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Okino K, Wakasugi S, Ichihara S. Hyperechogenicity and histopathological features of focal liver lesions. J Med Ultrason (2001) 2025; 52:55-67. [PMID: 38958787 DOI: 10.1007/s10396-024-01475-3] [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: 01/18/2024] [Accepted: 05/23/2024] [Indexed: 07/04/2024]
Abstract
The identification and accurate diagnosis of focal liver lesions are important in modern medicine, where diagnostic radiology plays an essential role. This review aimed to examine the hyperechogenicity and histopathological features of focal liver lesions. Hyperechogenic liver lesions can be either benign or malignant. Evidence shows that hyperechogenicity is caused by factors such as fat deposition, sinusoidal dilation, peliotic changes, and pseudoglandular patterns. Fat deposition is a common cause of increased echogenicity in hepatocellular carcinoma (HCC). Meanwhile, sinusoidal dilation and peliotic changes are more frequently observed in larger HCC nodules. Pseudoglandular patterns, characterized by the reflection of ultrasound waves at the walls of numerous acini, are associated with hyperechogenicity in well-to-moderately differentiated HCCs. Moreover, this review comprehensively examined the histological features that may cause hyperechogenic internal echoes in not only HCCs but also localized liver lesions (metastases of adenocarcinoma and neuroendocrine neoplasm, intrahepatic cholangiocarcinoma, cavernous hemangioma, focal nodular hyperplasia, and angiomyolipoma). To make an accurate diagnosis and provide appropriate management, it is important to understand the histopathological basis for hyperechogenicity in focal liver lesions. By maximizing the accuracy of imaging studies and enhancing the radiology-pathology correlation, unnecessary biopsies can be avoided, thereby reducing potential complications and mortality. This review can help facilitate the effective management of patients with focal liver lesions, thereby resulting in timely and appropriate treatment decision-making.
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Affiliation(s)
- Kumiko Okino
- Department of Clinical Laboratory Medicine, School of Medical Technology, Health Sciences University of Hokkaido, Sapporo, Japan
| | - Satoshi Wakasugi
- Department of Internal Medicine, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan
| | - Shin Ichihara
- Department of Surgical Pathology, Sapporo Kosei General Hospital, Sapporo, Japan.
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Zou W, Fang Z, Feng Y, Gong S, Li Z, Li M, Sun Y, Ruan X, Fang X, Qu H, Li H. Transcriptomic and genomic characteristics of intrahepatic metastases of primary liver cancer. BMC Cancer 2024; 24:672. [PMID: 38824541 PMCID: PMC11144329 DOI: 10.1186/s12885-024-12428-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 05/24/2024] [Indexed: 06/03/2024] Open
Abstract
BACKGROUND Patients with primary multifocal hepatocellular carcinoma (HCC) have a poor prognosis and often experience a high rate of treatment failure. Multifocal HCC is mainly caused by intrahepatic metastasis (IM), and though portal vein tumor thrombosis (PVTT) is considered a hallmark of IM, the molecular mechanism by which primary HCC cells invade the portal veins remains unclear. Therefore, it is necessary to recognize the early signs of metastasis of HCC to arrange better treatment for patients. RESULTS To determine the differential molecular features between primary HCC with and without phenotype of metastasis, we used the CIBERSORTx software to deconvolute cell types from bulk RNA-Seq based on a single-cell transcriptomic dataset. According to the relative abundance of tumorigenic and metastatic hepatoma cells, VEGFA+ macrophages, effector memory T cells, and natural killer cells, HCC samples were divided into five groups: Pro-T, Mix, Pro-Meta, NKC, and MemT, and the transcriptomic and genomic features of the first three groups were analyzed. We found that the Pro-T group appeared to retain native hepatic metabolic activity, whereas the Pro-Meta group underwent dedifferentiation. Genes highly expressed in the group Pro-Meta often signify a worse outcome. CONCLUSIONS The HCC cohort can be well-typed and prognosis predicted according to tumor microenvironment components. Primary hepatocellular carcinoma may have obtained corresponding molecular features before metastasis occurred.
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Affiliation(s)
- Weilong Zou
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Zhanjie Fang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yu Feng
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Shangjin Gong
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ziqiang Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Meng Li
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yong Sun
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Xiuyan Ruan
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiangdong Fang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Hongzhu Qu
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Haiyang Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
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Kasuga R, Taniki N, Chu PS, Tamura M, Tabuchi T, Yamaguchi A, Hayatsu S, Koizumi J, Ojiro K, Hoshi H, Kaneko F, Morikawa R, Noguchi F, Yamataka K, Usui S, Ebinuma H, Itano O, Hasegawa Y, Abe Y, Kitago M, Inoue M, Nakatsuka S, Jinzaki M, Kitagawa Y, Kanai T, Nakamoto N. Multiple asynchronous recurrence as a predictive factor for refractoriness against locoregional and surgical therapy in patients with intermediate-stage hepatocellular carcinoma. Sci Rep 2024; 14:10896. [PMID: 38740983 DOI: 10.1038/s41598-024-61611-4] [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: 08/14/2023] [Accepted: 05/07/2024] [Indexed: 05/16/2024] Open
Abstract
Development of subclassification of intermediate-stage hepatocellular carcinoma (HCC) by treatment suitability is in demand. We aimed to identify predictors that define treatment refractoriness against locoregional(transarterial chemoembolization(TACE) or thermal ablation) and surgical therapy. This multicenter retrospective study enrolled 1167 HCC patients between 2015 and 2021. Of those, 209 patients were initially diagnosed with intermediate-stage HCC. Treatment refractoriness was defined as clinical settings that meets the following untreatable progressive conditions by TACE (1) 25% increase of intrahepatic tumor, (2) transient deterioration to Child-Pugh class C, (3) macrovascular invasion or extrahepatic spread, within one year. We then analyzed factors contributing to treatment refractoriness. The Child-Pugh score/class, number of tumors, infiltrative radiological type, and recurrence were significant factors. Focusing on recurrence as a predictor, median time to untreatable progression (TTUP) was 17.2 months in the recurrence subgroup whereas 35.5 months in the initial occurrence subgroup (HR, 2.06; 95% CI, 1.44-2.96; P = 0.001). Median TTUP decreased in cases with more later times of recurrence (3-5 recurrences, 17.3 months; ≥ 6 recurrences, 7.7 months). Recurrence, even more at later times, leads to increased treatment refractoriness. Early introduction of multidisciplinary treatment should be considered against HCC patients after multiple recurrent episodes.
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Affiliation(s)
- Ryosuke Kasuga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masashi Tamura
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Takaya Tabuchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Akihiro Yamaguchi
- Division of Gastroenterology, Department of Internal Medicine, National Hospital Organization Saitama National Hospital, Saitama, Japan
| | - Shigeo Hayatsu
- Department of Surgery, National Hospital Organization Saitama National Hospital, Saitama, Japan
| | - Jun Koizumi
- Department of Diagnostic Radiology and Radiation Oncology, School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Ojiro
- Department of Gastroenterology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
| | - Hitomi Hoshi
- Department of Gastroenterology and Hepatology, Saitama City Hospital, Saitama, Japan
| | - Fumihiko Kaneko
- Department of Gastroenterology and Hepatology, Saitama City Hospital, Saitama, Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Fumie Noguchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Karin Yamataka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Shingo Usui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
- Department of Gastroenterology, School of Medicine, International University of Health and Welfare, Chiba, Japan
| | - Osamu Itano
- Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, International University of Health and Welfare School of Medicine, Chiba, Japan
| | - Yasushi Hasegawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuta Abe
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Minoru Kitago
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masanori Inoue
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Seishi Nakatsuka
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Masahiro Jinzaki
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Choi JH, Thung SN. Advances in Histological and Molecular Classification of Hepatocellular Carcinoma. Biomedicines 2023; 11:2582. [PMID: 37761023 PMCID: PMC10526317 DOI: 10.3390/biomedicines11092582] [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: 07/13/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by hepatocellular differentiation. HCC is molecularly heterogeneous with a wide spectrum of histopathology. The prognosis of patients with HCC is generally poor, especially in those with advanced stages. HCC remains a diagnostic challenge for pathologists because of its morphological and phenotypic diversity. However, recent advances have enhanced our understanding of the molecular genetics and histological subtypes of HCC. Accurate diagnosis of HCC is important for patient management and prognosis. This review provides an update on HCC pathology, focusing on molecular genetics, histological subtypes, and diagnostic approaches.
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Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, Daegu 42415, Republic of Korea
| | - Swan N. Thung
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA;
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Comprehensive Analysis on the Specific Role and Function of Mitochondrial Inner Membrane Protein MPV17 in Liver Hepatocellular Carcinoma. Genet Res (Camb) 2022; 2022:7236823. [PMID: 35919033 PMCID: PMC9325347 DOI: 10.1155/2022/7236823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/06/2022] [Indexed: 11/25/2022] Open
Abstract
Background Liver hepatocellular carcinoma (LIHC) is the predominant type of liver cancer, and its treatment still faces great challenges presently. Mitochondrial inner membrane protein MPV17 is reported to be involved in multiple biological activities of cancers. Here, we seek to investigate the specific role and functions of MPV17 in LIHC progression. Methods Firstly, MPV17 expressions in various tumors and corresponding normal samples and LIHC groups with various clinical features were analyzed, respectively. Next, the relationship between MPV17 expression and LIHC survival was analyzed and verified by AUC curves. Besides, differentially expressed genes (DEGs) for LIHC were screened from TCGA and then analyzed by GO and KEGG. Then, MPV17 was analyzed by prognostic model, Cox analysis, predictive nomogram, pathway correlation, and immunoassay. Finally, the functions of MPV17 were determined by CCK-8 and Tranwell assays. Results In most tumors, MPV17 expression was higher than that in the normal group, and it was related to LIHC clinical features. In the LIHC survival analysis, highly expressed MPV17 was associated with a poor prognosis. Besides, 314 upregulated and 193 downregulated DEGs are mainly involved in the TNF signaling pathway and tyrosine metabolism. Through prognostic model, Cox analysis, and predictive nomogram, MPV17 had the prognostic value for LIHC. Gene-pathway correlation analysis showed that MPV17 had the strongest correlation with the G2M_checkpoint pathway. In an immunoassay, MPV17 had a strong correlation with many immune cells. Functional assays showed that MPV17 reduction in LIHC cells could inhibit cell invasion, migration, and proliferation. Conclusion MPV17, as a tumor promoter, could be a new biomarker for LIHC diagnosis and prognosis and probably shed new light on the exploration of LIHC therapies.
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Hepatitis C Virus Elimination Using Direct Acting Antivirals after the Radical Cure of Hepatocellular Carcinoma Suppresses the Recurrence of the Cancer. Cancers (Basel) 2022; 14:cancers14092295. [PMID: 35565424 PMCID: PMC9103530 DOI: 10.3390/cancers14092295] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 04/29/2022] [Accepted: 04/29/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary In patients with hepatitis C virus-related liver disease, direct-acting antivirals (DAAs) suppress the development of hepatocellular carcinoma (HCC). However, it is unclear whether their use after curative HCC treatment suppresses its recurrence in patients with hepatitis C virus-related liver disease. We retrospectively evaluated the inhibitory effect of DAAs on HCC recurrence using propensity score matching. Both the first and second HCC recurrence rates in the DAA-treated group were lower than those in the non-DAA-treated group, suggesting that the inhibitory effect of DAA therapy on HCC recurrence is sustained. Abstract It remains unclear whether hepatocellular carcinoma (HCC) recurrence in hepatitis C virus (HCV)-infected patients can be suppressed by the elimination of the virus using direct-acting antivirals (DAAs) after radical HCC treatment. We evaluated the sustained inhibitory effect of DAAs on HCC recurrence after curative treatment. This multicenter retrospective study included 190 HCV-positive patients after radical treatment for early-stage HCC. Patients were classified into the DAA treatment group (n = 70) and the non-DAA treatment group (n = 120) after HCC treatment. After propensity score matching (PSM), 112 patients were assessed for first and second recurrences using the Kaplan–Meier method and analyzed using a log-rank test. The first recurrence rates at 1 and 3 years were 3.6% and 42.1% in the DAA treatment group and 21.7% and 61.9% in the non-DAA treatment group, respectively (p = 0.0026). Among 85 patients who received radical treatment, the second recurrence rate at 3 years was 2.2% in the DAA treatment group and 33.9% in the non-DAA treatment group (p = 0.0128). In HCV-positive patients with early-stage HCC, the first and second recurrences were suppressed by DAA therapy after radical treatment, suggesting that the inhibitory effect of DAA therapy on HCC recurrence was sustained.
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Diao P, Jia F, Wang X, Hu X, Kimura T, Nakajima T, Aoyama T, Moriya K, Koike K, Tanaka N. Mechanisms of Steatosis-Derived Hepatocarcinogenesis: Lessons from HCV Core Gene Transgenic Mice. ENGINEERING 2021; 7:1797-1805. [DOI: 10.1016/j.eng.2021.08.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
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Histological Heterogeneity of Primary Liver Cancers: Clinical Relevance, Diagnostic Pitfalls and the Pathologist's Role. Cancers (Basel) 2021; 13:cancers13122871. [PMID: 34201284 PMCID: PMC8228556 DOI: 10.3390/cancers13122871] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/05/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Primary liver cancers (PLCs) mainly comprise hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and combined (c)HCC-CCA. Both small duct types iCCA (a subtype pf iCCA) and cHCC-CCA are known to be tumors with histological heterogeneity. Understanding key tumor heterogeneity is crucial as it reflects tumor aggressiveness, patient outcome, treatment choice, and is predictive of treatment efficacy. In addition, PLCs often present with multiple liver tumors, which can be a combination of different types of PLCs or HCCs (intrahepatic metastasis or multicentric occurrence), and the pathological interpretation plays an important role in these cases. The aim of this review is to clarify the pathological features of HCC, iCCA, and cHCC-CCA, including their diagnostic pitfalls, molecular profiles, and the correlation between tumor subtypes and treatment choice. Abstract Primary liver cancers (PLCs) mainly comprise hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and cHCC-CCA. Combined HCC-CCA and small duct type iCCA show similar clinical presentations, and their histological features are more complex than seen in HCC. Therefore, while their treatment strategy differs, it is difficult to properly diagnose these tumors. Currently, HCC is the only tumor that can be treated by liver transplantation. In addition, small duct type iCCA harbors IDH1/2 mutations and FGFR2 fusions, which can be used for targeted therapy. Thus, improving diagnostic accuracy is crucial. A further point to note is that PLCs often present as multiple liver tumors, and they can be a combination of different types of PLCs or HCCs. In the case of HCCs, two different scenarios are possible, namely intrahepatic metastasis, or multicentric occurrence. Therefore, it is essential to characterize the type of multiple liver tumors. This review aims to clarify the pathological features of HCC, iCCA and cHCC-CCA, including their diagnostic pitfalls and clinical relevance. It is designed to be of use to clinicians who are dealing with PLCs, to provide a better understanding of the pathology of these tumors, and to enable a more accurate diagnosis and optimal treatment choice.
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Sun TG, Wang XJ, Cao L, Li JW, Chen J, Li XS, Liao KX, Cao Y, Zheng SG. Laparoscopic anterior hepatic transection for resecting lesions originating in the paracaval portion of the caudate lobe (with videos). Surg Endosc 2021; 35:5352-5358. [PMID: 33835250 DOI: 10.1007/s00464-021-08455-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 03/17/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND The paracaval portion of the caudate lobe is located in the core of the liver. Lesions originating in the paracaval portion often cling to or even invade major hepatic vascular structures. The traditional open anterior hepatic transection approach has been adopted to treat paracaval-originating lesions. With the development of laparoscopic surgery, paracaval-originating lesions are no longer an absolute contraindication for laparoscopic liver resection. This study aimed to evaluate the safety and feasibility of laparoscopic anterior hepatic transection for resecting paracaval-originating lesions. METHODS This study included 15 patients who underwent laparoscopic anterior hepatic transection for paracaval-originating lesion resection between August 2017 and April 2020. The perioperative indicators, follow-up results, operative techniques and surgical indications were retrospectively evaluated. RESULTS All patients underwent laparoscopic anterior hepatic transection for paracaval-originating lesion resection. The median operation time was 305 min (220-740 min), the median intraoperative blood loss was 400 ml (250-3600 ml), and the median length of postoperative hospital stay was 9 days (5-20 days). No conversion to laparotomy or perioperative deaths occurred. Six patients had Clavien grade III-IV complications (III/IV, 5/1). Two patients developed tumor recurrence after 13 months and 8 months. CONCLUSION Although technically challenging, laparoscopic anterior hepatic transection is still a safe and feasible procedure for resecting paracaval-originating lesions in select patients.
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Affiliation(s)
- Tian-Ge Sun
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China
| | - Xiao-Jun Wang
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China
| | - Li Cao
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China
| | - Jian-Wei Li
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China
| | - Jian Chen
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China
| | - Xue-Song Li
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China
| | - Ke-Xi Liao
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China
| | - Yong Cao
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China
| | - Shu-Guo Zheng
- Institute of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing, 400038, China.
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Wang H, Qian YW, Wu MC, Cong WM. Liver Resection Is Justified in Patients with BCLC Intermediate Stage Hepatocellular Carcinoma without Microvascular Invasion. J Gastrointest Surg 2020; 24:2737-2747. [PMID: 31768830 DOI: 10.1007/s11605-019-04251-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 04/24/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Large, multinodular (> 3 nodules and/or > 3 cm) hepatocellular carcinoma (HCC) is not an indication for liver resection based on the Barcelona Clinic Liver Cancer (BCLC) staging classification. We hypothesize that microvascular invasion (MVI) is a strong indication for surgery in these patients. METHODS Between December 2009 and December 2010, a retrospective cohort of the patients with BCLC intermediate stage HCC undergoing surgical resection at Eastern Hepatobiliary Surgery Hospital was analyzed. Propensity score matching (PSM) was conducted to balance the patients with regard to their baseline characteristics. Survival analysis was performed according to the Kaplan-Meier method. Logistic regression was conducted to identify the predictors of MVI. Risk factors were evaluated using the Cox proportional hazards model. RESULTS Among 323 patients, the MVI-negative group (26.0%) had a more favorable prognosis than did the MVI-positive group (5-year recurrence-free survival: 25.2% vs. 7.8%; 5-year overall survival: 49.5% vs. 24.0%). Similar results were identified after PSM. Compared with MVI-negative patients, MVI-positive patients experienced more early recurrence (< 2 years, P = 0.006), multinodular recurrence (P = 0.004), and extrahepatic recurrence (P = 0.026). Total bilirubin levels > 17.1 μmol/L, alpha fetal protein levels > 400 ng/mL, the presence of > 2 nodules, and the lack of a capsule were independent predictors of MVI. CONCLUSIONS In BCLC intermediate stage HCC, MVI predicted an adverse recurrence pattern and poor prognosis and has the potential to be used as a reference index when deciding whether to operate. Factors predictive of MVI could assist in choosing preoperative treatment and postoperative surveillance.
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Affiliation(s)
- Han Wang
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, China
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, The Second Military Medical University, Ministry of Education, Yangpu, Shanghai, 200438, China
- Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Yangpu, Shanghai, 200438, China
| | - You-Wen Qian
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, China
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, The Second Military Medical University, Ministry of Education, Yangpu, Shanghai, 200438, China
- Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Yangpu, Shanghai, 200438, China
| | - Meng-Chao Wu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, The Second Military Medical University, Ministry of Education, Yangpu, Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Yangpu, Shanghai, 200438, China.
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Takeda H, Takai A, Kumagai K, Iguchi E, Arasawa S, Eso Y, Shimizu T, Ueda Y, Taura K, Uemoto S, Kita R, Haga H, Marusawa H, Fujimoto A, Seno H. Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution. J Pathol 2020; 252:398-410. [PMID: 32815153 DOI: 10.1002/path.5533] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/22/2020] [Accepted: 08/10/2020] [Indexed: 01/04/2025]
Abstract
Recent genetic analyses revealed genetic heterogeneity in hepatocellular carcinoma (HCC), although it remains unclear how genetic alterations contribute to the multistage progression of HCC, especially the early step from hypovascular liver nodules to hypervascular HCC. We conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC surrounded by hypovascular HCC arising from a common origin, and identified point mutations, structural variations, and copy-number variations in each specimen. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, we examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. We first demonstrated that most tumor cells consisting of hypovascular well-differentiated HCCs already harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. Further, differences in the trunk and branch mutational signatures suggested a multistep contribution to the mutagenesis in each case. In conclusion, genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy. These data shed light on the process of multistep hepatocarcinogenesis and will be helpful toward investigating new therapeutic strategies for HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Kumagai
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eriko Iguchi
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Soichi Arasawa
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuji Eso
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Shimizu
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryuichi Kita
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Akihiro Fujimoto
- Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology; Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Ryu T, Takami Y, Wada Y, Sasaki S, Imamura H, Ureshino H, Saitsu H. Combined hepatectomy and microwave ablation for multifocal hepatocellular carcinoma: Long-term outcomes and prognostic factors. Asian J Surg 2020; 44:186-191. [PMID: 32473893 DOI: 10.1016/j.asjsur.2020.05.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 05/07/2020] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND It remains to be clarified whether combined hepatectomy and microwave ablation for multifocal hepatocellular carcinoma (HCC) is feasible. This aim of this study was to examine the perioperative and oncological outcomes after combined hepatectomy and microwave ablation for multifocal HCC. METHODS This retrospective study included 81 patients who underwent combined hepatectomy and microwave ablation for multifocal HCC in our institute between June 1998 and December 2017. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis. RESULTS Median follow-up time was 45.6 months for the entire cohort. OS rates were 1-year: 96%, 3-year: 72%, and 5-year: 54%; RFS rates were 1-year: 77%, 3-year: 37%, and 5-year: 22%. The major complication rate (Clavien-Dindo classification IIIa or above) after surgery was 10%, with one patient of in-hospital mortality. Multivariate analysis revealed that des-γ-carboxy prothrombin level >200 mAU/mL and >5 tumors were independent risk factors for OS, and des-γ-carboxy prothrombin level >200 mAU/mL, > 5 tumors, and maximum tumor size >5 cm were independent risk factors for RFS. CONCLUSIONS Our results indicate that combined hepatectomy and microwave ablation is safe and feasible for selected patients with multifocal HCC.
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Affiliation(s)
- Tomoki Ryu
- Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
| | - Yuko Takami
- Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yoshiyuki Wada
- Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Shin Sasaki
- Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Hajime Imamura
- Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Hiroki Ureshino
- Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Hideki Saitsu
- Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
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Dong LQ, Peng LH, Ma LJ, Liu DB, Zhang S, Luo SZ, Rao JH, Zhu HW, Yang SX, Xi SJ, Chen M, Xie FF, Li FQ, Li WH, Ye C, Lin LY, Wang YJ, Wang XY, Gao DM, Zhou H, Yang HM, Wang J, Zhu SD, Wang XD, Cao Y, Zhou J, Fan J, Wu K, Gao Q. Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma. J Hepatol 2020; 72:896-908. [PMID: 31887370 DOI: 10.1016/j.jhep.2019.12.014] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 10/29/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy. METHODS We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions. RESULTS IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038). CONCLUSION Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC. LAY SUMMARY Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC.
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Affiliation(s)
- Liang-Qing Dong
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | | | - Li-Jie Ma
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Dong-Bing Liu
- BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI-Shenzhen, Shenzhen 518083, China
| | - Shu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | | | | | - Hong-Wen Zhu
- Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Shuai-Xi Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Shui-Jun Xi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Min Chen
- CAS Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, CAS enter for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | | | | | | | - Chen Ye
- BGI-Shenzhen, Shenzhen 518083, China
| | - Li-Ya Lin
- BGI-Shenzhen, Shenzhen 518083, China
| | | | - Xiao-Ying Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
| | - Da-Ming Gao
- CAS Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, CAS enter for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hu Zhou
- Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Huan-Ming Yang
- BGI-Shenzhen, Shenzhen 518083, China; James D. Watson Institute of Genome Sciences, Hangzhou 310058, China
| | - Jian Wang
- BGI-Shenzhen, Shenzhen 518083, China; James D. Watson Institute of Genome Sciences, Hangzhou 310058, China
| | - Shi-da Zhu
- BGI-Shenzhen, Shenzhen 518083, China; Department of Biology, University of Copenhagen, Copenhagen N DK-2200, Denmark
| | - Xiang-Dong Wang
- Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ya Cao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China
| | - Kui Wu
- BGI-Shenzhen, Shenzhen 518083, China; Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI-Shenzhen, Shenzhen 518083, China; Department of Biology, University of Copenhagen, Copenhagen N DK-2200, Denmark.
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
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Abstract
Hepatocellular carcinoma (HCC) is characterized by high prevalence of multifocality. Multifocal HCC can arise synchronously or metachronously either from intrahepatic metastasis (IM) or multicentric occurrence (MO). To date, there have been no established criteria to accurately distinguish whether multifocal HCC originates from IM or MO. Histopathological features remain the most convenient strategy but with subjectivity and limited accuracy. Various molecular biological techniques involving assessment of TP53 mutation status, hepatitis B virus integration sites, and chromosomal alterations have been applied to determine the clonal origin. The introduction of next-generation sequencing facilitates a more comprehensive annotation of intertumor heterogeneity, resulting in more sensitive and accurate clonal discrimination. Generally, MO-HCC has better overall survival than IM-HCC after curative resection. Adjuvant antiviral treatment has been proved to decrease post-treatment recurrence probably by reducing MO-HCC recurrence, whereas adjuvant sorafenib treatment targeting prior micrometastasis failed to reduce IM-HCC recurrence. Recent studies recommended transcatheter arterial chemoembolization (TACE) and traditional Chinese medicine Huaier granule as effective adjuvant treatments probably by preventing IM and both types of recurrences respectively. Immunotherapy that inhibits immune checkpoint interaction may be an optimal choice for both MO- and IM-HCC. In the future, effective personalized therapy against multifocal HCC may be achieved.
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Takayama H, Ohta M, Iwashita Y, Uchida H, Shitomi Y, Yada K, Inomata M. Altered glycosylation associated with dedifferentiation of hepatocellular carcinoma: a lectin microarray-based study. BMC Cancer 2020; 20:192. [PMID: 32143591 PMCID: PMC7060603 DOI: 10.1186/s12885-020-6699-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 02/28/2020] [Indexed: 12/13/2022] Open
Abstract
Background Altered glycosylation associated with hepatocellular carcinoma (HCC) is well documented. However, few reports have investigated the association between dedifferentiation and glycosylation. Therefore, the aim of this study was to analyze glycosylation associated with dedifferentiation of HCC within the same nodule and to investigate glycosyltransferase related to the glycosylation. Methods We analyzed resected HCC specimens (n = 50) using lectin microarray to comprehensively and sensitively analyze glycan profiles, and identify changes to glycosylation between well- and moderately-differentiated components within the same nodule. Moreover, we performed immunohistochemical staining of mannosyl(α-1,3-)-glycoprotein β-1,2-N-acetylglucosaminyltransferase (MGAT1), which is an essential glycosyltransferase that converts high-mannose glycans to complex- or hybrid-type N-glycans. Results Four lectins from Narcissus pseudonarcissus agglutinin (NPA), Concanavalin A, Galanthus nivalis agglutinin, and Calystegia sepium agglutinin were significantly elevated in moderately-differentiated components of HCC compared with well-differentiated components, and all lectins showed binding specificity to high-mannose glycans. Therefore, these structures were represented to a greater extent in moderately-differentiated components than in well-differentiated ones. Immunohistochemical staining revealed significantly increased NPA expression and decreased MGAT1 expression in moderately-differentiated components. Low MGAT1 expression in moderately-differentiated components of tumors was associated with intrahepatic metastasis and had tendency for poor prognosis. Conclusion Dedifferentiation of well-differentiated HCC is associated with an increase in high-mannose glycans. MGAT1 may play a role in the dedifferentiation of HCC.
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Affiliation(s)
- Hiroomi Takayama
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.
| | - Masayuki Ohta
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.,Global Oita Medical Advanced Research Center for Health, Oita University, Oita, Japan
| | - Yukio Iwashita
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Hiroki Uchida
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Yuki Shitomi
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Kazuhiro Yada
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
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Wang H, Feng LH, Qian YW, Cao ZY, Wu MC, Cong WM. Does microvascular invasion in Barcelona Clinic Liver Cancer stage A multinodular hepatocellular carcinoma indicate early-stage behavior? ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:428. [PMID: 31700864 DOI: 10.21037/atm.2019.08.114] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background To identify the impact of tumor number on Barcelona Clinic Liver Cancer (BCLC) early-stage hepatocellular carcinoma (HCC) and the impact of microvascular invasion (MVI) on multinodular HCC (MHCC). Methods We retrospectively analyzed 1,548 patients who had early-stage HCC [solitary HCC (SHCC, n=1,481) and MHCC (n=67)], according to the BCLC classification, after curative resection. Recurrence-free survival (RFS) and overall survival (OS) were compared. Propensity score matching (PSM) was used to balance potential confounding factors. Results Both before and after PSM, significant differences were noted between the MHCC group and the SHCC group in RFS but not in OS. For the PSM cohort, the 5-year RFS rates were 7.5% and 41.2% for the MVI-positive MHCC group and the SHCC group, respectively (P<0.001). The 5-year OS rates were 48.9% and 75.2% for the MVI-positive MHCC group and the SHCC group, respectively (P=0.017). The RFS and OS were not significantly different between the MVI-negative MHCC group and the SHCC group. MVI (P=0.029) and multiple nodules (P=0.029) were associated with early recurrence. Conclusions The presence of MVI in BCLC early-stage MHCC was highly suggestive of a poor prognosis and should not be classified as early-stage biological behavior.
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Affiliation(s)
- Han Wang
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (The Second Military Medical University) Ministry of Education, Shanghai 200438, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (Eastern Hepatobiliary Surgery Hospital), Shanghai 200438, China
| | - Long-Hai Feng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, The Key Laboratory for Carcinogenesis and Cancer Invasion, The Ministry of Education of China, Shanghai 200032, China
| | - You-Wen Qian
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (The Second Military Medical University) Ministry of Education, Shanghai 200438, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (Eastern Hepatobiliary Surgery Hospital), Shanghai 200438, China
| | - Zhen-Ying Cao
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (The Second Military Medical University) Ministry of Education, Shanghai 200438, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (Eastern Hepatobiliary Surgery Hospital), Shanghai 200438, China
| | - Meng-Chao Wu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (The Second Military Medical University) Ministry of Education, Shanghai 200438, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (Eastern Hepatobiliary Surgery Hospital), Shanghai 200438, China
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Xu D, Liu X, Wang L, Xing B. Hepatectomy plus adjuvant transcatheter arterial chemoembolization improves the survival rate of patients with multicentric occurrence of hepatocellular carcinoma. Oncol Lett 2018; 16:5882-5890. [PMID: 30344739 PMCID: PMC6176366 DOI: 10.3892/ol.2018.9333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 06/29/2018] [Indexed: 01/27/2023] Open
Abstract
The aim of the present study was to evaluate the role of hepatectomy plus adjuvant transcatheter arterial chemoembolization (TACE) in patients with multicentric occurrence (MO) or intrahepatic metastases (IM) of hepatocellular carcinoma (HCC). Patients with multifocal HCC who underwent hepatic resection only (HR) or HR plus adjuvant TACE (HRT) between January 2005 and December 2015 were divided into MO or IM groups. The patient characteristics and outcomes were retrospectively analyzed. A total of 103 patients (59 and 44 in the MO and IM groups, respectively) were included in the analysis. The 1-, 3- and 5-year overall survival (OS) rates were 92.7, 76.8 and 56.8% for the MO group, and 93.1, 41.6 and 18.5% for the IM group, respectively (OS, P=0.001), and the 1-, 3- and 5-year disease-free survival (DFS) rates were 84.1, 44.6 and 40.5% for the MO group and 51.7, 22.5 and 15.0% for the IM group, respectively (DFS, P<0.001). In the subgroup analysis, the overall survival were significantly better in the MO-HRT group compared with those in the MO-HR group (P=0.019), which was also observed between the IM-HRT and IM-HR groups (P=0.132). Furthermore, the 1-, 3- and 5-year OS demonstrated non-significant differences between patients with <3 and ≥3 tumors in the MO-HR group (P=0.300), but significantly reduced OS for patients with ≥3 tumors in the IM-HR group compared with that for patients with <3 tumors (P=0.132). In conclusion, surgical resection combined with adjuvant TACE may result in significantly increased survival rates of patients with MO-HCC. Tumor number should not be an absolute contradiction to hepatectomy in patients with MO-HCC.
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Affiliation(s)
- Da Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Xiaofeng Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Lijun Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Baocai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-like Lesions of the Liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:780-879. [DOI: 10.1016/b978-0-7020-6697-9.00013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Higaki T, Midorikawa Y, Nakashima Y, Nakayama H, Matsuoka S, Moriyama M, Sugitani M, Takayama T. Clinical correspondence to hepatocellular carcinoma-related lesions with atypical radiological pattern. Biosci Trends 2017. [PMID: 28626210 DOI: 10.5582/bst.2017.01110] [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: 11/05/2022]
Abstract
In patients at risk of hepatocarcinogenesis, tumors are frequently detected with atypical radiological patterns related to hepatocellular carcinoma (HCC) on imaging studies. Despite their high potential for malignancy, whether to resect such lesions immediately is controversial. Based on histological findings, patients with non-enhanced tumors or enhanced tumors without washout were divided into two groups: those with tumors that should be treated containing well, moderately, and poorly differentiated HCC (Group 1), and those that can be observed containing early HCC, hepatocellular adenoma, focal nodular hyperplasia, dysplastic nodules, and regenerative nodules (Group 2), and we elucidated the clinical correspondence to these tumors. Seventy-two patients had a single tumor with atypical radiological pattern: 39 patients had HCC (Group 1), while 33 patients had benign tumors or early HCC (Group 2). Among nine baseline variables, serum α-fetoprotein (AFP) level in Group 1 (median, 13.2 ng/mL; range, 0.6-5881.6) was significantly higher than that in Group 2 (5.6 ng/mL; 0.8-86.3, P = 0.003). The cut-off value of AFP was 36.4 ng/mL for prediction of Group 1, and the median overall and recurrence-free survival periods of 23 patients in the high-AFP (≥ 36.4 ng/mL) group (5.3 years; 95%CI, 2.1 - N.A. and 1.6 years; 0.5-2.2) were significantly shorter than those of the 49 patients in the low-AFP (< 36.4) group (7.5 years; 7.5 - N.A., P = 0.047, and 2.8 years; 1.9-3.3, P = 0.001). Taken together, HCC-related tumors with an atypical radiological pattern could be observed unless serum AFP level is elevated.
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Affiliation(s)
- Tokio Higaki
- Department of Digestive Surgery, Nihon University School of Medicine
| | - Yutaka Midorikawa
- Department of Digestive Surgery, Nihon University School of Medicine
| | - Yosuke Nakashima
- Department of Digestive Surgery, Nihon University School of Medicine
| | - Hisashi Nakayama
- Department of Digestive Surgery, Nihon University School of Medicine
| | - Shunichi Matsuoka
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine
| | - Mitsuhiko Moriyama
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine
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Ebisawa K, Midorikawa Y, Higaki T, Nakayama H, Tsuji S, Nishimaki H, Haradome H, Abe O, Sugitani M, Moriyama M, Takayama T. Natural history of nonenhancing lesions incidentally detected during the diagnosis of hepatocellular carcinoma. Surgery 2016; 160:654-60. [DOI: 10.1016/j.surg.2016.04.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 03/30/2016] [Accepted: 04/13/2016] [Indexed: 02/06/2023]
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22
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Abraham JA, Golubnitschaja O. Time for paradigm change in management of hepatocellular carcinoma: is a personalized approach on the horizon? Per Med 2016; 13:455-467. [PMID: 29767598 DOI: 10.2217/pme-2016-0013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer form but the second leading cause of all cancer-related deaths. There are several reasons for high mortality in the HCC cohort: lack of effective screening programs and consequently late diagnosis, multifactorial origin with cumulative risk factors, complex carcinogenesis, tumor heterogeneity, unpredictable impacts of individual microenvironment on tumor development and progression, and, as the consequence, frequently untargeted therapy and cancer resistance toward currently applied treatment approaches. The currently applied 'treat and wait' approach is inappropriate in the overall HCC management. Urgent need in paradigm change toward predictive, preventive and personalized medicine is discussed in this review article. Innovative strategies for an advanced predictive, preventive and personalized medicine approach in the overall HCC management benefiting the patient are presented.
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Affiliation(s)
- Jella-Andrea Abraham
- Department of Radiology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
| | - Olga Golubnitschaja
- Department of Radiology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
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23
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Shi JY, Xing Q, Duan M, Wang ZC, Yang LX, Zhao YJ, Wang XY, Liu Y, Deng M, Ding ZB, Ke AW, Zhou J, Fan J, Cao Y, Wang J, Xi R, Gao Q. Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity. Oncotarget 2016; 7:2867-2877. [PMID: 26672766 PMCID: PMC4823077 DOI: 10.18632/oncotarget.6558] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 11/21/2015] [Indexed: 02/07/2023] Open
Abstract
Multifocal tumors developed either as independent tumors or as intrahepatic metastases, are very common in primary liver cancer. However, their molecular pathogenesis remains elusive. Herein, a patient with synchronous two hepatocellular carcinoma (HCC, designated as HCC-A and HCC-B) and one intrahepatic cholangiocarcinoma (ICC), as well as two postoperative recurrent tumors, was enrolled. Multiregional whole-exome sequencing was applied to these tumors to delineate the clonality and heterogeneity. The three primary tumors showed almost no overlaps in mutations and copy number variations. Within each tumor, multiregional sequencing data showed varied intratumoral heterogeneity (21.6% in HCC-A, 20.4% in HCC-B, 53.2% in ICC). The mutational profile of two recurrent tumors showed obvious similarity with HCC-A (86.7% and 86.6% respectively), rather than others, indicating that they originated from HCC-A. The evolutionary history of the two recurrent tumors indicated that intrahepatic micro-metastasis could be an early event during HCC progression. Notably, FAT4 was the only gene mutated in two primary HCCs and the recurrences. Mutation prevalence screen and functional experiments showed that FAT4, harboring somatic coding mutations in 26.7% of HCC, could potently inhibit growth and invasion of HCC cells. In HCC patients, both FAT4 expression and FAT4 mutational status significantly correlated with patient prognosis. Together, our findings suggest that spatial and temporal dissection of genomic alterations during the progression of multifocal liver cancer may help to elucidate the basis for its dismal prognosis. FAT4 acts as a putative tumor suppressor that is frequently inactivated in human HCC.
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Affiliation(s)
- Jie-Yi Shi
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
| | - Qingfeng Xing
- School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China
| | - Meng Duan
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
| | - Zhi-Chao Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
| | - Liu-Xiao Yang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
| | - Ying-Jun Zhao
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shangai, P. R. China
| | - Xiao-Ying Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
| | - Yun Liu
- School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China
| | - Minghua Deng
- School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China
| | - Zhen-Bin Ding
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
| | - Ai-Wu Ke
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
- Institute of Biomedical Sciences, Fudan University, Shanghai, P. R. China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
- Institute of Biomedical Sciences, Fudan University, Shanghai, P. R. China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, P. R. China
| | - Jiping Wang
- Division of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ruibin Xi
- School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, P. R. China
| | - Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
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24
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Kanda T, Ogasawara S, Chiba T, Haga Y, Omata M, Yokosuka O. Current management of patients with hepatocellular carcinoma. World J Hepatol 2015; 7:1913-1920. [PMID: 26244066 PMCID: PMC4517151 DOI: 10.4254/wjh.v7.i15.1913] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 05/02/2015] [Accepted: 06/04/2015] [Indexed: 02/06/2023] Open
Abstract
The current management therapies for hepatocellular carcinoma (HCC) patients are discussed in this review. Despite the development of new therapies, HCC remains a "difficult to treat" cancer because HCC typically occurs in advanced liver disease or hepatic cirrhosis. The progression of multistep and multicentric HCC hampers the prevention of the recurrence of HCC. Many HCC patients are treated with surgical resection and radiofrequency ablation (RFA), although these modalities should be considered in only selected cases with a certain HCC number and size. Although there is a shortage of grafts, liver transplantation has the highest survival rates for HCC. Several modalities are salvage treatments; however, intensive care in combination with other modalities or in combination with surgical resection or RFA might offer a better prognosis. Sorafenib is useful for patients with advanced HCC. In the near future, HCC treatment will include stronger molecular targeted drugs, which will have greater potency and fewer adverse events. Further studies will be ongoing.
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Affiliation(s)
- Tatsuo Kanda
- Tatsuo Kanda, Sadahisa Ogasawara, Tetsuhiro Chiba, Yuki Haga, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8677, Japan
| | - Sadahisa Ogasawara
- Tatsuo Kanda, Sadahisa Ogasawara, Tetsuhiro Chiba, Yuki Haga, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8677, Japan
| | - Tetsuhiro Chiba
- Tatsuo Kanda, Sadahisa Ogasawara, Tetsuhiro Chiba, Yuki Haga, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8677, Japan
| | - Yuki Haga
- Tatsuo Kanda, Sadahisa Ogasawara, Tetsuhiro Chiba, Yuki Haga, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8677, Japan
| | - Masao Omata
- Tatsuo Kanda, Sadahisa Ogasawara, Tetsuhiro Chiba, Yuki Haga, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8677, Japan
| | - Osamu Yokosuka
- Tatsuo Kanda, Sadahisa Ogasawara, Tetsuhiro Chiba, Yuki Haga, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8677, Japan
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25
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Gao Q, Wang XY, Zhou J, Fan J. Multiple carcinogenesis contributes to the heterogeneity of HCC. Nat Rev Gastroenterol Hepatol 2015; 12:13. [PMID: 25421581 DOI: 10.1038/nrgastro.2014.6-c1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, 180 Fenglin Road, Shanghai 200032, P. R. China
| | - Xiao-Ying Wang
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, 180 Fenglin Road, Shanghai 200032, P. R. China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, 180 Fenglin Road, Shanghai 200032, P. R. China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, 180 Fenglin Road, Shanghai 200032, P. R. China
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26
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Schlageter M, Terracciano LM, D’Angelo S, Sorrentino P. Histopathology of hepatocellular carcinoma. World J Gastroenterol 2014; 20:15955-15964. [PMID: 25473149 PMCID: PMC4239483 DOI: 10.3748/wjg.v20.i43.15955] [Citation(s) in RCA: 164] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 05/09/2014] [Accepted: 07/22/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.
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MESH Headings
- Animals
- Bile Duct Neoplasms/chemistry
- Bile Duct Neoplasms/classification
- Bile Duct Neoplasms/epidemiology
- Bile Duct Neoplasms/pathology
- Bile Ducts, Intrahepatic/chemistry
- Bile Ducts, Intrahepatic/pathology
- Biomarkers, Tumor/analysis
- Biopsy
- Carcinoma, Hepatocellular/chemistry
- Carcinoma, Hepatocellular/classification
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/pathology
- Cholangiocarcinoma/chemistry
- Cholangiocarcinoma/classification
- Cholangiocarcinoma/epidemiology
- Cholangiocarcinoma/pathology
- Diagnosis, Differential
- Humans
- Immunohistochemistry
- Liver Neoplasms/chemistry
- Liver Neoplasms/classification
- Liver Neoplasms/epidemiology
- Liver Neoplasms/pathology
- Neoplasm Grading
- Neoplasms, Complex and Mixed/chemistry
- Neoplasms, Complex and Mixed/classification
- Neoplasms, Complex and Mixed/epidemiology
- Neoplasms, Complex and Mixed/pathology
- Precancerous Conditions/chemistry
- Precancerous Conditions/classification
- Precancerous Conditions/epidemiology
- Precancerous Conditions/pathology
- Predictive Value of Tests
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27
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Zhang T, Zeng Y, Huang J, Liao M, Wu H. Combined resection with radiofrequency ablation for bilobar hepatocellular carcinoma: a single-center experience. J Surg Res 2014; 191:370-8. [DOI: 10.1016/j.jss.2014.03.048] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 03/13/2014] [Accepted: 03/14/2014] [Indexed: 02/07/2023]
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28
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Zhang W, Song TQ, Zhang T, Wu Q, Kong DAL, Li Q, Sun HC. Adjuvant interferon for early or late recurrence of hepatocellular carcinoma and mortality from hepatocellular carcinoma following curative treatment: A meta-analysis with comparison of different types of hepatitis. Mol Clin Oncol 2014; 2:1125-1134. [PMID: 25279210 DOI: 10.3892/mco.2014.386] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 07/30/2014] [Indexed: 01/27/2023] Open
Abstract
Adjuvant interferon (IFN) therapy following curative treatment for hepatocellular carcinoma (HCC) has been extensively investigated; however, the clinical benefits with different hepatitis backgrounds remain unclear. Medline, Embase, PubMed and the Cochrane Library databases were searched to identify randomized trials and cohort studies that enrolled HCC patients who received curative surgery or ablation therapy followed by IFN and control subjects; the studies were required to include data on early or late recurrence and mortality rates of HCC. Hepatitis B virus (HBV) associated with HCC (HBV-HCC) and hepatitis C virus (HCV) associated with HCC (HCV-HCC) were separately analyzed and recurrence, mortality and clinicopathological factors were compared. A total of 14 studies (9 randomized trials and 5 cohort studies, including 1,385 patients in total) were eligible for meta-analysis. IFN was found to decrease mortality and early recurrence rates, but exerted no effect on late recurrence rate. The effect of IFN differed between HBV-HCC and HCV-HCC cases. In HCV-HCC, IFN significantly reduced mortality as well as recurrence rates. However, in HBV-HCC patients, IFN reduced mortality rather than recurrence rates, although it also reduced the recurrence rate in certain subgroups. In conclusion, the effect of adjuvant IFN on postoperative recurrence differed between HBV-HCC and HCV-HCC cases; therefore, different strategies with adjuvant IFN should be used to treat HCC with different hepatitis backgrounds.
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Affiliation(s)
- Wei Zhang
- Key Laboratory of Cancer Prevention and Therapy, Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Tian-Qiang Song
- Key Laboratory of Cancer Prevention and Therapy, Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Ti Zhang
- Key Laboratory of Cancer Prevention and Therapy, Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Qiang Wu
- Key Laboratory of Cancer Prevention and Therapy, Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - DA-Lu Kong
- Key Laboratory of Cancer Prevention and Therapy, Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Qiang Li
- Key Laboratory of Cancer Prevention and Therapy, Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Hui-Chuan Sun
- Key Laboratory for Carcinogenesis and Cancer Invasion, Liver Cancer Institute and Zhongshan Hospital, Fudan University, The Chinese Ministry of Education, Shanghai 200032, P.R. China
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29
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Zhang T, Huang JW, Bai YN, Wu H, Zeng Y. Recurrence and survivals following hepatic resection for hepatocellular carcinoma with major portal/hepatic vein tumor thrombus. Hepatol Res 2014; 44:761-8. [PMID: 23763458 DOI: 10.1111/hepr.12185] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Revised: 04/24/2013] [Accepted: 06/10/2013] [Indexed: 02/05/2023]
Abstract
AIM To compare the recurrence and survivals between hepatocellular carcinoma (HCC) with major portal vein tumor thrombus (TT) and major hepatic vein TT after hepatic resection (HR). METHODS A retrospective study was carried out with the medical records of 272 patients who underwent hepatic resection and thrombectomy for HCC with major portal vein (group A) or hepatic vein (group B) TT. The clinicopathological parameters, recurrence, survivals and prognostic significance associated with major portal or hepatic vein TT were analyzed. RESULTS Patients in group A had a better median survival compared with their counterparts in group B (52 vs 38 weeks; P < 0.001). One-, 2- and 3-year survival rates were markedly greater in group A than in group B (50% vs 38.8%, 26% vs 15.9% and 11.4% vs 6.1%, respectively). There was no statistical difference in recurrence-free survival rate but extrahepatic recurrences were more often seen in group B. In multivariate analysis, TT location (hepatic veins vs portal veins), type of resection (anatomical vs non-anatomical) and liver cirrhosis (none/mild vs moderate/severe) were significant prognostic factors. CONCLUSION Patients with HCC and major hepatic vein TT had higher incidence of extrahepatic metastases and worse overall survival after hepatic resection compared with patients with major portal vein TT. With preserved liver function, patients can receive aggressive treatments and survivals could be prolonged.
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Affiliation(s)
- Tao Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
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30
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Takayasu K, Arii S, Sakamoto M, Matsuyama Y, Kudo M, Ichida T, Nakashima O, Matsui O, Izumi N, Ku Y, Kokudo N, Makuuchi M. Clinical implication of hypovascular hepatocellular carcinoma studied in 4,474 patients with solitary tumour equal or less than 3 cm. Liver Int 2013; 33:762-70. [PMID: 23445409 DOI: 10.1111/liv.12130] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2012] [Accepted: 01/21/2013] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS To clarify the biological behaviour of small hypovascular hepatocellular carcinoma (HCC) because of insufficient evidence even though frequently encountered. METHODS The study covered naïve 4,474 patients who met solitary HCC ≤ 3 cm (mean, 2.1 cm), histopathologically proven and Child Pugh A or B. Macroscopic vascular invasion and distant metastasis were excluded. The hypovascularity of tumour was defined as hypo- or iso-enhancement in arterial phase of multiple dynamic imaging techniques. RESULTS Of them, 802 (18%) were hypovascular. The ratio of hypovascular HCC decreased as tumour size increased (P < 0.001) and most of them developed to hypervascular type when they grew over 1.5 cm. Hypovascular group showed a significantly higher ratio of well differentiated grade (P < 0.001) and marginally less incidence of microvascular invasion and metastases compared with hypervascular group. The histologic dedifferentiation (less differentiation) developed step-by-step as tumour size increased in hyper- and even hypovascular group. The des-γ-carboxy prothrombin (DCP) value ≥ 300 mAU/ml was closely correlated with increase of tumour size in both groups. Logistic regression analysis revealed five variables were independent predictors for hypovascular HCC; tumour size ≤ 1.5 cm, alpha-fetoprotein < 200 ng/ml, DCP < 40 mAU/ml, well differentiated grade, and positivity for hepatitis C virus antibody. CONCLUSIONS Hypovascular HCC was biologically less aggressive and developed with stepwise dedifferentiation and transformation to hypervascular appearance along with tumour growth. These results will help in leading correct diagnosis of small hypovascular tumour and assessing optimal treatment for hypovascular HCC ≤ 3 cm.
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Affiliation(s)
- Kenichi Takayasu
- Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan.
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Sakon M, Ogawa H, Fujita M, Nagano H. Hepatic resection for hepatocellular carcinoma based on tumor hemodynamics. Hepatol Res 2013. [PMID: 23194466 DOI: 10.1111/hepr.12001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Survival or disease-free survival is not considered an appropriate surrogate outcome for the locoregional curability (i.e. surgical margin) of hepatectomy for hepatocellular carcinoma because these are greatly influenced by non-metastatic factors like multicentric carcinogenesis (MC) or liver function. Hepatocellular carcinoma metastasizes by hematogenous seeding; therefore, the tumor blood flow (TBF) drainage area is a high-risk area for intrahepatic metastasis, and can be identified by computed tomography under hepatic arteriography and completely resected as part of the surgical margin. The TBF pattern is classified into marginal, portal vein or hypovascular types. Partial hepatectomies were mostly performed in patients with marginal or hypovascular type, whereas anatomical surgery was frequently performed in those with portal vein type. Pathologically, nodules inside the TBF drainage area were moderately or poorly differentiated carcinomas, suggesting intrahepatic metastasis. In contrast, those outside the drainage area were frequently solitary and contained well-differentiated carcinoma, which is consistent with MC. The pattern of tumor recurrences after TBF-based hepatectomy is divided into two distinct groups - "a few nodules" and "many nodules in multiple segments or extrahepatic" - indicating that intrahepatic recurrences develop from MC and from circulating tumor cells in peripheral blood, respectively. Anatomical resection has not shown a survival benefit over that of TBF-based partial hepatectomy. TBF-based hepatectomy enables us to preserve liver function without compromising locoregional curability.
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Affiliation(s)
- Masato Sakon
- Department of Surgery, Nishinomiya Municipal Central Hospital, Nishinomiya, Japan
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32
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Midorikawa Y, Takayama T, Shimada K, Nakayama H, Higaki T, Moriguchi M, Nara S, Tsuji S, Tanaka M. Marginal survival benefit in the treatment of early hepatocellular carcinoma. J Hepatol 2013; 58:306-11. [PMID: 23063418 DOI: 10.1016/j.jhep.2012.09.026] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 08/23/2012] [Accepted: 09/20/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Early treatment has been recommended for hepatocellular carcinoma (HCC) due to its high cure rate. However, the reported survival benefits of treating early HCC may be affected by lead time. METHODS Early HCC was defined as a well-differentiated cancer containing Glisson's triad (carcinoma in situ). We applied the concept of lead time to chronic liver disease, which is originally the length of time between screen-detected and symptom-detected disease. To evaluate prolongation of survival with treatment of early HCC, survivals of patients with early and overt HCCs smaller than 2.0 cm treated with liver resection were compared. To calculate lead time and survival benefit of liver resection, survivals of untreated early and overt HCC patients were compared. RESULTS After liver resection, median overall survival of 46 patients with early HCC (8.8 years; 95% CI, 7.2-11.2) was significantly longer than that of the 202 with overt HCC (6.8 years; 95% CI, 6.2-8.3, p = 0.0257). The prolongation in survival time with liver resection for early HCC was 34.7 (95% CI, 22.1-46.5) months. On the other hand, comparing liver resection and natural history, the survival benefits of surgery for 12 patients with early and 16 with overt HCC were 74.7 (95% CI, 51.9-97.4) and 73.4 (95% CI, 57.9-88.9) months, respectively. Consequently, the lead time and survival benefit with resection for early HCC were estimated as 33.4 (95% CI, 18.9-47.8) and 1.3 (95% CI, -22.1-24.7) months, respectively. CONCLUSIONS Survival benefit of resection for early HCC is marginal because of a long lead time, and early HCC is therefore not a target lesion for surgery.
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Affiliation(s)
- Yutaka Midorikawa
- Department of Digestive Surgery, Nihon University School of Medicine, 30-1 Oyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan
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33
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Surgical resection for small hepatocellular carcinoma in cirrhosis: the Eastern experience. Recent Results Cancer Res 2013; 190:69-84. [PMID: 22941014 DOI: 10.1007/978-3-642-16037-0_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Detection of small Hepatocarcinoma (HCC) by screening of high-risk populations is important to increase the percentage of patients suitable for curative treatment, which would lead to prolongation of the mean survival of patients with HCC. It should be remembered that small HCC is not always necessarily equivalent to early HCC as defined histologically. With recent advances in diagnostic imaging modalities, including contrast-enhanced ultrasonography and magnetic resonance imaging with liver-specific contrast enhancement, accurate differential diagnosis of early HCCs from dysplastic nodules has become possible. Because a certain proportion of small HCCs is known to show microscopic vascular invasion, surgical resection would be the treatment of first choice. To minimize potential microscopic invasion, anatomic resection and/or resection with a wide margin should be performed, while preserving liver function to the maximum extent possible. Surgical resection, however, cannot prevent multicentric occurrence of HCC, which remains a major issue precluding curative treatment of HCC.
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34
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Yap AQ, Chen CL, Yong CC, Kuo FY, Wang SH, Lin CC, Liu YW, Lin TL, Li WF, Millan CA, Wang CC. Clinicopathological factors impact the survival outcome following the resection of combined hepatocellular carcinoma and cholangiocarcinoma. Surg Oncol 2012; 22:55-60. [PMID: 23102615 DOI: 10.1016/j.suronc.2012.09.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 09/25/2012] [Accepted: 09/29/2012] [Indexed: 12/14/2022]
Abstract
Studies have demonstrated poor survival outcomes for patients with resected combined hepatocellular carcinoma-cholangiocarcinoma tumours (CHCC-CC). Our objectives are to report on our institutional experience regarding the clinico-pathological and prognostic features of CHCC-CC and to compare our results with published series. The clinico-pathological features and outcomes of 11 patients with CHCC-CC who had a complete surgical resection for primary liver cancer were reviewed. There were 8 male and 3 female patients. The overall median age was 61 years. Active hepatitis B and hepatitis C infections were present in 6 (54%) and 2 (18%) patients, respectively. Alcoholism was present in one case. Cirrhosis was present in 8 (72%) cases. There were no causative factors identified in 2 patients with non-cirrhotic livers. The median AFP value was 30.56 ng/ml. A single mass located in the right lobe and a single mass located in the left lobe of the liver was noted in 6 (54%) and 4 (36%) patients, respectively. Bilobar involvement was observed in one case. Major and minor resections were performed in 2 (18%) and 9 (81%) cases, respectively. The median tumour size was 3 cm. Tumours measuring >5 cm were identified in only 2 (18%) cases. The majority of the cases were classified as stage I (54%) and stage II (36%). Four patients died 11-50 months after the surgery. Postoperative tumour recurrences were observed in 5 (45.45%) patients within 4 years of surgical resection. The overall 1- and 3-year survival rates in this series were 80% and 69.3%. Our series demonstrated cases of CHCC-CC with more favourable pathological traits and survival outcomes compared with similar studies.
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Affiliation(s)
- Anthony Q Yap
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
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Kim YK, Lee WJ, Park MJ, Kim SH, Rhim H, Choi D. Hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with cirrhosis: potential of DW imaging in predicting progression to hypervascular HCC. Radiology 2012; 265:104-14. [PMID: 22891358 DOI: 10.1148/radiol.12112649] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE To investigate the imaging features of hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced magnetic resonance (MR) images in patients with cirrhosis that may be associated with progression to hypervascular hepatocellular carcinoma (HCC). MATERIALS AND METHODS The institutional review board approved this retrospective study and waived informed patient consent. This study included 135 patients with a diagnosis of hepatitis B-induced liver cirrhosis and 214 hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images. MR images were analyzed with respect to nodule size, degree of hypointensity at hepatobiliary phase (four grades), presence of fat, and signal intensity on T1- and T2-weighted and diffusion-weighted (DW) images. Univariate and multivariate Cox regression analyses were used to identify variables that are associated with developing hypervascular HCC. RESULTS On follow-up MR images, 139 nodules (65.0%) had no evidence of HCC (mean follow-up, 522 days) (group 1), but 75 (35.0%) became hypervascular HCC (mean follow-up, 388 days) (group 2). Univariable Cox analysis revealed that the degree of hypointensity on hepatobiliary phase images (P=.044 and .001) and hyperintensity on T2-weighted and DW images (P=.001 and .0001) was significantly related to the development of hypervascular HCC. According to the multivariable Cox analysis, no other variable significantly adjusted the model once hyperintensity at initial DW imaging was already included as an associated variable, (hazard ratio, 7.44; 95% confidence interval: 4.28, 12.94; P=.0001). CONCLUSION Hyperintensity on DW images in hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with cirrhosis is strongly associated with progression to hypervascular HCC.
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Affiliation(s)
- Young Kon Kim
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea
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Hepatic resection can provide long-term survival of patients with non-early-stage hepatocellular carcinoma: extending the indication for resection? Surgery 2012; 152:809-20. [PMID: 22766361 DOI: 10.1016/j.surg.2012.03.024] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 03/22/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Indications for resection of non-early-stage hepatocellular carcinoma (HCC) remain controversial. This study aimed to identify factors that affect outcome of patients with Barcelona Clinical Liver Cancer Classification (BCLC) stage B or stage C HCC after hepatic resection. METHODS From 1991 to 2006, 478 patients with HCC (BCLC stage B, n = 318 and BCLC stage C, n = 160) who underwent resection were enrolled. Factors in terms of overall survival and recurrence were analyzed. RESULTS After a median follow-up of 29.5 months, 304 patients had died. The cumulative overall survival rate at 5 years was 46.5% in BCLC stage B patients and 29.1% in stage C patients (P < .001). Multivariate analysis disclosed that serum albumin levels ≤4 g/dL, indocyanine green retention rate at 15 minutes >10%, serum creatinine >1.2 mg/dL, multinodularity, Edmondson stage III or IV in tumor cell differentiation, and the presence of macroscopic vascular invasion were independent risk factors of poor overall survival. There were 331 patients with tumor recurrence after resection. Recurrence rate was less in BCLC stage B than that in BCLC stage C (P = .001). Multivariate analysis showed that serum albumin level ≤4 g/dL, multinodularity, cut margin ≤1 cm, and Edmondson stage III or IV were associated with the recurrence of HCC. CONCLUSION Hepatic resection can provide long-term survival benefit in selected BCLC stage B or C patients with compensated liver function, especially in those presenting with a single neoplasm without vascular invasion.
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Maruyama H, Takahashi M, Sekimoto T, Kamesaki H, Shimada T, Kanai F, Yokosuka O. Heterogeneity of microbubble accumulation: a novel approach to discriminate between well-differentiated hepatocellular carcinomas and regenerative nodules. ULTRASOUND IN MEDICINE & BIOLOGY 2012; 38:383-388. [PMID: 22261511 DOI: 10.1016/j.ultrasmedbio.2011.12.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Revised: 11/02/2011] [Accepted: 12/04/2011] [Indexed: 05/31/2023]
Abstract
This prospective study aimed to elucidate the possibility of differentiating well-differentiated hepatocellular carcinoma (wHCC) from regenerative nodule (RN) on the basis of the heterogeneity of microbubble accumulation. Intensity analysis was conducted on early-phase and late-phase (60 s and 900 s post-injection; perflubutane microbubble) harmonic sonograms in 33 focal hepatic lesions (≤ 15 mm; 30 patients with chronic liver disease) that were histologically proven as wHCC or RN. Heterogeneity of enhancement, an average of standard deviation of late-phase enhancement in three different sections in the lesions with late-phase iso-enhancement, was examined with respect to the histologic findings. Heterogeneity of enhancement was higher in wHCC (28.7 ± 3.8) than RN (19.8 ± 2.1, p = 0.0213) in the 29 late-phase iso-enhancement lesions. The best cut-off value of the heterogeneity for the diagnosis of wHCC was 25.58, and the sensitivity and specificity were 77.8% and 100%, respectively. A novel parameter, heterogeneity of microbubble accumulation, facilitates differentiation between wHCC and RN showing a late-phase, iso-enhancement appearance.
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Affiliation(s)
- Hitoshi Maruyama
- Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, Chiba, Japan.
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Goodman ZD, Terracciano LM, Wee A. Tumours and tumour-like lesions of the liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:761-851. [DOI: 10.1016/b978-0-7020-3398-8.00014-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kishi Y, Saiura A, Yamamoto J, Koga R, Seki M, Morimura R, Yoshioka R, Kokudo N, Yamaguchi T. Significance of anatomic resection for early and advanced hepatocellular carcinoma. Langenbecks Arch Surg 2011; 397:85-92. [DOI: 10.1007/s00423-011-0844-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2011] [Accepted: 08/29/2011] [Indexed: 12/22/2022]
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Lee JM, Zech CJ, Bolondi L, Jonas E, Kim MJ, Matsui O, Merkle EM, Sakamoto M, Choi BI. Consensus report of the 4th International Forum for Gadolinium-Ethoxybenzyl-Diethylenetriamine Pentaacetic Acid Magnetic Resonance Imaging. Korean J Radiol 2011; 12:403-15. [PMID: 21852900 PMCID: PMC3150667 DOI: 10.3348/kjr.2011.12.4.403] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Accepted: 05/27/2011] [Indexed: 12/16/2022] Open
Abstract
This paper reports on issues relating to the optimal use of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (Gd-EOB-DTPA MR imaging) together with the generation of consensus statements from a working group meeting, which was held in Seoul, Korea (2010). Gd-EOB-DTPA has been shown to improve the detection and characterization of liver lesions, and the information provided by the hepatobiliary phase is proving particularly useful in differential diagnoses and in the characterization of small lesions (around 1-1.5 cm). Discussion also focused on advances in the role of organic anion-transporting polypeptide 8 (OATP8) transporters. Gd-EOB-DTPA is also emerging as a promising tool for functional analysis, enabling the calculation of post-surgical liver function in the remaining segments. Updates to current algorithms were also discussed.
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Affiliation(s)
- Jeong Min Lee
- Department of Radiology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
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Contrast-Enhanced Ultrasound With Perflubutane Microbubble Agent: Evaluation of Differentiation of Hepatocellular Carcinoma. AJR Am J Roentgenol 2011; 196:W123-31. [DOI: 10.2214/ajr.10.4242] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Kawai H, Nomoto M, Suda T, Kamimura K, Tsuchiya A, Tamura Y, Yano M, Takamura M, Igarashi M, Wakai T, Yamagiwa S, Matsuda Y, Ohkoshi S, Kurosaki I, Shirai Y, Okada M, Aoyagi Y. Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis. World J Hepatol 2011; 3:15-23. [PMID: 21307983 PMCID: PMC3035698 DOI: 10.4254/wjh.v3.i1.15] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Revised: 11/11/2010] [Accepted: 11/18/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. METHODS We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. RESULTS MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO; an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. CONCLUSION The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH.
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Affiliation(s)
- Hirokazu Kawai
- Hirokazu Kawai, Department of Clinical Laboratory, Niigata University Medical and Dental Hospital, Niigata 951-8510, Japan
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Yachida S, Imaida K, Yokohira M, Hashimoto N, Suzuki S, Okano K, Wakabayashi H, Maeta H, Suzuki Y. Jun Activation Domain Binding Protein 1 is Overexpressed from the Very Early Stages of Hepatocarcinogenesis. Ann Surg Oncol 2010; 17:3386-3393. [DOI: 10.1245/s10434-010-1197-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Dancygier H. Malignant Tumors. CLINICAL HEPATOLOGY 2010:1305-1350. [DOI: 10.1007/978-3-642-04519-6_48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Arai E, Ushijima S, Gotoh M, Ojima H, Kosuge T, Hosoda F, Shibata T, Kondo T, Yokoi S, Imoto I, Inazawa J, Hirohashi S, Kanai Y. Genome-wide DNA methylation profiles in liver tissue at the precancerous stage and in hepatocellular carcinoma. Int J Cancer 2009; 125:2854-62. [PMID: 19569176 DOI: 10.1002/ijc.24708] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
To clarify genome-wide DNA methylation profiles during hepatocarcinogenesis, bacterial artificial chromosome (BAC) array-based methylated CpG island amplification was performed on 126 tissue samples. The average numbers of BAC clones showing DNA hypo- or hypermethylation increased from noncancerous liver tissue obtained from patients with hepatocellular carcinomas (HCCs) (N) to HCCs. N appeared to be at the precancerous stage, showing DNA methylation alterations that were correlated with the future development of HCC. Using Wilcoxon test, 25 BAC clones, whose DNA methylation status was inherited by HCCs from N and were able to discriminate 15 N samples from 10 samples of normal liver tissue obtained from patients without HCCs (C) with 100% sensitivity and specificity, were identified. The criteria using the 25 BAC clones were able to discriminate 24 additional N samples from 26 C samples in the validation set with 95.8% sensitivity and 96.2% specificity. Using Wilcoxon test, 41 BAC clones, whose DNA methylation status was able to discriminate patients who survived more than 4 years after hepatectomy from patients who suffered recurrence within 6 months and died within a year after hepatectomy, were identified. The DNA methylation status of the 41 BAC clones was correlated with the cancer-free and overall survival rates of patients with HCC. Multivariate analysis revealed that satisfying the criteria using the 41 BAC clones was an independent predictor of overall outcome. Genome-wide alterations of DNA methylation may participate in hepatocarcinogenesis from the precancerous stage, and DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication.
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Affiliation(s)
- Eri Arai
- Pathology Division, National Cancer Center Research Institute, Tokyo, Japan
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Yachida S, Sakamoto M, Imaida K, Yokohira M, Saoo K, Okano K, Wakabayashi H, Maeta H, Suzuki Y. p27(Kip1)is overexpressed in very early stages of hepatocarcinogenesis. Cancer Sci 2008; 99:2152-9. [PMID: 18808421 PMCID: PMC11159344 DOI: 10.1111/j.1349-7006.2008.00923.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) associated with chronic liver disease evolves from precancerous lesions and early HCC to more malignant forms. Despite the demonstrated importance of cell-cycle regulators in tumor biology, there have been few studies of their role in multistep hepatocarcinogenesis. Expression of p27(Kip1) and a degradation pathway associated protein, S-phase kinase-interacting protein 2 (Skp2), was therefore evaluated in surgically resected specimens of eight adenomatous hyperplasias, 16 early HCC and 126 classical HCC. Immunohistochemistry revealed no p27(Kip1) expression in the majority of hepatocytes from normal and cirrhotic liver, whereas positive staining for p27(Kip1) protein was found in 75.0% and 93.8% of adenomatous hyperplasias and early HCC, respectively. The average p27(Kip1) labeling indices (LI) for adenomatous hyperplasias, early HCC, well differentiated HCC, moderately differentiated HCC and poorly differentiated HCC were 36.99, 43.59, 47.73, 49.24, and 30.21, respectively. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses confirmed the increases. Skp2 LI were also significantly elevated in accordance with stepwise progression of hepatocarcinogenesis. Increased expression of Skp2 mRNA was observed most frequently in less differentiated tumors and Kaplan-Meier survival analysis showed a significantly association with a poor prognosis (P = 0.0496). In conclusion, a high level of p27(Kip1) expression is evident from early stages of hepatocarcinogenesis, indicating that this parameter could be a useful diagnostic marker for precancerous lesions and early HCC. In addition, Skp2 expression correlates with tumor dedifferentiation and may contribute to biological aggression in HCC.
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Affiliation(s)
- Shinichi Yachida
- Department of Surgery, Kagawa University, Kita-gun, Kagawa, Japan.
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Pulmonary Resection for Non-Small Cell Lung Cancer in Patients with Hepatocellular Carcinoma. World J Surg 2008; 32:2204-12. [DOI: 10.1007/s00268-008-9691-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Capanni M, Lorefice E, Benini MC, Biagini MR, Tozzi A, Salvadori E, Colagrande S, Surrenti C, Milani S. Occurrence of diffuse, poorly differentiated hepatocellular carcinoma during pegylated interferon plus ribavirin combination therapy for chronic hepatitis C. J Chemother 2008; 20:380-4. [PMID: 18606596 DOI: 10.1179/joc.2008.20.3.380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Interferon therapy is indicated for the treatment of chronic hepatitis C and prevention of hepatocellular carcinoma. We describe the case of a 66-year-old Italian woman who received pegylated interferon alpha-2a plus ribavirin combined therapy for HCV-related chronic liver disease. Preliminary hematochemical, ultrasound and bioptic investigations did not show liver cirrhosis or hepatocarcinoma. After 24 weeks of treatment transaminase serum levels were in the normal range and circulating HCVRNA was undetectable by PCR qualitative assay. On week 46 a serious adverse event occurred, with rapid transaminase increase, severe hyperpyrexia, and abdominal pain, leading to interruption of interferon and ribavirin. Liver biopsy was repeated and it revealed poorly differentiated hepatocellular carcinoma. Only palliative care could be performed and the patient died of liver failure within 2 months. The present case underlines that hepatocellular carcinoma can be misdiagnosed in spite of laboratory and instrumental follow-up. More sensitive tools are needed for tumor detection, to avoid IFN impairment of the liver, even though it eradicates HCV.
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Affiliation(s)
- M Capanni
- Liver Center and Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy.
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Maeda N, Osuga K, Mikami K, Higashihara H, Onishi H, Nakaya Y, Tatsumi M, Hori M, Kim T, Tomoda K, Nakamura H. Angiographic evaluation of hepatic arterial damage after transarterial chemoembolization for hepatocellular carcinoma. ACTA ACUST UNITED AC 2008; 26:206-12. [DOI: 10.1007/s11604-007-0216-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2007] [Accepted: 12/05/2007] [Indexed: 02/06/2023]
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Iizuka N, Hamamoto Y, Tsunedomi R, Oka M. Translational microarray systems for outcome prediction of hepatocellular carcinoma. Cancer Sci 2008; 99:659-65. [PMID: 18377418 PMCID: PMC11159982 DOI: 10.1111/j.1349-7006.2008.00751.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
DNA microarray technology has revolutionized our understanding of the molecular basis of hepatocellular carcinoma (HCC), one of the most fatal human cancers with a high recurrence rate. Many researchers have used DNA microarray technology to reclassify HCC with respect to metastatic potential and to develop predictors for the outcome of HCC. However, developed predictors have reached the level only of small retrospective studies, and their current status is far from that required for clinical use. This is due to the lack of transparent data, the high cost and data instability associated with the high dimensionality of the technique, the infancy of bioinformatics, and the complicated nature of recurrent HCC. This comprehensive review summarizes: (i) class comparison studies to identify genes or pathways involved in HCC metastasis (ii) class discovery studies that have resulted in the identification of a new molecular subclass of HCC with respect to metastasis, and (iii) class prediction studies to develop multidimensional predictors for HCC outcome. We also discuss issues that need to be addressed so that the power of array-based predictors can be estimated prospectively in large independent cohorts of HCC patients.
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Affiliation(s)
- Norio Iizuka
- Departments of Surgery II, Yamaguchi University Graduate School of Medicine, 10101 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
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