criteria provides valuable prognostic information in the post‐neoadjuvant setting of intestinal‐type GC and may be a considerable substitute for the conventional grading system in GCs after neoadjuvant therapy.
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Affiliation(s)
- Moritz Jesinghaus
- Institute of Pathology, University Hospital Marburg, Marburg, Germany.,Institute of Pathology, Technical University Munich, Munich, Germany
| | - Anna-Lina Herz
- Institute of Pathology, Technical University Munich, Munich, Germany
| | - Meike Kohlruss
- Institute of Pathology, Technical University Munich, Munich, Germany
| | - Miguel Silva
- Institute of Pathology, Technical University Munich, Munich, Germany
| | - Albert Grass
- Institute of Pathology, University Hospital Marburg, Marburg, Germany
| | - Sebastian Lange
- II Medizinische Klinik, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Alexander Novotny
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Katja Ott
- Department of Surgery, Klinikum Rosenheim, Rosenheim, Germany
| | - Thomas Schmidt
- Department of Surgery, University of Heidelberg, Heidelberg, Germany.,Department of Surgery, University Hospital Köln, Köln, Germany
| | - Matthias Gaida
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Hapfelmeier
- Institute of General Practice and Health Services Research, Technical University Munich, Munich, Germany.,Institute for AI and Informatics in Medicine, School of Medicine, Technical University Munich, Munich, Germany
| | - Carsten Denkert
- Institute of Pathology, University Hospital Marburg, Marburg, Germany
| | - Wilko Weichert
- Institute of Pathology, Technical University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.,Comprehensive Cancer Center Munich (CCCM), Munich, Germany
| | - Gisela Keller
- Institute of Pathology, Technical University Munich, Munich, Germany
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20
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Kucuk S. Prognostic value of tumour budding in stomach cancers. Int J Clin Pract 2021; 75:e14922. [PMID: 34580963 DOI: 10.1111/ijcp.14922] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The present study aimed to investigate the importance and prognostic value of tumour budding (TB) in Gastric Carcinoma (GC). METHODS Pathologic grading of tumours was performed according to the criteria specified by the American Joint Committee on Cancer (AJCC). Histopathologic types, histopathologic grading and all histopathologic characteristics were determined using the Lauren and World Health Organization (WHO) classifications. Forty-three surgically treated GC cases were examined in terms of TB according to the International Tumor Budding Consensus Conference (ITBCC) and budding grading [budding degree (Bd)] was performed. They were recorded as Bd1 (1-4 buddings), Bd2 (5-9 buddings) or Bd3 (10 buddings or more). Bd score, clinicopathologic parameters and prognostic factors were analysed. RESULTS There were 13 (30.2%) Bd1, 11 (25.6%) Bd2 and 19 (44.2%) Bd3 cases. A statistically significant relationship was found between Bd scores and pT, N, and histologic grade (P < .01, P < .05). In the Bd1 group, stage pT2 was statistically significantly more frequent than pT3 (P = .001). In the poorly differentiated group, Bd3 was statistically significantly higher than Bd1, but Bd1 was statistically significantly higher than Bd2 in the well-differentiated group (P = .001). In the N0 group, Bd1 was significantly higher than Bd2 and Bd3, whereas Bd2 was higher than Bd1 and Bd3 in the N2 group. Bd3 was higher than Bd1 and Bd2 in the N3 group (P = .001). CONCLUSION In the present study, Bd was statistically significantly related to characteristics such as pathologic stage, lymph node involvement, and grade. The data obtained here suggest that Bd can be applied to GC and it might contribute to the standardisation of diagnosis and prognostic factors.
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Affiliation(s)
- Sirin Kucuk
- Department of Pathology, Faculty of Medicine, Usak University, Usak, Turkey
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21
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Modified Tumor Budding as a Better Predictor of Lymph Node Metastasis in Early Gastric Cancer: Possible Real-World Applications. Cancers (Basel) 2021; 13:cancers13143405. [PMID: 34298621 PMCID: PMC8306932 DOI: 10.3390/cancers13143405] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/05/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary To obtain the optimal treatment effect of endoscopic resection (ER) in early gastric carcinoma (EGC), a well-established indication for post-ER surgery is needed. In addition, accurate prediction of lymph node metastasis (LNM) is necessary to achieve this goal. Here, we present modified tumor budding (mTB), which excludes signet ring cells from conventional tumor budding (TB) as a novel predictor for LNM. Conventional TB and mTB were the most predictive independent factors for LNM. Furthermore, mTB was superior to TB in predicting LNM (p = 0.0004–0.0008). In conclusion, mTB significantly enhanced the predictive power of LNM, which could be a novel indicator for determining post-ER surgery. Abstract Endoscopic resection (ER) is a minimally invasive treatment for early gastric cancer (EGC) with a low risk of lymph node metastasis (LNM). Recently, tumor budding (TB) has emerged as a potential predictor of LNM in EGC. We assessed the clinical significance of modified TB (mTB) that excludes the signet ring cell component and compared several TB assessment methods. Two hundred and eighty-nine patients with EGC at Uijeongbu St. Mary’s Hospital from 2010 to 2021 were enrolled. In univariate analysis, age, size, depth of invasion, tumor type, histologic type, Lauren classification, lymphatic invasion, venous invasion, poorly differentiated carcinoma (“not otherwise specified” predominant), and TB were significantly associated with LNM. Multivariate regression analysis showed that mTB (difference area under the curve [dAUC] = 0.085 and 0.087) was superior to TB (dAUC = 0.054 and 0.057) in predicting LNM. In addition, total TB counts on representative slide sections (dAUC = 0.087 and 0.057) in assessing TB and mTB and the ITBCC method (dAUC = 0.085) in mTB were superior to the presence or absence method (dAUC = 0.042 and 0.029). The mTB significantly increases LNM prediction ability, which can provide important information for patients with EGC.
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Díaz Del Arco C, Ortega Medina L, Estrada Muñoz L, García Gómez de Las Heras S, Fernández Aceñero MJ. Is there still a place for conventional histopathology in the age of molecular medicine? Laurén classification, inflammatory infiltration and other current topics in gastric cancer diagnosis and prognosis. Histol Histopathol 2021; 36:587-613. [PMID: 33565601 DOI: 10.14670/hh-18-309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer-related deaths worldwide. In western countries, more than half of GC patients are diagnosed at advanced stages and 5-year survival rates range between 20-30%. The only curative treatment is surgery, and despite recent advances in oncological therapies, GC prognosis is still poor. The main prognostic tool for patient categorization and treatment selection is the TNM classification, but its limitations are being increasingly recognized. Early recurrences may occur in early-stage disease, and patients at the same stage show heterogeneous outcomes. Thus, there is a need to improve GC stratification and to identify new prognostic factors, which may allow us to select drug-susceptible populations, refine patient grouping for clinical trials and discover new therapeutic targets. Molecular classifications have been developed, but they have not been translated to the clinical practice. On the other hand, histological assessment is cheap and widely available, and it is still a mainstay in the era of molecular medicine. Furthermore, histological features are acquiring new roles as reflectors of the genotype-phenotype correlation, and their potential impact on patient management is currently being analyzed. The aim of this literature review is to provide a modern overview of the histological assessment of GC. In this study, we discuss recent topics on the histological diagnosis of GC, focusing on the current role of Laurén classification and the potential value of new histological features in GC, such as inflammatory infiltration and tumor budding.
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Affiliation(s)
- Cristina Díaz Del Arco
- Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain. .,Complutense University of Madrid, Madrid, Spain
| | - Luis Ortega Medina
- Complutense University of Madrid, Madrid, Spain.,Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - Mª Jesús Fernández Aceñero
- Complutense University of Madrid, Madrid, Spain.,Department of Surgical Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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23
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Katoch A, Nayak D, Faheem MM, Kumar A, Sahu PK, Gupta AP, Kumar LD, Goswami A. Natural podophyllotoxin analog 4DPG attenuates EMT and colorectal cancer progression via activation of checkpoint kinase 2. Cell Death Discov 2021; 7:25. [PMID: 33500399 PMCID: PMC7838189 DOI: 10.1038/s41420-021-00405-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/17/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) is critical for the metastatic dissemination of cancer cells and contributes to drug resistance. In this study, we observed that epithelial colorectal cancer (CRC) cells transiently exposed to 5-fluorouracil (5-FU) (a chemotherapeutic drug for CRC) as well as 5-FU-resistant cells (5-FU-R) develop EMT characters as evidenced by activation of Vimentin and augmented invasive properties. On the other hand, 4DPG (4′-demethyl-deoxypodophyllotoxin glucoside), a natural podophyllotoxin analog attenuates EMT and invadopodia formation abilities of HCT-116/5-FU-R and SW-620/5-FU-R cells. Treatment with 4DPG restrains Vimentin phosphorylation (Ser38) in 5-FU-R cells, along with downregulation of mesenchymal markers Twist1 and MMP-2 while augmenting the expression of epithelial markers E-cadherin and TIMP-1. Moreover, 4DPG boosts the tumor-suppressor protein, checkpoint kinase 2 (Chk2) via phosphorylation at Thr68 in a dose-dependent manner in 5-FU-R cells. Mechanistically, SiRNA-mediated silencing of Chk2, as well as treatment with Chk2-specific small-molecule inhibitor (PV1019), divulges that 4DPG represses Vimentin activation in a Chk2-dependent manner. Furthermore, immunoprecipitation analysis unveiled that 4DPG prevents complex formation between Vimentin and p53 resulting in the rescue of p53 and its nuclear localization in aggressive 5-FU-R cells. In addition, 4DPG confers suitable pharmacokinetic properties and strongly abrogates tumor growth, polyps formation, and lung metastasis in an orthotopic rat colorectal carcinoma model. In conclusion, our findings demonstrate 4DPG as a targeted antitumor/anti-metastatic pharmacological lead compound to circumvent EMT-associated drug resistance and suggest its clinical benefits for the treatment of aggressive cancers.
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Affiliation(s)
- Archana Katoch
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, India.,Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir, 180001, India
| | - Debasis Nayak
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA
| | - Mir Mohd Faheem
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir, 180001, India.,School of Biotechnology, University of Jammu, Jammu, Jammu and Kashmir, 180006, India
| | - Aviral Kumar
- Cancer Biology, CSIR-Centre for Cellular & Molecular Biology, Hyderabad, Telangana, 500007, India
| | - Promod Kumar Sahu
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir, 180001, India
| | - Ajai Prakash Gupta
- Quality Control and Quality Assurance Division, CSIR-Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir, 180001, India
| | - Lekha Dinesh Kumar
- Cancer Biology, CSIR-Centre for Cellular & Molecular Biology, Hyderabad, Telangana, 500007, India
| | - Anindya Goswami
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, India. .,Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir, 180001, India.
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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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25
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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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Gurzu S, Jung I, Sugimura H, Stefan-van Staden RI, Yamada H, Natsume H, Iwashita Y, Szodorai R, Szederjesi J. Maspin subcellular expression in wild-type and mutant TP53 gastric cancers. World J Gastrointest Oncol 2020; 12:741-755. [PMID: 32864042 PMCID: PMC7428795 DOI: 10.4251/wjgo.v12.i7.741] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/06/2020] [Accepted: 05/27/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Although the role of p53 in the evolution and prognosis of gastric cancer (GC) has been extensively examined, the exact mechanism of action is incompletely understood. In the last years, p53-target genes were supposed to be involved in the p53 pathway. One of them is the tumor-suppressor gene Maspin, which codifies the protein with the same name. Maspin activity depends on its subcellular localization. To our knowledge, the possible role of TP53 gene in Maspin subcellular localization, in GC cells, has not yet been studied in a large number of human samples.
AIM To evaluate the possible role of wild-type and mutated p53 in Maspin subcellular localization.
METHODS The present study included 266 consecutive patients with GC in which TP53 gene status, and mutations in exons 2 to 11, respectively, were analyzed and correlated with immunohistochemical expression of p53 and Maspin.
RESULTS None of the 266 cases showed mutations in exon 9. The rate of TP53 mutations was 33.83%. The mutation rate was slightly higher in distally-located GCs, with a lower degree (≤ 5 buds/ high power fields) of dyscohesivity (P < 0.01). The wild-type cases had a longer survival, compared with mutant GCs, especially in patients without lymph node metastases, despite the high depth of tumor infiltration (P = 0.01). The Dukes-MAC-like staging system was proved to have the most significant independent prognostic value (P < 0.01). The statistical correlations proved that TP53 gene mutations in exon 7 might induce knockdown of Maspin, but wild-type p53 can partially restore nuclear Maspin expression and decrease the metastatic potential of gastric adenocarcinoma cells.
CONCLUSION Downregulated Maspin might be induced by mutations in exon 7 of the TP53 gene but wild-type p53 can partially restore nuclear Maspin expression. These findings should be proved in experimental studies.
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Affiliation(s)
- Simona Gurzu
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mureș 540139, Mureș, Romania
- Research Center, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mureș 540139, Mureș, Romania
| | - Ioan Jung
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mureș 540139, Mureș, Romania
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
| | | | - Hidetaka Yamada
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
| | - Hiroko Natsume
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
| | - Yuji Iwashita
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
| | - Rita Szodorai
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mureș 540139, Mureș, Romania
| | - Janos Szederjesi
- Intensive Care Unit, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mureș 540139, Mureș, Romania
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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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Qi B, Liu L, Pan Y, Xu S, Li J. Prognostic significance of peritumoural and intratumoural budding in intestinal-type gastric adenocarcinoma. Arab J Gastroenterol 2020; 21:111-116. [PMID: 32423856 DOI: 10.1016/j.ajg.2020.04.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 02/19/2020] [Accepted: 04/08/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND STUDY AIMS Tumour budding (TB) at the invasive front, termed peritumoural budding (PTB), is an established prognostic factor for many solid tumours. However, intratumoural budding (ITB) in gastric adenocarcinoma (GAC), which is frequently observed at the tumour centre, particularly in tumour biopsy tissues, remains poorly understood. Hence, we aimed to determine the correlation of ITB with PTB and their connection with clinicopathological characteristics as well as their prognostic value in GAC. PATIENTS AND METHODS We investigated a total of 153 cases of GAC wherein tissues were primarily resected and their related clinicopathological data. A continuous series of paraffin-embedded tissues was stained by haematoxylin-eosin staining, and budding cells were identified by immunohistochemical staining. PTB and ITB were counted in five fields with the highest density of tumour buds. The selected area was examined under 40 high-power field. Cases were divided into low-grade TB and high-grade TB groups according to the median bud count. RESULTS Among the 153 patients with GAC, 51 underwent simultaneous observation of ITB and PTB, which were found to have a significant positive correlation. A higher grade of ITB in tumours was associated with positive lymph node metastasis and could predict a worse prognosis. Additionally, patients with simultaneous PTB and ITB had a shorter overall survival than those with PTB alone, suggesting a worse prognosis. CONCLUSION PTB and ITB were found to be adverse prognostic factors and high-risk indicators of intestinal-type GAC, and ITB plays an important role in evaluating GAC prognosis in gastroscopic biopsy tissues. Additionally, TB might become a useful index for predicting GAC prognosis in the future.
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Affiliation(s)
- Baoning Qi
- Department of Public Health, Shaanxi University of Chinese Medicine, China.
| | - Longzhu Liu
- Department of Public Health, Shaanxi University of Chinese Medicine, China
| | - Yanfang Pan
- Department of Pathology, Shaanxi University of Chinese Medicine, China
| | - Shouzhu Xu
- Department of Public Health, Shaanxi University of Chinese Medicine, China
| | - Juan Li
- Department of Public Health, Shaanxi University of Chinese Medicine, China
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Tumor infiltrative growth pattern correlates with the immune microenvironment and is an independent factor for lymph node metastasis and prognosis in stage T1 esophageal squamous cell carcinoma. Virchows Arch 2020; 477:401-408. [PMID: 32232560 DOI: 10.1007/s00428-020-02801-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/12/2020] [Accepted: 03/18/2020] [Indexed: 12/17/2022]
Abstract
In this retrospective study, we analyzed the association between the tumor infiltrative growth pattern (INF) and tumor immune environment and its predictive value for lymph node metastasis and overall survival (OS) in stage T1 esophageal squamous cell carcinoma (ESCC). In total, 593 patients with a diagnosis of stage T1 ESCC who underwent esophagectomy and regional lymphadenectomy between 2009 and 2018 were included. The INF type and elements of the tumor immune microenvironment, including tumor infiltrative lymphocytes (TILs) and tertiary lymphoid structures (TLSs), were microscopically evaluated within the tumor invasive margin with hematoxylin and eosin (HE)-stained slices. The infiltrative-type INF (INFc) was associated with low-grade TILs and the absence of TLSs, deep tumor invasion, poorly differentiated phenotype. Multivariate logistic regression identified INFc as one of the independent risk factors for lymph node metastasis. INFc and low-grade TILs were independent inferior predictive factors for OS. A novel histologic risk stratification model was classified as INFa/b and high-grade TILs, INFa/b and low-grade TILs, INFc and high-grade TILs, and INFc and low-grade TILs. The Kaplan-Meier curves showed that INFa/b and high-grade TILs were associated with the best prognosis, and INFc and low-grade TILs were associated with the worst prognosis, and there was significant difference between groups. In conclusion, INFc is an independent risk factor for lymph node metastasis and an independent inferior prognostic factor for stage T1 ESCC. Furthermore, INFc is associated with immunosuppression, and the combination of the INF and TILs is useful for the risk stratification of prognosis.
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Dao TV, Nguyen CV, Nguyen QT, Vu HTN, Phung HT, Bui OT, Nguyen DK, Luong BV, Tran TV. Evaluation of Tumor Budding in Predicting Survival for Gastric Carcinoma Patients in Vietnam. Cancer Control 2020; 27:1073274820968883. [PMID: 33136444 PMCID: PMC7791444 DOI: 10.1177/1073274820968883] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Tumor budding (Bd) has been demonstrated to be a promising prognostic factor in many carcinomas and in gastric cancer. It may represent an optimal additional parameter that is helpful for risk stratification in gastric adenocarcinoma. Hence, the present research was designed to predict the survival outcomes of gastric cancer in Vietnam, applying the tumor budding criteria of the International Tumor Budding Consensus Conference (ITBCC) 2016. METHODS The present study was conducted on 109 gastric cancer patients who underwent surgery but did not receive neo-adjuvant chemotherapy from 2012 to 2015. The patients' clinicopathological features were recorded. Bd was evaluated according to the 2016 ITBCC criteria and classified as Bd1 (0-4 buds), Bd2 (5-9 buds), and Bd3 (≥10 buds) grades, in addition to being categorized into 2 main Bd groups: low (<10 buds) and high (≥10 buds) Bd. Kaplan-Meier and log-rank models were applied to analyze survival proportions. RESULTS Of all the patients, 22.9% were classified as Bd1, 31.2% as Bd2, and 45.9% as Bd3 grades. Furthermore, 54.1% patients were categorized into the low and 45.9% into the high Bd groups. Patients with Bd1 and Bd2 grades (the low Bd group) exhibited the best prognosis, with 5-year overall survival (OS) rates of 85.7%, 90.8%, and90.3%, respectively. Patients with Bd3 grade (the high Bd group exhibited the worst prognosis, and none of them lived for 5 years (p < 0.001). Similar to OS rates, disease-free survival (DFS) rates markedly reduced from the Bd1 to Bd3 grade: Bd1, 95.0%; Bd2, 84.7%; and Bd3, 0% (p < 0.001). CONCLUSION Patients with different gastric cancer Bd grades exhibited significantly different OS and DFS rates. The present study findings suggest that the ITBCC criteria can be used to stratify Bd for the treatment and prognosis of gastric cancer patients in Vietnam.
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Affiliation(s)
- Tu Van Dao
- Department of Quan Su Optional Treatment, National Cancer Hospital,
Hanoi, Vietnam
- Cancer Research and Clinical Trial Center, National Cancer Hospital,
Hanoi, Vietnam
| | - Chu Van Nguyen
- Department of Quan Su Pathology, National Cancer Hospital, Hanoi,
Vietnam
- Hanoi Medical University, Hanoi, Vietnam
| | - Quang Tien Nguyen
- Department of Quan Su Optional Treatment, National Cancer Hospital,
Hanoi, Vietnam
| | - Ha Thi Ngoc Vu
- Vietnam University of Traditional Medicine, Hanoi, Vietnam
| | - Huyen Thi Phung
- Department of Internal Medicine No6, National Cancer Hospital,
Hanoi, Vietnam
| | - Oanh Thi Bui
- Cancer Research and Clinical Trial Center, National Cancer Hospital,
Hanoi, Vietnam
| | - Dung Khac Nguyen
- Cancer Research and Clinical Trial Center, National Cancer Hospital,
Hanoi, Vietnam
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