Journal of Pathology and Translational Medicine

Original Article

C-reactive Protein Overexpression in the Background Liver of Hepatitis B Virus–Associated Hepatocellular Carcinoma Is a Prognostic Biomarker: Jin Ho Shin, Eunsil Yu, Eun Na Kim, Chong Jai Kim; J Pathol Transl Med. 2018;52(5):267-274. Published online July 27, 2018; DOI: https://doi.org/10.4132/jptm.2018.07.14

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Background
Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). Peripheral blood C-reactive protein (CRP) concentration and CRP overexpression in HCC cells are proven to be prognostic markers for HCC, but the significance of CRP expression in non-neoplastic hepatocytes, which are the primary origin of CRP, has not been studied. This study was conducted to determine the clinicopathologic significance of CRP immunoreactivity in the background liver of HBV-associated HCC.
Methods
CRP immunostaining was done on tissue microarrays of non-neoplastic liver tissues obtained from surgically resected, treatment-naïve HBV-associated HCCs (n = 156). The relationship between CRP immunoreactivity and other clinicopathologic parameters including cancer-specific survival was analyzed. CRP immunoreactivity was determined using a 4-tier grading system: grades 0, 1, 2, and 3.
Results
CRP was positive in 139 of 156 cases (89.1%) of non-neoplastic liver in patients with HCCs: grade 1 in 83 cases (53.2%); grade 2 in 50 cases (32.1%); and grade 3 in six cases (3.8%). The patients with diffuse CRP immunoreactivity (grade 3) had decreased cancer-specific survival (p = .031) and a tendency for shorter interval before early recurrence (p = .050). The degree of CRP immunoreactivity correlated with serum CRP concentration (p < .001).
Conclusions
CRP immunoreactivity in non-neoplastic liver is a novel biomarker for poor cancer-specific survival of HBV-associated HCC and correlates with serum CRP concentration.

Citations

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Analysis of Inflammatory and Thyroid Hormone Levels Based on Hepatitis A and B Virus Immunity Status: Age and Sex Stratification
Hyeokjun Yun, Jae-Sik Jeon, Jae Kyung Kim
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A prospective follow-up study of the relationship between high-sensitivity C-reactive protein and primary liver cancer
Sarah Tan Siyin, Tong Liu, Wenqiang Li, Nan Yao, Guoshuai Xu, Jun Qu, Yajun Chen
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CRP Levels in Viral Hepatitis: A Meta-Analysis Study
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Case Studies

Combined Hepatocellular Carcinoma and Neuroendocrine Carcinoma with Ectopic Secretion of Parathyroid Hormone: A Case Report and Review of the Literature: Hyun Jung Kwon, Ji-Won Kim, Haeryoung Kim, YoungRok Choi, Soomin Ahn; J Pathol Transl Med. 2018;52(4):232-237. Published online May 25, 2018; DOI: https://doi.org/10.4132/jptm.2018.05.17

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Abstract PDF

Primary combined hepatocellular carcinoma (HCC) and neuroendocrine carcinoma is a rare entity, and so is hypercalcemia due to ectopic parathyroid hormone (PTH) secretion by tumor. A 44-year old man with hepatitis B virus associated chronic liver disease presented with a hepatic mass. Hemihepatectomy discovered the mass as combined HCC and poorly differentiated cholangiocarcinoma. During adjuvant chemoradiation therapy, he presented with nausea, and multiple systemic metastases were found. Laboratory tests revealed hypercalcemia with markedly elevated PTH and neuron specific enolase. Parathyroid scan showed normal uptake in parathyroid glands, suggestive of ectopic PTH secretion. Subsequently, immunohistochemistry of neuroendocrine marker was performed on the primary lesion, and confirmed the neuroendocrine differentiation in non-HCC component. The patient died 71 days after surgery. This report may suggest the possibility of ectopic PTH secretion by neuroendocrine carcinoma of hepatic origin causing hypercalcemia. Caution for neuroendocrine differentiation should be exercised when diagnosing poorly differentiated HCC.

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Case report: mixed large-cell neuroendocrine and hepatocellular carcinoma of the liver
Xin Gao, Heng Wang, Zheyu Niu, Meng Liu, Xiaohan Kong, Hongrui Sun, Chaoqun Ma, Huaqiang Zhu, Jun Lu, Xu Zhou
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Mixed glandular neuroendocrine carcinoma of the endometrium with hypercalcemic crisis
Mei Luo, Xiaoxia Yu, Zhongpei Chen, Zhenhan Li
The American Journal of the Medical Sciences.2024;[Epub] CrossRef
Mixed Primary Hepatocellular Carcinoma and Hepatic Neuroendocrine Carcinoma: Case Report and Literature Review
Woo Young Shin, Keon Young Lee, Kyeong Deok Kim
Medicina.2023; 59(2): 418. CrossRef
Comparison of Metastatic Patterns Among Neuroendocrine Tumors, Neuroendocrine Carcinomas, and Nonneuroendocrine Carcinomas of Various Primary Organs
Hyung Kyu Park, Ghee Young Kwon
Journal of Korean Medical Science.2023;[Epub] CrossRef
Immunohistochemical characterization of a steroid-secreting oncocytic adrenal carcinoma responsible for paraneoplastic hyperparathyroidism
Magalie Haissaguerre, Estelle Louiset, Christofer C Juhlin, Adam Stenman, Christophe Laurent, Hélène Trouette, Hervé Lefebvre, Antoine Tabarin
European Journal of Endocrinology.2023; 188(4): K11. CrossRef
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Contrast-Enhanced Ultrasound Findings of Hepatocellular Carcinoma With Neuroendocrine Carcinoma: A Case Report
Hong Wang, Dan Yang, Zhenru Wu, Yan Luo, Wenwu Ling
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Nathaniel Hocker, Maria Story, Alysa Lerud, Sarat Kuppachi
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Filomena Cetani, Elena Pardi, Claudio Marcocci
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Primary hepatic neuroendocrine cancer coexisted with hepatocellular carcinoma: a case report
Chikara Ebisutani, Seitetsu Yoon, Toshiki Hyodo, Takafumi Watanabe, Hirofumi Okada, Yutaka Shirakawa, Yoshio Sakamoto, Shigeya Hirohata
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Two-in-one: A pooled analysis of primary hepatic neuroendocrine carcinoma combined/collided with hepatocellular carcinoma
Jia-Xi Mao, Fei Teng, Ke-Yan Sun, Cong Liu, Guo-Shan Ding, Wen-Yuan Guo
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Hepatocellular Carcinoma Arising in a Huge Hepatocellular Adenoma with Bone Marrow Metaplasia: Hyo Jeong Kang, Hui Jeong Jeong, So-Woon Kim, Eunsil Yu, Young-Joo Lee, So Yeon Kim, Jihun Kim; J Pathol Transl Med. 2018;52(4):226-231. Published online December 27, 2017; DOI: https://doi.org/10.4132/jptm.2017.11.12

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Abstract PDF

Hepatocellular adenoma (HCA) is the most common type of benign liver tumor, and its major complication is malignant transformation to hepatocellular carcinoma (HCC). Here, we report a case of HCC arising in HCA with bone marrow metaplasia in a 24-year-old Korean woman who presented with abdominal discomfort. A huge liver mass was found on abdominal ultrasonography. She underwent surgical hepatic resection, and the resected specimen was entirely involved by a 20-cm-sized tumor. Histological review revealed a well differentiated HCC arising from inflammatory HCA with β-catenin nuclear positivity and bone marrow metaplasia that contained hematopoietic cells. This case was unique because malignant transformation, inflammatory type HCA, β-catenin nuclear staining, and bone marrow metaplasia were simultaneously observed. Additionally, it should be noted that a large HCA with β-catenin activation can undergo malignant transformation and should be surgically resected in a timely manner.

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Adult Hepatocellular Carcinoma Coexisting with Extramedullary Hematopoiesis
Hirotsugu Noguchi, Michiyo Higashi, Ryo Desaki, Takashi Tasaki, Mari Kirishima, Ikumi Kitazono, Kazuhiro Tabata, Akihide Tanimoto
International Journal of Surgical Pathology.2022; 30(3): 339. CrossRef
Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice
Wenhua Shao, Orgil Jargalsaikhan, Mayuko Ichimura-Shimizu, Qinyi Cai, Hirohisa Ogawa, Yuko Miyakami, Kengo Atsumi, Mitsuru Tomita, Mitsuko Sutoh, Shunji Toyohara, Ryoji Hokao, Yasusei Kudo, Takeshi Oya, Koichi Tsuneyama
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Bilateral Diffuse Nodular Pulmonary Ossification Mimicking Metastatic Disease in a Patient with Fibrolamellar Hepatocellular Carcinoma
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Original Articles

The Clinicopathological and Prognostic Significance of the Gross Classification of Hepatocellular Carcinoma: Yangkyu Lee, Hyunjin Park, Hyejung Lee, Jai Young Cho, Yoo-Seok Yoon, Young-Rok Choi, Ho-Seong Han, Eun Sun Jang, Jin-Wook Kim, Sook-Hyang Jeong, Soomin Ahn, Haeryoung Kim; J Pathol Transl Med. 2018;52(2):85-92. Published online November 24, 2017; DOI: https://doi.org/10.4132/jptm.2017.11.13

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Abstract PDF

Background
We aimed to determine the clinicopathological significance of the gross classification of hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association (KLCA) guidelines.
Methods
A retrospective analysis was performed on 242 cases of consecutively resected solitary primary HCC between 2003 and 2012 at Seoul National University Bundang Hospital. The gross classification (vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP], and infiltrative [INF]) was reviewed for all cases, and were correlated with various clinicopathological features and the expression status of “stemness”-related (cytokeratin 19 [CK19], epithelial cell adhesion molecule [EpCAM]), and epithelial-mesenchymal transition (EMT)–related (urokinase plasminogen activator receptor [uPAR] and Ezrin) markers.
Results
Significant differences were seen in overall survival (p=.015) and disease-free survival (p = .034) according to the gross classification; INF type showed the worst prognosis while VN and EN types were more favorable. When the gross types were simplified into two groups, type 2 HCCs (MC/NP/INF) were more frequently larger and poorly differentiated, and showed more frequent microvascular and portal venous invasion, intratumoral fibrous stroma and higher pT stages compared to type 1 HCCs (EN/VN) (p<.05, all). CK19, EpCAM, uPAR, and ezrin expression was more frequently seen in type 2 HCCs (p<.05, all). Gross classification was an independent predictor of both overall and disease-free survival by multivariate analysis (overall survival: p=.030; hazard ratio, 4.118; 95% confidence interval, 1.142 to 14.844; disease-free survival: p=.016; hazard ratio, 1.617; 95% confidence interval, 1.092 to 2.394).
Conclusions
The gross classification of HCC had significant prognostic value and type 2 HCCs were associated with clinicopathological features of aggressive behavior, increased expression of “stemness”- and EMT-related markers, and decreased survival.

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SIRT7, H3K18ac, and ELK4 Immunohistochemical Expression in Hepatocellular Carcinoma: Hye Seung Lee, Wonkyung Jung, Eunjung Lee, Hyeyoon Chang, Jin Hyuk Choi, Han Gyeom Kim, Aeree Kim, Baek-hui Kim; J Pathol Transl Med. 2016;50(5):337-344. Published online August 5, 2016; DOI: https://doi.org/10.4132/jptm.2016.05.20

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Abstract PDF

Background
SIRT7 is one of the histone deacetylases and is NAD-dependent. It forms a complex with ETS-like transcription factor 4 (ELK4), which deacetylates H3K18ac and works as a transcriptional suppressor. Overexpression of SIRT7 and deacetylation of H3K18ac have been shown to be associated with aggressive clinical behavior in some cancers, including hepatocellular carcinoma (HCC). The present study investigated the immunohistochemical expression of SIRT7, H3K18ac, and ELK4 in hepatocellular carcinoma.
Methods
A total of 278 HCC patients were enrolled in this study. Tissue microarray blocks were made from existing paraffin-embedded blocks. Immunohistochemical expressions of SIRT7, H3K18ac and ELK4 were scored and analyzed.
Results
High SIRT7 (p = .034), high H3K18ac (p = .001), and low ELK4 (p = .021) groups were associated with poor outcomes. Age < 65 years (p = .028), tumor size ≥ 5 cm (p = .001), presence of vascular emboli (p = .003), involvement of surgical margin (p = .001), and high American Joint Committee on Cancer stage (III&V) (p < .001) were correlated with worse prognoses. In multivariate analysis, H3K18ac (p = .001) and ELK4 (p = .015) were the significant independent prognostic factors.
Conclusions
High SIRT7 expression with poor overall survival implies that deacetylation of H3K18ac contributes to progression of HCC. High H3K18ac expression with poor prognosis is predicted due to a compensation mechanism. In addition, high ELK4 expression with good prognosis suggests another role of ELK4 as a tumor suppressor beyond SIRT7’s helper. In conclusion, we could assume that the H3K18ac deacetylation pathway is influenced by many other factors.

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Romain Haider, Fabienne Massa, Lisa Kaminski, Stephan Clavel, Zied Djabari, Guillaume Robert, Kathiane Laurent, Jean-François Michiels, Matthieu Durand, Jean-Ehrland Ricci, Jean-François Tanti, Frédéric Bost, Damien Ambrosetti
Oncotarget.2017; 8(44): 77309. CrossRef

Immunohistochemical Expression and Clinical Significance of Suggested Stem Cell Markers in Hepatocellular Carcinoma: Jong Jin Sung, Sang Jae Noh, Jun Sang Bae, Ho Sung Park, Kyu Yun Jang, Myoung Ja Chung, Woo Sung Moon; J Pathol Transl Med. 2016;50(1):52-57. Published online November 18, 2015; DOI: https://doi.org/10.4132/jptm.2015.10.09

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Abstract PDF

Background
Increasing evidence has shown that tumor initiation and growth are nourished by a small subpopulation of cancer stem cells (CSCs) within the tumor mass. CSCs are posited to be responsible for tumor maintenance, growth, distant metastasis, and relapse after curative operation. We examined the expression of CSC markers in paraffin-embedded tissue sections of hepatocellular carcinoma (HCC) and correlated the results with clinicopathologic characteristics. Methods: Immunohistochemical staining for the markers believed to be expressed in the CSCs, including epithelial cell adhesion molecule (EpCAM), keratin 19 (K19), CD133, and CD56, was performed in 82 HCC specimens. Results: EpCAM expression was observed in 56% of the HCCs (46/82) and K19 in 6% (5/82). EpCAM expression in HCC significantly correlated with elevated α-fetoprotein level, microvessel invasion of tumor cells, and high histologic grade. In addition, Ep- CAM expression significantly correlated with K19 expression. The overall survival and relapsefree survival rates in patients with EpCAM-expressing HCC were relatively lower than those in patients with EpCAM-negative HCC. All but two of the 82 HCCs were negative for CD133 and CD56, respectively. Conclusions: Our results suggest that HCCs expressing EpCAM are associated with unfavorable prognostic factors and have a more aggressive clinical course than those not expressing EpCAM. Further, the expression of either CD133 or CD56 in paraffin-embedded HCC tissues appears to be rare.

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Recent Progress in Systemic Therapy for Advanced Hepatocellular Carcinoma
Narayanan Sadagopan, Aiwu Ruth He
International Journal of Molecular Sciences.2024; 25(2): 1259. CrossRef
Diagnostic value of expressions of cancer stem cell markers for adverse outcomes of hepatocellular carcinoma and their associations with prognosis: A Bayesian network meta‑analysis
Zhengrong Ou, Shoushuo Fu, Jian Yi, Jingxuan Huang, Weidong Zhu
Oncology Letters.2024;[Epub] CrossRef
Clinicopathological and prognostic value of epithelial cell adhesion molecule in solid tumours: a meta-analysis
Peiwen Ding, Panyu Chen, Jiqi Ouyang, Qiang Li, Shijie Li
Frontiers in Oncology.2023;[Epub] CrossRef
PD-L1 Downregulation and DNA Methylation Inhibition for Molecular Therapy against Cancer Stem Cells in Hepatocellular Carcinoma
Caecilia Sukowati, Loraine Kay D. Cabral, Beatrice Anfuso, Francesco Dituri, Roberto Negro, Gianluigi Giannelli, Claudio Tiribelli
International Journal of Molecular Sciences.2023; 24(17): 13357. CrossRef
EpCAM, Ki67, and ESM1 Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation
Aiat Shaban Hemida, Doha Maher Taie, Moshira Mohamed Abd El-Wahed, Mohammed Ibrahim Shabaan, Mona Saeed Tantawy, Nermine Ahmed Ehsan
Applied Immunohistochemistry & Molecular Morphology.2023; 31(9): 596. CrossRef
The clinical, prognostic and therapeutic significance of liver cancer stem cells and their markers
Izabela Zarębska, Arkadiusz Gzil, Justyna Durślewicz, Damian Jaworski, Paulina Antosik, Navid Ahmadi, Marta Smolińska-Świtała, Dariusz Grzanka, Łukasz Szylberg
Clinics and Research in Hepatology and Gastroenterology.2021; 45(3): 101664. CrossRef
Detection of oncogenic mutations in paired circulating tumor DNA and circulating tumor cells in patients with hepatocellular carcinoma
Zhouhong Ge, Jean C.A. Helmijr, Maurice P.H.M. Jansen, Patrick P.C. Boor, Lisanne Noordam, Maikel Peppelenbosch, Jaap Kwekkeboom, Jaco Kraan, Dave Sprengers
Translational Oncology.2021; 14(7): 101073. CrossRef
Hepatocellular Carcinoma Score and Subclassification Into Aggressive Subtypes Using Immunohistochemical Expression of p53, β-Catenin, CD133, and Ki-67
Asmaa G. Abdou, Nanis S. Holah, Dina S. Elazab, Walaa G. El-Gendy, Mohammed T. Badr, Dalia R. Al-Sharaky
Applied Immunohistochemistry & Molecular Morphology.2021; 29(1): 20. CrossRef
The prognostic significance of neuroendocrine markers and somatostatin receptor 2 in hepatocellular carcinoma
Keigo Murakami, Hiroyuki Kumata, Shigehito Miyagi, Takashi Kamei, Hironobu Sasano
Pathology International.2021; 71(10): 682. CrossRef
Predictors of recurrence and survival of hepatocellular carcinoma: A prospective study including transient elastography and cancer stem cell markers
Hend Ibrahim Shousha, Rabab Fouad, Tamer Mahmoud Elbaz, Dina Sabry, Mohamed Mahmoud Nabeel, Ahmed Hosni Abdelmaksoud, Aisha Mahmoud Elsharkawy, Zeinab Abdellatif Soliman, Ghada Habib, Ashraf Omar Abdelaziz
Arab Journal of Gastroenterology.2020; 21(2): 95. CrossRef
Napabucasin Reduces Cancer Stem Cell Characteristics in Hepatocellular Carcinoma
Ya Li, Qiuju Han, Huajun Zhao, Quanjuan Guo, Jian Zhang
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The mRNA Distribution of Cancer Stem Cell Marker CD90/Thy-1 Is Comparable in Hepatocellular Carcinoma of Eastern and Western Populations
An B. Luong, Huy Q. Do, Paola Tarchi, Deborah Bonazza, Cristina Bottin, Loraine Kay D. Cabral, Long D. C. Tran, Thao P. T. Doan, Lory S. Crocè, Hoa L. T. Pham, Claudio Tiribelli, Caecilia H. C. Sukowati
Cells.2020; 9(12): 2672. CrossRef
Histological architectural classification determines recurrence pattern and prognosis after curative hepatectomy in patients with hepatocellular carcinoma
Hirohisa Okabe, Tomoharu Yoshizumi, Yo-ichi Yamashita, Katsunori Imai, Hiromitsu Hayashi, Shigeki Nakagawa, Shinji Itoh, Norifumi Harimoto, Toru Ikegami, Hideaki Uchiyama, Toru Beppu, Shinichi Aishima, Ken Shirabe, Hideo Baba, Yoshihiko Maehara, Motoyuki
PLOS ONE.2018; 13(9): e0203856. CrossRef
Overexpression of epithelial cell adhesion molecule as a predictor of poor outcome in patients with hepatocellular carcinoma
Chih‑Jan Ko, Chia‑Jung Li, Meng‑Yu Wu, Pei‑Yi Chu
Experimental and Therapeutic Medicine.2018;[Epub] CrossRef
Clinicopathologic Significance of Survivin Expression in Relation to CD133 Expression in Surgically Resected Stage II or III Colorectal Cancer
Wanlu Li, Mi-Ra Lee, EunHee Choi, Mee-Yon Cho
Journal of Pathology and Translational Medicine.2017; 51(1): 17. CrossRef
PIN1 in hepatocellular carcinoma is associated with TP53 gene status
Jun Sang Bae, Sang Jae Noh, Kyoung Min Kim, Kyu Yun Jang, Ho Sung Park, Myoung Ja Chung, Byung-Hyun Park, Woo Sung Moon
Oncology Reports.2016; 36(4): 2405. CrossRef

SALL4 Expression in Hepatocellular Carcinomas Is Associated with EpCAM-Positivity and a Poor Prognosis: Hyunjin Park, Hyejung Lee, An Na Seo, Jai Young Cho, Young Rok Choi, Yoo-Seok Yoon, Ho-Seong Han, Young Nyun Park, Haeryoung Kim; J Pathol Transl Med. 2015;49(5):373-381. Published online August 10, 2015; DOI: https://doi.org/10.4132/jptm.2015.07.09

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Abstract PDF

Background
There is increasing interest in hepatocellular carcinomas (HCC) expressing “stemness”-related markers, as they have been associated with aggressive behavior and poor prognosis. In this study, we investigated the usefulness of Sal-like protein 4 (SALL4), a recently proposed candidate marker of “stemness.” Methods: Immunohistochemical stains were performed for SALL4, K19, and epithelial cellular adhesion molecule (EpCAM) on tissue microarrays constructed from 190 surgically resected HCCs, and the results were correlated with the clinicopathological features and patient survival data. Results: Nuclear SALL4 expression was observed in 39/190 HCCs (20.5%), while K19 and EpCAM were expressed in 30 (15.9%) and 92 (48.7%) HCCs, respectively. The nuclear expression was generally weak, punctate or clumped. SALL4 expression was significantly associated with a poor overall survival compared to SALL4-negative HCCs (p = .014) compared to SALL4-negative HCCs. On multivariate analysis adjusted for tumor size, multiplicity, vascular invasion, and pathological tumor stage, SALL4 remained as a significant independent predictor of decreased overall survival (p= .004). SALL4 expression was positively correlated with EpCAM expression (p = .013) but not with K19 expression. HCCs that expressed both SALL4 and EpCAM were associated with significantly decreased overall survival, compared to those cases which were negative for both of these markers (p = .031). Conclusions: Although SALL4 expression was not significantly correlated with other clinicopathological parameters suggestive of tumor aggressiveness, SALL4 expression was an independent predictor of poor overall survival in human HCCs, and was also positively correlated with EpCAM expression.

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Review

Pathology-MRI Correlation of Hepatocarcinogenesis: Recent Update: Jimi Huh, Kyung Won Kim, Jihun Kim, Eunsil Yu; J Pathol Transl Med. 2015;49(3):218-229. Published online May 15, 2015; DOI: https://doi.org/10.4132/jptm.2015.04.15

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Abstract PDF

Understanding the important alterations during hepatocarcinogenesis as well as the characteristic magnetic resonance imaging (MRI) and histopathological features will be helpful for managing patients with chronic liver disease and hepatocellular carcinoma. Recent advances in MRI techniques, such as fat/iron quantification, diffusion-weighted images, and gadoxetic acid-enhanced MRI, have greatly enhanced our understanding of hepatocarcinogenesis.

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Original Articles

Overexpression of C-reactive Protein as a Poor Prognostic Marker of Resectable Hepatocellular Carcinomas: Jin Ho Shin, Chong Jai Kim, Eun Jeong Jeon, Chang Ohk Sung, Hwa Jeong Shin, Jene Choi, Eunsil Yu; J Pathol Transl Med. 2015;49(2):105-111. Published online March 12, 2015; DOI: https://doi.org/10.4132/jptm.2015.01.19

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Abstract PDF

Background
C-reactive protein (CRP) is an acute phase reactant synthesized in the liver. CRP immunoreactivity is a feature of inflammatory hepatocellular adenomas with a higher risk of malignant transformation. A high serum CRP level denotes poor prognosis in hepatocellular carcinoma (HCC) patients. This study was conducted to determine whether CRP is produced in HCC and to assess the clinicopathologic significance of CRP expression in cancer cells. Methods: CRP immunoreactivity was examined in treatment-naïve HCCs (n=224) using tissue microarrays and was correlated with clinicopathologic parameters. The expression of CRP mRNA and protein was also assessed in 12 HCC cases by quantitative real-time polymerase chain reaction and immunoblotting. Hep3B and SNU-449 HCC cell lines were used for the analysis of CRP mRNA regulation by interleukin 6 (IL-6). Results: CRP was expressed in 133 of 224 HCCs (59.4%) with a variable degree of immunoreactivity (grade 1 in 25.9%; grade 2 in 20.1%; grade 3 in 13.4%). There was an inverse relationship between grade 3 CRP immunoreactivity and cancer-specific survival (p=.0047), while no associations were found with other parameters, including recurrence-free survival. The CRP mRNA expression level was significantly higher in CRP immunopositive cases than in immunonegative cases (p<.05). CRP mRNA expression was increased in Hep3B cells, but was not detected in SNU-449 cells even after IL-6 treatment. Conclusions: We report the expression of CRP in HCC for the first time. CRP expression was associated with poor cancer-specific survival in patients with resectable HCC.

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Peritumoral portal enhancement during transarterial chemoembolization: a potential prognostic factor for patients with hepatocellular carcinoma
Sofi Sennefelt Nyman, Angeliki Dimopoulou Creusen, Ulf Johnsson, Fredrik Rorsman, Johan Vessby, Charlotte Ebeling Barbier
Acta Radiologica.2022; 63(10): 1323. CrossRef
The quest for precision oncology with immune checkpoint inhibitors for hepatocellular carcinoma
Giuseppe Cabibbo, Amit G. Singal
Journal of Hepatology.2022; 76(2): 262. CrossRef
HNF-1β is a More Sensitive and Specific Marker Than C-Reactive Protein for Identifying Biliary Differentiation in Primary Hepatic Carcinomas
Pallavi A. Patil, Tamar Taddei, Dhanpat Jain, Xuchen Zhang
Archives of Pathology & Laboratory Medicine.2022; 146(2): 220. CrossRef
Malignant transformation of hepatocellular adenoma
Céline Julien, Brigitte Le Bail, Laurence Chiche, Charles Balabaud, Paulette Bioulac-Sage
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Erfan Razavi, Akam Ramezani, Asma Kazemi, Armin Attar, Baohui Xu
Cardiovascular Therapeutics.2022; 2022: 1. CrossRef
Steatotic and Steatohepatitic Hepatocellular Carcinomas
Umut Aykutlu, Asuman Argon, Mehmet Orman, Sezgin Ulukaya, Murat Zeytunlu, Zeki Karasu, Fulya Günşar, Deniz Nart, Ulus Akarca, Funda Yilmaz
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Cytochrome P450 4A11 expression in tumor cells: A favorable prognostic factor for hepatocellular carcinoma patients
Hyuk Soo Eun, Sang Yeon Cho, Byung Seok Lee, Sup Kim, In‐Sang Song, Kwangsik Chun, Cheong‐Hae Oh, Min‐Kyung Yeo, Seok Hyun Kim, Kyung‐Hee Kim
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Amit Kumar Ram, Biju Pottakat, Balasubramaniyan Vairappan
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C-reactive Protein Overexpression in the Background Liver of Hepatitis B Virus–Associated Hepatocellular Carcinoma Is a Prognostic Biomarker
Jin Ho Shin, Eunsil Yu, Eun Na Kim, Chong Jai Kim
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Prognostic Significance of BCL9 Expression in Hepatocellular Carcinoma: Jiyeon Hyeon, Soomin Ahn, Jae Jun Lee, Dae Hyun Song, Cheol-Keun Park; Korean J Pathol. 2013;47(2):130-136. Published online April 24, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.2.130

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Abstract PDF

Background

BCL9 enhances β-catenin-mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases the cell proliferation, migration, invasion, and metastatic potential of tumor cells. The goal of this study was to elucidate the prognostic significance of BCL9 protein expression in hepatocellular carcinoma (HCC) patients.

Methods

We evaluated BCL9 protein expression by immunohistochemistry in tumor tissue from 288 primary HCC patients who underwent curative hepatectomy. The impact of BCL9 expression on the survival of the patients was analyzed. The median follow-up period was 97.1 months.

Results

Nuclear BCL9 protein expression was observed in 74 (25.7%) of the 288 HCCs. BCL9 expression was significantly associated with younger age (p=0.038), higher Edmondson grade (p=0.001), microvascular invasion (p=0.013), and intrahepatic metastasis (p=0.017). Based on univariate analyses, BCL9 expression showed an unfavorable influence on both disease-free survival (DFS, p=0.012) and disease-specific survival (DSS, p=0.032). Multivariate analyses revealed that higher Barcelona Clinic Liver Cancer stage was an independent predictor of both shorter DFS (p<0.001) and shorter DSS (p<0.001). BCL9 expression tended to be an independent predictor of shorter DFS (p=0.078).

Conclusions

BCL9 protein expression might be a marker of shorter DFS in HCC patients after curative hepatectomy.

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BCL9, a coactivator for Wnt/β-catenin transcription, is targeted by miR-30c and is associated with prostate cancer progression
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CHD1L Is a Marker for Poor Prognosis of Hepatocellular Carcinoma after Surgical Resection: Jiyeon Hyeon, Soomin Ahn, Cheol-Keun Park; Korean J Pathol. 2013;47(1):9-15. Published online February 25, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.1.9

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Abstract PDF

Background

The gene for chromodomain helicase/ATPase DNA binding protein 1-like (CHD1L) was recently identified as a target oncogene within the 1q21 amplicon, which occurs in 46% to 86% of primary hepatocellular carcinoma (HCC) cases. However, the prognostic significance of CHD1L in HCC remains uncertain. In this study, we investigated the roles of CHD1L in the prognosis of HCC.

Methods

We investigated the expressions of CHD1L in tumor tissue microarrays of 281 primary HCC patients who underwent surgical resection using immunohistochemistry. Prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 75.6 months.

Results

CHD1L expression was observed in 48 of the 281 HCCs (17.1%). CHD1L expression was associated with a younger age (p=0.033), higher Edmondson grade (p=0.019), microvascular invasion (p<0.001), major portal vein invasion (p=0.037), higher American Joint Committee on Cancer T stage (p=0.001), lower albumin level (p=0.047), and higher α-fetoprotein level (p=0.002). Multivariate analyses revealed that CHD1L expression (p=0.027), Edmondson grade III (p=0.034), and higher Barcelona Clinic Liver Cancer stage (p<0.001) were independent predictors of shorter disease-free survival.

Conclusions

CHD1L expression might be a prognostic marker of shorter disease-free survival in HCC patients after surgical resection.

Citations

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Genome-wide scanning for CHD1L gene in papillary thyroid carcinoma complicated with type 2 diabetes mellitus
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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
BioMed Research International.2018; 2018: 1. CrossRef
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

Expression of Multidrug Resistance Protein 1 in Human Hepatocellular Carcinoma.: Yun Kyung Kang; Korean J Pathol. 2011;45(3):281-289.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.3.281

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Abstract PDF

BACKGROUND
Multidrug resistance protein 1 (MDR1) encoded by ATP-binding cassette, sub-family B (Mdr/Tap), member 1 (ABCB1) mediates cross-resistance to antineoplastic drugs, and its expression is related to tumor aggressiveness.
METHODS
MDR1 expression was investigated in 100 hepatocellular carcinomas (HCCs) by immunohistochemical staining. The epigenetic mechanisms underlying ABCB1 transcriptional regulation were investigated in cell lines.
RESULTS
MDR1 was normally localized in the bile canalicular surface of the hepatocytes. Among 100 HCCs, 45 showed canalicular/luminal (CL) staining similar to the normal pattern, another 45 displayed membranous/cytoplasmic (MC) overexpression, and the remaining 10 revealed loss of expression. MC pattern or null staining of HCCs correlated with a higher histological grade and had a poorer prognosis than HCCs with a CL pattern (p<0.05). They also tended to have a poor prognosis by multivariate survival analysis. The ABCB1 promoter was hypomethylated regardless of MDR1 expression or ABCB1 mRNA levels in 10 HCC cell lines. Histone deacetylase inhibitor treatment induced ABCB1 upregulation in 4 cell lines with low or moderate ABCB1 levels.
CONCLUSIONS
Our findings suggest that either an increase or a loss of MDR1 expression may contribute to the poor outcome of HCCs; histone deacetylation may be one of the epigenetic mechanisms directing the ABCB1 expression in HCCs.

Citations

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Preferential expression of prostate specific membrane in CD34 labeled Neo-vasculature of Hepatocellular carcinoma: Prognostic and therapeutic potentials
Safaa MM Abd El Khalek, Mona QR Mohammed, Amira M Al Balakosy
Egyptian Journal of Pathology.2023; 43(1): 66. CrossRef

Case Report

Adrenal Cortical Adenoma Developed in Adrenohepatic Fusion, a Mimicry of Hepatocellular Carcinoma: A Case Report.: Sun A Kim, Young Joo Lee, Kyoung Won Kim, Gyungyub Gong; Korean J Pathol. 2011;45(2):196-200.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.2.196

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Abstract PDF

Adrenohepatic fusion is the union of the liver and adrenal gland with close intermingling of their respective parenchymal cells. Adrenal cortical adenoma arising in adrenohepatic fusion tissue is extremely rare, although adrenohepatic fusion itself is relatively common. Here we report a case of a 59-year-old man with a mass in the right lobe of his liver. The mass showed slight hyperattenuation during arterial phase and hypoattenuation during portal phase on dynamic computed tomography with contrast enhancement. On pathology, the mass consisted of round to polygonal cells with clear microvesicular or eosinophilic cytoplasm, arranged in nests or in a trabecular pattern. The tumor cells were positive for inhibin and melan-A, but negative for Hep Par-1. In the periphery of the mass, adrenohepatic fusion was identified between the liver and adrenal gland, and was simultaneously resected with the mass. We report this rare case, and discuss its clinical implications, especially the differential diagnosis with hepatocellular carcinoma.

Citations

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Adrenal cortical adenoma arising in an adreno-hepatic fusion: Case report and literature review of a potential diagnostic pitfall
Adam Stenman, Ivan Shabo, Jan Zedenius, C. Christofer Juhlin
Human Pathology Reports.2022; 29: 300656. CrossRef
Intrahepatic adrenocortical adenoma arising from adrenohepatic fusion mimicking hepatic malignancy
Yong Soo Cho, Jin Woong Kim, Hyun Ju Seon, Ju-Yeon Cho, Jun-Hee Park, Hyung Joong Kim, Yoo Duk Choi, Young Hoe Hur
Medicine.2019; 98(23): e15901. CrossRef
Direct and indirect imaging features of adrenohepatic fusion
Jung Jae Park, Byung Kwan Park, Chan Kyo Kim
Abdominal Radiology.2016; 41(2): 377. CrossRef

Original Article

The Expression of Apolipoprotein D in Hepatocellular Carcinoma.: Hongxiu Han, Chan Kum Park; Korean J Pathol. 2010;44(2):187-190.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.2.187

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Abstract PDF: BACKGROUND
Apolipoprotein D (Apo D) has recently been identified as a novel tumor suppressor gene. Apo D may have a profound effect on the carcinogenesis and progression of hepatocellular carcinoma. This study was designed to evaluate the expression of Apo D in hepatocellular carcinoma and to investigate the relationship between the expression of Apo D and the clinicopathological characteristics and the patients' survival.
METHODS
An immunohistochemical study was performed on the tumors and tissues from 43 hepatocellular carcinoma (HCC) patients with controls to determine the expression of Apo D protein.
RESULTS
Our data showed that a higher expression of Apo D was seen in 10 of 43 cases (23.3%), while a lower and no expression of Apo D was observed in 28 of 43 cases (65.1%) and 5 of 43 cases (11.6%), respectively. A reduced expression of Apo D was correlated with the tumor stage (p = 0.037) and tumor size (p = 0.017). However, the patients' 5-year survival was not associated with the expression of Apo D (p = 0.903).
CONCLUSIONS
The results suggest that a reduced Apo D protein expression may play an important role in HCC progression as associated with the tumor stage and size, but it does not affect the survival of HCC patients.

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