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Han F, Xu Y, Li X, Song Z, Xie J, Yao J. Clinicopathological features and prognosis analysis of proximal colonic mucinous adenocarcinoma. Sci Rep 2024; 14:18682. [PMID: 39134655 PMCID: PMC11319726 DOI: 10.1038/s41598-024-69916-0] [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: 11/14/2023] [Accepted: 08/09/2024] [Indexed: 08/15/2024] Open
Abstract
Mucinous adenocarcinoma (MAC) is a distinct subtype of colorectal cancer. Previous studies have confirmed the poor prognosis of rectal or left-sided colon MAC, while the prognosis and response to chemotherapy in proximal colon MAC remains controversial. The aim of this study was to investigate the clinicopathological characteristics, prognosis, response to chemotherapy, and risk prediction factors of proximal colon MAC. Patients with proximal colon MAC and non-mucinous adenocarcinoma (NMAC) were retrospectively analyzed in this study. The analyzed variables included gender, age, smoking, drinking, chemotherapy, metastasis, pathological stage, and tumor size. Overall survival (OS) was the primary outcome. Kaplan-Meier analysis was used to assess the impact of mucinous subtype and chemotherapy on OS. We conducted univariate and multivariate Cox regression analyses to determine prognosis factors for proximal colon MAC and NMAC. A total of 284 cases of proximal colon MAC and 1384 cases of NMAC were included in the study. Compared to NMAC, proximal colon MAC was diagnosed at a younger age. The proportion of synchronous and metachronous metastasis was also higher, as well as the pathological stage and tumor size. Proximal colon MAC had a worse prognosis than NMAC, especially in stage 3. Moreover, the prognosis of proximal colon NMAC improved after chemotherapy, while MAC showed no improvement in prognosis after chemotherapy. Advanced age, N1 and N2 stage were independent prognostic factors for adverse outcomes in MAC. For proximal colon adenocarcinoma, the independent predictors of adverse outcomes included mucinous subtype, order age, N1 and N2 stages, and pathological stage 4. Proximal colon MAC had a worse prognosis compared to NMAC. Chemotherapy did not improve the prognosis of proximal colon mucinous adenocarcinoma.
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Affiliation(s)
- Fei Han
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Yue Xu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiangyu Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Zhaoxiang Song
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Jinlin Xie
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Jianning Yao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China.
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Ono Y, Yilmaz O. Emerging and under-recognised patterns of colorectal carcinoma morphologies: a comprehensive review. J Clin Pathol 2024; 77:439-451. [PMID: 38448211 DOI: 10.1136/jcp-2023-208816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/22/2024] [Indexed: 03/08/2024]
Abstract
While the overwhelming majority of colorectal carcinomas (CRC) are diagnosed as adenocarcinoma not otherwise specified, there are numerous under-recognised morphologic patterns of CRC. These patterns are recognised by the WHO, appear in reporting manuals for the American Joint Committee of Cancer, and/or are listed on synoptic reports, while many other variants have either fallen out of favour or are emerging as future bona fide patterns. Herein, we discuss 13 variants: serrated adenocarcinoma, micropapillary adenocarcinoma, medullary carcinoma, neuroendocrine carcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, adenosquamous carcinoma, adenoma-like adenocarcinoma, lymphoglandular complex-like CRC, carcinoma with sarcomatoid components, cribriform-comedo-type adenocarcinoma, undifferentiated carcinoma and low-grade tubuloglandular adenocarcinoma. The purpose of this review is to scrutinise these variants by assessing their clinical characteristics, morphologic cues, as well as pitfalls, and address their prognostic significance. Our analysis aims to bring clarity and updated understanding to these variants, offering valuable insights for pathologists. This contributes to more nuanced CRC diagnosis and treatment strategies, highlighting the importance of recognising a broad spectrum of morphologic patterns in CRC.
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Affiliation(s)
- Yuho Ono
- Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Osman Yilmaz
- Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Chen S, Du W, Cao Y, Kong J, Wang X, Wang Y, Lu Y, Li X. Preoperative contrast-enhanced CT imaging and clinicopathological characteristics analysis of mismatch repair-deficient colorectal cancer. Cancer Imaging 2023; 23:97. [PMID: 37828626 PMCID: PMC10568855 DOI: 10.1186/s40644-023-00591-6] [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: 03/02/2023] [Accepted: 07/08/2023] [Indexed: 10/14/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) can develop through various pathogenetic pathways, and one of the primary pathways is high microsatellite instability (MSI-H)/deficient mismatch repair (dMMR). This study investigated the correlation between preoperative contrast-enhanced CT (CECT) and clinicopathologic characteristics of colorectal cancer (CRC) according to different mismatch repair (MMR) statuses. METHODS From April 2021 to July 2022, a total of 281 CRC patients with preoperative CECT and available MMR status were enrolled from a single centre for this retrospective study. Preoperative CECT features and clinicopathologic characteristics were analysed. Univariate and multivariate logistic regression analyses were used for statistical analysis. A nomogram was established based on the multivariate logistic regression results. Preoperative and postoperative dynamic nomogram prediction models were established. The C-index, a calibration plot, and clinical applicability of the two models were evaluated, and internal validation was performed using three methods. RESULTS In total, 249 patients were enrolled in the proficient mismatch repair (pMMR) group and 32 patients in the deficient mismatch repair (dMMR) group. In multivariate analysis, tumour location (right-hemi colon vs. left-hemi colon, odds ratio (OR) = 2.90, p = .036), the hypoattenuation-within-tumour ratio (HR) (HR > 2/3 vs. HR < 1/3, OR = 36.7, p < .001; HR 1/3-2/3 vs. HR < 1/3, OR = 6.05, p = .031), the number of lymph nodes with long diameter ≥ 8 mm on CECT (OR = 1.32, p = .01), CEA status (CEA positive vs. CEA negative, OR = 0.07, p = .002) and lymph node metastasis (OR = 0.45, p = .008) were independent risk factors for dMMR. Pre- and postoperative C-statistic were 0.861 and 0.908, respectively. CONCLUSION The combination of pre-operative CECT and clinicopathological characteristics of CRC correlates with MMR status, providing possible non-invasive MMR prediction. Particularly for dMMR CRC, tumour-draining lymph node status should be prudently evaluated by CECT.
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Affiliation(s)
- Shuai Chen
- Department of Radiology, The Second Hospital of Dalian Medical University, Zhongshan Road No.467, Shahekou District, Dalian, Liaoning, 116023, China
| | - Wenzhe Du
- Department of Radiology, The Second Hospital of Dalian Medical University, Zhongshan Road No.467, Shahekou District, Dalian, Liaoning, 116023, China
| | - Yuhai Cao
- Department of Radiology, The Second Hospital of Dalian Medical University, Zhongshan Road No.467, Shahekou District, Dalian, Liaoning, 116023, China
| | - Jixia Kong
- Department of Pathology, The Second Hospital of Dalian Medical University, Zhongshan Road No.467, Shahekou District, Dalian, Liaoning, 116023, China
| | - Xin Wang
- Department of Radiology, The Second Hospital of Dalian Medical University, Zhongshan Road No.467, Shahekou District, Dalian, Liaoning, 116023, China
| | - Yisen Wang
- Department of Radiology, The Second Hospital of Dalian Medical University, Zhongshan Road No.467, Shahekou District, Dalian, Liaoning, 116023, China
| | - Yang Lu
- Department of Radiology, The Second Hospital of Dalian Medical University, Zhongshan Road No.467, Shahekou District, Dalian, Liaoning, 116023, China.
| | - Xiang Li
- Department of Radiology, The Second Hospital of Dalian Medical University, Zhongshan Road No.467, Shahekou District, Dalian, Liaoning, 116023, China.
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Correlation of clinical, pathologic, and genetic parameters with intratumoral immune milieu in mucinous adenocarcinoma of the colon. Mod Pathol 2022; 35:1723-1731. [PMID: 35590108 DOI: 10.1038/s41379-022-01095-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 11/08/2022]
Abstract
Mucinous adenocarcinoma (MAD), the most common subtype of colonic adenocarcinoma (CA), requires >50% intratumoral mucin. There is limited data regarding the impact of MAD on key lymphocyte subsets and therapeutically critical immune elements. In this study we address: (1) the definition of MAD, (2) grading of MAD, and (3) the impact of MAD and extracellular mucin on intratumoral immune milieu. Estimation of the percentage of intratumoral mucin was performed by two pathologists. Tissue microarrays were stained for immune markers including CD8, CD163, PD-L1, FoxP3, β2 microglobulin, HLA class I, and HLA class II. Immunohistochemistry for BRAF V600E was performed. MMR status was determined on immunohistochemistry for MSH2, MSH6, MLH1, PMS2. Manual and automated HALO platforms were used for quantification. The 903 CAs included 62 (6.9%) MAD and 841 CA with ≤ 50% mucin. We identified 225 CAs with mucinous differentiation, defined by ≥10% mucin. On univariate analysis neither cut point, 50% (p = 0.08) and 10% (p = 0.08) mucin, correlated with disease-specific survival (DSS). There were no differences in key clinical, histological and molecular features between MAD and CA with mucinous differentiation. On univariate analysis of patients with MAD, tumor grade correlated with DSS (p = 0.0001) while MMR status did not (p = 0.86). There was no statistically significant difference in CD8 (P = 0.17) and CD163 (P = 0.05) positive immune cells between MAD and conventional CA. However, deficient (d) MMR MADs showed fewer CD8 (P = 0.0001), CD163 (P = 0.0001) and PD-L1 (P = 0.003) positive immune cells compared to proficient (p)MMR MADs, a finding also seen with at 10% mucin cut point. Although MAD does not impact DSS, this study raises the possibility that the immune milieu of dMMR MADs and tumors with > =10% mucin may differ from pMMR MADs and tumors with <10% mucin, a finding that may impact immune-oncology based therapeutics.
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Hosseini S, Nguyen N, Mohammadianpanah M, Mirzaei S, Bananzadeh AM. Predictive Significance of Mucinous Histology on Pathologic Complete Response Rate Following Capecitabine-Based Neoadjuvant Chemoradiation in Rectal Cancer: a Comparative Study. J Gastrointest Cancer 2020; 50:716-722. [PMID: 29984382 DOI: 10.1007/s12029-018-0136-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Currently, neoadjuvant fluoropyrimidine-based chemoradiation followed by surgery is considered the standard of care for locally advanced rectal cancer. The current study aimed to investigate the predictive significance of mucinous histology on the pathologic complete response rate following neoadjuvant chemoradiation in locally advanced rectal cancer and to propose potential new treatment protocol for this specific histology. MATERIAL AND METHOD This retrospective study was conducted on 403 patients with locally advanced (clinically T3-4 and/or N1-2) rectal adenocarcinoma who had been treated at three tertiary academic hospitals between 2010 and 2015. Among those 403 patients, 46 (11%) had mucinous rectal cancer (MRC) and 358 (89%) had non-mucinous rectal cancer (NMRC). All patients underwent neoadjuvant chemoradiation with capecitabine followed by low anterior or abdominoperineal resection. RESULTS There were 268 men and 135 women with a median age of 55 years (range, 26-82 years). Patients with MRC were younger (p = 0.002) and presented with a larger tumor size (p < 0.001) and a more advanced tumor stage (p = 0.033) compared to the ones with MNRC. In the univariate analysis, female gender (p = 0.009), distal tumor location (p = 0.035), higher tumor stage (p = 0.049), node positivity (p = 0.001), MRC histology (p = 0.017), and high pretreatment CEA level (p = 0.013) were observed to be predictive of a poor pathologic complete response. However, in the multivariate analysis, tumor stage was the single most predictive factor of response to neoadjuvant chemoradiation. CONCLUSION Mucinous adenocarcinoma is a significant predictive factor for poor pathologic complete response to neoadjuvant capecitabine-based chemoradiation in patients with locally advanced rectal cancer. New treatment modality based on biomarkers may be considered in future prospective studies because of MRC poor prognosis. Immunotherapy combined with chemotherapy and/or radiotherapy may be an attractive option because of the tumor microsatellite instability-high status.
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Affiliation(s)
- Sare Hosseini
- Cancer Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - NamPhong Nguyen
- Department of Radiation Oncology, Howard University Hospital, 2401 Georgia Avenue, NW, Room 2055, Washington, DC, 20060, USA
| | - Mohammad Mohammadianpanah
- Colorectal Research Center, Department of Radiation Oncology, Shiraz University of Medical Sciences, Shiraz, 71936, Iran.
| | - Sepideh Mirzaei
- Department of Radiation Oncology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammad Bananzadeh
- Colorectal Research Center, Department of Colorectal Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
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Reynolds IS, Furney SJ, Kay EW, McNamara DA, Prehn JHM, Burke JP. Meta-analysis of the molecular associations of mucinous colorectal cancer. Br J Surg 2019; 106:682-691. [PMID: 30945755 DOI: 10.1002/bjs.11142] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/31/2018] [Accepted: 01/03/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Mucinous differentiation occurs in 5-15 per cent of colorectal adenocarcinomas. This subtype of colorectal cancer responds poorly to chemoradiotherapy and has a worse prognosis. The genetic aetiology underpinning this cancer subtype lacks consensus. The aim of this study was to use meta-analytical techniques to clarify the molecular associations of mucinous colorectal cancer. METHODS This study adhered to MOOSE guidelines. Databases were searched for studies comparing KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), p53 and p27 status between patients with mucinous and non-mucinous colorectal adenocarcinoma. A random-effects model was used for analysis. RESULTS Data from 46 studies describing 17 746 patients were included. Mucinous colorectal adenocarcinoma was associated positively with KRAS (odds ratio (OR) 1·46, 95 per cent c.i. 1·08 to 2·00, P = 0·014) and BRAF (OR 3·49, 2·50 to 4·87; P < 0·001) mutation, MSI (OR 3·98, 3·30 to 4·79; P < 0·001) and CIMP (OR 3·56, 2·85 to 4·43; P < 0·001), and negatively with altered p53 expression (OR 0·46, 0·31 to 0·67; P < 0·001). CONCLUSION The genetic origins of mucinous colorectal adenocarcinoma are predominantly associated with BRAF, MSI and CIMP pathways. This pattern of molecular alterations may in part explain the resistance to standard chemotherapy regimens seen in mucinous adenocarcinoma.
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Affiliation(s)
- I S Reynolds
- Department of Surgery, Beaumont Hospital, Dublin, Ireland.,Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - S J Furney
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - E W Kay
- Department Pathology, Beaumont Hospital, Dublin, Ireland.,Department of Pathology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - D A McNamara
- Department of Surgery, Beaumont Hospital, Dublin, Ireland.,Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - J H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - J P Burke
- Department of Surgery, Beaumont Hospital, Dublin, Ireland
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Chen MS, Lo YH, Chen X, Williams CS, Donnelly JM, Criss ZK, Patel S, Butkus JM, Dubrulle J, Finegold MJ, Shroyer NF. Growth Factor-Independent 1 Is a Tumor Suppressor Gene in Colorectal Cancer. Mol Cancer Res 2019; 17:697-708. [PMID: 30606770 DOI: 10.1158/1541-7786.mcr-18-0666] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/20/2018] [Accepted: 12/19/2018] [Indexed: 12/27/2022]
Abstract
Colorectal cancer is the third most common cancer and the third leading cause of cancer death in the United States. Growth factor-independent 1 (GFI1) is a zinc finger transcriptional repressor responsible for controlling secretory cell differentiation in the small intestine and colon. GFI1 plays a significant role in the development of human malignancies, including leukemia, lung cancer, and prostate cancer. However, the role of GFI1 in colorectal cancer progression is largely unknown. Our results demonstrate that RNA and protein expression of GFI1 are reduced in advanced-stage nonmucinous colorectal cancer. Subcutaneous tumor xenograft models demonstrated that the reexpression of GFI1 in 4 different human colorectal cancer cell lines inhibits tumor growth. To further investigate the role of Gfi1 in de novo colorectal tumorigenesis, we developed transgenic mice harboring a deletion of Gfi1 in the colon driven by CDX2-cre (Gfi1F/F; CDX2-cre) and crossed them with ApcMin/+ mice (ApcMin/+; Gfi1F/F; CDX2-cre). Loss of Gfi1 significantly increased the total number of colorectal adenomas compared with littermate controls with an APC mutation alone. Furthermore, we found that compound (ApcMin/+; Gfi1F/F; CDX2-cre) mice develop larger adenomas, invasive carcinoma, as well as hyperplastic lesions expressing the neuroendocrine marker chromogranin A, a feature that has not been previously described in APC-mutant tumors in mice. Collectively, these results demonstrate that GFI1 acts as a tumor suppressor gene in colorectal cancer, where deficiency of Gfi1 promotes malignancy in the colon. IMPLICATIONS: These findings reveal that GFI1 functions as a tumor suppressor gene in colorectal tumorigenesis.
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Affiliation(s)
- Min-Shan Chen
- Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas
| | - Yuan-Hung Lo
- Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas
| | - Xi Chen
- Department of Public Health Sciences, University of Miami, Miami, Florida
| | - Christopher S Williams
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University, Nashville, Tennessee
| | - Jessica M Donnelly
- Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
| | - Zachary K Criss
- Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, Texas
| | - Shreena Patel
- Department of Pediatrics, Section of Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine, Houston, Texas
| | - Joann M Butkus
- Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas.,Summer Undergraduate Research Training Program, Baylor College of Medicine, Houston Texas.,Susquehanna University, Selinsgrove, Pennsylvania
| | - Julien Dubrulle
- Integrated Microscopy Core, Baylor College of Medicine, Houston, Texas
| | - Milton J Finegold
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
| | - Noah F Shroyer
- Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas. .,Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas.,Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, Texas
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Kim E, Kim K, Kim SH, Han SW, Kim TY, Jeong SY, Park KJ, Koh J, Kang GH, Chie EK. Impact of Mucin Proportion in the Pretreatment MRI on the Outcomes of Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy. Cancer Res Treat 2018; 51:1188-1197. [PMID: 30590006 PMCID: PMC6639202 DOI: 10.4143/crt.2018.434] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 12/19/2018] [Indexed: 12/18/2022] Open
Abstract
Purpose The purpose of this study was to evaluate treatment response to neoadjuvant chemoradiotherapy (CRT) with regard to mucin status in pathology and pretreatment magnetic resonance imaging (MRI) in locally advanced rectal cancer. Materials and Methods Between 2003 and 2011, 306 patients with locally advanced rectal cancer received neoadjuvant CRT followed by surgery, and mucinous adenocarcinoma (MAC) was found in 27 (8.8%). All MAC patients had MRI before and after CRT and mucin proportion at MRI was measured. Therapeutic response was assessed by pathology after total mesorectal excision. To determine the optimal cut-off for mucin proportion in predicting good CRT response (near total or total regression) and negative circumferential resection margin (CRM), the receiver-operating characteristic analysis was performed. Results After neoadjuvant CRT, overall downstaging occurred in 44.4% of MAC and 72.4% of non-MAC (p=0.001), and positive CRM (≤1 mm) was observed more frequently in MAC (p<0.001). The optimal threshold for treatment response was 30% for mucin proportion, and there are nine with low mucin proportion (<30%) and 18 with high mucin proportion (≥30%) in pretreatment MRI. Negative CRM and tumor downstaging occurred more common in patients with mucin <30%, although statistically insignificant (p=0.071 and p=0.072, respectively). Regarding oncologic outcomes, lower mucin proportion in pretreatment MRI was associated with better disease-free and overall survival in MAC group (p=0.092 and 0.056, respectively), but the difference did not reach statistical significance. Conclusion Poor treatment outcome with neoadjuvant CRT was observed in patients with MAC, especially those with high mucin proportion at pretreatment MRI.
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Affiliation(s)
- Eunji Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.,Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Kyubo Kim
- Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Korea
| | - Se Hyung Kim
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Sae-Won Han
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Seung-Yong Jeong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kyu Joo Park
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jaemoon Koh
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Eui Kyu Chie
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
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Gonzalez RS, Cates JMM, Washington K. Associations among histological characteristics and patient outcomes in colorectal carcinoma with a mucinous component. Histopathology 2018; 74:406-414. [PMID: 30160323 DOI: 10.1111/his.13748] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/25/2018] [Indexed: 12/25/2022]
Abstract
AIMS Colorectal carcinoma (CRC) often has a mucinous component, with more than 50% mucin by volume defining the mucinous subtype of CRC. The prognostic impact of the mucinous phenotype remains unclear. METHODS AND RESULTS We evaluated 224 CRC with at least 5% mucinous component (herein 'mCRC') for patient sex, age, race and outcome; tumour size, location, stage and microsatellite instability (MSI) status; percentage of glands producing mucin; percentage of tumour volume composed of mucin; whether tumoral epithelium floated in mucin pools; tumour budding; signet ring cells (SRCs); and peritumoural inflammation (PI). We related these features to disease-specific survival and compared outcomes to 499 stage-matched, conventional colorectal adenocarcinomas. Factors predicting worse prognosis in mCRC on univariable analysis included non-MSI-high status (P = 0.0008), SRC (P = 0.0017) and lack of PI (P = 0.0034). No parameters were independently associated with outcome after adjusting for tumour stage in multivariate analysis. The percentage of glands producing mucin and percentage tumour volume composed of mucin did not affect prognosis, including at the recommended 50% cut-off for subtyping mCRC. Disease-specific survival for mCRC and adenocarcinomas were similar after accounting for stage. CONCLUSIONS Stage-matched mCRCs and adenocarcinomas have similar outcomes, with no prognostic significance to morphological subtyping. Histological characteristics of mCRC, including percentage of tumour volume comprised of mucin, were not predictive of outcome.
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Affiliation(s)
- Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Justin M M Cates
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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10
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Hugen N, Simmer F, Mekenkamp LJM, Koopman M, van den Broek E, de Wilt JHW, Punt CJA, Ylstra B, Meijer GA, Nagtegaal ID. Reduced rate of copy number aberrations in mucinous colorectal carcinoma. Oncotarget 2016; 6:25715-25. [PMID: 26329972 PMCID: PMC4694861 DOI: 10.18632/oncotarget.4706] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 07/13/2015] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Mucinous carcinoma (MC) is found in 10%-15% of colorectal cancer (CRC) patients. It differs from the common adenocarcinoma (AC) in histopathological appearance and clinical behavior. METHODS Genome-wide DNA copy number and survival data from MC and AC primary CRC samples from patients from two phase III trials (CAIRO and CAIRO2) was compared. Chromosomal copy number data from The Cancer Genome Atlas (TCGA) was used for validation. Altogether, 470 ACs were compared to 57 MCs. RESULTS MC showed a reduced amount of copy number aberrations (CNAs) compared with AC for the CAIRO/CAIRO2 cohort, with a median amount of CNAs that was 1.5-fold lower (P = 0.002). Data from TCGA also showed a reduced amount of CNAs for MC. MC samples in both cohorts displayed less gain at chromosome 20q and less loss of chromosome 18p. A high rate of chromosomal instability was a strong negative prognostic marker for survival in MC patients from the CAIRO cohorts (hazard ratio 15.60, 95% CI 3.24-75.05). CONCLUSIONS Results from this study indicate that the distinct MC phenotype is accompanied by a different genetic basis when compared with AC and show a strong association between the rate of chromosomal instability and survival in MC patients.
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Affiliation(s)
- Niek Hugen
- Department of Surgery, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Femke Simmer
- Department of Pathology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Leonie J M Mekenkamp
- Department of Internal Medicine, Medical Spectrum Twente Enschede, 7500 KA Enschede, The Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
| | - Evert van den Broek
- Department of Pathology, VU University Medical Centre, 1007 MB Amsterdam, The Netherlands
| | - Johannes H W de Wilt
- Department of Surgery, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Cornelis J A Punt
- Department of Medical Oncology, Academic Medical Center University of Amsterdam, 1100 DD Amsterdam, The Netherlands
| | - Bauke Ylstra
- Department of Pathology, VU University Medical Centre, 1007 MB Amsterdam, The Netherlands
| | - Gerrit A Meijer
- Department of Pathology, VU University Medical Centre, 1007 MB Amsterdam, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
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Lee HS, Soh JS, Lee S, Bae JH, Kim KJ, Ye BD, Byeon JS, Myung SJ, Yang SK, Kim SA, Park YS, Lim SB, Kim JC, Yu CS, Yang DH. Clinical Features and Prognosis of Resectable Primary Colorectal Signet-Ring Cell Carcinoma. Intest Res 2015; 13:332-8. [PMID: 26576139 PMCID: PMC4641860 DOI: 10.5217/ir.2015.13.4.332] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 02/06/2015] [Accepted: 02/09/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS We attempted to investigate the prognosis of signet-ring cell carcinoma (SRC) patients who underwent curative surgery by comparing them with age-, sex-, and stage-matched non-mucinous adenocarcinoma (NMAC) patients. METHODS Between January 2003 and December 2011, 19 patients with primary SRC of the colorectum underwent curative surgery. Four SRC patients under the age of 40 were excluded, and the clinicopathological data of 15 patients (7 men; median age, 56 years) were reviewed and compared with the data of 75 NMAC patients matched by age, sex, and pathologic stage. RESULTS The median follow-up duration was 30.1 months for the SRC group and 43.7 months for the NMAC group (P=0.141). Involvement of the left side of the colon (73.3% vs. 26.7%, P=0.003) and infiltrative lesions such as Borrmann types 3 and 4 (85.7% vs. 24.0%, P=0.001) were more common in the SRC group than in the NMAC group. The five-year overall survival rate was significantly lower for patients with SRC than for those with NMAC (46.0% vs. 88.7%, hazard ratio, 6.99; 95% confidence interval, 2.33-20.95, P=0.001). CONCLUSIONS Patients with even resectable primary colorectal SRC had a poorer prognosis than age-, sex-, and stage-matched colorectal NMAC patients.
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Affiliation(s)
- Ho-Su Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jae Seung Soh
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seohyun Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jung Ho Bae
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Kyung-Jo Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Byong Duk Ye
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sun A Kim
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Young Soo Park
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seok-Byung Lim
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jin Cheon Kim
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Chang Sik Yu
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Ishihara S, Watanabe T, Akahane T, Shimada R, Horiuchi A, Shibuya H, Hayama T, Yamada H, Nozawa K, Matsuda K, Maeda K, Sugihara K. Tumor location is a prognostic factor in poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma of the colon. Int J Colorectal Dis 2012; 27:371-9. [PMID: 22052041 DOI: 10.1007/s00384-011-1343-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/20/2011] [Indexed: 02/04/2023]
Abstract
PURPOSE Cancers which arise in the proximal and distal colon are suggested to be different clinically, pathologically, and genetically. The aim of this study is to clarify whether clinical behavior of colonic poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-cell carcinoma (Por/Muc/Sig cancers), minor and aggressive subpopulation in colonic cancers, differs in accordance with the tumor location. METHODS A total of 3,175 patients with curatively resected colonic cancers were studied. Clinical and pathological features were compared between Por/Muc/Sig cancers and well or moderately differentiated adenocarcinomas (Wel/Mod cancers) and between proximal and distal cancers in each histologic type. RESULTS Por/Muc/Sig cancers (n = 213) were more advanced in the TNM stage and showed worse disease-specific survival than Wel/Mod cancers (n = 2,692). In Por/Muc/Sig cancers, but not in Wel/Mod cancers, proximal cancers showed significantly better disease-specific survival than distal cancers (88.9% vs. 76.5%, p = 0.0234), and a multivariate analysis showed that proximal tumor location was an independent predictor of fair prognosis (hazard ratio (HR), 0.458; 95% confidence interval (CI), 0.218-0.961; p = 0.0390). In addition, female gender also was an independent predictor of fair prognosis in Por/Muc/Sig cancers (HR, 0.373; 95% CI, 0.151-0.922) and not in Wel/Mod cancers. CONCLUSIONS Proximal Por/Muc/Sig cancers were suggested to be a distinct subpopulation with a favorable oncologic outcome. Tumor location and gender might be helpful in the risk stratification after curative surgery for Por/Muc/Sig cancers.
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Affiliation(s)
- Soichiro Ishihara
- Department of Surgery, Teikyo University, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
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A genome-wide study of cytogenetic changes in colorectal cancer using SNP microarrays: opportunities for future personalized treatment. PLoS One 2012; 7:e31968. [PMID: 22363777 PMCID: PMC3282791 DOI: 10.1371/journal.pone.0031968] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Accepted: 01/19/2012] [Indexed: 01/10/2023] Open
Abstract
In colorectal cancer (CRC), chromosomal instability (CIN) is typically studied using comparative-genomic hybridization (CGH) arrays. We studied paired (tumor and surrounding healthy) fresh frozen tissue from 86 CRC patients using Illumina's Infinium-based SNP array. This method allowed us to study CIN in CRC, with simultaneous analysis of copy number (CN) and B-allele frequency (BAF)--a representation of allelic composition. These data helped us to detect mono-allelic and bi-allelic amplifications/deletion, copy neutral loss of heterozygosity, and levels of mosaicism for mixed cell populations, some of which can not be assessed with other methods that do not measure BAF. We identified associations between CN abnormalities and different CRC phenotypes (histological diagnosis, location, tumor grade, stage, MSI and presence of lymph node metastasis). We showed commonalities between regions of CN change observed in CRC and the regions reported in previous studies of other solid cancers (e.g. amplifications of 20q, 13q, 8q, 5p and deletions of 18q, 17p and 8p). From Therapeutic Target Database, we identified relevant drugs, targeted to the genes located in these regions with CN changes, approved or in trials for other cancers and common diseases. These drugs may be considered for future therapeutic trials in CRC, based on personalized cytogenetic diagnosis. We also found many regions, harboring genes, which are not currently targeted by any relevant drugs that may be considered for future drug discovery studies. Our study shows the application of high density SNP arrays for cytogenetic study in CRC and its potential utility for personalized treatment.
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14
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Tug E, Balaban YH, Sahin EK. Mapping of microsatellite instability in endoscopic normal colon. Genet Test Mol Biomarkers 2012; 16:388-95. [PMID: 22224632 DOI: 10.1089/gtmb.2011.0219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Genomic instability in colorectal cancer (CRC) occurs as either microsatellite instability (MSI) or chromosomal instability. The present study was aimed at examining the MSI for the MLH1 and MSH2 genes in normal colon and polyps, if detected. Four segments of the colon were sampled in 102 subjects during colonoscopy. DNA samples were analyzed for the MSI status according to the Bethesda consensus panel. Family history of any type of cancer or for colon cancer was present in 44.8% and 9.4% of the individuals, respectively. Forty-eight percent of individuals were microsatellite stable for all five markers at all locations, 20% had low MSI status (MSI-L), and 32% had high MSI status (MSI-H). The frequencies of MSI markers differed significantly from each other (p=0.003). The most frequent positive marker was D17S250. This is the first study which revealed that MSI is present in endoscopically normal-looking colon of normal individuals and, more frequently, in individuals with family histories of CRC. The detection of very early-stage CRC is possible by MSI analysis of DNA mismatch repair genes in colon tissues. This study has revealed crucial information for the use of molecular tests in CRC screening, such as high frequencies of MSI in endoscopically normal colon, which might cause false positivity.
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Affiliation(s)
- Esra Tug
- Department of Medical Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey.
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Mekenkamp LJM, Heesterbeek KJ, Koopman M, Tol J, Teerenstra S, Venderbosch S, Punt CJA, Nagtegaal ID. Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer 2012; 48:501-9. [PMID: 22226571 DOI: 10.1016/j.ejca.2011.12.004] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 12/06/2011] [Accepted: 12/09/2011] [Indexed: 12/28/2022]
Abstract
PURPOSE Mucinous histology of metastatic colorectal cancer (CRC) has been associated with poor prognosis, however this has never been assessed in large well-defined study populations treated with the current used systemic agents. We investigated the prognostic value of mucinous histology in two large phase III studies in metastatic CRC. PATIENTS AND METHODS The study population included 1010 metastatic CRC patients who were treated with chemotherapy and targeted therapies in two phase III studies. Patients were classified according to the histology of the primary tumour in mucinous adenocarcinomas (MC) and non-mucinous adenocarcinomas (AC). RESULTS Patients with MC (n=99) were older, had more often a normal serum lactate dehydrogenase (LDH), extrahepatic localisation of metastases, larger primary tumour diameter and a higher T classification compared to patients with AC (n=911). A deficient mismatch repair system and BRAF mutations were observed in 17% and 22% of patients with MC, compared to 3% and 7% in patients with AC, respectively. Clinical outcome was investigated in both studies separately, showing a worse overall survival (OS), progression free survival and overall response rate in patients with MC compared to patients with AC. Patients with MC received less cycles of treatment compared to AC, but did not suffer from a higher incidence of grade 3/4 toxicity. In multivariate analysis, mucinous histology was as an independent negative prognostic factor for OS, resulting in a combined hazard ratio of 1.78 (95%confidence interval (CI) 1.35-2.35). CONCLUSIONS Patients with metastatic mucinous CRC have distinct clinicopathological features and poor response to chemotherapy and targeted agents. The strong negative prognostic value of MC warrants the use of this pathological feature as a stratification factor for clinical trials in metastatic CRC.
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Affiliation(s)
- Leonie J M Mekenkamp
- Department of Pathology, Radboud University Nijmegen Medical Centre, The Netherlands
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16
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Kim YG, Jang BI, Kim DH, Moon HJ, Oh HJ, Kim TN, Lee HM. A Matched Case-Control Study Using the Propensity Score on Differences in the Characteristics of Colorectal Polyps between Younger and Older Koreans: Proximal Shift in the Distribution of Colorectal Polyps among Older Koreans. Gut Liver 2010; 4:481-7. [PMID: 21253296 DOI: 10.5009/gnl.2010.4.4.481] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Accepted: 04/28/2010] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS Several studies have found that the frequency of colorectal polyps increases significantly from the age of 50 years. The goal of this study was to determine the differences in the clinical characteristics of colorectal polyps between patients aged 50 years and older, and younger patients. METHODS The colonoscopy database of 3,304 patients at the Yeungnam University Medical Center between January 2009 and December 2009 was reviewed retrospectively. In total, 679 patients were divided into the younger group (n=170) and the older group (aged ≥50 years) (n=509). A matched case-control study was performed using propensity scores and 117 patients selected from each group. RESULTS Compared to the younger group, the older group had a significantly higher proportion of female patients, and patients with hypertension, a smoking history, and a history of taking medications. After performing the matched case-control study, 234 patients and 679 colon polyps were included in the analysis. Compared to the younger patients, the older patients had a significantly higher proportion of multiple lesions (57.3% vs 25.6%, p<0.001), left- and right-side distribution (35.9% vs 12.0%, p<0.001), and larger polyps (mean 9.1 mm vs 6.3 mm, p<0.001). A left-sided distribution was less common in the older group than in the younger group (35.0% vs 51.3%, p=0.025). CONCLUSIONS The methods used to screen for colorectal cancer in older patients should include colonoscopy due to the shift to the right side as a common location for colorectal polyps in that age group.
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Affiliation(s)
- Yong Gil Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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Arai T, Kasahara I, Sawabe M, Honma N, Aida J, Tabubo K. Role of methylation of the hMLH1 gene promoter in the development of gastric and colorectal carcinoma in the elderly. Geriatr Gerontol Int 2010; 10 Suppl 1:S207-12. [PMID: 20590835 DOI: 10.1111/j.1447-0594.2010.00590.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The occurrence of malignant neoplasms increases with advancing age. Although aging and carcinogenesis are basically different processes, they share phenomena such as the accumulation of DNA damage and abnormal proteins. Recent advances in molecular biology have shown an accumulation of genetic and epigenetic changes in both aging and carcinogenesis, as well as the alteration of metabolism, immunosenescence and shortened telomeres. DNA methylation is a representative epigenetic phenomenon and is frequently involved in controlling gene functions during development and tumorigenesis. We herein focused on methylation of genes in the development of gastrointestinal carcinomas in the elderly. The proportion of gastric and colorectal carcinomas with hypermethylation of the hMLH1 promoter increases with age, reaching 25-30% of all carcinomas of the stomach and large intestine in elderly patients. These tumors have clinicopathological and molecular characteristics such as loss of hMLH1 expression, microsatellite instability, poorly differentiated histology, peritumoral inflammatory cell infiltration, low incidence of lymph node metastasis and favorable prognosis. However, methylation-related carcinogenesis accounts for up to approximately one-third of tumors, and other mechanisms; for example chromosomal instability as a result of telomere dysfunction, are responsible for the development of most carcinomas in the elderly.
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Affiliation(s)
- Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
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18
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Kang J, Min BS, Park YA, Kim NK, Sohn SK, Cho CH, Lee KY. Mucinous Histology as a Predictive Marker of 5-Fluorouracil-based Adjuvant Chemotherapy for Colon Cancer. JOURNAL OF THE KOREAN SOCIETY OF COLOPROCTOLOGY 2009. [DOI: 10.3393/jksc.2009.25.4.241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Jeonghyun Kang
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Byung Soh Min
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Ah Park
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Nam Kyu Kim
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Kook Sohn
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Chang Hwan Cho
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Kang Young Lee
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
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Analysis of genomic instability in adult-onset celiac disease patients by microsatellite instability and loss of heterozygosis. Eur J Gastroenterol Hepatol 2008; 20:1159-66. [PMID: 18946361 DOI: 10.1097/meg.0b013e3283094ee9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS Malignant complications of celiac disease (CD) include carcinomas and lymphomas. The genetic basis behind cancer development in CD is not known, but acquisition of genetic abnormalities and genomic instability has been involved. The aim of this study was to explore molecular characteristics of genomic instability in CD patients by analyzing microsatellite instability (MSI) and loss of heterozygosis (LOH) with carefully selected microsatellites. METHODS We genotyped small bowel biopsies and peripheral blood samples from 20 untreated CD patients using five microsatellites related to MMR genes (panel A), and five repeats associated with tumor suppressor genes, chromosome instability, inflammation, and cancer (panel B). RESULTS Genomic instability was found in seven out of 20 (35%) cases at: D5S107, D18S58, GSTP, TP53 or DCC, being TP53 the most frequently affected (five out of seven cases; 71%). Microsatellite alterations were significantly found using panel B markers (P=0.04). No cases with high frequency of MSI and replication error phenotype were detected. Only one case displayed MSI-L alone. Three patients exhibited LOH and three other cases showed LOH with low level of MSI, being classified as having chromosome instability phenotype. CONCLUSION Two novel observations were found in this study: first, the finding that non-neoplastic cells from a group of untreated CD patients present genomic instability at nucleotide level; and second, the advantage to use carefully selected microsatellites to identify celiac patients with molecular instability. Our data support the existence of chromosome instability phenotype in CD, suggesting that stable and unstable patients are genomically distinct subtypes that may follow a different evolution.
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Horii J, Hiraoka S, Kato J, Harada K, Kuwaki K, Fujita H, Toyooka S, Yamamoto K. Age-related methylation in normal colon mucosa differs between the proximal and distal colon in patients who underwent colonoscopy. Clin Biochem 2008; 41:1440-8. [PMID: 18835263 DOI: 10.1016/j.clinbiochem.2008.08.089] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2008] [Revised: 08/12/2008] [Accepted: 08/26/2008] [Indexed: 01/11/2023]
Abstract
OBJECTIVES To examine the difference in the methylation status in normal colon mucosa between the proximal and distal colon, in relation to the correlation between the methylation status of normal mucosa and characteristics of neoplasia. DESIGN AND METHODS Paired biopsy specimens of normal mucosa from the proximal and distal colon of 82 patients who underwent colonoscopy were obtained. The methylation status of the promoter region of estrogen receptor 1 (ESR1) and myogenic differentiation 1 (MYOD1) was examined. RESULTS Normal mucosa was more highly methylated in the distal than in the proximal colon in both ESR1 and MYOD1 loci (p<0.0001 and p=0.0009, respectively). Advanced characteristics of polyps in the distal colon were frequently observed in patients with lower methylation of ESR1 in the distal colon normal mucosa. CONCLUSIONS Methylation levels in normal mucosa differ between the proximal and distal colon, and lower methylation of ESR1 in the distal colon normal mucosa may correlate with advanced features of neoplasia in the distal colon.
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Affiliation(s)
- Joichiro Horii
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Kazama Y, Watanabe T, Kanazawa T, Tanaka J, Tanaka T, Nagawa H. Poorly differentiated colorectal adenocarcinomas show higher rates of microsatellite instability and promoter methylation of p16 and hMLH1: a study matched for T classification and tumor location. J Surg Oncol 2008; 97:278-83. [PMID: 18161865 DOI: 10.1002/jso.20960] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Extensive genetic and epigenetic analysis of poorly differentiated colorectal adenocarcinomas (Por) has been difficult, as the number of cases is too small. METHODS We investigated genetic and epigenetic alterations of 53 cases of Por and 53 cases of well-differentiated colorectal adenocarcinomas (WD) to clarify their differences. The cases of WD were matched with the cases of Por for T classification and tumor location, which influence genetic and epigenetic alterations. We evaluated microsatellite instability (MSI) status and loss of heterozygosity (LOH) of four loci (2p, 5q, 17p, 18q), and defined "MSI tumors" as those that showed MSI-H, and "chromosomal instability (CIN) tumors" as those that showed LOH but not MSI-H. Further, we evaluated the methylation status of the hMLH1 and p16 promoter region. RESULTS MSI tumors were significantly more frequent in Por (22.6%) than in WD (3.8%; P = 0.0041). CIN tumors were significantly less frequent in Por (64.2%) than in WD (83.0%; P = 0.046). Further, methylation of the p16 and hMLH1 promoter region was significantly more frequent in Por than in WD (P = 0.037, P = 0.047, respectively). CONCLUSIONS Our results indicate that Por tumorigenesis strongly correlates with MSI and methylation of the p16 and hMLH1 promoter region.
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Affiliation(s)
- Yoshihiro Kazama
- Department of Surgical Oncology, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.
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High MUC2 immunohistochemical expression is a predictor of poor response to preoperative radiochemotherapy (RCT) in rectal adenocarcinoma. Appl Immunohistochem Mol Morphol 2008; 16:227-31. [PMID: 18301248 DOI: 10.1097/pai.0b013e3181545944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The purpose of this study is to establish if mucoid differentiation is associated with responsiveness to preoperative radiochemotherapy (RCT) in rectal adenocarcinomas. Thirty-two patients with rectal adenocarcinomas were preoperatively treated with 44 to 46 Gy in 22 to 23 fractions and with 5-fluorouracil (200 to 225 mg/m) before surgery. Mucoid differentiation was searched for both in pre-RCT biopsies with anti-MUC2 antiserum and in postoperative specimens. To evaluate the responsiveness to preoperative RCT, a regression grading was used (grades 0 to 4). Statistical analysis showed a significant negative correlation between immunohistochemical expression of MUC2 in pre-RCT biopsies and regression grade in postoperative specimens (r=-0.529; P=0.002). A significant cutoff value of 60% of MUC2 positive neoplastic cells in pre-RCT biopsies was observed (P=0.018): 13 cases with more than 60% exhibited a poor response to RCT (grade 0 in 5/13, grade 1 in 4/13, grade 2 in 4/13), whereas 19 cases with less than 60% showed a better response to RCT (grade 1 in 6/19, grade 2 in 9/19, grade 3 in 3/19, grade 4 in 1/19).
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Distinguishing benign dissecting mucin (stromal mucin pools) from invasive mucinous carcinoma. Adv Anat Pathol 2008; 15:1-17. [PMID: 18156808 DOI: 10.1097/pap.0b013e31815e52aa] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mucin dissecting stroma suggests the presence of an invasive mucinous (colloid) carcinoma. However, in virtually every organ in which invasive mucinous carcinoma exists, there exist benign mimickers associated with dissecting mucin. This article reviews diagnostic criteria for the differential diagnosis of mucinous lesions of the breast, pancreas, biliary tract, colon, appendix, and bladder, emphasizing practical points, which we find helpful in daily diagnostic surgical pathology practice.
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Arai T, Takubo K. Clinicopathological and molecular characteristics of gastric and colorectal carcinomas in the elderly. Pathol Int 2007; 57:303-14. [PMID: 17539960 DOI: 10.1111/j.1440-1827.2007.02101.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The occurrence of malignant neoplasms increases with advancing age. Although aging and carcinogenesis are basically different processes, there are phenomena common to each such as accumulation of DNA damage and abnormal proteins. Gastric and colorectal carcinomas are representative tumors in which the prevalence and the number of patients increase significantly with age. Compared with gastric and colorectal cancers occurring in younger patients, those occurring in older patients have clinicopathological differences in tumor location, gender distribution, histological type, histological diversity, multiplicity, incidence of lymph node metastasis, and prognosis. In the elderly there are peculiar types of carcinoma such as medullary-type poorly differentiated colorectal adenocarcinoma and solid-type poorly differentiated gastric adenocarcinoma, both of which occur in older women. Methylation, apoptosis, and telomere dysfunction play important roles in the development of gastric and colorectal cancers in the elderly.
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Affiliation(s)
- Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Sakaecho, Tokyo, Japan.
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Arai T, Kasahara I, Sawabe M, Kanazawa N, Kuroiwa K, Honma N, Aida J, Takubo K. Microsatellite-unstable mucinous colorectal carcinoma occurring in the elderly: comparison with medullary type poorly differentiated adenocarcinoma. Pathol Int 2007; 57:205-12. [PMID: 17316416 DOI: 10.1111/j.1440-1827.2007.02082.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Mucinous carcinoma and poorly differentiated adenocarcinoma of the large intestine have a high frequency of microsatellite instability, and their occurrence increases gradually with age. To elucidate the clinicopathological and immunohistochemical features of microsatellite-unstable mucinous carcinoma and compare the tumor with medullary type poorly differentiated adenocarcinoma, the clinicopathological status and expression of mucin core and hMLH1 proteins were studied in 15 microsatellite-unstable and 20 microsatellite-stable mucinous colorectal carcinomas occurring in elderly patients, and compared with 23 cases of medullary type poorly differentiated adenocarcinoma in which 21 cases were microsatellite-unstable. Thirteen (87%) of 15 microsatellite-unstable carcinomas exhibited absent hMLH1 expression compared with three (15%) of 20 microsatellite-stable carcinomas (P < 0.01). The proportion (87%) of positive MUC5AC expression in microsatellite-unstable mucinous carcinoma was significantly higher than that (45%) in microsatellite-stable mucinous carcinoma (P = 0.01). Compared with microsatellite-stable mucinous carcinoma, microsatellite-unstable mucinous carcinomas were significantly associated with a proximal location, intra- and peritumoral inflammatory cell infiltration, frequent MUC5AC expression, a low incidence of lymph node metastasis and absent hMLH1 protein expression, which is not different to medullary type poorly differentiated adenocarcinoma except for MUC2 expression and age-related occurrence. These results suggest that microsatellite-unstable mucinous carcinoma occurring in the elderly shares clinicopathological and molecular features with medullary type poorly differentiated adenocarcinoma and that microsatellite instability with absent hMLH1 expression plays an important role in the development of these two carcinomas.
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Affiliation(s)
- Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Sakaecho, Tokyo, Japan.
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Maestro ML, Vidaurreta M, Sanz-Casla MT, Rafael S, Veganzones S, Martínez A, Aguilera C, Herranz MD, Cerdán J, Arroyo M. Role of the BRAF mutations in the microsatellite instability genetic pathway in sporadic colorectal cancer. Ann Surg Oncol 2006; 14:1229-36. [PMID: 17195912 DOI: 10.1245/s10434-006-9111-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2006] [Revised: 05/19/2006] [Accepted: 05/23/2006] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Between 10 and 15% of all cases of colorectal cancer are the result of microsatellite instability (MSI) in the genetic pathway due to an alteration in the DNA repair genes. Tumors with high MSI are characterized by a better prognosis. The BRAF oncogene has been linked to the MSI pathway in tumorogenesis. The objective of this study was to determine whether alterations in BRAF are related to MSI and whether they can result in differences in survival rates. METHODS The study cohort comprised 351 patients diagnosed with sporadic colorectal cancer. MSI was determined in accordance with the National Cancer Institute's (NCI) recommendations by means of PCR and sequence analyses. Mutational analysis of the BRAF gene was performed by real-time PCR and subsequent sequencing of the altered samples. The methylation pattern of the hMLH1 gene was determined using methylation-specific PCR analyses of bisulfite-treated DNA and the results confirmed by sequencing. RESULTS Of the patients tested, 6.9% showed high MSI and 3.7% showed a BRAF gene mutation. hMLH1 methylation was observed in 67.2% of the patients with MSI and/or the BRAF alteration. The BRAF mutation was related to the MSI genetic pathway (P < 0.0001) and with hMLH1 methylation. In the analysis of overall survival only MSI had an independent prognostic value for the risk of death. Patients with the BRAF mutation showed a higher risk of death, although this association was found not to be statistically significant. CONCLUSIONS There is a subgroup of carcinomas which develop via the MSI pathway that carry an alteration of the BRAF gene. This alteration confers a poorer outcome on these patients within the total group of patients with MSI who have a better prognosis. This hypothesis should be further investigated in a larger study population due to the low incidence of BRAF mutations in colorectal cancer.
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Affiliation(s)
- M L Maestro
- Department of Clinical Analysis, Hospital Clínico San Carlos, Madrid, Spain.
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Stelow EB, Moskaluk CA, Mills SE. The mismatch repair protein status of colorectal small cell neuroendocrine carcinomas. Am J Surg Pathol 2006; 30:1401-4. [PMID: 17063080 DOI: 10.1097/01.pas.0000213272.15221.38] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Small cell neuroendocrine carcinoma (SCNC) of the colorectum is a rare and highly aggressive malignancy. It can be associated with conventional-type adenocarcinoma, and an overlying adenoma can often be identified. A disproportionate number has been noted to arise in the right colon. Although some phenotypes (eg, mucinous adenocarcinoma) have been shown to be associated with deficient mismatch repair (MMR) and thus microsatellite instability (MSI), the MMR protein status of colorectal SCNCs has not been investigated. This study investigated the status of 3 MMR proteins, hMLH1, hMSH2, and hMSH6, in SCNCs of the colorectum. Fifteen SCNCs were identified on the basis of previous descriptions and the World Health Organization histologic criteria for the diagnosis of pulmonary small cell carcinoma and immunohistochemical evidence of epithelial and neuroendocrine differentiation. Patient age and sex and tumor size and location were recorded. Immunohistochemistry was performed with antibodies to pancytokeratin (cocktail), CD56, neuron specific enolase, synaptophysin, chromogranin, hMLH1, hMSH2, and hMSH6. Patients' ages ranged from 44 to 87 years (mean age = 73 y) and there were 9 men and 6 women. Tumors were located in the right colon (6), sigmoid colon (4), and rectum (3) (the locations of 2 cases were not recorded) and ranged in size from 0.4 to 15 cm in greatest dimension (mean = 6.6 cm). All tumors showed immunoreactivity with antibodies to pancytokeratin and with antibodies to at least 1 neuroendocrine antigen. MMR proteins were intact by immunohistochemistry in all but a single case that had neither an identifiable precursor lesion nor positive internal control (hMLH1 loss). Colorectal SCNCs are rare and are often right-sided. They are aggressive and tend to occur in older individuals. Most colorectal SCNCs have intact MMR proteins, suggesting that they develop secondary to chromosomal instability rather than MSI. Our single case showing potential MMR protein loss suggests that this phenotype may be independent of the developmental pathway (ie, chromosomal instability vs. MSI). This may explain the rare cases of SCNC that have been identified in patients with hereditary nonpolyposis colon cancer.
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Affiliation(s)
- Edward B Stelow
- Robert E Fechner Surgical Pathology Laboratory, University of Virginia, Charlottesville, VA, USA.
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Watanabe T, Kobunai T, Toda E, Yamamoto Y, Kanazawa T, Kazama Y, Tanaka J, Tanaka T, Konishi T, Okayama Y, Sugimoto Y, Oka T, Sasaki S, Muto T, Nagawa H. Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers. Cancer Res 2006; 66:9804-8. [PMID: 17047040 DOI: 10.1158/0008-5472.can-06-1163] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Promoter methylation of the mismatch repair gene plays a key role in sporadic microsatellite instability (MSI) colorectal cancers. However, promoter methylation often occurs in proximal colon cancers, and molecular phenotypes underlying MSI cancers in distal colon have not been fully clarified. Our goal was to clarify the difference between MSI and microsatellite stability (MSS) cancers and, furthermore, to determine distinct characteristics of proximal and distal MSI cancers. By DNA microarray analysis of 84 cancers (33 MSI and 51 MSS), we identified discriminating genes (177 probe sets), which predicted MSI status with a high accuracy rate (97.6%). These genes were related to phenotypic characteristics of MSI cancers. Next, we identified 24 probe sets that were differentially expressed in proximal and distal MSI cancers. These genes included promoter methylation-mediated genes, whose expression was significantly down-regulated in proximal MSI cancers. Among discriminating genes between MSI and MSS, nine methylation-mediated genes showed down-regulation in MSI cancers. Of these, 7 (77.8%) showed down-regulation in proximal MSI cancers. Furthermore, methylation-specific PCR confirmed that frequency of hMLH1 promoter methylation was significantly higher in proximal MSI cancers (P = 0.0317). These results suggested that there is a difference between proximal and distal MSI cancers in methylation-mediated influence on gene silencing. In conclusion, using DNA microarray, we could distinguish MSI and MSS cancers. We also showed distinct characteristics of proximal and distal MSI cancers. The inactivation form of hMLH, per se, differed between proximal and distal MSI cancers. These results suggested that distal MSI cancers constitute a distinct subgroup of sporadic MSI cancers.
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Affiliation(s)
- Toshiaki Watanabe
- Department of Surgery, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
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Lim SB, Jeong SY, Kim IJ, Kim DY, Jung KH, Chang HJ, Choi HS, Sohn DK, Kang HC, Shin Y, Jang SG, Park JH, Park JG. Analysis of microsatellite instability in stool DNA of patients with colorectal cancer using denaturing high performance liquid chromatography. World J Gastroenterol 2006; 12:6689-92. [PMID: 17075985 PMCID: PMC4125677 DOI: 10.3748/wjg.v12.i41.6689] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) for analyzing microsatellite instability (MSI) status in stool DNA of patients with colorectal cancer.
METHODS: A total of 80 cancer tissues from patients with primary sporadic colorectal tumor (proximal cancer: 27, distal cancer: 53) and matched stool (which were employed for comparison with the tissues) were analyzed for MSI status in BAT 26. DNA samples extracted from stool were evaluated by nested polymerase chain reaction (PCR) and DHPLC for MSI analysis.
RESULTS: Six cases (7.5%) of MSI were identified in BAT 26 from 80 cancer tissues. All the stool DNA samples from patients whose cancer tissue showed MSI also displayed MSI in BAT 26.
CONCLUSION: As MSI is one of the established fecal DNA markers to screen colorectal cancer, we propose to use DHPLC for the MSI analysis in fecal DNA.
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Affiliation(s)
- Seok-Byung Lim
- Research Institute and Hospital, National Cancer Center, Goyang, and Cancer Research Institute and Cancer Research Center, Seoul National University, Seoul, Korea
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Park SY, Lee HS, Choe G, Chung JH, Kim WH. Clinicopathological characteristics, microsatellite instability, and expression of mucin core proteins and p53 in colorectal mucinous adenocarcinomas in relation to location. Virchows Arch 2006; 449:40-7. [PMID: 16645863 DOI: 10.1007/s00428-006-0212-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2006] [Accepted: 03/30/2006] [Indexed: 12/16/2022]
Abstract
It has been suggested that right-sided and left-sided colorectal cancer may arise by different mechanisms. However, there have been few studies of mucinous adenocarcinoma (MA) in relation to location. Therefore, we analyzed clinicopathological characteristics, microsatellite instability (MSI), and expression of MUC1, MUC2, MUC5AC mucin core proteins, and p53 by immunohistochemistry in relation to tumor location. Ninety-six consecutive colorectal MAs and ninety-eight nonmucinous adenocarcinomas (nMAs) were investigated. Right-sided MAs, by comparison with those on the left side, were characterized by older age, larger tumor size, lower stage at presentation, peritumoral lymphocytic response, background of serrated adenoma, MSI-H phenotype, higher MUC2 and MUC5AC expression, and lower p53 protein overexpression. Right-sided nMAs, relative to those on the left side, were associated with MSI-H phenotype, higher MUC2 and MUC5AC expression, and lower p53 protein overexpression. Thus, MSI-H phenotype, expression of MUC2 and MUC5AC, and infrequent p53 protein overexpression are associated with right-sided location as well as mucinous histology. In univariate analysis, right-sided location had a favorable effect on disease specific survival of the patients with MA, although it is not an independent predictor of survival. Our results indicate that MA is a distinctive form of colorectal cancer and has different phenotypes depending on tumor location.
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Affiliation(s)
- So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, South Korea
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