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1
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Melehy A, Agopian VG. Role of Liver Transplant in Primary and Secondary Liver Malignancies. Clin Liver Dis 2025; 29:217-234. [PMID: 40287268 DOI: 10.1016/j.cld.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma are the primary hepatic malignancies with established pathways to transplantation and model for end-stage liver disease (MELD) exception points. Other tumors managed with liver transplantation (LT) include hepatic epithelioid hemangioendothelioma and fibrolamellar HCC. LT for metastatic neuroendocrine tumor has been established with patient selection criteria and a path to MELD exception points. Additionally, recent data on LT for patients with unresectable hepatic colorectal metastases demonstrate increasingly encouraging initial results.
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Affiliation(s)
- Andrew Melehy
- Department of Surgery, Dumont-UCLA Transplant and Liver Cancer Centers, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
| | - Vatche G Agopian
- Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-UCLA Transplant and Liver Cancer Centers, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
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2
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Ye-Tran X, Bouattour M, Fresneau B, Turpin A, Perret A, Vitellius C, Coriat R, Blanc JF, Lequoy M, Regnault H, Pietrasz D, Sefrioui D, Lecomte T, Moati E, Caliez O, Nguyen-Khac E, Walter T, Hautefeuille V. Response to systemic treatments and survival of fibrolamellar carcinomas: An AGEO-SFCE French multicenter retrospective cohort. Dig Liver Dis 2025:S1590-8658(25)00328-7. [PMID: 40316454 DOI: 10.1016/j.dld.2025.04.016] [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: 11/15/2024] [Revised: 02/13/2025] [Accepted: 04/07/2025] [Indexed: 05/04/2025]
Abstract
INTRODUCTION Fibrolamellar carcinomas (FLC) are rare and predominantly advanced hepatic malignancies, lacking a clear consensus on anti-tumor treatments (ATT). The primary objective of the study was to determine whether any ATT appeared to give favorable outcomes in terms of morphological objective response (ORR) and disease control (DCR) rate according to RECIST 1.1 criteria. PATIENTS AND METHODS This retrospective multicentric French cohort from 14 centers included 44 patients with histologically proven FLC who received at least one ATT (chemotherapy and/or tyrosine kinase inhibitors, TKI) and underwent at least one morphological evaluation. . RESULTS A total of 40 anti-tumor responses were analyzed after a first line treatment. No complete response was observed, with an ORR in 13 % of cases, a DCR in 55 % of cases and 45 % of disease progression. GEMOX regimen (n = 9) showed an ORR of 11 % and a DCR of 33 %; the combination of doxorubicin and platinum-based chemotherapy (n = 6) achieved an ORR of 33 % and a DCR of 83 %. For TKI, sorafenib (n = 10) and sunitinib (n = 3), there was no objective response, with a DCR of 40 % and 33 % respectively. The median and the 5-years overall survival were 3.3 years and 35 % (95 %CI=[0.23-0.54]) respectively. CONCLUSION FLC have a poor prognosis; ATT show mild response rate. Further approaches and personalized medicine seem to be an unmet need for patients with FLC and new treatments should be urgently developed.
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Affiliation(s)
- Xixi Ye-Tran
- Gastroenterology Department, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Mohamed Bouattour
- Liver Cancer Unit, Assistance Publique - Hôpitaux de Paris, Beaujon University Hospital, Clichy, France
| | - Brice Fresneau
- Gustave Roussy, Department of Children and Adolescents Oncology, Villejuif, F-94805, France
| | - Anthony Turpin
- Medical Oncology - Lille University Hospital - Lille, France
| | - Audrey Perret
- Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Carole Vitellius
- Hepato-Gastroenterology Department, University Hospital, Angers, France
| | - Romain Coriat
- Department of gastroenterology and endoscopy, Hôpital Cochin, Université Paris Cité, Paris, France
| | - Jean Frederic Blanc
- Department of Digestive Oncology, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France
| | - Marie Lequoy
- Department of Hepatology, AP-HP, Saint-Antoine Hospital, F-75012, Paris, France
| | - Hélène Regnault
- Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France
| | - Daniel Pietrasz
- Department of Digestive, Oncological, and Transplant Surgery, Paul Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - David Sefrioui
- Department of Gastroenterology, Digestive Oncology Unit, Rouen University Hospital, Rouen, France
| | - Thierry Lecomte
- Hepato-gastroenterology and Digestive Oncology, Tours University Hospital, Tours, France
| | - Emilie Moati
- Department of Gastroenterology and Digestive Oncology, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, Institut du Cancer Paris Carpem, Paris, France
| | - Olivier Caliez
- Department of Hepato-gastroenterology, Assistance Publique, Hôpitaux de Paris, Pitié Salpêtrière University Hospital, Paris, France
| | - Eric Nguyen-Khac
- Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - Thomas Walter
- Gastroenterology and Digestive Oncology, Edouard Herriot University Hospital, Hospices Civils de Lyon, Lyon, France
| | - Vincent Hautefeuille
- Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France.
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3
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Einarsson H, Graham RP. How Do I Diagnose Fibrolamellar Carcinoma? Mod Pathol 2025; 38:100711. [PMID: 39814265 DOI: 10.1016/j.modpat.2025.100711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 01/07/2025] [Indexed: 01/18/2025]
Abstract
Fibrolamellar carcinoma (FLC) is a unique primary carcinoma of the liver that is characterized by distinct morphologic findings and a recurrent DNAJB1::PRKACA gene fusion. It typically presents in young individuals without underlying liver dysfunction. FLC is difficult to diagnose when based only on morphology, and misdiagnosis is common. Frequent differential diagnoses include conventional hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both of which can show similar morphologic and immunohistochemical features. If based only on molecular analysis, other differential diagnoses have recently emerged, as the DNAJB1::PRKACA fusion has now been reported in cases of intraductal oncocytic papillary neoplasm and intraductal papillary mucinous neoplasm. In this article, we review our diagnostic approach to FLC, which relies on both morphologic and immunohistochemical features, as well as molecular analysis.
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Affiliation(s)
- Haukur Einarsson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
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4
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Abou-Alfa GK, Meyer T, Do RKG, Piha-Paul SA, Light JS, Sherrin S, Yaqubie A, O’Neill AC, Harding JJ, Al-Rajabi R, Denlinger CS, Cano P, Cornelius AS, O’Reilly EM, DiPrimeo D, Eli LD, Gordan JD, Solit DB. Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma. Liver Cancer 2025; 14:58-67. [PMID: 40144471 PMCID: PMC11936434 DOI: 10.1159/000540290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/05/2024] [Indexed: 03/28/2025] Open
Abstract
Introduction Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. Methods Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. Results Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0-21.8) and the disease control rate was 13.3% (95% CI: 1.7-40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. Conclusion In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.
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Affiliation(s)
- Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
- Department of Medicine, Medical School, Trinity College Dublin University, Dublin, Ireland
| | - Tim Meyer
- Department of Oncology, Royal Free Hospital, London, UK
- Department of Oncology, UCL Cancer Institute, University College London, London, UK
| | - Richard Kinh Gian Do
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
| | - Sarina A. Piha-Paul
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph S. Light
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Scott Sherrin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amin Yaqubie
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - James J. Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
| | - Raed Al-Rajabi
- Department of Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Crystal S. Denlinger
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Pablo Cano
- Department of Hematology/Oncology, Sudbury Regional Hospital, Sudbury, ON, Canada
| | - Albert S. Cornelius
- Department of Medicine, Helen DeVos Children’s Hospital, Grand Rapids, MI, USA
| | - Eileen M. O’Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
| | | | - Lisa D. Eli
- Translational Medicine and Biometrics, Puma Biotechnology Inc., Los Angeles, CA, USA
| | - John D. Gordan
- Division of Hematology/Oncology, CSF GI Medical Oncology, San Francisco, CA, USA
| | - David B. Solit
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
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Requena D, Medico JA, Soto-Ugaldi LF, Shirani M, Saltsman JA, Torbenson MS, Coffino P, Simon SM. Liver cancer multiomics reveals diverse protein kinase A disruptions convergently produce fibrolamellar hepatocellular carcinoma. Nat Commun 2024; 15:10887. [PMID: 39738196 PMCID: PMC11685927 DOI: 10.1038/s41467-024-55238-2] [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: 05/07/2024] [Accepted: 12/03/2024] [Indexed: 01/01/2025] Open
Abstract
Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer characterized by a fusion oncokinase of the genes DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). A few FLC-like tumors have been reported showing other alterations involving PKA. To better understand FLC pathogenesis and the relationships among FLC, FLC-like, and other liver tumors, we performed a massive multi-omics analysis. RNA-seq data of 1412 liver tumors from FLC, hepatocellular carcinoma, hepatoblastoma and intrahepatic cholangiocarcinoma are analyzed, obtaining transcriptomic signatures unrestricted by experimental processing methods. These signatures reveal which dysregulations are unique to specific tumors and which are common to all liver cancers. Moreover, the transcriptomic FLC signature identifies a unifying phenotype for all FLC tumors regardless of how PKA was activated. We study this signature at multi-omics and single-cell levels in the first spatial transcriptomic characterization of FLC, identifying the contribution of tumor, normal, stromal, and infiltrating immune cells. Additionally, we study FLC metastases, finding small differences from the primary tumors.
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Affiliation(s)
- David Requena
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY, USA
| | - Jack A Medico
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY, USA
| | - Luis F Soto-Ugaldi
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY, USA
| | - Mahsa Shirani
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY, USA
| | - James A Saltsman
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY, USA
| | | | - Philip Coffino
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY, USA
| | - Sanford M Simon
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY, USA.
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Hagiwara S, Oda I, Ueshima K, Komeda Y, Nishida N, Yoshida A, Yamamoto T, Omaru N, Matsubara T, Kudo M. A Case of Fibrolamellar Hepatocellular Carcinoma in Which Tumor Control Was Achieved by Re-Administering Atezolizumab and Bevacizumab. Cancer Rep (Hoboken) 2024; 7:e70090. [PMID: 39702734 DOI: 10.1002/cnr2.70090] [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: 02/25/2024] [Revised: 11/21/2024] [Accepted: 11/28/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FL-HCC) clinically occurs in young people aged 20-30 years, who often have a normal liver background. We propose a treatment for such cases in which a combination therapy of atezolizumab and bevacizumab is followed by sandwiching radiation therapy to release tumor antigens and then re-administering the combination therapy of atezolizumab and bevacizumab (ABC conversion therapy). CASE The patient is a 15-year-old girl. On April 18, 2022, she noticed skin yellowing and visited her local doctor. Computed tomography (CT) revealed a large mass in the right lobe of the liver and bile duct obstruction due to the tumor. She also had a nodule on her chest that appeared to be a metastatic tumor and was referred to Kinki University Hospital in April 2023. She was suspected to have FL-HCC based on contrast-enhanced ultrasound and CT scan results. There were findings suggestive of lung metastasis; however, she underwent a right hepatic lobectomy on May 17, 2023, considering the risk of liver failure and intra-abdominal bleeding due to the large liver tumor. A CT scan conducted on July 25, 2022, showing increased lung metastases, and she started atezolizumab/bevacizumab combination treatment on October 20, 2022. On March 15, 2023, multiple lung metastases and new intrahepatic lesions appeared, which was diagnosed as progressive disease (PD), and lenvatinib was discontinued. On November 17, 2023, radiation therapy (25 Gy/5 Fr) was administered to the lung and intrahepatic lesions to release tumor antigens, and on November 27, 2023, atezolizumab and bevacizumab combination treatment was resumed to control the tumor. CONCLUSION Combination therapy with atezolizumab, bevacizumab, and radiation therapy may be an option for the treatment of FL-HCC.
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Affiliation(s)
- Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Itsuki Oda
- Department of Clinical Genetics, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yoriaki Komeda
- 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
| | - Akihiro Yoshida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Tomoki Yamamoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Naoya Omaru
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takuya Matsubara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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7
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Nicotra S, Melan L, Busetto A, Bonis A, Lione L, Verzeletti V, Pezzuto F, Dell’Amore A, Calabrese F, Rea F. Aggressive Surgical Management of Bilateral Metachronous Lung Metastases in Fibrolamellar Hepatocellular Carcinoma, a Case Report. LIVERS 2024; 4:398-405. [DOI: 10.3390/livers4030029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/18/2025] Open
Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant primary hepatic cancer that affects mainly adolescents and young adults without underlying liver disease. Its biology remains unknown, but it is pathologically distinct from traditional HCC. Therapeutic strategies are not well defined and, as chemotherapies seem to have limited efficacy, surgical resection remains the only effective treatment. Here we report on a case of a metastatic FL-HCC in an 18-year-old man successfully treated with aggressive intra-thoracic bilateral lung metastasectomy following primary tumour resection and adjuvant chemotherapy. Survival time after initial hepatectomy is 39 months, with no recurrence of disease to date. Aggressive surgical resection and redo surgery should be considered until more effective multimodality therapies are identified. Multidisciplinary team discussion and involvement of medical and surgical specialties are essential in managing these rare entities.
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Affiliation(s)
- Samuele Nicotra
- Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Luca Melan
- Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Alberto Busetto
- Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Alessandro Bonis
- Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Luigi Lione
- Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Vincenzo Verzeletti
- Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Federica Pezzuto
- Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Andrea Dell’Amore
- Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Fiorella Calabrese
- Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
| | - Federico Rea
- Thoracic Surgery Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, 35121 Padova, Italy
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Kirk AM, Crawford JC, Chou CH, Guy C, Pandey K, Kozlik T, Shah RK, Chung S, Nguyen P, Zhang X, Wang J, Bell M, Mettelman RC, Allen EK, Pogorelyy MV, Kim H, Minervina AA, Awad W, Bajracharya R, White T, Long D, Gordon B, Morrison M, Glazer ES, Murphy AJ, Jiang Y, Fitzpatrick EA, Yarchoan M, Sethupathy P, Croft NP, Purcell AW, Federico SM, Stewart E, Gottschalk S, Zamora AE, DeRenzo C, Strome SE, Thomas PG. DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma. Cell Rep Med 2024; 5:101469. [PMID: 38508137 PMCID: PMC10983114 DOI: 10.1016/j.xcrm.2024.101469] [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: 08/23/2023] [Revised: 11/29/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024]
Abstract
Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.
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Affiliation(s)
- Allison M Kirk
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jeremy Chase Crawford
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Ching-Heng Chou
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Cliff Guy
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Kirti Pandey
- Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
| | - Tanya Kozlik
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ravi K Shah
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shanzou Chung
- Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
| | - Phuong Nguyen
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Xiaoyu Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jin Wang
- Department of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Matthew Bell
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Robert C Mettelman
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - E Kaitlynn Allen
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Mikhail V Pogorelyy
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Hyunjin Kim
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Anastasia A Minervina
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Walid Awad
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Resha Bajracharya
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Toni White
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Donald Long
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14850, USA
| | - Brittney Gordon
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Michelle Morrison
- Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Evan S Glazer
- Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Andrew J Murphy
- Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Yixing Jiang
- Department of Medical Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Elizabeth A Fitzpatrick
- Department of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Mark Yarchoan
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Praveen Sethupathy
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14850, USA
| | - Nathan P Croft
- Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
| | - Anthony W Purcell
- Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
| | - Sara M Federico
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Elizabeth Stewart
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Anthony E Zamora
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Christopher DeRenzo
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Scott E Strome
- College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Paul G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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Ismail M, Singh S, Elaskandrany MA, Kim DS, Abboud Y, Bebawy M, Oduro A, Goyal RM, Mohamed O, Wang W. Fibrolamellar Hepatocellular Carcinoma (FLHCC) in a Young Patient Presenting With Nausea and Vomiting After a Greasy Meal. Cureus 2024; 16:e55863. [PMID: 38595871 PMCID: PMC11002470 DOI: 10.7759/cureus.55863] [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] [Accepted: 03/09/2024] [Indexed: 04/11/2024] Open
Abstract
Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare and distinct subtype of liver cancer, predominantly affecting younger patients without underlying liver diseases. This case report discusses a unique presentation of FLHCC in a 38-year-old male with a past medical history of a well-controlled seizure disorder. The patient presented with nausea, vomiting, and abdominal pain following a fatty meal. Laboratory tests revealed elevated liver enzymes and anemia, and imaging showed a large hepatic lesion. Initial management included a septic workup and broad-spectrum antibiotics. However, a liver biopsy performed subsequently revealed the presence of FLHCC. The patient underwent a successful open right hepatectomy and was managed postoperatively with consideration of his seizure disorder. Follow-up at six months showed a stable postoperative condition without any evidence of recurrence. The diagnosis of FLHCC is challenging due to its rarity and nonspecific presentation. The case emphasizes the importance of considering FLHCC in the differential diagnosis of hepatic lesions, particularly in young patients. Surgical resection remains the primary treatment modality. This case underscores the importance of a thorough evaluation of hepatic lesions, especially in younger patients. It also illustrates the complexities in managing patients with FLHCC, requiring a multidisciplinary approach for optimal outcomes. Further research is necessary to better understand the pathogenesis of FLHCC and to develop more effective treatment strategies.
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Affiliation(s)
- Mohamed Ismail
- Department of Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Sahiba Singh
- College of Osteopathic Medicine, Michigan State University, East Lansing, USA
| | | | - David S Kim
- Department of Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Yazan Abboud
- Department of Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Michael Bebawy
- Department of Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Abena Oduro
- Department of Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Ritik Mahaveer Goyal
- Department of Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Omar Mohamed
- Department of Medicine, Saint Barnabas Medical Center, Livingston, USA
| | - Weizheng Wang
- Gastroenterology and Hepatology, Rutgers University New Jersey Medical School, Newark, USA
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10
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Melehy A, Agopian V. Treating rare tumors with liver transplantation. Curr Opin Organ Transplant 2024; 29:30-36. [PMID: 37851086 DOI: 10.1097/mot.0000000000001118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023]
Abstract
PURPOSE OF REVIEW The success of liver transplantation (LT) in treating unresectable hepatocellular carcinoma (HCC) has resulted in interest in LT for other oncologic conditions. Here, we discuss the role of LT for rare oncologic indications including metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), hepatic epitheliod hemangioendothelioma (HEHE), fibrolamellar hepatocellular carcinoma (FLC), and hepatic angiosarcoma (HAS). RECENT FINDINGS Conditions reviewed have been documented indications for LT in the available literature. We summarize the experience of LT for these indications and proposed management guidelines. SUMMARY GEP-NETs with isolated metastases to the liver can be treated with LT with excellent long-term outcomes (10-year survival 88%) if strict selection criteria are used (low-intermediate grade, Ki-67% < 20%, complete resection of primary tumor, stable disease for 6 months, <50% hepatic involvement). HEHE is a rare hepatic tumor for which LT can be performed with reported 10-year survival around 70%. FLC is a distinct clinical entity to HCC and is optimally treated with surgical resection though experience with LT is described in observational series (5-year survival 50%, recurrence in 10%). HAS is a rapidly progressive tumor with a dismal prognosis with or without treatment, including LT.
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Affiliation(s)
- Andrew Melehy
- Dumont-UCLA Transplant and Liver Cancer Centers, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, California, USA
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11
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Da Fonseca LG, Yamamoto VJ, Trinconi Cunha M, Torre GS, Araujo RLC, Fonseca GM, Chen ATC, Chagas AL, Herman P, Alves VAF, Carrilho FJ. Treatment Outcomes in Patients with Advanced Fibrolamellar Hepatocellular Carcinoma Under Systemic Treatment: Analysis of Clinical Characteristics, Management, and Radiomics. J Hepatocell Carcinoma 2023; 10:1923-1933. [PMID: 37933267 PMCID: PMC10625783 DOI: 10.2147/jhc.s428741] [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: 07/31/2023] [Accepted: 10/24/2023] [Indexed: 11/08/2023] Open
Abstract
Purpose Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary liver malignancy often diagnosed at advanced stages. While there are limited data on the efficacy of specific agents, we aim to report outcomes of patients treated with systemic therapies and explore prognostic factors. Patients and Methods Medical records of patients treated between 2010 and 2022 were reviewed. Treatments were defined after multidisciplinary assessment. Descriptive statistics were used for baseline demographics. Time-to-event outcomes were estimated using the Kaplan-Meier method, compared by log-rank and adjusted by a regression model. Radiomic features (including size, shape, and texture) of the primary lesion were extracted and dimensionality reduced. An unsupervised Gaussian Mixture Model (GMM) clustering was performed, and survival was compared between clusters. Results We identified 23 patients: 12 males, with a median age of 23.6 years. At diagnosis, 82.6% had metastases, most frequently to the lungs (39.1%), lymph nodes (39.1%), and peritoneum (21.7%). Patients received a median of three lines (1-8) of treatment, including different regimens. Sorafenib (39.1%), capecitabine (30.4%), and capecitabine/interferon (13%) were the most used first-line regimens. The median time-to-failure was 3.8 months (95% CI: 3.2-8.7). Capecitabine + interferon (42.1%) and platinum combinations (39.1%) were the most used second-line regimens, with a time-to-failure of 3.5 months (95% CI: 1.5-11.6). Median overall survival was 26.7 months (95% CI: 15.1-40.4). A high baseline neutrophil-to-lymphocyte ratio (NLR) was associated with worse survival (p=0.02). Radiomic features identified three clusters, with one cluster (n=6) having better survival (40.4 vs 22.6 months, p=0.039). Tumor sphericity in the arterial phase was the most relevant characteristic associated with a better prognosis (accuracy=0.93). Conclusion FLHCC has unique features compared to conventional HCC, including young onset, gender balance, and absence of hepatopathy. Systemic therapies can provide encouraging survival, but lack of uniformity precludes defining a preferable regimen. Radiomics and NLR were suggested to correlate with prognosis and warrant further validation.
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Affiliation(s)
- Leonardo G Da Fonseca
- Department of Medical Oncology, ICESP - Instituto do Cancer DO Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Victor Junji Yamamoto
- Department of Medical Oncology, ICESP - Instituto do Cancer DO Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Mateus Trinconi Cunha
- Department of Medical Oncology, ICESP - Instituto do Cancer DO Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Giovanna Sawaya Torre
- Department of Radiology, ICESP - Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Raphael L C Araujo
- Digestive Surgery Division, Department of Surgery, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Gilton Marques Fonseca
- Digestive Surgery Division, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Andre Tsin Chih Chen
- Radiation Oncology Department - Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Aline Lopes Chagas
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Paulo Herman
- Digestive Surgery Division, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Flair Jose Carrilho
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil
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Watanabe A, Harimoto N, Saito H, Kawabata-Iwakawa R, Seki T, Muranushi R, Hoshino K, Hagiwara K, Ishii N, Tsukagoshi M, Igarashi T, Araki K, Ikota H, Ishige T, Mimori K, Shirabe K. Fibrolamellar hepatocellular carcinoma: a case report and gene analysis. Surg Case Rep 2023; 9:168. [PMID: 37728655 PMCID: PMC10511385 DOI: 10.1186/s40792-023-01751-3] [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: 07/02/2023] [Accepted: 09/07/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (HCC) (FL-HCC) is rare in Japan. FL-HCC develops in young patients with no history of cirrhosis and tends to manifest lymphatic metastasis with clinical features similar to those of HCC. We present a case of FL-HCC in a young male patient. CASE PRESENTATION A 14-year-old male patient underwent abdominal computed tomography (CT) to diagnose appendicitis, wherein a hepatic tumor was detected. Dynamic enhanced CT revealed a 35-mm solid tumor, which contrasted at the early phase of dynamic enhanced study of the right hepatic segments, with occlusion of the right portal vein. We performed right hepatectomy for these lesions. The patient experienced a single lymphatic recurrence on the hepatoduodenal ligament 12 months after the initial surgery. We performed lymphadenectomy for the recurrent tumor. We performed RNA sequencing (RNA-seq) and targeted DNA sequencing of the resected specimens (primary tumor, lymphatic metastasis, and normal liver). RNA-seq detected DNAJB1-PRKACA in both primary and metastatic lesions as previously reported. Furthermore, The Cancer Genome Atlas (TCGA) database was used to compare other gene expressions in this case with those of previously reported cases of FL-HCC and HCC in young patients. Principal component analysis of differentially expressed genes in the top 10% revealed that the gene expression in our case was similar to that of previous FL-HCC cases but was a different cluster from that in HCC cases in young patients. Mutational analysis did not detect any somatic mutations associated with carcinogenesis, including previously reported mutations (Kastenhuber et al. in Proc Natl Acad Sci USA 114: 13076-84, 2017). CONCLUSION We encountered a case of FL-HCC, a rare hepatic tumor in an adolescent patient, and evaluated the genetic background. Our findings could contribute to the elucidation of the mechanisms underlying carcinogenesis and progression in patients with FL-HCC and thereby contribute to the development of new therapeutic strategies in the future that may improve patient prognosis.
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Affiliation(s)
- Akira Watanabe
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Norifumi Harimoto
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan.
| | - Hideyuki Saito
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Reika Kawabata-Iwakawa
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Gunma University, Maebashi, Japan
| | - Takaomi Seki
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Ryo Muranushi
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Kouki Hoshino
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Kei Hagiwara
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Norihiro Ishii
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Mariko Tsukagoshi
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Takamichi Igarashi
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Kenichiro Araki
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Hayato Ikota
- Department of Diagnostic Pathology, Gunma University Hospital, Maebashi, Japan
| | - Takashi Ishige
- Department of Pediatrics, Graduate School of Medicine, Gunma University Maebashi, Maebashi, Japan
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Ken Shirabe
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
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Leiting JL, Hernandez MC, Bergquist JR, Yonkus JA, Abdelrahman AM, Torbenson MS, Tran NH, Halfdanarson TR, Graham RP, Smoot RL, Truty MJ. Therapeutic Efficacy of Temsirolimus in a Patient-derived Model of Metastatic Fibrolamellar Hepatocellular Carcinoma. In Vivo 2023; 37:1940-1950. [PMID: 37652480 PMCID: PMC10500502 DOI: 10.21873/invivo.13290] [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: 04/23/2023] [Revised: 06/14/2023] [Accepted: 06/28/2023] [Indexed: 09/02/2023]
Abstract
BACKGROUND/AIM Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumor presenting in younger patients without chronic liver disease. Up to 80-100% develop recurrent disease, necessitating additional surgery or systemic treatment. Systemic options and pre-clinical treatment studies are lacking. We previously described patient-derived xenograft (PDX) development, allowing for pre-clinical studies. Herein, we develop FLHCC PDX models and utilize these to define tumor characteristics and determine the efficacy of systemic agents. MATERIALS AND METHODS Primary and lymph node metastatic tumor tissues were obtained at the time of FLHCC resection in two patients. Tumor lysates were screened for protein upregulation. Cell lines were generated from metastatic and primary tumor tissue. The viability of the cell lines was assessed after treatment with temsirolimus, gemcitabine/oxaliplatin, and FOLFIRINOX. Two PDX models were developed from metastatic tissue. For in vivo studies, tumor-bearing mice were treated with temsirolimus, FOLFIRINOX, and Gemcitabine/oxaliplatin. RESULTS PDX models were successfully generated from metastatic FLHCC, which closely recapitulated the original tumor. Upregulation of mTOR was seen in metastatic tissue compared to primary tumors. Cell lines from metastatic tissue demonstrated significant sensitivity to temsirolimus. In vivo testing of PDX models demonstrated a significant response to single-agent temsirolimus with minimal toxicity. CONCLUSION Herein, we demonstrate the feasibility of developing PDX models that closely recapitulate FLHCC. Upregulation of mTOR was seen in metastatic tissue compared to primary tissue. The efficacy of mTOR inhibition with temsirolimus treatment suggests that the upregulation of the mTOR pathway may be a significant mechanism for growth in metastatic lesions and a potential target for therapeutics.
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Affiliation(s)
| | | | | | | | | | | | - Nguyen H Tran
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, U.S.A
| | | | | | - Rory L Smoot
- Department of Surgery, Mayo Clinic, Rochester, MN, U.S.A
| | - Mark J Truty
- Department of Surgery, Mayo Clinic, Rochester, MN, U.S.A.;
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14
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Gummadi J, Wang X, Xie C. Current Advances in the Treatment of Fibrolamellar Carcinoma of Liver. J Hepatocell Carcinoma 2023; 10:745-752. [PMID: 37215364 PMCID: PMC10198173 DOI: 10.2147/jhc.s406902] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/05/2023] [Indexed: 05/24/2023] Open
Abstract
Fibrolamellar carcinoma (FLC) of the liver is a rare type of liver cancer that is prevalent in children and young adults, often less than 40 years old. The etiology is unclear. It presents without underlying liver disease with distinctive histological features such as fibrous collagen bands surrounding the tumor cells. Fusion protein DNAJB1-PRKACA is found in most of the cases. The prognosis of FLC is poor. Even though curative treatment option is surgery for a certain patient population, other treatment modalities including radiation, chemotherapy are currently being used without significant improvement of overall survival. Recently, targeted therapy and immunotherapy have been studied which may provide survival advantage in the future. This review sought to compile data from clinical trials and case reports/series to outline the current state of FLC treatment.
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Affiliation(s)
- Jyotsna Gummadi
- Department of Medicine, MedStar Franklin Square Medical Center, Baltimore, MD, 21237, USA
| | - Xin Wang
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Changqing Xie
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
- NCI CCR Liver Cancer Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA
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15
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Glavas D, Bao QR, Scarpa M, Ruffolo C, Brown ZJ, Pawlik TM, Spolverato G. Treatment and Prognosis of Fibrolamellar Hepatocellular Carcinoma: a Systematic Review of the Recent Literature and Meta-analysis. J Gastrointest Surg 2023; 27:705-715. [PMID: 36797535 PMCID: PMC10073062 DOI: 10.1007/s11605-023-05621-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 01/24/2023] [Indexed: 02/18/2023]
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare disease and current efforts are focused on the prognosis and on the development of efficient and specific treatments. This study aimed to review the latest evidence regarding FL-HCC treatment and prognosis. METHODS A systematic review of the literature over the past 10 years regarding FL-HCC, and meta-analysis of 1-, 3-, and 5-year overall survival (OS) comparing FL-HCC and conventional HCC were performed. RESULTS Overall, 1567 articles were screened, of them 21 were selected for the systematic review, and 6 for meta-analysis. Twenty-one studies included a total of 2168 patients with FL-HCC, with a median age ranging from 11 to 56 years. The majority of patients underwent surgical resection or liver transplantation. After a median follow-up ranging from 24 to 58 months, 1-year OS was 67-100% and 5-year OS was 28-65%. A total of 743 patients with FL-HCC and 163,472 with conventional HCC were included in the meta-analysis. There was a significantly improved 1-, 3-, and 5-years OS in the FL-HCC group compared to the conventional HCC group, although high heterogeneity was found. When excluding population-based studies, and including 96 FL-HCC and 221 conventional HCC patients, the heterogeneity was low, and the meta-analysis showed a significantly longer 1-year OS in patients with FL-HCC than conventional HCC; however, there were no differences at 3- and 5-years OS. CONCLUSIONS Surgical resection for FL-HCC is currently the only curative treatment available. FL-HCC is plagued by high-recurrence rates and poor long-term outcomes which may be related to the absence of specific treatment for advanced and recurrent disease.
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Affiliation(s)
- Dajana Glavas
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy
| | - Quoc Riccardo Bao
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy
| | - Marco Scarpa
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy
| | - Cesare Ruffolo
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy
| | - Zachary J Brown
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Gaya Spolverato
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, Via Nicolò Giustiniani, 2, PD, 35128, Padova, Italy.
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16
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Fibrolamellar Hepatocellular Carcinoma: Comprehensive Review of Diagnosis, Imaging, and Management. J Am Coll Surg 2023; 236:399-410. [PMID: 36648268 DOI: 10.1097/xcs.0000000000000476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FLC) is a rare malignancy that primarily affects patients in late adolescence and young adulthood. FLC tumors are characterized by their unique histologic features and a recently discovered genomic alteration, a chimeric fusion protein found in nearly all tumors. This review article provides the latest advancements in diagnosing, imaging, and managing FLC. STUDY DESIGN A comprehensive systematic review was performed using MEDLINE/PubMed and Web of Science databases, with the end of search date being July 1, 2022, regarding FLC diagnosis, imaging, and management. RESULTS Surgical resection remains the mainstay of therapy offering a chance for cure; however, given the incidence of metastatic disease at diagnosis and high rates of distant relapse, systemic therapies remain a crucial component of disease control. Unfortunately, few systemic therapies have demonstrated proven benefits. Consequently, recent efforts have galvanized around single-institute or small consortia-based studies specifically focused on enrolling patients with FLC or using agents with a biologic rationale. CONCLUSIONS FLC has unique demographic, radiologic, and pathologic features. The rarity of these tumors, coupled with the only recent acknowledgment of the genomic abnormality, has likely led to disease underrecognition and deprioritization of collaborative efforts to establish an evidence-based standard of care. Despite R0 resection, most patients experience recurrence. However, surgical resection is feasible for many recurrences and is associated with good survival. The role of chemotherapy is evolving, and further research is required to define its role in managing this disease.
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Berkovitz A, Migler RD, Qureshi A, Rosemore C, Torbenson MS, Vaughan R, Marcotte E, Simon SM. Clinical and demographic predictors of survival for fibrolamellar carcinoma patients-A patient community, registry-based study. Hepatol Commun 2022; 6:3539-3549. [PMID: 36245434 PMCID: PMC9701473 DOI: 10.1002/hep4.2105] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/02/2022] [Accepted: 09/14/2022] [Indexed: 01/21/2023] Open
Abstract
Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer that affects primarily adolescents and young adults. It is associated with a poor overall prognosis. There is a need to better define risk factors, but small sample size has limited such studies. An FLC patient registry now provides data sufficient for statistically robust inferences. We leveraged a unique patient community-based FLC registry to analyze the prognostic impact of demographic and clinical characteristics evident at diagnosis. Variables were analyzed using Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). In multivariable models of 149 patients (88 females and 61 males), female gender was associated with statistically significant improved survival with HR of 0.52 (95% CI 0.29-0.93). Factors evident at diagnosis that are associated with worse survival included the presence of 10 or more tumors within the liver (HR 7.1; 95% CI 2.4-21.04), and metastases at diagnosis (HR 2.17; 95% CI 1.19-3.94). Positive lymph nodes at diagnosis, despite being found significantly associated with worse survival in a univariate analysis, did not remain significant when adjusted for covariates in a multivariable analysis. We found no statistically significant effect of age at diagnosis nor tumor size at diagnosis on survival. Female gender may confer a favorable prognosis in FLC. Established high-risk prognostic factors that we confirmed in this Registry included the diagnostic presence of numerous intrahepatic tumors, and metastases. This is the first study derived from a FLC patient community-based registry, and highlights how registries of rare tumors can empower patients to meaningfully advance clinical and scientific discoveries.
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Affiliation(s)
- Amichai Berkovitz
- Laboratory of Cellular BiophysicsThe Rockefeller UniversityNew YorkNew YorkUSA
| | | | - Adam Qureshi
- Hospital BiostatisticsThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Carly Rosemore
- Laboratory of Cellular BiophysicsThe Rockefeller UniversityNew YorkNew YorkUSA
- Department of PediatricsMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | | | - Roger Vaughan
- Hospital BiostatisticsThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Erin Marcotte
- Department of PediatricsUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Sanford M. Simon
- Laboratory of Cellular BiophysicsThe Rockefeller UniversityNew YorkNew YorkUSA
- The Fibrolamellar RegistryNew YorkNew YorkUSA
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18
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Schalm SS, O’Hearn E, Wilson K, LaBranche TP, Silva G, Zhang Z, DiPietro L, Bifulco N, Woessner R, Stransky N, Sappal D, Campbell R, Lobbardi R, Palmer M, Kim J, Ye C, Dorsch M, Lengauer C, Guzi T, Kadambi V, Garner A, Hoeflich KP. Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma. GASTRO HEP ADVANCES 2022; 2:307-321. [PMID: 39132655 PMCID: PMC11307690 DOI: 10.1016/j.gastha.2022.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 11/02/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as previously. Results Knockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment vs control (P = .003 and P = .0005, respectively). Conclusion We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.
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Affiliation(s)
| | - Erin O’Hearn
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | - Kevin Wilson
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | | | - Grace Silva
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | - Zhuo Zhang
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | | | - Neil Bifulco
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | | | | | - Darshan Sappal
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | | | - Riadh Lobbardi
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | - Michael Palmer
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | - Joseph Kim
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | - Chaoyang Ye
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | - Marion Dorsch
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | | | - Timothy Guzi
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | - Vivek Kadambi
- Blueprint Medicines Corporation, Cambridge, Massachusetts
| | - Andrew Garner
- Blueprint Medicines Corporation, Cambridge, Massachusetts
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19
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Chen KY, Popovic A, Hsiehchen D, Baretti M, Griffith P, Bista R, Baghdadi A, Kamel IR, Simon SM, Migler RD, Yarchoan M. Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors. Cancers (Basel) 2022; 14:5347. [PMID: 36358766 PMCID: PMC9655068 DOI: 10.3390/cancers14215347] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. METHODS We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan-Meier statistics were used for progression-free survival (PFS) and overall survival (OS). RESULTS FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/- cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3-4 immune related adverse events were observed in 4/19 (21.1%) patients. CONCLUSIONS ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed.
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Affiliation(s)
- Krista Y. Chen
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Aleksandra Popovic
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - David Hsiehchen
- Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Marina Baretti
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Paige Griffith
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Ranjan Bista
- Department of Pediatrics, Texas Tech University Health Sciences Center, El Paso, TX 79410, USA
| | - Azarakhsh Baghdadi
- Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ihab R. Kamel
- Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | | | | | - Mark Yarchoan
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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20
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Polychronidis G, Murtha-Lemekhova A, Fuchs J, Karathanasi E, Hoffmann K. A Multidisciplinary Approach to the Management of Fibrolamellar Carcinoma: Current Perspectives and Future Prospects. Onco Targets Ther 2022; 15:1095-1103. [PMID: 36212724 PMCID: PMC9541294 DOI: 10.2147/ott.s296127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/08/2022] [Indexed: 11/23/2022] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare primary liver tumor affecting predominantly younger and otherwise healthy patients. Typically, FLC presents with advanced disease due to the paucity of typical symptoms and no history of underlying liver disease. Depending on tumor characteristics and the patient's general condition, surgical treatment is the most promising treatment modality. Aggressive resection and liver transplantation have been utilized and are presently indispensable curative treatment options. Under certain circumstances surgical resection is also possible for metachronous metastases or local recurrence. Recent tumor biology discoveries have contributed to improved diagnostic specificity and systemic treatment options.
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Affiliation(s)
- Georgios Polychronidis
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany
| | - Anastasia Murtha-Lemekhova
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany
| | - Juri Fuchs
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany
| | - Evdokia Karathanasi
- Post-Graduate Program “Human Genetics- Genetic Counseling”, Faculty of Medicine, University of Thessaly, Larisa, Greece
| | - Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, 69120, Germany,Correspondence: Katrin Hoffmann, Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 420, Heidelberg, 69120, Germany, Email
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21
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Abdelhamed W, El-Kassas M. Fibrolamellar hepatocellular carcinoma: A rare but unpleasant event. World J Gastrointest Oncol 2022; 14:1103-1114. [PMID: 35949219 PMCID: PMC9244987 DOI: 10.4251/wjgo.v14.i6.1103] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/19/2022] [Accepted: 05/08/2022] [Indexed: 02/06/2023] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), comprising 1%-9% of all HCCs. FLC is a poorly understood malignancy, which seems to be more prevalent in young patients with no underlying liver diseases. The term "fibrolamellar" is derived from thick fibrous collagen bands surrounding the tumor cells. Unlike HCC, cirrhosis and viral hepatitis infection are not predisposing to FLC, and it is not associated with elevations in serum alpha-fetoprotein. FLC patients often present with vague abdominal pain, nausea, malaise, and weight loss. Most cases present are at an advanced stage at the time of initial diagnosis. However, curative treatment options can still be offered to up to 70% of patients. Surgery (resection/liver transplantation) is the mainstay of treatment and the only potentially curative option. FLCs have been less chemo-responsive than the conventional HCC, however, in advanced cases, multimodality treatments can be effective. Recent advances in molecular studies of FLC have found a unique DNAJB1-PRKACA fusion transcript in most of the cases studied. The review aims to describe clinical characteristics, diagnostic methods, and therapeutic modalities for this rare tumor to raise awareness among clinicians and surgeons.
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Affiliation(s)
- Walaa Abdelhamed
- Department of Endemic Medicine, Sohag University, Sohag 14322, Egypt
| | - Mohamed El-Kassas
- Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
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22
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Dinh TA, Utria AF, Barry KC, Ma R, Abou-Alfa GK, Gordan JD, Jaffee EM, Scott JD, Zucman-Rossi J, O’Neill AF, Furth ME, Sethupathy P. A framework for fibrolamellar carcinoma research and clinical trials. Nat Rev Gastroenterol Hepatol 2022; 19:328-342. [PMID: 35190728 PMCID: PMC9516439 DOI: 10.1038/s41575-022-00580-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/13/2022] [Indexed: 12/17/2022]
Abstract
Fibrolamellar carcinoma (FLC), a rare, lethal hepatic cancer, occurs primarily in adolescents and young adults. Unlike hepatocellular carcinoma, FLC has no known association with viral, metabolic or chemical agents that cause cirrhosis. Currently, surgical resection is the only treatment demonstrated to achieve cure, and no standard of care exists for systemic therapy. Progress in FLC research illuminates a transition from an obscure cancer to one for which an interactive community seems poised to uncover fundamental mechanisms and initiate translation towards novel therapies. In this Roadmap, we review advances since the seminal discovery in 2014 that nearly all FLC tumours express a signature oncogene (DNAJB1-PRKACA) encoding a fusion protein (DNAJ-PKAc) in which the J-domain of a heat shock protein 40 (HSP40) co-chaperone replaces an amino-terminal segment of the catalytic subunit of the cyclic AMP-dependent protein kinase (PKA). Important gains include increased understanding of oncogenic pathways driven by DNAJ-PKAc; identification of potential therapeutic targets; development of research models; elucidation of immune mechanisms with potential for the development of immunotherapies; and completion of the first multicentre clinical trials of targeted therapy for FLC. In each of these key areas we propose a Roadmap for future progress.
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Affiliation(s)
- Timothy A. Dinh
- Medical Scientist Training Program, University of North Carolina, Chapel Hill, NC, USA.,Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.,These authors contributed equally: Timothy A. Dinh, Alan F. Utria, Kevin C. Barry
| | - Alan F. Utria
- Department of Surgery, University of Washington, Seattle, WA, USA.,These authors contributed equally: Timothy A. Dinh, Alan F. Utria, Kevin C. Barry
| | - Kevin C. Barry
- Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,These authors contributed equally: Timothy A. Dinh, Alan F. Utria, Kevin C. Barry
| | - Rosanna Ma
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
| | - Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA
| | - John D. Gordan
- Gastrointestinal oncology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA, USA
| | - Elizabeth M. Jaffee
- Department of oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - John D. Scott
- Department of Pharmacology, University of Washington, Seattle, WA, USA
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne université, Inserm, Université de Paris, Functional Genomics of Solid Tumors, Paris, France
| | - Allison F. O’Neill
- Department of Paediatric Hematology/oncology, Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA
| | - Mark E. Furth
- Fibrolamellar Cancer Foundation, Greenwich, CT, USA.,;
| | - Praveen Sethupathy
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.,;
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23
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Kounis I, Lewin M, Laurent-Bellue A, Poli E, Coilly A, Duclos-Vallée JC, Guettier C, Adam R, Lerut J, Samuel D, Rosmorduc O. Advanced epithelioid hemangioendothelioma of the liver: could lenvatinib offer a bridge treatment to liver transplantation? Ther Adv Med Oncol 2022; 14:17588359221086909. [PMID: 35340695 PMCID: PMC8949775 DOI: 10.1177/17588359221086909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 02/23/2022] [Indexed: 01/27/2023] Open
Abstract
In this article, we describe the case of a 34-year-old woman presenting a multifocal and metastatic epithelioid hemangioendothelioma (HEHE) of the liver. Under classical chemotherapy using cyclophosphamide, there was a fast tumor progression in liver and extra-hepatic metastatic sites (lungs and mediastinal lymph node). Taking into account the patient’s age and the natural history of the HEHE, our goal was to try to bring her to liver transplantation (LT) and lenvatinib was an acceptable candidate for this reason. Shortly after the initiation of lenvatinib before LT and surgery, we observed the enlargement of large devascularized necrotic areas in most of the liver HEHE masses, suggesting a good response. The patient was finally transplanted 6 months after initiation of lenvatinib treatment. Eight months after LT, progression occurred (ascites, peritoneal recurrence, and mediastinal lymph node). After restarting lenvatinib, ascites disappeared and the lymph node decreased in size, suggesting a good response, more than 1 year after her transplantation. This is the first case report to our knowledge that illustrates the benefit of lenvatinib as a neoadjuvant bridge until LT for a multifocal and metastatic HEHE. In addition, this drug has also shown a benefit in term of disease control after a late recurrence of the tumor. We suggest that lenvatinib should be proposed as a bridge to the LT for nonresectable HEHE. Moreover, this drug was also beneficial in the treatment of late recurrence after LT. The absence of pharmacologic interactions between classical immunosuppressive drugs and lenvatinib may allow its use as an early adjuvant approach when the risk of recurrence is high. The strength of our case consists in the long follow-up and the innovative message allowing changing palliative strategies into curative ones in case of advanced HEHE.
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Affiliation(s)
- Ilias Kounis
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
| | - Maïté Lewin
- FHU Hepatinov, Centre Hépato-Biliaire, Villejuif, France
| | | | - Edoardo Poli
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
| | - Audrey Coilly
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
| | | | | | - René Adam
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
| | - Jan Lerut
- IREC, Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Didier Samuel
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
| | - Olivier Rosmorduc
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, 94800 Villejuif, France
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24
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Abstract
Malignant primary liver tumors are rare in children. Yet a wide histologic spectrum is seen, particularly in hepatoblastoma, the most common malignant liver tumor in children. Furthermore, there can be significant morphologic overlap with hepatocellular carcinoma, the second most common pediatric liver malignancy, and tumors with hybrid features of hepatoblastoma and hepatocellular carcinoma are also reported (currently placed in the provisional category of malignant hepatocellular neoplasm, not otherwise specified). This review provides detailed morphologic descriptions and updates in the evolving clinical context of these tumors, and presents recent molecular advances that may further help in accurate classification of these tumors, which is critical in their management.
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Affiliation(s)
- Soo-Jin Cho
- Department of Pathology, University of California San Francisco, 1825 4th Street Room M2369, Box 4066, San Francisco, CA 94143, USA.
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25
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Abstract
Fibrolamellar carcinoma (FLC) is a rare malignant entity arising from the liver and primarily affecting patients in late adolescence and young adulthood. FLC tumors are characterized by their unique histologic features and an only recently discovered genomic alteration: a chimeric fusion protein found in nearly all tumors. The rarity of these tumors coupled with the only recent acknowledgement of this genomic abnormality has likely led to disease under-recognition and de-prioritization of collaborative efforts aimed at establishing an evidence-guided standard of care. Surgical resection undoubtedly remains a mainstay of therapy and a necessity for cure but given the incidence of metastatic disease at diagnosis and high rates of distant relapse, systemic therapies remain a key component of disease control. There are few systemic therapies that have demonstrated proven benefit. Recent efforts have galvanized around single-institute or small consortia-based studies specifically focused on the enrollment of patients with FLC or use of agents with biologic rationale. This review will outline the current state of FLC epidemiology, histology, biology and trialed therapies derived from available published literature.
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26
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Al Zahrani A, Alfakeeh A. Fibrolamellar hepatocellular carcinoma treated with atezolizumab and bevacizumab: two case reports. J Med Case Rep 2021; 15:132. [PMID: 33722275 PMCID: PMC7962306 DOI: 10.1186/s13256-021-02695-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
Background Fibrolamellar hepatocellular carcinoma is a unique tumor of the liver that differs from the classical hepatocellular carcinoma in diagnosis, behavior, and possibly treatment. There is usually absent underlying liver disease, and it usually occurs in young patients. The survival outcomes in localized fibrolamellar hepatocellular carcinoma are perhaps better than in classical hepatocellular carcinoma if treated early and radically. On the other hand, the prognosis remains poor for locally advanced and metastatic fibrolamellar hepatocellular carcinoma. Many reports suggested a limited benefit from systemic chemotherapy. Sorafenib also did not show major effects on fibrolamellar hepatocellular carcinoma. Given the rarity of fibrolamellar hepatocellular carcinoma, lack of large studies, and absence of standard treatment, the treatment decisions rely on case reports, previously reported cases series, and expert opinions. Recent studies have shown promising effects of immunotherapy with checkpoint inhibitors in the first- and second-line therapy of hepatocellular carcinoma. Atezolizumab with bevacizumab regimen has been approved recently as a first-line treatment for classical hepatocellular carcinoma. Currently, there are no reports yet on the use of atezolizumab with bevacizumab for fibrolamellar hepatocellular carcinoma. Case report In this article, we present two Arabic patients with advanced fibrolamellar hepatocellular carcinoma who received atezolizumab and bevacizumab combinations but did not show any clinical benefits. Conclusion While atezolizumab and bevacizumab combinations had shown benefits in classical hepatocellular carcinoma, the current data showed a lack of benefit and tumor response in fibrolamellar hepatocellular carcinoma.
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Affiliation(s)
- Ali Al Zahrani
- Department of Medical Oncology, Comprehensive Cancer Center, King Fahad Medical City, Makkah Al Mukarramah Branch Road, Riyadh, 12231, Kingdom of Saudi Arabia.
| | - Ali Alfakeeh
- Department of Medical Oncology, Comprehensive Cancer Center, King Fahad Medical City, Makkah Al Mukarramah Branch Road, Riyadh, 12231, Kingdom of Saudi Arabia
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27
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Gottlieb S, O'Grady C, Gliksberg A, Kent P. Early Experiences with Triple Immunochemotherapy in Adolescents and Young Adults with High-Risk Fibrolamellar Carcinoma. Oncology 2021; 99:310-317. [PMID: 33690232 DOI: 10.1159/000513358] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/21/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION There are no standard systemic therapies for the treatment of fibrolamellar carcinoma (FLC), as surgery remains the only definitive option. We share our experiences using systemic "triple therapy" (TT) with 5-fluorouracil, interferon, and nivolumab for the treatment of relapsed, refractory, metastatic, or unresectable FLC. METHODS Data from all patients who received TT from May 2018 to July 2020 were reviewed to assess response, survival, and toxicity. RESULTS A total of 22 patients were treated with TT, of which 14 (median age of 21 years) were evaluable. They received a median of 18 cycles (8-44). At the time of analysis, the median progression-free survival was 9 months (4.5-26), 29% longer than prior to TT, with 5 patients achieving clinical remission, 8 patients stable or improving, and 1 progression. Overall objective response (clinical remission + partial response) was 50% and tumor control rate (clinical remission + partial response + stable disease) was 93%. Two patients withdrew from treatment due to side effects. DISCUSSION/CONCLUSION Our early results support TT as a promising medical option to slow disease progression and prolong survival in high-risk patients with FLC. TT can be administered in the outpatient setting and has shown good tolerability. Further longitudinal data is needed to confirm outcomes, especially in patients still early in their treatment.
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Affiliation(s)
- Sara Gottlieb
- Rush University Medical Center, Chicago, Illinois, USA
| | | | - Ariel Gliksberg
- Department of Pediatrics, Division of Hematology and Oncology, Rush University Medical Center, Chicago, Illinois, USA
| | - Paul Kent
- Department of Pediatrics, Division of Hematology and Oncology, Rush University Medical Center, Chicago, Illinois, USA,
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28
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Bacinschi X, Zgura AF, Mercan-Stanciu A, Grasu M, Herlea V, Toma L, Dodot M, Martiniuc A, Anghel R, Haineala B. Management of Diagnosis and Treatment in a Case of Fibrolamellar Carcinoma. CANCER DIAGNOSIS & PROGNOSIS 2021; 1:23-28. [PMID: 35399695 PMCID: PMC8962773 DOI: 10.21873/cdp.10004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/05/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM Fibrolamellar carcinoma is a rare primary hepatic malignancy that has recently been recognized as a distinct clinical entity, highly different from the well-known hepatocellular carcinoma. This report describes the clinical and paraclinical aspects of the fibrolamellar carcinoma, emphasizing its particularities. CASE REPORT A 30-year-old patient presented to the hospital with nonspecific symptoms and weight loss, with imaging findings showing abdominal and mediastinal masses. Multiple biopsies were performed, leading to a diagnosis of metastatic fibrolamellar carcinoma. Given the extent of the disease, systemic drug treatment was administered, although prognosis was poor with tumor growth, resulting in biliary duct invasion. CONCLUSION Fibrolamellar carcinoma is a rare type of malignancy, with a difficult differential diagnosis in which imaging techniques are important but for which biopsy remains the gold standard. The prognosis depends on tumor extent and may include surgical methods or chemotherapy.
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Affiliation(s)
- Xenia Bacinschi
- Department of Oncology-Radiotherapy, Prof. Dr. Alexandru Trestioreanu Institute of Oncology,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Anca Florina Zgura
- Department of Oncology-Radiotherapy, Prof. Dr. Alexandru Trestioreanu Institute of Oncology,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Adriana Mercan-Stanciu
- Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Mugur Grasu
- Department of Interventional Radiology, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Vlad Herlea
- Department of Pathology, Fundeni Clinical Institute, Bucharest, Romania
| | - Letitia Toma
- Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Mihai Dodot
- Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Alexandru Martiniuc
- Department of General Surgery, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Rodica Anghel
- Department of Oncology-Radiotherapy, Prof. Dr. Alexandru Trestioreanu Institute of Oncology,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Bogdan Haineala
- Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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29
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Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis. More than 80% of patients are diagnosed at an advanced stage, and most patients with HCC also have liver cirrhosis that complicates cancer management. No targeted treatment options currently exist outside genomics-based clinical trials. Multiple tyrosine kinase inhibitors (mTKIs) such as sorafenib, lenvatinib, cabozantinib, and regorafenib have been used to treat advanced hepatocellular carcinoma (aHCC). Immune checkpoint inhibitors including nivolumab and pembrolizumab have shown survival benefit. More recently, atezolizumab in combination with bevacizumab resulted in improved overall survival and progression-free survival, compared with sorafenib in patients with aHCC in the first-line setting. The combination of nivolumab with ipilimumab as an alternative in the treatment of patients treated with sorafenib has inspired various combination studies of immune checkpoint inhibitors. Currently, ongoing studies of systemic therapy consist of various immune-based combination therapies. Finally, there is no established adjuvant and neoadjuvant therapy although a few early phase studies show promising results. In this chapter, we summarize current approaches of systemic treatment in patients with liver cancer.
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Affiliation(s)
- Tarik Demir
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Sunyoung S Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
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30
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Ramai D, Ofosu A, Lai JK, Gao ZH, Adler DG. Fibrolamellar Hepatocellular Carcinoma: A Population-Based Observational Study. Dig Dis Sci 2021; 66:308-314. [PMID: 32052215 DOI: 10.1007/s10620-020-06135-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 02/04/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND In the USA, fibrolamellar hepatocellular carcinoma (FLC) accounts for 1-2% of all cases of hepatocellular carcinoma. FLC remains poorly understood. AIM We aim to investigate the incidence, demographics, tumor characteristics, treatment, and prognosis of patients with FLC. METHODS Data on FLC between 2000 and 2016 were extracted from the SEER database and analyzed. RESULTS A total of 300 patients with FLC were identified where 126 were male. Median age at diagnosis was 27 ± 22 years. The overall age-adjusted incidence of FLC between 2000 and 2016 was 0.02 per 100,000 per year. A bimodal distribution was observed where the highest incidences occurred between 15-19 years and 70-74 years. Most tumors on presentation were moderately differentiated (20.7%), while the most common stage at presentation was stage 1 (21.7%) followed by stages 3 and 4 (20.0% and 20.3%, respectively); 50.3% of these tumors were surgically resected, while 8.0% received radiation and 45.3% received chemotherapy. One- and 5-year cause-specific survival for FLC was 72.0% and 32.9%, respectively, with a median survival of 32.9 months. HCC had a median survival time of 11.7 months. Patients who were not treated with surgical intervention had about 3 times increased risk for death (HR 2.8, 95% CI 1.68-4.72, P = 0.000). Radiation and chemotherapy did not significantly affect outcomes. CONCLUSION FLC presents with a bimodal distribution in both early and elderly individuals. Compared to HCC, FLC has a higher recurrence rate but better survival outcome. Surgical intervention is superior to chemotherapy and radiation.
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Affiliation(s)
- Daryl Ramai
- Department of Medicine, The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY, 11201, USA
| | - Andrew Ofosu
- Division of Gastroenterology and Hepatology, The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY, 11201, USA
| | - Jonathan K Lai
- Department of Pathology, McGill University, Montreal, QC, Canada
| | - Zu-Hua Gao
- Department of Pathology, McGill University, Montreal, QC, Canada
| | - Douglas G Adler
- Division of Gastroenterology and Hepatology, Huntsman Cancer Center, University of Utah School of Medicine, Salt Lake City, UT, USA.
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31
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Lamarca A, Frizziero M, Fulton A, McNamara MG, Filobbos R, Hubner RA, Wardell S, Valle JW. Fibrolamellar carcinoma: Challenging the challenge. Eur J Cancer 2020; 137:144-147. [PMID: 32768872 DOI: 10.1016/j.ejca.2020.06.035] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 06/26/2020] [Indexed: 12/15/2022]
Abstract
Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon α-2B (IFN-α-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-α-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-α-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division Cancer Sciences, University of Manchester; Manchester, United Kingdom.
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Alexander Fulton
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division Cancer Sciences, University of Manchester; Manchester, United Kingdom
| | - Rafik Filobbos
- Department of Radiology, North Manchester General Hospital, Manchester, United Kingdom
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division Cancer Sciences, University of Manchester; Manchester, United Kingdom
| | - Steve Wardell
- Department of Pharmacy, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division Cancer Sciences, University of Manchester; Manchester, United Kingdom.
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McDonald JD, Gupta S, Shindorf ML, Gamble LA, Ruff SM, Drake J, Heller T, Wan JY, Dickson PV, Glazer ES, Davis JL, Deneve JL, Hernandez JM. Elevated Serum α-Fetoprotein is Associated with Abbreviated Survival for Patients with Fibrolamellar Hepatocellular Carcinoma Who Undergo a Curative Resection. Ann Surg Oncol 2020; 27:1900-1905. [PMID: 31925595 DOI: 10.1245/s10434-019-08178-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), with most clinical data stemming from single-institution series. The variability in the literature lends support for analysis using a large national dataset. In doing so, we sought to (1) define the characteristics and outcomes of patients with FLC; (2) determine factors associated with survival in patients undergoing resection; and (3) compare the overall survival (OS) of patients with FLC with a matched group of patients with HCC. METHODS The National Cancer Database was queried for patients with FLC, and their clinicopathologic features were recorded. Univariate and multivariate analyses were performed to delineate factors associated with survival. RESULTS Between 2004 and 2015, 496 patients were diagnosed with FLC, 229 of whom underwent a curative resection. The median OS for patients with FLC undergoing curative resection was 78.5 months. Factors associated with abbreviated OS in this surgical cohort include multiple tumors [hazard ratio (HR) 3.15, p = 0.025], positive regional lymph nodes (HR 2.83, p = 0.023), and elevated serum α-fetoprotein (AFP; HR 2.81, p = 0.034). When the OS of patients with FLC was compared with a matched group of patients with HCC, no difference was detected (p = 0.748); however, patients with FLC and elevated AFP had abbreviated OS compared with patients with HCC and elevated AFP (43 vs. 82 months, p ≤ 0.001). CONCLUSIONS Elevations in serum AFP occur more frequently than previously documented for patients with FLC and are associated with abbreviated OS. AFP levels may help guide the decision for operative intervention in patients with FLC.
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Affiliation(s)
- James D McDonald
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shreya Gupta
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mackenzie L Shindorf
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lauren A Gamble
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Samantha M Ruff
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Justin Drake
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jim Y Wan
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Paxton V Dickson
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Evan S Glazer
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jeremy L Davis
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeremiah L Deneve
- Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jonathan M Hernandez
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Cebrián A, Elosua A, González-de la Higuera B, Irisarri R, Ruiz-Clavijo D. Clavicle tumor as an initial manifestation of fibrolamellar hepatocellular carcinoma. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2020. [DOI: 10.1016/j.rgmxen.2019.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Cebrián A, Elosua A, González-de la Higuera B, Irisarri R, Ruiz-Clavijo D. Clavicle tumor as an initial manifestation of fibrolamellar hepatocellular carcinoma. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2019; 85:104-106. [PMID: 31677896 DOI: 10.1016/j.rgmx.2019.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/22/2019] [Accepted: 03/07/2019] [Indexed: 11/19/2022]
Affiliation(s)
- A Cebrián
- Aparato Digestivo, Hospital García Orcoyen, Estella, España.
| | - A Elosua
- Aparato Digestivo, Complejo Hospitalario de Navarra, Pamplona, España
| | | | - R Irisarri
- Aparato Digestivo, Hospital García Orcoyen, Estella, España
| | - D Ruiz-Clavijo
- Aparato Digestivo, Hospital García Orcoyen, Estella, España
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Zakka K, Jiang R, Alese OB, Shaib WL, Wu C, Wedd JP, Sellers MT, Behera M, El-Rayes BF, Akce M. Clinical outcomes of rare hepatocellular carcinoma variants compared to pure hepatocellular carcinoma. J Hepatocell Carcinoma 2019; 6:119-129. [PMID: 31413960 PMCID: PMC6660638 DOI: 10.2147/jhc.s215235] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 06/26/2019] [Indexed: 12/12/2022] Open
Abstract
Background HCC variants are rare primary hepatic tumors. The aim of this study is to compare clinical characteristics and outcomes of HCC variants with pure HCC. Methods Patients diagnosed between 2004 and 2013 with ICD-O-3 8180/3 and 8170/3-8175/3 were identified from the National Cancer Database. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p<0.001). Pure HCC (10.6%) underwent surgical resection without transplant less often than variants except for scirrhous (9.9%) (p<0.001). More than a third of patients in each histological type received chemotherapy. FLHCC had the best 5-year OS (38.7%), spindle cell and pleomorphic had the worst (9.6% and 13.0%). In multivariate analysis stratified by histology variants, chemotherapy was associated with improved OS in all histologies except for scirrhous and pleomorphic HCC. Conclusion HCC variants underwent surgical resection more often than pure HCC. FLHCC had the best 5-year OS. Liver transplant was commonly performed in HCC variants.
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Affiliation(s)
- Katerina Zakka
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Renjian Jiang
- Department of Research Informatics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Olatunji B Alese
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Walid L Shaib
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Christina Wu
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Joel P Wedd
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Marty T Sellers
- Division of General and GI Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Madhusmita Behera
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.,Department of Research Informatics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Bassel F El-Rayes
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
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Chakrabarti S, Tella SH, Kommalapati A, Huffman BM, Yadav S, Riaz IB, Goyal G, Mody K, Borad M, Cleary S, Smoot RL, Mahipal A. Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma. J Gastrointest Oncol 2019; 10:554-561. [PMID: 31183207 PMCID: PMC6534717 DOI: 10.21037/jgo.2019.01.35] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 01/26/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Clinicopathological features and the outcomes of patients with fibrolamellar hepatocellular carcinoma (FLHCC) are not clearly defined. METHODS Data were collected by retrospective chart review on 42 patients with FLHCC treated between 1990 and 2017 at Mayo Clinic. RESULTS Of 42 patients (median age at diagnosis 22 years), 10 patients (23.8%) had stage I disease and 32 patients (76.2%) had stage II to IVB disease. All 10 patients with stage I disease and 21 of 32 patients with stage II-IVB disease underwent resection at presentation. In stage I patient group, 6 patients experienced recurrence with a median time to recurrence of 30.5 months and a 5-year overall survival (OS) of 86%. Patients with stage II to IVB disease who underwent resection (n=21) upfront had a median OS of 32.5 months and 5-year OS of 44%. In the upfront surgery group, 71% of patients experienced recurrence. The median OS of patients with unresectable disease (n=11) was 10 months. Four out of nine patients treated with sorafenib had stable disease and one patient with programmed cell death ligand-1 (PD-L1) expressing tumor had a near complete response after 2 months of therapy with nivolumab. CONCLUSIONS In FLHCC, surgical resection was associated with prolonged OS; although most patients had a disease recurrence regardless of disease stage and resection margin status. The response to kinase inhibitor, sorafenib, was variable. In select cases, therapy with a checkpoint inhibitor may provide a viable treatment option.
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Affiliation(s)
| | - Sri Harsha Tella
- Department of Internal Medicine, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Anuhya Kommalapati
- Department of Internal Medicine, University of South Carolina School of Medicine, Columbia, SC, USA
| | | | | | - Irbaz Bin Riaz
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Gaurav Goyal
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Kabir Mody
- Department of Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Mitesh Borad
- Department of Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Sean Cleary
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Rory L. Smoot
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Amit Mahipal
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
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37
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Cytoreductive Surgery and HIPEC for Recurrent Fibrolamellar Hepatocellular Carcinoma with Peritoneal Carcinomatosis. J Gastrointest Cancer 2019; 51:300-303. [DOI: 10.1007/s12029-019-00236-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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38
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Bauer U, Mogler C, Braren RF, Algül H, Schmid RM, Ehmer U. Progression after Immunotherapy for Fibrolamellar Carcinoma. Visc Med 2019; 35:39-42. [PMID: 31312648 DOI: 10.1159/000497464] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 02/04/2019] [Indexed: 12/13/2022] Open
Abstract
Background Fibrolamellar carcinoma (FLC) is a rare malignancy of the liver that differs from typical hepatocellular carcinoma (HCC) in several aspects such as the absence of underlying liver disease and occurrence in younger patients. Even though the survival rates in FLC are slightly better than in typical HCC, the prognosis of metastatic FLC remains deleterious. Several reports suggest that systemic chemotherapy regimens can successfully be used to halt disease progression in FLC, while targeted tumor therapy with sorafenib seems to be of limited efficiency. However, results from controlled clinical trials investigating systemic therapies in FLC are virtually nonexistent. Therefore, the choice of treatment often relies on case series with limited numbers of patients. Immunotherapy with checkpoint inhibitors is an emerging cancer therapy in several solid malignancies including HCC. Currently, there do not exist any reports on the use of checkpoint inhibitors in FLC. Case Report Here, we describe a case of advanced FLC in a young man receiving immunotherapy, who progressed after 3 months of treatment - similar to 2 other patients with advanced FLC at our hospital. Conclusion While immunotherapy seems to be a promising treatment with limited side effects in several other tumor entities, there is currently no data supporting tumor response in FLC.
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Affiliation(s)
- Ulrike Bauer
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Carolin Mogler
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Rickmer F Braren
- Institute for Diagnostic and Interventional Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Hana Algül
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Roland M Schmid
- Department of Internal Medicine II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Ursula Ehmer
- Institute of Pathology, Technische Universität München, Munich, Germany
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Kastenhuber ER, Craig J, Ramsey J, Sullivan KM, Sage J, de Oliveira S, Riehle KJ, Scott JD, Gordan JD, Bardeesy N, Abou-Alfa GK. Road map for fibrolamellar carcinoma: progress and goals of a diversified approach. J Hepatocell Carcinoma 2019; 6:41-48. [PMID: 30951568 PMCID: PMC6362920 DOI: 10.2147/jhc.s194764] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Fibrolamellar carcinoma is a rare liver cancer, which primarily afflicts adolescents and young adults worldwide and is frequently lethal. Given the rarity of this disease, patient recruitment for clinical trials remains a challenge. In November 2017, the Second Fibrolamellar Cancer Foundation Scientific Summit (Stamford, CT, USA) provided an opportunity for investigators to discuss recent advances in the characterization of the disease and its surrounding liver and immune context. The Fibrolamellar Cancer Foundation has thus set out a road map to identify and test therapeutic targets in the most efficient possible manner.
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Affiliation(s)
- Edward R Kastenhuber
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA, .,Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - John Craig
- Fibrolamellar Cancer Foundation, Greenwich, CT, USA
| | - Jon Ramsey
- Department of Biochemistry, University of Vermont Cancer Center, Burlington, VT, USA
| | - Kevin M Sullivan
- Northwest Liver Research Program, University of Washington, Seattle, WA, USA
| | - Julien Sage
- Department of Pediatrics, Stanford University, Stanford, CA, USA.,Department of Genetics, Stanford University, Stanford, CA, USA
| | - Sofia de Oliveira
- Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA
| | - Kimberly J Riehle
- Northwest Liver Research Program, University of Washington, Seattle, WA, USA
| | - John D Scott
- Northwest Liver Research Program, University of Washington, Seattle, WA, USA
| | - John D Gordan
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Nabeel Bardeesy
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ghassan K Abou-Alfa
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA, .,Department of Medicine, Weill Cornell School of Medicine, New York, NY, USA,
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Tanaka H, Hijioka S, Iwaya H, Mizuno N, Kuwahara T, Okuno N, Ito A, Kuraoka N, Matsumoto S, Obata M, Kurita Y, Yasuda M, Shimizu Y, Kuroda H, Sato Y, Haneda M, Sasaki E, Yatabe Y, Hara K. Fibrolamellar Hepatocellular Carcinoma with Multiple Lung Metastases Treated with Multidisciplinary Therapy. Intern Med 2018; 57:3537-3543. [PMID: 30101933 PMCID: PMC6355421 DOI: 10.2169/internalmedicine.1243-18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
A 20-year old man was diagnosed with fibrolamellar hepatocellular carcinoma (FLHCC) with multiple lung metastases, and chemotherapy with FOLFOX was administered. Contrast enhanced CT after 3 cycles of FOLFOX showed no disease progression. We therefore performed surgical resection and radiofrequency ablation of the liver lesions and lung metastases, after obtaining the patient's informed consent. The liver lesions and lung metastases tested positive for DNAJB1-PRKACA. The treatment for FLHCC with extrahepatic metastasis has not been established; however, in a few cases, good long-term prognoses were obtained with multidisciplinary therapy. We herein report a case of FLHCC with multiple lung metastases that was treated with multidisciplinary therapies.
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Affiliation(s)
- Hiroki Tanaka
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
- Department of Gastroenterology, Suzuka General Hospital, Japan
| | - Susumu Hijioka
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Hiromichi Iwaya
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
| | - Nobumasa Mizuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
| | | | - Nozomi Okuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
| | - Ayako Ito
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
| | - Naosuke Kuraoka
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
| | | | - Masahiro Obata
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
| | - Yusuke Kurita
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
| | - Muneji Yasuda
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Japan
| | - Hiroaki Kuroda
- Department of Thoracic Surgery, Aichi Cancer Center Hospital, Japan
| | - Yozo Sato
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Japan
| | - Masataka Haneda
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Japan
| | - Eiichi Sasaki
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Japan
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Japan
| | - Kazuo Hara
- Department of Gastroenterology, Aichi Cancer Center Hospital, Japan
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41
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Fibrolamellar Hepatocellular Carcinoma and Noncirrhotic Hyperammonemic Encephalopathy. Case Reports Hepatol 2018; 2018:7521986. [PMID: 30631612 PMCID: PMC6304646 DOI: 10.1155/2018/7521986] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 11/19/2018] [Indexed: 02/06/2023] Open
Abstract
Fibrolamellar hepatocarcinoma is an infrequent liver tumor, currently considered to be a variant different from hepatocarcinoma. The differences lie in genomic alterations, a greater prevalence of fibrolamellar hepatocarcinoma in young patients, and its lack of association with underlying liver disease. The clinical presentation is unspecific, with symptoms ranging from abdominal pain, malaise, and weight loss to atypical manifestation which include hyperammonemic encephalopathy. We present the case of a 33-year-old woman with no prior medical history who presented with a coma and a diagnosis of inoperable fibrolamellar hepatocarcinoma requiring a cadaver donor transplant. While she was on the waiting list, she received hemofiltration and ammonium benzoate treatment, with progressive improvement in her state of consciousness.
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Abstract
Many advances have developed in the pathology of liver tumors in the recent decade. Examples of these advances include the use of glutamine synthetase in the diagnosis of focal nodular hyperplasia, subtyping of hepatocellular adenomas using molecular and immunohistochemical methods, the unraveling of the fusion transcript between the DNAJB1 gene and the PRKACA gene in fibrolamellar carcinoma, and the more unified classification and terminology in intrahepatic bile duct tumors and their precursor lesions. Nevertheless, challenges still remain, e.g., the differential diagnosis between well-differentiated hepatocellular carcinoma and hepatocellular adenoma; distinction among poorly differentiated hepatocellular carcinoma, cholangiocarcinoma and metastatic neoplasm; terminology of the combined hepatocellular carcinoma-cholangiocarcinoma, etc. This review aims to address updates in the pathologic diagnosis and clinical relevance of tumors of the liver and intrahepatic bile ducts in adults and their differential diagnosis and diagnostic pitfalls.
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Hammond WJ, Lalazar G, Saltsman JA, Farber BA, Danzer E, Sherpa TC, Banda CD, Andolina JR, Karimi S, Brennan CW, Torbenson MS, La Quaglia MP, Simon SM. Intracranial metastasis in fibrolamellar hepatocellular carcinoma. Pediatr Blood Cancer 2018; 65:10.1002/pbc.26919. [PMID: 29286561 PMCID: PMC6028006 DOI: 10.1002/pbc.26919] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/01/2017] [Accepted: 11/09/2017] [Indexed: 01/16/2023]
Abstract
Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1-PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.
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Affiliation(s)
- William J. Hammond
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA,Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Gadi Lalazar
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - James A. Saltsman
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA,Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Benjamin A. Farber
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA,Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Enrico Danzer
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Tshering C. Sherpa
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Charles D. Banda
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Jeffrey R. Andolina
- Department of Pediatrics, Golisano Children’s Hospital, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
| | - Sasan Karimi
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Cameron W. Brennan
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA,Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Michael S. Torbenson
- Division of Anatomic Pathology, Department of Pathology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Michael P. La Quaglia
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Sanford M. Simon
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
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Abstract
Fibrolamellar carcinoma is distinctive at clinical and histologic levels. A novel DNAJB1-PRKACA fusion gene characterizes almost all cases, distinguishes it from other hepatocellular neoplasms, and drives the pathogenesis of this unique tumor. A subset of cases of fibrolamellar carcinoma is associated with alternate mechanisms of protein kinase A activation. This review article discusses common and unusual histologic features of fibrolamellar carcinoma, its differential diagnoses, and how to make the diagnosis while avoiding key pitfalls. The impact of the discovery of the fusion gene on the understanding of the tumor and the prognosis of fibrolamellar carcinoma are also discussed.
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Affiliation(s)
- Rondell P Graham
- Division of Anatomic Pathology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Division of Laboratory Genetics and Genomics, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
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45
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Palm V, Sheng R, Mayer P, Weiss KH, Springfeld C, Mehrabi A, Longerich T, Berger AK, Kauczor HU, Weber TF. Imaging features of fibrolamellar hepatocellular carcinoma in gadoxetic acid-enhanced MRI. Cancer Imaging 2018; 18:9. [PMID: 29490696 PMCID: PMC5831838 DOI: 10.1186/s40644-018-0143-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/22/2018] [Indexed: 02/07/2023] Open
Abstract
Background Fibrolamellar hepatocellular carcinoma (FLC) is a rare malignancy occurring in young patients without cirrhosis. Objectives of our study were to analyze contrast material uptake in hepatobiliary phase imaging (HBP) in gadoxetic acid-enhanced liver MRI in patients with FLC and to characterize imaging features in sequence techniques other than HBP. Methods In this retrospective study on histology-proven FLC, contrast material uptake in HBP was quantitatively assessed by calculating the corrected FLC enhancement index (CEI) using mean signal intensities of FLC and lumbar muscle on pre-contrast imaging and HBP, respectively. Moreover, enhancement patterns in dynamic contrast-enhanced MRI and relative signal intensities compared with background liver parenchyma were determined by two radiologists in consensus for HBP, diffusion-weighted imaging using high b-values (DWI), and T2 and T1 weighted pre-contrast imaging. Results In 6 of 13 patients with FLC gadoxetic acid-enhanced liver MRI was available. The CEI suggested presence of HBP contrast material uptake in all FLCs. A mean CEI of 1.35 indicated FLC signal increase of 35% in HBP compared with pre-contrast imaging. All FLCs were hypointense in HBP compared with background liver parenchyma. Three of 6 FLCs had arterial hyperenhancement and venous wash-out. In DWI and T2 weighted imaging, 5 of 6 FLCs were hyperintense. In T1 weighted imaging, 5 of 6 FLCs were hypointense. Conclusion Hepatobiliary uptake of gadoxetic acid was quantitatively measurable in all FLCs investigated in our study. The observation of hypointensity of FLCs in HBP compared with background liver parenchyma emphasizes the role of gadoxetic acid-enhanced liver MRI for non-invasive diagnosis of FLC and its importance in the diagnostic work-up of indeterminate liver lesions.
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Affiliation(s)
- Viktoria Palm
- Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany
| | - Ruofan Sheng
- Department of Radiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Philipp Mayer
- Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany.,Liver Cancer Center Heidelberg, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany
| | - Karl-Heinz Weiss
- Liver Cancer Center Heidelberg, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany.,Department of Gastroenterology, Infectious Diseases, Intoxication, Heidelberg University Hospital, INF 410, 69120, Heidelberg, Germany
| | - Christoph Springfeld
- Liver Cancer Center Heidelberg, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany.,Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, INF 460, 69120, Heidelberg, Germany
| | - Arianeb Mehrabi
- Liver Cancer Center Heidelberg, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany.,Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany
| | - Thomas Longerich
- Liver Cancer Center Heidelberg, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany.,Division Translational Gastrointestinal Pathology, Institute of Pathology, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany
| | - Anne Katrin Berger
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, INF 460, 69120, Heidelberg, Germany
| | - Hans-Ulrich Kauczor
- Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany.,Liver Cancer Center Heidelberg, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany
| | - Tim Frederik Weber
- Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany. .,Liver Cancer Center Heidelberg, Heidelberg University Hospital, INF 224, 69120, Heidelberg, Germany.
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46
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Abstract
Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer found in adolescents and young adults without underlying liver disease. A deletion of ~400 kD has been found in one copy of chromosome 19 in the tumor tissue of all patients tested. This produces a fusion of the genes DNAJB1 and PRKACA which, in turn, produces a chimeric transcript and protein. Transcriptomic analysis of the tumor has shown upregulation of various oncologically relevant pathways, including EGF/ErbB, Aurora Kinase A, pak21 and wnt. To explore other factors that may contribute to oncogenesis, we examined the microRNA (miRNA) and long non-coding RNA (lncRNA) expression in FLC. The non-coding RNA expression profile in tumor tissue samples is distinctly different from the adjacent normal liver and from other liver tumors. Furthermore, miRZip knock down or over expression of certain miRNAs led to changes in the levels of coding genes that recapitulated changes observed in FLC, suggesting mechanistically that the changes in the cellular levels of miRNA are not merely correlative. Thus, in addition to serving as diagnostic tools for FLC, non-coding RNAs may serve as therapeutic targets.
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DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proc Natl Acad Sci U S A 2017; 114:13076-13084. [PMID: 29162699 DOI: 10.1073/pnas.1716483114] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here we implement CRISPR-Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of either the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild-type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which causes tissue injury, inflammation, and fibrosis. Our study validates the DNAJB1-PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC, and establishes a practical model for preclinical studies to identify strategies to treat this disease.
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Sorenson EC, Khanin R, Bamboat ZM, Cavnar MJ, Kim TS, Sadot E, Zeng S, Greer JB, Seifert AM, Cohen NA, Crawley MH, Green BL, Klimstra DS, DeMatteo RP. Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation. PLoS One 2017; 12:e0176562. [PMID: 28486549 PMCID: PMC5423588 DOI: 10.1371/journal.pone.0176562] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 04/12/2017] [Indexed: 01/17/2023] Open
Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC.
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Affiliation(s)
- Eric C. Sorenson
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Raya Khanin
- Department of Computational Biology and Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Zubin M. Bamboat
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Michael J. Cavnar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Teresa S. Kim
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Eran Sadot
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Shan Zeng
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Jonathan B. Greer
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Adrian M. Seifert
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Noah A. Cohen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Megan H. Crawley
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Benjamin L. Green
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - David S. Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Ronald P. DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- * E-mail:
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49
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Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma. Sci Rep 2017; 7:44653. [PMID: 28304380 PMCID: PMC5356346 DOI: 10.1038/srep44653] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 02/13/2017] [Indexed: 12/13/2022] Open
Abstract
Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.
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50
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Graham RP, Torbenson MS. Fibrolamellar carcinoma: A histologically unique tumor with unique molecular findings. Semin Diagn Pathol 2016; 34:146-152. [PMID: 28110996 DOI: 10.1053/j.semdp.2016.12.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fibrolamellar carcinoma is a unique type of hepatocellular carcinoma with a distinctive predilection for young patients without underlying liver disease, characteristic large neoplastic cells with intervening, dense fibrosis, co-expression of keratin 7 and CD68 and activation of protein kinase A (most often by formation of DNAJB1-PRKACA). Fibrolamellar carcinoma has a similar prognosis to conventional hepatocellular carcinomas arising in non-cirrhotic livers. The current American Joint Cancer Committee staging system does not provide optimal stratification of patients with fibrolamellar carcinoma and an alternate systems should be considered in the future. The only effective treatment for fibrolamellar carcinoma is complete resection. Novel therapies may be on the horizon as investigation into the molecular biology of fibrolamellar carcinoma continues.
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Affiliation(s)
- Rondell P Graham
- Division of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, United States
| | - Michael S Torbenson
- Division of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, United States
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