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NagiReddy TV, Gupta S, Bavikar R, Londhe M, Chandra P, Vaidya AA. A Novel 4-Tier Classification for Tumor Budding and the Importance of Tumor Invasive Patterns in the Prognosis of Colorectal Cancer. World J Surg 2025; 49:830-839. [PMID: 40056400 DOI: 10.1002/wjs.12534] [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: 11/08/2024] [Revised: 02/03/2025] [Accepted: 02/16/2025] [Indexed: 03/10/2025]
Abstract
BACKGROUND Colorectal carcinoma (CRC) is a major global health issue, with significant morbidity and mortality. Although the TNM staging system remains the standard for prognosticating CRC, it fails to capture the full complexity of tumor behavior. Tumor budding (TB) and tumor invasive patterns (TIPs) are emerging as promising histopathological markers that may provide additional prognostic insights, particularly in predicting the nodal metastasis (N), lymphovascular invasion (LVI), and perineural invasion (PNI). This study aims to assess the correlation between TB, TIP, and CRC prognosis. MATERIALS AND METHODS This ambidirectional observational study, conducted at our tertiary care center, included 60 biopsy-proven CRC patients, the majority of whom were at stages 2 and 3. Histopathological evaluation of TB and TIP were performed on Hematoxylin and Eosin (H&E) stained slides. TB and TIP categories are then compared against various histopathological parameters. Statistical analysis was performed. RESULTS In the 60 CRC cases studied, low TB was observed in 60% of cases, whereas high TB was seen in 5%. TIP analysis showed that 57% of cases had expansile patterns and 35% of cases had infiltrative patterns. A significant association was found between TB and N (p - 0.018) as well as TIP and PNI (p - 0.016). Multivariate analysis revealed that TB remained a strong predictor for N (OR (odds ratio) = 12.8 and p < 0.001). Although not statistically significant, distinct trends were observed between low and zero TB. Our study's findings on TB and TIP align with several historical studies, reinforcing their prognostic significance in CRC. Despite being a small cohort, our study aligns with these findings, emphasizing TB and TIP as critical prognostic markers in CRC. CONCLUSION TB and TIP are valuable prognostic tools in CRC, offering insights into tumor behavior and metastasis potential. Their incorporation into routine histopathological evaluation could enhance prognostic accuracy.
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Affiliation(s)
- Tejus V NagiReddy
- Dept. of Surgical Oncology, Dr. D. Y. Patil Medical College, Hospital & Research Center, Pune, India
| | - Samir Gupta
- Dept. of Surgical Oncology, Dr. D. Y. Patil Medical College, Hospital & Research Center, Pune, India
| | - Rupali Bavikar
- Dept. of Pathology, Dr. D. Y. Patil Medical College, Hospital & Research Center, Pune, India
| | - Mangesh Londhe
- Dept. of Pathology, Dr. D. Y. Patil Medical College, Hospital & Research Center, Pune, India
| | - Prasant Chandra
- Dept. of Surgical Oncology, Dr. D. Y. Patil Medical College, Hospital & Research Center, Pune, India
| | - Advait A Vaidya
- Dept. of Surgical Oncology, Dr. D. Y. Patil Medical College, Hospital & Research Center, Pune, India
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Haddad TS, Bokhorst JM, Berger MD, Dobbelsteen LVD, Simmer F, Ciompi F, Galon J, Laak JVD, Pagès F, Zlobec I, Lugli A, Nagtegaal ID. Combining immunoscore and tumor budding in colon cancer: an insightful prognostication based on the tumor-host interface. J Transl Med 2024; 22:1090. [PMID: 39623479 PMCID: PMC11610196 DOI: 10.1186/s12967-024-05818-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/31/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Tumor Budding (TB) and Immunoscore are independent prognostic markers in colon cancer (CC). Given their respective representation of tumor aggressiveness and immune response, we examined their combination in association with patient disease-free survival (DFS) in pTNM stage I-III CC. METHODS In a series of pTNM stage I-III CCs (n = 654), the Immunoscore was computed and TB detected automatically using a deep learning network. Two-tiered systems for both biomarkers were used with cut-offs of 25% and ten buds for Immunoscore and TB according to clinical guidelines, respectively. Associations of Immunoscore with TB with 5-year DFS were examined using Kaplan-Meier survival analysis in addition to multivariable modeling and relative contribution analysis using Cox regression. RESULTS Immunoscore and TB independently are prognostic with hazard ratio (HR) = 2.0, 95% confidence interval (CI) 1.4-2.8 and HR 2.5, with 95% CI 1.4-4.5, respectively; P value < 0.0001. By combining Immunoscore with TB, patients with Immunoscore Low, TB High tumors had a significantly poorer DFS (HR 5.6, 95% CI 2.6-12.0; P value < 0.0001) than those with Immunoscore High, TB Low tumors. The combined Immunoscore with TB score was independently prognostic (P value = 0.009) in comparison to N-stage, T-stage, and MSI. Immunoscore with TB had the highest relative contribution (35%) to DFS in pTNM stage I-II CCs. CONCLUSIONS The association of Immunoscore and TB with patient survival suggests that both biomarkers are complementary and should be interpreted in combination to identify high-risk Stage I-II patients who should be considered for adjuvant therapy or further diagnostic testing.
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Affiliation(s)
- T S Haddad
- Radboud University Medical Center, Nijmegen, Netherlands
| | - J M Bokhorst
- Radboud University Medical Center, Nijmegen, Netherlands
| | - M D Berger
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | | | - F Simmer
- Radboud University Medical Center, Nijmegen, Netherlands
| | - F Ciompi
- Radboud University Medical Center, Nijmegen, Netherlands
| | - J Galon
- Centre de Recherche Des Cordeliers, Sorbonne Université, Université Paris Cité, 75006, Paris, France
| | - J V D Laak
- Radboud University Medical Center, Nijmegen, Netherlands
| | - F Pagès
- Centre de Recherche Des Cordeliers, Sorbonne Université, Université Paris Cité, 75006, Paris, France
| | - I Zlobec
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - A Lugli
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - I D Nagtegaal
- Radboud University Medical Center, Nijmegen, Netherlands.
- Department of Pathology, RadboudUMC, 6525 GA, Nijmegen, The Netherlands.
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Unal Kocabey D, Cakir IE. The prognostic significance of growth pattern, tumor budding, poorly differentiated clusters, desmoplastic reaction pattern and tumor-stroma ratio in colorectal cancer and an evaluation of their relationship with KRAS, NRAS, BRAF mutations. Ann Diagn Pathol 2024; 73:152375. [PMID: 39312865 DOI: 10.1016/j.anndiagpath.2024.152375] [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: 07/27/2024] [Revised: 09/07/2024] [Accepted: 09/11/2024] [Indexed: 09/25/2024]
Abstract
Growth pattern (GP), tumor budding (TB), poorly differentiated clusters (PDC), desmoplastic reaction pattern (DRP) and tumor-stroma ratio (TSR) are prognostic histomorphological parameters in colorectal cancer (CRC). Correlations between these parameters, their individual prognostic values, and their relationship with KRAS/NRAS/BRAF mutations have not been comprehensively examined. We aimed to investigate these associations, which have not been previously explored in this combination. 126 CRC cases were included. GP, TB, PDC, DRP and TSR were evaluated by two experienced pathologists. KRAS/NRAS/BRAF mutation profile were determined using qPCR. Demographic, clinicopathological and survival data were recorded. Interrelations were investigated by statistical analysis. Infiltrative GP was more frequent in high-score TB, PDC-G3, and stroma-high tumors (p < 0.05). High-score TB was more common in PDC-G3 and stroma-high tumors (p < 0.05). Immature DRP was more frequent in stroma-high tumors (p = 0.014). Among histomorphological parameters, a significant relationship was found only between infiltrative GP and the presence of KRAS mutation (p = 0.023). Moreover, GP was significantly associated with pT, lymphatic invasion, perineural invasion (p < 0.05). Effects on survival were assessed using Kaplan-Meier method and Cox proportional hazards model. TB and PDC were identified as independent predictors of overall survival. Higher TB score (p = 0.008) and higher PDC grade (p = 0.013) lead to worse survival. Interestingly, GP, DRP, TSR or KRAS/NRAS/BRAF mutations were not associated with overall survival. Our results highlight the prognostic significance of TB and PDC. We suggest incorporating TB and PDC into routine CRC reports. The association of KRAS mutation with infiltrative GP supports its role in the acquisition of invasive behavior.
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Affiliation(s)
- Duygu Unal Kocabey
- Izmir Katip Celebi University, Ataturk Training and Research Hospital, Department of Pathology, IZMIR, Turkey.
| | - I Ebru Cakir
- Izmir Katip Celebi University, Ataturk Training and Research Hospital, Department of Pathology, IZMIR, Turkey
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Zheng BW, Zheng BY, Yang Z, Niu HQ, Zhu GQ, Zou MX, Liu FS, Xia C. Clinicopathologic and prognostic characteristics of tumor budding-like in giant cell tumor of bone. Cancer 2024; 130:4085-4095. [PMID: 39239786 DOI: 10.1002/cncr.35551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/13/2024] [Accepted: 08/19/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND Currently, tumor budding (TB) is defined as an important factor for a poor prognosis in various types of cancers. The authors identified a significant presence of TB-like structures at the tumor invasive front in giant cell tumor of bone (GCTB), which may have the same biologic function as TB. The objective of this report was to describe the distribution of TB in GCTB and investigate its correlation with clinicopathologic characteristics, the immune microenvironment, survival prognosis, and response to denosumab treatment. METHODS This multicenter cohort study included 426 patients with GCTB who received treatment between 2012 and 2021 at four centers. Two independent pathologists performed visual assessments of TBL structures in hematoxylin-and-eosin-stained tumor sections. Immunohistochemistry was used to evaluate tumor-infiltrating lymphocyte subtypes (CD3-positive, CD4-positive, CD8-positive, CD20-positive, programmed cell death protein-1-positive, programmed cell death-ligand 1positive, and FoxP3-positive) as well as Ki-67 expression levels in 426 tissue samples. These parameters were then analyzed for associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]), clinicopathologic characteristics, and response to denosumab treatment. RESULTS High-grade TB was associated with poorer LRFS and OS in both patient groups. In addition, TB was correlated with various clinicopathologic features, tumor-infiltrating lymphocyte expression, and response to denosumab treatment. TB outperformed the traditional Enneking and Campanacci staging systems in predicting patient LRFS and OS. CONCLUSIONS The current data support the assessment of TBL structures as a reliable prognostic tool in GCTB, potentially aiding in the development of personalized treatment strategies for patients.
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Affiliation(s)
- Bo-Wen Zheng
- Musculoskeletal Tumor Center, Peking University People's Hospital, Peking University, Beijing, China
| | - Bo-Yv Zheng
- Department of Orthopedic Surgery, General Hospital of the Central Theater Command, Wuhan, China
| | - Zhen Yang
- Arthritis Clinical and Research Center, Peking University People's Hospital, Peking University, Beijing, China
| | - Hua-Qing Niu
- Department of Ophthalmology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guo-Qiang Zhu
- Department of Orthopedic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Xiang Zou
- Department of Spine Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Fu-Sheng Liu
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chao Xia
- Department of Spine Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
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Hou X, Li X, Han Y, Xu H, Xie Y, Zhou T, Xue T, Qian X, Li J, Wang HC, Yan J, Guo X, Liu Y, Liu J. Triple-negative breast cancer survival prediction using artificial intelligence through integrated analysis of tertiary lymphoid structures and tumor budding. Cancer 2024; 130:1499-1512. [PMID: 38422056 DOI: 10.1002/cncr.35261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/14/2024] [Accepted: 01/16/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a highly heterogeneous and clinically aggressive disease. Accumulating evidence indicates that tertiary lymphoid structures (TLSs) and tumor budding (TB) are significantly correlated with the outcomes of patients who have TNBC, but no integrated TLS-TB profile has been established to predict their survival. The objective of this study was to investigate the relationship between the TLS/TB ratio and clinical outcomes of patients with TNBC using artificial intelligence (AI)-based analysis. METHODS The infiltration levels of TLSs and TB were evaluated using hematoxylin and eosin staining, immunohistochemistry staining, and AI-based analysis. Various cellular subtypes within TLS were determined by multiplex immunofluorescence. Subsequently, the authors established a nomogram model, conducted calibration curve analyses, and performed decision curve analyses using R software. RESULTS In both the training and validation cohorts, the antitumor/protumor model established by the authors demonstrated a positive correlation between the TLS/TB index and the overall survival (OS) and relapse-free survival (RFS) of patients with TNBC. Notably, patients who had a high percentage of CD8-positive T cells, CD45RO-positive T cells, or CD20-positive B cells within the TLSs experienced improved OS and RFS. Furthermore, the authors developed a comprehensive TLS-TB profile nomogram based on the TLS/TB index. This novel model outperformed the classical tumor-lymph node-metastasis staging system in predicting the OS and RFS of patients with TNBC. CONCLUSIONS A novel strategy for predicting the prognosis of patients with TNBC was established through integrated AI-based analysis and a machine-learning workflow. The TLS/TB index was identified as an independent prognostic factor for TNBC. This nomogram-based TLS-TB profile would help improve the accuracy of predicting the prognosis of patients who have TNBC.
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Affiliation(s)
- Xupeng Hou
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- People's Republic of China. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xueyang Li
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Yunwei Han
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Hua Xu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongjie Xie
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Tianxing Zhou
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Tongyuan Xue
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Xiaolong Qian
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Jiazhen Li
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Hayson Chenyu Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingrui Yan
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Xiaojing Guo
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Ying Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Liu
- Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- People's Republic of China. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
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Dawson H, Bokhorst J, Studer L, Vieth M, Oguz Erdogan AS, Kus Öztürk S, Kirsch R, Brockmoeller S, Cathomas G, Buslei R, Fink D, Roumet M, Zlobec I, van der Laak J, Nagtegaal ID, Lugli A. Lymph node metastases and recurrence in pT1 colorectal cancer: Prediction with the International Budding Consortium Score-A retrospective, multi-centric study. United European Gastroenterol J 2024; 12:299-308. [PMID: 38193866 PMCID: PMC11017758 DOI: 10.1002/ueg2.12521] [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: 05/26/2023] [Accepted: 11/03/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND The International Collaboration on Cancer Reporting proposes histological tumour type, lymphovascular invasion, tumour grade, perineural invasion, extent, and dimensions of invasion as risk factors for lymph node metastases and tumour progression in completely endoscopically resected pT1 colorectal cancer (CRC). OBJECTIVE The aim of the study was to propose a predictive and reliable score to optimise the clinical management of endoscopically resected pT1 CRC patients. METHODS This multi-centric, retrospective International Budding Consortium (IBC) study included an international pT1 CRC cohort of 565 patients. All cases were reviewed by eight expert gastrointestinal pathologists. All risk factors were reported according to international guidelines. Tumour budding and immune response (CD8+ T-cells) were assessed with automated models using artificial intelligence. We used the information on risk factors and least absolute shrinkage and selection operator logistic regression to develop a prediction model and generate a score to predict the occurrence of lymph node metastasis or cancer recurrence. RESULTS The IBC prediction score included the following parameters: lymphovascular invasion, tumour buds, infiltration depth and tumour grade. The score has an acceptable discrimination power (area under the curve of 0.68 [95% confidence intervals (CI) 0.61-0.75]; 0.64 [95% CI 0.57-0.71] after internal validation). At a cut-off of 6.8 points to discriminate high-and low-risk patients, the score had a sensitivity and specificity of 0.9 [95% CI 0.8-0.95] and 0.26 [95% 0.22, 0.3], respectively. CONCLUSION The IBC score is based on well-established risk factors and is a promising tool with clinical utility to support the management of pT1 CRC patients.
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Affiliation(s)
- Heather Dawson
- Institute of Tissue Medicine and PathologyUniversity of BernBernSwitzerland
| | | | - Linda Studer
- Institute of Tissue Medicine and PathologyUniversity of BernBernSwitzerland
- Institute of Artificial Intelligence and Complex SystemsUniversity of Applied Sciences and Arts Western SwitzerlandFribourgSwitzerland
| | - Michael Vieth
- Institute of PathologyFriedrich‐Alexander‐University Erlangen‐NurembergKlinikum BayreuthBayreuthGermany
| | | | | | - Richard Kirsch
- Pathology and Laboratory MedicineMount Sinai HospitalUniversity of TorontoTorontoOntarioCanada
| | - Scarlett Brockmoeller
- Pathology and Data AnalyticsLeeds Institute of Medical Research at St. James's School of MedicineLeedsUK
| | - Gieri Cathomas
- Institute of PathologyKantonsspital BasellandLiestalSwitzerland
- Present address:
Institute of Tissue Medicine and PathologyUniversity of BernBernSwitzerland.
| | - Rolf Buslei
- Institut und Praxis für Pathologie, Neuropathologie, Molekulare Diagnostik und ZytologieSozialstiftung BambergBambergGermany
| | - David Fink
- Department of Pathology and ImmunologyBaylor College of MedicineHoustonTexasUSA
| | - Marie Roumet
- Clinical Trials UnitUniversity of BernBernSwitzerland
| | - Inti Zlobec
- Institute of Tissue Medicine and PathologyUniversity of BernBernSwitzerland
| | | | | | - Alessandro Lugli
- Institute of Tissue Medicine and PathologyUniversity of BernBernSwitzerland
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Liang W, Jie H, Xie H, Zhou Y, Li W, Huang L, Liang Z, Liu H, Zheng X, Zeng Z, Kang L. High KRT17 expression in tumour budding indicates immunologically 'hot' tumour budding and predicts good survival in patients with colorectal cancer. Clin Transl Immunology 2024; 13:e1495. [PMID: 38433762 PMCID: PMC10903186 DOI: 10.1002/cti2.1495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 02/07/2024] [Accepted: 02/18/2024] [Indexed: 03/05/2024] Open
Abstract
Objectives Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically 'hot' TB remain poorly understood. Methods We quantified the number of TB by haematoxylin-eosin (H&E) sections and the densities of CD3+ and CD8+ T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed. Results In a CRC cohort of 351 cases, low-grade TB was associated with high CD3+ and CD8+ T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3+ and CD8+ T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration. Conclusions KRT17 can be employed as a new indicator for distinguishing different immunological TBs.
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Affiliation(s)
- Wenfeng Liang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Haiqing Jie
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Hao Xie
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Yebohao Zhou
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Wenxin Li
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Liang Huang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Zhenxing Liang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Huashan Liu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Xiaobin Zheng
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Ziwei Zeng
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Liang Kang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
- Biomedical Innovation Center, The Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdongChina
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8
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Luo YH, Yan ZC, Liu JY, Li XY, Yang M, Fan J, Huang B, Ma CG, Chang XN, Nie X. Association of tumor budding with clinicopathological features and prognostic value in stage III-IV colorectal cancer. World J Gastroenterol 2024; 30:158-169. [PMID: 38312121 PMCID: PMC10835523 DOI: 10.3748/wjg.v30.i2.158] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/23/2023] [Accepted: 12/14/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Tumor budding (TB) has emerged as a promising independent prognostic biomarker in colorectal cancer (CRC). The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC. However, existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies. Consequently, this study investigated the correlation among TB categories, clinicopathological features, and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification. AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC. METHODS The clinical data of 547 CRC patients were collected for this retrospective study. Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines. RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy (P = 0.004), clinical stage IV (P < 0.001), ≥ 4 regional lymph node metastases (P = 0.004), left-sided colonic cancer (P = 0.040), and Bd 2-3 (P = 0.002) were independent prognostic factors in patients with stage III-IV CRC. Moreover, the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3, both in the tumor stroma and its invasive margin. CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC. It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.
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Affiliation(s)
- Yue-Hao Luo
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Zhe-Cheng Yan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Jia-Ying Liu
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xin-Yi Li
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Ming Yang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Jun Fan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Bo Huang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Cheng-Gong Ma
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xiao-Na Chang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xiu Nie
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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9
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Luo L, Liu H. High-grade tumor budding is a risk factor for survival in patients with laryngeal squamous cell carcinoma. Braz J Otorhinolaryngol 2023; 89:101310. [PMID: 37678011 PMCID: PMC10495643 DOI: 10.1016/j.bjorl.2023.101310] [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: 06/27/2023] [Revised: 08/07/2023] [Accepted: 08/12/2023] [Indexed: 09/09/2023] Open
Abstract
OBJECTIVE With the increasing incidence and mortality of laryngeal squamous cell carcinoma worldwide, researchers continue to search for novel prognostic factors and treatment methods for preventing early laryngeal squamous cell carcinoma from becoming advanced laryngeal squamous cell carcinoma. This study aims to determine if tumor budding is an independent risk factor associated with the survival of patients with laryngeal squamous cell carcinoma. METHODS 268 cases of laryngeal squamous cell carcinoma were studied, and tumor budding was analyzed for associations with clinicopathological features and clinical outcomes. RESULTS Tumor budding was divided into low-grade tumor budding (0-6/0.785 mm2) and high-grade tumor budding (≥7/0.785 mm2) based on the results of the receiver operating characteristics curve analysis. Logistic regression analysis showed that smaller tumor cell nests, the low levels of tumor-infiltrating lymphocytes, and higher pathological T staging were the risk factors for high-grade tumor budding (p < 0.05). In the low-grade tumor budding group, there was no statistic difference in survival between patients without tumor budding and those with 1-6/0.785 mm2 tumor budding. Multivariate survival analysis showed high-grade tumor budding (p < 0.001) was independent prognostic factors for disease-free survival and overall survival in laryngeal squamous cell carcinoma. High-grade tumor budding was also an independent prognostic factor for disease-free survival (p = 0.037) and overall survival (p = 0.009) in T1-2N0 laryngeal squamous cell carcinoma. CONCLUSIONS Smaller tumor cell nests, the low levels of tumor-infiltrating lymphocytes, and higher pathological T staging were closely associated with high-grade tumor budding in laryngeal squamous cell carcinoma. High-grade tumor budding may be an adverse risk factor that affects not only the disease-free survival and overall survival of laryngeal squamous cell carcinoma patients but also the survival of T1-2N0 laryngeal squamous cell carcinoma patients. LEVEL OF EVIDENCE Level 4.
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Affiliation(s)
- Li Luo
- Capital Medical University, Beijing Tongren Hospital, Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, Department of Pathology, Beijing, China; Capital Medical University, Beijing Luhe Hospital, Department of Pathology, Beijing, China
| | - Honggang Liu
- Capital Medical University, Beijing Tongren Hospital, Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, Department of Pathology, Beijing, China.
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10
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Karjula T, Kemi N, Niskakangas A, Mustonen O, Puro I, Pohjanen VM, Kuopio T, Elomaa H, Ahtiainen M, Mecklin JP, Seppälä TT, Wirta EV, Sihvo E, Väyrynen JP, Yannopoulos F, Helminen O. The prognostic role of tumor budding and tumor-stroma ratio in pulmonary metastasis of colorectal carcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:1298-1306. [PMID: 36841693 DOI: 10.1016/j.ejso.2023.02.009] [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: 12/07/2022] [Revised: 01/25/2023] [Accepted: 02/14/2023] [Indexed: 02/25/2023]
Abstract
OBJECTIVE To evaluate the prognostic value of tumor budding and tumor-stroma ratio (TSR) in resected pulmonary metastases of colorectal carcinoma (CRC). METHODS In total, 106 pulmonary metastasectomies were performed to 74 patients in two study hospitals during 2000-2020. All relevant clinical data were retrospectively collected. Tumor budding based on the International Tumor Budding Consensus Conference recommendations and TSR in the first resected pulmonary metastases and primary tumors were evaluated from diagnostic hematoxylin-eosin-stained histopathological slides. RESULTS 60 patients (85.7%) had low tumor budding (≤5 buds/field) and 10 patients (14.3%) had high tumor budding (>5 buds/field) in their first pulmonary metastases of CRC. 5-year overall survival rates of pulmonary metastasectomy in low and high total tumor budding were 28.3% and 37.3% (p = 0.387), respectively. 19 patients (27.1%) had low TSR and 51 patients (72.9%) had high TSR. The 5-year overall survival rates were 32.9% in low and 28.6% in high TSR of first pulmonary metastases (p = 0.746). Tumor budding and TSR did not provide prognostic value in Cox multivariate analysis. Tumor budding and TSR in resected pulmonary metastases were not associated with those of the primary tumor. CONCLUSION Tumor budding and TSR in the resected pulmonary metastases of CRC showed no statistically significant prognostic value, however, additional well-powered confirmatory studies are needed.
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Affiliation(s)
- Topias Karjula
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
| | - Niko Kemi
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Anne Niskakangas
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Olli Mustonen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Iiris Puro
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Vesa-Matti Pohjanen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Teijo Kuopio
- Department of Biological and Environmental Science, University of Jyväskylä, 40014, Jyväskylä, Finland; Department of Pathology, Central Finland Health Care District, 40620, Jyväskylä, Finland
| | - Hanna Elomaa
- Department of Biological and Environmental Science, University of Jyväskylä, 40014, Jyväskylä, Finland; Department of Education and Research, Central Finland Health Care District, 40620, Jyväskylä, Finland
| | - Maarit Ahtiainen
- Department of Pathology, Central Finland Health Care District, 40620, Jyväskylä, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Research, Central Finland Health Care District, 40620, Jyväskylä, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä, 40014, Jyväskylä, Finland
| | - Toni T Seppälä
- Faculty of Medicine and Health Technology, Tampere University and TAYS Cancer Center, Tampere University Hospital, 33520, Tampere, Finland; Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, 00290, Helsinki, Finland; Applied Tumor Genomics, Research Program Unit, University of Helsinki, 00290, Helsinki, Finland
| | - Erkki-Ville Wirta
- Faculty of Medicine and Health Technology, Tampere University and TAYS Cancer Center, Tampere University Hospital, 33520, Tampere, Finland; Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, 33520, Tampere, Finland
| | - Eero Sihvo
- Central Hospital of Central Finland, 40014, Jyväskylä, Finland
| | - Juha P Väyrynen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Fredrik Yannopoulos
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Cardiothoracic Surgery, Oulu University Hospital, Oulu, Finland; University Hospital and University of Oulu, 90014, Oulu, Finland
| | - Olli Helminen
- Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
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11
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Lang-Schwarz C, Vieth M, Dregelies T, Sterlacci W. Frequency of Her2-low in colorectal cancer and its relations with the tumor microenvironment. Pathol Res Pract 2023; 244:154417. [PMID: 36947983 DOI: 10.1016/j.prp.2023.154417] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/09/2023] [Accepted: 03/16/2023] [Indexed: 03/19/2023]
Abstract
BACKGROUND To date, little is known regarding human epithelial growth factor receptor (HER2) low-expressing colorectal cancer (CRC). Due to promising rising therapies with HER2-antibody-drug conjugates we aimed to analyze the frequency of HER2-low in patients with CRC. Additionally we characterized the clinicopathologic background of this group and its potential relationship with the tumor microenvironment represented by budding and tumor infiltrating lymphocytes (TILs). METHODS 319 patients with CRC, stages I-IV, were enrolled. HER2-immunohistochemistry (IHC) as well as fluorescence in situ hybridization (FISH) were performed on tissue microarrays. IHC was evaluated semiquantitatively and software-assisted using the HERACLES Diagnostic Criteria for CRC. HER2-low was defined as IHC 1 + or 2 +/FISH negative. HER2-IHC results were compared with budding, TILs and their combinations. RESULTS The HER2 low-expressing subset represented almost one half of all CRC (47.1 %). Assessment was highly reproducible with different methods. HER2-low cases were significantly more often lower T-, N-, and tumor stage and had less L1 compared with HER2-0. Additionally, they showed more often TILs > 5 % (p = 0.001). The difference between HER2-0 and HER2-low was highly significant between the four budding/TILs-groups (p < 0.001). Cases with low budding/high TILs were more often HER2-low. The highest difference was seen between the low budding/high TILs-group and the low budding/low TILs-group (p < 0.001). CONCLUSIONS HER2-low expression in CRC is frequent and involves nearly one half of all patients. We could show a relationsship between HER2-low expression and the tumor microenvironment. Special attention should be paid to the low budding/high TILs group in future research.
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Affiliation(s)
- Corinna Lang-Schwarz
- Institute of Pathology, Klinikum Bayreuth GmbH, Friedrich-Alexander-University Erlangen-Nuremberg, Preuschwitzer Str. 101, 95445 Bayreuth, Germany.
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth GmbH, Friedrich-Alexander-University Erlangen-Nuremberg, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Theresa Dregelies
- Institute of Pathology, Klinikum Bayreuth GmbH, Friedrich-Alexander-University Erlangen-Nuremberg, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - William Sterlacci
- Institute of Pathology, Klinikum Bayreuth GmbH, Friedrich-Alexander-University Erlangen-Nuremberg, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
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12
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Kmeid M, Brar R, Sullivan L, Arslan ME, Shrestha N, Lee EC, Chen A, Jennings TA, Lee H. Diagnostic yield and repeat biopsies in rectal and nonrectal colorectal adenocarcinoma: Are we hedging on rectal biopsies? Acad Pathol 2023; 10:100063. [PMID: 36970329 PMCID: PMC10031322 DOI: 10.1016/j.acpath.2022.100063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/09/2022] [Accepted: 11/12/2022] [Indexed: 02/05/2023] Open
Abstract
Patients with rectal cancer undergo more repeat biopsies compared to those with nonrectal colon cancer prior to management. We investigated the factors driving the higher frequency of repeat biopsies in patients with rectal cancer. We compared clinicopathologic features of diagnostic and nondiagnostic (in regard to invasion) rectal (n = 64) and colonic (n = 57) biopsies from colorectal cancer patients and characterized corresponding resections. Despite similar diagnostic yield, repeat biopsy was more common in rectal carcinoma, especially in patients receiving neoadjuvant therapy (p < 0.05). The presence of desmoplasia (odds ratio 12.9, p < 0.05) was a strong predictor of making a diagnosis of invasion in both rectal and nonrectal colon cancer biopsies. Diagnostic biopsies had more desmoplasia, intramucosal carcinoma component and marked inflammation, and less low-grade dysplasia component (p < 0.05). Diagnostic yield of biopsy was higher for tumors with high-grade tumor budding, mucosal involvement by high-grade dysplasia/intramucosal carcinoma without low-grade dysplasia and diffuse surface desmoplasia irrespective of tumor location. Sample size, amount of benign tissue, appearance, and T stage did not affect diagnostic yield. Repeat biopsy of rectal cancer is primarily driven by management implications. Diagnostic yield in colorectal cancer biopsies is multifactorial and is not due to differing pathologists' diagnostic approach per tumor site. For rectal tumors, a multidisciplinary strategic approach is warranted to avoid repeat biopsy when unnecessary.
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Affiliation(s)
- Michel Kmeid
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | - Rupinder Brar
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | - Luz Sullivan
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | | | | | - Edward C. Lee
- Department of Surgery, Albany Medical Center, Albany, NY, USA
| | - Anne Chen
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | | | - Hwajeong Lee
- Department of Pathology, Albany Medical Center, Albany, NY, USA
- Corresponding author. Department of Pathology, Albany Medical Center, 47 New Scotland Ave., MC81, Albany, NY 12208, USA.
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13
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Simultaneous analysis of tumor-infiltrating immune cells density, tumor budding status, and presence of lymphoid follicles in CRC tissue. Sci Rep 2022; 12:21732. [PMID: 36526699 PMCID: PMC9758132 DOI: 10.1038/s41598-022-26225-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) affects more than 1,000,000 people worldwide each year. Recently, the number of young patients with early-onset colorectal cancer has increased, and right-sided colorectal cancer is still often diagnosed only in advanced stages. The TNM classification is not perfect for CRC staging. This study aimed to perform, for the first time, simultaneous analysis of tumor-infiltrating immune cell density, presence of lymphoid follicles, and budding status in CRC tissue. Intraoperative samples of neoplastic tissue were collected from 195 consecutive patients who were admitted to the surgical ward for elective colorectal surgery. Histological parameters were assessed in the tissue samples: tumor budding foci, poorly differentiated clusters and areas of poorly differentiated components. Tumor-infiltrating immune cells (tumor-associated neutrophils and tumor-infiltrating lymphocytes) were detected in five randomly chosen, areas at the tumor center and at the invasive front. Additionally, the presence of lymphoid follicles in CRC tissue was assessed. Tumor budding parameters were positively correlated with colorectal cancer advancement or histologic (mucinous) type of CRC. The number of poorly differentiated clusters was higher in younger patients. Lower densities of CD3 and CD4 lymphocytes were seen in CRC with a greater depth of tumor invasion. Lower densities of CD3 and CD8 lymphocytes were found in CRC with metastases to the surrounding lymph nodes. The lower density of CD8 lymphocytes was observed in CRC with distant metastases. Lower densities of tumor-associated neutrophils and tumor-infiltrating lymphocytes (CD3 and CD8) were revealed in CRC without lymphoid follicles. The number of lymphoid follicles was higher in patients with less advanced CRCs. Three histopathology markers, such as high tumor budding, scanty lymphocyte infiltration, and the poverty of lymphoid follicles, complement each other, appear to be reliable indicators of colorectal cancer progression, and could be useful in everyday medical practice, but their widespread use requires further research. We propose to take into account these markers, in the assessment of colorectal cancer advancement, in addition to the TNM classification.
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14
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Yao G, Fang Y, Fu Y, Xu J, Song H, Zhu H, Gu M, Ding X. Tumor budding as an indicator for lymph node metastasis and prognosis of early gastric cancer. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04522-z. [PMID: 36512103 DOI: 10.1007/s00432-022-04522-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Tumor budding, considered as an independent risk factor reflecting prognosis of some malignant tumors, has been recognized as an important clinicopathological indicator of colorectal carcinoma. However, the evaluation of tumor budding and its clinicopathological significance in gastric cancer remain controversial. AIM To investigate the relationship between tumor budding and clinical biological behavior of early gastric cancer (EGC) and assess the predictive value of tumor budding for lymph node metastasis as well as its impact on prognosis of EGC patients. METHODS Tissue specimens of 164 EGC patients who underwent radical gastrectomy between June 2011 and January 2017 from a single center were selected to carry out HE and CK staining respectively, so as to evaluate tumor budding under light microscopy. Clinicopathological data and follow-up results of all EGC patients were collected for statistical analysis among tumor budding, EGC clinicopathological factors and prognosis. RESULTS Of all 164 EGC patients, there were 84 (51.2%) cases with mucosal invasion and 80 (48.8%) cases with submucosal invasion. Meanwhile, 32 cases (19.5%) had lymph node metastasis, 19 (11.6%) had lympho-vascular invasion and 4 (2.4%) had early recurrence. Tumor budding were observed in 90 (54.9%) patients, with low-grade budding 68 (41.5%) cases and high-grade budding 22 (13.4%) cases. Tumor budding was closely correlated with tumor size (c2 = 6.609, P = 0.037), tumor histologic differentiation (c2 = 10.522, P = 0.032), depth of invasion (c2 = 8.787, P = 0.012), lymph node metastasis (c2 = 24.226, P < 0.01), TNM stage (c2 = 24.226, P < 0.01), lympho-vascular invasion (c2 = 8.225, P = 0.016) and early recurrence (c2 = 6.462, P = 0.040). Additionally, tumor budding was correlated with postoperative survival rate as well. Multiple regression analysis revealed that tumor budding was an independent influencing factor of postoperative 3-year survival rate, 5-year survival rate, OS, DFS and DSS (P < 0.05). Furthermore, tumor budding was an independent risk factor of lymph node metastasis of EGC patients, and high-grade budding was a high-risk indicator of lymph node metastasis. CONCLUSION Tumor budding is related to tumor size, tumor histologic differentiation, depth of invasion, lymph node metastasis, lympho-vascular invasion and early recurrence of EGC. Tumor budding, especially high-grade budding can serve as an indicator for predicting lymph node metastasis of EGC, and high-grade budding could be an important parameter for evaluating prognosis of EGC patients.
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15
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Gaafar NM, Osman TA, Elsheikh M, Ahmed IA, Dongre H, Fromreide S, Suleiman AM, Johannessen AC, Nginamau ES, Costea D. Epithelial PD-L1 expression at tumor front predicts overall survival in a cohort of oral squamous cell carcinomas from Sudan. Clin Exp Dent Res 2022; 8:1467-1477. [PMID: 36177667 PMCID: PMC9760153 DOI: 10.1002/cre2.666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 09/03/2022] [Accepted: 09/14/2022] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND We recently described the tumor immune microenvironment (TIME) in oral squamous cell carcinomas (OSCC) from Sudan by assessing the core of the lesions. However, the invasive tumor front (ITF) is the most active part of OSCC lesions; thus, TIME should also be characterized at the ITF in this patient cohort. OBJECTIVES We aimed to evaluate patterns of immune cell infiltration at the ITF in a cohort of OSCC patients from Sudan previously investigated at the tumor center and their association with clinicopathological parameters. METHODS This study was performed on a prospective cohort of 22 OSCC patients attending Khartoum Dental Teaching Hospital with a median follow-up of 48 months. Inflammatory infiltrate densities of CD4-, CD8-, FoxP3-, CD20-, CD66b-, M1 (CD80/CD68)-, M2 (CD163/CD68)-, and PD-L1-positive cells were assessed at the ITF by immunohistochemistry, followed by digital quantitative analysis at the stromal and epithelial compartments separately. Histopathological parameters such as the worst pattern of invasion, differentiation, and tumor budding (TB) were also assessed. Correlations between clinicopathological parameters and survival analysis were investigated using SPSS. RESULTS All inflammatory cell subsets investigated were found to be higher in the stromal compartment as compared to the epithelial one, except for the PD-L1+ subset. Stromal infiltration with the CD8+ cell subset was associated with low TB. Kaplan-Meier analyses identified higher epithelial and stromal CD4+ cell subsets. The presence of PD-L1 was found to be associated with unfavorable overall survival. Further, Cox's regression analysis using an age- and tumor-stage-adjusted model identified epithelial PD-L1 expression at the ITF as the only independent prognosticator. CONCLUSIONS Epithelial PD-L1 expression at the ITF was found to be an independent prognostic biomarker for OSCC in a cohort of Sudanese patients.
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Affiliation(s)
- Nuha M. Gaafar
- The Gade Laboratory for Pathology and Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, Faculty of MedicineUniversity of BergenBergenNorway,Centre for International Health, Department of Global Public Health and Primary Care, Faculty of MedicineUniversity of BergenBergenNorway,Department of Oral and Maxillofacial Surgery, Faculty of DentistryUniversity of KhartoumKhartoumSudan
| | - Tarig Al‐Hadi Osman
- The Gade Laboratory for Pathology and Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, Faculty of MedicineUniversity of BergenBergenNorway,Department of PathologyHaukeland University HospitalBergenNorway
| | - Mariam Elsheikh
- Department of Oral and Maxillofacial Surgery, Faculty of DentistryUniversity of KhartoumKhartoumSudan,Khartoum Dental Teaching HospitalKhartoumSudan
| | - Israa Abdulrahman Ahmed
- The Gade Laboratory for Pathology and Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, Faculty of MedicineUniversity of BergenBergenNorway,Centre for International Health, Department of Global Public Health and Primary Care, Faculty of MedicineUniversity of BergenBergenNorway
| | - Harsh Dongre
- The Gade Laboratory for Pathology and Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, Faculty of MedicineUniversity of BergenBergenNorway
| | - Siren Fromreide
- The Gade Laboratory for Pathology and Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, Faculty of MedicineUniversity of BergenBergenNorway
| | - Ahmed M. Suleiman
- Department of Oral and Maxillofacial Surgery, Faculty of DentistryUniversity of KhartoumKhartoumSudan,Khartoum Dental Teaching HospitalKhartoumSudan
| | - Anne C. Johannessen
- The Gade Laboratory for Pathology and Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, Faculty of MedicineUniversity of BergenBergenNorway,Centre for International Health, Department of Global Public Health and Primary Care, Faculty of MedicineUniversity of BergenBergenNorway,Department of PathologyHaukeland University HospitalBergenNorway
| | - Elisabeth S. Nginamau
- The Gade Laboratory for Pathology and Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, Faculty of MedicineUniversity of BergenBergenNorway,Department of PathologyHaukeland University HospitalBergenNorway
| | - Daniela‐Elena Costea
- The Gade Laboratory for Pathology and Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, Faculty of MedicineUniversity of BergenBergenNorway,Centre for International Health, Department of Global Public Health and Primary Care, Faculty of MedicineUniversity of BergenBergenNorway,Department of PathologyHaukeland University HospitalBergenNorway
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Noh BJ, Choi G, Jang H, Ma C, Oh HS, Kim M, Eom DW. Prognostic implications of immune classification using IDO1 expression in extrahepatic bile duct carcinoma. Oncol Lett 2022; 24:373. [PMID: 36238847 PMCID: PMC9494626 DOI: 10.3892/ol.2022.13493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/23/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Byeong-Joo Noh
- Department of Pathology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Gun Choi
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Hyuk Jang
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Chung Ma
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Ho-Suk Oh
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Moonho Kim
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
| | - Dae-Woon Eom
- Department of Pathology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon‑do 25440, Republic of Korea
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Qian L, Zhang J, Lu S, He X, Feng J, Shi J, Liu Y. Potential key roles of tumour budding: a representative malignant pathological feature of non-small cell lung cancer and a sensitive indicator of prognosis. BMJ Open 2022; 12:e054009. [PMID: 35361643 PMCID: PMC8971788 DOI: 10.1136/bmjopen-2021-054009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES To investigate the relationship between tumour budding, clinicopathological characteristics of patients and prognosis in non-small cell lung cancer. STUDY DESIGN A retrospective study was used. PARTICIPANTS We selected 532 patients with non-small cell lung cancer from China, including 380 patients with adenocarcinoma and 152 with squamous cell carcinoma. PRIMARY AND SECONDARY OUTCOME MEASURES Tumour budding was visible using H&E staining as well as pancytokeratin staining. The count data and measurement data were compared using the χ2 test and the t-test, respectively. The overall survival rate was the follow-up result. The survival curves were drawn using the Kaplan-Meier method, and the differences between groups were analysed using the log-rank method. The independent prognostic factor of patients with lung cancer was determined using a multivariate Cox proportional hazard model. RESULTS In patients with lung adenocarcinoma, there was a correlation between tumour budding and spread through air spaces (OR 36.698; 95% CI 13.925 to 96.715; p<0.001), and in patients with squamous cell carcinoma, tumour budding state was closely related to the peritumoural space (OR 11.667; 95% CI 4.041 to 33.683; p<0.001). On Cox regression analysis, multivariate analysis showed that tumour budding, pleural and vascular invasion, spread through air spaces, tumour size, lymph node metastasis, and tumour node metastasis stage were independent risk factors of prognosis for patients with non-small cell lung cancer. CONCLUSIONS As an effective and simple pathological diagnostic index, it is necessary to establish an effective grading system in the clinical diagnosis of lung cancer to verify the value of tumour budding as a prognostic indicator. We hope that this analysis of Chinese patients with non-small cell lung cancer can provide useful reference material for the continued study of tumour budding.
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Affiliation(s)
- Li Qian
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jianguo Zhang
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Shumin Lu
- Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xin He
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jia Feng
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jiahai Shi
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, China
| | - Yifei Liu
- Pathology, Affiliated Hospital of Nantong University, Nantong, China
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Basile D, Broudin C, Emile J, Falcoz A, Pagès F, Mineur L, Bennouna J, Louvet C, Artru P, Fratte S, Ghiringhelli F, André T, Derangère V, Vernerey D, Taieb J, Svrcek M. Tumor budding is an independent prognostic factor in stage III colon cancer patients: A post-hoc analysis of the IDEA-France phase III trial (PRODIGE-GERCOR). Ann Oncol 2022; 33:628-637. [DOI: 10.1016/j.annonc.2022.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/04/2022] [Accepted: 03/11/2022] [Indexed: 12/23/2022] Open
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Pour Farid P, Eckstein M, Merkel S, Grützmann R, Hartmann A, Bruns V, Benz M, Schneider-Stock R, Geppert CI. Novel Criteria for Intratumoral Budding with Prognostic Relevance for Colon Cancer and Its Histological Subtypes. Int J Mol Sci 2021; 22:ijms222313108. [PMID: 34884913 PMCID: PMC8658236 DOI: 10.3390/ijms222313108] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/29/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022] Open
Abstract
Peritumoral budding and intratumoral budding (ITB) are important prognostic factors for colorectal cancer patients. Scientists worldwide have investigated the role of budding in tumor progression and its prognosis, but guidelines for reliably identifying tumor buds based on morphology are lacking. In this study, next-generation tissue microarray (ngTMA®) construction was used for tumor bud evaluation, and highly detailed rule-out annotation was used for tumor definition in pancytokeratin-stained tissue sections. Initially, tissues of 245 colon cancer patients were evaluated with high interobserver reliability, and a concordance of 96% was achieved. It was shown that high ITB scores were associated with poor distant metastasis-free survival (p = 0.006 with a cut-off of ≥10 buds). This cut-off was defined as the best maximum value from one of two/three ngTMA® cores (0.6 mm diameter). ITB in 30 cases of mucinous, medullary, and signet ring cell carcinoma was analyzed for the subsequent determination of differences in tumor bud analyses between those subtypes. In conclusion, blinded randomized punched cores in the tumor center can be useful for ITB detection. It can be assumed that this method is suitable for its adoption in clinical routines.
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Affiliation(s)
- Pantea Pour Farid
- Experimental Tumorpathology, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (P.P.F.); (R.S.-S.)
- Institute of Pathology, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (M.E.); (A.H.)
- Comprehensive Cancer Center-EMN (CCC), University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (S.M.); (R.G.)
| | - Markus Eckstein
- Institute of Pathology, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (M.E.); (A.H.)
- Comprehensive Cancer Center-EMN (CCC), University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (S.M.); (R.G.)
| | - Susanne Merkel
- Comprehensive Cancer Center-EMN (CCC), University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (S.M.); (R.G.)
- Department of Surgery, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany
| | - Robert Grützmann
- Comprehensive Cancer Center-EMN (CCC), University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (S.M.); (R.G.)
- Department of Surgery, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (M.E.); (A.H.)
- Comprehensive Cancer Center-EMN (CCC), University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (S.M.); (R.G.)
| | - Volker Bruns
- Fraunhofer Institute for Integrated Circuits IIS, Am Wolfsmantel 33, 91058 Erlangen, Germany; (V.B.); (M.B.)
| | - Michaela Benz
- Fraunhofer Institute for Integrated Circuits IIS, Am Wolfsmantel 33, 91058 Erlangen, Germany; (V.B.); (M.B.)
| | - Regine Schneider-Stock
- Experimental Tumorpathology, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (P.P.F.); (R.S.-S.)
- Institute of Pathology, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (M.E.); (A.H.)
- Comprehensive Cancer Center-EMN (CCC), University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (S.M.); (R.G.)
| | - Carol I. Geppert
- Institute of Pathology, University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (M.E.); (A.H.)
- Comprehensive Cancer Center-EMN (CCC), University Hospital, Friedrich-Alexander-University of Erlangen-Nüremberg (FAU), 91054 Erlangen, Germany; (S.M.); (R.G.)
- Correspondence: ; Tel.: +49-9131-85-43649
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20
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A novel self-learning framework for bladder cancer grading using histopathological images. Comput Biol Med 2021; 138:104932. [PMID: 34673472 DOI: 10.1016/j.compbiomed.2021.104932] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/07/2021] [Accepted: 10/07/2021] [Indexed: 11/23/2022]
Abstract
In recent times, bladder cancer has increased significantly in terms of incidence and mortality. Currently, two subtypes are known based on tumour growth: non-muscle invasive (NMIBC) and muscle-invasive bladder cancer (MIBC). In this work, we focus on the MIBC subtype because it has the worst prognosis and can spread to adjacent organs. We present a self-learning framework to grade bladder cancer from histological images stained by immunohistochemical techniques. Specifically, we propose a novel Deep Convolutional Embedded Attention Clustering (DCEAC) which allows for the classification of histological patches into different levels of disease severity, according to established patterns in the literature. The proposed DCEAC model follows a fully unsupervised two-step learning methodology to discern between non-tumour, mild and infiltrative patterns from high-resolution 512 × 512 pixel samples. Our system outperforms previous clustering-based methods by including a convolutional attention module, which enables the refinement of the features of the latent space prior to the classification stage. The proposed network surpasses state-of-the-art approaches by 2-3% across different metrics, reaching a final average accuracy of 0.9034 in a multi-class scenario. Furthermore, the reported class activation maps evidence that our model is able to learn by itself the same patterns that clinicians consider relevant, without requiring previous annotation steps. This represents a breakthrough in MIBC grading that bridges the gap with respect to training the model on labelled data.
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Hatthakarnkul P, Quinn JA, Matly AAM, Ammar A, van Wyk HC, McMillan DC, Edwards J. Systematic review of tumour budding and association with common mutations in patients with colorectal cancer. Crit Rev Oncol Hematol 2021; 167:103490. [PMID: 34619332 DOI: 10.1016/j.critrevonc.2021.103490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Despite a well-known prognostic role in colorectal cancer, the genomic profiling of tumour budding remains to be elucidated. We aim to review the association of common mutations with tumour budding. METHODS A systematic review of studies relating to tumour budding and genetic mutation in CRC was performed. The relationship between mutational status and tumour budding was evaluated using meta-analysis. RESULTS A total of 6153 patients from 17 articles were included. According to the meta-analysis, high-grade tumour budding was significantly associated with KRAS mutation (OR = 1.52, 95 %CI: 1.13-2.02, P = 0.005) and MSS/pMMR (OR = 2.06, 95 %CI: 1.42-2.97, P = 0.0001). CONCLUSION The significant association between high-grade tumour budding and mutated KRAS or MSS/pMMR may suggest a role of these mutations in the development of the tumour budding phenotype and be useful for stratifying patient outcome in CRC.
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Affiliation(s)
- Phimmada Hatthakarnkul
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Jean A Quinn
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Amna Ahmed Mohemmd Matly
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Aula Ammar
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Hester C van Wyk
- School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Alexandria Parade, Glasgow, G31 2ER, United Kingdom.
| | - Donald C McMillan
- School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Alexandria Parade, Glasgow, G31 2ER, United Kingdom.
| | - Joanne Edwards
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
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22
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Jun SY, Lee EJ, Hong SM, Jung ES, Chung JY. Tumor Microenvironmental Prognostic Risk in Primary Operable Small Intestinal Adenocarcinoma. Am J Surg Pathol 2021; 45:917-929. [PMID: 33443865 DOI: 10.1097/pas.0000000000001668] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The tumor microenvironment (TME) has become an important area of investigation with respect to improving prognosis in malignancies. Here we evaluated TME prognostic risk in small intestinal adenocarcinomas based on histologic assessment of tumor budding at the peritumoral-invasive front (pTB) and stromal tumor-infiltrating lymphocytes (sTILs). pTB and sTILs were analyzed in 230 surgically resected small intestinal adenocarcinomas, as recommended by the International Tumor Budding Consensus Conference (ITBCC) and the International TILs Working Group (ITWG). On the basis of high levels of pTB count (≥10) and sTIL density (≥20%), we combined pTB and sTIL to produce a collective TME-based prognostic risk index: low-risk (pTBLow/sTILHigh; n=39, 17.0%), intermediate-risk (pTBLow/sTILLow or pTBHigh/sTILHigh; n=99, 43.0%), and high-risk groups (pTBHigh/sTILLow; n=92, 40.0%). TME risk index provided better prognostic stratification than the individual pTB and sTIL (14.9 vs. 6.7 vs. 10.3). Tumors with higher TME prognostic risk were associated with an infiltrative growth pattern and nonintestinal immunophenotype (both P=0.001), pancreatic invasion (P=0.010), lymphovascular (P<0.001) or perineural invasion (P=0.006), higher T-category (P<0.001), N-category (P=0.004), and stage grouping (P=0.002), and KRAS mutation (P=0.008). In multivariate analysis, higher TME prognostic risk index (P<0.001), distal tumor location and nonintestinal immunophenotype (both P=0.001), higher N-category (P<0.001), and microsatellite stable (P=0.015) were worse-independent prognosticators. TME prognostic risk index consistently stratified patient survival regardless of tumor location (P<0.001 in proximal; P=0.002 in distal), stages (P<0.001 in lower stages I to II; P=0.028 in stage III), and DNA mismatch repair gene status (P<0.001 in microsatellite stable; P=0.001 in microsatellite instability). TME risk index is a powerful prognostic predictor for risk stratification of patients with small intestinal adenocarcinoma.
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Affiliation(s)
| | - Eui-Jin Lee
- Clinical Research Center, Incheon St. Mary's Hospital
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun Sun Jung
- Department of Pathology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea
| | - Joon-Yong Chung
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont A, Fridman WH, Sautès-Fridman C, Ma Y, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology 2021; 1:1323-1343. [PMID: 23243596 PMCID: PMC3518505 DOI: 10.4161/onci.22009] [Citation(s) in RCA: 188] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8+ cytotoxic T lymphocytes, Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4+CD25+FOXP3+ regulatory T cells, Th2 CD4+ T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that—at least in some clinical settings—the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies.
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Affiliation(s)
- Laura Senovilla
- Institut Gustave Roussy; Villejuif, France ; Université Paris-Sud/Paris XI; Orsay, France ; INSERM, U848; Villejuif, France
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Lang-Schwarz C, Melcher B, Hartmann A, Bertz S, Dregelies T, Lang-Schwarz K, Vieth M, Sterlacci W. Programmed death ligand 1 (PD-L1) in colon cancer and its interaction with budding and tumor-infiltrating lymphocytes (TILs) as tumor-host antagonists. Int J Colorectal Dis 2021; 36:2497-2510. [PMID: 34170390 PMCID: PMC8505298 DOI: 10.1007/s00384-021-03985-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/16/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE To analyze the role of programmed death ligand 1 (PD-L1) immunohistochemisty in the context of tumor microenvironment in colon cancer (CC) with focus on the interaction between tumor budding and tumor-infiltrating lymphocytes (TILs) and to elucidate its potential value for immunooncologic treatment decisions. METHODS Three hundred forty seven patients with CC, stages I to IV, were enrolled. PD-L1 immunohistochemistry was performed using two different antibodies (clone 22C3 pharmDx, Agilent and clone QR1, Quartett). Tumor proportion score (TPS) as well as immune cell score (IC) was assessed. Budding and TILs were assessed according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) and International TILs Working Group (ITWG). Correlation analyses as well as survival analyses were performed. RESULTS PD-L1 positivity significantly correlated with TILs > 5% and MMR deficiency, and PD-L1-positive cases (overall and IC) showed significantly longer overall survival (OS) with both antibodies.The parameters "high grade," "right-sidedness," and "TILS > 5% regardless of MMR status" evolved as potential parameters for additional immunological treatment decisions. Additionally, TPS positivity correlated with low budding. More PD-L1-positive cases were seen in both high TIL groups. The low budding/high TIL group showed longer disease-free survival and longer OS in PD-L1-positive cases. CONCLUSION Overall, PD-L1 positivity correlated with markers of good prognosis. PD-L1 immunohistochemistry was able to identify parameters as additional potential candidates for immune therapy. Furthermore, it was able to stratify patients within the low budding/high TIL group with significant prognostic impact.
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Affiliation(s)
- Corinna Lang-Schwarz
- Institute of Pathology, Klinikum Bayreuth, Preuschwitzer Str. 101, 95445 Bayreuth, Germany ,Institute of Pathology, Friedrich-Alexander-University, Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - Balint Melcher
- Institute of Pathology, Koblenz, Franz-Weis-Str. 13, 56073 Koblenz, Germany
| | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander-University, Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - Simone Bertz
- Institute of Pathology, Friedrich-Alexander-University, Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - Theresa Dregelies
- Institute of Pathology, Klinikum Bayreuth, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Klaus Lang-Schwarz
- Department of Anesthesiology, Klinikum Bayreuth, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Preuschwitzer Str. 101, 95445 Bayreuth, Germany ,Institute of Pathology, Friedrich-Alexander-University, Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - William Sterlacci
- Institute of Pathology, Klinikum Bayreuth, Preuschwitzer Str. 101, 95445 Bayreuth, Germany ,Institute of Pathology, Friedrich-Alexander-University, Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
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Lang-Schwarz C, Melcher B, Dregelies T, Norouzzadeh Z, Rund-Küffner S, Lang-Schwarz K, Vieth M, Sterlacci W. Adjuvant chemotherapy in stage II and III colon cancer: the role of the "budding and TILs-(tumor-infiltrating lymphocytes) combination" as tumor-host antagonists. Int J Colorectal Dis 2021; 36:1765-1779. [PMID: 33745027 PMCID: PMC8279987 DOI: 10.1007/s00384-021-03896-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE To analyze the influence of adjuvant chemotherapy on the combination of tumor budding and tumor-infiltrating lymphocytes (TILs) in stage II and III colon cancer and to elucidate its potential value for adjuvant treatment decisions. METHODS 306 patients with stage II and 205 patients with stage III colon cancer diagnosed between 2005 and 2016 who had undergone surgery in a curative setting were enrolled. Budding and TILs were assessed according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) and the criteria of the International TILs Working Group (ITWG). Combinations of budding and TILs were analyzed, and the influence of adjuvant chemotherapy was assessed. RESULTS In stage II colon cancer, stratification into the four budding/TILs groups showed no significant differences in overall survival (OS) between the chemotherapy and the surgery-alone group, not even in cases with high-risk features. In stage III colon cancer, patients with low budding/high TILs benefited significantly from chemotherapy (p=0.005). Patients with high budding/low TILs as well as high budding/high TILs showed a trend to benefit from adjuvant treatment. However, no chemotherapy benefit was seen for the low budding/low TIL group. CONCLUSIONS The budding/TIL combination identified subgroups in stage II and III colon cancer with and without benefit from adjuvant treatment. The results this study suggest that the combination of budding and TILs as tumor-host antagonists might be an additional helpful tool in adjuvant treatment decisions in stage II and III colon cancer.
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Affiliation(s)
- Corinna Lang-Schwarz
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Balint Melcher
- Institute of Pathology, Koblenz, Franz-Weis-Str. 13, 56073 Koblenz, Germany
| | - Theresa Dregelies
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Zahra Norouzzadeh
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Stefanie Rund-Küffner
- Department of Internal Medicine, Sana Klinik Pegnitz, GmbH, Langer Berg 12, 91257 Pegnitz, Germany
| | - Klaus Lang-Schwarz
- Department of Anesthesiology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany ,Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - William Sterlacci
- Institute of Pathology, Klinikum Bayreuth GmbH, Preuschwitzer Str. 101, 95445 Bayreuth, Germany ,Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
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Haak F, Obrecht I, Tosti N, Weixler B, Mechera R, Däster S, von Strauss M, Delko T, Spagnoli GC, Terracciano L, Sconocchia G, von Flüe M, Kraljević M, Droeser RA. Tumor Infiltration by OX40+ Cells Enhances the Prognostic Significance of CD16+ Cell Infiltration in Colorectal Cancer. Cancer Control 2020; 27:1073274820903383. [PMID: 32107932 PMCID: PMC7053789 DOI: 10.1177/1073274820903383] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Objectives: Analysis of tumor immune infiltration has been suggested to outperform tumor,
node, metastasis staging in predicting clinical course of colorectal cancer
(CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis
factor receptor family, or CD16, expressed by natural killer cells,
monocytes, and dendritic cells, has been associated with favorable prognosis
in patients with CRC. We hypothesized that assessment of CRC infiltration by
both OX40+ and CD16+ cells might result in enhanced prognostic
significance. Methods: Colorectal cancer infiltration by OX40 and CD16 expressing cells was
investigated in 441 primary CRCs using tissue microarrays and specific
antibodies, by immunohistochemistry. Patients’ survival was evaluated by
Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis,
hazard ratios, and 95% confidence intervals were also used to evaluate
prognostic significance of OX40+ and CD16+ cell infiltration. Results: Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified
into 4 groups with high or low infiltration levels in all possible
combinations. High levels of infiltration by both OX40+ and CD16+ cells were
associated with lower pT stage, absence of peritumoral lymphocytic (PTL)
inflammation, and a positive prognostic impact. Patients bearing tumors with
high infiltration by CD16+ and OX40+ cells were also characterized by
significantly longer overall survival, as compared with the other groups.
These results were confirmed by analyzing an independent validation
cohort. Conclusions: Combined infiltration by OX40+ and CD16+ immune cells is an independent
favorable prognostic marker in CRC. The prognostic value of CD16+ immune
cell infiltration is significantly improved by the combined analysis with
OX40+ cell infiltration.
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Affiliation(s)
- Fabian Haak
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Isabelle Obrecht
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Nadia Tosti
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Benjamin Weixler
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland.,Department of General, Visceral and Vascular Surgery, Charite Campus Benjamin Franklin, Berlin, Germany
| | - Robert Mechera
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Silvio Däster
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Marco von Strauss
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Tarik Delko
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Giulio C Spagnoli
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland.,Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Luigi Terracciano
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Giuseppe Sconocchia
- Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Markus von Flüe
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Marko Kraljević
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Raoul A Droeser
- Department of Abdominal Surgery, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland.,Department of Biomedicine, University Hospital Basel, Basel, Switzerland
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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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The battle for prognosis at the invasive front of colorectal cancer. EBioMedicine 2020; 58:102918. [PMID: 32711249 PMCID: PMC7387774 DOI: 10.1016/j.ebiom.2020.102918] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 07/10/2020] [Indexed: 12/15/2022] Open
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Fujiyoshi K, Väyrynen JP, Borowsky J, Papke DJ, Arima K, Haruki K, Kishikawa J, Akimoto N, Ugai T, Lau MC, Gu S, Shi S, Zhao M, Da Silva AFL, Twombly TS, Nan H, Meyerhardt JA, Song M, Zhang X, Wu K, Chan AT, Fuchs CS, Lennerz JK, Giannakis M, Nowak JA, Ogino S. Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer. EBioMedicine 2020; 57:102860. [PMID: 32652320 PMCID: PMC7347996 DOI: 10.1016/j.ebiom.2020.102860] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/02/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Tumour budding and poorly differentiated clusters (PDC) represent forms of tumour invasion. We hypothesised that T-cell densities (reflecting adaptive anti-tumour immunity) might be inversely associated with tumour budding and PDC in colorectal carcinoma. METHODS Utilising 915 colon and rectal carcinomas in two U.S.-wide prospective cohort studies, and multiplex immunofluorescence combined with machine learning algorithms, we assessed CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 co-expression patterns in lymphocytes. Tumour budding and PDC at invasive fronts were quantified by digital pathology and image analysis using the International tumour Budding Consensus Conference criteria. Using covariate data of 4,420 incident colorectal cancer cases, inverse probability weighting (IPW) was integrated with multivariable logistic regression analysis that assessed the association of T-cell subset densities with tumour budding and PDC while adjusting for selection bias due to tissue availability and potential confounders, including microsatellite instability status. FINDINGS Tumour budding counts were inversely associated with density of CD3+CD8+ [lowest vs. highest: multivariable odds ratio (OR), 0.50; 95% confidence interval (CI), 0.35-0.70; Ptrend < 0.001] and CD3+CD8+CD45RO+ cells (lowest vs. highest: multivariable OR, 0.44; 95% CI, 0.31-0.63; Ptrend < 0.001) in tumour epithelial region. Tumour budding levels were associated with higher colorectal cancer-specific mortality (multivariable hazard ratio, 2.13; 95% CI, 1.57-2.89; Ptrend < 0.001) in Cox regression analysis. There were no significant associations of PDC with T-cell subsets. INTERPRETATION Tumour epithelial naïve and memory cytotoxic T cell densities are inversely associated with tumour budding at invasive fronts, suggesting that cytotoxic anti-tumour immunity suppresses tumour microinvasion.
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Affiliation(s)
- Kenji Fujiyoshi
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Kurume University, Kurume, Fukuoka, Japan
| | - Juha P Väyrynen
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA; Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
| | - Jennifer Borowsky
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - David J Papke
- Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
| | - Kota Arima
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Koichiro Haruki
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Junko Kishikawa
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Naohiko Akimoto
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tomotaka Ugai
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Mai Chan Lau
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Simeng Gu
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Shanshan Shi
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Melissa Zhao
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Annacarolina Fabiana Lucia Da Silva
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tyler S Twombly
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hongmei Nan
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Illinois, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Illinois, USA
| | - Jeffrey A Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Xuehong Zhang
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Charles S Fuchs
- Yale Cancer Center, New Haven, Connecticut, USA; Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Smilow Cancer Hospital, New Haven, Connecticut, USA
| | - Jochen K Lennerz
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts, USA.
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Zhang N, Wang D, Duan Y, Ayarick VA, Cao M, Wang Y, Zhang G, Wang Y. The special immune microenvironment of tumor budding and its impact on prognosis in gastric adenocarcinoma. Pathol Res Pract 2020; 216:152926. [PMID: 32327282 DOI: 10.1016/j.prp.2020.152926] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 02/23/2020] [Accepted: 03/14/2020] [Indexed: 12/30/2022]
Abstract
Recent studies showed that the tumor-infiltrating lymphocytes (TILs) are not randomly distributed, but organized to accumulate more or less densely in different regions within tumors, which have provoked new thoughts on cancer management. In this study we explored the characteristics of tumor immunemicroenvironment (TIME) for the tumor budding (TB) and lymphocytes in patients with gastric adenocarcinoma (GAC) as well as their prognostic significance. The TILs around the TB at the invasive margin were assessed by double-immunohistochemistry staining for the CD8, FOXP3, OX40 and GrB phenotypes. Results showed that there was a negative correlation between the density of TB and TILs in the budding area, tumor stroma and parenchyma. And the number of TILs around the TB was evidently reduced, compared with TILs in the non-budding region (P < 0.001). Additionally, the number of TILs in turn changed from non-budding area CD8+>FOXP3+>OX40+> GrB + T cells to FOXP3+>CD8+>OX40 + T > GrB + T cells in budding area. Survival rate was significantly lower in patients who had a higher density of TB (P < 0.001) and a lower density of TILs (P = 0.013). We concluded that TB was surrounded by a weak immune surveillance and immunosuppressive response supported the spatial heterogeneity in the TIME of gastric adenocarcinomas. The regional heterogeneity should be attached importance for identifying the influence of the TIME on cancer development and evolution.
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Affiliation(s)
- Nana Zhang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Depu Wang
- Department of Science and Technology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yixin Duan
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Vivian Adiila Ayarick
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Meng Cao
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Ying Wang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Guanjun Zhang
- Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xian, Shaanxi, 710061, China.
| | - Yili Wang
- Institute for Cancer Research, School of Basic Medical Science, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
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Novel Internationally Verified Method Reports Desmoplastic Reaction as the Most Significant Prognostic Feature For Disease-specific Survival in Stage II Colorectal Cancer. Am J Surg Pathol 2020; 43:1239-1248. [PMID: 31206364 DOI: 10.1097/pas.0000000000001304] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Multiple histopathologic features have been reported as candidates for predicting aggressive stage II colorectal cancer (CRC). These include tumor budding (TB), poorly differentiated clusters (PDC), Crohn-like lymphoid reaction and desmoplastic reaction (DR) categorization. Although their individual prognostic significance has been established, their association with disease-specific survival (DSS) has not been compared in stage II CRC. This study aimed to evaluate and compare the prognostic value of the above features in a Japanese (n=283) and a Scottish (n=163) cohort, as well as to compare 2 different reporting methodologies: analyzing each feature from across every tissue slide from the whole tumor and a more efficient methodology reporting each feature from a single slide containing the deepest tumor invasion. In the Japanese cohort, there was an excellent agreement between the multi-slide and single-slide methodologies for TB, PDC, and DR (κ=0.798 to 0.898) and a good agreement when assessing Crohn-like lymphoid reaction (κ=0.616). TB (hazard ratio [HR]=1.773; P=0.016), PDC (HR=1.706; P=0.028), and DR (HR=2.982; P<0.001) based on the single-slide method were all significantly associated with DSS. DR was the only candidate feature reported to be a significant independent prognostic factor (HR=2.982; P<0.001) with both multi-slide and single-slide methods. The single-slide result was verified in the Scottish cohort, where multivariate Cox regression analysis reported that DR was the only significant independent feature (HR=1.778; P=0.002) associated with DSS. DR was shown to be the most significant of all the analyzed histopathologic features to predict disease-specific death in stage II CRC. We further show that analyzing the features from a single-slide containing the tumor's deepest invasion is an efficient and quicker method of evaluation.
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Dawson H, Christe L, Eichmann M, Reinhard S, Zlobec I, Blank A, Lugli A. Tumour budding/T cell infiltrates in colorectal cancer: proposal of a novel combined score. Histopathology 2020; 76:572-580. [PMID: 31560788 DOI: 10.1111/his.14006] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 09/25/2019] [Indexed: 01/07/2023]
Abstract
AIMS The tumour-node-metastasis classification system is used for prognostication purposes and to guide patient management. However, in colorectal cancer (CRC), additional markers are needed to stratify prognostic subgroups. Two promising markers have emerged from large bodies of research: tumour budding and T cell host response (CD3, CD8 and CD45RO infiltrates). However, attempts to combine these two parameters have been sparse. The aim of this study was to perform an assessment of potential protagonists that could be used in a combined score (budding/T cell score, BTS). METHODS AND RESULTS This descriptive, retrospective study was performed on a multipunch tissue microarray containing material from 345 patients with stages I-IV CRC. Areas from tumour centre, front and microenvironment were stained for pancytokeratin/CD3, pancytokeratin/CD8 and pancytokeratin/CD45RO. Tumour buds were scored manually and T cell infiltrates digitally using open-source software. Tumour buds, T cell counts and combined BTS were associated with clinicopathological features and overall survival (OS). A higher combined BTS score (buds/CD8, tumour centre) performed better than budding or CD8/CD3 alone in predicting nodal metastases (P < 0.0001, OR = 1.466, 95% CI = 1.115-1.928). Only higher BTS (buds/CD3) were significantly associated with poorer OS on multivariate analysis (P = 0.012, hazard ratio = 1.218, 95% confidence interval = 1.044-1.419). CONCLUSIONS Although CD8+ /CD3+ T cells are predictive of tumour biology in CRC, we found a combined BTS to be stronger in predicting survival and certain features with high clinical relevance, such as nodal metastases, in comparison to budding or T cells alone. Further studies combining T cell infiltrates and tumour budding are necessary to optimise risk assessment of CRC.
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Affiliation(s)
- Heather Dawson
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Lucine Christe
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Micha Eichmann
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Stefan Reinhard
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Inti Zlobec
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Annika Blank
- Institute of Pathology, University of Bern, Bern, Switzerland
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Alexander PG, McMillan DC, Park JH. The local inflammatory response in colorectal cancer - Type, location or density? A systematic review and meta-analysis. Cancer Treat Rev 2019; 83:101949. [PMID: 31869737 DOI: 10.1016/j.ctrv.2019.101949] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role alongside TNM assessment in dictating future management. However, there is wide disagreement regarding the most efficacious and cost-effective method of assessment. METHODS A comprehensive literature search was performed of EMBASE, MedLine and PubMed as well as an assessment of references to identify all relevant studies relating to the assessment of the peri-tumoural inflammatory response or TILs and prognosis in colorectal cancer (CRC). A meta-analysis was performed of 67 studies meeting the REMARK criteria using RevMan software. RESULTS Intratumoural assessment of both CD3 and CD8 in CRC were significant for disease-free survival (DFS) (combined HRs 0.46; 95%CI: 0.39-0.54 and 0.54; 95%CI: 0.45-0.65), as well as overall survival (OS) and disease-specific survival (DSS). The same was true for assessment of CD3 and CD8 at the invasive margin (DFS: combined HRs 0.45; 95%CI: 0.33-0.61 and 0.51; 95%CI: 0.41-0.62). However, similar fixed effects summaries were also observed for H&E-based methods, like Klintrup-Makinen grade (DFS: HR 0.62; 95%CI: 0.43-0.88). Furthermore, inflammatory assessments were independent of MSI status. CONCLUSION The evidence suggests that it is the density of a co-ordinated local inflammatory infiltrate that confers survival benefit, rather than any individual immune cell subtype. Furthermore, the location of individual cells within the tumour microenvironment does not appear to influence survival. The authors advocate a standardised assessment of the local inflammatory response, but caution against emphasizing the importance of any individual immune cell subtype.
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Affiliation(s)
| | | | - James H Park
- School of Medicine, University of Glasgow, Glasgow, United Kingdom
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Wei L, Delin Z, Kefei Y, Hong W, Jiwei H, Yange Z. A classification based on tumor budding and immune score for patients with hepatocellular carcinoma. Oncoimmunology 2019; 9:1672495. [PMID: 32002283 PMCID: PMC6959452 DOI: 10.1080/2162402x.2019.1672495] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 09/18/2019] [Accepted: 09/21/2019] [Indexed: 02/06/2023] Open
Abstract
Background: The role of immune profiling and tumor budding in hepatocellular carcinoma (HCC) remains largely unknown. This study evaluated the association between tumor budding and lymphocytic infiltration in HCC. Meanwhile, HCC patients were stratified based on tumor budding grade and immune score. Patients and methods: A total of 423 HCC patients were divided into training (n = 212) and validation (n = 211) cohort. Tumor slides from resected HCC samples were used for tumor budding assessment. A prognosis-relevant immune score was developed based on five types of immune cells out of eleven immune markers. A classification based on tumor budding grade and immune type was established (IS-TB type). To explore the association of IS-TB type and molecular alterations of HCC, 100 HCC samples and adjacent non-tumor tissues from 100 patients were investigated by whole-exome sequencing. Results: Tumor budding was an independent adverse prognostic factor for OS and DFS in both of the training and validation cohorts (all P values <.05). The rate of high-grade tumor budding was significantly higher in HCC with immature stroma (P < .001), strong α-SMA expression (P = .005), non-steatotic tumors and non-fibrolamellar-HCC (P < .001). Additionally, tumor budding was related to both anti- and pro-tumor immune responses. Patients were classified into immune type A and immune type B according to the immune score. Based on tumor budding grade and immunotype, patients were classified into four subgroups: ISA-TBhigh (type I), ISB-TBhigh (type II), ISA-TBlow (type III) and ISB-TBlow (type IV). Patients with type III tumor had the best OS and DFS, whereas OS and DFS were the worst for cases with type II tumor. TP53 mutation was more frequent in IS-TB type I (ISATBhigh) patients, while IS-TB type IV (ISBTBlow) harbored high number of CTNNB1 mutation. Conclusion: Tumor-immune cell interactions in HCC is heterogeneous. HCC classification based on tumor budding and immune score correlates with patient survival and molecular alterations. The defined subtypes may have significance for utilizing individualized treatment in patients with HCC.
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Affiliation(s)
- Li Wei
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Zhang Delin
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yuan Kefei
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Wu Hong
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Huang Jiwei
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Zhang Yange
- Department of Plastic and Burns Surgery, West China Hospital, Sichuan University, Chengdu, China
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Trabelsi M, Farah F, Zouari B, Jaafoura MH, Kharrat M. An Immunoscore System Based On CD3 + And CD8 + Infiltrating Lymphocytes Densities To Predict The Outcome Of Patients With Colorectal Adenocarcinoma. Onco Targets Ther 2019; 12:8663-8673. [PMID: 31695425 PMCID: PMC6814319 DOI: 10.2147/ott.s211048] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 09/18/2019] [Indexed: 12/30/2022] Open
Abstract
Purpose The aim of this study was to evaluate the Immunoscore (IS) methodology as a prognostic marker of colorectal adenocarcinoma in Tunisian population. Tumor blocks were retrospectively collected from 106 patients with sporadic colorectal cancer. Methods Immunohistochemical staining and images analysis software were used to quantify the density of CD3+ and CD8+ tumor-infiltrating lymphocytes in the center of the tumor and invasive margin. Results The density of CD3+ and CD8+ was significantly associated with 5-year overall survival (P=0.001 and P=0.00098, respectively) and 5-year disease-free survival (P=0.0006 and P=0.0056, respectively). The earlier stage and the absence of vascular emboli showed a significant association with IS analysis. Cox multivariate regression analysis revealed that Immunoscore (from I0 to I4) was more significantly correlated with overall survival (P=0.00011) and disease-free survival (P=0.0008) than Tumor-Node-Metastasis (TNM) staging (P=0.057 and P=0.039, respectively). Patients with low IS were associated with inferior disease-free survival and overall survival, contrary to patients with high IS. Conclusion This is the first study which evaluated the prognostic value of IS methodology in colorectal cancer in African and Arabic population. The IS methodology carries out in this study allows to estimate the risk of relapse in patients with colorectal cancer. Overall, our results support the implementation of the consensus Immunoscore as a new component for the classification of cancer, designated TNM-Immune.
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Affiliation(s)
- Mouna Trabelsi
- Department of Human Genetic (LR99ES10), Faculty of Medicine, University of Tunis El Manar, Tunis 1006, Tunisia.,Faculty of Sciences, University of Tunis El Manar, Foyer Universitaire, Tunis 2092, Tunisia
| | - Faten Farah
- Department of Human Genetic (LR99ES10), Faculty of Medicine, University of Tunis El Manar, Tunis 1006, Tunisia
| | - Bechir Zouari
- Department of Preventive Medicine, Faculty of Medicine, University of Tunis El Manar, Tunis 1006, Tunisia
| | - Mohamed Habib Jaafoura
- Department of Anatomopathology, Faculty of Medicine, University of Tunis El Manar, Tunis 1006, Tunisia
| | - Maher Kharrat
- Department of Human Genetic (LR99ES10), Faculty of Medicine, University of Tunis El Manar, Tunis 1006, Tunisia
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van Wyk HC, Roseweir A, Alexander P, Park JH, Horgan PG, McMillan DC, Edwards J. The Relationship Between Tumor Budding, Tumor Microenvironment, and Survival in Patients with Primary Operable Colorectal Cancer. Ann Surg Oncol 2019; 26:4397-4404. [PMID: 31605345 PMCID: PMC6863941 DOI: 10.1245/s10434-019-07931-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Indexed: 01/02/2023]
Abstract
Background Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC). Objective The aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC. Methods Hematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup–Makinen (KM) grade to assess the tumor inflammatory cell infiltrate. Results High budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30–11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors. Conclusions Tumor budding effectively stratifies patients’ survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC.
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Affiliation(s)
- Hester C van Wyk
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK.
| | - Antonia Roseweir
- Unit of Gastrointestinal Cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Peter Alexander
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
| | - James H Park
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
| | - Paul G Horgan
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
| | - Donald C McMillan
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
| | - Joanne Edwards
- Unit of Gastrointestinal Cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
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Ueno H, Ishiguro M, Nakatani E, Ishikawa T, Uetake H, Matsuda C, Nakamoto Y, Kotake M, Kurachi K, Egawa T, Yasumasa K, Murata K, Ikawa O, Shinji S, Murotani K, Matsui S, Teramukai S, Tomita N, Sugihara K, on behalf of the SACURA Study Group. Prospective Multicenter Study on the Prognostic and Predictive Impact of Tumor Budding in Stage II Colon Cancer: Results From the SACURA Trial. J Clin Oncol 2019; 37:1886-1894. [PMID: 31180819 PMCID: PMC6675595 DOI: 10.1200/jco.18.02059] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2019] [Indexed: 01/26/2023] Open
Abstract
PURPOSE The International Union Against Cancer highlighted tumor budding as a tumor-related prognostic factor. International assessment criteria for tumor budding were recently defined by the 2016 International Tumor Budding Consensus Conference (ITBCC2016). This study aimed to clarify the prognostic and predictive values of tumor budding in a randomized controlled trial evaluating the superiority of adjuvant chemotherapy with oral tegafur-uracil over surgery alone for stage II colon cancer (SACURA trial; ClinicalTrials.gov identifier: NCT00392899). PATIENTS AND METHODS Between 2006 and 2010, we enrolled 991 patients from 123 institutions with stage II colon cancer. Tumor budding was diagnosed by central review on the basis of the criteria adopted in the ITBCC2016. We prospectively recorded all clinical and pathologic data, including the budding grade, and performed prognostic analyses after 5 years of completing the patients' registration. RESULTS Of 991 tumors, 376, 331, and 284 were classified as BD1, BD2, and BD3, respectively; the 5-year relapse-free survival (RFS) rate was 90.9%, 85.1%, and 74.4%, respectively (P < .001), and ranged widely in T4 tumors (86.6% to 53.3%). The budding grade significantly correlated with recurrence in the liver, lungs, lymph nodes, and peritoneum (P < .001 to .01). Multivariable analysis revealed that budding and T stage exerted an independent impact on RFS, and on the basis of the Harrell concordance index, these two factors substantially contributed to the improvement of the Cox model for predicting RFS. Both the BD2 and BD3 groups demonstrated greater improvement in the 5-year recurrence rate in the adjuvant chemotherapy group than the surgery-alone group by approximately 5%, but the difference was statistically nonsignificant. CONCLUSION Tumor budding grade on the basis of the ITBCC2016 criteria should be routinely evaluated in pathologic practice and could improve the benefit of adjuvant chemotherapy for stage II colon cancer.
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Affiliation(s)
- Hideki Ueno
- National Defense Medical College, Saitama, Japan
| | | | - Eiji Nakatani
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
| | | | | | | | | | | | | | | | - Keigo Yasumasa
- Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
| | | | - Osamu Ikawa
- Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
| | - Seiichi Shinji
- Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | | | | | | | | | | | - on behalf of the SACURA Study Group
- National Defense Medical College, Saitama, Japan
- Tokyo Medical and Dental University, Tokyo, Japan
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan
- Osaka General Medical Center, Osaka, Japan
- Kobe City Medical Center West Hospital, Hyogo, Japan
- Kouseiren Takaoka Hospital, Toyama, Japan
- Hamamatsu University School of Medicine, Shizuoka, Japan
- Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Japan
- Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
- Suita Municipal Hospital, Osaka, Japan
- Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
- Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
- Kurume University, Fukuoka, Japan
- Nagoya University, Aichi, Japan
- Kyoto Prefectural University of Medicine, Kyoto, Japan
- Hyogo College of Medicine, Hyogo, Japan
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Poorly Differentiated Clusters Predict Colon Cancer Recurrence: An In-Depth Comparative Analysis of Invasive-Front Prognostic Markers. Am J Surg Pathol 2019; 42:705-714. [PMID: 29624511 DOI: 10.1097/pas.0000000000001059] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This study aimed to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. Consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution in 2007 to 2014 were identified. Poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor, were analyzed. Prognostic accuracies for recurrence-free survival (RFS) were compared, and interobserver agreement among 3 pathologists was assessed. The study cohort consisted of 851 patients. Although all the histologic markers except WHO grade were significantly associated with RFS (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P<0.001; Crohn-like lymphoid reaction: P=0.021), PDCs (grade 1 [G1]: n=581; G2: n=145; G3: n=125) showed the largest separation of 3-year RFS in the full cohort (G1: 94.1%; G3: 63.7%; hazard ratio [HR], 6.39; 95% confidence interval [CI], 4.11-9.95; P<0.001), stage II patients (G1: 94.0%; G3: 67.3%; HR, 4.15; 95% CI, 1.96-8.82; P<0.001), and stage III patients (G1: 89.0%; G3: 59.4%; HR, 4.50; 95% CI, 2.41-8.41; P<0.001). PDCs had the highest prognostic accuracy for RFS with the concordance probability estimate of 0.642, whereas WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. Our findings indicate that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. PDCs may replace WHO grade as a prognostic indicator.
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Lang-Schwarz C, Melcher B, Haumaier F, Schneider-Fuchs A, Lang-Schwarz K, Krugmann J, Vieth M, Sterlacci W. Budding, tumor-infiltrating lymphocytes, gland formation: scoring leads to new prognostic groups in World Health Organization low-grade colorectal cancer with impact on survival. Hum Pathol 2019; 89:81-89. [PMID: 31054898 DOI: 10.1016/j.humpath.2019.04.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/11/2019] [Accepted: 04/25/2019] [Indexed: 01/27/2023]
Abstract
Grading for colorectal carcinoma (CRC) is traditionally based on the percentage of gland formation. In recent years, high-grade CRC has become subject to more precise molecular grading strategies. Most, however, are low-grade cases according to the World Health Organization (WHO) with inhomogenous outcomes due to still insufficient characterization. On the other hand, budding and tumor-infiltrating lymphocytes have developed as interesting additive prognostic factors in CRC. Especially budding has been very well defined by the International Tumor Budding Consensus Conference recently. We analyzed a large collective of 576 WHO low-grade CRC cases, stages I to IV, diagnosed between 2005 and 2016 in terms of gland formation, budding, and tumor-infiltrating lymphocytes and developed a new, morphology-based risk score, taking into account each of the 3 parameters. For each parameter, 1 to 2 points were given, resulting in a sum score, dividing the CRC cases into a low-, an intermediate-, and a high-risk group. By our score, 179 (34.9%) of the cases were grouped as low risk, 241 (53.5) as intermediate risk, and 92 (35.5%) as high risk. The 3 groups differed significantly in pT, pN, and M as well as tumor stages, lymphatic vessel invasion, venous invasion, and overall survival (0.;P < .001 for low risk versus high risk, P = .038 for low versus intermediate risk, and P = .036 for intermediate versus high risk; log rank: median, 94.0 months [95% confidence interval {CI}, 74.9-113.1] for low risk; median, 63.0 months [95% CI, 44.0-82.0] for intermediate risk; and median, 40.0 months [95% CI, 23.4-56.7] for high risk) in Kaplan-Meier-analysis. Our proposed Bayreuth score enables separating the large group of WHO low-grade CRC cases into subgroups, which differ significantly in outcome.
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Affiliation(s)
| | - Balint Melcher
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | | | | | - Klaus Lang-Schwarz
- Department of Anesthesiology, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | - Jens Krugmann
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
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40
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Yamadera M, Shinto E, Kajiwara Y, Mochizuki S, Okamoto K, Shimazaki H, Hase K, Ueno H. Differential clinical impacts of tumour budding evaluated by the use of immunohistochemical and haematoxylin and eosin staining in stage II colorectal cancer. Histopathology 2019; 74:1005-1013. [PMID: 30698857 DOI: 10.1111/his.13830] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 01/26/2019] [Indexed: 12/15/2022]
Abstract
AIMS The aim of this study was to clarify the quantitative and qualitative differences in tumour budding identification between haematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for cytokeratin, and to estimate the respective clinical impacts in stage II colorectal cancer. METHODS AND RESULTS We retrospectively examined 314 surgically resected cases of stage II colorectal cancer, and assessed tumour budding on serial section slides with H&E staining and IHC staining for cytokeratin. Tumour budding counts based on cytokeratin-stained slides were strongly correlated with those based on H&E-stained slides, and had higher detection and reproducibility. On the basis of receiver operating characteristic analyses, the optimal cut-off values of budding counts for relapse-free survival (RFS) were 7 and 16 in a ×200 microscopic field with H&E and IHC staining, respectively. With these cut-off values, tumour budding based on H&E staining had a significant correlation with RFS (80.3% and 93.2% of 5-year RFS in the high-budding group and the low-budding group, respectively), and similar results were observed for IHC staining (79.9% and 91.7%, respectively). The Akaike Information Criterion value for RFS with H&E staining was favourable as compared with that with IHC staining. CONCLUSIONS Tumour budding counts based on cytokeratin-stained slides showed higher detection and better reproducibility, but did not have as satisfactory clinical impacts as those based on H&E staining.
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Affiliation(s)
- Masato Yamadera
- Department of Surgery, National Defence Medical College, Saitama, Japan
| | - Eiji Shinto
- Department of Surgery, National Defence Medical College, Saitama, Japan
| | - Yoshiki Kajiwara
- Department of Surgery, National Defence Medical College, Saitama, Japan
| | - Satsuki Mochizuki
- Department of Surgery, National Defence Medical College, Saitama, Japan
| | - Koichi Okamoto
- Department of Surgery, National Defence Medical College, Saitama, Japan
| | - Hideyuki Shimazaki
- Department of Laboratory Medicine, National Defence Medical College, Saitama, Japan
| | - Kazuo Hase
- Department of Surgery, National Defence Medical College, Saitama, Japan
| | - Hideki Ueno
- Department of Surgery, National Defence Medical College, Saitama, Japan
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41
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Brieu N, Gavriel CG, Nearchou IP, Harrison DJ, Schmidt G, Caie PD. Automated tumour budding quantification by machine learning augments TNM staging in muscle-invasive bladder cancer prognosis. Sci Rep 2019; 9:5174. [PMID: 30914794 PMCID: PMC6435679 DOI: 10.1038/s41598-019-41595-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 03/11/2019] [Indexed: 12/12/2022] Open
Abstract
Tumour budding has been described as an independent prognostic feature in several tumour types. We report for the first time the relationship between tumour budding and survival evaluated in patients with muscle invasive bladder cancer. A machine learning-based methodology was applied to accurately quantify tumour buds across immunofluorescence labelled whole slide images from 100 muscle invasive bladder cancer patients. Furthermore, tumour budding was found to be correlated to TNM (p = 0.00089) and pT (p = 0.0078) staging. A novel classification and regression tree model was constructed to stratify all stage II, III, and IV patients into three new staging criteria based on disease specific survival. For the stratification of non-metastatic patients into high or low risk of disease specific death, our decision tree model reported that tumour budding was the most significant feature (HR = 2.59, p = 0.0091), and no clinical feature was utilised to categorise these patients. Our findings demonstrate that tumour budding, quantified using automated image analysis provides prognostic value for muscle invasive bladder cancer patients and a better model fit than TNM staging.
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Affiliation(s)
- Nicolas Brieu
- Definiens AG, Bernhard-Wicki-Straße 5, 80636, München, Germany
| | - Christos G Gavriel
- School of Medicine, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9TF, UK
| | - Ines P Nearchou
- School of Medicine, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9TF, UK
| | - David J Harrison
- School of Medicine, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9TF, UK
| | - Günter Schmidt
- Definiens AG, Bernhard-Wicki-Straße 5, 80636, München, Germany
| | - Peter D Caie
- School of Medicine, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9TF, UK.
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42
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Nearchou IP, Lillard K, Gavriel CG, Ueno H, Harrison DJ, Caie PD. Automated Analysis of Lymphocytic Infiltration, Tumor Budding, and Their Spatial Relationship Improves Prognostic Accuracy in Colorectal Cancer. Cancer Immunol Res 2019; 7:609-620. [PMID: 30846441 DOI: 10.1158/2326-6066.cir-18-0377] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 11/15/2018] [Accepted: 01/24/2019] [Indexed: 11/16/2022]
Abstract
Both immune profiling and tumor budding significantly correlate with colorectal cancer patient outcome but are traditionally reported independently. This study evaluated the association and interaction between lymphocytic infiltration and tumor budding, coregistered on a single slide, in order to determine a more precise prognostic algorithm for patients with stage II colorectal cancer. Multiplexed immunofluorescence and automated image analysis were used for the quantification of CD3+CD8+ T cells, and tumor buds (TBs), across whole slide images of three independent cohorts (training cohort: n = 114, validation cohort 1: n = 56, validation cohort 2: n = 62). Machine learning algorithms were used for feature selection and prognostic risk model development. High numbers of TBs [HR = 5.899; 95% confidence interval (CI) 1.875-18.55], low CD3+ T-cell density (HR = 9.964; 95% CI, 3.156-31.46), and low mean number of CD3+CD8+ T cells within 50 μm of TBs (HR = 8.907; 95% CI, 2.834-28.0) were associated with reduced disease-specific survival. A prognostic signature, derived from integrating TBs, lymphocyte infiltration, and their spatial relationship, reported a more significant cohort stratification (HR = 18.75; 95% CI, 6.46-54.43), than TBs, Immunoscore, or pT stage. This was confirmed in two independent validation cohorts (HR = 12.27; 95% CI, 3.524-42.73; HR = 15.61; 95% CI, 4.692-51.91). The investigation of the spatial relationship between lymphocytes and TBs within the tumor microenvironment improves accuracy of prognosis of patients with stage II colorectal cancer through an automated image analysis and machine learning workflow.
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Affiliation(s)
- Ines P Nearchou
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK.
| | | | - Christos G Gavriel
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, Saitama, Japan
| | - David J Harrison
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK
| | - Peter D Caie
- Quantitative and Digital Pathology, School of Medicine, University of St. Andrews, St. Andrews, UK
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43
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Yu P, Wang W, Zhuang Z, Xie N, Xu J, Wang C, Hou J, Han X, Liu X. A novel prognostic model for tongue squamous cell carcinoma based on the characteristics of tumour and its microenvironment: iBD score. Histopathology 2019; 74:766-779. [PMID: 30444275 DOI: 10.1111/his.13790] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 11/12/2018] [Indexed: 01/08/2023]
Abstract
AIMS Tumour budding and invasive depth can predict survival of patients with tongue squamous cell carcinoma (TSCC), while the prognostic value of tumour microenvironment (TME) remains unknown. Here, both characteristics of the tumour and its microenvironment were examined and a novel prognostic model has been proposed. METHODS AND RESULTS A total of 246 patients with TSCC were included. Using H&E-stained sections, pathological parameters of tumour and the TME were assessed. Inflammatory response (i), tumour budding (B) and invasive depth (D) were combined as iBD score. The association between these variables and the patient survival was determined. Both tumour budding and inflammatory status were independent variables for predicting overall survival (OS) and disease-free survival (DFS) of TSCC patients. Invasive depth was correlated with differentiation, T classification, lymph node metastasis, clinical stage and recurrence (P < 0.05). The novel iBD model was strongly correlated with T classification, lymph node metastasis, clinical stage and recurrence, and showed clear distinction of scores 0, 1 and 2. High iBD score had a strong association with reduced OS and DFS (P < 0.01). CONCLUSIONS The iBD scoring model is strongly associated with lymph node metastasis and recurrence in TSCC and could be a promising survival predictor for TSCC patients.
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Affiliation(s)
- Pei Yu
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Department of Oral Maxillofacial Surgery, Guanghua School of Stomatology and Hospital of Stomatology, Guangzhou, China
| | - Weiwang Wang
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Department of Oral Maxillofacial Surgery, Guanghua School of Stomatology and Hospital of Stomatology, Guangzhou, China
| | - Zehang Zhuang
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Department of Oral Maxillofacial Surgery, Guanghua School of Stomatology and Hospital of Stomatology, Guangzhou, China
| | - Nan Xie
- Department of Oral Maxillofacial Surgery, Guanghua School of Stomatology and Hospital of Stomatology, Guangzhou, China.,Department of Oral Pathology, Guanghua School and Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Jieyun Xu
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Department of Oral Maxillofacial Surgery, Guanghua School of Stomatology and Hospital of Stomatology, Guangzhou, China
| | - Cheng Wang
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Department of Oral Maxillofacial Surgery, Guanghua School of Stomatology and Hospital of Stomatology, Guangzhou, China
| | - Jingsong Hou
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Department of Oral Maxillofacial Surgery, Guanghua School of Stomatology and Hospital of Stomatology, Guangzhou, China
| | - Xiaozhe Han
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.,Department of Oral Medicine, Infection and Immunity, Harvard University School of Dental Medicine, Boston, MA, USA
| | - Xiqiang Liu
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Department of Oral Maxillofacial Surgery, Guanghua School of Stomatology and Hospital of Stomatology, Guangzhou, China
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Baek TH, Kang DW, Kim JH, Son HJ. Gland Attenuation, a Novel Morphological Feature of Colorectal Cancer: Evidence for an Epithelial-Mesenchymal Transition. Ann Coloproctol 2018; 34:187-196. [PMID: 30208682 PMCID: PMC6140364 DOI: 10.3393/ac.2017.12.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 12/02/2017] [Indexed: 12/11/2022] Open
Abstract
Purpose Along the invasive margin, colorectal cancer may show distinctive morphologic changes characterized by an asymmetrically attenuating tumor gland with loss of polarity. The author coined the term ‘gland attenuation (GA)’ for these peculiar changes. The aims of this study were to compare the immunoreactivity of the epithelial-mesenchymal transition (EMT) markers E-cadherin and β-catenin and thus determine whether EMTs occurs at tumor budding (TB) or GA sites and to assess the association of TB and/or GA levels with clinicopathological parameters and prognosis. Methods Expression patterns of E-cadherin and β-catenin in the tumor centers at GA and TB sites were examined in 101 patients with well or moderately differentiated CRCs, and the prognostic significance of TB and/or GA was statistically evaluated. Results GA foci, as well as TB foci, revealed loss of membranous and cytoplasmic E-cadherin expressions and aberrant β-catenin expression with reduced membranous expression and increased localization to the nucleus, suggesting that EMTs occur in GA as well as in TB. The high-TB and the TB-dominant groups were significantly correlated with advanced invasion depth, presence of lymph node metastasis, advanced pathologic staging and presence of lymphovascular invasion. The high-TB and the TB-dominant groups showed poor overall survival (OS) and recurrence-free survival (RFS), and high TB was an independent prognostic factor in the multivariate analyses for OS and RFS. Conclusion This study showed evidence that EMTs occurs at GA sites as well as TB foci. TB is a strong and independent prognostic factor, and TB-dominance may be an indicator of adverse clinical outcome.
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Affiliation(s)
- Tae-Hwa Baek
- Department of Pathology, Eulji University School of Medicine, Daejeon, Korea
| | - Dong-Wook Kang
- Department of Pathology, Eulji University School of Medicine, Daejeon, Korea
| | - Joo-Heon Kim
- Department of Pathology, Eulji University School of Medicine, Daejeon, Korea
| | - Hyun-Jin Son
- Department of Pathology, Eulji University School of Medicine, Daejeon, Korea
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45
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Lino-Silva LS, Salcedo-Hernández RA, Gamboa-Domínguez A. Tumour budding in rectal cancer. A comprehensive review. Contemp Oncol (Pozn) 2018; 22:61-74. [PMID: 30150882 PMCID: PMC6103233 DOI: 10.5114/wo.2018.77043] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 04/03/2018] [Indexed: 12/18/2022] Open
Abstract
A unique and fundamental characteristic of malignant neoplastic cells is their ability to invade other tissues and metastasise. The first step in this process is the dissociation of some of these cells from the tumour invasion front, named tumour budding (TB). This phenomenon has become increasingly relevant in recent years due to its association with adverse clinicopathological characteristics and with the epithelial-mesenchymal transition. TB has been studied by mixing colon with rectal tumours, but it is clinically important to differentiate these types of tumours. A review in two databases without language restriction was performed from 1950 to 2017 about TB with an emphasis on rectal cancer. We present various aspects of TB, from its terminology and evaluation to its molecular aspects, through its clinical associations. TB is associated with adverse clinicopathological features, like lymphovascular invasion, lymph node metastasis, and decreased survival. More studies of the clinicopathological, molecular, and epidemiological characteristics of TB in rectal cancer are needed.
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46
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Athanasakis E, Xenaki S, Venianaki M, Chalkiadakis G, Chrysos E. Newly recognized extratumoral features of colorectal cancer challenge the current tumor-node-metastasis staging system. Ann Gastroenterol 2018; 31:525-534. [PMID: 30174388 PMCID: PMC6102465 DOI: 10.20524/aog.2018.0284] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 03/13/2018] [Indexed: 12/12/2022] Open
Abstract
One of the most common malignant tumors in humans, colorectal cancer has been extensively studied during the past few decades. Staging colorectal cancer allows clinicians to obtain precise prognostic information and apply specific treatment procedures. Apart from remote metastases, the depth of tumor infiltration and lymph node involvement have traditionally been recognized as the most important factors predicting outcome. Variations in the molecular signature of colorectal cancer have also revealed differences in phenotypic aggressiveness and therapeutic response rates. This article presents a review of the extratumoral environment in colorectal surgery.
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Affiliation(s)
- Elias Athanasakis
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
| | - Sofia Xenaki
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
| | - Maria Venianaki
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
| | - George Chalkiadakis
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
| | - Emmanuel Chrysos
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
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47
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Lang-Schwarz C, Melcher B, Haumaier F, Lang-Schwarz K, Rupprecht T, Vieth M, Sterlacci W. Budding and tumor-infiltrating lymphocytes - combination of both parameters predicts survival in colorectal cancer and leads to new prognostic subgroups. Hum Pathol 2018; 79:160-167. [PMID: 29787819 DOI: 10.1016/j.humpath.2018.05.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 04/25/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023]
Abstract
Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well defined by the International Concensus Conference on Tumor Budding (ITBCC). Tumor-infiltrating lymphocytes (TILs) are also an issue in different human cancers and correlate with prognosis in CRC. Here we evaluate the combination of budding and TILs in CRC with regard to prognosis. Hematoxylin and eosin (H&E)-stained slides of 501 CRC patients, diagnosed between 2005 and 2010, were reevaluated for tumor budding according to the ITBCC criteria. Low (n = 331) was compared to intermediate/high budding (n = 170). The percentage of TILs was also assessed, and the following four groups were established: low budding + TILs >5% (n = 162), low budding + TILS ≤5% (n = 169), high budding + TILS >5% (n = 68), high budding + TILs ≤5% (n = 93). The combination of both markers revealed highly significant differences in overall survival (OS) between the four groups (P = .001). The low budding/>5% TILs group showed longest OS, followed by high budding/>5% TILs cases, followed by tumors with low budding/≤5% TILs. OS was worst for the high budding/≤ 5% TILs group. The combined score also correlated with T, N, M, L, Vstaging, development of disease relapse and distant metastasis. Our study shows that - even in the age of molecular pathology - it is still important to pay special attention to tumor morphology for additional information on tumor behavior and prognosis. Combining different morphological parameters of tumor and tumor environment can help to further subdivide CRC into new prognostic groups.
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Affiliation(s)
| | - Balint Melcher
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | | | - Klaus Lang-Schwarz
- Department of Anesthesiology, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | | | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
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48
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Zlobec I, Lugli A. Tumour budding in colorectal cancer: molecular rationale for clinical translation. Nat Rev Cancer 2018; 18:203-204. [PMID: 29376521 DOI: 10.1038/nrc.2018.1] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Inti Zlobec
- Institute of Pathology, University of Bern, Bern, Switzerland
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49
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Tumor Budding and PDC Grade Are Stage Independent Predictors of Clinical Outcome in Mismatch Repair Deficient Colorectal Cancer. Am J Surg Pathol 2018; 42:60-68. [DOI: 10.1097/pas.0000000000000931] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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50
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Georges LM, Verset L, Zlobec I, Demetter P, De Wever O. Impact of the Microenvironment on Tumour Budding in Colorectal Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1110:101-111. [PMID: 30623368 DOI: 10.1007/978-3-030-02771-1_7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Tumour Budding (TB) is recognized as an adverse prognostic factor in colorectal cancer (CRC). TB is the detachment of isolated cancer cells or small clusters of such cells mainly at the invasion front. One question that arises is of the role of the tumour stroma regarding the permissiveness of the formation and progression of TB. In this review, we will examine potential factors affecting TB, in particular we will analyse the potential effect of inflammation, hypoxia, extracellular matrix and Cancer-Associated Fibroblasts (CAFs).
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Affiliation(s)
- Laurent Mc Georges
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Laurine Verset
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Inti Zlobec
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Pieter Demetter
- Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium. .,Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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