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Original Article
Prognostic and clinicopathological significance of Fusobacterium nucleatum in colorectal cancer: a systemic review and meta-analysis
Younghoon Kim, Nam Yun Cho, Gyeong Hoon Kang
J Pathol Transl Med. 2022;56(3):144-151.   Published online May 15, 2022
DOI: https://doi.org/10.4132/jptm.2022.03.13
  • 2,235 View
  • 72 Download
  • 1 Citations
AbstractAbstract PDFSupplementary Material
Background
Fusobacterium nucleatum has been identified to promote tumor progression in colorectal cancer (CRC). However, association between F. nucleatum and prognostic or clinicopathological features has been diverse among studies, which could be affected by type of biospecimen (formalin-fixed paraffin-embedded or fresh frozen [FF]).
Methods
Articles were systemically reviewed for studies that included the correlation between F. nucleatum and prognosis or clinicopathological features in CRC.
Results
Ten articles, eight studies with survival-related features involving 3,199 patients and nine studies with clinical features involving 2,655 patients, were eligible for the meta-analysis. Overall survival, disease-free survival, and cancer-specific survival were all associated with worse prognosis in F. nucleatum–high patients (p<.05). In subgroup analysis, only studies with FF tissues retained prognostic significance with F. nucleatum. In meta-analysis of clinicopathological variables, F. nucleatum level was associated with location within colon, pT category, MLH1 hypermethylation, microsatellite instability status, and BRAF mutation regardless of type of biospecimen. However, lymph node metastasis and KRAS mutation was only associated with F. nucleatum level in FF-based studies.
Conclusions
In conclusion, type of biospecimen could affect the role of F. nucleatum as a biomarker associated with clinicopathological features and prognosis.

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  • Tumour Colonisation of Parvimonas micra Is Associated with Decreased Survival in Colorectal Cancer Patients
    Thyra Löwenmark, Anna Löfgren-Burström, Carl Zingmark, Ingrid Ljuslinder, Michael Dahlberg, Sofia Edin, Richard Palmqvist
    Cancers.2022; 14(23): 5937.     CrossRef
Case Study
Colorectal adenocarcinoma with enteroblastic differentiation: diagnostic challenges of a rare case encountered in clinical practice
Evi Abada, Ifeoma C. Anaya, Othuke Abada, Anthony Lebbos, Rafic Beydoun
J Pathol Transl Med. 2022;56(2):97-102.   Published online January 21, 2022
DOI: https://doi.org/10.4132/jptm.2021.10.28
  • 3,029 View
  • 127 Download
  • 3 Citations
AbstractAbstract PDF
Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of colonic adenocarcinoma characterized by increased α-fetoprotein (AFP) production and the expression of at least one enteroblastic marker including AFP, glypican 3 (GPC3), or Spalt like transcription factor 4 (SALL4). We report a case of a 26-year-old female who presented with low back pain and constipation which persisted despite supportive measures. Imaging revealed multiple liver lesions and enlarged retroperitoneal nodes. Tumor markers including AFP were markedly elevated. On biopsy, samples from the liver revealed infiltrating glands lined by columnar-type epithelium with mostly eosinophilic granular to focally clear cytoplasm. By immunohistochemistry, the tumor showed immunoreactivity with AFP, hepatocyte antigen, GPC3, SALL4, CDX2, SATB2, and cytokeratin 20. A colonoscopy performed subsequently revealed a mass in the sigmoid colon and biopsy of this mass revealed a similar histology as that seen in the liver. A diagnosis of CAED was made, following the results of gene expression profiling by the tumor with next-generation sequencing which identified pathogenic variants in MUTYH, TP53, and KDM6A genes and therefore supported its colonic origin. Cases such as this underscores the use of ancillary diagnostic techniques in arriving at the correct diagnosis in lesions with overlapping clinicopathologic characteristics.

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  • Ureteral Metastasis of Colonic Adenocarcinoma with Enteroblastic Differentiation: A Rare Case to be Distinguished from Clear Cell Adenocarcinoma of the Urinary Tract
    Hiroshi Minato, Akane Yoshikawa, Sho Tsuyama, Kazuyoshi Katayanagi, Kengo Hayashi, Yusuke Sakimura, Hiroyuki Bando, Tomohiro Hori, Yosuke Kito
    International Journal of Surgical Pathology.2023; : 106689692311602.     CrossRef
  • AIEgens assisted label free DNA supersandwich immunoassay for ultrasensitive α-fetoprotein detection
    Xiaowen Ou, Jingman Dai, Yiting Huang, Xiaoqin Xiong, Zhi Zheng, Xiaoding Lou, Fan Xia
    Giant.2022; 11: 100110.     CrossRef
  • Rectal carcinoma with dual differentiation toward enteroblastic and neuroendocrine features arising in a patient with ulcerative colitis: a case report
    Takako Kihara, Ryuichi Kuwahara, Kurando Kusunoki, Tomohiro Minagawa, Yuki Horio, Motoi Uchino, Hiroki Ikeuchi, Seiichi Hirota
    World Journal of Surgical Oncology.2022;[Epub]     CrossRef
Original Articles
MicroRNA-552 expression in colorectal cancer and its clinicopathological significance
Joon Im, Soo Kyung Nam, Hye Seung Lee
J Pathol Transl Med. 2021;55(2):125-131.   Published online February 19, 2021
DOI: https://doi.org/10.4132/jptm.2021.01.17
  • 2,409 View
  • 97 Download
  • 1 Citations
AbstractAbstract PDFSupplementary Material
Background
MicroRNA-552 (miR-552) has been reported to correlate with the development and progression of various cancers, including colorectal cancer (CRC). This study aimed to investigate miR-552 expression in cancer tissue samples compared to normal mucosal tissue and its role as a diagnostic or prognostic marker in CRC patients.
Methods
Normal mucosal tissues and primary cancer tissues from 80 surgically resected CRC specimens were used. Quantitative real-time polymerase chain reaction was performed for miR-552 and U6 small nuclear RNA to analyze miR-552 expression and its clinicopathological significance. Immunohistochemistry for p53 and phosphatase and tension homolog (PTEN) was performed to evaluate their association with miR-552 expression.
Results
miR-552 expression was significantly higher in primary cancer tissues compared to normal mucosal tissues (p<.001). The expression level of miR552 was inversely correlated with that of PTEN (p=.068) and p53 (p=.004). Survival analysis showed that high miR-552 expression was associated with worse prognosis but this was not statistically significant (p=.255). However, patients with CRC having high miR-552 expression and loss of PTEN expression had significantly worse prognosis than others (p=.029).
Conclusions
Our results suggest that high miR-552 expression might be a potential diagnostic biomarker for CRC, and its combined analysis with PTEN expression can possibly be used as a prognostic marker.

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  • Integration of TE Induces Cancer Specific Alternative Splicing Events
    Woo Ryung Kim, Eun Gyung Park, Yun Ju Lee, Woo Hyeon Bae, Du Hyeong Lee, Heui-Soo Kim
    International Journal of Molecular Sciences.2022; 23(18): 10918.     CrossRef
A comparative prognostic performance of definitions of Crohn-like lymphoid reaction in colorectal carcinoma
Younghoon Kim, Jeong Mo Bae, Jung Ho Kim, Nam-Yun Cho, Gyeong Hoon Kang
J Pathol Transl Med. 2021;55(1):53-59.   Published online November 27, 2020
DOI: https://doi.org/10.4132/jptm.2020.10.06
  • 2,693 View
  • 108 Download
AbstractAbstract PDFSupplementary Material
Background
The prognostic potential of Crohn-like lymphoid reaction (CLR) in colorectal carcinoma (CRC) has been investigated through the assessment of different criteria.
Methods
The prognostic impact of CLR was investigated in 636 CRC patients to compare methods from previously published articles. These methods included CLR measured by number of lymphoid aggregates (LAs) (CLR count), LA size greater than or equal to 1 mm (CLR size), CLR density with a cutoff value of 0.38, and subjective criteria as defined by intense CLR.
Results
In univariate survival analysis, CLR-positive CRC as defined by the four aforementioned methods was associated with better overall survival (OS) (hazard ratio [HR], 0.463; 95% confidence interval [CI], 0.305 to 0.702; p <.001; HR, 0.656; 95% CI, 0.411 to 1.046; p=.077; HR, 0.363; 95% CI, 0.197 to 0.669; p=.001; and HR, 0.433; 95% CI, 0.271 to 0.690; p<.001, respectively) and disease-free survival (DFS) (HR, 0.411; 95% CI, 0.304 to 0.639; p<.001; HR, 0.528; 95% CI, 0.340 to 0.821; p=.004; HR, 0.382; 95% CI, 0.226 to 0.645, p=.004; and HR, 0.501; 95% CI, 0.339 to 0.741; p<.001, respectively) than CLR-negative CRC, regardless of criteria with the exception of OS for CLR density. In multivariate analysis, two objective criteria (CLR count and CLR density) and one subjective criterion (intense CLR) for defining CLR were considered independent prognostic factors of OS and DFS in CRC patients.
Conclusions
CLR has similar traits regardless of criteria, but CLR-positivity should be defined by objective criteria for better reproducibility and prognostic value.
Reviews
Immune landscape and biomarkers for immuno-oncology in colorectal cancers
Jeong Mo Bae, Seung-Yeon Yoo, Jung Ho Kim, Gyeong Hoon Kang
J Pathol Transl Med. 2020;54(5):351-360.   Published online June 26, 2020
DOI: https://doi.org/10.4132/jptm.2020.05.15
  • 4,997 View
  • 273 Download
  • 5 Citations
AbstractAbstract PDF
Recent advances in immuno-oncology have increased understanding of the tumor immune microenvironment (TIME), and clinical trials for immune checkpoint inhibitor treatment have shown remission and/or durable response in certain proportions of patients stratified by predictive biomarkers. The TIME in colorectal cancer (CRC) was initially evaluated several decades ago. The prognostic value of the immune response to tumors, including tumor-infiltrating lymphocytes, peritumoral lymphoid reaction, and Crohn’s-like lymphoid reaction, has been well demonstrated. In this review, we describe the chronology of TIME research and review the up-to-date high-dimensional TIME landscape of CRC. We also summarize the clinical relevance of several biomarkers associated with immunotherapy in CRC, such as microsatellite instability, tumor mutational burden, POLE/POLD mutation, consensus molecular subtype, and programmed death-ligand 1 expression.

Citations

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  • Evaluation on Braking Stability of Autonomous Vehicles Running along Curved Sections Based on Asphalt Pavement Adhesion Properties
    Binshuang Zheng, Xiaoming Huang, Junyao Tang, Jiaying Chen, Runmin Zhao, Zhengqiang Hong, Tao Tang, Meiling Han, Yang Yang
    Journal of Advanced Transportation.2022; 2022: 1.     CrossRef
  • Intratumoral spatial heterogeneity of tumor-infiltrating lymphocytes is a significant factor for precisely stratifying prognostic immune subgroups of microsatellite instability-high colorectal carcinomas
    Minsun Jung, Ji Ae Lee, Seung-Yeon Yoo, Jeong Mo Bae, Gyeong Hoon Kang, Jung Ho Kim
    Modern Pathology.2022; 35(12): 2011.     CrossRef
  • Association of Tumor-Infiltrating Lymphocytes With Survival in Stages II and III Colorectal Cancer
    Marina Vitorino, Inês Eiriz, Tiago C Tomás, Rodrigo Vicente, Ana Mendes, Ana Rita Freitas, Sofia Braga, Catarina Alves-Vale, Paula Borralho, André Ferreira, Luisa Leal da Costa
    Cureus.2022;[Epub]     CrossRef
  • Tumor Mutational Burden Predicting the Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer: A Systematic Review and Meta-Analysis
    Yan Li, Yiqi Ma, Zijun Wu, Fanxin Zeng, Bin Song, Yanrong Zhang, Jinxing Li, Su Lui, Min Wu
    Frontiers in Immunology.2021;[Epub]     CrossRef
  • Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers
    Jung Ho Kim, Mi-Kyoung Seo, Ji Ae Lee, Seung-Yeon Yoo, Hyeon Jeong Oh, Hyundeok Kang, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang, Sangwoo Kim
    Journal for ImmunoTherapy of Cancer.2021; 9(12): e003414.     CrossRef
Evolving pathologic concepts of serrated lesions of the colorectum
Jung Ho Kim, Gyeong Hoon Kang
J Pathol Transl Med. 2020;54(4):276-289.   Published online June 26, 2020
DOI: https://doi.org/10.4132/jptm.2020.04.15
  • 8,329 View
  • 566 Download
  • 15 Citations
AbstractAbstract PDFSupplementary Material
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.

Citations

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  • Impact of comprehensive optical diagnosis training using Workgroup serrAted polypS and Polyposis classification on detection of adenoma and sessile serrated lesion
    Jooyoung Lee, Jung Ho Bae, Su Jin Chung, Hae Yeon Kang, Seung Joo Kang, Min‐Sun Kwak, Ji Yeon Seo, Ji Hyun Song, Sun Young Yang, Jong In Yang, Seon Hee Lim, Jeong Yoon Yim, Joo Hyun Lim, Goh Eun Chung, Eun Hyo Jin, Ji Min Choi, Yoo Min Han, Joo Sung Kim
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  • Clinicopathological and molecular analyses of hyperplastic lesions including microvesicular variant and goblet cell rich variant hyperplastic polyps and hyperplastic nodules—Hyperplastic nodule is an independent histological entity
    Noriyuki Uesugi, Yoichi Ajioka, Tomio Arai, Yoshihito Tanaka, Tamotsu Sugai
    Pathology International.2022; 72(2): 128.     CrossRef
  • Comprehensive clinicopathologic, molecular, and immunologic characterization of colorectal carcinomas with loss of three intestinal markers, CDX2, SATB2, and KRT20
    Ji Ae Lee, Mi-Kyoung Seo, Seung-Yeon Yoo, Nam-Yun Cho, Yoonjin Kwak, Kyoungbun Lee, Jung Ho Kim, Gyeong Hoon Kang
    Virchows Archiv.2022; 480(3): 543.     CrossRef
  • Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis
    Martino Mezzapesa, Giuseppe Losurdo, Francesca Celiberto, Salvatore Rizzi, Antonio d’Amati, Domenico Piscitelli, Enzo Ierardi, Alfredo Di Leo
    International Journal of Molecular Sciences.2022; 23(8): 4461.     CrossRef
  • Arterial stiffness is associated with high-risk colorectal adenomas and serrated lesions: A cross-sectional study in a Taiwanese population
    Hung-Yu Chen, Wen-Huang Lee, Hung-Lung Hsu, Yu-Tsung Chou, Fei-Lin Su, I-Hsuan Wu, Ting-Hsing Chao
    Journal of Cardiology.2022; 80(2): 139.     CrossRef
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    Filippo Cappello, Valentina Angerilli, Luca Dal Santo, Giada Munari, Marianna Sabbadin, Marcello Lo Mele, Gianmaria Pennelli, Claudio Luchini, Paola Parente, Stefano Lazzi, Matteo Fassan
    Pathology - Research and Practice.2022; 240: 154214.     CrossRef
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    Jonathan Fawkes
    Gastrointestinal Nursing.2022; 20(9): 24.     CrossRef
  • Comparison of adenoma detection rate and proximal serrated polyp detection rate and their effect on post-colonoscopy colorectal cancer mortality in screening patients
    Jasmin Zessner-Spitzenberg, Elisabeth Waldmann, Lena Jiricka, Lisa-Maria Rockenbauer, Anna Hinterberger, Jeremy Cook, Arno Asaturi, Aleksandra Szymanska, Barbara Majcher, Michael Trauner, Monika Ferlitsch
    Endoscopy.2022;[Epub]     CrossRef
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    Shin Ju Oh, Jung-Wook Kim, Chi Hyuk Oh
    Medicine.2022; 101(51): e32287.     CrossRef
  • WHICH LESIONS ARE AT HIGHER RISK OF DEVELOPING COLORECTAL CARCINOMAS: SUPERFICIALLY ELEVATED SERRATED LESIONS OR DEPRESSED LESIONS?
    Artur Adolfo PARADA, Filadelfio Euclydes VENCO, Miguel Reynaldo VARCA-NETO, Roberto EL IBRAHIM, Paula Bechara POLETTI, Helcio Pedrosa BRITO, Heloisa de Fátima SARE, Osvaldo MALAFAIA
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  • WNT5a in Colorectal Cancer: Research Progress and Challenges
    Guangshun Sun, Liangliang Wu, Guoqiang Sun, Xuesong Shi, Hongyong Cao, Weiwei Tang
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  • Endoscopic diagnosis for colorectal sessile serrated lesions
    Toshihiro Nishizawa, Shuntaro Yoshida, Akira Toyoshima, Tomoharu Yamada, Yoshiki Sakaguchi, Taiga Irako, Hirotoshi Ebinuma, Takanori Kanai, Kazuhiko Koike, Osamu Toyoshima
    World Journal of Gastroenterology.2021; 27(13): 1321.     CrossRef
  • NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions
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    Bob Chen, Cherie’ R. Scurrah, Eliot T. McKinley, Alan J. Simmons, Marisol A. Ramirez-Solano, Xiangzhu Zhu, Nicholas O. Markham, Cody N. Heiser, Paige N. Vega, Andrea Rolong, Hyeyon Kim, Quanhu Sheng, Julia L. Drewes, Yuan Zhou, Austin N. Southard-Smith, Y
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  • Molecular Insights Into Colorectal Carcinoma
    Domenika Ortiz Requena, Monica Garcia-Buitrago
    Archives of Medical Research.2020; 51(8): 839.     CrossRef
Original Article
Colorectal epithelial neoplasm associated with gut-associated lymphoid tissue
Yo Han Jeon, Ji Hyun Ahn, Hee Kyung Chang
J Pathol Transl Med. 2020;54(2):135-145.   Published online January 29, 2020
DOI: https://doi.org/10.4132/jptm.2019.11.06
  • 5,354 View
  • 183 Download
AbstractAbstract PDF
Background
Colorectal epithelial neoplasm extending into the submucosal gut-associated lymphoid tissue (GALT) can cause difficulties in the differential diagnosis. Regarding GALT-associated epithelial neoplasms, a few studies favor the term “GALT carcinoma” while other studies have mentioned the term “GALT-associated pseudoinvasion/epithelial misplacement (PEM)”.
Methods
The clinicopathologic characteristics of 11 cases of colorectal epithelial neoplasm associated with submucosal GALT diagnosed via endoscopic submucosal dissection were studied.
Results
Eight cases (72.7%) were in males. The median age was 59 years, and age ranged from 53 to 73. All cases had a submucosal tumor component more compatible with GALT-associated PEM. Eight cases (72.7%) were located in the right colon. Ten cases (90.9%) had a non-protruding endoscopic appearance. Nine cases (81.8%) showed continuity between the submucosal and surface adenomatous components. Nine cases showed (81.8%) focal defects or discontinuation of the muscularis mucosae adjacent to the submucosal GALT. No case showed hemosiderin deposits in the submucosa or desmoplastic reaction. No case showed single tumor cells or small clusters of tumor cells in the submucosal GALT. Seven cases (63.6%) showed goblet cells in the submucosa. No cases showed oncocytic columnar cells lining submucosal glands.
Conclusions
Our experience suggests that pathologists should be aware of the differential diagnosis of GALT-associated submucosal extension by colorectal adenomatous neoplasm. Further studies are needed to validate classification of GALT-associated epithelial neoplasms.
Review
Standardized Pathology Report for Colorectal Cancer, 2nd Edition
Baek-hui Kim, Joon Mee Kim, Gyeong Hoon Kang, Hee Jin Chang, Dong Wook Kang, Jung Ho Kim, Jeong Mo Bae, An Na Seo, Ho Sung Park, Yun Kyung Kang, Kyung-Hwa Lee, Mee Yon Cho, In-Gu Do, Hye Seung Lee, Hee Kyung Chang, Do Youn Park, Hyo Jeong Kang, Jin Hee Sohn, Mee Soo Chang, Eun Sun Jung, So-Young Jin, Eunsil Yu, Hye Seung Han, Youn Wha Kim
J Pathol Transl Med. 2020;54(1):1-19.   Published online November 13, 2019
DOI: https://doi.org/10.4132/jptm.2019.09.28
  • 15,236 View
  • 960 Download
  • 27 Citations
AbstractAbstract PDFSupplementary Material
The first edition of the ‘Standardized Pathology Report for Colorectal Cancer,’ which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of “standard data elements” and “conditional data elements.” Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as “standard data elements,” while other prognostic factors and factors related to adjuvant therapy are classified as “conditional data elements” so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.

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  • IGFL2-AS1, a Long Non-Coding RNA, Is Associated with Radioresistance in Colorectal Cancer
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  • Composite scoring system and optimal tumor budding cut-off number for estimating lymph node metastasis in submucosal colorectal cancer
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    Jiyoon Jung, Eunsu Kim, Hyeseong Lee, Sung Hak Lee, Sangjeong Ahn
    Applied Sciences.2022; 12(18): 9159.     CrossRef
  • Clinical Implication of Perineural and Lymphovascular Invasion in Rectal Cancer Patients Who Underwent Surgery After Preoperative Chemoradiotherapy
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Original Articles
Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma
Seung-Yeon Yoo, Ji-Ae Lee, Yunjoo Shin, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang
J Pathol Transl Med. 2019;53(5):289-297.   Published online June 24, 2019
DOI: https://doi.org/10.4132/jptm.2019.06.07
  • 5,517 View
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  • 6 Citations
AbstractAbstract PDFSupplementary Material
Background
SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC.
Methods
We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs.
Results
A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancerspecific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022).
Conclusions
We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

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CpG Island Methylation in Sessile Serrated Adenoma/Polyp of the Colorectum: Implications for Differential Diagnosis of Molecularly High-Risk Lesions among Non-dysplastic Sessile Serrated Adenomas/Polyps
Ji Ae Lee, Hye Eun Park, Seung-Yeon Yoo, Seorin Jeong, Nam-Yun Cho, Gyeong Hoon Kang, Jung Ho Kim
J Pathol Transl Med. 2019;53(4):225-235.   Published online March 19, 2019
DOI: https://doi.org/10.4132/jptm.2019.03.12
  • 5,860 View
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  • 3 Citations
AbstractAbstract PDFSupplementary Material
Background
Although colorectal sessile serrated adenomas/polyps (SSA/Ps) with morphologic dysplasia are regarded as definite high-risk premalignant lesions, no reliable grading or risk-stratifying system exists for non-dysplastic SSA/Ps. The accumulation of CpG island methylation is a molecular hallmark of progression of SSA/Ps. Thus, we decided to classify non-dysplastic SSA/Ps into risk subgroups based on the extent of CpG island methylation.
Methods
The CpG island methylator phenotype (CIMP) status of 132 non-dysplastic SSA/Ps was determined using eight CIMP-specific promoter markers. SSA/Ps with CIMP-high and/or MLH1 promoter methylation were regarded as a high-risk subgroup.
Results
Based on the CIMP analysis results, methylation frequency of each CIMP marker suggested a sequential pattern of CpG island methylation during progression of SSA/P, indicating MLH1 as a late-methylated marker. Among the 132 non-dysplastic SSA/Ps, 34 (26%) were determined to be high-risk lesions (33 CIMP-high and 8 MLH1-methylated cases; seven cases overlapped). All 34 high-risk SSA/Ps were located exclusively in the proximal colon (100%, p = .001) and were significantly associated with older age (≥ 50 years, 100%; p = .003) and a larger histologically measured lesion size (> 5 mm, 100%; p = .004). In addition, the high-risk SSA/Ps were characterized by a relatively higher number of typical base-dilated serrated crypts.
Conclusions
Both CIMP-high and MLH1 methylation are late-step molecular events during progression of SSA/Ps and rarely occur in SSA/Ps of young patients. Comprehensive consideration of age (≥ 50), location (proximal colon), and histologic size (> 5 mm) may be important for the prediction of high-risk lesions among non-dysplastic SSA/Ps.

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Prognostic Impact of Fusobacterium nucleatum Depends on Combined Tumor Location and Microsatellite Instability Status in Stage II/III Colorectal Cancers Treated with Adjuvant Chemotherapy
Hyeon Jeong Oh, Jung Ho Kim, Jeong Mo Bae, Hyun Jung Kim, Nam-Yun Cho, Gyeong Hoon Kang
J Pathol Transl Med. 2019;53(1):40-49.   Published online December 26, 2018
DOI: https://doi.org/10.4132/jptm.2018.11.29
  • 14,417 View
  • 222 Download
  • 29 Citations
AbstractAbstract PDFSupplementary Material
Background
This study aimed to investigate the prognostic impact of intratumoral Fusobacterium nucleatum in colorectal cancer (CRC) treated with adjuvant chemotherapy.
Methods
F. nucleatumDNA was quantitatively measured in a total of 593 CRC tissues retrospectively collectedfrom surgically resected specimens of stage III or high-risk stage II CRC patients who had receivedcurative surgery and subsequent oxaliplatin-based adjuvant chemotherapy (either FOLFOXor CAPOX). Each case was classified into one of the three categories: F. nucleatum–high, –low, or –negative.
Results
No significant differences in survival were observed between the F.nucleatum–high and –low/negative groups in the 593 CRCs (p = .671). Subgroup analyses accordingto tumor location demonstrated that disease-free survival was significantly better in F.nucleatum–high than in –low/negative patients with non-sigmoid colon cancer (including cecal,ascending, transverse, and descending colon cancers; n = 219; log-rank p = .026). In multivariateanalysis, F. nucleatum was determined to be an independent prognostic factor in non-sigmoidcolon cancers (hazard ratio, 0.42; 95% confidence interval, 0.18 to 0.97; p = .043). Furthermore,the favorable prognostic effect of F. nucleatum–high was observed only in a non-microsatellite instability-high (non-MSI-high) subset of non-sigmoid colon cancers (log-rank p = 0.014), but not ina MSI-high subset (log-rank p = 0.844), suggesting that the combined status of tumor locationand MSI may be a critical factor for different prognostic impacts of F. nucleatum in CRCs treatedwith adjuvant chemotherapy.
Conclusions
Intratumoral F. nucleatum load is a potential prognosticfactor in a non-MSI-high/non-sigmoid/non-rectal cancer subset of stage II/III CRCs treatedwith oxaliplatin-based adjuvant chemotherapy.

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Prognostic Significance of EPHB2 Expression in Colorectal Cancer Progression
Bo Gun Jang, Hye Sung Kim, Weon Young Chang, Jeong Mo Bae, Gyeong Hoon Kang
J Pathol Transl Med. 2018;52(5):298-306.   Published online July 18, 2018
DOI: https://doi.org/10.4132/jptm.2018.06.29
  • 5,474 View
  • 136 Download
  • 10 Citations
AbstractAbstract PDF
Background
A receptor tyrosine kinase for ephrin ligands, EPHB2, is expressed in normal colorectal tissues and colorectal cancers (CRCs). The aim of this study was to investigate EPHB2 expression over CRC progression and determine its prognostic significance in CRC.
Methods
To measure EPHB2 mRNA and protein expression, real-time polymerase chain reaction and immunohistochemistry were performed in 32 fresh-frozen and 567 formalin-fixed paraffin-embedded CRC samples, respectively. We further investigated clinicopathological features and overall and recurrence-free survival according to EPHB2 protein expression.
Results
The EPHB2 level was upregulated in CRC samples compared to non-cancerous tissue in most samples and showed a strong positive correlation with AXIN2. Notably, CD44 had a positive association with both mRNA and protein levels of EPHB2. Immunohistochemical analysis revealed no difference in EPHB2 expression between adenoma and carcinoma areas. Although EPHB2 expression was slightly lower in invasive fronts compared to surface area (p < .05), there was no difference between superficial and metastatic areas. EPHB2 positivity was associated with lymphatic (p < .001) and venous (p = .001) invasion, TNM stage (p < .001), and microsatellite instability (p = .036). Kaplan–Meier analysis demonstrated that CRC patients with EPHB2 positivity showed better clinical outcomes in both overall (p = .049) and recurrence-free survival (p = .015). However, multivariate analysis failed to show that EPHB2 is an independent prognostic marker in CRCs (hazard ratio, 0.692; p = .692).
Conclusions
Our results suggest that EPHB2 is overexpressed in a subset of CRCs and is a significant prognostic marker.

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Utility of BRAF VE1 Immunohistochemistry as a Screening Tool for Colorectal Cancer Harboring BRAF V600E Mutation
Jeong-Hwa Kwon, Byung-Kwan Jeong, Yong Sik Yoon, Chang Sik Yu, Jihun Kim
J Pathol Transl Med. 2018;52(3):157-163.   Published online March 29, 2018
DOI: https://doi.org/10.4132/jptm.2018.03.28
  • 5,429 View
  • 148 Download
  • 4 Citations
AbstractAbstract PDFSupplementary Material
Background
BRAF mutation has been recognized as an important biomarker of colorectal cancer (CRC) for targeted therapy and prognosis prediction. However, sequencing for every CRC case is not cost-effective. An antibody specific for BRAF V600E mutant protein has been introduced, and we thus examined the utility of BRAF VE1 immunohistochemistry for evaluating BRAF mutations in CRC.
Methods
Fifty-one BRAF-mutated CRCs and 100 age and sexmatched BRAF wild-type CRCs between 2005 and 2015 were selected from the archives of Asan Medical Center. Tissue microarrays were constructed and stained with BRAF VE1 antibody.
Results
Forty-nine of the 51 BRAF-mutant CRCs (96.1%) showed more than moderate cytoplasmic staining, except for two weakly stained cases. Six of 100 BRAF wild-type cases also stained positive with BRAF VE1 antibody; four stained weakly and two stained moderately. Normal colonic crypts showed nonspecific weak staining, and a few CRC cases exhibited moderate nuclear reactivity (3 BRAF-mutant and 10 BRAF wild-type cases). BRAF-mutated CRC patients had higher pathologic stages and worse survival than BRAF wild-type patients.
Conclusions
BRAF VE1 immunohistochemistry showed high sensitivity and specificity, but occasional nonspecific staining in tumor cell nuclei and normal colonic crypts may limit their routine clinical use. Thus, BRAF VE1 immunohistochemistry may be a useful screening tool for BRAF V600E mutation in CRCs, provided that additional sequencing studies can be done to confirm the mutation in BRAF VE1 antibody-positive cases.

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Prognostic Utility of Histological Growth Patterns of Colorectal Lung Oligometastasis
Son Jae Yeong, Min Gyoung Pak, Hyoun Wook Lee, Seung Yeon Ha, Mee Sook Roh
J Pathol Transl Med. 2018;52(2):98-104.   Published online February 12, 2018
DOI: https://doi.org/10.4132/jptm.2017.12.27
  • 5,042 View
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  • 2 Citations
AbstractAbstract PDF
Background
Patients with resectable colorectal lung oligometastasis (CLOM) demonstrate a heterogeneous oncological outcome. However, the parameters for predicting tumor aggressiveness have not yet been fully investigated in CLOM. This study was performed to determine the prognostic value of histological growth patterns in patients who underwent surgery for CLOM.
Methods
The study included 92 patients who were diagnosed with CLOM among the first resection cases. CLOMs grow according to three histological patterns: aerogenous, pushing, and desmoplastic patterns. The growth patterns were evaluated on archival hematoxylin and eosin–stained tissue sections.
Results
The aerogenous pattern was found in 29.4% (n=27) of patients, the pushing pattern in 34.7% (n=32), the desmoplastic pattern in 6.5% (n=6), and a mix of two growth patterns in 29.4% (n=27). The size of the aerogenous pattern was significantly smaller than that of metastases with other patterns (p=.033). Kaplan-Meier analysis demonstrated that patients showing an aerogenous pattern appeared to have a poorer prognosis, which was calculated from the time of diagnosis of the CLOM (p=.044). The 5-year survival rate from the diagnosis of colorectal cancer tended to be lower in patients with an aerogenous pattern than in those who had a non-aerogenous pattern; however, the difference was marginally significant (p=.051). In the multivariate Cox analysis, the aerogenous pattern appeared as an independent predictor of poor overall survival (hazard ratio, 3.122; 95% confidence interval, 1.196 to 8.145; p=.020).
Conclusions
These results suggest that the growth patterns may play a part as a histology-based prognostic parameter for patients with CLOM.

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  • Predicting liver metastases growth patterns: Current status and future possibilities
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Overexpression of POSTN in Tumor Stroma Is a Poor Prognostic Indicator of Colorectal Cancer
Hyeon Jeong Oh, Jeong Mo Bae, Xian-Yu Wen, Nam-Yun Cho, Jung Ho Kim, Gyeong Hoon Kang
J Pathol Transl Med. 2017;51(3):306-313.   Published online April 12, 2017
DOI: https://doi.org/10.4132/jptm.2017.01.19
  • 12,026 View
  • 241 Download
  • 35 Citations
AbstractAbstract PDF
Background
Tumor microenvironment has recently drawn attention in that it is related with tumor prognosis. Cancer-associated fibroblast also plays a critical role in cancer invasiveness and progression in colorectal cancers. Periostin (POSTN), originally identified to be expressed in osteoblasts and osteoblast-derived cells, is expressed in cancer-associated fibroblasts in several tissue types of cancer. Recent studies suggest an association between stromal overexpression of POSTN and poor prognosis of cancer patients.
Methods
We analyzed colorectal cancer cases for their expression status of POSTN in tumor stroma using immunohistochemistry and correlated the expression status with clinicopathological and molecular features.
Results
High level of POSTN expression in tumor stroma was closely associated with tumor location in proximal colon, infiltrative growth pattern, undifferentiated histology, tumor budding, luminal necrosis, and higher TNM stage. High expression status of POSTN in tumor stroma was found to be an independent prognostic parameter implicating poor 5-year cancer-specific survival and 5-year progression-free survival.
Conclusions
Our findings suggest that POSTN overexpression in tumor stroma of colorectal cancers could be a possible candidate marker for predicting poor prognosis in patients with colorectal cancers.

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JPTM : Journal of Pathology and Translational Medicine