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Sugai T, Uesugi N, Hamada K, Nagahashi T, Horikawa Y, Suzuki M, Sugimoto R, Yanagawa N. A gastric invasive tubular adenocarcinomatous lesion arising from foveolar-type neoplasia: molecular histogenesis. Clin J Gastroenterol 2024; 17:617-621. [PMID: 38662253 PMCID: PMC11284181 DOI: 10.1007/s12328-024-01974-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/15/2024] [Indexed: 04/26/2024]
Abstract
Here, we report a rare case of a depressed lesion exhibiting both tubular differentiated adenocarcinomatous (TDA) and intraepithelial foveolar neoplasia (IFN) components (with the histological appearance of foveolar hyperplasia due to low-grade atypia). Histologically, the TDA surrounded the IFN, suggesting that the TDA may have originated from the IFN. Therefore, we examined molecular alterations in the TDA and IFN components separately. MUC5AC and MUC6 expression was observed immunohistochemically in both components. p53 expression was wild type in both components, suggesting no mutation of TP53. We investigated allelic imbalances at multiple loci (1p, 3p, 4p, 5q, 8q, 9p, 13q, TP53, 18q, and 22q), mutations (KRAS, BRAF, and GNAS), and DNA methylation and microsatellite status in both components using PCR-based analyses. Although multiple allelic imbalances were common to both components, allelic imbalances at 3p and TP53 were found only in the TDA component. No mutations were found, and DNA methylation status was low epigenotype for both components. Ultimately, this tumor was considered microsatellite stable. Considering the origin of TDA, which is frequently encountered in routine practice, IFN may develop into TDA.
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Affiliation(s)
- Tamotsu Sugai
- Diagnostic Pathology Center, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan.
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, Iwate, 028-3695, Japan.
| | - Noriyuki Uesugi
- Diagnostic Pathology Center, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, Iwate, 028-3695, Japan
| | - Koichi Hamada
- Department of Gastroenterology, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan
| | - Takayuki Nagahashi
- Department of Gastroenterology, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan
| | - Yoshinori Horikawa
- Department of Gastroenterology, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan
| | - Masamichi Suzuki
- Diagnostic Pathology Center, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, Iwate, 028-3695, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Shiwa, Iwate, 028-3695, Japan
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Chen J, Cui X, Wu H, Zhou C. Case report: A rare case of very well-differentiated gastric adenocarcinoma of gastric type with a lymphovascular invasion. Front Oncol 2024; 14:1396281. [PMID: 38725617 PMCID: PMC11079201 DOI: 10.3389/fonc.2024.1396281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/04/2024] [Indexed: 05/12/2024] Open
Abstract
Background Very well-differentiated gastric adenocarcinoma (VWDA) is a rare variant of gastric cancer, for which the diagnostic criteria and clinical behavior are not fully established. We reported a case of an intramucosal VWDA of gastric type with a lymphovascular invasion (LVI). Case presentation A 67-year-old female was diagnosed as intramucosal gastric adenocarcinoma after a biopsy at the local hospital 3 weeks ago and then visited our hospital for further treatment. The endoscopic examination in our hospital showed a rough, slightly faded, 30-mm, flat, and elevated lesion on the lesser curvature of the middle gastric body. Histopathologically, the lesion consisted of superficial foveolar-type papillary adenocarcinoma and deep pyloric gland-type tubular adenocarcinoma. The immunostaining results showed that the foveolar-type papillary adenocarcinoma was positive for MUC5AC and had a high index of Ki-67, but the pyloric gland-type tubular adenocarcinoma was positive for MUC6 and had a low index of Ki-67. Both components were negative for MSH2 and MSH6, which suggested the high microsatellite instability phenotype. Moreover, a LVI was detected in the lesion. The pathological diagnosis was VWDA of gastric type. Conclusion The case has unique histological and immunophenotypic characteristics, which not only indicates the importance of architectural features in the diagnosis of VWDA but also further proves that the aggressive behavior of VWDA is correlated with tumor histological type and immunophenotype.
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Affiliation(s)
- Jiaqi Chen
- Department of Pathology, The Second Hospital of Shandong University, Jinan, Shandong, China
| | - Xiujie Cui
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Honglei Wu
- Department of Gastroenterology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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Molecular alterations in gastric cancer and the surrounding intestinal metaplastic mucosa: an analysis of isolated glands. Gastric Cancer 2021; 24:382-391. [PMID: 33141339 DOI: 10.1007/s10120-020-01130-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 10/11/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intestinal metaplasias (IMs) are generally regarded as pre-neoplastic gastric lesions. However, molecular alterations including genetic and epigenetic changes occurring in individual IM glands are not well defined. AIMS We sought to identify DNA methylation status, microsatellite instability (MSI) and allelic imbalance (AI) occurring in individual IM glands and non-IM glands within the same mucosa. METHODS We divided examined isolated gland obtained from GC into 4 components: isolated cancer, antral isolated intestinal metaplastic tissue, antral isolated non-metaplastic gland and isolated non-metaplastic gland derived from the greater curvature of the most distant gastric body without mucosal atrophy. We examined AI and microsatellite instability statuses using PCR-based microsatellite analysis. Next, the DNA methylation status (high methylation epigenome [HME], intermediate methylation epigenome [IME], and low methylation epigenome [LME]) was investigated. DNA methylation analysis of CDKN2A, mir34-b/c and MLHI genes was also performed. RESULTS Although antral isolated IM glands were characterized by IME, isolated non-IM glands showed LME. In isolated cancer glands, HME was frequently found, compared with isolated non-IM glands. DNA methylation of mir34-b/c was common in isolated cancer and IM glands, whereas DNA methylation of CDKN2A was a rare event in isolated samples. The MLH1 gene was not methylated in isolated non-IM glands. Although multiple AIs were frequently found in isolated cancer glands, a few AIs were detected in isolated IM glands. CONCLUSIONS We suggest that the DNA methylation status and the status of the mir34-b/c gene among isolated samples of IMs and isolated non-IM glands have an impact on IM development.
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Ji D, Yin JY, Li DF, Zhu CT, Ye JP, Pan YQ. Effects of inflammatory and anti-inflammatory environments on the macrophage mitochondrial function. Sci Rep 2020; 10:20324. [PMID: 33230189 PMCID: PMC7684315 DOI: 10.1038/s41598-020-77370-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 11/09/2020] [Indexed: 12/22/2022] Open
Abstract
Mitochondrial response to inflammation is crucial in the metabolic adaptation to infection. This study aimed to explore the mitochondrial response under inflammatory and anti-inflammatory environments, with a focus on the tricarboxylic acid (TCA) cycle. Expression levels of key TCA cycle enzymes and the autophagy-related protein light chain 3b (LC3b) were determined in raw 264.7 cells treated with lipopolysaccharide (LPS) and metformin (Met). Additionally, reactive oxygen species (ROS) levels and mitochondrial membrane potential were assessed using flow cytometry. Moreover, 8-week-old C57BL/6J mice were intraperitoneally injected with LPS and Met to assess the mitochondrial response in vivo. Upon LPS stimulation, the expression of key TCA enzymes, including citrate synthase, α-ketoglutarate dehydrogenase, and isocitrate dehydrogenase 2, and the mitochondrial membrane potential decreased, whereas the levels of LC3b and ROS increased. However, treatment with Met inhibited the reduction of LPS-induced enzyme levels as well as the elevation of LC3b and ROS levels. In conclusion, the mitochondrial TCA cycle is affected by the inflammatory environment, and the LPS-induced effects can be reversed by Met treatment.
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Affiliation(s)
- Dong Ji
- Central Laboratory, Shanghai Sixth People's Hospital, Shanghai University of Medicine & Health Sciences, No. 600 Yishan Road, Shanghai, 200233, China
| | - Jian-Yun Yin
- Department of Thyroid Breast Surgery, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, 215300, Jiangsu Province, China
| | - Dan-Feng Li
- Central Laboratory, Shanghai Sixth People's Hospital, Shanghai University of Medicine & Health Sciences, No. 600 Yishan Road, Shanghai, 200233, China
| | - Chang-Tai Zhu
- Central Laboratory, Shanghai Sixth People's Hospital, Shanghai University of Medicine & Health Sciences, No. 600 Yishan Road, Shanghai, 200233, China.
| | - Jian-Ping Ye
- Central Laboratory, Shanghai Sixth People's Hospital, Shanghai University of Medicine & Health Sciences, No. 600 Yishan Road, Shanghai, 200233, China.
| | - Yuan-Qing Pan
- Department of Medical Psychology, Guilin Medical University, Tianjin University of Technology and Education, Campbell China Network, No.1 Zhiyuan Road, Guilin, 541010, China.
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Sugai T, Uesugi N, Habano W, Sugimoto R, Eizuka M, Fujita Y, Osakabe M, Toya Y, Suzuki H, Matsumoto T. The clinicopathological and molecular features of sporadic gastric foveolar type neoplasia. Virchows Arch 2020; 477:835-844. [PMID: 32533343 PMCID: PMC7683467 DOI: 10.1007/s00428-020-02846-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 04/15/2020] [Accepted: 05/13/2020] [Indexed: 12/18/2022]
Abstract
Gastric intraepithelial foveolar type neoplasia (IEFN) is not well defined. In addition, atrophic mucosa (AM) is an important issue to consider when evaluating gastric tumorigenesis. Here, we assessed the clinicopathological characteristics and molecular alterations contributing to the development of IEFN compared with intestinal type neoplasia. We examined the clinicopathological and molecular features of 42 cases of IEFN with low-grade dysplasia (LGD) and those of 77 cases of intraepithelial intestinal type neoplasia (IEIN) with LGD. The clinicopathological and molecular features examined included the AM status, mucin phenotype expression, CDX2 expression, p53 overexpression, β-catenin intranuclear accumulation, microsatellite instability (MSI), DNA methylation status (low methylation epigenotype [LME], intermediate ME, or high ME), allelic imbalances (AIs), and APC promoter 1B mutations. There were no differences in the frequencies of AM and rates of CDX2 expression between IEFN and IEIN cases. Although no differences in the frequencies of p53 overexpression and MSI were observed between the two histological types, intranuclear expression of β-catenin was significantly higher in IEIN than in IEFN. In addition, although the rate of LME was significantly higher in IEFN cases than in IEIN cases, IEFN was characterized by AIs at multiple foci. Finally, mutation of the APC promoter 1B, which is a characteristic of gastric adenocarcinoma and proximal polyposis of the stomach (potentially resembling IEFN), was detected in only one IEFN case. These findings suggested that IEFN may be an independent entity in terms of molecular alterations including the presence of multiple AIs and LME.
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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.
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan
| | - Yosuke Toya
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou, 028-3695, Japan
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Identification of early genetic changes in well-differentiated intramucosal gastric carcinoma by target deep sequencing. Gastric Cancer 2019; 22:742-750. [PMID: 30756200 DOI: 10.1007/s10120-019-00926-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 01/03/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The recent advancement of next-generation sequencing (NGS) has enabled the identification of cancer-related somatic aberrations in advanced gastric cancer. However, these remain unclear in early gastric cancers, especially in intramucosal gastric cancers. PATIENTS AND METHODS Thirty-one well-differentiated (tub1) intramucosal gastric cancers obtained by endoscopic submucosal dissection (ESD) from 29 patients were analyzed. After precise collection of tumors and non-tumors from formalin-fixed paraffin-embedded tissues using laser-captured microdissection (LCM), target sequencing analysis of 50 cancer-related genes was performed using an Ion-Proton sequencer. RESULTS The most frequent hotspot mutation was found in TP53 (17 lesions, 54.8%) followed by the Wnt-signaling pathway genes, APC and CTNNB1 (6 lesions, 19.4%). The mutations in TP53 and the Wnt-signaling genes were mutually exclusive (p = 0.004). There was a tendency that H. pylori infection (p = 0.082) and macroscopic protrusion (p = 0.095) was associated with the presence of these mutations. Only 10 lesions (59%) among 17 lesions with proven TP53 mutations were positive for p53 immunostaining demonstrating the superiority of the mutational analysis. In addition, focal gene amplification of ERBB2 (16%) was found frequently in these early stage lesions. CONCLUSIONS Using LCM and NGS, mutations in TP53 and the Wnt-signaling pathway were frequently found and were mutually exclusive in the earliest stage of gastric carcinogenesis.
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Oikawa SI, Shiga K, Saito D, Katagiri K, Ikeda A, Tuchida K, Miyaguchi J, Ishida K, Sugai T. Association between contrast-enhanced ultrasonography and histopathological findings of the metastatic lymph nodes of patients with head and neck cancer: A preliminary study. Oncol Lett 2018. [PMID: 29541182 PMCID: PMC5835891 DOI: 10.3892/ol.2018.7835] [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] [Indexed: 12/28/2022] Open
Abstract
The present study aimed to investigate the usefulness of contrast-enhanced ultrasonography (CEUS) and a newly developed analysis software for the detection of microcapillary network distribution in lymph nodes of patients with head and neck cancer (HNC) by comparing the CEUS and histopathological findings. Patients that were diagnosed with HNC between February and September 2016 were enrolled. A total of five patients underwent resection of the primary tumor and neck dissection as their initial treatment. The cervical lymph nodes of these patients were analyzed by CEUS intraoperatively, and their surgical specimens were examined histopathologically. The patients were diagnosed using a combination of physical examination, computed tomography, magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography. For CEUS examination, the microbubble contrast agent Sonazoid™ was injected into a peripheral vein. Video images of the metastatic lymph nodes were captured, and these were subjected to analysis by a newly developed image-analysis software. It was possible to perform intraoperative CEUS of metastatic lymph nodes and obtain accurate matched sections for histopathological examination. Hematoxylin and eosin and cluster of differentiation (CD)34 staining revealed that the software was able to accurately detect capillary vessels in metastatic lymph nodes. However, a number of perfusion deficits were observed in these lymph nodes. In conclusion, by using CEUS with the analysis software, the density and distribution of blood vessels in the metastatic lymph nodes of patients with HNC was revealed. Although the present study was limited and preliminary, it was concluded that this method may be useful to evaluate and to map the capillary vessels in the metastatic lymph nodes of patients with HNC.
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Affiliation(s)
- Shin-Ichi Oikawa
- Department of Head and Neck Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Kiyoto Shiga
- Department of Head and Neck Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Daisuke Saito
- Department of Head and Neck Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Katsunori Katagiri
- Department of Head and Neck Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Aya Ikeda
- Department of Head and Neck Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Kodai Tuchida
- Department of Head and Neck Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Jun Miyaguchi
- Department of Head and Neck Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Kazuyuki Ishida
- Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
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Sugai T, Eizuka M, Arakawa N, Osakabe M, Habano W, Fujita Y, Yamamoto E, Yamano H, Endoh M, Matsumoto T, Suzuki H. Molecular profiling and comprehensive genome-wide analysis of somatic copy number alterations in gastric intramucosal neoplasias based on microsatellite status. Gastric Cancer 2018; 21:765-775. [PMID: 29468422 PMCID: PMC6097076 DOI: 10.1007/s10120-018-0810-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 02/09/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND We attempted to identify the molecular profiles of gastric intramucosal neoplasia (IMN; low-grade dysplasia, LGD; high-grade dysplasia, HGD; intramucosal cancer, IMC) by assessing somatic copy number alterations (SCNAs) stratified by microsatellite status (microsatellite stable, MSS; microsatellite instable, MSI). Thus, microsatellite status was determined in 84 tumors with MSS status and 16 tumors with MSI status. METHODS One hundred differentiated type IMNs were examined using SCNAs. In addition, genetic mutations (KRAS, BRAF, PIK3CA, and TP53) and DNA methylation status (low, intermediate and high) were also analyzed. Finally, we attempted to identify molecular profiles using a hierarchical clustering analysis. RESULTS Three patterns could be categorized according to SCNAs in IMNs with the MSS phenotype: subgroups 1 and 2 showing a high frequency of SCNAs, and subgroup 3 displaying a low frequency of SCNAs (subgroup 1 > 2 > 3 for SCNA). Subgroup 1 could be distinguished from subgroup 2 by the numbers of total SCNAs (gains and losses) and SCN gains (subgroup 1 > 2). The SCNA pattern of LGD was different from that of HGD and IMC. Moreover, IMNs with the MSI phenotype could be categorized into two subtypes: high frequency of SCNAs and low frequency of SCNAs. Genetic mutations and DNA methylation status did not differ among subgroups in IMNs. CONCLUSION Molecular profiles stratified by SCNAs based on microsatellite status may be useful for elucidation of the mechanisms of early gastric carcinogenesis.
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Affiliation(s)
- Tamotsu Sugai
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Makoto Eizuka
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Noriyuki Arakawa
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Mitsumasa Osakabe
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Wataru Habano
- 0000 0000 9613 6383grid.411790.aDepartment of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Yasuko Fujita
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Eiichiro Yamamoto
- 0000 0001 0691 0855grid.263171.0Department of Molecular Biology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, 060-0061 Japan
| | - Hiroo Yamano
- 0000 0001 0691 0855grid.263171.0Department of Gastroenterology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, 060-0061 Japan
| | - Masaki Endoh
- 0000 0000 9613 6383grid.411790.aDivision of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Takayuki Matsumoto
- 0000 0000 9613 6383grid.411790.aDivision of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Hiromu Suzuki
- 0000 0001 0691 0855grid.263171.0Department of Molecular Biology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, 060-0061 Japan
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Hondo FY, Kishi H, Safatle-Ribeiro AV, Pessorrusso FCS, Ribeiro U, Maluf-Filho F. CHARACTERIZATION OF THE MUCIN PHENOTYPE CAN PREDICT GASTRIC CANCER RECURRENCE AFTER ENDOSCOPIC MUCOSAL RESECTION. ARQUIVOS DE GASTROENTEROLOGIA 2017; 54:308-314. [PMID: 28954038 DOI: 10.1590/s0004-2803.201700000-38] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 05/22/2017] [Indexed: 01/27/2023]
Abstract
BACKGROUND Endoscopic mucosal resection is still considered an accepted treatment for early gastric cancer for selected cases. Histopathologic criteria for curative endoscopic resection are intramucosal well-differentiated adenocarcinoma, lateral and deep margins free of tumor, no histological ulceration, and no venous or lymphatic embolism. A 5% local recurrence rate has been described even when all the above-mentioned criteria are met. On the other hand, antigen expression by tumoral cells has been related to the biological behavior of several tumors. OBJECTIVE To evaluate whether early gastric cancer mucin immunoexpression, p53 and Ki-67, can predict recurrence after endoscopic mucosal resection, even when standard histopathologic criteria for curative measures have been attempted. METHODS Twenty-two patients with early gastric cancer were considered to have been completely resected by endoscopic mucosal resection. Local recurrence occurred in 5/22 (22.7%). Immunohistochemical study was possible in 18 (81.8%) resected specimens. Patients were divided in two groups: those with and those without local recurrence. They were compared across demographic, endoscopic, histologic data, and immunohistochemical factors for MUC2, MUC5a, CD10, p53, and Ki-67. RESULTS Mucin immunoexpression allowed a reclassification of gastric adenocarcinoma in intestinal (10), gastric (2), mixed (4), and null phenotypes (2). Mixed phenotype (positive for both MUC2 and MUC5a) was found in 80% of cases in the local recurrence group, while the intestinal type (positive MUC2 and negative MUC5a) was found in 76.9% of cases without local recurrence (P=0.004). Other observed features did not correlate with neoplastic recurrence. CONCLUSION The mixed phenotype of early gastric adenocarcinoma is associated with a higher probability of local recurrence after endoscopic mucosal resection.
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Affiliation(s)
- Fabio Yuji Hondo
- Gastrocirurgia, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
| | - Humberto Kishi
- Patologia, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
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Uesugi N, Sugai T, Sugimoto R, Eizuka M, Fujita Y, Sato A, Osakabe M, Ishida K, Koeda K, Sasaki A, Matsumoto T. Clinicopathological and molecular stability and methylation analyses of gastric papillary adenocarcinoma. Pathology 2017; 49:596-603. [PMID: 28830689 DOI: 10.1016/j.pathol.2017.07.004] [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: 05/25/2017] [Revised: 07/20/2017] [Accepted: 07/24/2017] [Indexed: 02/07/2023]
Abstract
The molecular alterations and pathological features of gastric papillary adenocarcinoma (GPA) remain unknown. We examined GPA samples and compared their molecular and pathological characteristics with those of gastric tubular adenocarcinoma (GTA). Additionally, we identified pathological and molecular features of GPA that vary with microsatellite stability. In the present study, samples from 63 GPA patients and 47 GTA patients were examined using a combination of polymerase chain reaction (PCR)-microsatellite assays and PCR-pyrosequencing in order to detect microsatellite instability (microsatellite instability, MSI; microsatellite stable, MSS), methylation status (low methylation, intermediate methylation and high methylation level), and chromosomal AI in multiple cancer-related loci. Additionally, the expression levels of TP53 and Her2 were evaluated using immunohistochemistry. GTA and GPA are statistically different in their frequency of pathological features, including mucinous, poorly differentiated and invasive micropapillary components. Clear genetic patterns differentiating GPA and GTA could not be identified with a hierarchical cluster analysis, but microsatellite stability was linked with TP53 and Her2 overexpression. Methylation status in GPA was also associated with the development of high microsatellite instability. However, no pathological differences were associated with microsatellite stability. We suggest that although molecular alterations in a subset of GPAs are closely associated with microsatellite stability, they play a minor role in GPA carcinogenesis.
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Affiliation(s)
- Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan.
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Ayaka Sato
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Kazuyuki Ishida
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Keisuke Koeda
- Department of Surgery, Iwate Medical University, Morioka, Japan
| | - Akira Sasaki
- Department of Surgery, Iwate Medical University, Morioka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
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Sugai T, Eizuka M, Takahashi Y, Fukagawa T, Habano W, Yamamoto E, Akasaka R, Otuska K, Matsumoto T, Suzuki H. Molecular subtypes of colorectal cancers determined by PCR-based analysis. Cancer Sci 2017; 108:427-434. [PMID: 28083970 PMCID: PMC5378279 DOI: 10.1111/cas.13164] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 12/05/2016] [Accepted: 01/02/2017] [Indexed: 12/15/2022] Open
Abstract
Tumor tissue consists of a heterogeneous cell population. The allelic imbalance (AI) ratio, determined in isolated tumor glands, is a good index of tumor heterogeneity. However, associations of the patterns of AI and microsatellite instability (MSI) development, observed in most cases of colorectal cancer (CRC), with tumor progression have not been reported previously. In this study, we examined whether CRC genetic profiles stratified by a combination of the AI ratio and MSI facilitate categorization of CRC, and whether these genetic profiles are associated with specific molecular alterations in CRC. A crypt isolation method was used to isolate DNA from tumors and normal glands obtained from 147 sporadic CRCs. AI and MSI statuses were determined using PCR‐based microsatellite analysis and stratified based on AI ratio and MSI status. DNA methylation status (high methylation, intermediate methylation and low methylation status and mutations in KRAS,BRAF, and TP53 were examined. In addition, mucin markers were immunostained. Based on this analysis, four subgroups were categorized. Subgroup 1 was characterized by a high MSI status and BRAF mutation; subgroup 2 was closely associated with a high AI ratio, which accumulated during the early phases of colorectal carcinogenesis, and TP53 mutation; subgroup 3 was associated with a low AI ratio, seen during the later phases of colorectal carcinogenesis, and KRAS mutation; and subgroup 4 was defined as a minor subgroup. These results confirmed that classification of distinct molecular profiles provides important insights into colorectal carcinogenesis.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Yayoi Takahashi
- Department of Molecular Diagnostic Pathology, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Tomoyuki Fukagawa
- Department of Molecular Diagnostic Pathology, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Wataru Habano
- Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
| | - Risaburo Akasaka
- Division of Gastroenterology, Department of Internal Medicine, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Kouki Otuska
- Department of Surgery, School of Medicine, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
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12
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Arakawa N, Sugai T, Habano W, Eizuka M, Sugimoto R, Akasaka R, Toya Y, Yamamoto E, Koeda K, Sasaki A, Matsumoto T, Suzuki H. Genome-wide analysis of DNA copy number alterations in early and advanced gastric cancers. Mol Carcinog 2016; 56:527-537. [PMID: 27312513 DOI: 10.1002/mc.22514] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 06/07/2016] [Accepted: 06/14/2016] [Indexed: 12/11/2022]
Abstract
To better understand progressive changes in gastric cancer (GC), early and advanced GCs (EGC and AGC, respectively) were examined for copy number alterations (CNAs). A crypt isolation method was used to isolate DNA from tumors and normal glands in 20 AGCs, and fresh tumor samples were obtained from 45 EGCs. We assessed CNAs for differentiated-type GCs using an Infinium HumanCytoSNP-12v2.1 BeadChip in EGCs and AGCs. The most frequent aberrations in EGC were gains at 8q23.3 (42.2%) and 8q23.2 (40%), and loss of heterozygosity (LOH) at 3p14.2 (24.2%), suggesting that these CNAs were involved in the development of EGC. On the other hand, the highest frequencies of gains in AGC were found at 8q24.21 (65%) and 8q24.3 (60%). The most frequent LOHs in AGC were at 11q24.3-25, 11q23.2-24.1, 11q14.1, and 12p11.21-13.33, whereas that in EGC was at 3p14.2. In addition, regions of copy-neutral LOHs in AGC were detected at 11q21, 11q13.3-14.3, 11q11, 11p13-15.3, 12q21.1, 12q12-13.3 and 5q33.3-35.1. Comparisons of gains in EGC and AGC showed significant differences at 12q22-q23.2, 12q21.33, 11p12, 11p14.1, 12q21.31-32.32, 3p12.3, 3p14.1, 10p15.1, 1q24.2 and 2q12.1. Copy neutral LOHs were significantly higher in AGC than in EGC at 14q32.11-32.33, 14q21.3, 14q11.2, 5q11.2, 5q 13.3, 14q21.1-23.2, 14q13.2-13.3, 5q12.1-12.3, 5q11.1, and 17p13.3. The total lengths of the CNAs were significantly greater in AGC than in EGC. We found that the pattern of CNAs in AGC was quite different from that in EGC. We suggest that increasing numbers of CNAs are associated with disease progression from EGC to AGC. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Noriyuki Arakawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Risaburo Akasaka
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Yosuke Toya
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Cyuouku, Sapporo City, Japan
| | - Keisuke Koeda
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Akira Sasaki
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Cyuouku, Sapporo City, Japan
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13
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Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness. Gastric Cancer 2015; 18:720-8. [PMID: 25146833 DOI: 10.1007/s10120-014-0416-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 07/28/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric dysplasia is classified as adenomatous/type I (intestinal phenotype) and foveolar or pyloric/type II (gastric phenotype) according to morphological (architectural and cytological) features. The immunophenotypic classification of dysplasia, based on the expression of the mucins, CD10 and CDX2, recognizes the following immunophenotypes: intestinal (MUC2, CD10, and CDX2); gastric (MUC5AC and/or MUC6, absence of CD10, and absent or low expression of CDX2); hybrid (gastric and intestinal markers); and null. METHODS Sixty-six cases of nonpolypoid epithelial dysplasia of the stomach were classified according to morphological features (histotype and grade) and immunophenotype. Immunohistochemical staining was performed with antibodies against MUC2, MUC5AC, MUC6, CD10, CDX2, chromogranin, synaptophysin, Ki-67, and TP53. HER2 alterations were analyzed by immunohistochemistry and silver-enhanced in situ hybridization. RESULTS By conventional histology, dysplasia was classified as adenomatous/intestinal (n = 42; 64 %) and foveolar or pyloric/gastric (n = 24; 36 %) and graded as low grade (n = 37; 56 %) or high grade (n = 29; 44 %). Immunophenotypic classification showed intestinal (n = 22; 33.3 %), gastric (n = 25; 37.9 %), hybrid (n = 17; 25.8 %), or null (n = 2; 3.0 %) phenotypes. In 20 cases a coexistent intramucosal carcinoma was identified. The intestinal immunophenotype was shown to be significantly associated with low-grade dysplasia (p = 0.001), high expression of CDX2 (p = 0.015), TP53 (p = 0.034), synaptophysin (p = 0.003), and chromogranin (p < 0.0001); the gastric immunophenotype was significantly associated with high-grade dysplasia (p = 0.001), high Ki-67 proliferative index (p = 0.05), and coexistence of intramucosal carcinoma (p = 0.013). HER2 amplification was observed in 3 cases, typed as gastric or hybrid. CONCLUSIONS Epithelial nonpolypoid dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness and may represent the putative precursor lesion in a pathway of gastric carcinogenesis originated de novo from the native gastric mucosa, leading to gastric-type adenocarcinoma.
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Assessment of gastric phenotypes using magnifying narrow-band imaging for differentiation of gastric carcinomas from adenomas. Gastroenterol Res Pract 2014; 2014:274301. [PMID: 25371671 PMCID: PMC4211251 DOI: 10.1155/2014/274301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 09/10/2014] [Indexed: 11/29/2022] Open
Abstract
Background. Conventional white-light endoscopy and forceps biopsy are insufficient for definitive diagnosis of gastric adenoma. Immunohistochemical studies have reported an obvious phenotypic difference between adenomas and carcinomas. We investigated the utility of narrow-band imaging with magnifying endoscopy (NBI-ME) for mucin phenotypic assessment to differentiate carcinomas from adenomas. Methods. NBI-ME findings were classified into A, B, and AB types, which revealed papillary, tubular pits and groove microstructures, respectively. To investigate A-B classifications retrospectively, 137 patients (155 lesions) that were diagnosed pretherapeutically with adenoma or borderline lesions by biopsy were enrolled. The mucin phenotype was analyzed immunohistochemically in the first 60 lesions. Results. After endoscopic submucosal dissection, A type and AB type lesions were determined histologically as carcinoma (81/82, 99%). B type lesions were adenoma (29/73, 40%) and carcinoma (44/73, 60%). A or AB type correlated to histological carcinomas (sensitivity 65%, specificity 97%, and accuracy 71%). Mucin phenotypes were gastric or gastrointestinal in A type and AB type carcinomas (31/37, 84%) and intestinal in B type adenomas and carcinomas (21/23, 91%). Conclusions. NBI-ME has the advantage of the assessment of mucin phenotypes in gastric carcinomas and adenomas. The proposed A-B classification is useful, especially for differentiation of gastric or gastrointestinal carcinomas from adenomas.
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Abstract
Endoscopic procedures are the gold standard in identifying, monitoring and treating gastrointestinal system lesions. The evaluation of benign, precancerous and malignant characteristics of these lesions requires good endoscopic inspection and precise pathological examination. Pyloric gland adenoma is a rare precancerous lesion defined in recent years and herein is reviewed in the present case along with the literature.
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Affiliation(s)
- Ekrem Cakar
- Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey
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16
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Nagata K, Shimizu M. Pathological evaluation of gastrointestinal endoscopic submucosal dissection materials based on Japanese guidelines. World J Gastrointest Endosc 2012; 4:489-99. [PMID: 23189220 PMCID: PMC3506966 DOI: 10.4253/wjge.v4.i11.489] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Revised: 10/17/2012] [Accepted: 10/26/2012] [Indexed: 02/05/2023] Open
Abstract
Endoscopic surgery first started as snare polypectomy and then progressed to endoscopic mucosal resection (EMR). In order to resect a lesion that is more than 2 cm, endoscopic submucosal dissection (ESD) was developed. ESD therapy has now been established and is being used for early stage neoplastic lesions in the stomach, colon, esophagus, larynx and pharynx. In ESD specimens, we deal with relatively small lesions; therefore, more meticulous and precise pathological diagnosis is required compared to that in surgically resected specimens. In addition, we should be expert in the eligibility criteria of the different organs for ESD therapy. Here, we explain the biopsy diagnosis, including the Japanese group classification as well as the Vienna classification, handling the specimen, including fixation, photography, cutting and paraffin embedding, histological type, depth, vascular invasion and evaluation of the surgical margins, based on the latest Japanese guidelines. Japanese histopathology diagnostic criteria for the stomach, colon and esophagus are also described. We also demonstrate some examples of those mentioned above.
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Affiliation(s)
- Koji Nagata
- Koji Nagata, Michio Shimizu, Department of Pathology, Saitama Medical University, International Medical Center, 1397-1 Yamane, Hidaka, Saitama 169-8050, Japan
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17
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Sugai T, Habano W, Endoh M, Konishi Y, Akasaka R, Toyota M, Yamano H, Koeda K, Wakabayashi G, Suzuki K. Molecular analysis of gastric differentiated-type intramucosal and submucosal cancers. Int J Cancer 2010; 127:2500-9. [PMID: 20178104 DOI: 10.1002/ijc.25271] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Identification of the molecular characteristics of intramucosal (IMCs) and submucosal cancers (SMCs) is essential to our understanding of early gastric carcinogenesis. However, little is known regarding the differences between the 2 lesions. One hundred and forty-eight patients with primary early gastric cancer [IMC, 106; SMC, 42] were characterized for expression of cell cycle-related proteins and loss of heterozygosity (LOH). We also examined microsatellite instability (MSI) and methylation status. For LOH and methylation studies, we used a panel of 17 microsatellite markers (3p, 4p, 5q, 9p. 13q, 17p, 18q and 22q) and promoter regions of 9 genes (MLH-1, RUNX3, p16, HPP1, RASSF2A, SFRP1, DKK-1, ZFP64 and SALL4) that are frequently altered or methylated in gastric cancers. Overexpression of p53 and cyclin D1 was observed in SMC. In addition, low expression of p27 was more frequent in SMC than in IMC. Frequencies of 4p, 9p, 13q and 22q were significantly higher in SMC than in IMC. The SALL4 gene was frequently methylated in SMC compared with IMC. However, other gene methylations were common in both IMC and SMC. The frequency of LOH-high status/methylation-low status was significantly higher in SMC than in IMC. However, LOH-low status/methylation-high status in SMC was more frequently found in IMC. Our data confirm that methylation of cancer-related genes plays a major role in the development of IMCs. Importantly, the results also show that gastric submucosal progression is characterized by the accumulation of specific genetic alterations. In addition, changes of cell cycle-related proteins are associated with cancer progression.
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Affiliation(s)
- Tamotsu Sugai
- Division of Molecular Diagnostic Pathology, Department of Pathology, School of Medicine, Iwate Medical University, Morioka, Japan.
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18
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Sugai T, Tsukahara M, Endoh M, Shioi Y, Takebe N, Mue Y, Matsushita H, Toyota M, Suzuki K. Analysis of cell cycle-related proteins in gastric intramucosal differentiated-type cancers based on mucin phenotypes: a novel hypothesis of early gastric carcinogenesis based on mucin phenotype. BMC Gastroenterol 2010; 10:55. [PMID: 20525401 PMCID: PMC2903504 DOI: 10.1186/1471-230x-10-55] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2009] [Accepted: 06/07/2010] [Indexed: 12/15/2022] Open
Abstract
Background Abnormalities of cell cycle regulators are common features in human cancers, and several of these factors are associated with the early development of gastric cancers. However, recent studies have shown that gastric cancer tumorigenesis was characterized by mucin expression. Thus, expression patterns of cell cycle-related proteins were investigated in the early phase of differentiated-type gastric cancers to ascertain any mechanistic relationships with mucin phenotypes. Methods Immunostaining for Cyclins D1, A, E, and p21, p27, p53 and β-catenin was used to examine impairments of the cell cycle in 190 gastric intramucosal differentiated-type cancers. Mucin phenotypes were determined by the expressions of MUC5AC, MUC6, MUC2 and CD10. A Ki-67 positive rate (PR) was also examined. Results Overexpressions of p53, cyclin D1 and cyclin A were significantly more frequent in a gastric phenotype than an intestinal phenotype. Cyclin A was overexpressed in a mixed phenotype compared with an intestinal phenotype, while p27 overexpression was more frequent in an intestinal phenotype than in a mixed phenotype. Reduction of p21 was a common feature of the gastric intramucosal differentiated-type cancers examined. Conclusions Our results suggest that the levels of some cell cycle regulators appear to be associated with mucin phenotypes of early gastric differentiated-type cancers.
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Affiliation(s)
- Tamotsu Sugai
- Division of Diagnostic Molecular Pathology, Department of Pathology, School of Medicine, Iwate Medical University, 19-1 Morioka City 020-8505, Japan.
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Differential expression of basement membrane type IV collagen alpha chains in gastric intramucosal neoplastic lesions. J Gastroenterol 2007; 42:874-80. [PMID: 18008031 DOI: 10.1007/s00535-007-2112-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2007] [Accepted: 08/29/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND The histological diagnosis of gastric intramucosal neoplastic lesions (GINLs) is controversial among experienced pathologists. Although the destruction of the epithelial basement membrane (BM) and the invasion of neoplastic epithelial cells into the interstitium of the lamina propria is distinct proof of "intramucosal carcinoma," histological evaluation of GINLs is difficult and ambiguous, especially intestinal-type adenocarcinoma. Type IV collagen is a major component of the BM, and comprises six genetically distinct alpha(IV) chains, alpha1(IV) to alpha6(IV). In several types of carcinomas, the loss of alpha5/alpha6(IV) chains of the epithelial BM at an early invasive stage has been reported. However, the expression of alpha5/alpha6(IV) chains in GINLs is still unclear. We examined the immunohistochemical expression of alpha(IV) chains in GINLs and investigated whether the expression pattern was a diagnostic marker of gastric intramucosal carcinoma. METHODS The expression of alpha(IV) chains and Ki-67 in 60 resected GINL specimens was immunohistochemically examined. RESULTS In normal gastric epithelium, alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) chains were expressed continuously in the BM. In most tubular adenomas (Japanese classification), these four chains were stained continuously in the BM, whereas in tubular adenocarcinomas (Japanese classification), the alpha5/alpha6(IV) chains had disappeared, partially or completely. The expression of alpha5/alpha6(IV) chains was closely related to the grade of histological atypia. In addition, the loss of alpha5/alpha6(IV) chains was significantly correlated with tumor cell growth activity. CONCLUSIONS The loss of alpha5/alpha6(IV) chains might be a useful diagnostic finding for gastric intramucosal carcinoma in GINL cases.
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Liu C, Russell RM, Wang XD. Lycopene supplementation prevents smoke-induced changes in p53, p53 phosphorylation, cell proliferation, and apoptosis in the gastric mucosa of ferrets. J Nutr 2006; 136:106-11. [PMID: 16365067 DOI: 10.1093/jn/136.1.106] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Cigarette smoking increases the risk for gastric cancer. Higher intakes or blood levels of lycopene are associated with a decreased risk of gastric cancer. However, the biological mechanisms by which lycopene may protect against gastric carcinogenesis are poorly understood. We evaluated the effects of lycopene supplementation on smoke-induced changes in protein levels of p53, p53 target genes (p21(Waf1/Cip1) and Bax-1), cell proliferation, and apoptosis in the gastric mucosa of ferrets. Ferrets were assigned to cigarette smoke exposure or to no exposure and to no, low-dose, or high-dose lycopene supplementation (2 x 3 factorial design) for 9 wk. Lycopene concentrations were significantly elevated in a dose-dependent manner in the gastric mucosa of ferrets supplemented with lycopene alone, but were markedly reduced in ferrets supplemented with lycopene and exposed to smoke. Although ferrets were given lycopene containing 95% all-trans isomers, cis isomers were the predominant forms in the gastric mucosa. Total p53 and phosphorylated p53 levels were greater in ferrets exposed to smoke alone than in all other groups. Levels were approximately 300 and 500% of the controls, respectively. However, smoke-elevated total p53 and phosphorylated p53 were markedly attenuated by both doses of lycopene. p21(Waf1/Cip1), Bax-1, and cleaved caspase 3 were substantially decreased, whereas cyclin D1 and proliferating cellular nuclear antigen (PCNA) were increased in ferrets exposed to smoke alone. Lycopene prevented smoke-induced changes in p21(Waf1/Cip1), Bax-1, cleaved caspase 3, cyclin D1, and PCNA in a dose-dependent fashion. These data indicate that lycopene may prevent smoke exposure-induced changes in p53, p53 phosphorylation, p53 target genes, cell proliferation, and apoptosis in the gastric mucosa of ferrets.
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Affiliation(s)
- Chun Liu
- Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
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Dong B, Xie YQ, Chen K, Wang T, Tang W, You WC, Li JY. Differences in biological features of gastric dysplasia, indefinite dysplasia, reactive hyperplasia and discriminant analysis of these lesions. World J Gastroenterol 2005; 11:3595-600. [PMID: 15962383 PMCID: PMC4315969 DOI: 10.3748/wjg.v11.i23.3595] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the differences in biological features of gastric dysplasia (Dys), indefinite dysplasia (IDys) and reactive hyperplasia (RH) by studying the biomarker alterations in cell proliferation, cell differentiation, cell cycle control and the expression of house-keeping genes, and further to search for markers which could be used in guiding the pathological diagnosis of three lesions.
METHODS: Expressions of MUC5AC, MUC6, adenomatous polyposis coli (APC), p53, Ki-67, proliferation cell nuclear antigen (PCNA) and EGFR were studied by immunohistochemistry with a standard Envision technique in formalin-fixed and paraffin-embedded specimens from 43 RH, 35 IDys, 35 Dys and 36 intestinal type gastric carcinomas (IGC). In addition, Bayes discriminant analysis was used to investigate the value of markers studied in differential diagnosis of RH, IDys, Dys and IGC.
RESULTS: The MUC5AC and MUC6 antigen expressions in RH, IDys, Dys and IGC decreased gradually (MUC5AC: 86.04%, 77.14%, 28.57%, 6.67%; MUC6: 65.15%, 54.29%, 20.00%, 25.00%, respectively). The expressions of the two markers had no significant difference between RH and IDys, but were all significantly higher than those of the other two lesions (MUC5AC: χ2 = 27.607, 38.027 and 17.33, 26.092; MUC6: χ2 = 16.54, 12.665 and 9.282, 6.737, P<0.01). There was no significant difference between RH and IDys, Dys and IGC in MUC6 expression. The APC gene expression in the four lesions had a similar decreasing tendency (RH 69.76%, IDys 68.57%, Dys 39.39%, IGC 22.86%), and it was significantly higher in the first two lesions than in the last two (χ2 = 7.011, 16.995 and 14.737, 19.817, P<0.05). The p53 expression in RH, IDys, Dys and IGC was 6.98%, 20%, 57.14% and 50%, respectively. There was no significant difference between RH and IDys or Dys and IGC, but the p53 expression in RH and IDys was significantly lower than that in Dys and IGC (χ2 = 7.011, 16.995 and 14.737, 19.817, P<0.01). The Ki-67 label index was significantly different among four lesions (RH: 0.298±8.92%, IDys: 0.358±9.25%, Dys: 0.498±9.03%, IGC: 0.620±10.8%, P<0.001). Positive immunostaining of PCNA was though observed in all specimens, significant differences were detected among four lesions (F = 95.318, P<0.01). In addition, we used Bayes discriminant analysis to investigate molecular pathological classification of the lesions, and obtained the best result with the combination of MUC5AC, Ki-67 and PCNA. The overall rate of correct classification was 67.4% (RH), 68.6% (IDys), 70.6% (Dys) and 84.8% (IGC), respectively.
CONCLUSION: Dys has neoplastic biological characteristics, while RH and IDys display hyperplastic characteristics. MUC5AC and proliferation-related biomarkers (Ki-67, PCNA) are more specific in distinguishing Dys from RH and IDys.
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Affiliation(s)
- Bin Dong
- Department of Pathology, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing Cancer Hospital, Beijing 100036, China
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