Journal of Pathology and Translational Medicine

Original Articles

The combination of CDX2 expression status and tumor-infiltrating lymphocyte density as a prognostic factor in adjuvant FOLFOX-treated patients with stage III colorectal cancers: Ji-Ae Lee, Hye Eun Park, Hye-Yeong Jin, Lingyan Jin, Seung Yeon Yoo, Nam-Yun Cho, Jeong Mo Bae, Jung Ho Kim, Gyeong Hoon Kang; J Pathol Transl Med. 2025;59(1):50-59. Published online October 24, 2024; DOI: https://doi.org/10.4132/jptm.2024.09.26

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Abstract PDF Supplementary Material: Background
Colorectal carcinomas (CRCs) with caudal-type homeobox 2 (CDX2) loss are recognized to pursue an aggressive behavior but tend to be accompanied by a high density of tumor-infiltrating lymphocytes (TILs). However, little is known about whether there is an interplay between CDX2 loss and TIL density in the survival of patients with CRC.
Methods
Stage III CRC tissues were assessed for CDX2 loss using immunohistochemistry and analyzed for their densities of CD8 TILs in both intraepithelial (iTILs) and stromal areas using a machine learning-based analytic method.
Results
CDX2 loss was significantly associated with a higher density of CD8 TILs in both intraepithelial and stromal areas. Both CDX2 loss and a high CD8 iTIL density were found to be prognostic parameters and showed hazard ratios of 2.314 (1.050–5.100) and 0.378 (0.175–0.817), respectively, for cancer-specific survival. A subset of CRCs with retained CDX2 expression and a high density of CD8 iTILs showed the best clinical outcome (hazard ratio of 0.138 [0.023–0.826]), whereas a subset with CDX2 loss and a high density of CD8 iTILs exhibited the worst clinical outcome (15.781 [3.939–63.230]).
Conclusions
Altogether, a high density of CD8 iTILs did not make a difference in the survival of patients with CRC with CDX2 loss. The combination of CDX2 expression and intraepithelial CD8 TIL density was an independent prognostic marker in adjuvant chemotherapy-treated patients with stage III CRC.

Senescent tumor cells in colorectal cancer are characterized by elevated enzymatic activity of complexes 1 and 2 in oxidative phosphorylation: Jun Sang Shin, Tae-Gyu Kim, Young Hwa Kim, So Yeong Eom, So Hyun Park, Dong Hyun Lee, Tae Jun Park, Soon Sang Park, Jang-Hee Kim; J Pathol Transl Med. 2023;57(6):305-314. Published online November 7, 2023; DOI: https://doi.org/10.4132/jptm.2023.10.09

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Background
Cellular senescence is defined as an irreversible cell cycle arrest caused by various internal and external insults. While the metabolic dysfunction of senescent cells in normal tissue is relatively well-established, there is a lack of information regarding the metabolic features of senescent tumor cells.
Methods
Publicly available single-cell RNA-sequencing data from the GSE166555 and GSE178341 datasets were utilized to investigate the metabolic features of senescent tumor cells. To validate the single-cell RNA-sequencing data, we performed senescence-associated β-galactosidase (SA-β-Gal) staining to identify senescent tumor cells in fresh frozen colorectal cancer tissue. We also evaluated nicotinamide adenine dinucleotide dehydrogenase–tetrazolium reductase (NADH-TR) and succinate dehydrogenase (SDH) activity using enzyme histochemical methods and compared the staining with SA-β-Gal staining. MTT assay was performed to reveal the complex 1 activity of the respiratory chain in in-vitro senescence model.
Results
Single-cell RNA-sequencing data revealed an upregulation in the activity of complexes 1 and 2 in oxidative phosphorylation, despite overall mitochondrial dysfunction in senescent tumor cells. Both SA-β-Gal and enzyme histochemical staining using fresh frozen colorectal cancer tissues indicated a high correlation between SA-β-Gal positivity and NADH-TR/SDH staining positivity. MTT assay showed that senescent colorectal cancer cells exhibit higher absorbance in 600 nm wavelength.
Conclusions
Senescent tumor cells exhibit distinct metabolic features, characterized by upregulation of complexes 1 and 2 in the oxidative phosphorylation pathway. NADH-TR and SDH staining represent efficient methods for detecting senescent tumor cells in colorectal cancer.

Citations

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Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants
Muhammad Tufail, Yu-Qi Huang, Jia-Ju Hu, Jie Liang, Cai-Yun He, Wen-Dong Wan, Can-Hua Jiang, Hong Wu, Ning Li
Aging and disease.2024;[Epub] CrossRef
Real-time assessment of relative mitochondrial ATP synthesis response against inhibiting and stimulating substrates (MitoRAISE)
Eun Sol Chang, Kyoung Song, Ji-Young Song, Minjung Sung, Mi-Sook Lee, Jung Han Oh, Ji-Yeon Kim, Yeon Hee Park, Kyungsoo Jung, Yoon-La Choi
Cancer & Metabolism.2024;[Epub] CrossRef

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

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Abstract PDF Supplementary 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.

Citations

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Unraveling the Role of Fusobacterium nucleatum in Colorectal Cancer: Molecular Mechanisms and Pathogenic Insights
Linda Galasso, Fabrizio Termite, Irene Mignini, Giorgio Esposto, Raffaele Borriello, Federica Vitale, Alberto Nicoletti, Mattia Paratore, Maria Elena Ainora, Antonio Gasbarrini, Maria Assunta Zocco
Cancers.2025; 17(3): 368. CrossRef
Intratumoural pks Escherichia coli is associated with risk of metachronous colorectal cancer and adenoma development in people with Lynch syndrome
Yen Lin Chu, Peter Georgeson, Mark Clendenning, Khalid Mahmood, Romy Walker, Julia Como, Sharelle Joseland, Susan G. Preston, Toni Rice, Brigid M. Lynch, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Amanda I. Phipps, John L. Hopper, Aung K. Win, C
eBioMedicine.2025; 114: 105661. CrossRef
Intratumoral presence of the genotoxic gut bacteria pks+ E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer
Jihoon E. Joo, Yen Lin Chu, Peter Georgeson, Romy Walker, Khalid Mahmood, Mark Clendenning, Aaron L. Meyers, Julia Como, Sharelle Joseland, Susan G. Preston, Natalie Diepenhorst, Julie Toner, Danielle J. Ingle, Norelle L. Sherry, Andrew Metz, Brigid M. Ly
British Journal of Cancer.2024; 130(5): 728. CrossRef
The role of Fusobacterium nucleatum in cancer and its implications for clinical applications
Wanyi Luo, Juxi Han, Xian Peng, Xuedong Zhou, Tao Gong, Xin Zheng
Molecular Oral Microbiology.2024; 39(6): 417. CrossRef
Fusobacterium nucleatum Load Correlates with KRAS Mutation and Sessile Serrated Pathogenesis in Colorectal Adenocarcinoma
Koki Takeda, Minoru Koi, Yoshiki Okita, Sija Sajibu, Temitope O. Keku, John M. Carethers
Cancer Research Communications.2023; 3(9): 1940. CrossRef
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

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Abstract 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.

Citations

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SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms
Tairan Wang, Yan Jin, Mengyao Wang, Boya Chen, Jinyu Sun, Jiaying Zhang, Hui Yang, Xinyao Deng, Xingyue Cao, Lidong Wang, Yuanyuan Tang
Molecular Medicine.2024;[Epub] CrossRef
Gastric adenocarcinoma with enteroblastic differentiation in a 67-year-old man in Korea: a case report
Hae Rin Lee, Gwang Ha Kim, Dong Chan Joo, Moon Won Lee, Bong Eun Lee, Kyung Bin Kim
The Ewha Medical Journal.2024;[Epub] CrossRef
Colorectal adenocarcinoma with clear cell changes: immunohistological and molecular findings in three cases
Andreas Gocht, Carsten Heidel, Jutta Kirfel, Rita Vesce, Pamela Lazar-Karsten, Helen Pasternack, Madelaine Melzer, Phillip Hildebrand, Nicole Warkentin, Hendrik Schimmelpenning, Verena-Wilbeth Sailer
Virchows Archiv.2024; 485(3): 569. CrossRef
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; 31(8): 1553. CrossRef
Beyond liver cancer, more application scenarios for alpha-fetoprotein in clinical practice
Chenyu Ma, Yuexinzi Jin, Yuhan Wang, Huaguo Xu, Jiexin Zhang
Frontiers in Oncology.2023;[Epub] 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
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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

Polo-like kinase 4 as a potential predictive biomarker of chemoradioresistance in locally advanced rectal cancer: Hyunseung Oh, Soon Gu Kim, Sung Uk Bae, Sang Jun Byun, Shin Kim, Jae-Ho Lee, Ilseon Hwang, Sun Young Kwon, Hye Won Lee; J Pathol Transl Med. 2022;56(1):40-47. Published online November 16, 2021; DOI: https://doi.org/10.4132/jptm.2021.10.07

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Abstract PDF Supplementary Material: Background
Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase located in the centriole of the chromosome during the cell cycle. PLK4 overexpression has been described in a variety of many common human epithelial tumors. Conversely, PLK4 acts as a haploinsufficient tumor suppressor in some situations, highlighting the importance of strict regulation of PLK4 expression, activity, and function. Meanwhile, the importance of chemoradiation resistance in rectal cancer is being emphasized more than ever. We aimed to analyze PLK4 expression and the tumor regression grade (TRG) in patients with rectal cancer, treated with chemoradiotherapy (CRT).
Methods
A retrospective study was conducted on 102 patients with rectal cancer who received preoperative CRT. Immunohistochemistry for PLK4 in paraffin-embedded tissue was performed from the biopsy and surgical specimens.
Results
We found significant association between high expression of PLK4 and poor response to neoadjuvant CRT (according to both Mandard and The Korean Society of Pathologists TRG systems) in the pre-CRT specimens. Other clinicopathologic parameters did not reveal any correlation with PLK4 expression.
Conclusions
This study revealed an association between high expression of PLK4 in the pre-CRT specimens and TRG. Our results indicated that PLK4 could potentially be a new predictor for CRT effect in patients with rectal cancer.

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

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Abstract PDF Supplementary 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.

Citations

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Blood miRNAs miR-549a, miR-552, and miR-592 serve as potential disease-specific panels to diagnose colorectal cancer
Soroush Akbar, Samaneh Mashreghi, Mohammad Reza Kalani, Akram Valanik, Farzaneh Ahmadi, Mahdi Aalikhani, Zahra Bazi
Heliyon.2024; 10(7): e28492. CrossRef
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

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Abstract PDF Supplementary 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

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Abstract 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.

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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

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Abstract PDF Supplementary 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.

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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

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Abstract 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

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Abstract PDF Supplementary 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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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

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Abstract PDF Supplementary 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

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Abstract PDF Supplementary 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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International Journal of Molecular Sciences.2022; 23(8): 4461. 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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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

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Abstract PDF Supplementary 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

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Abstract 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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