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Zhang SL, Wang HL. Ancillary tests for hepatobiliary neoplasms: what we know and what we need to know. Hum Pathol 2023; 141:183-200. [PMID: 36775105 DOI: 10.1016/j.humpath.2023.02.001] [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: 12/19/2022] [Revised: 01/29/2023] [Accepted: 02/04/2023] [Indexed: 02/12/2023]
Abstract
Ancillary tests are commonly used in the surgical pathology setting for diagnosing challenging neoplastic diseases of the liver and biliary tract, while histology and clinical correlation remain to be critically important. With continuous discoveries, more and more useful ancillary tests have become available, which can help distinguish between malignant and benign hepatocellular neoplasms, malignant and benign biliary tract entities, and intrahepatic and metastatic carcinomas. This review will focus on existing and emerging biomarkers (such as glutamine synthetase, organic anion transporting polypeptide 1B3, insulin-like growth factor-II mRNA binding protein-3, S100P, SMAD4, enhancer of zeste homolog 2, albumin, hepatocyte nuclear factor-1β, etc.) that can be used for the diagnosis, classification and prognostication of hepatobiliary neoplasms.
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Affiliation(s)
- Sarah L Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine and Ronald Reagan Medical Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine and Ronald Reagan Medical Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
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2
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Ye J, Pang Y, Yang X, Zhang C, Shi L, Chen Z, Huang G, Wang X, Lu F. PPIH gene regulation system and its prognostic significance in hepatocellular carcinoma: a comprehensive analysis. Aging (Albany NY) 2023; 15:11448-11470. [PMID: 37874737 PMCID: PMC10637785 DOI: 10.18632/aging.205134] [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: 05/17/2023] [Accepted: 09/26/2023] [Indexed: 10/26/2023]
Abstract
BACKGROUND Peptidyl-prolyl isomerase H (PPIH) is a member of the cyclophilin protein family, which functions as a molecular chaperone and is involved in the splicing of pre-mRNA. According to reports, the malignant progression of HCC related to hepatitis B virus (HBV) is tightly associated with RNA-binding proteins. Nevertheless, there is no research on PPIH expression or its function in the occurrence and progression of HCC. RESULTS We are the first to reveal that the mRNA and protein levels of Ppih are substantially overexpressed in HCC, as the outcomes show. A significant correlation existed between enriched expression of Ppih within HCC and more advanced, poorly differentiated, and TP53-mutated tumors. CONCLUSION These findings, which suggest that Ppih may serve as a predictive biomarker for people with HCC, serve as a starting point for further investigation into the function of Ppih in the progression of carcinogenesis. METHODS Accordingly, we utilized clinical samples and bioinformatics analysis to assess Ppih's mRNA, protein expression, and gene regulatory system in HCC. Additionally, Wilcoxon signed-rank testing and logistic regression were utilized to inspect the association between clinicopathological factors and Ppih. Clinical pathological traits linked to overall survival (OS) among HCC patients were examined via TCGA data via Cox regression and the Kaplan-Meier approach. Additionally, via TCGA data collection, gene set enrichment assessment was also conducted.
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Affiliation(s)
- Jun Ye
- Department of Clinical Laboratory, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou 556000, China
| | - Yilin Pang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xunjun Yang
- Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Chuan Zhang
- Department of Pathology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou 556000, China
| | - Lei Shi
- Department of Pathology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou 556000, China
| | - Zhitao Chen
- Department of Pathology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou 556000, China
| | - Guijia Huang
- Department of Oncology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou 556000, China
| | - Xianhe Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou 556000, China
| | - Fangyang Lu
- Department of Oncology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou 556000, China
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3
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Mocan LP, Rusu I, Melincovici CS, Boșca BA, Mocan T, Crăciun R, Spârchez Z, Iacobescu M, Mihu CM. The Role of Immunohistochemistry in the Differential Diagnosis between Intrahepatic Cholangiocarcinoma, Hepatocellular Carcinoma and Liver Metastasis, as Well as Its Prognostic Value. Diagnostics (Basel) 2023; 13:diagnostics13091542. [PMID: 37174934 PMCID: PMC10177238 DOI: 10.3390/diagnostics13091542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary hepatic malignant tumor, after hepatocellular carcinoma (HCC). Its incidence has risen worldwide, yet the only potentially curative treatment, surgical resection, is seldom applicable, and the median overall survival remains extremely low. So far, there are no personalized therapy regimens. This study investigated whether routine immunohistochemical stains have diagnostic and/or prognostic value in iCCA. Clinical, imaging, and pathology data were retrospectively gathered for patients diagnosed with iCCA, HCC, or liver metastases assessed using liver needle biopsies. Three study groups with an equal number of cases (n = 65) were formed. In the iCCA group, CK19, CA19-9, CK7, and CEA demonstrated the highest sensitivities (100%, 100%, 93.7%, and 82.6%, respectively). The most relevant stains used for diagnosing HCCs were Glypican 3, CD34 (sinusoidal pattern), and Hep Par 1, with corresponding sensitivities of 100%, 100%, and 98.2%. The immunohistochemical panels for diagnosing metastatic tumors were chosen after correlating the clinical data and morphologic H&E aspects. Moderate/intensely positive CK7 expression and absent/low amount of intratumoral immune cells were favorable prognostic factors and correlated with increased overall survival in both the univariate analysis and the multivariate regression adjusted for age, existence of cirrhosis, number of tumors, and tumor differentiation.
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Affiliation(s)
- Lavinia Patricia Mocan
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Ioana Rusu
- Department of Pathology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Carmen Stanca Melincovici
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Bianca Adina Boșca
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Tudor Mocan
- UBBMed Department, Babeș-Balyai University, 400347 Cluj-Napoca, Romania
- Department of Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Rareș Crăciun
- Department of Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Medical Department, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Zeno Spârchez
- Department of Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Medical Department, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Maria Iacobescu
- Department of Proteomics and Metabolomics, MedFUTURE Research Center for Advanced Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Carmen Mihaela Mihu
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
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4
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Agarwal A, Handa U, Kundu R, Sachdev A, Kochhar S. Hepatocyte paraffin-1, CD10, and CD34 immunostaining as a diagnostic aid in cytologic diagnosis of hepatic cancer. J Cancer Res Ther 2022; 18:S434-S438. [PMID: 36510999 DOI: 10.4103/jcrt.jcrt_467_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Cytomorphological distinction between hepatocellular carcinoma and metastatic tumors to the liver may be difficult, especially when these have poor differentiation. The present study was done to assess the diagnostic utility of hepatocyte paraffin-1 (HepPar-1), CD10, and CD34 in differentiating hepatocellular carcinoma from metastatic carcinoma. Materials and Methods Ultrasound-guided fine-needle aspiration was performed on 50 patients with space-occupying lesions of liver suspicious for malignancy on clinical/radiologic findings. The cytological assessment was done on smears stained with May-Grünwald-Giemsa and hematoxylin and eosin. Cell blocks were prepared, and immunostaining for HepPar-1, CD10, and CD34 was done. Results In these 50 patients, hepatocellular carcinoma was diagnosed in 7 and metastatic tumors in 43 cases. The sensitivity of smears in diagnosing hepatocellular carcinoma was 100% and the specificity was 95.3%, while the sensitivity and specificity of cell block were 100%. A canalicular pattern of CD10 immunoreactivity had a 100% positive predictive value for diagnosing hepatocellular carcinoma. CD10 had a sensitivity of 57.1% and 41.9% in identification of HCC and metastatic tumors, respectively. For the diagnosis of hepatocellular carcinoma, the sensitivity of CD34 was 85.7% and the specificity of sinusoidal pattern of immunoreactivity was 100%. The sensitivity and specificity of granular cytoplasmic staining pattern of HepPar-1 were 100% in hepatocellular carcinoma. Conclusions The staining patterns of HepPar-1, CD10, and CD34 are highly specific in distinguishing hepatocellular carcinoma from metastasis. These three immunomarkers should be included in the immunocytochemical panel for differentiating hepatocellular carcinoma from metastatic carcinoma to the liver.
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Affiliation(s)
- Anushree Agarwal
- Department of Pathology, Government Medical College and Hospital, Chandigarh, India
| | - Uma Handa
- Department of Pathology, Government Medical College and Hospital, Chandigarh, India
| | - Reetu Kundu
- Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Atul Sachdev
- Department of Medicine, Government Medical College and Hospital, Chandigarh, India
| | - Suman Kochhar
- Department of Radiodiagnosis, Government Medical College and Hospital, Chandigarh, India
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Marcus R, Ferri-Borgogno S, Hosein A, Foo WC, Ghosh B, Zhao J, Rajapakshe K, Brugarolas J, Maitra A, Gupta S. Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma. Cancers (Basel) 2021; 13:cancers13225709. [PMID: 34830866 PMCID: PMC8616431 DOI: 10.3390/cancers13225709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/12/2021] [Accepted: 11/12/2021] [Indexed: 12/21/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss-of-function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing Albumin-Cre mice bearing conditional alleles of mutant Kras and/or floxed Bap1, Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant KrasG12D alone (KA), bi-allelic loss of hepatic Bap1 (BhomoA), and heterozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhetKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhomoKA) developed discrete foci of HCC and ICC. Further, the median survival of BhomoKA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in BhetKA mice and approximately 50 weeks in BhomoA and KA mice (p < 0.001). Microarray analysis performed on liver tissue from KA and BhomoKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.
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Affiliation(s)
- Rebecca Marcus
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
- Department of Surgical Oncology, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
- Correspondence:
| | - Sammy Ferri-Borgogno
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Abdel Hosein
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
- Advocate Aurora Health, Vince Lombardi Cancer Clinic, Sheboygan, WI 53081, USA
| | - Wai Chin Foo
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Bidyut Ghosh
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
| | - Jun Zhao
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
| | - Kimal Rajapakshe
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
| | - James Brugarolas
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Anirban Maitra
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sonal Gupta
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
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6
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Lu SX, Huang YH, Liu LL, Zhang CZ, Yang X, Yang YZ, Shao CK, Li JM, Xie D, Zhang X, Jain D, Yun JP. α-Fetoprotein mRNA in situ hybridisation is a highly specific marker of hepatocellular carcinoma: a multi-centre study. Br J Cancer 2021; 124:1988-1996. [PMID: 33824478 PMCID: PMC8184895 DOI: 10.1038/s41416-021-01363-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 02/23/2021] [Accepted: 03/08/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Pathologic diagnosis of hepatocellular carcinoma (HCC) can be challenging in differentiating from benign and non-hepatocytic malignancy lesions. The aim of this study was to investigate the potential utility of α-fetoprotein (AFP) mRNA RNAscope, a sensitive and specific method, in the diagnosis of HCC. METHODS Three independent retrospective cohorts containing 2216 patients with HCC, benign liver lesions, and non-hepatocytic tumours were examined. AFP was detected using ELISA, IHC (Immunohistochemistry), and RNAscope. Glypican3 (GPC3), hepatocyte paraffin-1 (HepPar-1), and arginase-1 (Arg-1) proteins were detected using IHC. RESULTS AFP RNAscope improved the HCC detection sensitivity by 24.7-32.7% compared with IHC. In two surgical cohorts, a panel of AFP RNAscope and GPC3 provided the best diagnostic value in differentiating HCC from benign hepatocytic lesions (AUC = 0.905 and 0.811), and a panel including AFP RNAscope, GPC3, HepPar-1, and Arg-1 yielded the best AUC (0.971 and 0.977) when distinguishing HCC from non-hepatocytic malignancies. The results from the liver biopsy cohort were similar, and additional application of AFP RNAscope improved the sensitivity by 18% when distinguishing HCC from benign hepatocytic lesions. CONCLUSIONS AFP mRNA detected by RNAscope is highly specific for hepatocytic malignancy and may serve as a novel diagnostic biomarker for HCC.
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Affiliation(s)
- Shi-Xun Lu
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yu-Hua Huang
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Li-Li Liu
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chris Zhiyi Zhang
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xia Yang
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yuan-Zhong Yang
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chun-Kui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jian-Ming Li
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dan Xie
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Jing-Ping Yun
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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7
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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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8
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Jeong JS, Kang HJ, Jo U, Song MJ, Nam SY, Song JS. Hepatoid thymic carcinoma: a case report of a rare subtype of thymic carcinoma. J Pathol Transl Med 2021; 55:230-234. [PMID: 33845553 PMCID: PMC8141974 DOI: 10.4132/jptm.2021.03.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/10/2021] [Indexed: 11/24/2022] Open
Abstract
Hepatoid thymic carcinoma is an extremely rare subtype of primary thymus tumor resembling "pure" hepatoid adenocarcinomas with hepatocyte paraffin 1 (Hep-Par-1) expression. A 53-year-old man presented with voice change and a neck mass. Multiple masses involving the thyroid, cervical and mediastinal lymph nodes, and lung were detected on computed tomography. Papillary thyroid carcinoma was confirmed by biopsy, and the patient underwent neoadjuvant chemoradiation therapy. However, the anterior mediastinal mass was enlarged after the treatment whereas the multiple masses in the thyroid and neck decreased in size. Microscopically, polygonal tumor cells formed solid sheets or trabeculae resembling hepatocytes and infiltrated remnant thymus. The tumor cells showed immunopositivity for cytokeratin 7, cytokeratin 19, and Hep-Par-1 and negativity for α-fetoprotein. Possibilities of germ cell tumor, squamous cell carcinoma, and metastasis of thyroid papillary carcinoma were excluded by immunohistochemistry. This report on the new subtype of thymic carcinoma is the third in English literature thus far.
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Affiliation(s)
- Ji-Seon Jeong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyo Jeong Kang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Uiree Jo
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Min Jeong Song
- Department of Pathology, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul, Korea
| | - Soon Yeol Nam
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of medicine, Seoul, Korea
| | - Joon Seon Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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9
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Qiu M, Glass Z, Chen J, Haas M, Jin X, Zhao X, Rui X, Ye Z, Li Y, Zhang F, Xu Q. Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. Proc Natl Acad Sci U S A 2021; 118:e2020401118. [PMID: 33649229 PMCID: PMC7958351 DOI: 10.1073/pnas.2020401118] [Citation(s) in RCA: 224] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Loss-of-function mutations in Angiopoietin-like 3 (Angptl3) are associated with lowered blood lipid levels, making Angptl3 an attractive therapeutic target for the treatment of human lipoprotein metabolism disorders. In this study, we developed a lipid nanoparticle delivery platform carrying Cas9 messenger RNA (mRNA) and guide RNA for CRISPR-Cas9-based genome editing of Angptl3 in vivo. This system mediated specific and efficient Angptl3 gene knockdown in the liver of wild-type C57BL/6 mice, resulting in profound reductions in serum ANGPTL3 protein, low density lipoprotein cholesterol, and triglyceride levels. Our delivery platform is significantly more efficient than the FDA-approved MC-3 LNP, the current gold standard. No evidence of off-target mutagenesis was detected at any of the nine top-predicted sites, and no evidence of toxicity was detected in the liver. Importantly, the therapeutic effect of genome editing was stable for at least 100 d after a single dose administration. This study highlights the potential of LNP-mediated delivery as a specific, effective, and safe platform for Cas9-based therapeutics.
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MESH Headings
- Angiopoietin-Like Protein 3
- Angiopoietin-like Proteins/genetics
- Angiopoietin-like Proteins/metabolism
- Animals
- CRISPR-Associated Protein 9/genetics
- Drug Carriers/chemistry
- Drug Carriers/pharmacokinetics
- Drug Carriers/pharmacology
- Female
- Gene Editing
- Lipids/chemistry
- Lipids/pharmacokinetics
- Lipids/pharmacology
- Liver/metabolism
- Mice
- Mice, Inbred BALB C
- Nanoparticles/chemistry
- Organ Specificity
- RNA, Guide, CRISPR-Cas Systems/chemistry
- RNA, Guide, CRISPR-Cas Systems/genetics
- RNA, Guide, CRISPR-Cas Systems/pharmacokinetics
- RNA, Guide, CRISPR-Cas Systems/pharmacology
- RNA, Messenger/chemistry
- RNA, Messenger/genetics
- RNA, Messenger/pharmacokinetics
- RNA, Messenger/pharmacology
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Affiliation(s)
- Min Qiu
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155
| | - Zachary Glass
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155
| | - Jinjin Chen
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155
| | - Mary Haas
- Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Xin Jin
- Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Xuewei Zhao
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155
| | - Xuehui Rui
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155
| | - Zhongfeng Ye
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155
| | - Yamin Li
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155
| | - Feng Zhang
- Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Qiaobing Xu
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155;
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10
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Bhattacharya JB, Jain SL, Devi S. The Role of Immunocytochemical Markers to Differentiate Primary from Secondary Neoplastic Hepatic Masses: A Diagnostic Challenge on Cytology. Turk Patoloji Derg 2021; 37:196-202. [PMID: 34514559 PMCID: PMC10510624 DOI: 10.5146/tjpath.2021.01527] [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: 12/21/2020] [Accepted: 01/21/2021] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE It is challenging and difficult to differentiate primary from metastatic hepatic masses solely on cytology. The present study aimed to correlate cytomorphological spectrum of hepatic masses with immunocytochemical markers to differentiate primary from metastases in liver. MATERIAL AND METHOD The present study comprised of 30 clinico-radiologically suspicious cases of neoplastic hepatic masses. Ultrasound-guided fine needle aspiration smears and cell blocks were prepared as per standard technique; two of the smears were air-dried and Giemsa stained to study cytomorphological features. A panel of markers (HepPar-1, CD 10, CK7, CK19, CD34, and MOC-31) were studied both in smears and cell blocks. RESULTS Cytomorphological features on smears were evaluated and correlated with immunocytochemistry in all cases; the final diagnosis was: Hepatocellular carcinoma (n=7), cholangiocarcinoma (n=2), hepatoblastoma (n=1) and metastatic carcinoma (n=20). HepPar-1, CD10 and CD34 demonstrated 86%, 72%, 86% sensitivity and 100% specificity respectively for hepatocellular carcinoma; CK7&CK19 showed 100% sensitivity for cholangiocarcinoma, MOC 31 showed 90% sensitivity and 100% specificity for metastatic carcinoma. CONCLUSION The present study recommends a panel of minimum three markers (HepPar-1, CD10, and MOC-31) which were helpful to differentiate hepatocellular carcinoma from metastatic carcinoma that was a major diagnostic challenge solely on cytomorphology. Correlating cytomorphology with these three markers, 100% of the cases could be diagnosed as primary malignancy and distinguished accurately from metastatic carcinoma.
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11
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Liu HT, Cheng SB, Lai CY, Chen YJ, Su TC, Wu CC. Locoregional therapies in patients with recurrent intrahepatic cholangiocarcinoma after curative resection. Therap Adv Gastroenterol 2020; 13:1756284820976974. [PMID: 33354228 PMCID: PMC7734491 DOI: 10.1177/1756284820976974] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/29/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Hepatectomy is one potential treatment for intrahepatic cholangiocarcinoma (IHCC). Recurrent rate is high after curative resection and most recurrences occur within residual liver parenchyma. The aim of this study was to elucidate the impact of different treatment modalities on recurrent diseases in patients with IHCC after primary liver resection. METHODS Between February 1999 and December 2015, we retrospectively identified patients who received curative resection for IHCC. Patients who experienced recurrences were included. Locoregional therapies included re-hepatectomy, radiofrequent ablation, and transhepatic arterial chemoembolization. These patients were categorized into three groups: intrahepatic recurrence without locoregional therapies (group A), intrahepatic recurrence with locoregional therapies (group B) and extrahepatic metastases (group C). RESULTS Forty-three patients were included and there were 12, 15, and 16 patients in groups A, B, and C, respectively. The median disease-free survival times were 8.3, 9.1, and 8.7 months in groups A, B, and C (p = 0.099). The median after-recurrence overall survival times (period between recurrence and death/censor) were 6.4, 34.0, and 8.3 months in groups A, B, and C (p = 0.001). Locoregional therapies showed favorable benefit in multivariant analysis (hazard ratio: 0.274, confidence interval: 0.083-0.908, p = 0.010). CONCLUSION Locoregional therapies offered favorable benefits for patients with recurrent intrahepatic cholangiocarcinoma.
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Affiliation(s)
| | - Shao-Bin Cheng
- Department of Surgery, Taichung Veterans General Hospital,School of Medicine, Chung Shan Medical University, Taichung
| | - Chia-Yu Lai
- Department of Surgery, Taichung Veterans General Hospital
| | - Yi-Ju Chen
- Department of Surgery, Taichung Veterans General Hospital
| | - Te-Cheng Su
- Department of Radiology, Taichung Veterans General Hospital
| | - Cheng-Chung Wu
- Department of Surgery, Taichung Veterans General Hospital School of Medicine, Chung Shan Medical University, Taichung
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12
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Italian Clinical Practice Guidelines on Cholangiocarcinoma - Part I: Classification, diagnosis and staging. Dig Liver Dis 2020; 52:1282-1293. [PMID: 32893173 DOI: 10.1016/j.dld.2020.06.045] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 12/11/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer, characterized by a poor prognosis and resistance to chemotherapeutics. The progressive increase in CCA incidence and mortality registered worldwide in the last two decades and the need to clarify various aspects of clinical management have prompted the Italian Association for the Study of the Liver (AISF) to commission the drafting of dedicated guidelines in collaboration with a group of Italian scientific societies. These guidelines have been formulated in accordance with the Italian National Institute of Health indications and developed by following the GRADE method and related advancements.
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13
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Vyas M, Zhang X. Hepatocellular Carcinoma: Role of Pathology in the Era of Precision Medicine. Clin Liver Dis 2020; 24:591-610. [PMID: 33012447 DOI: 10.1016/j.cld.2020.07.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is a morphologically heterogeneous tumor with variable architectural growth patterns and several distinct histologic subtypes. Large-scale attempts have been made over the past decade to identify targetable genomic alterations in HCC; however, its translation into clinical personalized care remains a challenge to precision oncology. The role of pathology is no longer limited to confirmation of diagnosis when radiologic features are atypical. Pathology is now in a position to predict the underlying molecular alteration, prognosis, and behavior of HCC. This review outlines various aspects of histopathologic diagnosis and role of pathology in cutting-edge diagnostics of HCC.
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Affiliation(s)
- Monika Vyas
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 303 Brookline Avenue, Boston, MA 02215, USA
| | - Xuchen Zhang
- Department of Pathology, Yale School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA.
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14
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Vielmo A, Panziera W, Bianchi MV, Argenta FF, Lorenzo CD, Vielmo LA, Pavarini SP, Driemeier D. Primary hepatic neoplasms in cattle. PESQUISA VETERINARIA BRASILEIRA 2020. [DOI: 10.1590/1678-5150-pvb-6629] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
ABSTRACT: Primary hepatic neoplasms are mostly detected in cattle as incidental findings in slaughterhouses or diagnosed at the necropsy, wherein it may be related to the cause of death. A proper characterization of primary hepatic neoplasms is essential to provide an accurate diagnosis, especially at the slaughter lines, in order to reduce erroneous condemnations. This work aimed to characterize the gross, histological, and immunohistochemical features of primary liver neoplasms detected in slaughtered cattle in Southern Brazil. Nineteen primary hepatic neoplasms were identified. Grossly, these lesions were classified according to their distribution, as focal, multifocal, or diffuse. Histologically, the shape and arrangement of the cells, as well as possible malignant features were evaluated. Immunohistochemistry (IHC) was also performed for biliary epithelium (anti-CK7) and hepatocytes (anti-Hep Par-1) markers. Hepatocellular carcinoma (84.2%) was the most frequently detected hepatic neoplasm, followed by cholangiocarcinoma (15.8%), and these were only identified in adult cows. Hepatocellular carcinomas occurred as solitary masses or multifocal nodules, which on the cut surface were often green. Cholangiocarcinomas occurred as multifocal nodules, occasionally showing an umbilicated appearance. Histologically, hepatocellular carcinomas had mostly trabecular and solid patterns, while cholangiocarcinomas presented mostly a solid arrangement. Upon IHC, all hepatocellular carcinomas were immunolabeled for anti-Hep Par-1, ranging from mild (25%), moderate (31.2%) to marked (43.7%), while immunolabeling for anti-CK7 was detected only in one case of cholangiocarcinoma.
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15
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Zheng B, Ma J, Tian L, Dong L, Song G, Pan J, Liu Y, Yang S, Wang X, Zhang X, Zhou J, Fan J, Shi J, Gao Q. The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome. Clin Transl Med 2020; 10:45-56. [PMID: 32508015 PMCID: PMC7239312 DOI: 10.1002/ctm2.11] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 03/06/2020] [Accepted: 03/06/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND This study aimed to investigate the clinical relevance of the immune microenvironment in patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-ICC). PATIENTS AND METHODS The density of tumor-infiltrating CD3+ , CD8+ , CD163+ , and Foxp3+ immune cells, as well as Programmed cell death 1, Programmed cell death-ligand 1, and Tumor necrosis factor receptor superfamily member 4, was measured in the peritumor liver, tumor invasive margin, and intratumor subregions of 56 cHCC-ICC by immunohistochemistry. The immune index was established to stratify patients. Prognostic significance of immune cell subsets and immune indices was evaluated. RESULTS The distribution of immune cells was highly heterogeneous among different subregions of cHCC-ICC. As compared with the hepatocellular carcinoma (HCC) component, the lower density of CD8+ T cells and higher intensity of Foxp3+ Tregs and immune checkpoints in the intrahepatic cholangiocarcinoma (ICC) component may indicate a stronger immune evasive ability of ICC. Based on clustering classification or a combination of random forest and lasso-cox, two models of immune indices were established and both were identified as independent prognostic factors for cHCC-ICC patients. The selected immune variables in the immune prognostic models derived from both HCC and ICC subregions, indicating that the prognosis of cHCC-ICC patients was a complex interaction of both components. CONCLUSIONS The immune contexture was heterogeneous among different subregions of cHCC-ICC patients and contributed differently to patient prognosis. Immune score based on the densities of immune cells might serve as a promising prognostic predictor for cHCC-ICC patients.
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Affiliation(s)
- Bo‐Hao Zheng
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
- Department of General SurgeryZhongshan HospitalFudan UniversityShanghaiChina
| | - Jia‐Qiang Ma
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
- The Center for MicrobesDevelopment, and HealthKey Laboratory of Molecular Virology & ImmunologyInstitute Pasteur of ShanghaiChinese Academy of Sciences/University of Chinese Academy of SciencesShanghaiChina
| | - Ling‐Yu Tian
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Liang‐Qing Dong
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Guo‐He Song
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Jiao‐Men Pan
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Yu‐Ming Liu
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Shuai‐Xi Yang
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Xiao‐Ying Wang
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Xiao‐Ming Zhang
- The Center for MicrobesDevelopment, and HealthKey Laboratory of Molecular Virology & ImmunologyInstitute Pasteur of ShanghaiChinese Academy of Sciences/University of Chinese Academy of SciencesShanghaiChina
| | - Jian Zhou
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
| | - Jia Fan
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
| | - Jie‐Yi Shi
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
| | - Qiang Gao
- Department of Liver Surgery and Transplantationand Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
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Pham BV, Phan HH, Ngo LL, Nguyen HTT, Le KV, Dinh TC, Bac ND. A Rare Colonic Metastasis Case from Hepatocellular Carcinoma. Open Access Maced J Med Sci 2019; 7:4368-4371. [PMID: 32215096 PMCID: PMC7084010 DOI: 10.3889/oamjms.2019.837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Hepatocellularcarcinoma (HCC) metastasis include intrahepatic and extrahepatic metastasis. Similar to intrahepatic metastasis, extrahepatic metastases are not unusual in cases with HCC. However, colonic metastasis is infrequent. CASE REPORT We describe a clinical case, he was diagnosed with HCC a year ago, treated with TACE (transarterialchemoembolisation), re-examined with abdominal pain and defecation disorder. The tests such as CT scan, colorectal endoscopy, fine needle aspiration (FNA) revealed secondary metastatic lesion of HCC in sigmoid colon. This is the first gastrointestinal (GI) tract metastatic we have encountered. CONCLUSION HCC metastases of the colon are rare, especially cases of hematogenous spread. The prognosis of these patients is often very critical. Indications for surgical removal of the lesion may be used if the general situation of patient is acceptable.
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Affiliation(s)
| | | | - Lam Le Ngo
- Vietnam National Cancer Hospital, Hanoi, Vietnam
| | | | - Ky Van Le
- Vietnam National Cancer Hospital, Hanoi, Vietnam
| | - Thien Chu Dinh
- Institute for Research and Development, Duy Tan University, 03 Quang Trung, Danang, Vietnam
| | - Nguyen Duy Bac
- Vietnam Military Medical University (VMMU), Hanoi, Vietnam
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17
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Obiorah IE, Chahine J, Park BU, Ko K, deGuzman J, Kallakury B. Well differentiated arginase-1 negative hepatocellular carcinoma. Transl Gastroenterol Hepatol 2019; 4:66. [PMID: 31620648 DOI: 10.21037/tgh.2019.08.01] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 07/31/2019] [Indexed: 12/20/2022] Open
Abstract
Background The diagnosis of hepatocellular carcinoma (HCC) is dependent on the histologic and immunohistochemical analysis of biopsy and resection specimens. The distinction of HCC from metastatic neoplasms is pertinent for treatment and prognostic purposes. Arginase-1 (Arg-1), a marker of hepatocellular differentiation, has shown superior sensitivity and specificity when compared to other immunohistochemical markers of detection of HCC such as hepatocyte paraffin antigen (HepPar-1). Studies have shown that poorly differentiated HCC can lose arginase expression, however well differentiated HCC are rarely ever arginase negative. Methods In this study Arg-1 expression was detected using immunohistochemical staining on tissue specimens from 40 confirmed cases of well differentiated HCC specimens using a highly specific monoclonal antibody for Arg-1. Specificity of the Arg-1 antibody was evaluated by immunostaining of 24 non-HCC tumors in the liver and 200 non-liver neoplasms using paraffin block and tissue micro-array (TMA) based immunohistochemistry. Results Four well differentiated HCC cases were found to be completely negative for Arg-1 and similarly all 224 non-HCC tumors did not express Arg-1. The arginase negative well differentiated tumors were positive for other hepatocellular markers such as HepPar-1 and polyclonal carcinoembryonic antigen (pCEA). Of the four tumors, only one recurred at 28 months. All patients are currently stable with a mean survival of 43 months. Conclusions Arg-1 negative well differentiated HCC can be a clinical dilemma which can lead to misdiagnosis. Confirmation with other hepatocellular markers such as HepPar1 and pCEA is essential in making the correct diagnosis. The clinicopathologic outcomes of arginase negative well differentiated HCC has been poorly characterized, thus our findings are of utmost importance in understanding the clinical behavior of these tumors. This may have a potential role in understanding the mechanism of the use of targeted therapy in HCC tumors.
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Affiliation(s)
- Ifeyinwa E Obiorah
- Department of Pathology, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Joeffrey Chahine
- Department of Pathology, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Byoung Uk Park
- Department of Pathology, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Kyungmin Ko
- Department of Pathology, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Jose deGuzman
- Department of Pathology, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Bhaskar Kallakury
- Department of Pathology, Medstar Georgetown University Hospital, Washington, DC, USA
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18
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The strengths and weaknesses of gross and histopathological evaluation in hepatocellular carcinoma: a brief review. SURGICAL AND EXPERIMENTAL PATHOLOGY 2019. [DOI: 10.1186/s42047-019-0047-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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Queen D, Fisher J, Husain S, Linos K, Niedt GW, Samie FH. Cutaneous metastasis of hepatocellular carcinoma following liver transplantation. J Cutan Pathol 2019; 47:47-51. [PMID: 31381162 DOI: 10.1111/cup.13555] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 06/09/2019] [Accepted: 07/29/2019] [Indexed: 11/28/2022]
Abstract
Cutaneous metastases from hepatocellular carcinoma (HCC) are extremely rare and can represent a sign of an underlying malignancy or relapse/progression from an existing tumor. We report a case of a cutaneous metastasis arising in a patient with metastatic HCC following orthotopic liver transplantation. Diagnosis is a multistep process as cutaneous HCC metastases must be differentiated from primary cutaneous malignancies as well as other cutaneous metastases. Making this even more challenging, HCC metastases have heterogeneous clinical and histologic appearances. Therefore, the use of immunohistochemical stains, including hepatocyte paraffin-1, arginase-1, and glypican-3, and correlation with the clinical context are essential for a correct diagnosis.
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Affiliation(s)
- Dawn Queen
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Juliya Fisher
- Department of Dermatology, Columbia University Irving Medical Center, New York, New York
| | - Sameera Husain
- Department of Pathology, Columbia University Irving Medical Center, New York, New York
| | - Konstantinos Linos
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.,Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - George W Niedt
- Department of Pathology, Columbia University Irving Medical Center, New York, New York
| | - Faramarz H Samie
- Department of Dermatology, Columbia University Irving Medical Center, New York, New York
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20
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Singha J, Khan K, Chatterjee S. Diagnostic utility of CD10 immunohistochemical staining on cellblock in differentiating hepatocellular carcinoma from secondary malignancies of liver. INDIAN J PATHOL MICR 2019; 61:510-515. [PMID: 30303139 DOI: 10.4103/ijpm.ijpm_788_16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Differentiation of hepatocellular carcinoma (HCC) from metastatic malignancy in liver may be difficult at times on fine-needle aspiration cytology, especially in case of moderate-to-poorly differentiated tumors. The benefit of cell-block technique is the recognition of histologic pattern of diseases along with application of a wide variety of immunohistochemical (IHC) stains to differentiate hepatic malignancies. In this study, CD10 IHC staining was done on cellblocks prepared from aspirates of clinicoradiologically/cytologically suspected malignant liver neoplasms to differentiate HCC from malignancies metastasizing to liver. Objective The objective of the study was to assess the diagnostic utility of CD10 IHC stain on cell-block preparation for differentiating primary from Secondary malignancies of liver. Materials and Methods Formalin-fixed, paraffin-embedded cellblocks of 61 cases (25 cases of HCC and 36 cases of metastatic carcinoma) were prepared from a fine-needle aspirate of the suspected malignant liver neoplasm and immunostained using monoclonal antibody against CD10. Results Twenty-two (88%) of 25 cases of HCC were positive for CD10 with a canalicular staining pattern. Two (8%) were positive for CD10 with membranous and one (4%) with cytoplasmic staining pattern. Conclusion CD10 immunostaining on cellblock is useful in discriminating HCC and metastatic carcinoma of the liver with a diagnostic accuracy of 88.52%.
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Affiliation(s)
- Joydeb Singha
- Department of Pathology, North Bengal Medical College, Siliguri, West Bengal, India
| | - Kalyan Khan
- Department of Pathology, North Bengal Medical College, Siliguri, West Bengal, India
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21
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Senthil R, Nair AVR, Pratap T, Gangadharan VP, Mahadevan P. A Rare Case of Liver Metastasis from Prostate Cancer Mimicking Hepatocellular Carcinoma on Immunohistochemistry: Role of F-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Diagnosis. Indian J Nucl Med 2019; 34:54-56. [PMID: 30713383 PMCID: PMC6352627 DOI: 10.4103/ijnm.ijnm_110_18] [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] [Indexed: 12/24/2022] Open
Abstract
We present a case with space-occupying lesion in cirrhotic liver, diagnosed as hepatocellular carcinoma on immunohistochemistry, who underwent F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and showed FDG-avid lesions in liver as well as in the prostate. These findings guided in establishing the diagnosis of prostate cancer, metastasizing to liver by performing additional immunohistochemical markers. PET/CT was also useful in identifying coexisting non-Hodgkin's lymphoma.
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Affiliation(s)
- Raja Senthil
- Department of Nuclear Medicine and PET/CT, VPS Lakeshore Hospital, Kochi, Kerala, India
| | | | - Thara Pratap
- Department of Radiology, VPS Lakeshore Hospital, Kochi, Kerala, India
| | | | - Pushpa Mahadevan
- Department of Pathology, VPS Lakeshore Hospital, Kochi, Kerala, India
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22
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Hass HG, Vogel U, Scheurlen M, Jobst J. Subclassification and Detection of New Markers for the Discrimination of Primary Liver Tumors by Gene Expression Analysis Using Oligonucleotide Arrays. Gut Liver 2018; 12:306-315. [PMID: 29271183 PMCID: PMC5945262 DOI: 10.5009/gnl17277] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 08/09/2017] [Accepted: 08/14/2017] [Indexed: 12/17/2022] Open
Abstract
Background/Aims The failure to correctly differentiate between intrahepatic cholangiocarcinoma (CC) and hepatocellular carcinoma (HCC) is a significant clinical problem, particularly in terms of the different treatment goals for both cancers. In this study a specific gene expression profile to discriminate these two subgroups of liver cancer was established and potential diagnostic markers for clinical use were analyzed. Methods To evaluate the gene expression profiles of HCC and intrahepatic CC, Oligonucleotide arrays (AffymetrixU133A) were used. Overexpressed genes were checked for their potential use as new markers for discrimination and their expression values were validated by reverse transcription polymerase chain reaction and immunohistochemistry analyses. Results 695 genes/expressed sequence tags (ESTs) in HCC (245 up-/450 down-regulated) and 552 genes/ESTs in CC (221 up-/331 down-regulated) were significantly dysregulated (p＜0.05, fold change >2, ≥70%). Using a supervised learning method, and one-way analysis of variance a specific 270-gene expression profile that enabled rapid, reproducible differentiation between both tumors and nonmalignant liver tissues was established. A panel of 12 genes (e.g., HSP90β, ERG1, GPC3, TKT, ACLY, and NME1 for HCC; SPT2, T4S3, CNX43, TTD1, HBD01 for CC) were detected and partly described for the first time as potential discrimination markers. Conclusions A specific gene expression profile for discrimination of primary liver cancer was identified and potential marker genes with feasible clinical impact were described.
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Affiliation(s)
- Holger G Hass
- Department of Internal Medicine, Oncology and Rehabilitation, Paracelsus Hospital, Scheidegg, Germany
| | - Ulrich Vogel
- Department of Pathology, University of Tübingen, Tübingen, Germany
| | - Michael Scheurlen
- Department of Gastroenterology, Oncology, Rheumatology, University of Würzburg, Würzburg, Germany
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Chan S, Leow WQ. Sudden Collapse due to Medullary and Cervical Cord Infarction-An Unusual Presentation of Hepatocellular Carcinoma. J Forensic Sci 2018; 64:925-929. [PMID: 30352122 DOI: 10.1111/1556-4029.13929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 09/11/2018] [Accepted: 09/26/2018] [Indexed: 11/29/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common cancer worldwide with a great potential for metastatic spread. Hepatocellular carcinoma often arises in people with underlying viral hepatitides or liver cirrhosis and may present in various ways including abdominal pain, liver mass, and signs of hepatocellular decompensation. Many tumors may have metastasized to other organs such as the lungs, lymph nodes, bone, and adrenal glands at the time of diagnosis. However, it is uncommon for HCC to present purely due to its metastasis, such as spinal cord compression from vertebral metastasis. Here, an unusual presentation of a sudden cardiovascular collapse due to medullary and cervical cord infarction from compression of the cervical cord is presented. The importance of clinical investigations, the usefulness of postmortem computed tomography scans, and the examination of the cervical spine and cervical cord in people with no obvious cause of death after standard autopsy procedures are emphasized.
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Affiliation(s)
- Shijia Chan
- Forensic Medicine Division, Health Sciences Authority, 11 Outram Road, Singapore, 169078, Singapore
| | - Wei Qiang Leow
- Department of Anatomical Pathology, Singapore General Hospital, 20 College Road, Singapore, 169856, Singapore.,Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
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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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Lin F, Shi J, Wang HL, Ma XJ, Monroe R, Luo Y, Chen Z, Liu H. Detection of Albumin Expression by RNA In Situ Hybridization Is a Sensitive and Specific Method for Identification of Hepatocellular Carcinomas and Intrahepatic Cholangiocarcinomas. Am J Clin Pathol 2018; 150:58-64. [PMID: 29746696 DOI: 10.1093/ajcp/aqy030] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Inconsistent data on detection of albumin expression by ribonucleic acid (RNA) in situ hybridization have been reported. We investigated the utility of RNAscope (Advanced Cell Diagnostics, Hayward, CA) in detection of albumin in hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (ICCs), and carcinomas from various organs using manual and automated staining. METHODS RNAscope for albumin detection was performed on 482 cases on tissue microarray sections and on 22 cases of ICC, including 14 surgical resection and eight core biopsy specimens. RESULTS Thirty-six of 37 (97%) HCCs had detectable mRNA, whereas all non-HCC and non-ICC cases, except one lung adenocarcinoma, were negative for albumin. Fourteen of 22 ICCs (64%) were positive for albumin. CONCLUSIONS RNAscope for albumin is highly sensitive and specific for identifying HCCs and is highly specific and moderately sensitive for detection of ICCs; however, rare carcinomas (non-HCC, non-ICC, and those with no hepatoid histomorphology) can also have aberrant expression of albumin.
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Affiliation(s)
- Fan Lin
- Geisinger Medical Center, Danville, PA
| | | | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles
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Koehne de Gonzalez A, Lagana SM. Update on Ancillary Testing in the Evaluation of High-Grade Liver Tumors. Surg Pathol Clin 2018; 11:367-375. [PMID: 29751880 DOI: 10.1016/j.path.2018.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tissue diagnosis is the gold standard for mass lesions of the liver, but needle core biopsies may sometimes prove challenging. Presented here is a review of a panel of immunohistochemical stains, including hepatocyte in paraffin 1, arginase-1, polyclonal carcinoembryonic antigen, CD10, bile salt export pump, glypican-3, as well as in situ hybridization for albumin RNA, to establish hepatocellular origin in cases in which hepatocellular carcinoma is suspected but the sample is limited or the morphology is challenging, as it may be with cases of scirrhous, fibrolamellar carcinoma, intrahepatic cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma.
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Affiliation(s)
- Anne Koehne de Gonzalez
- Department of Pathology and Cell Biology, Columbia University, 622 W 168th Street, Vanderbilt Clinic 14-209, New York, NY 10032, USA
| | - Stephen M Lagana
- Department of Pathology and Cell Biology, Columbia University, 622 W 168th Street, Vanderbilt Clinic 14-209, New York, NY 10032, USA.
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Kaseb AO, Hassan M, Lacin S, Abdel-Wahab R, Amin HM, Shalaby A, Wolff RA, Yao J, Rashid A, Vennapusa B, Feng J, Ohtomo T. Evaluating clinical and prognostic implications of Glypican-3 in hepatocellular carcinoma. Oncotarget 2018; 7:69916-69926. [PMID: 27655712 PMCID: PMC5342524 DOI: 10.18632/oncotarget.12066] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 09/05/2016] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide. In patients with HCC, histopathogical differentiation is an important indicator of prognosis; however, because determination of HCC differentiation is difficult, the recently described immunohistochemical (IHC) marker glypican3 (GPC3) might assist in HCC prognostication.The goal of our study was to investigate GPC3's IHC staining pattern and define the relationship between its expression and patients' clinicopathologic features and overall survival. We retrieved clinical parameters from 101 pathologically diagnosed HCC patients' medical records and classified these patients into 4 clinical score categories (0–3) based on increasing GPC3 staining intensity and the percentage of stained tumor cells in their resection and biopsy specimens. Histopathological samples were well, moderately, and poorly differentiated in 33, 22, and 12 patients, respectively, and the GPC3 expression rate was 63%, 86%, and 92%,respectively. The median overall survival was 49.9 months (confidence interval (CI): 35.3–64.6 months) for clinical scores 0–1 and 30.7 months (CI: 19.4–41.9 months) for clinical scores 2–3. This difference was not statistically significant (P = .06) but showed a strong trend. In conclusion, a greater GPC3 expression is associated with a worse HCC prognosis and may be a promising prognostic marker.
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Affiliation(s)
- Ahmed Omar Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Manal Hassan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sahin Lacin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Medical Oncology, Hacettepe University, Medical Faculty, Ankara, Turkey
| | - Reham Abdel-Wahab
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Clinical Oncology, Assiut University Hospital, Assiut, Egypt
| | - Hesham M Amin
- Division of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ahmed Shalaby
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Robert A Wolff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - James Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Asif Rashid
- Division of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Janine Feng
- Ventana Medical Systems, Inc., Tucson, Arizona, USA
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Nakamura T. Changes in Expression of Bile Canalicular CD10 and Sinusoidal CD105 (Endoglin) in Peritumoral Hepatic Tissue. TUMORI JOURNAL 2018; 95:495-500. [DOI: 10.1177/030089160909500415] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Aims and background Hepatic tissues, including bile canaliculi and sinusoids, around primary or metastatic tumors are destructed and regenerate associated with tumor growth, and may show some phenotypic changes. The present study was undertaken to examine the expression of CD10 in bile canaliculi [CD10(BC)] and CD105 (endoglin) along hepatic sinusoids [CD105(HS)] in peritumoral hepatic tissue (PTH). Methods Fifty samples of resected liver bearing hepatocellular carcinoma (HCC) or metastatic carcinoma were immunostained for CD10 and CD105. The immunoreactivity for CD10(BC) and CD105(HS) in the background hepatic tissue of tumors and PTH was scored separately. Results CD10(BC) was moderately or markedly expressed in the background hepatic tissue without chronic hepatitis or cirrhosis in most of the cases, and was significantly downregulated in chronic hepatitis and cirrhosis. CD105(HS) was negative or minimally positive in most of the cases of hepatic tissue bearing metastatic carcinoma, and showed a significant increase in chronic hepatitis and cirrhosis. Compared with the background, PTH revealed significantly decreased CD10(BC) staining irrespective of HCC or metastatic carcinoma, and showed belt-like CD105(HS) expression in 66.7% of the cases of metastatic carcinoma and in 88.6% of those with HCC. Conclusions These data indicate that the expression patterns of CD10(BC) and CD105(HS) in PTH are similar to those in chronic hepatitis and cirrhosis, which may be caused by persistent injury and resultant regeneration of hepatic tissue.
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Ryu HS, Lee K, Shin E, Kim SH, Jing J, Jung HY, Lee H, Jang JJ. Comparative Analysis of Immunohistochemical Markers for Differential Diagnosis of Hepatocelluar Carcinoma and Cholangiocarcinoma. TUMORI JOURNAL 2018; 98:478-84. [DOI: 10.1177/030089161209800413] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and background Differential diagnosis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma is sometimes difficult to accurately perform. Methods Eight markers including cytokeratin 7 (CK7), cytokeratin 19 (CK19), MOC31, CD10, glypican 3 (GPC3), claudin 4, biglycan and high mobility group A1 (HMGA1) were immunohistochemically stained in samples from 179 surgically resected hepatocellular carcinomas and 127 intrahepatic cholangiocarcinomas, and the rates of marker expression were statistically compared. Results With the exception of biglycan, 7 of the 8 markers were found to have significantly different expression patterns when comparing the two types of cancer (P <0.05). In intrahepatic cholangiocarcinomas, the expression rates of CK7, CK19, MOC31, claudin 4 and HMGA1 were 83.4%, 89.0%, 88.2%, 69.2%, and 31.5%, respectively. These rates of expression in intrahepatic cholangiocarcinomas were all higher than in those in hepatocellular carcinomas (CK7, 31.3%; CK19, 10.1%; MOC31, 34.0%; claudin 4, 11.2%; and HMGA1, 19.5%). The expression rates of GPC3, CD10, and biglycan were 72.6%, 39.7% and 10.0%, respectively, in hepatocellular carcinoma. These were higher than the rates found in intrahepatic cholangiocarcinomas (GPC3, 7.0%; CD10, 18.1%; and biglycan, 7.0%). In a multivariate logistic regression analysis, GPC3, CK19, MOC31 and claudin 4 were found to be independent markers for differentially diagnosing intrahepatic cholangiocarcinoma. Conclusions Based on our results, GPC3 and CK19 can be used as first-line markers for differential diagnoses of hepatocellular carcinoma and intrahepatic cholangiocarcinoma (accuracy rate, 73.5%), and additional combined screening for claudin 4 and MOC31 markers in GPC3(-) and CK19(-) tumors might increase the accuracy rate for distinguishing hepatocellular carcinoma from intrahepatic cholangiocarcinoma to 88.5%.
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Affiliation(s)
- Han Suk Ryu
- Department of Pathology, Chung-Ang University Medical Center, Chung-Ang University College of Medicine, Seoul
| | - Kyounbun Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul
| | - Eun Shin
- Department of Pathology, Seoul National University College of Medicine, Seoul
| | - Soo Hee Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul
| | - Jin Jing
- Department of Pathology, Seoul National University College of Medicine, Seoul
| | - Hae Yeon Jung
- Department of Pathology, Seoul National University College of Medicine, Seoul
| | - Hyebin Lee
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ja-June Jang
- Department of Pathology, Seoul National University College of Medicine, Seoul
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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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Lu JG, Farukhi MA, Mayeda D, French SW. Hepatocellular carcinoma with neuroendocrine differentiation: a case report. Exp Mol Pathol 2017; 103:200-203. [DOI: 10.1016/j.yexmp.2017.09.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 09/18/2017] [Indexed: 12/17/2022]
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Abstract
BACKGROUND The liver is the most frequent site of metastatic disease, and metastatic disease to the liver is far more common than primary liver carcinoma in the United States. Pathologic evaluation of biopsy samples is key to establishing a correct diagnosis for patient management. Morphologic and immunoperoxidase studies, which are the standard for pathologic practice, accurately classify most tumors. Subclassification of carcinoma of unknown primary remains problematic. METHODS The author reviewed the literature for articles pertaining to liver biopsy, diagnosis of specific tumor types, utility of immunohistochemical markers, and microarray and proteomic analysis. RESULTS Sampling of liver lesions is best accomplished by combining fine-needle aspiration and needle core biopsy. Many malignancies have distinct morphologic and immunohistochemical patterns and can be correctly subclassified. Adenocarcinoma of unknown primary remains enigmatic since current immunohistochemical markers for this differential diagnosis lack specificity. Microarray analysis and proteomic analysis of tumors can provide distinct gene or protein expression profiles, respectively, for tumor classification. These technologies can be used with fine-needle aspiration and needle core biopsy samples. CONCLUSIONS Most metastatic malignancies in the liver may be correctly diagnosed using standard morphology and immunohistochemical techniques. However, subtyping of some carcinomas and identification of site of unknown primary remains problematic. New technologies may help to further refine our diagnostic capabilities.
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Affiliation(s)
- Barbara A Centeno
- Pathology Services, H. Lee Moffitt Cancer Center & Research Institute, Tampa FL 33612, USA.
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Choi WT, Kakar S. Immunohistochemistry in the Diagnosis of Hepatocellular Carcinoma. Gastroenterol Clin North Am 2017; 46:311-325. [PMID: 28506367 DOI: 10.1016/j.gtc.2017.01.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) can be difficult to distinguish from its mimics, including metastatic tumor, benign hepatocellular lesion, and high-grade dysplastic nodule, especially when limited biopsy material is available. Hence, the judicious use of immunohistochemical stains is necessary to establish a correct diagnosis. This article describes advantages and disadvantages of immunohistochemical markers that are most commonly used to distinguish between these lesions. Diagnostic workup of malignant liver mass (HCC and its histologic variants vs metastatic tumor) as well as well-differentiated hepatocellular lesion (well-differentiated HCC vs focal nodular hyperplasia vs hepatocellular adenoma) is also discussed.
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Affiliation(s)
- Won-Tak Choi
- Department of Pathology, University of California at San Francisco, 505 Parnassus Avenue, M552, Box 0102, San Francisco, CA 94143, USA.
| | - Sanjay Kakar
- Department of Pathology, University of California at San Francisco, 505 Parnassus Avenue, M543, Box 0102, San Francisco, CA 94143, USA
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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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Swaid F, Downs D, Rosemurgy AS. A practical approach to liver metastasis from unknown primary cancer: What surgeons need to know. Cancer Genet 2016; 209:559-566. [DOI: 10.1016/j.cancergen.2016.08.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 08/04/2016] [Indexed: 12/18/2022]
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Jin M, Zhou X, Yearsley M, Frankel WL. Liver Metastases of Neuroendocrine Tumors Rarely Show Overlapping Immunoprofile with Hepatocellular Carcinomas. Endocr Pathol 2016; 27:253-8. [PMID: 27300354 PMCID: PMC7090388 DOI: 10.1007/s12022-016-9442-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The distinction of hepatocellular carcinoma (HCC), neuroendocrine tumor (NET) metastatic to the liver, and cholangiocarcinoma (CC) can sometimes be challenging on small biopsies. Tissue microarrays were constructed from HCCs, NETs, and CCs. The immunoprofile was evaluated using HepPar1, glypican-3 (GPC3), synaptophysin (SYN), chromogranin A (CHR), CD56, MOC-31, and pCEA. One hundred thirteen HCCs, 48 NETs, and 44 CCs were included. Of HCCs, 107 (95 %) expressed HepPar1 and/or GPC3, 52 (46 %) both, and 97 (88 %) marked with pCEA (canalicular pattern). Seven (6 %) expressed CD56, of which 3 (3 %) expressed SYN. All 7 HCCs that expressed CD56 and/or SYN also expressed HepPar1 and/or GPC3, and none of the HCCs expressed CHR. Fourteen (13 %) expressed MOC-31. All 48 NETs expressed at least one neuroendocrine marker: 47 (98 %) positive for SYN, 40 (83 %) for CHR, 39 (81 %) for CD56, and 34 (71 %) for all three markers. None expressed HepPar1 or GPC3. All 44 CCs showed at least focal reactivity with MOC-31 and pCEA (membranous/cytoplasmic). One (2 %) was positive for HepPar1, 4 (9 %) for GPC3, 1 (2 %) for SYN and CHR, and 7 (16 %) for CD56. HCCs rarely express CD56 and SYN, while all express either HepPar1 or GPC3. NETs do not express HepPar1 or GPC3 and almost always express SYN, while CHR and CD56 are seen in most cases. Rare CCs focally express HepPar1 and GPC3. Utilizing a limited staining panel can efficiently distinguish HCCs, NETs, and CCs and help avoid diagnostic pitfalls on small biopsies.
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Affiliation(s)
- Ming Jin
- Department of Pathology, The Ohio State University Wexner Medical Center, 129 Hamilton Hall, Columbus, OH, 43210, USA
| | - Xiaoping Zhou
- Department of Pathology, The Ohio State University Wexner Medical Center, 129 Hamilton Hall, Columbus, OH, 43210, USA
| | - Martha Yearsley
- Department of Pathology, The Ohio State University Wexner Medical Center, 129 Hamilton Hall, Columbus, OH, 43210, USA
| | - Wendy L Frankel
- Department of Pathology, The Ohio State University Wexner Medical Center, 129 Hamilton Hall, Columbus, OH, 43210, USA.
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BSEP and MDR3: Useful Immunohistochemical Markers to Discriminate Hepatocellular Carcinomas From Intrahepatic Cholangiocarcinomas and Hepatoid Carcinomas. Am J Surg Pathol 2016; 40:689-96. [PMID: 26735860 DOI: 10.1097/pas.0000000000000585] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We herein examined the immunohistochemical expression of 2 hepatocyte-specific transporters (bile salt export pump [BSEP] and multidrug-resistance protein 3 [MDR3]) in hepatocellular carcinomas (HCCs, n=54), intrahepatic cholangiocarcinomas (n=34), combined hepatocellular and cholangiocarcinomas (n=23), and hepatoid carcinomas originated from extrahepatic organs (n=27) to compare their diagnostic values with those of arginase-1 (ARG1) and hepatocyte paraffin-1 (HepPar-1). BSEP was expressed in 91% of HCCs and MDR3 in 83%. Although their sensitivities were slightly lower than those of ARG1 (96%) and HepPar-1 (93%), the 2 transporters appeared to be more specific for HCCs. ARG1 and HepPar-1 were expressed in intrahepatic cholangiocarcinomas (9% and 6%) and hepatoid carcinomas (22% and 44%, respectively), whereas BSEP and MDR3 were entirely negative in these neoplasms, except for 1 case of BSEP-positive hepatoid carcinoma of the esophagus. The highly specific expression of BSEP and MDR3 in hepatocytes was recapitulated in additional examinations of combined hepatocellular and cholangiocarcinomas, in which the expression of the transporters was restricted to morphologically hepatocellular areas. In contrast, ARG1 and HepPar-1 were also variably positive in areas of biliary or indeterminate differentiation. We also applied BSEP and MDR3 immunohistochemistry to 8 biopsy cases of poorly differentiated primary liver cancer, in which the original diagnosis was not conclusive. The diagnosis of HCC was retrospectively suggested in 2 cases expressing both BSEP and MDR3. In conclusion, given the highly specific expression of BSEP and MDR3 in HCCs, immunohistochemistry for these transporters will be useful not only for determining hepatocellular differentiation in primary liver cancers but also for discriminating HCCs from hepatoid carcinomas.
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Askan G, Deshpande V, Klimstra DS, Adsay V, Sigel C, Shia J, Basturk O. Expression of Markers of Hepatocellular Differentiation in Pancreatic Acinar Cell Neoplasms: A Potential Diagnostic Pitfall. Am J Clin Pathol 2016; 146:163-9. [PMID: 27425386 DOI: 10.1093/ajcp/aqw096] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Pancreatic acinar cell carcinoma (ACC) is a rare tumor that frequently metastasizes to the liver and may present a diagnostic challenge due to its morphologic similarity to hepatocellular carcinoma. We investigated α-fetoprotein (AFP), hepatocyte paraffin antigen 1 (HepPar 1), glypican 3, arginase 1, and albumin messenger RNA (mRNA) in situ hybridization (ISH) in pancreatic neoplasms with ACC differentiation to assess their diagnostic value. METHODS AFP, HepPar 1, glypican 3, and arginase 1 immunohistochemical staining was performed on 28 ACCs using a tissue microarray. Albumin mRNA ISH was performed on full-faced sections. RESULTS Fifteen tumors were positive for at least one marker. Glypican 3 was positive in seven of 28, AFP in five 28, and albumin mRNA ISH in five of 20. None expressed arginase 1. CONCLUSIONS Hepatocellular differentiation markers, including albumin mRNA ISH, may be positive in ACC, but arginase 1 appears to be uniformly negative. Thus, its use may improve the accuracy in distinguishing these neoplasms from hepatocellular carcinoma. If ACC diagnosis is considered, acinar differentiation can be reliably demonstrated by trypsin/chymotrypsin.
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Affiliation(s)
- Gokce Askan
- From the Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | | | - Carlie Sigel
- From the Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jinru Shia
- From the Memorial Sloan Kettering Cancer Center, New York, NY
| | - Olca Basturk
- From the Memorial Sloan Kettering Cancer Center, New York, NY
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Tacha DE, Yu C, Zhou D, Haas T. A novel rabbit monoclonal antibody arginase-1 is highly specific and highly sensitive in hepatocellular carcinoma. J Histotechnol 2016. [DOI: 10.1179/2046023615y.0000000010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Xiong XL, Qin H, Yan SQ, Zhou LS, Chen P, Zhao DC. Expression of glypican-3 is highly associated with pediatric hepatoblastoma: a systemic analysis. Asian Pac J Cancer Prev 2015; 16:1029-31. [PMID: 25735325 DOI: 10.7314/apjcp.2015.16.3.1029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Glypican-3 (GPC3) is reported to be an oncofetal protein that is a useful diagnostic immunomarker for hepatoblastoma. However, the results are not inclusive. This study systemically investigated the association between expression of GPC3 and pediatric hepatoblastoma. METHODS Clinical studies evaluating the association were identified using a predefined search strategy. GPC3 immunohistochemistry was applied in the pathological diagnosis of hepatoblastoma using the monoclonal antibodies with formalin-fixed and paraffin-embedded specimens. Positive predictive rates for the association between expression of GPC3 and pediatric hepatoblastoma were calculated. RESULTS Specimens from four clinical studies which including 134 patients with pediatric hepatoblastoma tested by GPC3 immunohistochemistry were considered eligible for inclusion. Systemic analysis showed that, in all patients, pooled positive predictive rate of the association between expression of GPC3 and pediatric hepatoblastoma was 95.5% (128/134). CONCLUSION This systemic analysis suggests that the expression of glypican-3 is highly associated with the diagnosis of pediatric hepatoblastoma.
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Affiliation(s)
- Xiao-Li Xiong
- Dept. of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, China E-mail :
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Chiang KC, Yen CL, Yeh CN, Hsu JT, Chen LW, Kuo SF, Wang SY, Sun CC, Kittaka A, Chen TC, Yeh TS, Hsu SY, Juang HH. Hepatocellular carcinoma cells express 25(OH)D-1α-hydroxylase and are able to convert 25(OH)D to 1α,25(OH)₂D, leading to the 25(OH)D-induced growth inhibition. J Steroid Biochem Mol Biol 2015; 154:47-52. [PMID: 26170242 DOI: 10.1016/j.jsbmb.2015.06.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 06/14/2015] [Accepted: 06/16/2015] [Indexed: 01/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most diagnosed liver cancer without effective treatments available for advanced HCC. Vitamin D is getting popular due to its anti-cancer characteristics. However, the clinical application of 1α,25(OH)2D, the active form of vitamin, is hampered by its hypercalcemia side effect. 1α,25(OH)2D is converted from 25(OH)D, the index of serum vitamin D status, by CYP27B1, which is originally found in kidneys but recently detected in non-renal tissues. 25(OH)D has been shown to repress some cancers expressing CYP27B1 due to the local conversion of 25(OH)D to 1α,25(OH)2D, which works in a intra-, auto-, or paracrine manner and thus minimizes the risk of hypercalcemia. In this study, we found CYP27B1 expression in human hepatocyte, HCC, and HepG2 cells. As we treated HepG2 cells with 25(OH)D, the 1α,25(OH)2D target gene CYP24A1 expression was increased and was further upregulated as CYP27B1 transfection or downregulated as CYP27B1 knockdown. Other 1α,25(OH)2D target genes in HepG2 cells, p21 and p27 were also stimulated by 25(OH)D after CYP27B1 transfection. Further, 25(OH)D could inhibit HepG2 cells growth, which was potentiated by CYP27B1 transfection. Collectively, we showed for the first time that HCC expressed CYP27B1 and was able to covert 25(OH)D to 1α,25(OH)2D in vitro, thus responsive to 25(OH)D treatment. Our data justifies the application of 25(OH)D and CYP27B1 gene transfection therapy in further HCC treatment studies.
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Affiliation(s)
- Kun-Chun Chiang
- General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan, ROC
| | - Cho-Li Yen
- Gastroenterology Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan, ROC
| | - Chun-Nan Yeh
- General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC
| | - Jun-Te Hsu
- General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC
| | - Li-Wei Chen
- Gastroenterology Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan, ROC
| | - Sheng-Fong Kuo
- Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC
| | - Shang-Yu Wang
- General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC
| | - Chi-Chin Sun
- Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC
| | - Atsushi Kittaka
- Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo, Japan
| | - Tai C Chen
- Boston University School of Medicine, Boston, MA 02118, USA
| | - Ta-Sen Yeh
- General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan, ROC
| | - Shu-Yuan Hsu
- Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, TaoYuan, Taiwan, ROC
| | - Horng-Heng Juang
- Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, TaoYuan, Taiwan, ROC.
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Nguyen T, Phillips D, Jain D, Torbenson M, Wu TT, Yeh MM, Kakar S. Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma. Arch Pathol Lab Med 2015; 139:1028-34. [PMID: 26230595 DOI: 10.5858/arpa.2014-0479-oa] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
CONTEXT Several immunohistochemical markers are available to establish the diagnosis of hepatocellular carcinoma. Judicious selection is essential to achieve a reliable diagnosis in limited tissue provided by liver biopsy. OBJECTIVE To compare the efficacy of 5 hepatocellular markers for the diagnosis of hepatocellular carcinoma across various levels of differentiations. DESIGN Immunohistochemistry for hepatocyte paraffin antigen 1 (Hep Par 1), polyclonal carcinoembryonic antigen (CEA), glypican-3, arginase-1, and bile salt export pump transporter was performed in 79 hepatocellular carcinomas, yielding 93 observations (13 well-differentiated [14%], 41 moderately differentiated [44%], and 39 poorly differentiated [42%] tumors). RESULTS Arginase-1 and Hep Par 1 had the highest sensitivity for well-differentiated hepatocellular carcinoma, whereas arginase-1 and glypican-3 had the highest sensitivity for poorly differentiated hepatocellular carcinoma. When staining of more than 50% of the tumor was considered a positive result, arginase-1 remained the most sensitive marker for all differentiations, whereas sensitivity for Hep Par 1 in poorly differentiated hepatocellular carcinoma dropped to 30% and that of glypican-3 in well-differentiated hepatocellular carcinoma was 15%. The addition of Hep Par 1 and/or polyclonal CEA to arginase-1 did not lead to an increase in sensitivity for any differentiation. The combined use of arginase-1 and glypican-3 yielded 100% sensitivity for poorly differentiated hepatocellular carcinoma. CONCLUSION Arginase-1 was the most sensitive marker in all differentiations of hepatocellular carcinoma. Glypican-3 had high sensitivity for poorly differentiated cases and its combined use with arginase-1 enabled identification of nearly all cases of poorly differentiated hepatocellular carcinoma. Although bile salt export pump transporter has good overall sensitivity, it has a limited role in establishing hepatocellular differentiation when added to a panel of arginase-1 with either glypican-3 or Hep Par 1.
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Affiliation(s)
| | | | | | | | | | | | - Sanjay Kakar
- From the Department of Anatomic Pathology, University of California, San Francisco, (Drs Nguyen, Phillips, and Kakar); the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Dr Jain); the Department of Pathology, Johns Hopkins, Baltimore, Maryland (Dr Torbenson); the Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota (Dr Wu); the Department of Pathology, University of Washington, Seattle, (Dr Yeh); and the Department of Anatomic Pathology, Veteran Affairs Medical Center, San Francisco (Dr Kakar)
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43
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Kandalaft PL, Gown AM. Practical Applications in Immunohistochemistry: Carcinomas of Unknown Primary Site. Arch Pathol Lab Med 2015; 140:508-23. [PMID: 26457625 DOI: 10.5858/arpa.2015-0173-cp] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT -Identification of the site of origin of carcinoma of unknown primary using immunohistochemistry is a frequent requirement of anatomic pathologists. Diagnostic accuracy is crucial, particularly in the current era of targeted therapies and smaller sample sizes. OBJECTIVES -To provide practical guidance and suggestions for classifying carcinoma of unknown primary using both proven and new antibodies, as well as targeting panels based on integration of morphologic and clinical features. DATA SOURCES -Literature review, the authors' practice experience, and authors' research. CONCLUSIONS -With well-performed and interpreted immunohistochemistry panels, anatomic pathologists can successfully identify the site of origin of carcinoma of unknown primary. It is crucial to understand not only the diagnostic uses of the many available antibodies but also the potential limits and pitfalls.
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Affiliation(s)
- Patricia L Kandalaft
- Department of Immunohistochemistry and Anatomic Services, Pacific Pathology Partners, Seattle, Washington (Dr Kandalaft); PhenoPath Laboratories, Seattle (Dr Gown); and Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada (Dr Gown)
| | - Allen M Gown
- Department of Immunohistochemistry and Anatomic Services, Pacific Pathology Partners, Seattle, Washington (Dr Kandalaft); PhenoPath Laboratories, Seattle (Dr Gown); and Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada (Dr Gown)
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Yeh MM, Yeung RS, Apisarnthanarax S, Bhattacharya R, Cuevas C, Harris WP, Hon TLK, Padia SA, Park JO, Riggle KM, Daoud SS. Multidisciplinary perspective of hepatocellular carcinoma: A Pacific Northwest experience. World J Hepatol 2015; 7:1460-83. [PMID: 26085907 PMCID: PMC4462686 DOI: 10.4254/wjh.v7.i11.1460] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 04/03/2015] [Accepted: 04/27/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most rapidly increasing type of cancer in the United States. HCC is a highly malignant cancer, accounting for at least 14000 deaths in the United States annually, and it ranks third as a cause of cancer mortality in men. One major difficulty is that most patients with HCC are diagnosed when the disease is already at an advanced stage, and the cancer cannot be surgically removed. Furthermore, because almost all patients have cirrhosis, neither chemotherapy nor major resections are well tolerated. Clearly there is need of a multidisciplinary approach for the management of HCC. For example, there is a need for better understanding of the fundamental etiologic mechanisms that are involved in hepatocarcinogenesis, which could lead to the development of successful preventive and therapeutic modalities. It is also essential to define the cellular and molecular bases for malignant transformation of hepatocytes. Such knowledge would: (1) greatly facilitate the identification of patients at risk; (2) prompt efforts to decrease risk factors; and (3) improve surveillance and early diagnosis through diagnostic imaging modalities. Possible benefits extend also to the clinical management of this disease. Because there are many factors involved in pathogenesis of HCC, this paper reviews a multidisciplinary perspective of recent advances in basic and clinical understanding of HCC that include: molecular hepatocarcinogenesis, non-invasive diagnostics modalities, diagnostic pathology, surgical modality, transplantation, local therapy and oncological/target therapeutics.
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Affiliation(s)
- Matthew M Yeh
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - Raymond S Yeung
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - Smith Apisarnthanarax
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - Renuka Bhattacharya
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - Carlos Cuevas
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - William P Harris
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - Tony Lim Kiat Hon
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - Siddharth A Padia
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - James O Park
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - Kevin M Riggle
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
| | - Sayed S Daoud
- Matthew M Yeh, Raymond S Yeung, Department of Pathology, University of Washington School of Medicine, Seattle, WA 99210, United States
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Koehne de Gonzalez AK, Salomao MA, Lagana SM. Current concepts in the immunohistochemical evaluation of liver tumors. World J Hepatol 2015; 7:1403-1411. [PMID: 26052385 PMCID: PMC4450203 DOI: 10.4254/wjh.v7.i10.1403] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 01/01/2015] [Accepted: 03/05/2015] [Indexed: 02/06/2023] Open
Abstract
Immunohistochemistry often plays an important role in the evaluation of liver tumors. Recent advances have established a classification system for hepatocellular adenomas (HCAs) based on morphology, molecular alterations, and immunohistochemistry. Specifically, loss of liver fatty acid binding protein is seen in HNF1α-inactivated HCA, staining with serum amyloid A is seen in inflammatory HCA, and diffuse staining with glutamine synthetase (GS) is seen in β-catenin activated HCA. A panel of immunohistochemical stains including glypican-3 (GPC-3), heat shock protein 70, and GS are useful in distinguishing HCC from non-malignant dysplastic nodules. Immunohistochemistry is also useful to determine whether a liver tumor is of primary hepatocellular or metastatic origin. Recently described markers useful for this purpose include arginase-1, GPC-3, and bile salt export pump. These newer markers may offer superior utility when compared to traditional markers of hepatocellular differentiation such as alpha-fetoprotein, hepatocyte paraffin-1, polyclonal carcinoembryonic antigen, and CD10. This paper will review recent advances in the immunohistochemical evaluation of liver tumors.
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46
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Larson BK, Dhall D, Guindi M. Immunohistochemistry as a surrogate for molecular diagnosis in hepatic tumours. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/j.mpdhp.2015.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Branched chain in situ hybridization for albumin as a marker of hepatocellular differentiation: evaluation of manual and automated in situ hybridization platforms. Am J Surg Pathol 2015; 39:25-34. [PMID: 25353287 DOI: 10.1097/pas.0000000000000343] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Albumin, widely recognized as a highly sensitive and specific marker of hepatocellular carcinoma (HCC), is currently unavailable in the diagnostic laboratory because of the lack of a robust platform. In a prior study we detected albumin mRNA in the majority of intrahepatic cholangiocarcinomas using a novel branched chain RNA in situ hybridization (ISH) platform. We now explore the utility of albumin ISH as a marker of hepatocellular differentiation in HCCs, and compare its sensitivity with Hep Par 1 and Arginase-1. We evaluated 93 HCCs and its mimics including neuroendocrine tumors of the gastrointestinal tract (n=31), neuroendocrine tumors of the pancreas (n=163), melanoma (n=15), and gallbladder carcinoma (n=34). We performed ISH for albumin and immunohistochemistry for Hep Par 1 and Arginase-1. Five previously uncharacterized hepatic neoplasms from our files were also evaluated. Immunohistochemistry for Arginase-1 was performed on 59 intrahepatic cholangiocarcinomas. In addition, 43 HCCs evaluated on the manual platform were also examined on the automated instrument. Fifty-five percent of HCCs were moderately differentiated and 39% poorly differentiated. The sensitivity of ISH for albumin was 99%, with 92 of 93 HCCs staining positive for albumin. In contrast to ISH, the sensitivity of immunohistochemistry for Hep Par 1 and Arginase-1 was 84% and 83%, respectively. The sensitivity of albumin for poorly differentiated HCCs was 99%, whereas that for Arginase-1 and Hep Par 1 was 71% and 64%, respectively. Ninety-seven percent of the HCCs showed albumin positivity in >50% of tumor cells using the ISH platform, as compared with 76% and 70% for Hep Par 1 and Arginase-1 immunohistochemistry, respectively. Three of the 5 previously uncharacterized neoplasms were positive for albumin ISH. Automated albumin ISH platform performed equivalently to the manual format, with albumin reactivity in >50% of tumor cells in all 43 cases that were tested on both platforms. All non-HCCs were negative for albumin. All 59 intrahepatic cholangiocarcinomas were negative for Arginase-1. In conclusion, branched chain ISH performed on manual and automated mode is a robust assay for detecting albumin with sensitivity for poorly differentiated HCCs superior to Arginase-1 and Hep Par 1. When interpreted in conjunction with Arginase-1, albumin ISH offers a high level of sensitivity and specificity.
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48
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Lin F, Liu H. Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med 2015; 138:1583-610. [PMID: 25427040 DOI: 10.5858/arpa.2014-0061-ra] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Immunohistochemistry has become an indispensable ancillary study in the identification and classification of undifferentiated neoplasms/tumors of uncertain origin. The diagnostic accuracy has significantly improved because of the continuous discoveries of tissue-specific biomarkers and the development of effective immunohistochemical panels. OBJECTIVES To identify and classify undifferentiated neoplasms/tumors of uncertain origin by immunohistochemistry. DATA SOURCES Literature review and authors' research data and personal practice experience were used. CONCLUSIONS To better guide therapeutic decisions and predict prognostic outcomes, it is crucial to differentiate the specific lineage of an undifferentiated neoplasm. Application of appropriate immunohistochemical panels enables the accurate classification of most undifferentiated neoplasms. Knowing the utilities and pitfalls of each tissue-specific biomarker is essential for avoiding potential diagnostic errors because an absolutely tissue-specific biomarker is exceptionally rare. We review frequently used tissue-specific biomarkers, provide effective panels, and recommend diagnostic algorithms as a standard approach to undifferentiated neoplasms.
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Affiliation(s)
- Fan Lin
- From the Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania
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49
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Sang W, Zhang W, Cui W, Li X, Abulajiang G, Li Q. Arginase-1 is a more sensitive marker than HepPar-1 and AFP in differential diagnosis of hepatocellular carcinoma from nonhepatocellular carcinoma. Tumour Biol 2015; 36:3881-6. [DOI: 10.1007/s13277-014-3030-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 12/30/2014] [Indexed: 12/31/2022] Open
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50
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Aref AM, Hoa NT, Ge L, Agrawal A, Dacosta-Iyer M, Lambrecht N, Ouyang Y, Cornforth AN, Jadus MR. HCA519/TPX2: a potential T-cell tumor-associated antigen for human hepatocellular carcinoma. Onco Targets Ther 2014; 7:1061-70. [PMID: 24966688 PMCID: PMC4063820 DOI: 10.2147/ott.s61442] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background Immunotherapy for human hepatocellular cancer (HCC) is slowly making progress towards treating these fatal cancers. The identification of new antigens can improve this approach. We describe a possible new antigen, hepatocellular carcinoma‐associated antigen‐519/targeting protein for Xklp‐2 (HCA519/TPX2), for HCC that might be beneficial for T‐cell specific HCC immunotherapy. Methods HCC was studied for the expression for 15 tumor‐associated antigens considered useful for immunotherapy within three HCC cell lines (HepG2, Hep3B, and PLC/PRF/5), lymphocytes, non‐cancerous livers, and clinical HCC. The expression of tumor antigenic precursor proteins (TAPPs) messenger RNA was first screened by reverse transcriptase quantitative real‐time polymerase chain reaction. Results Four antigens (alpha fetoprotein, aspartyl/asparaginyl βhydroxylase, glypican3 and HCA519/TPX2) proved to be the best expressed TAPPs within the HCC specimens by molecular analyses. HCA519/TPX2 was detected by intracellular cell flow cytometry within HCC cell lines by using a specific antibody towards this TAPP. This antibody also detected the protein within primary HCCs. We synthesized two HCA519/TPX2 peptides (HCA519464–472 and HCA519351–359) which can bind to human leukocyte antigen (HLA)‐A*0201. Dendritic cells pulsed with these peptides stimulated cytolytic T lymphocytes (CTLs). These killer T‐cells lysed HLA‐A*0201+ T2 cells exogenously loaded with the correct specific peptide. The CTLs killed HepG2 (HLA‐A2+ and HCA519+), but not the Hep3B and PLC/PRF/5 cell lines, which are HCA519+ but HLA‐A2‐negative. In silico analysis reveals that HCA519/TPX2 has the inherent ability to bind to a very wide variety of HLA antigens. Conclusion HCA519/TPX2 is a viable immunotarget that should be further investigated within HCC patients.
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Affiliation(s)
- Ahmed M Aref
- Biological Science Department, Modern Sciences and Arts University, Faculty of Dentistry, Cairo, Egypt ; Southern California Institute for Research and Education, Veterans Affairs Medical Center, Long Beach, CA, USA ; Research Health Care Group, Veterans Affairs Medical Center Long Beach, CA, USA
| | - Neil T Hoa
- Research Health Care Group, Veterans Affairs Medical Center Long Beach, CA, USA
| | - Lisheng Ge
- Research Health Care Group, Veterans Affairs Medical Center Long Beach, CA, USA
| | - Anshu Agrawal
- Department of Medicine, Division of Basic and Clinical Immunology, University of California, Irvine, CA, USA
| | - Maria Dacosta-Iyer
- Pathology and Laboratory Medicine Department, Veterans Affairs Medical Center Long Beach, CA, USA ; Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA
| | - Nils Lambrecht
- Pathology and Laboratory Medicine Department, Veterans Affairs Medical Center Long Beach, CA, USA ; Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA
| | - Yi Ouyang
- Pathology and Laboratory Medicine Department, Veterans Affairs Medical Center Long Beach, CA, USA ; Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA
| | | | - Martin R Jadus
- Pathology and Laboratory Medicine Department, Veterans Affairs Medical Center Long Beach, CA, USA ; Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA ; Neuro-Oncology Program, Chao Comprehensive Cancer Center, University of California, Irvine, CA, USA
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