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Thomas CE, Takashima Y, Wesselink E, Ugai T, Steinfelder RS, Buchanan DD, Qu C, Hsu L, Dias Costa A, Gallinger S, Grant RC, Huyghe JR, Thomas SS, Ogino S, Phipps AI, Nowak JA, Peters U. Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors. Front Immunol 2024; 15:1505896. [PMID: 39763680 PMCID: PMC11701007 DOI: 10.3389/fimmu.2024.1505896] [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: 10/03/2024] [Accepted: 12/03/2024] [Indexed: 01/11/2025] Open
Abstract
Background Microsatellite instability-high (MSI-high) tumors comprise ~15% of sporadic colorectal cancers (CRC) and are associated with elevated T cell infiltration. However, the universality of this response across T cell subtypes with distinct functions is unknown. Methods Including 1,236 CRC tumors from three observational studies, we conducted in-situ T cell profiling using a customized 9-plex (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT, MKI67, and DAPI) multispectral immunofluorescence assay. MSI status was assessed through polymerase chain reaction or immunohistochemical assays. We used multivariable ordinal logistic regression to estimate odds ratios (OR per increasing quantile) and 95% confidence intervals (CIs) for the association of MSI status with quantiles of T cell densities in either tumor epithelial or stromal tissue areas. Results Compared to microsatellite instability low or microsatellite stable (MSI-low/MSS) tumors, MSI-high status was associated with higher density for the majority of immune subsets (twelve out of eighteen) in both epithelial and stromal tissue areas. The strongest associations were for CD3+CD8+ T cells in epithelial areas [OR (95% CI) for naive, memory, and regulatory subsets = 3.49 (2.57, 4.75); 2.82 (2.10, 3.78); 3.04 (2.24, 4.13), respectively]. Conversely, stromal area CD3+CD4+ memory T cells were inversely associated [OR (95% CI) = 0.68 (0.51, 0.91)]. Discussion MSI-high status was strongly associated with higher densities of most T cell subsets in both epithelial and stromal tissue areas. Our investigation supports efforts to identify patients who may be more likely to respond to current immunotherapy treatments. Significance This study helps us better understand how a clinically relevant tumor phenotype, microsatellite instability status, is related to different functioning T cell densities in colorectal tumors, which may impact future immunotherapy strategies.
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Affiliation(s)
- Claire E. Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Yasutoshi Takashima
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Evertine Wesselink
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, Netherlands
| | - Tomotaka Ugai
- Program in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- Cancer Epidemiology Program, Dana-Farber/Harvard Cancer Center, Boston, MA, United States
| | - Robert S. Steinfelder
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia
- University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, VIC, Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Department of Biostatistics, University of Washington, Seattle, WA, United States
| | - Andressa Dias Costa
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States
| | - Steven Gallinger
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Robert C. Grant
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Sushma S. Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Shuji Ogino
- Program in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Institute of Science Tokyo, Tokyo, Japan
| | - Amanda I. Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Department of Epidemiology, University of Washington, Seattle, WA, United States
| | - Jonathan A. Nowak
- Program in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Department of Epidemiology, University of Washington, Seattle, WA, United States
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Sowter P, Gallon R, Hayes C, Phelps R, Borthwick G, Prior S, Combe J, Buist H, Pearlman R, Hampel H, Goodfellow P, Evans DG, Crosbie EJ, Ryan N, Burn J, Santibanez-Koref M, Jackson MS. Detection of Mismatch Repair Deficiency in Endometrial Cancer: Assessment of IHC, Fragment Length Analysis, and Amplicon Sequencing Based MSI Testing. Cancers (Basel) 2024; 16:3970. [PMID: 39682157 DOI: 10.3390/cancers16233970] [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: 10/04/2024] [Revised: 11/07/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
Background/Objectives: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors. Colorectal cancers (CRCs) and endometrial cancers (ECs) are routinely screened to identify LS, primarily using immunohistochemistry (IHC) or microsatellite instability (MSI) testing, but concordance between these methods is variable in ECs. Here, we investigate this variability in 361 ECs from the Ohio OCCPI/OPTEC (n = 196) and Manchester PETALS (n = 165) trials, where concordance between assays differed significantly. Methods: Samples were re-tested using the amplicon-sequencing-based Newcastle MSI assay (NCL_MSI), and analysed with respect to existing IHC, MSI and MLH1 promoter hypermethylation data. Results: NCL_MSI showed consistency with the Ohio results (94% and 97% concordance with IHC and original MSI assays, respectively) and increased concordance within the Manchester cohort from 78% to 86% (MSI) and 84% (IHC). Among discordant Manchester samples, NCL_MSI was significantly associated with MLH1 promoter methylation status (p = 0.0028) and had the highest concordance with methylation, (62/69 samples, 90%), indicating utility as a screening tool in this tumour type. However, tumours with germline MSH6 defects were only detected efficiently with IHC; seven out of eight LS tumours classified as MSS by either MSI assay had isolated MSH6 loss, compared to four out of twelve classified as MSI-H by both (p = 0.028). Furthermore, reduced MSI signal was observed in tumours with isolated MSH6 loss (p = 0.009 Ohio, p = 6.2 × 10-5 Manchester) and in both ECs and CRCs with germline defects, although this only reached significance in CRCs (p = 0.002). Conclusions: These results provide further evidence that ECs with MSH6 loss in particular and LS tumours in general have an attenuated MSI signal, providing support for current guidelines specifically recommending IHC for LS detection and immune checkpoint therapy assessment in EC.
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Affiliation(s)
- Peter Sowter
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Richard Gallon
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Christine Hayes
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Rachel Phelps
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Gillian Borthwick
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Shaun Prior
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Jenny Combe
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Holly Buist
- Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
| | - Rachel Pearlman
- Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Heather Hampel
- Department of Internal Medicine, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Paul Goodfellow
- Department of Obstetrics and Gynecology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - D Gareth Evans
- Division of Evolution Infection and Genomic Science, University of Manchester, Manchester M13 9PL, UK
| | - Emma J Crosbie
- Division of Gynaecology, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
- Division of Cancer Sciences, St Mary's Hospital, University of Manchester, Manchester M13 9WL, UK
| | - Neil Ryan
- College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16 4SB, UK
| | - John Burn
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
- Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
| | | | - Michael S Jackson
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
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Jun SY, An S, Hong SM, Kim JY, Kim KP. Prognostic value of tumor-infiltrating lymphocytes in distal extrahepatic bile duct carcinoma. ESMO Open 2024; 9:103969. [PMID: 39510021 PMCID: PMC11575191 DOI: 10.1016/j.esmoop.2024.103969] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/09/2024] [Accepted: 09/27/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND The assessment of tumor-infiltrating lymphocytes (TILs) has led to the development of various immunotherapies beyond their predictive potential in gastrointestinal malignancies. However, the clinicopathologic and prognostic values of TILs have yet to be well elucidated in distal extrahepatic bile duct carcinoma (DBDC). PATIENTS AND METHODS We evaluated stromal TILs (sTILs) and intraepithelial TILs (iTILs) in 405 surgically resected DBDCs to analyze their correlations with overall survival (OS) and recurrence-free survival (RFS) and with clinicopathologic parameters according to the eighth edition of the American Joint Committee on Cancer scheme. RESULTS High levels of sTIL density (sTILHigh; >5%) and iTIL count (iTILHigh; >3) were found in 245 (61%) and 74 cases (18%), respectively. sTILHigh was more commonly found in larger tumors (P = 0.048) diffusely involving both intra- and extrapancreatic bile ducts (P = 0.013), in tumors with lower T category (P = 0.002), and in tumors without pancreatic (P = 0.003) or duodenal invasion (P < 0.001). iTILHigh was associated with tumors with papillary or nodular growth pattern (P < 0.001) without perineural invasion (P = 0.006). Both sTILHigh and iTILHigh significantly predicted better OS (P = 0.009 and 0.036, respectively) and RFS (P = 0.003 and 0.026, respectively). sTIL consistently provided prognostic predictability in OS, even when tested with different quantitative cut-offs and prognostically stratified OS (P = 0.006) and RFS (P = 0.005) on multivariate analysis. The survival benefit of sTILHigh persisted regardless of the stage in both OS (P = 0.010 for lower stages I and II and P = 0.001 for higher stages III and IV) and RFS (P = 0.004 and 0.025 for lower- and higher-stage tumors, respectively). CONCLUSIONS sTILs were superior to iTILs in predicting survival, and it was shown to be a strong prognosticator for DBDC patients regardless of the stage. The utility of sTILs may extend beyond prognostication to aid in predicting therapeutic responses in DBDC patients.
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Affiliation(s)
- S-Y Jun
- Department of Pathology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul.
| | - S An
- Department of Pathology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul
| | - S-M Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - J-Y Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul
| | - K-P Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Wu YW, Wei LJ, Yang X, Liang HY, Cai MY, Luo RZ, Liu LL. Clinicopathological and immune characterization of mismatch repair deficient endocervical adenocarcinoma. Oncologist 2024; 29:e1302-e1314. [PMID: 39110901 PMCID: PMC11448880 DOI: 10.1093/oncolo/oyae192] [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: 11/22/2023] [Accepted: 05/23/2024] [Indexed: 10/05/2024] Open
Abstract
Endocervical adenocarcinoma (ECA) is reported increasingly often in young women, and this aggressive disease lacks effective methods of targeted therapy. Since mismatch repair deficiency (dMMR) is an important biomarker for predicting response to immune checkpoint inhibitors, it is important to investigate the clinicopathological features and immune microenvironment of dMMR ECAs. We assessed 617 ECAs from representative tissue microarray sections, gathered clinicopathologic information, reviewed histological characteristics, and performed immunohistochemical staining for MMR, programmed cell death 1 (PD-L1), and other immune markers. Of 617 ECA samples, 20 (3.2%) cases had dMMR. Among them, loss of MMR-related proteins expression was observed in 17/562 (3.0%) human papilloma virus-associated (HPVA) adenocarcinoma and 3/55 (5.5%) non-HPV-associated (NHPVA) adenocarcinoma. In NHPVA cohort, dMMR status was observed in 3 (3/14, 15.0%) patients with clear cells. dMMR ECAs had a higher tendency to have a family history of cancer, larger tumor size, p16 negative, HPV E6/E7 mRNA in situ hybridization (HPV E6/E7 RNAscope) negative, and lower ki-67 index. Among the morphological variables evaluated, poor differentiation, necrosis, stromal tumor-infiltrating lymphocytes, peritumoral lymphocytes, and lymphoid follicles were easily recognized in the dMMR ECAs. In addition, dMMR ECAs had higher CD3+, CD8+, CD38+, CD68+ and PD-1+ immune cells. A relatively high prevalence of PD-L1 expression was observed in dMMR ECAs. dMMR ECAs were significantly more likely to present with a tumor-infiltrating lymphocytes -high/PD-L1-positive status. In conclusion, dMMR ECAs have some specific morphological features and a critical impact on the immune microenvironment, which may provide insights into improving responses to immunotherapy-included comprehensive treatment for ECAs in the future.
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Affiliation(s)
- Ying-Wen Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China
- Department of Pathology, Guangdong Sanjiu Brain Hospital, Guangzhou, People’s Republic of China
| | - Li-Jun Wei
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China
| | - Xia Yang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China
| | - Hao-Yu Liang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China
| | - Mu-Yan Cai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China
| | - Rong-Zhen Luo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China
| | - Li-Li Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China
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Pavelescu LA, Enache RM, Roşu OA, Profir M, Creţoiu SM, Gaspar BS. Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors. Int J Mol Sci 2024; 25:9659. [PMID: 39273605 PMCID: PMC11395316 DOI: 10.3390/ijms25179659] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
Predictive biomarkers for immune checkpoint inhibitors (ICIs) in solid tumors such as melanoma, hepatocellular carcinoma (HCC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial carcinoma, renal cell carcinoma (RCC), or urothelial carcinoma (UC) include programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), defective deoxyribonucleic acid (DNA) mismatch repair (dMMR), microsatellite instability (MSI), and the tumor microenvironment (TME). Over the past decade, several types of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, anti-programmed cell death 1 (PD-1) antibodies, anti-programmed cell death ligand 1 (PD-L1) antibodies, and anti-lymphocyte activation gene-3 (LAG-3) antibodies have been studied and approved by the Food and Drug Administration (FDA), with ongoing research on others. Recent studies highlight the critical role of the gut microbiome in influencing a positive therapeutic response to ICIs, emphasizing the importance of modeling factors that can maintain a healthy microbiome. However, resistance mechanisms can emerge, such as increased expression of alternative immune checkpoints, T-cell immunoglobulin (Ig), mucin domain-containing protein 3 (TIM-3), LAG-3, impaired antigen presentation, and alterations in the TME. This review aims to synthesize the data regarding the interactions between microbiota and immunotherapy (IT). Understanding these mechanisms is essential for optimizing ICI therapy and developing effective combination strategies.
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Affiliation(s)
- Luciana Alexandra Pavelescu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Robert Mihai Enache
- Department of Radiology and Medical Imaging, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Oana Alexandra Roşu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania
| | - Monica Profir
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania
| | - Sanda Maria Creţoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Bogdan Severus Gaspar
- Department of Surgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Surgery Clinic, Bucharest Emergency Clinical Hospital, 014461 Bucharest, Romania
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Nobin H, Garvin S, Hagman H, Nodin B, Jirström K, Brunnström H. The prognostic value of programmed death-ligand 1 (PD-L1) expression in resected colorectal cancer without neoadjuvant therapy - differences between antibody clones and cell types. BMC Cancer 2024; 24:1051. [PMID: 39187798 PMCID: PMC11346183 DOI: 10.1186/s12885-024-12812-7] [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: 06/14/2024] [Accepted: 08/14/2024] [Indexed: 08/28/2024] Open
Abstract
BACKGROUND Programmed death-ligand 1 (PD-L1) expression on tumor cells is associated with poor prognosis in several malignancies, while partly contradictory and inconclusive results have been presented for colorectal cancer (CRC). This study aimed to evaluate PD-L1 as a prognostic biomarker in CRC by comparing three different antibody clones. METHODS Patients surgically treated for CRC between January 1st, 2007, and December 31st, 2015, in Kalmar County, Sweden, were retrospectively included. Tissue microarrays from 862 primary tumors without neoadjuvant treatment were assessed for immunohistochemical expression of PD-L1 in tumor cells (TC) and immune cells (IC) using clones 73-10, SP263, and 22C3. Cox regression proportional hazard models were used to estimate hazard ratios for overall survival (OS) and disease-free interval (DFI) in univariable and multivariable analyses, with 1% and 5% set as cut-offs for positive expression in TC and IC respectively. RESULTS PD-L1 expression in TC was found in 89 (10%) cases for clone 73-10, 76 (9%) for clone SP263, and 38 (4%) for clone 22C3, while the numbers for IC were 317 (37%) cases for clone 73-10, 264 (31%) for clone SP263, and 89 (10%) for clone 22C3. PD-L1 expression in IC was associated with prolonged OS and DFI in univariable analysis for all three clones. The link to prolonged DFI remained in multivariable analysis for 73-10 and SP263, but only for 73-10 regarding OS. PD-L1 expression in TC was not prognostic of OS in any analysis, while it was associated with prolonged DFI for SP263, and a trend was seen for 73-10. The link to prolonged DFI remained for SP263 and was strengthened for 73-10 in multivariable analysis. CONCLUSIONS The prognostic value of PD-L1 expression in both IC and TC differs between antibody clones, with 73-10 and SP263 being more reliable for prognostic information than 22C3 in resected CRC.
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Affiliation(s)
- Hampus Nobin
- Department of Pathology, Region Kalmar, Kalmar County Hospital, Kalmar, Sweden.
- Department of Clinical Sciences Lund, Division of Pathology, Lund University, Lund, Sweden.
| | - Stina Garvin
- Department of Clinical Pathology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Helga Hagman
- Department of Clinical Sciences Lund, Division of Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Björn Nodin
- Department of Clinical Sciences Lund, Division of Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
| | - Karin Jirström
- Department of Clinical Sciences Lund, Division of Oncology and Therapeutic Pathology, Lund University, Lund, Sweden
- Department of Genetics, Pathology, and Molecular Diagnostics, Regional University Laboratories, Skåne University Hospital, Lund, Sweden
| | - Hans Brunnström
- Department of Clinical Sciences Lund, Division of Pathology, Lund University, Lund, Sweden
- Department of Genetics, Pathology, and Molecular Diagnostics, Regional University Laboratories, Skåne University Hospital, Lund, Sweden
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Baranov E, Nowak JA. Pathologic Evaluation of Therapeutic Biomarkers in Colorectal Adenocarcinoma. Surg Pathol Clin 2023; 16:635-650. [PMID: 37863556 DOI: 10.1016/j.path.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2023]
Abstract
Molecular testing is an essential component of the pathologic evaluation of colorectal carcinoma providing diagnostic, prognostic, and predictive therapeutic information. Mismatch repair status evaluation is required for all tumors. Advanced and metastatic tumors also require determination of tumor mutational burden, KRAS, NRAS, and BRAF mutation status, ERBB2 amplification status, and NTRK and RET gene rearrangement status to guide therapy. Multiple assays, including immunohistochemistry, microsatellite instability testing, MLH1 promoter methylation, and next-generation sequencing, are typically needed. Pathologists must be aware of these requirements to optimally triage tissue. Advances in colorectal cancer molecular diagnostics will continue to drive refinements in colorectal cancer personalized therapy.
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Affiliation(s)
- Esther Baranov
- Department of Pathology, Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Jonathan A Nowak
- Department of Pathology, Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
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Song Y, Kerr TD, Sanders C, Dai L, Baxter SS, Somerville B, Baugher RN, Mellott SD, Young TB, Lawhorn HE, Plona TM, Xu B, Wei L, Hu Q, Liu S, Hutson A, Karim B, Burkett S, Difilippantonio S, Pinto L, Gebert J, Kloor M, Lipkin SM, Sei S, Shoemaker RH. Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer. Front Oncol 2023; 13:1223915. [PMID: 37746286 PMCID: PMC10516605 DOI: 10.3389/fonc.2023.1223915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Background Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed. Methods To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization. Results The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node. Conclusions The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.
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Affiliation(s)
- Yurong Song
- Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United States
| | - Travis D. Kerr
- Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United States
| | - Chelsea Sanders
- Frederick National Laboratory for Cancer Research, Laboratory Animal Sciences Program, Frederick, MD, United States
| | - Lisheng Dai
- Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United States
| | - Shaneen S. Baxter
- Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United States
| | - Brandon Somerville
- Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United States
| | - Ryan N. Baugher
- Frederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United States
| | - Stephanie D. Mellott
- Frederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United States
| | - Todd B. Young
- Frederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United States
| | - Heidi E. Lawhorn
- Frederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United States
| | - Teri M. Plona
- Frederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United States
| | - Bingfang Xu
- Frederick National Laboratory for Cancer Research, Genomics Laboratory, Frederick, MD, United States
| | - Lei Wei
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Qiang Hu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Alan Hutson
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Baktiar Karim
- Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Sandra Burkett
- Molecular Cytogenetics Core Facility, National Cancer Institute, Frederick, MD, United States
| | - Simone Difilippantonio
- Frederick National Laboratory for Cancer Research, Laboratory Animal Sciences Program, Frederick, MD, United States
| | - Ligia Pinto
- Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United States
| | - Johannes Gebert
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Steven M. Lipkin
- Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, United States
| | - Shizuko Sei
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, United States
| | - Robert H. Shoemaker
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, United States
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9
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Kaczmarzyk JR, Gupta R, Kurc TM, Abousamra S, Saltz JH, Koo PK. ChampKit: A framework for rapid evaluation of deep neural networks for patch-based histopathology classification. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2023; 239:107631. [PMID: 37271050 PMCID: PMC11093625 DOI: 10.1016/j.cmpb.2023.107631] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 04/23/2023] [Accepted: 05/28/2023] [Indexed: 06/06/2023]
Abstract
BACKGROUND AND OBJECTIVE Histopathology is the gold standard for diagnosis of many cancers. Recent advances in computer vision, specifically deep learning, have facilitated the analysis of histopathology images for many tasks, including the detection of immune cells and microsatellite instability. However, it remains difficult to identify optimal models and training configurations for different histopathology classification tasks due to the abundance of available architectures and the lack of systematic evaluations. Our objective in this work is to present a software tool that addresses this need and enables robust, systematic evaluation of neural network models for patch classification in histology in a light-weight, easy-to-use package for both algorithm developers and biomedical researchers. METHODS Here we present ChampKit (Comprehensive Histopathology Assessment of Model Predictions toolKit): an extensible, fully reproducible evaluation toolkit that is a one-stop-shop to train and evaluate deep neural networks for patch classification. ChampKit curates a broad range of public datasets. It enables training and evaluation of models supported by timm directly from the command line, without the need for users to write any code. External models are enabled through a straightforward API and minimal coding. As a result, Champkit facilitates the evaluation of existing and new models and deep learning architectures on pathology datasets, making it more accessible to the broader scientific community. To demonstrate the utility of ChampKit, we establish baseline performance for a subset of possible models that could be employed with ChampKit, focusing on several popular deep learning models, namely ResNet18, ResNet50, and R26-ViT, a hybrid vision transformer. In addition, we compare each model trained either from random weight initialization or with transfer learning from ImageNet pretrained models. For ResNet18, we also consider transfer learning from a self-supervised pretrained model. RESULTS The main result of this paper is the ChampKit software. Using ChampKit, we were able to systemically evaluate multiple neural networks across six datasets. We observed mixed results when evaluating the benefits of pretraining versus random intialization, with no clear benefit except in the low data regime, where transfer learning was found to be beneficial. Surprisingly, we found that transfer learning from self-supervised weights rarely improved performance, which is counter to other areas of computer vision. CONCLUSIONS Choosing the right model for a given digital pathology dataset is nontrivial. ChampKit provides a valuable tool to fill this gap by enabling the evaluation of hundreds of existing (or user-defined) deep learning models across a variety of pathology tasks. Source code and data for the tool are freely accessible at https://github.com/SBU-BMI/champkit.
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Affiliation(s)
- Jakub R Kaczmarzyk
- Department of Biomedical Informatics, Stony Brook Medicine, 101 Nicolls Rd, Stony Brook, 11794, NY, USA; Simons Center for Quantitative Biology, 1 Bungtown Rd, Cold Spring Harbor, 11724, NY, USA.
| | - Rajarsi Gupta
- Department of Biomedical Informatics, Stony Brook Medicine, 101 Nicolls Rd, Stony Brook, 11794, NY, USA
| | - Tahsin M Kurc
- Department of Biomedical Informatics, Stony Brook Medicine, 101 Nicolls Rd, Stony Brook, 11794, NY, USA
| | - Shahira Abousamra
- Department of Computer Science, Stony Brook University, Stony Brook, NY, USA
| | - Joel H Saltz
- Department of Biomedical Informatics, Stony Brook Medicine, 101 Nicolls Rd, Stony Brook, 11794, NY, USA.
| | - Peter K Koo
- Simons Center for Quantitative Biology, 1 Bungtown Rd, Cold Spring Harbor, 11724, NY, USA.
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10
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van der Werf-'t Lam AS, Terlouw D, Tops CM, van Kan MS, van Hest LP, Gille HJP, Duijkers FAM, Wagner A, Eikenboom EL, Letteboer TGW, de Jong MM, Bajwa-Ten Broeke SW, Bleeker FE, Gomez Garcia EB, de Wind N, van Wezel JT, Morreau H, Suerink M, Nielsen M. Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers. Mod Pathol 2023; 36:100240. [PMID: 37307877 DOI: 10.1016/j.modpat.2023.100240] [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: 12/01/2022] [Revised: 05/05/2023] [Accepted: 06/06/2023] [Indexed: 06/14/2023]
Abstract
Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.
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Affiliation(s)
| | - Diantha Terlouw
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Carli M Tops
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Merel S van Kan
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Liselotte P van Hest
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Hans J P Gille
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Floor A M Duijkers
- Department of Clinical Genetics, Amsterdam Medical Center, Amsterdam, The Netherlands
| | - Anja Wagner
- Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Ellis L Eikenboom
- Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Tom G W Letteboer
- Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mirjam M de Jong
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sanne W Bajwa-Ten Broeke
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Fonnet E Bleeker
- Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Encarna B Gomez Garcia
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Niels de Wind
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - J Tom van Wezel
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Hans Morreau
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Manon Suerink
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
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11
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Arai T, Komatsu A, Kanazawa N, Nonaka K, Ishiwata T. Clinicopathological and molecular characteristics of gastric papillary adenocarcinoma. Pathol Int 2023; 73:358-366. [PMID: 37341602 DOI: 10.1111/pin.13345] [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: 11/23/2022] [Accepted: 05/25/2023] [Indexed: 06/22/2023]
Abstract
Papillary adenocarcinoma is defined as carcinoma with a well-defined papillary or villous structure. Despite sharing clinicopathological and morphological features with tubular adenocarcinomas, papillary adenocarcinomas frequently show microsatellite instability. The present study aimed to clarify the clinicopathological features, molecular classification, and programmed death-ligand 1 (PD-L1) expression characteristics of papillary adenocarcinoma, especially tumors with microsatellite instability. We examined the microsatellite status and expression of mucin core proteins and PD-L1 as well as the clinicopathological features in 40 gastric papillary adenocarcinomas. Surrogate immunohistochemical analysis of p53 and mismatch repair proteins along with Epstein-Barr virus-encoded RNA in situ hybridization were performed for molecular classification. Female predominance and frequent microsatellite instability were observed in papillary adenocarcinoma in comparison with tubular adenocarcinoma. The presence of microsatellite instability in papillary adenocarcinoma was significantly correlated with older age, tumor-infiltrating lymphocytes, and Crohn's-like lymphoid reactions. Surrogate examination demonstrated that the genomically stable type (17 cases, 42.5%) was the most common, followed by the microsatellite-unstable type (14 cases, 35%). Among the seven cases showing PD-L1-positive expression in tumor cells, four involved carcinomas with microsatellite instability. These results reveal the clinicopathological and molecular characteristics of gastric papillary adenocarcinoma.
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Affiliation(s)
- Tomio Arai
- Department of Pathology, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
| | - Akiko Komatsu
- Department of Pathology, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
| | - Nobuo Kanazawa
- Department of Surgery, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
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12
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Greco L, Rubbino F, Dal Buono A, Laghi L. Microsatellite Instability and Immune Response: From Microenvironment Features to Therapeutic Actionability-Lessons from Colorectal Cancer. Genes (Basel) 2023; 14:1169. [PMID: 37372349 DOI: 10.3390/genes14061169] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Microsatellite instability (MSI) can be found in 15-20% of all colorectal cancers (CRC) and is the key feature of a defective DNA mismatch repair (MMR) system. Currently, MSI has been established as a unique and pivotal biomarker in the diagnosis, prognosis, and treatment of CRC. MSI tumors display a strong lymphocytic activation and a shift toward a tumoral microenvironment restraining metastatic potential and ensuing in a high responsiveness to immunotherapy of MSI CRC. Indeed, neoplastic cells with an MMR defect overexpress several immune checkpoint proteins, such as programmed death-1 (PD-1) and programmed death-ligand 1(PD-L1), that can be pharmacologically targeted, allowing for the revival the cytotoxic immune response toward the tumor. This review aims to illustrate the role of MSI in the tumor biology of colorectal cancer, focusing on the immune interactions with the microenvironment and their therapeutic implications.
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Affiliation(s)
- Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Arianna Dal Buono
- Division of Gastroenterology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
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13
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Kobayashi T, Matsui Y, Miki H, Hatta M, Ishida M, Satake H, Sekimoto M. Case report: administration of immune checkpoint inhibitor for SMARCB1 (INI1)-negative rhabdoid carcinoma with microsatellite instability (MSI)-high in the right colon. Surg Case Rep 2023; 9:17. [PMID: 36732357 PMCID: PMC9895154 DOI: 10.1186/s40792-023-01594-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 01/22/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Malignant tumors with rhabdoid features are rare, highly aggressive, and some of them are characterized by SMARCB1 (INI1) loss. Although cases of rhabdoid carcinoma are extremely rare, its occurrence in the colon has been reported previously. CASE PRESENTATION A 71-year-old Japanese female patient presented with loss of appetite, fatigue, and weight loss. Computed tomography demonstrated a tumor in the right colon that infiltrated the surrounding kidneys and swelling of the left supraclavicular and periaortic lymph nodes. Laparotomy revealed that the tumor was unresectable because it had directly invaded the head of the pancreas and duodenum. Therefore, ileocecal vascularized bulky lymph nodes were sampled, and gastrojejunostomy with Braun's anastomosis and ileotransversostomy were performed as palliative procedures. Histopathological examination of the lymph nodes revealed that the neoplastic cells had rich eosinophilic cytoplasm and eccentrically located large nuclei characteristic of rhabdoid carcinoma. In addition, these neoplastic cells lacked SMARCB1 expression; therefore, the patient was diagnosed with SMARCB1-negative rhabdoid carcinoma. The postoperative course was uneventful. Molecular analysis confirmed that the neoplastic cells had high microsatellite instability (MSI); therefore, two cycles of pembrolizumab were administered. However, no clinical benefit was noted, and the patient died 3 months postoperatively. CONCLUSION This is the first report of a case of SMARCB1-negative rhabdoid colon carcinoma with high MSI treated with pembrolizumab. Rhabdoid carcinoma is highly aggressive; therefore, additional studies are required to determine the therapeutic strategy for SMARCB1-negative rhabdoid colorectal carcinoma.
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Affiliation(s)
- Toshinori Kobayashi
- grid.410783.90000 0001 2172 5041Department of Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010 Japan
| | - Yuki Matsui
- grid.410783.90000 0001 2172 5041Department of Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010 Japan
| | - Hisanori Miki
- grid.410783.90000 0001 2172 5041Department of Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010 Japan
| | - Masahiko Hatta
- grid.410783.90000 0001 2172 5041Department of Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010 Japan
| | - Mitsuaki Ishida
- grid.410783.90000 0001 2172 5041Department of Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010 Japan ,Department of Pathology, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-Machi, Takatsuki, Osaka 569-8686 Japan
| | - Hironaga Satake
- grid.410783.90000 0001 2172 5041Department of Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010 Japan ,grid.278276.e0000 0001 0659 9825Department of Medical Oncology, Kochi Medical School, Nankoku, 7838505 Japan
| | - Mitsugu Sekimoto
- grid.410783.90000 0001 2172 5041Department of Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010 Japan
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14
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Luchini C, Scarpa A. Microsatellite instability in pancreatic and ampullary carcinomas: histology, molecular pathology, and clinical implications. Hum Pathol 2023; 132:176-182. [PMID: 35714836 DOI: 10.1016/j.humpath.2022.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 06/08/2022] [Indexed: 02/07/2023]
Abstract
Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) represents an important molecular alteration with diagnostic, prognostic, and predictive value. The increasing interest toward this genetic alteration is given to the high response rate of MSI/dMMR tumors to immunotherapy. There are different cancers in the periampullary region that can harbor MSI/dMMR, and significant morphological-molecular correlates should be acknowledged in this district: (1) pancreatic ductal adenocarcinoma (PDAC): in this tumor category, the prevalence of MSI/dMMR is about 1-2%, and medullary and colloid variants are the most typically involved; (2) ampullary adenocarcinoma: here the prevalence of MSI/dMMR is up to 18%, and in this neoplastic group, MSI/dMMR is more commonly found in the intestinal subtype; (3) pancreatic acinar cell carcinoma: here the prevalence of MSI/dMMR is up to 14%; and (4) pancreatic and ampullary neuroendocrine carcinoma: in this tumor category, the prevalence of MSI/dMMR is up to 5-8%, and this molecular alteration should be assessed also in cases of mixed neuroendocrine-non-neuroendocrine neoplasms. Given the clinical importance of MSI/dMMR and its not-negligible prevalence among the different carcinomas arising in this district, its assessment should become part of the routine diagnostic workflow at least for the most typical histotypes. The test of choice is represented by immunohistochemistry for PDAC and ampullary carcinomas, and by direct molecular analyses including MSI-based polymerase chain reaction and next-generation sequencing for acinar cell and neuroendocrine carcinomas.
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Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, 37134, Italy; ARC-Net Research Center for Applied Research on Cancer, University of Verona, Verona, 37134, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, 37134, Italy; ARC-Net Research Center for Applied Research on Cancer, University of Verona, Verona, 37134, Italy.
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15
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Metabolic activity via 18F-FDG PET/CT is predictive of microsatellite instability status in colorectal cancer. BMC Cancer 2022; 22:808. [PMID: 35869469 PMCID: PMC9306059 DOI: 10.1186/s12885-022-09871-z] [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: 08/23/2021] [Accepted: 07/05/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose Identification of microsatellite instability high (MSI-H) colorectal cancer (CRC) is crucial for screening patients most likely to benefit from immunotherapy. We aim to investigate whether the metabolic characteristics is related to MSI status and can be used to predict the MSI-H CRC. Methods A retrospective analysis was conducted on 420 CRC patients who were identified via [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography(CT) prior to therapy. Maximum standardized uptake (SUVmax), mean standardized uptake (SUVmean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of the primary tumor were calculated and compared between MSI-H and microsatellite stability (MSS). Predictive factors of MSI status were selected from metabolic parameters and clinicopathological profiles via a multivariate analysis. Results Of 420 colorectal cancers, 44 exhibited a high incidence of MSI. Both MTV and TLG were significantly higher in MSI-H group compared with the MSS group (P = 0.004 and P = 0.010, respectively). Logistic regression analysis indicated that CRC with MSI-H were related to younger age (P = 0.013), primary lesion located at right hemi-colon (P < 0.001) and larger MTV on PET/CT imaging (P = 0.019). MTV more than 32.19 of colorectal cancer was linked to the presence of MSI (P = 0.019). Conclusion Tumor metabolic burden were higher in MSI-H CRC which may be useful for predicting the MSI status of CRC patient and thus aid in determination of immunotherapy for patients with CRC.
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16
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Hashimoto T, Takayanagi D, Yonemaru J, Naka T, Nagashima K, Yatabe Y, Shida D, Hamamoto R, Kleeman SO, Leedham SJ, Maughan T, Takashima A, Shiraishi K, Sekine S. Clinicopathological and molecular characteristics of RSPO fusion-positive colorectal cancer. Br J Cancer 2022; 127:1043-1050. [PMID: 35715628 PMCID: PMC9470590 DOI: 10.1038/s41416-022-01880-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 05/26/2022] [Accepted: 06/01/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND RSPO fusions that lead to WNT pathway activation are potential therapeutic targets in colorectal cancer (CRC), but their clinicopathological significance remains unclear. METHODS We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription-PCR. The RSPO fusion-positive tumours were subjected to whole-exome sequencing (WES). RESULTS Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of five with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 women and 12 men. Thirteen tumours (45%) were right-sided. Histologically, approximately half of the tumours (13/29, 45%) had a focal or extensive mucinous component that was significantly more frequent than the RSPO fusion-negative tumours (13%; P = 8.1 × 10-7). Four tumours (14%) were mismatch repair-deficient. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 tumours (93%). In contrast, pathogenic mutations in major WNT pathway genes, such as APC, CTNNB1 and RNF43, were absent. RSPO fusion status did not have a statistically significant influence on the overall or recurrence-free survival. These clinicopathological and genetic features were also confirmed in a pooled analysis of previous studies. CONCLUSION RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features.
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Affiliation(s)
- Taiki Hashimoto
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Daisuke Takayanagi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Junpei Yonemaru
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Tomoaki Naka
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Kengo Nagashima
- Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan
| | - Yasushi Yatabe
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Dai Shida
- Division of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
- Division of Frontier Surgery, The Institute of Medical Science, Tokyo, Japan
| | - Ryuji Hamamoto
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
| | | | - Simon J Leedham
- Intestinal Stem Cell Biology Lab, Welcome Trust Centre Human Genetics, University of Oxford, Oxford, UK
| | | | - Atsuo Takashima
- Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Shigeki Sekine
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
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17
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Bohaumilitzky L, Kluck K, Hüneburg R, Gallon R, Nattermann J, Kirchner M, Kristiansen G, Hommerding O, Pfuderer PL, Wagner L, Echterdiek F, Kösegi S, Müller N, Fischer K, Nelius N, Hartog B, Borthwick G, Busch E, Haag GM, Bläker H, Möslein G, von Knebel Doeberitz M, Seppälä TT, Ahtiainen M, Mecklin JP, Bishop DT, Burn J, Stenzinger A, Budczies J, Kloor M, Ahadova A. The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients. Gastroenterology 2022; 162:907-919.e10. [PMID: 34863788 DOI: 10.1053/j.gastro.2021.11.029] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 11/02/2021] [Accepted: 11/22/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Owing to the high load of immunogenic frameshift neoantigens, tumors arising in individuals with Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, are characterized by a pronounced immune infiltration. However, the immune status of normal colorectal mucosa in LS is not well characterized. We assessed the immune infiltrate in tumor-distant normal colorectal mucosa from LS CRC patients, sporadic microsatellite-unstable (MSI) and microsatellite-stable (MSS) CRC patients, and cancer-free LS carriers. METHODS CD3-positive, FOXP3-positive, and CD8-positive T cells were quantified in, respectively, 219, 233, and 201 formalin-fixed paraffin-embedded (FFPE) normal colonic mucosa tissue sections from CRC patients and cancer-free LS carriers and 26, 22, and 19 LS CRCs. CD3-positive T cells were also quantified in an independent cohort of 97 FFPE normal rectal mucosa tissue sections from LS carriers enrolled in the CAPP2 clinical trial. The expression of 770 immune-relevant genes was analyzed in a subset of samples with the use of the NanoString nCounter platform. RESULTS LS normal mucosa specimens showed significantly elevated CD3-, FOXP3-, and CD8-positive T-cell densities compared with non-LS control specimens. Gene expression profiling and cluster analysis revealed distinct immune profiles in LS carrier mucosa with and without cancer manifestation. Long-term follow-up of LS carriers within the CAPP2 trial found a correlation between mucosal T-cell infiltrate and time to subsequent tumor occurrence. CONCLUSIONS LS carriers show elevated mucosal T-cell infiltration even in the absence of cancer. The normal mucosa immune profile may be a temporary or permanent tumor risk modifier in LS carriers.
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Affiliation(s)
- Lena Bohaumilitzky
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Klaus Kluck
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Robert Hüneburg
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Richard Gallon
- Translational and Clinical Research Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Martina Kirchner
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | | | - Pauline L Pfuderer
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lelia Wagner
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Fabian Echterdiek
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Nephrology, Klinikum Stuttgart-Katharinenhospital, Stuttgart, Germany
| | - Svenja Kösegi
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nico Müller
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Konstantin Fischer
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nina Nelius
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ben Hartog
- Translational and Clinical Research Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom
| | - Gillian Borthwick
- Translational and Clinical Research Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom
| | - Elena Busch
- Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - Georg Martin Haag
- Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - Hendrik Bläker
- Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
| | - Gabriela Möslein
- Department of Surgery, Ev. Krankenhaus Bethesda Hospital, Duisburg, Germany
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Toni T Seppälä
- Department of Gastrointestinal Surgery, Helsinki University Central Hospital, Helsinki, Finland; Applied Tumor Genomics Research Program, University of Helsinki, Helsinki, Finland
| | - Maarit Ahtiainen
- Department of Molecular Pathology, Central Finland Hospital Nova, Jyväskylä, Finland
| | - Jukka-Pekka Mecklin
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland; Department of Surgery, Central Finland Hospital Nova, Jyväskylä, Finland
| | - D Timothy Bishop
- Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - John Burn
- Translational and Clinical Research Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jan Budczies
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Aysel Ahadova
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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18
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Adhikari C, Bandyopadhyay R, Bandyopadhyay U, Sarkar S, Basu K. Mismatch repair protein deficiency assessed by immunohistochemistry in sporadic colorectal carcinoma. INDIAN J PATHOL MICR 2022; 66:252-257. [PMID: 37077064 DOI: 10.4103/ijpm.ijpm_531_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Context Globally, colorectal carcinoma (CRC) ranks the third most commonly diagnosed malignant disease, one of the leading causes of cancer deaths. Aims To study the spectrum of clinicopathological characteristics of sporadic colorectal carcinoma and to assess mismatch repair gene deficiency by the expression pattern of the proteins assessed by immunohistochemistry. Setting and Design Observational study conducted in a tertiary care hospital in West Bengal. Materials and Methods Fifty-two surgically resected specimens of CRC received from January 2018 to May 2019 were studied for clinical, morphological, MSI status. Statistical Analysis Used IBM SPSS 23. Results A total of 50% of the cases belonged to younger and 50% to the older population, with male predominance being 53.8%. The most common histologic type was adenocarcinoma (88.5%). The majority was found to be well-differentiated carcinoma (50%). The majority cases were of the T3 stage accounting to 38.5%. A total of 24 out of 52 cases (46.15%) had an absent expression of at least one mismatch repair (MMR) protein. A significant correlation was found between the young age group and microsatellite instability (MSI) with a P value of 0.001. A significant association was found between MSI and tumor differentiation with P value of 0.018. A significant association was found between MSH6 and histological type with P value of 0.012. A significant association was found between MSI and tumor stage with P value of 0.032. Conclusions This study shows a significantly higher number of sporadic colon cancers involving the young age group, and younger cases showed significant association with MSI. This alarming trend needs validation by studies involving larger populations and can be helpful prognostically as well as in formulating chemotherapeutic regimens.
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Zaborowski AM, Winter DC, Lynch L. The therapeutic and prognostic implications of immunobiology in colorectal cancer: a review. Br J Cancer 2021; 125:1341-1349. [PMID: 34302062 PMCID: PMC8575924 DOI: 10.1038/s41416-021-01475-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/13/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer represents the second leading cause of cancer-related death worldwide. The therapeutic field of immuno-oncology has rapidly gained momentum, with strikingly promising results observed in clinical practice. Increasing emphasis has been placed on the role of the immune response in tumorigenesis, therapy and predicting prognosis. Enhanced understanding of the dynamic and complex tumour-immune microenvironment has enabled the development of molecularly directed, individualised treatment. Analysis of intra-tumoural lymphocyte infiltration and the dichotomisation of colorectal cancer into microsatellite stable and unstable disease has important therapeutic and prognostic implications, with potential to capitalise further on this data. This review discusses the latest evidence surrounding the tumour biology and immune landscape of colorectal cancer, novel immunotherapies and the interaction of the immune system with each apex of the tripartite of cancer management (oncotherapeutics, radiotherapy and surgery). By utilising the synergy of chemotherapeutic agents and immunotherapies, and identifying prognostic and predictive immunological biomarkers, we may enter an era of unprecedented disease control, survivorship and cure rates.
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Affiliation(s)
- Alexandra M. Zaborowski
- grid.412751.40000 0001 0315 8143Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin 4, Ireland ,grid.8217.c0000 0004 1936 9705School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Des C. Winter
- grid.412751.40000 0001 0315 8143Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin 4, Ireland ,grid.7886.10000 0001 0768 2743School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Lydia Lynch
- grid.8217.c0000 0004 1936 9705School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland ,grid.38142.3c000000041936754XHarvard Institutes of Medicine, Harvard Medical School, Boston, MA USA
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20
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Piredda ML, Ammendola S, Sciammarella C, Turri G, Bagante F, Fassan M, Mafficini A, Mombello A, Cataldi S, Paolino G, Mattiolo P, Florena AM, Genna M, Fior F, Cheng L, Lawlor RT, Scarpa A, Pedrazzani C, Luchini C. Colorectal cancer with microsatellite instability: Right-sided location and signet ring cell histology are associated with nodal metastases, and extranodal extension influences disease-free survival. Pathol Res Pract 2021; 224:153519. [PMID: 34119815 DOI: 10.1016/j.prp.2021.153519] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/06/2021] [Accepted: 06/07/2021] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) with microsatellite instability (MSI) accounts for 15-18 % of all CRCs and represents the category with the best prognosis. This study aimed at determining any possible clinical/pathological features associated with a higher risk of nodal metastasization in MSI-CRC, and at defining any possible prognostic moderators in this setting. All surgically resected CRCs of the last 20 years (mono-institutional series) with a PCR-based diagnosis of MSI, with and without nodal metastasis, have been retrieved for histological review, which was performed following WHO guidelines. Furthermore, the most important prognostic moderators have been investigated with a survival analysis. The study of 33 cases of MSI-CRCs with nodal metastasis highlighted a high fidelity of histology maintenance between primary tumors and matched nodal metastases. At survival analysis, the strongest prognostic variable in MSI-CRCs with nodal metastasis was the extranodal extension (multivariate analysis, HR: 14.4, 95 %CI: 1.46-140.9, p = 0.022). Furthermore, through a comparison between nodal positive (33 cases) and nodal negative (71 cases) MSI-CRCs, right-sided location (p < 0.0001), pT4 stage (p = 0.0004) and signet-ring histology (p = 0.0089) emerged as parameters more commonly associated with nodal metastasization. These findings shed new light on the biology of MSI-CRC and can be of help for the prognostic stratification of MSI-CRC patients.
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Affiliation(s)
- Maria L Piredda
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Serena Ammendola
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | | | - Giulia Turri
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University of Verona, Verona, Italy
| | - Fabio Bagante
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University of Verona, Verona, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy
| | - Andrea Mafficini
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Mombello
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Simone Cataldi
- Department of Sciences for Promotion of Health and Mother and Child Care, Anatomic Pathology, University of Palermo, Palermo, Italy
| | - Gaetano Paolino
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Ada M Florena
- Department of Sciences for Promotion of Health and Mother and Child Care, Anatomic Pathology, University of Palermo, Palermo, Italy
| | - Michele Genna
- Department of General Surgery, Unit of General and Obesity Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Francesca Fior
- Department of General Surgery, Unit of General and Obesity Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Rita T Lawlor
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Corrado Pedrazzani
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University of Verona, Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.
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21
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Shimada Y, Okuda S, Watanabe Y, Tajima Y, Nagahashi M, Ichikawa H, Nakano M, Sakata J, Takii Y, Kawasaki T, Homma KI, Kamori T, Oki E, Ling Y, Takeuchi S, Wakai T. Histopathological characteristics and artificial intelligence for predicting tumor mutational burden-high colorectal cancer. J Gastroenterol 2021; 56:547-559. [PMID: 33909150 DOI: 10.1007/s00535-021-01789-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 04/15/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides. METHODS We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images. RESULTS Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934. CONCLUSIONS TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.
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Affiliation(s)
- Yoshifumi Shimada
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.,Medical Genome Center, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Shujiro Okuda
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. .,Medical Genome Center, Niigata University Medical and Dental Hospital, Niigata, Japan.
| | - Yu Watanabe
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.,Division of Cancer Genome Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yosuke Tajima
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Masayuki Nagahashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Hiroshi Ichikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Masato Nakano
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Jun Sakata
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Yasumasa Takii
- Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Takashi Kawasaki
- Department of Pathology, Niigata Cancer Center Hospital, Niigata, Japan
| | - Kei-Ichi Homma
- Department of Pathology, Niigata Cancer Center Hospital, Niigata, Japan
| | - Tomohiro Kamori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yiwei Ling
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Shiho Takeuchi
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.,Division of Cancer Genome Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. .,Medical Genome Center, Niigata University Medical and Dental Hospital, Niigata, Japan.
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22
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Keshinro A, Vanderbilt C, Kim JK, Firat C, Chen CT, Yaeger R, Ganesh K, Segal NH, Gonen M, Shia J, Stadler Z, Weiser MR. Tumor-Infiltrating Lymphocytes, Tumor Mutational Burden, and Genetic Alterations in Microsatellite Unstable, Microsatellite Stable, or Mutant POLE/POLD1 Colon Cancer. JCO Precis Oncol 2021; 5:PO.20.00456. [PMID: 34250404 PMCID: PMC8232557 DOI: 10.1200/po.20.00456] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/28/2021] [Accepted: 03/30/2021] [Indexed: 12/19/2022] Open
Abstract
To characterize the relationship between tumor-infiltrating lymphocytes (TIL), tumor mutational burden (TMB), and genetic alterations in microsatellite stable (MSS), microsatellite instability (MSI), or mutant POLE/POLD1 colon cancer. MATERIALS AND METHODS Four hundred ninety-nine resected stage I-III colon tumors treated between 2014 and 2019 were assessed for TIL; somatic mutations, copy number alterations, and structural changes in > 400 oncogenes; and MSI status. RESULTS Of the 499 tumors analyzed, 313 were MSS, 175 were MSI, and 11 had POLE/POLD1 pathogenic mutations. Both the percentage of tumors with a high level of TIL (≥ 4 lymphocytes per high-power field) and the median TMB differed significantly between the three phenotypes: MSS, 4.5% and 6 mutations/Mb; MSI, 68% and 54 mutations/Mb; POLE/POLD1, 82% and 158 mutations/Mb (P < .05). Within each phenotype, TMB did not vary significantly with TIL level. Among MSI tumors, the median number of frameshift indels was significantly higher in tumors with high levels of TIL (20 v 17; P = .018). In the MSS group, significantly higher proportions of tumors with high levels of TIL had mutations in the transforming growth factor-β (36% v 12%; P = .01), RAS (86% v 54%; P = .02), and Hippo (7% v 1%; P = .046) pathways; in contrast, TP53 alterations were associated with low levels of TIL (74% v 43%; P = .01). CONCLUSION The association between TIL, TMB, and genetic alterations varies significantly between MSI, MSS, and mutant POLE/POLD1 colon tumors. These differences may help explain tumoral immunity and lead to predictors of response to immunotherapy.
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Affiliation(s)
- Ajaratu Keshinro
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Chad Vanderbilt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jin K. Kim
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Canan Firat
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Chin-Tung Chen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Karuna Ganesh
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Neil H. Segal
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mithat Gonen
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Zsofia Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Martin R. Weiser
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
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23
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Lin SY, Hang JF, Lin YY, Lai CR, Ho HL, Chou TY. Diffuse Intratumoral Stromal Inflammation in Ovarian Clear Cell Carcinoma is Associated With Loss of Mismatch Repair Protein and High PD-L1 Expression. Int J Gynecol Pathol 2021; 40:148-155. [PMID: 32897958 DOI: 10.1097/pgp.0000000000000682] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Ovarian clear cell carcinoma (OCCC) is an aggressive chemotherapy-resistant cancer with limited treatment options, and some OCCCs have mismatch repair (MMR) deficiency (MMRD). Emerging evidence has revealed that various cancers with MMRD are susceptible to anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1) immunotherapy, and certain histologic features are associated with MMRD. However, few studies have addressed this in OCCC. We reviewed 76 OCCCs for tumor-associated inflammation (intratumoral stromal inflammation and peritumoral lymphocytes) and performed immunohistochemistry for 4 MMR proteins and PD-L1. MMR-deficient OCCCs were analyzed for microsatellite instability (MSI), and those with MLH1 loss were tested for MLH1 promoter methylation. No patients fulfilled the Amsterdam II criteria for the diagnosis of Lynch syndrome. Four (5.3%) tumors showed diffuse intratumoral stromal inflammation obliterating the tumor-stroma interfaces, and none had peritumoral lymphoid aggregates. MMRD was found in 2 (2.6%) tumors; one had MLH1/PMS2 loss (MSI-high and MLH1 promoter methylation was detected) and the other had MSH2/MSH6 loss (MSI-low). Twenty (26.3%) tumors showed tumoral PD-L1 expression ≥1%. Both MMR-deficient tumors showed diffuse intratumoral stromal inflammation and tumoral PD-L1 expression ≥50%. Three of the 4 (75%) tumors with diffuse intratumoral stromal inflammation also showed tumoral PD-L1 expression ≥50%. None of the tumors without diffuse intratumoral stromal inflammation showed MMRD (P=0.021) or tumoral PD-L1 expression ≥50% (P=0.0001). We identified a strong correlation among diffuse intratumoral stromal inflammation, MMRD, and high tumoral PD-L1 expression in a small but significant subset of OCCCs. Histologic evaluation can facilitate patient selection for subsequent anti-PD-1/PD-L1 immunotherapy.
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24
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Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors. Cancers (Basel) 2021; 13:cancers13030467. [PMID: 33530449 PMCID: PMC7865821 DOI: 10.3390/cancers13030467] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific, as most of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Therefore, the identification of MSI/dMMR requires additional diagnostic tools to identify LS. In this review, we address the hallmarks of LS and present recent advances in diagnostic and screening strategies to identify LS patients. We also discuss the pitfalls associated with current strategies, which should be taken into account in order to improve the diagnosis of LS. Abstract Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific to it, as approximately 80% of MSI/mismatch repair-deficient (dMMR) tumors are sporadic. Methods leading to the diagnosis of LS have considerably evolved in recent years and so have tumoral tests for LS screening and for the discrimination of LS-related to MSI-sporadic tumors. In this review, we address the hallmarks of LS, including the clinical, histopathological, and molecular features. We present recent advances in diagnostic and screening strategies to identify LS patients. We also discuss the pitfalls associated with the current strategies, which should be taken into account to improve the diagnosis of LS and avoid inappropriate clinical management.
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25
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Zang Y, Dong Q, Lu Y, Dong K, Wang R, Liang Z. Lumican inhibits immune escape and carcinogenic pathways in colorectal adenocarcinoma. Aging (Albany NY) 2021; 13:4388-4408. [PMID: 33493133 PMCID: PMC7906189 DOI: 10.18632/aging.202401] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/23/2020] [Indexed: 12/18/2022]
Abstract
Lumican (LUM), a small leucine-rich proteoglycan, is a component of the extracellular matrix. Abnormal LUM expression is potentially associated with cancer progression. In the present study, we confirmed high LUM mRNA expression in colorectal adenocarcinoma (COAD) through the UALCAN database. The Kaplan-Meier method, univariate, and multivariate COX analysis showed that high LUM expression is an independent determinant of poor prognosis in COAD. A COX regression model was constructed based on clinical information and LUM expression. The receiver operating characteristic (ROC) curve indicated that this model was highly accurate in monitoring COAD prognosis. The co-expression network of LUM was determined by LinkedOmics, which showed that LUM expression was closely related to immune escape and the miR200 family. Furthermore, we studied the co-expression network of LUM and found that LUM could promote tumor metastasis and invasion. The Tumor Immune Estimation Resource website showed that LUM was closely related to immune infiltration and correlated with regulatory T cells, tumour-associated macrophages, and dendritic cells. We found that LUM cultivated cancer progression by targeting the miR200 family to promote epithelial-to-mesenchymal transition. These findings suggest that LUM is a potential target for inhibiting immune escape and carcinogenic pathways.
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Affiliation(s)
- Yiqing Zang
- Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Qiuping Dong
- Department of Cancer Cell Biology, Tianjin's Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
| | - Yi Lu
- Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Kaiti Dong
- Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Rong Wang
- Department of Laboratory Medicine, Tianjin Medical University, Tianjin 300060, China
| | - Zheng Liang
- Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China
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Jimenez-Rodriguez RM, Patil S, Keshinro A, Shia J, Vakiani E, Stadler Z, Segal NH, Yaeger R, Konishi T, Shimada Y, Widmar M, Wei I, Pappou E, Smith JJ, Nash G, Paty P, Garcia-Aguilar J, Weiser MR. Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer. Oncoimmunology 2020; 9:1841948. [PMID: 33235819 PMCID: PMC7671050 DOI: 10.1080/2162402x.2020.1841948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/21/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor infiltrating lymphocytes (TIL), which represent host adaptive response to the tumor, were first identified at scanning magnification to select areas with the highest counts on hematoxylin and eosin slides, quantitated per high-power field (HPF), and analyzed for association with recurrence-free survival (RFS) in 848 patients. Highest TIL in a single HPF was analyzed as a continuous and categorical variable, and optimal cutoff analysis was performed to predict RFS. Highest TIL count in a single HPF ranged from 0 to 45, and the optimal cutoff for TIL high vs TIL low was determined to be ≥ 3 vs < 3 with a concordance probability estimate of 0.74. In the entire cohort, 5-year RFS was 90.2% (95% CI = 83.7-94.2) in TIL high compared to 78.9% (95% CI = 74.1-82.9) in TIL low (log rank P < .0001). TIL remained significant in the mismatch repair-proficient (pMMR) cohort where 5-year RFS was 94.6% (95% CI = 88.3-97.5) in TIL high compared to 77.9% (95% CI = 69.2-84.4) in TIL low (P = .008). On multivariable analysis, TIL and AJCC Stage were independently associated with RFS in the pMMR cohort. Qualitatively in the pMMR cohort, RFS in Stage II TIL high patients was similar to that in Stage I patients and RFS in Stage III TIL high was similar to that in Stage II TIL low patients. Assessment of TIL in a single HPF using standard H&E slides provides important prognostic information independent of MMR status and AJCC stage.
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Affiliation(s)
| | - Sujata Patil
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ajaratu Keshinro
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Efsevia Vakiani
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zsofia Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Neil H. Segal
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tsuyoshi Konishi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Tokyo
| | - Yoshifumi Shimada
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Maria Widmar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Iris Wei
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Emmanouil Pappou
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - J. Joshua Smith
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Garrett Nash
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Philip Paty
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Julio Garcia-Aguilar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Martin R. Weiser
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Eriksson J, Amonkar M, Al-Jassar G, Lambert J, Malmenäs M, Chase M, Sun L, Kollmar L, Vichnin M. Experience of mismatch repair/microsatellite instability (MMR/MSI) testing among patients with advanced/metastatic colorectal cancer in the US. Curr Med Res Opin 2020; 36:1355-1361. [PMID: 32468869 DOI: 10.1080/03007995.2020.1776235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Objective: We assessed knowledge and awareness of MMR/MSI testing among advanced/metastatic CRC patients in the US who had previously taken the test.Methods: A non-interventional, cross-sectional online survey was conducted among 150 US CRC patients invited through a research panel. Eligible patients had to be ≥18 years, with stage III or IV CRC (self-reported), had undergone MMR/MSI testing for CRC in past 12 months and could recall the test, and provided informed consent. Descriptive analyses were performed.Results: 81.3% of patients received MMR/MSI testing information from their doctor. Of 64.7% of patients who were a member of a patient support group, 86.6% received information from their groups. Most patients (82.7%) also searched for information on their own (internet searches). Most patients (93.5 to 96.9%) were satisfied with information received from these sources. Reasons for having testing done included increasing knowledge about their cancer (69.3%), being beneficial to determining treatment options (60.7%), and doctor recommendation (62.7%). Key barriers to testing included personal reservations regarding benefits of the test (29.3%), insurance coverage (27.3%), and out-of-pocket costs (18.7%); 45.3% reported no barriers.Conclusions: Patients were well informed about MMR/MSI testing. Increased education of testing benefits and addressing financial barriers may help to further improve testing rates.
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Bohaumilitzky L, von Knebel Doeberitz M, Kloor M, Ahadova A. Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review. J Clin Med 2020; 9:E1741. [PMID: 32512823 PMCID: PMC7357024 DOI: 10.3390/jcm9061741] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 02/07/2023] Open
Abstract
Microsatellite instability (MSI) represents one of the major types of genomic instability in human cancers and is most common in colorectal cancer (CRC) and endometrial cancer (EC). MSI develops as a consequence of DNA mismatch repair (MMR) deficiency, which can occur sporadically or in the context of Lynch syndrome (LS), the most common inherited tumor syndrome. MMR deficiency triggers the accumulation of high numbers of somatic mutations in the affected cells, mostly indel mutations at microsatellite sequences. MSI tumors are among the most immunogenic human tumors and are often characterized by pronounced local immune responses. However, so far, little is known about immunological differences between sporadic and hereditary MSI tumors. Therefore, a systematic literature search was conducted to comprehensively collect data on the differences in local T cell infiltration and immune evasion mechanisms between sporadic and LS-associated MSI tumors. The vast majority of collected studies were focusing on CRC and EC. Generally, more pronounced T cell infiltration and a higher frequency of B2M mutations were reported for LS-associated compared to sporadic MSI tumors. In addition, phenotypic features associated with enhanced lymphocyte recruitment were reported to be specifically associated with hereditary MSI CRCs. The quantitative and qualitative differences clearly indicate a distinct biology of sporadic and hereditary MSI tumors. Clinically, these findings underline the need for differentiating sporadic and hereditary tumors in basic science studies and clinical trials, including trials evaluating immune checkpoint blockade therapy in MSI tumors.
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Affiliation(s)
- Lena Bohaumilitzky
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (L.B.); (M.v.K.D.); (M.K.)
- Clinical Cooperation Unit Applied Tumor Biology, DKFZ, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (L.B.); (M.v.K.D.); (M.K.)
- Clinical Cooperation Unit Applied Tumor Biology, DKFZ, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (L.B.); (M.v.K.D.); (M.K.)
- Clinical Cooperation Unit Applied Tumor Biology, DKFZ, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Aysel Ahadova
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (L.B.); (M.v.K.D.); (M.K.)
- Clinical Cooperation Unit Applied Tumor Biology, DKFZ, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, 69120 Heidelberg, Germany
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Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer. Nat Med 2020; 26:919-931. [DOI: 10.1038/s41591-020-0882-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 04/10/2020] [Indexed: 12/16/2022]
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Jun SY, Park ES, Lee JJ, Chang HK, Jung ES, Oh YH, Hong SM. Prognostic Significance of Stromal and Intraepithelial Tumor-Infiltrating Lymphocytes in Small Intestinal Adenocarcinoma. Am J Clin Pathol 2020; 153:105-118. [PMID: 31576398 DOI: 10.1093/ajcp/aqz136] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Assessment of tumor-infiltrating lymphocytes (TILs) may predict the prognosis and therapeutic benefit of immunotherapy in small intestinal adenocarcinoma (SIAC) patients. METHODS TILs were evaluated in 231 surgically resected SIACs and compared with microsatellite instability (MSI) and clinicopathologic variables. The average number of intraepithelial TILs (iTILs) and the average density of stromal TILs (sTILs) were calculated separately. RESULTS High iTIL count (≥2 per high-power field) was associated with MSI-high, whereas high sTIL density (≥20% on ×200 magnification) was not. High iTIL count and high sTIL density were related to distal tumor location, medullary carcinoma, high Crohn-like lymphoid reaction counts, and fewer pancreatic invasions. SIAC patients with high iTIL count or high sTIL density had better survival than those with low values. On multivariate analysis, MSI, high sTIL density, proximal locations, lower N category, and absence of lymphovascular invasions and retroperitoneal seeding were the best independent prognostic predictors. CONCLUSIONS High sTIL density can be used as a prognostic indicator and high iTIL count may provide a basis for the clinical use of targeted immunotherapy in SIAC patients.
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Affiliation(s)
- Sun-Young Jun
- Department of Pathology, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Su Park
- Department of Pathology, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Jun Lee
- Department of Pathology, Good Morning Hospital, Pyeongtaek, Republic of Korea
| | - Hee-Kyung Chang
- Department of Pathology, Kosin University College of Medicine, Pusan, Republic of Korea
| | - Eun Sun Jung
- Department of Pathology, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young-Ha Oh
- Department of Pathology, Hanyang University College of Medicine, Guri, Republic of Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Bienfait L, Doukoure B, Verset L, Demetter P. Comparaison du « deficit mismatch repair » des cancers colorectaux entre des cohortes africaines et européennes. Ann Pathol 2020; 40:12-18. [DOI: 10.1016/j.annpat.2019.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 08/09/2019] [Accepted: 08/28/2019] [Indexed: 11/28/2022]
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Pfuderer PL, Ballhausen A, Seidler F, Stark HJ, Grabe N, Frayling IM, Ager A, von Knebel Doeberitz M, Kloor M, Ahadova A. High endothelial venules are associated with microsatellite instability, hereditary background and immune evasion in colorectal cancer. Br J Cancer 2019; 121:395-404. [PMID: 31358939 PMCID: PMC6738093 DOI: 10.1038/s41416-019-0514-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 06/18/2019] [Accepted: 06/21/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Microsatellite-unstable (MSI) tumours show a high load of mutational neoantigens, as a consequence of DNA mismatch repair deficiency. Consequently, MSI tumours commonly present with dense immune infiltration and develop immune evasion mechanisms. Whether improved lymphocyte recruitment contributes to the pronounced immune infiltration in MSI tumours is unknown. We analysed the density of high endothelial venules (HEV) and postcapillary blood vessels specialised for lymphocyte trafficking, in MSI colorectal cancers (CRC). METHODS HEV density was determined by immunohistochemical staining of FFPE tissue sections from MSI (n = 48) and microsatellite-stable (MSS, n = 35) CRCs. Associations with clinical and pathological variables were analysed. RESULTS We found elevated HEV densities in MSI compared with MSS CRCs (median 0.049 vs 0.000 counts/mm2, respectively, p = 0.0002), with the highest densities in Lynch syndrome MSI CRCs. Dramatically elevated HEV densities were observed in B2M-mutant Lynch syndrome CRCs, pointing towards a link between lymphocyte recruitment and immune evasion (median 0.485 vs 0.0885 counts/mm2 in B2M-wild-type tumours, p = 0.0237). CONCLUSIONS Our findings for the first time indicate a significant contribution of lymphocyte trafficking in immune responses against MSI CRC, particularly in the context of Lynch syndrome. High HEV densities in B2M-mutant tumours underline the significance of immunoediting during tumour evolution.
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Affiliation(s)
- Pauline L Pfuderer
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumour Biology, DKFZ, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany
| | - Alexej Ballhausen
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumour Biology, DKFZ, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany
| | - Florian Seidler
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumour Biology, DKFZ, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany
| | - Hans-Jürgen Stark
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumour Biology, DKFZ, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany
| | - Niels Grabe
- Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Heidelberg, Germany
- Department of Medical Oncology, National Center for Tumour Diseases (NCT), Heidelberg, Germany
| | - Ian M Frayling
- Inherited Tumour Syndromes Research Group, Institute of Cancer & Genetics, Cardiff University School of Medicine, Cardiff, UK
| | - Ann Ager
- Division of Infection and Immunity, School of Medicine and Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumour Biology, DKFZ, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias Kloor
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumour Biology, DKFZ, Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany
| | - Aysel Ahadova
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
- Clinical Cooperation Unit Applied Tumour Biology, DKFZ, Heidelberg, Germany.
- Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany.
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Poorly Differentiated Clusters Predict Colon Cancer Recurrence: An In-Depth Comparative Analysis of Invasive-Front Prognostic Markers. Am J Surg Pathol 2019; 42:705-714. [PMID: 29624511 DOI: 10.1097/pas.0000000000001059] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This study aimed to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. Consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution in 2007 to 2014 were identified. Poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor, were analyzed. Prognostic accuracies for recurrence-free survival (RFS) were compared, and interobserver agreement among 3 pathologists was assessed. The study cohort consisted of 851 patients. Although all the histologic markers except WHO grade were significantly associated with RFS (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P<0.001; Crohn-like lymphoid reaction: P=0.021), PDCs (grade 1 [G1]: n=581; G2: n=145; G3: n=125) showed the largest separation of 3-year RFS in the full cohort (G1: 94.1%; G3: 63.7%; hazard ratio [HR], 6.39; 95% confidence interval [CI], 4.11-9.95; P<0.001), stage II patients (G1: 94.0%; G3: 67.3%; HR, 4.15; 95% CI, 1.96-8.82; P<0.001), and stage III patients (G1: 89.0%; G3: 59.4%; HR, 4.50; 95% CI, 2.41-8.41; P<0.001). PDCs had the highest prognostic accuracy for RFS with the concordance probability estimate of 0.642, whereas WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. Our findings indicate that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. PDCs may replace WHO grade as a prognostic indicator.
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Goeppert B, Roessler S, Renner M, Loeffler M, Singer S, Rausch M, Albrecht T, Mehrabi A, Vogel MN, Pathil A, Czink E, Köhler B, Springfeld C, Rupp C, Weiss KH, Schirmacher P, von Knebel Doeberitz M, Kloor M. Low frequency of mismatch repair deficiency in gallbladder cancer. Diagn Pathol 2019; 14:36. [PMID: 31068195 PMCID: PMC6506936 DOI: 10.1186/s13000-019-0813-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 04/16/2019] [Indexed: 01/08/2023] Open
Abstract
Background DNA mismatch repair (MMR) deficiency is a major pathway of genomic instability in cancer. It leads to the accumulation of numerous mutations predominantly at microsatellite sequences, a phenotype known as microsatellite instability (MSI). MSI tumors have a distinct clinical behavior and commonly respond well to immune checkpoint blockade, irrespective of their origin. Data about the prevalence of MSI among gallbladder cancer (GBC) have been conflicting. We here analyzed a well-characterized cohort of 69 Western-world GBCs. Methods We analyzed the mononucleotide MSI marker panel consisting of BAT25, BAT26, and CAT25 to determine the prevalence of MMR deficiency-induced MSI. Results MSI was detected in 1/69 (1.4%) of analyzed GBCs. The detected MSI GBC had a classical histomorphology, i.e. of acinar/tubular/glandular pancreatobiliary phenotype, and showed nuclear expression of all four MMR proteins MLH1, MSH2, MSH6, and PMS2. The MSI GBC patient showed a prolonged overall survival, despite having a high tumor stage at diagnosis. The patient had no known background or family history indicative of Lynch syndrome. Conclusions Even though the overall number of MSI tumors is low in GBC, the potentially therapeutic benefit of checkpoint blockade in the respective patients may justify MSI analysis of GBC. Electronic supplementary material The online version of this article (10.1186/s13000-019-0813-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany. .,Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.,Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Marcus Renner
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany
| | - Moritz Loeffler
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany
| | - Stephan Singer
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany
| | - Melina Rausch
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany
| | - Thomas Albrecht
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.,Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Arianeb Mehrabi
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Monika Nadja Vogel
- Diagnostic and Interventional Radiology, Thoraxklinik at University Hospital of Heidelberg, Heidelberg, Germany
| | - Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Elena Czink
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Bruno Köhler
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Christoph Springfeld
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Rupp
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Karl Heinz Weiss
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.,Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.,Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | | | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
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Tampakis A, Tampaki EC, Nonni A, Droeser R, Posabella A, Tsourouflis G, Kontzoglou K, Patsouris E, von Flüe M, Kouraklis G. Nectin-1 Expression in Colorectal Cancer: Is There a Group of Patients with High Risk for Early Disease Recurrence? Oncology 2019; 96:318-325. [PMID: 30917374 DOI: 10.1159/000499569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/07/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Despite improvements in therapy of colorectal cancer, some patients will present occurrence of recurrence either locally or distantly. Tumor metastasis constitutes the major cause of cancer-associated morbidity and mortality. Nectin-1 belongs to the family of immunoglobulin-like cell adhesion molecules that contribute to the formation of cell-cell adhesions and regulate a series of cellular activities including cell polarization, differentiation, movement, proliferation, and survival. Expression of Nectin-1 in malignant tumors has been associated with aggressive tumor phenotypes. OBJECTIVES The aim of the present study was to assess Nectin-1 expression patterns in colorectal cancer and to investigate its clinical significance. METHODS Nectin-1 expression was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 111 patients with primary resectable colorectal cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival was defined as the primary outcome of the present study. RESULTS Nectin-1 was strongly expressed in the cytoplasm of colorectal cancer cells. High Nectin-1 expression was associated with advanced stage of disease (p = 0.012) and lymph node metastasis (p = 0.007). Progression-free survival of patients exhibiting high expression of Nectin-1 in the first 36 months after surgery was significantly worse compared to patients with low expression of Nectin-1 (55.7%, 95% CI = 47-70, vs. 82.1%, 95% CI = 69-93, p = 0.014) and independent of other clinicopathological characteristics (HR = 0.389, 95% CI = 0.156-0.972, p = 0.043). CONCLUSION Nectin-1 expression in colorectal cancer is associated with a significantly worse 3-year progression-free survival identifying therefore a group of patients with high risk for early disease recurrence.
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Affiliation(s)
- Athanasios Tampakis
- Clarunis University Center of Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland, .,2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece,
| | - Ekaterini Christina Tampaki
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Afroditi Nonni
- 1st Department of Pathology, School of Medicine, National University of Athens, Athens, Greece
| | - Raoul Droeser
- Clarunis University Center of Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland
| | - Alberto Posabella
- Clarunis University Center of Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland
| | - Gerasimos Tsourouflis
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Konstantinos Kontzoglou
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
| | - Efstratios Patsouris
- 1st Department of Pathology, School of Medicine, National University of Athens, Athens, Greece
| | - Markus von Flüe
- Clarunis University Center of Gastrointestinal and Liver Disorders, Department of Visceral Surgery, University Hospital Basel, Basel, Switzerland
| | - Gregory Kouraklis
- 2nd Department of Propedeutic Surgery, Athens University Medical School, Laiko General Hospital, Athens, Greece
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Nayak SS, Roy P, Arora N, Arun I, Roy MK, Banerjee S, Mallick I, Mallath MK. Prevalence estimation of microsatellite instability in colorectal cancers using tissue microarray based methods - A tertiary care center experience. INDIAN J PATHOL MICR 2019; 61:520-525. [PMID: 30303141 DOI: 10.4103/ijpm.ijpm_430_17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Aim Microsatellite instability (MSI) pathway is known to be implicated in carcinogenesis of 15% colorectal carcinomas (CRC), including 2%-3% of cases of Lynch syndrome, as per western literature. MSI status has important prognostic and therapeutic implications. The prevalence of MSI in Indian CRC patients is unknown. We aimed to determine the prevalence by studying 231 consecutive unselected cases of CRC. Methods Tissue microarrays using duplicate cores per case for 141 cases, and whole tissue sections for 90 cases, were used. Immunohistochemistry with four mismatch repair (MMR) markers - MLH1, MSH2, MSH6, and PMS2 was performed. Molecular analysis for MSI status was performed in 18 randomly selected cases. Correlation with various clinical and histopathological features was done using univariate and multivariate analysis. Results Loss of MMR immunohistochemical (IHC) was seen in 53/231 cases, i.e. 22.94% (95% confidence interval 17.52%-28.36%). MLH1-PMS2 dual loss comprised 13.9%, MSH2-MSH6 7.4%, and isolated PMS2 loss in 1.73% of cases. Univariate analysis showed significant association with age (<60 years), right-sided tumor location, histologic type, high grade, the presence of severe intratumoral lymphocytic (ITL) and peri-tumoral lymphocytic response, and N0 nodal stage. On multivariate analysis, independent variables were age < 60 years, right-sided location, and severe ITL. Molecular testing for MSI corroborated with the IHC results. Conclusion The study results show a slightly higher prevalence of MSI-H phenotype, compared to Western literature, stressing the need for more widespread testing for better clinical management and identification of possible hereditary colon cancer syndrome.
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Affiliation(s)
| | - Paromita Roy
- Department of Pathology, Tata Medical Centre, Kolkata, West Bengal, India
| | - Neeraj Arora
- Department of Laboratory Medicine and Molecular Genetics, Tata Medical Centre, Kolkata, West Bengal, India
| | - Indu Arun
- Department of Pathology, Tata Medical Centre, Kolkata, West Bengal, India
| | - Manas Kumar Roy
- Department of Surgical Oncology, Tata Medical Centre, Kolkata, West Bengal, India
| | - Sudeep Banerjee
- Department of Surgical Oncology, Tata Medical Centre, Kolkata, West Bengal, India
| | - Indranil Mallick
- Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal, India
| | - Mohandas K Mallath
- Department of GI Medicine, Tata Medical Center, Kolkata, West Bengal, India
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Gandhi JS, Goswami M, Sharma A, Tanwar P, Gupta G, Gupta N, Pasricha S, Mehta A, Singh S, Agarwal M, Gupta N. Clinical Impact of Mismatch Repair Protein Testing on Outcome of Early Staged Colorectal Carcinomas. J Gastrointest Cancer 2019; 49:406-414. [PMID: 28585041 DOI: 10.1007/s12029-017-9954-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Colorectal cancer is the third most common cancer in men and second most common in women globally. In the present study, we aimed to analyse the proportion of patients with loss of immunostaining for mismatch repair (MMR) proteins in all newly diagnosed stage II cases of colorectal cancer for the purpose of prognostication, for determination of further chemotherapeutic strategy and for familial screening. METHOD From January 2014 to December 2015, 62 consecutive newly diagnosed cases of stage II colorectal cancer were included in the study. Details of each patient related to their demographic profile and tumour profile were recorded. All the cases were grossed and staged according to College of American Pathologist (CAP) guidelines. The expression of MMR proteins (which was earlier validated on normal as well as tumour tissue) in FFPE tumour tissue using IHC for mut L homologue 1 (MLH1), mut S homologue 2 (MSH2), mut S homologue 6 (MSH6) and post-meiotic segregation increased 2 (PMS2) was studied. Information regarding stage, treatment, clinical outcome and overall survival was retrieved when available. RESULTS Out of a total of 371 cases, 62 (16.7%) cases were of stage II CRC, out of which 43 (12%) were treatment naive. Among the selected 62 cases, 26 (41.9%) demonstrated loss of MMR proteins and 36 (58.0%) cases had intact nuclear expression. Out of the cases with MMR loss, 38.4% showed loss of MLH1 and PMS2, 30.7% showed loss of MSH2 and MSH6, 26.9% showed isolated loss of PMS2 and 3.8% showed isolated loss of MSH6. Right-sided location (57.6%) was more common than left-sided (19.2%) and transverse colon (23.0%). Majority of the cases were moderately differentiated (65.3%) in morphology. There was no intratumoural infiltrate in most of the cases (53.8%), and only 3.8% cases showed marked intratumoural infiltrate. Also, peritumoural lymphocytic infiltrate was mild to moderate in most of the cases (26.9%) and marked Crohn's-like infiltrate was seen in only 7.6% cases. CONCLUSION Our study shows that the routine evaluation of MMR proteins is achievable and essential for the purpose of prognostication, planning of treatment strategies and ascertaining a hereditary basis of CRC. The incidence of MMR protein loss was quite high in our study compared to other studies probably due to a difference in ethnicity. Though a right-sided predominance was supported, none of the typical morphological features of microsatellite instability (MSI) tumours were substantiated by our study, highlighting the lack of importance of histology for predicting MSI, and emphasising the point that MSI testing should be done as a routine procedure in all stage II CRC. A short follow-up was done for all our cases and comparison between the survival of the chemotherapy treated MSI cases versus those which were treatment naïve was performed and revealed that chemotherapy (CT) did not provide additional benefit to survival; MSI tumours in general are a better prognostic category and do not require additional chemotherapy.
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Affiliation(s)
- Jatin Sundersham Gandhi
- Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India.
| | - Malini Goswami
- Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Anila Sharma
- Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Parul Tanwar
- Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Gurudutt Gupta
- Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Nikhil Gupta
- Department of Gastrointestinal Surgery, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Sunil Pasricha
- Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Anurag Mehta
- Department of Histopathology and Cytopathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Shivender Singh
- Department of Gastrointestinal Surgery, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Mohit Agarwal
- Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
| | - Nitin Gupta
- Department of Gastroenterology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
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Wasserman I, Lee LH, Ogino S, Marco MR, Wu C, Chen X, Datta J, Sadot E, Szeglin B, Guillem JG, Paty PB, Weiser MR, Nash GM, Saltz L, Barlas A, Manova-Todorova K, Uppada SPB, Elghouayel AE, Ntiamoah P, Glickman JN, Hamada T, Kosumi K, Inamura K, Chan AT, Nishihara R, Cercek A, Ganesh K, Kemeny NE, Dhawan P, Yaeger R, Sawyers CL, Garcia-Aguilar J, Giannakis M, Shia J, Smith JJ. SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance. Clin Cancer Res 2018; 25:1948-1956. [PMID: 30587545 DOI: 10.1158/1078-0432.ccr-18-1726] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 09/21/2018] [Accepted: 12/18/2018] [Indexed: 12/21/2022]
Abstract
PURPOSE SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. RESULTS The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. CONCLUSIONS Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.
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Affiliation(s)
- Isaac Wasserman
- Icahn School of Medicine at Mount Sinai, New York, New York.,Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lik Hang Lee
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Shuji Ogino
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.,Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Michael R Marco
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chao Wu
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Xi Chen
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Jashodeep Datta
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eran Sadot
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Bryan Szeglin
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.,Albert Einstein College of Medicine, New York, New York
| | - Jose G Guillem
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Philip B Paty
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Martin R Weiser
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Garrett M Nash
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Leonard Saltz
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Afsar Barlas
- Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Katia Manova-Todorova
- Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Srijaya Prakash Babu Uppada
- Department of Biochemistry and Molecular Biology, Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Arthur E Elghouayel
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,College of William and Mary, Williamsburg, Virginia
| | - Peter Ntiamoah
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jonathan N Glickman
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Keisuke Kosumi
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Kentaro Inamura
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Andrew T Chan
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.,Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Reiko Nishihara
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.,Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Andrea Cercek
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Karuna Ganesh
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy E Kemeny
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Rona Yaeger
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Charles L Sawyers
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Julio Garcia-Aguilar
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marios Giannakis
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.,Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - J Joshua Smith
- Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York. .,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
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40
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Goeppert B, Roessler S, Renner M, Singer S, Mehrabi A, Vogel MN, Pathil A, Czink E, Köhler B, Springfeld C, Pfeiffenberger J, Rupp C, Weiss KH, Schirmacher P, von Knebel Doeberitz M, Kloor M. Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma. Br J Cancer 2018; 120:109-114. [PMID: 30377340 PMCID: PMC6325153 DOI: 10.1038/s41416-018-0199-2] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 07/06/2018] [Accepted: 07/06/2018] [Indexed: 02/08/2023] Open
Abstract
Background A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency. High-level microsatellite instability (MSI-H) is currently the best predictor of responsiveness towards immune checkpoint blockade. Data about the prevalence of high-level microsatellite instability in cholangiocarcinoma (CCA) has been conflicting. Methods We employed a cohort comprising 308 Western-world, non-liver fluke-associated CCAs (159 intrahepatic, 106 perihilar, and 43 distal). We analysed the mononucleotide microsatellite instability marker panel consisting of BAT25, BAT26, and CAT25 and detected MSI-H in 4/308 CCAs (1.3%). Results Patients affected by MSI-H CCA had mostly an atypical histomorphology (p = 0.004), showed a longer overall survival, although having a high tumour stage, and were of younger age. Correlation analysis of microsatellite instability status with tumour-infiltrating immune cells, MHC I, and PD-L1 expression in the same cholangiocarcinoma cohort showed higher numbers of CD8 + T cells, FOXP3 + regulatory T cells, CD20 + B cells and high or at least moderate MHC I expression levels in MSI-H CCAs. Conclusions Even though the overall number of MSI-H CCAs is low, the dismal prognosis of the disease and the therapeutic option of immune checkpoint blockade in the respective patients justify MSI testing of cholangiocarcinoma, particularly in younger patients showing an atypical histomorphology.
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Affiliation(s)
- Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany. .,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany.
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Marcus Renner
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany
| | - Stephan Singer
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany
| | - Arianeb Mehrabi
- Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Monika Nadja Vogel
- Diagnostic and Interventional Radiology, Thoraxklinik at University Hospital of Heidelberg, Heidelberg, Germany
| | - Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany
| | - Elena Czink
- National Center for Tumor Diseases, Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Bruno Köhler
- National Center for Tumor Diseases, Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Christoph Springfeld
- National Center for Tumor Diseases, Department of Medical Oncology, University Hospital Heidelberg, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Jan Pfeiffenberger
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Christian Rupp
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.,Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany
| | | | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
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Acosta-Gonzalez G, Ouseph M, Lombardo K, Lu S, Glickman J, Resnick MB. Immune environment in serrated lesions of the colon: intraepithelial lymphocyte density, PD-1, and PD-L1 expression correlate with serrated neoplasia pathway progression. Hum Pathol 2018; 83:115-123. [PMID: 30172913 DOI: 10.1016/j.humpath.2018.08.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/17/2018] [Accepted: 08/23/2018] [Indexed: 12/30/2022]
Abstract
The serrated neoplasia pathway accounts for approximately 20% of colorectal carcinomas (CRCs). Sessile serrated adenomas (SSAs), the main precursor lesion of the serrated pathway, are molecularly driven by MLH1 promoter methylation and microsatellite instability (MSI) in their progression to CRC. MSI-high (MSI-H) lesions are highly immunogenic and associated with a high density of tumor-infiltrating lymphocytes. Our study's aim was to determine how the kinetics of this immune environment relates to SSAs in their progression through low-grade (SSA-LD) to high-grade dysplasia (SSA-HD) and CRC. We analyzed 74 cases (16 CRCs, 14 SSAs-HD, and 44 SSAs-LD). Cases of hyperplastic polyp and SSA without dysplasia were analyzed for comparison. MSI status, intraepithelial lymphocyte (IEL) density, and immune checkpoint expression were assessed by immunohistochemistry for mismatch repair proteins, CD3, and PD-1/PD-L1, respectively. Average IEL density was 12, 18.6, 21.6, and 31 for SSA, SSA-LD, SSA-HD, and CRC, respectively, as opposed to 8.1 in normal colon (P < .0001). Average PD-1/PD-L1 lymphocytic expression was 1.1/1.0, 1.2/2.9, 4.8/6.9, and 12.4/15.2 in SSA, SSA-LD, SSA-HD, and CRC, respectively, compared with 0.5/0 in normal crypts (P < .0001). IEL and PD-1/PD-L1 lymphocytic expression values of MSI-H lesions were 22.6, 27.7, and 36.8, and 3/6.5, 6.2/10.6, and 18.3/17.6 in MSI-H SSA-LD, SSA-HD, and CRCs, respectively (P ranged from .0478 to .3529). PD-L1 epithelial expression was positive in 40% of SSAs, 59.1% of SSAs-LD, 100% of SSAs-HD, and 60% of CRCs (P < .0001). Increased IELs and PD-1/PD-L1 expression correlate with sequential progression of SSAs, through development of cytologic dysplasia, to CRC and MSI-H status.
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Affiliation(s)
- Gabriel Acosta-Gonzalez
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA
| | - Madhu Ouseph
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA
| | - Kara Lombardo
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA
| | - Shaolei Lu
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA
| | - Jonathan Glickman
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Murray B Resnick
- Department of Pathology, Brown University Warren Alpert Medical School, Rhode Island Hospital, Providence, RI 02903, USA.
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Abstract
Background Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2. Methods Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials.gov. Based on the recent research data, we provide an update on the MSI testing, along with the evolving role of MSI in diagnosis, prognosis and treatment of colorectal cancers. Results Studies have led to significant advances in the molecular pathogenesis and clinicopathological characteristics of MSI-H colorectal cancers. Emerging evidence suggests that colorectal cancers with MSI-H show different outcome and treatment response from those with microsatellite stable (MSS) tumors. Therefore, MSI testing is essential not only in the genetic context, but it may also have important prognostic and predictive value of response to chemotherapy and immunotherapy. Conclusions Many experts and professional authorities have recommended a universal MSI testing in all individuals newly diagnosed with colorectal cancers.
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43
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Hemminger JA, Pearlman R, Haraldsdottir S, Knight D, Jonasson JG, Pritchard CC, Hampel H, Frankel WL. Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome. Hum Pathol 2018; 78:125-130. [PMID: 29723603 DOI: 10.1016/j.humpath.2018.04.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 04/17/2018] [Accepted: 04/20/2018] [Indexed: 02/06/2023]
Abstract
Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.
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Affiliation(s)
- Jessica A Hemminger
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Rachel Pearlman
- Department of Internal Medicine, Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Sigurdis Haraldsdottir
- Department of Medicine/Oncology, Stanford University Medical Center, Stanford, CA 94305, USA
| | - Deborah Knight
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | | | - Colin C Pritchard
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
| | - Heather Hampel
- Department of Internal Medicine, Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Wendy L Frankel
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
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Olevian DC, Pai RK. Histologic Features Do Not Reliably Predict Mismatch Repair Protein Deficiency in Colorectal Carcinoma: The Results of a 5-Year Prospective Evaluation. Appl Immunohistochem Mol Morphol 2018; 26:231-238. [PMID: 29189259 DOI: 10.1097/pai.0000000000000611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Most major professional medical organizations advocate universal screening for Lynch syndrome in colorectal carcinoma; however, some allow for a selective screening approach based on clinicopathologic factors including assessment of histologic features of mismatch repair protein deficiency (MMRD). We performed a prospective evaluation for histopathologic features of MMRD in colorectal carcinomas that underwent universal screening for Lynch syndrome to evaluate the ability of histology to predict MMRD. In total, 947 resected colorectal carcinomas over a 5-year period were prospectively analyzed for histologic features of MMRD and for DNA mismatch repair protein abnormalities. Histologic features of MMRD were reported as present in 281 of 947 (30%) tumors with only 109 (39%) cases demonstrating MMRD by immunohistochemistry. Histologic features of MMRD had a sensitivity of 74% [95% confidence interval (CI), 66%-80%], specificity of 78% (95% CI, 75%-81%), positive predictive value of 39% (95% CI, 32%-44%), and negative predictive value of 94% (95% CI, 92%-96%). Histologic features of MMRD in left colon/rectal tumors had a significantly lower sensitivity of 56% (95% CI, 41%-77%) compared with right colon tumors (P=0.02). Histologic rereview identified that tumor-infiltrating lymphocytes (TILs) were most likely to be incorrectly reported as absent, and 72% of cases incorrectly assessed as lacking TILs demonstrated MMRD by immunohistochemistry. We demonstrate that histologic features of MMRD do not reliably predict the presence of MMRD by immunohistochemistry. Interpretative errors in the assessment of histologic features of MMRD occur, particularly for TILs and in tumors of the left colon/rectum.
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Affiliation(s)
- Dane C Olevian
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
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O’Brien O, Ryan É, Creavin B, Kelly ME, Mohan HM, Geraghty R, Winter DC, Sheahan K. Correlation of immunohistochemical mismatch repair protein status between colorectal carcinoma endoscopic biopsy and resection specimens. J Clin Pathol 2018; 71:631-636. [DOI: 10.1136/jclinpath-2017-204946] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/11/2018] [Accepted: 01/13/2018] [Indexed: 12/15/2022]
Abstract
BackgroundMicrosatellite instability is reflective of a deficient mismatch repair system (dMMR), which may be due to either sporadic or germline mutations in the relevant mismatch repair (MMR) gene. MMR status is frequently determined by immunohistochemistry (IHC) for mismatch repair proteins (MMRPs) on colorectal cancer (CRC) resection specimens. However, IHC testing performed on endoscopic biopsy may be as reliable as that performed on surgical resections.AimWe aimed to evaluate the reliability of MMR IHC staining on preoperative CRC endoscopic biopsies compared with matched-surgical resection specimens.MethodsA retrospective search of our institution’s histopathology electronic database was performed. Patients with CRC who had MMR IHC performed on both their preoperative endoscopic biopsy and subsequent resection from January 2010 to January 2016 were included. Concordance of MMR staining between biopsy and resection specimens was assessed.ResultsFrom 2000 to 2016, 53 patients had MMR IHC performed on both their preoperative colorectal endoscopic biopsy and resection specimens; 10 patients (18.87%) demonstrated loss of ≥1 MMRP on their initial endoscopic tumour biopsy. The remainder (81.13%) showed preservation of staining for all MMRPs. There was complete agreement in MMR IHC status between the preoperative endoscopic biopsies and corresponding resection specimens in all cases (κ=1.000, P<0.000) with a sensitivity of 100% (95% CI 69.15 to 100) and specificity of 100% (95% CI 91.78 to 100) for detection of dMMR.ConclusionEndoscopic biopsies are a suitable source of tissue for MMR IHC analysis. This may provide a number of advantages to both patients and clinicians in the management of CRC.
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Alpert L, Pai RK, Srivastava A, McKinnon W, Wilcox R, Yantiss RK, Arcega R, Wang HL, Robert ME, Liu X, Pai RK, Zhao L, Westerhoff M, Hampel H, Kupfer S, Setia N, Xiao SY, Hart J, Frankel WL. Colorectal Carcinomas With Isolated Loss of PMS2 Staining by Immunohistochemistry. Arch Pathol Lab Med 2018; 142:523-528. [DOI: 10.5858/arpa.2017-0156-oa] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Context.—
Isolated loss of PMS2 staining is an uncommon immunophenotype in colorectal carcinomas, accounting for approximately 4% of tumors with microsatellite instability. Limited information regarding these tumors is available in the literature.
Objective.—
To compare the clinicopathologic features of colorectal carcinomas with isolated PMS2 loss by immunohistochemistry to those with other forms of mismatch repair deficiency.
Design.—
Ninety-three colorectal carcinomas with isolated PMS2 loss by immunohistochemistry and 193 with other forms of mismatch repair deficiency were identified. Forty (43%) of the isolated PMS2 loss cases and 35 control cases (18%) had a known germline mutation or a clinical diagnosis of Lynch syndrome.
Results.—
Overall, isolated PMS2-loss tumors occurred in significantly younger patients (P < .001) and in fewer female patients (P = .006). These tumors were significantly less likely to be right-sided (P = .001), high-grade (P = .01), or display histologic features of microsatellite instability (P < .001). The isolated PMS2-loss group also exhibited increased odds of disease-specific death (odds ratio [OR], 3.09; 95% CI, 1.41–6.85; P = .007). When the analysis was restricted to germline mutation/Lynch syndrome cases and controls, no significant differences were detected for age, sex, tumor location, tumor grade, histologic features, or distant metastases, although a trend toward increased odds of disease-specific death in the isolated PMS2-loss group was evident (OR, 3.87; 95% CI, 0.89–27.04; P = .10).
Conclusions.—
Unusual clinicopathologic features observed in colorectal carcinomas with isolated PMS2 loss are likely related to the high proportion of cases caused by germline mutations. Isolated PMS2-loss tumors may demonstrate more aggressive behavior than other tumors with microsatellite instability, but larger studies are needed to investigate that possibility further.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Wendy L. Frankel
- From the Departments of Pathology (Drs Alpert, Setia, Xiao, and Hart) and Medicine (Dr Kupfer), University of Chicago, Chicago, Illinois; the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Reetesh Pai); the Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts (Dr Srivastava); the Departments of Medicine (Ms McKinnon) and Patho
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Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer. Int J Clin Oncol 2018; 23:504-513. [PMID: 29327160 DOI: 10.1007/s10147-018-1238-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 12/31/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. METHODS Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations. RESULTS The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55-37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50-45.0, P = 0.176). CONCLUSIONS Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.
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Matos P, Jordan P. Targeting Colon Cancers with Mutated BRAF and Microsatellite Instability. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1110:7-21. [PMID: 30623363 DOI: 10.1007/978-3-030-02771-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The subgroup of colon cancer (CRC) characterized by mutation in the BRAF gene and high mutation rate in the genomic DNA sequence, known as the microsatellite instability (MSI) phenotype, accounts for roughly 10% of the patients and derives from polyps with a serrated morphology. In this review, both features are discussed with regard to therapeutic opportunities. The most prevalent cancer-associated BRAF mutation is BRAF V600E that causes constitutive activation of the pro-proliferative MAPK pathway. Unfortunately, the available BRAF-specific inhibitors had little clinical benefit for metastatic CRC patients due to adaptive MAPK reactivation. Recent contributions for the development of new combination therapy approaches to pathway inhibition will be highlighted. In addition, we review the promising role of the recently developed immune checkpoint therapy for the treatment of this CRC subtype. The MSI phenotype of this subgroup results from an inactivated DNA mismatch repair system and leads to frameshift mutations with translation of new amino acid stretches and the generation of neo-antigens. This most likely explains the observed high degree of infiltration by tumour-associated lymphocytes. As cytotoxic lymphocytes are already part of the tumour environment, their activation by immune checkpoint therapy approaches is highly promising.
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Affiliation(s)
- Paulo Matos
- Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.,BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.,Department of Human Genetics, National Health Institute 'Dr. Ricardo Jorge', Lisbon, Portugal
| | - Peter Jordan
- BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal. .,Department of Human Genetics, National Health Institute 'Dr. Ricardo Jorge', Lisbon, Portugal.
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Marginean EC, Melosky B. Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part I-Colorectal Cancer: Microsatellite Instability, Testing, and Clinical Implications. Arch Pathol Lab Med 2017; 142:17-25. [PMID: 29144791 DOI: 10.5858/arpa.2017-0040-ra] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT - Colorectal cancer (CRC) represents the third most-common cancer in developed countries and is a leading cause of cancer deaths worldwide. Two recognized pathways contribute to CRC development: a more-common chromosomal instability pathway and, in 15% of cases, a deficient mismatch repair or microsatellite instability-high (MSI-H) pathway. The MSI-H CRC can be associated with somatic or germline mutations. Microsatellite status has been recognized as a prognostic and predictive biomarker. OBJECTIVES - To summarize the molecular pathways of CRC, with an emphasis on the MSI (mismatch repair) pathway; the recommended MSI testing algorithms and interpretation; and the prognostic and predictive role of MSI-H status in personalized treatment, including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy. DATA SOURCES - A PubMed (US National Library of Medicine, Bethesda, Maryland) review was performed for articles pertaining to CRC, MSI and mismatch repair systems, molecular classification, immune response, programmed death receptor-1/programmed death ligand-1, and immunotherapy. CONCLUSIONS - Although the TNM classification of malignant tumor stage remains the key determinant of CRC prognosis and treatment, there are considerable stage-independent, interindividual differences in clinical outcome and therapy response by patients. In addition, MSI-H status has an important role in CRC management and can be reliably detected by molecular and immunohistochemistry techniques and genetic testing. Efforts must be made to identify whether MSI-H CRC is germline or sporadic to ensure appropriate treatment, accurate prognosis, and risk assessment for relatives. Microsatellite status has been recognized as a good prognostic indicator and is predictive of a poor response to 5-fluorouracil-based chemotherapy and a good response to programmed death ligand-1 inhibitor pembrolizumab in metastatic/refractory MSI-H CRC.
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Affiliation(s)
- Esmeralda Celia Marginean
- From the Department of Pathology, University of Ottawa, Ottawa, Ontario, Canada (Dr Marginean); the Gastrointestinal Pathology Section, Ottawa Hospital, Ottawa (Dr Marginean); the Department of Medical Oncology, University of British Columbia, Vancouver, Canada (Dr Melosky); and the Department of Oncology, British Columbia Cancer Agency, Vancouver (Dr Melosky)
| | - Barbara Melosky
- From the Department of Pathology, University of Ottawa, Ottawa, Ontario, Canada (Dr Marginean); the Gastrointestinal Pathology Section, Ottawa Hospital, Ottawa (Dr Marginean); the Department of Medical Oncology, University of British Columbia, Vancouver, Canada (Dr Melosky); and the Department of Oncology, British Columbia Cancer Agency, Vancouver (Dr Melosky)
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Jarosch A, Sommer U, Bogner A, Reißfelder C, Weitz J, Krause M, Folprecht G, Baretton GB, Aust DE. Neoadjuvant radiochemotherapy decreases the total amount of tumor infiltrating lymphocytes, but increases the number of CD8+/Granzyme B+ (GrzB) cytotoxic T-cells in rectal cancer. Oncoimmunology 2017; 7:e1393133. [PMID: 29308324 DOI: 10.1080/2162402x.2017.1393133] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/10/2017] [Accepted: 10/11/2017] [Indexed: 10/18/2022] Open
Abstract
Although neoadjuvant radiochemotherapy (nRCTx) is an established oncological treatment in patients with advanced rectal cancer, little is known about its effects on the tumor microenvironment. Quantity and composition of tumor infiltrating lymphocytes (TILs) are known to influence patients' prognosis but nRCTx-induced modifications are still unclear. We determined the composition of the immune cell infiltrate in rectal cancer after nRCTx and its influence on tumor regression, local recurrence rate and survival. We investigated density and composition of tumor infiltrating CD3+ and CD8+ T-cells and the quantity and ratio of CD8+/GrzB+ T-cells to CD8+ T-cells in 130 rectal cancers after nRCTx compared to a cohort of 30 primarily resected rectal cancers. Furthermore, we analyzed 22 pretherapeutic rectal cancer biopsies, later treated with nRCTx and surgery to evaluate nRCTx-induced modifications of the tumor microenvironment. The total numbers of CD3+ and CD8+ T-cells in tumor stroma (p < 0.001) and tumor epithelium (p < 0.001 CD3; 0.002 CD8) were significantly lower in rectal cancers after nRCTx compared to primarily resected cases, while the ratio of CD8+/GrzB+ T-cells to CD8+ T-cells was significantly increased in the nRCTx cohort (p < 0.001). In multivariate analyses, CD8+/GrzB+ T-cells in the tumor stroma were significantly associated with high regression grade and a lower likelihood of local recurrence (p = 0.029). nRCTx modifies the tumor microenvironment of rectal cancer leading to a total decrease of TILs, but a relative increase in CD8+/GrzB+ T-cells in the tumor stroma. CD8+/GrzB+ T-cells may contribute to local tumor control and the better outcome.
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Affiliation(s)
- Armin Jarosch
- Institute of Pathology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumor Diseases (NCT) partner site Dresden
| | - Ulrich Sommer
- Institute of Pathology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumor Diseases (NCT) partner site Dresden
| | - Andreas Bogner
- Department for Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumor Diseases (NCT) partner site Dresden
| | - Christoph Reißfelder
- Department for Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumor Diseases (NCT) partner site Dresden.,German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany
| | - Jürgen Weitz
- Institute of Pathology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumor Diseases (NCT) partner site Dresden.,German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany
| | - Mechthild Krause
- National Center for Tumor Diseases (NCT) partner site Dresden.,Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden.,German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany.,OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Dresden, Germany
| | - Gunnar Folprecht
- Medical Department I, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumor Diseases (NCT) partner site Dresden.,German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany
| | - Gustavo B Baretton
- Institute of Pathology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumor Diseases (NCT) partner site Dresden.,German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany.,Tumor and normal tissue bank of Universitäts KrebsCentrum (UCC), University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Daniela E Aust
- Institute of Pathology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.,National Center for Tumor Diseases (NCT) partner site Dresden.,German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany.,Tumor and normal tissue bank of Universitäts KrebsCentrum (UCC), University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany
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