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Gu Y, Jin K, Gao S, Sun W, Yin M, Han J, Zhang Y, Wang X, Zeng M, Sheng R. A preoperative nomogram with MR elastography in identifying cytokeratin 19 status of hepatocellular carcinoma. Br J Radiol 2025; 98:210-219. [PMID: 39657213 DOI: 10.1093/bjr/tqae193] [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: 02/18/2024] [Revised: 08/30/2024] [Accepted: 09/15/2024] [Indexed: 12/17/2024] Open
Abstract
OBJECTIVES Developing a nomogram integrating MR elastography (MRE)-based tumour stiffness and contrast-enhanced MRI in identifying cytokeratin 19 (CK19) status of hepatocellular carcinoma (HCC) preoperatively. METHODS One hundred twenty CK19-negative HCC and 39 CK19-positive HCC patients undergoing curative resection were prospectively evaluated. All received MRE and contrast-enhanced MRI. Clinical and MRI tumour features were compared. Univariate and multivariate logistic regression analyses identified independent predictors for CK19 status. Receiver operating characteristic curve analysis evaluated diagnostic performance. A nomogram was established with calibration and decision curve analysis. RESULTS Multivariate analysis revealed serum alpha fetoprotein (AFP) level (P < 0.001), targetoid appearance (P = 0.007), and tumour stiffness (P = 0.011) as independent significant variables for CK19-positive HCC. The area under the curve for tumour stiffness was 0.729 (95% confidence interval [CI] 0.653, 0.796). Combining these features, a nomogram-based model achieved an area under the curve value of 0.844 (95% CI 0.778, 0.897), with sensitivity, specificity, and accuracy of 76.92%, 85.00%, and 83.02%, respectively. Calibration and decision curve analyses demonstrated good agreement and optimal net benefit. CONCLUSIONS MRE-measured tumour stiffness aids in predicting CK19 status in HCC. The combined nomogram incorporating tumour stiffness, targetoid appearance, and AFP provides a reliable biomarker for CK19-positive HCC. ADVANCES IN KNOWLEDGE MRE-measured tumour stiffness can be used to predict CK19 status in HCC. The nomogram, which integrates tumour stiffness, targetoid appearance, and AFP levels, has shown improved diagnostic performance. It offers a comprehensive preoperative tool for clinical decision-making, further advancing personalized treatment strategies in HCC management.
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Affiliation(s)
- Yanan Gu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Medical Imaging, Shanghai 200032, China
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Kaipu Jin
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Geriatric Medical Center, Zhongshan Hospital, Fudan University, Shanghai 201104, China
| | - Shanshan Gao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Medical Imaging, Shanghai 200032, China
| | - Wei Sun
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Medical Imaging, Shanghai 200032, China
| | - Minyan Yin
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Medical Imaging, Shanghai 200032, China
| | - Jing Han
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yunfei Zhang
- Shanghai Institute of Medical Imaging, Shanghai 200032, China
| | - Xiaolin Wang
- Shanghai Institute of Medical Imaging, Shanghai 200032, China
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Medical Imaging, Shanghai 200032, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ruofan Sheng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Medical Imaging, Shanghai 200032, China
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Yu ZC, Fang ZK, Yu Y, Liu SY, Wang KD, Shi ZJ, Jin LM, Huang XK, Lu Y, Shen GL, Liu JW, Huang DS, Zhang CW, Liang L. The Clinical Characteristics, Patterns of Recurrence, and Long-Term Survival Outcomes of Dual-Phenotype Hepatocellular Carcinoma After Curative Liver Resection. J Hepatocell Carcinoma 2025; 12:183-192. [PMID: 39902378 PMCID: PMC11789503 DOI: 10.2147/jhc.s493094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/23/2025] [Indexed: 02/05/2025] Open
Abstract
Background & Aims Dual-phenotype hepatocellular carcinoma (DPHCC) is discernible from classical HCC (CHCC) in its morphology and is characterized by the co-expression of both CHCC and cholangiocyte markers. This study aimed to clarify the difference between DPHCC and CHCC after surgery. Methods Patients with HCC after surgery were collected. The clinical characteristics, patterns of recurrence, and survival outcomes of patients with DPHCC and CHCC were compared. Multivariate analyses were used to determine the independent risk factors that influence the prognosis of patients. Results Patients with DPHCC (n = 141) account for 26% of the total patients (n = 541). Compared to patients with CHCC, patients with DPHCC are significantly associated with incomplete capsules, microvascular invasion, and poor differentiation (all P < 0.05). Compared to patients with CHCC, the 5-year overall survival (OS) (56% vs 43%) and recurrence-free survival (RFS) (35% vs 28%) are lower in patients with DPHCC. Meanwhile, among patients with tumor recurrence after surgery, patients with DPHCC have a higher proportion of advanced-stage tumors, and extrahepatic metastasis (all P < 0.05). Moreover, multivariate analysis showed that DPHCC is an independent risk factor for both OS (HR 1.399, 95% CI 1.061-1.845, P = 0.017) and RFS (HR 1.313, 95% CI 1.033-1.669, P = 0.026). Conclusion DPHCC, an aggressive HCC subtype with poor differentiation and high invasiveness, shows inferior RFS and OS post-liver resection compared to CHCC. Clinicians' recognition and addressing of its unique challenges can improve DPHCC patients' prognosis and QoL.
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Affiliation(s)
- Zi-Chen Yu
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
- Department of Postgraduate Training Base Alliance of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Zheng-Kang Fang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
- Department of Postgraduate Training Base Alliance of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Yang Yu
- Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Si-Yu Liu
- Department of Laboratory Medicine, The Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Zhejiang University Lishui Hospital, Lishui, Zhejiang, People’s Republic of China
| | - Kai-Di Wang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
- Department of the second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Zhe-Jin Shi
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
- Department of the second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Li-Ming Jin
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Xiao-Kun Huang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
- Department of Postgraduate Training Base Alliance of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Yi Lu
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Guo-Liang Shen
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Jun-Wei Liu
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Dong-Sheng Huang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Cheng-Wu Zhang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Lei Liang
- Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, General Surgery, Cancer Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
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Yang C, Xiang W, Wu Z, Li N, Xie G, Huang J, Zeng L, Yu H, Xiang B. CK19 protein expression: the best cutoff value on the prognosis and the prognosis model of hepatocellular carcinoma. BMC Cancer 2025; 25:55. [PMID: 39789507 PMCID: PMC11720332 DOI: 10.1186/s12885-024-13399-9] [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: 03/13/2024] [Accepted: 12/25/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND AND OBJECTIVE In clinical practice, CK19 can be an important predictor for the prognosis of HCC. Due to the high incidence and mortality rates of HCC, more effective and practical prognostic prediction models need to be developed urgently. METHODS A total of 1,168 HCC patients, who underwent radical surgery at the Guangxi Medical University Cancer Hospital, between January 2014 and July 2019, were recruited, and their clinicopathological data were collected. Among the clinicopathological data, the optimal cutoff value of CK19-positive HCC was determined by calculating the area under the curve (AUC) using survival analysis and time-dependent receiver operating characteristic (timeROC) curve analysis. The predictors were screened using univariate and multivariate COX regression and least absolute shrinkage and selection operator (LASSO) regression to construct nomogram prediction models, and their predictive potentials were assessed using calibration curves and AUC values. RESULTS The 0% positive rate of CK19 was considered the optimal cutoff value to predict the poor prognosis of CK19-positive HCC. The survival analysis of 335 CK19-positive HCC showed no significant statistical differences in the overall survival (OS) and disease-free survival (DFS) of CK19-positive HCC patients. A five-factor risk (CK19, CA125, Edmondson, BMI, and tumor number) scoring model and an OS nomograph model were constructed and established, and the OS nomograph model showed a good predictive performance and was subsequently verified. CONCLUSION A 0% expression level of CK19 protein may be an optimal threshold for predicting the prognosis of CK19-positive HCC. Based on this, CK19 marker a good nomogram model was constructed to predict HCC prognosis.
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Affiliation(s)
- Chenglei Yang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
- Guangxi Hepatocellular Carcinoma Diagnosis and Treatment Engineering Technology Research Center, Nanning, Guangxi Province, 530021, China
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China
| | - Wanyan Xiang
- The First Clinical Medical College of Guangxi Medical University, Nanning, Guangxi Province, 530021, China
| | - Zongze Wu
- The First Clinical Medical College of Guangxi Medical University, Nanning, Guangxi Province, 530021, China
| | - Nannan Li
- Department of Ultrasound, Guangxi Zhuang Autonomous Region Workers' Hospital, Nanning, Guangxi Province, 530021, China
| | - Guoliang Xie
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
- Guangxi Hepatocellular Carcinoma Diagnosis and Treatment Engineering Technology Research Center, Nanning, Guangxi Province, 530021, China
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China
| | - Juntao Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
- Guangxi Hepatocellular Carcinoma Diagnosis and Treatment Engineering Technology Research Center, Nanning, Guangxi Province, 530021, China
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China
| | - Lixia Zeng
- Department of Pathology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China
| | - Hongping Yu
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China.
- Tumor Prevention and Control Office, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China.
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, 530021, China.
- Guangxi Hepatocellular Carcinoma Diagnosis and Treatment Engineering Technology Research Center, Nanning, Guangxi Province, 530021, China.
- Regional Key Laboratory for Early Prevention and Treatment of High Incidence Tumor, Ministry of Education, Nanning, Guangxi Province, 530021, China.
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Vij M, Raju LP, Jothimani D, Subbiah K, Simon E, Gowrishankar G, Rajalingam R, Kaliamoorthy I, Rammohan A, Rela M. Clinicopathological Characteristics of Neutrophil-Rich Hepatocellular Carcinoma: An Uncommon Subtype of Primary Liver Cancer. Int J Surg Pathol 2024:10668969241291882. [PMID: 39533751 DOI: 10.1177/10668969241291882] [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: 11/16/2024]
Abstract
Introduction. Neutrophil-rich hepatocellular carcinoma (HCC) is an extremely uncommon subtype of HCC with an overall incidence of <1%. Neutrophil-rich HCC shows poor cellular differentiation and sarcomatoid transformation in most patients. There is prominent neutrophilic inflammatory cell infiltration in the tumor. These tumors are associated with poor prognosis, high rate of recurrence, and metastasis. Methods. Herein, we investigated 4 patients with neutrophil-rich HCC reported at our center. Clinical, radiological, and pathological findings were reviewed. Immunophenotypic characterization of the tumors were done. Granulocyte colony-stimulating factor (G-CSF), programmed cell death ligand 1 (PD-L1), and mismatch repair immunostains were performed in all 4 tumors. Results. We report 4 neutrophil-rich HCCs in 3 male patients and one female patient with an age range of 43 to 64 years. Three underwent living donor liver transplantation and one underwent right hepatectomy. Tumor measured 0.5 cm to 12 cm in maximum dimension. Histologically, tumors demonstrated moderate to marked cellular pleomorphism. Spindle cell transformation was noted in 3 tumors. Three tumors showed vascular invasion, and one tumor showed bile duct invasion. Immunopositivity for Hep Par-1, arginase-1, and glypican-3 was present in all tumors. Tumors also expressed stemness markers including KRT19 and EpCAM. Cytoplasmic positivity for G-CSF and immunoexpression of PD-L1 was demonstrated. We also report proficient mismatch repair by immunohistochemistry in all tumors. Conclusion. Neutrophil-rich HCC is an aggressive primary liver cancer which demonstrates stemness-related features. Programmed cell death ligand 1 expression in tumor cells suggests distinct immunogenic features and potential role of anti-PD-L1 therapies in inoperable disease.
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Lexmi Priya Raju
- Department of Pathology, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Dinesh Jothimani
- The Institute of Liver Disease & Transplantation, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Komalavalli Subbiah
- The Institute of Liver Disease & Transplantation, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Evangeline Simon
- The Institute of Liver Disease & Transplantation, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | | | - Rajesh Rajalingam
- The Institute of Liver Disease & Transplantation, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- The Institute of Liver Disease & Transplantation, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Ashwin Rammohan
- The Institute of Liver Disease & Transplantation, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India
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Qu H, Zhang S, Guo M, Miao Y, Han Y, Ju R, Cui X, Li Y. Deep Learning Model for Predicting Proliferative Hepatocellular Carcinoma Using Dynamic Contrast-Enhanced MRI: Implications for Early Recurrence Prediction Following Radical Resection. Acad Radiol 2024; 31:4445-4455. [PMID: 38749868 DOI: 10.1016/j.acra.2024.04.028] [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: 01/05/2024] [Revised: 02/29/2024] [Accepted: 04/15/2024] [Indexed: 11/01/2024]
Abstract
RATIONALE AND OBJECTIVES The proliferative nature of hepatocellular carcinoma (HCC) is closely related to early recurrence following radical resection. This study develops and validates a deep learning (DL) prediction model to distinguish between proliferative and non-proliferative HCCs using dynamic contrast-enhanced MRI (DCE-MRI), aiming to refine preoperative assessments and optimize treatment strategies by assessing early recurrence risk. MATERIALS AND METHODS In this retrospective study, 355 HCC patients from two Chinese medical centers (April 2018-February 2023) who underwent radical resection were included. Patient data were collected from medical records, imaging databases, and pathology reports. The cohort was divided into a training set (n = 251), an internal test set (n = 62), and external test sets (n = 42). A DL model was developed using DCE-MRI images of primary tumors. Clinical and radiological models were generated from their respective features, and fusion strategies were employed for combined model development. The discriminative abilities of the clinical, radiological, DL, and combined models were extensively analyzed. The performances of these models were evaluated against pathological diagnoses, with independent and fusion DL-based models validated for clinical utility in predicting early recurrence. RESULTS The DL model, using DCE-MRI, outperformed clinical and radiological feature-based models in predicting proliferative HCC. The area under the curve (AUC) for the DL model was 0.98, 0.89, and 0.83 in the training, internal validation, and external validation sets, respectively. The AUCs for the combined DL and clinical feature models were 0.99, 0.86, and 0.83 in these sets, while the AUCs for the combined DL, clinical, and radiological model were 0.99, 0.87, and 0.8, respectively. Among models predicting early recurrence, the DL plus clinical features model showed superior performance. CONCLUSION The DL-based DCE-MRI model demonstrated robust performance in predicting proliferative HCC and stratifying patient risk for early postoperative recurrence. As a non-invasive tool, it shows promise in enhancing decision-making for individualized HCC management strategies.
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Affiliation(s)
- Hui Qu
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, China
| | - Shuairan Zhang
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Miaoran Guo
- Department of Radiology, The First Hospital of China Medical University, Shenyang, PR China
| | - Yuan Miao
- Department of Pathology, the College of Basic Medical Science and the First Hospital of China Medical University, Shenyang, PR China
| | - Yuxi Han
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Ronghui Ju
- Department of Radiology, The People's Hospital of Liaoning Province, Shenyang, PR China
| | - Xiaoyu Cui
- College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, China
| | - Yiling Li
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China.
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Chen J, Sun W, Wang W, Fu C, Grimm R, Zeng M, Rao S. Diffusion-based virtual MR elastography for predicting recurrence of solitary hepatocellular carcinoma after hepatectomy. Cancer Imaging 2024; 24:106. [PMID: 39138500 PMCID: PMC11320769 DOI: 10.1186/s40644-024-00759-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 08/07/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND To explore the capability of diffusion-based virtual MR elastography (vMRE) in the preoperative prediction of recurrence in hepatocellular carcinoma (HCC) and to investigate the underlying relevant histopathological characteristics. METHODS Between August 2015 and December 2016, patients underwent preoperative MRI examination with a dedicated DWI sequence (b-values: 200,1500 s/mm2) were recruited. The ADC values and diffusion-based virtual shear modulus (μdiff) of HCCs were calculated and MR morphological features were also analyzed. The Cox proportional hazards model was used to identify the risk factors associated with tumor recurrence. A preoperative radiologic model and postoperative model including pathological features were built to predict tumor recurrence after hepatectomy. RESULTS A total of 87 patients with solitary surgically confirmed HCCs were included in this study. Thirty-five patients (40.2%) were found to have tumor recurrence after hepatectomy. The preoperative model included higher μdiff and corona enhancement, while the postoperative model included higher μdiff, microvascular invasion, and histologic tumor grade. These factors were identified as significant prognostic factors for recurrence-free survival (RFS) (all p < 0.05). The HCC patients with μdiff values > 2.325 kPa showed poorer 5-year RFS after hepatectomy than patients with μdiff values ≤ 2.325 kPa (p < 0.001). Moreover, the higher μdiff values was correlated with the expression of CK19 (3.95 ± 2.37 vs. 3.15 ± 1.77, p = 0.017) and high Ki-67 labeling index (4.22 ± 1.63 vs. 2.72 ± 2.12, p = 0.001). CONCLUSIONS The μdiff values related to the expression of CK19 and Ki-67 labeling index potentially predict RFS after hepatectomy in HCC patients.
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Affiliation(s)
- Jiejun Chen
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Sun
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Wentao Wang
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Caixia Fu
- MR Application development, Siemens Shenzhen Magnetic Resonance Ltd, Shenzhen, China
| | - Robert Grimm
- MR Application Predevelopment, Siemens Healthineers AG, Erlangen, Germany
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shengxiang Rao
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
- Shanghai Institute of Medical Imaging, Shanghai, China.
- Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
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Heo S, Kang HJ, Choi SH, Kim S, Yoo Y, Choi WM, Kim SY, Lee SS. Proliferative hepatocellular carcinomas in cirrhosis: patient outcomes of LI-RADS category 4/5 and category M. Eur Radiol 2024; 34:2974-2985. [PMID: 37848775 DOI: 10.1007/s00330-023-10305-y] [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: 02/06/2023] [Revised: 07/15/2023] [Accepted: 08/10/2023] [Indexed: 10/19/2023]
Abstract
OBJECTIVES We aimed to compare Liver Imaging Reporting and Data System (LI-RADS) category 4/5 and category M (LR-M) of proliferative hepatocellular carcinomas (HCCs) in cirrhotic patients and evaluate their impacts on prognosis. METHODS This retrospective multi-reader study included cirrhotic patients with single treatment-naïve HCC ≤ 5.0 cm who underwent contrast-enhanced CT, MRI, and subsequent hepatic resection within 2 months. The percentages of CT/MRI LR-4/5 and LR-M in proliferative and non-proliferative HCCs were compared. Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the association of LI-RADS categories (LR-4/5 vs. LR-M) and pathologic classification (proliferative vs. non-proliferative) with overall survival (OS) and recurrence-free survival (RFS). Subgroups of patients with proliferative and non-proliferative HCCs were analyzed to compare OS and RFS between LR-4/5 and LR-M. RESULTS Of the 204 included patients, 38 were classified as having proliferative HCC. The percentages of LR-M were higher in proliferative than non-proliferative HCC on both CT (15.8% vs. 3.0%, p = 0.007) and MRI (26.3% vs. 9.6%, p = 0.016). Independent of pathologic classification, CT and MRI LR-M were significantly associated with poorer OS (hazard ratio (HR) = 4.58, p = 0.013, and HR = 6.45, p < 0.001) and RFS (HR = 3.66, p = 0.005, and HR = 6.44, p < 0.001) than LR-4/5. MRI LR-M was associated with significantly poorer OS (p ≤ 0.003) and RFS (p < 0.001) than MRI LR-4/5 in both proliferative and non-proliferative HCCs. CONCLUSIONS This multi-reader study showed that the percentages of LR-M were significantly higher in proliferative than non-proliferative HCCs. CT/MRI LR-M was significantly associated with poor OS and RFS, independent of the pathologic classification of proliferative versus non-proliferative HCCs. CLINICAL RELEVANCE STATEMENT CT and MRI LI-RADS category M can be clinically useful in predicting poor outcomes in patients with proliferative and non-proliferative hepatocellular carcinomas. KEY POINTS • The percentages of LR-M tumors on both CT and MRI were significantly higher in proliferative than non-proliferative hepatocellular carcinomas. • Independent of pathologic classification, CT/MRI LR-M categories were correlated with poor overall survival and recurrence-free survival. • Patients with both proliferative and non-proliferative hepatocellular carcinomas categorized as MRI LR-M had significantly poorer overall survival and recurrence-free survival than those categorized as MRI LR-4/5.
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Affiliation(s)
- Subin Heo
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Hyo Jeong Kang
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Sang Hyun Choi
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
| | - Sehee Kim
- Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Youngeun Yoo
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - So Yeon Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Seung Soo Lee
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
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Huang K, He Y, Liang T, Mo S, Liao Y, Gao Q, Liao X, Han C, Zhu G, Peng T. Analysis of clinicopathologic and imaging features of dual-phenotype hepatocellular carcinoma. Sci Rep 2024; 14:3314. [PMID: 38332165 PMCID: PMC10853567 DOI: 10.1038/s41598-024-53831-5] [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: 09/01/2023] [Accepted: 02/05/2024] [Indexed: 02/10/2024] Open
Abstract
Dual-phenotype hepatocellular carcinoma (DPHCC) is a new subtype of hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between the computerized tomography scan (CT) imaging and clinicopathologic features of DPHCC. The CT imaging and clinicopathologic data of 97 HCC cases who underwent radical resection were collected retrospectively. The CT imaging feature was evaluated by the ratio of the average CT value of tumor to liver (TLR) in the plain scan, arterial, portal vein and delayed phases. The association between CT imaging and clinicopathologic features was analyzed using the t-test or chi-square test. Univariate and multivariate recurrence-free survival (RFS) analysis and overall survival (OS) were performed. The positive rates of cytokeratin 7 (CK7) and CK19 were 35.1% and 20.6% respectively. The positive rate of CK19 was significantly higher in cases with age < 47 years (P = 0.005), tumor diameter > 4 cm (P = 0.016) or AFP ≥ 400 ng/ml (P = 0.007). The TLR in the portal vein phase was significantly lower in CK19 positive group (P = 0.024). The recurrence risk was significantly higher in cases with CK19 positive (HR: 2.17, 95% CI 1.16 to 4.04, P = 0.013), tumor diameter > 4 cm (HR: 2.05, 95% CI 1.11 to 3.78, P = 0.019), AFP ≥ 400 ng/ml (HR: 2.50, 95% CI 1.37 to 4.54, P = 0.002) or CA199 ≥ 37 U/ml (HR: 2.23, 95% CI 1.12 to 4.42, P = 0.020). However, imaging features, pathological subtype, CK7 or CK19 expression were not significantly related to HCC OS in the univariate and multivariate analysis (all P > 0.05). The expression of CK19 may be associated with the enhancement feature of the portal vein phase CT image, and CK19 positive may suggest a worse RFS.
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Affiliation(s)
- Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yongfei He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tianyi Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Shutian Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yuan Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Qiang Gao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang-Yong Rd. 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.
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KAWAGUCHI N, FUKE N, NUEANGPHUET P, PORNTHUMMAWAT A, NIAZI AM, IZZATI UZ, HIRAI T, YAMAGUCHI R. Hepatocellular carcinoma with lung metastasis showing hemochromatosis in an Egyptian fruit bat (Rousettus aegyptiacus). J Vet Med Sci 2024; 86:49-53. [PMID: 37940547 PMCID: PMC10849857 DOI: 10.1292/jvms.23-0152] [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: 04/06/2023] [Accepted: 10/26/2023] [Indexed: 11/10/2023] Open
Abstract
After an Egyptian fruit bat (Rousettus aegyptiacus) in a zoo became emaciated and died, a necropsy revealed multiple nodules on the liver and lung surfaces. Microscopy revealed that the liver nodules consisted of neoplastic hepatocytes and showed metastasis in the lung lobes. Most of the neoplastic cells in the liver and lung showed positive labeling for HepPar-1, cytokeratin 19, glypican-3, and Ki-67. Hepatocellular degeneration and necrosis were diffuse in the liver parenchyma. Berlin blue staining revealed large amounts of iron in normal and neoplastic cells. Based on these pieces of evidence, this case was diagnosed as hepatocellular carcinoma with hemochromatosis. This is believed to be the first report of hepatocellular carcinoma in an Egyptian fruit bat that has been immunophenotypically examined in detail by pathological examination.
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Affiliation(s)
- Nijiho KAWAGUCHI
- Department of Veterinary Pathology, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
| | - Naoyuki FUKE
- Department of Veterinary Pathology, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Phawut NUEANGPHUET
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Apisit PORNTHUMMAWAT
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
- Department of Pre-Clinic and Applied Animal Science, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | - Ahmad Massoud NIAZI
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Uda Zahli IZZATI
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Takuya HIRAI
- Department of Veterinary Pathology, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
| | - Ryoji YAMAGUCHI
- Department of Veterinary Pathology, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan
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10
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Espírito Santo J, Ladeirinha A, Alarcão A, Strelet E, Reis M, Santos R, Carvalho L. Preoperative Locoregional Therapy May Relate with Stemness and Distinct Transitions Between Epithelial and Mesenchymal States in Hepatocellular Carcinoma. J Clin Exp Hepatol 2024; 14:101268. [PMID: 38076372 PMCID: PMC10709210 DOI: 10.1016/j.jceh.2023.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/12/2023] [Indexed: 01/05/2025] Open
Abstract
Background/Objectives Locoregional therapy (LRT) might impel hepatocellular carcinoma (HCC) to exhibit different phenotypes by modulating tumoral cell adaptation. HCCs presurgically treated with LRT were studied, focusing on stemness and mesenchymal features. Methods Clinicopathological and immunohistochemical data (Ki67, p53, EpCAM, CK19, CK7, ASMA and vimentin expression) were considered in 89 HCC nodules (30 treated with LRT; 59 non-treated), comprising 46 liver transplanted/surgically resected patients. Results In LRT group, well and poorly differentiated tumors without fibrous encapsulation were predominant (P < 0.05) and peritumoral necroinflammation severity tended to be greater. Peritumoral Ki67 expression was higher (P < 0.05) and p53, EpCAM, CK19 and CK7 peritumoral expression was relevant after LRT, where ablated carcinomas displayed higher peritumoral CK19 expression (P < 0.05). Tumoral ASMA and vimentin expression was higher in non-LRT group (P < 0.05). In LRT group, an exclusive association between progenitor/cholangiocytic cell and mesenchymal markers expressed by tumoral cells was observed (P < 0.05): EpCAM tumoral expression associated with vimentin stromal expression; tumoral CK19 expression associated with stromal ASMA expression; tumoral CK7 expression associated with tumoral vimentin expression. Conclusion Peritumoral cellular proliferation and expression of progenitor/cholangiocytic cell markers seem to be more frequent after LRT, with a distinctive epithelial-mesenchymal interplay and plasticity in peritumoral and tumoral compartments.
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Affiliation(s)
- Joana Espírito Santo
- Coimbra Hospital and University Centre, Adult Liver Transplantation Unit, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
| | - Ana Ladeirinha
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
| | - Ana Alarcão
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
| | - Eugeniu Strelet
- Chemical Process Engineering and Forest Products Research Centre, University of Coimbra, Department of Chemical Engineering, Rua Sílvio Lima, Pólo II – Pinhal de Marrocos, 3030-790 Coimbra, Portugal
| | - Marco Reis
- Chemical Process Engineering and Forest Products Research Centre, University of Coimbra, Department of Chemical Engineering, Rua Sílvio Lima, Pólo II – Pinhal de Marrocos, 3030-790 Coimbra, Portugal
| | - Rui Santos
- Coimbra Hospital and University Centre, Internal Medicine Department, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal
| | - Lina Carvalho
- Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
- Coimbra Hospital and University Centre, Pathology Department, Praceta Professor Mota Pinto, 3004-561 Coimbra, Portugal
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11
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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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12
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Rushbrook SM, Kendall TJ, Zen Y, Albazaz R, Manoharan P, Pereira SP, Sturgess R, Davidson BR, Malik HZ, Manas D, Heaton N, Prasad KR, Bridgewater J, Valle JW, Goody R, Hawkins M, Prentice W, Morement H, Walmsley M, Khan SA. British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma. Gut 2023; 73:16-46. [PMID: 37770126 PMCID: PMC10715509 DOI: 10.1136/gutjnl-2023-330029] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 09/05/2023] [Indexed: 10/03/2023]
Abstract
These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.
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Affiliation(s)
- Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | - Timothy James Kendall
- Division of Pathology, University of Edinburgh, Edinburgh, UK
- University of Edinburgh MRC Centre for Inflammation Research, Edinburgh, UK
| | - Yoh Zen
- Department of Pathology, King's College London, London, UK
| | - Raneem Albazaz
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | | | | | - Richard Sturgess
- Digestive Diseases Unit, Aintree University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Brian R Davidson
- Department of Surgery, Royal Free Campus, UCL Medical School, London, UK
| | - Hassan Z Malik
- Department of Surgery, University Hospital Aintree, Liverpool, UK
| | - Derek Manas
- Department of Surgery, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Nigel Heaton
- Department of Hepatobiliary and Pancreatic Surgery, King's College London, London, UK
| | - K Raj Prasad
- John Goligher Colorectal Unit, St. James University Hospital, Leeds, UK
| | - John Bridgewater
- Department of Oncology, UCL Cancer Institute, University College London, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK
| | - Rebecca Goody
- Department of Oncology, St James's University Hospital, Leeds, UK
| | - Maria Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | - Wendy Prentice
- King's College Hospital NHS Foundation Trust, London, UK
| | | | | | - Shahid A Khan
- Hepatology and Gastroenterology Section, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Imperial College Healthcare NHS Trust, London, UK
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13
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Qin Q, Deng LP, Chen J, Ye Z, Wu YY, Yuan Y, Song B. The value of MRI in predicting hepatocellular carcinoma with cytokeratin 19 expression: a systematic review and meta-analysis. Clin Radiol 2023; 78:e975-e984. [PMID: 37783612 DOI: 10.1016/j.crad.2023.08.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 08/03/2023] [Accepted: 08/14/2023] [Indexed: 10/04/2023]
Abstract
AIM To evaluate the overall diagnostic performance of magnetic resonance imaging (MRI), different image features, and different image analysis methods in predicting hepatocellular carcinoma (HCC) with cytokeratin 19 (CK19) expression. MATERIALS AND METHODS A systematic literature search was performed to identify studies using MRI to predict HCC with CK19 expression between 2012 and 2023. Data were extracted to calculate the pooled sensitivity and specificity. Overall diagnostic performance was assessed using areas under the summary receiver operating characteristic curve (AUC). Subgroup analyses were conducted for specific image features and according to image analysis methods (traditional image feature, radiomics, and combined methods). Z-test statistics was used to analyse the differences in diagnostic performance between combined and individual methods. RESULTS Eleven studies with 14 datasets (1,278 lesions from 1,264 patients) were included. The overall pooled sensitivity, specificity, and AUC with corresponding 95% confidence intervals were estimated to be 0.72 (0.55, 0.85), 0.88 (0.80, 0.93), and 0.89 (0.86, 0.91) for MRI in predicting HCC with CK19 expression. Combined methods had higher sensitivity than image feature methods (0.86 versus 0.54, p=0.001), with no difference in specificity (0.85 versus 0.87, p=0.641). There were no significant differences between radiomics and combined methods regarding sensitivity (p=0.796) and specificity (p=0.535), respectively. CONCLUSION MRI shows moderate sensitivity and high specificity in identifying HCC with CK19 expression. The application of radiomics can improve the sensitivity of MRI in identifying HCC with CK19 expression.
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Affiliation(s)
- Q Qin
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - L P Deng
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - J Chen
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Z Ye
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Y Y Wu
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Y Yuan
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - B Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Radiology, Sanya People's Hospital, Sanya, Hainan, China.
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14
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Huang P, Shi Q, Ni X, Liu L, Zhou C, Wu F, Wang C, Xiao Y, Miao G, Yang C, Zeng M. Subcentimeter hepatocellular carcinoma (HCC) on gadoxetic-acid-enhanced MRI: less frequent typical imaging features compared to 1-2 cm HCC but better prognosis after surgical resection. Abdom Radiol (NY) 2023; 48:3391-3400. [PMID: 37656218 DOI: 10.1007/s00261-023-04024-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/05/2023] [Accepted: 08/08/2023] [Indexed: 09/02/2023]
Abstract
PURPOSE To compare the imaging features, pathologic characteristics, and survival outcomes between subcentimeter and 1-2 cm hepatocellular carcinoma (HCC). METHODS This retrospective observational study evaluated the imaging features and medical records of patients with HCC smaller than 2 cm who underwent surgical resection with preoperative gadoxetic-acid-enhanced MRI (EOB-MRI) from January 2013 to December 2021. The incidence of EOB-MRI features and pathological characteristics between the subcentimeter and 1-2 cm HCC were compared. The recurrence-free survival (RFS), including early and overall tumor recurrence, and overall survival (OS) were assessed. RESULTS A total of 223 patients (82 with subcentimeter HCC and 141 with 1-2 cm HCC, 179 men) were enrolled. Compared with 1-2 cm HCC, subcentimeter HCC showed fewer restricted diffusion (87.8 vs. 95.7%, P = 0.027), portal-phase washout (58.5% vs. 73.8%, P = 0.013), typical enhancement pattern (50.0% vs. 66.7%, P =0.014), and microvascular invasion (4.9% vs. 14.9%, P = 0.022). Patients with subcentimeter HCC had higher RFS (P = 0.027) and better OS (P = 0.029). The estimated RFS rates at 5 years was 83.3% for subcentimeter HCC and 67.3% for 1-2 cm HCC, respectively. The estimated OS rates at 5 years was 97.3% for subcentimeter HCC and 89.5% for 1-2 cm HCC, respectively. CONCLUSION Subcentimeter HCC showed less frequent EOB-MRI features seen typically in 1-2 cm HCC but better survival outcomes. Therefore, tailored early diagnostic criteria and immediate treatment for subcentimeter HCC may be warranted.
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Affiliation(s)
- Peng Huang
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Qin Shi
- Shanghai Institute of Medical Imaging, Shanghai, China
| | - Xiaoyan Ni
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Lincheng Liu
- Department of Radiology, People's Hospital of Rizhao, Shandong, China
| | - Changwu Zhou
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Fei Wu
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Cheng Wang
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Yuyao Xiao
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Gengyun Miao
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
- Shanghai Institute of Medical Imaging, Shanghai, China.
- Department of Cancer Center, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
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15
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Zhang SL, Wang HL. Ancillary tests for hepatobiliary neoplasms: what we know and what we need to know. Hum Pathol 2023; 141:183-200. [PMID: 36775105 DOI: 10.1016/j.humpath.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/29/2023] [Accepted: 02/04/2023] [Indexed: 02/12/2023]
Abstract
Ancillary tests are commonly used in the surgical pathology setting for diagnosing challenging neoplastic diseases of the liver and biliary tract, while histology and clinical correlation remain to be critically important. With continuous discoveries, more and more useful ancillary tests have become available, which can help distinguish between malignant and benign hepatocellular neoplasms, malignant and benign biliary tract entities, and intrahepatic and metastatic carcinomas. This review will focus on existing and emerging biomarkers (such as glutamine synthetase, organic anion transporting polypeptide 1B3, insulin-like growth factor-II mRNA binding protein-3, S100P, SMAD4, enhancer of zeste homolog 2, albumin, hepatocyte nuclear factor-1β, etc.) that can be used for the diagnosis, classification and prognostication of hepatobiliary neoplasms.
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Affiliation(s)
- Sarah L Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine and Ronald Reagan Medical Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine and Ronald Reagan Medical Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
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16
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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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17
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El Jabbour T, Molnar A, Lagana SM. Challenges in Diagnosing and Reporting Cholangiocarcinoma. Surg Pathol Clin 2023; 16:599-608. [PMID: 37536891 DOI: 10.1016/j.path.2023.04.012] [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: 08/05/2023]
Abstract
Intrahepatic cholangiocarcinoma is a challenge to the practicing surgical pathologist for several reasons. It is rare in many parts of the world, and thus practical exposure may be limited. Related to the fact of its rarity is the fact that more common tumors which frequently metastasize to the liver can be morphologically indistinguishable (eg, pancreatic ductal adenocarcinoma). Immunohistochemical testing is generally non-contributory in this context. Other difficulties arise from the protean morphologic manifestations of cholangiocarcinoma (ie, small duct vs. large duct) and the existence of combined cholangiocarcinoma and hepatocellular carcinoma. These, and other issues of concern to the practicing diagnostic pathologist are discussed herein.
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Affiliation(s)
| | - Attila Molnar
- Mount Sinai Morningside and Mount Sinai West, Department of Pathology, 1000 Tenth Avenue, First floor, Room G183, New York, NY 10019, USA
| | - Stephen M Lagana
- New York-Presbyterian /Columbia University, Irving Medical Center, 622 W168th St, Vc14-209, New York, NY 10032, USA.
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Debnath P, Dalal K, Dalal B, Athalye S, Chandnani S, Jain S, Shukla A, Rathi P, Shankarkumar A. Characterization of Circulating Tumor Cells Using Imaging Flow Cytometry in Liver Disease Patients. J Clin Exp Hepatol 2023; 13:608-617. [PMID: 37440955 PMCID: PMC10333953 DOI: 10.1016/j.jceh.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/03/2023] [Indexed: 07/15/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is asymptomatic at an early stage which delays its timely diagnosis and treatment. Circulating tumor cells (CTCs), derived from a primary or secondary tumor, may help in the management of HCC. Here, we evaluate and characterize CTCs in liver disease patients. Methods In total, 65 patients, categorized into liver cirrhosis (LC) (n = 30) and HCC (n = 35), were enrolled. Using ImagestreamX MkII imaging flow cytometer, CTCs were detected and characterized using biomarker expression of EpCAM, CK, AFP, CD45, and DRAQ5 in LC and HCC patients. Results CTCs were detected in 33/35 (94%) HCC patients and in 28/30 (93%) LC patients. In the HCC group, the number of biomarker-positive CTCs was higher in BCLC stage D when compared with others. EpCAM + CK was the most expressed biomarker on CTCs in LC versus HCC (83.3% vs. 77.14%), followed by AFP (80% vs. 65.71%), EpCAM (30% vs. 28.57%), and CK (16.6% vs. 14.28%). The EpCAM cell area was significantly associated (P value = 0.031) with the CTC-positive status. The combination biomarker expression of CTCs cell area (EpCAM, CK, and AFP) performed well with the area under the curve of 0.92, high sensitivity, and specificity in detecting early-stage and AFP-negative HCC as well as in AFP-negative LC cases. Conclusion Enumeration and cell area of CTCs may be used as a biomarker for early detection of HCC and guiding treatment.
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Affiliation(s)
- Partha Debnath
- Department of Gastroenterology, Topiwala National Medical College and BYL Ch Hospital, Dr. A.L Nair Road, Mumbai 400 008, Maharashtra, India
| | - Kruti Dalal
- Transfusion Transmitted Diseases Department, National Institute of Immunohaematology, 13th Floor, New Multi-storeyed Bldg, KEM Hospital Campus, Parel, Mumbai 400 012, Maharashtra, India
| | - Bhavik Dalal
- Transfusion Transmitted Diseases Department, National Institute of Immunohaematology, 13th Floor, New Multi-storeyed Bldg, KEM Hospital Campus, Parel, Mumbai 400 012, Maharashtra, India
| | - Shreyasi Athalye
- Transfusion Transmitted Diseases Department, National Institute of Immunohaematology, 13th Floor, New Multi-storeyed Bldg, KEM Hospital Campus, Parel, Mumbai 400 012, Maharashtra, India
| | - Sanjay Chandnani
- Department of Gastroenterology, Topiwala National Medical College and BYL Ch Hospital, Dr. A.L Nair Road, Mumbai 400 008, Maharashtra, India
| | - Shubham Jain
- Department of Gastroenterology, Topiwala National Medical College and BYL Ch Hospital, Dr. A.L Nair Road, Mumbai 400 008, Maharashtra, India
| | - Akash Shukla
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Acharya Donde Marg, Parel East, Parel, Mumbai, Maharashtra 400012, India
| | - Pravin Rathi
- Department of Gastroenterology, Topiwala National Medical College and BYL Ch Hospital, Dr. A.L Nair Road, Mumbai 400 008, Maharashtra, India
| | - Aruna Shankarkumar
- Transfusion Transmitted Diseases Department, National Institute of Immunohaematology, 13th Floor, New Multi-storeyed Bldg, KEM Hospital Campus, Parel, Mumbai 400 012, Maharashtra, India
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Liu G, Ma D, Wang H, Zhou J, Shen Z, Yang Y, Chen Y, Sack I, Guo J, Li R, Yan F. Three-dimensional multifrequency magnetic resonance elastography improves preoperative assessment of proliferative hepatocellular carcinoma. Insights Imaging 2023; 14:89. [PMID: 37198348 PMCID: PMC10192481 DOI: 10.1186/s13244-023-01427-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 04/14/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND To investigate the viscoelastic signatures of proliferative hepatocellular carcinoma (HCC) using three-dimensional (3D) magnetic resonance elastography (MRE). METHODS This prospective study included 121 patients with 124 HCCs as training cohort, and validation cohort included 33 HCCs. They all underwent preoperative conventional magnetic resonance imaging (MRI) and tomoelastography based on 3D multifrequency MRE. Viscoelastic parameters of the tumor and liver were quantified as shear wave speed (c, m/s) and loss angle (φ, rad), representing stiffness and fluidity, respectively. Five MRI features were evaluated. Multivariate logistic regression analyses were used to determine predictors of proliferative HCC to construct corresponding nomograms. RESULTS In training cohort, model 1 (Combining cirrhosis, hepatitis virus, rim APHE, peritumoral enhancement, and tumor margin) yielded an area under the curve (AUC), sensitivity, specificity, accuracy of 0.72, 58.73%,78.69%, 67.74%, respectively. When adding MRE properties (tumor c and tumor φ), established model 2, the AUC increased to 0.81 (95% CI 0.72-0.87), with sensitivity, specificity, accuracy of 71.43%, 81.97%, 75%, respectively. The C-index of nomogram of model 2 was 0.81, showing good performance for proliferative HCC. Therefore, integrating tumor c and tumor φ can significantly improve the performance of preoperative diagnosis of proliferative HCC (AUC increased from 0.72 to 0.81, p = 0.012). The same finding was observed in the validation cohort, with AUC increasing from 0.62 to 0.77 (p = 0.021). CONCLUSIONS Proliferative HCC exhibits low stiffness and high fluidity. Adding MRE properties (tumor c and tumor φ) can improve performance of conventional MRI for preoperative diagnosis of proliferative HCC. CRITICAL RELEVANCE STATEMENT We investigated the viscoelastic signatures of proliferative hepatocellular carcinoma (HCC) using three-dimensional (3D) magnetic resonance elastography (MRE), and find that adding MRE properties (tumor c and tumor φ) can improve performance of conventional MRI for preoperative diagnosis of proliferative HCC.
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Affiliation(s)
- Guixue Liu
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China
| | - Di Ma
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huafeng Wang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiahao Zhou
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China
| | - Zhehan Shen
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China
| | - Yuchen Yang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongjun Chen
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ingolf Sack
- Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jing Guo
- Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ruokun Li
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China.
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, China.
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20
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Mocan LP, Rusu I, Melincovici CS, Boșca BA, Mocan T, Crăciun R, Spârchez Z, Iacobescu M, Mihu CM. The Role of Immunohistochemistry in the Differential Diagnosis between Intrahepatic Cholangiocarcinoma, Hepatocellular Carcinoma and Liver Metastasis, as Well as Its Prognostic Value. Diagnostics (Basel) 2023; 13:diagnostics13091542. [PMID: 37174934 PMCID: PMC10177238 DOI: 10.3390/diagnostics13091542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary hepatic malignant tumor, after hepatocellular carcinoma (HCC). Its incidence has risen worldwide, yet the only potentially curative treatment, surgical resection, is seldom applicable, and the median overall survival remains extremely low. So far, there are no personalized therapy regimens. This study investigated whether routine immunohistochemical stains have diagnostic and/or prognostic value in iCCA. Clinical, imaging, and pathology data were retrospectively gathered for patients diagnosed with iCCA, HCC, or liver metastases assessed using liver needle biopsies. Three study groups with an equal number of cases (n = 65) were formed. In the iCCA group, CK19, CA19-9, CK7, and CEA demonstrated the highest sensitivities (100%, 100%, 93.7%, and 82.6%, respectively). The most relevant stains used for diagnosing HCCs were Glypican 3, CD34 (sinusoidal pattern), and Hep Par 1, with corresponding sensitivities of 100%, 100%, and 98.2%. The immunohistochemical panels for diagnosing metastatic tumors were chosen after correlating the clinical data and morphologic H&E aspects. Moderate/intensely positive CK7 expression and absent/low amount of intratumoral immune cells were favorable prognostic factors and correlated with increased overall survival in both the univariate analysis and the multivariate regression adjusted for age, existence of cirrhosis, number of tumors, and tumor differentiation.
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Affiliation(s)
- Lavinia Patricia Mocan
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Ioana Rusu
- Department of Pathology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Carmen Stanca Melincovici
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Bianca Adina Boșca
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Tudor Mocan
- UBBMed Department, Babeș-Balyai University, 400347 Cluj-Napoca, Romania
- Department of Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Rareș Crăciun
- Department of Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Medical Department, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Zeno Spârchez
- Department of Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Medical Department, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Maria Iacobescu
- Department of Proteomics and Metabolomics, MedFUTURE Research Center for Advanced Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Carmen Mihaela Mihu
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
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21
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Burciu C, Șirli R, Bende R, Popa A, Vuletici D, Miuțescu B, Rațiu I, Popescu A, Sporea I, Dănilă M. A Statistical Approach to the Diagnosis and Prediction of HCC Using CK19 and Glypican 3 Biomarkers. Diagnostics (Basel) 2023; 13:diagnostics13071253. [PMID: 37046471 PMCID: PMC10092964 DOI: 10.3390/diagnostics13071253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/24/2023] [Accepted: 03/25/2023] [Indexed: 03/29/2023] Open
Abstract
Various statistical models predict the probability of developing hepatocellular carcinoma (HCC) in patients with cirrhosis, with GALAD being one of the most extensively studied scores. Biomarkers like alpha-fetoprotein (AFP), AFP-L3, and des-g-carboxyprothrombin (DCP) are widely used alone or in conjunction with ultrasound to screen for HCC. Our study aimed to compare the effectiveness of Cytokeratin 19 (CK19) and Glypican-3 (GPC3) as standalone biomarkers and in a statistical model to predict the likelihood of HCC. We conducted a monocentric prospective study involving 154 participants with previously diagnosed liver cirrhosis, divided into two groups: 95 patients with confirmed HCC based on clinical, biological, and imaging features and 59 patients without HCC. We measured the levels of AFP, AFP-L3, DCP, GPC3, and CK19 in both groups. We used univariate and multivariate statistical analyses to evaluate the ability of GPC3 and CK19 to predict the presence of HCC and incorporated them into a statistical model—the GALKA score—which was then compared to the GALAD score. AFP performed better than AFP-F3, DCP, GPC3, and CK19 in predicting the presence of HCC in our cohort. Additionally, GPC3 outperformed CK19. We used multivariate analysis to compute the GALKA score to predict the presence of HCC. Using these predictors, the following score was formulated: 0.005*AFP-L3 + 0.00069*AFP + 0.000066*GPC3 + 0.01*CK19 + 0.235*Serum Albumin—0.277. The optimal cutoff was >0.32 (AUROC = 0.98, sensitivity: 96.8%, specificity: 93%, positive predictive value—95.8%, negative predictive value—94.8%). The GALKA score had a similar predictive value to the GALAD score for the presence of HCC. In conclusion, AFP, AFP-L3, and DCP were the best biomarkers for predicting the likelihood of HCC. Our score performed well overall and was comparable to the GALAD score.
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Affiliation(s)
- Călin Burciu
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
| | - Roxana Șirli
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
- Correspondence:
| | - Renata Bende
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
| | - Alexandru Popa
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
| | - Deiana Vuletici
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
| | - Bogdan Miuțescu
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
| | - Iulia Rațiu
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
| | - Alina Popescu
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
| | - Ioan Sporea
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
| | - Mirela Dănilă
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 300041 Timișoara, Romania
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, 30041 Timisoara, Romania
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22
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Mukhopadhyay B, Holovac K, Schuebel K, Mukhopadhyay P, Cinar R, Iyer S, Marietta C, Goldman D, Kunos G. The endocannabinoid system promotes hepatocyte progenitor cell proliferation and maturation by modulating cellular energetics. Cell Death Discov 2023; 9:104. [PMID: 36966147 PMCID: PMC10039889 DOI: 10.1038/s41420-023-01400-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/01/2023] [Accepted: 03/06/2023] [Indexed: 03/27/2023] Open
Abstract
The proliferation and differentiation of hepatic progenitor cells (HPCs) drive the homeostatic renewal of the liver under diverse conditions. Liver regeneration is associated with an increase in Axin2+Cnr1+ HPCs, along with a marked increase in the levels of the endocannabinoid anandamide (AEA). But the molecular mechanism linking AEA signaling to HPC proliferation and/or differentiation has not been explored. Here, we show that in vitro exposure of HPCs to AEA triggers both cell cycling and differentiation along with increased expression of Cnr1, Krt19, and Axin2. Mechanistically, we found that AEA promotes the nuclear localization of the transcription factor β-catenin, with subsequent induction of its downstream targets. Systemic analyses of cells after CRISPR-mediated knockout of the β-catenin-regulated transcriptome revealed that AEA modulates β-catenin-dependent cell cycling and differentiation, as well as interleukin pathways. Further, we found that AEA promotes OXPHOS in HPCs when amino acids and glucose are readily available as substrates, but AEA inhibits it when the cells rely primarily on fatty acid oxidation. Thus, the endocannabinoid system promotes hepatocyte renewal and maturation by stimulating the proliferation of Axin2+Cnr1+ HPCs via the β-catenin pathways while modulating the metabolic activity of their precursor cells.
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Affiliation(s)
- Bani Mukhopadhyay
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
| | - Kellie Holovac
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Kornel Schuebel
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Partha Mukhopadhyay
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Resat Cinar
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Sindhu Iyer
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Cheryl Marietta
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - David Goldman
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
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23
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Restaino S, Pellecchia G, Poli A, Arcieri M, Andreetta C, Mariuzzi L, Orsaria M, Biasioli A, Della Martina M, Intini SG, Scambia G, Driul L, Vizzielli G. A Rare Case of Hepatocellular Carcinoma Recurrence in Ovarian Site after 12 Years Mimicking a Hepatoid Adenocarcinoma: Case Report. J Clin Med 2023; 12:jcm12072468. [PMID: 37048552 PMCID: PMC10095375 DOI: 10.3390/jcm12072468] [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: 02/05/2023] [Revised: 03/12/2023] [Accepted: 03/20/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatoid carcinoma of the ovary (HCO) is a tumor that resembles, both histologically and cytologically, hepatocarcinoma (HCC) in a patient with a non-cirrhotic liver not involved by the disease. Hepatoid carcinoma is an extremely rare histologic subtype of ovarian cancer and should be distinguished from metastatic HCC. Here, we report the rare case of a 67-year-old woman with ovarian recurrence of HCC 12 years after first diagnosis. The patient was being followed by oncologists because she had been diagnosed with HCV-related HCC (Edmonson and Stainer grade 2, pT2 N0 M0, G2, V1) in 2009. She had undergone surgery for enlarged left hepatectomy to the 4th hepatic segment with cholecystectomy and subsequent placement of a Kehr drain. The preoperative alpha-fetoprotein (AFP) level was 8600 ng/mL, while the postoperative value was only 2.7 ng/mL. At the first diagnosis, no other localizations of the disease, including the genital tract, were found. At the time of recurrence, however, the patient was completely asymptomatic: her liver function was within normal limits with negative blood indices, except for an increased blood dosage of AFP (467 ng/mL), and CA125, which became borderline (37.4 IU/mL). The oncologist placed an indication for a thoracic abdominal CT scan, which showed that the residual liver was free of disease, and the presence of a formation with a solid-cystic appearance and some calcifications at the left adnexal site. The radiological findings were confirmed on level II gynecological ultrasound. The patient then underwent a radical surgery of hysterectomy, bilateral oophorectomy, pelvic peritonectomy, and omentectomy by a laparotomic approach, with the sending of intraoperative extemporaneous histological examination on the annexus site of the tumor mass, obtaining RT = 0. Currently, the patient continues her gyneco-oncology follow-up simultaneously clinically, in laboratory, and instrumentally every 4 months. Our study currently represents the longest elapsed time interval between first diagnosis and disease recurrence, as evidenced by current data in the literature. This was a rather unique and difficult clinical case because of the rarity of the disease, the lack of scientific evidence, and the difficulty in differentiating the primary hepatoid phenotype of the ovary from an ovarian metastasis of HCC. Several multidisciplinary meetings for proper interpretation of clinical and anamnestic data, with the aid of immunohistochemistry (IHC) on histological slides were essential for case management.
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Affiliation(s)
- Stefano Restaino
- Department of Maternal and Child Health, University-Hospital of Udine, P.le S. Maria della Misericordia n°15, 33100 Udine, Italy
| | - Giulia Pellecchia
- Gynecology and Obstetrics Clinic, Department of Medicine, University of Udine, Via Colugna n° 50, 33100 Udine, Italy
| | - Alice Poli
- Gynecology and Obstetrics Clinic, Department of Medicine, University of Udine, Via Colugna n° 50, 33100 Udine, Italy
| | - Martina Arcieri
- Department of Maternal and Child Health, University-Hospital of Udine, P.le S. Maria della Misericordia n°15, 33100 Udine, Italy
- Department of Biomedical, Dental, Morphological and Functional Imaging Science, University of Messina, 98122 Messina, Italy
| | - Claudia Andreetta
- Department of Medical Oncology, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC)-Ospedale S. Maria della Misericordia, 33100 Udine, Italy
| | - Laura Mariuzzi
- Medical Area Department, Institute of Pathological Anatomy, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale, 33100 Udine, Italy
| | - Maria Orsaria
- Medical Area Department, Institute of Pathological Anatomy, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale, 33100 Udine, Italy
| | - Anna Biasioli
- Department of Maternal and Child Health, University-Hospital of Udine, P.le S. Maria della Misericordia n°15, 33100 Udine, Italy
| | - Monica Della Martina
- Department of Maternal and Child Health, University-Hospital of Udine, P.le S. Maria della Misericordia n°15, 33100 Udine, Italy
| | - Sergio Giuseppe Intini
- Department of General Surgery, Academic Hospital of Udine, University of Udine, 33100 Udine, Italy
| | - Giovanni Scambia
- Institute of Gynaecology and Obstetrics Clinic, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Lorenza Driul
- Department of Maternal and Child Health, University-Hospital of Udine, P.le S. Maria della Misericordia n°15, 33100 Udine, Italy
- Gynecology and Obstetrics Clinic, Department of Medicine, University of Udine, Via Colugna n° 50, 33100 Udine, Italy
- Department of Medical Area (DAME), University of Udine, Azienda Ospedaliera Universitaria Friuli Centrale, ASUFC, 33100 Udine, Italy
| | - Giuseppe Vizzielli
- Department of Maternal and Child Health, University-Hospital of Udine, P.le S. Maria della Misericordia n°15, 33100 Udine, Italy
- Gynecology and Obstetrics Clinic, Department of Medicine, University of Udine, Via Colugna n° 50, 33100 Udine, Italy
- Department of Medical Area (DAME), University of Udine, Azienda Ospedaliera Universitaria Friuli Centrale, ASUFC, 33100 Udine, Italy
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Ait-Ahmed Y, Lafdil F. Novel insights into the impact of liver inflammatory responses on primary liver cancer development. LIVER RESEARCH 2023; 7:26-34. [PMID: 39959704 PMCID: PMC11791919 DOI: 10.1016/j.livres.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/05/2022] [Accepted: 01/27/2023] [Indexed: 03/10/2023]
Abstract
Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.
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Affiliation(s)
- Yeni Ait-Ahmed
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
| | - Fouad Lafdil
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
- Institut Universitaire de France (IUF), Paris, France
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25
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Gadoxetic Acid-Enhanced MRI-Based Radiomics Signature: A Potential Imaging Biomarker for Identifying Cytokeratin 19-Positive Hepatocellular Carcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2023; 2023:5424204. [PMID: 36814805 PMCID: PMC9940957 DOI: 10.1155/2023/5424204] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/19/2023] [Accepted: 01/27/2023] [Indexed: 02/16/2023]
Abstract
Purpose One subtype of hepatocellular carcinoma (HCC), with cytokeratin 19 expression (CK19+), has shown to be more aggressive and has a poor prognosis. However, CK19+ is determined by immunohistochemical examination using a surgically resected specimen. This study is aimed at establishing a radiomics signature based on preoperative gadoxetic acid-enhanced MRI for predicting CK19 status in HCC. Patients and Methods. Clinicopathological and imaging data were retrospectively collected from patients who underwent hepatectomy between February 2015 and December 2020. Patients who underwent gadoxetic acid-enhanced MRI and had CK19 results of histopathological examination were included. Radiomics features of the manually segmented lesion during the arterial, portal venous, and hepatobiliary phases were extracted. The 10 most reproducible and robust features at each phase were selected for construction of radiomics signatures, and their performance was evaluated by analyzing the area under the curve (AUC). The goodness of fit of the model was assessed by the Hosmer-Lemeshow test. Results A total of 110 patients were included. The incidence of CK19(+) HCC was 17% (19/110). Alpha fetoprotein was the only significant clinicopathological variable different between CK19(-) and CK19(+) groups. A majority of the selected radiomics features were wavelet filter-derived features. The AUCs of the three radiomics signatures based on arterial, portal venous, and hepatobiliary phases were 0.70 (95% CI: 0.56-0.83), 0.83 (95% CI: 0.73-0.92), and 0.89 (95% CI: 0.82-0.96), respectively. The three radiomics signatures were integrated, and the fusion signature yielded an AUC of 0.92 (95% CI: 0.86-0.98) and was used as the final model for CK19(+) prediction. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the fusion signature was 0.84, 0.89, 0.88, 0.62, and 0.96, respectively. The Hosmer-Lemeshow test showed a good fit of the fusion signature (p > 0.05). Conclusion The established radiomics signature based on preoperative gadoxetic acid-enhanced MRI could be an accurate and potential imaging biomarker for HCC CK19(+) prediction.
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Huang P, Ni X, Zhou C, Shi Z, Wu F, Xiao Y, Yang C, Zeng M. Subcentimeter Nodules with Diagnostic Hallmarks of Hepatocellular Carcinoma: Comparison of Pathological Features and Survival Outcomes with Nodules Measuring 1-2 cm. J Hepatocell Carcinoma 2023; 10:169-180. [PMID: 36789251 PMCID: PMC9922505 DOI: 10.2147/jhc.s401027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
Objective To compare the pathologic diagnosis and survival of patients with subcentimeter and 1-2 cm nodules that present with diagnostic hallmarks of hepatocellular carcinoma (HCC). Methods Diagnostic hallmarks of HCC were defined as hyperintensity on T2 weighted imaging, restricted diffusion, arterial phase hyperenhancement, washout on portal venous phase, and hypointensity on hepatobiliary phase. We retrospectively included 139 patients undergoing curative resection with single nodules ≤2 cm that present imaging features described above on gadoxetic acid-enhanced MRI. The final diagnosis was confirmed by histopathological assessment. Recurrence-free survival (RFS) was compared using Kaplan-Meier analysis with the Log-rank test. Factors associated with overall and early recurrence were identified using Cox regression analysis. Results Among 139 nodules (49 nodules <1 cm), there was no significant difference in the percentage of HCC between subcentimeter and 1-2 cm nodules (94.0% vs 94.4%, P > 0.999). Microvascular invasion (MVI) was less common in subcentimeter HCC (4.3% vs 17.6%, P = 0.032). There were 27 recurrences during a median follow-up time of 46.7 months. Patients with subcentimeter HCC achieved less recurrence, with a 5-year RFS rate of 87.3%. The MVI-positive patients had more early and overall recurrence. A tumor size <1 cm was associated with lower overall recurrence (HR, 0.336; P = 0.047). No factors were independently associated with early recurrence. Conclusion Subcentimeter nodules with diagnostic hallmarks of HCC are highly associated with HCC diagnosis and achieve less tumor recurrence after resection. Early diagnosis and treatment of subcentimeter HCC may be more appropriate.
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Affiliation(s)
- Peng Huang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xiaoyan Ni
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Changwu Zhou
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Shanghai Institute of Medical Imaging, Shanghai, People’s Republic of China
| | - Zhang Shi
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Fei Wu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yuyao Xiao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Chun Yang, Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, People’s Republic of China, Tel +86 18702135336, Email
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China,Shanghai Institute of Medical Imaging, Shanghai, People’s Republic of China,Correspondence: Mengsu Zeng, Shanghai Institute of Medical Imaging, Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, People’s Republic of China, Tel +86 13501922963, Email
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Kitao A, Matsui O, Zhang Y, Ogi T, Nakada S, Sato Y, Harada K, Yoneda N, Kozaka K, Inoue D, Yoshida K, Koda W, Yamashita T, Yamashita T, Kaneko S, Kobayashi S, Gabata T. Dynamic CT and Gadoxetic Acid-enhanced MRI Characteristics of P53-mutated Hepatocellular Carcinoma. Radiology 2023; 306:e220531. [PMID: 36219111 DOI: 10.1148/radiol.220531] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Background Imaging markers of hepatocellular carcinoma (HCC) on the basis of molecular classification are important for predicting malignancy grade and prognosis. P53-mutated HCC is a major aggressive subtype; however, its imaging characteristics have not been clarified. Purpose To clarify the imaging characteristics of P53-mutated HCC at dynamic CT and gadoxetic acid-enhanced MRI that are correlated with its clinical features, pathologic findings, and prognosis. Materials and Methods In this retrospective single-center study, patients with surgically resected HCC between January 2015 and May 2018 in a university hospital were evaluated. HCC was classified into P53-mutated HCC and non-P53-mutated HCC using immunostaining. Dynamic CT and gadoxetic acid-enhanced MRI findings, clinical features, pathologic findings, and prognosis were compared using Mann-Whitney test, χ2 test, multivariable regression analysis, receiver operating characteristic analysis, Kaplan-Meier method, and log-rank test. Immunohistochemical expression of P53, organic anion transporting polypeptide 1B3 (OATP1B3), and CD34 were evaluated, and the correlations were analyzed using the Pearson correlation test. Results In total, 149 patients (mean age, 67 years ± 9 [SD]; 103 men) with 173 HCCs were evaluated. P53-mutated HCC (n = 28) demonstrated higher serum α-fetoprotein (median, 127.5 ng/mL vs 5.5 ng/mL; P < .001), larger size (40.4 mm ± 29.7 vs 26.4 mm ± 20.5; P = .001), and higher rates of poorly differentiated HCC (22 of 28 [79%] vs 24 of 145 [17%]; P < .001). Dilated vasculature in the arterial phase of dynamic CT (odds ratio, 14; 95% CI: 3, 80; P = .002) and a lower relative enhancement ratio in the hepatobiliary phase (odds ratio, 0.05; 95% CI: 0.01, 0.34; cutoff value, 0.69; P = .002) independently predicted P53-mutated HCC. OATP1B3 expression and P53 expression were inversely correlated (P = .002; R = -0.24). Five-year overall survival was worse for P53-mutated HCC (50.0% vs 72.6%; P = .02). Conclusion Dilated vasculature at the arterial phase of dynamic CT and a lower relative enhancement ratio at the hepatobiliary phase of gadoxetic acid-enhanced MRI were useful markers for P53-mutated hepatocellular carcinoma with poor prognosis. © RSNA, 2022 Online supplemental material is available for this article.
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Affiliation(s)
- Azusa Kitao
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Osamu Matsui
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Yu Zhang
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Takahiro Ogi
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Satoko Nakada
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Yasunori Sato
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Kenichi Harada
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Norihide Yoneda
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Kazuto Kozaka
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Dai Inoue
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Kotaro Yoshida
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Wataru Koda
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Taro Yamashita
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Tatsuya Yamashita
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Shuichi Kaneko
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Satoshi Kobayashi
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
| | - Toshifumi Gabata
- From the Departments of Radiology (A.K., O.M., Y.Z., T.O., N.Y., K.K., D.I., K.Y., W.K., T.G.), Pathology (S.N., Y.S., K.H.), Gastroenterology (Taro Yamashita, Tatsuya Yamashita, S. Kaneko), and Quantum Medical Technology (S. Kobayashi), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa 920-8641, Japan
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Rigual MDM, Sánchez Sánchez P, Djouder N. Is liver regeneration key in hepatocellular carcinoma development? Trends Cancer 2023; 9:140-157. [PMID: 36347768 DOI: 10.1016/j.trecan.2022.10.005] [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: 07/13/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
The liver is the largest organ of the mammalian body and has the remarkable ability to fully regenerate in order to maintain tissue homeostasis. The adult liver consists of hexagonal lobules, each with a central vein surrounded by six portal triads localized in the lobule border containing distinct parenchymal and nonparenchymal cells. Because the liver is continuously exposed to diverse stress signals, several sophisticated regenerative processes exist to restore its functional status following impairment. However, these stress signals can affect the liver's capacity to regenerate and may lead to the development of hepatocellular carcinoma (HCC), one of the most aggressive liver cancers. Here, we review the mechanisms of hepatic regeneration and their potential to influence HCC development.
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Affiliation(s)
- María Del Mar Rigual
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Paula Sánchez Sánchez
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain.
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Pathology of Combined Hepatocellular Carcinoma-Cholangiocarcinoma: An Update. Cancers (Basel) 2023; 15:cancers15020494. [PMID: 36672443 PMCID: PMC9856551 DOI: 10.3390/cancers15020494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/08/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that is composed of both hepatocellular and cholangiocellular differentiated cells. It is slightly more common in men and among Asian and Pacific islanders. Overall, risk factors are similar to classic risk factors of hepatocellular carcinoma (HCC). The classification has significantly evolved over time. The last WHO classification (2019) mainly emphasized diagnosis on morphological basis with routine stainings, discarded previously recognized classifications with carcinomas with stem cell features, introduced intermediate cell carcinoma as a specific subtype and considered cholangiolocarcinoma as a subtype of cholangiocellular carcinoma. Immunohistochemical markers may be applied for further specification but have limited value for diagnosis. Recent discoveries in molecular pathway regulation may pioneer new therapeutic approaches for this poor prognostic and challenging diagnosis.
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SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma. Am J Surg Pathol 2023; 47:1-11. [PMID: 36322988 DOI: 10.1097/pas.0000000000001990] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with SOX9 -high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High SOX9 mRNA level, but not increased expression of EpCAM mRNA or K19 mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High SOX9 mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased SOX9 mRNA and can be used to predict prognosis in HCC cases.
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Wei H, Yang T, Chen J, Duan T, Jiang H, Song B. Prognostic implications of CT/MRI LI-RADS in hepatocellular carcinoma: State of the art and future directions. Liver Int 2022; 42:2131-2144. [PMID: 35808845 DOI: 10.1111/liv.15362] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/13/2022] [Accepted: 07/05/2022] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most lethal malignancy with an increasing incidence worldwide. Management of HCC has followed several clinical staging systems that rely on tumour morphologic characteristics and clinical variables. However, these algorithms are unlikely to profile the full landscape of tumour aggressiveness and allow accurate prognosis stratification. Noninvasive imaging biomarkers on computed tomography (CT) or magnetic resonance imaging (MRI) exhibit a promising prospect to refine the prognostication of HCC. The Liver Imaging Reporting and Data System (LI-RADS) is a comprehensive system for standardizing the terminology, techniques, interpretation, reporting and data collection of liver imaging. At present, it has been widely accepted as an effective diagnostic system for HCC in at-risk patients. Emerging data have provided new insights into the potential of CT/MRI LI-RADS in HCC prognostication, which may help refine the prognostic paradigm of HCC that promises to direct individualized management and improve patient outcomes. Therefore, this review aims to summarize several prognostic imaging features at CT/MRI for patients with HCC; the available evidence regarding the use of LI-RDAS for evaluation of tumour biology and clinical outcomes, pitfalls of current literature, and future directions for LI-RADS in the management of HCC.
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Affiliation(s)
- Hong Wei
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Yang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Chen
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Duan
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Hanyu Jiang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.,Department of Radiology, Sanya People's Hospital, Sanya, China
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Zhang L, Qi Q, Li Q, Ren S, Liu S, Mao B, Li X, Wu Y, Yang L, Liu L, Li Y, Duan S, Zhang L. Ultrasomics prediction for cytokeratin 19 expression in hepatocellular carcinoma: A multicenter study. Front Oncol 2022; 12:994456. [PMID: 36119507 PMCID: PMC9478580 DOI: 10.3389/fonc.2022.994456] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022] Open
Abstract
Objective The purpose of this study was to investigate the preoperative prediction of Cytokeratin (CK) 19 expression in patients with hepatocellular carcinoma (HCC) by machine learning-based ultrasomics. Methods We retrospectively analyzed 214 patients with pathologically confirmed HCC who received CK19 immunohistochemical staining. Through random stratified sampling (ratio, 8:2), patients from institutions I and II were divided into training dataset (n = 143) and test dataset (n = 36), and patients from institution III served as external validation dataset (n = 35). All gray-scale ultrasound images were preprocessed, and then the regions of interest were then manually segmented by two sonographers. A total of 1409 ultrasomics features were extracted from the original and derived images. Next, the intraclass correlation coefficient, variance threshold, mutual information, and embedded method were applied to feature dimension reduction. Finally, the clinical model, ultrasonics model, and combined model were constructed by eXtreme Gradient Boosting algorithm. Model performance was assessed by area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Results A total of 12 ultrasomics signatures were used to construct the ultrasomics models. In addition, 21 clinical features were used to construct the clinical model, including gender, age, Child-Pugh classification, hepatitis B surface antigen/hepatitis C virus antibody (positive/negative), cirrhosis (yes/no), splenomegaly (yes/no), tumor location, tumor maximum diameter, tumor number, alpha-fetoprotein, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glutamyl-transpeptidase, albumin, total bilirubin, conjugated bilirubin, creatinine, prothrombin time, fibrinogen, and international normalized ratio. The AUC of the ultrasomics model was 0.789 (0.621 – 0.907) and 0.787 (0.616 – 0.907) in the test and validation datasets, respectively. However, the performance of the combined model covering clinical features and ultrasomics signatures improved significantly. Additionally, the AUC (95% CI), sensitivity, specificity, and accuracy were 0.867 (0.712 – 0.957), 0.750, 0.875, 0.861, and 0.862 (0.703 – 0.955), 0.833, 0.862, and 0.857 in the test dataset and external validation dataset, respectively. Conclusion Ultrasomics signatures could be used to predict the expression of CK19 in HCC patients. The combination of clinical features and ultrasomics signatures showed excellent effects, which significantly improved prediction accuracy and robustness.
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Affiliation(s)
- Linlin Zhang
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Qinghua Qi
- Department of Ultrasound, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qian Li
- Department of Ultrasound, Henan Provincial Cancer Hospital, Zhengzhou, China
| | - Shanshan Ren
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shunhua Liu
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Bing Mao
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Xin Li
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yuejin Wu
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Lanling Yang
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Luwen Liu
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yaqiong Li
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shaobo Duan
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Health Management, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- *Correspondence: Lianzhong Zhang, ; Shaobo Duan,
| | - Lianzhong Zhang
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
- *Correspondence: Lianzhong Zhang, ; Shaobo Duan,
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MRI features of histologic subtypes of hepatocellular carcinoma: correlation with histologic, genetic, and molecular biologic classification. Eur Radiol 2022; 32:5119-5133. [PMID: 35258675 DOI: 10.1007/s00330-022-08643-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 01/31/2022] [Accepted: 02/11/2022] [Indexed: 02/07/2023]
Abstract
HCC is a heterogeneous group of tumors in terms of histology, genetic aberration, and protein expression. Advancements in imaging techniques have allowed imaging diagnosis to become a critical part of managing HCC in the clinical setting, even without pathologic diagnosis. With the identification of many HCC subtypes, there is increasing correlative evidence between imaging phenotypes and histologic, molecular, and genetic characteristics of various HCC subtypes. In this review, current knowledge of histologic heterogeneity of HCC correlated to features on gadolinium-enhanced dynamic liver MRI will be discussed. In addition, HCC subtype classification according to transcriptomic profiles will be outlined with descriptions of histologic, genetic, and molecular characteristics of some relatively well-established morphologic subtypes, namely the low proliferation class (steatohepatitic HCC and CTNNB1-mutated HCC) and the high proliferation class (macrotrabecular-massive HCC (MTM-HCC), scirrhous HCC, and CK19-positive HCC). Characteristics of sarcomatoid HCC and fibrolamellar HCC will also be discussed. Further research on radiological characteristics of HCC subtypes may ultimately enable non-invasive diagnosis and serve as a biomarker in predicting prognosis, molecular characteristics, and therapeutic response. In the era of precision medicine, a multidisciplinary effort to develop an integrated radiologic and clinical diagnostic system of various HCC subtypes is necessary. KEY POINTS: • HCC is a heterogeneous group of tumors in terms of histology, genetic aberration, and protein expression, which can be divided into many subtypes according to transcriptome profiles. • There is increasing evidence of a correlation between imaging phenotypes and histologic, genetic, and molecular biologic characteristics of various HCC subtypes. • Imaging characteristics may ultimately enable non-invasive diagnosis and subtype characterization, serving as a biomarker for predicting prognosis, molecular characteristics, and therapeutic response.
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Robveille C, Cullen JM. Hepatocellular carcinomas in captive prosimians. Vet Pathol 2022; 59:1012-1021. [PMID: 35876312 DOI: 10.1177/03009858221114471] [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: 11/17/2022]
Abstract
We performed a retrospective examination of spontaneous hepatocellular carcinomas (HCCs) (primary and metastatic tumors) in 14 captive prosimians brought to the Veterinary Medical Diagnostic Laboratory in North Carolina State University over a period of 11 years (2003 to 2014) to characterize the tumors. These animals are endangered primates; a better understanding of the main fatal neoplasms is crucial. In addition to the histologic evaluation, an immunohistochemical study was also performed, using a hepatocyte marker (hepatocyte paraffin 1 [HepPar-1]) and 2 cholangiocyte markers (keratin 7 [K7] and keratin 19 [K19]), in an attempt to identify a specific profile for HCCs with metastatic behavior. Six of the 14 HCCs had pulmonary metastases. The most frequent histopathological findings were a trabecular pattern (14/14, 100%), presence of multinucleated cells (12/14, 85.7%), and foci of extramedullary hematopoiesis (9/14, 64.3%). The mitotic count was significantly higher in the metastatic HCCs (P < .05). HepPar-1 was detected in all primary and metastatic HCCs, with a strong intensity of staining. Labeling for K7 and K19 was positive in 12 HCCs (85.7%) and 1 HCC (7.1%), respectively. Contrary to the less aggressive HCCs, most of the metastatic HCCs (5/6) expressed K7 in more than 15% of cells. The percentage of K7-positive neoplastic hepatocytes was significantly higher in metastatic HCCs. This study suggests that K7 might be a prognostically relevant marker in HCCs of captive prosimians.
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Zanotti S, Boot GF, Coto-Llerena M, Gallon J, Hess GF, Soysal SD, Kollmar O, Ng CKY, Piscuoglio S. The Role of Chronic Liver Diseases in the Emergence and Recurrence of Hepatocellular Carcinoma: An Omics Perspective. Front Med (Lausanne) 2022; 9:888850. [PMID: 35814741 PMCID: PMC9263082 DOI: 10.3389/fmed.2022.888850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/23/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma (HCC) typically develops from a background of cirrhosis resulting from chronic inflammation. This inflammation is frequently associated with chronic liver diseases (CLD). The advent of next generation sequencing has enabled extensive analyses of molecular aberrations in HCC. However, less attention has been directed to the chronically inflamed background of the liver, prior to HCC emergence and during recurrence following surgery. Hepatocytes within chronically inflamed liver tissues present highly activated inflammatory signaling pathways and accumulation of a complex mutational landscape. In this altered environment, cells may transform in a stepwise manner toward tumorigenesis. Similarly, the chronically inflamed environment which persists after resection may impact the timing of HCC recurrence. Advances in research are allowing an extensive epigenomic, transcriptomic and proteomic characterization of CLD which define the emergence of HCC or its recurrence. The amount of data generated will enable the understanding of oncogenic mechanisms in HCC from the CLD perspective and provide the possibility to identify robust biomarkers or novel therapeutic targets for the treatment of primary and recurrent HCC. Importantly, biomarkers defined by the analysis of CLD tissue may permit the early detection or prevention of HCC emergence and recurrence. In this review, we compile the current omics based evidence of the contribution of CLD tissues to the emergence and recurrence of HCC.
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Affiliation(s)
- Sofia Zanotti
- Anatomic Pathology Unit, IRCCS Humanitas University Research Hospital, Milan, Italy
| | - Gina F. Boot
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Mairene Coto-Llerena
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - John Gallon
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Gabriel F. Hess
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Savas D. Soysal
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Otto Kollmar
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Charlotte K. Y. Ng
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Bern Center for Precision Medicine, Bern, Switzerland
| | - Salvatore Piscuoglio
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
- *Correspondence: Salvatore Piscuoglio
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Individual and joint influence of cytokeratin 19 and microvascular invasion on the prognosis of patients with hepatocellular carcinoma after hepatectomy. World J Surg Oncol 2022; 20:209. [PMID: 35725470 PMCID: PMC9210815 DOI: 10.1186/s12957-022-02632-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/03/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND AND OBJECTIVES To evaluate the individual and combined associations of cytokeratin 19 (CK19) and microvascular invasion (MVI) with prognosis of patients with hepatocellular carcinoma (HCC). METHODS Clinicopathological data on 352 patients with HCC who underwent radical resection at our hospital between January 2013 and December 2015 were retrospectively analyzed. Patients were divided into four groups: CK19(-)/MVI(-), CK19(-)/MVI(+), CK19(+)/MVI(-), and CK19(+)/MVI(+). RESULTS Of the 352 HCC patients, 154 (43.8%) were CK19(-)/MVI(-); 116 (33.0%), CK19(-)/MVI(+); 31 (8.8%), CK19(+)/MVI(-); and 51 (14.5%), CK19(+)/MVI(+). The disease-free survival of CK19(-)/MVI(-) patients was significantly higher than that of CK19(-)/MVI(+) patients and CK19(+)/MVI(+) patients. Similar results were observed for overall survival. CK19(+)/MVI(+) patients showed significantly lower overall survival than the other three groups. CONCLUSIONS CK19 expression and MVI predict poor prognosis after radical resection of HCC, and the two markers jointly contribute to poor OS. Combining CK19 and MVI may predict post-resection prognosis better than using either factor on its own.
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Guo Y, Chen J, Zhang Y, Guo Y, Jiang M, Dai Y, Yao X. Differentiating Cytokeratin 19 expression of hepatocellular carcinoma by using multi-b-value diffusion-weighted MR imaging with mono-exponential, stretched exponential, intravoxel incoherent motion, diffusion kurtosis imaging and fractional order calculus models. Eur J Radiol 2022; 150:110237. [DOI: 10.1016/j.ejrad.2022.110237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 02/02/2022] [Accepted: 03/03/2022] [Indexed: 12/25/2022]
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Shigematsu Y, Amori G, Kanda H, Takahashi Y, Takazawa Y, Takeuchi K, Inamura K. Decreased ARG1 expression as an adverse prognostic phenotype in non-alcoholic non-virus-related hepatocellular carcinoma. Virchows Arch 2022; 481:253-263. [PMID: 35459975 DOI: 10.1007/s00428-022-03318-3] [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: 11/26/2021] [Revised: 02/21/2022] [Accepted: 03/26/2022] [Indexed: 11/29/2022]
Abstract
The incidence of non-alcoholic non-virus-related hepatocellular carcinoma (NANV-HCC) is increasing along with the growing prevalence of metabolic disorders. In this subset, few useful biomarkers are available to narrow down the high-risk group for recurrence. This study aimed to evaluate the prognostic impact of decreased ARG1 (arginase-1), which is pathologically known as a marker reflecting hepatocyte differentiation, in NANV-HCC. Besides, its relationship with biliary/progenitor cell markers, whose expressions are associated with poor prognosis, was also assessed. To reveal the clinicopathological association of decreased ARG1 expression in NANV-HCC, we investigated 99 patients who underwent curative-intent hepatectomy for NANV-HCC. Tissue microarrays were employed for immunohistochemical analysis. A total of 21 NANV-HCC cases (21%; 21/99) showed decreased ARG1 expression. Decreased ARG1 expression was an independent prognostic factor for both poor DFS (hazard ratio 2.17; 95% confidence interval 1.15-4.09; p = 0.02) and OS (hazard ratio 4.09; 95% confidence interval 1.71-9.80; p = 0.002). In addition, decreased ARG1 expression was significantly associated with expressions of biliary/progenitor cell markers, CK19 and CD56 (p < 0.01). As cytologic features of tumor cells, decreased ARG1 expression was significantly associated with lipid-less cytologic morphology (p = 0.045). These findings indicate that decreased ARG1 expression is a predictive phenotype of postoperative recurrence with poor prognosis in patients with NANV-HCC. Decreased ARG1 expression may be a precursor or overlapping feature with biliary/progenitor cell marker expressions in NANV-HCC.
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Affiliation(s)
- Yasuyuki Shigematsu
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.,Division of Pathology, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Gulanbar Amori
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.,Division of Pathology, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Hiroaki Kanda
- Department of Pathology, Saitama Cancer Center, 780 Omuro Kitaadachi-gun, Ina-machi, Saitama, 362-0806, Japan
| | - Yu Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Yutaka Takazawa
- Department of Pathology, Toranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo, 105-8470, Japan
| | - Kengo Takeuchi
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.,Division of Pathology, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.,Pathology Project for Molecular Targets, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Kentaro Inamura
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan. .,Division of Pathology, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.
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Dum D, Menz A, Völkel C, De Wispelaere N, Hinsch A, Gorbokon N, Lennartz M, Luebke AM, Hube-Magg C, Kluth M, Fraune C, Möller K, Bernreuther C, Lebok P, Clauditz TS, Jacobsen F, Sauter G, Uhlig R, Wilczak W, Steurer S, Minner S, Marx AH, Simon R, Burandt E, Krech T. Cytokeratin 7 and cytokeratin 20 expression in cancer: A tissue microarray study on 15,424 cancers. Exp Mol Pathol 2022; 126:104762. [PMID: 35390310 DOI: 10.1016/j.yexmp.2022.104762] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 03/23/2022] [Accepted: 03/30/2022] [Indexed: 01/15/2023]
Abstract
Combined analysis of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) is often used for assessing the origin of metastatic cancer. To evaluate the diagnostic utility of CK7 and CK20, tissue microarrays containing 15,424 samples from 120 different tumor types and subtypes and 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. CK7 positivity was seen in 52% (8.7% weak, 5.9% moderate, 37% strong) and CK20 positivity in 23% (5.1% weak, 3.4% moderate, 15% strong) of interpretable tumors. Of 8390 positive tumors, 1181 (14%) showed positivity for CK7 and CK20, 5380 (64%) showed positivity for CK7 alone, and 1829 (22%) showed positivity for CK20 alone. CK20 predominated in gastrointestinal tract, urothelial and Merkel cell carcinomas. CK7 was usually negative in prostate cancer and colorectal cancer. Combined evaluation of CK7/CK20 revealed the best diagnostic utility in CK20 positive tumors, where CK7 negativity is often linked to colorectal origin while CK7 positivity argues for urothelial origin or mucinous ovarian cancer. Associations with unfavorable tumor features were found for cytokeratin 7 loss in breast cancer of no special type, urothelial and renal cell carcinomas, for CK7 overexpression in high-grade serous ovarian and gastric cancer, and for CK20 overexpression in urothelial carcinoma. CK20 loss was linked to MSI in gastric (p = 0.0291) and colorectal adenocarcinoma (p < 0.0001). These analyses provide comprehensive data on the frequency of CK7 and CK20 immunostaining - alone or in combination - in human cancers. These data facilitate interpretation of CK7/CK20 immunostaining in cancers.
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Affiliation(s)
- David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cosima Völkel
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Noémi De Wispelaere
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
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Risk stratification of LI-RADS M and LI-RADS 4/5 combined hepatocellular cholangiocarcinoma: prognostic values of MR imaging features and clinicopathological factors. Eur Radiol 2022; 32:5166-5178. [PMID: 35316365 DOI: 10.1007/s00330-022-08691-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 02/17/2022] [Accepted: 02/24/2022] [Indexed: 12/17/2022]
Abstract
OBJECTIVES To investigate the role of clinicopathological factors and MR imaging factors in risk stratification of combined hepatocellular cholangiocarcinoma (cHCC-CCA) patients who were classified as LR-M and LR-4/5. METHODS We retrospectively identified consecutive patients who were confirmed as cHCC-CCA after surgical surgery in our institution from June 2015 to November 2020. Two radiologists evaluated the preoperative MR imaging features independently, and each lesion was assigned with a LI-RADS category. Preoperative clinical data were also collected. Multivariate Cox proportional hazards model was applied to separately identify the independent factors correlated with the recurrence of cHCC-CCAs in LR-M and LR-4/5. Risk stratifications were conducted separately in LR-M and LR-4/5. Recurrence-free survival (RFS) rates and overall survival (OS) rates were analyzed by using the Kaplan-Meier survival curves and log-rank test. RESULTS A total of 131 patients with single primary lesion which met the 2019 WHO classification criteria were finally included. Corona enhancement, delayed central enhancement, and microvascular invasion (MVI) were identified as predictors of RFS in LR-M. Mosaic architecture, CA19-9, and MVI were independently associated with RFS in LR-4/5. Based on the number of these independent predictors, patients were stratified into favorable-outcome groups (LR-ML subgroup and LR-4/5L subgroup) and dismal-outcome groups (LR-MH subgroup and LR-4/5H subgroup). The corresponding median RFS for LR-ML, LR-MH, LR-5L, and LR-5H were 25.6 months, 8.2 months, 51.7 months, and 18.1 months. CONCLUSION Our study explored the prognostic values of imaging and clinicopathological factors for LR-M and LR-4/5 cHCC-CCA patients, and different survival outcomes were observed among four subgroups after conducting risk stratifications. KEY POINTS • Corona enhancement, delayed central enhancement, and MVI were identified as predictors of RFS in cHCC-CCAs which were classified into LR-M. Mosaic architecture, CA19-9, and MVI were independently associated with RFS in cHCC-CCAs which were classified into LR-4/5. • Based on the identified risk factors, LR-M and LR-4/5 cHCC-CCA patients could be stratified into two subgroups respectively, with significantly different RFS and OS. • cHCC-CCA patients from LR-M did not always have worse RFS and OS than those from LR-4/5 in some cases.
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Correlation between Immunohistochemical Markers in Hepatocellular Carcinoma Cells and In Vitro High-Throughput Drug Sensitivity Screening. Can J Gastroenterol Hepatol 2022; 2022:5969716. [PMID: 35127582 PMCID: PMC8808116 DOI: 10.1155/2022/5969716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 11/17/2022] Open
Abstract
AIM This study analyzed the correlation between immunohistochemical markers in hepatocellular carcinoma cells and the results of in vitro high-throughput drug sensitivity screening, to provide a reference for individualized drug treatment in patients with liver cancer. METHODS Seventy-four patients with hepatocellular carcinoma were included in this study from December 2019 to June 2021, and their liver cancer cells were used for in vitro high-throughput drug sensitivity screening. According to the screening results, the patients were divided into relatively sensitive and insensitive groups, and the correlations between sensitivity and immunohistochemistry results were analyzed statistically. RESULTS Alpha-fetoprotein (AFP)-positive liver cancer cells were significantly more sensitive to gemcitabine than AFP-negative cells (χ 2 = 6.102, P=0.014). AFP was also positively correlated with sensitivity of liver cancer cells to three combined regimens containing oxaliplatin (L-OHP) and epirubicin (EPI) : L-OHP + EPI + irinotecan + 5-fluorouracil (5-FU), L-OHP + irinotecan + EPI, and L-OHP + EPI (χ 2 = 8.168, P=0.004, χ 2 = 5.705, P=0.017, and χ 2 = 8.275, P=0.004, respectively). CONCLUSION Gemcitabine and L-OHP + EPI + irinotecan + 5-FU, L-OHP + EPI, and L-OHP + irinotecan + EPI were more effective against AFP-positive compared with AFP-negative liver cancer cells according to in vitro high-throughput drug sensitivity screening. These results may guide the selection of personalized drug treatments for patients with advanced liver cancer in the future but still need further clinical studies to confirm.
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Komuta M. Intrahepatic cholangiocarcinoma: tumour heterogeneity and its clinical relevance. Clin Mol Hepatol 2022; 28:396-407. [PMID: 35032970 PMCID: PMC9293614 DOI: 10.3350/cmh.2021.0287] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 01/13/2022] [Indexed: 11/27/2022] Open
Abstract
Treatment of intrahepatic cholangiocarcinoma (iCCA) is currently at a significant turning point due to the identification of isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted with currently available therapies. Clinical trials of these targeted therapies have been promising, and the iCCA patients who may benefit from these targeted treatments can be identified by pathological examination prior to molecular investigations. This is because IDH mutations and FGFR fusions are mainly seen in the small duct type iCCA, a subtype of iCCA defined by the 5th World Health Organization classification, which can be recognized by the pathological diagnostic process. Therefore, pathology plays an important role in precision medicine for iCCA, not only in confirming the diagnosis, but also in identifying the iCCA patients who may benefit from targeted treatments. However, caution is advised with the pathological diagnosis, as iCCA shows tumour heterogeneity, making it difficult to distinguish small duct type iCCA from hepatocellular carcinoma (HCC), and combined HCC-CCA. This review focuses on the pathological/molecular features of both subtypes of iCCA (large and small duct types), as well as their diagnostic pitfalls, clinical relevance, and future perspectives.
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Affiliation(s)
- Mina Komuta
- Department of Pathology, International University of Health and Welfare, School of Medicine, Narita Hospital, Chiba, Japan.,Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.,Department of Pathology, School of Medicine, Kurume University, Fukuoka, Japan
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Castro-Gil MP, Torres-Mena JE, Salgado RM, Muñoz-Montero SA, Martínez-Garcés JM, López-Torres CD, Mendoza-Vargas A, Gabiño-López NB, Villa-Treviño S, Del Pozo-Yauner L, Arellanes-Robledo J, Krötzsch E, Pérez-Carreón JI. The transcriptome of early GGT/KRT19-positive hepatocellular carcinoma reveals a downregulated gene expression profile associated with fatty acid metabolism. Genomics 2021; 114:72-83. [PMID: 34861383 DOI: 10.1016/j.ygeno.2021.11.035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/05/2021] [Accepted: 11/26/2021] [Indexed: 01/14/2023]
Abstract
Hepatocellular carcinoma expressing hepatobiliary progenitor markers, is considered of poor prognosis. By using a hepatocarcinogenesis model, laser capture microdissection, and RNA-Sequencing analysis, we identified an expression profile in GGT/KRT19-positive experimental tumors; 438 differentially expressed genes were found in early and late nodules along with increased collagen deposition. Dysregulated genes were involved in Fatty Acid Metabolism, RXR function, and Hepatic Stellate Cells Activation. Downregulation of Slc27a5, Acsl1, and Cyp2e1, demonstrated that Retinoid X Receptor α (RXRα) function is compromised in GGT/KRT19-positive nodules. Since RXRα controls NRF2 pathway activation, we determined the expression of NRF2 targeted genes; Akr1b8, Akr7a3, Gstp1, Abcc3, Ptgr1, and Txnrd1 were upregulated, indicating NRF2 pathway activation. A comparative analysis in human HCC showed that SLC27A5, ACSL1, CYP2E1, and RXRα gene expression is mutually exclusive with KRT19 gene expression. Our results indicate that the downregulation of Slc27a5, Acsl1, Rxrα, and Cyp2e1 genes is an early event within GGT/KRT19-positive HCC.
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Affiliation(s)
| | | | - Rosa M Salgado
- Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", CDMX, Mexico
| | - Said A Muñoz-Montero
- Department of Computational Genomics, National Institute of Genomic Medicine, CDMX, Mexico
| | | | | | | | | | - Saúl Villa-Treviño
- Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, CDMX, Mexico
| | - Luis Del Pozo-Yauner
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
| | - Jaime Arellanes-Robledo
- Laboratory of Liver Diseases, National Institute of Genomic Medicine, CDMX, Mexico; Directorate of Cátedras, National Council of Science and Technology, CDMX, Mexico
| | - Edgar Krötzsch
- Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", CDMX, Mexico
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Zhuo J, Lu D, Lin Z, Yang X, Yang M, Wang J, Tao Y, Wen X, Li H, Lian Z, Cen B, Dong S, Wei X, Xie H, Zheng S, Shen Y, Xu X. The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib. Cell Death Dis 2021; 12:1084. [PMID: 34785656 PMCID: PMC8595883 DOI: 10.1038/s41419-021-04320-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 10/11/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023]
Abstract
Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19-/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19- cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19-/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19- HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19- cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.
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Affiliation(s)
- Jianyong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zuyuan Lin
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyu Yang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Modan Yang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaoye Tao
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue Wen
- Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huihui Li
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengxing Lian
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Beini Cen
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Siyi Dong
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Xie
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Shusen Zheng
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Youqing Shen
- Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China.
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China.
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Global DNA 5hmC and CK19 5hmC+ Contents: A Promising Biomarker for Predicting Prognosis in Small Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2021; 28:3758-3770. [PMID: 34677239 PMCID: PMC8534723 DOI: 10.3390/curroncol28050321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/15/2021] [Accepted: 09/23/2021] [Indexed: 11/16/2022]
Abstract
Background: 5-Hydroxymethylcytosine (5hmC) with dynamic existence possesses multiple regulatory functions. Whereas, 5hmC’s impact on small hepatocellular carcinoma (SHCC) remains unclear. The present work focused on characterizing 5hmC content within SHCC and assessing the possibility of using global genomic 5hmC level as the predicative factor of clinical outcome. Methods: This study applied ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in measuring 5mC, 5fC and 5hmC contents. In addition, immunohistochemistry (IHC) was adopted to measure CK19 and 5hmC contents. Results: Research showed 5mC, 5hmC, and 5fC contents from global genomics of SHCC reduced extensively compared with healthy samples (p < 0.001). Moreover, SHCC was associated with lymph node metastasis (LNM). Greater 5mC and 5hmC levels were observed in non-metastasis group compared with the metastasis group (p < 0.001). Correlation analysis between the HBV DNA level and 5mC, 5fC and 5hmC levels exhibited that HBV DNA was associated with 5mC, 5hmC, and 5fC content reduction, which was verified in the cytological experiments. Moreover, 5hmC content had a negative correlation with the expression level of CK19 in SHCC. The decrease in 5hmC and CK19 containing 5hmC positive cell (called CK195hmC+) should be ascribed to the bad prognosis among SHCC patients. Conclusions: The contents of 5hmC and CK195hmC+ of genomic DNA might be adopted for predicting SHCC survival as an important biomarker.
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Yang F, Wan Y, Xu L, Wu Y, Shen X, Wang J, Lu D, Shao C, Zheng S, Niu T, Xu X. MRI-Radiomics Prediction for Cytokeratin 19-Positive Hepatocellular Carcinoma: A Multicenter Study. Front Oncol 2021; 11:672126. [PMID: 34476208 PMCID: PMC8406635 DOI: 10.3389/fonc.2021.672126] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has poor prognosis. Cytokeratin (CK)19-positive (CK19+) HCC is especially aggressive; early identification of this subtype and timely intervention can potentially improve clinical outcomes. In the present study, we developed a preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI)-based radiomics model for noninvasive and accurate classification of CK19+ HCC. A multicenter and time-independent cohort of 257 patients were retrospectively enrolled (training cohort, n = 143; validation cohort A, n = 75; validation cohort B, n = 39). A total of 968 radiomics features were extracted from preoperative multisequence MR images. The maximum relevance minimum redundancy algorithm was applied for feature selection. Multiple logistic regression, support vector machine, random forest, and artificial neural network (ANN) algorithms were used to construct the radiomics model, and the area under the receiver operating characteristic (AUROC) curve was used to evaluate the diagnostic performance of corresponding classifiers. The incidence of CK19+ HCC was significantly higher in male patients. The ANN-derived combined classifier comprising 12 optimal radiomics features showed the best diagnostic performance, with AUROCs of 0.857, 0.726, and 0.790 in the training cohort and validation cohorts A and B, respectively. The combined model based on multisequence MRI radiomics features can be used for preoperative noninvasive and accurate classification of CK19+ HCC, so that personalized management strategies can be developed.
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Affiliation(s)
- Fan Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yidong Wan
- Institute of Translational Medicine, Zhejiang University, Hangzhou, China.,Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lei Xu
- Institute of Translational Medicine, Zhejiang University, Hangzhou, China.,Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yichao Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoyong Shen
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chuxiao Shao
- Department of General Surgery, Lishui Central Hospital, Lishui, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan Health Hangzhou Hospital, Hangzhou, China
| | - Tianye Niu
- Nucelar & Radiological Engineering and Medical Physics Programs, Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University Cancer Center, Hangzhou, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
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Zhuo J, Lu D, Wang J, Lian Z, Zhang J, Li H, Cen B, Wei X, Wei Q, Xie H, Xu X. Molecular phenotypes reveal heterogeneous engraftments of patient-derived hepatocellular carcinoma xenografts. Chin J Cancer Res 2021; 33:470-479. [PMID: 34584372 PMCID: PMC8435819 DOI: 10.21147/j.issn.1000-9604.2021.04.04] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 07/20/2021] [Indexed: 12/21/2022] Open
Abstract
Objective Patient-derived xenograft (PDX) models provide a promising preclinical platform for hepatocellular carcinoma (HCC). However, the molecular features associated with successful engraftment of PDX models have not been revealed. Methods HCC tumor samples from 76 patients were implanted in immunodeficient mice. The molecular expression was evaluated by immunohistochemistry. Patient and tumor characteristics as well as tumor molecular expressions were compared for PDX engraftment using the Chi-square test. The independent prediction parameters were identified by logistic regression analyses. Results The engraftment rate for PDX models from patients with HCC was 39.47% (30/76). Tumors from younger patients and patients with elevated preoperative alpha-fetoprotein level had higher engraftment rates. Tumors with poor differentiation and vascular invasion were related to engraftment success. The positive expression of CK19, CD133, glypican-3 (GPC3), and Ki67 in tumor samples was associated with engraftment success. Logistic regression analyses indicated that GPC3 and Ki67 were two of the strongest predictors of PDX engraftment. Tumors with GPC3/Ki67 phenotypes showed heterogeneous engraftment rates, with 71.9% in GPC3+/Ki67+ tumors, 30.8% in GPC3−/Ki67+ tumors, 15.0% in GPC3+/Ki67− tumors, and 0 in GPC3−/Ki67− tumors.
Conclusions Successful engraftment of HCC PDXs was significantly related to molecular features. Tumors with the GPC3+/Ki67+ phenotype were the most likely to successfully establish HCC PDXs.
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Affiliation(s)
- Jianyong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,National Health Commission Key Laboratory of Combined Multi-organ Transplantation; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jianguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhengxing Lian
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
| | - Jiali Zhang
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
| | - Huihui Li
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
| | - Beini Cen
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Haiyang Xie
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,National Health Commission Key Laboratory of Combined Multi-organ Transplantation; Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
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Usefulness of Circulating CYFRA21-1 in Patients as a Biomarker in Patients Taking Sorafenib or Lenvatinib for Unresectable Hepatocellular Carcinoma. REPORTS 2021. [DOI: 10.3390/reports4030025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: This study investigated the impact of serum cytokeratin 19 fragment (CYFRA21-1) level on the clinical outcomes of patients with unresectable hepatocellular carcinoma (HCC) treated with sorafenib (SOR) or lenvatinib (LEN). Methods: A total of 71 cases with unresectable HCC taking SOR or LEN were included. Univariate and multivariate analyses were performed to identify the prognostic factors in patients taking SOR or LEN. Results: Among the 71 patients taking SOR or LEN, the frequency of cases showing high CYFRA21-1 levels after administration increased compared to before the administration. There was no association between the CYFRA21-1 level and the result of treatment response using modified Response Evaluation Criteria in Solid Tumors (mRECIST) 12 weeks after the administration. Univariate analysis identified a maximum intrahepatic tumor diameter of 70 mm or more, extrahepatic metastasis, baseline alpha-fetoprotein (AFP) ≥ 2000 ng/mL, baseline AFP-L3 index ≥ 15%, baseline des-gamma-carboxy prothrombin (DCP) ≥ 1000 mAU/mL, baseline CYFRA21-1 > 3.5 ng/mL, 12-week mRECIST progressive disease (PD), 12-week DCP ratio ≥ 4, 12-week CYFRA21-1 ratio ≥ 2, administration period less than 12 weeks, ALBI grade 3 at PD, and no additional treatment after discontinuation of SOR/LEN as prognostic factors. Multivariate analysis revealed that AFP-L3 index ≥ 15%, 12-week mRECIST PD, 12-week DCP ratio ≥ 4, 12-week CYFRA21-1 ratio ≥ 2, administration period less than 12 weeks, and no additional treatment after discontinuation of SOR/LEN were independent factors. Conclusions: Patients with a high CYFRA21-1 level at baseline tend to have poor prognosis, and patients with a high CYFRA21-1 ratio 12 weeks after administration have poor prognosis. Serum CYFRA21-1 measurement may have additional effects on prognostic prediction, and it may be necessary to pay close attention to the transition to the next HCC treatment in cases whose CYFRA21-1 level is high.
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Kang HJ, Kim H, Lee DH, Hur BY, Hwang YJ, Suh KS, Han JK. Gadoxetate-enhanced MRI Features of Proliferative Hepatocellular Carcinoma Are Prognostic after Surgery. Radiology 2021; 300:572-582. [PMID: 34227881 DOI: 10.1148/radiol.2021204352] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background Hepatocellular carcinomas (HCCs) are heterogeneous neoplasms, and the prognosis varies based on the subtype. Two broad molecular classes of HCC have been proposed: a proliferative and a nonproliferative class. Purpose To evaluate the gadoxetate-enhanced MRI findings of the proliferative class HCC and its prognostic significance after surgery. Materials and Methods This retrospective cohort study evaluated patients with surgically resected treatment-naive single HCC (≤5 cm) who underwent hepatic resection from January 2010 through February 2013 and preoperative gadoxetate-enhanced MRI. A Cox proportional hazards model was used to determine the predictive factors for overall survival (OS), intrahepatic distant recurrence, and extrahepatic metastasis (EM). The mean follow-up period was 75.5 months ± 30.2 (standard deviation). Multivariable logistic regression was performed to determine factors associated with proliferative class HCC. Results A total of 158 patients (mean age, 57 years ± 11; 128 men and 30 women) were evaluated. Forty-two of the 158 HCCs (26.6%) were proliferative class HCCs (17 macrotrabecular-massive HCCs, 14 keratin 19-positive HCCs, 10 scirrhous HCCs, and one sarcomatoid HCC). The proliferative class was associated with worse OS (hazard ratio [HR], 3.1; 95% CI: 1.5, 6.0; P = .01) and higher rates of intrahepatic distant recurrence (HR, 1.83; 95% CI: 1.1, 2.9; P = .01) and EM (HR, 9.97; 95% CI: 3.2, 31.4; P < .001). Rim arterial phase hyperenhancement (APHE) at gadoxetate-enhanced MRI (odds ratio [OR], 6.35; 95% CI: 1.9, 21.7; P = .01) and high serum α-fetoprotein (>100 ng/mL) (OR, 4.18; 95% CI: 1.64, 10.7; P = .01) were independent predictors for proliferative HCC. The presence of rim APHE was associated with poor OS (HR, 2.4; 95% CI: 1.2, 4.9; P = .02) and higher rates of EM (HR, 7.4; 95% CI: 2.5, 21.7; P < .01). Conclusion The proliferative class of hepatocellular carcinoma (HCC) is an independent factor for poor overall survival with increased rates of intrahepatic and extrahepatic metastasis. Rim arterial phase hyperenhancement at gadoxetate-enhanced MRI may help to identify proliferative class HCC and predict poor overall survival and an increased incidence of extrahepatic metastasis. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Krinsky and Shanbhogue in this issue.
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Affiliation(s)
- Hyo-Jin Kang
- From the Departments of Radiology (H.J.K., D.H.L., J.K.H.) and Pathology (H.K., Y.J.H.), Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 03080, Korea; Departments of Radiology (H.J.K., D.H.L., J.K.H.), Pathology (H.K., Y.J.H.), and Surgery (K.S.S.), Seoul National University College of Medicine, Seoul, Korea; and Department of Radiology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea (B.Y.H.)
| | - Haeryoung Kim
- From the Departments of Radiology (H.J.K., D.H.L., J.K.H.) and Pathology (H.K., Y.J.H.), Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 03080, Korea; Departments of Radiology (H.J.K., D.H.L., J.K.H.), Pathology (H.K., Y.J.H.), and Surgery (K.S.S.), Seoul National University College of Medicine, Seoul, Korea; and Department of Radiology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea (B.Y.H.)
| | - Dong Ho Lee
- From the Departments of Radiology (H.J.K., D.H.L., J.K.H.) and Pathology (H.K., Y.J.H.), Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 03080, Korea; Departments of Radiology (H.J.K., D.H.L., J.K.H.), Pathology (H.K., Y.J.H.), and Surgery (K.S.S.), Seoul National University College of Medicine, Seoul, Korea; and Department of Radiology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea (B.Y.H.)
| | - Bo Yun Hur
- From the Departments of Radiology (H.J.K., D.H.L., J.K.H.) and Pathology (H.K., Y.J.H.), Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 03080, Korea; Departments of Radiology (H.J.K., D.H.L., J.K.H.), Pathology (H.K., Y.J.H.), and Surgery (K.S.S.), Seoul National University College of Medicine, Seoul, Korea; and Department of Radiology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea (B.Y.H.)
| | - Yoon Jung Hwang
- From the Departments of Radiology (H.J.K., D.H.L., J.K.H.) and Pathology (H.K., Y.J.H.), Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 03080, Korea; Departments of Radiology (H.J.K., D.H.L., J.K.H.), Pathology (H.K., Y.J.H.), and Surgery (K.S.S.), Seoul National University College of Medicine, Seoul, Korea; and Department of Radiology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea (B.Y.H.)
| | - Kyung-Suk Suh
- From the Departments of Radiology (H.J.K., D.H.L., J.K.H.) and Pathology (H.K., Y.J.H.), Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 03080, Korea; Departments of Radiology (H.J.K., D.H.L., J.K.H.), Pathology (H.K., Y.J.H.), and Surgery (K.S.S.), Seoul National University College of Medicine, Seoul, Korea; and Department of Radiology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea (B.Y.H.)
| | - Joon Koo Han
- From the Departments of Radiology (H.J.K., D.H.L., J.K.H.) and Pathology (H.K., Y.J.H.), Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 03080, Korea; Departments of Radiology (H.J.K., D.H.L., J.K.H.), Pathology (H.K., Y.J.H.), and Surgery (K.S.S.), Seoul National University College of Medicine, Seoul, Korea; and Department of Radiology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea (B.Y.H.)
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Morita M, Nishida N, Sakai K, Aoki T, Chishina H, Takita M, Ida H, Hagiwara S, Minami Y, Ueshima K, Nishio K, Kobayashi Y, Kakimi K, Kudo M. Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody. Liver Cancer 2021; 10:380-393. [PMID: 34414125 PMCID: PMC8339510 DOI: 10.1159/000516899] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/28/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC. METHODS Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in β-catenin and those without the mutations using transcriptome-based immunogram. RESULTS Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein < 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8+ cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8+ tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS (p < 0.0001 and p = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γ response, inhibitory molecules, and regulatory T cells. DISCUSSION/CONCLUSION The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8+ TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI.
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Affiliation(s)
- Masahiro Morita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan,*Naoshi Nishida,
| | - Kazuko Sakai
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hirokazu Chishina
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yukari Kobayashi
- Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan
| | - Kazuhiro Kakimi
- Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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