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.

Establishing molecular pathology curriculum for pathology trainees and continued medical education: a collaborative work from the Molecular Pathology Study Group of the Korean Society of Pathologists: Jiwon Koh, Ha Young Park, Jeong Mo Bae, Jun Kang, Uiju Cho, Seung Eun Lee, Haeyoun Kang, Min Eui Hong, Jae Kyung Won, Youn-La Choi, Wan-Seop Kim, Ahwon Lee; J Pathol Transl Med. 2023;57(5):265-272. Published online September 15, 2023; DOI: https://doi.org/10.4132/jptm.2023.08.26

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Abstract PDF: Background
The importance of molecular pathology tests has increased during the last decade, and there is a great need for efficient training of molecular pathology for pathology trainees and as continued medical education.
Methods
The Molecular Pathology Study Group of the Korean Society of Pathologists appointed a task force composed of experienced molecular pathologists to develop a refined educational curriculum of molecular pathology. A 3-day online educational session was held based on the newly established structure of learning objectives; the audience were asked to score their understanding of 22 selected learning objectives before and after the session to assess the effect of structured education.
Results
The structured objectives and goals of molecular pathology was established and posted as a web-based interface which can serve as a knowledge bank of molecular pathology. A total of 201 pathologists participated in the educational session. For all 22 learning objectives, the scores of self-reported understanding increased after educational session by 9.9 points on average (range, 6.6 to 17.0). The most effectively improved items were objectives from next-generation sequencing (NGS) section: ‘NGS library preparation and quality control’ (score increased from 51.8 to 68.8), ‘NGS interpretation of variants and reference database’ (score increased from 54.1 to 68.0), and ‘whole genome, whole exome, and targeted gene sequencing’ (score increased from 58.2 to 71.2). Qualitative responses regarding the adequacy of refined educational curriculum were collected, where favorable comments dominated.
Conclusions
Approach toward the education of molecular pathology was refined, which would greatly benefit the future trainees.

Development of quality assurance program for digital pathology by the Korean Society of Pathologists: Yosep Chong, Jeong Mo Bae, Dong Wook Kang, Gwangil Kim, Hye Seung Han; J Pathol Transl Med. 2022;56(6):370-382. Published online November 15, 2022; DOI: https://doi.org/10.4132/jptm.2022.09.30

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Abstract PDF Supplementary Material

Background
Digital pathology (DP) using whole slide imaging is a recently emerging game changer technology that can fundamentally change the way of working in pathology. The Digital Pathology Study Group (DPSG) of the Korean Society of Pathologists (KSP) published a consensus report on the recommendations for pathologic practice using DP. Accordingly, the need for the development and implementation of a quality assurance program (QAP) for DP has been raised.
Methods
To provide a standard baseline reference for internal and external QAP for DP, the members of the Committee of Quality Assurance of the KSP developed a checklist for the Redbook and a QAP trial for DP based on the prior DPSG consensus report. Four leading institutes participated in the QAP trial in the first year, and we gathered feedback from these institutes afterwards.
Results
The newly developed checklists of QAP for DP contain 39 items (216 score): eight items for quality control of DP systems; three for DP personnel; nine for hardware and software requirements for DP systems; 15 for validation, operation, and management of DP systems; and four for data security and personal information protection. Most participants in the QAP trial replied that continuous education on unfamiliar terminology and more practical experience is demanding.
Conclusions
The QAP for DP is essential for the safe implementation of DP in pathologic practice. Each laboratory should prepare an institutional QAP according to this checklist, and consecutive revision of the checklist with feedback from the QAP trial for DP needs to follow.

Citations

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An equivalency and efficiency study for one year digital pathology for clinical routine diagnostics in an accredited tertiary academic center
Viola Iwuajoku, Kübra Ekici, Anette Haas, Mohammed Zaid Khan, Azar Kazemi, Atsuko Kasajima, Claire Delbridge, Alexander Muckenhuber, Elisa Schmoeckel, Fabian Stögbauer, Christine Bollwein, Kristina Schwamborn, Katja Steiger, Carolin Mogler, Peter J. Schüf
Virchows Archiv.2025;[Epub] CrossRef
Diagnostic proficiency test using digital cytopathology and comparative assessment of whole slide images of cytologic samples for quality assurance program in Korea
Yosep Chong, Soon Auck Hong, Hoon Kyu Oh, Soo Jin Jung, Bo-Sung Kim, Ji Yun Jeong, Ho-Chang Lee, Gyungyub Gong
Journal of Pathology and Translational Medicine.2023; 57(5): 251. CrossRef

Case Study

An unusual case of microsatellite instability–high/deficient mismatch repair (MSI-H/dMMR) diffuse large B-cell lymphoma revealed by targeted gene sequencing: Bogyeong Han, Sehui Kim, Jiwon Koh, Jeong Mo Bae, Hongseok Yun, Yoon Kyung Jeon; J Pathol Transl Med. 2022;56(2):92-96. Published online November 16, 2021; DOI: https://doi.org/10.4132/jptm.2021.10.15

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Abstract PDF

Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status has been approved as a tissue-agnostic biomarker for immune checkpoint inhibitor therapy in patients with solid tumors. We report the case of an MSI-H/dMMR diffuse large B-cell lymphoma (DLBCL) identified by targeted gene sequencing (TGS). A 90-year-old female who presented with vaginal bleeding and a large mass in the upper vagina was diagnosed with germinal center-B-cell-like DLBCL, which recurred at the uterine cervix at 9 months after chemotherapy. Based on TGS of 121 lymphoma-related genes and the LymphGen algorithm, the tumor was classified genetically as DLBCL of EZB subtype. Mutations in multiple genes, including frequent frameshift mutations, were detected by TGS and further suggested MSI. The MSI-H/dMMR and loss of MLH1 and PMS2 expression were determined in MSI-fragment analysis, MSI real-time polymerase chain reaction, and immunohistochemical tests. This case demonstrates the potential diagnostic and therapeutic utility of lymphoma panel sequencing for DLBCL with MSI-H/dMMR.

Citations

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Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family
Jens Staal, Yasmine Driege, Femke Van Gaever, Jill Steels, Rudi Beyaert
The FEBS Journal.2024; 291(6): 1220. CrossRef
PD-L1+diffuse large B-cell lymphoma with extremely high mutational burden and microsatellite instability due to acquiredPMS2mutation
Andrew W. Allbee, James Gerson, Guang Yang, Adam Bagg
Molecular Case Studies.2023; 9(4): a006318. CrossRef

Original Article

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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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
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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
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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

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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Association between the expression of epithelial–mesenchymal transition (EMT)-related markers and oncologic outcomes of colorectal cancer
Mona Hany Emile, Sameh Hany Emile, Amr Awad El-Karef, Mohamed Awad Ebrahim, Ibrahim Eldosoky Mohammed, Dina Abdallah Ibrahim
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TGF-β and SMAD2/4 Expression in Nonmetastatic and Metastatic Colorectal Cancer Patients
Ainul Mardiah, Hendra Susanto, Sri Rahayu Lestari, A. Taufiq, H. Susanto, H. Nur, M. Diantoro, M. Aziz, N.A.N.N. Malek
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Ronald Heregger, Florian Huemer, Markus Steiner, Alejandra Gonzalez-Martinez, Richard Greil, Lukas Weiss
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Jiwon Koh, Soo Kyung Nam, Yoonjin Kwak, Gilhyang Kim, Ka‐Kyung Kim, Byung‐Chul Lee, Sang‐Hoon Ahn, Do Joong Park, Hyung‐Ho Kim, Kyoung Un Park, Woo Ho Kim, Hye Seung Lee
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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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Multiplicity of Advanced T Category–Tumors Is a Risk Factor for Survival in Patients with Colorectal Carcinoma: Hye Eun Park, Seungyeon Yoo, Jeong Mo Bae, Seorin Jeong, Nam-Yun Cho, Gyeong Hoon Kang; J Pathol Transl Med. 2018;52(6):386-395. Published online November 14, 2018; DOI: https://doi.org/10.4132/jptm.2018.10.02

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Abstract PDF

Background
Previous studies on synchronous colorectal carcinoma (SCRC) have reported inconsistent results about its clinicopathologic and molecular features and prognostic significance.
Methods
Forty-six patients with multiple advanced tumors (T2 or higher category) who did not receive neoadjuvant chemotherapy and/or radiotherapy and who are not associated with familial adenomatous polyposis were selected and 99 tumors from them were subjected to clinicopathologic and molecular analysis. Ninety-two cases of solitary colorectal carcinoma (CRC) were selected as a control considering the distributions of types of surgeries performed on patients with SCRC and T categories of individual tumors from SCRC.
Results
SCRC with multiple advanced tumors was significantly associated with more frequent nodal metastasis (p = .003) and distant metastasis (p = .001) than solitary CRC. KRAS mutation, microsatellite instability, and CpG island methylator phenotype statuses were not different between SCRC and solitary CRC groups. In univariate survival analysis, overall and recurrence-free survival were significantly lower in patients with SCRC than in patients with solitary CRC, even after adjusting for the extensiveness of surgical procedure, adjuvant chemotherapy, or staging. Multivariate Cox regression analysis revealed that tumor multiplicity was an independent prognostic factor for overall survival (hazard ratio, 4.618; 95% confidence interval, 2.126 to 10.030; p < .001), but not for recurrence-free survival (p = .151).
Conclusions
Findings suggested that multiplicity of advanced T category–tumors might be associated with an increased risk of nodal metastasis and a risk factor for poor survival, which raises a concern about the guideline of American Joint Committee on Cancer’s tumor-node-metastasis staging that T staging of an index tumor determines T staging of SCRC.

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Zuojing Yin, Qiming Wang, Xinmiao Yan, Lu Zhang, Kailin Tang, Zhiwei Cao, Tianyi Qiu
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Clinical Cancer Research.2020; 26(4): 870. CrossRef

Case Study

Primary Peripheral Gamma Delta T-Cell Lymphoma of the Central Nervous System: Report of a Case Involving the Intramedullary Spinal Cord and Presenting with Myelopathy: Jeemin Yim, Seung Geun Song, Sehui Kim, Jae Won Choi, Kyu-Chong Lee, Jeong Mo Bae, Yoon Kyung Jeon; J Pathol Transl Med. 2019;53(1):57-61. Published online October 1, 2018; DOI: https://doi.org/10.4132/jptm.2018.08.21

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Abstract PDF

Primary central nervous system lymphoma of T-cell origin (T-PCNSL) is rare, and its clinicopathological features remain unclear. Peripheral T-cell lymphoma of γδ T-cell origin is an aggressive lymphoma mainly involving extranodal sites. Here, we report a case of γδ T-PCNSL involving the intramedullary spinal cord and presenting with paraplegia. A 75-year-old Korean woman visited the hospital complaining of back pain and lower extremity weakness. Magnetic resonance imaging revealed multifocal enhancing intramedullary nodular lesions in the thoracic and lumbar spinal cord. An enhancing nodular lesion was observed in the periventricular white matter of the lateral ventricle in the brain. There were no other abnormalities in systemic organs or skin. Laminectomy and tumor removal were performed. The tumor consisted of monomorphic, medium-to-large atypical lymphocytes with pale-to-eosinophilic cytoplasm. Immunohistochemically, the tumor cells were CD3(+), TCRβF1(-), TCRγ(+), CD30(-), CD4(-), CD8(-), CD56(+), TIA1(+), granzyme B(+), and CD103(+). Epstein-Barr virus in situ was negative. This case represents a unique T-PCNSL of γδ T-cell origin involving the spinal cord.

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Daniel Gregório Gonsalves, Paulo Eduardo Albuquerque Zito Raffa, Gabriela Gerenutti de Sousa, Melissa Esposito Gomes Rigueiral, Iracema Araújo Estevão, Cesar Cozar Pacheco, Roger Thomaz Rotta Medeiros, Paulo Roberto Franceschini, Paulo Henrique Pires de A
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Huizhen Ge, Li Xu, Huajie Gao, Suqiong Ji
BMC Neurology.2023;[Epub] CrossRef
Clinicopathologic and Genetic Features of Primary T-cell Lymphomas of the Central Nervous System
Jeemin Yim, Jiwon Koh, Sehui Kim, Seung Geun Song, Jeong Mo Bae, Hongseok Yun, Ji-Youn Sung, Tae Min Kim, Sung-Hye Park, Yoon Kyung Jeon
American Journal of Surgical Pathology.2022; 46(4): 486. CrossRef
Peripheral T-Cell Lymphomas Involving the Central Nervous System: A Report From the Czech Lymphoma Study Group Registry
Heidi Mocikova, Robert Pytlík, Katerina Benesova, Andrea Janikova, Juraj Duras, Alice Sykorova, Katerina Steinerova, Vit Prochazka, Vit Campr, David Belada, Marek Trneny
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Original Article

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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Review

Thyroid Fine-Needle Aspiration Cytology Practice in Korea: Yoon Jin Cha, Ju Yeon Pyo, SoonWon Hong, Jae Yeon Seok, Kyung-Ju Kim, Jee-Young Han, Jeong Mo Bae, Hyeong Ju Kwon, Yeejeong Kim, Kyueng-Whan Min, Soonae Oak, Sunhee Chang; J Pathol Transl Med. 2017;51(6):521-527. Published online October 11, 2017; DOI: https://doi.org/10.4132/jptm.2017.09.26

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We reviewed the current status of thyroid fine-needle aspiration cytology (FNAC) in Korea. Thyroid aspiration biopsy was first introduced in Korea in 1977. Currently, radiologists aspirate the thyroid nodule under the guidance of ultrasonography, and cytologic interpretation is only legally approved when a cytopathologist makes the diagnosis. In 2008, eight thyroid-related societies came together to form the Korean Thyroid Association. The Korean Society for Cytopathology and the endocrine pathology study group of the Korean Society for Pathologists have been updating the cytologic diagnostic guidelines. The Bethesda System for Reporting Thyroid Cytopathology was first introduced in 2009, and has been used by up to 94% of institutions by 2016. The average diagnosis rates are as follows for each category: I (12.4%), II (57.9%), III (10.4%), IV (2.9%), V (3.7%), and VI (12.7%). The malignancy rates in surgical cases are as follows for each category: I (28.7%), II (27.8%), III (50.6%), IV (52.3%), V (90.7%), and VI (100.0%). Liquid-based cytology has been used since 2010, and it was utilized by 68% of institutions in 2016. The categorization of thyroid lesions into “atypia of undetermined significance” or “follicular lesion of undetermined significance” is necessary to draw consensus in our society. Immunocytochemistry for galectin-3 and BRAF is used. Additionally, a molecular test for BRAF in thyroid FNACs is actively used. Core biopsies were performed in only 44% of institutions. Even the institutions that perform core biopsies only perform them for less than 3% of all FNACs. However, only 5% of institutions performed core biopsies up to three times more than FNAC.

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Original Article

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

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Abstract 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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Review

Molecular Testing for Gastrointestinal Cancer: Hye Seung Lee, Woo Ho Kim, Yoonjin Kwak, Jiwon Koh, Jeong Mo Bae, Kyoung-Mee Kim, Mee Soo Chang, Hye Seung Han, Joon Mee Kim, Hwal Woong Kim, Hee Kyung Chang, Young Hee Choi, Ji Y. Park, Mi Jin Gu, Min Jin Lhee, Jung Yeon Kim, Hee Sung Kim, Mee-Yon Cho; J Pathol Transl Med. 2017;51(2):103-121. Published online February 19, 2017; DOI: https://doi.org/10.4132/jptm.2017.01.24

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Abstract PDF

With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2–4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus–positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

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