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Yilmaz O, Arora K, Lee SH, Hosseini S, Chen F, Padmanabha N, Eng G, Kantekure K, Yilmaz O, Deshpande V. LGR5 as a diagnostic marker for dysplasia in serrated polyps. J Clin Pathol 2025:jcp-2024-209856. [PMID: 39788729 DOI: 10.1136/jcp-2024-209856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
AIMS WNT signalling pathway dysregulation is often a critical early component in colorectal neoplasia, particularly the chromosomal instability pathway. Using two WNT reporters, LGR5 and AXIN2, we sought to assess whether these polyps demonstrate predictable expression patterns and if these patterns show diagnostic value. METHODS We evaluated 23 adenomas (TA), 23 sessile serrated lesions (SSLs), 14 SSL with dysplasia and 38 traditional serrated adenomas (TSA). Chromogenic in situ hybridisation stains (ISH) for LGR5 and AXIN2 were performed. Reactivity was defined as strong, intermediate or weak. Upper third crypt reactivity was defined as full-thickness staining. Accentuation within ectopic crypts (ECF) was recorded. RESULTS TAs (91%) showed strong reactivity and full-thickness staining with LGR5. TSAs showed full-thickness and weak to intermediate LGR5 reactivity (79%) and ECF with LGR5 accentuation was exclusively seen in TSA. SSL showed weak LGR5 reactivity confined to the basal crypt region (100%). SSL with dysplasia also showed weak or intermediate (100%) LGR5 reactivity, but the reactivity pattern was full thickness (88%). AXIN2 expression parallels LGR5 expression (Pearson coefficient=0.63) regarding signal intensity for the examined polyp groups. CONCLUSIONS Qualitative and quantitative differences in AXIN2 and LGR5 expression assist in the diagnosis of SSL with dysplasia.
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Affiliation(s)
- Osman Yilmaz
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Kshtij Arora
- Massachusetts General Hospital, Wuincy, Massachusetts, USA
| | - Soo Hyun Lee
- Boston Medical Center, Boston, Massachusetts, USA
| | | | - Feidi Chen
- Harvard Medical School, Boston, Massachusetts, USA
| | - Nandan Padmanabha
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - George Eng
- Harvard Medical School, Boston, Massachusetts, USA
| | | | - Omer Yilmaz
- Massachusetts General Hospital, Boston, Massachusetts, USA
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Sugai T, Uesugi N, Osakabe M, Yao T, Yanagawa N, Ajioka Y. Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype. Hum Pathol 2024; 145:9-15. [PMID: 38218351 DOI: 10.1016/j.humpath.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/03/2023] [Accepted: 12/19/2023] [Indexed: 01/15/2024]
Abstract
Recent studies have shown that sessile serrated lesions (SSLs) lead to the development of colorectal cancer (CRC) with a microsatellite instability (MSI) phenotype via a dysplasia-carcinoma sequence. However, the pathological and molecular mechanisms of SSL with dysplasia (SSLD) are unclear. Here, we aimed to examine the clinicopathological and molecular alterations in SSLD and to evaluate the significance of such alterations with regard to lesion progression. Fifty-four SSLDs (20 serrated dysplasia cases and 17 intestinal dysplasia cases, including 30 low-grade dysplasia [LGD] cases, 7 high-grade dysplasia [HGD] cases, and 17 intramucosal adenocarcinomas [IMAs]) were evaluated. Molecular alterations, including immunohistochemical expression of various markers, DNA methylation status, and multiple genetic mutations (using next-generation sequencing), were assessed. Additionally, such alterations were also investigated in 41 CRCs with an MSI phenotype (invasion beyond submucosa). The frequency of mismatch repair (MMR) deficiency in SSLD was 12 of 39 cases (32.4 %), whereas the MMR proficient type was observed in 17 of 39 SSLD cases. SSLD with serrated dysplasia showed a significantly higher frequency of loss of MMR protein expression and methylation status. Moreover, loss of MMR protein expression differed significantly between LGD and IMA. Furthermore, the frequency of TP53 mutation was significantly higher in IMA than in LGD. The current findings demonstrated that SSL with serrated dysplasia may be associated with an increased risk of malignant transformation compared with intestinal dysplasia. Loss of MMR proteins and mutation of TP53 may play important roles in tumor progression from dysplasia to carcinomatous lesions.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan; Diagnostic Pathology Center, Southern Tohoku General Hospital, 7-115, Yatsuyamada, Kooriyama City, Fukushima, 963-8563, Japan.
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan; Diagnostic Pathology Center, Southern Tohoku General Hospital, 7-115, Yatsuyamada, Kooriyama City, Fukushima, 963-8563, Japan
| | - Mistumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan
| | - Takashi Yao
- Department of Diagnostic Pathology, Juntendo University, Tokyo, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun'yahabachou, 028-3695, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, 757, Cyuo-Asahi, 951-8510, Niigata, Japan
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Vu NTH, Le HM, Vo DTN, Vu HA, Le NQ, Ho DDQ, Quach DT. Prevalence, risk factors, and BRAF mutation of colorectal sessile serrated lesions among Vietnamese patients. World J Clin Oncol 2024; 15:290-301. [PMID: 38455129 PMCID: PMC10915949 DOI: 10.5306/wjco.v15.i2.290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 12/25/2023] [Accepted: 01/12/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Sessile serrated lesions (SSLs) are considered precancerous colorectal lesions that should be detected and removed to prevent colorectal cancer. Previous studies in Vietnam mainly investigated the adenoma pathway, with limited data on the serrated pathway. AIM To evaluate the prevalence, risk factors, and BRAF mutations of SSLs in the Vietnamese population. METHODS This is a cross-sectional study conducted on patients with lower gastrointestinal symptoms who underwent colonoscopy at a tertiary hospital in Vietnam. SSLs were diagnosed on histopathology according to the 2019 World Health Organization classification. BRAF mutation analysis was performed using the Sanger DNA sequencing method. The multivariate logistic regression model was used to determine SSL-associated factors. RESULTS There were 2489 patients, with a mean age of 52.1 ± 13.1 and a female-to-male ratio of 1:1.1. The prevalence of SSLs was 4.2% [95% confidence interval (CI): 3.5-5.1]. In the multivariate analysis, factors significantly associated with SSLs were age ≥ 40 [odds ratio (OR): 3.303; 95%CI: 1.607-6.790], male sex (OR: 2.032; 95%CI: 1.204-3.429), diabetes mellitus (OR: 2.721; 95%CI: 1.551-4.772), and hypertension (OR: 1.650, 95%CI: 1.045-2.605). The rate of BRAF mutations in SSLs was 35.5%. CONCLUSION The prevalence of SSLs was 4.2%. BRAF mutations were present in one-third of SSLs. Significant risk factors for SSLs included age ≥ 40, male sex, diabetes mellitus, and hypertension.
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Affiliation(s)
- Nhu Thi Hanh Vu
- Department of Internal Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
- GI Endoscopy Department, University Medical Center at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Huy Minh Le
- GI Endoscopy Department, University Medical Center at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
- Department of Histology-Embryology and Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Diem Thi-Ngoc Vo
- Department of Histology-Embryology and Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Hoang Anh Vu
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Nhan Quang Le
- GI Endoscopy Department, University Medical Center at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
| | - Dung Dang Quy Ho
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh 700000, Viet Nam
| | - Duc Trong Quach
- Department of Internal Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
- GI Endoscopy Department, University Medical Center at Ho Chi Minh City, Ho Chi Minh 700000, Viet Nam
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Lee JWJ, Plichta DR, Asher S, Delsignore M, Jeong T, McGoldrick J, Staller K, Khalili H, Xavier RJ, Chung DC. Association of distinct microbial signatures with premalignant colorectal adenomas. Cell Host Microbe 2023; 31:827-838.e3. [PMID: 37130517 PMCID: PMC10477964 DOI: 10.1016/j.chom.2023.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 02/24/2023] [Accepted: 04/04/2023] [Indexed: 05/04/2023]
Abstract
Environmental exposures are a major risk factor for developing colorectal cancer, and the gut microbiome may serve as an integrator of such environmental risk. To study the microbiome associated with premalignant colon lesions, such as tubular adenomas (TAs) and sessile serrated adenomas (SSAs), we profiled stool samples from 971 participants undergoing colonoscopy and paired these data with dietary and medication history. The microbial signatures associated with either SSA or TA are distinct. SSA associates with multiple microbial antioxidant defense systems, whereas TA associates with a depletion of microbial methanogenesis and mevalonate metabolism. Environmental factors, such as diet and medications, link with the majority of identified microbial species. Mediation analyses found that Flavonifractor plautii and Bacteroides stercoris transmit the protective or carcinogenic effects of these factors to early carcinogenesis. Our findings suggest that the unique dependencies of each premalignant lesion may be exploited therapeutically or through dietary intervention.
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Affiliation(s)
- Jonathan Wei Jie Lee
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore 119228, Singapore; iHealthtech, National University of Singapore, Singapore 117599, Singapore; SynCTI, National University of Singapore, Singapore 117456, Singapore.
| | | | - Shreya Asher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Marisa Delsignore
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Tiffany Jeong
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Jessica McGoldrick
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Kyle Staller
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
| | - Daniel C Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Cancer Risk Assessment, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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5
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Murakami T, Kurosawa T, Fukushima H, Shibuya T, Yao T, Nagahara A. Sessile serrated lesions: Clinicopathological characteristics, endoscopic diagnosis, and management. Dig Endosc 2022; 34:1096-1109. [PMID: 35352394 DOI: 10.1111/den.14273] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/30/2022] [Accepted: 02/13/2022] [Indexed: 02/08/2023]
Abstract
The 2019 World Health Organization (WHO) Classification of Tumours of the Digestive System (5th edition) introduced the term "sessile serrated lesion" (SSL) to replace the term "sessile serrated adenoma/polyp" (SSA/P). SSLs are early precursor lesions in the serrated neoplasia pathway that result in colorectal carcinomas with BRAF mutations, methylation for DNA repair genes, a CpG island methylator phenotype, and high levels of microsatellite instability. Some of these lesions can rapidly become dysplastic or invasive carcinomas that exhibit high lymphatic invasion and lymph node metastasis potential. The 2019 WHO classification noted that dysplasia arising in an SSL most likely is an advanced polyp, regardless of the morphologic grade of the dysplasia. Detecting SSLs with or without dysplasia is critical; however, detection of SSLs is challenging, and their identification by endoscopists and pathologists is inconsistent. Furthermore, indications for their endoscopic treatment have not been established. Moreover, SSLs are considered to contribute to the development of post-colonoscopy colorectal cancers. Herein, the clinicopathological and endoscopic characteristics of SSLs, including features determined using white light and image-enhanced endoscopy, therapeutic indications, therapeutic methods, and surveillance are reviewed based on the literature. This information may lead to more intensive research to improve detection, diagnosis, and rates of complete resection of these lesions and reduce post-colonoscopy colorectal cancer rates.
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Affiliation(s)
- Takashi Murakami
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Taro Kurosawa
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.,Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hirofumi Fukushima
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Shibuya
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takashi Yao
- Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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6
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Lamba M, Brown I, Bettington M, Ryan K, Hanigan K, Lasenby K, Dixon A, Grimpen F, Gan C, Tutticci N, Appleyard M, Leggett B. Clinicopathological Correlates of Dysplastic Sessile Serrated Lesion: A Prospective Cohort Study With a High Detection Rate. GASTRO HEP ADVANCES 2022; 1:313-320. [PMID: 39131677 PMCID: PMC11308794 DOI: 10.1016/j.gastha.2021.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/27/2021] [Indexed: 08/13/2024]
Abstract
Background and Aims Sessile serrated lesions (SSLs) develop colorectal cancer (CRC), through a critical intermediary stage of SSL with dysplasia (SSLd). In this prospective observational study, we aimed to assess clinicopathological correlates of SSLd in the setting of a high lesion-detection rate. Methods Patients diagnosed with SSL and SSLd from February 2018 until January 2020 were prospectively recruited, and SSLd specimens were re-evaluated by 2 expert pathologists in a blinded manner. Associations were analyzed using multivariate logistic regression models. Results A total of 6425 patients underwent 7423 colonoscopies, and 2671 SSLs were resected from 1047 patients. The overall SSL detection rate per colonoscopy was 15.9%. The median age of patients with SSL was 54 years (interquartile range, 39-66), and 43.3% were male. After pathologist review, 24 SSLds were confirmed in 20 patients. The median size of SSLd was 8 mm (interquartile range, 5.75-15.25), and 13 of 24 SSLds were <10 mm in size. After multivariate analysis, older age (odds ratio = 1.07, 95% confidence interval = 1.03-1.1) and higher number of synchronous SSLs (odds ratio = 1.12, 95% confidence interval = 1.02-1.23) were associated with the presence of dysplasia. Patient sex and number and size of synchronous adenomas were not associated with the presence of SSLd. Seven of 20 patients with SSLd had synchronous or metachronous SSLd. Six of 20 patients with SSLd met the diagnostic criteria for serrated polyposis syndrome. Conclusion The overall SSL detection rate was 15.9%, and 0.9% of SSLs were dysplastic. Older age and higher number of synchronous SSL were risk factors for the presence of dysplasia in SSLs. Thirty percent of patients with SSLd had serrated polyposis syndrome, and 35% had multiple SSLd.
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Affiliation(s)
- Mehul Lamba
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Ian Brown
- Department of Pathology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- Envoi Specialists Pathologists, Brisbane, Queensland, Australia
| | - Mark Bettington
- Envoi Specialists Pathologists, Brisbane, Queensland, Australia
| | - Kimberley Ryan
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Katherine Hanigan
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Kay Lasenby
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Alicia Dixon
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Florian Grimpen
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Chun Gan
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Nicholas Tutticci
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Mark Appleyard
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
| | - Barbara Leggett
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
- The School of Medicine, University of Queensland, Brisbane, Australia
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7
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Nishimura H, Fukui H, Wang X, Ebisutani N, Nakanishi T, Tomita T, Oshima T, Hirota S, Miwa H. Role of the β-Catenin/REG Iα Axis in the Proliferation of Sessile Serrated Adenoma/Polyps Associated with Fusobacterium nucleatum. Pathogens 2021; 10:pathogens10040434. [PMID: 33917384 PMCID: PMC8067346 DOI: 10.3390/pathogens10040434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 12/24/2022] Open
Abstract
Although sessile serrated adenoma/polyps (SSA/Ps) may arise through a pathway different from the traditional adenoma–carcinoma sequence, details of SSA/P tumorigenesis still remain unclear. Fusobacterium nucleatum (Fn) is frequently detected in colorectal cancer (CRC) tissues and may play a pivotal role in colorectal carcinogenesis. Here, we investigated the relationship between Fn and the β-catenin/REG Iα axis in SSA/Ps and their involvement in the proliferation of these lesions. Fn was detected in SSA/Ps by fluorescence in situ hybridization using a Fn-targeted probe, and expression of β-catenin, REG Iα and Ki67 was examined using immunohistochemistry. Sixteen of 30 SSA/P lesions (53.3%) were positive for Fn. Eighteen SSA/P lesions (60%) showed β-catenin immunoreactivity in the tumor cell nuclei. A significant majority of Fn-positive lesions showed nuclear expression of β-catenin (87.5%) and higher REG Iα scores and Ki67 labeling indices relative to Fn-negative lesions. The SSA/P lesions expressing β-catenin in nuclei had significantly higher REG Iα scores and Ki67 labeling indices than those expressing β-catenin on cytomembranes. The REG Iα score was positively correlated with the Ki67 labeling index in SSA/P lesions. The treatment with Wnt agonist SKL2001 promoted nuclear β-catenin translocation and enhanced REG Ia expression in Caco2 cells. Fn may play a role in the proliferation of SSA/P lesions through promotion of β-catenin nuclear translocation and REG Iα expression.
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Affiliation(s)
- Heihachiro Nishimura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
- Correspondence: ; Tel.: +81-798-456-662
| | - Xuan Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Nobuhiko Ebisutani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Takashi Nakanishi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan;
| | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
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8
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Murakami T, Sakamoto N, Fukushima H, Shibuya T, Yao T, Nagahara A. Usefulness of the Japan narrow-band imaging expert team classification system for the diagnosis of sessile serrated lesion with dysplasia/carcinoma. Surg Endosc 2020; 35:4528-4538. [PMID: 32909209 DOI: 10.1007/s00464-020-07967-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 08/27/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Sessile serrated lesion (SSL) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSL can be difficult to diagnose with conventional endoscopy, because most SSLs with dysplasia/carcinoma have subtle mucosal features. Many studies have indicated that narrow-band imaging (NBI) observations of colorectal polyps are very useful, accurate predictors of histology. We aimed to verify the usefulness of the Japan NBI Expert Team (JNET) classification system for the diagnosis of SSLs with dysplasia/carcinoma. METHODS We examined 709 endoscopically or surgically resected lesions that were pathologically diagnosed as SSL, including 647 with no dysplasia, 37 with low-grade dysplasia, 15 with high-grade dysplasia, and 10 with submucosal invasive carcinoma. We retrospectively evaluated their clinicopathologic characteristics and conventional endoscopic and magnifying NBI endoscopic findings using the JNET system. RESULTS Cases in all groups were more frequently located in the proximal colon. Submucosal invasive carcinomas were significantly larger than no dysplasia and low-grade dysplasia lesions. Almost all studied lesions (96.3%) were covered with a mucus cap. Five hundred and eighty (81.8%) lesions exhibited dark spots inside the crypts, which are NBI findings' characteristic of SSL. As for the JNET classification of magnifying NBI endoscopic findings, all 709 lesions showed Type 1. Six hundred and eighteen (95.5%) SSLs with no dysplasia lesions exhibited Type 1 only, whereas 52 (83.9%) SSLs with dysplasia/carcinoma had a combination of Type 1 and Type 2A, 2B, or 3, corresponding to SSL and dysplasia/carcinoma, respectively. The JNET classification had high sensitivity (83.9%), specificity (95.5%), and overall diagnostic accuracy (94.5%) for diagnosing SSLs with dysplasia/carcinoma. CONCLUSIONS Use of magnifying NBI endoscopy with the JNET classification might be useful for diagnosing SSLs with dysplasia/carcinoma. This increased awareness may also improve the recognition of SSLs with dysplasia/carcinoma.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hirofumi Fukushima
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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9
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Amemori S, Yamano HO, Tanaka Y, Yoshikawa K, Matsushita HO, Takagi R, Harada E, Yoshida Y, Tsuda K, Kato B, Tamura E, Eizuka M, Sugai T, Adachi Y, Yamamoto E, Suzuki H, Nakase H. Sessile serrated adenoma/polyp showed rapid malignant transformation in the final 13 months. Dig Endosc 2020; 32:979-983. [PMID: 31677187 DOI: 10.1111/den.13572] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 10/27/2019] [Indexed: 02/06/2023]
Abstract
Based on the concept of the adenoma-carcinoma sequence, most colorectal cancers are considered to arise from conventional adenomas. However, recent studies suggested that a subset of colorectal cancers develop through the serrated neoplastic pathway. It has also been documented that serrated polyps can rapidly transform into invasive cancers even when they are small in size. We now describe a case of a sessile serrated adenoma/polyp which had been followed up for 4 years but eventually showed rapid transformation into an advanced cancer accompanied by a remarkable morphological change within only 13 months. Retrospective genetic and epigenetic analyses showed microsatellite instability, CpG island methylator phenotype-positive, and BRAF mutation in the lesion, suggesting the tumor had developed through the serrated neoplastic pathway. This case may provide valuable information about the natural history of sessile serrated adenoma/polyps which eventually progress to advanced cancers.
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Affiliation(s)
- Sadahiro Amemori
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.,Medical Corporations Tenshindo Shida Hospital, Ibaraki, Japan
| | - Hiro-O Yamano
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.,Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Yoshihito Tanaka
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Kenjiro Yoshikawa
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Hiro-O Matsushita
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Ryo Takagi
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Eiji Harada
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Yuko Yoshida
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Kazunori Tsuda
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Bunichiro Kato
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Eri Tamura
- Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan
| | - Makoto Eizuka
- Department of Pathology, Iwate Medical University, Iwate, Japan
| | - Tamotsu Sugai
- Department of Pathology, Iwate Medical University, Iwate, Japan
| | - Yasushi Adachi
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Eiichiro Yamamoto
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Hokkaido, Japan.,Department of Molecular Biology, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Hokkaido, Japan
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10
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Kim JH, Kang GH. Evolving pathologic concepts of serrated lesions of the colorectum. J Pathol Transl Med 2020; 54:276-289. [PMID: 32580537 PMCID: PMC7385269 DOI: 10.4132/jptm.2020.04.15] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/13/2020] [Accepted: 04/15/2020] [Indexed: 12/12/2022] Open
Abstract
Here, we provide an up-to-date review of the histopathology and molecular pathology of serrated colorectal lesions. First, we introduce the updated contents of the 2019 World Health Organization classification for serrated lesions. The sessile serrated lesion (SSL) is a new diagnostic terminology that replaces sessile serrated adenoma and sessile serrated polyp. The diagnostic criteria for SSL were revised to require only one unequivocal distorted serrated crypt, which is sufficient for diagnosis. Unclassified serrated adenomas have been included as a new category of serrated lesions. Second, we review ongoing issues concerning the morphology of serrated lesions. Minor morphologic variants with distinct molecular features were recently defined, including serrated tubulovillous adenoma, mucin-rich variant of traditional serrated adenoma (TSA), and superficially serrated adenoma. In addition to intestinal dysplasia and serrated dysplasia, minimal deviation dysplasia and not otherwise specified dysplasia were newly suggested as dysplasia subtypes of SSLs. Third, we summarize the molecular features of serrated lesions. The critical determinant of CpG island methylation development in SSLs is patient age. Interestingly, there may be ethnic differences in BRAF/KRAS mutation frequencies in SSLs. The molecular pathogenesis of TSAs is divided into KRAS and BRAF mutation pathways. SSLs with MLH1 methylation can progress into favorable prognostic microsatellite instability-positive (MSI+)/CpG island methylator phenotype-positive (CIMP+) carcinomas, whereas MLH1-unmethylated SSLs and BRAF-mutated TSAs can be precursors of poor-prognostic MSI-/CIMP+ carcinomas. Finally, based on our recent data, we propose an algorithm for stratifying risk subgroups of non-dysplastic SSLs.
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Affiliation(s)
- Jung Ho Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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11
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Tsuruta S, Kohashi K, Yamada Y, Fujiwara M, Koga Y, Ihara E, Ogawa Y, Oki E, Nakamura M, Oda Y. Solid-type poorly differentiated adenocarcinoma of the stomach: Deficiency of mismatch repair and SWI/SNF complex. Cancer Sci 2020; 111:1008-1019. [PMID: 31922331 PMCID: PMC7060473 DOI: 10.1111/cas.14301] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 12/08/2019] [Accepted: 12/21/2019] [Indexed: 12/22/2022] Open
Abstract
ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid-type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA.
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Affiliation(s)
- Shinichi Tsuruta
- Department of Anatomic PathologyGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kenichi Kohashi
- Department of Anatomic PathologyGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yuichi Yamada
- Department of Anatomic PathologyGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Minako Fujiwara
- Department of Anatomic PathologyGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yutaka Koga
- Department of Anatomic PathologyGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Eiji Oki
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Masafumi Nakamura
- Department of Surgery and OncologyGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yoshinao Oda
- Department of Anatomic PathologyGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
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12
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Murakami T, Sakamoto N, Nagahara A. Clinicopathological features, diagnosis, and treatment of sessile serrated adenoma/polyp with dysplasia/carcinoma. J Gastroenterol Hepatol 2019; 34:1685-1695. [PMID: 31158302 DOI: 10.1111/jgh.14752] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 12/17/2022]
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in BRAF-mutated colorectal carcinomas with not only high levels of microsatellite instability but also microsatellite stable. SSA/Ps with advanced histology, including cytological dysplasia or minimally invasive carcinomas, are important lesions because SSA/Ps are considered major contributors to "interval cancers" and these lesions can rapidly become dysplastic or invasive carcinomas. Clinicopathologically, SSA/Ps with dysplasia or invasive carcinoma were associated with advanced age, female sex, and proximal colon. Although SSA/Ps with submucosal invasive carcinoma were smaller and invaded less deeply into the submucosal layer than conventional tubular adenomas with submucosal invasive carcinoma, SSA/Ps with submucosal invasive carcinoma frequently had a mucinous component and exhibited a higher potential for lymphatic invasion and lymph node metastasis. In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, may help accurately diagnose SSA/Ps with advanced histology. Removal of SSA/Ps with dysplasia or invasive carcinoma was recommended. Endoscopic treatment such as endoscopic mucosal resection or endoscopic submucosal dissection is useful for those lesions. However, surgical resection with lymph node dissection might be indicated when SSA/Ps with invasive carcinoma are endoscopically suspected, because these have the high risk of lymph node metastasis. Greater awareness may promote further research into improving the detection, recognition, and complete resection rates of SSA/Ps with dysplasia or invasive carcinoma and reduce the interval cancer rates.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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13
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Koga Y, Hirahashi M, Ohishi Y, Oda Y. Clinicopathological features and phenotypic classification of de novo-type colorectal carcinomas differ from those of colorectal carcinomas derived from flat adenomas. Pathol Int 2019; 69:331-340. [PMID: 31282116 DOI: 10.1111/pin.12803] [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: 08/28/2018] [Revised: 01/16/2019] [Accepted: 03/22/2019] [Indexed: 12/23/2022]
Abstract
Since adenoma components disappear with tumor progression, it is not known whether colorectal carcinomas (CRCs) are derived from an adenoma-carcinoma sequence or are de novo. We compared 38 cases of ≤10-mm flat CRCs without an adenoma component (de novo type) with 39 cases of ≤10-mm flat CRCs with an adenoma component (carcinoma in adenoma (CIA) type). Compared to the CIA type, the de novo-type CRCs were more frequently located in the proximal colon; more frequently invaded submucosa, and more frequently had venous permeation. Regarding the phenotypic classification based on the immunohistochemical expressions of CD10, MUC2 and MUC5AC, the incidence of unclassified type (CD10-, MUC2- and MUC5AC-) was significantly more frequent in the de novo (32%) than CIA (5%) type. In one de novo-type case, mismatch repair (MMR) protein loss was judged, because MLH1 and PMS2 protein expressions were immunohistochemically negative. BRAF mutation (V600E) was seen in one de novo-type case and two CIA-type cases, but none of these cases had MMR protein loss. In conclusion, small-intestinal type (CD10+ and MUC5AC-) is the most common in flat CRC and unclassified type is mainly characteristic of de novo type. In this study, small flat CRCs with BRAF mutation do not have MMR protein loss.
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Affiliation(s)
- Yutaka Koga
- Division of Diagnostic Pathology, Kyushu University Hospital, Fukuoka, Japan.,Departments of Anatomic Pathology and Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Minako Hirahashi
- Departments of Anatomic Pathology and Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ohishi
- Departments of Anatomic Pathology and Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Division of Diagnostic Pathology, Kyushu University Hospital, Fukuoka, Japan.,Departments of Anatomic Pathology and Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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14
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Travaglino A, D'Armiento FP, Cassese G, Campanino MR, Borrelli G, Pignatiello S, Luglio G, Maione F, De Palma GD, D'Armiento M. Clinicopathological factors associated with BRAF-V600E mutation in colorectal serrated adenomas. Histopathology 2019; 75:160-173. [PMID: 30815911 DOI: 10.1111/his.13846] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Serrated adenomas are genetically heterogeneous, and the histological classification into sessile serrated (SSA) adenoma and traditional serrated adenoma (TSA) does not reflect the molecular landscape. The objective of this study was to assess clinical or pathological factors associated with BRAF-V600E mutation in serrated adenomas. Systematic review and meta-analysis was performed by searching electronic databases from January 2011 to January 2019 for studies assessing the association of BRAF-V600E mutation with clinical or pathological features of serrated adenomas. Odds ratio (OR) was calculated for each factor; a P-value <0.05 was considered significant. Forty studies assessing 3511 serrated adenomas (2375 SSAs and 1136 TSAs) were included. BRAF-V600E mutation was significantly associated with proximal localisation (OR = 2.71; P < 0.00001) and CIMP-H status (OR = 4.81; P < 0.0001) in both SSA and TSA, with polyp size <10 mm (OR = 0.41; P = 0.02) in TSA, and with endoscopic pit pattern II-O (OR = 13.11; P < 0.00001) and expression of MUC5A5 (OR = 4.43; P = 0.003) and MUC6 (OR = 2.28; P < 0.05) in SSA. Conversely, BRAF mutation was not associated with age <70 years (OR = 1.63; P = 0.34), age <60 years (OR = 0.86; P = 0.79), female sex (OR = 0.77; P = 0.12), flat morphology (OR = 1.52; P = 0.16), presence of any dysplasia (OR = 1.01; P = 0.59), serrated dysplasia (OR = 1.23; P = 0.72) and invasive cancer (OR = 0.67; P = 0.32), nuclear β-catenin expression (OR = 0.73; P = 0.21) and p53 overexpression (OR = 1.24; P = 0.82). In conclusion, BRAF-V600E mutation is associated with proximal localisation and CIMP-H status in both SSA and TSA, with size <10 mm only in TSA, and with expression of MUC5A5 and MUC6 and endoscopic pit pattern II-O at least in SSA. In serrated adenomas, BRAF-V600E mutation does not seem to be associated with age and sex, with the prevalence of dysplasia and cancer and with the morphology of the dysplastic component.
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Affiliation(s)
- Antonio Travaglino
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Francesco P D'Armiento
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Gianluca Cassese
- Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Maria R Campanino
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giorgio Borrelli
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Sara Pignatiello
- Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Gaetano Luglio
- Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Francesco Maione
- Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giovanni D De Palma
- Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Maria D'Armiento
- Department of Public Health, School of Medicine, University of Naples Federico II, Naples, Italy
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15
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Clinical and endoscopic characteristics of sessile serrated adenomas/polyps with dysplasia/adenocarcinoma in a Korean population: A Korean Association for the Study of Intestinal Diseases (KASID) multicenter study. Sci Rep 2019; 9:3946. [PMID: 30850671 PMCID: PMC6408487 DOI: 10.1038/s41598-019-40559-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 02/19/2019] [Indexed: 12/27/2022] Open
Abstract
Sessile serrated adenomas/polyps (SSA/Ps) are precancerous lesions that account for one-third of colorectal cancers. The endoscopic and pathologic differentiation between SSA/Ps without dysplasia (SSA/POs) and SSA/Ps with dysplasia or adenocarcinoma (SSA/PDAs) can be difficult. This study aimed to assess the clinical characteristics of SSA/PDs. This multicenter retrospective cohort study included 532 patients who underwent endoscopic resection and were pathologically diagnosed with SSA/POs and SSA/PDAs. Initially, medical, endoscopic, and histopathological records of patients who underwent endoscopic resection of SSA/POs and SSA/PDAs at eight university hospitals in Korea between January 2005 and December 2015 were reviewed. A total of 307 (57.7%) patients were detected in men and 319 (60.0%) were located in the proximal colon. Most SSA/Ps had a flat, slightly elevated, or sessile morphology. The most prevalent endoscopic findings of SSA/Ps were nodular surface (244, 45.9%), disrupted vascular pattern (232, 43.6%), altered fold contour (141, 26.5%), dome-shaped morphology (135, 25.4%), and pale color (115, 21.6%). SSA/POs were more commonly found in the proximal colon, compared to SSA/PDAs. SSA/PDAs displayed 0-Ip, Isp, IIb or IIa + IIc morphologies more frequently, while SSA/POs displayed 0-Is or IIa morphology more frequently. The frequency of a rim of debris/bubbles was significantly higher in SSA/POs, while nodular surface and disrupted vascular pattern were significantly higher in SSA/PDAs. In the univariate analysis of endoscopic features, SSA/PDAs were significantly associated with the distal colon location, 0-Isp and IIb morphologies, nodular surface, and disrupted vascular pattern. In the multivariate analysis, 0-IIb, nodular surface, and disrupted vascular pattern were significantly associated with SSA/PDAs. SSA/Ps with 0-IIb morphology, nodular surface and disrupted vascular pattern are associated with an increased risk of dysplasia or adenocarcinoma.
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16
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Clinicopathologic and Molecular Characteristics of Synchronous Colorectal Carcinoma With Mismatch Repair Deficiency. Am J Surg Pathol 2019; 42:172-182. [PMID: 28877066 DOI: 10.1097/pas.0000000000000947] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Synchronous colorectal carcinoma (CRC) is a unique disease associated with a high prevalence (∼35%) of microsatellite instability and occasionally with Lynch syndrome. The clinicopathologic and molecular features of synchronous CRC are poorly understood, particularly in Japanese patients. We examined 118 Japanese patients (236 tumors) with synchronous CRC and 117 Japanese patients (117 tumors) with solitary CRC with immunohistochemical staining for TP53 and mismatch repair (MMR) protein (MLH1, MSH2, PMS2, and MSH6) and mutation analyses of KRAS and BRAF genes. The results revealed no significant differences in clinicopathologic, histologic, and molecular findings between the synchronous and solitary CRC groups. Among the 118 synchronous CRC patients, 15 (12.7%) showed loss of MMR protein(s) expression in at least 1 tumor, whereas 103 (87.3%) showed intact expression of all 4 MMR proteins in both tumors. Of note, all patients with MMR deficiency had excellent prognoses. The 15 patients were further subdivided into 2 groups: the Concordant group, with concordant MMR loss (n=9, 7.6%) and the Discordant group, with discordant MMR loss (n=6, 5.1%). The Concordant patients showed concurrent MLH1/PMS2 loss (n=3), concurrent MSH2/MSH6 loss (n=4) and isolated MSH6 loss (n=2) in both tumors, whereas the Discordant patients showed concurrent MLH1/PMS2 loss (n=2), isolated PMS2 loss (n=2) and isolated MSH6 loss (n=2) in a single tumor. On the basis of the MMR expression pattern and BRAF mutation, the Concordant and Discordant groups were suspected to include Lynch syndrome, Lynch-like syndrome and sporadic MLH1 promoter hypermethylated CRC. In addition, KRAS mutation was present in only 1 tumor in a single patient in each group. In conclusion, the frequency of MMR protein deficiency in synchronous CRC in the Japanese population may be lower compared with the reported data from Western populations. MMR protein loss and KRAS and BRAF mutations in synchronous CRCs were heterogenous even in an individual patient.
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17
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Cappellesso R, Lo Mele M, Munari G, Rosa-Rizzotto E, Guido E, De Lazzari F, Pilati P, Tonello M, Farinati F, Realdon S, Fassan M, Rugge M. Molecular characterization of "sessile serrated" adenoma to carcinoma transition in six early colorectal cancers. Pathol Res Pract 2019; 215:957-962. [PMID: 30738693 DOI: 10.1016/j.prp.2019.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 01/21/2019] [Accepted: 02/01/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is a heterogeneous group of diseases both from the morphological and molecular point of view. The sessile serrated adenoma/polyp (SSA/P) has been proposed as the precursor lesion of CRCs characterized by CpG island methylator phenotype (CIMP), DNA mismatch repair (MMR) system deficiency, and BRAF gene mutations. However, no study so far investigated the molecular landscape of "sessile serrated" adenoma to carcinoma transition in early CRCs. Six formalin-fixed paraffin-embedded CRCs developed within SSA/P were profiled for the immunohistochemical expression of MMR proteins (MLH1, MSH2, MSH6, PMS2, and Ep-CAM), p16, and β-catenin. DNA was extracted from the two components of each sample, after microdissection, and characterized for CIMP status and by applying a custom hotspot multigene mutational profiling of 164 hotspot regions of eleven CRC-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, and TP53). Five out of the six CRCs shared the same molecular profile (i.e. CIMP positive, MSI status, and BRAF mutation) with their SSA/P components. One out of five CRCs was also APC mutated, whereas another one showed an additional TP53 mutation. The remaining case was CIMP negative and MMR proficient in both the components, harbored a BRAF mutation in the SSA/P counterpart, whereas the CRC one was APC and TP53 mutated and showed p16 and β-catenin dysregulation. This study provides the molecular evidence that SSA/P, even without cytological dysplasia, is a precursor lesion of CRC and that conventional CRC might arise from mixed polyp.
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Affiliation(s)
- Rocco Cappellesso
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy
| | - Marcello Lo Mele
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy
| | - Giada Munari
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy; Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy
| | | | - Ennio Guido
- Gastroenterology Unit, S. Antonio Hospital, Padua, 35128, Italy
| | | | - Pierluigi Pilati
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy
| | - Marco Tonello
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy; Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, 35128, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padua, 35128, Italy
| | - Stefano Realdon
- Unit of Digestive Endoscopy, Veneto Institute of Oncology - I.R.C.S.S, Padua, 35128, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy.
| | - Massimo Rugge
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, 35121, Italy
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18
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Murakami T, Akazawa Y, Yatagai N, Hiromoto T, Sasahara N, Saito T, Sakamoto N, Nagahara A, Yao T. Molecular characterization of sessile serrated adenoma/polyps with dysplasia/carcinoma based on immunohistochemistry, next-generation sequencing, and microsatellite instability testing: a case series study. Diagn Pathol 2018; 13:88. [PMID: 30458818 PMCID: PMC6247685 DOI: 10.1186/s13000-018-0771-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/08/2018] [Indexed: 01/03/2023] Open
Abstract
Background Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway. Methods We performed immunostaining for β-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma. Results Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation. Conclusions SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/β-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. .,Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
| | - Yoichi Akazawa
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Noboru Yatagai
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takafumi Hiromoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Noriko Sasahara
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
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19
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Bettington M, Rosty C, Whitehall V, Leggett B, McKeone D, Pearson SA, Walker N. A morphological and molecular study of proposed early forms of traditional serrated adenoma. Histopathology 2018; 73:1023-1029. [PMID: 30007084 DOI: 10.1111/his.13714] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 07/13/2018] [Indexed: 12/20/2022]
Abstract
AIMS Traditional serrated adenoma (TSA) is the least common subtype of serrated colorectal polyp. Large protuberant lesions are easily recognised; however, the origins of TSAs are not known, and early forms have not been described. Some large TSAs present with a flat 'shoulder' component surrounding the central protuberant component. We hypothesised that small polyps with the same histology as these shoulder regions may represent early TSAs. Thus the primary aim of the study is to describe the histology of these presumptive early TSAs. METHODS AND RESULTS We collected 70 small (<10 mm) polyps that may represent early TSAs on the basis of typical TSA cytology covering the luminal surface. We also identified 12 large TSAs with a shoulder component resembling these small polyps. The study polyp patients had a mean age of 58 years, and 54% were female; the polyps had a mean diameter of 4.1 mm and were predominantly distal (71%). Morphologically, slit-like serrations were present in 81%, ectopic crypt formations were present in 67%, and a villous component was present in 47%. These histological features were similar to those of the 12 shoulder lesions. Immunohistochemical stains showed an absence of β-catenin nuclear expression in 96% of the small polyps, retained expression of MLH1 in 100%, and Ki67 positivity restricted to the crypt bases and ectopic crypt formations. BRAF and KRAS mutations were identified in 47% and 31% of the polyps, respectively. BRAF-mutated polyps were more likely than KRAS-mutated polyps to arise in a precursor polyp (82% versus 18%, P < 0.001), and were more likely to have slit-like serrations (100% versus 73%, P = 0.003). CONCLUSIONS These morphological, immunohistochemical and molecular findings are similar to what has been reported in large TSAs, and support the hypothesis that these polyps represent early forms of TSA.
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Affiliation(s)
- Mark Bettington
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Christophe Rosty
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.,Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
| | - Vicki Whitehall
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.,Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia
| | - Barbara Leggett
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.,Department of Gastroenterology and Hepatology, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Diane McKeone
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Sally-Ann Pearson
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Neal Walker
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
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20
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21
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Dunkin D, Iuga AC, Mimouna S, Harris CL, Haure-Mirande JV, Bozec D, Yeretssian G, Dahan S. Intestinal epithelial Notch-1 protects from colorectal mucinous adenocarcinoma. Oncotarget 2018; 9:33536-33548. [PMID: 30323897 PMCID: PMC6173356 DOI: 10.18632/oncotarget.26086] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 08/23/2018] [Indexed: 12/30/2022] Open
Abstract
Increasing evidence links Notch-1 signaling with the maintenance of intestinal architecture and homeostasis. Dysfunction in the common Notch-1 pathway transcription factor recombinant binding protein suppressor of hairless (RBP-J) is associated with loss of epithelial barrier integrity and aberrant conversion of proliferative crypt cells into goblet cells. Furthermore, we have recently discovered that epithelial Notch-1 is indispensable in bridging innate and adaptive immunity in the gut and is required for supporting protective epithelial pro-inflammatory responses. Yet, the epithelial specific function of Notch-1 in intestinal tumorigenesis remains unknown. We generated Villin-Cre/Notch-1fl/fl (VN-/-) mice that are selectively deficient in Notch-1 in intestinal epithelial cells. Intestinal epithelial Notch-1 preserved barrier function and integrity, whereas lack of epithelial Notch-1 induced goblet cell hyperplasia, spontaneous serrated lesions, multifocal low- and high-grade dysplasia and colonic mucinous neoplasms in mice. Over time, VN-/- mice displayed high occurrence of colorectal mucinous adenocarcinomas, which correlated with increased levels of mitogenic, angiogenic and pro-tumorigenic gene expression. Finally, we found that the expression of Notch-1 is significantly reduced in human colorectal mucinous adenocarcinoma when compared to colorectal adenocarcinoma. Taken together, our findings reveal a novel and critical protective role for Notch-1 in controlling intestinal tumorigenesis.
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Affiliation(s)
- David Dunkin
- Department of Pediatric Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Alina C Iuga
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - Sanda Mimouna
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Immunology and Autoimmunity Research Department, Hospital for Special Surgery Research Institute, New York, NY 10021, USA.,Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Carolyn L Harris
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jean-Vianney Haure-Mirande
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Dominique Bozec
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Garabet Yeretssian
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,The Leona M. and Harry B. Helmsley Charitable Trust, New York, NY 10169, USA
| | - Stephanie Dahan
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Sobi, Inc. Waltham, MA 02452, USA
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22
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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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23
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Murakami T, Sakamoto N, Nagahara A. Endoscopic diagnosis of sessile serrated adenoma/polyp with and without dysplasia/carcinoma. World J Gastroenterol 2018; 24:3250-3259. [PMID: 30090005 PMCID: PMC6079289 DOI: 10.3748/wjg.v24.i29.3250] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in colorectal carcinomas with BRAF mutations, methylation for DNA repair genes, a CpG island methylator phenotype, and high levels of microsatellite instability. Some of these lesions can rapidly become dysplastic or invasive carcinomas that exhibit high lymphatic invasion and lymph node metastasis potentials. Detecting serrated lesions, including SSA/Ps with and without dysplasia/carcinoma, is critical, but SSA/Ps can be difficult to detect, are inconsistently identified by endoscopists and pathologists, and are often incompletely resected. Therefore, SSA/Ps are considered to be major contributors to “interval cancers”. If colonoscopists can identify the specific endoscopic characteristics of SSA/Ps, their detection and the effectiveness of colonoscopy may improve. Here, the endoscopic features of SSA/Ps with and without dysplasia/carcinoma, including the characteristics determined using magnifying endoscopy, are reviewed in the context of previous reports. Endoscopically, these subtle polyps are like hyperplastic polyps, because they are slightly elevated and pale. Unlike hyperplastic polyps, SSA/Ps are usually larger than 5 mm, frequently covered by a thin layer called the ‘‘mucus cap’’, and are more commonly located in the proximal colon. Magnifying narrow-band imaging findings, which include dark spots inside the crypts and varicose microvascular vessels, in addition to the type II-open pit patterns detected using magnifying chromoendoscopy, effectively differentiate SSA/Ps from hyperplastic polyps. The lesions’ endoscopic characteristics, which include their (semi)pedunculated morphologies, double elevations, central depressions, and reddishness, and the use of magnifying endoscopy, might help to detect dysplasia/carcinoma within SSA/Ps. Greater awareness may promote further research into improving the detection, identification, and complete resection rates of SSA/Ps with and without dysplasia/carcinoma and reduce the interval cancer rates.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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24
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Mikami Y, Fujii S, Kohashi KI, Yamada Y, Moriyama M, Kawano S, Nakamura S, Oda Y, Kiyoshima T. Low-grade myofibroblastic sarcoma arising in the tip of the tongue with intravascular invasion: A case report. Oncol Lett 2018; 16:3889-3894. [PMID: 30128003 DOI: 10.3892/ol.2018.9115] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 06/28/2018] [Indexed: 12/19/2022] Open
Abstract
Low-grade myofibroblastic sarcoma (LGMS) is a rare intermediate tumor, which rarely metastasizes and has myofibroblastic differentiation in various sites. It is particularly associated with the tongue in the head and neck region. The lack of any pathological features means it is difficult to make a conclusive diagnosis of LGMS. The immunohistochemical features and genomic rearrangements, including SS18-SSXs and MYH9-USP6s and the genetic mutations of cancer-associated genes, including APC, CTNNB1, EGFR, KRAS, PIK3CA and p53 were examined in a case of LGMS arising in the tip of the tongue. Immunohistochemically, the tumor cells were positive for alpha-smooth muscle actin and vimentin, as in previous reports. They demonstrated neither genomic rearrangements nor point mutations of cancer-associated genes. Although several tumor cells demonstrated intravascular invasion, the MIB-l labeling index of the cells was the same as the original lesion. To the best of our knowledge, this is the first case report of LGMS arising in the tip of the tongue with intravascular invasion.
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Affiliation(s)
- Yurie Mikami
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.,Section of Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Shinsuke Fujii
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Ken-Ichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yuichi Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Masafumi Moriyama
- Section of Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Shintaro Kawano
- Section of Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Seiji Nakamura
- Section of Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
| | - Tamotsu Kiyoshima
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
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25
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Kumagae Y, Hirahashi M, Takizawa K, Yamamoto H, Gushima M, Esaki M, Matsumoto T, Nakamura M, Kitazono T, Oda Y. Overexpression of MTH1 and OGG1 proteins in ulcerative colitis-associated carcinogenesis. Oncol Lett 2018; 16:1765-1776. [PMID: 30008864 DOI: 10.3892/ol.2018.8812] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 09/05/2017] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress, demonstrated by an accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), results in DNA damage, which is normally repaired by base excision repair enzymes including 8-OHdG DNA glycosylase (OGG1) and human MutY homolog (MUTYH), in addition to nucleotide pool sanitizing enzymes including MutT Homolog 1 (MTH1). Abnormalities of this repair system are present in various cancer types. The present study aimed to elucidate the clinicopathological significance of altered expression levels of inducible nitric oxide synthase (iNOS), 8-OHdG, OGG1, MTH1 and MUTYH in ulcerative colitis (UC) and UC-associated neoplasms. Immunohistochemical staining for these markers and p53 in 23 cases of UC-associated neoplasm (Group A, 14 carcinomas and nine dysplasias), 16 cases of UC without neoplasm (Group B) and 17 cases of normal colon specimens (Group C) was performed. Mutation analyses was conducted for KRAS proto-oncogene, GTPase (K-ras), tumor protein P53 (TP53) and isocitrate dehydrogenase (NADP (+)) 1, cytosolic (IDH1) genes. Immunohistochemically, the iNOS, 8-OHdG, OGG1 and MTH1 expression levels were increased in Groups A and B compared with Group C. The OGG1 and MTH1 expression levels in Group A were also increased compared with Group B. Group A and Group B exhibited increased cytoplasmic expression and decreased nuclear expression of MUTYH compared with Group C. Mutations of K-ras and TP53 were detected in 2/21 (9.5%) and 10/22 (45.5%) cases of Group A, respectively. IDH1 mutation was not detected in any cases. These findings suggest that, as a response to oxidative damage, OGG1 and MTH1 may be upregulated in UC through an inflammatory condition that progresses to cancer formation. Persisting oxidative damage stress may play a role in the pathogenesis of UC-associated tumors.
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Affiliation(s)
- Yoshiteru Kumagae
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Minako Hirahashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Katsumi Takizawa
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Hidetaka Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Masaki Gushima
- Department of Medical Gastroenterology, Shimonoseki Hospital, Yamaguchi, Yamaguchi 750-8520, Japan
| | - Motohiro Esaki
- Department of Medicine and Clinical Science, Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Iwate 020-8505, Japan
| | - Masafumi Nakamura
- Department of Medicine and Clinical Science, Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
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26
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Clinicopathologic and outcome study of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. Mod Pathol 2018; 31:633-642. [PMID: 29271414 DOI: 10.1038/modpathol.2017.169] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 10/15/2017] [Accepted: 10/16/2017] [Indexed: 01/12/2023]
Abstract
It is believed that sessile serrated adenomas/polyps lead to the development of microsatellite unstable cancer via a dysplasia-carcinoma sequence. Little is known regarding the morphologic and biologic features, and outcome of sessile serrated adenomas/polyps with dysplasia, or of its specific dysplasia subtypes (intestinal versus serrated). The aims of this study were to analyze and compare the clinical, pathologic, and outcome characteristics of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia. The study included 86 patients with sessile serrated adenomas/polyps with dysplasia (50 serrated dysplasia, 22 intestinal dysplasia, 14 mixed serrated and intestinal dysplasia). The clinical and pathologic features, and the prevalence rate of prior, concurrent, and future neoplastic lesions, were compared between sessile serrated adenomas/polyps with intestinal versus serrated dysplasia and with matched control patients with ≥1 conventional adenoma. The mean age of the patients, polyp size, and prevalence of adenocarcinoma within the polyps were significantly higher in sessile serrated adenomas/polyps with high versus low-grade dysplasia. Sessile serrated adenomas/polyps with intestinal dysplasia showed a significantly higher rate of adenocarcinoma (23%) compared with those with serrated dysplasia (6%, P=0.05), and the high-grade lesions occurred at a significantly younger age in the former compared with the latter (65 versus 76 years, P=0.05). Compared with patients with conventional adenomas, patients with sessile serrated adenomas/polyps with dysplasia showed a significantly higher rate of invasive carcinoma within the polyps (12 versus 0%, P=0.01) and a significantly lower association with prior or future conventional adenomas. Sessile serrated adenomas/polyps with dysplasia should be considered high-risk neoplastic precursor lesions, particularly those with intestinal dysplasia. Cancer may develop from sessile serrated adenomas/polyps with either type of dysplasia.
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27
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Development and endoscopic appearance of colorectal tumors are characterized by the expression profiles of miRNAs. Med Mol Morphol 2018; 51:82-88. [DOI: 10.1007/s00795-018-0186-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 03/06/2018] [Indexed: 12/17/2022]
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28
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Borowsky J, Dumenil T, Bettington M, Pearson SA, Bond C, Fennell L, Liu C, McKeone D, Rosty C, Brown I, Walker N, Leggett B, Whitehall V. The role of APC in WNT pathway activation in serrated neoplasia. Mod Pathol 2018; 31:495-504. [PMID: 29148535 DOI: 10.1038/modpathol.2017.150] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 02/07/2023]
Abstract
Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.
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Affiliation(s)
- Jennifer Borowsky
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Troy Dumenil
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Mark Bettington
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Sally-Ann Pearson
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Catherine Bond
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Lochlan Fennell
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Cheng Liu
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Diane McKeone
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Christophe Rosty
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Ian Brown
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia.,Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
| | - Neal Walker
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Barbara Leggett
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Vicki Whitehall
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
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Clinicopathologic distribution of KRAS and BRAF mutations in a Chinese population with colorectal cancer precursor lesions. Oncotarget 2017; 7:17265-74. [PMID: 26910894 PMCID: PMC4941386 DOI: 10.18632/oncotarget.7504] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 01/13/2016] [Indexed: 12/21/2022] Open
Abstract
Investigating the clinical features and corresponding histomorphologic and molecular profiles of precursor lesions of colorectal cancer in a natural population provides new insights into the nature of colorectal cancer, uncovers new screening markers and establishes new prevention strategies for colorectal cancer. In this study, 4302 patients with at least one colorectal polyp from a large colorectal cancer screening program were evaluated and genetic mutations in either KRAS or BRAF were detected in 495 patients. The population-based mutation rates of KRAS and BRAF genes in colorectal polyps within this Chinese patient population were 21.8% and 12.1% respectively. Interestingly, considerable variability in the KRAS and BRAF mutations rates were found among different types of polyps. In a multivariate analysis, presence of villous histology and high-grade dysplasia was associated with KRAS mutations (OR, 3.0; 95% CI, 1.7-5.4 and OR, 3.5; 95% CI 1.9-6.5, respectively), while serrated adenomas and hyperplastic polyps were associated with BRAF V600E mutations (OR, 20.6; 95% CI, 8.2–51.8 and OR, 11.9; 95% CI 4.9–29.0, respectively). KRAS mutations may, in part, drive the histologic progression of adenomas toward a villous histology and higher grades of dysplasia. Mutant BRAF may, in part, drive the histologic progression of adenomas toward serrated histology. Dysplasia may arise from hyperplastic polyps, resulting in the formation of serrated adenomas and potentially the development of colorectal carcinoma.
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Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry. Mod Pathol 2017; 30:1728-1738. [PMID: 28752838 PMCID: PMC5719122 DOI: 10.1038/modpathol.2017.92] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 05/30/2017] [Accepted: 06/02/2017] [Indexed: 12/30/2022]
Abstract
Sessile serrated adenomas are the precursor polyp of approximately 20% of colorectal carcinomas. Sessile serrated adenomas with dysplasia are rarely encountered and represent an intermediate step to malignant progression, frequently associated with loss of MLH1 expression. Accurate diagnosis of these lesions is important to facilitate appropriate surveillance, particularly because progression from dysplasia to carcinoma can be rapid. The current World Health Organization classification describes two main patterns of dysplasia occurring in sessile serrated adenomas, namely, serrated and conventional. However, this may not adequately reflect the spectrum of changes seen by pathologists in routine practice. Furthermore, subtle patterns of dysplasia that are nevertheless associated with loss of MLH1 expression are not encompassed in this classification. We performed a morphological analysis of 266 sessile serrated adenomas with dysplasia with concurrent MLH1 immunohistochemistry with the aims of better defining the spectrum of dysplasia occurring in these lesions and correlating dysplasia patterns with MLH1 expression. We found that dysplasia can be divided morphologically into four major patterns, comprising minimal deviation (19%), serrated (12%), adenomatous (8%) and not otherwise specified (79%) groups. Minimal deviation dysplasia is defined by minor architectural and cytological changes that typically requires loss of MLH1 immunohistochemical expression to support the diagnosis. Serrated dysplasia and adenomatous dysplasia have distinctive histological features and are less frequently associated with loss of MLH1 expression (13 and 5%, respectively). Finally, dysplasia not otherwise specified encompasses most cases and shows a diverse range of morphological changes that do not fall into the other subgroups and are frequently associated with loss of MLH1 expression (83%). This morphological classification of sessile serrated adenomas with dysplasia may represent an improvement on the current description as it correlates with the underlying mismatch repair protein status of the polyps and better highlights the range of morphologies seen by pathologists.
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31
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Horpaopan S, Kirfel J, Peters S, Kloth M, Hüneburg R, Altmüller J, Drichel D, Odenthal M, Kristiansen G, Strassburg C, Nattermann J, Hoffmann P, Nürnberg P, Büttner R, Thiele H, Kahl P, Spier I, Aretz S. Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS). Hered Cancer Clin Pract 2017; 15:22. [PMID: 29213343 PMCID: PMC5707812 DOI: 10.1186/s13053-017-0082-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 11/21/2017] [Indexed: 01/01/2023] Open
Abstract
Background Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (BRAF, KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified. Methods To identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing. Results The BRAF p.V600E or KRAS p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in ABI3BP and CATSPERB are predicted to be deleterious. No established cancer gene or candidate genes related to serrated tumorigenesis were affected. Conclusions Somatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS. Electronic supplementary material The online version of this article (10.1186/s13053-017-0082-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sukanya Horpaopan
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.,Center of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok, Thailand
| | - Jutta Kirfel
- Institute of Pathology, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Sophia Peters
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Michael Kloth
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Robert Hüneburg
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Janine Altmüller
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Dmitriy Drichel
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | | | - Glen Kristiansen
- Institute of Pathology, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Christian Strassburg
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jacob Nattermann
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Per Hoffmann
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.,Institute of Medical Genetics and Pathology, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Peter Nürnberg
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | | | - Holger Thiele
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | - Philip Kahl
- Heinz-Werner-Seifert-Institut für Dermatopathologie Bonn, Bonn, Germany
| | - Isabel Spier
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Stefan Aretz
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Institute of Human Genetics, Center for Hereditary Tumor Syndromes, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany
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Murakami T, Mitomi H, Yao T, Saito T, Shibuya T, Sakamoto N, Osada T, Watanabe S. Distinct histopathological characteristics in colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp and conventional tubular adenoma. Virchows Arch 2017; 472:383-393. [PMID: 28929387 DOI: 10.1007/s00428-017-2234-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/27/2017] [Accepted: 09/13/2017] [Indexed: 12/31/2022]
Abstract
The histopathological characteristics of colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp (SSA/P), a rare malignant tumour, have not yet been fully elucidated. To investigate the features of such, we retrospectively analysed 40 submucosal invasive carcinomas with SSA/P (CA-SSA/P) and compared them to 129 cases of submucosal invasive carcinoma with conventional tubular adenoma (CA-AD). We additionally performed hMLH1 immunostaining. CA-SSA/Ps were significantly smaller than CA-ADs (P < 0.001). Histologically, well to moderately differentiated adenocarcinoma was predominant in both CA-SSA/Ps and CA-ADs. No significant differences in depth of invasion were found between the two groups. However, lymphatic invasion was more often found in CA-SSA/Ps (30%) than in CA-ADs (13%; P = 0.028), as was lymph node metastasis (CA-SSA/Ps, 28%; CA-ADs, 7%; P = 0.011). Furthermore, mucinous component and serrated architecture were significantly more frequent in CA-SSA/Ps (30 and 63%) than in CA-ADs (5 and 18%; P < 0.001, respectively). Tumour-infiltrating lymphocytes and Crohn-like inflammatory reaction were also more frequently found in CA-SSA/Ps (70 and 30%) than in CA-ADs (31 and 9%; P ≤ 0.001, respectively), whereas the opposite was true of desmoplastic reaction (CA-SSA/Ps, 35%; CA-ADs, 67%; P < 0.001). Loss of hMLH1 expression was more frequent in CA-SSA/P cases (93%) than in CA-AD cases (5%; P < 0.001). In conclusion, CA-SSA/P lesions exhibit a higher potential for lymphatic invasion and lymph node metastasis and have distinct histopathological features, including mucinous component, serrated architecture, tumour-infiltrating lymphocytes, Crohn-like inflammatory reaction, and absence of desmoplastic reaction, compared to their conventional counterparts.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. .,Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Hiroyuki Mitomi
- Department of Diagnostic Pathology and Laboratory Medicine, Odawara Municipal Hospital, Odawara, Kanagawa, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Taro Osada
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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Hashimoto T, Yamashita S, Yoshida H, Taniguchi H, Ushijima T, Yamada T, Saito Y, Ochiai A, Sekine S, Hiraoka N. WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps. Am J Surg Pathol 2017; 41:1188-1197. [PMID: 28614199 DOI: 10.1097/pas.0000000000000877] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are believed to be the major precursor of serrated pathway-derived colorectal carcinomas. To better characterize the process of progression from SSA/Ps to carcinomas, we analyzed 46 SSA/Ps with dysplasia and 45 SSA/Ps without dysplasia using targeted next-generation sequencing and immunohistochemistry. Among the WNT pathway genes analyzed, protein-truncating mutations of RNF43, APC, and ZNRF3 were identified in 23 (50%), 4 (9%), and 3 (7%) SSA/Ps with dysplasia, respectively. In contrast, SSA/Ps without dysplasia rarely had WNT pathway gene mutations, except for 3 lesions with RNF43 mutations (7%). None of the SSA/Ps had CTNNB1 mutations or RSPO fusions. Thus, WNT pathway gene mutations were more common in SSA/Ps with dysplasia than in SSA/Ps without dysplasia (P=3.0×10). Consistently, nuclear β-catenin accumulation and MYC overexpression, indicative of active WNT signaling, were present in most of the SSA/Ps with dysplasia, but were rare in those without dysplasia. BRAF (86%) or KRAS mutations (7%) were identified in the majority of SSA/Ps, regardless of the presence or absence of dysplasia. MLH1 expression was lost in 14 SSA/Ps with dysplasia (30%). The majority of MLH1-deficient SSA/Ps with dysplasia had RNF43 mutations (86%), most of which were frameshift mutations involving mononucleotide repeats. In contrast, MLH1-retained lesions had less frequent RNF43 mutations with no hot spots (34%), and 4 had APC mutations (13%). These results suggest that WNT pathway gene mutations are involved in the development of dysplasia in SSA/Ps and that MLH1-deficient and MLH1-retained SSA/Ps with dysplasia exhibit distinct mutation profiles of WNT pathway genes.
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Affiliation(s)
- Taiki Hashimoto
- *Division of Pathology and Clinical Laboratories ∥Endoscopy Division, National Cancer Center Hospital †Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine ‡Division of Epigenomics §Division of Chemotherapy and Clinical Research #Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo ¶Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Japan
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Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system. Br J Cancer 2017; 116:1012-1020. [PMID: 28278514 PMCID: PMC5396110 DOI: 10.1038/bjc.2017.52] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 02/06/2017] [Accepted: 02/08/2017] [Indexed: 12/22/2022] Open
Abstract
Background: Colorectal cancer (CRC) is a heterogeneous disease in terms of molecular carcinogenic pathways. Based on recent findings regarding the multiple serrated neoplasia pathway, we revised an eight-marker panel for a new CIMP classification system. Methods: 1370 patients who received surgical resection for CRCs were classified into three CIMP subtypes (CIMP-N: 0–4 methylated markers, CIMP-P1: 5–6 methylated markers and CIMP-P2: 7–8 methylated markers). Our findings were validated in a separate set of high-risk stage II or stage III CRCs receiving adjuvant fluoropyrimidine plus oxaliplatin (n=950). Results: A total of 1287/62/21 CRCs cases were classified as CIMP-N/CIMP-P1/CIMP-P2, respectively. CIMP-N showed male predominance, distal location, lower T, N category and devoid of BRAF mutation, microsatellite instability (MSI) and MLH1 methylation. CIMP-P1 showed female predominance, proximal location, advanced TNM stage, mild decrease of CK20 and CDX2 expression, mild increase of CK7 expression, BRAF mutation, MSI and MLH1 methylation. CIMP-P2 showed older age, female predominance, proximal location, advanced T category, markedly reduced CK20 and CDX2 expression, rare KRAS mutation, high frequency of CK7 expression, BRAF mutation, MSI and MLH1 methylation. CIMP-N showed better 5-year cancer-specific survival (CSS; HR=0.47; 95% CI: 0.28–0.78) in discovery set and better 5-year relapse-free survival (RFS; HR=0.50; 95% CI: 0.29–0.88) in validation set compared with CIMP-P1. CIMP-P2 showed marginally better 5-year CSS (HR=0.28, 95% CI: 0.07–1.22) in discovery set and marginally better 5-year RFS (HR=0.21, 95% CI: 0.05–0.92) in validation set compared with CIMP-P1. Conclusions: CIMP subtypes classified using our revised system showed different clinical outcomes, demonstrating the heterogeneity of multiple serrated precursors of CIMP-positive CRCs.
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Murakami T, Sakamoto N, Ritsuno H, Shibuya T, Osada T, Mitomi H, Yao T, Watanabe S. Distinct endoscopic characteristics of sessile serrated adenoma/polyp with and without dysplasia/carcinoma. Gastrointest Endosc 2017; 85:590-600. [PMID: 27663716 DOI: 10.1016/j.gie.2016.09.018] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 09/13/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Sessile serrated adenoma/polyp (SSA/P) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSA/P can be difficult to detect. This study aimed to clarify the endoscopic characteristics of SSA/P with advanced histology. METHODS We examined 462 endoscopically or surgically resected lesions that were pathologically diagnosed as SSA/P, including 414 without and 41 with cytologic dysplasia, and 7 with invasive carcinoma. We retrospectively studied the clinicopathologic and endoscopic characteristics and performed pit pattern analysis. RESULTS A stepwise increase in the size of the SSA/P series was identified along with their dysplastic progression, although 19 of 48 (39.6%) SSA/Ps with dysplasia/carcinoma were ≤10 mm in size. Most lesions were covered with a mucus cap. Macroscopically, (semi)pedunculated morphology, double elevation, central depression, and reddishness were found more frequently in SSA/P with cytologic dysplasia and invasive carcinoma ([semi]pedunculated morphology, 17.1%/28.6%; double elevation, 63.4%/57.1%; central depression, 9.8%/28.6%; reddishness, 39.0%/85.7%) than in those without dysplasia (4.6%, 4.6%, 3.9%, and 3.4%, respectively). Furthermore, the presence of at least 1 of these 4 markers had high sensitivity (91.7%) for identifying the dysplasia/carcinoma within a SSA/P, with a specificity of 85.3%. In the pit pattern analysis, all SSA/Ps without dysplasia exhibited type II pit pattern only, whereas 94.4% of SSA/Ps with dysplasia/carcinoma showed type II in addition to type IIIL, IV, VI, or VN pit patterns. CONCLUSIONS In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, in addition to the use of magnifying endoscopy, may be useful to accurately diagnose advanced histology within an SSA/P.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan; Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hideaki Ritsuno
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Taro Osada
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroyuki Mitomi
- Department of Pathology, Japan Labor Health and Welfare Organization, Kanto Rosai Hospital, Kanagawa, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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37
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Okamoto K, Kitamura S, Kimura T, Nakagawa T, Sogabe M, Miyamoto H, Muguruma N, Takayama T. Clinicopathological characteristics of serrated polyps as precursors to colorectal cancer: Current status and management. J Gastroenterol Hepatol 2017; 32:358-367. [PMID: 27376251 DOI: 10.1111/jgh.13482] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2016] [Indexed: 12/13/2022]
Abstract
Serrated polyps have long been thought to lack malignant potential in the human colorectum. However, identification of the serrated pathway to colorectal cancer based on molecular biology has improved our understanding of the pathogenesis of colorectal cancers. Accordingly, serrated polyps such as traditional serrated adenoma and sessile serrated adenoma/polyps (SSA/P) are now considered to be precursor lesions of the serrated pathway. Recently, serrated polyps were classified into three subtypes, consisting of hyperplastic polyp, SSA/P, and traditional serrated adenoma, according to the World Health Organization classification. It has been suggested that SSA/P in the proximal colon are a precursor lesion of pathogenesis of colorectal cancer and are characterized by BRAF mutation and a CpG island methylator phenotype with or without microsatellite instability. However, SSA/P is more challenging to detect by colonoscopy and is likely to account for some interval cancers, particularly in the proximal colon because it presents flat or sessile, isochroous appearance, and occasionally has a mucous cap. Furthermore, the possibility has been raised that pathologists misclassify SSA/P as hyperplastic polyp. It is important for gastroenterologists to recognize the endoscopic features of serrated polyps to facilitate their detection and removal and also to establish postpolypectomy surveillance guidelines. In this review, we discuss the recent classification of serrated polyps; the molecular characteristics of the serrated pathway; appropriate diagnostic methods using endoscopy, including a new image-enhanced endoscopic technique; and management of these lesions.
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Affiliation(s)
- Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Shinji Kitamura
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuo Kimura
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tadahiko Nakagawa
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
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Bettington M, Walker N, Rosty C, Brown I, Clouston A, McKeone D, Pearson SA, Leggett B, Whitehall V. Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma. Gut 2017; 66:97-106. [PMID: 26475632 DOI: 10.1136/gutjnl-2015-310456] [Citation(s) in RCA: 147] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 09/15/2015] [Accepted: 09/20/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Sessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma. DESIGN A cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAF and KRAS mutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, β-catenin and 0-6-methylguanine DNA methyltransferase (MGMT). RESULTS The median polyp size was 9 mm and 86.5% were proximal. Most were BRAF mutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear β-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status. CONCLUSIONS SSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these 'caught in the act' lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.
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Affiliation(s)
- Mark Bettington
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Neal Walker
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Christophe Rosty
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Ian Brown
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Andrew Clouston
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Diane McKeone
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Sally-Ann Pearson
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Barbara Leggett
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Vicki Whitehall
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Department of Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia
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Chin M, Karnes W, Jamal MM, Lee JG, Lee R, Samarasena J, Bechtold ML, Nguyen DL. Use of the Endocuff during routine colonoscopy examination improves adenoma detection: A meta-analysis. World J Gastroenterol 2016; 22:9642-9649. [PMID: 27920485 PMCID: PMC5116608 DOI: 10.3748/wjg.v22.i43.9642] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 09/24/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To perform meta-analysis of the use of Endocuff during average risk screening colonoscopy. METHODS Scopus, Cochrane databases, MEDLINE/PubMed, and CINAHL were searched in April 2016. Abstracts from Digestive Disease Week, United European Gastroenterology, and the American College of Gastroenterology meeting were also searched from 2004-2015. Studies comparing EC-assisted colonoscopy (EAC) to standard colonoscopy, for any indication, were included in the analysis. The analysis was conducted by using the Mantel-Haenszel or DerSimonian and Laird models with the odds ratio (OR) to assess adenoma detection, cecal intubation rate, and complications performed. RESULTS Nine studies (n = 5624 patients) were included in the analysis. Compared to standard colonoscopy, procedures performed with EC had higher frequencies for adenoma (OR = 1.49, 95%CI: 1.23-1.80; P = 0.03), and sessile serrated adenomas detection (OR = 2.34 95%CI: 1.63-3.36; P < 0.001). There was no significant difference in cecal intubation rates between the EAC group and standard colonoscopy (OR = 1.26, 95%CI: 0.70-2.27, I2 = 0%; P = 0.44). EAC was associated with a higher risk of complications, most commonly being superficial mucosal injury without higher frequency for perforation. CONCLUSION The use of an EC on colonoscopy appears to improve pre-cancerous polyp detection without any difference in cecal intubation rates compared to standard colonoscopy.
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Parada AA, Ribas CAPM, Venco FE, Ardengh JC, Reis MA, Degiovani M, Varca-Neto MR, Diger NR, Ibrahim RE, Cordova KF, Fagundes MDAC, Moreira H, Kubrusly LF. Comparative analysis of endoscopic and histopathological features of superficial elevated lesions resected by endoscopic mucosal resection in the distal and proximal colon. Rev Col Bras Cir 2016; 43:178-84. [PMID: 27556542 DOI: 10.1590/0100-69912016003010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 04/28/2016] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE to compare endoscopic and histopathologic features of superficial, elevated lesions with one or more centimeters in diameter, diagnosed by videocolonoscopy on the distal and proximal colon, and subjected to mucosal resection. METHODS we conducted a retrospective, cross-sectional, observational study involving 8,075 videocolonoscopies. From this total, we evaluated 166 mucosectomies in 145 patients with superficial, elevated lesions with a diameter equal to or greater than 1cm. RESULTS the lesion prevalence was lower in G1 than in G2 (34.9% vs. 65%). The mean age, gender distribution and size (1.9cm in G1 versus 2.0cm in G2, p=0.921) were similar. There was no difference of mucosal surfaces in relation to the location (p=0.575). Considering Intraepithelial neoplasias, both the low grade, high grade (including carcinomas) and hyperplasic ones showedd no difference (p=0.527), nor did the neoplastic lesions when divided into serrated and non-serrated (p=0.124). Excluding 13 hyperplastic lesions and two carcinomas, 124 (82.1%) were non-serrated and 27 (17.9%), serrated. CONCLUSION were found no significant differences between endoscopic and histopathological aspects of superficial, elevated lesions of 1cm or more in diameter in distal colon compared with the proximal, when resected by mucosectomy. Although not significant, there was a tendency of association between the location of the lesion and the presence of serrated features. OBJETIVO comparar aspectos endoscópicos e histopatológicos de lesões superficialmente elevadas, com um ou mais centímetros de diâmetro, diagnosticadas por videocolonoscopias e ressecadas por mucosectomias do cólon distal com as do cólon proximal. MÉTODOS estudo foi retrospectivo, transversal, observacional, envolvendo 8075 videocolonoscopias. Avaliou-se 166 mucosectomias em 145 pacientes com lesões superficialmente elevadas com diâmetro igual ou maior do que 1cm. RESULTADOS a prevalência de lesões foi menor no G1 do que no G2 (34,9% x 65%). A média de idade, a distribuição por sexo e o tamanho (1,9cm no G1 e 2cm no G2, p=0,921) foram semelhantes. Não houve diferenças das superfícies em relação à localização (p=0,575). Considerando neoplasia intraepitelial de baixo grau, neoplasia intraepitelial de alto grau (incluindo carcinomas) e hiperplásicas, não houve diferença (p=0,527), assim como quando foram divididas as lesões neoplásicas em serrilhadas e não serrilhadas (p=0,124). Excluindo-se 13 lesões hiperplásicas e duas com carcinomas, 124 (82,1%) foram não serrilhadas e 27 (17,9%) serrilhadas. CONCLUSÃO não foram observadas diferenças significativas entre os aspectos endoscópicos e os histopatológicos das lesões superficialmente elevadas, com 1cm ou mais de diâmetro, ressecadas por mucosectomia do cólon distal em relação ao proximal. Embora não significante, há tendência à associação entre a localização da lesão e a presença de características serrilhadas.
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Affiliation(s)
- Artur Adolfo Parada
- - Programa de Pós-Graduação em Princípios da Cirurgia, Faculdade Evangélica do Paraná/Hospital Universitário Evangélico de Curitiba/ Instituto de Pesquisas Médicas, Curitiba, PR, Brasil.,- Serviço de Endoscopia Gastrointestinal do Hospital Nove de Julho, São Paulo, SP, Brasil
| | - Carmen Australia Parede Marcondes Ribas
- - Programa de Pós-Graduação em Princípios da Cirurgia, Faculdade Evangélica do Paraná/Hospital Universitário Evangélico de Curitiba/ Instituto de Pesquisas Médicas, Curitiba, PR, Brasil
| | | | - José Celso Ardengh
- - Serviço de Endoscopia Gastrointestinal do Hospital Nove de Julho, São Paulo, SP, Brasil
| | - Mariana Amaral Reis
- - Serviço de Endoscopia Gastrointestinal do Hospital Nove de Julho, São Paulo, SP, Brasil
| | - Matheus Degiovani
- - Programa de Pós-Graduação em Princípios da Cirurgia, Faculdade Evangélica do Paraná/Hospital Universitário Evangélico de Curitiba/ Instituto de Pesquisas Médicas, Curitiba, PR, Brasil.,- Serviço de Endoscopia Gastrointestinal do Hospital Nove de Julho, São Paulo, SP, Brasil
| | | | - Nildede Rodrigues Diger
- - Programa de Pós-Graduação em Princípios da Cirurgia, Faculdade Evangélica do Paraná/Hospital Universitário Evangélico de Curitiba/ Instituto de Pesquisas Médicas, Curitiba, PR, Brasil.,- Serviço de Endoscopia Gastrointestinal do Hospital Nove de Julho, São Paulo, SP, Brasil
| | - Roberto El Ibrahim
- - Laboratório Diagnóstika Patologia Cirúrgica e Citologia, São Paulo, SP, Brasil
| | - Kassia Fernanda Cordova
- - Programa de Pós-Graduação em Princípios da Cirurgia, Faculdade Evangélica do Paraná/Hospital Universitário Evangélico de Curitiba/ Instituto de Pesquisas Médicas, Curitiba, PR, Brasil
| | - Marília DA Cruz Fagundes
- - Programa de Pós-Graduação em Princípios da Cirurgia, Faculdade Evangélica do Paraná/Hospital Universitário Evangélico de Curitiba/ Instituto de Pesquisas Médicas, Curitiba, PR, Brasil
| | - Hamilton Moreira
- - Programa de Pós-Graduação em Princípios da Cirurgia, Faculdade Evangélica do Paraná/Hospital Universitário Evangélico de Curitiba/ Instituto de Pesquisas Médicas, Curitiba, PR, Brasil
| | - Luiz Fernando Kubrusly
- - Programa de Pós-Graduação em Princípios da Cirurgia, Faculdade Evangélica do Paraná/Hospital Universitário Evangélico de Curitiba/ Instituto de Pesquisas Médicas, Curitiba, PR, Brasil
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Risk of Metachronous Advanced Neoplastic Lesions in Patients with Sporadic Sessile Serrated Adenomas Undergoing Colonoscopic Surveillance. Am J Gastroenterol 2016; 111:871-8. [PMID: 27068719 DOI: 10.1038/ajg.2016.120] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 03/07/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The risk of developing metachronous advanced neoplastic lesions (ANLs) during surveillance after resection of sessile serrated adenomas (SSAs) has not been quantified. METHODS Patients with sporadic SSAs resected between 1 April 2007 and 31 December 2009 who underwent surveillance colonoscopy in our institution were prospectively evaluated. Patients with low-risk adenomas (LRAs), high-risk adenomas (HRAs), and negative index colonoscopy (NIC) during the same period were identified using the pathology database and electronic medical records, and were also included as a comparison cohort. The primary outcome was the comparison of the study groups with regard to incidence of metachronous ANLs during surveillance colonoscopy. RESULTS A total of 185 patients had SSAs, of whom 75 with 101 resected polyps were finally included. The comparison cohort consisted of 564 patients: 140 LRAs (160 polyps), 87 HRAs (478 polyps), and 337 NICs. The overall mean colonoscopy follow-up was for 54.5 months (±s.d. 14). SSA patients with synchronous HRA on index colonoscopy presented a higher incidence rate of metachronous ANL (12.96 per 1,000 person-months) compared with patients with HRA (5.07 per 1,000 person-months), whereas those with synchronous LRA and without synchronous adenoma on index colonoscopy presented a low incidence rate of metachronous ANL (0 and 1.41 per 1,000 person-months, respectively) similar to LRA (1.47 per 1,000 person-months). Among patients with SSA the 3- and 5-year ANL free-cumulative probability was 64.3 and 32.1% in those with synchronous HRA, 100 and 100% in those with synchronous LRA, and 95.1 and 91.7% if no synchronous adenoma was found. CONCLUSIONS Among patients with resected sporadic SSAs the risk of developing metachronous ANL is influenced by the presence of synchronous HRA on index colonoscopy. Patients with SSAs and synchronous HRA on index colonoscopy require closer surveillance, whereas those with synchronous LRA and those without synchronous adenomas may be followed up in the same way as those with LRAs.
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Abstract
Sessile serrated adenoma/polyp (SSA/p) is a precancerous lesion, and its differential diagnosis from hyperplastic polyp (HP) could be challenging in certain circumstances based on morphology alone. Hes1 is a downstream target of Notch-signaling pathway and plays an important role in intestinal development by regulating differentiation of enterocytes. In this study, we evaluated the expression patterns of Hes1 in SSA/p and HP, and determine whether Hes1 immunostaining can help differentiate between these 2 entities. Serrated polyps with cytologic dysplasia (SSA with cytologic dysplasia, tubular adenoma, and traditional serrated adenoma) were also studied. Hes1 is ubiquitously expressed in the nuclei of normal colon epithelial cells. The complete loss or a very weak expression of Hes1 is observed in the majority of the SSA/p in the study (58/63, 92%) compared with the normal expression of Hes1 in HP (35/35,100%). In SSA/p with cytologic dysplasia, dysplastic area demonstrated cytoplasmic and/or nuclear staining for Hes1. Tubular adenoma and traditional serrated adenoma showed variability of Hes1 staining within the polyp with a mixed positive and negative staining pattern. Our study suggests that loss of Hes1 could be used as a sensitive and specific marker to differentiate SSA/p from HP, which helps the diagnosis in morphologically challenging cases.
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Burgess NG, Pellise M, Nanda KS, Hourigan LF, Zanati SA, Brown GJ, Singh R, Williams SJ, Raftopoulos SC, Ormonde D, Moss A, Byth K, P'Ng H, McLeod D, Bourke MJ. Clinical and endoscopic predictors of cytological dysplasia or cancer in a prospective multicentre study of large sessile serrated adenomas/polyps. Gut 2016; 65:437-46. [PMID: 25731869 DOI: 10.1136/gutjnl-2014-308603] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 02/07/2015] [Indexed: 12/29/2022]
Abstract
OBJECTIVE The serrated neoplasia pathway accounts for up to 30% of all sporadic colorectal cancers (CRCs). Sessile serrated adenomas/polyps (SSA/Ps) with cytological dysplasia (SSA/P-D) are a high-risk serrated CRC precursor with little existing data. We aimed to describe the clinical and endoscopic predictors of SSA/P-D and high grade dysplasia (HGD) or cancer. DESIGN Prospective multicentre data of SSA/Ps ≥20 mm referred for treatment by endoscopic mucosal resection (September 2008-July 2013) were analysed. Imaging and lesion assessment was standardised. Histological findings were correlated with clinical and endoscopic findings. RESULTS 268 SSA/Ps were found in 207/1546 patients (13.4%). SSA/P-D comprised 32.4% of SSA/Ps ≥20 mm. Cancer occurred in 3.9%. On multivariable analysis, SSA/P-D was associated with increasing age (OR=1.69 per decade; 95% CI (1.19 to 2.40), p0.004) and increasing lesion size (OR=1.90 per 10 mm; 95% CI (1.30 to 2.78), p0.001), an 'adenomatous' pit pattern (Kudo III, IV or V) (OR=3.98; 95% CI (1.94 to 8.15), p<0.001) and any 0-Is component within a SSA/P (OR=3.10; 95% CI (1.19 to 8.12) p0.021). Conventional type dysplasia was more likely to exhibit an adenomatous pit pattern than serrated dysplasia. HGD or cancer was present in 7.2% and on multivariable analysis, was associated with increasing age (OR=2.0 per decade; 95% CI 1.13 to 3.56) p0.017) and any Paris 0-Is component (OR=10.2; 95% CI 3.18 to 32.4, p<0.001). CONCLUSIONS Simple assessment tools allow endoscopists to predict SSA/P-D or HGD/cancer in SSA/Ps ≥20 mm. Correct prediction is limited by failure to recognise SSA/P-D which may mimic conventional adenoma. Understanding the concept of SSA/P-D and the pitfalls of SSA/P assessment may improve detection, recognition and resection and potentially reduce interval cancer. TRIAL REGISTRATION NUMBER NCT01368289.
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Affiliation(s)
- Nicholas G Burgess
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Maria Pellise
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Kavinderjit S Nanda
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Luke F Hourigan
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia Department of Gastroenterology and Hepatology, Greenslopes Private Hospital, Brisbane, Queensland, Australia
| | - Simon A Zanati
- Department of Gastroenterology and Hepatology, The Alfred Hospital, Melbourne, Victoria, Australia Department of Gastroenterology and Hepatology, Western Hospital, Melbourne, Victoria, Australia
| | - Gregor J Brown
- Department of Gastroenterology and Hepatology, The Alfred Hospital, Melbourne, Victoria, Australia Department of Gastroenterology and Hepatology, Epworth Hospital, Melbourne, Victoria, Australia
| | - Rajvinder Singh
- Department of Gastroenterology and Hepatology, Lyell McEwin Hospital, Adelaide, South Australia, Australia
| | - Stephen J Williams
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia
| | - Spiro C Raftopoulos
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Donald Ormonde
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Alan Moss
- Department of Gastroenterology and Hepatology, Western Hospital, Melbourne, Victoria, Australia
| | - Karen Byth
- University of Sydney NHMRC Clinical Trials Centre, Sydney, New South Wales, Australia
| | - Heok P'Ng
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia
| | - Duncan McLeod
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia
| | - Michael J Bourke
- Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
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Lee EJ, Chun SM, Kim MJ, Jang SJ, Kim DS, Lee DH, Youk EG. Reappraisal of hMLH1 promoter methylation and protein expression status in the serrated neoplasia pathway. Histopathology 2016; 69:198-210. [PMID: 26713412 DOI: 10.1111/his.12925] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 12/23/2015] [Indexed: 12/12/2022]
Abstract
AIMS The aim of this study was to determine whether human mutL homologue 1 (hMLH1) inactivation precedes the progression of sessile serrated lesion (SSL) into SSL with cytological dysplasia (SSL/D) and to define the histological stage at which promoter methylation and inactivation of hMLH1 occur. METHODS AND RESULTS Using the MassARRAY EpiTYPER assay and immunohistochemistry, we examined methylation levels and the protein expression status of hMLH1 in 33 SSL/Ds with conventional epithelial dysplasia and compared the results with those of control hyperplastic polyps (HPs) and SSLs. The methylation level of hMLH1 was higher in the dysplastic component than in the non-dysplastic component of SSL/Ds (P = 0.005), and differed significantly with regard to the degree of dysplasia (P = 0.002). The methylation levels of hMLH1 in the dysplastic component of SSL/Ds tended to be higher than those of control SSLs and HPs (P = 0.063 and P = 0.017, respectively). The loss of hMLH1 protein expression was identified in only 13 of 33 (39.39%) dysplastic components of SSL/Ds. CONCLUSION Promoter methylation and loss of protein expression of hMLH1 are not parallel processes that occur concurrently. hMLH1 methylation is an early molecular event which occurs even in HP. However, the loss of hMLH1 expression is a much later step, found in approximately 40% of SSL/Ds at various histological stages. Notably, the loss of hMLH1 protein expression does not necessarily precede the development of cytological dysplasia in SSL.
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Affiliation(s)
- Eun-Jung Lee
- Department of Surgery, Daehang Hospital, Seoul, Korea
| | - Sung-Min Chun
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Mi-Jung Kim
- Department of Pathology, Daehang Hospital, Seoul, Korea
| | - Se-Jin Jang
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Do Sun Kim
- Department of Surgery, Daehang Hospital, Seoul, Korea
| | - Doo Han Lee
- Department of Surgery, Daehang Hospital, Seoul, Korea
| | - Eui Gon Youk
- Department of Surgery, Daehang Hospital, Seoul, Korea
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Rau TT, Atreya R, Aust D, Baretton G, Eck M, Erlenbach-Wünsch K, Hartmann A, Lugli A, Stöhr R, Vieth M, Wirsing AM, Zlobec I, Katzenberger T. Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities, clinical parameters and phenotype-genotype correlation. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2016; 2:113-24. [PMID: 27499921 PMCID: PMC4907061 DOI: 10.1002/cjp2.41] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 01/23/2016] [Indexed: 12/14/2022]
Abstract
Studies on traditional serrated adenoma (TSA) and sessile serrated adenoma with dysplasia (SSA‐D) are rare due to the low frequency of these lesions, which are well defined by the latest WHO classification. However, introducing new morphological criteria such as intra‐epithelial lymphocytes (IELs) might facilitate colorectal polyp diagnoses. Additionally, the phenotype–genotype correlation needs to be updated as the terminology has repeatedly changed. This study analysed 516 polyps, consisting of 118 classical adenomas (CAD), 116 hyperplastic polyps (HPP), 179 SSAs, 41 SSA‐Ds, and 62 TSAs. The lesions were analysed in relation to the patients’ clinical parameters including gender, age, localisation, and size. The inflammatory background of the polyps was quantified and BRAF and KRAS mutations as well as MLH1 and CDKN2A promoter methylation were assessed. In multivariate analyses, an increase in IELs was an independent and robust new criterion for the diagnosis of SSA‐D (p < 0.001). Superficial erosions and acute neutrophil granulocytes led to reactive changes potentially resembling dysplasia. KRAS and BRAF mutations were associated with CAD/TSA and HPP/SSA, respectively. However, almost half of TSAs had a BRAF mutation and were KRAS wild type. CDKN2A seems to precede MLH1 hyper‐methylation within the serrated carcinogenesis model. The genotyping of WHO‐based entities – and especially SSA – has sharpened in comparison to previously published data. TSAs can be sub‐grouped according to their mutation status. Of note, the higher number of IELs in SSA‐D reflects their close relationship to colorectal cancers with micro‐satellite instability. Therefore, IELs might represent a new diagnostic tool for SSA‐D.
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Affiliation(s)
- Tilman T Rau
- Institute of Pathology, University Bern, BernSwitzerland; Institute of Pathology, Friedrich-Alexander University Erlangen-NurembergErlangenGermany
| | - Raja Atreya
- Medical Clinic 1, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | - Daniela Aust
- Institute of Pathology, University Hospital Dresden Carl Gustav Carus Dresden Germany
| | - Gustavo Baretton
- Institute of Pathology, University Hospital Dresden Carl Gustav Carus Dresden Germany
| | - Matthias Eck
- Institute of Pathology, Hospital Aschaffenburg Aschaffenburg Germany
| | | | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | | | - Robert Stöhr
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | - Michael Vieth
- Institute of Pathology, Hospital Bayreuth Bayreuth Germany
| | - Anna M Wirsing
- Institute of Pathology, Friedrich-Alexander University Erlangen-NurembergErlangenGermany; Department of Medical Biology, Faculty of Health SciencesUniversity of TromsøTromsøNorway
| | - Inti Zlobec
- Institute of Pathology, University Bern, Bern Switzerland
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Renaud F, Mariette C, Vincent A, Wacrenier A, Maunoury V, Leclerc J, Coppin L, Crépin M, Van Seuningen I, Leteurtre E, Buisine MP. The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential. Int J Cancer 2015; 138:1472-81. [PMID: 26476272 DOI: 10.1002/ijc.29891] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 10/05/2015] [Indexed: 12/25/2022]
Abstract
The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention.
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Affiliation(s)
- Florence Renaud
- Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.,Pathology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.,North of France Lille 2 University, Lille, France
| | - Christophe Mariette
- Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.,North of France Lille 2 University, Lille, France.,Department of Digestive Surgery, Claude Huriez Hospital, Lille University Hospital, Lille, France
| | - Audrey Vincent
- Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.,North of France Lille 2 University, Lille, France.,Lille University Hospital, Lille, France
| | - Agnès Wacrenier
- Pathology Institute, Biology Pathology Center, Lille University Hospital, Lille, France
| | - Vincent Maunoury
- Department of Gastroenterology, Claude Huriez Hospital, Lille University Hospital, Lille, France
| | - Julie Leclerc
- Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.,North of France Lille 2 University, Lille, France.,Department of Molecular Oncology and Genetics, Biochemistry and Molecular Biology Institute, Biology Pathology Center, Lille University Hospital, Lille, France
| | - Lucie Coppin
- Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.,North of France Lille 2 University, Lille, France.,Department of Molecular Oncology and Genetics, Biochemistry and Molecular Biology Institute, Biology Pathology Center, Lille University Hospital, Lille, France
| | - Michel Crépin
- Department of Molecular Oncology and Genetics, Biochemistry and Molecular Biology Institute, Biology Pathology Center, Lille University Hospital, Lille, France
| | - Isabelle Van Seuningen
- Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.,North of France Lille 2 University, Lille, France.,Lille University Hospital, Lille, France
| | - Emmanuelle Leteurtre
- Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.,Pathology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.,North of France Lille 2 University, Lille, France
| | - Marie-Pierre Buisine
- Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.,North of France Lille 2 University, Lille, France.,Department of Molecular Oncology and Genetics, Biochemistry and Molecular Biology Institute, Biology Pathology Center, Lille University Hospital, Lille, France
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Nosho K, Igarashi H, Ito M, Mitsuhashi K, Kurihara H, Kanno S, Yoshii S, Mikami M, Takahashi H, Kusumi T, Hosokawa M, Sukawa Y, Adachi Y, Hasegawa T, Okita K, Hirata K, Maruyama R, Suzuki H, Imai K, Yamamoto H, Shinomura Y. Clinicopathological and molecular characteristics of serrated lesions in Japanese elderly patients. Digestion 2015; 91:57-63. [PMID: 25632919 DOI: 10.1159/000368820] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The population in Japan is aging more rapidly than in any other country. However, no studies have determined the characteristics of the large population of elderly patients with colorectal tumors. Therefore, we examined the clinicopathological and molecular features of these tumors in elderly patients. METHODS In total, 1,627 colorectal tumors (393 serrated lesions, 277 non-serrated adenomas and 957 colorectal cancers) were acquired from patients. Tumor specimens were analyzed for BRAF and KRAS mutations, CpG island methylator phenotype-specific promoters (CACNA1G, CDKN2A, IGF2 and RUNX3), IGFBP7, MGMT, MLH1 and RASSF2 methylation, microsatellite instability (MSI) and microRNA- 31 (miR-31). RESULTS The frequency of elderly patients (aged ≥75 years) with sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that of those with other serrated lesions and non-serrated adenomas (p < 0.0001). In elderly patients, all SSAs were located in the proximal colon (particularly the cecum to ascending colon). High miR-31 expression, MLH1 methylation and MSI-high status were more frequently detected in SSAs from elderly patients than in those from non-elderly patients. In contrast, no significant differences were found between older age of onset and high-grade dysplasia for traditional serrated adenomas or non-serrated adenomas in any of these molecular alterations. CONCLUSION In elderly patients, all SSAs were located in the proximal colon. Furthermore, cytological dysplasia and molecular alterations were more frequently detected in elderly patients with SSAs than in non-elderly patients. Thus, careful colonoscopic examinations of the proximal colon are necessary for elderly patients because SSAs in those patients may exhibit malignant potential.
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Affiliation(s)
- Katsuhiko Nosho
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Brown IS, Bettington ML, Bettington A, Miller G, Rosty C. Adverse histological features in malignant colorectal polyps: a contemporary series of 239 cases. J Clin Pathol 2015; 69:292-9. [PMID: 26424814 DOI: 10.1136/jclinpath-2015-203203] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/10/2015] [Indexed: 12/24/2022]
Abstract
AIMS Screening colonoscopy has led to more colorectal carcinomas presenting at an early stage potentially curable by endoscopic resection. In this study, we examined the clinical and histological features of a contemporary series of malignant colorectal polyps (MCPs) with subsequent surgical resection. METHODS We conducted a retrospective study on a consecutive series of MCPs from 239 patients, predominantly males (57.7%) with a median age of 66 years, and assessed histological parameters associated with residual disease on the surgical specimens. RESULTS Median MCP size was 18.6 mm, with 23.1% polyps measuring ≤10 mm. From the 140 surgical resection specimens, residual disease was identified in 20 cases, including 12 cases with metastatic lymph nodes and/or 9 cases with residual carcinoma in the large bowel wall. Histological parameters associated with nodal metastases were greater width and greater depth of the invasive component (p=0.001 and 0.006, respectively), poor differentiation (p=0.003) and a cribriform pattern (p=0.01). The risk of nodal metastases was 23.3% if two or three of these features were identified, while it was 0% and 4.5% if none or one was present, respectively. A positive margin was not associated with nodal metastasis and might be adequately treated by local endoscopic resection. CONCLUSIONS Surgical resection should be recommended if ≥2 of these adverse histological features are present and may be warranted if one feature is present. A positive margin may require additional local resection but not necessarily surgery if no other adverse factors are present.
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Affiliation(s)
- Ian S Brown
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia Department of Anatomical Pathology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Mark L Bettington
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia School of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | | | - Gregory Miller
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia School of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Christophe Rosty
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia School of Medicine, University of Queensland, Brisbane, Queensland, Australia Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia
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Expression of adhesion molecules and epithelial-mesenchymal transition factors in medullary carcinoma of the colorectum. Hum Pathol 2015. [PMID: 26208847 DOI: 10.1016/j.humpath.2015.05.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Abstract
"Invasive micropapillary serous carcinoma" has been proposed as a synonym for low-grade serous carcinoma by some expert pathologists. In contrast, Singer and colleagues reported that some serous carcinomas with conspicuous invasive micropapillary pattern (SC-IMPs) can show high-grade nuclear atypia. However, the molecular features of such tumors have not been well documented. The aim of this study was to demonstrate and emphasize the fact that high-grade serous carcinoma confirmed by immunohistochemistry and molecular analysis can show conspicuous invasive micropapillary pattern. We selected 24 "SC-IMPs" and investigated: (1) their morphologic features; (2) the immunostaining pattern of p53 protein; and (3) KRAS/BRAF/TP53 gene mutations. The 24 SC-IMPs were subdivided into low-grade and high-grade tumors based primarily on the nuclear atypia, with the mitotic rate used as a secondary feature: low grade (n=5) and high grade (n=19). Low-grade SC-IMPs were characterized by low-mitotic activity, absence of abnormal mitosis, presence of serous borderline tumor, occasional BRAF mutation, and infrequent TP53 mutation. High-grade SC-IMPs were characterized by high-mitotic activity, presence of abnormal mitosis, conventional high-grade serous carcinoma, frequent TP53 mutation, and lack of KRAS/BRAF mutation. We demonstrated that high-grade serous carcinoma confirmed by aberrant p53 immunostaining and molecular analysis can show conspicuous invasive micropapillary pattern, validating Singer and colleague's report. Serous carcinoma with conspicuous invasive micropapillary pattern should not be readily regarded as low-grade serous carcinoma. Nuclear grade is the most important diagnostic feature in the SC-IMPs.
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