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Kuwano A, Tanaka K, Takahira J, Suzuki H, Ohishi Y, Motomura K. WNT/β-catenin Signaling and CD8+ Tumor-infiltrating Lymphocytes in Tremelimumab Plus Durvalumab for Advanced Hepatocellular Carcinoma. In Vivo 2024; 38:2774-2781. [PMID: 39477407 PMCID: PMC11535945 DOI: 10.21873/invivo.13757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 11/07/2024]
Abstract
BACKGROUND/AIM Tremelimumab plus durvalumab is an approved first-line therapy for advanced hepatocellular carcinoma (HCC). Previous studies identified WNT/β-catenin mutations or CD8+ tumor-infiltrating lymphocytes (TILs) as biomarkers that can predict responsiveness to immune checkpoint inhibitor therapy in HCC. However, biomarkers for effectiveness of tremelimumab plus durvalumab in HCC have not been reported. This study investigated whether evaluation of WNT/β-catenin signaling and CD8+ TILs by immunohistochemical staining of tumor biopsy tissues can predict the response to tremelimumab plus durvalumab in patients with HCC. PATIENTS AND METHODS Fifteen HCC patients who underwent tumor biopsies were classified into three groups based on WNT/β-catenin signal activation and CD8+ TIL infiltration. The clinical responses to treatment in the groups were evaluated. RESULTS Four patients had HCC with WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration, four patients had HCC with WNT/β-catenin signal activation and low-level CD8+ TIL infiltration, and seven patients had WNT/β-catenin signal activation and high-level CD8+ TIL infiltration or WNT/β-catenin signal inactivation and low-level CD8+ TIL infiltration. A better response rate was observed in the WNT/β-catenin signal inactivation and high-level CD8+ TIL infiltration group, and a worse response rate was observed in the WNT/β-catenin signal activation and low-level CD8+ TIL infiltration group. CONCLUSION Although the present study involved a small number of patients, the findings suggest that the efficacy of tremelimumab plus durvalumab may be affected by WNT/β-catenin signaling and CD8+ TIL infiltration.
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MESH Headings
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/drug effects
- Lymphocytes, Tumor-Infiltrating/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Male
- Wnt Signaling Pathway/drug effects
- Female
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/metabolism
- Middle Aged
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/therapeutic use
- Aged
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Neoplasm Staging
- Treatment Outcome
- Adult
- beta Catenin/genetics
- beta Catenin/metabolism
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Affiliation(s)
- Akifumi Kuwano
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
| | - Kosuke Tanaka
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan;
| | - Junro Takahira
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
| | - Hideo Suzuki
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
| | - Yoshihiro Ohishi
- Department of Diagnostic Pathology, Aso Iizuka Hospital, Iizuka, Japan
| | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Japan
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2
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Choi JH, Thung SN. Pathology and diagnostic approaches to well-differentiated hepatocellular lesions: a narrative review. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2024; 42:5. [PMID: 39442859 PMCID: PMC11812079 DOI: 10.12701/jyms.2024.00766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/09/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024]
Abstract
Well-differentiated hepatocellular lesions (WDHLs) are liver tumors or nonneoplastic lesions in which the cells closely resemble normal hepatocytes. These lesions often include focal nodular hyperplasia, hepatocellular adenoma, macroregenerative nodule, dysplastic nodule, and well-differentiated hepatocellular carcinoma. The diagnosis of these lesions remains challenging because of their morphological similarities, particularly when examined using needle biopsy. The accurate diagnosis of WDHLs is crucial for patient management and prognosis. This review addresses the histopathological characteristics and diagnostic approaches of WDHLs.
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Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea
| | - Swan N. Thung
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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3
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Gedekar P, Chavhan A, Hiwale KM, Sagar S. A Case Presentation of Well-Differentiated Hepatocellular Carcinoma With No Sign of Liver Disease. Cureus 2024; 16:e61635. [PMID: 38966460 PMCID: PMC11223716 DOI: 10.7759/cureus.61635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 06/04/2024] [Indexed: 07/06/2024] Open
Abstract
The type of liver cancer that occurs most frequently is hepatocellular carcinoma (HCC). The majority of cases of HCC are secondary to alcoholic cirrhosis or viral hepatitis. The presence of malignant cells with modest nuclear atypia that resemble normal hepatocytes and the lack of bare nuclei in the smears, which shows the neoplastic hepatocytes' capacity, are characteristics of a well-differentiated HCC plasma membrane to tolerate smearing. We present the case of an 83-year-old male patient with a well-differentiated HCC, who had no etiological factors and no signs of alcohol cirrhotic liver, or any symptoms of liver disease which are the main causes of the HCC.
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Affiliation(s)
- Prachi Gedekar
- Medicine, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Atul Chavhan
- Pathology, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - K M Hiwale
- Pathology, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Shakti Sagar
- Pathology, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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4
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Sun C, Pan Q, Du M, Zheng J, Bai M, Sun W. Decoding the roles of heat shock proteins in liver cancer. Cytokine Growth Factor Rev 2024; 75:81-92. [PMID: 38182465 DOI: 10.1016/j.cytogfr.2023.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/07/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal malignancies, characterized by insidious onset and high propensity for metastasis and recurrence. Apart from surgical resection, there are no effective curative methods for HCC in recent years, due to resistance to radiotherapy and chemotherapy. Heat shock proteins (HSP) play a crucial role in maintaining cellular homeostasis and normal organism development as molecular chaperones for intracellular proteins. Both basic research and clinical data have shown that HSPs are crucial participants in the HCC microenvironment, as well as the occurrence, development, metastasis, and resistance to radiotherapy and chemotherapy in various malignancies, particularly liver cancer. This review aims to discuss the molecular mechanisms and potential clinical value of HSPs in HCC, which may provide new insights for HSP-based therapeutic interventions for HCC.
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Affiliation(s)
- Chen Sun
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Qi Pan
- Department of Hepatobiliary Surgery and Organ Transplantation, First Hospital of China Medical University, Shenyang 110004, China
| | - Mingyang Du
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Jiahe Zheng
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Ming Bai
- Second Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
| | - Wei Sun
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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5
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Wang J, Zhang J, Guo Z, Hua H, Zhang H, Liu Y, Jiang Y. Targeting HSP70 chaperones by rhein sensitizes liver cancer to artemisinin derivatives. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 122:155156. [PMID: 37897861 DOI: 10.1016/j.phymed.2023.155156] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/15/2023] [Accepted: 10/17/2023] [Indexed: 10/30/2023]
Abstract
BACKGROUND Liver cancer is one of common types of cancer with poor prognosis and limited therapies. Heat shock proteins (HSP) are molecular chaperones that have important roles in tumorigenesis, and emerging as therapeutic targets. Artemisinin and rhein are natural agents from Artemisia annua L. and Rheum undulatum L., respectively. Both rhein and artemisinin have anticancer effects; however, the molecular targets of rhein remain to be identified. It is also unclear whether rhein can synergize with artemisinin derivatives to inhibit liver cancer. PURPOSE We aim to identify the targets of rhein in the treatment of hepatocarcinoma and determine the effects of combining rhein and artemisinin derivatives on liver cancer cells. METHODS The targets of rhein were detected by mass spectrometry and validated by rhein-proteins interaction assays. The effects of rhein on the chaperone activity of HSP72/HSC70/GRP78 were determined by luciferase refolding assays. Cell viability and apoptosis were determined by CCK8 and flow cytometry assays. For in vivo study, xenograft tumor models were established and treated with rhein and artesunate. Tumor growth was monitored regularly. RESULTS Mass spectrometry analysis of rhein-binding proteins in HepG2 cells revealed that HSP72, HSC70 and GRP78 were more profoundly pulled down by rhein-crosslinked sepharose 4B beads compared to the control beads. Further experiments demonstrated that rhein directly interacted with HSP72/HSC70/GRP78 proteins, and inhibit their activity of refolding denatured luciferase. Meanwhile, rhein induced proteasomal degradation of HIF1α and β-catenin. Artesunate or dihydroartemisinin in combination with knockdown of both HSP72 and HSC70 significantly inhibited cell viability. The HSP70/HSC70/GRP78 inhibitors VER-155,008 and rhein phenocopied HSP72/HSC70 knockdown, synergizing with artesunate or dihydroartemisinin to inhibit hepatocarcinoma cell viability. Combinatorial treatment with rhein and artemisinin derivatives significantly induced hepatocarcinoma cell apoptosis, and inhibited tumor growth in vivo. CONCLUSIONS The current study demonstrates that rhein is a novel HSP72/HSC70/GRP78 inhibitor that suppresses the chaperone activity of HSP70s. Dual inhibition of HSP72 and HSC70 can enhance the sensitivity of hepatocarcinoma cells to artemisinin derivatives. Combined treatment with artemisinin derivative and rhein significantly inhibits hepatocarcinoma. Artemisinin derivatives in combination with dual inhibition of HSP72 and HSC70 represents a new approach to improve cancer therapy.
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Affiliation(s)
- Jiao Wang
- Cancer center, Laboratory of Oncogene, West China Hospital, Sichuan University, China; School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, China
| | - Jin Zhang
- Cancer center, Laboratory of Oncogene, West China Hospital, Sichuan University, China
| | - Zeyu Guo
- Cancer center, Laboratory of Oncogene, West China Hospital, Sichuan University, China
| | - Hui Hua
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, China
| | - Hongying Zhang
- Cancer center, Laboratory of Oncogene, West China Hospital, Sichuan University, China
| | - Yongliang Liu
- Cancer center, Laboratory of Oncogene, West China Hospital, Sichuan University, China
| | - Yangfu Jiang
- Cancer center, Laboratory of Oncogene, West China Hospital, Sichuan University, China.
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6
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Jiang J, Hu Y, Fang D, Luo J. Glutamine synthetase and hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2023; 47:102248. [PMID: 37979911 DOI: 10.1016/j.clinre.2023.102248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/02/2023] [Accepted: 11/15/2023] [Indexed: 11/20/2023]
Abstract
Glutamine synthetase (GS) is an enzyme that converts ammonia and glutamate to glutamine using adenosine triphosphate. GS is expressed in the brain, kidney, and liver tissues under normal physiological conditions. GS is involved in abnormal lipid metabolism of the liver by catalyzing de novo synthesis of glutamine, thereby inducing liver inflammation. Metabolic dysfunction-associated steatotic liver diseases (MASLD), such as Metabolic Associated Fatty Liver Disease and Metabolic Associated Steato Hepatitis, are considered risk factors for HCC. GS may also be involved in the development and progression of hepatocellular carcinoma (HCC) through other signaling pathways, including the rapamycin (mTOR) and Wnt/β-catenin signaling pathways. Furthermore, the correct combination of HSP70, GPC3, and GS can improve the accuracy and precision of HCC diagnosis. However, the prognostic value of GS in different HCC populations remains controversial. The expression of GS affects the sensitivity of HCC cells to radiotherapy and chemotherapy. In addition, immunotherapy has been approved for the treatment of advanced HCC. This article delves into the development and application of GS in HCC, laying a theoretical foundation for the subsequent exploration of GS as a potential target for treating HCC.
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Affiliation(s)
- Jinghua Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - Yiting Hu
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University, Shulan International Medical College, Hangzhou, Zhejiang, China
| | - Dazhang Fang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - JianSheng Luo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China.
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7
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Nassar-Reis JP, Umeta PF, Stefano JT, Longatto-Filho A, Carrilho FJ, Alves VAF, Cogliati B, Oliveira CP. P53 and VEGF are promising biomarkers for sorafenib efficacy in an experimental model of NASH-related HCC. J Mol Histol 2023; 54:473-488. [PMID: 37605073 DOI: 10.1007/s10735-023-10142-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 07/23/2023] [Indexed: 08/23/2023]
Abstract
The efficacy of systemic therapy for hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is poorly understood. In this study we evaluated the effects of sorafenib based on the expression of molecular markers related to major hepatocarcinogenesis pathways and angiogenesis in a NASH-related HCC model. Forty male rats were submitted to NASH-HCC induction through the combination of a high-fat and choline deficient diet and diethylnitrosamine (100 mg/L) administration in the drinking water for 13 and 16 weeks. After the induction period, the rats received daily gavage administration of saline solution (control) or Sorafenib (5 mg/kg/day) for 3 weeks. Thereafter, the animals were euthanized and samples from liver nodules were collected for histopathological analysis and immunohistochemical assessment of HEP-PAR-1, glutamine-synthetase, VEGF, survivin, β-catenin and p53. A semi-quantitative score was used for VEGF, survivin and β-catenin analysis. For p53, the percentage of positive cells was determined. Results were processed by Wilcoxon's test or Student's t-test. Both protocols efficiently induced HCC, most of them being moderately to poorly differentiated. Sorafenib-treated animals showed a decreased expression of VEGF and p53 in HCCs generated at 13 weeks when compared to control animals (p = 0.03; p = 0.04, respectively). No significant difference in β-catenin and survivin were observed. There was a significant decrease in VEGF and p53 expression when comparing the two control groups (13 vs. 16 weeks, p < 0.01). p53 and VEGF are promising biomarkers for assessment of efficacy of Sorafenib, whereas survivin and β-catenin were not found useful. Decreased immunohistochemical expression of p53 and VEGF in the 16 week control group may indicate a different metabolic status of HCC.
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Affiliation(s)
- João Pedro Nassar-Reis
- Laboratory of Experimental and Comparative Liver Research (Liver Lab), Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, 05508-270, Brazil
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, 01246-903, Brazil
| | - Pedro Fukui Umeta
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, 01246-903, Brazil
| | - José Tadeu Stefano
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, 01246-903, Brazil
| | - Adhemar Longatto-Filho
- Department of Pathology (LIM-14), University of São Paulo School of Medicine, São Paulo, 05808-010, Brazil
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, 4704-553, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, 4710-057, Braga, Portugal
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, 14784-400, Brazil
| | - Flair José Carrilho
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, 01246-903, Brazil
| | | | - Bruno Cogliati
- Laboratory of Experimental and Comparative Liver Research (Liver Lab), Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, 05508-270, Brazil
| | - Claudia P Oliveira
- Laboratório de Gastroenterologia Clínica e Experimental (LIM-07), Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, 01246-903, Brazil.
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Poté N, Caruso S, Caderaro J, Cauchy F, Lagadec F, Couchy G, Raffenne J, Augustin J, Vernuccio F, Vilgrain V, Hercent A, Theou-Anton N, Zucman-Rossi J, Paradis V. Borderline Hepatocellular Adenomas: A Practical Diagnostic Approach Based on Pathologic and Molecular Features. Mod Pathol 2023; 36:100211. [PMID: 37169258 DOI: 10.1016/j.modpat.2023.100211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 04/24/2023] [Accepted: 05/03/2023] [Indexed: 05/13/2023]
Abstract
Borderline hepatocellular adenomas (BL-HCA) are characterized by focal architectural/cytologic atypia and reticulin loss, features that are insufficient for a definitive diagnosis of hepatocellular carcinoma (HCC). The diagnosis and management of BL-HCA are challenging as their biological behavior, especially in terms of malignant potential, is still debated. We aimed to compare the clinicopathologic and molecular features of BL-HCA with those of typical HCA (T-HCA), HCA with malignant transformation (HCC on HCA), and HCC to assess the risk of malignancy. One hundred six liver resection specimens were retrospectively selected from 2 reference centers, including 39 BL-HCA, 42 T-HCA, 12 HCC on HCA, and 13 HCC specimens. Somatic mutations, including TERT promoter mutations associated with HCA malignant transformation and the gene expression levels of 96 genes, were investigated in 93 frozen samples. Additionally, TERT promoter mutations were investigated in 44 formalin-fixed, paraffin-embedded samples. The clinical features of patients with BL-HCA were similar to those of patients with T-HCA, patients being mainly women (69%) with a median age of 37 years. The median tumor size was 7.5 cm, 64% of patients had a single nodule, and no recurrence was observed. Compared with T-HCA, BL-HCA was significantly enriched in β-catenin-mutated HCA in exon 3 (41% vs 6%; P < .001). Unsupervised statistical analysis based on gene expression showed that BL-HCA overlapped with T-HCA and HCC on HCA, favoring a molecular continuum of the tumors. TERT promoter mutations were observed only in HCC on HCA (42%) and in HCC (38%). In conclusion, these results suggest that despite their worrisome morphologic features, the clinicopathologic and molecular features of BL-HCA are much closer to those of T-HCA than those of HCC on HCA or HCC. This strongly supports the usefulness of combining morphologic and molecular analyses in a practical diagnostic approach for guiding the management of BL-HCA.
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Affiliation(s)
- Nicolas Poté
- Université Paris Cité, INSERM UMR-1149, Paris, France; Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.
| | - Stefano Caruso
- Centre de Recherche des Cordeliers, Sorbonne Université-Université Paris Cité, INSERM, Paris, France; Team Fungest, Equipe labellisée Ligue Nationale Contre le Cancer, Labex immuno-Oncology, Paris, France
| | - Julien Caderaro
- Department of Pathology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France; Team 18, Faculté de Médecine, Université Paris-Est Créteil, INSERM UMR-955, Institut Mondor de Recherche Biomédicale, Créteil, France
| | - François Cauchy
- Department of Hepatobiliary Surgery and Liver Transplantation, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Floriane Lagadec
- Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Gabrielle Couchy
- Centre de Recherche des Cordeliers, Sorbonne Université-Université Paris Cité, INSERM, Paris, France; Team Fungest, Equipe labellisée Ligue Nationale Contre le Cancer, Labex immuno-Oncology, Paris, France
| | | | - Jeremy Augustin
- Department of Pathology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Federica Vernuccio
- Department of Radiology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Valérie Vilgrain
- Université Paris Cité, INSERM UMR-1149, Paris, France; Department of Radiology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Agathe Hercent
- Department of Genetics, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Nathalie Theou-Anton
- Department of Genetics, Bichat Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université-Université Paris Cité, INSERM, Paris, France; Team Fungest, Equipe labellisée Ligue Nationale Contre le Cancer, Labex immuno-Oncology, Paris, France; Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Valérie Paradis
- Université Paris Cité, INSERM UMR-1149, Paris, France; Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France
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9
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Umetsu SE, Kakar S. Evaluating Liver Biopsies with Well-Differentiated Hepatocellular Lesions. Surg Pathol Clin 2023; 16:581-598. [PMID: 37536890 DOI: 10.1016/j.path.2023.04.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
Needle core biopsies of liver lesions can be challenging, particularly in cases with limited material. The differential diagnosis for well-differentiated hepatocellular lesions includes focal nodular hyperplasia, hepatocellular adenoma, and well-differentiated hepatocellular carcinoma (HCC) in noncirrhotic liver, while dysplastic nodules and well-differentiated HCC are the primary considerations in cirrhotic liver. The first part of this review focuses on histochemical and immunohistochemical stains as well as molecular assays that are useful in the differential diagnosis. The second portion describes the features of hepatocellular adenoma subtypes and focuses on the differential diagnoses in commonly encountered clinicopathologic scenarios.
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Affiliation(s)
- Sarah E Umetsu
- Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, Box 0102, San Francisco, CA 94143, USA.
| | - Sanjay Kakar
- Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, Box 0102, San Francisco, CA 94143, USA
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10
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Pagarigan AKL, Mendoza PGL. Adult hepatoblastoma: making the challenging distinction from hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:219-224. [PMID: 37384033 PMCID: PMC10202245 DOI: 10.17998/jlc.2023.02.24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 06/30/2023]
Abstract
Hepatoblastoma is an exceptionally rare malignancy in adults with just over 70 non-pediatric cases reported in literature. Recounted is a case of a 49-year-old female who presented with acute right upper quadrant abdominal pain, elevated serum alpha fetoprotein and a large liver mass on imaging. Hepatectomy was performed under clinical suspicion of hepatocellular carcinoma. Immunomorphologic characteristics of the tumor proved consistent with hepatoblastoma of mixed epithelial and mesenchymal type. Hepatocellular carcinoma remains to be the primary differential diagnosis for adult hepatoblastoma, however, distinguishing between these two neoplasms requires close histomorphologic assessment and immunohistochemical profiling as clinical, radiologic and gross pathologic findings typically overlap. Making this distinction is highly crucial in the timely initiation of surgical and chemotherapeutic interventions for this inherently aggressive and rapidly fatal disease.
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Affiliation(s)
- Allison Kaye L. Pagarigan
- Department of Pathology and Laboratory Medicine, National Kidney and Transplant Institute, Quezon City, Philippines
| | - Paulo Giovanni L. Mendoza
- Department of Pathology and Laboratory Medicine, National Kidney and Transplant Institute, Quezon City, Philippines
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11
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Luo L, Wang T, Cheng M, Ge X, Song S, Zhu G, Xiao Y, Deng W, Xie J, Shan R. Rare benign liver tumors that require differentiation from hepatocellular carcinoma: focus on diagnosis and treatment. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04169-w. [PMID: 35789428 DOI: 10.1007/s00432-022-04169-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 06/21/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND/AIM Recently, an increase in the number of asymptomatic rare benign liver tumors (BLTs) has been reported during health check-ups. It is difficult to determine the nature of partial rare BLTs and not easy to distinguish from malignant liver tumors. This study aimed to analysis clinical features, diagnosis and treatment of rare BLTs to reduce misdiagnosis and provide reference for clinical practice. METHODS From January 2012 to January 2021, we treated 112 rare BLTs by hepatectomy, including 54 focal nodular hyperplasias, 14 hepatocellular adenomas, 28 hepatic angiomyolipomas, 3 hepatic granulomas, 2 inflammatory pseudotumors of the liver, 2 nodular regenerative hyperplasia, 2 hepatic lipomas, 1 solitary fibrous tumor of the liver, 1 hepatic schwannoma and 1 hepatic myelolipoma. RESULTS The majority of patients were middle-aged female and asymptomatic. Single tumors were dominant. The diagnostic accuracies of computed tomography (CT) and magnetic resonance imaging (MRI) were 32.5% and 44.2%, respectively. The majority of tumors were likely to be misdiagnosed as hepatocellular carcinoma (HCC) or difficult to distinguish from HCC. All patients underwent surgical treatment. Postoperative pathological and immunohistochemical examination can confirm the diagnosis. No patients without tumor recurrence or metastasis during follow-up period. CONCLUSION Altogether, the clinical symptoms of rare BLTs lack specificity, and their preoperative diagnosis largely depends on imaging examination, with a low diagnostic accuracy rate and high chances of misdiagnosis as HCC. Diagnosis is confirmed by pathological and immunohistochemical examination. Surgical resection for rare BLT is safe and effective, regular postoperative follow-up is necessary.
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Affiliation(s)
- Laihui Luo
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Tao Wang
- Department of Day Surgery Ward, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Mengting Cheng
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Xian Ge
- Department of Pathology, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Shengjiang Song
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Guoqing Zhu
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Yongqiang Xiao
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Wei Deng
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Jin Xie
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Renfeng Shan
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China.
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12
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Cheng N, Ren Y, Zhou J, Zhang Y, Wang D, Zhang X, Chen B, Liu F, Lv J, Cao Q, Chen S, Du H, Hui D, Weng Z, Liang Q, Su B, Tang L, Han L, Chen J, Shao C. Deep Learning-Based Classification of Hepatocellular Nodular Lesions on Whole-Slide Histopathologic Images. Gastroenterology 2022; 162:1948-1961.e7. [PMID: 35202643 DOI: 10.1053/j.gastro.2022.02.025] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 12/21/2021] [Accepted: 02/15/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Hepatocellular nodular lesions (HNLs) constitute a heterogeneous group of disorders. Differential diagnosis among these lesions, especially high-grade dysplastic nodules (HGDNs) and well-differentiated hepatocellular carcinoma (WD-HCC), can be challenging, let alone biopsy specimens. We aimed to develop a deep learning system to solve these puzzles, improving the histopathologic diagnosis of HNLs (WD-HCC, HGDN, low-grade DN, focal nodular hyperplasia, hepatocellular adenoma), and background tissues (nodular cirrhosis, normal liver tissue). METHODS The samples consisting of surgical and biopsy specimens were collected from 6 hospitals. Each specimen was reviewed by 2 to 3 subspecialists. Four deep neural networks (ResNet50, InceptionV3, Xception, and the Ensemble) were used. Their performances were evaluated by confusion matrix, receiver operating characteristic curve, classification map, and heat map. The predictive efficiency of the optimal model was further verified by comparing with that of 9 pathologists. RESULTS We obtained 213,280 patches from 1115 whole-slide images of 738 patients. An optimal model was finally chosen based on F1 score and area under the curve value, named hepatocellular-nodular artificial intelligence model (HnAIM), with the overall 7-category area under the curve of 0.935 in the independent external validation cohort. For biopsy specimens, the agreement rate with subspecialists' majority opinion was higher for HnAIM than 9 pathologists on both patch level and whole-slide images level. CONCLUSIONS We first developed a deep learning diagnostic model for HNLs, which performed well and contributed to enhancing the diagnosis rate of early HCC and risk stratification of patients with HNLs. Furthermore, HnAIM had significant advantages in patch-level recognition, with important diagnostic implications for fragmentary or scarce biopsy specimens.
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Affiliation(s)
- Na Cheng
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yong Ren
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China; Center for Artificial Intelligence in Medicine, Research Institute of Tsinghua, Pearl River Delta, Guangzhou, China
| | - Jing Zhou
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yiwang Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Deyu Wang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaofang Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bing Chen
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University Yuedong Hospital, Meizhou, China
| | - Fang Liu
- Department of Pathology, FoShan First People's Hospital, Foshan, China
| | - Jin Lv
- Department of Pathology, FoShan First People's Hospital, Foshan, China
| | - Qinghua Cao
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sijin Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hong Du
- Department of Pathology, GuangZhou First People's Hospital, Guangzhou, China
| | - Dayang Hui
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zijin Weng
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiong Liang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bojin Su
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Luying Tang
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University Lingnan Hospital, Guangzhou, China
| | - Lanqing Han
- Center for Artificial Intelligence in Medicine, Research Institute of Tsinghua, Pearl River Delta, Guangzhou, China.
| | - Jianning Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Chunkui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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13
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Kuwano A, Yada M, Narutomi F, Nagasawa S, Tanaka K, Kurosaka K, Ohishi Y, Masumoto A, Motomura K. Therapeutic efficacy of atezolizumab plus bevacizumab for hepatocellular carcinoma with WNT/β‑catenin signal activation. Oncol Lett 2022; 24:216. [PMID: 35720502 PMCID: PMC9178725 DOI: 10.3892/ol.2022.13337] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 04/27/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Akifumi Kuwano
- Department of Hepatology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
| | - Masayoshi Yada
- Department of Hepatology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
| | - Fumiya Narutomi
- Department of Diagnostic Pathology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
| | - Shigehiro Nagasawa
- Department of Hepatology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
| | - Kosuke Tanaka
- Department of Hepatology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
| | - Kazuki Kurosaka
- Department of Hepatology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
| | - Yoshihiro Ohishi
- Department of Diagnostic Pathology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
| | - Akihide Masumoto
- Department of Hepatology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
| | - Kenta Motomura
- Department of Hepatology, Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan
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14
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Bioulac-Sage P, Gouw ASH, Balabaud C, Sempoux C. Hepatocellular Adenoma: What We Know, What We Do Not Know, and Why It Matters. Histopathology 2021; 80:878-897. [PMID: 34856012 DOI: 10.1111/his.14605] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/21/2021] [Accepted: 11/25/2021] [Indexed: 11/27/2022]
Abstract
In the last 2 decades there has been significant progress in research and diagnosis of hepatocellular adenoma (HCA), resulting in the establishment of a molecular and immunohistological HCA classification. This review aims to fine-tune the current expertise in order to enhance the histopathological diagnostic possibilities, by refining issues that are already known, addressing diagnostic difficulties and identifying still unknown aspects of HCA. We will discuss novel methods to identify HCA subtypes, in particular the sonic hedgehog HCAs and the interpretation of glutamine synthetase patterns for the recognition of beta-catenin mutated HCAs. The major complications of HCAs, bleeding and malignant transformation, will be considered, including the dilemmas of atypical and borderline lesions. Paragraphs on HCAs in different clinical and geographical settings, e.g. pregnancy, cirrhosis and non-western countries are included. The natural history of the different HCA subtypes in relation with age, sex and risk factors is a feature still insufficiently investigated. This is also true for the risks of clinical bleeding and malignant transformation in association with HCA subtypes. As HCA is a relatively rare tumor, a multicenter and multidisciplinary approach across geographical boundaries will be the appropriate method to establish prospective programs to identify, classify and manage HCAs, focusing on several aspects, e.g. etiology, underlying liver disease, complications, regression and growth. Updating what we know, identifying and addressing features that we do not know matters to warrant optimal patient management.
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Affiliation(s)
| | - Annette S H Gouw
- Departement of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
| | | | - Christine Sempoux
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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15
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Yasunaka T, Takeuchi Y, Takaki A, Kondo F, Yoshizumi T, Kohashi K, Oyama A, Adachi T, Wada N, Onishi H, Shiraha H, Okada H. A case of focal nodular hyperplasia with hepatic failure treated with liver transplantation. Clin J Gastroenterol 2021; 15:171-176. [PMID: 34807397 DOI: 10.1007/s12328-021-01529-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 09/30/2021] [Indexed: 12/18/2022]
Abstract
Focal nodular hyperplasia (FNH) is a benign nodular lesion, but because of its feature of portal tract vessel abnormality, it may induce portal hypertension. A 27-year-old woman was admitted with a fever. A large nodule with satellite lesions was found in the liver and cotton wool-like feature of arteries were detected on angiography. Technetium galactosyl serum albumin scintigraphy and diagnostic laparoscopy showed that the tumor site was functional, while the surrounding area was a non-functional fibrotic area. A biopsy specimen indicated that the nodular lesion was an FNH-like lesion. She experienced several instances of variceal rupture and suffered liver failure, receiving liver transplantation. The excised liver showed a centrally scarred area in the nodule, indicating that the diagnosis was FNH. We herein report this case as a rare case of FNH that progressed to liver failure.
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Affiliation(s)
- Tetsuya Yasunaka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yasuto Takeuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
| | - Fukuo Kondo
- Department of Pathology, School of Medicine, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Atsushi Oyama
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Takuya Adachi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Nozomu Wada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Hideki Onishi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Hidenori Shiraha
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
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16
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Application of Immunohistochemistry in the Pathological Diagnosis of Liver Tumors. Int J Mol Sci 2021; 22:ijms22115780. [PMID: 34071338 PMCID: PMC8198626 DOI: 10.3390/ijms22115780] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/22/2021] [Accepted: 05/23/2021] [Indexed: 12/17/2022] Open
Abstract
Although radiological diagnostics have been progressing, pathological diagnosis remains the most reliable method for diagnosing liver tumors. In some cases, definite pathological diagnosis cannot be obtained by histological evaluation alone, especially when the sample is a small biopsy; in such cases, immunohistochemical staining is very useful. Immunohistochemistry is the most frequently used technique for molecular pathological diagnosis due to its broad application, ease of performance and evaluation, and reasonable cost. The results occasionally reflect specific genetic mutations. The immunohistochemical markers of hepatocellular carcinoma include those of hepatocellular differentiation—such as hepatocyte paraffin 1 and arginase-1—and those of malignant hepatocytes—such as glypican-3, heat shock protein 70, and glutamine synthetase (GS). To classify the subtypes of hepatocellular adenoma, examination of several immunohistochemical markers, such as liver fatty acid-binding protein, GS, and serum amyloid A, is indispensable. Immunohistochemical staining for GS is also important for the diagnosis of focal nodular hyperplasia. The representative immunohistochemical markers of intrahepatic cholangiocarcinoma include cytokeratin (CK) 7 and CK19. In this article, we provide an overview of the application of immunohistochemistry in the pathological diagnosis of liver tumors referring to the association with genetic alterations. Furthermore, we aimed to explain the practical points in the differential diagnosis of liver tumors by immunohistochemical staining.
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17
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Predictive Patterns of Glutamine Synthetase Immunohistochemical Staining in CTNNB1-mutated Hepatocellular Adenomas. Am J Surg Pathol 2021; 45:477-487. [PMID: 33560657 DOI: 10.1097/pas.0000000000001675] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Some hepatocellular adenoma (HCA) subtypes are characterized by different CTNNB1 mutations, leading to different beta-catenin activation levels, hence variable immunostaining patterns of glutamine synthetase (GS) expression, and different risks of malignant transformation. In a retrospective multicentric study of 63 resected inflammatory (n=33) and noninflammatory (n=30) molecularly confirmed CTNNB1-mutated b-(I)HCA, we investigated the predictive potential of 3 known GS patterns as markers for CTNNB1 exon 3, 7/8 mutations. Pattern 1 (diffuse homogenous) allowed recognition of 17/21 exon 3 non-S45 mutated b-(I)HCA. Pattern 2 (diffuse heterogenous) identified all b-(I)HCA harboring exon 3 S45 mutation (20/20). Pattern 3 (focal patchy) distinguished 12/22 b-(I)HCA with exon 7/8 mutations. In exon 3 S45 and 7/8 mutations, both b-HCA and b-IHCA showed a GS+/CD34- rim with diffuse CD34 positivity in the center of the lesion. Interobserver reproducibility was excellent for exon 3 mutations. Comparative analysis of GS patterns with molecular data showed 83% and 80% sensitivity (b-HCA/b-IHCA) and 100% specificity for exon 3 non-S45. For exon 3 S45, sensitivity was 100% for b-(I)HCA, and specificity 93% and 92% (b-HCA/b-IHCA). For exon 7/8, sensitivity was 55% for both subtypes and specificity 100% and 96% (b-HCA/b-IHCA). Preliminary data from 16 preoperative needle biopsies from the same patients suggest that this panel may also be applicable to small samples. In surgically resected HCA, 2 distinct GS patterns can reliably predict CTNNB1 exon 3 mutations, which are relevant because of the higher risk for malignant transformation. The third pattern, although specific, was less sensitive for the identification of exon 7/8 mutation, but the GS+/CD34- rim is a valuable aid to indicate either an exon 3 S45 or exon 7/8 mutation.
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18
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Yasir S, Chen ZE, Said S, Wu TT, Torbenson M. Biopsies of hepatocellular carcinoma with no reticulin loss: an important diagnostic pitfall. Hum Pathol 2021; 107:20-28. [PMID: 33039370 PMCID: PMC9177079 DOI: 10.1016/j.humpath.2020.09.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/24/2020] [Accepted: 09/27/2020] [Indexed: 12/30/2022]
Abstract
The reticulin stain is a critical diagnostic aide used to differentiate benign hepatocellular proliferations from well differentiated hepatocellular carcinoma (HCC). Rarely, however, hepatocellular carcinomas do not show definitive loss of reticulin in liver biopsy specimens. To study this group of tumors, 11 HCC with no reticulin loss in 10 patients were collected and studied. Analysis of demographics showed a typical enrichment for men with a typical age for HCC presentation of 69 ± 7 years for adults. The background livers showed advanced fibrosis or cirrhosis in 6 of 6 cases with available information. The tumors were all well differentiated. Cytological atypia was mild and consisted of very mild nuclear atypia (8 cases), mild increase in N:C ratio (3 cases), and pseudorosette formation (4 cases). The cytological/architectural atypia was insufficient in isolation to diagnose HCC. Additional studies, however, showed an increased Ki-67 proliferative rate (N = 10/10 stained cases). The Ki-67 proliferative rate was estimated to be between 5 and 10% in all tested cases and was clearly increased from adjacent liver at low power. Glypican 3 positivity (4 tumors) and alpha fetoprotein (AFP) (1/8 stained cases) positivity also helped make the diagnosis of HCC. Morphologically, the HCC had conventional morphology with five showing steatosis/steatohepatitic features and one showing intratumoral fibrosis. A control group of macroregenerative/dysplastic nodules showed no increase in Ki-67 proliferation and no staining for glypican 3. These findings highlight an important diagnostic pitfall: rare HCC show no reticulin loss on biopsy. In these challenging cases, additional findings are useful to make a diagnosis of HCC: increased Ki-67 and positive staining for aberrant expression of proteins such as glypican 3 or AFP.
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Affiliation(s)
- Saba Yasir
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA
| | - Zongming Eric Chen
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA
| | - Samar Said
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA
| | - Tsung-Teh Wu
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA
| | - Michael Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA.
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19
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Ren X, Dong Y, Duan M, Zhang H, Gao P. Abnormal expression of HNRNPA3 in multistep hepatocarcinogenesis. Oncol Lett 2020; 21:46. [PMID: 33281957 PMCID: PMC7709557 DOI: 10.3892/ol.2020.12307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 09/08/2020] [Indexed: 12/30/2022] Open
Abstract
Hepatocarcinogenesis is a multistep process involving progression from cirrhosis, to low-grade dysplastic nodule, to high-grade dysplastic nodule (HGDN) and, eventually, to hepatocellular carcinoma (HCC). Early detection of HCC is challenging as the differential diagnosis between HGDN and early HCC (eHCC) is difficult. The aim of the present study was to identify a novel biomarker to specifically differentiate between HGDN and eHCC, which may facilitate early diagnosis of HCC. Immunohistochemistry was performed to determine the expression of heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) in cirrhosis, dysplastic nodules (DNs), well-differentiated HCC and progressed HCC. The staining was evaluated by assigning a staining intensity score of 0–3 and a percentage of positively stained cells score of 0–4. Receiver operator characteristic (ROC) curve analysis was used to assess the ability of HNRNPA3 expression to differentiate between DNs and HCC. HNRNPA3 expression increased in a stepwise trend in non-tumor hepatic tissue, DNs, eHCC and progressed HCC. ROC curves revealed that HNRNPA3 expression could be used to differentiate between HGDN and eHCC, particularly in combination with glypican 3 (GPC3), with a specificity of 100%. Moreover, HNRNPA3 expression was associated with HCC differentiation. In addition, high expression of HNRNPA3 was found to be associated with poor survival rates in patients with HCC. These findings demonstrated that HNRNPA3 combined with GPC3 is a helpful diagnostic biomarker in the differential diagnosis during the multistep process of hepatocarcinogenesis, particularly in the differential diagnosis between HGDN and eHCC. To the best of our knowledge, this is the first study to report the significance of HNRNPA3 in hepatocarcinogenesis and its potential role in carcinogenesis.
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Affiliation(s)
- Xinlu Ren
- Department of Clinical Medicine, Queen Mary College of Nanchang University, Nanchang, Jiangxi 330031, P.R. China
| | - Yi Dong
- Key Laboratory for Experimental Teratology of The Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Miao Duan
- Key Laboratory for Experimental Teratology of The Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hui Zhang
- Key Laboratory for Experimental Teratology of The Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Peng Gao
- Key Laboratory for Experimental Teratology of The Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
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20
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Jones A, Kroneman TN, Blahnik AJ, Graham RP, Mounajjed T, Torbenson MS, Moreira RK. Ki-67 "hot spot" digital analysis is useful in the distinction of hepatic adenomas and well-differentiated hepatocellular carcinomas. Virchows Arch 2020; 478:201-207. [PMID: 32583014 DOI: 10.1007/s00428-020-02868-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/28/2020] [Accepted: 06/08/2020] [Indexed: 12/30/2022]
Abstract
This study aims to investigate the utility of digital protocols for Ki-67 immunohistochemistry quantitative analysis ("hot spot" method) in the setting of well-differentiated hepatocellular neoplasms. Resection cases of typical hepatic adenomas (HAs) (n = 40), atypical HAs (n = 9), and well-differentiated hepatocellular carcinomas (WD HCCs) (n = 56) were selected. HAs were further classified by immunohistochemistry using antibodies against liver fatty acid binding protein, glutamine synthetase, B-catenin, hepatic serum amyloid A, and C-reactive protein. Ki-67 proliferative index by immunohistochemistry was evaluated in all cases by digital analysis using a modified neuroendocrine tumor "hot spot" protocol. The proliferative rate of HAs (typical, median 1.2% (range 0-7.4%) and atypical, median 1.0% (range 0.3-3%)) was significantly lower than that of WD HCCs (median 4.5%, range 0-49.8%) (P < 0.0001). Only a few (7.5%) of the adenomas (all inflammatory/telangiectatic type) had proliferative rates higher than 4%, compared to most (51%) of HCCs. Ki-67 is a potentially useful adjunct marker in the evaluation of WD hepatocellular neoplasms, as "hot spot" proliferative rates are consistently very low in HAs but vary significantly in WD HCCs.
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Affiliation(s)
| | | | | | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Taofic Mounajjed
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Michael S Torbenson
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Roger K Moreira
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
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Gao YX, Yang TW, Yin JM, Yang PX, Kou BX, Chai MY, Liu XN, Chen DX. Progress and prospects of biomarkers in primary liver cancer (Review). Int J Oncol 2020; 57:54-66. [PMID: 32236573 DOI: 10.3892/ijo.2020.5035] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/17/2020] [Indexed: 12/24/2022] Open
Abstract
Tumor biomarkers are important in the early screening, diagnosis, therapeutic evaluation, recurrence and prognosis prediction of tumors. Primary liver cancer is one of the most common malignant tumors; it has high incidence and mortality rates and seriously endangers human health. The main pathological types of primary liver cancer include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined HCC‑cholangiocarcinoma (cHCC‑CC). In the present review, a systematic outline of the current biomarkers of primary liver cancer is presented, from conventional blood biomarkers, histochemical biomarkers and potential biomarkers to resistance‑associated biomarkers. The important relationships are deeply elucidated between biomarkers and diagnosis, prognosis, clinicopathological features and resistance, as well as their clinical significance, in patients with the three main types of primary liver cancer. Moreover, a summary of several important biomarker signaling pathways is provided, which is helpful for studying the biological mechanism of liver cancer. The purpose of this review is to provide help for clinical or medical researchers in the early diagnosis, differential diagnosis, prognosis and treatment of HCC.
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Affiliation(s)
- Yu-Xue Gao
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Tong-Wang Yang
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Ji-Ming Yin
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Peng-Xiang Yang
- Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bu-Xin Kou
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Meng-Yin Chai
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Xiao-Ni Liu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - De-Xi Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
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22
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Putra J, Ferrell LD, Gouw ASH, Paradis V, Rishi A, Sempoux C, Balabaud C, Thung SN, Bioulac-Sage P. Malignant transformation of liver fatty acid binding protein-deficient hepatocellular adenomas: histopathologic spectrum of a rare phenomenon. Mod Pathol 2020; 33:665-675. [PMID: 31570768 DOI: 10.1038/s41379-019-0374-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/10/2019] [Accepted: 09/10/2019] [Indexed: 02/08/2023]
Abstract
The molecular classification of hepatocellular adenomas highlights a distinctive genotype-phenotype correlation. Malignant transformation is an exceptionally rare complication of hepatocyte nuclear factor 1α (HNF1A)-inactivated hepatocellular adenomas. This subtype is characterized by loss of liver fatty acid binding protein immunoexpression. In this study, we characterized the histopathologic spectrum of 13 liver fatty acid binding protein-deficient hepatocellular adenoma cases showing malignant transformation from multiple centers. Clinicopathologic characteristics of these patients were evaluated. Stains for reticulin, liver fatty acid binding protein, beta-catenin and glutamine synthetase were applied to these lesions. Moreover, the findings were compared to patients with β-catenin mutated hepatocellular adenoma. Liver fatty acid binding protein-deficient hepatocellular adenomas with borderline features/carcinoma were seen predominantly in females (77%) with an average age of 46 ± 18 years and multiple lesions (77%; five patients with adenomatosis). Meanwhile, β-catenin mutated hepatocellular adenoma patients with malignant transformation were predominantly male (67%, p = 0.018) with single lesion (86%, p = 0.0009). The largest liver fatty acid binding protein-deficient hepatocellular adenoma nodule in each patient ranged from 4 to 15.5 cm. Loss of liver fatty acid binding protein by immunohistochemistry was noted in all adenoma and borderline/carcinoma components. Features of malignant transformation were pseudoglandular architecture (85%), cytologic atypia (85%), architectural atypia (100%) and lack of steatosis (100%). Other findings included myxoid change (39%), peliosis (46%) and sinusoidal dilatation (46%). Molecular studies confirmed somatic inactivation of HNF1A in 3 cases and absence of TERT promotor and exon 3 CTNNB1 mutations in five cases. To summarize, liver fatty acid binding protein-deficient hepatocellular adenoma with malignant transformation is most frequently seen in female patients with multiple lesions. Most of these lesions demonstrate pseudoglandular architecture, cytologic and architectural atypia, with lack of steatosis. The natural history of these lesions is relatively benign with the exception of disease recurrence in 1 patient.
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Affiliation(s)
- Juan Putra
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Division of Pathology, Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada.
| | - Linda D Ferrell
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Annette S H Gouw
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Arvind Rishi
- Department of Pathology, Long Island Jewish Medical Center, New Hyde Park, NY, USA
| | - Christine Sempoux
- Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland
| | - Charles Balabaud
- BaRITOn Bordeaux Research in Translational Oncology, Univ Bordeaux, INSERM UMR1053, F-33000, Bordeaux, France
| | - Swan N Thung
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Paulette Bioulac-Sage
- BaRITOn Bordeaux Research in Translational Oncology, Univ Bordeaux, INSERM UMR1053, F-33000, Bordeaux, France
- Department of Pathology, CHU Bordeaux, F-33000, Bordeaux, France
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23
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Mansouri V, Razzaghi M, Nikzamir A, Ahmadzadeh A, Iranshahi M, Haghazali M, Hamdieh M. Assessment of liver cancer biomarkers. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2020; 13:S29-S39. [PMID: 33585001 PMCID: PMC7881406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Liver cancer is the third cause of cancer-related deaths in the world. It is primarily divides into two main types, namely hepatocellular carcinoma (HC) and cholangiocarcinoma (IC). Due to the increasing number of patients with liver cancer and the high mortality rate, early diagnosis of the disease can be helpful in treatment, but most patients are diagnosed atlate stages of HC. The aim of this study is to screen and provide an overview on candidate biomarkers related to primary liver cancer to introduce the critical ones. In this study, various biomarkers related to the diagnosis of primary liver cancer have been studied. Accordingly, biomarkers are divided into different groups as blood biomarkers classified as serum and plasma biomarkers, tissue biomarkers, microRNA biomarkers, proteomic biomarkers and altered genes. Previous researches have focused on liver cells and bile ducts, the surround cellular environment, how cells differentiate, and the types of genes expressed in liver cancer. Some even have focused on the origin of tumor cells and how they differentiate and develop. In all these studies, the expression of specific proteins and genes in liver cancer has been considered. Based on available sources, biomarkers can be considered as candidates to diagnose and prognosis of various types of primary liver cancer, from sources such as blood, tissue, mic-RNA, proteome and genes. However, more investigations are required to introduce a biomarker for precise detection of early liver cancer.
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Affiliation(s)
- Vahid Mansouri
- Proteomics Research Center, School of Rehabilitation, ShahidBeheshti University of Medical Sciences, Tehran, Iran
| | - Mohhamadreza Razzaghi
- Laser Application in Medical Sciences Research Center, ShahidBeheshti University of Medical Sciences, Tehran, Iran
| | - Abdolrahim Nikzamir
- Faculty of Medicine, ShahidBeheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Ahmadzadeh
- Proteomics Research Center, Faculty of Paramedical Sciences, ShahidBeheshti University of Medical Sciences, Tehran, Iran
| | - Majid Iranshahi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Haghazali
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mostafa Hamdieh
- Department of Psychosomatic, Taleghani Hospital, Faculty of Medicine, ShahidBeheshti University of Medical Sciences, Tehran, Iran
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24
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Wu M, Zhou RH, Xu F, Li XP, Zhao P, Yuan R, Lan YP, Zhou WX. Multi-parameter ultrasound based on the logistic regression model in the differential diagnosis of hepatocellular adenoma and focal nodular hyperplasia. World J Gastrointest Oncol 2019; 11:1193-1205. [PMID: 31908724 PMCID: PMC6937441 DOI: 10.4251/wjgo.v11.i12.1193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/13/2019] [Accepted: 09/10/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Focal nodular hyperplasia (FNH) has very low potential risk, and a tendency to spontaneously resolve. Hepatocellular adenoma (HCA) has a certain malignant tendency, and its prognosis is significantly different from FNH. Accurate identification of HCA and FNH is critical for clinical treatment.
AIM To analyze the value of multi-parameter ultrasound index based on logistic regression for the differential diagnosis of HCA and FNH.
METHODS Thirty-one patients with HCA were included in the HCA group. Fifty patients with FNH were included in the FNH group. The clinical data were collected and recorded in the two groups. Conventional ultrasound, shear wave elastography, and contrast-enhanced ultrasound were performed, and the lesion location, lesion echo, Young’s modulus (YM) value, YM ratio, and changes of time intense curve (TIC) were recorded. Multivariate logistic regression analysis was used to screen the indicators that can be used for the differential diagnosis of HCA and FNH. A ROC curve was established for the potential indicators to analyze the accuracy of the differential diagnosis of HCA and FNH. The value of the combined indicators for distinguishing HCA and FNH were explored.
RESULTS Multivariate logistic regression analysis showed that lesion echo (P = 0.000), YM value (P = 0.000) and TIC decreasing slope (P = 0.000) were the potential indicators identifying HCA and FNH. In the ROC curve analysis, the accuracy of the YM value distinguishing HCA and FNH was the highest (AUC = 0.891), which was significantly higher than the AUC of the lesion echo and the TIC decreasing slope (P < 0.05). The accuracy of the combined diagnosis was the highest (AUC = 0.938), which was significantly higher than the AUC of the indicators diagnosing HCA individually (P < 0.05). This sensitivity was 91.23%, and the specificity was 83.33%.
CONCLUSION The combination of lesion echo, YM value and TIC decreasing slope can accurately differentiate between HCA and FNH.
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Affiliation(s)
- Meng Wu
- Department of Ultrasound, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
| | - Ru-Hai Zhou
- Department of Ultrasound, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
| | - Feng Xu
- Department of Ultrasound, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
- Department of Gastroenterology, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
| | - Xian-Peng Li
- Department of Ultrasound, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
- Department of Gastroenterology, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
| | - Ping Zhao
- Department of Ultrasound, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
| | - Rui Yuan
- Department of Ultrasound, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
| | - Yu-Peng Lan
- Department of Ultrasound, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
| | - Wei-Xia Zhou
- Department of Ultrasound, Yinzhou Hospital Affiliated to Ningbo University School of Medicine, Ningbo 315000, Zhejiang Province, China
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25
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Xu D, Su C, Sun L, Gao Y, Li Y. Performance of Serum Glypican 3 in Diagnosis of Hepatocellular Carcinoma: A meta-analysis. Ann Hepatol 2019; 18:58-67. [PMID: 31113610 DOI: 10.5604/01.3001.0012.7863] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 12/11/2017] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Serum glypican-3 (GPC3) has been explored as a non-invasive biomarker of hepatocellular carcinoma (HCC). However, controversy remains on its diagnostic accuracy. Therefore, we aimed to conduct a systematic review and metaanalysis to evaluate the differential diagnostic accuracy of serum GPC3 between HCC and liver cirrhosis (LC) cases. MATERIAL AND METHODS After the strict filtering and screening of studies from NCBI, PUBMED, Clinical Trials, Cochrane library, Embase, Prospero and Web of Science databases, 11 studies were selected. All studies provided the sensitivity and specificity of GPC3 and the alpha-fetoprotein (AFP) in the HCC and LC diagnosis. The sensitivity and specificity, and the area under the receiver operating characteristic curve (AUC) were determined and compared between GPC3 and AFP, which was set as a positive control. RESULTS Pooled sensitivity (95% CI) and specificity (95% CI) were 0.55 (0.52-0.58) and 0.58 (0.54-0.61) for GPC3, 0.54 (0.51-0.57) and 0.83 (0.80-0.85) for AFP, and 0.85 (0.81-0.89) and 0.79 (0.73-0.84) for GPC3 + AFP, respectively. The AUCs of GPC3, AFP and GPC3 + AfP were 0.7793, 0.7867 and 0.9366, respectively. GPC3 had a nearly similar sensitivity as AFP, while the specificity and AUC of GPC3 was lower than that of AFP. The combination of GPC3 and AFP yielded a better sensitivity and AUC than GPC3 or AFP. CONCLUSION Serum GPC3 is inferior to AFP in the differential diagnosis between HCC and LC. However, the combination of GPC3 and AFP exhibited a much better performance.
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Affiliation(s)
- Dahai Xu
- Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China; Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chang Su
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Liang Sun
- Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Yuanyuan Gao
- Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Youjun Li
- Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
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26
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Ahmed HH, Galal AF, Shalby AB, Abd-Rabou AA, Mehaya FM. Improving Anti-Cancer Potentiality and Bioavailability of Gallic Acid by Designing Polymeric Nanocomposite Formulation. Asian Pac J Cancer Prev 2018; 19:3137-3146. [PMID: 30486601 PMCID: PMC6318406 DOI: 10.31557/apjcp.2018.19.11.3137] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective: In this study, we investigated the in vivo antitumor activity and pharmacokinetic characteristics of encapsulated GA-NC (gallic acid nanocomposite) in normal and hepatocellular carcinoma (HCC)-induced rats. Methods: Rats were distributed into 4 groups; negative control, HCC, gallic acid (GA), and GA-NC. Serum levels of alpha-fetoprotein (AFP), endoglin (ENG), heat shock protein-70 (HSP-70), pro-caspase 3, lipocalin-2 (LCN-2) and β-cell leukemia/lymphoma 2 (Bcl-2) were assayed by ELISA. The pharmacokinetic parameters for GA or GA-NC were determined by means of non-compartmental approach based on the serum– concentration profiles of free GA and GA-NC after oral administration. Also, histological procedures were used for examination of liver tissue sections. Results: Anaplastic changes in liver tissues were observed in untreated HCC group, as well as a significant increase in the serum AFP level. In addition, significant elevation in the serum ENG level as an angiogenic marker and the serum levels of the apoptotic mediators; HSP-70, Bcl-2 and pro-caspase 3 beside significant amplification in the serum inflammatory modulator, LCN-2 were recorded. Treatment with free GA or GA-NC markedly recovered the anaplastic changes in the rat liver tissues. In addition, they restored serum levels of AFP, ENG, HSP-70, Bcl-2, pro-caspase-3, and LCN-2. Pharmacokinetic analysis revealed that GA–NC displayed a characteristic sustained release profile with 4-fold increase in bioavailability in normal and HCC-induced rats. Conclusions: The results of this study suggest that encapsulation of GA into PLGA-CS-PEG enhances its oral bioavailability and anti-cancer activity. GA-NC may be a new therapeutic candidate for the mitigation of hepatocarcinogenesis.
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Affiliation(s)
- Hanaa H Ahmed
- Department of Hormones, Medical Research Division, National Research Centre, Dokki, Giza, Egypt.
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27
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Baek JA, Choi JH, Gu MJ. The loss of CD44 and HSP70 overexpression is related to aggressive clinicopathologic factors in prostate cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:5466-5472. [PMID: 31949631 PMCID: PMC6963035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 10/25/2018] [Indexed: 06/10/2023]
Abstract
Prostate cancer (PC) is the most common cancer in men with biologically highly heterogeneous clinical outcomes despite early detection. Therefore, the identification of novel molecular markers that are associated with biological aggressiveness is essential for predicting clinical outcomes and deciding the treatment of PC. We examined the expression of cluster of differentiation 44 (CD44) and heat shock protein 70 (HSP70) in PC cells using immunohistochemistry on tissue microarrays and evaluated their clinicopathological significance. A loss of CD44 expression and HSP70 overexpression were observed in 62 (57.9%) and 54 (50.5%) out of 107 cases of PC, respectively. CD44-negative PC showed more vascular invasion, more extra-prostatic extension, more capsular invasion, higher pT stages, higher pathological tumor stages, higher prostate-specific antigen levels (> 20 ng/mL), and higher grades groups. Overexpression of HSP70 was significantly associated with PC with capsular invasion, higher pT stages, and higher pathological tumor stages. The loss of CD44 expression is correlated with tumor invasiveness and higher Gleason grades, reflecting the features of aggressive tumors. Consequently, CD44 could be an important biomarker and a potential therapeutic target.
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Affiliation(s)
- Jin A Baek
- Department of Pathology, Yeungnam University College of Medicine Daegu, South Korea
| | - Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine Daegu, South Korea
| | - Mi Jin Gu
- Department of Pathology, Yeungnam University College of Medicine Daegu, South Korea
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28
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Rastogi A. Changing role of histopathology in the diagnosis and management of hepatocellular carcinoma. World J Gastroenterol 2018; 24:4000-4013. [PMID: 30254404 PMCID: PMC6148422 DOI: 10.3748/wjg.v24.i35.4000] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 07/23/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and fatal cancer in the world. HCC frequently presents with advanced disease, has a high recurrence rate and limited treatment options, which leads to very poor prognosis. This warrants urgent improvement in the diagnosis and treatment. Liver biopsy plays very important role in the diagnosis and prognosis of HCC, but with technical advancements and progression in the field of imaging, clinical guidelines have restricted the role of biopsy to very limited situations. Biopsy also has its own problems of needle tract seeding of tumor, small risk of complications, technical and sampling errors along with interpretative errors. Despite this, tissue analysis is often required because imaging is not always specific, limited expertise and lack of advanced imaging in many centers and limitations of imaging in the diagnosis of small, mixed and other variant forms of HCC. In addition, biopsy confirmation is often required for clinical trials of new drugs and targeted therapies. Tissue biomarkers along with certain morphological features, phenotypes and immune-phenotypes that serve as important prognostic and outcome predictors and as decisive factors for therapy decisions, add to the continuing role of histopathology. Advancements in cancer biology and development of molecular classification of HCC with clinic pathological correlation, lead to discovery of HCC phenotypic surrogates of prognostic and therapeutically significant molecular signatures. Thus tissue characteristics and morphology based correlates of molecular subtypes provide invaluable information for management and prognosis. This review thus focuses on the importance of histopathology and resurgence of role of biopsy in the diagnosis, management and prognostication of HCC.
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Affiliation(s)
- Archana Rastogi
- Department of Pathology, Institute of Liver & Biliary Sciences, New Delhi 110070, India
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29
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Miller GC, Campbell CM, Manoharan B, Bryant R, Cavallucci D, O'Rourke N, Clouston AD. Subclassification of hepatocellular adenomas: practical considerations in the implementation of the Bordeaux criteria. Pathology 2018; 50:593-599. [PMID: 30149989 DOI: 10.1016/j.pathol.2018.05.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 05/04/2018] [Accepted: 05/11/2018] [Indexed: 12/30/2022]
Abstract
Hepatocellular adenomas are benign liver lesions with a risk of rupture and malignant transformation. Various molecular subgroups have been identified which appear to have characteristic morphological and immunohistochemical features. We examined the morphology and immunohistochemical profile of a series of 121 HCA from 97 patients to identify the HCA subtypes present and determine the number at risk for malignant transformation according to the World Health Organization (WHO) criteria for hepatocellular adenomas. There were 34 HNF1α inactivated HCA (28%), 61 inflammatory HCA (50%), 15 β-catenin activated HCA (12%) and 11 unclassified adenomas (9%). This proportion of cases was similar to that seen in other series utilising molecular classification. The morphological features of the adenomas were suggestive but not definite indicators of the subtypes present. Morphological features that showed overlap between the subtypes included steatosis within the lesion, a ductular reaction and focal atypia, so that immunohistochemical typing was required for accurate classification. In conclusion, immunohistochemistry is a clinically useful surrogate for identifying underlying molecular changes in the HCA subtypes.
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Affiliation(s)
- Gregory C Miller
- Envoi Specialist Pathologists, Brisbane, Qld, Australia; Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia.
| | | | | | - Richard Bryant
- Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia; Department of Surgery, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
| | - David Cavallucci
- Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia; Department of Surgery, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
| | - Nicholas O'Rourke
- Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia; Department of Surgery, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
| | - Andrew D Clouston
- Envoi Specialist Pathologists, Brisbane, Qld, Australia; Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia
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30
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Jiang K, Al-Diffhala S, Centeno BA. Primary Liver Cancers-Part 1: Histopathology, Differential Diagnoses, and Risk Stratification. Cancer Control 2018; 25:1073274817744625. [PMID: 29350068 PMCID: PMC5933592 DOI: 10.1177/1073274817744625] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the 2 most common primary malignant liver tumors, with hepatocellular and bile ductular differentiation, respectively. This article reviews the key histopathological findings of these 2 primary liver cancers and includes a review of the role of ancillary testing for differential diagnosis, risk stratification according to the American Joint Committee on Cancer (AJCC) staging recommendation, and a review of precancerous lesions. A literature review was conducted to identify articles with information relevant to precancerous precursors, current histopathological classification, ancillary testing, and risk stratification of primary malignant liver tumors. The histomorphology of normal liver, preinvasive precursors, primary malignancies, and morphological variants, and the utilization of ancillary tests for the pathological diagnosis are described. Dysplastic nodules are the preinvasive precursors of HCC, and intraductal papillary neoplasms of bile ducts and biliary intraepithelial neoplasia are the preinvasive precursors of CC. Benign liver nodules including focal nodular hyperplasia and adenomas are included in this review, since some forms of adenomas progress to HCC and often they have to be differentiated from well-differentiated HCC. A number of morphological variants of HCC have been described in the literature, and it is necessary to be aware of them in order to render the correct diagnosis. Risk stratification is still dependent on the AJCC staging system. The diagnosis of primary liver carcinomas is usually straightforward. Application of the appropriate ancillary studies aids in the differential diagnosis of difficult cases. The understanding of the carcinogenesis of these malignancies has improved with the standardization of the pathological classification of preinvasive precursors and studies of the molecular pathogenesis. Risk stratification still depends on pathological staging.
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Affiliation(s)
- Kun Jiang
- 1 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
| | - Sameer Al-Diffhala
- 3 Division of Anatomic Pathology, Department of Pathology, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Barbara A Centeno
- 1 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
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31
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Atypical Hepatocellular Neoplasms: Review of Clinical, Morphologic, Immunohistochemical, Molecular, and Cytogenetic Features. Adv Anat Pathol 2018; 25:254-262. [PMID: 29649004 DOI: 10.1097/pap.0000000000000189] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The distinction of hepatocellular adenoma from well-differentiated hepatocellular carcinoma (HCC) can be difficult in some cases, especially on biopsy specimens. These borderline cases often occur in men or older patients and may have β-catenin activation or focal atypical morphologic features (such as small cell change, prominent pseudoacinar formation, cytologic atypia, focally thick plates, and/or focal reticulin loss) that are insufficient for an unequivocal diagnosis of HCC. The term "atypical hepatocellular neoplasm" has been advocated for these tumors, but a number of other terms, including "atypical adenoma," "hepatocellular neoplasm of uncertain malignant potential," and "well-differentiated hepatocellular neoplasm with atypical or borderline features" have also been proposed. This review proposes guidelines for designating tumors as atypical hepatocellular neoplasm and describes clinical, morphologic, immunohistochemical, molecular, and cytogenetic features that distinguish these tumors from typical hepatocellular adenoma and HCC.
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32
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Chen Q, Wang M, Wang M, Jin S, Xiao SY, Tian S. Expansile invasive growth pattern is definite evidence for the diagnosis of small hepatocellular carcinomas: a comparative study of 37 cases. Hum Pathol 2018; 80:130-137. [PMID: 29936057 DOI: 10.1016/j.humpath.2018.06.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 05/26/2018] [Accepted: 06/09/2018] [Indexed: 12/11/2022]
Abstract
Small HCCs, including seHCC and spHCC, are rarely encountered in daily practice. Definite diagnosis is difficult for general pathologists. In this study, we reviewed 1025 cases of HCC and examined the histologic characteristics of small HCCs to facilitate more accurate diagnosis. Slides of archived HCC cases were reviewed by 2 senior pathologists, and small HCCs were identified according to the canonical criteria. Additional immunohistochemical stains were performed. Thirty-seven cases of small HCC were identified, including 22 cases of seHCC and 15 cases of spHCC. We found 2 types of invasive growth patterns in these lesions. The first is the expansile invasive growth pattern, with monomorphic tumor cells penetrating through the incomplete fibrous capsules and expanding into the adjacent noncancerous liver with a spherical, hemispheric, or mushroom shape. The second is the classic stromal invasion pattern. At least one type of invasive pattern was observed in all of the 37 cases of small HCC, and the seHCCs exhibit the expansile invasive growth pattern more frequently than the classic stromal invasion pattern. On the contrary, stromal invasive pattern was more common in spHCC nodules. In conclusion, with the background of chronic hepatitis and cirrhosis, histologic features including crowdedness of hepatocytic trabeculae and the expansile invasive growth pattern are strong evidence for the diagnoses of small HCC.
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Affiliation(s)
- Qiongrong Chen
- Department of Pathology, Wuhan University Zhongnan Hospital, and Wuhan University Pathology Center, Wuhan 430071, Hubei Province, China
| | - Manxiang Wang
- Department of Pathology, Hubei Cancer Hospital, Wuhan 430079, Hubei Province, China
| | - Mingwei Wang
- Department of Pathology, Hubei Cancer Hospital, Wuhan 430079, Hubei Province, China
| | - Su Jin
- Department of Pathology, Hubei Cancer Hospital, Wuhan 430079, Hubei Province, China
| | - Shu-Yuan Xiao
- Department of Pathology, Wuhan University Zhongnan Hospital, and Wuhan University Pathology Center, Wuhan 430071, Hubei Province, China
| | - Sufang Tian
- Department of Pathology, Wuhan University Zhongnan Hospital, and Wuhan University Pathology Center, Wuhan 430071, Hubei Province, China.
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Wang HL, Kim CJ, Koo J, Zhou W, Choi EK, Arcega R, Chen ZE, Wang H, Zhang L, Lin F. Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas. Arch Pathol Lab Med 2017; 141:1155-1180. [PMID: 28854347 DOI: 10.5858/arpa.2016-0489-ra] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
CONTEXT - Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. OBJECTIVES - To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. DATA SOURCES - Data sources include literature review, authors' research data, and personal practice experience. CONCLUSIONS - Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.
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Di Tommaso L, Roncalli M. Tissue Biomarkers in Hepatocellular Tumors: Which, When, and How. Front Med (Lausanne) 2017; 4:10. [PMID: 28280721 PMCID: PMC5322593 DOI: 10.3389/fmed.2017.00010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 01/27/2017] [Indexed: 12/13/2022] Open
Abstract
Few tissue markers are currently available to pathologists in the study of hepatocellular tumors. These markers should be used carefully taking into consideration not only morphology but also, and sometimes even more important, the clinical setting where the lesion to be diagnosed had developed. Glypican-3, heat shock protein 70, and glutamine synthetase (GS) are markers currently used, as a single panel, to discriminate the nature of a <2 cm hepatocellular lesion lacking radiological features of hepatocellular carcinoma (HCC) detected in a cirrhotic patient under surveillance. Their use, which can be improved by clathrin heavy chain, is mostly requested on liver biopsy. Hepatocyte paraffin 1, arginase-1, polyclonal carcinoembryonic antigen, CD10, and bile salt export pump are tissue markers used to confirm, at histology, the diagnosis of HCC made by imaging before enrollment for phase III studies on novel anti-HCC drugs. In this setting, pathologists are usually requested a conclusive diagnosis on a liver biopsy of a poorly differentiated, necrotic, enriched in stem-phenotype, carcinoma. Liver fatty acid-binding protein, serum amyloid A, C-reactive protein, prostaglandin D2 synthetase, GS, and β-catenin can be used either on biopsy or surgical specimen to classify hepatocellular adenoma into hepatocyte nuclear factor (HNF-1α) inactivated (steatotic), inflammatory, with dysregulation of sonic hedgehog and prostaglandin pathways, β-catenin mutated, and unclassified.
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Affiliation(s)
- Luca Di Tommaso
- Pathology Unit, Humanitas Clinical and Research Center , Rozzano, Milan , Italy
| | - Massimo Roncalli
- Department of Biomedical Sciences, Humanitas University , Rozzano, Milan , Italy
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Immunohistochemical approach for the diagnosis of a liver mass on small biopsy specimens. Hum Pathol 2017; 63:1-13. [PMID: 28087475 DOI: 10.1016/j.humpath.2016.12.025] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/18/2016] [Accepted: 12/28/2016] [Indexed: 12/14/2022]
Abstract
Well-differentiated hepatocellular carcinoma (HCC) shares overlapping histological features with benign hepatocellular lesions, including hepatocellular adenoma and focal nodular hyperplasia in non-cirrhotic liver, and with high-grade dysplastic nodule in cirrhotic liver. Several metastatic tumors, such as neuroendocrine tumor, renal cell carcinoma, adrenocortical carcinoma, melanoma, and epithelioid angiomyolipoma, can be indistinguishable from HCC on histologic grounds. Since this distinction has important therapeutic implications, judicious use of immunohistochemical markers plays an important role in establishing an accurate diagnosis, especially when limited material of tumor is available on cell block or a small core biopsy. This review describes commonly used immunohistochemical markers used in the diagnosis of HCC, highlighting advantages and disadvantages of each marker, and suggests appropriate immunohistochemical panels for specific clinicopathologic situations.
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Bioulac-Sage P, Sempoux C, Balabaud C. Hepatocellular adenoma: Classification, variants and clinical relevance. Semin Diagn Pathol 2016; 34:112-125. [PMID: 28131467 DOI: 10.1053/j.semdp.2016.12.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatocellular adenomas are benign tumors with two major complications, bleeding and malignant transformation. The overall narrative of hepatocellular adenoma has evolved over time. Solitary or multiple hepatocellular developing in the normal liver of women of child bearing age exposed to oral contraceptives still represents the most frequent clinical context, however, new associations are being recognized. Hepatocellular adenoma is discovered on a background of liver diseases such as non-alcoholic steatohepatitis, vascular diseases, and alcoholic cirrhosis. Hepatocellular adenoma is also reported in men, young or older adults, and even in infants. On the morpho-molecular side, the great leap forward was the discovery that hepatocellular adenoma was not a single entity and that at least 3 different subtypes exist, with specific underlying gene mutations. These mutations affect the HNF1A gene, several genes leading to JAK/STAT3 pathway activation and the CTNNB1 gene. All of them are associated with more or less specific histopathological characteristics and can be recognized using immunohistochemistry either with specific antibodies or with surrogate markers. Liver pathologists and radiologists are the key actors in the identification of the different subtypes of hepatocellular adenoma by the recognition of their specific morphological features. The major impact of the classification of hepatocellular adenoma is to identify subjects who are at higher risk of malignant transformation. With the development of new molecular technologies, there is hope for a better understanding of the natural history of the different subtypes, and, particularly for their mechanisms of malignant transformation.
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Affiliation(s)
| | - Christine Sempoux
- Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Rue du Bugnon 25, CH-1011 Lausanne, Switzerland.
| | - Charles Balabaud
- Inserm U 1053, Université Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux, France.
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Hytiroglou P. Well-differentiated hepatocellular nodule: Making a diagnosis on biopsy and resection specimens of patients with advanced stage chronic liver disease. Semin Diagn Pathol 2016; 34:138-145. [PMID: 28117103 DOI: 10.1053/j.semdp.2016.12.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Guided liver biopsy is commonly employed to determine the identity of distinct hepatic nodules detected on imaging studies of patients with advanced stage chronic liver diseases. Discrimination among large regenerative nodule, dysplastic nodule and well-differentiated hepatocellular carcinoma is often difficult and relies on subtle histologic findings. Sampling is an important consideration in biopsy material, as compared to resection specimens, because the diagnostic features may be focal within the nodule. Immunohistochemical stains may be useful in distinguishing between large regenerative and dysplastic nodule on the one hand, versus early and classic hepatocellular carcinoma on the other. Ongoing research on the early lesions of hepatocarcinogenesis is enhancing our understanding of the sequential steps of this process and provides novel tools for histopathologic differential diagnosis.
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Affiliation(s)
- Prodromos Hytiroglou
- Department of Pathology, Aristotle University School of Medicine, Thessaloniki 54006, Greece.
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Roncalli M, Sciarra A, Tommaso LD. Benign hepatocellular nodules of healthy liver: focal nodular hyperplasia and hepatocellular adenoma. Clin Mol Hepatol 2016; 22:199-211. [PMID: 27189732 PMCID: PMC4946404 DOI: 10.3350/cmh.2016.0101] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 04/01/2016] [Indexed: 02/06/2023] Open
Abstract
Owing to the progress of imaging techniques, benign hepatocellular nodules are increasingly discovered in the clinical practice. This group of lesions mostly arises in the context of a putatively normal healthy liver and includes either pseudotumoral and tumoral nodules. Focal nodular hyperplasia and hepatocellular adenoma are prototypical examples of these two categories of nodules. In this review we aim to report the main pathological criteria of differential diagnosis between focal nodular hyperplasia and hepatocellular adenoma, which mainly rests upon morphological and phenotypical features. We also emphasize that for a correct diagnosis the clinical context such as sex, age, assumption of oral contraceptives, associated metabolic or vascular disturbances is of paramount importance. While focal nodular hyperplasia is a single entity epidemiologically more frequent than adenoma, the latter is representative of a more heterogeneous group which has been recently and extensively characterized from a clinical, morphological, phenotypical and molecular profile. The use of the liver biopsy in addition to imaging and the clinical context are important diagnostic tools of these lesions. In this review we will survey their systematic pathobiology and propose a diagnostic algorithm helpful to increase the diagnostic accuracy of not dedicated liver pathologists. The differential diagnosis between so-called typical and atypical adenoma and well differentiated hepatocellular carcinoma will also be discussed.
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Affiliation(s)
- Massimo Roncalli
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
| | - Amedeo Sciarra
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,University of Milan School of Medicine, Milan, Italy
| | - Luca Di Tommaso
- Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
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Chai Y, Wang G, Fan L, Zhao M. A proteomic analysis of mushroom polysaccharide-treated HepG2 cells. Sci Rep 2016; 6:23565. [PMID: 27020667 PMCID: PMC4810362 DOI: 10.1038/srep23565] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 02/19/2016] [Indexed: 12/30/2022] Open
Abstract
The anti-tumor properties of fungal polysaccharides have gained significant recognition in Asia and tropical America. In this study, the differential expression of proteins in normal HepG2 cells and those treated with polysaccharides that had been isolated from Phellinus linteus (PL), Ganoderma lucidum (GL) and Auricularia auricula (AA) was investigated. Using two-dimensional electrophoresis (2DE), a total of 104 protein spots were determined to be overexpressed in these cells compared with noncancerous regions. A total of 59 differentially expressed proteins were identified through MALDI-TOF-MS. In addition, 400 biological processes (BP), 133 cell components (CC) and 146 molecular functions (MF) were enriched by Gene Ontology (GO) analysis, and 78 KEGG pathways were enriched by pathway enrichment. Protein-Protein Interaction (PPI) analysis demonstrated the interaction networks affected by polysaccharides in HepG2 cells. Then, DJ-1 and 14-3-3 were identified as the key proteins in the networks, and the expression of the mRNA and proteins were evaluated using Real-time quantitative PCR (qRT-PCR) and Western blotting (WB), respectively. The results were in agreement with the 2DE. These results provided information on significant proteins of hepatocellular carcinoma (HCC) and form an important basis for the future development of valuable medicinal mushroom resources.
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Affiliation(s)
- Yangyang Chai
- College of Life Sciences, Northeast Forestry University, Harbin, PR China
| | - Guibin Wang
- College of Life Sciences, Northeast Forestry University, Harbin, PR China
| | - Lili Fan
- Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences,Harbin, PR China
| | - Min Zhao
- College of Life Sciences, Northeast Forestry University, Harbin, PR China
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