Journal of Pathology and Translational Medicine

Original Article

Nuclear Expression of Hepatitis B Virus X Protein Is Associated with Recurrence of Early-Stage Hepatocellular Carcinomas: Role of Viral Protein in Tumor Recurrence: Jing Jin, Hae Yoen Jung, KyuHo Lee, Nam-Joon Yi, Kyung-Suk Suh, Ja-June Jang, Kyoung-Bun Lee; J Pathol Transl Med. 2016;50(3):181-189. Published online April 17, 2016; DOI: https://doi.org/10.4132/jptm.2016.03.18

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Background
Hepatitis B virus (HBV) plays well-known roles in tumorigenesis of hepatocellular carcinoma (HCC) in infected patients. However, HBV-associated protein status in tumor tissues and the relevance to tumor behavior has not been reported. Our study aimed to examine the expression of HBV-associated proteins in HCC and adjacent nontumorous tissue and their clinicopathologic implication in HCC patients.
Methods
HBV surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) were assessed in 328 HBV-associated HCCs and in 155 matched nontumorous tissues by immunohistochemistry staining.
Results
The positive rates of HBsAg and cytoplasmic HBx staining in tumor tissue were lower than those in nontumorous tissue (7.3% vs. 57.4%, p < .001; 43.4% vs. 81.3%, p < .001). Conversely, nuclear HBx was detected more frequently in tumors than in nontumorous tissue (52.1% vs. 30.3%, p < .001). HCCs expressing HBsAg, HBcAg, or cytoplasmic HBx had smaller size; lower Edmondson-Steiner (ES) nuclear grade, pT stage, and serum alpha-fetoprotein, and less angioinvasion than HCCs not expressing HBV-associated proteins. Exceptionally, nuclear HBx-positive HCCs showed higher ES nuclear grade and more frequent large-vessel invasion than did nuclear HBx-negative HCCs. In survival analysis, only nuclear HBx-positive HCCs had shorter disease-free survival than nuclear HBx-negative HCCs in pT1 and ES nuclear grade 1–2 HCC subgroup (median, 126 months vs. 35 months; p = .015).
Conclusions
Our data confirmed that expression of normal HBV-associated proteins generally decreases in tumor cells in comparison to nontumorous hepatocytes, with the exception of nuclear HBx, which suggests that nuclear HBx plays a role in recurrence of well-differentiated and early-stage HCCs.

Citations

Citations to this article as recorded by

Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis
Anja Schollmeier, Mirco Glitscher, Eberhard Hildt
International Journal of Molecular Sciences.2023; 24(5): 4964. CrossRef
Nomogram to predict the prognosis of patients with AFP-negative hepatocellular carcinoma undergoing chemotherapy: A SEER based study
Lei Wang, Jin-Lin Peng, Ji-Zhou Wu
Medicine.2023; 102(13): e33319. CrossRef
Tertiary Prevention of HCC in Chronic Hepatitis B or C Infected Patients
Wei Teng, Yen-Chun Liu, Wen-Juei Jeng, Chien-Wei Su
Cancers.2021; 13(7): 1729. CrossRef
Suppression of hepatitis b virus by a combined activity of CRISPR/Cas9 and HBx proteins
S. A. Brezgin, A. P. Kostyusheva, V. N. Simirsky, E. V. Volchkova, D. S. Chistyakov, D. S. Kostyushev, V. P. Chulanov
Russian Journal of Infection and Immunity.2019; 9(3-4): 476. CrossRef
Hepatitis B virus surface gene pre‐S2 mutant as a high‐risk serum marker for hepatoma recurrence after curative hepatic resection
Chia‐Jui Yen, Yu‐Lin Ai, Hung‐Wen Tsai, Shih‐Huang Chan, Chia‐Sheng Yen, Kuang‐Hsiung Cheng, Yun‐Ping Lee, Chia‐Wei Kao, Yu‐Chun Wang, Yi‐Lin Chen, Cheng‐Han Lin, Tsunglin Liu, Huey‐Pin Tsai, Jen‐Ren Wang, Ih‐Jen Su, Wenya Huang
Hepatology.2018; 68(3): 815. CrossRef
Integrin α6 as an invasiveness marker for hepatitis B viral X-driven hepatocellular carcinoma
Yi Rang Kim, Mi Ran Byun, Jin Woo Choi
Cancer Biomarkers.2018; 23(1): 135. CrossRef

Case Studies

Mediastinal Glomus Tumor: A Case Report and Literature Review: Si-Hyong Jang, Hyun Deuk Cho, Ji-Hye Lee, Hyun Ju Lee, Hae Yoen Jung, Kyung-Ju Kim, Sung Sik Cho, Mee-Hye Oh; J Pathol Transl Med. 2015;49(6):520-524. Published online August 4, 2015; DOI: https://doi.org/10.4132/jptm.2015.07.02

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Abstract PDF

A glomus tumor in the mediastinum is very uncommon, and only five cases have been reported in the English literature. We recently encountered a 21-year-old woman with an asymptomatic mediastinal mass that measured 5.3 × 4.0 cm. Surgical excision was performed, and the tumor was finally diagnosed as mediastinal glomus tumor with an uncertain malignant potential. After reviewing this case and previous reports, we analyzed the clinicopathologic features associated with progression of such a tumor.

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An unusual case of chest wall glomus tumor presenting with axillary pain: a case report and literature review
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Symplastic glomus tumor of the urinary bladder treated by robot-assisted partial cystectomy: a case report and literature review
Franco Palmisano, Franco Gadda, Matteo G. Spinelli, Marco Maggioni, Bernardo Rocco, Emanuele Montanari
Urologia Journal.2018; 85(3): 130. CrossRef
Thoracoscopic Surgery for Glomus Tumor: An Uncommon Mediastinal Neoplasm and Iatrogenic Tracheal Rupture
Zhongjie Fang, Dehua Ma, Baofu Chen, Huarong Luo
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Asymptomatic Glomus Tumor of the Mediastinum
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A Rare Case of Primary Tubular Adenocarcinoma of the Thymus, Enteric Immunophenotype: A Case Study and Review of the Literature: Hae Yoen Jung, Hyundeuk Cho, Jin-Haeng Chung, Sang Byoung Bae, Ji-Hye Lee, Hyun Ju Lee, Si-Hyong Jang, Mee-Hye Oh; J Pathol Transl Med. 2015;49(4):331-334. Published online June 1, 2015; DOI: https://doi.org/10.4132/jptm.2015.04.16

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Abstract PDF

Thymic carcinomas are uncommon malignant tumors, and thymic adenocarcinomas are extremely rare. Here, we describe a case of primary thymic adenocarcinoma in a 59-year-old woman. Histological examination of the tumor revealed tubular morphology with expression of cytokeratin 20 and caudal-type homeobox 2 according to immunohistochemistry, suggesting enteric features. Extensive clinical and radiological studies excluded the possibility of an extrathymic primary tumor. A review of the literature revealed only two global cases of primary tubular adenocarcinomas of the thymus with enteric immunophenotype.

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Jonathan Willner, Osvaldo Hernandez, Lea Azour, Andre L. Moreira
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Rurika Hamanaka, Kei Nakano, Takaaki Tsuboi, Kazuhito Hatanaka, Mitsutomo Kohno, Ryota Masuda, Masayuki Iwazaki
General Thoracic and Cardiovascular Surgery.2022; 70(5): 501. CrossRef
Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report
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A case report: primary thymic adenocarcinoma with enteric differentiation
Yuuki Kou, Hirokazu Tanaka, Nobuhisa Yamazaki, Hiroyoshi Watanabe, Makoto Sonobe
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Thymic enteric type adenocarcinoma: A case report with cytological features
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Diagnostic Cytopathology.2018; 46(1): 92. CrossRef
Histologic characteristics of thymic adenocarcinomas: Clinicopathologic study of a nine-case series and a review of the literature
Ah-Young Kwon, Joungho Han, Jinah Chu, Yong Soo Choi, Byeong-Ho Jeong, Myung-Ju Ahn, Yong Chan Ahn
Pathology - Research and Practice.2017; 213(2): 106. CrossRef
Characterization of genetic aberrations in a single case of metastatic thymic adenocarcinoma
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BMC Cancer.2017;[Epub] CrossRef
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Journal of Pathology and Translational Medicine.2017; 51(5): 509. CrossRef
Mucinous cystic tumor with CK20 and CDX2 expression of the thymus: Is this a benign counterpart of adenocarcinoma of the thymus, enteric type?
Jun Akiba, Hiroshi Harada, Shintaro Yokoyama, Toshihiro Hashiguchi, Akihiko Kawahara, Masahiro Mitsuoka, Shinzo Takamori, Hirohisa Yano
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Colon cancer chemotherapy for a patient with CDX2-expressing metastatic thymic adenocarcinoma: a case report and literature review
Akihiko Sawaki, Mikiya Ishihara, Yuji Kozuka, Hiroyasu Oda, Satoshi Tamaru, Yumiko Sugawara, Yoshiki Yamashita, Toshiro Mizuno, Taizo Shiraishi, Naoyuki Katayama
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Original Articles

The Histologic Cut-off Point for Adjacent and Remote Non-neoplastic Liver Parenchyma of Hepatocellular Carcinoma in Chronic Hepatitis B Patients: Hae Yoen Jung, Soo Hee Kim, Jin Jing, Jae Moon Gwak, Chul Ju Han, Ja-June Jang, Kyoung-Bun Lee; Korean J Pathol. 2012;46(4):349-358. Published online August 23, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.4.349

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Abstract PDF

Background

The molecular profile of peritumoral non-neoplastic liver parenchyma (PNLP) has recently been suggested as predictive factor of early and late recurrence of hepatocellular carcinoma (HCC). However, there is no definite cut-off point for tumor-free PNLP in terms of either histological or molecular changes. Therefore, our aim is to determine the numerical cut-off point for separating adjacent PNLP and remote PNLP in histopathologic perspective.

Methods

Peritumoral tissues from 20 resected HCC patients were sampled from 0 to 40 mm distance from the tumor border (divided into 5-mm columns). Histopathologic parameters such as necroinflammatory activity, fibrosis, bile ductular reaction, hepatic venulitis, peliosis, and steatosis were compared between each column.

Results

The morphologic changes just adjacent to the tumor were notably severe and faded with distance. The parenchyma within 10 mm of the tumor showed significantly severe inflammation, fibrosis, peliosis and hepatic venulitis compared with those from farther areas. The histopathologic changes of the parenchyma became stable beyond 20 mm.

Conclusions

Results of this study revealed that the parenchyma within 10 mm distance from the tumor, or adjacent PNLP, has histopathologic changes that are directly affected by the tumor, and the parenchyma beyond 20 mm as the remote PNLP without tumor effect.

Citations

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Peritumoral histopathologic findings in patients with chronic viral hepatitis‐associated hepatocellular carcinoma
Burcin Pehlivanoglu, Anil Aysal, Cihan Agalar, Tufan Egeli, Mucahit Ozbilgin, Tarkan Unek, Tugba Unek, Ilhan Oztop, Ozgul Sagol
APMIS.2022; 130(6): 346. CrossRef
Prognostic value of non-invasive fibrosis indices post-curative resection in hepatitis-B-associated hepatocellular carcinoma patients
Ting-Ting Zhang, Si-Si Ye, Jun Liang, Li Bai
Experimental Biology and Medicine.2020; 245(8): 703. CrossRef
Evaluation of Peritumoral Fibrosis in Metastatic Colorectal Adenocarcinoma to the Liver Using Digital Image Analysis
Kevin M Waters, Tricia R Cottrell, Sepideh Besharati, Qingfeng Zhu, Robert A Anders
American Journal of Clinical Pathology.2019; 151(2): 226. CrossRef
Fibrosis-4 Model Influences Results of Patients with Hepatocellular Carcinoma Undergoing Hepatectomy
Haiqing Wang, Aixiang Liu, Wentao Bo, Xielin Feng, Yong Hu, Lang Tian, Hui Zhang, Xiaoli Tang, Lixia Zhang
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Forns index predicts recurrence and death in patients with hepatitis B‐related hepatocellular carcinoma after curative resection
Won‐Mook Choi, Jeong‐Hoon Lee, Hongkeun Ahn, Hyeki Cho, Young Youn Cho, Minjong Lee, Jeong‐ju Yoo, Yuri Cho, Dong Hyeon Lee, Yun Bin Lee, Eun Ju Cho, Su Jong Yu, Nam‐Joon Yi, Kwang‐Woong Lee, Yoon Jun Kim, Jung‐Hwan Yoon, Kyung‐Suk Suh, Chung Yong Kim, Hy
Liver International.2015; 35(8): 1992. CrossRef
Renal Histologic Parameters Influencing Postoperative Renal Function in Renal Cell Carcinoma Patients
Myoung Ju Koh, Beom Jin Lim, Kyu Hun Choi, Yon Hee Kim, Hyeon Joo Jeong
Korean Journal of Pathology.2013; 47(6): 557. CrossRef

Cyclooxygenase-2 Expression and Its Prognostic Significance in Clear Cell Renal Cell Carcinoma: Ji Won Lee, Jeong Hwan Park, Ja Hee Suh, Kyung Han Nam, Ji-Young Choe, Hae Yoen Jung, Ji Yoen Chae, Kyung Chul Moon; Korean J Pathol. 2012;46(3):237-245. Published online June 22, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.3.237

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Abstract PDF

Background

The prognostic value of cyclooxygenase-2 (COX-2) in human renal cell carcinoma (RCC) remains unclear. The purposes of this study are to elucidate the clinical significance of COX-2 in clear cell RCC (CCRCC) and to assess the treatment effect of COX-2 inhibition on CCRCC cell lines.

Methods

Using tumor samples obtained from 137 patients who had undergone nephrectomy at Seoul National University Hospital, we evaluated COX-2 expression on immunohistochemistry. Moreover, we performed the cell proliferation assay using 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) and cell invasion assay. Thus, we evaluated the effect of meloxicam, an inhibitor of COX-2, in two human CCRCC cell lines.

Results

Cancer-specific survival (p=0.038) and progression-free survival (p=0.031) were shorter in the COX-2 high expression group. A multivariate logistic regression model showed that COX-2 expression was an independent risk factor for pTNM stage and Fuhrman nuclear grade. The MTT assay revealed that COX-2 inhibition led to the suppression of the proliferation of CCRCC cell lines. Moreover, it also reduced their invasion capacity.

Conclusions

This study postulates that COX-2 is a poor prognostic indicator in human CCRCC, suggesting that COX-2 inhibition can be a potential therapy in CCRCC.

Citations

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