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Petrov K, Ivanov I, Popovska S, Betova T, Kamburova Z. Colorectal Cancer: A Brief and Simplified Analysis of a Complex Disease. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:2034. [PMID: 39768914 PMCID: PMC11727892 DOI: 10.3390/medicina60122034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/20/2024] [Accepted: 12/06/2024] [Indexed: 01/16/2025]
Abstract
Background and Objectives: This study examined factors influencing the onset and progression of colorectal tumors, including patients' epidemiological data, tumor location (right-sided, left-sided, and rectal), histomorphology, perineural or intraneural invasion, lymph node status, immune reactions, mismatch repair (MMR) status, and commonly observed mutations. Our primary goal was to evaluate their predictive and prognostic value and interactions. Materials and Methods: We analyzed a retrospective cohort of 100 patients with colorectal adenocarcinoma diagnosed between 2020 and 2023, using formalin-fixed paraffin-embedded (FFPE) tumor blocks. The methods included routine H&E microscopy, immunohistochemistry, Next-Generation Sequencing (NGS), and subsequent statistical analysis. Results: The findings showed a median diagnosis age of 70 years, with no gender-specific tumor localization. Right-sided tumors were prevalent, especially among patients with a defective MMR (dMMR), which represented 89% of dMMR cases. MMR status significantly correlated with tumor localization. We observed significant relationships between tumor grade, lymphovascular invasion, and overall tumor stage. Higher tumor grades and stages correlated with increased lymphovascular invasion and lymph node involvement. Interestingly, tumor budding did not correlate with lymph node metastasis but was significantly associated with higher tumor grades. Most BRAF mutations were found in right-sided tumors, indicating a significant correlation with this localization. Conclusions: This study focuses on the diversity of colorectal cancer (CRC) by examining how genetic and histological characteristics vary based on tumor location or other tumor variables.
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Affiliation(s)
- Krasimir Petrov
- Department of Pathology, Faculty of Medicine, Medical University, 5800 Pleven, Bulgaria
- Department of General and Clinical Pathology, University Multi-profile Hospital for Active Treatment “Georgi Stranski”, 5800 Pleven, Bulgaria
| | - Ivan Ivanov
- Department of Pathology, Faculty of Medicine, Medical University, 5800 Pleven, Bulgaria
- Department of General and Clinical Pathology, University Multi-profile Hospital for Active Treatment “Georgi Stranski”, 5800 Pleven, Bulgaria
| | - Savelina Popovska
- Department of Pathology, Faculty of Medicine, Medical University, 5800 Pleven, Bulgaria
- Department of General and Clinical Pathology, University Multi-profile Hospital for Active Treatment “Georgi Stranski”, 5800 Pleven, Bulgaria
| | - Tatyana Betova
- Department of Pathology, Faculty of Medicine, Medical University, 5800 Pleven, Bulgaria
- Department of General and Clinical Pathology, University Multi-profile Hospital for Active Treatment “Georgi Stranski”, 5800 Pleven, Bulgaria
| | - Zornitsa Kamburova
- Department of Medical Genetics, Faculty of Pharmacy, Medical University, 5800 Pleven, Bulgaria
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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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Liang L, Guo X, Ye W, Liu Y. KRAS Gene Mutation Associated with Grade of Tumor Budding and Peripheral Immunoinflammatory Indices in Patients with Colorectal Cancer. Int J Gen Med 2024; 17:4769-4780. [PMID: 39440104 PMCID: PMC11495189 DOI: 10.2147/ijgm.s487525] [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: 08/28/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024] Open
Abstract
Background The efficacy of targeted therapy for colorectal cancer (CRC) is affected by hub genes of epidermal growth factor receptor (EGFR) signaling pathways, such as KRAS. Immune cell infiltration may lead to gene mutation, but the relationship between KRAS status and peripheral immune-inflammatory indices has not been clarified in CRC. Methods Clinical records of CRC patients were collected. The relationship between KRAS status and clinicopathological characteristics, peripheral immune-inflammatory indices (pan-immune inflammation value (PIV) (monocyte×neutrophil×platelet/lymphocyte), systemic immune inflammation index (SII) (platelet×neutrophil/lymphocyte), and system inflammation response index (SIRI) (monocyte×neutrophil/lymphocyte)) were analyzed. Results 1033 CRC patients were collected, there were 514 (49.8%) patients with KRAS wild-type and 519 (50.2%) with KRAS mutation. Patients with KRAS mutation had higher proportions of female, III-IV stage, and lymph node metastasis and lower proportion of low grade of tumor budding (the presence of single tumor cells or small clusters of up to 5 cells in mesenchyma at the front of tumor invasion) than those with KRAS wild-type. The PIV, SII, and SIRI levels in KRAS mutation patients were significantly higher than those in KRAS wild-type patients. The proportion of aged ≥65 years old, dMMR, distant metastasis, and KRAS mutation were high in patients with high PIV, SII, and SIRI levels. Logistic regression analysis showed that non-low grade of tumor budding (odds ratio (OR): 1.970, 95% confidence interval (CI): 1.287-3.016, p=0.002), and high SII level (≥807.81 vs <807.81, OR: 1.915, 95% CI: 1.120-3.272, p=0.018) were independently associated with KRAS mutation. Conclusion Non-low grade of tumor budding, and high SII level were independently associated with KRAS mutation in CRC. It provides additional references for diagnosis and treatment options for patients with CRC.
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Affiliation(s)
- Liu Liang
- Department of Laboratory Medicine, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Xuemin Guo
- Department of Laboratory Medicine, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Wei Ye
- Department of Laboratory Medicine, Meizhou People’s Hospital, Meizhou, People’s Republic of China
| | - Yuxiang Liu
- Department of Medical Oncology, Meizhou People’s Hospital, Meizhou, People’s Republic of China
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Pihlmann Kristensen M, Korsgaard U, Timm S, Frøstrup Hansen T, Zlobec I, Kjær-Frifeldt S, Hager H. Immunohistochemical analysis of tumor budding in stage II colon cancer: exploring zero budding as a prognostic marker. Virchows Arch 2024; 485:691-701. [PMID: 38977466 PMCID: PMC11522105 DOI: 10.1007/s00428-024-03860-2] [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: 03/26/2024] [Revised: 05/30/2024] [Accepted: 06/26/2024] [Indexed: 07/10/2024]
Abstract
Tumor budding, a biomarker traditionally evaluated using hematoxylin and eosin (H&E) staining, has gained recognition as a prognostic biomarker for stage II colon cancer. Nevertheless, while H&E staining offers valuable insights, its limitations prompt the utilization of pan-cytokeratin immunohistochemistry (IHC). Consequently, this study seeks to evaluate the prognostic significance of tumor budding using IHC in a contemporary cohort of stage II colon cancer patients, aiming to deepen our understanding of this critical facet in cancer prognosis. We conducted a retrospective, population-based cohort study including 493 patients with stage II colon cancer and evaluated tumor budding using IHC, following the H&E-based guidelines proposed by the International Tumor Budding Consensus Conference Group. Correlation between H&E-based and IHC-based tumor budding was assessed using a four-tiered scoring system that included a zero budding (Bd0) category. Survival analyses explored the prognostic significance of tumor budding assessed by IHC and H&E. As expected, IHC-based tumor budding evaluation yielded significantly higher bud counts compared to H&E (p < 0.01). Interestingly, 21 patients were identified with no tumor budding using IHC. This was associated with significantly improved recurrence-free survival (HR = 5.19, p = 0.02) and overall survival (HR = 4.47, p = 0.04) in a multivariate analysis when compared to tumors with budding. The Bd0 category demonstrated a 100% predictive value for the absence of recurrence. In conclusion, IHC-based tumor budding evaluation in stage II colon cancer provides additional prognostic information. The absence of tumor budding is associated with a favorable prognosis and may serve as a potential marker for identifying patients with no risk of recurrence.
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Affiliation(s)
- Maria Pihlmann Kristensen
- Department of Pathology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark.
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
- Danish Colorectal Cancer Center South, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark.
| | - Ulrik Korsgaard
- Department of Pathology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
- Danish Colorectal Cancer Center South, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Signe Timm
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
- Danish Colorectal Cancer Center South, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
- Department of Oncology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Torben Frøstrup Hansen
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
- Danish Colorectal Cancer Center South, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
- Department of Oncology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Inti Zlobec
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Sanne Kjær-Frifeldt
- Department of Pathology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
- Danish Colorectal Cancer Center South, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Henrik Hager
- Department of Pathology, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
- Danish Colorectal Cancer Center South, Lillebaelt Hospital, University Hospital of Southern Denmark, Vejle, Denmark
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
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Laohawetwanit T, Apornvirat S, Kantasiripitak C. The association between histopathological growth patterns with tumor budding and poorly differentiated clusters in colorectal liver metastasis treated with preoperative systemic therapy. Pathol Int 2024; 74:583-591. [PMID: 39185662 DOI: 10.1111/pin.13473] [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: 02/16/2024] [Revised: 06/24/2024] [Accepted: 08/13/2024] [Indexed: 08/27/2024]
Abstract
The liver's unique cellular structure makes it a frequent site for metastatic cancer. In colorectal liver metastasis (CRLM), surgical resection is essential for long-term survival. Histopathological growth patterns (HGPs) in CRLM, including desmoplastic and nondesmoplastic patterns, provide critical prognostic information. Tumor budding (TB) and poorly differentiated clusters (PDCs), indicators of aggressive cancer behavior, are evaluated using standardized histological scoring systems and are linked to epithelial-mesenchymal transition. This study explored the correlation between HGPs, TB, and PDCs in CRLM. Archived data from Thammasat University Hospital, including resected CRLM specimens, were analyzed. This study evaluated 51 CRLM resection specimens treated with preoperative systemic therapy, finding most to be nondesmoplastic with low TB and grade 1 PDC. Desmoplastic growth was significantly more prevalent in cases receiving preoperative chemotherapy than those that did not. Higher 3-year mortality was noted in nondesmoplastic groups and those with higher TB and tumor regression grade (TRG) scores. Significant correlations were observed between HGPs, TB, and PDCs, despite challenges in assessing these parameters due to issues with noncancer cells, extracellular mucin, bile ductular proliferation, and retraction artifacts. This study underscores the prognostic significance of HGPs, TB, PDCs, and TRG scores in CRLM, highlighting the need for precise histopathological evaluation for more accurate prognostic implications.
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Affiliation(s)
- Thiyaphat Laohawetwanit
- Division of Pathology, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
- Division of Pathology, Thammasat University Hospital, Pathum Thani, Thailand
| | - Sompon Apornvirat
- Division of Pathology, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
- Division of Pathology, Thammasat University Hospital, Pathum Thani, Thailand
| | - Charinee Kantasiripitak
- Division of Pathology, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
- Division of Pathology, Thammasat University Hospital, Pathum Thani, Thailand
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Ran X, Chen Y, Liu C, Xiao H, Su X, Chen Z, Du J, He J, Zhong P, Li M, Dai N, Chen C. Differential effect of tumor budding on the benefit of adjuvant chemotherapy in stage II colorectal cancer: a retrospective observational study. J Gastrointest Oncol 2024; 15:1545-1555. [PMID: 39279933 PMCID: PMC11399822 DOI: 10.21037/jgo-24-278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/27/2024] [Indexed: 09/18/2024] Open
Abstract
Background Tumor budding (TB) has been shown to be a poor prognostic indicator after colorectal cancer (CRC) surgery. The aim of the present study is to evaluate the predictive role of morphological features (e.g., the number, structure, and location of tumor buds, and their reaction with the extracellular mesenchyme) in postoperative adjuvant chemotherapy in surgically resectable stage II CRC. Methods Between 2016 and 2019, 336 patients with stage II CRC who underwent radical surgery were enrolled in this study. TB status was determined according to the criteria adopted at the 2016 International Tumor Budding Consensus Conference (ITBCC). We retrospectively recorded all the clinical and pathological data and assessed the effect of different types of TB status on patients' recurrence-free survival (RFS) and overall survival (OS). Results Of the 336 patients, 173, 88, and 75 were budding grade 1 (BD1), BD2, and BD3, respectively. The 5-year RFS rates were 84.6%, 81.2%, and 68.0% (P=0.01), and the 5-year OS rates were 91.0%, 83.3%, and 76.2% (P=0.007) in BD1, BD2, and BD3, respectively. TB grade was strongly associated with vascular invasion status and mucinous adenocarcinoma, and BD3 was detected in 51.7% of patients with positive vascular invasion. The multivariate analysis showed that only age, perineural invasion, and TB grade [BD2 vs. BD1, hazard ratio (HR) =1.468, 95% confidence interval (CI): 0.703-3.063, P=0.30; BD3 vs. BD1, HR =2.310, 95% CI: 1.154-4.625, P=0.01] had an independent effect on RFS. In addition, the Kaplan-Meier curve analysis showed that BD3 patients had the worst RFS (P=0.01). The OS of the adjuvant chemotherapy group was significantly improved compared to that of the surgery-only group in the BD1/2 patients (HR =0.278, 95% CI: 0.114-0.676, P=0.005) but not in the BD3 patients with significant interaction (Pinteraction=0.03). Conclusions Our results indicate that TB could play a subsidiary role in selecting stage II CRC patients who could achieve a favorable prognosis with chemotherapy.
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Affiliation(s)
- Xin Ran
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Yan Chen
- Department of Pathology, Daping Hospital, Army Medical University, Chongqing, China
| | - Chengxiang Liu
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - He Xiao
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaona Su
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Zhuo Chen
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Jia Du
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Juan He
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Peng Zhong
- Department of Pathology, Daping Hospital, Army Medical University, Chongqing, China
| | - Mengxia Li
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Nan Dai
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Chuan Chen
- Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
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Sanchez DF, Oliveira P. Pathology of Squamous Cell Carcinoma of the Penis: Back to Square One. Urol Clin North Am 2024; 51:313-325. [PMID: 38925734 DOI: 10.1016/j.ucl.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2024]
Abstract
The landscape of squamous cell carcinoma of the penis (SCC-P) has undergone a significant transformation since the new World Health Organization classification of genitourinary cancers and recent European Association of Urology/American Association of Clinical Oncology guidelines. These changes emphasize the necessity to categorize SCC-P into 2 groups based on its association with human papillomavirus (HPV) infection. This shift has major implications, considering that prior knowledge was derived from a mix of both groups. Given the distinct prognosis, treatment options, and staging systems observed for HPV-associated tumors in other body areas, the question now arises: will similar patterns emerge for SCC-P?
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Affiliation(s)
- Diego F Sanchez
- Translational Oncogenomics Group, Manchester Cancer Research Centre & CRUK-MI, Wilmslow Road, Manchester M20 4GJ, UK.
| | - Pedro Oliveira
- Department of Pathology, Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK
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McCaughey T, Mooney SS, Newman M, Constable L, Reddington C, McNamara HC, Healey M. International Delphi consensus on the histopathological diagnosis of adenomyosis. J Clin Pathol 2024; 77:502. [PMID: 38429094 DOI: 10.1136/jcp-2024-209447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 01/31/2024] [Indexed: 03/03/2024]
Affiliation(s)
- Tristan McCaughey
- Gynaecology 2 Unit (Endometriosis and Pelvic Pain), The Royal Women's Hospital, Parkville, Victoria, Australia
| | - Samantha S Mooney
- The Julia Argyrou Endometriosis Centre, Epworth Medical Foundation, Richmond, Victoria, Australia
- Endosurgery Unit, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Marsali Newman
- Austin Health, Heidelberg, Victoria, Australia
- Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | | | - Charlotte Reddington
- Gynaecology 2 Unit (Endometriosis and Pelvic Pain), The Royal Women's Hospital, Parkville, Victoria, Australia
- Department of Obstetrics, Gynaecology and Newborn Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Helen C McNamara
- Gynaecology 2 Unit (Endometriosis and Pelvic Pain), The Royal Women's Hospital, Parkville, Victoria, Australia
- Endosurgery Unit, Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Martin Healey
- Gynaecology 2 Unit (Endometriosis and Pelvic Pain), The Royal Women's Hospital, Parkville, Victoria, Australia
- The Julia Argyrou Endometriosis Centre, Epworth Medical Foundation, Richmond, Victoria, Australia
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Bilić Z, Zovak M, Glavčić G, Mužina D, Ibukić A, Košec A, Tomas D, Demirović A. The Relationship between Tumor Budding and Tumor Deposits in Patients with Stage III Colorectal Carcinoma. J Clin Med 2024; 13:2583. [PMID: 38731112 PMCID: PMC11084198 DOI: 10.3390/jcm13092583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/25/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Background/Objectives: Recently, some new morphological features of colorectal cancer have been discovered as important prognostic factors; in this paper, we study the relationship between tumor budding (TB) and tumor deposits (TDs). Methods: The retrospective cohort study included 90 patients with pathohistologically confirmed stage III CRC who were treated with radical surgical resection. All hematoxylin and eosin (H and E)-stained slides from each patient were reviewed, and histological parameters were recorded. The samples were divided into two groups with similar sizes: a group without TDs (N = 51) and a control group with TDs (N = 39). The presence and TB grade were further analyzed in these groups and compared with other clinical and histological features. Results: The prevalence of TB in the investigated cohort was unexpectedly high (94.4%). Overall, there were 23 (25.6%) Bd1, 20 (22.2%) Bd2, and 47 (52.2%) Bd3 cases. The presence of TDs was significantly associated with a higher number of TB (p < 0.001, OR 16.3) and, consequently, with a higher TB grade (p = 0.004, OR 11.04). A higher TB grade (p = 0.001, HR 2.28; 95% CI 1.93-4.76) and a growing number of TDs (p = 0.014, HR 1.52; 95% CI 1.09-2.1) were statistically significantly associated with shorter survival. Conclusions: TDs appear more often in patients with higher TB grades in stage III CRC. A higher TB grade and a growing number of TDs were statistically significantly associated with shorter overall survival. These results could give additional emphasis to the importance of TB as an adverse prognostic factor since a strong relationship with TDs has been demonstrated.
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Affiliation(s)
- Zdenko Bilić
- Department of Surgery, Sestre Milosrdnice University Hospital Center, 10 000 Zagreb, Croatia; (Z.B.); (M.Z.); (G.G.); (D.M.); (A.I.)
| | - Mario Zovak
- Department of Surgery, Sestre Milosrdnice University Hospital Center, 10 000 Zagreb, Croatia; (Z.B.); (M.Z.); (G.G.); (D.M.); (A.I.)
- School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (A.K.); (D.T.)
- School of Dental Medicine, University of Zagreb, 10 000 Zagreb, Croatia
| | - Goran Glavčić
- Department of Surgery, Sestre Milosrdnice University Hospital Center, 10 000 Zagreb, Croatia; (Z.B.); (M.Z.); (G.G.); (D.M.); (A.I.)
| | - Dubravka Mužina
- Department of Surgery, Sestre Milosrdnice University Hospital Center, 10 000 Zagreb, Croatia; (Z.B.); (M.Z.); (G.G.); (D.M.); (A.I.)
| | - Amir Ibukić
- Department of Surgery, Sestre Milosrdnice University Hospital Center, 10 000 Zagreb, Croatia; (Z.B.); (M.Z.); (G.G.); (D.M.); (A.I.)
| | - Andro Košec
- School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (A.K.); (D.T.)
- Department of Otorhinolaryngology & Head and Neck Surgery, University Hospital Center Sestre Milosrdnice, 10 000 Zagreb, Croatia
| | - Davor Tomas
- School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia; (A.K.); (D.T.)
- Department of Pathology and Cytology, Sestre Milosrdnice University Hospital Center, 10 000 Zagreb, Croatia
| | - Alma Demirović
- School of Dental Medicine, University of Zagreb, 10 000 Zagreb, Croatia
- Department of Pathology and Cytology, Sestre Milosrdnice University Hospital Center, 10 000 Zagreb, Croatia
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Yavuz A, Simsek K, Alpsoy A, Altunay B, Gedik EO, Unal B, Bassorgun CI, Tatli AM, Elpek GO. Prognostic significance of tumor budding, desmoplastic reaction, and lymphocytic infiltration in patients with gastric adenocarcinoma. World J Gastrointest Pathophysiol 2024; 15:91237. [PMID: 38682027 PMCID: PMC11045359 DOI: 10.4291/wjgp.v15.i1.91237] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 03/08/2024] [Accepted: 03/22/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Recent studies have shown that the tumor microenvironment significantly influences the behavior of solid tumors. In this context, Accumulated data suggests that pathological evaluation of tumor budding (TB), desmoplastic reaction (DR), and tumor-infiltrating lymphocytes (TILs) may be crucial in determining tumor behavior in the gastrointestinal tract. Regarding gastric adenocarcinoma (GAC), although some results suggest that TB and TILs may be effective in determining the course of the disease, the data do not agree. Moreover, very few studies have investigated the relationship between DR and survival. At present, the associations between tumor TB, DR and TILs in GAC patients have not been determined. AIM To establish the relationships between TB, DR, and TILs in patients with GAC and to assess their influence on prognosis. METHODS Our study group comprised 130 patients diagnosed with GAC. The definition of TB was established based on the International TB Consensus Conference. The DR was categorized into three groups according to the level of tumor stroma maturation. The assessment of TILs was conducted using a semiquantitative approach, employing a cutoff value of 5%. The statistical analysis of the whole group and 100 patients with an intestinal subtype of GAC was performed using SPSS version 27. RESULTS A significant correlation between peritumoral budding (PTB) and intratumoral budding (ITB) was noted (r = 0.943). Tumors with high PTBs and ITBs had a greater incidence of immature DRs and low TILs (P < 0.01). PTB and ITB were associated with histological subtype, lymph node metastasis (LNM), and stage (P < 0.01). ITB, PTB, LNM, DR, and stage were significant risk factors associated with poor prognosis. The multivariate Cox regression analysis identified ITB, PTB, and LNM as independent prognostic variables (P < 0.05). In intestinal-type adenocarcinomas, a positive correlation between PTB and ITB was noted (r = 0.972). While univariate analysis revealed that LNM, stage, PTB, ITB, and DR were strong parameters for predicting survival (P < 0.05), only PTB and ITB were found to be independent prognostic factors (P < 0.001). CONCLUSION TB may be a potential prognostic marker in GAC. However, further studies are needed to delineate its role in pathology reporting protocols and the predictive effects of DR and TILs.
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Affiliation(s)
- Aysen Yavuz
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Kubra Simsek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Anil Alpsoy
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Busra Altunay
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Elif Ocak Gedik
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Betul Unal
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | | | - Ali Murat Tatli
- Department of Medical Oncology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
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11
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Cyr DP, Pun C, Shivji S, Mitrovic B, Duan K, Tomin R, Sari A, Brar A, Zerhouni S, Brar MS, Kennedy ED, Swallow CJ, Kirsch R, Conner JR. Tumor Budding Assessment in Colorectal Carcinoma: Normalization Revisited. Am J Surg Pathol 2024; 48:251-265. [PMID: 38108373 DOI: 10.1097/pas.0000000000002166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Tumor budding (TB) is a powerful prognostic factor in colorectal cancer (CRC). An internationally standardized method for its assessment (International Tumor Budding Consensus Conference [ITBCC] method) has been adopted by most CRC pathology protocols. This method requires that TB counts are reported by field area (0.785 mm 2 ) rather than objective lens and a normalization factor is applied for this purpose. However, the validity of this approach is yet to be tested. We sought to validate the ITBCC method with a particular emphasis on normalization as a tool for standardization. In a cohort of 365 stage I-III CRC, both normalized and non-normalized TB were significantly associated with disease-specific survival and recurrence-free survival ( P <0.0001). Examining both 0.95 and 0.785 mm 2 field areas in a subset of patients (n=200), we found that normalization markedly overcorrects TB counts: Counts obtained in a 0.95 mm 2 hotspot field were reduced by an average of 17.5% following normalization compared with only 3.8% when counts were performed in an actual 0.785 mm 2 field. This resulted in 45 (11.3%) cases being downgraded using ITBCC grading criteria following normalization, compared with only 5 cases (1.3%, P =0.0007) downgraded when a true 0.785 mm 2 field was examined. In summary, the prognostic value of TB was retained regardless of whether TB counts in a 0.95 mm 2 field were normalized. Normalization resulted in overcorrecting TB counts with consequent downgrading of most borderline cases. This has implications for risk stratification and adjuvant treatment decisions, and suggests the need to re-evaluate the role of normalization in TB assessment.
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Affiliation(s)
- David P Cyr
- Lunenfeld-Tanenbaum Research Institute
- Institute of Medical Science
- Department of Surgery, Division of General Surgery, University of Toronto
- Department of Surgical Oncology, Princess Margaret Cancer Centre and Sinai Health System
| | - Cherry Pun
- Department of Pathology and Laboratory Medicine, Sinai Health System
- Department of Laboratory Medicine Pathobiology, University of Toronto
| | - Sameer Shivji
- Department of Pathology and Laboratory Medicine, Sinai Health System
| | - Bojana Mitrovic
- Department of Pathology and Laboratory Medicine, Health Sciences North, Sudbury, ON, Canada
| | - Kai Duan
- Department of Laboratory Medicine Pathobiology, University of Toronto
- Laboratory Medicine Program, University Health Network, Toronto
| | - Rossi Tomin
- Department of Pathology and Laboratory Medicine, Sinai Health System
| | - Aysegul Sari
- Department of Pathology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Amanpreet Brar
- Department of Surgery, Division of General Surgery, University of Toronto
| | - Siham Zerhouni
- Department of Surgery, Division of General Surgery, University of Toronto
- Department of Surgical Oncology, Princess Margaret Cancer Centre and Sinai Health System
| | - Mantaj S Brar
- Department of Surgery, Division of General Surgery, University of Toronto
| | - Erin D Kennedy
- Department of Surgery, Division of General Surgery, University of Toronto
- Department of Surgical Oncology, Princess Margaret Cancer Centre and Sinai Health System
| | - Carol J Swallow
- Lunenfeld-Tanenbaum Research Institute
- Institute of Medical Science
- Department of Surgery, Division of General Surgery, University of Toronto
- Department of Surgical Oncology, Princess Margaret Cancer Centre and Sinai Health System
| | - Richard Kirsch
- Lunenfeld-Tanenbaum Research Institute
- Department of Pathology and Laboratory Medicine, Sinai Health System
- Department of Laboratory Medicine Pathobiology, University of Toronto
| | - James R Conner
- Lunenfeld-Tanenbaum Research Institute
- Department of Pathology and Laboratory Medicine, Sinai Health System
- Department of Laboratory Medicine Pathobiology, University of Toronto
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12
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Su Z, Chen W, Annem S, Sajjad U, Rezapour M, Frankel WL, Gurcan MN, Niazi MKK. Adapting SAM to Histopathology Images for Tumor Bud Segmentation in Colorectal Cancer. PROCEEDINGS OF SPIE--THE INTERNATIONAL SOCIETY FOR OPTICAL ENGINEERING 2024; 12933:129330C. [PMID: 38765185 PMCID: PMC11099868 DOI: 10.1117/12.3006517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the United States. Tumor Budding (TB) detection and quantification are crucial yet labor-intensive steps in determining the CRC stage through the analysis of histopathology images. To help with this process, we adapt the Segment Anything Model (SAM) on the CRC histopathology images to segment TBs using SAM-Adapter. In this approach, we automatically take task-specific prompts from CRC images and train the SAM model in a parameter-efficient way. We compare the predictions of our model with the predictions from a trained-from-scratch model using the annotations from a pathologist. As a result, our model achieves an intersection over union (IoU) of 0.65 and an instance-level Dice score of 0.75, which are promising in matching the pathologist's TB annotation. We believe our study offers a novel solution to identify TBs on H&E-stained histopathology images. Our study also demonstrates the value of adapting the foundation model for pathology image segmentation tasks.
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Affiliation(s)
- Ziyu Su
- Center for Artificial Intelligence Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Wei Chen
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Sony Annem
- Department of Computer Science, The University of North Carolina at Greensboro, Greensboro, NC, USA
| | - Usama Sajjad
- Center for Artificial Intelligence Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Mostafa Rezapour
- Center for Artificial Intelligence Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Wendy L. Frankel
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Metin N. Gurcan
- Center for Artificial Intelligence Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - M. Khalid Khan Niazi
- Center for Artificial Intelligence Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
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13
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Su Z, Chen W, Leigh PJ, Sajjad U, Niu S, Rezapour M, Frankel WL, Gurcan MN, Niazi MKK. Few-shot Tumor Bud Segmentation Using Generative Model in Colorectal Carcinoma. PROCEEDINGS OF SPIE--THE INTERNATIONAL SOCIETY FOR OPTICAL ENGINEERING 2024; 12933:129330A. [PMID: 38756441 PMCID: PMC11098595 DOI: 10.1117/12.3006418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2024]
Abstract
Current deep learning methods in histopathology are limited by the small amount of available data and time consumption in labeling the data. Colorectal cancer (CRC) tumor budding quantification performed using H&E-stained slides is crucial for cancer staging and prognosis but is subject to labor-intensive annotation and human bias. Thus, acquiring a large-scale, fully annotated dataset for training a tumor budding (TB) segmentation/detection system is difficult. Here, we present a DatasetGAN-based approach that can generate essentially an unlimited number of images with TB masks from a moderate number of unlabeled images and a few annotated images. The images generated by our model closely resemble the real colon tissue on H&E-stained slides. We test the performance of this model by training a downstream segmentation model, UNet++, on the generated images and masks. Our results show that the trained UNet++ model can achieve reasonable TB segmentation performance, especially at the instance level. This study demonstrates the potential of developing an annotation-efficient segmentation model for automatic TB detection and quantification.
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Affiliation(s)
- Ziyu Su
- Center for Artificial Intelligence Research, Wake Forest University, School of Medicine, Winston-Salem, NC, USA
| | - Wei Chen
- Department of Pathology, The Ohio State University
| | | | - Usama Sajjad
- Center for Artificial Intelligence Research, Wake Forest University, School of Medicine, Winston-Salem, NC, USA
| | - Shuo Niu
- Department of Pathology, Wake Forest University, School of Medicine, Winston-Salem, NC, USA
| | - Mostafa Rezapour
- Center for Artificial Intelligence Research, Wake Forest University, School of Medicine, Winston-Salem, NC, USA
| | | | - Metin N. Gurcan
- Center for Artificial Intelligence Research, Wake Forest University, School of Medicine, Winston-Salem, NC, USA
| | - M. Khalid Khan Niazi
- Center for Artificial Intelligence Research, Wake Forest University, School of Medicine, Winston-Salem, NC, USA
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14
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Li Q, Liu G, Qiu Q, Zhang J, Li R, Zhao J, She J, Chen Y. Establish a novel tumor budding-related signature to predict prognosis and guide clinical therapy in colorectal cancer. Sci Rep 2024; 14:2180. [PMID: 38273073 PMCID: PMC10810877 DOI: 10.1038/s41598-024-52596-1] [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] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 01/21/2024] [Indexed: 01/27/2024] Open
Abstract
Tumor budding is a long-established independent adverse prognostic marker for colorectal cancer (CRC), yet assessment of tumor budding was not reproducible. Therefore, development of precise diagnostic approaches to tumor budding is in demand. In this study, we first performed bioinformatic analysis in our single-center CRC patients' cohort (n = 84) and identified tumor budding-associated hub genes using the weighted gene co-expression network analysis (WGCNA). A machine learning methodology was used to identify hub genes and construct a prognostic signature. Nomogram model was used to identified hub genes score for tumor budding, and the receiver operating characteristic (ROC) curve and calibration plot indicated high accuracy and stability of hub gene score for predicted the prognosis of CRC. The association between budding-associated hub genes and score and prognosis of CRC were further verified in TCGA CRC cohort (n = 342). Then gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to explore the signaling pathways related to the tumor budding and validated by immunohistochemistry (IHC) of our clinical samples. Subsequently, immune infiltration analysis demonstrated that there was a high correlation between hub genes score and M2-like macrophages infiltrated in tumor tissue. In addition, somatic mutation and chemotherapeutic response prediction were analyzed based on the risk signature. In summary, we established a tumor budding diagnostic molecular model, which can improve tumor budding assessment and provides a promising novel molecular marker for immunotherapy and prognosis of CRC.
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Affiliation(s)
- Qixin Li
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Gaixia Liu
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Quanpeng Qiu
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jiaqi Zhang
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ruizhe Li
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jiamian Zhao
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Junjun She
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China.
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Yinnan Chen
- Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi, China.
- Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
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15
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Saez de Gordoa K, Rodrigo-Calvo MT, Archilla I, Lopez-Prades S, Diaz A, Tarragona J, Machado I, Ruiz Martín J, Zaffalon D, Daca-Alvarez M, Pellisé M, Camps J, Cuatrecasas M. Lymph Node Molecular Analysis with OSNA Enables the Identification of pT1 CRC Patients at Risk of Recurrence: A Multicentre Study. Cancers (Basel) 2023; 15:5481. [PMID: 38001742 PMCID: PMC10670609 DOI: 10.3390/cancers15225481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/11/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Early-stage colorectal carcinoma (CRC)-pT1-is a therapeutic challenge and presents some histological features related to lymph node metastasis (LNM). A significant proportion of pT1 CRCs are treated surgically, resulting in a non-negligible surgical-associated mortality rate of 1.5-2%. Among these cases, approximately 6-16% exhibit LNM, but the impact on survival is unclear. Therefore, there is an unmet need to establish an objective and reliable lymph node (LN) staging method to optimise the therapeutic management of pT1 CRC patients and to avoid overtreating or undertreating them. In this multicentre study, 89 patients with pT1 CRC were included. All histological features associated with LNM were evaluated. LNs were assessed using two methods, One-Step Nucleic Acid Amplification (OSNA) and the conventional FFPE plus haematoxylin and eosin (H&E) staining. OSNA is an RT-PCR-based method for amplifying CK19 mRNA. Our aim was to assess the performance of OSNA and H&E in evaluating LNs to identify patients at risk of recurrence and to optimise their clinical management. We observed an 80.9% concordance in LN assessment using the two methods. In 9% of cases, LNs were found to be positive using H&E, and in 24.7% of cases, LNs were found to be positive using OSNA. The OSNA results are provided as the total tumour load (TTL), defined as the total tumour burden present in all the LNs of a surgical specimen. In CRC, a TTL ≥ 6000 CK19 m-RNA copies/µL is associated with poor prognosis. Three patients had TTL > 6000 copies/μL, which was associated with higher tumour budding. The discrepancies observed between the OSNA and H&E results were mostly attributed to tumour allocation bias. We concluded that LN assessment with OSNA enables the identification of pT1 CRC patients at some risk of recurrence and helps to optimise their clinical management.
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Affiliation(s)
- Karmele Saez de Gordoa
- Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, 08036 Barcelona, Spain; (K.S.d.G.); (M.T.R.-C.); (I.A.); (S.L.-P.); (A.D.)
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (M.P.); (J.C.)
| | - Maria Teresa Rodrigo-Calvo
- Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, 08036 Barcelona, Spain; (K.S.d.G.); (M.T.R.-C.); (I.A.); (S.L.-P.); (A.D.)
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (M.P.); (J.C.)
| | - Ivan Archilla
- Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, 08036 Barcelona, Spain; (K.S.d.G.); (M.T.R.-C.); (I.A.); (S.L.-P.); (A.D.)
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (M.P.); (J.C.)
| | - Sandra Lopez-Prades
- Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, 08036 Barcelona, Spain; (K.S.d.G.); (M.T.R.-C.); (I.A.); (S.L.-P.); (A.D.)
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (M.P.); (J.C.)
| | - Alba Diaz
- Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, 08036 Barcelona, Spain; (K.S.d.G.); (M.T.R.-C.); (I.A.); (S.L.-P.); (A.D.)
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (M.P.); (J.C.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Department of Clinical Foundations, University of Barcelona (UB), 08036 Barcelona, Spain
| | - Jordi Tarragona
- Pathology Department, Hospital Arnau de Vilanova, 25198 Lleida, Spain;
| | - Isidro Machado
- Pathology Department, Instituto Valenciano de Oncología, Hospital Quirón-Salud Valencia, University of Valencia, 46010 Valencia, Spain;
- Centro de Investigación Biomédica en Red en Cancer (CIBERONC), 28029 Madrid, Spain
| | - Juan Ruiz Martín
- Pathology Department, Virgen de la Salud Hospital, 45071 Toledo, Spain;
| | - Diana Zaffalon
- Gastroenterology Department, Consorci Sanitari de Terrassa, 08227 Terrassa, Spain;
| | - Maria Daca-Alvarez
- Gastroenterology Department, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain;
| | - Maria Pellisé
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (M.P.); (J.C.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Gastroenterology Department, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain;
| | - Jordi Camps
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (M.P.); (J.C.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Cell Biology and Medical Genetics Unit, Department of Cell Biology, Physiology and Immunology, Faculty of Medicine, Autonomous University of Barcelona (UAB), 08193 Bellaterra, Spain
| | - Miriam Cuatrecasas
- Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, 08036 Barcelona, Spain; (K.S.d.G.); (M.T.R.-C.); (I.A.); (S.L.-P.); (A.D.)
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain; (M.P.); (J.C.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Department of Clinical Foundations, University of Barcelona (UB), 08036 Barcelona, Spain
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16
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Vural Topuz Ö, Aksu A, Yılmaz Özgüven MB. A different perspective on 18F-FDG PET radiomics in colorectal cancer patients: The relationship between intra & peritumoral analysis and pathological findings. Rev Esp Med Nucl Imagen Mol 2023; 42:359-366. [PMID: 37088299 DOI: 10.1016/j.remnie.2023.04.005] [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: 02/05/2023] [Revised: 04/06/2023] [Accepted: 04/12/2023] [Indexed: 04/25/2023]
Abstract
OBJECTIVE We aimed to determine the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) based primary tumoral and peritumoral radiomics in the prediction of tumor deposits (TDs), tumor budding (TB) and extramural venous invasion (EMVI) of colorectal cancer (CRC). METHODS Our retrospective study included 77 CRC patients who had preoperative 18F-FDG PET/CT between June 2020 and February 2022. A total of 131 radiomic features were extracted from primary tumors and peritumoral areas on PET/CT fusion images. The relationship between TDs, TB, EMVI and T stage in the postoperative pathology of the tumors and radiomic features was investigated. Features with a correlation coefficient (CC) less than 0.8 were analyzed by logistic regression. The area under curve (AUC) obtained from the receiver operating characteristic analysis was used to measure the model performance. RESULTS A model was developed from primary tumoral and peritumoral radiomics data to predict T stage (AUC 0.931), and also a predictive model was constructed from primary tumor derived radiomics to predict EMVI (AUC 0.739). Radiomic data derived from the primary tumor was obtained as a predictive prognostic factor in predicting TDs and a peritumoral feature was found to be a prognostic factor in predicting TB. CONCLUSIONS Intratumoral and peritumoral radiomics derived from 18F-FDG PET/CT are useful for non-invasive early prediction of pathological features that have important implications in the management of CRC.
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Affiliation(s)
- Özge Vural Topuz
- University of Health Sciences, Başakşehir Cam and Sakura City Hospital, Department of Nuclear Medicine, Istanbul, Turkey.
| | - Ayşegül Aksu
- İzmir Katip Çelebi University, Atatürk Training and Research Hospital, Department of Nuclear Medicine, İzmir, Turkey
| | - Müveddet Banu Yılmaz Özgüven
- University of Health Sciences, Başakşehir Cam and Sakura City Hospital, Department of Pathology, Istanbul, Turkey
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17
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Bokhorst JM, Ciompi F, Öztürk SK, Oguz Erdogan AS, Vieth M, Dawson H, Kirsch R, Simmer F, Sheahan K, Lugli A, Zlobec I, van der Laak J, Nagtegaal ID. Fully Automated Tumor Bud Assessment in Hematoxylin and Eosin-Stained Whole Slide Images of Colorectal Cancer. Mod Pathol 2023; 36:100233. [PMID: 37257824 DOI: 10.1016/j.modpat.2023.100233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 04/25/2023] [Accepted: 05/20/2023] [Indexed: 06/02/2023]
Abstract
Tumor budding (TB), the presence of single cells or small clusters of up to 4 tumor cells at the invasive front of colorectal cancer (CRC), is a proven risk factor for adverse outcomes. International definitions are necessary to reduce interobserver variability. According to the current international guidelines, hotspots at the invasive front should be counted in hematoxylin and eosin (H&E)-stained slides. This is time-consuming and prone to interobserver variability; therefore, there is a need for computer-aided diagnosis solutions. In this study, we report an artificial intelligence-based method for detecting TB in H&E-stained whole slide images. We propose a fully automated pipeline to identify the tumor border, detect tumor buds, characterize them based on the number of tumor cells, and produce a TB density map to identify the TB hotspot. The method outputs the TB count in the hotspot as a computational biomarker. We show that the proposed automated TB detection workflow performs on par with a panel of 5 pathologists at detecting tumor buds and that the hotspot-based TB count is an independent prognosticator in both the univariate and the multivariate analysis, validated on a cohort of n = 981 patients with CRC. Computer-aided detection of tumor buds based on deep learning can perform on par with expert pathologists for the detection and quantification of tumor buds in H&E-stained CRC histopathology slides, strongly facilitating the introduction of budding as an independent prognosticator in clinical routine and clinical trials.
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Affiliation(s)
- John-Melle Bokhorst
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Francesco Ciompi
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sonay Kus Öztürk
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Michael Vieth
- Klinikum of Pathology, Bayreuth University, Bayreuth, Germany
| | - Heather Dawson
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Richard Kirsch
- University of Toronto, Mount Sinai Hospital, Toronto, Canada
| | - Femke Simmer
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Kieran Sheahan
- Department of Pathology, St Vincent's Hospital, Dublin, Ireland
| | | | - Inti Zlobec
- Klinikum of Pathology, Bayreuth University, Bayreuth, Germany
| | - Jeroen van der Laak
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands; Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
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18
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Bonilla CE, Montenegro P, O’Connor JM, Hernando-Requejo O, Aranda E, Pinto Llerena J, Llontop A, Gallardo Escobar J, Díaz Romero MDC, Bautista Hernández Y, Graña Suárez B, Batagelj EJ, Wali Mushtaq A, García-Foncillas J. Ibero-American Consensus Review and Incorporation of New Biomarkers for Clinical Practice in Colorectal Cancer. Cancers (Basel) 2023; 15:4373. [PMID: 37686649 PMCID: PMC10487247 DOI: 10.3390/cancers15174373] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Advances in genomic technologies have significantly improved the management of colorectal cancer (CRC). Several biomarkers have been identified in CRC that enable personalization in the use of biologic agents that have shown to enhance the clinical outcomes of patients. However, technologies used for their determination generate massive amounts of information that can be difficult for the clinician to interpret and use adequately. Through several discussion meetings, a group of oncology experts from Spain and several Latin American countries reviewed the latest literature to provide practical recommendations on the determination of biomarkers in CRC based on their clinical experience. The article also describes the importance of looking for additional prognostic biomarkers and the use of histopathology to establish an adequate molecular classification. Present and future of immunotherapy biomarkers in CRC patients are also discussed, together with several techniques for marker determination, including liquid biopsy, next-generation sequencing (NGS), polymerase chain reaction (PCR), and fecal immunohistochemical tests. Finally, the role of Molecular Tumor Boards in the diagnosis and treatment of CRC is described. All of this information will allow us to highlight the importance of biomarker determination in CRC.
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Affiliation(s)
- Carlos Eduardo Bonilla
- Fundación CTIC—Centro de Tratamiento e Investigación sobre Cáncer, Bogotá 1681442, Colombia
| | - Paola Montenegro
- Institución AUNA OncoSalud e Instituto Nacional de Enfermedades Neoplásicas, Lima 15023, Peru
| | | | | | - Enrique Aranda
- Departamento de Oncología Médica, Hospital Reina Sofía, IMIBIC, UCO, CIBERONC, 14004 Cordoba, Spain;
| | | | - Alejandra Llontop
- Instituto de Oncología Ángel H. Roffo, Ciudad Autónoma de Buenos Aires C1437FBG, Argentina
| | | | | | | | - Begoña Graña Suárez
- Servicio de Oncología Médica, Hospital Universitario de A Coruña, Servicio Galego de Saúde (SERGAS), 15006 A Coruña, Spain;
| | | | | | - Jesús García-Foncillas
- Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain
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19
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Haddad TS, van den Dobbelsteen L, Öztürk SK, Geene R, Nijman IJ, Verrijp K, Jamieson NB, Wood C, van Vliet S, Reuvers L, Achouiti S, Rutgers N, Brouwer N, Simmer F, Zlobec I, Lugli A, Nagtegaal ID. Pseudobudding: ruptured glands do not represent true tumor buds. J Pathol 2023; 261:19-27. [PMID: 37403270 DOI: 10.1002/path.6146] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/20/2023] [Accepted: 05/23/2023] [Indexed: 07/06/2023]
Abstract
Tumor budding (TB) is a strong biomarker of poor prognosis in colorectal cancer and other solid cancers. TB is defined as isolated single cancer cells or clusters of up to four cancer cells at the invasive tumor front. In areas with a large inflammatory response at the invasive front, single cells and cell clusters surrounding fragmented glands are observed appearing like TB. Occurrence of these small groups is referred to as pseudobudding (PsB), which arises due to external influences such as inflammation and glandular disruption. Using a combination of orthogonal approaches, we show that there are clear biological differences between TB and PsB. TB is representative of active invasion by presenting features of epithelial-mesenchymal transition and exhibiting increased deposition of extracellular matrix within the surrounding tumor microenvironment (TME), whereas PsB represents a reactive response to heavy inflammation where increased levels of granulocytes within the surrounding TME are observed. Our study provides evidence that areas with a strong inflammatory reaction should be avoided in the routine diagnostic assessment of TB. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
| | | | - Sonay K Öztürk
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - Robin Geene
- USEQ, CMM, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Isaäc J Nijman
- USEQ, CMM, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Kiek Verrijp
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nigel B Jamieson
- University of Glasgow, Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, Glasgow, UK
| | - Colin Wood
- University of Glasgow, Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, Glasgow, UK
| | | | - Luuk Reuvers
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - Soumia Achouiti
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - Natasja Rutgers
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nelleke Brouwer
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - Femke Simmer
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - Inti Zlobec
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Alessandro Lugli
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
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20
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Savli TB, Pasaoglu HE, Savli TC, Muhammedoglu A, Tokocin M, Öztürk Ç. Expression of cytotoxic T lymphocyte-associated antigen 4, CD44, and E-cadherin in the microenvironment of breast carcinomas. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2023; 69:e20230371. [PMID: 37466609 PMCID: PMC10351999 DOI: 10.1590/1806-9282.20230371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 04/28/2023] [Indexed: 07/20/2023]
Abstract
OBJECTIVE The expression of cytotoxic T lymphocyte-associated antigen 4, E-cadherin, and CD44 in the area of tumor budding was investigated in breast carcinomas in our study. METHODS Tumor budding was counted at the invasive margins in 179 breast carcinomas. To understand the microenvironment of tumor budding, we examined the expression status of the immune checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4, E-cadherin, and CD44. RESULTS Tumors were separated into low (≤5) and high tumor budding groups (>5) based on the median budding number. Lymphovascular, perineural invasion, and the number of metastatic lymph nodes were significantly higher in high-grade budding tumors (p=0.001, p<0.001, and p=0.019, respectively). Tumor-infiltrating lymphocytes were significantly higher in tumors without tumor buddings (p<0.001). When the number of budding increases by one unit, overall survival decreases by 1.07 times (p=0.013). Also, it increases the risk of progression by 1.06 times (p=0.048). In high tumor budding groups, the cytotoxic T lymphocyte-associated antigen 4 staining percentage of lymphocytes was significantly higher (p=0.026). With each increase in the number of buds, an increase in the percentage of cytotoxic T lymphocyte-associated antigen 4 staining was seen in lymphocytes in the microenvironment of TB (p=0.034). CONCLUSION Tumor budding could predict poor prognosis in breast carcinomas, and anti-cytotoxic T lymphocyte-associated antigen 4 immunotherapies may be beneficial in patients with high tumor budding tumors.
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Affiliation(s)
- Tugce Bolme Savli
- Gaziantep Cengiz Gokcek Maternity and Child Health Hospital, Department of Pathology - Gaziantep, Turkey
| | - Husniye Esra Pasaoglu
- Istanbul Bagcilar Training and Research Hospital, Department of Pathology - Istanbul, Turkey
| | - Taha Cumhan Savli
- Medipol Mega University Hospital, Department of Pathology - Istanbul, Turkey
| | - Ali Muhammedoglu
- Istanbul Bagcilar Training and Research Hospital, Department of Pathology - Istanbul, Turkey
| | - Merve Tokocin
- Istanbul Bagcilar Training and Research Hospital, Department of General Surgery - Istanbul, Turkey
| | - Çiğdem Öztürk
- Recep Tayyip Erdoğan University Training and Research Hospital, Pathology Department - Rize, Turkey
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21
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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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22
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Xiao SM, Li J. Tumor budding in gastric cancer. World J Gastrointest Surg 2023; 15:578-591. [PMID: 37206064 PMCID: PMC10190737 DOI: 10.4240/wjgs.v15.i4.578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/04/2023] [Accepted: 03/21/2023] [Indexed: 04/22/2023] Open
Abstract
The tumor, nodes, metastasis (TNM) staging system has long been the gold standard for the classification and prognosis of solid tumors. However, the TNM staging system is not without limitations. Prognostic heterogeneity exists within patients at the same stage. Therefore, the pursuit of other biomarkers with the potential to classify patients with cancer has never stopped. One of them, tumor budding (TB), has gained much success in colorectal cancer. In recent years, TB in gastric cancer has attracted much attention from researchers, beginning to reveal the molecular and biological aspects of this phenomenon in gastric cancer, and has emerged as a promising prognostic biomarker in gastric cancer, predicting disease progression and unfavorable survival. Therefore, it is time and essential to provide a holistic overview of TB in gastric cancer, which has not been achieved and is the aim of this review.
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Affiliation(s)
- Shuo-Meng Xiao
- Department of Gastric Surgery, Sichuan Cancer Hospital, Chengdu 610041, Sichuan Province, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang 621000, Sichuan Province, China
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23
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High-yield areas to grade tumor budding in colorectal cancer: A practical approach for pathologists. Ann Diagn Pathol 2023; 63:152085. [PMID: 36577186 DOI: 10.1016/j.anndiagpath.2022.152085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 12/11/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tumor budding (TB) has significant prognostic implication in stage II colorectal cancer (CRC) and is graded based on the International Tumor Budding Consensus Conference (ITBCC) protocol. In the current study, we evaluate tumor budding and its relationship to multiple histologic features in 104 tumors. METHODS One-hundred four resected CRC cases were retrieved. Tumor bud count and TB grade were compared to the final tumor bud count/TB grade of the tumor per ITBCC protocol. The following high-yield co-features were assessed in each slide: highest T stage, presence of benign mucosa, presence of a precursor lesion, and highest tumor volume. RESULTS Twenty-nine (28 %) cases had discrepancies between slide TB grade and final TB grade. The least discrepancies were seen in slides with benign mucosa (7 %) and precursor lesions (7 %). Among stage II patients without high-risk features, no discrepancies were observed in slides with benign mucosa. Slides with deepest invasion (rs = 1.000, p = 0.01) and benign mucosa (rs = 0.957, p < 0.001) had the strongest correlation with final tumor bud count in the same stage II subgroup. Similar relationships were observed when comparing final TB grade. Deepest invasion, tumor volume, as well as lymphovascular invasion, when present, also showed strong correlations with final TB grade in the entire cohort (rs = 0.828-0.845, p < 0.001). CONCLUSION Our study is the first study to evaluate the relationship between TB grade and co-existing histologic features. We highlight the benefit of focusing on slides with high-yield co-features, with the strongest correlation seen in slides with adjacent benign mucosa and precursor lesions.
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24
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Bokhorst JM, Nagtegaal ID, Zlobec I, Dawson H, Sheahan K, Simmer F, Kirsch R, Vieth M, Lugli A, van der Laak J, Ciompi F. Semi-Supervised Learning to Automate Tumor Bud Detection in Cytokeratin-Stained Whole-Slide Images of Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15072079. [PMID: 37046742 PMCID: PMC10093661 DOI: 10.3390/cancers15072079] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/24/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
Tumor budding is a histopathological biomarker associated with metastases and adverse survival outcomes in colorectal carcinoma (CRC) patients. It is characterized by the presence of single tumor cells or small clusters of cells within the tumor or at the tumor-invasion front. In order to obtain a tumor budding score for a patient, the region with the highest tumor bud density must first be visually identified by a pathologist, after which buds will be counted in the chosen hotspot field. The automation of this process will expectedly increase efficiency and reproducibility. Here, we present a deep learning convolutional neural network model that automates the above procedure. For model training, we used a semi-supervised learning method, to maximize the detection performance despite the limited amount of labeled training data. The model was tested on an independent dataset in which human- and machine-selected hotspots were mapped in relation to each other and manual and machine detected tumor bud numbers in the manually selected fields were compared. We report the results of the proposed method in comparison with visual assessment by pathologists. We show that the automated tumor bud count achieves a prognostic value comparable with visual estimation, while based on an objective and reproducible quantification. We also explore novel metrics to quantify buds such as density and dispersion and report their prognostic value. We have made the model available for research use on the grand-challenge platform.
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25
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van der Strate I, Kazemzadeh F, Nagtegaal ID, Robbrecht D, van de Wouw A, Padilla CS, Duijts S, Esteller M, Greco FA, Pavlidis N, Qaseem A, Snaebjornsson P, van Zanten SV, Loef C. International consensus on the initial diagnostic workup of cancer of unknown primary. Crit Rev Oncol Hematol 2023; 181:103868. [PMID: 36435296 DOI: 10.1016/j.critrevonc.2022.103868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/04/2022] [Accepted: 11/04/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Although the incidence of Cancer of Unknown Primary (CUP) is estimated to be 1-2 % of all cancers worldwide, no international standards for diagnostic workup are yet established. Such an international guideline would facilitate international comparison, provide adequate incidence and survival rates, and ultimately improve care of patients with CUP. METHODS Participants for a four round modified Delphi study were selected via a CUP literature search in PubMed and an international network of cancer researchers. A total of 90 CUP experts were invited, and 34 experts from 15 countries over four continents completed all Delphi survey rounds. FINDINGS The Delphi procedure resulted in a multi-layer CUP classification for the diagnostic workup. Initial diagnostic workup should at least consist of history and physical examination, full blood count, analysis of serum markers, a biopsy of the most accessible lesion, a CT scan of chest/abdomen/pelvis, and immunohistochemical testing. Additionally, the expert panel agreed on the need of an ideal diagnostic lead time for CUP patients. There was no full consensus on the place in diagnostic workup of symptom-guided MRI or ultrasound, a PET/CT scan, targeted gene panels, immunohistochemical markers, and whole genome sequencing. INTERPRETATION Consensus was reached on the contents of the first diagnostic layer of a multi-layer CUP classification. This is a first step towards full consensus on CUP diagnostics, that should also include supplementary and advanced diagnostics.
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Affiliation(s)
- Iris van der Strate
- Department of Research and Development, Comprehensive Cancer Organization the Netherlands, Utrecht, the Netherlands.
| | - Fatemeh Kazemzadeh
- Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Debbie Robbrecht
- Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Agnes van de Wouw
- Department of Medical Oncology, VieCuri Medical Center, Venlo, the Netherlands
| | - Catarina S Padilla
- Department of Research and Development, Comprehensive Cancer Organization the Netherlands, Utrecht, the Netherlands
| | - Saskia Duijts
- Department of Research and Development, Comprehensive Cancer Organization the Netherlands, Utrecht, the Netherlands; Department of Medical Psychology, Cancer Center Amsterdam, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Manel Esteller
- Josep Carreras Leukemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain
| | - F Anthony Greco
- Sarah Cannon Research Institute and Cancer Center, Tennessee Oncology, Nashville, TN, USA
| | - Nicholas Pavlidis
- Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110, Ioannina, Greece
| | - Amir Qaseem
- American College of Physicians, Philadelphia, PA, USA
| | - Petur Snaebjornsson
- Department of Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, the Netherlands
| | - Sophie Veldhuijzen van Zanten
- Department of Radiology and Nuclear Medicine, Erasmus MC, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Caroline Loef
- Department of Research and Development, Comprehensive Cancer Organization the Netherlands, Utrecht, the Netherlands
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Immunohistochemical analysis of the distribution of RANKL: a case of disseminated carcinomatosis of bone marrow as the first presentation of relapse in curatively resected colorectal cancer. Med Mol Morphol 2022; 56:138-143. [PMID: 36478259 DOI: 10.1007/s00795-022-00342-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Poorly differentiated adenocarcinoma of colorectal carcinoma (CRC) is a rare condition with poor prognosis. In this report, we describe a case of a 69-year-old man who underwent laparoscopic low anterior resection after being diagnosed with stage IIIB CRC. At 10 months post-operation, he developed fever and loss of appetite. Laboratory examination revealed > 120.0 μg/dL fibrin degradation products and > 60.0 μg/dL D-dimer. Bone marrow (BM) examination showed malignant epithelioid infiltrate with CK20 and CDX2 expression, leading to diagnosis of disseminated carcinomatosis of BM, which is rare in CRC and indicative of widespread disease throughout the body. Furthermore, immunohistochemistry revealed high expression of receptor activator of nuclear factor κB ligand (RANKL) in tumor cells, including budding cells of CRC and BM tissues. Thus, RANKL expression, which is known to indicate metastatic behavior of cancer cells, may play a critical role in promoting osteoclast formation, which has been associated with the pathogenesis of BM lesions.
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27
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Pavlič A, Boštjančič E, Kavalar R, Ilijevec B, Bonin S, Zanconati F, Zidar N. Tumour budding and poorly differentiated clusters in colon cancer - different manifestations of partial epithelial-mesenchymal transition. J Pathol 2022; 258:278-288. [PMID: 36062412 PMCID: PMC9825925 DOI: 10.1002/path.5998] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/24/2022] [Accepted: 08/04/2022] [Indexed: 01/11/2023]
Abstract
Morphological features including infiltrative growth, tumour budding (TB), and poorly differentiated clusters (PDCs) have a firmly established negative predictive value in colorectal cancer (CRC). Despite extensive research, the mechanisms underlying different tumour growth patterns remain poorly understood. The aim of this study was to investigate the involvement of epithelial-mesenchymal transition (EMT) in TB and PDCs in CRC. Using laser-capture microdissection, we obtained distinct parts of the primary CRC including TB, PDCs, expansive tumour front, and the central part of the tumour, and analysed the expression of EMT-related markers, i.e. the miR-200 family, ZEB1/2, RND3, and CDH1. In TB, the miR-200 family and CDH1 were significantly downregulated, while ZEB2 was significantly upregulated. In PDCs, miR-141, miR-200c, and CDH1 were significantly downregulated. No significant differences were observed in the expression of any EMT-related markers between the expansive tumour front and the central part of the tumour. Our results suggest that both TB and PDCs are related to partial EMT. Discrete differences in morphology and expression of EMT-related markers between TB and PDCs indicate that they represent different manifestations of partial EMT. TB seems to be closer to complete EMT than PDCs. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Ana Pavlič
- Institute of Pathology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
| | - Emanuela Boštjančič
- Institute of Pathology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
| | - Rajko Kavalar
- Department of PathologyUniversity Medical Centre MariborMariborSlovenia
| | - Bojan Ilijevec
- Department of Abdominal and General SurgeryUniversity Medical Centre MariborMariborSlovenia
| | - Serena Bonin
- Department of Medical SciencesUniversity of TriesteTriesteItaly
| | | | - Nina Zidar
- Institute of Pathology, Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
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H3K27me3 Immunohistochemical Loss Predicts Lower Response to Neo-Adjuvant Chemo-Radiotherapy in Rectal Carcinoma. Biomedicines 2022; 10:biomedicines10082042. [PMID: 36009589 PMCID: PMC9405749 DOI: 10.3390/biomedicines10082042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/24/2022] Open
Abstract
A watch-and-wait approach was suggested to avoid the possible complications related to surgery in patients with rectal carcinoma showing clinical complete response after neoadjuvant chemo-radiotherapy (CRT). Since clinical response may not correlate with pathological response, markers with higher accuracy are needed to identify patients who are likely responders and could be spared surgery. This study aims to assess whether H3K27me3 immunohistochemical expression in pre-treatment rectal carcinoma predicts response to neoadjuvant CRT or shows prognostic relevance. We assessed H3K27me3 immunostaining in 46 endoscopic biopsies of rectal carcinomas treated with neoadjuvant CRT and surgery. H3K27me3 immunostaining was lost in 20, retained in 19, and inconclusive (absent in neoplastic and non-neoplastic cells) in 7 cases. Retained H3K27me3 immuno-expression was significantly associated with ypTNM stage 0 (p = 0.0111) and high tumor regression, measured using either five-tiered (p = 0.0042) or two-tiered Dworak tumor regression grade (p = 0.0009). Poor differentiation, determined counting the number of poorly differentiated clusters (PDC grade) or tumor budding (TB) foci (TB grade), in the pre-treatment biopsy, was significantly associated with a shorter time to progression after surgery (p = 0.008; p = 0.0093). However, only PDC grade (p = 0.0023), together with radial margin involvement (p = 0.0001), retained prognostic significance in the multivariate analysis. The assessment of H3K27me3 immunostaining in pre-treatment endoscopic biopsy of rectal carcinoma could be useful to predict response to neo-adjuvant CRT and to identify patients who could safely undergo watch-and-wait approach. PDC and TB grade in the pre-treatment biopsy could provide additional prognostic information in patients with rectal carcinoma treated with neoadjuvant CRT and surgery.
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Zombori-Tóth N, Paróczai D, Lantos J, Almási S, Sejben A, Tiszlavicz L, Cserni G, Furák J, Zombori T. The More Extensive the Spread through Air Spaces, the Worse the Prognosis Is: Semi-Quantitative Evaluation of Spread through Air Spaces in Pulmonary Adenocarcinomas. Pathobiology 2022; 90:104-113. [PMID: 35947971 PMCID: PMC10129026 DOI: 10.1159/000525456] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 05/09/2022] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION The extent of spread through air spaces (STAS) is less investigated among patients with lung adenocarcinoma who underwent sublobar resection. Therefore, we aimed to evaluate the extent of STAS semi-quantitatively, to assess its prognostic impact on overall survival (OS) and recurrence-free survival (RFS), and to investigate the reproducibility of this assessment. METHODS The number of tumour cell clusters and single tumour cells within air spaces was recorded in three different most prominent areas (200x field of view). The extent of STAS was categorized into three groups, and the presence of free tumour cluster (FTC) was recorded. RESULTS Sixty-one patients were included. Recurrence was more frequent with higher grade (p = 0.003), presence of lymphovascular invasion (p = 0.027), and presence of STAS of any extent (p = 0.007). In multivariate analysis, presence of FTC (HR: 5.89; 95% CI: 1.63-21.26; p = 0.005) and more pronounced STAS (HR: 7.46; 95% CI: 1.60-34.6; p = 0.01) had adverse impact on OS and RFS, respectively. Concerning reproducibility, excellent agreement was found among STAS parameters (ICC range: 0.92-0.94). DISCUSSION More extensive STAS is an unfavourable prognostic factor in adenocarcinomas treated with sublobar resection. As the evaluation of extent of STAS is reproducible, further investigation is required to gather more evidence.
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Affiliation(s)
| | - Dóra Paróczai
- Csongrád-Csanád County Hospital of Chest Diseases, Deszk, Hungary
| | - Judit Lantos
- Department of Neurology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary
| | - Szintia Almási
- Department of Pathology, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary
| | - Anita Sejben
- Department of Pathology, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary
| | - László Tiszlavicz
- Department of Pathology, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary
| | - Gábor Cserni
- Department of Pathology, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary.,Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary
| | - József Furák
- Department of Surgery, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary
| | - Tamás Zombori
- Department of Pathology, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary
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Taze D, Hartley C, Morgan AW, Chakrabarty A, Mackie SL, Griffin KJ. Developing consensus in Histopathology: the role of the Delphi method. Histopathology 2022; 81:159-167. [PMID: 35322456 PMCID: PMC9541891 DOI: 10.1111/his.14650] [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: 03/01/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 11/30/2022]
Abstract
The Delphi method is a well-established research tool, used for consensus building across a number of fields. Despite its widespread use, and popularity in many medical specialities, there is a paucity of literature on the use of the Delphi method in Histopathology. This literature review seeks to critique the Delphi methodology and explore its potential applications to histopathology-based clinical and research questions. We review those published studies that have utilized the Delphi methodology in Histopathology settings and specifically outline the advantages and limitations of this technique, highlighting situations where its application can be most effective.
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Affiliation(s)
- Dilek Taze
- St James' University Hospital NHS TrustLeedsUK,Leeds Institute of Cardiovascular and Metabolic Medicine, School of MedicineUniversity of LeedsLeedsUK,NIHR Leeds Biomedical Research CentreLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Collette Hartley
- Leeds Institute of Cardiovascular and Metabolic Medicine, School of MedicineUniversity of LeedsLeedsUK,NIHR Leeds Medtech and In Vitro Diagnostics Co‐operativeLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Ann W Morgan
- St James' University Hospital NHS TrustLeedsUK,Leeds Institute of Cardiovascular and Metabolic Medicine, School of MedicineUniversity of LeedsLeedsUK,NIHR Leeds Biomedical Research CentreLeeds Teaching Hospitals NHS TrustLeedsUK,NIHR Leeds Medtech and In Vitro Diagnostics Co‐operativeLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Aruna Chakrabarty
- St James' University Hospital NHS TrustLeedsUK,NIHR Leeds Biomedical Research CentreLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Sarah L Mackie
- NIHR Leeds Biomedical Research CentreLeeds Teaching Hospitals NHS TrustLeedsUK,Leeds Institute of Rheumatic and Musculoskeletal MedicineUniversity of LeedsLeedsUK
| | - Kathryn J Griffin
- St James' University Hospital NHS TrustLeedsUK,Leeds Institute of Cardiovascular and Metabolic Medicine, School of MedicineUniversity of LeedsLeedsUK,NIHR Leeds Biomedical Research CentreLeeds Teaching Hospitals NHS TrustLeedsUK
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Müller F, Lugli A, Dawson H. [Tumor budding in colorectal cancer-Information for clinical use and instructions for practical evaluation]. DER PATHOLOGE 2022; 43:45-50. [PMID: 34724116 PMCID: PMC8789725 DOI: 10.1007/s00292-021-01016-6] [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] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND Some patients with high-risk colorectal cancer show a worse prognosis within the same UICC stage. Therefore, the identification of additional risk factors is necessary to find the best treatment for these patients. OBJECTIVE In which settings can tumor budding help the clinical decision-making process for treatment planning and how should scoring be performed? MATERIAL AND METHODS Evaluation of current publications on tumor budding with an emphasis on practical grading and potential problems in the determination of tumor budding. RESULTS Tumor budding is a significant risk factor for worse clinical outcome of colorectal cancer and can influence clinical decision-making in pT1 and stage II colorectal cancer. A scoring method was standardized by the ITBCC 2016 and is feasible in everyday practice. Challenges in assessment can be addressed by increasing awareness of potential problem cases.
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Affiliation(s)
- Felix Müller
- Institut für Pathologie, Universität Bern, Murtenstraße 31, 3008, Bern, Schweiz.
| | - Alessandro Lugli
- Institut für Pathologie, Universität Bern, Murtenstraße 31, 3008, Bern, Schweiz
| | - Heather Dawson
- Institut für Pathologie, Universität Bern, Murtenstraße 31, 3008, Bern, Schweiz
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Fisher NC, Loughrey MB, Coleman HG, Gelbard MD, Bankhead P, Dunne PD. Development of a semi-automated method for tumour budding assessment in colorectal cancer and comparison with manual methods. Histopathology 2022; 80:485-500. [PMID: 34580909 DOI: 10.1111/his.14574] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/07/2021] [Accepted: 09/25/2021] [Indexed: 12/17/2022]
Abstract
AIMS Tumour budding (TB) is an established prognostic feature in multiple cancers but is not routinely assessed in pathology practice. Efforts to standardise and automate assessment have shifted from haematoxylin and eosin (H&E)-stained images towards cytokeratin immunohistochemistry. The aim of this study was to compare manual H&E and cytokeratin assessment methods with a semi-automated approach built within QuPath open-source software. METHODS AND RESULTS TB was assessed in cores from the advancing tumour edge in a cohort of stage II/III colon cancers (n = 186). The total numbers of buds detected with each method were as follows: manual H&E, n = 503; manual cytokeratin, n = 2290; and semi-automated, n = 5138. More than four times the number of buds were identified manually with cytokeratin assessment than with H&E assessment. One thousand seven hundred and thirty-four individual buds were identified with both manual and semi-automated assessments applied to cytokeratin images, representing 75.7% of the buds identified manually (n = 2290) and 33.7% of the buds detected with the semi-automated method (n = 5138). Higher semi-automated TB scores were due to any discrete area of cytokeratin immunopositivity within an accepted area range being identified as a bud, regardless of shape or crispness of definition, and to the inclusion of tumour cell clusters within glandular lumina ('luminal pseudobuds'). Although absolute numbers differed, semi-automated and manual bud counts were strongly correlated across cores (ρ = 0.81, P < 0.0001). All methods of TB assessment demonstrated poorer survival associated with higher TB scores. CONCLUSIONS We present a new QuPath-based approach to TB assessment, which compares favourably with established methods and offers a freely available, rapid and transparent tool that is also applicable to whole slide images.
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Affiliation(s)
- Natalie C Fisher
- The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Maurice B Loughrey
- The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
- Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - Helen G Coleman
- The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | | | - Peter Bankhead
- Edinburgh Pathology, Edinburgh, UK
- Centre for Genomic & Experimental Medicine, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Philip D Dunne
- The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
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Barresi V. Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches. Biomedicines 2021; 9:biomedicines9121858. [PMID: 34944674 PMCID: PMC8698346 DOI: 10.3390/biomedicines9121858] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 12/03/2021] [Indexed: 11/26/2022] Open
Affiliation(s)
- Valeria Barresi
- Dipartimento di Diagnostica e Sanità Pubblica, Sezione di Anatomia Patologica, Università di Verona, 37134 Verona, Italy
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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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