Journal of Pathology and Translational Medicine

Original Articles

Clinicopathologic significance of the delta-like ligand 4, vascular endothelial growth factor, and hypoxia-inducible factor-2α in gallbladder cancer: Sujin Park, Junsik Kim, Woncheol Jang, Kyoung-Mee Kim, Kee-Taek Jang; J Pathol Transl Med. 2023;57(2):113-122. Published online March 14, 2023; DOI: https://doi.org/10.4132/jptm.2023.02.01

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Background
Gallbladder cancer (GBC) is usually detected in advanced stages with a low 5-year survival rate. Delta-like ligand 4 (DLL4), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-2alpha (HIF2α) have been studied for their role in tumorigenesis and potential for therapeutic target, and multiple clinical trials of the agents targeting them are ongoing. We investigated the expression of these markers in surgically resected GBC and tried to reveal their association with the clinicopathologic features, mutual correlation of their expression, and prognosis of the GBC patients by their expression.
Methods
We constructed the tissue microarray blocks of 99 surgically resected GBC specimens and performed immunohistochemistry of DLL4, VEGF, and HIF2α. We used the quantitative digital image analysis to evaluate DLL4 and VEGF expression, while the expression of HIF2α was scored manually.
Results
The expression of VEGF and HIF2α showed a significant trend with tumor differentiation (p= .028 and p= .006, respectively). We found that the high DLL4 and VEGF expression were significantly correlated with lymph node metastasis (p= .047, both). The expression of VEGF and HIF2α were significantly correlated (p < .001). The GBC patients with low HIF2α expression showed shorter recurrence-free survival than those with high HIF2α expression.
Conclusions
This study suggested the possibility of the usage of DLL4 and VEGF to predict the lymph node metastasis and the possibility of VEGF and HIF2α to predict the expression level mutually. Further studies may be needed to validate our study results and eventually accelerate the introduction of the targeted therapy in GBC.

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Dedifferentiated Leiomyosarcoma of the Uterine Corpus with Heterologous Component: Clinicopathological Analysis of Five Consecutive Cases from a Single Institution and Comprehensive Literature Review
Suyeon Kim, Hyunsik Bae, Hyun-Soo Kim
Diagnostics.2024; 14(2): 160. CrossRef
Identification of Key Immune Infiltration Related Genes Involved in Aortic Dissection Using Bioinformatic Analyses and Experimental Verification
Lin Zheng, Yusi Yang, Jie Liu, Tianliang Zhao, Xin Zhang, Lihua Chen
Journal of Inflammation Research.2024; Volume 17: 2119. CrossRef

The proteomic landscape shows oncologic relevance in cystitis glandularis: Jun Yong Kim, Dohyun Han, Hyeyoon Kim, Minsun Jung, Han Suk Ryu; J Pathol Transl Med. 2023;57(1):67-74. Published online December 22, 2022; DOI: https://doi.org/10.4132/jptm.2022.10.24

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Abstract PDF: Background
The relationship between cystitis glandularis (CG) and bladder malignancy remains unclear.
Methods
We identified the oncologic significance of CG at the molecular level using liquid chromatography-tandem mass spectrometry-based proteomic analysis of 10 CG, 12 urothelial carcinoma (UC), and nine normal urothelium (NU) specimens. Differentially expressed proteins (DEPs) were identified based on an analysis of variance false discovery rate < 0.05, and their functional enrichment was analyzed using a network model, Gene Set Enrichment Analysis, and Gene Ontology annotation.
Results
We identified 9,890 proteins across all samples and 1,139 DEPs among the three entities. A substantial number of DEPs overlapped in CG/NU, distinct from UC. Interestingly, we found that a subset of DEP clusters (n = 53, 5%) was differentially expressed in NU but similarly between CG and UC. This “UC-like signature” was enriched for reactive oxygen species (ROS) and energy metabolism, growth and DNA repair, transport, motility, epithelial-mesenchymal transition, and cell survival. Using the top 10 shortlisted DEPs, including SOD2, PRKCD, CYCS, and HCLS1, we identified functional elements related to ROS metabolism, development, and transport using network analysis. The abundance of these four molecules in UC/CG than in NU was consistent with the oncologic functions in CG.
Conclusions
Using a proteomic approach, we identified a predominantly non-neoplastic landscape of CG, which was closer to NU than to UC. We also confirmed a small subset of common DEPs in UC and CG, suggesting that altered ROS metabolism might imply potential cancerous risks in CG.

Histologically confirmed distant metastatic urothelial carcinoma from the urinary bladder: a retrospective review of one institution’s 20-year experience: Youngeun Yoo, Junghye Lee, Heae Surng Park, Min-Sun Cho, Sun Hee Sung, Sanghui Park, Euno Choi; J Pathol Transl Med. 2021;55(2):94-101. Published online December 3, 2020; DOI: https://doi.org/10.4132/jptm.2020.10.19

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Abstract PDF

Background
Urothelial carcinoma (UC) accounts for roughly 90% of bladder cancer, and has a high propensity for diverse differentiation. Recently, certain histologic variants of UC have been recognized to be associated with unfavorable clinical outcomes. Several UC studies have also suggested that tumor budding is a poor prognostic marker. Distant metastasis of UC after radical cystectomy is not uncommon. However, these metastatic lesions are not routinely confirmed with histology.
Methods
We investigated the histopathologic features of 13 cases of UC with biopsy-proven distant metastases, with a special emphasis on histologic variants and tumor budding.
Results
Lymph nodes (6/13, 46%) were the most common metastatic sites, followed by the lung (4/13, 31%), liver (4/13, 31%), and the adrenal gland (2/13, 15%). The histologic variants including squamous (n=1), micropapillary (n=4), and plasmacytoid (n=1) variants in five cases of UC. Most histologic variants (4/5, 80%) of primary UCs appeared in the metastatic lesions. In contrast, high-grade tumor budding was detected in six cases (46%), including one case of non-muscle invasive UC. Our study demonstrates that histologic variants are not uncommonly detected in distant metastatic UCs. Most histologic variants seen in primary UCs persist in the distant metastatic lesions. In addition, high-grade tumor budding, which occurs frequently in primary tumors, may contribute to the development of distant metastasis.
Conclusions
Therefore, assessing the presence or absence of histologic variants and tumor budding in UCs of the urinary bladder, even in non-muscle invasive UCs, may be useful to predict distant metastasis.

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Do Histology and Primary Tumor Location Influence Metastatic Patterns in Bladder Cancer?
Hyung Kyu Park
Current Oncology.2023; 30(10): 9078. CrossRef

Evaluation of Urine Cytology in Urothelial Carcinoma Patients: A Comparison of CellprepPlus® Liquid-Based Cytology and Conventional Smear: Seung-Myoung Son, Ji Hae Koo, Song-Yi Choi, Ho-Chang Lee, Yong-Moon Lee, Hyung Geun Song, Hae-Kyung Hwang, Hye-Suk Han, Seok-Joong Yun, Wun-Jae Kim, Eun-Joong Kim, Ok-Jun Lee; Korean J Pathol. 2012;46(1):68-74. Published online February 23, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.1.68

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Abstract PDF

Background

Urine cytology is an important test in the screening of urothlelial neoplasms. The conventional smear (CS) method of testing urine samples has a low sensitivity, approximately 50% result accuracy for detecting urothelial carcinomas, while liquid-based cytology (LBC) has much improved diagnostic accuracy, sensitivity, and specificity. The aim of this study was to compare the morphologic features and diagnostic efficacy of CellprepPlus® LBC with those of CS for urine cytology.

Methods

A total of 713 cases of urine specimens collected from November 2009 to September 2010 were included. All specimens were divided equally for the preparation of CellprepPlus® LBC and CS for each case.

Results

CellprepPlus® revealed more cellularity, a cleaner background and better cytomorphologic features, but it showed a less intact architectural pattern compared to that of CS. Of the 88 histologically confirmed cases, the diagnostic sensitivity for CellprepPlus® was 50% and higher than the 37.5% for CS. The specificity of both preparations was 100%.

Conclusions

The CellprepPlus® showed an improved quality of slides and provided better diagnostic accuracy, thus CellprepPlus® could be a first-line screening tool in urinary tract cytology.

Citations

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Deep Learning-Based Screening of Urothelial Carcinoma in Whole Slide Images of Liquid-Based Cytology Urine Specimens
Masayuki Tsuneki, Makoto Abe, Fahdi Kanavati
Cancers.2022; 15(1): 226. CrossRef
Diagnostic efficacy of smear plus liquid-based cytology for EUS-FNA of solid pancreatic lesions
Masahiro Itonaga, Shin-Ichi Murata, Keiichi Hatamaru, Takashi Tamura, Junya Nuta, Yuki Kawaji, Takao Maekita, Mikitaka Iguchi, Jun Kato, Fumiyoshi Kojima, Hiroki Yamaue, Manabu Kawai, Ken-Ichi Okada, Seiko Hirono, Toshio Shimokawa, Kensuke Tanioka, Masayu
Medicine.2019; 98(19): e15575. CrossRef
Evaluation and application of Cellprep for cervical cytology
Rinko OZEKI, Keiichi IWAYA, Yuko UMAYAHARA, Yuka MORITA, Mie ARAI, Yukari TAKASUGI, Ryoko KIKUCHI, Kiyohiko MIYAKE, Atsuhiko SAKAMOTO, Masaru SAKAMOTO
The Journal of the Japanese Society of Clinical Cytology.2018; 57(3): 159. CrossRef
Quantitative Proteomic Analysis Identifies AHNAK (Neuroblast Differentiation-associated Protein AHNAK) as a Novel Candidate Biomarker for Bladder Urothelial Carcinoma Diagnosis by Liquid-based Cytology
Hyebin Lee, Kwangsoo Kim, Jongmin Woo, Joonho Park, Hyeyoon Kim, Kyung Eun Lee, Hyeyeon Kim, Youngsoo Kim, Kyung Chul Moon, Ji Young Kim, In Ae Park, Bo Bae Shim, Ji Hye Moon, Dohyun Han, Han Suk Ryu
Molecular & Cellular Proteomics.2018; 17(9): 1788. CrossRef
Reliability of Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Expression on Breast Cancer Cells Stored in Cellprep® Vials
Ayumi Ryu, Jyun-ichi Ashimura, Takahiro Nakayama, Yasuhiro Tamaki, Shin-ichi Nakatsuka, Yasuhiko Tomita
Acta Cytologica.2018; 62(5-6): 360. CrossRef
Morphologic Analysis of Cytomegalovirus Infected Cells in Bronchial Washing Cytology: Comparison of Liquid-Based Preparation and Conventional Smear
Jae Yeon Seok, Jungsuk An, Seung Yeon Ha, Dong Hae Chung, Sangho Lee, Hyunchul Kim
Journal of Pathology and Translational Medicine.2016; 50(2): 147. CrossRef
Romanowsky staining using liquid‐based cytology: A pilot study using Cytolyt®/HESPANDER® processing solution for ThinPrep® preparations
Yuichi Kinoshita, Takashi Yuri, Katsuhiko Yoshizawa, Kosho Takasu, Yuko Emoto, Airo Tsubura, Nobuaki Shikata
Diagnostic Cytopathology.2015; 43(12): 960. CrossRef
Diagnostic Value of Liquid-Based Cytology in Urothelial Carcinoma Diagnosis: A Systematic Review and Meta-Analysis
You Luo, Dong-Li She, Hu Xiong, Li Yang, Sheng-Jun Fu, Francisco X. Real
PLOS ONE.2015; 10(8): e0134940. CrossRef
Comparison of diagnostic accuracy between CellprepPlus® and ThinPrep® liquid‐based preparations in effusion cytology
Yong‐Moon Lee, Ji‐Yong Hwang, Seung‐Myoung Son, Song‐Yi Choi, Ho‐Chang Lee, Eun‐Joong Kim, Hye‐Suk Han, Jin young An, Joung‐Ho Han, Ok‐Jun Lee
Diagnostic Cytopathology.2014; 42(5): 384. CrossRef
Diagnostic Efficacy of Cell Block Immunohistochemistry, Smear Cytology, and Liquid-Based Cytology in Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Pancreatic Lesions: A Single-Institution Experience
Shan-yu Qin, You Zhou, Ping Li, Hai-xing Jiang, Robert L. Schmidt
PLoS ONE.2014; 9(9): e108762. CrossRef

Expression of Cyclooxygenase-2 and Embryonic Lethal Abnormal Vision-Like Protein HuR in Gallbladder Carcinoma.: Sung Im Do, Gou Young Kim, Sung Jig Lim, Youn Wha Kim; Korean J Pathol. 2010;44(1):42-47.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.1.42

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Abstract PDF

BACKGROUND
Cyclooxygenase-2 (COX-2) is an enzyme that promotes proliferation of tumor cells. HuR is a member of the family of embryonic lethal abnormal vision-like proteins. Recent studies show that cytoplasmic HuR stabilizes the mRNA of COX-2 and regulates the expression of COX-2. Moreover, cytoplasmic HuR expression is associated with a poorer prognosis for patients with some cancers. The aim of this study was to investigate the expression patterns of and the relationship between COX-2 and HuR in gallbladder carcinoma.
METHODS
We analyzed COX-2 and HuR expression by immunohistochemical staining of 108 gallbladder carcinomas.
RESULTS
COX-2 expression and nuclear and cytoplasmic HuR expression were seen in, respectively, 61 (56.5%), 77 (71.3%), and 4 (3.7%) cases. COX-2 and nuclear HuR were simultaneously expressed in 44 of the 108 samples without any quantitative association between the levels of each. COX-2 expression correlated with tumor stage, differentiation (based on histology), lymph node metastasis, perineural invasion, and survival. Nuclear and cytological expression of HuR did not correlate with any clinical parameters.
CONCLUSIONS
COX-2 expression but not HuR may play an important role in the prognosis of patients with gallbladder carcinoma.

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Prognostic molecular markers in resected extrahepatic biliary tract cancers; a systematic review and meta-analysis of immunohistochemically detected biomarkers
Robert P Jones, Nicholas TE Bird, Richard A Smith, Daniel H Palmer, Steven W Fenwick, Graeme J Poston, Hassan Z Malik
Biomarkers in Medicine.2015; 9(8): 763. CrossRef

Study on Creating A Classifier for Grading of Bladder Carcinoma Based on Computerized Method.: Hyun Ju Choi, Hye Kyoung Yoon, Heung Kook Choi; Korean J Pathol. 2002;36(3):154-162.

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Abstract PDF: BACKGROUND
We have described an objective and reproducible classification method for grading malignancy in the Feulgen stained bladder carcinoma. To create an optimized classifier for malignancy grading of histological bladder carcinoma cell images, it is necessary to extract the features that accurately describle the order/disorder of the nuclear variation and to evaluate the significance of the features. Above all, features selection considered about the correlation of features is very important, because the performance of the classification method depends on the selected features.
METHODS
First, we acquired 40 representative histological bladder carcinoma cell images from each of four groups (Grade 1, Grade 2A, Grade 2B, Grade 3) and extracted morphology features, texture features and the texture features of wavelet transformed images. Second, we evaluated the significance of the extracted features using variance analysis. Third, we created classifiers for each selected feature and its combination set using discriminant analysis. Finally, we compared and analyzed the correct classification rate of each classifer.
RESULTS
The optimized classifier was created from the combination of morphology features, texture features and the texture features of wavelet transformed images.
CONCLUSIONS
We found that the correlation of features is more important than one feature's great significance in grading the malignancy of bladder carcinoma, and we have confirmed that the correct classification rate is determined by feature extractin, feature evaluation and feature selection.

Expression of Matrix Metalloproteinase (MMP)-2, MMP-9, Tissue Inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2 in Adenocarcinomas of The Gallbladder.: Jong Yup Bae, Jinsub Choi, Hyun Cheol Chung, Chanil Park, Young Nyun Park; Korean J Pathol. 2003;37(1):1-9.

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Abstract PDF: BACKGROUND
Matrix metalloproteinase (MMP)-2 and MMP-9 degrade type IV collagen and are antagonized by the tissue inhibitors of metalloproteinase (TIMP)-2 and TIMP-1, respectively.
METHODS
We studied by immunohistochemistry the expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 in 72 cases of adenocarcinoma of the gallbladder.
RESULTS
The MMP-2, MMP-9 and TIMP-1 expressions were significantly higher in well/moderately differentiated adenocarcinomas than in poorly differentiated adenocarcinomas, in adenocarcinomas that had invaded the lamina propria/proper muscle than in those that had invaded the perimuscular connective tissue or beyond the serosa, and in adenocarcinomas with fungating growth than in those with infiltrative growth. The TIMP-2 expression showed a similar pattern without statistical significance. Regarding the status of lymph node metastasis, the MMP-2 expression was significantly higher in cases without lymph node metastasis. The MMP-2 and MMP-9 expressions were significantly related to those of TIMP-2 and TIMP-1, respectively, with regard to depth of invasion, differentiation, and growth patterns of the adenocarcinomas.
CONCLUSIONS
MMP-2, MMP-9, TIMP-1 and TIMP-2 are suggested to play important roles in the progression to early invasion of adenocarcinomas, in which the function of MMP-2 is inhibited by TIMP-2.

Case Report

ISUP/WHO Classification of Papillary Urothelial Neoplasms of Urinary Bladder: Consensus Study Conducted by Korean Society of Urogenital Pathology.: Jung Weon Shim, Jae Y Ro, Nam Hoon Cho, Young Sik Kim, Yong Wook Park, Sang In Shim, Dong Wha Lee, Yeong Jin Choi, Woon Sup Han; Korean J Pathol. 2006;40(4):282-288.

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Abstract PDF: BACKGROUND
Pathologic grading, one of the most important prognostic factors of papillary urothelial neoplasia (PUN) of the urinary bladder, has been revised continuously. The current study focused on the analysis of interobserver agreement on PUN of the urinary bladder bet- ween 1973 WHO classification (WHO 1973) and 1998 WHO/ISUP classification.
METHODS
Seventy five cases from 15 institutions were collected, and after review by Korean Society of Urogenital Pathology (KSUP), 30 cases were selected as follows; group I, WHO grade 1 and papillary urothelial neoplasm of low malignant potential by ISUP (7 cases), group II, WHO grade 2 and low-grade papillary urothelial carcinoma (16 cases), and group III, WHO grade 3 and high-grade papillary urothelial carcinoma (7 cases). Seventy five general surgical pathologists who participated in this study were asked to grade the tumors based on WHO/ISUP classification. Interobserver agreement between the participants' diagnosis and KSUP consensus diagnosis was analyzed by kappa value.
RESULTS
Interobserver agreement assessed by kappa value for all diagnostic groups was very low; for group I, kappa value was -0.900893722; for group II, -0.944650025, and for group III, -0.876728996. The overall kappa value of pathology residents was better than that of practicing pathologists.
CONCLUSIONS
The 1998 WHO/ ISUP classification could not be easily translated from the 1973 WHO classification and because of poor interobserver agreement, it appears that further work would be needed before it can be practically applied.

Original Articles

Expression of Epidermal Growth Factor Receptor Related Protein in Gallbladder Cancer: An Association with p53 Mutation.: Ho Sung Park, Kyu Yun Jang, Kyung Ryoul Kim, Hak Yong Lee, Andrzej S Tarnawski, Adhip P N Majumdar, Myoung Jae Kang, Dong Geun Lee, Woo Sung Moon; Korean J Pathol. 2005;39(6):385-390.

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Abstract PDF: BACKGROUND
It has been well demonstrated that the overexpression of epidermal growth factor receptor (EGFR) is associated with numerous gastrointestinal malignancies, including gallbladder carcinoma. However, the cellular events that regulate EGFR in cancer cells have not been fully elucidated. A novel negative regulator of EGFR that is referred to as EGFR related protein (ERRP) has recently been identified. The aim of this study was to investigate the expression and localization of ERRP in gallbladder carcinoma and to examine a possible role for ERRP.
METHODS
We examined the immunohistochemical expressions of ERRP, p53 and proliferating cell nuclear antigen labeling index (PCNA-LI) in formalin-fixed, paraffinembedded specimens of 43 cases of gallbladder carcinoma, 7 cases of adenoma and 3 cases of dysplasia.
RESULTS
In the normal mucosa, ERRP immunoreactivity was positive in over 64% of specimens. In contrast, the ERRP staining was positive in only 46% of the cancer specimens. The expression of ERRP in cancer cells was inversely correlated with tumor cell proliferation. The loss of ERRP expression correlated with the p53 overexpression.
CONCLUSIONS
Our data indicate that the down-regulation or loss of ERRP could play an important role in the progression of gallbladder carcinoma. The inverse relationship between the ERRP expression and PCNA-LI suggests that ERRP may play a role in the inhibition of tumor cell proliferation in gallbladder cancer.

Expression of Urokinase-type Plasminogen Activator (uPA) and Plasminogen Activator Inhibitor-1 (PAI-1) in Gallbladder Carcinoma.: Kee Hyung Lee, Haeng Ji Kang, Seung Yeoun Lee, Moon Hyang Park; Korean J Pathol. 2003;37(6):384-392.

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Abstract PDF: BACKGROUND
There are evidences that uPA and its inhibitor play a key role in tumor spread. We studied whether uPA and PAI-1 expressions could serve as prognostic parameters along with clinical, gross and microscopic findings in gallbladder carcinomas.
METHODS
We analyzed 42 cases of gallbladder carcinomas by immunohistochemical staining and clinicopathologic parameters.
RESULTS
uPA and PAI-1 were more frequently expressed in the adenocarcinoma than in the normal or benign gallbladder tissue. The uPA expression in the glands of low grade adenocarcinoma was significantly correlated with both distant and lymph node metastases. The uPA expression in the stroma around the low grade adenocarcinoma was significantly correlated with either distant or lymph node metastasis. The PAI-1 expression was significantly correlated with lymph node metastasis only for both distant and lymph node metastases. In multivariate analysis, the lymphatic invasion was significantly related to poor survival (p= 0.0115). In univariate analysis, the cases without lymphatic invasion had prolonged survival. Positive expression of uPA in the glands of low-grade adenocarcinoma was significantly correlated with poor survival (p=0.0391).
CONCLUSION
In conjunction with clinicopathologic findings, expressions of uPA and PAI-1 may be useful prognostic markers in gallbladder carcinomas.

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